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Best Practice & Research Clinical Obstetrics and Gynaecology


Vol. xx, No. xx, pp. 117, 2007
doi:10.1016/j.bpobgyn.2007.03.001
available online at http://www.sciencedirect.com

3
Epidemiology and environmental
factors in preterm labour
Deirdre J. Murphy *

MD, MRCOG

Professor of Obstetrics and Gynaecology, Trinity College, University of Dublin


Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St Jamess Hospital, Dublin 8, Ireland

An epidemiological and environmental approach is the appropriate starting point to understanding


preterm labour. Although there are multiple aetiologies it seems likely that anthropometric
and environmental risk factors in combination with inherent genetic susceptibilities contribute
to an increased risk of preterm labour for certain women. Poct 2pulation-based studies identifying risk factors and quantifying outcomes facilitate informed counselling and provide a framework for developing prediction tools. Carefully conducted case-control and cohort studies
identify associations that may contribute to an understanding of causation. A combined approach
encompassing epidemiology, pathophysiology and clinical research is required to understand the
aetiologies, prevention and optimal management of preterm labour. This review focuses on the
epidemiology of preterm labour and the role of environmental factors.
Key words: preterm labour; epidemiology; environmental factors; risk factor; risk assessment.

The precise aetiologies of preterm labour remain elusive, limiting the development of
preventative and therapeutic strategies. An understanding of the pathogenesis and
mechanisms of preterm labour should start with an exploration of epidemiological
and environmental factors. There may be clues within patient demographics, fetal
demographics, the intrauterine and extrauterine environment, genetic profiling (maternal, paternal and fetal) and interactions between these factors. Epidemiological
research aims to identify causative risk factors and, although our current knowledge
may not prevent preterm labour, it may allow prediction and early intervention with
optimisation of the clinical circumstances around birth. Risk-based screening and
assessment can influence the type of care received, place of birth and judicious use
of steroids, all determinants of perinatal outcome. Epidemiological research has an
important role in patient counselling for any pregnancy complicated by preterm labour

* Tel.: 353 (0)1 4531888; Fax: 353 (0)1 4531614.


E-mail address: deirdre.j.murphy@tcd.ie
1521-6934/$ - see front matter 2007 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
j.bpobgyn.2007.03.001

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2 D. J. Murphy

but particularly for future potential pregnancies where there may be significant risks
for the mother and baby.
EPIDEMIOLOGY
Defining the problem
Preterm birth may result from preterm labour, spontaneous or induced, or it may be
planned by caesarean section due to maternal or fetal complications. The term indicated delivery is used to describe circumstances where preterm birth is the preferred
management approach and preterm labour usually refers to unplanned spontaneous
labour. It is now recognised that there is a degree of overlap between indicated preterm
birth and spontaneous preterm labour, and that these two clinical subtypes may share
common aetiologies.1,2 For example, a woman may present at 36 weeks gestation
and be diagnosed clinically with a placental abruption. The decision may be to proceed
to delivery (induced labour or caesarean section) because of unacceptable maternal
and fetal risks. Equally, it is likely that she would labour spontaneously with an evolving
retroplacental bleed. The former would be described as an indicated delivery in many
studies although clearly antepartum haemorrhage is a recognised aetiology of preterm
labour. For the purposes of this review the emphasis will be on spontaneous preterm
labour with recognition that there is an overlap with indicated delivery.
Preterm labour refers to labour with an onset before 37 weeks gestation. This is
essentially an arbitrary lower cut-off for a term pregnancy and there is clearly a big
difference between labour at 27 weeks gestation and labour at 36 weeks and 6 days.
From an epidemiological perspective it is possible to evaluate exposures (potential risk
factors) and outcomes (morbidity or mortality) on a gestational week by week basis
and this approach offers certain statistical advantages. However, most studies categorise births to allow comparisons of gestational age groups that share similarities and
are of a reasonable sample size. Epidemiological studies of preterm labour vary in
terms of categorisation but in general terms labour at <24 weeks is considered
pre-viable, <28 weeks is extremely preterm, 2831 weeks very preterm and 3236
weeks mildly (or moderately) preterm.3 The risk factors for worsening degrees of
prematurity may be similar but there is evidence that the strength of associations
increases.4 The emphasis in this review will be on preterm labour at <32 weeks
gestation where there is greatest risk and the strongest evidence base.
Many studies categorise neonatal events and outcomes by birth weight but clearly
this has the added complication of including small for gestational age babies who may
not be preterm. In addition the presence within a cohort of small for gestational age
babies, some of whom may be growth restricted, may confound associations.5 Therefore, studies that are defined by gestational age are preferred when exploring the
aetiologies and outcomes of preterm labour.
The critics of epidemiology will argue that population-based studies may describe
any number of associations but they do not define the cause of disease. The argument
between association and causation is an old one and in fact the epidemiological approach has remarkable similarities to laboratory-based approaches. Careful systematic
research of clearly defined questions with biologically plausible mechanisms repeated
in different settings and different populations, and with a doseresponse relationship
leads to a tentative suggestion of causation. These criteria were laid down by Bradford
Hill in 19656 and are outlined in Table 1. This approach can be demonstrated in some
Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
j.bpobgyn.2007.03.001

