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Seminars in Fetal & Neonatal Medicine
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Aims and Scope

Seminars in Fetal & Neonatal Medicine (formerly Seminars in Neonatology) is a bi-monthly journal which publishes topic-based issues, including current Hot Topics on the latest advances in fetal and neonatal medicine. The change in title relates to the growing interest amongst obstetricians, midwives and fetal medicine specialists. The Journal commissions review-based content covering current clinical opinion on the care and treatment of the neonate and draws on the necessary specialist knowledge, including that of the respiratory physician, the infectious disease physician, the surgeon, as well as the paediatrician and obstetrician. Each topic-based issue is edited by an authority in their field and contains 810 articles. Current and forthcoming events can be viewed on the Internet at: http://www.elsevier.com/locate/siny Seminars in Fetal & Neonatal Medicine provides: coverage of major developments in neonatal care; value to practising neonatologists, consultant and trainee p aediatricians, obstetricians, midwives and fetal medicine specialists wishing to extend their knowledge in this field; up-to-date information in an attractive and relevant format.
Editorial Board
Editor-in-Chief
University of Leeds School of Medicine D Floor, Clarendon Wing The General Infirmary at Leeds Leeds LS2 9NS, UK
Professor M I Levene
Associate Editors
M Blennow, Huddinge, Sweden L Cornette, Brugge, Belgium D J Field, Leicester, UK I Laing, Edinburgh, UK K Marl, Lund, Sweden D Peebles, London, UK S Sinha, Middlesbrough, UK A M Weindling, Liverpool, UK
Advisory Board
F A Chervenak, USA S M Donn, USA N Evans, Australia V Fellman, Sweden N N Finer, USA P C NG, Hong Kong J M Perlman, USA E Saliba, France M Vento, Spain L de Vries, The Netherlands
Seminars in Fetal & Neonatal Medicine 17 (2012) 119
Contents lists available at SciVerse ScienceDirect

journal homepage: www.elsevier.com/locate/siny
Editorial
The late and moderate preterm baby
This edition of Seminars in Fetal and Neonatal Medicine considers birth at moderate and late preterm gestations, dened throughout as birth at 320336 weeks and 340366 weeks of gestation respectively. Moderate and late preterm births account for over 75% of all preterm births and around 67% of all births; yet research in this group has been relatively limited, with the focus having been predominantly on extreme prematurity. During recent years, epidemiological studies have reported adverse outcomes in these more mature preterm babies and this has led to an upsurge in interest in this group. Within this rapidly growing area of research, results of many new studies are conrming previous ndings. As might be expected, mortality, severe neonatal morbidity and profound neurodevelopmental disability are certainly much less common outcomes in the moderate and late preterm group than in extremely preterm infants. However, the sheer numbers of babies born at these gestations mean that even a modest increase in adverse outcomes is likely to have an impact that should not be underestimated. The extent to which long term health and developmental problems can be attributed simply to prematurity is not clear and it is likely that a number of other factors also contribute, to a greater or lesser degree. These might include the effects of longstanding maternal illness,
pregnancy-related complications, fetal compromise, timing and mode of delivery, neonatal or post-neonatal management and social risk as well as other, perhaps as yet unidentied risk factors. Exploration of these issues is in its infancy; there is much work still to be done to optimise care for women who deliver just a few weeks prematurely and their babies. In the papers that follow, we are fortunate to be able to present reviews from authors who have generated and collated much of the available evidence in the eld of moderate and late prematurity. They provide a comprehensive and current review of key topics, as well as pointing to areas that are ripe for future research, of which there are many. We are extremely grateful for their contributions and trust that you will enjoy and learn from this interesting and stimulating collection of articles. Elaine M. Boyle* Department of Health Sciences, 22-28 Princess Road West, University of Leicester, Leicester LE1 6TP, UK * Tel.: 44 116 252 5447. E-mail address: eb124@le.ac.uk
1744-165X/$ see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.005
Seminars in Fetal & Neonatal Medicine 17 (2012) 120e125

Epidemiology of late and moderate preterm birth

Carrie K. Shapiro-Mendoza*, Eve M. Lackritz
Maternal and Infant Health Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, Mailstop K-23, 4770 Buford Highway, NE, Atlanta, GA 30341-3717, USA
s u m m a r y
Keywords: Epidemiology Obstetrics standards Pregnancy outcome Premature birth Prenatal care Risk factors
Preterm birth affects 12.5% of all births in the USA. Infants of Black mothers are disproportionately affected, with 1.5 times the risk of preterm birth and 3.4 times the risk of preterm-related mortality. The preterm birth rate has increased by 33% in the last 25 years, almost entirely due to the rise in late preterm births (34e36 weeks gestation). Recently attention has been given to uncovering the often subtle morbidity and mortality risks associated with moderate (32e33 weeks gestation) and late preterm delivery, including respiratory, infectious, and neurocognitive complications and infant mortality. This section summarizes the epidemiology of moderate and late preterm birth, case denitions, risk factors, recent trends, and the emerging body of knowledge of morbidity and mortality associated with moderate and late preterm birth. Published by Elsevier Ltd.
1. Introduction Preterm birth (<37 weeks gestation) affects approximately one in eight (12.5% in 2008) of all births in the USA each year.1 Preterm birth is the most frequent cause of infant mortality, as well as the leading cause of long term neurologic disabilities in children, including cerebral palsy and developmental delays. It is estimated that preterm birth costs the US healthcare system more than $26 billion each year.2 Black infants are disproportionately affected; infants of non-Hispanic Black women have >1.5 times the risk of preterm birth and 3.4 times the risk of preterm-related mortality compared with infants of White mothers.3 Reducing the high burden of preterm birth, and its associated morbidity, mortality, and racial disparities, has thus been identied as a public health priority, as reected by the 2006 PREEMIE Act,4 the 2007 Institute of Medicine Report on preterm birth,2 the 2006 Surgeon Generals conference,5 the 2007 US Department of Health and Human Services public awareness campaign,6 and Healthy People 2010 and 2020 objectives.7 The survival of preterm infants improved greatly in recent decades, primarily due to advances in clinical management including neonatal intensive care units (NICUs), paediatric ventilators, and use of surfactant and antenatal steroids. Concomitant with improvements in preterm survival, the preterm birth rate increased by 33% from 1981 to 2006, almost exclusively due to
a rise in late preterm births (34e36 weeks gestation).1,8 Currently, w72% of all preterm births are due to infants born late preterm and 84% are due to late and moderate (32e33 weeks) preterm combined (Fig. 1). Although the majority of preterm-related deaths occur among very preterm infants (<32 weeks gestation), increased attention has recently been given to better understanding the reasons for the high rate of late and moderate preterm birth, its causes, short and long term sequelae, and opportunities for prevention. Research is uncovering signicant, though often subtle, increased risks for late preterm infants compared with those born at term (i.e. 39e41 weeks gestation) for complications at birth and long term neurodevelopmental problems. Increased knowledge about the epidemiology of these moderate and late preterm births is critical for informing practices and guidelines related to the prevention of preterm-related morbidity and mortality. 2. Preterm birth denitions and subcategories Fetal growth and maturation occur along a continuum throughout pregnancy. As such, case denitions based on discrete categories of gestational age may appear somewhat arbitrary. However, standard categorization of preterm infants based on gestational age is valuable for assessments of morbidity and mortality risk, comparisons across populations and research studies, generating health policy guidelines, and guiding patient care.9 Generally, preterm birth is dened as birth of an infant at <37 weeks completed gestation. However, there has traditionally been a lack of consensus on standard gestational age categories for infants born in the period near to term, i.e. from 32 to <37 weeks
* Corresponding author. Tel.: 1 770 488 6263; fax: 1 770 488 6283. E-mail address: ayn9@cdc.gov (C.K. Shapiro-Mendoza). 1744-165X/$ e see front matter Published by Elsevier Ltd. doi:10.1016/j.siny.2012.01.007
C.K. Shapiro-Mendoza, E.M. Lackritz / Seminars in Fetal & Neonatal Medicine 17 (2012) 120e125
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(w5% of all births). This reliance on LMP results in a high percentage of deliveries in which gestational age is misclassied. Basso and Wilcox12 reported that preterm births are more likely to be misclassied than term births. Qin et al.13 found that US preterm birth rates were lower when gestational age was based on the clinical estimate or on an LMP/clinical estimate composite measurement than when it was based on the LMP alone. When Qin et al.13 applied different data editing methods in an attempt to correct for misclassication, they found that the increase in preterm delivery rates from 1990 through 2002 persisted, but was attenuated. 4. Causes of late and moderate preterm birth Preterm birth is not a single entity, but a common nal outcome of a heterogeneous collection of underlying maternal and fetal factors. Approximately two-thirds of all singleton preterm births are spontaneous, often with no known cause, and approximately one-third are the result of medical intervention (i.e. medically indicated) to protect the health of the mother or infant.14 Complications of pregnancy that lead to both spontaneous and indicated preterm birth are multiple, complex, and vary according to gestational age. Although the rates of indicated deliveries remain similar throughout pregnancy, the medical reasons for intervention vary according to the changing biological processes and complications that occur at different periods of gestation. For example, placental insufciency becomes increasingly important later in pregnancy due to the increased demands for oxygen and nutrients during a crucial period of fetal growth. The risks of some maternal complications also increase later in pregnancy, such as hypertension, pre-eclampsia, diabetes, and placenta praevia. Decisions regarding obstetric intervention must weigh the risks of continuing the pregnancy in a suboptimal uterine environment compared with the risks of early delivery. Thus, understanding the risks of moderate and late preterm birth is critical to informing optimal clinical decision-making.15,16 5. Epidemiology of preterm birth Surveillance of preterm birth is essential for informing and evaluating clinical practices, research, programs, and policies aimed at reducing infant morbidity and mortality. Surveillance and epidemiologic analyses can measure the contribution of preterm birth to infant morbidity and mortality, identify populations at highest risk, detect changes in obstetric practices, and guide the development, implementation, and evaluation of programs.17 Increases in the singleton preterm birth rate since 1990 have been almost entirely due to infants born late preterm (Fig. 2). During 1990e2006, the late preterm birth rate for singleton births increased 20.9%, from 6.7% to 8.1%. This rate declined slightly in 2007 and 2008 to 8.0% and 7.8%, respectively. Preliminary data from 2009, the latest year available, suggest that this decline is continuing.18 Although the reasons for the increasing rates of moderate preterm and late preterm birth during the last two decades are not well understood, several theories have been postulated. These include improved risk assessment and timing for maternal and fetal disorders, more elective inductions and caesarean sections to reduce adverse fetal outcomes, increasing maternal age (>35 years), and increasing rates of multiple gestations.10,19,20 Growing concerns have been raised about more invasive medical management without clear indication, driving late preterm and early term rates due to providers concerns about medical malpractice, patient requests, or even convenience of the family or obstetrician. The actual prevalence of these practices is unknown. One recent study
Fig. 1. Distribution of preterm births by gestational age: United States, 2008. Source: Centers for Disease Control and Prevention. National Center for Health Statistics. VitalStats. http://www.cdc.gov/nchs/vitalstats.htm. [August 26, 2011].
gestation. These infants have been grouped by different gestational categories and identied by different names, such as near term, late preterm, marginally preterm, moderate preterm, and borderline preterm. Unfortunately, these terms have not adequately captured the important implications that these infants are still premature and vulnerable.9,10 Lack of recognition of prematurity, and its important physical and neurocognitive sequelae, could lead to increased comfort with early elective deliveries, less rigorous newborn assessment, early discharge, or inadequate monitoring. The 2005 National Institutes of Health workshop recommended that infants born at 34 0/7 through 36 6/7 weeks gestation after the onset of the mothers last menstrual period (LMP) be referred to as late preterm.10 We will use this denition to dene late preterm births in this review and dene infants born at 32 0/7 to 33 6/7 weeks gestation as moderate preterm. 3. Estimating gestational age Ensuring accurate and standardized estimation and reporting of gestational age may often be challenging. Gestational age is routinely estimated according to the number of weeks gestation after the onset of the mothers LMP. However, this estimate may be unreliable and prone to error in maternal recall. The gold standard for accurate determination of gestational age is rst trimester ultrasound.11 Nevertheless, early ultrasound is currently not recommended for routine gestational age dating and, in the USA, is often not reimbursed by public and private payers unless there is uncertainty about dates. In addition, women who seek prenatal care late may be less likely to have accurate dating. Inaccurate determination of gestational age can affect multiple downstream factors, including estimation of fetal maturity before elective delivery, clinical and epidemiologic investigations, and program evaluation. US birth certicate records are the only source of national data for surveillance and epidemiologic studies about preterm birth. Typically, reported gestational age is based on the interval between the rst day of the mothers LMP and the date of birth.1 When information on the date of LMP is missing or when the birth weight is incongruent with the gestational age, the clinical or obstetric estimate of gestation is used in place of the LMP gestational age
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Fig. 2. Trends in singleton preterm birth rates: United States, nal 1990, 1995, 2000, and 2005e2008. Source: Centers for Disease Control and Prevention. National Center for Health Statistics. VitalStats. http://www.cdc.gov/nchs/vitalstats.htm. [August 26, 2011].
reviewed medical records and estimated that more than half of all late preterm infants delivered by obstetric intervention could be non-evidence based iatrogenic preterm birth.21 However, cautious interpretation of this study is warranted, as information on the indication for the delivery was often missing in the medical record.22 Concern about the practice of elective induction or caesarean delivery without medical indication prompted the March of Dimes to launch a national campaign, Healthy Babies are Worth the Wait,23 to raise awareness among patients and providers on the importance of preventing non-indicated intervention. Also, several large health insurance groups have moved to limit elective inductions and caesarean sections without medical indication before 39 weeks.24,25 Preliminary results of these programs appear promising, demonstrating rapid declines in elective inductions and caesarean section without indication prior to 39 weeks gestation, as well as cost savings due to NICU and hospital stays.25 More information is needed to determine the extent of changes that have occurred in clinical practice, or just changes in reporting of indications. The reduction in US preterm birth rates in 2007e2009, the reversal of a long term trend in increasing rates, may indicate that these programs are having a positive impact (Fig. 2). 5.1. Risk factors for moderate and late preterm birth Multiple maternal and infant characteristics are associated with spontaneous preterm births, such as multiple gestations, birth defects, maternal age, and race and ethnicity. Although many of these variables are not modiable, knowledge of these risk factors is important for targeting interventions to those at highest risk. 5.1.1. Multiple gestations Twins and higher order multiples have elevated rates of late and moderate preterm birth compared with singletons. Between 1990 and 2008, the rate of singleton infants born late preterm increased by 14.7%, whereas among multiples the rate increased by 27.4%.26 Much of the increase in multiples is thought to be attributable to delayed childbirth and increased use of assisted reproductive technologies (ART).1 The proportion of multiples due to ART is quite high (w48%),27 but the overall contribution of ART to the national preterm birth rate is more limited; only about 1% of all US births in
2006 were attributable to ART.27 ART is also associated with increased risk of preterm birth among singleton births, but it is not known whether ART or the underlying biological reasons for infertility increase the risk of preterm birth.28 5.1.2. Congenital malformations Congenital malformations are associated with increased preterm birth rates. A US multi-state study from 1995 to 2000 showed that infants born at 32e36 weeks gestation had more than a two-fold risk of having congenital malformations than their term counterparts.29 The risk was ve times higher for those born at earlier gestations. 5.1.3. Maternal age A U-shaped distribution is observed between maternal age and late preterm birth (Fig. 3). In 2008, late preterm birth rates were highest among women of <20 and >35 years of age; women of 20e34 years of age had the lowest preterm rates. A similar pattern is observed for those born moderately preterm (Fig. 3). Increased preterm risk among older women may be due to an increased prevalence of co-morbid conditions such as diabetes and hypertension, as well as higher multiple birth rates and use of ART.27 Among teens, increased preterm risk may be due to biologic immaturity, lower socioeconomic status, and behavioral risk factors such as tobacco use.30 The increase in the preterm birth rate since 1990 has been greater for older mothers and less so for teens.8 5.1.4. Race and ethnicity Preterm birth rates vary for different racial and ethnic groups. In 2008, late preterm birth rates were highest for infants of nonHispanic black mothers (11.3%), followed by American Indian or Alaskan Natives (9.7%), Hispanics (8.8%), non-Hispanic whites (8.2%) and Asian or Pacic Islanders (7.9%) (Fig. 4). A similar pattern is observed for moderate preterm births. The reasons for these racial and ethnic disparities remain poorly understood. Possible explanations include differences in access to care and quality of care, social determinants of health including the effects of psychosocial stress, poverty, and the environment; prevalence of co-morbidities; and genetic factors.3 Although preterm birth risk declines with increasing level of maternal education and income, Black women with a college education still have higher preterm
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Fig. 3. Percent of live births born moderate and late preterm by maternal age: United States, 2008. Source: Centers for Disease Control and Prevention. National Center for Health Statistics. VitalStats. http://www.cdc.gov/nchs/vitalstats.htm. [August 26, 2011].
birth rates than White women with a college education.31 Despite social and economic disadvantages, Hispanic women tend to have a lower risk of preterm birth compared with Black women, often termed the Hispanic paradox.32 Reasons for disparities in late preterm birth and preterm-related mortality for non-Hispanic blacks, American Indian or Alaskan Natives, adolescent, and older mothers have not been fully elucidated and represent a critical area for research. 5.2. Morbidity and mortality rates Risk of infant morbidity and mortality declines dramatically with increasing gestational age up until term and then increases again post-term.33 Understanding which infants are at greatest risk for morbidity and mortality can assist providers in anticipating potential complications and with successful management, early intervention, and follow-up.19 During the last decade, studies have shown consistently that late preterm infants are at higher risk than term infants for a number of neonatal complications including respiratory distress requiring ventilation, transient tachypnea of
Fig. 4. Percent of live births born moderate and late preterm by maternal race and Hispanic origin: United States, 2008. Source: Centers for Disease Control and Prevention. National Center for Health Statistics. VitalStats. http://www.cdc.gov/nchs/ vitalstats.htm. [August 26, 2011].
the newborn, intraventricular hemorrhage, bacterial sepsis, apnoea, hypoglycemia, temperature instability, jaundice and hyperbilirubinaemia, feeding problems, neonatal intensive care admission, and even death.34e36 Although moderate and late preterm birth is associated with increased neonatal complications, it is important to note that the direction of causality remains unclear. Preterm delivery may cause adverse infant outcomes, or the medical indications leading to the need for the preterm delivery, such as intrauterine growth restriction or fetal anomalies, may be the cause of the adverse outcomes. A growing body of evidence suggests that infants born late and moderate preterm also have higher risks of later childhood morbidity and disability, including cerebral palsy, poor school performance, early intervention services, special education needs, and asthma.37e41 Infant mortality rates are highest among the most preterm infants (Fig. 5). During 2006e2008 infants born <28 weeks gestation had by far the highest infant mortality rate (378.2 per 1000 live births), whereas infants born at 39e41 weeks had the lowest mortality rates (2.1 per 1000 live births). It is important to note that mortality risk continues to decline up to 39e41 weeks gestation, including those born late preterm (7.1 per 1000 live births) and moderate preterm (16.2 per 1000 live). Infants born at 32e33 and 34e36 weeks gestation have, respectively, w8 and 3 times the rate of infant mortality compared with their term counterparts. Several studies have attempted to examine neonatal complications and mortality by underlying factors resulting in preterm birth. Using 2001 US vital statistics data, Chen et al.15 compared neonatal mortality risk by preterm birth subcategory (i.e. spontaneous preterm birth with intact fetal membranes, preterm premature rupture of membranes before labor onset, and indicated preterm birth). Compared with spontaneous preterm deliveries, late and moderate preterm infants delivered for medical indications had twice the risk of neonatal death. In another study restricted to late preterm births, Reddy et al.16 reported similar ndings. Deliveries with recorded obstetric complications (e.g. polyhydramnios, oligohydramnios, incompetent cervix, cord prolapse, fetal distress) had at least twice the risk of neonatal and infant mortality compared with deliveries with no recorded indication.
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Fig. 5. Infant mortality rates (per 1000 live births) by gestational age: United States, 2006. Source: United States Department of Health and Human Services (US DHHS), Centers of Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Ofce of Analysis and Epidemiology (OAE), Division of Vital Statistics (DVS), Linked Birth/Infant Death Records 2003-2006 on CDC WONDER On-line Database. Accessed at http://wonder.cdc.gov/lbd-current.html on Sep 27, 2011 03:40:20 PM.
Another large retrospective cohort study using vital statistics and hospital discharge records in Massachusetts found that morbidity risk during birth hospitalization among late preterm infants decreased with increasing gestational age.42 Morbidity rates were similar among infants born between 39 and 41 weeks gestation (ranging from 2.5% to 2.8%). However, morbidity rates approximately doubled for each additional gestational week earlier than 38 weeks, from 5.9% with morbidities if born at 37 weeks gestation to 51.7% morbidity at 34 weeks gestation. Importantly, this study also found that the risk of neonatal morbidity increased among infants born late preterm if the pregnancy was complicated by an underlying medical condition, especially for antepartum haemorrhage and hypertensive disorders of pregnancy. Because fetal lung maturation is completed late in gestation, respiratory morbidities are a frequent concern for late and moderate preterm infants.43,44 In a comprehensive review, Colin et al. found that infants born 32e36 weeks gestation had a greater risk of respiratory morbidities compared with term infants.43 Rates of infant deaths due to respiratory distress syndrome have been found to increase with each week of decreasing gestational age before 37 weeks (0.06 infant deaths per 1000 live births at 36 weeks, 0.11 at 35 weeks, 0.26 at 34 weeks, 0.44 at 33 weeks, and 3.09 at 28e32 weeks).44 5.3. Late preterm birth and fetal death
precipitated by obstetric intervention correlated with a reduction in perinatal mortality.47 Though more direct assessments are needed, these associations suggest that the rise in moderate and late preterm births, perhaps due to increased obstetric intervention, may be conferring some improvement in perinatal outcomes.14 In summary, late preterm birth accounts for the vast majority of preterm births in the USA and for the rise in the national preterm birth rate over the past two decades. Late and moderate preterm infants are both physiologically and developmentally immature and have higher risks for morbidity and mortality compared with infants born at term. Attention to increasing rates of late preterm births during the last decade have led to several campaigns aimed at reducing non-medically indicated preterm births.23,25 It will be important to document the health and economic impact of these initiatives in the years to come. Prospective studies will further strengthen our knowledge about decisions regarding obstetric intervention. We must go beyond crude measures such as race, ethnicity, and age, and explore the complex mediators of disparities to further advance identication of effective prevention strategies.
Practice points Many argue that advances in obstetric practice have led to more intensive monitoring during pregnancy, which has led to increased obstetric interventions. It follows that this increase in medical interventions resulting in early delivery would lead to a decrease in stillbirths. Some evidence exists to support this argument.45e47 Joseph et al.46 examined US vital records from 1988e1999 to evaluate the temporal associations between trends in late preterm births and fetal deaths. The increase in obstetric intervention at 34e36 weeks gestation appeared to be temporally associated with a signicant decline in late fetal death rates. Others have examined similar data and have shown that increases in preterm birth Among infants born preterm, 72% are born late preterm, i.e. at 34 0/7 through 36 6/7 completed weeks gestation. Although mortality risk declines with increasing gestational age, even infants born close to term are at increased risk for mortality. Compared with term births, infants born late preterm experience higher rates of infant morbidity and mortality, as well as higher risks of childhood disabilities.
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Research directions Detailed prospectively collected data would increase knowledge about decisions regarding obstetric intervention. Racial and ethnic disparities in late preterm birth mortality are complex and remain poorly understood.
Conict of interest statement None declared. The ndings and conclusions in this paper are those of the authors and do not necessarily represent the ofcial position of the Centers for Disease Control and Prevention. Funding sources None. References
1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: nal data for 2008. Natl Vital Stat Rep 2010;59:1e72. 2. Behrman RE, Butler AS, Institute of medicine (U.S.). Committee on understanding premature birth and assuring healthy outcomes. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press; 2007. 3. MacDorman MF. Race and ethnic disparities in fetal mortality, preterm birth, and infant mortality in the United States: an overview. Semin Perinatol 2011;35:200e8. 4. Prematurity Research Expansion and Education for Mothers who deliver Infants Early Act (PREEMIE Act); 2006. [Available from: http://frwebgate.access.gpo.gov/ cgi-bin/getdoc.cgi?dbname109_cong_public_laws&docidf:publ450.109]. 5. Surgeon generals conference on the prevention of preterm birth; 2008. [Available at http://www.surgeongeneral.gov/library/preterm_birth/background.html]. 6. A Healthy Baby Begins with You Campaign. [Available at http:// minorityhealth.hhs.gov/templates/browse.aspx?lvl2&lvlID117]. 7. Healthy People. [Available at: http://www.healthypeople.gov/2010/default. htm]. 8. Martin JA, Osterman MJ, Sutton PD. Are preterm births on the decline in the United States? Recent data from the National vital statistics system. NCHS Data Brief 2010:1e8. 9. Engle WA. A recommendation for the denition of late preterm (near-term) and the birth weightegestational age classication system. Semin Perinatol 2006;30:2e7. 10. Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 2006;118:1207e14. 11. Kramer MS, McLean FH, Boyd ME, Usher RH. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations. JAMA 1988;260:3306e8. 12. Basso O, Wilcox A. Mortality risk among preterm babies: immaturity versus underlying pathology. Epidemiology 2010;21:521e7. 13. Qin C, Dietz PM, England LJ, Martin JA, Callaghan WM. Effects of different dataediting methods on trends in race-specic preterm delivery rates, United States, 1990e2002. Paediatr Perinat Epidemiol 2007;21(Suppl. 2):41e9. 14. Ananth CV, Joseph KS, Oyelese Y, Demissie K, Vintzileos AM. Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet Gynecol 2005;105:1084e91. 15. Chen A, Feresu SA, Barsoom MJ. Heterogeneity of preterm birth subtypes in relation to neonatal death. Obstet Gynecol 2009;114:516e22. 16. Reddy UM, Ko CW, Raju TN, Willinger M. Delivery indications at late-preterm gestations and infant mortality rates in the United States. Pediatrics 2009;124:234e40. 17. German RR, Lee LM, Horan JM, Milstein RL, Pertowski CA, Waller MN. Updated guidelines for evaluating public health surveillance systems: recommendations from the Guidelines Working Group. MMWR Recomm Rep 2001;50:1e35. quiz CE1e7.
18. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2009. Natl Vital Stat Rep 2010;59:1e19. 19. Engle WA, Tomashek KM, Wallman C. Late-preterm infants: a population at risk. Pediatrics 2007;120:1390e401. 20. Davidoff MJ, Dias T, Damus K, et al. Changes in the gestational age distribution among U.S. singleton births: impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol 2006;30:8e15. 21. Bannerman CG, Fuchs KM, Young OM, Hoffman MK. Non-spontaneous late preterm birth: etiology and outcomes. Am J Obstet Gynecol 2011;205: 456.e1e6. 22. Iams JD. Late preterm birth: more and better data needed. Am J Obstet Gynecol 2011;205:395. 23. Healthy Babies are Worth the Wait; 2011. [Available at: http://www. marchofdimes.com/professionals/medicalresources_hbww.html]. 24. Oshiro BT, Henry E, Wilson J, Branch DW, Varner MW. Decreasing elective deliveries before 39 weeks of gestation in an integrated health care system. Obstet Gynecol 2009;113:804e11. 25. Clark SL, Frye DR, Meyers JA, et al. Reduction in elective delivery at <39 weeks of gestation: comparative effectiveness of 3 approaches to change and the impact on neonatal intensive care admission and stillbirth. Am J Obstet Gynecol 2010;203. 449 e1e449 e6. 26. VitalStats. [Available at: http://www.cdc.gov/nchs/vitalstats.htm]. 27. Sunderam S, Chang J, Flowers L, et al. Assisted reproductive technology surveillance e United States, 2006. MMWR Surveill Summ 2009;58:1e25. 28. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003;18:2478e84. 29. Honein M, Kirby R, Meyer R, et al. The association between major birth defects and preterm birth. Matern Child Health J 2009;13:164e75. 30. Strobino DM, Ensminger ME, Kim YJ, Nanda J. Mechanisms for maternal age differences in birth weight. Am J Epidemiol 1995;142:504e14. 31. McGrady GA, Sung JF, Rowley DL, Hogue CJ. Preterm delivery and low birth weight among rst-born infants of black and white college graduates. Am J Epidemiol 1992;136:266e76. 32. Brown HL, Chireau MV, Jallah Y, Howard D. The Hispanic paradox: an investigation of racial disparity in pregnancy outcomes at a tertiary care medical center. Am J Obstet Gynecol 2007;197. 197 e1e197 e7; discussion e7e9. 33. Kirby RS, Wingate MS. Late preterm birth and neonatal outcome: is 37 weeks gestation a threshold level or a road marker on the highway of perinatal risk? Birth 2010;37:169e71. 34. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114:372e6. 35. Escobar GJ, Greene JD, Hulac P, et al. Rehospitalisation after birth hospitalisation: patterns among infants of all gestations. Arch Dis Child 2005;90:125e31. 36. Hibbard JU, Wilkins I, Sun L, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419e25. 37. Abe K, Shapiro-Mendoza CK, Hall LR, Satten GA. Late preterm birth and risk of developing asthma. J Pediatr 2010;157:74e8. 38. Chyi LJ, Lee HC, Hintz SR, Gould JB, Sutcliffe TL. School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr 2008;153:25e31. 39. Gurka MJ, LoCasale-Crouch J, Blackman JA. Long-term cognition, achievement, socioemotional, and behavioral development of healthy late-preterm infants. Arch Pediatr Adolesc Med 2010;164:525e32. 40. Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009;154:169e76. 41. Romeo DM, Di Stefano A, Conversano M, et al. Neurodevelopmental outcome at 12 and 18 months in late preterm infants. Eur J Paediatr Neurol 2010;14:503e7. 42. Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, et al. Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 2008;121:e223e32. 43. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks gestational age. Pediatrics 2010;126:115e28. 44. Joseph KS, Nette F, Scott H, Vincer MJ. Prenatal corticosteroid prophylaxis for women delivering at late preterm gestation. Pediatrics 2009;124:e835e43. 45. Ananth CV, Liu S, Joseph KS, Kramer MS. A comparison of foetal and infant mortality in the United States and Canada. Int J Epidemiol 2009;38:480e9. 46. Joseph KS, Demissie K, Kramer MS. Obstetric intervention, stillbirth, and preterm birth. Semin Perinatol 2002;26:250e9. 47. Lisonkova S, Hutcheon JA, Joseph KS. Temporal trends in neonatal outcomes following iatrogenic preterm delivery. BMC Pregn Childbirth 2011;11:39.

