INTRAUTERINE GROWTH RESTRICTION: Risk Factors and Pathogenesis Joserizal Serudji

Department./FMU of Obstetrics and Gynecology Faculty of Medicine of Andalas University/M. Djamil Hospital Padang ABSTRACT The fetus is thought to have an inherent growth potential that, under normal circumstances, yields a healthy newborn of appropriate size. The ability to reach an optimal birth weight results from the interaction between the fetal growth potential and the environment. The fetus requires several substrates for normal growth. Any persistent decrease in the availability of any of these substrates will limit the ability of the fetus to reach its growth potential. Certain pregnancies are at high risk for restricted fetal growth. Intrauterin growth restriction (IUGR) itself carries an increased risk of perinatal mortality and morbidity. There are two factors necessary to define IUGR fetus: first, the fetal weight is at or below the tenth percentile for gestational age and sex; second, there is a pathological process present that prevents expression of normal growth potential. Growth inhibition during the first stage (hyperplastic stage) produces an undersized fetus with fewer cells, but normal cell size, causing symmetric IUGR. Growth inhibition during stage two (hyperplastic and hypertrophic stages) and three (hypertrophic stage) causes a decrease of cell size and fetal weight with less effect on total cell number and fetal length and fetal head circumfernce, causing asymmetric IUGR. Keywords: Intrauterine growth restriction, risk factors, pathogenesis INTRODUCTION Fetal growth is dependent on genetic, placental and maternal factors. The fetus is though to have an inherent growth potential that, under normal circumstances, yields a healthy newborn of appropriate size. The maternal-placental-fetal units act in harmony to provide the needs of the fetus while supporting the physiologic changes of the mother.1 The ability to reach an optimal birth weight results from the interaction between the fetal growth potential and the environment. The growth potential varies from race to race and from individual to individual.2 Human fetal development has four periods of growth:3 1. Slow growth: 0 to 1516 weeks, less than 10 grams per week. 2. Accdelerating growth: 1017 to 2627 weeks, 85 grams per week. 3. Maximum growth: 2627 to 3738 weeks, 200 grams per week. 4. Decelerating growth: 3738 to 44 weeks, more than 70 grams per week. The normal rate of fetal growth in an ideal case is limited by its internal constraints, which may be genetic in nature. Eventually, however, placental function is no longer sufficient to satisfy the demands of maximal fetal growth, which then decelerates.3 The fetus requires several substrates for normal growth. The most important are oxygen, glucose, and amino acids. Oxygen crosses the placenta by simple diffusion and is necessary for the formation of chemical energy in the form of adenosine triphosphate (ATP). Glucose crosses the placenta by facilitated diffusion, is used in the formation of energy, and provides the carbon building blocks for the synthesis of lypids, glycogen, nucleotides, and other molecules. Amino acids cross the placenta by active transport and are essential for the synthesis of protein. Any persistent decrease in the availability of any

of these substrates will limit the ability of the fetus to reach his or her growth potential. Persistent and severe substrate deficiency may threaten the ability of the fetus to survive.2 There are so many factors associated with reducing substrates supplies to the fetus. Understanding and recognizing these factors may promote the awareness of providers roling in obstetrics services to closely monitor fetal wellbeing, especially fetal growth. The purpose of writing this paper is to refresh our mind about: a) the risk factors of IUGR, so that we may ensure ourselves about the important of early detection of risk factor(s) in the effort to comprehensively overcome IUGR issues; and b) the pathogenesis of IUGR in such extent, so that it may generate our idea(s) about how to properly diagnose and how to effetively manage IUGR fetus. TERMINOLOGY The term intrauterine growth restriction has largely replaced the term intrauterine growth retardation. The term fetal growth restriction is now preferred, to avoid undue alarm in parents, to whom the term retardation implies abnormal mental function.4 Intrauterine growth restriction (IUGR) refers to a condition in which a fetus is unable to achieve its genetically determined potential size. It means that babys growth slows or ceases when it is in the uterus. This functional definition seeks to identify a population of fetuses at risk for modifiable but otherwise poor outcomes. The definition intentionally exludes of fetuses that are small for gestational ages (SGA) but are not pathologically small.5 Most of authors prefer 10th percentile as a cut-off point.6 Thus, SGA is defined as growth at the 10th or less percentile for weight of all fetuses at that gestational age. It is reported that by using 10th percentile cut-off, the incidence of SGA is about 37 %. The others pointed out 5th percentile, 3rd percentile, or two standard deviations below the mean for gestational ages.7 The implication of this various cut-off point is, the lower the cut-off point, the lower the incidence and the higher the morbidity and mortality. SGA fetus includes fetuses that have failed to achieve their growth potential and fetuses that are constitutionally small.8 In other word, not all fetuses that are SGA are pathologically growth restricted and, in fact, may be constitutionally small. Similarly, not all fetuses that have not met their genetic growth potential are in less than 10th percentile for estimated fetal weight (EFW).5 The problem derived from the definition of IUGR as mentioned above is, we do not know the inherent growth potential of the fetus. Nevertheless, there are two factors necessary to define intrauterine growth restriction fetus: first, the fetal weight is at or below the tenth percentile for gestational age and sex; second, there is a pathological process present that prevents expression of normal growth potential.9 So, the term IUGR should not be used where there is no evidence of abnormal genetic or environmental influences affecting growth. RISK FACTORS IUGR occurs when gas exchange and nutrient delivery to the fetus are not sufficient to allow it to thriven in utero. This prosess can occur primarily because of maternal disease causing decreased oxygen-carrying capacity, a dysfunctional oxygen delivery system secondary to maternal vascular disease, or placental damage resulting from mamternal disease.5 Thus, of many different factors causing IUGR, they may divided into two large categories, based on etiology. These categories include fetoplacental factors and maternal factors. Several factors contributing fetal growth restriction are:4 Constitutionally small mother Small women typically have smaller babies. There are intergeneration effects on birthweight that are transmitted through the maternal line. Reduced of intrauterine growth of the mother is a risk factor for reduced intrauterine growth of her children. It is unclear, whether or not the phenomenon of a small mother giving birth to a small infant is nature