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Epidemiology and environmental factors 3

Table 1. Epidemiological studies association or causation.


Bradford Hill criteria for causation6
Strength e strong magnitude of association
Consistency e consistent findings between different studies/settings
Specificity e exposure associated with very specific disease
Temporality e plausible temporal relationship
Biological gradient e doseeresponse relationship; increased risk with greater exposure
Plausibility e credible scientific mechanism
Coherence e consistent with natural history of disease
Experimental evidence e exposure shows results consistent with association
Analogy e similar result we can draw a relationship to

carefully designed epidemiological studies of preterm labour and has been exploited by
geneticists and laboratory-based scientists within the relatively new fields of genetic
epidemiology and bioinformatics. Recent studies have recognised the importance
of looking at the interaction between epidemiological, environmental and genetic
factors when seeking to understand the origins of preterm labour.

Changing epidemiology
Preterm births comprise 610% of all births in Western countries and account for
more than two-thirds of all perinatal deaths. Even small changes in rates of preterm
birth could have a major impact on perinatal mortality, disability and healthcare needs
within communities. There are challenges in comparing rates of preterm labour over
time and between different settings due to inconsistent approaches to registration,
ascertainment and classification of preterm birth.7 Nonetheless, factors that might
be contributing to epidemiological changes in preterm birth include social inequality,
maternal age, marital status, immigration, maternal anthropometry and exposure to
cigarettes, drugs and alcohol.7
A Swedish population-based register study reported that the preterm birth rate
had decreased from 6.3% in 1984 to 5.6% in 2001 ( p < 0.0001) but with an increase
in the proportion of multiple births born preterm from 0.34% to 0.71%.8 The
composition of different subtypes in the Scandinavian low-risk population appeared
to be similar to populations with higher incidence of preterm birth and perinatal infections. In contrast, the overall proportion of preterm deliveries in Denmark increased
by 22% from 1995 to 2004.9 Spontaneous preterm deliveries in primiparous women at
low risk rose 51% from 3.8% to 5.7%. There was also a significant increase in multiple
births. There was a similar increase in singleton preterm rates in New Zealand over
a 20 year period (19801999) and of note, the greatest increase (72%) was among
those living in the most affluent areas.10 There was evidence of a change in risk factors
for preterm births in France between 1981 and 1995, suggesting that the classification
of high-risk groups should be brought up to date regularly.11
Recently evaluated risk factors for preterm labour are summarised in Table 2. The
search for epidemiological risk factors for preterm labour needs to be a dynamic
process as the profile of populations and the environment in which we live is subject
to change over time.
Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
j.bpobgyn.2007.03.001

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4 D. J. Murphy

Table 2. Epidemiological and environmental risk factors for preterm labour.


Maternal

Demographic
AfricaneAmerican/Aboriginal/Hispanic races
Low BMI/poor weight gain/excess weight gain
Young maternal age
Obstetric
Previous early pregnancy loss e induced/miscarriage
Previous preterm birth e indicated or spontaneous labour
Short inter-pregnancy interval (<12 months)
Medical
Procedures e LLETZ/amniocentesis

Fetal

Male gender
Multi-fetal pregnancy
Assisted conception

Paternal

Older paternal age

Environmental

Infection
Bacterial vaginosis/sexually transmitted infection
Periodontal infection
Socioeconomic/psychosocial
Social inequality/poverty/neighbourhood disadvantage
Physical violence
Marital status e single/cohabitation in context of high marriage rates
Stressful/traumatic life events/anxiety/depression
Substance use/toxins
Excess alcohol e 3 drinks per day/7 drinks per week
Smoking e any but particularly moderate or heavy
Cocaine e usually influenced by smoking
Pollutants e sulphur dioxide, particulate matter
Nutrition
Elevated homocysteine/suboptimal vitamin B-12 and B-6
Unbalanced polyunsaturated fatty acids (PUFA)
Multivitamin (non-use)