Developmental physiology of late and moderate prematurity

Tonse N.K. Raju a, b, *
a b
Center for Developmental Biology and Perinatal Medicine, National Institutes of Health, Bethesda, Maryland, USA Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
s u m m a r y
Keywords: Apnea Hypoglycemia Hypothermia Infection Preterm Respiratory distress
This is a brief review of the developmental physiology of selected organ and functional systems in moderate and late preterm infants. This outline provides a discussion of the physiological underpinnings for some of the clinical conditions seen in this group of infants, including hypothermia, hypoglycemia, respiratory distress syndrome, transient tachypnea, severe respiratory failure, apnea, feeding difculties, jaundice, and increased susceptibility to infections. Published by Elsevier Ltd.
1. Introduction In a 2005 workshop organized by the National Institute of Health and Human Development (NICHD), this author made a proposal to replace the vague and imprecise phrase near term with late preterm, to reect the physiological and developmental immaturity of this group of infants. The expert panel agreed, and suggested a denition for late preterm as births between 340/7 and 366/7 weeks of gestation. As discussed in the workshop summary,1 there were compelling reasons for the choice of the new phrase and its lower boundaries. The most important reason was to underscore that infants born even by a few weeks prior to term were immature, with higher morbidity and mortality risks compared to those born at term gestations.2 The NICHD expert panel could not have predicted the degree of impact of introducing the new phrase late preterm into the lexicon of perinatal medicine. Several professional societies and organizations in the USA3,4 and in other countries adopted the new term. The Centers for Disease Control and Prevention began tracking late preterm births rates.5 The phrase also shifted the paradigm, and stimulated a huge wave of research interest. More than 300 papers have been published since 2006 on late preterm, including observational and intervention studies, systematic reviews, editorials, and committee opinions. The obstetric and pediatric communities began an important dialogue about this vulnerable group of infants. These developments seem to have made an impact. As discussed elsewhere in this issue, the US preterm and late preterm birth rates have begun to decline signicantly.5
This review will focus on the developmental physiology of the organ systems in moderate and late preterm infants that are the underpinning of their morbidity and mortality risk. 2. Generic aspects of developmental maturation Maturation is a continuous process with no specic endpoints or goals to be achieved. By contrast, maturational milestones are developed by us as useful signposts to assess maturation, and to make clinical decisions. The milestones are also useful for statistical and denitional purposes, and for developing management guidelines. The duration of gestation (or time) is only one of the many factors that inuence fetal and neonatal developmental maturation and trajectory. Others include intrauterine environment, maternal health and disease status, maternal medication use, diet, nutrition, and lifestyle (e.g. exercise, stress, smoking, drug abuse etc.), the number of fetuses, fetal sex, and fetal health/diseases. Maturation is non-linear, in that it is programmed to meet the needs of the organism for an independent extrauterine existence at various time points. Thus, different organs tend to mature at different trajectories relative to each other. For instance, soon after birth, most late preterm infants can breathe on their own without assisted respiratory support, reecting their mature breathing apparatus. However, most of them will have difculty in initiating and maintaining breastfeeding, reecting their immature brainstem, sucking and swallowing mechanisms. 3. Developmental basis for clinical problems The following presentation is organized in an approximate chronological order of clinical disorders in moderate and late preterm infants.
* 6100 Executive Blvd, Room 4B03, Bethesda, MD 20952, USA. E-mail address: rajut@mail.nih.gov. 1744-165X/$ e see front matter Published by Elsevier Ltd. doi:10.1016/j.siny.2012.01.010
T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131
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3.1. Thermal instability/cold stress Fetal thermal homeostasis is controlled and regulated by the maternal thermal homeostasis.6 Because the temperature of the amniotic uid reects mothers core temperature, the fetus is constantly nurtured in a warm intrauterine environment. In addition, with an average fetal oxygen consumption of 8 ml/min/kg, it generates 3e4 W/kg of heat. Since the fetus has to eliminate its heat through the mother, its temperature remains about 0.5e1.0 C higher than that of the mother. Through mechanisms not well understood, fetal thermoregulatory pathways remain dormant until birth, and fetal temperature is thus passively clamped to that of the mother, changing along with her temperature. Even at term, the fetus has little ability to generate heat if challenged by maternal hypothermia, or lose heat if challenged by maternal hyperthermia, as in pyrexia. Under normal circumstances, the placenta eliminates 85% of fetal heat into maternal circulation. Thus, the fetus and the placenta are often considered an engine and a radiator, respectively. The remaining 15% of fetal heat loss occurs through the conductance from the fetal skin to the amniotic uid, and to the uterine wall.6 As the fetus emerges from a warm intrauterine environment to the cold external world, hypothermia is inevitable.7,8 In response, the newborn has to mount a variety of physiological responses immediately to conserve heat loss, increase heat production and maintain core temperate with the least amount of oxygen consumption in the process.6,9,10 Most healthy term infants mount such responses, but moderate and late preterm infants may not, or cannot, mount such responses due to the decient, immature or non-existent thermoregulatory processes (Box 1).6e10 3.2. Respiratory morbidities (Box 2) Studies using large datasets and systematic reviews11e13 conrm that compared with term infants, all forms of pulmonary disorders occur at higher frequencies in moderate and late preterm infants. Developmental immaturity-related pulmonary conditions are respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), pneumonia, hypoxic respiratory failure and pulmonary hypertension and apnea of prematurity. Maturation of the pulmonary apparatus occurs through progressive stages. By about the 16th week of gestation, the 16 generations of bronchioloar branching are completed. By 24 weeks gestation, the primitive alveoli can engage in some gas exchange; but major surge in alveolar generation (alveolization) occurs by term and continues through early childhood. Between 25 and 36 weeks gestation, the alveolization process goes through a transient saccular phase. The saccules participate in gas exchange, but they are compact, thick and primitive. Due to such structural immaturity, they are susceptible for barotraumas. By a process of septation, the saccules mature into alveoli beginning from 32 weeks gestation, with dramatic, weekly increments. By term, the alveolar count reaches about 80% of that of the adult alveolar count.14 A study published by the Consortium on Safe Labor11 reported an incidence of RDS in late preterm infants to be 5.2%, compared to 0.4% in infants born at 37e40 weeks gestation (computed from their Table 3, Reference11). RDS thus remains the most common cause of signicant respiratory morbidity in late preterm infants. RDS is the consequence of qualitative and/or quantitative deciency of pulmonary surfactants superimposed upon an immature cardiopulmonary system. Pulmonary surfactants are predominantly phospholipids. In the mature fetus, about 80% of phospholipids is phosphatidylcholine, 5e10% is phosphatidylglycerol, with other minor lipids making up the remainder. However, preterm fetuses completely lack phosphatidylglycerol, which is an
Box 1. Physiological basis for hypothermia. Heat loss soon after birth: w135e155 W/m2 B Channels of heat loss Evaporative: along with evaporative water loss (w125 g/m2/h ) at room temperature of w26 C and 40% humidity. Heat loss through this route: w60e80 W/m2 Radiation: direct loss of heat through electromagnetic radiation in the infrared spectrum (into the cooler walls of the nursery or the incubator). This can be up to 50 W/m2 Convection: through the air; a negligible route of heat loss up to w25 W/m2 especially when the incubator walls are cold Conductive heat loss: direct contact through a cooler object, such as the mattress e this is a negligible route of heat loss. Hypothermia and physiological immaturity B Decient subcutaneous fat and non-keratinized, thin skin: increases the speed and severity of hypothermia with exposure to cool, extrauterine environment. High ratio of surface area:body mass B Common to all newborn infants, but especially worse for preterm infants, thus a large surface area is exposed to environmental cooling and hypothermia. Inability to shiver B Neither term nor preterm infants can mount a shivering response (generating heat through the muscles) to environmental cooling. Deciency of brown adipose tissue (BAT) B Oxidation of BAT is the main source of heat production in term infants B BAT development begins around the 20th week of gestation, reaching a peak at term, accounting for up to 1% of body weight B Lack of sufcient BAT mass leads to decreased ability for generating heat to offset hypothermia from environmental cooling. Immature response of the temperature sensors in the posterior hypothalamus B Insufcient release of thermogenic hormones (T4 and norepinephrine) B Brainstem serotonin deciency can lead to homeostatic decits owing to a reduced sympathetic response to mild cold stress.
important cause of decient surfactant function leading to RDS in preterm infants. Around 32 weeks gestation, the surfactant pool size begins to increase, with a signicant surge around 35 weeks gestation, reaching a peak at term. Uterine contractions preceding labor and delivery, and the associated surge of catecholamines and endogenous steroids, enhance pulmonary surfactant secretion from Type II cells into the alveoli. Initiation of ventilation also contributes to additional surfactant release. In moderate and late preterm infants, most of the above processes are either decient or non-existent, thus setting up a stage for clinical RDS.12e14 TTN is diagnosed in about 4% of late preterm infants making it the second most common pulmonary disorder.15e17 A lack of timely clearance of the pulmonary uid from the alveolar airspaces is the pathophysiological basis for TTN. The risk of TTN is high in infants born precipitously, without active labor, and in those delivered by elective cesarean section. These observations gave rise to the
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Box 2. Physiological basis for respiratory disorders. Respiratory distress syndrome B Qualitative and/or quantitative deciency in surfactant and its function Deciency of phospatidylglycerol in preterm lungs, or its delayed maturation in diabetic pregnancy B Elective caesarean delivery, depriving laborassociated catecholamine and steroid surge, causing decreased pulmonary surfactant release. Transient tachypnea of the newborn (TTN) B Elective caesarean delivery, depriving labourassociated catecholamine and steroid surge, preventing lung uid clearance B Delayed transition to postnatal life, due to diminished transepithelial absorption of lung uid from disrupted functions of the amiloride-sensitive epithelial sodium channels. Hypoxic respiratory failure B Mild respiratory distress due to TTN is initially treated with oxygen using oxy-hoods, which can lead to nitrogen washout, oxygen absorption and alveolar atelectasis B Persistent mild-to-moderate hypoxia leading to development of pulmonary hypertension, often requiring treatment with inhaled nitric oxide and/or extracorporeal membrane oxygenation. Pneumonia B Fetal infection as a cause for preterm delivery, predisposing to sepsis and pulmonary infection B Mechanical ventilation leading to injury to the immature lungs, increasing the risk for pulmonary infections. Central, obstructive and mixed apnea B Increased chest wall and upper airway compliance leading to their collapse when the diaphragm contracts, especially during rapid eye movement sleep, which is >;60% of total sleep time B Biphasic ventilatory response to hypoxia B Blunted ventilatory response to hypercapnea B Higher incidence of acute life-threatening events and sudden infant death syndrome in late preterm.
hypoxic respiratory failure. Such infants initially would have received high concentrations of inspired oxygen via an oxygen hood or a nasal cannula, which can lead to pulmonary nitrogen washout and alveolar atelectasis. This can be followed by severe hypoxia, metabolic and respiratory acidosis, and pulmonary hypertension. Such infants often require inhaled nitric oxide therapy or extracorporeal membrane oxygenation.12 Keszler et al.17 reported that late preterm infants delivered by elective cesarean and managed as mild TTN in small hospitals were at great risk for such complications. 3.4. Other respiratory problems Moderate and late preterm infants are prone for apnea of prematurity. Similar to other aspects of developmental phenomena, maturation of brainstem regions and control of breathing apparatus in the moderate and late preterm infants lie in between those of extremely preterm and term infants. Brainstem increases in length and volume throughout gestation, with rapid increase in rst half of pregnancy, but progressive increments occurring later.18e20 Obstructive and mixed apnea occur less frequently in moderate and late preterm infants compared to those born <28 weeks of gestation. However, they occur at greater frequency and severity compared to those born at term. Many underlying developmental features are at play in causing apnea of prematurity.18e20 The chest wall and the upper airways are highly compliant, which tend to collapse paradoxically when the diaphragm contracts and generates negative intrathoracic pressure. The contraction of the muscles of the lower jaw and the tongue tend to dilate the upper airways and prevent their collapse. However, it is the balance between these forces that determines whether or not the upper airways remain open during breathing (Box 2). 3.5. Hypoglycemia Low plasma glucose, usually dened as 2.0e2.5 mmol/l (<40e45 mg/dl), has been reported in 5e15% of normal newborn infants. The frequency and severity of this complication is probably much higher in moderate and late preterm infants. The energy demands of the fetus are met by the mother through the placental transfer of glucose, amino acids, free fatty acids, ketone, and glycerol. Although normal fetus does not produce endogenous glucose, throughout gestation its blood glucose concentration remains >3 mmol/l (54 mg/dl). Soon after birth, the blood glucose concentration falls precipitously due to the interruption of the placental glucose supply. The magnitude and duration of such a fall depends upon the fetal concentrations of glucose and plasma insulin, the infants ability to mobilize glucose from hepatic glycogen, to initiate gluconeogenesis, and to feed adequately.21,22 In low birth weight and premature infants, gluconeogenesis is active, accounting for 30e70% of endogenous glucose production. However, the risk of hypoglycemia remains high due to many factors (Box 3), including caregiver complacency of not monitoring them, since many such infants appear normal. 3.6. Hepatic immaturity and jaundice Jaundice is the most common reason for readmission after initial hospital discharge in late preterm infants. Although accurate epidemiological data are lacking, compared to term infants, the risk of bilirubin-induced neurological injury is more common in moderate and late preterm infants.23 In all infants, hyperbilirubinemia is a consequence of increased bilirubin production, diminished metabolism and elimination, or
hypothesis that the squeeze on the infant chest during vaginal birth helps clear fetal lung uid. However, a large body of evidence contradicts this. The transition from uid-lled fetal lung to airlled postnatal breathing occurs via a multitude of coordinated hormonal and biochemical events during fetal life, labor and delivery, and into the hours and days after birth.15e17 Around near-term gestation, the rate of fetal lung uid production begins slowdown. With the onset of labor, and uterine contraction-induced hormonal surge, the lung uid gets cleared via the pulmonary interstitial lymphatics, blood vessels, upper airway, mediastinum, and the plural spaces. In addition, recent studies show that amiloride-sensitive epithelial sodium channels (ENaCs) in the alveolar cells also play a crucial role in lung uid sodium transport, facilitating water clearance.16,17 Both Type I and Type II cells in the alveoli are involved in this process, but since Type I cells constitute >95% of alveolar surface, their contribution to lung uid clearance appears to be greater than previously considered.16 3.3. Hypoxic respiratory failure Although TTN is considered a mild condition, sometimes there are serious complications leading to malignant TTN and severe
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Box 3. Developmental physiological basis for hypoglycemia. Decreased glycogen stores B In moderate and late preterm infants, hepatic glycogen stores are lower relative to term infants B In infants with intrauterine growth restriction, glycogen stores are depleted in fetal life, perhaps due to reduced placental supply of energy needs. Insulin concentrations and insulin response to changing glucose levels B Immaturity of the glucose-regulated insulin response in the b-islet cells of the pancreas, resulting in unregulated, continued insulin secretion despite falls in postnatal glucose concentrations B High circulating insulin concentrations secondary to maternal diabetes. Increased energy demands B Cold stress B Hypoxia B Sepsis. Diminished intake B Difculty in sucking and swallowing, and initiation and maintenance of breastfeeding.
Box 4. Developmental immaturity of bilirubin metabolism. Bilirubin load B Higher rates of bilirubin production due to higher proportion of senescent RBCs B Lack of feeding leading to increased enterohepatic load of bilirubin. Hepatic bilirubin metabolism B Limited bilirubin uptake in part due to deciency of organic anion transport proteins B Immaturity of hepatic endoplasmic reticular enzyme, uridine diphosphoglucuronate glucuronosyltransferase (UGT) that is required for conjugating the fatsoluble indirect bilirubin to water-soluble direct bilirubin. Enterophepatic absorption of bilirubin B Conversion of the relatively unstable monoglucuronide and diglucuronide bilirubin conjugates from the duodenum and colon by the enteric mucosal enzyme, b-glucuronidase causes about 25% of the excreted bilirubin to be reloaded B Breastfeeding and delayed ingestion of any milk leads to persistent activity of b-glucuronidase activity.
a combination of both. The catabolic breakdown of haemoglobin from the senescent red blood is the predominant source of bilirubin during the neonatal period. Heme from hemoglobin is converted into biliverdin with the catalytic activity of heme oxygenase-1 enzyme (HMOX-1); and biliverdin reductase converts the latter to bilirubin, which is taken up by the liver for conjugation. The conjugated bilirubin is then released into the intestines for excretion through the bowel. During the process of breakdown of 1 mole of heme into 1 mole of bilirubin, 1 mole of carbon monoxide is released. Thus, by measuring carbon monoxide (or the carboxy hemoglobin) in the exhaled breath, one can estimate the rate of bilirubin production. Studies utilizing such methods have estimated that compared to term infants, the bilirubin production rates are slightly higher in preterm infants, perhaps due to higher proportion of senescent red blood cells. The placenta is the primary route of fetal bilirubin excretion, because of which the hepatic conjugating system remains dormant in fetal life and for a few days following birth. (In fact, conjugated bilirubin is impermeable through the placenta.) Therefore, visible jaundice is seen in >70% of infants during the rst week of life. In preterm infants, the hepatic conjugation system remains immature to a greater degree and for longer durations, which explains the reasons for early, more severe, and prolonged hyperbilirubinemia. In addition, feeding difculties lead to a delay in the resolution of the enterohepatic re-circulation of bilirubin, resulting in further increase in hepatic bilirubin load. Other factors for prematurityrelated hyperbilirubinemia are listed in Box 4. 3.7. Gastrointestinal immaturity and feeding Oro-buccal coordination and swallowing mechanisms are immature in most moderate and late preterm infants. These infants have considerable difculty in establishing successful breastfeeding.18,24 Because of lack of prior experience, the problem is compounded in primiparous mothers. Mild hypotonia, cold stress, and general lack of strength add to the difculty of moderate and late preterm infants to establish and maintain adequate breastfeeding. All preterm infants have a higher frequency of gastro-oesophageal
reux, further reducing food intake and affecting weight gain. This chain of events may lead to dehydration and hypernatremia during the rst few weeks of life. The Academy of Breastfeeding Medicine has developed a useful protocol to help breastfeed late preterm infants.24 3.8. Immunological maturation The topic of fetal and neonatal immune maturation is broad and complex, and only a few aspects are highlighted here.25e38 It is traditionally taught that newborn infants are decient in acquired or adaptive immune responses; however, immune maturational processes are more complex. Due to the nonexposure to antigens during intrauterine life, neonates lack immunological memory, and hence cannot mount an adequate Tcell response soon after exposure to a pathogenic microbe. However, in a study of lymphocyte subpopulations, Walker et al.25 found that the pattern of T-cell responses was similar in preterm and term infants. Yet, with increasing prematurity, the absolute counts of nave helper T-lymphocytes were lower. With postnatal antigenic stimulation, the T- and B-lymphocyte populations predictably increased to signicant levels. The ability to produce immunoglobulin in response to specic antigenic stimulation is acquired early in fetal life. The predominant circulating immunoglobulin in the healthy fetus is placentally derived, actively secreted IgG, with a concentration of about 5e10% higher than that of the mother. Colostrum and human milk are the major sources of immunological protective agents. Thus, breastfed infants quickly acquire other immunoglobulins, and a host of nonspecic protective factors (Box 5),29,30 which promote the development of specic immune functions. However, due to the inability to feed at the breast, or to suck and swallow ineffectively, moderate and late preterm infants may not receive adequate human milk e a great source of immunologically valuable diet, increasing their risks for sepsis, including necrotizing enterocolitis. Despite a reasonably well-developed adaptive immune system, the innate immune system is relatively immature in the newborn. The polymorphonuclear neutrophils (PMNs) from term infants cannot mount an adequate chemotactic response (directed migration towards the chemo-attracting antigen). This is even worse
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Box 5. Immunological advantages from breastfeeding and feeding of human milk. Immunoglobulin B Secretory IgA, IgM and IgG B IgE, secretory component of IgD. Hormones and other biochemical components B Epidermal growth factor B Prostaglandin B Thyroid-releasing hormone B Thyroid-stimulating hormone B Thyroxine and triiodothyronine B Adrenocortical hormone B Melatonin with diurnal variations matching circadian rhythm B Somatostatin B Neurotensin B Prolactin B Erythropoietin. Cellular B Immunologically specic T- and B-lymphocytes B Neutrophils, macrophages and epithelial cells B Commensal bacteria colonized on maternal skin B Other microbiota matching maternal dietary intake. Other non-specic factors B Complement B Chemotactic factors B Lactoferrin B Transferrin B Several variety of biniding proteins B Enzymes: lipoproteinlipase, lysozyme, and leukocyte enzymes.
Box 6. Developmental immaturity of the innate immunological system. Immunoglobulin and complements B Due to earlier than term birth, preterm infants receive lesser amounts of IgG via the placenta B The complement system is decreased in preterm infants. Antimicrobial proteins and peptides B The maturation of leukocyte-secreted antimicrobial proteins and peptides increases in a gestational agedependent manner. Some of the critical ones are: abactericidal/permeability-increasing protein; defensins; and several phospholipases. Mannose binding lectin B Required for activating complement pathways, low in infants <28 weeks, increasing their risk for severe sepsis. Microbial-killing abilities B Diminished chemotaxis, lower neutrophil pool, decient opsonization, and other factors due to immaturity limit the ability for phagocytosis. Other recently discovered factors B Functionally impaired dendritic cells B Functional immaturity of toll-like receptors B Reduced cytokine-producing capacity of neonatal monocytes.
development is non-linear, the extent of maturity among various organs in a given infant might also vary. An understanding of these principles can help guide treatment strategies. Conict of interest statement None declared. Funding sources None
among the PMNs from preterm infants. PMNs, however, maintain adequate phagocytic activity, but because of the deciency of complement receptors on their surface, phagocytosis is not effective, especially when the invading microbial load is massive relative to the PMN counts. Other aspects of the immunological basis for increased susceptibility for neonatal infections in moderate and late preterm are listed in Box 6. The human intestinal system is also a major immunological organ. Soon after birth, the intestinal surface is exposed to a variety of microbial and dietary antigens. Since the newborn infant is immunologically nave, during vaginal birth and soon thereafter, they become colonized by multitudes of microbes, including Escherichia coli and streptococci. By the end of the rst week of life, anerobes such as Bacteroides spp., Bidobacterium spp. and Clostridium spp. also colonize the infant gut. The diversity of microbial ecology in preterm infants is affected by many factors, including chorioamnionitis, maternal intrapartum antibiotic exposure, and infant feeding type.38 Infants delivered by caesarean have less diverse microbial ecology compared to those delivered vaginally.39 They tend to have fewer E. coli and Bidobacteria spp., but more Klebsiella spp. and Enterobacter spp. The immunological implications of diversity of infant intestinal microbial ecology needs to be studied to explore their possible effects on sepsis, necrotizing enterocolitis, infant atopy, allergy, and food intolerance. 4. Summary and conclusions The foregoing discussion is intended to be a brief overview of some critical aspects of fetal maturation that operate as underpinnings for common problems seen in moderate and late preterm infants. One should note that variation in the degree of maturation among infants of similar gestational ages is very common. Since
Practice points Preterm birth, even by a few weeks prior to term, is associated with a high prevalence of clinical problems due to: B immaturity of organ systems (e.g. the lungs, brain; the gastrointestinal system). B acquired problems (e.g. infections, hypothermia). B inadequate monitoring and/or follow-up plans (e.g. hypoxic respiratory failure; hypoglycemia; kernicterus). Developmental processes are non-linear, therefore: B different organ systems mature at specic rates and trajectories that are specic to their functions (e.g infants breathing normally may not feed well, due to immature sucking/swallowing mechanisms). The degree of maturation can vary among infants born at comparable gestations because time is only one of the many factors inuencing maturation. Others are B maternal health and disease B medication use B lifestyle factors (nutritional status; smoking; illicit drug use; exercise) B fetal sex; number of fetuses; fetal disorders B the dynamics of the intrauterine environment.
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Research directions Understanding the mechanisms that affect the rate and trajectory of fetal/neonatal organ maturation and development. Assessing the role of intrauterine environment on fetal organ maturation during the second half of pregnancy. Developing biomarkers to: B identify the status of maturation of specic organ systems B predict outcomes of adverse clinical conditions. Study impact of preterm birth on the pattern of intestinal microbiota, and their variations to understand how they affect the current and future health and disease. Study how the extrauterine environment affects organ maturation and development in infants born preterm, and uncover the underlying process involved in such effects. Use the above knowledge to optimize care and followup of moderate and late preterm infants.
References
1. Raju TNK, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late preterm (near-term) infants: a summary of the workshop sponsored by the NICHD. Pediatrics 2006;118:1207e14. 2. Wang ML, Dorer DJ, Fleming MP, Catlin E. Clinical outcomes of near-term infants. Pediatrics 2004;114:372e6. 3. Engle WA, Tomashek KM, Wallman C. the Committee on Fetus and Newborn, American Academy of Pediatrics. Pediatrics 2007;120:1390e401. 4. ACOG Committee Opinion No. 404, 2008. Late-preterm infants. Committee on Obstetric Practice. Obstet Gynecol 2008;111:1029e32. 5. Martin JA, Hamilton BE, Sutton PD, et al. Births: nal data for 2008. National Vital Statistics Reports; vol. 59, no. 1. Hyattsville, MD: National Center for Health Statistics; 2010. 6. Schroder HJ, Power GG. Engine and radiator: fetal and placental interactions for heat dissipation. Exp Physiol 1997;82:403e14. 7. Laptook A, Jackson GL. Cold stress and hypoglycemia in late preterm (near term) infant: impact on nursery admission. Semin Perinatol 2006;30:24e7. 8. Fairchild KD, Sun CCJ, Gross GC, Okogbule-Wonodi AC, Chasm RM, Viscardi RM. NICU admission hypothermia, chorioamnionitis, and cytokines. J Perinat Med 2011;39:731e6. 9. Cummings KJ, Li A, Nattie EE. Brainstem serotonin deciency in the neonatal period: autonomic dysregulation during mild cold stress. J Physiol 2011;589:2055e64. 10. Tews D, Wabitsch M. Renaissance of brown adipose tissue. Horm Res Paediatr 2011;75:231e9. 11. Consortium on Safe Labor, Hibbard JU, Wilkins I, et al. Respiratory morbidity in late preterm births. JAMA 2010;28(304):419e25. 12. Ramachandrappa A, Rosenber ES, Wagoner S, Jain L. Morbidity and mortality in late preterm infants with severe hypoxic respiratory failure on extracorporeal membrane oxygenation. J Pediatr 2011;159:192e8. 13. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks gestational age. Pediatrics 2010;126:115e28.
14. Smith LJ, McKay KO, van Asperen PP, Selvadurai H, Fitzgerald DA. Normal development of the lung and premature birth. Pediatr Respir Rev 2010;11:135e42. 15. Jain L, Eaton DC. Physiology of fetal lung uid clearance and the effect of labor. Semin Perinatol 2006;30:34e43. 16. Eaton DC, Helms MN, Koval M, Bao HF, Jain L. The contribution of epithelial sodium channels to alveolar function in health and disease. Annu Rev Physiol 2009;71:403e23. 17. Keszler M, Carbone MT, Cox C, Schumacher RE. Severe respiratory failure after elective repeat cesarean delivery: a potentially preventable condition leading to extracorporeal membrane oxygenation. Pediatrics 1992;89:670e2. 18. Darnall RA, Ariagno RL, Kinney HC. The late preterm infant and the control of breathing, sleep, and brainstem development: a review. Clin Perinatol 2006;33:883e914. 19. Barlow SM. Central pattern generation involved in oral and respiratory control for feeding in the term infant. Curr Opin Otolaryngol Head Neck Surg 2009;17:187e93. 20. Barlow SM. Oral and respiratory control for preterm feeding. Curr Opin Otolaryngol Head Neck Surg 2009;17:179e86. 21. Garg M, Devaskar SU. Glucose metabolism in late preterm infants. Clin Perinatol 2006;33:853e70. 22. Committee on Fetus and Newborn, Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575e9. 23. Watchko JF. Hyperbilirubinemia and bilirubin toxicity in the late preterm infant. Clin Perinatol 2006;33:839e52. 24. Academy of Breastfeeding Medicine. ABM clinical protocol #10: breastfeeding the late preterm infant (34(0/7) to 36(6/7) weeks gestation) (rst revision June 2011). Breastfeed Med 2011;6:151e6. 25. Walker JC, Smolders MA, Gemen EF, et al. Development of lymphocyte subpopulations in preterm infants. Scand J Immunol 2011;73:53e8. 26. Strunk T, Currie A, Richmond P, Simmer K, Burgner D. Innate immunity in human newborn infants: prematurity means more than immaturity. J Matern Fetal Neonatal Med 2011;24:25e31. 27. Blumer N, Pfefferle PI, Renz H. Development of mucosal immune function in the intrauterine and early postnatal environment. Curr Opin Gastroenterol 2007;23:655e60. 28. Prez A, Gurbindo MD, Resino S, Aguarn A, Muoz-Fernndez MA. NK cell increase in neonates from the preterm to the full-term period of gestation. Neonatology 2007;92:158e63. 29. Calder PC, Krauss-Etschmann S, de Jong EC, et al. Early nutrition and immunity e progress and perspectives. Br J Nutr 2006;96:774e90. 30. Kapur R, Yoder M, Polin RA. The immune system. In: Martin RJ, Fanaroff AA, Walsh M, editors. Neonatal perinatal medicine. 9th ed. St Louis: Elsevier; 2011. p. 761e885. 31. Wagner CL, Taylor SN, Johnson D. Host factors in amniotic uid and breast milk that contribute to gut maturation. Clin Rev Allerg Immunol 2008;34:191e204. 32. van Nimwegen FA, Penders J, Stobberingh EE, et al. Mode and place of delivery, gastrointestinal microbiota, and their inuence on asthma and atopy. J Allergy Clin Immunol 2011;128:948e55. e1e3. 33. Murgas Torrazza R, Neu J. The developing intestinal microbiome and its relationship to health and disease in the neonate. J Perinatol 2011;311:S29e34. 34. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010;107:11971e5. 35. Sangild PT. Gut responses to enteral nutrition in preterm infants and animals. Exp Biol Med 2006;231:1695e711. 36. Newell SJ, Sarkar PK, Durbin GM, Booth IW, McNeish AS. Maturation of the lower oesophageal sphincter in the preterm baby. Gut 1988;29:167e72. 37. Neu J. Gastrointestinal development and meeting the nutritional needs of premature infants. Am J Clin Nutr 2007;85(Suppl.):629Se34S. 38. Mshvidadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V. Intestinal microbial ecology in premature infants assessed with non-culture based techniques. J Pediatr 2010;156:20e5. 39. Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr 2008;138:1796Se800S.