Genetic

TNF-a pro-inflammatory cytokine e polymorphisms


Factor VII/XIII e polymorphisms

Maternal factors
Race and ethnicity
AfricanAmerican women are over-represented in rates of preterm birth which is
thought to reflect multiple aetiologies. The race/ethnic-specific relations between
pre-pregnancy body mass index (BMI) and vaginal inflammation have been explored
in a multicentre cohort of over 11,000 American women.12 Ethnicity substantially
modified the magnitude of the BMI effect with underweight having a greater impact
on preterm birth among blacks and Hispanics than among whites. Low BMI also
Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
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Epidemiology and environmental factors 5

increased the risk of a high level of neutrophils and high vaginal pH measurement.
Cardiovascular reactivity was examined in another US study of black and white military
women. The two-fold increase in risk of preterm delivery among black women may
reflect their higher cardiac reactivity on computerised stress testing (autonomic
dysfunction) compared to white women.13
In Minnesota, USA, native-born black women were at almost 1.5 times the risk
of foreign-born blacks for delivery preterm, suggesting an association with residential
racial segregation.14 The social context has been explored further in a study in Ohio,
USA, including measures of neighbourhood disadvantage.15 Neighbourhood poverty
rates and housing vacancy rates increased the rate of very preterm birth for blacks
but with direct effects of cumulative exposure to inequality only for Hispanics.
There are higher rates of spontaneous preterm birth among aboriginal women in
Canada compared to non-aboriginal women with modifiable risk factors, including
low weight gain during pregnancy, inadequate prenatal care and high levels of perceived
stress.16 Similarly, rates of preterm birth are much higher for women living in France
who were born in the overseas French territories in the Caribbean, Indian Ocean and
sub-Saharan Africa. Excess risk was reported for spontaneous and medically indicated
preterm delivery.17
Anthropometric and demographic factors
There has been a growing awareness of the adverse pregnancy consequences of maternal obesity; however, preterm labour may be associated with extremes of maternal
weight. Three anthropometric measurements were evaluated as predictors for spontaneous preterm birth in a systematic review.18 The predictive value of BMI, weight
gain in pregnancy and maternal height were reported in eight primary studies of
122,647 women. All three maternal factors were poor predictors of preterm labour
with heterogeneity between studies. The main criticism of the studies related to
the use of a 37 weeks gestation cut-off with a recommendation for future studies
to use a more clinically appropriate reference standard of birth before 3234 weeks
gestation. A more recent study has evaluated the combined effects of pre-pregnancy
BMI and weight gain during pregnancy with categorisation of prematurity as very
(2031 weeks) and moderately (3236 weeks) preterm.18 There was a strong
association between very low weight gain and very preterm delivery that was of greatest magnitude among underweight women (adjusted OR 9.8, 95% CI 7.013.8).
Women with very high weight gain had approximately twice the odds of very preterm
delivery, regardless of pre-pregnancy BMI.
Physical activity correlates with weight and weight gain but there is a need to
differentiate between leisure time exercise and the activities of daily living. In a study
of low income women in Maryland, USA, leisure-time exercise (60 days in first and
second trimester) had a protective effect on preterm delivery (<37 weeks) (OR 0.51,
95% CI 0.270.95) but the risk was increased for women who had to climb stairs
more than ten times per day (OR 1.60, 95% CI 1.052.46).19 There was a U-shaped
relationship with television watching. These findings warrant further investigation
with attention to potential confounding or interaction with maternal weight. Similarly,
women with poor physical function reflecting the mothers pre-pregnancy health
status were nearly twice as likely to deliver preterm (OR 1.97; 95% CI 1.183.30)
even after adjusting for sociodemographic and pregnancy risk factors.20
The association between young maternal age and preterm labour remains controversial. In a Brazilian study where the prevalence of teenage pregnancy was high (29%)
Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
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6 D. J. Murphy

the risks of preterm birth were compared for women aged under 18 years, 1819
years and a reference group aged 2529 years.21 In the analysis adjusted for relevant
confounding factors, the risk of preterm birth was higher for women aged under
18 years (OR 1.70, 95% CI 1.023.08) but the risk was no higher for woman aged
1819 years or among non-primiparous teenagers. This suggests that the association
between young maternal age and preterm birth may have a biological basis or may be
due to residual confounding. The adolescents in a US study were significantly more
likely to be AfricanAmerican, single and to have been diagnosed with a sexually transmitted infection in pregnancy which may confound the reported association with preterm delivery (RR 1.12, 95% CI 1.041.21).22
Previous obstetric history
There is an increased tendency for preterm birth to recur in subsequent pregnancies.
In a US study of over 150,000 consecutive singleton births, if the first pregnancy
resulted in a spontaneous preterm birth, then affected women were more likely to
deliver preterm spontaneously in the subsequent pregnancy (adjusted OR 3.6, 95%
CI 3.24.0).2 This applied even if the first pregnancy was a medically indicated preterm
birth (OR 1.6, 95% CI 1.32.1). The greatest risk of recurrence tended to occur
around the same gestational age as the preterm birth in the first pregnancy.
The inter-pregnancy interval appears to contribute to the recurrence of preterm
birth. Women in Taiwan with inter-pregnancy intervals of <12 months were at
increased risk for a preterm birth in the subsequent pregnancy (OR 4.2, 95% CI
3.06.0).23 The risk decreased as the inter-pregnancy interval increased with a relatively low risk at 1848 months. Similarly, in a case-control study in Israel an interval
of <12 months was associated with an increased risk of preterm labour before
34 weeks.24
In a Swedish study of over 600,000 women, previous spontaneous and missed miscarriages were associated with an increased risk of preterm premature rupture of
membranes and preterm labour with the strongest association for delivery before
32 weeks.25 Similarly, threatened miscarriage in the first trimester has been associated
with preterm delivery (OR 3.0) in a large US prospective study.26 Induced abortion has
been associated with very preterm delivery (<33 weeks) in the French regional
EPIPAGE study (OR 1.5, 95% CI 1.12.0)27 and this was confirmed by the International
EUROPOP study across ten European countries.28 The strength of association
increased with decreasing gestational age and was consistent across countries with
varying rates of induced abortion. The increased risk included idiopathic preterm labour, preterm premature rupture of membranes and antepartum haemorrhage, but
not maternal hypertension indicated delivery. In a high-risk population of American
women a previous second trimester delivery or termination before 20 weeks was associated with pre-viable premature rupture of membranes or labour (1424 weeks).29
Medical procedures
A systematic review of obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions explored the relationship between large loop
excision of the transformation zone (LLETZ) and the risk of preterm delivery.30 The
risk of preterm delivery was increased (RR 1.70, 95% CI 1.242.35) as was the risk of
premature rupture of the membranes (RR 2.69, 95% CI 1.624.46).
Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm
labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
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Epidemiology and environmental factors 7

For the index pregnancy, genetic amniocentesis performed in the second trimester
is associated with an increased risk of both spontaneous and induced preterm delivery
(adjusted OR 1.59, 95% CI 1.311.92).31
Fetal factors
The existence of a male excess among preterm births may shed some light on the aetiology of preterm labour. A study measuring the association between fetal sex and
preterm birth in four original datasets reported more males among preterm and
very preterm births in most populations, including in vitro fertilisation (IVF) births
(OR 1.091.24).32 There was no male excess for two cohorts of black births or for
spontaneous onset births after IVF. The male excess appeared to be strongest for
spontaneous preterm births but not for induced births in the general population,
and remains unexplained.
Multi-fetal pregnancy is a well known contributor to spontaneous preterm labour
and accounts for 10% of all preterm births.3 The impact of increasing numbers of twins
and triplets on rates of preterm births has been investigated in an International
study.33 In each country (Canada, England and Wales, France, United States) the
increase in preterm delivery among multiple births contributed to the rise or stabilisation of the overall rates of preterm delivery. The increase in multi-fetal pregnancy as
a result of subfertility treatment has an important role to play as twins resulting from
subfertility treatment have an increased risk of preterm birth compared with naturally
conceived twins, albeit confined to mildly preterm birth (3436 weeks) (OR 1.6, 95%
CI 1.31.8).34
Paternal factors
Advanced paternal age has been reported to impair pregnancy outcome. In an Italian
study of women aged 2029 years the odds of preterm birth increased with paternal
age, with the strongest association for very preterm birth (<32 weeks).35 The OR
among men aged 4549 years reached 1.91 (95% CI 1.083.38). Similarly, in a Danish
study of first born babies to mothers aged 2029 years the risk of preterm birth increased with paternal age almost entirely resulting from an association with very preterm birth (<32 weeks).36 Compared with fathers aged 2024 years the odds ratios
increased linearly to 2.1 for fathers aged 50. The relationship between paternal and
maternal age differences and adverse perinatal outcomes was investigated in a US
study of almost 9 million births.37 An increase in preterm delivery was reported
among white women who were older than their partners but there was little evidence
of an increase for black women with varying parental age differences. This study
demonstrated that race and maternal age contribute to the effects of parental age
difference on the risk of preterm birth.
ENVIRONMENTAL FACTORS
Infection
Many studies have confirmed associations between genital tract infection and preterm
labour. A large number of clinical trials have evaluated antibiotic regimens as potential
therapeutic strategies. Bacterial vaginosis and Trichomonas vaginalis are two of the most
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8 D. J. Murphy