Obstetric decision-making and the late and moderately preterm infant

Cynthia Gyam-Bannerman*
Division of MaternaleFetal Medicine, Columbia University Medical Center, 622 W 168th St, New York, NY, USA
s u m m a r y
Keywords: Late preterm birth Prematurity Respiratory morbidity
The decision of when to deliver a patient for medical or obstetric complication directly affects the neonatal outcome. When the fetus is in danger due to suspected utero-placental insufciency, the decision to deliver is thought to benet the neonate. However, the opposite may be true when a normally developing fetus needs to be delivered for a maternal indication such as a persistently bleeding placenta praevia. These decisions are made daily by obstetric providers. The following is a review of obstetric decision-making for moderate and late preterm pregnancies. 2012 Published by Elsevier Ltd.
1. Introduction In 2005 the phrase late preterm was introduced by the National Institute of Child Health and Human Development (NICHD) to identify infants born between 340/7 and 366/7 weeks of gestation as a high risk group with increased morbidities when compared with term infants. This replaced the earlier phrase near term, which implied that these infants behaved similarly to term infants. Limiting this group to neonates born from 34 to 36 weeks also helped focus research on this cohort, allowing investigators to better characterize their outcomes. Unfortunately, the same consensus has not been reached for moderate preterm infants, so the literature regarding this group of infants has various gestational age denitions starting at 30e32 weeks of gestation and ending at 34e36 weeks.1,2 We now have ample data showing that most morbidities related to prematurity are increased in the late preterm group when compared with infants born at term, most markedly where respiratory morbidities are concerned.3e5 Intuitively, these morbidities are also higher in the moderate preterm group. Therefore, the decision for delivery in these patients should be weighed against the known morbidities associated with prematurity in these groups. This article discusses both morbidity and common obstetric indications for delivery among moderate preterm and late preterm infants.
2. Common complications warranting delivery and their management in the late preterm period 2.1. Obstetric 2.1.1. Preterm labour Preterm labour is dened as contractions leading to cervical change prior to 37 weeks gestation. Though the etiology of preterm labour is multifactorial, it is thought to result from one of the following pathways: infection, decidual haemorrhage, uterine overdistention, or hypothalamicepituitaryeadrenal (HPA) axis.6 Traditional treatments for active preterm labour include tocolysis to decrease contractions; antibiotics to prevent early onset group B streptococcus infection; and antenatal corticosteroids, generally in the form of betamethasone or dexamethasone, to promote fetal lung maturity as well as to decrease the rates of necrotizing enterocolitis and intraventricular haemorrhage.7 While the treatment of preterm labour is fairly consistent among most medical centres in the USA, the decision as to the gestational age beyond which intervention is no longer warranted is not clear. The most recent guidelines from the American College of Obstetricians and Gynecologists (ACOG) suggest that the decision of when to intervene with preterm labour should be based on the neonatal intervention capacities at the hospital of the practising obstetrician since it is known that the neonatal morbidity is inversely proportional to the gestational age at delivery.7 Because the role of tocolysis is primarily to allow for administration of antenatal corticosteroids since the efcacy beyond 48e72 h is unclear, and since antenatal corticosteroids are traditionally administered up to 34 weeks gestation, many tertiary care centres will not prevent delivery in an actively labouring patient before 34 weeks gestation. In two reviews of indications for late preterm
* Tel.: 44 212 305 6293; fax: 44 212 342 2717. E-mail address: cg2231@columbia.edu. 1744-165X/$ e see front matter 2012 Published by Elsevier Ltd. doi:10.1016/j.siny.2012.01.014
C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137
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birth from different regions in the USA, Holland et al. found that 36.2% of late preterm birth was spontaneous, while GyamBannerman et al. found this proportion to be higher at 53.1%.8,9 Both of these numbers reect a large population of infants who will be affected by practice patterns where they are born. 2.1.2. Preterm premature rupture of the membranes (PPROM) Similar to preterm labour with intact membranes, PPROM is a spontaneous event with management options directly linked to the gestational age. The American College of Obstetricians and Gynecologists has advocated for delivery at or beyond 34 weeks gestation if PPROM is to occur; however, they acknowledge that these recommendations are based on limited and inconsistent (Level B) data.10 Regardless, regional practice patterns and hospital neonatal intensive care unit (NICU) capabilities have led to variations in gestational age at delivery. A survey of practice patterns by maternalefetal medicine (MFM) providers showed that nearly 50% delivered pregnancies complicated by PPROM at later than 34 weeks gestation.11 The question of whether a delay in delivery is harmful for patients with PPROM was recently addressed by a review in the Cochrane database of the use of antibiotics with ruptured membranes. They showed that administration of antibiotics signicantly decreased the rates of both neonatal infection (odds ratio: 0.67; 95% condence interval: 0.52e0.85) and chorioamnionitis (0.66; 0.46e0.96) at up to 37 weeks gestation.12 Antibiotics also made it less likely that a patient with ruptured membranes would deliver by 48 h (0.71; 0.58e0.87). Patients who were included in this review delivered at up to 37 weeks gestation. A different Cochrane database review of expectantly managed PPROM to 37 weeks gestation showed that there were no differences in the rates of neonatal sepsis (relative risk: 1.33; 95% condence interval: 0.72e2.47), perinatal mortality (0.98; 0.41e2.36), intrauterine deaths (0.26; 0.04e1.52) or neonatal deaths (1.59; 0.61e4.16) when comparing early delivery with expectant management.13 Interestingly, early delivery increased the incidence of caesarean delivery (1.51; 1.08e2.10) and endometritis (2.32; 1.33e4.07), likely secondary to a higher caesarean delivery rate in that group. However, there was no statistical difference in the rates of chorioamnionitis (0.44; 0.17e1.14) suggesting safety, at least with short term delay. Ongoing prospective trials, including PPROMT and PPROMEXIL, will help to further elucidate whether prolonged expectant management to 37 weeks gestation is appropriate for late preterm PPROM.14,15 2.1.3. Pre-eclampsia/gestational hypertension There is some debate and regional variation regarding the appropriate gestational age for delivery for some of the hypertensive disorders of pregnancy. While most experts agree that patients with clinically stable severe pre-eclampsia should be delivered by 34 weeks gestation, there remains discussion regarding the appropriate gestational age for delivery of mild pre-eclampsia and gestational hypertension. A recent clinical trial evaluating labour induction versus expectant management for mild pre-eclampsia and gestational hypertension at 36 weeks found that maternal outcomes were improved with labour induction after 37 weeks.16 The authors did not nd this trend with delivery between 36 and 37 weeks, but they cited low numbers in that subgroup as a reason for further study at that gestational age. Habli et al. performed a secondary analysis of data from an NICHD clinical trial on calcium to prevent pre-eclampsia.17 Specically, they tried to assess whether the poorer neonatal outcomes related to gestational hypertension and pre-eclampsia were secondary to the disease process or iatrogenic delivery resulting from these diagnoses in a cohort of both hypertensive and normotensive women delivering
at 35, 36, or 37 weeks gestation. The authors found a higher rate of small for gestational age, NICU admission, and neonatal length of stay in the hypertensive compared with the normotensive group. These differences did not vary by the severity of hypertension; rather, they seemed to be related to labour induction. The authors concluded that the need for intervention at these earlier gestational ages should be carefully evaluated. Recently, Barton et al. reviewed outcomes specically associated with gestational hypertension and late preterm delivery using a retrospective database.18 They found that elective delivery from 34 to 36 weeks resulted in increased neonatal morbidity without maternal benet. The cited literature suggests that patients with mild pre-eclampsia or gestational hypertension can be delivered at term (37 weeks). The NICHD/ Society for MaternaleFetal Medicine (SMFM) workshop had a similar conclusion recommending delivery at 37 weeks for mild pre-eclampsia and 37e38 weeks for gestational hypertension.19 A recent study randomized 756 patients to labour induction versus expectant management at 36 weeks gestation.16 They included women with mild pre-eclampsia (dened as a diastolic blood pressure of >90 mmHg with proteinuria, or gestational hypertension with blood pressures <170/110 mmHg). They found improved maternal outcomes in the subgroup of women who were induced at 37 weeks gestation. Women pregnant from 36 to 37 weeks gestation beneted from expectant management. We can conclude from their ndings that it is likely that women with mild pre-eclampsia or gestational hypertension would benet from delivery at 37 weeks gestation rather than waiting until 39 weeks. However, it would be interesting to see whether the same benet would be found in the subgroup of women who had only gestational hypertension. 2.1.4. Oligohydramnios Oligohydramnios, dened either as an amniotic uid index (AFI) of <5, an AFI <5th percentile for gestational age, or a maximum vertical pocket of <2 cm is a complication of pregnancy that leads to concern both for patients and their providers. Since amniotic uid decreases with advancing gestational age, this complication is often noted in the late preterm period. Isolated oligohydramnios is not thought to be related to adverse perinatal outcome.20 However, the most commonly followed practice for this complication is delivery at term (>37 weeks gestation). Sverker et al.21 randomized 54 women at 40 completed weeks gestation with isolated oligohydramnios to labour induction versus expectant management. The primary neonatal outcomes were Apgar scores and cord pH. There were no differences between groups. There were also no differences between NICU admission rates. With regards to maternal complications, there was no increase in complications in the expectantly managed group, and the rate of caesarean delivery was similar between groups. More recently, Melamed et al. reviewed 108 cases of isolated oligohydramnios diagnosed from 240/7 to 366/7 weeks matched 3:1 (controls:cases) to controls with normal uid.19 They found that the majority of adverse perinatal outcomes in cases could be attributed to iatrogenic prematurity related to early delivery, rather than the oligohydramnios itself. These data suggest that isolated oligohydramnios, while certainly warranting closer evaluation, should not be an indication for delivery without other complicating factors before term. 2.1.5. Prior caesarean delivery Although the timing of an elective repeat caesarean after a prior low transverse cesarean is unambiguous at 39 weeks gestation, it is less obvious when the prior scar is from a classical uterine incision. The rate of uterine rupture in women with a prior classical scar is thought to be between 4% and 9%.22 Chauhan et al. reviewed uterine rupture and dehiscence rates in a cohort of 157 women who
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had had a prior classical cesarean.7 All were planned for repeat caesarean. There was one uterine rupture in this series resulting in an IUFD, which was of a woman who presented with bleeding at 29 weeks gestation. Otherwise, there was a 9% dehiscence rate noted at the time of repeat caesarean, which did not alter maternal or neonatal outcomes compared with those women without dehiscence. Of note, almost 50% of these patients presented in labour, before an amniocentesis could be performed to document fetal lung maturity. Although the mean duration of labour was 7.3 5.6 h, there were no episodes of uterine rupture in that group. The authors concluded that uterine rupture and dehiscence could not be accurately predicted or prevented. Other data not specic to classical caesarean are supplied from a review of >40,000 deliveries in an Irish hospital.23 Of the 1355 women with one or more prior caesareans attempting a trial of labour, there were six uterine ruptures. There was one pre-labour rupture in a woman with a prior classical caesarean, but the authors did not provide information on how many patients had had a prior classical caesarean. There is very little other evidence to help guide timing of delivery in these patients. Expert opinion regarding timing of delivery in these cases still favours delivery prior to the onset of labour. This is consistent with the recommendation from the NICHD/SMFM workshop for delivery at 36e37 weeks gestation.24 2.1.6. Accreta/praevia The SMFM clinical opinion paper on placenta accreta states that planned late preterm delivery (340/7 to 366/7 weeks gestation) is an acceptable management strategy since there are data showing increased rates of haemorrhage once delivery occurs beyond 36 weeks gestation.25 A decision analysis on the optimal timing of delivery for patients with placenta accreta suggested that 34 weeks gestation optimized both maternal and neonatal outcomes.26 Therefore, it is likely appropriate to deliver a patient suspected to have placenta accreta if the pregnancy continues to the early term period. The optimal gestational age at delivery for women with placenta praevia is based primarily on expert opinion and has been quoted as between 36 and 38 weeks gestation.27,28 Some authorities advocate fetal lung maturity testing in a stable patient if delivery is planned at 37 weeks.27 The gestational age of delivery weighs the risk of prematurity versus the risk of maternal haemorrhage, which increases in the presence of contractions. Therefore, based on few data, it is likely appropriate to deliver women with placenta praevia in the early term period if the pregnancy remains ongoing. However, the optimal timing of delivery in this group is unknown. 2.2. Maternal Chronic maternal disease during pregnancy is common due both to the high prevalence of obesity and to an increase in women waiting for advanced maternal age to attempt their rst pregnancy. Exacerbation of chronic disease resulting from older age and obesity can lead to preterm delivery. Obesity is considered endemic in the USA.29 Aside from a higher prevalence of chronic hypertension and diabetes in obese women, they are also noted to be at increased risk of pre-eclampsia. An epidemiologic study of more than 1.4 million women found that the risk of pre-eclampsia is doubled for every 5e7 kg/m2 increase in pre-pregnancy body mass index.30 As noted previously, preeclampsia is a common cause of preterm birth. Thus, obesity is linked to prematurity. Obese women also have a 10-fold increase in the rate of chronic hypertension compared with non-obese women, further increasing the risk of pre-eclampsia.29 Since weight loss during pregnancy is not recommended, this risk factor can be
modied postpartum, but ideally should be modied before attempting pregnancy. Chronic hypertension is another common cause of prematurity. The prevalence of this disease is thought to be w7% in women aged <40 years.31 Pregnant women are given this diagnosis if they have hypertension outside of pregnancy, or if they rst manifest elevated blood pressures before 20 weeks gestation. Increased vascular resistance noted in hypertensive patients can lead to intrauterine growth restriction (IUGR, discussed below) which, in the setting of abnormal testing, can lead to preterm delivery. Chronic hypertensive parturients are also more likely to develop pre-eclampsia compared to their normotensive counterparts. A MaternaleFetal Medicine Units Network trial found that 25% of women with chronic hypertension develop superimposed pre-eclampsia, increasing the likelihood that preterm pregnancy interruption would be necessary.32 A secondary analysis of the aforementioned Network study showed that 33% of women with chronic hypertension delivered prior to 37 weeks with 18% delivering prior to 35 weeks,33 making chronic hypertension a common obstetric problem leading to prematurity. Finally, connective tissue disorders, known to be more common in females compared with males, are another common cause of prematurity. Disorders such as lupus or antiphospholipid antibody syndrome have in common immune-mediated complexes that can affect various organ systems leading to end-organ damage and shortened life-spans. The 10- and 20-year survival rates for women with lupus are 75% and 50%, respectively.34 Pregnancy outcome with lupus is related to the presence or absence of hypertension and proteinuria. Even women with lupus in remission have a higher risk of pre-eclampsia. This risk is increased if both hypertension and renal insufciency are present. The diagnosis of pre-eclampsia versus a lupus are can be difcult during pregnancy. Complement levels may be helpful to distinguish the two disease processes, so these could be obtained at the rst prenatal visit.29 While lupus patients with severe pre-eclampsia should be delivered, patients with a lupus are can be managed conservatively. Both late preterm and moderate preterm deliveries are not uncommon in this group of women. Similarly, women with antiphospholipid antibody syndrome are known to have an increase in adverse fetal outcomes. Treatment with aspirin and heparin has been the mainstay in the cohort and allows many of these women to go to term. However, fetal growth restriction and abnormal fetal testing are causes of preterm delivery for these women.29 2.3. Fetal 2.3.1. IUGR Although it is well documented that fetuses with IUGR have an increase in both fetal and neonatal morbidity and mortality,35 there are few prospective data that evaluate risks associated with delayed delivery of IUGR at term. Most available data are related to delaying delivery in preterm IUGR.36 Because of the increase in adverse outcomes in this group, many authorities state that delivery for IUGR should occur at term.37 However, there is one recent prospective, randomized controlled trial of management of IUGR beyond 360/7 weeks gestation.38 The authors randomized 321 patients with IUGR with either normal or abnormal Doppler ultrasound to either induction or expectant monitoring. The primary outcome was short term neonatal morbidity and included death before discharge from the hospital, 5 min Apgar of <7, umbilical artery pH of <7.05, or admission to the NICU; and the study was powered to assess for equivalence of this outcome. The average gestational age in the induction group was 380/7 weeks, whereas the average gestational age in the expectant management group was 393/7 weeks. There was no difference in their primary
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outcome. Additionally, signicantly more women in the expectant monitoring group presented in spontaneous labour (46.0% vs 3.7%), but there was no difference in the caesarean delivery rate. The data on longer term outcomes in this group is limited to delayed delivery of preterm infants with IUGR, but these data also suggest no difference in the rates of death or disability at age 2 years.39 The most recent ACOG bulletin on IUGR (January, 2000; Number 12) states that delivery should be considered once there is complete cessation of growth or a non-reassuring fetal assessment; a specic gestational age for delivery is not supplied. Many cases of suspected IUGR are from constitutionally small parents. Based on the above information, the optimal timing of delivery for women with IUGR and otherwise reassuring testing remains unknown, with at least one study suggesting that delivery after 37 weeks does not increase the rate of short term morbidity. Recommendations from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Society for MaternaleFetal Medicine workshop titled Timing of Indicated Late Preterm and Early Term Births suggest that delivery occur between 38 and 39 weeks in cases of IUGR without other comorbidities and otherwise reassuring fetal testing.24 2.3.2. Multiple gestation It is known that twin gestations deliver earlier than singletons; the average gestational age of delivery is thought to be in the late preterm period. However, there are very few indications for elective delivery of dichorionic, diamniotic twins in this gestational age window outside of coexisting maternal or obstetric complications indicating delivery. The consensus of the NICHD/SMFM workshop participants regarding elective late preterm delivery for dichorionic twins is in the situation of an intrauterine fetal demise (IUFD) of a co-twin.24 However, the appropriate gestational age for delivery of uncomplicated monochorionic, diamniotic (mono/di) twins is highly debated with some authorities arguing that it should occur in the moderate preterm period. The recommendations vary from 32 to 37 weeks gestation.40e42 Barigye et al.40 identied a group of 151 uncomplicated mono/dichorionic twin gestations and evaluated the risk of fetal demise. They found that the risk of IUFD at 32 weeks in these seemingly normal twins was 1 in 23. Furthermore, 4.6% of pregnancies had an IUFD within 2 weeks of a normal scan. They suggested that a policy of elective preterm delivery at 32 weeks would obviate this risk. On the other end of the spectrum Smith et al.41 reviewed 236 ongoing mono/dichorionic twin pregnancies and found that the likelihood of two live births in the uncomplicated group was 99.5% at 32 weeks. They recommended against elective preterm delivery of uncomplicated mono/ dichorionic twins. Consensus and expert opinion suggest that delivery for uncomplicated mono/dichorionic twins should occur in the late preterm period between 34 and 37 weeks gestation.24 2.3.3. Anomalies Dening an appropriate gestational age for delivery in the setting of fetal anomalies is nearly impossible due to the large numbers and varied complications related to the numerous anomalies. It has been suggested that there are >100 different categories of anomalies; however, most of these do not have outcomes that will be improved by delivery prior to term.43 One notable exception to this is an anomaly that had led to fetal hydrops. Obstructive lesions and fetal heart failure can often lead to hydrops, which confers a poor prognosis for the fetus. Most authorities believe that hydrops presenting beyond 34 weeks gestation is an indication for late preterm delivery.43 Another exception is in the setting of fetal arrhythmias. Specically, isolated fetal tachyarrhythmias can lead to hydrops from heart failure. The
rst line treatment for this type of anomaly involves treatment of the mother with medications such as digoxin, procainamide, ecainide, or amiodarone. Because of the potential for both maternal and fetal toxicity from some of these medications, late preterm delivery may be indicated for fetuses refractory to treatment or when the initial diagnosis occurs near term.44 3. Common complications and their management in the Moderately preterm (MP) period 3.1. Intrauterine growth restriction (IUGR) Whereas intrauterine growth restriction without comorbidities can be delivered at term, there are certain cases of pathological IUGR that will require preterm delivery regardless of the gestational age. Timing of delivery in pregnancies complicated by IUGR was evaluated by the Growth Restriction Intervention Trial (GRIT). They randomized women with growth-restricted fetuses from 24 to 36 weeks gestation to immediate delivery, specically after 48 h for steroids, versus delayed delivery, specically, abnormal testing or other factor requiring delivery. They found equal proportions of stillbirth in both groups.45 The 2-year follow-up to this study showed that gestational age at delivery was the primary determinant of neonatal outcome. Infants born at <31 weeks had lower developmental scores than infants born at >31 weeks, regardless of whether they were in the immediate or delayed delivery group.39 Results from the GRIT study group suggest that gestational age is the primary determinant of neonatal outcome. While Doppler waveforms were recorded by the GRIT study group, they were not used in the randomization scheme or as part of the protocol. This is in contrast to a retrospective cohort study by Chalubinski et al. where they identied a cohort of IUGR fetuses over a 10-year period at a single institution and evaluated perinatal outcomes based on Doppler ndings within 7 days of delivery.46 They divided identied pregnancies into three groups: (1) abnormal umbilical artery (UA) pulsatility index (PI) or absent UA end-diastolic ow, and normal median cerebral artery (MCA) PI; (2) abnormal UA PI, or absent or reversed UA end-diastolic ow, and abnormal MCA PI with normal ductus venosus (DV) PI; and (3) absent or reversed UA end-diastolic ow, and abnormal MCA PI, and abnormal DV PI (mean >2 SD, a-wave present or absent or reversed end-diastolic ow). They found rates of neonatal demise of 0/17 (0%), 2/44 (4.5%), and 7/30 (23.3%) in infants from Doppler groups 1, 2, and 3, respectively (P 0.019). Gestational age also played a role, suggesting that information on Doppler indices should be used in delivery planning after 28 weeks gestation. Therefore, moderate preterm infants with IUGR and comorbidities, specically severe Doppler abnormalities such as those in group 3, are likely to be delivered by obstetricians to prevent demise. 3.2. Severe pre-eclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet count) Severe pre-eclampsia complicates 0.3% of pregnancies at <34 weeks gestation.47 The decision of whether to expectantly manage these patients has direct implications on neonatal outcomes. Traditionally, severe pre-eclampsia is dened by a blood pressure of >160/110 mmHg in the presence of proteinuria. Clinicians weigh the decision for delivery versus expectant management on the maternal and fetal status at the time of initial diagnosis. Conditions considered contraindications to conservative management are pulmonary edema, abruption, signicant renal dysfunction, HELLP syndrome, non-reassuring fetal status and eclampsia.48 Studies that have evaluated conservative management of severe pre-eclampsia have used several gestational age parameters to
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dene when this management should end by delivery. Most notably, data from expectant management to both 32 and 34 weeks gestation suggest improved neonatal outcomes from these strategies.49,50 Therefore, women with severe pre-eclampsia are likely to be delivered in both the moderate and late preterm periods, adding to the numbers of indicated preterm births. Importantly, denitive treatment of severe pre-eclampsia and HELLP syndrome remains by delivery. Hence, a clinician faced with severe pre-eclampsia not amenable to expectant management will rightly deliver the mother. 3.3. Spontaneous preterm labour or PPROM (preterm premature rupture of the membranes) Finally, whereas management of spontaneous preterm labour or PPROM in the late preterm period may be varied, treatment of these conditions prior to 34 weeks is fairly straightforward. ACOG advocates for tocolysis, antenatal corticosteroid administration, and antibiotic to prevent group B streptococcal sepsis in women presenting in preterm labour between 24 and 34 weeks gestation.7 For women with PPROM, in addition to the interventions used for preterm labour, the management includes broader spectrum antibiotics to increase the latency from ruptured membranes to delivery.10 For both conditions, moderate preterm delivery would be indicated if chorioamnionitis were diagnosed. 4. Conclusion There are many clinical presentations, both spontaneous and indicated, that lead to moderate and late preterm delivery. While the optimal treatment and prevention of spontaneous preterm birth is an ongoing conundrum that has had little inuence on the proportion of patients that deliver preterm, there remain many medically indicated preterm births in both gestational age windows that have coincided with a decrease in the number of stillbirths.51,52 Thus, obstetric practice continues to directly impact the numbers of preterm infants delivered annually, which confers a signicant health care burden. Further evaluation of these practices may help to decrease the rates of prematurity.
References
1. Altman M, Vanpee M, Cnattingius S, Norman M. Moderately preterm infants and determinants of length of hospital stay. Arch Dis Child Fetal Neonatal Ed 2009;94:F414e8. 2. Wooldridge J, Hall WA. Posthospitalization breastfeeding patterns of moderately preterm infants. J Perinat Neonatal Nurs 2003;17:50e64. 3. Hibbard JU, Wilkins I, Sun L, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419e25. 4. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008;111:35e41. 5. Yoder BA, Gordon MC, Barth Jr WH. Late-preterm birth: does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstet Gynecol 2008;111:814e22. 6. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5e20. 7. Anonymous. ACOG practice bulletin: management of preterm labor 2003. 8. Holland MG, Refuerzo JS, Ramin SM, Saade GR, Blackwell SC. Late preterm birth: how often is it avoidable? Am J Obstet Gynecol 2009;201:404.e1e4. 9. Gyam-Bannerman C, Fuchs KM, Young OM, Hoffman MK. Nonspontaneous late preterm birth: etiology and outcomes. Am J Obstet Gynecol 2011;205:456.e1e6. 10. American College of Obstetricians and Gynecologists. ACOG practice bulletin: premature rupture of membranes 2007. Number 80. 11. Ramsey PS, Nuthalapaty FS, Lu G, Ramin S, Nuthalapaty ES, Ramin KD. Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternalefetal medicine providers. Am J Obstet Gynecol 2004;191:1497e502. 12. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2010:CD001058. 13. Buchanan SL, Crowther CA, Levett KM, Middleton P, Morris J. Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks gestation for improving pregnancy outcome. Cochrane Database Syst Rev 2010:CD004735. 14. Morris JM, Roberts CL, Crowther CA, Buchanan SL, Henderson-Smart DJ, Salkeld G. Protocol for the immediate delivery versus expectant care of women with preterm prelabour rupture of the membranes close to term (PPROMT) Trial [ISRCTN44485060]. BMC Pregn Childbirth 2006;6:9. 15. van der Ham DP, Nijhuis JG, Mol BW, et al. Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks (the PPROMEXIL-trial). BMC Pregn Childbirth 2007;7:11. 16. Koopmans CM, Bijlenga D, Groen H, et al. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet 2009;374:979e88. 17. Habli M, Levine RJ, Qian C, Sibai B. Neonatal outcomes in pregnancies with preeclampsia or gestational hypertension and in normotensive pregnancies that delivered at 35, 36, or 37 weeks of gestation. Am J Obstet Gynecol 2007;197:406.e1e7. 18. Barton JR, Barton LA, Istwan NB, et al. Elective delivery at 34(/) to 36(/) weeks gestation and its impact on neonatal outcomes in women with stable mild gestational hypertension. Am J Obstet Gynecol 2011;204:44.e1e5. 19. Melamed N, Pardo J, Milstein R, Chen R, Hod M, Yogev Y. Perinatal outcome in pregnancies complicated by isolated oligohydramnios diagnosed before 37 weeks of gestation. Am J Obstet Gynecol 2011;205:241.e1e6. 20. Zhang J, Troendle J, Meikle S, Klebanoff MA, Rayburn WF. Isolated oligohydramnios is not associated with adverse perinatal outcomes. BJOG 2004;111:220e5. 21. Sverker E, Andersson A, Johansson A, Kublicas M. Oligohydramnios in uncomplicated pregnancies beyond 40 completed weeks. Fetal Diagn Ther 2005;20:182e5. 22. Cunningham FG, Hauth JC, Leveno KJ, Gilstrap III LC, Bloom SL, Wenstrom KD, editors. Williams obstetrics. 22nd ed. New York: McGraw-Hill; 2005. 23. Meehan FP, Magani IM. True rupture of the caesarean section scar (a 15 year review, 1972e1987). Eur J Obstet Gynecol Reprod Biol 1989;30:129e35. 24. Spong CY, Mercer BM, DAlton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstet Gynecol 2011;118:323e33. 25. Belfort MA. Placenta accreta. Am J Obstet Gynecol 2010;203:430e9. 26. Robinson BK, Grobman WA. Effectiveness of timing strategies for delivery of individuals with placenta previa and accreta. Obstet Gynecol 2010;116:835e42. 27. Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol 2006;107:927e41. 28. Hull AD, Resnik R. Placenta previa, placenta accreta, abruptio placentae, and vasa previa. In: Creasy RK, Resnik R, Iams JD, editors. Maternalefetal medicine: principles and practice. 6th ed. Philadelphia: Saunders/Elsevier; 2009. p. 725e37. 29. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY, editors. Williams obstetrics. 23rd ed. New York: McGraw-Hill; 2010. 30. OBrien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology 2003;14:368e74. 31. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988e2000. JAMA 2003;290:199e206. 32. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of MaternaleFetal Medicine Units. N Engl J Med 1998;338:701e5.
Practice points There are many medical indications that result in preterm delivery. Some common indications for late preterm birth, specically mild pre-eclampsia and gestational hypertension, may not be justied. Indicated moderate preterm birth is much less common and generally is related to pathologic fetal growth or severe pre-eclampsia/HELLP. Obstetric practice has a direct impact on the rates of prematurity.
Conict of interest statement None declared.
Funding sources None.
C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137 33. Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of MaternaleFetal Medicine Units. N Engl J Med 1998;339:667e71. 34. Jacobsen S, Petersen J, Ullman S, et al. Mortality and causes of death of 513 Danish patients with systemic lupus erythematosus. Scand J Rheumatol 1999;28:75e80. 35. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol 1982;59:624e32. 36. Group TGS. A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. Br J Obstet Gynaecol 2003;110:27e32. 37. Resnik R, Creasy RK. Intrauterine growth restriction. In: Creasy RK, Resnik R, Iams JD, editors. Maternalefetal medicine: principles and practice. 6th ed. Philadelphia: Saunders/Elsevier; 2009. p. 635e50. 38. Boers KE, Vijgen SM, Bijlenga D, et al. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010;341:c7087. 39. Thornton JG, Hornbuckle J, Vail A, Spiegelhalter DJ, Levene M. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet 2004;364:513e20. 40. Barigye O, Pasquini L, Galea P, Chambers H, Chappell L, Fisk NM. High risk of unexpected late fetal death in monochorionic twins despite intensive ultrasound surveillance: a cohort study. PLoS Med 2005;2:e172. 41. Smith NA, Wilkins-Haug L, Santolaya-Forgas J, et al. Contemporary management of monochorionic diamniotic twins: outcomes and delivery recommendations revisited. Am J Obstet Gynecol 2010;203:133.e1e6.
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42. Lee YM, Wylie BJ, Simpson LL, DAlton ME. Twin chorionicity and the risk of stillbirth. Obstet Gynecol 2008;111:301e8. 43. Craigo SD. Indicated preterm birth for fetal anomalies. Semin Perinatol 2011;35:270e6. 44. Tachyarrhythmias. In: Bianchi DW, Crombleholme T, DAlton ME, Malone FD, editors. Fetology. New York: McGraw-Hill; 2010. p. 313e9. 45. GRIT Study Group. A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. BJOG 2003;110:27e32. 46. Chalubinski KM, Repa A, Stammler-Safar M, Ott J. The impact of doppler sonography on intrauterine management and neonatal outcome in preterm fetuses with intrauterine growth retardation. Ultrasound Obstet Gynecol 2011 May 5. doi:10.1002/uog.9039 [Epub ahead of print]. 47. Catov JM, Ness RB, Kip KE, Olsen J. Risk of early or severe pre-eclampsia related to pre-existing conditions. Int J Epidemiol 2007;36:412e9. 48. Sibai BM. Evaluation and management of severe preeclampsia before 34 weeks gestation. Am J Obstet Gynecol 2011;205:191e8. 49. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. Aggressive or expectant management for patients with severe preeclampsia between 28e34 weeks gestation: a randomized controlled trial. Obstet Gynecol 1990;76:1070e5. 50. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks gestation: a randomized controlled trial. Am J Obstet Gynecol 1994;171:818e22. 51. Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006;19:773e82. 52. Ananth CV, Gyam C, Jain L. Characterizing risk proles of infants who are delivered at late preterm gestations: does it matter? Am J Obstet Gynecol 2008;199:329e31.

Obstetric management of moderate and late preterm labour

P.C. McParland*
University Hospitals of Leicester, Kensington Building, Leicester Royal Inrmary, Inrmary Square, Leicester LE1 5WW, UK
s u m m a r y
Keywords: Fibronectin Preterm labour Preterm rupture of membranes Progesterone
Moderate and late preterm births account for the majority of preterm babies. The common perception that birth at 32e36 weeks gestation carries few risks is now being challenged, as these babies have increased risk of neonatal mortality and morbidity. However, spontaneous labour at this gestation frequently has no specic, easily identiable precursor, although preterm birth per se has a number of epidemiological and clinical associations. Prediction and prevention of preterm birth is currently largely aimed at identifying women at high risk such as those with previous preterm birth, and targeting intervention at this group. Both cervical length assessment and bronectin testing permit some modication of the likelihood of preterm birth in this group. Progesterone treatment for the prevention of preterm birth is currently being researched widely, and appears a potentially promising strategy. Babies born at 32e36 weeks gestation need careful monitoring in labour, with modication of intervention in labour due to their prematurity. 2012 Elsevier Ltd. All rights reserved.
1. Introduction Preterm birth has been identied internationally as a research priority in reproductive medicine. It accounts for 6e10% of all births, and accounts for the majority of the perinatal deaths of normally formed babies.1 Most of those mortalities occur in babies born at <32 weeks of gestation, and it is this group towards which most of the research and clinical effort is targeted. However the overall rate of preterm birth is steadily increasing.2 Preterm was dened by the World Health Organization in 1950 as birth at <37 weeks gestation.2 There have been a number of renements, including denitions of subgroups of preterm birth, with late preterm birth now widely accepted as birth at 34e36 weeks gestation. Moderate preterm birth has been dened as birth at 32e33 weeks, very preterm birth at <32 weeks and extremely preterm birth at <28 weeks gestation.2 Moderate and late preterm births account for the majority of preterm births. Late preterm births account for 60e70% of all preterm births, and a further 20% are moderate preterm births.3 Many of these births will be iatrogenic or clinically indicated births for maternal or fetal reasons (these account for w20% of late preterm births). Mortality and serious morbidity are considered rare, hence increased willingness to deliver at these gestations for maternal and fetal indications. A recent study in the USA has
estimated that 1 in 15 of late preterm babies was delivered for soft or elective precursors,4 and was thus avoidable. There is ongoing debate regarding whether reduction in late preterm births is either possible or desirable.5,6 It must be remembered that infant mortality among late preterm babies is three times higher than that of term babies (7.7 per 1000 live births for late preterm births compared with 2.5 per 1000 live births at term). Early and late neonatal complications are increased, including respiratory distress, jaundice, sepsis, poor feeding and hypoglycaemia, with higher subsequent readmission rates and increased risk of cerebral palsy.7 This review focuses on the obstetric management of spontaneous moderate and late preterm labour, which may be preceded by preterm prelabour rupture of the membranes. 2. Aetiology of moderate and late preterm birth Preterm labour is a multifactorial condition. For any one individual, a single cause is rarely identied, although in population studies and clinical investigations several associations are found. Preterm labour may be considered to represent early activation of the normal physiological pathway of labour, or to be the result of a pathological insult. Its cause may be considered on two levels: the biochemical and endocrine pathways associated with the onset of normal labour and those triggered by a pathological insult; and the epidemiology and clinical associations of preterm birth. Only a few of these associations and processes can be linked to moderate and late preterm birth specically, compared with preterm birth per se.
* Tel./fax: 44 116 2585923. E-mail address: pcm7@le.ac.uk. 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.01.013
P.C. McParland / Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142
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2.1. Pathophysiology of preterm labour The pathophysiological mechanism of normal term labour is not well understood, let alone that of preterm labour. The process of parturition has been described as a continuum, with ve recognised phases: implantation, uterine quiescence, activation, stimulation and involution.8 The activation and stimulation phases that comprise labour have been studied in most detail. There are three principal theories underlying the onset of labour, at any gestation: progesterone withdrawal, oxytocin initiation and decidual activation. Progesterone withdrawal is recognised as a mechanism in other mammals, as evidenced by a fall in the circulating levels of progesterone. This phenomenon is not seen in the human; rather a theory has been generated of functional progesterone withdrawal, with modulation of progesterone receptors in the tissues of the myometrium and fetal membranes.9 Although oxytocin is required to stimulate contractions in labour, in the human there is no evidence of an increase in oxytocin levels related to the onset of labour, although modulation of oxytocin receptors is possible. However, the last pathway, decidual activation, mediated by inammation, infection, bleeding or uteroplacental ischaemia appears a more important pathway.3,10 Preterm labour is the endpoint of a number of multifactorial processes, not a single well-dened condition. Those processes may lead to preterm labour at different gestations. Considering clinically recognised pathways leading to preterm labour, it is possible to identify infection, decidual haemorrhage, maternal/fetal hypothalamicepituitaryeadrenal activation (stress), uterine distension, and cervical insufciency. The rst and last of these causes are specically associated with early preterm birth; moderate/late preterm birth may be the consequence of any of the others.8 Intrauterine infection is the single most clear underlying aetiology that has been identied in association with the initiation of preterm labour, preceding 25e40% of preterm births.3 However, it is identied in the majority of births at extreme preterm gestations, and only in 10% of births at late preterm gestations.3 This suggests that other mechanisms, perhaps the early activation of physiological labour, predominate as the trigger for later preterm births.
identies cigarette smoking and vaginal bleeding as independent risk factors for PPROM.15 2.2.3. Bacterial vaginosis Bacterial vaginosis (BV) was rst identied as associated with subsequent late miscarriage and preterm birth in 1994.16 BV is a complex alteration of the vaginal ora, rather than a vaginal infection. It is characterised by reduction in numbers of lactobacilli, increase in vaginal pH, and overgrowth of pathogens including Gardnerella and Bacteroides spp. Prevalence of BV in asymptomatic women is 12e25%. BV doubles the risk of preterm birth at <37 weeks [odds ratio (OR): 2.19; 95% condence interval (CI): 1.54e3.12].17 However, BV diagnosed at <16 weeks gestation gives the highest risk of preterm birth (OR: 7.55).18 2.2.4. LLETZ (large loop excision of the transformation zone) Excision cervical procedures for cervical intraepithelial neoplasia increase the risk of preterm birth prior to 37 weeks.19e21 The greater the amount of tissue removed, and the more procedures undertaken, the greater the risk (2.8-fold increased risk of delivery at <37 weeks with one procedure, 9.9-fold increase with two procedures19). The mechanism is unclear, but may be by compromising the cervical mucus barrier to ascending infection from the vagina into the uterine cavity. At present this is an area of ongoing research, and the best management options for such women in pregnancy are yet to be conrmed. 3. Prediction and prevention of preterm labour Strategies to prevent preterm labour can be considered as strategies targeted at the whole obstetric population, or those targeted at high risk women after risk assessment. They can also be considered by stratifying for asymptomatic or symptomatic women. Whole population strategies aimed at reducing the risk of preterm birth include smoking cessation programmes and screening for asymptomatic bacteriuria. Women may be identied at high risk of preterm birth based on risk factor assessment. One of the strongest risk factors that may be identied is having a prior preterm birth (recurrence risk w15% after one prior preterm birth, 30% after two prior preterm births). They can be further stratied, as the majority of women who have a recurrent preterm birth do so within 2 weeks gestation of the previous preterm birth.22 Other clinical risk factors that may be identied in the history include congenital uterine abnormality and prior cervical surgery. 3.1. Cervical length Cervical length assessment for risk of preterm birth is carried out at 20e24 weeks gestation by transvaginal ultrasound. It has not been demonstrated to be benecial to screen the low risk obstetric population. To et al. scanned 47 123 women at 22e24 weeks, and identied cervical length of <15 mm in 470 women.23 Of these women, 253 participated in their study, and were randomised to cerclage or expectant management. The proportion of preterm birth <33 weeks was similar in each group, with no difference in perinatal morbidity or mortality.23 However, strategies targeting the high risk group of women have been demonstrated to be more benecial. Meta-analysis studying the strategy of cervical length scanning of women with prior preterm birth, and cervical cerclage if cervical length is <25 mm, demonstrates a reduction in preterm birth at <37, <35, <32, <28 and <24 weeks with cerclage compared to expectant management [relative risk (RR): 0.70; 0.58e0.83 at <37 weeks]. Composite perinatal mortality/morbidity was also improved with
2.2. Clinical associations with preterm labour Many epidemiological and environmental factors have been identied associated with increased risk of preterm birth. These include socioeconomic and psychosocial factors, substance misuse, nutritional factors and infection. Many of these risk factors overlap, and may represent associations rather than direct cause.11 The principal clinical risk factors for moderate and late preterm labour are identied below. 2.2.1. Multiple pregnancy A rise in multiple pregnancies has been associated with later childbearing and assisted reproductive technology. Fifty-eight percent of all twins are born preterm, the majority of whom are born after 32 weeks gestation.12 The mechanism of preterm birth in multiple pregnancy is more commonly physiological, such as stretch-mediated, with lower incidence of infection than in singleton preterm births.13 2.2.2. Preterm prelabour rupture of the membranes Preterm prelabour rupture of the membranes (PPROM) contributes to approximately one-third of preterm births. Aetiology is multifactorial, and overlaps with preterm labour with intact membranes. Up to 30% have intrauterine infection prior to rupture of membranes,14 more so at lower gestations. Multivariate analysis
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cerclage (RR: 0.64; 95% CI: 0.45e0.91).24 Moreover the strategy of cervical length scanning with selective cerclage gave comparable outcomes to elective history-indicated cerclage (31% vs 32% risk of delivery at <37 weeks; RR: 0.97; 95% CI: 0.73e1.29).25 3.2. Cervical cerclage Cervical cerclage has a role in prevention of preterm birth in a selected small group of women. Exact indications for its use remain controversial. It may be placed either electively based on obstetric history, ultrasound indicated after a short cervix is found on ultrasound scan, or as a rescue procedure when the cervix is already dilated and membranes are visible at or beyond the external cervical os. Many of the studies on its efcacy are poorly dened, and as such, the current clinical indications for the placement of a cervical cerclage are not clear. However, its primary function is in overcoming cervical insufciency, a condition most likely to lead to early preterm birth rather than moderate or late preterm birth. It may act by providing physical support to a structurally weak cervix, or perhaps more likely in maintaining cervical length and the mucus barrier to ascending infection.26 3.3. Biochemical markers A large number of biochemical markers have been studied for the prediction of preterm labour, the most widely used being bronectin. Originally identied as a putative diagnostic marker for fetal membrane rupture due to the high levels in amniotic uid, its release from the fetomaternal interface into the cervicovaginal secretions prior to labour lead to its development as a marker for preterm labour. The accuracy of bronectin testing is limited by the large number of false-positive test results, false-negative results being uncommon. The overall sensitivity and specicity of this test for predicting delivery at <37 weeks are 53% and 89% respectively. Among high risk women, a positive bronectin test at 22 weeks has sensitivity of 78% and specicity of 78% for prediction of birth <37 weeks.22 Perhaps greater clinical utility is found in bronectin testing among women with symptoms of preterm labour, where a positive bronectin test predicts birth within 7 days with sensitivity and specicity of 77% and 87% respectively.27 3.4. Progesterone Progesterone treatment is currently a major research focus in the prevention of preterm birth. A study by Meis et al. administered weekly injections of 17a-hydroxyprogesterone caproate to women with a history of prior preterm birth. A reduction in the preterm birth rate <37 weeks (36.3% vs 54.9%; OR: 0.66; 95% CI: 0.54e0.81), <35 weeks (20.6% vs 30.7%; 0.67; 0.48e0.93) and <32 weeks (11.4% vs 19.6%; 0.58; 0.37e0.91) was observed.28 Da Fonseca et al. administered 100 mg progesterone as a daily vaginal suppository to women at high risk of preterm birth, and observed a signicant reduction in preterm delivery rates at <37 weeks (13.8% vs 28.5%; P 0.03) and <34 weeks (2.8% vs 18.6%; P 0.002).29 Subsequent studies suggest that the effect of progesterone on prevention of preterm birth is greatest in women with an earlier prior preterm birth (<34 weeks).30 Administration to women with a sonographically identied short cervix in the second trimester also reduces the risk of delivery at <34 weeks gestation (19.2% vs 34.4%; RR: 0.56; CI: 0.36e0.86).31 Several large randomised controlled trials under way internationally to conrm the fetal and neonatal safety and benet from such treatment (e.g. OPPTIMUM), and current advice is to administer only in the context of randomised clinical trials.
3.5. Antibiotics The use of prophylactic antibiotics to prevent preterm birth, either in asymptomatic high risk women or in women with threatened preterm labour, has not been shown to be benecial. As a substantial proportion of preterm births are infection-associated, the idea of giving antibiotics to women at high risk of preterm birth (based on prior history, prior to conception) appears attractive. However, trials have demonstrated that this strategy will does not decrease the risk of preterm birth, conversely there may be a trend towards an increased risk.32 Administration of metronidazole to women with a prior preterm birth and a positive bronectin test, but no clinical evidence of infection, also increased the risk of preterm birth.33 Routine prophylactic antibiotic administration in preterm labour has not been demonstrated to be benecial. The ORACLE Trial randomised 6295 women in preterm labour with intact membranes to (i) co-amoxiclav, (ii) erythromycin, (iii) both antibiotics or (iv) placebo, and found no neonatal benets.34 Of concern was a higher incidence of cerebral palsy in children born after treatment with antibiotics in the 7-year follow-up after this trial.35 Antibiotics may also be used to treat bacterial vaginosis in an attempt to reduce the risk of preterm birth. There is little evidence to routinely screen and treat the low risk obstetric population. The principle role of antibacterial treatment for bacterial vaginosis is in treating women at high risk of preterm birth due to prior preterm birth, and those identied prior to 20 weeks gestation.36
4. Clinical management in threatened preterm labour 4.1. Tocolysis Tocolytic drugs are considered in the acute management when a clinical diagnosis of preterm labour is made. This diagnosis may be aided by the use of bronectin or insulin-like growth factor binding protein (IGPBP-1) testing. Drugs used for tocolysis include oxytocin antagonists (atosiban), calcium channel blockers (nifedipine), b-mimetics (e.g. terbutaline), and non-steroidal antiinammatory agents (e.g. indomethacin). Although these agents reduce the number of births occurring within 7 days of administration, they do not reduce the overall risk of preterm birth.37 Moreover there is no clear evidence of improvement in neonatal outcome with their use. Their use is only recommended when short delay in delivery may gain clinical benet (e.g. time for administration of corticosteroids or in-utero transfer). In clinical practice this means that administration beyond 34 weeks gestation is rarely indicated.
4.2. Antenatal corticosteroids Administration of corticosteroids prior to preterm birth entered routine obstetric practice following the systematic review of Crowley et al. in 1990.38 The most recent Cochrane review demonstrates that a single course of corticosteroids prior to preterm birth reduces the risk of neonatal death (RR: 0.69; CI: 0.58e0.81), respiratory distress syndrome (0.66; 0.59e0.73), intraventricular haemorrhage (0.54; 0.43e0.69) and necrotising enterocolitis (0.46; 0.29e0.74).39 The current Royal College of Obstetricians and Gynaecologists (RCOG) guideline recommends administration of a single course of either betamethasone or dexamethasone prior to preterm birth up to 346 weeks gestation.40 There is currently no evidence of benet from the administration of steroids at gestations beyond 34 weeks.39,41
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4.3. Timing of delivery for preterm prelabour rupture of the membranes Management of prelabour rupture of the membranes after 37 weeks gestation is evidence-based, and induction of labour either immediately or after 24e48 h to reduce the risk of maternal infection is established. Prior to 34 weeks gestation, conservative management is recommended, in the absence of infection or other fetal indication for delivery. Between 34 and 37 weeks gestation the management is more controversial. RCOG advises that delivery should be considered at 34 weeks gestation.42 Not surprisingly early induction is associated with a higher risk of neonatal respiratory morbidity (oxygen requirement after 24 h, 7% vs 1.6%; P 0.05), and conservative management with a higher risk of infection (4.8% vs 09%; P 0.07).43 Naef et al. examined PPROM at 34e37 weeks, and also found that expectant management was associated with a higher incidence of chorioamnionitis (16% vs 2%; P 0.007). They concluded that early delivery was considered safe for the neonate.44 A further study examining early induction of labour versus expectant management at 32e36 weeks gestation with PPROM found longer hospitalisation for the neonate with expectant management.45 Two large ongoing randomised controlled trials may clarify the evidence further.46,47 4.4. Intrapartum care Good practice in the management of preterm labour would require the attendance of a neonatologist at any preterm birth, to assess the baby and the need for either admission to the neonatal unit, or need for further monitoring on the delivery suite or postnatal ward. 4.4.1. Intrapartum fetal monitoring Continuous fetal monitoring by cardiotocograph (CTG) would be expected in all preterm labours where intervention for fetal indications is considered appropriate. This would be expected to include all moderate and late preterm labours with structurally normal babies. Further assessment of fetal wellbeing in labour may require fetal blood sampling from the scalp; however, this is contraindicated at <34 weeks gestation,48 and management in labour should be based on clinical ndings and interpretation of CTG alone. 4.4.2. Mode of delivery There is no benet to delivery by caesarean section for the cephalic presenting baby at late preterm gestations.49 The mode of delivery for the preterm breech has caused signicant controversy over the years, with no consensus available from the evidence.50 The only attempted randomised controlled trial aiming to clarify the best mode of delivery for the preterm breech baby failed to recruit more than a handful of women, with signicant ethical issues highlighted surrounding recruitment and randomisation.51 Retrospective studies of outcomes following breech presentation in preterm labour demonstrate mixed results with some showing improved outcomes in those preterm breech babies born by caesarean section, and others showing no benet. In day-to-day obstetric practice, the management of the preterm breech baby in labour depends on the clinical skill and assessment of the obstetrician present during labour, with a vaginal breech delivery remaining a reasonable option providing that fetal condition is good and that a skilled obstetrician is in attendance for the birth. The risk of entrapment of the aftercoming fetal head is minimised by maintaining intact fetal membranes for as long as possible, consideration of epidural analgesia, and delaying pushing until full cervical dilatation is conrmed by an experienced practitioner.
Where assisted vaginal delivery is required for the cephalic presenting baby, the instrument of choice will depend on gestational age as well as the clinical skill and preference of the obstetrician. Vacuum delivery is considered to be contraindicated at <34 weeks gestation due to risk of cerebral bleeding, and should be used with caution at <36 weeks gestation.52 Forceps may therefore be most appropriate when assisted delivery is indicated.
Practice points Birth at 32e26 weeks gestation is associated with increased neonatal morbidity and mortality. The majority of women who labour spontaneously at 32 e36 weeks gestation have no single identiable underlying cause. Prediction and prevention strategies are currently targeted at women at high risk for preterm birth. Additional care is required in managing labour at 32e36 weeks gestation with modication of the interventions carried out during labour.
Research directions The neonatal benets and safety of antenatal progesterone for prevention of preterm labour. The role of LLETZ in the aetiology of preterm labour. Conict of interest statement None declared. Funding sources None. References
1. Green NS, Damus K, Simpson JL, et al. Research agenda for preterm birth: recommendations from the March of Dimes. Am J Obstet Gynecol 2005;193:626e35. 2. Raju TNK. Epidemiology of late preterm (near-term) births. Clin Perinatol 2006;33:751e63. 3. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75e84. 4. Laughon SK, Reddy UM, Sun L, Zhang J. Precursors for late preterm birth in singleton gestations. Obstet Gynecol 2010;116:1047e55. 5. Bannerman CG. Late preterm birth: can be reduced. Am J Obstet Gynecol 2011;204:459e60. 6. Chauhan SP. Late preterm births: irreducible because E mc2. Am J Obstet Gynecol 2011;204:459e60. 7. Engle WA, Tomashek KM, Wallman C. Late preterm infants: a population at risk. Pediatrics 2007;120:1390e401. 8. Simmons LE, Rubens CE, Darmstadt GL, Gravett MG. Preventing preterm birth and neonatal mortality: exploring the epidemiology, causes, and interventions. Semin Perinatol 2010;34:408e15. 9. Zakar T, Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol 2007;196:289e96. 10. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG 2006;113(Suppl. 3):17e42. 11. Murphy DJ. Epidemiology and environmental factors in preterm labour. Best Pract Res Clin Obstet Gynaecol 2007;21:773e89. 12. Chauhan SP, Scardo JA, Hayes E, Abuhamad AZ, Berghella V. Twins: prevalence, problems and preterm births. Am J Obstet Gynecol 2010;203:305e15. 13. Stock S, Norman J. Preterm and term labour in multiple pregnancies. Semin Fetal Neonatal Med 2010;15:336e41. 14. Romero R, Quintero R, Oyarzun E, et al. Intraamniotic infection and the onset of labour in preterm premature rupture of the membranes. Am J Obstet Gynecol 1988;159:661e6.
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P.C. McParland / Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142 35. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7 year follow up of the ORACLE II trial. Lancet 2008;372:1319e27. 36. McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2007;1:CD000262. 37. Royal College of Obstetricians and Gynaecologists. Tocolysis for women in preterm labour. Green-top Guideline 1b. London: RCOG; 2011. 38. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11e25. 39. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3:CD004454. 40. Royal College of Obstetricians and Gynaecologists. Antenatal corticosteroids to reduce neonatal morbidity. Green-top Guideline 7. London: RCOG; 2010. 41. Porto AMF, Coutinho IC, Correia JB, Amorim MMR. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomised clinical trial. BMJ 2011;342:d1696. 42. Royal College of Obstetricians and Gynaecologists. Preterm prelabour rupture of membranes. Green-top Guideline 44. London: RCOG; 2010. 43. Kayem G, Bernier-Dupreelle A, Gofnet F, Cabrol D, Haddad B. Active versus expectant management for preterm prelabour rupture of membranes at 34e36 weeks completed gestation: comparison of maternal and neonatal outcomes. Acta Obstet Gynecol Scand 2010;89:776e81. 44. Naef RW, Allbert JR, Ross EL, et al. Premature rupture of membranes at 34 to 37 weeks gestation: aggressive versus conservative management. Am J Obstet Gynecol 1998;178:126e30. 45. Mercer BM, Crocker LG, Boe NM, Sibai BM. Induction versus expectant management in premature rupture of the membranes with mature amniotic uid at 32 to 36 weeks: a randomised trial. Am J Obstet Gynecol 1993;169:775e82. 46. Morris JM, Roberts CL, Crowther CA, et al. Protocol for the immediate delivery versus expectant care of women with preterm prelabour rupture of the membranes close to term (PPROMT) Trial [ISRCTN44485060]. BMC Pregn Childbirth 2006;6:9. 47. Van der Ham DP, Nijhuis JG, Mol BW, et al. Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks (the PPROMEXIL-trial). BMC Pregn Childbirth 2007;7:11. 48. National Institute for Health and Clinical Excellence. Intrapartum care. Care of healthy women and their babies during childbirth. NICE clinical guideline 55. London: NICE; 2007. 49. Dobak WJ, Gardner MO. Late preterm gestation: physiology of labor and implications for delivery. Clin Perinatol 2006;33:765e76. 50. Royal College of Obstetricians and Gynaecologists. The management of breech presentation. Green-Top guideline 20b. London: RCOG; 2006. 51. Penn ZJ, Steer PJ, Grant A. A multicentre randomised controlled trial comparing elective and selective caesarean section for the delivery of the preterm breech infant. Br J Obstet Gynaecol 1996;103:684e9. 52. Royal College of Obstetricians and Gynaecologists. Operative vaginal delivery. Green-Top guideline 26. London: RCOG; 2011.
15. Harger JH, Hsing AW, Tuomala RE, et al. Risk factors for preterm premature rupture of fetal membranes: a multicentre caseecontrol study. Am J Obstet Gynecol 1990;163:130e7. 16. Hay PE, Lamont RF, Taylor-Robinson D, et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295e8. 17. Leitich H, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189:139e47. 18. Guaschino S, De Seta F, Piccoli M, Maso G, Alberico S. Aetiology of preterm labour: bacterial vaginosis. BJOG 2006;113(Suppl. 3):46e51. 19. Ortoft G, Henriksen TB, Hansen ES, Petersen LK. After conisation of the cervix, the perinatal mortality as a result of preterm delivery increases in a subsequent pregnancy. BJOG 2010;117:258e367. 20. Quenby S. Obstetric management of women after treatment for CIN. BJOG 2010;117:243e4. 21. Van der Vijver A, Poppe W, Verguts J, Arbyn M. Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital. BJOG 2010;117:268e73. 22. Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol 2007;110:405e15. 23. To MS, Alrevic Z, Heath VC, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849e53. 24. Berghella V, Rafael TJ, Szychowski JM, Rust AO, Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth. Obstet Gynecol 2011;117:663e71. 25. Berghella V, Mackeen AD. Cervical length screening with ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth. Obstet Gynecol 2011;118:148e55. 26. Royal College of Obstetricians and Gynaecologists. Cervical cerclage. Green-top guideline 60. London: RCOG; 2011. 27. Norman JE. Cervical function and prematurity. Best Pract Res Clin Obstet Gynaecol 2007;21:791e806. 28. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379e85. 29. Da Fonseca EB, Bittar RE, Carvalho MH, et al. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomised placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419e24. 30. Spong CY, Meis PJ, Thom EA, et al. Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery. Am J Obstet Gynecol 2005;193:1127e31. 31. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and preterm birth among women with a short cervix. N Engl J Med 2008;357:462e9. 32. Andrews WW, Goldenberg RL, Hauth JC, et al. Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am J Obstet Gynecol 2006;194:617e23. 33. Shennan A, Crawshaw S, Briley A, et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal bronectin: the PREMET study. BJOG 2006;113:65e74. 34. Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet 2001;357:989e94.

Impact of multiple births on late and moderate prematurity

Jerrie S. Refuerzo*
Division of MaternaleFetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, 6431 Fannin, Suite 3.270, Houston, TX 77030, USA
s u m m a r y
Keywords: Late preterm birth Moderately preterm birth Multiple gestations Triplets Twins
Multiple gestations have an increased risk of pregnancy complications compared with singletons. Delay in childbearing and assisted reproductive techniques have remained common reasons for the increase in multiple gestations over the last few decades. Higher rates of both spontaneous and indicated preterm birth in twins and triplets lead to a signicant proportion of the moderate preterm birth and late preterm birth rates. The article is a review of the causes of preterm birth and morbidities associated with these pregnancies. 2012 Elsevier Ltd. All rights reserved.
1. Introduction Multiple gestations such as twins and triplet pregnancies are a unique pregnancy population with inherent risks for moderate preterm birth and late preterm birth. For decades, twins represented one of the most rapidly growing conditions in pregnancy, increasing by 70% from 1980 to 2004.1 Since then, this twin birth rate seems to have remained constant at 32.2 per 1000 births according to the vital statistics in 2007.2 The triplet, quadruplet and other higher order multiples (HOM) rate has had a similar trend. From 1980 to 1990, there was a large increase in triplets and HOM. Since 1998, there has been a gradual decrease in this high risk obstetric group. Because of the perinatal risks associated with twin and triplet gestations, multiple gestations contribute a considerable amount to the moderate and late preterm birth rates. The majority of twins deliver within the moderate and late preterm birth period.3,4 Twins represent 3% of all births in the USA.5 However, twins and triplets account for w26% of all births in the late preterm birth period.6 Among twins, the moderate preterm birth rate is 14.5%, late preterm 49.8% and term birth rate 35.7% (Table 1).4 The mean gestational age at delivery for singletons is 38.8 weeks. By contrast, twins have a mean age of delivery of 35.3 weeks, triplets 32.2 weeks and quadruplets 29.9 weeks.3 Thus, multiple gestations represent a considerable proportion of pregnancies delivering moderate or late preterm. 2. Risk factors for moderate and late preterm birth Multiple gestations have inherent factors that place them at higher risk for a preterm birth compared with singletons. Among both twins and triplets, 30% of preterm births are due to
* Tel.: 1 713 500 6416; fax: 1 713 500 7860. E-mail address: Jerrie.S.Refuerzo@uth.tmc.edu. 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.01.012
spontaneous preterm labour.7 Although twins and triplet pregnancies have an increased rate of spontaneous preterm birth, they also have a 50% rate of indicated preterm birth due to fetal or maternal pregnancy complications. The rate of maternal hypertensive conditions in twins ranges from 12% to 22% vs from 5% to 8% in singletons.8 The rate of pre-eclampsia is two to three times higher in twins in the late preterm period compared with singletons.3,8 Low birth weight also occurs more frequently in twins and triplets. Twenty-four percent of infants with low birth weight are born to multiple gestations, particularly in the late preterm period.8 Preterm premature rupture of membranes (PPROM) occurs in w10% of deliveries.7 The average gestational age at PPROM is w31 weeks and only 22.4% achieve a latency period >7 days.9 Of those that have a prolonged latency period, iatrogenic delivery typically occurs at 34 weeks at the start of the late preterm birth period.
3. Morbidities of twins with moderate and late preterm birth Over the last few decades, the rate of preterm birth among twin pregnancies has risen from 48% to 60%, with the largest group comprised of late preterm births between 34 and 36 weeks of pregnancy.1 The overall rate of preterm birth is w69.9%.9 The moderate preterm birth rate was 14.5%, late preterm 49.8% and term birth rate 35.7%.4 In singleton pregnancies, both neonatal mortality and morbidity including respiratory distress syndrome (RDS), sepsis, intraventricular hemorrhage (IVH), phototherapy and intubation in the delivery room in those born late preterm are increased compared with those born after 37 weeks.10,11 Similar ndings also occur in twin gestations. Nonetheless, the overall outcomes for twins born within the late preterm period are favorable. A secondary analysis was conducted by Refuerzo et al.4 of a multicenter, randomized controlled trial of multiple gestations. The primary outcome was a neonatal outcome
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Table 1 Rate of moderate preterm birth (MPTB) and late preterm birth (LPTB) in twins and triplet pregnancies. Neonatal outcome Twins4 Triplets18 MPTB 14.5% 35.5% LPTB 49.8% 43.6% Term 35.7% 20.9%
composite consisting of one or more of the following: neonatal death, RDS, sepsis, stage 2 or 3 necrotizing enterocolitis (NEC), bronchopulmonary dysplasia, grade 3 or 4 IVH, periventricular leukomalacia, pneumonia or severe retinopathy of prematurity (ROP). Because respiratory complications represent a large proportion of morbidity in the moderate and late preterm birth period, they examined a respiratory composite consisting of one or more of the following outcomes per pregnancy: RDS, transient tachypnea of the newborn (TTN), need for mechanical ventilation (MV) or need for oxygen. The rate of the primary outcome was progressively higher in those twins born moderate and late preterm compared with term, (moderate 30.0% vs late 12.8% vs term 0.5%; P < 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following moderate [relative risk (RR): 58.5; 95% condence interval (CI): 11.3e1693.0] and late (RR: 24.9; 95% CI: 4.8e732.2) preterm birth. The rate of the secondary respiratory composite was also progressively higher in moderate and late preterm twins compared with term (moderate 67.5% vs late 33.8% vs term 8.1%; P < 0.001). The respiratory outcome composite was increased following moderate (RR: 8.3; 95% CI: 5.1e13.6) and late (RR: 4.2; 95% CI: 2.5e6.9) preterm birth compared with term neonates. Most of the differences in neonatal outcomes were respiratory morbidities. RDS contributed the greatest effect to the primary outcome. Both moderate and late preterm twins had signicantly higher rates of RDS, neonatal sepsis, TTN, MV, and neonatal intensive care unit (NICU) admissions compared with term. Additionally, the lengths of NICU stay, MV and supplemental oxygen were signicantly longer in those twins with moderate and late preterm birth compared with term. Other investigators have found similar ndings in morbidity and mortality. In comparison with singletons, risks of neonatal morbidity and mortality are higher.3,4,6 The rate of neonatal mortality is increased ve to seven times compared with singletons.5 Major morbidity including grade 3 or 4 IVH, NEC and ROP do not appear increased in moderate or late preterm twins with compared with singletons.4,12 In general, the risk of cerebral palsy is low in the late preterm birth period. However, twin pregnancies have a fourfold higher risk of cerebral palsy in the late preterm birth period compared with singletons.13 4. Chorionicity Although it is known that twin gestations have a higher rate of pregnancy complications and neonatal morbidity compared with singletons, these risks are further dichotomized based on chorionicity.14 Investigators have reviewed risks of stillbirth of twins with expectant management compared with elective delivery according to chorionicity in the late preterm and early term period. Multiple studies have shown that the rate of stillbirth increases after 37e39 weeks in dichorionic twins.14e17 The fetal mortality rate for twins was lowest at 36e37 weeks gestation.17 Thus, Newman et al.13 concluded that due to the increased mortality risk after 38e39 weeks, elective delivery is reasonable at 38 weeks in a well-dated, uncomplicated dichorionic twin pregnancy. Monochorionic twins have different risks compared with dichorionic twins. These types of twins have a higher rate of stillbirth (monochorionic 3.6% vs dichorionic 1.1%).14 This may be due to acute episodes of twin-to-twin transfusion syndrome (TTTS) or failure of close fetal surveillance.18 Thus, Newman et al.13 recommend offering
elective delivery at 34e37 weeks in uncomplicated monochorionic twins. Monoamniotic twins occur in only 1% of all monozygotic twin pregnancies but carry the highest risk of stillbirth.14 The etiology for stillbirth includes fetal growth restriction, TTTS and fetal anomalies, but the largest proportion of perinatal mortality in monoamniotic twins is due to umbilical cord entanglement resulting in cord accident. Despite variations in management of these high risk cases, the mean gestational age at delivery occurs in the moderate preterm birth period at 32.9 weeks. The current recommended timing of delivery for this group is between 32 and 34 weeks. 5. Morbidity of triplets Triplets have higher risks than twins and therefore have an earlier gestational age at delivery and morbidity. In a retrospective study of 55 triplets conducted by Kaufman et al., the rate of moderate preterm birth was 35.5% and the rate of late preterm birth was 43.6%.18 Those born moderate preterm had higher morbidity than those born in the late preterm period. In those born moderate preterm, survival was 100%, NICU admission 23.6%, need for MV 33.1%, RDS 16.6% and there were no cases of chronic lung disease. In late preterm infants, survival was 100%, NICU admission 28.5%, need for MV 6.9% and there were no cases of RDS or chronic lung disease. A randomized controlled trial conducted between 2004 and 2006 of 134 triplets receiving 17a-hydyroxyprogesterone caproate compared with placebo showed similar rates of preterm birth.19 The mean gestational age at delivery occurred in the moderate preterm period at 33.0 weeks (range: 31.6e34.3). The rate of delivery at <35 weeks due to spontaneous labor was 43% and was 41% in indicated births. Garite et al. conducted a prospective study of 2155 triplets between 1997 and 2002.12 The mean gestational age at delivery was 31 3 weeks. The cesarean section rate was 95%. Concordant growth was demonstrated in all triplets up until 29e30 weeks, at which time birth weight signicantly diverged primarily due to fetal growth restriction. Investigators in Norway found similar ndings.20 In a populationbased cohort study of 1007 triplets between 1988 and 2006, the triplet rate was 2.7 per 10,000 pregnancies. The mean gestational age at delivery occurred in the moderate preterm birth period at 32.1 3.3 weeks. The cesarean section rate was 95% and the perinatal death rate was 7.1%. The average birth weight was 1736 544 g. Thus, monitoring closely is important in triplet pregnancies. 6. Morbidities associated with assisted reproductive techniques Over the past few decades, the option to delay childbearing has contributed to an increase in the rate of pregnancy in women aged 40 years.2 An increased rate in assisted reproductive techniques (ART) has paralleled this trend. The birth rate for women aged between 40 and 45 years was 9.9 births per 100 women in 2008, an all-time high over the past four decades. The birth rate for women between 45 and 49 years was 0.7 births per 1000 women. This rate has more than tripled since 1990. Because of reduced fertility and potential to conceive spontaneously in women aged 40 years, the rate of ART is higher in this group of women including in-vitro fertilization (IVF). A known risk factor to such ART is multiple gestation. Studies have compared outcomes of both twins and triplets conceived spontaneously to those conceived with ART. Fitzsimmons et al.21 examined both twins and triplets between 1985 and 1996. They compared 56 IVF twins with 108 non-IVF twins and 16 IVF triplets with 16 non-IVF triplets. The gestational age at delivery was similar in the IVF pregnancies compared with non-IVF pregnancies. The mean gestational age at
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145
delivery for the IVF twin was 35.4 3.3 weeks compared with 34.6 4.5 weeks non-IVF twins. The mean gestational age was 32.4 3.3 weeks in IVF triplets compared with 32.6 3.8 weeks in the non-IVF triplets. By contrast, there were signicantly higher rates of perinatal mortality in non-IVF twins (24%) compared with IVF twins (2%). The triplet mortality rate was similar between groups (w3%). The rate of monochorionic, diamniotic twins was greater in the non-IVF group (34 sets IVF vs 2 sets non-IVF). Monochorionic triplets occurred in one set of non-IVF gestation. There were no signicant differences between birth weight, rate of spontaneous preterm labor, PPROM, pre-eclampsia or gestational diabetes between groups. There were also no differences in neonatal morbidity including NICU admission, days of MV, IVH, sepsis or NEC. Nassar et al.22 conducted a case-controlled study of 56 IVF twins vs 112 non-IVF twins between 1996 and 2000. Compared with Fitzsimmons et al., they found a higher rate of preterm birth among the IVF twins (51.5%) vs non-IVF twins (22.3%). There was a signicant increase in the rate of delivery at <37 weeks gestation (IVF twins 76.3% vs non-IVF twins 46.1%). There was also an increase in the rate of moderate and late preterm birth in IVF twins (IVF twins 57.1% vs non-IVF twins 35.7%). The gestational age was lower in IVF twins (IVF 35 3 weeks vs non-IVF 36 3 weeks). The rate of both spontaneous and medically indicated inductions was similar (spontaneous: IVF 69.6% vs non-IVF 67.9%) and (induction: IVF 5.4%% vs non-IVF 6.3%). In Norway, 365 triplets conceived by IVF had similar outcomes to 1007 non-IVF triplets.20 The mean gestational age at delivery was 31.8 3.3 weeks. The cesarean section rate was 93.7% and the mortality rate was 8.5%. The mean birth weight was 1686 542 g. 7. Conclusion Multiple gestations comprise w3% of all births. This rate increased steadily from the 1990s up until 2006, since when the rate has remained constant. Because of the increase in both spontaneous and indicated preterm birth, the mean gestational age at delivery of twins occurs in the late preterm period and triplets in the moderate preterm birth period. Outcomes for late preterm twins are generally favorable. The majority of morbidities are respiratory and typically temporary. Chorionicity of multiple gestations plays an important role in morbidity. Morbidity for triplets is generally higher and primarily related to earlier gestational age at delivery. Delay in childbearing age has increased the rate of ART including IVF. This has contributed greatly to the rate of multiple gestations. Although there are some conicting reports on outcomes, women who conceive with IVF have overall favorable outcomes due to delivery rates within the moderate and late preterm birth periods. In summary, multifetal pregnancies carry inherent risk factors leading to delivery in the late and moderate preterm birth periods.
Research directions Assess inherent risk factors and clinical practices that lead to indicated preterm birth in twins and triplets. Assessing interventions in the late preterm period such as antenatal corticosteroids that may impact neonatal respiratory outcomes.
Conict of interest statement None declared. Funding sources None. References

1. Martin JA, Kung HC, Mathews TJ, Hoyert DL, Strobino DM, Guyer B, Sutton SR. Annual summary of vital statistics. Pediatrics 2006;2008(121):788e801. 2. Mathews TJ, Minino AM, Osterman MJ, Strobino DM, Guyer B. Annual summary of vital statistics. Pediatrics 2008;2011(127):146e57. 3. Lee YM, Cleary-Goldman J, DAlton ME. Multiple gestations and late preterm (near-term) deliveries. Semin Perinatol 2006;30:103e12. 4. Refuerzo JS, Momirova V, Peaceman AM, et al. Neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm and term. Am J Perinatol 2010;27:537e42. 5. American College of Obstetricians and Gynecologists. Multiple gestation; complicated twin, triplet and higher order multifetal pregnancy. Practice Bulletin 56. Washington, DC: ACOG; 2004. 6. Vachharajani AJ, Vachharajani NA, Dawson JG. Comparison of short-term outcomes of late preterm singletons and multiple births: an institutional experience. Clin Pediatr 2009;49:922e5. 7. Chauhan SP, Scardo JA, Hayes E, Abuhamad AZ, Berghella V. Twins: prevalence, problems and preterm birth. Am J Obstet Gynecol 2010;203:305e15. 8. Lee YM, Cleary-Goldman J, DAlton ME. The impact of multiple gestations on late preter (near-term) births. Clin Perinatol 2006;33:777e92. 9. Trentacost SV, Jean-Pierre C, Baergen R, Chasen ST. Outcomes of preterm premature rupture of membranes in twin pregnancies. J Matern Fetal Neonatal Med 2008;21:555e7. 10. Rouse DJ, Caritis SN, Peaceman AM, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357:454e61. 11. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008;111:35e41. 12. Newman RB, Unal ER. Multiple gestations: timing of indicated late preterm and early-term births in uncomplicated dichorionic, monochorionic and monoamniotic twins. Semin Perinatol 2011;35:277e85. 13. Garite TJ, Clark RH, Elliot JP, Thorp JA. Twins and triplets: the effect of plurality and growth on neonatal outcome compared with singleton infants. Am J Obstet Gynecol 2004;191:700e7. 14. Kahn B, Lumey LH, Zybert PA, Lorenz JM, Cleary-Goldman J, DAlton ME, Robinson JN. Prospective risk of fetal death in singleton, twin and triplet gestations: implications for practice. Obstet Gynecol 2003;102:685e92. 15. Sairam S, Costeloe K, Thilaganathan B. Prospective risk of stillbirth in multiple gestation pregnancies: a population-based analysis. Obstet Gynecol 2002;100: 638e41. 16. Luke B, Keith LG. The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. J Reprod Med 1992;37:661e6. 17. Lee YM, Wylie BJ, Simpson LL, DAlton ME. Twin chorionicity and risk of stillbirth. Obstet Gynecol 2008;111:301e8. 18. Kaufman GE, Malone FD, Harvey-Wilkes KB, Chelmow D, Penzias AS, DAlton ME. Neonatal morbidity and mortality associated with triplet pregnancy. Obstet Gynecol 1998;91:342e8. 19. Caritis SN, Rouse DJ, Peaceman AM, et al. Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate. Obstet Gynecol 2009;113: 285e92. 20. Tandberg A, Bjorge T, Nygard O, Bordahl PE, Skjaerven R. Trends in incidence and mortality for triplets in Norway 1967e2006: the inuence of assisted reproductive technologies. BJOG 2010;117:667e75. 21. Fitzsimmons BP, Bebbington MW, Fluker MR. Perinatal and neonatal outcomes in multiple gestations: assisted reproduction versus spontaneous conception. Am J Obstet Gynecol 1998;179:1162e7. 22. Nassar AH, Usta IM, Rechdan JB, Harb TS, Adra AM, Abu-Musa AA. Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization. Am J Obstet Gynecol 2003;189:513e8.
Practice points Inherent risk factors for multiple gestations increase the rate of both spontaneous and indicated preterm birth compared with singletons. Twins mean gestational age is within the late preterm birth period and triplets within the moderate preterm birth period. Although the neonatal morbidity and mortality of twins and triplets is higher compared with singleton pregnancies, the outcomes are overall very favourable. Assisted reproductive techniques such as IVF have contributed to the increase in multiple gestations. There remain conicting results on neonatal outcomes in IVF pregnancies compared with non-IVF pregnancies.

Neonatal problems of late and moderate preterm infants

J.-B. Gouyon a, b, c, d, *, S. Iacobelli a, c, C. Ferdynus a, b, F. Bonsante a, c
a
Centre dEtudes Prinatales de lOcan Indien, Centre dInvestigation Clinique et dEpidmiologie Clinique (CIC-EC), La Runion, France Centre dEpidmiologie des Populations (EA 4184), Universit de Dijon, Dijon, France c Service de Nonatologie et Ranimation Nonatale, GHSR, La Runion, France d Service de Nonatologie et Ranimation Nonatale, CHU de Dijon, France
b
s u m m a r y
Keywords: Hypoglycaemia Hypothermia Jaundice Mortality Preterm Respiratory disease
Late and moderate preterm infants account for >80% of premature births. These newborns experience considerable mortality and morbidity in comparison with full-term born infants. The purpose of this paper is to summarise the most common morbidities of late and moderate preterm infants in the neonatal period, their incidence, severity, risk factors and need for admission to the different levels of care. The recent ndings on preventive strategies and management priorities for clinical care of these vulnerable babies are also reviewed. 2012 Elsevier Ltd. All rights reserved.
1. Introduction In the previous decade, research on mortality and morbidity in preterm births focused mainly on the highest risk births, those occurring at <32 weeks gestation. However, the category of infants born at 32e36 weeks represents >80% of preterm births and includes moderate preterm (320/7 and 336/7) and late preterm infants (340/7 to 366/7 weeks). Late preterm infants, who are often viewed as normal newborns by parents and care providers, experience morbidity during the birth hospitalisation 3.5 times more frequently than term infants and their neonatal mortality is 4.6 times higher.1 They represent one-third of the neonatal intensive care unit (NICU) admissions in the USA.1 Moderate preterm infants have an intermediate rate of morbidity and mortality between late preterm and very preterm infants but they receive little attention. This review aims to describe neonatal problems in infants born between 32 and 36 weeks gestation. Practice points Four-fths of premature babies are born at 32e36 weeks gestation.
2. Rates of neonatal morbidities The relationship between gestational age and neonatal morbidity is continuous between 32 and 36 weeks gestation1e3 without any threshold of gestational age.2 For instance, the rate of severe respiratory disorders (treated by mechanical ventilation and/or nasal continuous positive airway pressure, nCPAP) continuously declined with gestation from 19.8% at 34 weeks to 0.28% at 39e41 weeks in a French epidemiological study of singleton live-born babies.3 Similarly, the risk of hypoglycaemia, hyperbilirubinaemia and poor prognosis as well as the length of the hospital stay has been inversely correlated with gestational age.3e5 Clinicians should also be aware that the outcome of late preterm infants also depends on maternal complications during pregnancy and on obstetrical practice.1,3 Late preterm birth and, to a lesser extent, maternal conditions are each independent risk factors of severe newborn morbidity (particularly severe respiratory disorders) especially when late preterm infants have been exposed to antepartum haemorrhage, hypertensive disorders of pregnancy, diabetes, elective caesarean section (CS) and intrauterine growth restriction (IUGR).2e4,6 Finally, the adaptation of professional practices to the risk level recorded in epidemiological studies is of prime importance. For instance, Reddy et al.7 have recently shown that the highest mortality rate in late preterm infants was observed when no indication for delivery was recorded in the medical les of the USA Birth Cohort, thus suggesting that the absence of medical indications for delivery at 34e36 weeks was associated with an excess risk of mortality.
* Corresponding author. Service de Nonatologie et Ranimation Nonatale, GHSR, BP350, 97448 Saint-Pierre Cedex, France. Tel.: 33 6 81 48 32 70. E-mail address: jean-bernard.gouyon@chr-reunion.fr (J.-B. Gouyon). 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.01.015
J.-B. Gouyon et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 146e152
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4. Respiratory diseases Practice points A continuous relationship exists between gestational age and neonatal morbidity/mortality between 32 and 36 weeks of gestation.1 4.1. Rates of respiratory diseases Twenty-four studies published between 2000 and 2009 consistently revealed that infants born at 32e36 weeks experience respiratory distress syndrome (RDS), transient tachypnoea of the newborn (TTN), pneumonia and pulmonary hypertension of the newborn (PPHN) at higher rates than term infants.10 Subsequent studies delivered similar conclusions. The rate of severe respiratory disorders e treated by mechanical ventilation and/or nasal CPAP (nCPAP) e in a population-based study of 150,426 live-born singleton neonates was 8.31% in late preterm, 0.84% in early term (37e38 weeks) and 0.28% in late term infants (39e41 weeks).3 The rate of respiratory compromise in 19 US hospitals was 10.5% of 19,334 late preterm and 1.13% of 165,993 term infants.9 In this study, all forms of respiratory morbidity and overall respiratory failure decreased signicantly with gestational age until 39 weeks with the exception of meconium aspiration syndrome which increased.9 Extended data from Burgundy (Fig. 2) show a similar trend when moderate and late preterm infants are considered together.
3. Hospitalisation and organisation of care The incidence of hospitalisation of moderate and late preterm infants depends on gestational age, comorbidities and organisation of care. The latter probably explains the variation in rates of hospitalisation of late preterm infants in NICUs: 62% in a French study1; 100% for all babies born at <35 weeks in hospitals of the Kaiser Permanente Medical Care Program8; 36.5% in 19 other US hospitals.9 In all studies the rate of hospitalisation in NICU declined when gestational age increased. This point was well illustrated when the population of the Burgundy study3 was extended by adding neonates of 32 and 33 weeks gestation and by one further year of data collection as shown in Fig. 1 (J-B. Gouyon et al., unpublished data). The pragmatic choice of the appropriate level of care for moderate and late preterm infants closely relies on the universal medical risks related to each gestational age and also to the technical limitations of the local neonatal care units (well baby nursery, intermediate care, special care, intensive care). These infants should be managed according to precise medical guidelines1 including the admission criteria in the different neonatal care units of the birth place or in another hospital as necessary. The guidelines have also to consider the increased need of resuscitation at birth in moderate and late preterm infants. A comprehensive understanding of the neonatal issues of infants born between 32 and 36 weeks gestation by health care providers and administrators of hospitals and insurance companies is essential to determine the resources needed to take care of those infants.
Practice points Each week gained until 39 weeks gestation reduces the risk of respiratory morbidity and improves the prognosis of the newborn.
4.2. Elective caesarean section and neonatal iatrogeny Elective caesarean section is now regarded as a major contributor to respiratory morbidities in both late preterm and early term neonates.11,12 Elective caesarean section has been shown to be iatrogenic in 25.5% of late preterm deliveries among 1251 singleton pregnancies with mild gestational hypertension without proteinuria.12 A large retrospective study has shown that late preterm and term infants delivered via elective caesarean section had increased respiratory morbidity but also signicantly higher rates of mortality [adjusted risk ratio (aRR): 2.1; 95% condence interval (CI): 1.1e4.1] and risk of special care admission (aRR: 1.4; 95% CI: 1.2e1.6) compared with infants delivered via planned vaginal delivery.13
Practice points Guidelines for care providers should include admission criteria in neonatal units. Give information about characteristics of MPI and LPI to administrators.
50%
45,87
Poor prognosis
Severe respiratory disorders
70% 60% 50% 40% 30% 20% 10% 0%
Antenatal steroids Nasal CPAP Mechanical ventilation Surfactant Admission in NICU
40%
30%
26,05
20%
17,65
10%
1,60 2,52 1,61
8,22 3,65 0,65 0,58 0,26 1,11 0,16 0,48 0,16 0,21
33
34
35
32
36
37
38
-4 1
0% 32 33 34 35 36 37 38 39-41
Weeks of gestion
39
Weeks of gestion
Fig. 2. Gestational age and rates of poor prognosis (death and/or severe neurological condition) and severe respiratory disorders (treated by nasal continuous positive airway pressure and/or mechanical ventilation) in a population of 173,058 live-born infants (years 2000e2009). Adapted and extended from Gouyon et al.3
Fig. 1. Gestational age and rates of respiratory treatments and admission in neonatal intensive care unit (NICU) in a population of 173,058 live-born infants (years 2000e2009). CPAP, continuous positive airway pressure. Adapted and extended from Gouyon et al.3
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Obstetric management strategies probably play an important role in delaying deliveries and reducing late preterm birth rates, as was recently suggested by the national USA results.14 A recent randomised trial has provided results indicating that antenatal steroid administration reduces the risk of respiratory distress in term infants born by elective caesarean section.15 Similar studies should be addressed in late preterm infants born by caesarean section.
administration but to a much lesser degree than do preterm births at <33 weeks. Therefore, clinicians should follow current guidelines on antenatal corticosteroid administration up to 34 weeks and await new data on antenatal corticosteroids before considering any changes in the practice of antenatal corticosteroid administration at 34 weeks.
Practice points Practice points Overall, elective caesarean section increases the risk of neonatal morbidities and mortality, special care admission and separation from the mother. Follow current guidelines on antenatal corticosteroid administration up to 34 weeks gestation.
4.5. Treatment of respiratory diseases 4.3. Clinical characteristics of respiratory diseases The respiratory disease in late preterm infants often begins as delayed respiratory transition. The course of the respiratory distress can be unpredictable at its outset and many of these infants who have no or a few respiratory symptoms at birth subsequently demonstrate a growing need for respiratory support leading in a few cases to PPHN.16 The aetiology of the respiratory disease is frequently unclear as late preterm infants often present characteristics of RDS, TTN and PPHN in the course of the same respiratory disease. Because of their birth weight and a misleading clinical picture, the respiratory disease severity in late preterm infants is frequently underestimated. The initial diagnosis is often TTN as these infants usually have tachypnoea with few retraction symptoms. Consequently, treatment and monitoring are often inappropriate. Among singleton neonates with gestational age ranging from 32 to 41 weeks the rates of antenatal corticosteroid exposure, nCPAP, mechanical ventilation and surfactant administration in a French population are shown in Fig. 1 for each week of gestation (J-B. Gouyon et al., unpublished data). The potential severity of a moderate preterm birth is obvious as w30% of moderate preterm infants needed nCPAP alone, another 30% were mechanically ventilated and 35% were administered surfactant. In late preterm infants with respiratory failure, 45% were intubated and received exogenous surfactant which is similar to the 41% recently reported by Cond et al.22 Therefore, care providers have to anticipate that moderate preterm birth is often associated with severe respiratory disorders whereas this condition is less frequent in late preterm infants. In every case, a high level of neonatal care is required. Because respiratory diseases in moderate and late preterm infants may be severe, inhaled nitric oxide (INO) has been assessed as a selective pulmonary vasodilator in preterm as well as in term infants with hypoxaemic respiratory failure. A pooled analysis of data from three clinical trials in late preterm and term infants with hypoxic respiratory failure requiring mechanical ventilation found that INO at a starting dose of 20 ppm was acutely associated with improved oxygenation and a reduced median duration of mechanical ventilation.23 Whether or not infants have clear echocardiographic evidence of PPHN does not appear to affect the outcome for the baby.24 Echocardiographic examination is recommended by the American Academy of Paediatrics (AAP),25 and allows the exclusion of congenital cardiac malformation. The benecial effect of INO in moderate preterm infants with hypoxic respiratory failure is not established. The most recent Cochrane review26 about INO in preterm infants has included 14 studies in infants of 34 weeks gestation and has concluded that preterm infants cannot benet from INO given as early rescue treatment or as a routine treatment or as a late treatment based on the risk of bronchopulmonary dysplasia. Unfortunately the design of the studies does not allow the identication of specic outcomes for moderate preterm infants. Denitive results of a meta-analysis using the individual patient data from all infants enrolled in these trials (MAPPiNO collaboration) are expected.27 Therefore, it appears reasonable to use INO in cases of hypoxic respiratory failure in late preterm infants if they do not have a diaphragmatic hernia, the outcome for which could be worsened by INO.24 At the moment, INO cannot be recommended in a systematic approach of moderate preterm infants with severe respiratory failure. However, INO administration in this group can be discussed on an individual basis as a rescue therapy.
Practice points Initial picture of severe respiratory diseases in LPI is often misleading.
4.4. Prevention of respiratory diseases by antenatal corticosteroids Antenatal corticosteroids enhance maturity of surfactant production and lung liquid clearance. National guidelines17,18 endorse the use of a single course of antenatal corticosteroids to the mother if birth up to 34 weeks gestation is a risk. This statement is supported by a Cochrane review19 showing that RDS was signicantly reduced in corticosteroid-treated infants entering a trial from 33 to 346 weeks gestation (RR: 0.53; 95% CI: 0.31e0.91; 434 infants) but not from 350 to 366 weeks (RR: 0.61; 95% CI: 0.11e3.26; 189 infants). These results were obtained from data limited to two studies. A recent single centre randomised controlled trial specically addressed the use of antenatal corticosteroids at 34 to 366 weeks and concluded that antenatal betamethasone failed to reduce the risk of respiratory morbidity, even after adjustment for subgroups of gestational age.20 However, this study was markedly underpowered especially for preterm infants born at 340 to 346 weeks. In addition, it is of concern that studies performed in Canada21 and the USA8 showed that moderately preterm births benet from antenatal steroid
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4.7. Hypoglycaemia Practice points Severe respiratory morbidity is frequent in moderate preterm infants and can also be observed in late preterm infants. Efcacy of inhaled NO in hypoxic respiratory failure is demonstrated in late preterm infants and can be discussed in moderate preterm infants on an individual basis. Neonatal hypoglycaemia may be considered a part of multiple adaptational pathologies particularly for moderate and late preterm infants, in whom hypoglycaemia is frequently investigated in association with RDS, hypothermia, feeding problems and hyperbilirubinaemia.4,29,31,34 The risk of hypoglycaemia approaches 8% in different series of late preterm infants4,30,31 and increases up to 16% in moderate preterm infants.35 Late preterm infants cared for in the nursery are exposed to hypoglycaemia with a RR of 12.4 (95% CI: 10.1e15.4) compared with term infants.36 In growth-restricted late preterm infants, hypoglycaemia is a leading cause for NICU admission and prolonged hospital stay. The chief causes of hypoglycaemia in moderate and late preterm infants are limited enteral intake, poor suckeswallow coordination, delayed or ineffective oral feeding, associated pathologies (cold stress, sepsis) and limited compensatory mechanisms.30,31 The management of this common condition remains difcult. Indeed, no specic value or range of plasma glucose potentially resulting in brain injury has been identied for infants born at 32e36 weeks. With specic regard to moderate preterm infants, there is a paucity of data on the optimal prevention and management of neonatal hypoglycaemia. However, recent works have extensively addressed the importance of correct management of postnatal glucose homeostasis in late preterm infants34 and a practical guide for the screening and subsequent treatment of hypoglycaemia in late preterm infants has recently been provided by the AAP.37 Preventive strategies for neonatal hypoglycaemia are mainly based on encouraging and establishing early breastfeeding. Babies should be fed within 1 h after birth. After the rst feed, blood glucose levels should be systematically checked as early as 3 h of life and subsequently tailored to the infants individual adaptation of glucose homeostasis. Finally, interventions for treatment of low glucose concentrations may range from enteral re-feeding to intravenous glucose infusion, according to the infants postnatal age, glucose values, and associated clinical signs of hypoglycaemia and concomitant pathologies. For instance, asymptomatic infants with glucose concentrations <25 mg/dL (birth to 4 h of life) or <35 mg/dL (4e24 h of life) should be rstly re-fed and receive intravenous glucose infusion only in case of failure to increase their glycaemia after enteral feeding. Symptomatic babies should conversely be treated by intravenous infusion as plasma glucose values fall to <40 mg/dL.37 Even with the tool of these practical guides, care providers for late preterm infants nally have the unique challenge to ensure safe management of postnatal glucose homeostasis together with the preservation of mothereinfant bonding. This consideration may also apply for moderate preterm infants, especially when relatively healthy.
4.6. Hypothermia Irrespective of the infants gestational age, neonatal hypothermia has been dened as body temperature below 36.5 C.28 However, a normal body temperature is not sufcient to assert that the thermal environment is optimal in premature babies, as they might show clinical signs of cold stress, such as peripheral vasoconstriction, even though rectal temperature remains at 37 C. In moderate and late preterm infants, as in smaller babies, thermal instability may extend from birth to the early hours and days of life. In the delivery room, the attention taken by health care professionals to prevent heat loss may determine whether the baby will be admitted to the NICU or to the neonatal nursery rather than remaining with the mother. Indeed, clinical symptoms induced by cold stress may alter early adaptation of the otherwise well baby and can be misinterpreted as presenting signs of neonatal sepsis, this in turn resulting in triage to higher than necessary levels of care.29 Unfortunately, a large number of infants born at 32e36 weeks have admission temperatures of 34.5e36.5 C and the course of their hospital stay has been associated with hypothermia in up to 10% of cases.5,30,31 Interventions to minimise the extent of heat loss in the delivery room should be tailored according to the infants gestation and needs for assistance following birth: a meta-analysis of three randomised controlled trials reported that increasing gestational age from 23 to 33 weeks was independently associated with increasing admission temperature and that moderate preterm infants at 32e33 weeks may benet from the use of occlusive wraps for preventing heat loss in the delivery room.32 It is also suggested that late preterm infants who necessitate no or minimal intervention after birth should be managed by the same protective intervention recommended for term babies, that is rapid drying on a warm surface such as the mothers chest or abdomen (skin-toskin contact). Early starting of breastfeeding will further provide infants with warmth. When carefully performed skin-to-skin contact is not possible, wrapping and placement under an overhead heat source may be an alternative option.28,33 Of course, more active interventions for preventing heat loss and providing active warming are needed for the sickest infants immediately after birth and during transport to the neonatal unit, considering that cold stress may worsen concomitant RDS and precipitate PPHN. In cases of hypothermia, the means and the rapidity chosen to rewarm the baby depend on the degree of hypothermia and on the infant response to rewarming.1,28
Practice points Neonatal hypoglycaemia: 8% of late preterm infants; 16% of moderate preterm infants. Prevention: favour early enteral nutrition. Use guidelines.37
Practice points Hypothermia and cold stress threaten moderate and late preterm infants during the rst days of life.
4.8. Feeding problems Some evidence suggests that both moderate and late preterm infants are more likely to present feeding intolerance than their term counterparts.4,5,36 Specic considerations are needed with
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respect to gestational age ranges. Nutritional requirements after birth change according to gestation and it may be difcult to achieve the recommended protein and caloric intakes without parenteral nutrition support at lower gestations, especially during the transitional period.38 Some evidence suggests that moderate preterm infants hospitalised in the NICU fail to achieve intrauterine growth rates.39 Early initiation of enteral feeding, use of gavage, caloric supplementation and parenteral nutrition support should rapidly be considered for nutritional management of moderately preterm infants and according to the infants needs, as they currently are for smaller babies. This approach should be used jointly with care policies that promote breastfeeding. For late preterm infants, feeding difculties such as poor sucking, milk intolerance and poor weight gain are more usually interrelated with all the minor morbidities, i.e. neonatal hypoglycaemia and hyperbilirubinaemia, often putting the baby in a vicious circle which prolongs hospitalisation and increases the risk of late morbidity. So, avoidance of feeding problems remains based on the global strategy described for promoting early breastfeeding. Although some papers reported that exclusive breastfeeding represents an independent risk factor for morbidity and subsequent need for hospital care or readmission in late preterm infants, these studies do not allow conclusions on this point as they did not assess breastfeeding quality in the analysed populations.
For preterm infants of 35e36 weeks and >2500 g, the AAP45 recommendations for term and near term infants may be applied. They suggest accurate estimation of the risk of developing severe hyperbilirubinaemia before discharge (bilirubin level based on the infants age in hours, peak and evolution), correct discharge instructions to parents, and close follow-up especially in exclusively breastfed infants.45 The formal recommendation of the same institution to avoid early discharge in these infants (<48 h) has to be respected.45
Practice points An increased risk of jaundice and hyperbilirubinaemiainduced neurological injury in moderate and late preterm infants. Be aware of the bilirubin kinetic pattern and use nomograms.44 Avoid early discharge.
6. Infections Moderate and late preterm infants are more likely to develop severe infections such as sepsis, meningitis and pneumonia than term infants. In a large retrospective population report, McIntire and Leveno46 found an increased risk of sepsis [odds ratio (OR): 2.18] and of work-up for infection (OR: 1.73) in late preterm versus term infants. The rate of sepsis in moderate preterm infants has also been shown to be almost double that in late preterm infants: in a twin population, Refuerzo et al.47 found 5% of sepsis in moderate versus 2.2% in the late preterm infants. Cohen-Wolkowiez et al.47 analysed the prevalence of infections in a very large cohort of late preterm infants. Early onset sepsis was established in 0.44% of late preterm infants. Gram-positive organisms caused the majority of early onset sepsis (66%) and Gram-negative organisms represented 27%. Group B streptococcus and Escherichia coli accounted for most episodes. Only 1% of late preterm infants with early onset sepsis died. Late onset sepsis was found in 0.63% of infants, most being caused by Gram-positive bacteria (59%), Gram-negative bacteria (30%) and yeast (7%). The most commonly observed pathogens responsible for late onset sepsis were coagulase-negative staphylococcus, Staphylococcus aureus, and Escherichia sp. A total of 7% of infants with late onset sepsis died.47
Practice points Increased risk of extrauterine growth restriction in moderate preterm infants. Prevention: early nutrition; favour breastfeeding.
5. Jaundice Premature birth is known to place infants at risk of hyperbilirubinaemia. Preterm infants are exposed because of exaggerated bilirubin production, hepatic immaturity in the uptake and conjugation of bilirubin, and excessive re-uptake due to intestinal immaturity and delayed enteral feeding. Although this risk decreases with increasing gestational age due to a progressive developmental maturity, jaundice rates remain elevated in moderate and late preterm infants when compared with term ones.2,31 Jaundice also appears to be one of the most important causes of hospital readmission, accounting for almost half of cases in late preterm infants.40 Preterm infants are vulnerable to brain damage induced by hyperbilirubinaemia, with particular relevance for kernicterus cases with bilirubin levels <20 mg/dL, so-called low bilirubin kernicterus.41 Despite a clear reduction in the prevalence of low bilirubin kernicterus among preterm infants in recent decades, an increased risk persists in moderate preterm infants.42 Concerning late preterm infants, a retrospective study based on the Pilot Kernicterus Registry showed that kernicterus was more frequent in late preterm than in term infants. In this population of late preterm infants, the large for gestational age babies were over-represented; many infants had a suboptimal lactation experience and they were cared for as healthy term infants.43 Guidelines for hyperbilirubinaemia are missing for infants <35 weeks or <2500 g. Attention should be paid to bilirubin kinetic patterns, by reporting several measures on specic nomograms for preterm babies44 and clinicians should also determine all possible jaundice causes and risk factors.
Practice points Increased risk of early and late onset sepsis in moderate and late preterm infants.
7. Other problems Some common problems of very preterm babies may rarely affect the moderate and late preterm infant.35 In two large retrospective cohorts the prevalence of necrotising enterocolitis (NEC) was signicantly increased in late preterm compared with term newborns2,46 but the NEC rate shows large variations from one study to another: 0.7% in US babies at 33e34 weeks8; 4.8% in Turkish late preterm infants hospitalised in NICU.30 Intraventricular haemorrhage (IVH), often limited to grades 1 or 2, is rare in population-based cohorts of late preterm infants although it is more frequently observed than in term infants.2,46
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Higher rates of IVH in late preterm infants have been reported by single centre studies conducted in tertiary hospitals but a bias at inclusion was likely. It is worth noting that IUGR was the main predisposing factor of IVH in the late preterm infant.30 Chronic lung disease (CLD, i.e. oxygen dependency at 36 weeks postconceptional age) decreases with gestational age in moderate and late preterm infants. In Californian hospitals the CLD rate was 6.7% at 30e326/7 weeks and 1.0% at 33e346/7 weeks.8 Another study found an incidence of 3.7% among late preterm infants when respiratory failure was present at birth.22 Apnoea of prematurity decreases with advancing gestational age. Recurrent apnoea may be a symptom of infection, anaemia, hypoxia, respiratory failure, intracerebral haemorrhage, drug sideeffect, hypoglycaemia and other metabolic disorders. Caffeine has been found to be an effective treatment of recurrent apnoea up to 37 weeks.48 The routine use of caffeine cannot be recommended in babies born from 32 weeks gestation but may be valuable in those infants with recurrent apnoea and/or weaning from respiratory support. Moderate and late preterm infants show a reduction in drug clearance and prolonged half-lives, exposing them to an increased risk of drug toxicity especially when drugs have a narrow therapeutic index. Reduction in drug absorption and protein binding of drugs contribute to the immaturity of the metabolic system. Some clinical conditions (hypoxaemia, acidosis, low serum albumin concentration, hypotension) may modify drug metabolism. A point of concern is the consequence on prognosis of late prematurity in an infant born with a severe congenital malformation. Natarajan et al.49 showed the particular vulnerability of late preterm infants with congenital cardiac defects. The association between late prematurity and cardiac malformation showed a greater than additive effect on both morbidity and mortality, although this conclusion is not universal for all malformations. For instance, a Canadian study of a national cohort of congenital diaphragmatic hernia (CDH) did not show an optimal gestational age for prenatally diagnosed CDH.50 Therefore further studies are needed to assess the role of gestation in the prognosis of infants born with severe malformations.
Funding sources None. References