studied organisms in this context, with two recent large scale trials.38,39 Concomitant
infection with Chlamydia trachomatis among women with bacterial vaginosis or Trichomonas vaginalis was not associated with a statistically increased risk of preterm birth.40
Similarly, the gestational age at which bacterial vaginosis was screened and diagnosed
did not influence the increased risk of preterm birth.41 However, in a prospective longitudinal study of 3614 women, increased psychosocial stress was associated with
greater bacterial vaginosis prevalence and incidence independent of other risk
factors.42 There is also evidence to suggest that a change in vaginal flora following antibiotic therapy, with an increase in Escherichia coli or Klebsiella pneumoniae, results in
an increased risk of preterm birth (OR 1.5, 95% CI 1.052.1).43
The role of oral pathogens in the aetiology of preterm labour is a relatively recent
area of research. The hypothesis is that chronic periodontal infection serves as a reservoir for bacterial products and/or inflammatory mediators that play a role in the development of preterm labour and preterm low birth weight.44 The Oral Conditions
and Pregnancy (OCAP) study investigated 1020 women with antepartum and postpartum periodontal examination.45 Antepartum moderatesevere periodontal disease
was associated with an increased incidence of spontaneous preterm births (adjusted
RR 2.0, 95% CI 1.23.2). There was also a higher rate of very preterm delivery among
women with periodontal disease progression (RR 2.4, 95% CI 1.15.2). A case-control
study of 161 mothers in Hungary reported an association between maternal periodontal disease and preterm delivery with more than six implicated pathogens (e.g. Prevotella and Pophyromomas species).46 However, earlier results conflict with studies
reporting no association.47 There appears to be an association between vaginal bleeding, fetal exposure to oral pathogens and preterm birth at <35 weeks.48 It remains to
be determined whether the bleeding is the cause or result of fetal exposure to oral
pathogens but it is certainly a plausible hypothesis.
Socioeconomic factors
Preterm labour is strongly associated with social disadvantage and recurs in successive
pregnancies, increasing the burden of healthcare needs and disability on vulnerable
families. The role of social class inequality was examined in a Scottish cohort study between 1980 and 2000.49 The distribution of social class changed over time with greater
inequalities by the end of the 1990s than at the start of the 1980s. Over that time
period the relative index of inequality (RII) for preterm birth increased from 1.52
(95% CI 1.441.61) to 1.75 (95% CI 1.651.86). Despite a previous decrease in the
1980s, social inequality and its effects on preterm birth increased in the 1990s. Social
factors are also reported to be important determinants of preterm birth in transitional
Russia with increased risk among women with lower levels of education and in students.50
Physical violence during pregnancy has been evaluated in a number of studies.
Severe physical violence was significantly associated with spontaneous preterm labour
in a study of 550 participants in North Carolina, USA.51 The body site injured, timing
of violence and number of violent incidents were significant factors. A further study in
Birmingham, Alabama, USA confirmed this finding with preterm birth in 10.2% of
women subjected to physical violence (OR 1.6, 95% CI 1.32.5).52 In a South African
study of 229 interviewees, violence alone did not seem to cause preterm labour but
was part of a low socioeconomic lifestyle, including high maternal alcohol use.53
There is a significant elevated risk of preterm birth associated with both cohabitation (OR 1.29, 95% CI 1.081.55) and single motherhood (OR 1.61, 95% CI 1.262.07)
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Epidemiology and environmental factors 9