*1. Engle WA. Morbidity and mortality in late preterm and early term newborns: a continuum. Clin Perinatol 2011;38(3):493e516. 2. Melamed N, Klinger G, Tenenbaum-Gavish K, et al. Short-term neonatal outcome in low-risk, spontaneous, singleton, late preterm deliveries. Obstet Gynecol 2009;114(2 Pt 1):253e60. 3. Gouyon JB, Vintejoux A, Sagot P, et al. Neonatal outcome associated with singleton birth at 34e41 weeks of gestation. Int J Epidemiol 2010;39:769e76. 4. Dimitriou G, Fouzas S, Georgakis V, et al. Determinants of morbidity in late preterm infants. Early Hum Dev 2010;86:587e91. 5. Bird TM, Bronstein JM, Hall RW, Lowery CL, Nugent R, Mays GP. Late preterm infants: birth outcomes and health care utilization in the rst year. Pediatrics 2010;126:e311e9. 6. Pulver LS, Guest-Warnick G, Stoddard GJ, Byington CL, Young PC. Weight for gestational age affects the mortality of late preterm infants. Pediatrics 2009;123:e1072e7. 7. Reddy UM, Ko CW, Raju TN, Willinger M. Delivery indications at late-preterm gestations and infant mortality rates in the United States. Pediatrics 2009;124:234e40. 8. Escobar GJ, McCormick MC, Zupancic JA, et al. Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit. Arch Dis Child Fetal Neonatal Ed 2006;91:F238e44. 9. Hibbard JU, Wilkins I, Sun L, et al, Consortium on Safe Labor. Respiratory morbidity in late preterm births. JAMA 2010;304:419e25. 10. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks gestational age. Pediatrics 2010;126:115e28. 11. Gouyon JB, Ribakovsky C, Ferdynus C, et al. Severe respiratory disorders in term neonates. Paediatr Perinat Epidemiol 2008;22:22e30. 12. Barton JR, Barton LA, Istwan NB, et al. Elective delivery at 340/7 to 366/7 weeks gestation and its impact on neonatal outcomes in women with stable mild gestational hypertension. Am J Obstet Gynecol 2011;204:44.e1e5. 13. De Luca R, Boulvain M, Irion O, Berner M, Pster RE. Incidence of early neonatal mortality and morbidity after late-preterm and term cesarean delivery. Pediatrics 2009;123:e1064e71. *14. Mathews TJ, Minio AM, Osterman MJ, Strobino DM, Guyer B. Annual summary of vital statistics: 2008. Pediatrics 2011;127(1):146e57. 15. Stutcheld P, Whitaker R, Russel I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective cesarean section: pragmatic randomised trial. BMJ 2005;331:662. 16. Ramachandrappa A, Jain L. Elective cesarean section: its impact on neonatal respiratory outcome. Clin Perinatol 2008;35:373e93. vii. *17. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 475: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2011;117(2 Pt 1):422e4. 18. Roberts D, Antenatal corticosteroids to reduce neonatal morbidity and mortality. Greentop guideline no. 7. London: Royal College of Obstetrics and Gynaecology; 2010. 19. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(3):CD004454. 20. Porto AM, Coutinho IC, Correia JB, Amorim MM. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomised clinical trial. BMJ 2011;342:d1696. 21. Joseph KS, Nette F, Scott H, Vincer MJ. Prenatal corticosteroid prophylaxis for women delivering at late preterm gestation. Pediatrics 2009;124:e835e43. 22. Cond V, Colnaghi M, Vanzatiz M, et al. Respiratory failure in late preterm infants: a retrospective cohort study. Pediatr Med Chir 2009;31:241e5. 23. Golombek SG, Young JN. Efcacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials. Clin Ther 2010;32:939e48. 24. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006;(18):CD000399. 25. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000;106(2 Pt 1):344e5. *26. Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2010;(12):CD000509. 27. Askie LM, Ballard RA, Cutter G, et al. Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration. BMC Pediatr 2010;23:10e5. 28. World Health Organization: Department of Reproductive Health and Research (RHR). Thermal protection of the newborn: a practical guide. Geneva: WHO. Available from, http://www.who.int/making_pregnancy_safer/MSM_97_2; 1997. *29. Laptook AR, Jackson GL. Cold stress and hypoglycemia in the late preterm (near term) infant: impact on nursery of admission. Semin Perinatol 2006;30(1):24e7. lu E, Kkdk S. Neonatal morbidity and 30. Kalyoncu O, Aygn C, Cetinog mortality of late-preterm babies. J Matern Fetal Neonatal Med 2010;23:607e12. 31. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114:372e6.
Practice points A moderately increased risk of NEC, low grade IVH, CLD and apnoea in moderate and late preterm infants. Drug metabolism is modied in moderate and late preterm infants. Birth between 32 and 36 weeks gestation may markedly worsen the prognosis of some congenital malformations. 8. Conclusion The rate of morbidity and mortality declines continuously when gestational age increases up to 39 weeks. This nding renders obsolete the classication of births by categories of gestational age <39 weeks (very preterm, moderate preterm, late preterm, early term). Clinicians should bear in mind that infants born at 34e36 weeks are not near term infants and that infants born at 37e38 weeks are not full term infants. There is a particular need to educate health care providers and parents about the vulnerability of infants born between 34 and 36 weeks gestation. Conict of interest statement None declared.
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J.-B. Gouyon et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 146e152 42. Watchko JF, Oski FA. Kernicterus in preterm newborns: past, present, and future. Pediatrics 1992;90:707e15. 43. Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol 2006;30:89e97. 44. Van Imhoff DE, Dijk PH, Hulzebos CV. BARTrial study group, Netherlands Neonatal Research Network. Uniform treatment thresholds for hyperbilirubinemia in preterm infants: background and synopsis of a national guideline. Early Hum Dev 2011;87:521e5. *45. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297e316. 46. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008;111:35e41. 47. Cohen-Wolkowiez M, Moran C, Benjamin DK, et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J 2009;28:1052e6. *48. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database Syst Rev 2010;(12):CD000140. 49. Natarajan G, Anne SR, Aggarwal S. Outcomes of congenital heart disease in late preterm infants: double jeopardy? Acta Paediatr 2011;100:1104e7. 50. Safavi A, Lin Y, Skarsgard ED. Canadian Pediatric Surgery Network. Perinatal management of congenital diaphragmatic hernia: when and how should babies be delivered? Results from the Canadian Pediatric Surgery Network. J Pediatr Surg 2010;45:2334e9.
32. Cramer K, Wiebe N, Hartling L, Crumley E, Vohra S. Heat loss prevention: a systematic review of occlusive skin wrap for premature neonates. J Perinatol 2005;25:763e9. *33. Laptook AR, Watkinson M. Temperature management in the delivery room. Semin Fetal Neonatal Med 2008;13(6):383e91. 34. Adamkin DH. Late preterm infants: severe hyperbilirubinemia and postnatal glucose homeostasis. J Perinatol 2009;29(Suppl. 2):S12e7. 35. Altman M, Vanpe M, Cnattingius S, Norman M. Neonatal morbidity in moderately preterm infants: a Swedish national population-based study. J Pediatr 2011;158:239e44. 36. Dani C, Corsini I, Piergentili L, Bertini G, Pratesi S, Rubaltelli FF. Neonatal mobidity in late preterm and term infants in the nursery of a tertiary hospital. Acta Paediatr 2009;98:1841e3. *37. Adamkin DH, Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127(3):575e9. 38. Rigo J, De Curtis M. Parenteral nutrition in premature infants. In: Guandalini S, editor. Textbook of pediatric gastroenterology and nutrition. New York: Taylor & Francis; 2004. p. 619e37. 39. Blackwell MT, Eichenwald EC, McAlmon C, et al. Interneonatal intensive care unit variation in growth rates and feeding practices in healthy moderately premature infants. J Perinatol 2005;25:478e85. 40. Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics 1998;101:995e8. 41. Gartner LM, Snyder RN, Chabon RS, Bernstein J. Kernicterus: high incidence in premature infants with low serum bilirubin concentrations. Pediatrics 1970;45:906e17.

Neonatal management and safe discharge of late and moderate preterm infants
Robin K. Whyte*
Dalhousie University, IWK Health Centre G2216, 5980 University Avenue, Halifax, Nova Scotia, Canada B3J 6R8
s u m m a r y
Keywords: Apnea Body temperature regulation Feeding methods Late preterm infants Low birth weight Moderate preterm infants
Late and moderate preterm infants form the majority of admissions for prematurity to special care neonatal nurseries. Although at risk for acute disorders of prematurity, they do not suffer the serious long term risks and chronic illnesses of the extremely premature. The special challenges addressed here are of transition and of thermal adaptation, nutritional compensation for postnatal growth restriction, the establishment of early feeding, and the avoidance of post-discharge jaundice or apnea. These healthy premature infants provide challenges for discharge planning, in that opportunities may be available for discharge well before the expected date of delivery, which should be pursued. Barriers to early discharge are rigid conservative protocols and unwarranted investigations; facilitators of discharge are individualized care by nurses expert in cue-based feeding, early management of the thermal environment, support of family preferences and encouragement of motherebaby interactions. Safe discharge depends on recognizing these opportunities and applying strategies to address them. 2012 Elsevier Ltd. All rights reserved.
1. Introduction The denitions of moderate and late preterm infants are accepted as infants of 32 and 33 and of 34, 35 and 36 weeks respectively. This review addresses management issues particular to prematurity but does not address in detail the disease-specic interventions of intensive care. The management issues of premature infants addressed here will be conned to discussing the selection of infants for admission to special or intensive neonatal care units (hereafter called special care nurseries) and their preparation for discharge in industrialized countries with established maternity and neonatal intensive care services. The birth weights of this population overlap with infants of very low and even extremely low birth weight (Table 1).1 Most morbidity of prematurity is related to gestational age, but some challenges (such as the maintenance of thermal homeostasis or the re-establishment of growth) are related to size at birth. Moderate preterm infants form a continuum with very preterm infants (<32 weeks gestation) and will therefore occasionally require discharge plans usually applied to this group of smaller infants. Neonatal follow-up programmes do not routinely enrol infants >32 weeks gestation, and infants with chronic lung disease requiring home oxygen are rarely included this group. Infants of >32 weeks gestation are not ordinarily at risk of retinopathy of prematurity.2,3
Aspects of discharge related to more extreme prematurity will not be addressed here. 2. Triage at birth 2.1. The delivery room A resuscitation physician or team, with appropriate equipment, capable of assessing the newborn, of establishing an airway and of achieving thermal neutrality must be present. If the birth is anticipated the team should have reviewed the maternal antenatal record and should be, in particular, knowledgeable as to the estimated gestational age and the condence with which this has been estimated, and to the use of antenatal steroids, the estimated fetal weight and the presence or absence of maternal drugs or infection. Resuscitation and its controversies will not be addressed here, other than to say that the risks of respiratory depression and distress are much higher in this population than at term. There is no prerequisite for prophylactic surfactant, added oxygen or antibiotics and a minimal-handling, expectant approach may be taken, with close attention to thermal homeostasis. 2.2. Post-delivery triage of the premature infant A decision must be made to admit the baby either to a special care nursery or to a postnatal ward, which in practice includes a decision either to separate the baby from the mother or to maintain the mothereinfant dyad. Admission to a special care
* Tel.: 1 902 470 6466. E-mail address: Robin.whyte@dal.ca. 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.004
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R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158
Table 1 Distribution of birth weight by gestational age for singletons. Approximated from the data of Kramer et al.1 Gestational age (weeks) 32 33 34 35 36 Median birth weight (g) 1862 2081 2313 2553 2795 Cumulative percentage below birth weight limits <1000 g 1% 0% 0% 0% 0% <1250 g 5% 1% 0% 0% 0% <1500 g 16% 6% 2% 0% 0% <1750 g 38% 19% 7% 2% 1% <2000 g 65% 41% 21% 8% 3% <2250 g 86% 67% 44% 22% 9% <2500 g 96% 87% 69% 45% 23%
nursery is generally required for infants who need incubator care, cardiorespiratory monitoring, assessment of adaptation or management of the complications of prematurity. This triage is specic to institutions and depends greatly on nursing skills and resources allocated to postnatal wards and the availability of pediatric expertise. Early separation can be usefully delayed if delivery room staff has the resources to monitor premature infants with their mothers and has the skills to manage the neonatal environment with skin-to-skin contact and early breast-nippling.4,5 The stable maintenance of an axillary temperature in the range 36.7e37.3 C, the absence of respiratory distress and the presence of resources for ongoing surveillance are prerequisites for a prolongation of maternaleinfant contact in the delivery room; skin-to-skin contact requires continued surveillance of the infants by nursing staff.6 Blood sugar screening in the delivery room is of unclear benet and the consequences of intervention unevaluated; screening for hypoglycemia is advocated for preterm infants at 1 to 2 h of age.7,8 The abilities and benets to the mother of continued shared care with their infants must also be addressed. Exhausted mothers or those recovering from anesthesia cannot be expected to participate in infant care, but innovative and individualized strategies (sometimes involving other family members) may reduce separation and support the early establishment of breastfeeding. Limitation of nursing resources and medical skills in the delivery room and postnatal wards reduces the safety of individualized triage decision-making; in these circumstances clear guidelines must be imposed which determine the criteria that will permit admission of the infant to the postnatal ward.
acquired infection from the maternal history or clinical ndings. The requirement for blood sugar measurements on admission and at selected intervals thereafter is inescapable,8 but these must be limited by protocol or to response to clinical suspicion of hypoglycemia; repeated unsolicited estimations lead to false-positive observations, further confusion and unwarranted intervention. 4. Establishing thermoneutrality All caregivers should have a good understanding of the components of the thermal environment.9 In order to facilitate observation, incubator placement may be a prerequisite for admission in some units, in which case great care must be exercised not to overheat larger infants. Thermoneutrality can be assumed if the axillary temperature is between 36.7 and 37.3 C.10 5. Early feeding The importance of the establishment of very early nutrition has recently been recognised, with the goal of establishing, so far as the constraints of uid allowances permit, full nutrition within the rst 2e5 days of life.11,12 Whereas these discussions have focused more on extremely low birth weight infants, the nutritional deciencies of moderate and late preterm infants must be similarly addressed, as these infants have been born before the major part of fetal growth has been completed. The special needs of the small-for-dates preterm have long been recognised, but all premature infants including those born of appropriate size-for-dates suffer from postnatal growth restriction attributable to the prolonged delay in re-attaining birth weight characteristic of the preterm infant.13 Feeding should be fully enteral where possible, often by gavage, and should be the expectation in infants of >1500 g birthweight. Mothers milk will generally not be immediately available, and human milk banks are not universally accessible, in which case an individualized decision must be taken, preferably with the mother, to feed with infant formula, using additional maternal colostrum or milk as it comes available, or to feed by an intravenous route. Early enteral feeding and advancement are not risk factors for necrotizing enterocolitis.14e16 Trophic feeding may be introduced when full enteral tolerance cannot be achieved, and it may accelerate the achievement of full feeding.16,17 Where intravenous feeding is unavoidable, amino acids and lipids should be introduced as soon as these are available in fully supportive quantities.12,18,19 6. Ongoing care and preparation for discharge Safe discharge of late preterm infants has been addressed in reviews20,21 but including moderate premature infants requires the consideration of an expanded prole of precedent conditions. Despite the greatly increased morbidity of the late preterm as compared with the term infant20,22 there is still a considerable proportion of infants who appear sufciently stable at birth to be managed in a low risk newborn nursery and discharged according
3. Admission to and early management in the special care nursery Many special care nurseries have universal admission protocols for premature infants, which include incubator care and cardiorespiratory monitoring. An early medical assessment, including review of the maternal perinatal history, birth events and physical examination of the newborn should determine whether an infant is to be admitted for care limited to observation of adaptation or for specic investigation and management of disorder of prematurity (such as respiratory distress). For many infants, where there are no risk factors for infection and no signs of delayed adaptation or cardiorespiratory disease, management can be conned to observation, establishment of feeding, monitoring and care of the thermal environment. The admission process must not result in additional morbidity or prolonged hospital stay. There is no place for routine investigations such as blood sampling; in the presence of low disease prevalence (risk) such pursuits generate a high rate of false-positive results which frequently result in further investigation, intervention and prolongation of stay. Likewise there is no role for routine blood culture or recourse to antibiotics; these strategies must be reserved for infants in whom there is a dened risk of perinatally
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to protocols offered to healthy term infants. Discharges at 2e5 days of age can be characterized as low risk newborn discharges; in recent years there has been an increase in discharges within 2 days (and sometimes within hours) of birth. These have been termed early discharges. To qualify for early discharge American23 and Canadian24 guidelines specify that an infant must be term (i.e. 37 weeks gestation). British guidelines do not apply this limitation to early discharge,25 preferring instead to stress the individualized decision-making for all mothereinfant dyads concerning discharge. Infants who experienced some of the morbidities of prematurity, such as respiratory distress, cannot be discharged until their requirements for intensive care support have been addressed. Moderate preterm infants, even if free of otherwise serious morbidity of prematurity, do not qualify for low risk newborn discharges and will always have to be demonstrably physiologically stable enough for the home environment. Guidelines specic to this group of infants are not available, but may be adapted from those made for smaller infants.26,27 Infants born at 32e34 weeks tend to go home before due date, as they have had time to recover from early complications and opportunities for early feeding and parental planning can be addressed.28 7. Conditions required for discharge Conditions for discharge include infant, community and family factors. Preterm infants must be breathing room air without respiratory embarrassment or interruption, feeding adequately to establish and maintain weight gain, and capable of maintaining thermal homeostasis without stress in the receiving environment. These achievements depend in part on physiological maturation, and they tend to mature together in individual infants.29 A further condition, which applies to late preterm infants who may qualify for term discharge, is that the metabolic adaptations of early postnatal life are either complete or provided for. 8. Resolution of jaundice All newborn infants should now be screened for hyperbilirubinemia, but current guidelines address late preterm but not moderate premature infants.30 Phototherapy is very effective at reducing high levels of bilirubin and has few adverse effects,31 but it disturbs maternal access and impedes nursing care. Unless there are clear indications to the contrary (such as established hemolysis or early jaundice) bilirubin measurements should be made when phototherapy is likely to be effective and the predictive power of the test greatest (i.e. at >24 h of age). The preterm infant has a slower rise in serum bilirubin than the term infant, reaching its peak at 4e9 days.32 Moderate and late premature infants are at greater risk for kernicterus33; more conservative levels for phototherapy, currently undened, should be used for these infants.34 Moderate premature infants, with their more prolonged admissions, can more readily receive phototherapy, but the late preterm infant is at risk of discharge before the peak bilirubin has been reached or even before the bilirubin has risen to moderate risk values. Late preterm infants who are breastfeeding are at particular risk of kernicterus35 or extreme hyperbilirubinemia,36 and this complication can be avoided by ensuring adequate post-discharge supervision for all infants who are not known to be both free of jaundice and in a low risk category from earlier screening. 9. Maintenance of thermal homeostasis Infants must be adapted to the thermal environment of the home to achieve a successful discharge. Several trials, combined in
a Cochrane review,37 have conrmed the feasibility of transfer of medically stable infants to a cot at 1600 g (as compared with 1800 g) for infants of 32 weeks gestation. Furthermore, early transfer to a cot is associated with greater weight gain and earlier discharge. The larger and more recent of these trials38,39 took place in nursery temperatures of 24 C with humidities approaching 50%, with infants dressed in light clothing with single blankets. Possibly the reported increased weight gain reects a more optimal selfregulated thermal environment for these dressed infants than is provided by an incubator. It is important not to exceed the thermal insulation described in these and other studies40; overbundling is associated with sudden infant death syndrome.41 Current guidelines for term infants cared for at home suggest that the infant should be lightly clothed for sleep,40 and the room temperature should be kept comfortable for a lightly clothed adult.42 10. Establishment of feeding to discharge Enteral feeding is often delayed by respiratory and other illnesses. Late and moderate preterm babies may retain the premature patterns of poor suck, swallow and breathing coordination,43 as well as reux or poor satiety associated with slow gastric emptying.44 Staged, timed introduction of scheduled feeds of predetermined volume has traditionally been achieved by prolonged gavage feeding. There is now substantial evidence that early maturation of sucking may be accelerated by the early cue-based introduction of suckling feeding on demand (where the infant controls the timing) and ad libitum (where the infant controls the amount).45 The skilled recognition of and response to infant signs of hunger and satiety can result in successful infant-cued feeding at or before 32 weeks gestation and a shortened length of stay.46 Non-nutritive sucking may be used as either a tool for cue recognition or as an infant training technique and may also contribute to the earlier establishment of feeding.47 For breastfeeding infants, a staged sequence from feeding expressed milk by gavage or bottle may be safely combined with early breast nippling to achieve early infant-cued and maternally responsive breast-nipple feeding. 11. Goals and content of feeding The practice of staged increases in feeds in the rst week to life to achieve a goal of 150 ml/kg/day have changed little from the original 2 oz/lb/day from which this number was derived. Models of ideal postnatal weight gain are based on estimates of fetal growth combined with growth rates of healthy term infants.11,48 From 32 to 50 weeks postconceptional age (pca) these idealized weight gains can be approximated by a daily weight gain of 30 g/day. Weight gain is close to linear, despite feeding being increased on a per bodyweight basis, because the energy and nutrient costs of weight gain increase with postnatal age.11,49,50 Matching the fetal rate of weight gain may not be enough, as this does not compensate for the prolonged postnatal delay in weight gain experienced by the more preterm infants, who may, despite establishing adequate rates of weight gain, be discharged below the tenth centile for weight at discharge.11e13 This postnatal growth restriction can only be addressed by strategies designed to increase nutrient intake to the maximum tolerated.50 Recommended protein intakes for infants >1200 g are 3.6 g/kg/ day with a protein:energy ratio of 2.8.11 Strategies for achieving these goals include fortication of human milk with commercial fortiers, the use of high nutrient preterm formulas, and the addition of protein sources to the limit of metabolic tolerance, as dened by urea levels.51 Weight gain goals of 35 g/day may be achieved with such strategies. Some concern has been addressed that rapid weight gain in infancy is associated with adverse outcomes in adult life52; clarication of this
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dilemma must await further long term follow-up of early feeding trials, but as previous enriched nutritional intervention was predominantly focused on increased energy intake, resulting in excess growth of fat mass,53 it may be that re-establishing lean body mass with high protein:energy and phosphate:energy ratios will address this concern. 12. Feeding beyond discharge Full enteral feeding is generally a prerequisite for discharge, although in specic circumstances infants may be discharged with gavage feeds.54 In most circumstances safe tolerance and retention of feeds and at least a reasonable expectation of weight gain are requirements for discharge home. High nutrient post-discharge formulas are available,55,56 as are human milk fortiers57; their use has not been fully evaluated or compared to a strategy of fully liberalizing infant intake to demand.58 13. Respiratory stability Respiratory stability depends on complete recovery from respiratory illness and the absence of apnea of prematurity. Well preterm and term infants have median pulse oximetry readings in excess of 97% after the rst days of life59,60 (partly because pulse oximeters may read errantly high in the range 97e100%). When additional oxygen therapy has been withdrawn, oximetry readings should be 93% when the infant is asleep or quietly awake in room air for a least one night prior to discharge.61 14. Apnea of prematurity Apnea of prematurity increases in frequency and severity with decreasing gestational62 and postconceptional age,63 and is a particular component of discharge planning for the moderate preterm. Apnea may persist well beyond term,29 but this phenomenon is far more common in very premature infants and rare for infants born at or after 32 weeks gestation.63,64 The required apnea/bradycardia-free interval that safely denes this period has been estimated conservatively at 8 days64 where apnea is dened as apnea for >20 s, bradycardia <60 bpm or oxygen saturation of <80%, not provoked by feeding. Infants who have apnea of increasing frequency or a new episode beyond an 8-day apnea-free interval are likely to be manifesting new illnesses, such as infection.64 There is a reassuring tendency for apnea for all infants to resolve by 44 weeks pca.65 Apnea at home is a frightening event which usually leads to emergency readmission, but it rarely results in mortality and does not appear to be a predictor of sudden infant death syndrome.65,66 Families should be so reassured and instructed on the simple stimulatory techniques required to resolve such an event; their knowledge of access to emergency services should be reviewed on discharge. Caffeine has been used on an ambulatory basis, but its discontinuation may require readmission for monitoring.26,67 15. Resources for care: transition between hospital and home resources The resources that are provided by ongoing hospitalization of an infant are facility-based, health profession-based and physicianbased; discharge may take place when these are no longer required. Health profession support includes individualized expert patient care from nursing and allied health professions. The physician, in most systems, provides medical expertise as intermittent care, and generally bears the responsibility for the decision to discharge to the community. Expert continuous nursing care and
observation is the cornerstone of evaluation of readiness for discharge. The community, on the other hand, generally includes a highly variable (but often superior) home environment, family care which may be continuous, community health resources which can be intermittent, and physician resources which require access and often transport. A supportive home environment is an opportunity for earlier discharge which should be seized. The convalescent preterm infant is at increased risk of infection, but more so of serious nosocomial bacterial infection in a hospital nursery than of a sibling-acquired viral infection in a well-managed home. Continuous observation of the infant may be more effectively and reliably conducted (and reported) by a parent supported by an extended family than by a nurse sharing responsibilities with other sicker infants and working intermittent shifts. Marked improvements in feeding may follow discharge.68 Merritt et al.25,69 have critically reviewed strategies for effecting safe, early discharge of very low birth weight infants that can be applied to moderate and late preterm infants. Parent involvement, empowerment and education70 can and should be used to reduce the length of hospital stay where the opportunity arises. 16. Anticipating discharge Safe discharge of a healthy infant is the primary goal of neonatal care, and plans should be clear and documented from admission. Parents should be expected to plan for discharge home from the time of birth, and this date should be estimated with them soon after admission; if there are uncertainties, these should be explicit and the estimation repeatedly adjusted. Planning for discharge following premature birth is more difcult for parents than it is for institutions, as it may involve adjustment of parental leave, changes in domestic planning, recruitment of family support, earlier acquisition of baby needs, and changes or improvements to housing. Maternal medical needs, twins or other multiples, and parental separation or discord may further impede timely discharge. A nurse discharge specialist or team can evaluate and address parenting skills and condence, community resources, and access to health care and resources. These evaluations and arrangements are timeconsuming and require excellent coordination and communication skills, but may be expected to be cost-effective.69 Attention must be paid to the safe transport of the infant to the community. Recommendations for car seat use for premature infants should be applied.26 17. Types of discharge Hospital discharge may take the following forms: 1. Complete discharge home with support from local community care services (health visitors, family doctor appointments). 2. Provisional discharge home with ongoing daily management by hospital personnel, which may include daily blood testing and management (for example, in hyperbilirubinemia or anemia) or monitoring (e.g. weight gain). 3. Suspended discharge, where a hospital admission (bed) is maintained for the infant who goes home on a pass, usually with a daily return for evaluation or care. The hospital staff retains the responsibility although not the direct administration of infant care. 4. Rooming in or placing the baby under family care in accommodation within the hospital, supervised by hospital staff, is an important step in evaluating and managing the infant with the family outside the directly monitored environment of the nursery.
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Institutions should recognize and develop exibility in discharge arrangements with a view to making opportunities for safe, earlier but sometimes graduated discharge available. The following is a list of requirements for safe discharge of the moderate or late preterm infant, modied from a plan for the very low birth weight infant.26 1. Sustained or anticipated weight gain sufcient to attain antenatal growth expectations. 2. Stable feeding and infant cue-driven feeding patterns. 3. Stable temperature when lightly clothed at room temperature. 4. A scheduled immunization plan. 5. Nutritional supplementation, where indicated, to include iron, vitamin D or fortication. 6. Review of requirements for retinal fundoscopy (generally limited to infants of 32 weeks gestation). 7. Written copy of discharge summary for parents to share with medical care services. 8. Satisfactory evaluation of, or education of, parenting skills. 9. Review of medications with parents. 10. Home environment evaluation and availability of community support services. 11. Community-based home or ofce assessment within 48 h of discharge.
Is the body composition of the preterm newborn at term due date predictive of body habitus in later childhood? Can we safely identify full vascularization of the preterm retina? If so, can we release our restraints on higher levels of oxygen in respiratory therapy? How effective is replacement of breast milk with formula in the treatment of prolonged hyperbilirubinemia in the breast-fed, late preterm infant? When should phototherapy be applied or discontinued in the prevention of exchange transfusion or kernicterus in otherwise-healthy preterm infants? Are blood glucose levels in otherwise-healthy preterm infants predictive of anything, and should they be treated?
References
1. Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;108:E35. 2. Smith LE. Through the eyes of a child: understanding retinopathy through ROP. The Friedenwald lecture. Invest Ophthalmol Vis Sci 2008;49:5177e82. 3. Reynolds JD, Dobson V, Quinn GE, et al. Evidence-based screening criteria for retinopathy of prematurity: natural history data from the CRYO-ROP and LIGHT-ROP studies. Arch Ophthalmol 2002;120:1470e6. 4. Moore ER, Anderson GC, Bergman N. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev 2007;3:CD003519. 5. Bergman NJ, Linley LL, Fawcus SR. Randomized controlled trial of skin-to-skin contact from birth versus conventional incubator for physiological stabilization in 1200- to 2199-gram newborns. Acta Paediatr 2004;93:779e85. 6. Andres V, Garcia P, Rimet Y, Nicaise C, Simeoni U. Apparent life-threatening events in presumably healthy newborns during early skin-to-skin contact. Pediatrics 2011;127:e1073e6. 7. Adamkin DH, Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575e9. 8. Aziz K, Fetus and Newborn Committee. Canadian Paediatric Society (CPS). Screening guidelines for newborns at risk for low blood glucose. Paediatr Child Health 2004;9:723e40. 9. Schwartz RH, Hey EN, Baum JD. Management of the newborns thermal environment. In: Sinclair JC, editor. Temperature regulation and energy metabolism in the newborn. New York: Grune & Stratton Ltd; 1978. p. 205e25. 10. Sauer PJ, Dane HJ, Visser HK. New standards for neutral thermal environment of healthy very low birthweight infants in week one of life. Archs Dis Childh 1984;59:18e22. 11. Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 2011;58(Suppl. 1):8e18. 12. Ehrenkranz RA. Early nutritional support and outcomes in ELBW infants. Early Hum Dev 2010;86(Suppl. 1):21e5. 13. Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280e9. 14. Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre caseecontrol study. Archs Dis Childh Fetal Neonatal Ed 2009;94:F120e3. *15. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011;3:CD001970. *16. Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011;3:CD001241. 17. Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database Syst Rev 2009;3:CD000504. 18. Van Goudoever JB, Colen T, Wattimena JL, Huijmans JG, Carnielli VP, Sauer PJ. Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the rst day of life. J Pediatr 1995;127:458e65. 19. Rivera Jr A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the rst three days of life. Pediatr Res 1993;33:106e11. 20. Engle WA, Tomashek KM, Wallman C. Committee on Fetus and Newborn, American Academy of Pediatrics. Late-preterm infants: a population at risk. Pediatrics 2007;120:1390e401. *21. Whyte RK, Fetus and Newborn Committee, Canadian Paediatric Society. Safe discharge of the late preterm infant. Paediatr Child Health 2010;15:655e60. 22. Pulver LS, Denney JM, Silver RM, Young PC. Morbidity and discharge timing of late preterm newborns. Clin Pediatr 2010;49:1061e7. 23. American Academy of Pediatrics Committee on Fetus and Newborn. Hospital stay for healthy term newborns. Pediatrics 2004;113:1434e6. 24. MacMillan D, Fetus and Newborn Committee, Canadian Paediatric Society, Maternal Fetal Medicine Committee, Society of Obstetricians and
Practice points Moderate and late preterm infants are increasingly vulnerable to disorders of prematurity with decreasing gestational age. An individualized approach to care (expecting different babies to respond in different ways) leads to safe, earlier discharge in selected infants. Otherwise-healthy preterm babies should be evaluated at 1600 g for selected transfer from an incubator to a cot. Otherwise-healthy preterm babies should be evaluated early for early oral feeding and satiety cuing; selected infants may be nipple fed from 32 weeks on. Some stable preterm babies will do better at home and be safer and more successfully fed than in a nursery environment. Individual review of metabolic tolerance should be used to maximize and optimize nutrient intakes to achieve weight gains sufcient to compensate for the postnatal malnutrition of the premature. Discharge plans and expectations should be shared with parents and community resources from the day of admission. Discharge, and preparation for discharge, may take many forms and should be exible, with easy recourse to readmission or to suspended discharge schemes.
Research directions More on cue-based feeding: does recognition of early satiety signals lead to better weight gain or avoidance of later onset obesity or metabolic syndrome? Does early servocontrol lead to earlier or later successful response to transfer from incubator to cot? What are the long term neurodevelopmental and physical health outcomes of early aggressive adaptive feeding of the preterm newborn?
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R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158 Gynaecologists of Canada, Clinical Practice Obstetrics Committee, Society of Obstetricians and Gynaecologists of Canada. Facilitating discharge home following a normal term birth. Paediatr Child Health 1996;1:165e8. National Institute for Health and Clinical Excellence. Routine post-natal care of women and their babies. Clinical Guideline 37. London: NICE; 2006. Merritt TA, Pillers D, Prows SL. Early NICU discharge of very low birth weight infants: a critical review and analysis. Semin Neonatol 2003;8:95e115. American Academy of Pediatrics Committee on Fetus and Newborn. Hospital discharge of the high-risk neonate. Pediatrics 2008;122:1119e26. Rawlings JS, Scott JS. Postconceptional age of surviving preterm low-birthweight infants at hospital discharge. Arch Pediatr Adolesc Med 1996;150:260e2. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics 1997;100:354e9. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297e316. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920e8. Sarici SU, Serdar MA, Korkmaz A, et al. Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns. Pediatrics 2004;113:775e80. Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Archs Dis Childh Fetal Neonatal Ed 2003;88:F455e8. Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Archs Dis Childh Fetal Neonatal Ed 2003;88:F459e63. Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol 2006;30:89e97. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000;154:1140e7. New K, Flenady V, Davies MW. Transfer of preterm infants from incubator to open cot at lower versus higher body weight. Cochrane Database Syst Rev 2011;9:CD004214. New K, Flint A, Bogossian F, East C, Davies MW. Transferring preterm infants from incubators to open cots at 1600 g: a multicentre randomised controlled trial. Archs Dis Childh Fetal Neonatal Ed 2011 Aug 13 [Epub ahead of print]. Zecca E, Corsello M, Priolo F, Tiberi E, Barone G, Romagnoli C. Early weaning from incubator and early discharge of preterm infants: randomized clinical trial. Pediatrics 2010;126:e651e6. Wigeld RE, Fleming PJ, Azaz YE, et al. How much wrapping do babies need at night? Archs Dis Childh 1993;69:181e6. Fleming PJ, Gilbert R, Azaz Y, et al. Interaction between bedding and sleeping position in the sudden infant death syndrome: a population based caseecontrol study. BMJ 1990;301:85e9. American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics 2005;116:1245e55. Mizuno K, Ueda A. The maturation and coordination of sucking, swallowing, and respiration in preterm infants. J Pediatr 2003;142:36e40. Berseth CL. Gastrointestinal motility in the neonate. Clin Perinatol 1996;23:179e90. Breton S, Steinwender S. Timing introduction and transition to oral feeding in preterm infants: current trends and practice. Newborn Infant Nurs Rev 2008;8:153e9. Puckett B, Grover VK, Holt T, Sankaran K. Cue-based feeding for preterm infants: a prospective trial. Am J Perinatol 2008;25:623e8. Pinelli J, Symington A. Non-nutritive sucking for promoting physiologic stability and nutrition in preterm infants. Cochrane Database Syst Rev 2005;4:CD001071. Sparks JW. Human intrauterine growth and nutrient accretion. Semin Perinatol 1984;8:74e93. Whyte RK, Bayley HS, Sinclair JC. Energy intake and the nature of growth in low birth weight infants. Can J Physiol Pharmacol 1985;63:565e70. 50. Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85e91. 51. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortication of human milk fed to preterm infants: does it make a difference? J Perinatol 2006;26: 614e21. 52. Thureen PJ. The neonatologists dilemma: catch-up growth or benecial undernutrition in very low birth weight infants-what are optimal growth rates? J Pediatr Gastroenterol Nutr 2007;45(Suppl. 3):S152e4. 53. van Goudoever JB, Sulkers EJ, Lafeber HN, Sauer PJ. Short-term growth and substrate use in very-low-birth-weight infants fed formulas with different energy contents. Am J Clin Nutr 2000;71:816e21. 54. Collins CT, Makrides M, McPhee AJ. Early discharge with home support of gavage feeding for stable preterm infants who have not established full oral feeds. Cochrane Database Syst Rev 2003;4:CD003743. 55. Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal growth and lower fat mass in preterm infants fed a protein-enriched postdischarge formula. J Pediatr Gastroenterol Nutr 2010;50:200e7. 56. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: benecial outcomes of feeding fortied human milk versus preterm formula. Pediatrics 1999;103:1150e7. 57. Zachariassen G, Faerk J, Grytter C, et al. Nutrient enrichment of mothers milk and growth of very preterm infants after hospital discharge. Pediatrics 2011;127:e995e1003. 58. Henderson G, Fahey T, McGuire W. Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge. Cochrane Database Syst Rev 2007;4:CD004696. 59. Brockmann PE, Poets A, Urschitz MS, Sokollik C, Poets CF. Reference values for pulse oximetry recordings in healthy term neonates during their rst 5 days of life. Archs Dis Childh Fetal Neonatal Ed 2011;96:F335e8. 60. Richard D, Poets CF, Neale S, Stebbens VA, Alexander JR, Southall DP. Arterial oxygen saturation in preterm neonates without respiratory failure. J Pediatr 1993;123:963e8. 61. Poets CF. When do infants need additional inspired oxygen? A review of the current literature. Pediatr Pulmonol 1998;26:424e8. 62. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Paediatr J 1981; 17:273e6. *63. Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS. JAMA 2001;285:2199e207. 64. Darnall RA, Kattwinkel J, Nattie C, Robinson M. Margin of safety for discharge after apnea in preterm infants. Pediatrics 1997;100:795e801. 65. Hunt CE, Corwin MJ, Lister G, et al. Longitudinal assessment of hemoglobin oxygen saturation in healthy infants during the rst 6 months of age. Collaborative Home Infant Monitoring Evaluation (CHIME) Study Group. J Pediatr 1999;135:580e6. 66. Esani N, Hodgman JE, Ehsani N, Hoppenbrouwers T. Apparent life-threatening events and sudden infant death syndrome: comparison of risk factors. J Pediatr 2008;152:365e70. 67. Ducrocq S, Biran-Mucignat V, Boelle PY, Lebas F, Baudon JJ, Gold F. Apnea of prematurity: risk factors and ambulatory treatment with caffeine citrate. Arch Pediatr 2006;13:1299e304. 68. Lucas A, King F, Bishop NB. Postdischarge formula consumption in infants born preterm. Archs Dis Childh 1992;67:691e2. 69. Merritt TA, Raddish M. A review of guidelines for the discharge of premature infants: opportunities for improving cost effectiveness. J Perinatol 1998;18:S27e37. 70. Melnyk BM, Feinstein NF, Alpert-Gillis L, et al. Reducing premature infants length of stay and improving parents mental health outcomes with the Creating Opportunities for Parent Empowerment (COPE) neonatal intensive care unit program: a randomized, controlled trial. Pediatrics 2006; 118:e1414e27.
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48. 49.

Health outcomes in infancy and childhood of moderate and late preterm infants
Pooja Harijan, Elaine M. Boyle*
Department of Health Sciences, University of Leicester, 22e28 Princess Road West, Leicester LE1 6TP, UK
s u m m a r y
Keywords: Health Late preterm Moderate preterm Outcomes Preterm
There has been a long-held belief that outcomes for babies born at moderate and late preterm gestations do not differ substantially from those of infants born at full term. This has recently been challenged by studies highlighting an increased risk of adverse neonatal outcomes, and of poorer cognitive, behavioural and educational outcomes in this population. Data about the effects of birth at moderate and late preterm gestations on later health outcomes are limited, but emerging evidence suggests that ongoing physical health may also be worse in those born just a few weeks before full term. This review summarises the available evidence, considers the factors inuencing health outcomes and discusses the implications for the planning and provision of childrens health care services. 2012 Elsevier Ltd. All rights reserved.
1. Introduction Historically, interest in health outcomes of preterm infants has been centred on very preterm infants, i.e. those born at <32 weeks of gestation. This is understandable, as this group includes those babies for whom severity of neonatal illness is likely to be greatest and in whom adverse long-term outcomes are most likely to occur.1e4 Most neonatologists, therefore, routinely follow up infants born at <32 weeks until around 2 years of age and most research studies to date have been concentrated on this population. By contrast, few centres have a programme of ongoing surveillance for more mature preterm infants, as their outcomes have been assumed to be similar to those of term-born infants. In the UK there is currently no routine neonatal data collection for this group. However, it has become apparent over recent years, from retrospective analyses of large cohorts in North America, that the risk of signicant neonatal morbidity is greater in moderate (32e33 weeks) and late (34e36 weeks) preterm infants compared with infants born at 37 weeks of gestation.5e8 Published data on later health outcomes in children who have been born at 32e36 weeks of gestation are relatively few, but emerging evidence suggests that for some, health problems may persist into later infancy and childhood.9
2. Hospitalisation during infancy and childhood Increased likelihood of readmission of late preterm infants to hospital following discharge from neonatal care is well
* Corresponding author. Tel.: 44 (0) 116 252 5447. E-mail address: eb124@leicester.ac.uk (E.M. Boyle). 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.002
documented. In a US study, 4.4% of 2153 infants born at 34 to 366 weeks of gestation were readmitted within the rst 15 days after discharge, compared with 2.0% of 30 261 infants born at >37 weeks.10 Following early neonatal discharge in a UK cohort, readmission in the rst month occurred in 6.3% of infants born at 35e37 weeks of gestation compared with 3.4% and 2.4% respectively of those born at 38e40 and >40 weeks.11 Jain and Cheng found that emergency department attendances in the neonatal period were also increased in late preterm infants, with the greatest proportion of these being in infants born at 36 weeks of gestation.12 Jaundice has consistently been found to be the most frequent reason for hospital readmission in the rst month of life.10,13,14 Other common reasons are infection,14 feeding difculties and dehydration.5 An important risk factor for early post-discharge morbidity appears to be failure to successfully establish adequate breastfeeding,13,15 but early hospital discharge has also been implicated.14 Hospitalisation beyond the neonatal period has been less well investigated. Escobar found that late preterm infants were more likely to require at least one hospital admission within the rst six months after birth.5 McLaurin et al.16 showed that health carerelated costs were higher for late preterm infants than for term born infants, with the greatest costs being related to hospital inpatient admissions; regardless of the timing of discharge from neonatal care, infants born late preterm were almost twice as likely to have received inpatient hospital care during the rst year. Secondary analysis of data from the Millennium Cohort Study (MCS), a UK nationally representative prospective cohort study, examined parental reports of their childrens hospital admissions. Compared with infants born at full term (39e41 weeks of gestation), the odds of having three or more admissions within the rst nine months of life was higher for both moderate preterm [adjusted
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odds ratio (aOR): 7.8; 95% CI: 2.9e20.7] and late preterm (aOR: 5.1; 95% CI: 3.0e8.8) infants. The most common reasons for hospitalisation were respiratory disorders such as chest infection and wheezing, and gastrointestinal problems including infection and gastro-oesophageal reux. The odds of being admitted to hospital three or more times between nine months and 5 years of age were also higher in children born moderate and late preterm than in those born at full term (aOR: 3.0; 95% CI: 1.4e6.2; and 1.9; 95% CI: 1.3e2.7 respectively).9 3. Respiratory morbidities Acute respiratory disorders immediately after birth such as respiratory distress syndrome, transient tachypnoea of the newborn and pneumonia are more common, and incur a greater risk of respiratory failure, in late preterm than in full term infants.17 This increased respiratory morbidity is thought to be related to functional immaturity of the lung structure at 34e37 weeks of gestation, which predisposes to delayed intrapulmonary uid absorption, surfactant insufciency, and ultimately to inefcient gas exchange.18 The risk of ongoing respiratory morbidity after the early neonatal period is unclear. Although respiratory outcomes have been investigated in only a small number of studies, some suggest a continued risk of respiratory problems into infancy and childhood. It has been suggested that preterm birth, even when there has been no signicant neonatal respiratory disease, may have adverse effects on lung growth and development with subsequent reduced pulmonary function.19 Kotecha et al.20 conducted an analysis of data from children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC; n 14 049) who had spirometry measurements taken at ages 8e9 years (n 6705) and/or 14e17 years (n 4508). This study included 691 children who had been born between 33 and 36 weeks of gestation. The researchers demonstrated decreased lung function at school age in children born at 33e34 weeks of gestation. At 8e9 years of age, all spirometry measures in the 33e34 week gestation group were signicantly lower than in those born at 37 weeks and spirometry decrements were similar to those observed in children who had been born between 25 and 32 weeks of gestation. At 14e17 years of age, some differences between the groups had resolved, but forced expiratory volume (FEV1)/forced vital capacity (FVC) and forced expiratory ow at 25e75% FVC (FEF 25e75%) remained signicantly lower in the preterm group than that in term controls. By contrast, children born at 35e36 weeks had values similar to those of children born at 37 weeks. As might be expected, mechanical ventilation in the neonatal period was more common in the lower gestational age groups; this may contribute to the later differences observed. Although there was considerable loss to follow-up from this study, non-attenders were from families of lower socioeconomic status and in which maternal smoking was more prevalent, raising the possibility that the study results might provide an underrepresentation of the true differences. It has been suggested that there is increased susceptibility to respiratory infection in infants born at moderate and late preterm gestations. In particular, a number of studies have investigated the risk of respiratory syncytial virus (RSV) bronchiolitis.21 There is some evidence for this being associated with risk of wheezing and other respiratory events in the year following RSV infection, to a greater extent than in term infants.22,23 Law et al. conducted a multicentre prospective cohort study of infants born at 33e35 weeks of gestation to identify risk factors for RSV infection requiring hospitalisation in this group. The most important of these were day-care attendance, birth during winter months and
preschool age sibling(s).24 A risk assessment tool for RSV infection in late preterm infants was devised25 and its predictive validity was found to be good.26 A Canadian health economics study suggested that the use of prophylaxis may be cost-effective in the subgroup of moderate to late preterm infants identied as being at high risk for RSV infection.27 Asthma is a major cause of respiratory morbidity in children. There is conicting evidence regarding the association between moderate and late preterm birth and a diagnosis of asthma in early childhood. A retrospective cohort study included 582 late preterm infants born in 2007 and found evidence of more diagnoses of persistent asthma (aOR: 1.68; 95% CI: 1.01e2.80), inhaled corticosteroid use (aOR: 1.66; 95% CI: 1.20e2.29), and numbers of acute respiratory visits (incidence rate ratio 1.44; 95% CI: 1.24e1.67) in late preterm infants compared with those born at 37e38 weeks of gestation.28 Vogt et al. examined inhaled corticosteroid use in 6e19-year-olds and found an increased use of medication in those born at 33e34 weeks (aOR: 1.35; 95% CI: 1.25e1.46) and 35e36 weeks gestation (aOR: 1.24; 95% CI: 1.19e1.30) compared with those who were born at more mature gestations.29 In the Millennium Cohort Study group, Boyle et al.9 found an increased incidence of asthma and wheeze at 3 and 5 years in children born moderate or late preterm, and medication for asthma was the most prescribed medication at 5 years (aOR: 2.2; 95% CI: 1.6e3.1). By contrast, Abe et al.30 found no statistically signicant association between late preterm birth and the risk of developing asthma in childhood.
4. Feeding and growth Adequate feeding in infancy is crucial for healthy weight gain. Ongoing feeding problems are not infrequently seen in very preterm infants and are often attributed to immaturity of suck and swallowing coordination. There is, however, very limited evidence in more mature preterm infants, and the number in this group affected by feeding difculties is not known. A prospective cohort study used parent questionnaires to collect information about feeding behaviour during the rst year of life in infants who were born preterm, from 25 to 36 weeks of gestation.31 The study examined outcomes such as appetite, oromotor dysfunction and feeding avoidance, comparing 571 late preterm infants with 319 infants born before 34 weeks. Although the researchers had expected to nd evidence of more mature feeding patterns and fewer difculties in the late preterm infants, parents in both groups reported similar rates of feeding dysfunction. Feeding difculties improved during the rst 12 months of life in both groups and episodes of hospitalisation for feeding problems did not differ between the two groups. The study was limited by the lack of comparison with term-born infants, but is supportive of the ndings of an earlier small study in 20 infants of 32e37 weeks gestation, who showed delayed feeding development compared when compared with 10 full term infants at 11e17 months of age.32 Whereas very preterm infants are known to have patterns of later growth and weight gain that are poorer than those of termborn infants, there is a paucity of data for those born between 32 and 36 weeks. A Brazilian population-based study found signicantly increased risks of poor weight and height attainment in late preterm infants at 12 and 24 months of age (aOR: 3.36; 95% CI: 1.56e7.23; and aOR: 2.30; 95% CI: 1.40e3.77, respectively) compared with those born at term.33 Data from the Millennium Cohort Study9 showed lower height attainment at both 3 and 5 years in late preterm infants when compared with infants born at 39e41 weeks.
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5. Longstanding illness A large longitudinal study of all births in Norway between 1967 and 1983 showed that those born late preterm had an increased risk of major disabilities that included epilepsy and visual and hearing impairments.34 As adults, they were more likely to experience disability affecting their work capacity. Advances in obstetric, neonatal and paediatric care since the birth of these children may mean that these ndings are less relevant today. However, more recent data from the Millennium Cohort Study showed that longstanding illness at 3 and 5 years was more common in children born moderate or late preterm than those born at full term and that their illness was more likely to limit their activities.9 Parents of the children born preterm were more likely to report their childs health as being poor than those with term-born children. There has been only one study assessing health-related quality of life in children born at 32e36 weeks of gestation.35 This study included 362 pre-school children and showed lower health-related quality of life scores for lung problems in those who had received continuous positive airway pressure in the neonatal period. 6. Mortality A number of studies have consistently reported increased mortality during the neonatal period in infants born moderate and late preterm,36e39 but until recently there have been no published data specically addressing the relationship between gestational age at birth and later mortality. A national cohort study in Sweden of 674 820 singletons, born between 1973 and 1979, recently reported a gradient of increasing mortality with decreasing gestation.40 The study included 22 590 late preterm infants, and birth between 34 and 36 weeks was associated with increased mortality in early childhood (age 1e5 years) and young adulthood (aged 18e36 years). The adjusted hazard ratio for all-cause mortality in the late preterm group compared with the 37e42 week gestation group was 1.31 (95% CI: 1.13e1.5). There was a non-signicant association between late preterm birth and mortality in late childhood and adolescence. The strongest associations with mortality in adulthood were congenital anomalies, respiratory, endocrine and cardiovascular disorders; no association was found with mortality from neurological disorders, cancer or injury. Sensitivity analyses showed that the association was not explained by congenital anomalies. 7. Inuences on health outcomes in moderate and late preterm infants Despite a recent increase in interest in moderate and late preterm birth, considerably less is known about the long term risks associated with birth at more mature preterm gestations compared with those of very preterm birth. Nevertheless, although sparse, much of the available information to date points to worse outcomes in this group than in individuals born at term. Also poorly understood are the factors leading to birth at 32e36 weeks of gestation and those inuencing long term health in infants, children and adults. Such inuences may originate before or during pregnancy, in the perinatal or neonatal period or during childhood. In deciding to what extent outcomes are due to prematurity per se, many other factors must be considered. Infants with congenital anomalies and multiple births commonly deliver spontaneously at moderate and late preterm gestations. In addition, obstetric concerns about either maternal or fetal condition often lead to medically indicated deliveries during this period of gestation. Obstetric decision-making with respect to indications
for delivery, timing of delivery and mode of delivery may therefore inuence outcomes. During the neonatal period place of care, discharge policies and duration of postnatal hospitalisation vary and the consequences of this variation have not been fully explored. Following discharge, parental education and family lifestyle are other factors that may potentially affect longer term health outcomes in these infants. Many of these are inextricably linked and their relative contributions to infant and child health outcomes remain to be disentangled.
8. Implications for provision of childrens health care services Reasons for preterm birth at 32e36 weeks of gestation are not always clearly understood, but a recent small decrease in the rates of late preterm birth suggests that strategies for reducing avoidable births at these gestations may be having some success. Despite this, moderate and late preterm births continue to represent >75% of all preterm births. Emerging evidence about health outcomes in these infants appears to mirror reports of worse neurodevelopmental and educational outcomes, although contemporary and prospective data remain limited. Poor health in large numbers of infants and children is likely to have a substantial impact on primary care and public health services. Many preterm infants born at 32 weeks do not receive follow-up or surveillance for their health care or developmental needs. Now that these children are increasingly being highlighted as a group at greater risk than has previously been appreciated, it is important to ensure that their ongoing health care needs are being adequately met. Reports of adverse outcomes have led to many calls for routine follow-up in this group until at least 18 months of age.41e43 Such a strategy would have important nancial and logistic implications for the provision of health care services for children. Further work is required to identify those at greatest risk of poor health outcomes in order to allow appropriate and, if possible, targeted follow-up in children born moderate or late preterm.
Practice points Children born moderate or late preterm are more likely to be admitted to hospital in infancy and childhood than those born at full term. Children born moderate or late preterm may be more susceptible to respiratory disease than those born at full term. Large numbers of moderate and late preterm infants mean that the impact of this group on health care services may be substantial.
Research directions Contemporary prospective longitudinal studies are needed to: clarify long term outcomes of moderate and late preterm infants; identify risk factors and predictors for poor health outcomes in children born moderate or late preterm; determine appropriate follow-up strategies for infants born at moderate and late preterm gestations.
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P. Harijan, E.M. Boyle / Seminars in Fetal & Neonatal Medicine 17 (2012) 159e162 21. Resch B, Paes B. Are late preterm infants as susceptible to RSV infection as full term infants? Early Hum Dev 2011;87(Suppl. 1):S47e9. 22. Palmer L, Hall CB, Katkin JP, et al. Healthcare costs within a year of respiratory syncytial virus among Medicaid infants. Pediatr Pulmonol 2010;45:772e81. 23. Shi N, Palmer L, Chu BC, et al. Association of RSV lower respiratory tract infection and subsequent healthcare use and costs: a Medicaid claims analysis in early-preterm, late-preterm, and full-term infants. J Med Econ 2011;14:335e40. 24. Law BJ, Langley JM, Allen U, et al. The Pediatric Investigators Collaborative Network on Infections in Canada study of predictors of hospitalization for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation. Pediatr Infect Dis J 2004;23:806e14. 25. Sampalis JS, Langley J, Carbonell-Estrany X, et al. Development and validation of a risk scoring tool to predict respiratory syncytial virus hospitalization in premature infants born at 33 through 35 completed weeks of gestation. Med Decision Making 2008;28:471e80. 26. Paes B, Steele S, Janes M, Pinelli J. Risk-Scoring Tool for respiratory syncytial virus prophylaxis in premature infants born at 33e35 completed weeks gestational age in Canada. Curr Med Res Opin 2009;25:1585e91. 27. Lanctot KL, Masoud ST, Paes BA, et al. The cost-effectiveness of palivizumab for respiratory syncytial virus prophylaxis in premature infants with a gestational age of 32e35 weeks: a Canadian-based analysis. Curr Med Res Opin 2008;24:3223e37. 28. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830e8. 29. Vogt H, Lindstrom K, Braback L, Hjern A. Preterm birth and inhaled corticosteroid use in 6- to 19-year-olds: a Swedish national cohort study. Pediatrics 2011;127:1052e9. 30. Abe K, Shapiro-Mendoza CK, Hall LR, Satten GA. Late preterm birth and risk of developing asthma. J Pediatr 2010;157:74e8. 31. DeMauro SB, Patel PR, Medoff-Cooper B, Posencheg M, Abbasi S. Postdischarge feeding patterns in early- and late-preterm infants. Clin Pediatr 2011;50:957e62. 32. Dodrill P, McMahon S, Ward E, Weir K, Donovan T, Riddle B. Long-term oral sensitivity and feeding skills of low-risk pre-term infants. Early Hum Dev 2004;76:23e37. 33. Santos IS, Matijasevich A, Domingues MR, Barros AJ, Victora CG, Barros FC. Late preterm birth is a risk factor for growth faltering in early childhood: a cohort study. BMC Pediatr 2009;9:71. 34. Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262e73. 35. Ketharanathan N, Lee W, de Mol AC. Health-related quality of life, emotional and behavioral problems in mild to moderate prematures at (pre-)school age. Early Hum Dev 2011;87:705e9. 36. Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA 2000;284:843e9. 37. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol 2008;111:35e41. 38. Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR. Differences in mortality between late-preterm and term singleton infants in the United States, 1995e2002. J Pediatr 2007;151:450e6. 56 e1. 39. Young PC, Glasgow TS, Li X, Guest-Warnick G, Stoddard G. Mortality of latepreterm (near-term) newborns in Utah. Pediatrics 2007;119:e659e65. 40. Crump C, Sundquist K, Sundquist J, Winkleby MA. Gestational age at birth and mortality in young adulthood. JAMA 2011;306:1233e40. 41. Chyi LJ, Lee HC, Hintz SR, Gould JB, Sutcliffe TL. School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr 2008;153:25e31. 42. Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009;154:169e76. 43. Talge NM, Holzman C, Wang J, Lucia V, Gardiner J, Breslau N. Late-preterm birth and its association with cognitive and socioemotional outcomes at 6 years of age. Pediatrics 2010;126:1124e31.
Conict of interest statement None declared. Funding sources None. References

1. Hack M. Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med 2006;11:127e37. 2. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993e1994. Pediatrics 2000;105:1216e26. 3. Wood NS, Costeloe K, Gibson AT, Hennessy EM, Marlow N, Wilkinson AR. The EPICure study: growth and associated problems in children born at 25 weeks of gestational age or less. Arch Dis Child Fetal Neonatal Ed 2003;88:F492e500. 4. Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med 2000;343:378e84. 5. Escobar GJ, Clark RH, Greene JD. Short-term outcomes of infants born at 35 and 36 weeks gestation: we need to ask more questions. Semin Perinatol 2006;30:28e33. 6. Khashu M, Narayanan M, Bhargava S, Osiovich H. Perinatal outcomes associated with preterm birth at 33 to 36 weeks gestation: a population-based cohort study. Pediatrics 2009;123:109e13. 7. Kitsommart R, Janes M, Mahajan V, et al. Outcomes of late-preterm infants: a retrospective, single-center, Canadian study. Clin Pediatr 2009;48:844e50. 8. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114:372e6. 9. Boyle EM, Poulsen G, Field DJ, et al. Population-based cohort study of the effects of gestational age at birth on health outcomes at three and ve years. BMJ 2012;344:e896. 10. Escobar GJ, Greene JD, Hulac P, et al. Rehospitalisation after birth hospitalisation: patterns among infants of all gestations. Archs Dis Childh 2005;90:125e31. 11. Oddie SJ, Hammal D, Richmond S, Parker L. Early discharge and readmission to hospital in the rst month of life in the Northern Region of the UK during 1998: a case cohort study. Archs Dis Childh 2005;90:119e24. 12. Jain S, Cheng J. Emergency department visits and rehospitalizations in late preterm infants. Clin Perinatol 2006;33:935e45. abstract xi. 13. Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Bareld W, Weiss J, Evans S. Risk factors for neonatal morbidity and mortality among healthy, late preterm newborns. Semin Perinatol 2006;30:54e60. 14. Tomashek KM, Shapiro-Mendoza CK, Weiss J, et al. Early discharge among late preterm and term newborns and risk of neonatal morbidity. Semin Perinatol 2006;30:61e8. 15. Radtke JV. The paradox of breastfeeding-associated morbidity among late preterm infants. J Obstet Gynecol Neonatal Nurs 2011;40:9e24. 16. McLaurin KK, Hall CB, Jackson EA, Owens OV, Mahadevia PJ. Persistence of morbidity and cost differences between late-preterm and term infants during the rst year of life. Pediatrics 2009;123:653e9. 17. Hibbard JU, Wilkins I, Sun L, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419e25. 18. Dudell GG, Jain L. Hypoxic respiratory failure in the late preterm infant. Clin Perinatol 2006;33:803e30. abstract viiieix. 19. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks gestational age. Pediatrics 2010;126:115e28. 20. Kotecha SJ, Watkins WJ, Paranjothy S, Dunstan FD, Henderson AJ, Kotecha S. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax 2012;67:54e61.

School outcome, cognitive functioning, and behaviour problems in moderate and late preterm children and adults: A review
Marjanneke de Jong*, Marjolein Verhoeven, Anneloes L. van Baar
Department of Child and Adolescent Studies, Utrecht University, The Netherlands
s u m m a r y
Keywords: Behaviour problems Cognitive functioning Late preterm Moderate preterm Psychiatric disorders School problems
A large number of children (6 to 11% of all births) are born at a gestational age between 32 and 36 weeks. Little is known of long term outcomes for these moderate and late preterm children. In this review, results of 28 studies on school outcome, cognitive functioning, behaviour problems, and psychiatric disorders are presented. Overall, more school problems, less advanced cognitive functioning, more behaviour problems, and higher prevalence of psychiatric disorders were found in moderate and late preterm born infants, children, and adults compared with full term peers. Suggestions for future research are discussed. 2012 Elsevier Ltd. All rights reserved.
1. Introduction Many infants are born too soon and therefore are at risk for developmental problems. In 2007, 10.7% of all children in the USA (6.1% in The Netherlands1) were born at a gestational age between 32 and 36 weeks, i.e. moderate (32e33 weeks) and late (34e36 weeks) preterm.2 This entails 84% of all preterm births. During the last two decades, the number of preterm births increased by almost 25%, with a 4% increase in very preterm births (i.e. below 32 weeks gestation) versus a 30% increase in moderate and late preterm births.2 Hence, the number of children in this group especially has increased over the last 20 years. Although mortality rates are much lower (7.5 times) in these children than in very preterm children, these rates are almost 10 times higher than in full term children.3 With respect to neonatal complications, moderate and late preterm infants experience fewer illnesses than very preterm infants, but they are at elevated risk for breathing and feeding difculties, hypoglycaemia, and hyperbilirubinaemia compared with full term infants.4 Another risk factor results from the fact that the brain of moderate and late preterm children is still immature; at 34 weeks of gestation, the brain weighs only 65% of the weight at 40 weeks of gestation.5 Despite the high prevalence and increased medical risk of moderate and late preterm birth, little is known of long-term developmental outcomes of these children. In this review the available information on school outcome, cognitive functioning, behaviour problems, and psychiatric
disorders of infants, children, and adults born moderate or late preterm is presented. 2. Method 2.1. Search strategy and study selection The Scopus database was searched until 23 June 2011, using the terms: late preterm, moderately preterm, and moderate preterm. In addition, reference lists of selected articles were examined to nd additional studies. Studies were included if: (i) these were published after 1 January 2000; (ii) gestational age of participants was between 32 and 366 weeks; and (iii) these investigated school outcome, cognitive functioning, behaviour problems or psychiatric disorders. 3. Results 3.1. Included studies The three search terms resulted in 485 hits. Based on title and abstract, 449 studies were excluded. Thirty-six articles were read full text and 16 of these were excluded because outcome measures were beyond the scope of this review (n 11) or because the studies did not concern empirical data collection and analyses (n 5). In four of the included studies, gestational age of the participants differed slightly from our inclusion criterion (i.e. selected 31 and/or 37 weeks of gestation).6e9 Nevertheless, we decided to include these studies as most participants fell in our dened range of gestational age. An additional eight papers were
* Corresponding author. Address: P.O. Box 80.140, 3508 TC Utrecht, The Netherlands. Tel.: 31 30 2534601. E-mail address: M.deJong1@uu.nl (M. de Jong). 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.003
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M. de Jong et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 163e169
included, based on the reference lists of the selected articles. Finally a total number of 28 papers were included in this review. 3.2. Characteristics of included studies Characteristics and results of the included studies are presented in Table 1. Regarding the participants, 17 studies focused on moderate and late preterm children (32e36 weeks of gestational age),6e8,10e23 10 focused on late preterm children (34e36 weeks of gestational age),9,24e32 and one focused on children born between 32e34 weeks of gestational age.33 Twenty-three studies investigated outcomes in infancy or childhood (0e15 years of age),8e11,13,15e17,19e33 four studies reported outcomes in (young) adulthood (18e36 years of age),7,12,14,18 and one reported on outcomes in both childhood and adulthood.6 School outcome was investigated in seven studies,6,11,16,17,23,27,29 cognitive functioning in 19,6,7,9,12e15,20e26,29e33 behaviour problems in six,8,13,16,23,25,29 and psychiatric disorders in seven.7,10,12,18,19,21,28 3.3. School outcome All seven studies found an increased risk for school problems for moderate and late preterm children compared with full term children. Compared with full term children, they were at 1.3e2.8fold increased risk for attending special education11,16,23,29 and had repeated grades between 1.3 and 2.2 times more often at 5e10 years of age.23,27 Three studies focused on specic school abilities in 5e10-year-olds and found lower scores for moderate/late preterm children on reading, spelling, and arithmetic compared with full term children.6,11,16 A higher risk for reading and spelling difculties was also found in the preterm children at age 9e11 years.17 With regard to educational attainment in adults, it was found that individuals born moderate or late preterm had more learningrelated disabilities at age 7 years, which was related to lower educational attainment in adulthood.6 3.4. Cognitive functioning Five studies investigated cognitive functioning in infancy (0e24 months of age).9,13,15,20,24 One of these found lower developmental scores for preterm children compared with full term children at 24 months of age (not corrected for prematurity).24 In a longitudinal study by Romeo et al.,20 a delay in cognitive functioning was found for children born at 33e36 weeks compared with full term children at 12 and 18 months of age. These group differences were no longer signicant when age was corrected for prematurity. Two other studies that corrected age for prematurity also found no differences in scores between moderate/late preterm and full term children at 12 and 24 months of age.9,13 Hillemeier et al.15 performed a longitudinal study in which cognitive functioning was investigated at 9 and 24 months of age (corrected for prematurity). They found a two-fold higher risk for scoring in the lowest 10% in moderate/late preterm children compared with full term children at 9 months of age, but this difference was no longer seen at 24 months of age. Different results emerge from 11 studies concerning cognitive functioning in moderate/late preterm children at 3e15 years of age.6,21e23,25,26,29e33 Two studies on large samples of more than 100,000 and 300,000 children found an increased risk of 1.3e1.9 for mental retardation (i.e. IQ scores <70) in moderate/late preterm children compared with full term children.21,26 In line with this, the preterm children were twice as likely to score <85 on an IQ test than their full term peers at age 5, 6 and 10 years.22,25,33 In two of these studies (at ages 5 and 6 years), no differences were found between mean scores of moderate/late preterm and full term children,25,33 which suggests a different distribution in scores with
more moderate/late preterm children showing developmental delay than in the population. Six studies did nd differences in mean IQ scores between moderate/late preterm and full term children aged 3e10 years, with preterm children scoring below their full term peers.6,22,23,30e32 Medical risk of the children regarding their need for neonatal intensive care unit treatment seemed to differ between these six studies. Three of these studies only investigated moderate/late preterm children with a high medical risk,22,31,32 one included only low risk children,23 and another study did not report any neonatal characteristics regarding high or low risk.6 Baron et al.30 showed that medical risk might be important, as they found lower scores for late preterm children only in those children that were at high risk, but not for low risk children. Gurka et al.29 also found no differences in mean IQ scores between low risk late preterm and full term children in their longitudinal study following children from 4 to 15 years of age. Results regarding cognitive functioning in adulthood are somewhat inconsistent.7,12,14 An increased risk for mental retardation was found in adults born moderate/late preterm compared with adults born at full term in a large epidemiological study.7 Ekeus et al.14 also found slightly lower scores on a general intellectual performance test used for the military service in 18e19year-old preterm born men, compared with full term. By contrast, Dalziel et al.12 found no differences between moderate/late preterm and full term born adults at 30 years of age regarding their scores on the Wechsler Abbreviated Scale of Intelligence. 3.5. Behaviour 3.5.1. Behaviour problems as reported by parents and teachers Six studies examined the prevalence of behaviour problems in moderate/late preterm children as reported by parents and teachers.8,13,16,23,25,29 A longitudinal study showed that at ages 3, 5 and 8 years, w20% of the preterm children scored in the clinical range of the Child Behavior Check List total problem scale as reported by their parents; twice as much as the expected 10%.8 Likewise, Darlow et al.13 found that parents reported slightly more behaviour problems in 2-year-old preterm compared with full term children, as indicated by the presence of two or more out of ve problem behaviours (i.e. poor positive affect, frequent negative affect, poor attention, highly active, low self-condence). Teachers of 6-year-old children reported more internalizing behaviour and attention problems, and slightly more externalizing behaviour in late preterm children compared with full term children.25 Similarly, in the study by Van Baar et al.,23 both mothers and teachers reported more internalizing behaviour and attention problems in moderate/ late preterm children compared with full term children at 8 year of age. Next to that, mothers reported more symptoms of hyperactivity in moderate/late preterm children than in full term children. At 7 years of age, Huddy et al.16 also found that parents and teachers rated moderate/late preterm children more often as being hyperactive, but did not report higher levels of emotional symptoms, conduct problems, peer problems, or prosocial behaviour for these children. A longitudinal study investigating children between 4 and 15 years of age found no differences in parent-reported externalizing, internalizing, aggressive, and anxiety/depressive behaviour between a small group of late preterm (n 53) and a large group of full term children (n 1254).29 3.5.2. Prevalence of psychiatric disorders Seven studies reported on the prevalence of psychiatric disorders.7,10,12,18,19,21,28 Lindstrm et al.18 found a 30% higher risk for psychiatric disorders in moderate/late preterm adults compared with full term adults, especially in the domain of organic/neuropsychiatric disorders. Moster et al.7 found a 30e40% higher risk for
Table 1 Characteristics and results of included studies. Authors Gestational age range (weeks) preterm MPT/LPT: 33e37 Subject characteristics No. of subjects School outcomes Cognitive functioning [mean (SD)/(range) or condence interval] MPT/LPT < FT; 89 (11.8) vs 94 (11.6). Behaviour problems and/or psychiatric disorders
Nomura et al.6
7e8 and 27e33 years old; born in 1960e1964
MPT/LPT: 226 FT: 1393
Reading: MPT/LPT < FT. Spelling: MPT/LPT < FT. Arithmetic: MPT/LPT < FT (age 7e8 years). This is associated with lower educational attainment in adulthood.
Moster et al.7
MPT/LPT: 31e36 MPT: 31e33 LPT: 34e36
20e36 years old; born in 1967e1983
MPT: 6363 LPT: 31 169 FT: 828 227
Mental retardation: MPT: OR 2.1 LPT: OR 1.6.
Gray et al.8
Cheatham et al.9 Buchmayer et al. Chyi et al.