for women living in European countries where fewer than 20% of births occur outside
marriage.54 In contrast, there is no excess risk associated with marital status when
out-of-marriage births are more common.
Stress and psychosocial factors
It has been postulated that maternal stress may modulate the pregnant womans
susceptibility to preterm labour. A biobehavioural model has been proposed wherein
maternal stress may act via a neuroendocrine pathway that activates the maternal
placentalfetal endocrine systems that promote parturition, and/or via an immune/
inflammatory pathway where maternal stress may increase susceptibility to intrauterine
and fetal infectiousinflammatory processes.55 A review of published studies reports
conflicting results but the combined evidence from the three largest Scandinavian studies
suggests an association between perceived maternal life event stress and preterm
delivery.56 The concept of premature ageing has been suggested as a result of
cumulative stress or a major traumatic event.57 Maternal stress has been suggested as
an explanation for racial disparity in preterm labour; however, the results of the few
studies to date are mixed.58
In a study of French women, anxiety and depression combined with specific biomedical factors (underweight) was associated with spontaneous preterm labour.59
Similarly, thin women with a poor psychosocial profile who were depressed during
pregnancy were at increased risk of preterm birth in a prospective study of low income, predominantly AfricanAmerican, women in Alabama, USA.60 In another study
of maternal psychosocial factors, an unplanned pregnancy was not associated with an
increased risk of preterm birth.61
Substance use
The difficulty with studies evaluating alcohol exposure in pregnancy relates to underreporting of intake and discrepancies in the description of a drink or unit of alcohol.
Moderate intake defined as three or more drinks a day increased the risk of preterm
birth in an Italian study (OR 2.0, 1.8 and 1.9, respectively, for each trimester of pregnancy).62 There appeared to be a doseresponse effect in a large Danish study with
the highest risk for very preterm delivery among women consuming seven or more
drinks per week (RR 3.26, 95% CI 0.8013.24).63
The relationship between smoking and adverse pregnancy outcomes, including
preterm birth, has been described. Smokers were more likely to give birth to very preterm babies in a French study (adjusted OR 1.7, 95% CI 1.32.2).64,65 The relationship
between heavy smoking and very preterm birth was complex with a reduced risk of
very preterm birth due to gestational hypertension but an increased risk due to other
causes for both low to moderate and heavy smoking. Similarly, in a Swedish study,
moderate and heavy smokers were at increased risk of preterm labour from all causes
(OR 1.9; 95% CI 1.03.6,and OR 2.6, 95% CI 1.11.6, respectively).66
Prenatal cocaine exposure increased the risk of prematurity (OR 2.24) in a study of
women in Kentucky, USA.67 Tobacco but not marijuana significantly influenced the
outcome with a greater aetiological fraction attributable to tobacco. In another study
of psychiatric and substance use disorders, each had an independent association with
preterm delivery (OR 2.4, 95% CI 2.32.6 for substance use).68
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10 D. J. Murphy