11 10
MPT/LPT: 31e37 MPT: 31e34 LPT: 35e37 LPT: 35e37 MPT/LPT: 32e36 MPT/LPT: 32e36 MPT: 32e33 LPT: 34e36
3, 5 and 8 years old; born in 1985 12 months; year of birth unknown 0e10 years old; born in 1987e2002 5e10 years old; born in w1993e1994
MPT: 435 LPT: 262 LPT: 29 FT: 20 MPT/LPT: 420 FT: 6207 MPT: 203 LPT: 767 FT: 13 671 LPT FT: 97 (81e111) and 95 (77e112) respectively.
Schizophrenia: MPT: OR 1.4 LPT: OR 1.3. Disorders of psychological development, behaviour, and emotion: MPT: OR 1.4 LPT: OR 1.5. Autism: NS. w20% of MPT/LPT had clinical scores on CBCL.
Autism: OR 1.55 Poor school outcomes: MPT: OR 1.0e2.0 LPT: OR 1.0e1.3. Need for help: MPT: OR 1.9e2.8 LPT: OR 1.1e1.4. Special education: MPT: OR 2.0e2.9 LPT: OR 1.2e2.1. MPT/LPT FT: 103 (13.4) and 104 (12.2) respectively. MPT/LPT FT for depression, anxiety, schizophrenia and attention decit disorder. Showing two or more out of ve problematic behaviours: MPT/LPT (26%) > FT (20%).
Dalziel et al.12
MPT/LPT: 32e35
30 years old; born in 1969e1974
MPT/LPT: 126 FT: 66
Darlow et al.13
MPT/LPT: 33e36
2 years old; born in 2001e2002; NICU admittance for MPT/LPT group
MPT/LPT: 112 FT: 94
MPT/LPT FT: 90 (14.2) and 92 (11.0) respectively.
Ekeus et al.14
Hillemeier et al.15
MPT/LPT: 33e36 MPT: 33e34 LPT: 35e36 MPT/LPT: 33e36
18e19 years old; born in 1973e1976; males conscripted for military service 9 and 24 months; born in 2001
MPT: 1088 LPT: 3981 FT: 94 821 MPT/LPT: 1224 (592 singletons, 632 multiple births) FT: 7173 (6570 singletons, 603 multiple births)
MPT (4.8) and LPT (4.9) < FT (5.1).
Scoring in lowest 10%: 9 months OR 2.4 (singletons), 3.6 (multiple births); 24 months OR 0.9 (singletons), 1.3 (multiple births), NS. (continued on next page) 165
Table 1 (continued ) Authors Gestational age range (weeks) preterm MPT/LPT: 32e35 Subject characteristics No. of subjects School outcomes Cognitive functioning [mean (SD)/(range) or condence interval] Behaviour problems and/or psychiatric disorders Abnormal hyperactivity scores: MPT/LPT (parents: 18%, teachers: 18.8%) > population norm (10%)
166
Huddy et al.16
7 years old; born in 1990
MPT/LPT: 117
Kirkegaard et al.17
MPT/LPT: 33e36
MPT/LPT: 169 FT: 3081
Lindstrm et al.18
School problems: MPT/LPT (w30%) > population (10e20%). Special education: MPT/LPT (4%) > population (1.7%). Need help at school: w25% of MPT/LPT. Spelling difculties: OR 1.6. Reading difculties: OR 1.2.
MPT/LPT: 33e36
MPT/LPT: 2037 FT: 450 165
Lindstrm et al.19
Romeo et al.20
MPT/LPT: 33e36 MPT: 33e34 LPT: 35e36 MPT/LPT: 33e36
6e19 years old; born in 1987e2000 12 and 18 months old; born in 2005e2006; low risk group (e.g. no serious illness)
MPT/LPT: 56 650 FT: 813 606 MPT/LPT: 61 FT: 60 MPT/LPT < FT [at 12 months 92 (9.3) vs 100 (8.7) and at 18 months 88 (9.9) vs 98 (8.1)], only when age was not corrected for prematurity. Mental retardation: OR 1.9. MPT/LPT < FT; 101 (12.9) vs 109 (14.4). MPT/LPT < FT; 105 (14) vs 108 (15).
Psychiatric disorders: OR 1.3 Neuropsychiatric disorders (e.g. ADHD): OR 2.1 ADHD: MPT: OR 1.4 LPT: OR 1.3
Schendel and Bhasin21 Schermann and Sedin Van Baar et al.23

22
MPT/LPT: 33e36 MPT/LPT: 32e36 MPT/LPT: 32e36 MPT: 32e33 LPT: 34e36
3e10 years old; born in 1981e1993 10 years old; born in 1986e1989; NICU admittance for preterm group 8 years old; born in 1996e1998; low risk group (e.g. no NICU admittance)
MPT/LPT: 26 319 FT: 241 888 MPT/LPT: 82 FT: 72 MPT/LPT: 377 MPT: 62 LPT: 315 FT: 182
Autism: MPT/LPT FT
Special education: MPT/LPT (7.7%) > FT (2.8%) MPT (9.7%) LPT (7.3%). Grade retention: MPT/LPT (19%) > FT (8.8%) MPT (30%) > LPT (17%).
Woythaler et al.24
Internalizing problems: MPT/LPT > FT. Externalizing problems: MPT/LPT FT. Attention problems: MPT/LPT > FT. Behaviour problems: MPT < LPT.
LPT: 34e36
24 months old; born in 2001
LPT: 1200 FT: 6300 LPT: 168 FT: 168
Talge et al.25
LPT: 34e36
6 years old; born in 1983e1985
LPT < FT, 126 (10.3) vs 128 (10.4). Percentage <70: LPT (21.2%) > FT (16.4%). LPT FT; 101 (SE 1.3) and 102 (SE 1.3) respectively.
Petrini et al.26 Morse et al.

27
Internalizing problems: LPT > FT. Externalizing problems: LPT > FT (slightly). Attention problems: LPT > FT.
LPT: 34e36 LPT: 34e36
0e5.5 years old; born in 2000e2004 0e5 years old; born in 1996e1997; low risk group (<3 days hospitalization)
LPT: 8341 FT: 128 955 LPT: 7152 FT: 152 661
Developmental delay/mental retardation compared: OR 1.4. School-related problems (e.g. grade retention, special learning needs): OR 1.1e1.3.
M. de Jong et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 163e169 MPT, moderate preterm; LPT, late preterm; FT, full term; OR, odds ratio; NS, non-signicant; CBCL, Child Behavior Check List; ADHD, attention decit/hyperactivity disorder; NICU, neonatal intensive care unit; HKD, hyperkinetic disorder.
167
Complicated LPT (103e109) < FT (109e115). Uncomplicated LPT (104e115) FT.
LPT < FT: 105 (15.9) vs 112 (12.9).
LPT < FT: 106 (15.0) vs 116 (10.3).
Scores < 85: MPT (w24%) > population (15%).
LPT FT
schizophrenia and 40e50% higher risk for psychiatric disorders in moderate/late preterm adults compared with full term adults, including developmental, behavioural, and emotional disorders. Three studies reported the prevalence of autism in large samples.7,10,21 Buchmayer et al.10 found a 50% increased risk for autism in moderate and late preterm children compared with full term children, whereas the other two studies found no differences in prevalence of autism.7,21 Two studies examining the prevalence of attention decit/hyperactivity disorder (ADHD) or hyperkinetic disorder (HKD) in large samples both reported a higher risk (30e80%) for these disorders in moderate/late preterm children.19,28 On the other hand, Dalziel et al.12 found no negative effect of moderate/late preterm birth on the presence of attention decit disorder, as well as depression, anxiety, and schizophrenia in adulthood. It should, however, be noted that the sample used in this study was relatively small (126 preterm and 66 full term adults) compared with the above-mentioned studies, which were all epidemiological7,18,19 or nested caseecontrol10,21,28 designs. 4. Discussion The aim of this review has been to gain more insight into long term developmental outcomes of moderate and late preterm children, specically in school outcome, cognitive functioning, behaviour problems, and psychiatric disorders. Based upon the 28 studies included in this review, we conclude that moderate/late preterm children show more school problems, have lower IQ scores, and more behaviour problems than their full term peers. For psychiatric disorders it is concluded that especially ADHD is more frequently reported for these preterm children; concerning autism, inconsistent ndings have been reported. The rst explanation for the developmental problems of moderate/late preterm children lies in their immature (brain) development at birth. At 34 weeks of gestation, the brain weighs only 65% of the weight at 40 weeks of gestation,5 so a lot of the hardware brain tissue still has to grow during this period. In addition, other organs of the preterm infant, such as the lungs and the heart, have to adapt to extrauterine life at an earlier stage of development, which may stress brain development. Correction for prematurity is important, as it provides at least the same amount of time for moderate or late preterm children to develop as could be used by full term children. This correction for prematurity explained the differences in results of several studies done in infancy from 0 to 2 years of age.9,13,15,20,24 Lower scores on developmental tests were found for moderate/late preterm children compared with full term children only when age was not corrected for prematurity. However, when age was corrected and both groups of children could be considered equally mature, differences in developmental tests were no longer visible. The contrasting nding of Hillemeier et al.,15 that at 9 months of age moderate/late preterm children performed worse than full term children even after age correction for prematurity whereas no group differences appeared at 24 months, may be very important. It might be that differences between the preterm and full term born children are larger at younger ages (<12 months). This suggests a different developmental pattern for young moderate or late preterm infants. Further research is needed on such developmental trajectories of these infants over the rst years. Moderate and late preterm children were found to be at risk for school problems and low scores on IQ tests. This might result from the regulation difculties, or more specically from attention difculties involved in ADHD symptoms.23 In very preterm children, attention difculties were repeatedly found,34,35 and differences in attention capacities were suggested as a mechanism partially explaining cognitive and school problems.36 In this review
HKD: OR 1.8
LPT: 37 cases, 544 controls. FT: 456 cases, 12 365 controls LPT: 53 FT: 1254 LPT: 118 (90 complicated; 28 uncomplicated) FT: 100 LPT: 60 FT: 35 All children born in 1980e1994 diagnosed with HKD and control children 4.5e15 years old; born in 1991; low risk group (e.g. no serious illness) 3 years old; born in 2004e2006; both complicated and uncomplicated groups
Special education: OR 1.3
LPT FT on CBCL
Baron et al.31
Marret et al.33
Linnet et al.28
Gurka et al.29
30
Baron et al.32
Baron et al.
MPT: 32e34
LPT: 34e36
LPT: 34e36
LPT: 35e36
LPT: 34e36
LPT: 34e36
3 years old; born in 2004e2005; complicated group (e.g. NICU admittance) 3 years old; born in 2004e2006; complicated group 5 years old; born in 1997
LPT: 75 FT: 40 MPT: 788
168
it was found that ADHD symptoms and attention problems are more common in moderate/late preterm children.19,23,28 The rst years of life are very important in the development of attention capacities.37 Neurological maturation is one of the factors inuencing the development of attention capacities. Important brain development takes place between 32 and 37 weeks gestation and preterm children cannot benet from the neurobiological processes (e.g. related to maternal thyroid hormone exchange) during this period in the womb. Attention capacities of moderate and late preterm children should be studied in detail and compared with the development of processes in attention of full term children. Not all moderate/late preterm children actually show developmental problems. The nding that a higher percentage of these children had an IQ score <85 compared with full term children, although mean scores on a standardized intelligence test did not differ between the preterm and full term children,25,33 indicates differences within the moderate/late preterm group. Even within the moderate/late preterm group, gestational age may be important. In only two studies included in the review were differences between moderate and late preterm born children discussed or analysed.11,23 Chyi et al.11 found that the moderate preterm children showed more difculties than the late preterm children. Van Baar et al.23 found that moderate preterm children more frequently repeated a grade, but also found that late preterm children showed more behaviour problems than moderate preterm children. Hence, further study in relation to a further differentiation of gestational age, as well as in relation to different developmental outcomes, is necessary. Another factor of inuence might be differences in neonatal complications that may have occurred. Some of the preterm children needed neonatal intensive care treatment and are considered to be at high medical risk. Looking at the studies that investigated specic samples of high or low medical risk children, it seems that high risk moderate/late preterm children in particular score lower on standardized intelligence tests than full term children.22,23,29e32 In general not much attention has been paid to the importance of specic neonatal complications and the medical treatments in relation to developmental outcome of moderate or late preterm children. Future research could focus on the association between medical treatments (e.g. for hypoglycaemia or infections), caretaking habits during the hospital stay [e.g. caregiving or kangarooing by parents, Newborn Individualized Developmental Care and Assessment Program (NIDCAP) or individualised caretaking], or hospital discharge routines and developmental outcome. Another factor in explaining differences within the preterm group might be parentechild interaction and the quality of caregiver stimulation. Regarding very preterm infants, it was found that individual differences in cognitive development at infant and toddler age could be explained by maternal behaviours such as the amount of stimulation provided.38 Further research is needed on the inuence of parentechild interaction on the development of moderate and late preterm children. Only a few studies investigated cognitive functioning in adults born moderate or late preterm, and comparison between these is hampered by their differences in selection criteria. As these studies showed inconsistent results, more research is needed before any conclusions on outcome in adulthood can be drawn. A general problem with studies on adults born preterm is that they were treated a long time ago (in these studies from 1967 to 1983). Information on the quality of their functioning may not be appropriate any more for infants treated with the current medical techniques and nursing methods. Nevertheless such information may provide some insight into developmental trajectories and the severity of problems in developmental outcome. A strength of this review is that it presents an overview of long term outcome of moderate and late preterm birth across the life
span on the domains of school, cognitive, and behavioral functioning. Furthermore, the focus was not solely on late preterm (34e36 weeks) infants but also included studies investigating children born after 32e33 weeks of gestation. A limitation may be that the focus was on recent ndings, as only studies published after 2000 were included. Second, the studies included varied in design and sample size (varying from 29 to 56 650 moderate preterm children). Finally, year of birth of the samples varied strongly across the studies from 1960 to 2006. Because quality of neonatal care has increased a great deal during the last several decades, year of birth might inuence the outcome for moderate and late preterm children. However, this review shows no clear association between developmental outcome and year of birth. A clinical implication of the information from this review is that careful follow-up monitoring of moderate and late preterm children is required to provide early intervention when needed and to try to reduce the amount of school and behavior problems. Selective intervention, perhaps based on early indications of insufcient attention capacities, might be worthwhile. In conclusion, moderate and late preterm children are at risk for school problems, lower cognitive functioning, behaviour problems, and psychiatric disorders. Future research should focus on developmental trajectories over the rst years. Also the associations between medical treatments, caretaking practice during the hospital stay in the neonatal period, hospital discharge routines and developmental outcome need to be studied in greater detail. Research should focus on attention capacities of moderate and late preterm children, as well as on differences within the group and factors explaining these differences. Intervention programmes based on improvement of attention skills could be worthwhile. Finally, consequences of moderate and late preterm birth in adulthood might be the subject of study. In short: moderate and late preterm children need attention!
Practice points Follow-up of moderate and late preterm children is indicated. Design of intervention programmes based on early indications of insufcient attention capacities.
Research directions Developmental trajectories after hospital discharge over the rst years in moderate and late preterm children. Medical treatment, caretaking practice during the hospital stay and discharge routines in relation to developmental outcome. Development of attention capacities of moderate and late preterm children. Differences within the moderate and late preterm group and factors explaining these differences. Consequences of moderate and late preterm birth in adulthood. Conict of interest statement None declared. Funding sources None.
169
References
1. Stichting Perinatale Registratie Nederland. Perinatale Zorg in Nederland 2007. Utrecht, Netherlands: Stichting Perinatale Registratie Nederland; 2009. 2. Martin JA, Hamilton BE, Sutton PD, et al. Births: nal data for 2007. Natl Vital Stat Rep 2010;58:1e85. 3. Mathews TJ, MacDorman MF. Infant mortality statistics from the 2005 period linked birth/infant death data set. Natl Vital Stat Rep 2008;57:1e32. 4. Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, et al. Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 2008;121:e223e32. 5. Kinney HC. The near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. Semin Perinatol 2006;30:81e8. 6. Nomura Y, Halperin JM, Newcorn JH, et al. The risk for impaired learningrelated abilities in childhood and educational attainment among adults born near-term. J Pediatr Psychol 2009;34:406e18. 7. Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262e73. 8. Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically signicant behavior problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics 2004;114:736e43. 9. Cheatham CL, Bauer PJ, Georgieff MK. Predicting individual differences in recall by infants born preterm and full term. Infancy 2006;10:17e42. 10. Buchmayer S, Johansson S, Johansson A, Hultman CM, Sparn P, Cnattingius S. Can association between preterm birth and autism be explained by maternal or neonatal morbidity? Pediatrics 2009;124:e817e25. 11. Chyi LJ, Lee HC, Hintz SR, Gould JB, Sutcliffe TL. School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr 2008;153:25e31. 12. Dalziel SR, Lim VK, Lambert A, et al. Psychological functioning and healthrelated quality of life in adulthood after preterm birth. Dev Med Child Neurol 2007;49:597e602. 13. Darlow BA, Horwood LJ, Wynn-Williams MB, Mogridge N, Austin NC. Admissions of all gestations to a regional neonatal unit versus controls: 2-year outcome. J Paediatr Child Health 2009;45:187e93. 14. Ekeus C, Lindstrm K, Lindblad F, Rasmussen F, Hjern A. Preterm birth, social disadvantage, and cognitive competence in Swedish 18- to 19-year-old men. Pediatrics 2010;125:e67e73. 15. Hillemeier MM, Farkas G, Morgan PL, Martin MA, MacZuga SA. Disparities in the prevalence of cognitive delay: how early do they appear? Paediatr Perinat Epidemiol 2009;23:186e98. 16. Huddy CLJ, Johnson A, Hope PL. Educational and behavioural problems in babies of 32e35 weeks gestation. Arch Dis Child 2001;85. F23e8. 17. Kirkegaard I, Obel C, Hedegaard M, Henriksen TB. Gestational age and birth weight in relation to school performance of 10-year-old children: a follow-up study of children born after 32 completed weeks. Pediatrics 2006;118:1600e6. 18. Lindstrm K, Lindblad F, Hjern A. Psychiatric morbidity in adolescents and young adults born preterm: a Swedish national cohort study. Pediatrics 2009;123:e47e53. 19. Lindstrm K, Lindblad F, Hjern A. Preterm birth and attention-decit/ hyperactivity disorder in schoolchildren. Pediatrics 2011;127:858e65.
20. Romeo DM, Di Stefano A, Conversano M, et al. Neurodevelopmental outcome at 12 and 18 months in late preterm infants. Eur J Paediatr Neurol 2010;14:503e7. 21. Schendel D, Bhasin TK. Birth weight and gestational age characteristics of children with autism, including a comparison with other developmental disabilities. Pediatrics 2008;121:1155e64. 22. Schermann L, Sedin G. Cognitive function at 10 years of age in children who have required neonatal intensive care. Acta Paediatr 2004;93:1619e29. 23. van Baar AL, Vermaas J, Knots E, de Kleine MJK, Soons P. Functioning at school age of moderately preterm children born at 32 to 36 weeks gestational age. Pediatrics 2009;124:251e7. 24. Woythaler MA, McCormick MC, Smith VC. Late preterm infants have worse 24-month neurodevelopmental outcomes than term infants. Pediatrics 2011;127:e622e9. 25. Talge NM, Holzman C, Wang J, Lucia V, Gardiner J, Breslau N. Late-preterm birth and its association with cognitive and socioemotional outcomes at 6 years of age. Pediatrics 2010;126:1124e31. 26. Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009;154:169e176.e3. 27. Morse SB, Zheng H, Tang Y, Roth J. Early school-age outcomes of late preterm infants. Pediatrics 2009;123:e622e9. 28. Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH, Henriksen TB. Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child 2006;91:655e60. 29. Gurka MJ, Locasale-Crouch J, Blackman JA. Long-term cognition, achievement, socioemotional, and behavioral development of healthy late-preterm infants. Arch Pediatr Adolesc Med 2010;164:525e32. 30. Baron IS, Erickson K, Ahronovich MD, Baker R, Litman FR. Cognitive decit in preschoolers born late-preterm. Early Hum Dev 2011;87:115e9. 31. Baron IS, Erickson K, Ahronovich MD, Coulehan K, Baker R, Litman FR. Visuospatial and verbal uency relative decits in complicated late-preterm preschool children. Early Hum Dev 2009;85:751e4. 32. Baron IS, Erickson K, Ahronovich MD, Litman FR, Brandt J. Spatial location memory discriminates children born at extremely low birth weight and late-preterm at age three. Neuropsychology 2010;24:787e94. 33. Marret S, Ancel P, Marpeau L, et al. Neonatal and 5-year outcomes after birth at 30e34 weeks of gestation. Obstet Gynecol 2007;110:72e80. 34. Rose SA, Feldman JF, Jankowski JJ. Attention and recognition memory in the 1st year of life: a longitudinal study of preterm and full-term infants. Dev Psychol 2001;37:135e51. 35. Landry SH. The development of joint attention in premature low birth weight infants: effects of early medical complications and maternal attention-directing behaviors. In: Moore C, Dunham P, editors. Joint attention: its origins and role in development. Hillsdale, NJ: Lawrence Erlbaum; 1995. p. 223e50. 36. van de Weijer-Bergsma E, Wijnroks L, Jongmans MJ. Attention development in infants and preschool children born preterm: a review. Infant Behav Dev 2008;31:333e51. 37. Ruff HA, Rothbart MK. Attention in early development. New York: Oxford University Press; 1996. 38. Landry SH, Smith KE, Miller-Loncar CL, Swank PR. Predicting cognitivelanguage and social growth curves from early maternal behaviors in children at varying degrees of biological risk. Dev Psychol 1997;33:1040e53.

Economic costs associated with moderate and late preterm birth: Primary and secondary evidence
Stavros Petrou*, Kamran Khan
Warwick Clinical Trials Unit, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
s u m m a r y
Keywords: Cost Economic Moderate Preterm birth Review
Despite constituting the vast majority of preterm births, relatively little is known about the clinical and economic outcomes of children born either moderately or late preterm. This paper outlines the economic consequences of moderate and late preterm birth for the health services, for other sectors of the economy, for families and carers and, more broadly, for society. The paper reviews both the peerreviewed literature and additional sources for information on the economic consequences of moderate and late preterm birth. It then goes on to present the results of a decision-analytic modelling study that aimed to estimate the societal costs associated with moderate and late preterm birth throughout the childhood years. Finally, the requirements for future methodological and applied research in this area are briey outlined. 2012 Elsevier Ltd. All rights reserved.
1. Introduction Preterm births are generally considered to occur before 37 weeks of completed gestation.1 Despite advancing knowledge about the causes of preterm birth and the introduction of many public health and medical interventions targeted at its prevention, the incidence of preterm birth has continued to increase in many industrialized countries.1 Factors that have been postulated as contributing to its increasing incidence include increasing rates of multiple births, greater use of assisted reproduction, increased obstetric intervention, such as induced labour and caesarean section, and developments in clinical practice, such as the use of ultrasonography to estimate gestational age.1e3 The mortality and morbidity arising from preterm birth imposes an immense burden on nite public sector resources. Babies born preterm are at increased risk of adverse neonatal outcomes, including chronic lung disease,4 intraventricular haemorrhage,5 retinopathy of prematurity,6 necrotizing enterocolitis7 and neonatal sepsis,8 and on average they require more intensive and longer stays of neonatal care. Following this initial period of hospitalization, preterm infants are more likely to be readmitted to hospital and have more frequent contact with community health and social care professionals than infants born at term.9 In the longer term, preterm infants are also at increased risk of impairment, disability and handicap, including motor and sensory impairment,10 learning difculties,11 and social
* Corresponding author. Tel.: 44 2476 151124. E-mail address: s.petrou@warwick.ac.uk (S. Petrou). 1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.001
and behavioural problems.12 The health and neurodevelopmental outcomes of children born extremely preterm (usually dened as <28 weeks gestation) or very preterm (usually dened as <32 weeks gestation) are reasonably well documented; a number of studies report on the early outcomes and follow-up assessments of several extremely and very preterm birth cohorts in countries predominately in North America, Western Europe, and Australasia.7 Despite constituting the vast majority of all preterm births, less is known about those born moderately preterm (between 320 and 336 weeks gestation) or late preterm (between 340 and 366 weeks gestation). Although data on the consequences of moderate and late preterm birth are sparse, those that are available suggest that infants born at between 32 and 36 weeks gestation inclusive may be at substantial risk of adverse growth,13,14 neuropsychological,13,15 educational16 and behavioural16 outcomes. This paper outlines the economic consequences of moderate and late preterm birth for the health services, for other sectors of the economy, for families and carers and, more broadly, for society. It builds on previous research by one of the authors (S.P.)17 with the distinguishing feature that it focuses on moderate and late preterm birth rather than preterm birth as a whole. We review both the peer-reviewed literature and additional sources for information on the economic consequences of moderate and late preterm birth. We then go on to present the results of a decision-analytic modelling study that aimed to estimate the societal costs associated with moderate and late preterm birth. Finally, we outline the requirements for future methodological and applied research in this area.
S. Petrou, K. Khan / Seminars in Fetal & Neonatal Medicine 17 (2012) 170e178
171
2. Methods We conducted a literature search of relevant economic studies through the following databases: MEDLINE, CINAHL, EconLit, Science Citation Index (SCI), Social Science Citation Index, Index to Scientic and Technical Proceedings (ISTP), British Library Inside Information (BLII), EMBASE, Cochrane Library (CDSR), York Database of Abstracts of Reviews of Effectiveness (DARE), National Health Service (NHS) Economic Evaluation Database (NEED) and the Database of Consortium of University Research Libraries (COPAC). Our search strategy was piloted on MEDLINE and our search terms eventually included all minor and major topics covered by MeSH terms for preterm birth, prematurity and low birthweight combined with cost, economic, nancial and burden. We also examined the bibliographies of identied papers for additional studies that estimated the economic costs associated with moderate or late preterm birth. The search strategy covered the period January 1980 to September 2011. Studies were excluded from the literature searches if they had been conducted in nondeveloped countries [dened, for the purposes of this review, as countries outside of the Organisation for Economic Co-operation and Development (OECD)], if the abstract had not been published in the English language or if the focus was animal research. A twostage screening process of studies was followed: rst, a screen of the title and abstract using predetermined criteria; second, a screen of the full report to determine whether the study explicitly described, measured and valued the economic implications of care provided to moderate or late preterm infants. A total of 20 relevant studies were identied by the searches: 10 reported the costs associated with the initial period of hospitalisation; 13 reported costs incurred following the initial hospital discharge, three of which also reported costs associated with the initial period of hospitalisation. Methodological variations between studies prevented a pooling of economic data akin to the meta-analyses performed on the clinical effectiveness literature. Rather, the results of the studies are presented and discussed in a qualitative manner. 3. Results 3.1. Costs associated with the initial hospitalisation A total of 10 studies were identied that reported the economic costs associated with moderate or late preterm birth during the infants initial hospitalisation.18e27 Overviews of the location, sample size and methodology of each of these studies are summarised in Table 1; overviews of the economic results of each of these studies are summarised in Table 2. For live-born infants, mean hospital costs associated with the initial hospitalisation varied between $1,929 for a term infant (US$, 2003 prices)25 and V13,655 for a moderate or late preterm infant (2001 prices).24 For surviving infants, mean hospital costs associated with the initial hospitalisation varied between $1,334 for a term infant and 32,153 for a moderate or late preterm infant (US$, 2008 prices).20 Variation in costs between studies can be explained by a number of factors, including the wide time-frame over which studies were conducted, with some older studies conducted before the widespread use of effective perinatal and neonatal practices; geographical diversity of studies across systems that vary in the way that perinatal and neonatal care is organised and delivered; methodological diversity with some economic studies based on prospective cohorts and others based on retrospective analyses of routine observational datasets; and variations in the underpinning costing methodologies with some studies valuing hospital stays in terms of charges rather than costs generated through rigorous accounting procedures.18,21,27 Nevertheless, regardless of date of study, location of
study or economic methodology, a consistent inverse relationship is observed between gestational age at birth and hospital costs associated with the initial hospitalisation. In studies estimating the economic costs of preterm birth across the gestational age spectrum, mean hospital costs associated with the initial hospitalisation for infants born either moderate or late preterm appear closer to those for infants born at term rather than to infants born either extremely or very preterm; nevertheless, they are consistently at least double those for infants born at term (Table 2). In addition to estimates of economic costs, a number of studies provide information on resource use associated with moderate or late preterm birth, most commonly in the form of the number of days of hospitalisation by level of intensity (Table 2). For live-born infants, the mean duration of initial hospitalisation varied between 1.9 days for a term infant19 and 29.9 days for a moderate preterm infant.24 For surviving infants, the mean duration of initial hospitalisation varied between 1.2 days for a term infant26 and 22.6 days for a moderate preterm infant.23 A relatively small number of studies also report increased lengths of stay for the mother following birth of a moderate or a late preterm infant.19,24 A number of recent studies have used population-based data to estimate the potential economic benets of interventions that are effective at delaying moderate or late premature delivery. An interesting example of this line of enquiry is provided by the study by Phibbs and Schmitt.23 Using cohort data for all births in California in 1998e2000, the authors estimated that the mean (median) economic savings (in terms of neonatal costs prevented) for a 1-week increase in gestational age at birth were US$15,972 (US$12,387) for infants born at 32 gestational weeks and US$4,528 (US$1,116) for infants born at 34 gestational weeks (2003 prices). Similarly, the mean (median) economic savings for a 2-week increase in gestational age at birth were estimated at US$35,583 (US$30,652) for infants born at 32 gestational weeks and US$7,090 (US$1,287) for infants born at 34 gestational weeks. Data of this type can be incorporated into future economic evaluations of preventive interventions for moderate or late preterm birth. 3.2. Costs following the initial hospital discharge A total of 13 studies were identied that reported the economic costs associated with moderate or late preterm birth following the infants initial hospitalisation,18,20,24,28e37 three of which also reported costs associated with the initial period of hospitalisation.18,20,24 Overviews of the location, sample size and methodology of each of these studies are summarised in Table 3; overviews of the economic results of each of these studies are summarised in Table 4. As with interpretation of studies that focused on the costs associated with the initial hospitalisation, comparability of results across studies is complicated by a number of factors. In particular, the cohort dates of these studies varied between 1970 and 2006, over which time there were several developments in the way that perinatal and neonatal care was organised and delivered with concomitant variations in mortality and morbidity outcomes; this, in turn, is likely to have led to variation in demand for health and broader services following the initial hospital discharge. In addition, the studies vary in terms of their epidemiological design for selecting the underpinning patient data, their cost categories and costing methodologies, and their period of follow-up. All but two studies28,30 focused on hospital costs following initial discharge, thereby excluding costs to other sectors of the economy, to families and carers and, more broadly, to society. Studies that estimated costs across the gestational age spectrum revealed an inverse relationship between gestational age at birth and costs following the initial hospital discharge. In general, mean
172
Table 1 Studies reporting the costs of initial hospitalisation associated with moderate or late preterm birth (studies since 1980). Reference Chollet et al.18 Gilbert et al.19 Date of cohort 1989e1991 Location USA Type of cohort Convenience sample Geographic (state) Sample size Extreme PT: 986 Normal PT: 946 Term: 44 041 27 weeks: 771 28e31 weeks: 2978 32e36 weeks: 37 388 (32e33 weeks: 5093) (34e36 weeks: 32 295) 37 weeks: 106 087 23 weeks: 17 24e25 weeks: 135 26e27 weeks: 231 28e29 weeks: 385 30e31 weeks: 756 32 weeks: 228 Term: 200 609 Total 240 179 Singletons: 106 Twins: 111 27 weeks: 2820 28e31 weeks: 5868 32e36 weeks: 92 058 (32e33 weeks: 7518) (34e36 weeks: 84 540) 37 weeks 92 421 27 weeks: 418 28e31 weeks: 1136 32e36 weeks: 6092 (32e33 weeks: 1365) (34e36 weeks: 4727) 37 weeks: 16 852 32 weeks: 8282 33e36 weeks: 34 800 Other: 394 432 Currency US$ Price date Not specied Not specied Gestational age(s) All Type of costs Hospital; professional Hospital Cost vs charges Costs Billed charges CCR (hospital specic) Data sources Claims database Stateelevel linked vital statistics and discharge records Hospital databases
1996
USA (California)
US$
25e38 weeks
Korvenranta et al.20
2000e2003
Finland
National
2008
All
Hospital
Costs
Lo et al.21 Luke et al.22 Phibbs and Schmitt23
2000e2008 1991e1992 1998e2000
USA USA (Illinois) USA (California)
Not stated Hospital specic Geographic (state)
US$ US$ US$
Not specied Not specied Dec 2003 CPI
All All All
Hospital Hospital Hospital
Charges Not specied CCR (hospital specic
Not specied Hospital bills Hospital chart State-level linked vital statistics and discharge records Discharge records
Ringborg et al.24
1998e2001
Sweden
National
2001
All
Hospital
Costs
Schmitt et al.25
2000
USA (California)
Geographic (state)
US$
2003
All
Hospital
CCR (hospital specic)
St John et al.26
1989e1992
USA (Alabama)
Hospital specic
Xu et al.27
2003
USA (Michigan)
Geographic (state)
27 weeks: 180 28e31 weeks: 315 32e36 weeks: 266 (32e33 weeks: 163) (34e36 weeks: 103) 37 weeks: 197 Total 111 264
US$
Not specied
24e32 vs 33e42 weeks
Hospital; professional
CCR (hospital specic)
State-level linked vital statistics and discharge records Hospital chart review and billing database
US$
2007
All
Hospital
Charges
State-level linked vital statistics and discharge records
PT, preterm; CCR, cost-to-charge ratio; CPI, consumer price index.
costs for infants born either moderate or late preterm appear closer to those for infants born at term rather than to infants born either extremely or very preterm (Table 4). However, the differential in cost following initial hospital discharge between infants born between 32 and 36 weeks gestation and those born at term varied between a 1.3-fold difference30 and an almost 10-fold difference.20 Notably, only six studies have estimated economic costs associated with moderate or late preterm birth beyond the rst 2 years of life,20,28,30,32,33,37 one of which did not include a term comparison group.37 Korvenranta et al.20 estimated the economic costs of preterm birth during the rst 4 years of life using Finnish population-based national registry data. Total hospitalisation costs averaged V43,325 for children born either moderate or late preterm compared to V4,580 for children born at term (2008 prices). Duration of rehospitalisations following initial discharge averaged 5.5 days for children born either moderate or late preterm compared with 2 days for children born at term. Similarly, the number of non-emergency outpatient visits averaged
17.2 for children born either moderate or late preterm compared with 2.5 for children born at term. Petrou et al.32,33 have also conducted a number of economic studies in this area based on data extracted from the Oxford Record Linkage Study, a large collection of linked, anonymised birth registrations, death certicates and statistical abstracts of NHS hospital inpatient and day-case admissions for part of southern England. A multivariate negative binomial regression performed on the 5-year hospital service use prole of 239,694 infants born in Oxfordshire and West Berkshire during 1970e1993 revealed that the total duration of hospital admissions for infants born between 32 and 36 gestational weeks was three times that for term infants, taking into account duration of life.32 A subsequent multi-level multiple regression model revealed that the adjusted effect regarding hospital inpatient admissions, days and costs over the rst 10 years of life was 1.37, 1.41 and 1.86, respectively, for children between 32 and 36 gestational weeks when compared with children born at term.33
S. Petrou, K. Khan / Seminars in Fetal & Neonatal Medicine 17 (2012) 170e178 Table 2 Studies reporting the costs of initial hospitalisation associated with moderate or late preterm birth: Resource use and cost results. Reference Gestational age(s) Extreme PT Normal PT Term 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks 23 weeks 24e25 weeks 26e27 weeks 28e29 weeks 30e31 weeks 32 weeks Term All 25e27 weeks 28e30 weeks 31e34 weeks 35e38 weeks 39e42 weeks 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks 32 weeks 33e36 weeks Other 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks All Per patient infant cost (mean) $55,424 $15,363 $2,376 N/A Cost per survivor (mean) N/A Cost per live birth (mean) N/A Per patient maternal cost (mean) $14,815 $13,017 $7,850 $7,843 $7,057 $3,524 ($4,776) ($33,26) $2,535 N/A LOS infant days (mean) N/A LOS survivors days (mean) N/A
173
LOS maternal days (mean) N/A
Chollet et al.18
Gilbert et al.19
N/A
Lo et al.21 Luke et al.22
$156,937 $55,350 $8,800 ($18,744) ($7,232) $3,860 V147,398 V120,179 V88,188 V56,588 V35,147 V32,153 V1,334 N/A
N/A
N/A
76.0 31.6 4.7 (11.2) (3.7) 1.9 N/A
N/A
136.7 122.1 94.4 67.5 48.0 43.6 3.5 N/A
6.8 5.9 3.0 (4.2) (2.9) 2.0 N/A
Phibbs and Schmitt23
$195,254 $91,343 $18,367 $4,308 $2,230 N/A
N/A
Ringborg et al.24
N/A
$231,852 $98,599 $7,694 ($35,635) ($5,238) $1,966 N/A
Schmitt et al.25
N/A
N/A
St John et al.26
$100,717 $41,567 $13,338 ($18,385) ($5,041) $1,351