Few therapeutic drugs are tested in pregnancy but inadvertent or clinically indicated
exposure can occur. A pharmaco-epidemiological study of Danish women reported
that sumatriptan (for headache) was associated with an increased risk of preterm
delivery and low birth weight.69 The authors acknowledged that this may reflect the
impact of disease severity or residual confounding rather than the treatment itself.
Nutrition
A few studies have explored nutritional factors as potential aetiological factors for
preterm labour. A small case-control study of Chinese women reported elevated
homocysteine and suboptimal vitamin B-12 and B-6 status in association with preterm
birth (<37 weeks).70 Folate status was not associated with preterm birth. These
results would need to be confirmed in larger studies. Women who take preconceptional multivitamins appear to have a lower risk of both early (<35 weeks)
and late (3536 weeks) preterm birth (OR 0.59, 95% CI 0.122.76, and OR 0.40,
95% CI 0.121.40, respectively).71
Dietary supplementation of omega-3 has been suggested as secondary prophylaxis
of preterm delivery in response to data suggesting that omega-3 fatty acids are capable
of prolonging the duration of gestation in the range of 47 days and that dietary intake
is marginal in Western populations.72 Carefully conducted randomised controlled trials would be required to establish the efficacy and effectiveness of such an approach.
The research on polyunsaturated fatty acids (PUFA) is not entirely consistent and may
depend on the environmental setting. The relation between intake of seafood in pregnancy and preterm delivery was evaluated in a Danish prospective cohort of 8729
women73, Adjusted odds for preterm delivery were increased by a factor of 3.6
(95% CI 1.211.2) in the zero consumption group compared with the highest consumption group. There was a doseresponse relation reflecting an intake of up to
0.15 g n-3 fatty acids. It was postulated that small amounts of fish or fish oil may confer
protection against preterm delivery. However, in a US study of seafood intake and
length of gestation, elongated n-3 PUFA intake and seafood intake were not associated
with length of gestation or risk of preterm birth.74
Coffee drinking in pregnancy was evaluated in a case-control study of over 2000
women in Italy. Compared with no consumption, a low consumption of coffee during
pregnancy did not have any significant effects on preterm birth, with results close to
unity for overall intake of caffeine.75
Pollution
Low level air pollution was evaluated in a cohort of 3988 newborn singletons in the
city of Kaunas, Lithuania.76 The risk of preterm birth increased by 25% (adjusted
OR 1.25; 95% CI 1.071.46) per 10 mg/m3 increase in nitrogen dioxide concentration
but there was no association with formaldehyde exposure. A time series analysis of
preterm births in Pennsylvania, USA provided evidence of an increase in preterm birth
with exposure to particulate matter 10 mm (PM10) and increasing levels of sulphur
dioxide.77 Traffic air pollution in Los Angeles, USA disproportionately affected low
socioeconomic status neighbourhoods in a study of traffic-related air pollution,
economic hardship and preterm birth.78 The authors concluded that efforts need to
focus not only on individual risk factors but also on the reduction of localised air
pollution in any strategy to reduce preterm births.
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Epidemiology and environmental factors 11

There was little effect of occupational exposures to pesticides on pregnancy outcomes among gardeners and farmers in Denmark, although the authors emphasised
that these findings may not apply to other countries.79 Similarly the risk of preterm
birth was not increased with use of the pesticides DDT and DDE in a study of
20,754 pregnancies in San Francisco, USA, but more robust studies were recommended prior to concluding safety, especially given the continuing role of these agents in
malaria control.80 A number of studies from Taiwan have addressed industrial air pollution from the petrochemical, petroleum, cement and thermal power industries.8184
Each study reported a significant association between air pollution and the risk of
preterm delivery with varying odds ratios (1.141.30).
GENETIC EPIDEMIOLOGY
Recent attention has focussed on the potential for genetic epidemiology to contribute
to our understanding of preterm labour. The emphasis is not only on identifying
potential maternal and fetal genetic susceptibilities but on exploring how these factors
interact with demographic, socioeconomic and psychosocial factors in activating
neuroendocrine and inflammatory pathophysiological processes.
In a review of 18 studies that examined associations between polymorphisms in the
maternal or fetal genome and preterm birth, polymorphisms in tumour necrosis factor
alpha (TNF-a), a proinflammatory cytokine, showed the most consistent increase in
the risk of preterm birth.85 A case-control study from Philadelphia, USA reported
an increased risk of spontaneous preterm birth with maternal carriage of the TNF2 allele and the association was modified by the presence of bacterial vaginosis (OR
6.1, 95% CI 1.921.0).86 This study provides preliminary evidence that an interaction
between TNF genetic susceptibility and environmental factors (i.e. bacterial vaginosis)
is associated with an increased risk of spontaneous preterm birth. In a further study,
selected TNF haplotypes were associated with spontaneous preterm birth in both
AfricanAmerican and white subjects.87
The impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth has been investigated in a large cohort of
very low birth weight infants and their mothers.88 Factor V Leiden, Factor VII, Factor
XIII and the prothrombin G20210A mutation were examined. The maternal carrier
status of the Factor VII-121del/ins polymorphism (OR 1.7, 95% CI 1.12.5) and
the lower frequency of infants factor XIII-Val34Leu polymorphism (OR 0.5, 95% CI
0.30.96) were found to be independently associated with preterm delivery.
Dihydrofolate reductase (DHFR) is required to convert the folic acid used in supplements and food fortification to the reduced folate forms used for cell division. The
DHFR 19-base pair deletion allele was associated with a greater risk of preterm delivery in a US study of 324 women (adjusted OR 3.0, 95% CI 1.08.8).89 In the presence
of low dietary folate, the allele may be a risk factor for preterm birth, reflecting
a geneenvironment interaction.
Intergenerational effects would support the role for genetic susceptibility in the
aetiology of preterm labour, although clearly environmental factors may persist through
generations of families. The Scandinavian countries have high quality longitudinal birth
registries that allow an evaluation of intergenerational effects on perinatal outcomes.
In a study of over 38,000 Swedish motherfirst born offspring pairs, there was no
consistent evidence of an intergenerational effect for preterm birth, although such an
association was present for reduced intrauterine growth.90 Changes in putative genetic
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j.bpobgyn.2007.03.001

ARTICLE IN PRESS
12 D. J. Murphy

and environmental risk factors were investigated in a Danish study of over 10,000
women with successive births.91 There was a strong tendency to repeat preterm
delivery with a moderate increase in recurrence with social decline and moving from
a rural to an urban municipality, but no change in recurrence risk with change of
male partner.
PREDICTION OF PRETERM LABOUR
The epidemiological and environmental risk factors for preterm labour can be exploited to allow identification of high-risk women. The challenge lies in identifying
the high-risk first time mother given the wide range of risk factors that could apply
to the entire pregnant population in settings of deprivation. The woman who has laboured preterm in a previous pregnancy is readily identifiable and this is one of the
strongest predictors of recurrent preterm labour.
The accuracy of risk scores in predicting preterm birth has been explored in a systematic review of 19 primary accuracy articles evaluating 12 different risk-scoring
systems.92 The point estimates for the likelihood ratios varied widely among the
different risk-scoring systems. In otherwise asymptomatic women risk scoring in early
pregnancy had a wide range of accuracy in predicting spontaneous preterm birth and
poor specificity.
The combination of individual patient factors with cervical length scanning and/
or rapid fetal fibronectin testing has been proposed to allow prediction of preterm
delivery in patients with preterm labour. One such risk score (CLEOPATRA) has
been evaluated in 170 patients with preterm labour at 2434 weeks.93 The
model with fetal fibronectin (CLEOPATRA II) performed better, with a discriminatory power 0.81 (95% CI 0.690.93). In contrast, for twins the prediction of spontaneous preterm delivery was not improved by combining maternal characteristics
and measurement of cervical length at 2224 weeks.94 It has been proposed that
new screening tests (epidemiological and clinical) should not be applied systematically to all pregnant women until their advantages and drawbacks are fully
evaluated.95
SUMMARY
There are many clues to the aetiologies of preterm labour within carefully conducted epidemiological and environmental studies. It is clear that no single approach
will be effective for prevention or treatment as there appear to be complex interactions between maternal anthropometry, environmental exposures and genetic susceptibility of the mother and fetus. In some ways this should be a source of
optimism as there may be several targets for intervention once the complete pathway to preterm labour is understood. Risk-scoring tools have been disappointing for
low-risk populations but the woman who has laboured and delivered preterm in
a previous pregnancy should be advised to delay pregnancy for at least a year and
can be monitored closely for recurrence. Women should be counselled on modifiable risk factors which will also encourage a healthier lifestyle. A coordinated research approach that brings together the disciplines of epidemiology, laboratorybased science and clinical trials offers the best hope of significant advances in this
important aspect of perinatal care.
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labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/
j.bpobgyn.2007.03.001

ARTICLE IN PRESS
Epidemiology and environmental factors 13

Practice points
 a careful antenatal booking history can screen for risk factors for preterm
labour, although the predictive value and specificity of scoring systems are poor
 advise women about modifiable risks factors for preterm labour, including low
pregnancy weight gain, excess weight gain, smoking, alcohol consumption and
use of recreational drugs
 advise women who have delivered preterm in a previous pregnancy that the
optimal inter-pregnancy interval is between 18 and 48 months
 social contributors to preterm labour include poor housing, environmental
pollution, domestic violence and stressful life events and require a public health
policy approach
 polymorphisms of the proinflammatory cytokine TNF-a and possibly some key
prothrombotic factors may interact with maternal and environmental factors
to increase the risk of preterm labour

Research agenda
 a combined approach to research encompassing epidemiology, pathophysiology
and clinical care is required to understand the aetiologies, prevention and optimal management of preterm labour
 the March of Dimes (US-based research charity) Scientific Advisory Committee on Prematurity recommend targeting of six overlapping categories: epidemiology, genetics, disparities (social inequality), inflammation, biological stress
and clinical trials96

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