b
$207,004 $99,261 $7,928 ($36,091) ($5,424) $2,027 V61,886 V27,074 V13,655 (V16,917) (V12,713) V5,543 $66,813 $7,081 $1,929 $71,643 $40,671 $17,018 ($20,845) ($10,961) $6,953
$84,892 $81,971 $23,759 $8,532 $7,573 N/A
V4,788 V4,785 V3,462 (V4,243) (V3,340) V2,679 N/A
71.2 39.0 11.8 3.8 3.1 79.4 49.8 5.9 (22.6) (4.4) 2.6 95.3 54.1 17.9 (29.9) (14.6) 7.0 N/A
N/A
91.8 50.8 5.9 (22.6) (4.4) 2.6 N/A
N/A
N/A
9.7 9.6 6.9 (8.4) (6.6) 3.0 N/A
N/A
N/A
80.5 40.3 13.8 (18.9) (5.4) 1.2
N/A
Xu et al.27
LOS, length of stay; PT, preterm; N/A, not available. a 24 weeks: $98,162; 25 weeks: $83,070; 26 weeks: $90,936; 27 weeks: $79,463; 28 weeks: $59,928; 29 weeks: $52,998; 30 weeks: $40,568; 31 weeks: $30,853; 32 weeks: $22,612; 33 weeks: $16,597; 34 weeks: $9,740; 35 weeks: $5,015; 36 weeks: $2,413; 37 weeks: $1,469; 38 weeks: $1,070; 39 weeks: $994; 40 weeks: $1,017; 41 weeks: $1,058; 42 weeks: $1,072. b 20 weeks: $11,397; 21 weeks: $11,703; 22 weeks: $25,367; 23 weeks: $48,908; 24 weeks: $99,477; 25 weeks: $82,296; 26 weeks: $103,980; 27 weeks: $72,212; 28 weeks: $56,933; 29 weeks: $45,598; 30 weeks: $34,642; 31 weeks: $29,679; 32 weeks: $24,623; 33 weeks: $21,887; 34 weeks: $18,617; 35 weeks: $15,864; 36 weeks: $12,305; 37 weeks: $6,368.
3.3. Modelling economic costs throughout childhood Building on previous research by one of the authors (S.P.),30 we constructed and populated a Markov model to estimate the societal costs associated with preterm birth over the rst 18 years of life. The model structure is presented in Figure 1. A hypothetical cohort of children, the size of which was set at 669,601 to reect the number of live births in England and Wales in 2006, was assumed to enter the model on live birth. Subsequently, children were assumed to proceed to hospital discharge or neonatal care, with the exception of a small proportion assumed to die in the delivery room or during transfer. Admission to a neonatal unit was treated as a proxy for neonatal complications, with length of neonatal stay acting as an indicator for the severity of morbidity. Following discharge from hospital, children were assumed to enter a health state dened by the time period between discharge and 2 years of
age. Survivors at 2 years were then allocated to one of four states that described their overall level of disability: none, mild, moderate or severe. For each subsequent year of childhood, children were assumed to remain in the same disability state, move to another disability state, or to die. Model parameter inputs, including gestation-specic transitional probabilities and costs, were largely drawn from three cohorts that incorporated parallel economic studies: (i) the EPICure cohort of infants born in the UK and Republic of Ireland between March and December 1995 at <26 weeks gestation; (ii) the 1991e1992 cohort of the Victorian Infant Collaborative Study Group (VICSG) of infants born in the Victoria state of Australia at 26 or 27 weeks gestation; and (iii) the Oxford Record Linkage Study for infants born in Oxfordshire or Berkshire between 1990 and 1993 at 28 weeks gestation or later.30 Cost estimates were further disaggregated into cost categories. Notably, using evidence drawn from a parallel economic study,38 we also
174
Table 3 Studies reporting the costs following initial hospitalisation discharge associated with moderate or late preterm birth (studies since 1980). Reference Bird et al.35 Chollet et al.18 Date of cohort 2001e2005 1989e1991 Location USA (Arkansas) USA Type of cohort Geographic (state) Convenience sample Sample size 34e36 weeks: 5199 37e42 weeks: 50 907 Extreme PT: 986 Normal PT: 946 Term: 44 041 27 weeks: 253 28e31 weeks: 695 32e36 weeks: 6679 (32e33: 997 weeks; 34e36 weeks: 5682) 37 weeks: 69 274 32 weeks: 1221 33 weeks: 1507 34 weeks: 2204 23 weeks: 17 24e25 weeks: 135 26e27 weeks: 231 28e29 weeks: 385 30e31 weeks: 756 32 weeks: 228 Term: 200 609 27 weeks: 3185 28e31 weeks: 5575 32e36 weeks: 39 222 (32e33 weeks: 6410; 34e36 weeks: 32 812) 37 weeks: 621 618 LPT 1683 Term 33 745 <28 weeks: 500 28e31 weeks: 1346 32e36 weeks: 11 728 >37 weeks: 226 120 <28 weeks: 241 28e31 weeks: 596 32e36 weeks: 4485 >37 weeks: 90 236 24e26 weeks: 9200 27e29 weeks: 16 500 30e33 weeks: 58 300 27 weeks: 418 28e31 weeks: 1136 32e36 weeks: 6092 (32e33 weeks: 1365; 34e36 weeks: 4727) 37 weeks: 16 852 <28 weeks: 29 200 28e36 weeks: 305 500 27 weeks: 11 619 28e31 weeks: 34 005 32e36 weeks: 218 259 (32e33 weeks: 1365; 34e36 weeks: 4727) Currency US$ US$ Price date Not specied Not specied Gestational age(s) Late PT and term All Type of costs Hospital Hospital; professional Health and social services Cost vs charges Charges Costs Billed charges Charges Data sources Claims Claims database Time frame First year of life First 2 years
Clements et al.28
1999e2000
USA (Massachusetts)
Geographic (state)
US$
2003
All
Claims database
Discharge to 3 years
Kirkby et al.29
2001e2004
USA
Hospital specic
US$
Not specied
32e34 weeks All
Hospital
Charges
Claims database
2000e2003
Finland
National
2008
Hospital
Costs
Hospital databases
Birth to 2 weeks post initial discharge First 4 years of life
Mangham et al.30
2006
UK England and Wales
National
2006
All
Public Sector
Costs
Secondary data
First 18 years of life
McLaurin et al.31 Petrou et al.32
2004 1970e1993
USA UK (Oxfordshire and West Berkshire) UK (Oxfordshire and West Berkshire) Mexico
National (insurance membership specic) Geographic (region)
US$
Not specied 1998e1999
33e36 weeks All GA
Hospital Hospital
Charges Costs
Claims Linked vital statistics and NHS records nancial returns Linked vital statistics and NHS records nancial returns Secondary data
Birth to 1 year First 5 years
Petrou33
1978e1988
Geographic (region)
1998e1999
All GA
Hospital
Costs
First 10 years
Prot et al.37
Not specied
National
US$
2005
24e33 weeks All
Hospital
Costs
Lifetime
Ringborg et al.24
1998e2001
Sweden
National
2001
Hospital
Costs
Discharge records
First 12 months
Russell et al.34 Underwood et al.36
2001 1992e2000
USA USA (California)
Hospital specic Geographic (state)
US$ US$
Not specied Not specied
All All
Hospital Hospital
CCR (hospital specic) CCR (hospital specic)
Database Stateelevel linked vital statistics and discharge records
First 12 months Discharge to 1 year
PT, preterm; LPT, late preterm; CCR, cost-to-charge ratio; GA, gestational age; NHS, National Health Service.
Table 4 Studies reporting the costs following initial hospitalisation discharge associated with moderate or late preterm birth: Resource use and cost results. Reference Gestational age(s) 34e36 weeks 37e42 weeks Extreme PT Normal PT Term 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks 32 weeks 33 weeks 34 weeks 23 weeks 24e25 weeks 26e27 weeks 28e29 weeks 30e31 weeks 32 weeks Term 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks Late PT Term <28 weeks 28e31 32e36 >37 weeks <28 weeks 28e31 32e36 >37 weeks
37
Total cost per patient including initial hospitalisation (mean) N/A
Total cost per survivor including initial hospitalisation (mean) $4,541 $3,472 N/A
Total cost per live birth including initial hospitalisation (mean) N/A
Inpatient costs per patient (mean) $3,027 $2,183 $63,910 $23,916 $7,984 N/A
Outpatient cost per patient (mean) $1,560 $1,316 $6,329 $4,463 $2,243 N/A
Birth hospitalisation costs (mean) N/A
Rehospitalisation costs (mean) N/A
Rehospitalisation LOS (mean) 0.65 0.48 N/A
Bird et al.35
Chollet et al.18
$70,239 $28,380 $10,226 N/A
N/A
N/A
N/A
Clements et al.28
$7,439 $4,648 $1,579 ($2,756) ($1,372) $725 N/A
N/A
N/A
N/A
N/A
Kirkby et al.29
$43,667 $31,535 $22,575 N/A
N/A
N/A
N/A
N/A
N/A
N/A
175,490 143,570 105,631 72,366 45,714 43,325 4,580 136,748 101,649 56,683 (77,305) (52,761) 42,049
N/A
N/A
N/A
147,398 120,179 88,188 56,588 35,147 32,153 1,334 N/A
28,092 23,391 17,443 15,778 10,567 11,172 3,246 N/A
14.6 12.1 8.6 8.2 5.7 5.5 2.0 N/A
Mangham et al.30
N/A
75,832 93,935 55,593 (74,145) (51,969) 41,813 N/A
N/A
N/A
McLaurin et al.
31
$38,301 $6,156 N/A
N/A
N/A
N/A
$26,054 $2,087 6,569 6,700 1,922 752 N/A
$12,247 $4,069 7,070 7,359 2,456 581 N/A
4.5 3.4 N/A
Petrou et al.32
N/A
13,639 14,059 4,378 1,333 N/A
N/A
N/A
Petrou33
17,820 17,751 7,394 1,659 Admitted to NICU: $12,000 $11,100 $7,700 Not admitted to NICU: $600 $1,600 $4,700
N/A
N/A
N/A
N/A
Prot et al.
24e26 weeks 27e29 weeks 30e33 weeks 24e26 weeks 27e29 weeks 30e33 weeks
175
(continued on next page)
176
Birth hospitalisation costs (mean)
incorporated estimates of economic costs beyond those falling on the public sector, including direct costs borne by parents and carers, and indirect costs associated with lost productivity. Costs accruing after the rst year of life were discounted at an annual rate of 3.5%. The results of this economic modelling study are summarised in Table 5. In keeping with the broader literature, an inverse relationship is observed between gestational age at birth and public sector costs. We also report, to our knowledge for the rst time, a clear inverse relationship between gestational age at birth and costs falling beyond the public sector, including costs borne by parents and carers, and indirect costs associated with lost productivity. The incremental societal cost per moderate preterm child surviving to 18 years compared with a term survivor was estimated at 36,291. The corresponding incremental societal cost estimate for a late preterm child was 10,828. The bulk of these additional costs fell on the health and social care sectors. 4. Discussion This paper has reviewed the recent published evidence on the economic consequences of moderate and late preterm birth for the health services, for other sectors of the economy, for families and carers and, more broadly, for society. Although data on the economic consequences of moderate and late preterm birth are sparse, they consistently suggest that service provision for infants born between 33 and 36 weeks gestation is associated with substantial incremental costs during the initial hospital stay and throughout childhood. Moreover, our economic modelling study is the rst, to our knowledge, to highlight the substantial incremental societal costs associated with moderate and late preterm birth throughout childhood. It should be noted that existing economic research in this area is hampered by a paucity of epidemiological studies that accurately quantify neonatal morbidity and longer term adverse outcomes for this population or that identify risk factors contributing to these outcomes. There is therefore a clear need for prospective, comprehensive data collection for infants born between 33 and 36 weeks gestation to allow quantication of the clinical and economic outcomes for this group. This is essential, rst, to highlight areas in which changes in perinatal and neonatal care may improve outcomes and, second, to inform equitable and efcient allocation of scarce public sector resources for children born at these gestational ages. In addition to the costs highlighted by our review, both moderate and late preterm births are likely to have broader consequences that require further evaluation from an economic perspective. A recent literature review highlighted the signicant costs that are borne by families and carers among those who care for a child with conrmed disability,39 and it is likely that these categories of costs are relevant to some families and carers of children born either moderate or late preterm. In addition to the costs of travel, child care and accommodation that we included in our economic modelling study, other potential costs faced by families and informal carers include incremental expenditures on health goods, such as alternative therapies, and non-health goods, such as nutritional requirements, laundry, clothing, heating utilities and repairs to the home. Furthermore, no monetary valuation of the intangible consequences of moderate and late preterm birth, such as the pain, fear, suffering and emotional and social isolation that might be experienced by the individuals themselves and their carers, has been attempted. Given recent evidence of an increasing incidence of preterm birth, it is imperative that clinical decision-makers and budgetary and service planners recognise the overall economic impact of moderate and late preterm birth in their service planning, as well as the potential contribution of clinical and sociodemographic factors to future public sector and broader societal costs. Both our research
Rehospitalisation LOS (mean)
N/A
N/A
Rehospitalisation costs (mean)
6,520 2,888 1,496 (1,607) (1,464)
1,258
N/A
N/A
N/A
Outpatient cost per patient (mean)
N/A
N/A
Inpatient costs per patient (mean)
61,886 27,074 13,655 (16,917) (12,713)
5,543
N/A
Total cost per live birth including initial hospitalisation (mean)
Total cost per survivor including initial hospitalisation (mean)
68,406 29,962 15,151 (18,524) (14,177)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Table 4 (continued )
LOS, length of stay; N/A, not available; PT, preterm; NICU, neonatal intensive care unit.
6,801
Total cost per patient including initial hospitalisation (mean)
27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks
$65,600 $12,100 Russell et al.34 Underwood et al.36 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) <28 weeks 28e36 weeks
Gestational age(s)
Ringborg et al.24
Reference
N/A
$5,207 $2,267 $1,065 ($1,351) ($968)
N/A
177
Key: Cost of health state
Live birth
Probability of moving between health states
Admitted to neonatal care
From discharge to 2 years
No disability
Mild disability
Moderate disability
Severe disability
Death
Figure 1. Structure of the Markov model estimating the childhood economic costs of preterm birth. 3. Tucker J, McGuire W. Epidemiology of preterm birth. BMJ 2004;329:675e8. 4. Lefebvre F, Glorieux J, St-Laurent-Gagnon T. Neonatal survival and disability rate at age 18 months for infants born between 23 and 28 weeks of gestation. Am J Obstet Gynecol 1996;174:833e8. 5. OShea TM, Klinepeter KL, Goldstein DJ, Jackson BW, Dillard RG. Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994. Pediatrics 1997;100:982e6. 6. Allen MC, Donohue PK, Dusman AE. The limit of viability e neonatal outcome of infants born at 22 to 25 weeks gestation. N Engl J Med 1993;329:1597e601. 7. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008;371:261e9. 8. Hack M, Friedman H, Fanaroff AA. Outcomes of extremely low birth weight infants. Pediatrics 1996;98:931e7. 9. Petrou S, Sach T, Davidson L. The long-term costs of preterm birth and low birth weight: results of a systematic review. Child Care Health Dev 2001;27:97e115. 10. Bracewell M, Marlow N. Patterns of motor disability in very preterm children. Mental Retard Dev Disabil Res Rev 2002;8:241e8. 11. Saigal S, Ouden LD, Wolke D, et al. School-age outcomes in children who were extremely low birth weight from four international population-based cohorts. Pediatrics 2003;112:943e50. 12. Hille ETM, den Ouden AL, Saigal S, et al. Behavioural problems in children who weigh 1000 g or less at birth in four countries. Lancet 2001;357:1641e3. 13. Pietz J, Peter J, Graf R, et al. Physical growth and neurodevelopmental outcome of nonhandicapped low-risk children born preterm. Early Hum Dev 2004;79:131e43. 14. Blackwell MT, Eichenwald EC, McAlmon K, et al. Interneonatal intensive care unit variation in growth rates and feeding practices in healthy moderately premature infants. J Perinatol 2005;25:478e85. 15. Holmqvist P, Regefalk C, Svenningsen NW. Low risk vaginally born preterm infants: a four year psychological and neurodevelopmental follow-up study. J Perinat Med 1987;15:61e72. 16. Huddy CL, Johnson A, Hope PL. Educational and behavioural problems in babies of 32e35 weeks gestation. Arch Dis Child Fetal Neonatal Ed 2001;85:F23e8. 17. Petrou S, Eddama O, Mangham L. A structured review of the recent literature on the economic consequences of preterm birth. Archs Dis Childh Fet Neonat Ed 2011;96:F225e32. 18. Chollet DJ, Newman Jr JF, Sumner AT. The cost of poor birth outcomes in employer-sponsored health plans. Med Care 1996;34:1219e34. 19. Gilbert WM, Nesbitt TS, Danielsen B. The cost of prematurity: quantication by gestational age and birth weight. Obstet Gynecol 2003;102:488e92. 20. Korvenranta E, Linna M, Rautava L, et al. Hospital costs and quality of life during 4 years after very preterm birth. Arch Pediatr Adolesc Med 2010;164:657e63. 21. Lo JMK, Henry E, Weng H, Hopkins P, Esplin MS. The cost of prematurity: the association between gestational age at delivery and overall neonatal cost. Reproductive Sciences 2011;18:69Ae384A. 22. Luke B, Bigger HR, Leurgans S, Sietsema D. The cost of prematurity: a caseecontrol study of twins vs singletons. Am J Public Health 1996;86:809e14. 23. Phibbs CS, Schmitt SK. Estimates of the cost and length of stay changes that can be attributed to one-week increases in gestational age for premature infants. Early Hum Dev 2006;82:85e95. 24. Ringborg A, Berg J, Norman M, Westgren M, Jnsson B. Preterm birth in Sweden: what are the average lengths of hospital stay and the associated inpatient costs? Acta Pdiatrica 2006;95:1550e5.
Table 5 Societal costs of care through the childhood years; mean costs per survivor (, 2006 prices). Gestational age 27 weeks 28e31 weeks 32e36 weeks (32e33 weeks) (34e36 weeks) 37 weeks Health and social care 98,528 66,188 22,123 42,460 18,255 7,757 Education 38,505 35,326 34,549 34,814 34,499 34,292 Parental expenses 9,626 8,540 7,695 7,971 7,642 7,583 Lost productivity 5,096 3,300 1,924 2,440 1,825 1,773 All costs 151,189 113,160 66,291 87,685 62,222 51,394
and research by other investigators30,36 suggests that children born moderate or late preterm contribute the largest share of total public sector costs since they account for the vast majority of preterm births. In addition to informing the planning of services, our data should be of interest and use to researchers planning to evaluate new or existing interventions from an economic perspective, particularly those wishing to incorporate within a decision-analytic framework the long term economic impact of moderate and late preterm birth and the cost-effectiveness of prevention and treatment strategies. Conicts of interest None declared. The views contained in the paper are those of the authors and not necessarily of the funding bodies. Funding sources The Warwick Clinical Trials Unit beneted from facilities funded through the Birmingham Science City Translational Medicine Clinical Research and Infrastructure Trials Platform, with support from Advantage West Midlands. References
1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75e84. 2. Anonymous. Critical care decisions in fetal and neonatal medicine: ethical issues. London: Nufeld Council on Bioethics; 2006.
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S. Petrou, K. Khan / Seminars in Fetal & Neonatal Medicine 17 (2012) 170e178 32. Petrou S, Mehta Z, Hockley C, Cook-Mozaffari P, Henderson J, Goldacre M. The impact of preterm birth on hospital inpatient admissions and costs during the rst 5 years of life. Pediatrics 2003;112:1290e7. 33. Petrou S. The economic consequences of preterm birth during the rst 10 years of life. BJOG 2005;112:10e5. 34. Russell RB, Green NS, Steiner CA, et al. Cost of hospitalization for preterm and low birth weight infants in the United States. Pediatrics 2007;120:e1e9. 35. Bird TM, Bronstein JM, Hall RW, Lowery CL, Nugent R, Mays GP. Late preterm infants: birth outcomes and health care utilization in the rst year. Pediatrics 2010;126:e311e9. 36. Underwood MA, Danielsen B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. J Perinatol 2007;27:614e9. 37. Prot J, Lee D, Zupancic JA, et al. Clinical benets, costs, and cost-effectiveness of neonatal intensive care in Mexico. PLoS Med 2010;7:e1000379. 38. Petrou SJS, Wolke D, Marlow N. The association between neurodevelopmental disability and economic outcomes during mid-childhood. Child: Care Health Dev (in press). 39. Anderson D, Dumont S, Jacobs P, Azzaria L. The personal costs of caring for a child with a disability: a review of the literature. Publ Hlth Rep 2007;122:3e16.
25. Schmitt SK, Sneed L, Phibbs CS. Costs of newborn care in California: a population-based study. Pediatrics 2006;117:154e60. 26. St John EB, Nelson KG, Cliver SP, Bishnoi RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182:170e5. 27. Xu X, Grigorescu V, Siefert KA, Lori JR, Ransom SB. Cost of racial disparity in preterm birth: evidence from Michigan. J Health Care Poor Underserved 2009;20:729e47. 28. Clements KM, Bareld WD, Ayadi MF, Wilber N. Preterm birth-associated cost of early intervention services: an analysis by gestational age. Pediatrics 2007;119:e866e74. 29. Kirkby S, Greenspan J, Kornhauser M, Schneiderman R. Clinical outcomes and cost of the moderately preterm infant. Adv Neonat Care 2007;7:80e7. 30. Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N. The cost of preterm birth throughout childhood in England and Wales. Pediatrics 2009;123:e312e27. 31. McLaurin KK, Hall CB, Jackson EA, Owens OV, Mahadevia PJ. Persistence of morbidity and cost differences between late-preterm and term infants during the rst year of life. Pediatrics 2009;123:653e9.

Correspondence
Re: Myth: Group B streptococcal infection in pregnancy: Comprehended and conquered published in volume 16 (2011) pp 254258
Dear Sir, We are writing with reference to the article Myth: Group B streptococcal infection in pregnancy: Comprehended and conquered published in volume 16 (2011) pp 254258. We are concerned about the accuracy of some of the articles key assumptions relating to screening. The authors estimate that 700 babies will be affected by early onset group B streptococcal disease (eogbs) each year in the absence of any antibiotic prophylaxis. However this assumes that there is no current management strategy. This is not the case; an RCOG and management of at risk women.1 The gure is hypothetical and a misleading starting point. The best data we have were published in 2004 and suggests that the rate of culture proven eogbs is w0.5/1000 births or 380 babies per year.2 This is comparable to the rate of culture proven eogbs in countries which offer screening. The authors state that testing using an enriched culture medium will detect more than 90% of pregnant carriers. The supporting citation is a 1996 study comparing the detection rate from direct inoculation of swabs into selective media with that from delayed inoculation of swabs stored in Stuarts transport medium. However, the results from other studies of culture-based testing have not been consistently as high as this. Those cited elsewhere by the authors suggest a sensitivity of 86.6%3 and 76%4 respectively. The most recent CDC screening guidelines report a study which found test sensitivity to be as low as 54%.5 A recent systematic review of test effectiveness studies concluded that 69% of carriers detected in late pregnancy will remain positive at term.6 This compares unfavourably with the gure of 87% cited from a much older, single, study by the authors.3 A recent review of the experience of screening in the US suggests that this latter study overestimated the specicity of culture testing. The number of babies born to women with negative tests has been higher than expected and has emerged as a cause for concern in recent publications in the US and Europe.710 Clearly there are uncertainties regarding the characteristics of this test. In the UK w30% of eogbs is in preterm babies born too early for screening to impact signicantly on disease in this group.2 The effectiveness of IAP in labour is uncertain11,12 but estimated to be 85 89% effective in preventing eogbs.5 This, combined with the already mentioned issues relating to the characteristics of the
test, makes it extremely doubtful that screening and IAP in labour can prevent up to, about or more than 90% of eogbs disease in neonates. We are concerned that this article creates its own myths, particularly in relation to the effectiveness of screening. Yours sincerely
References
1. RCOG, Prevention of Early Onset Neonatal Group B Streptococcal Disease, Greentop Guideline 36, 2003. 2. Heath PT, Balfour G, Weisner AM, et al. Group B streptococcal disease in UK and Irish infants younger than 90 days. Lancet 2004;363:2924. 3. Yancey MK, Schuchat A, Brown LK, Ventura VL, Markenson GR. The Accuracy of Late Antenatal Screening Cultures in Predicting Genital Group B Streptococcal Colonization at Delivery. Obstet Gynecol 1996;vol. 88(5):8115. 4. Kaambwa B, Bryan S, Gray J, et al. Cost effectiveness of rapid tests and other existing strategies for screening and management of early onset group B streptococcus during labour. BJOG 2010;117:161627. 5. Centers for Disease Control and Prevention. Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC. MMWR 2010;59(RR-10): 136. 6. Valkenburg van den Burg AW. Timing of Group B Streptococcus Screening in Pregnancy: A Systematic Review. Gynecol Obstet Invest 2010;69:17483. 7. Van Dyke MK, Phares CR, Lyneld R, et al. Evaluation of Universal Antenatal Screening for Group B Streptococcus. N Eng J Med 2009;360:262636. 8. Berardi A, Di Fazzio G, Gavioli S, et al. Universal antenatal screening for group B streptococcus in Emilia-Romagna. J Med Screen June 2011;18:604. 9. Albouy-Llaty M, Nadeau C, Descombes E, Pierre F, Migeot V, et al. Improving perinatal Group B streptococcus screening with process indicators, Journal of Evaluation in Clinical Practice 2011 Mar 18:17. 10. Randis TM, Polin RA. Early-onset group B Streptococcal sepsis: new recommendations from the Centres for Disease Control and Prevention, Arch Dis Child Fetal Neonatal Ed 2011;fetalneonatal-2011-300627 Published Online First: 4 November 2011. 11. Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B streptococcal colonization, Cochrane Database of Systematic Reviews. (3), 2009. Article Number: CD007467. 12. Carbonell-Estrany X, Figueras-Aloy J, Salcedo-Abizanda S, de al Rosa-Fraile M. Probably early-onset group B streptococcal neonatal sepsis: a serious clinical condition related to intrauterine infection. Arch Dis Child Neonatal Ed 2008; 93:F859.
John Marshall* UK National Screening Committee, UK Catherine Peckham Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, UK * Corresponding author. E-mail address: John.Marshall@imperial.nhs.uk (J. Marshall)
DOI of original article: 10.1016/j.siny.2011.03.005. 1744-165X/$ see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.006

Correspondence
Reply to Letter to the Editor Re: Myth: Group B streptococcal infection in pregnancy: Comprehended and conquered published in volume 16 (2011) pp. 254258
Dear Sir, Thank you for allowing us to respond to the letter from Mr Marshall and Professor Peckham. Marshall and Peckham state that in our article we estimated that in the absence of any antibiotic prophylaxis 700 babies will be affected by early onset group B streptococcal disease (eogbs) each year. In fact, we referred to serious GBS infections, which includes late onset. While it is true that the Royal College of Obstetricians and Gynaecologists (RCOG) 2003 guidelines recommended risk factor screening, according to a survey commissioned by the National Screening Committee, carried out by the RCOG and published in 2007 (http://www.rcog.org.uk/ourprofession/good-practice/audit/prevention-neonatal-group-bstreptoccocal-disease-audit), these guidelines have resulted in only a slight improvement in the proportion of units offering IAP to appropriate women since the previous surveys in 1999 and 2001. Moreover, recent UK cost-effectiveness surveys have repeatedly concluded that Testing (only) high-risk women for maternal GBS colonisation would not be cost-effective,1 The current strategy of risk-factor-based screening is not costeffective compared with screening based on culture2 and that screening, based on a culture test at 3537 weeks gestation, with the provision of antibiotics to all women who screened positive (is) most cost-effective.3 While historically, the rate of culture proven eogbs in the UK was low, the Health Protection Agency (HPA) reports that voluntarily reported cases in England Wales and Northern Ireland have risen from 229 in 2003 to 302 in 2010. This rising trend is contrary to the major falls seen in the many countries that have introduced culture based screening, and we see no reason why such falls could not be replicated in the UK. The sensitivity of tests employed for screening has to be judged against a gold standard such as that currently employed by the HPA an enriched culture medium with two selective chromogenic media (personal communication from Androulla Efstratiou). It is obviously true that if an insensitive test is used, the pickup rate will be low, and the CDC report quoted by Marshall and Peckham4 says that when direct agar plating is used instead of selective enrichment broth, as many as 50% of women who are GBS carriers have false-negative culture results. Unfortunately, it is
the direct agar plating method that is routinely available in NHS hospitals, and part of the GBSS campaign is for the sensitive test to be used instead. Marshall and Peckham suggest that only 69% of carriers detected in late pregnancy will remain positive at term, but the paper they quote5 reviews nine articles and says that Positive predictive values for antenatal GBS cultures ranged from 43 to 100% (mean 69%) and negative predictive values from 80 to 100% (mean 94%). GBS cultures collected in late pregnancy had high positive predictive values for colonization during delivery. The negative predictive value was high and relatively constant regardless of GA. Again, the sensitivity of the test used is crucial to get good results, one must use the most sensitive test. Marshall and Peckham report concerns that The number of babies born to women with negative tests has been higher than expected. This may in part reect the use of suboptimal culture techniques, but can also be attributed to the treatment paradox. Assuming a sensitivity of carriage detection as low as 85%, of 100 babies who would develop eogbs without screening, 85 would have mothers detected as carriers by screening. If as Marshall and Peckham concede, intrapartum antibiotic prophylaxis is at least 85% effective, eogbs would occur in 15 cases where the mother was not identied as a carrier, compared with 13 cases where she was. So more than 50% of cases with eogbs will result from false negative screening. But the key point here is that the overall burden of disease will be reduced from 100 to 28 a 72% reduction. Increasing sensitivity to 90% and treatment efcacy to 90% results in an 81% reduction. To decry this impressive reduction because there remain false negatives seems perverse. Finally, optimal approaches to eogbs prevention involve giving intravenous penicillin to all women in preterm labour, which renders prior screening unnecessary. Yours sincerely,
References
1. Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses. Health Technol Assess 2007; 11(29):1226. iii. 2. Kaambwa B, Bryan S, Gray J, Milner P, Daniels J, Khan KS, et al. Cost-effectiveness of rapid tests and other existing strategies for screening and management of early-onset group B streptococcus during labour. BJOG 2010; 117(13):161627.
DOI of original article: 10.1016/j.siny.2012.02.006. 1744-165X/$ see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.02.007
Correspondence / Seminars in Fetal & Neonatal Medicine 17 (2012) 180181 3. Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness. Health Technol Assess 2009; 13(42):1. iv. 4. MMWR. Centers for Disease Control and Prevention, Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC. 59, No. RR-10, 1 36. 2010. 5. Valkenburg-van den Berg AW, Houtman-Roelofsen RL, Oostvogel PM, Dekker FW, Dorr PJ, Sprij AJ. Timing of group B streptococcus screening in pregnancy: a systematic review. Gynecol Obstet Invest 2010; 69 (3):174 83.
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Philip Steer* Emeritus Professor, Imperial College London, United Kingdom Jane Plumb Group B Strep Support, PO Box 203, Haywards Heath, West Sussex, RH16 1GF, United Kingdom * Corresponding author. E-mail address: p.steer@imperial.ac.uk (P. Steer)

Lessons from the current literature
Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants
Luc Cornette
Department of Neonatology, AZ St-Jan Bruges-Ostend AV, Ruddershove 10, 8000 Bruges, Belgium
VS Kuppala, J Meinzen-Derr, AL Morrow, KR Schibler J Pediatr 2011;159:720e5 Abstract In this retrospective cohort study, the authors investigate the relationship between prolonged (5 days) empirical antibiotic administration to n 365 premature infants (32 weeks GA and 1500 g birth weight), who survived free of sepsis and necrotizing enterocolitis (NEC) for 7 days during their rst week of life and late onset sepsis (LOS), NEC and death. Multivariable logistic regression is conducted, controlling e.g. for race, prolonged premature rupture of membranes, as well as degree of respiratory support. In n 131/365 infants (36%), the prolonged course of antibiotics is independently associated with LOS (OR, 2.45 [95% CI, 1.28-4.67]) and with the combination of LOS, NEC, or death (OR, 2.66 [95% CI, 1.12-6.3]). It is concluded that prolonged administration of empirical antibiotics to premature infants with sterile cultures in the rst week of life is associated with subsequent severe outcome. Comment Antibiotics are the most commonly used therapeutics in neonatal intensive care units. Clinicians have a low threshold for initiating empiric antibiotic therapy in high-risk newborns, mostly in view of the devastating consequences of untreated sepsis. Virtually all extremely low birth weight infants receive empirical
antibiotics in the rst postnatal days, although cultures remain sterile. However, prolonged or continued initial empirical antibiotic therapy with little if any microbiological justication may not be benign, as antibiotic therapy itself can result in elimination of commensal ora as well as colonization by multi-drug resistant organisms, including Candida. The current study by Kuppala et al. conrms such association in a rather impressive way: each extra day of antibiotic therapy is associated with a signicant increase in the odds of NEC, LOS or death. How to rationally curtail any possible excessive use of antibiotics in preterm infants ? In this respect, and hopefully in a not too distant future, our decision to treat preterm infants with sterile cultures and without signs of sepsis beyond the rst 3 postnatal days may be more informed with the development of adjunctive diagnostic tests such as levels of procalcitonin, cell surface markers, cytokines (IL-6 and IL-8) and leukocyte adhesion factors. Sensitivity, specicity, and predictive values are promising for many of these tests, but most are not yet available in clinical settings. In the meantime, we must continue to do everything possible to ascertain whether an infant truly has an infection that requires antibiotic therapy. Such is rstly obtained by educating our junior doctors towards correct blood sampling, i.e. 2 mL of blood volume is needed to obtain reliable culture results. Such may be technically difcult, but it is well-known that low blood volume decreases the sensitivity of blood cultures. Secondly, we could reduce overtreatment by reducing the likelihood of treating contaminants, e.g. by obtaining blood cultures at 2 separate sites, using meticulous sterile conditions. Finally, close adherence to GBS screening and hospital intra-partum antibiotic prophylaxis guidelines remains crucial, in order to reduce the number of unnecessary sepsis evaluations in newborn infants, resulting in less empiric antibiotic treatment.
E-mail address: Luc.Cornette@azsintjan.be. 1744-165X/$ e see front matter doi:10.1016/j.siny.2012.02.009

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Seminars in Fetal & Neonatal Medicine

Aims and Scope

Seminars in Fetal & Neonatal Medicine 17 (2012) 119

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

The late and moderate preterm baby

Seminars in Fetal & Neonatal Medicine 17 (2012) 120e125

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Epidemiology of late and moderate preterm birth

Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Developmental physiology of late and moderate prematurity

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

T.N.K. Raju / Seminars in Fetal & Neonatal Medicine 17 (2012) 126e131

Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Obstetric decision-making and the late and moderately preterm infant

C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137

C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137

C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137

C. Gyam-Bannerman / Seminars in Fetal & Neonatal Medicine 17 (2012) 132e137

Conict of interest statement None declared.

Funding sources None.

Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Obstetric management of moderate and late preterm labour

P.C. McParland / Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142

P.C. McParland / Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142

P.C. McParland / Seminars in Fetal & Neonatal Medicine 17 (2012) 138e142

Seminars in Fetal & Neonatal Medicine 17 (2012) 143e145

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Impact of multiple births on late and moderate prematurity

J.S. Refuerzo / Seminars in Fetal & Neonatal Medicine 17 (2012) 143e145

J.S. Refuerzo / Seminars in Fetal & Neonatal Medicine 17 (2012) 143e145

Conict of interest statement None declared. Funding sources None. References

Seminars in Fetal & Neonatal Medicine 17 (2012) 146e152

Contents lists available at SciVerse ScienceDirect

Seminars in Fetal & Neonatal Medicine

Neonatal problems of late and moderate preterm infants

Severe respiratory disorders

70% 60% 50% 40% 30% 20% 10% 0%

Antenatal steroids Nasal CPAP Mechanical ventilation Surfactant Admission in NICU

Funding sources None. References

Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158

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Seminars in Fetal & Neonatal Medicine

R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158

R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158

R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158

R.K. Whyte / Seminars in Fetal & Neonatal Medicine 17 (2012) 153e158

25. *26. 27. 28. 29. 30.

*33. 34. 35. 36.

43. 44. *45.

Seminars in Fetal & Neonatal Medicine 17 (2012) 159e162

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