or nurture. Nevertheless, the environment provided by the mother was more important than her genetic contribution to birthweight. Poor maternal weight gain and nutrition In the woman of average or low weight, lack of weight gain throughout pregnancy may be associated with fetal growth restriction. Lack of weight gain in the second trimester is strongly correlated with decreased birthweight. If the mother is large and otherwise healthy, however, below-average maternal weight gain without maternal disease is unlikely to be associated with appreciable fetal growth restriction. Social deprivation The effect of social deprivation on birth weight is interconnected to the effects of associated lifestyle factors such as smoking, alcohol or other substances abuse, and poor nutrition. Fetal infections Viral, bacterial, protozoon, and spirochaetal infections have been implicated on fetal growth restriction. Cytomegalovirus is associated with direct cytolysis and loss of functional cells. Rubella infection causes vascular insufficiency by damaging the endothelium of small vessels. Cell division rate is also reduced in congenital rubella infection. Hepatitis A and B are associated with preterm delivery, but may also adversly affect fetal growth. Listeriosis, tuberculosis, and syphilis have been reported to cause fetal growth restriction.Toxoplasmosis is the protozoon infection most often associated with compromised fetal growth, but congenital malaria may produce the same result. Congenital malformations In general, the more severe the malformation, the more likely the fetus is to be small for gestational age. This especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations. Chromosomal abnormalities Placenta of the fetuses with autosomal trisomies have a reduced number of small muscular arteries in the tertiary stem villi; so both placental insufficiency and primary abnormal cellular growth and differentiation may contribute to the significant degree of fetal growth restriction often associated with karyotype abnormalities. Among chromosomal abnormalities, trisomy 18 is the most related to growth restriction, followed by trisomy 13 and trisomy 21. Significant growth restriction is not seen with Turner syndrome or Klineferlter syndrome. Trisomy 16 Patches of trisomy 16 in placenta called confined placental mosaicism -- lead to placental insufficiency that may account for many cases of previously unexplained fetal growth restriction. In these pregnancy, chromosome abnormality is confined to the placenta. Primary disorders of cartilage and bone Numerous inherited syndromes such as osteogenesis inferfecta and various chondrodystrophies are associated with fetal growth restriction. Chemical teratogens Any teratogen is capable of adversly affecting fetal growth. Some anticonvulsants, such as phenitoin and trimethadione, may produce specific and characteristic syndromes that include fetal growth restriction. Cigarette smoking causes growth restriction as well as preterm delivery in a direct relationship with the number of cigarettes smoked. Narcotics and related drugs act by decreasing maternal food intake and fetal cell number. Alcohol is a potent teratogen that acts in a linear dose-realated fashion. Cocaine use is also associated with poor fetal weight gain, and it is suggested that this may be a result of frequent cigarette use and poor prenatal care rather than a direct effect of cocaine. Vascular disease Chronic vascuar disease, especially when further complicated by superimposed preeclampsia, commonly causes growth restriction. Preeclampsia itself may cause fetal growth failure, especially when the onset is before 37 weeks.

Chronic renal disease Renal disease may be accompanied by restricted fetal growth. Chronic hypoxia When exposed to a chronically hypoxic environment, such as women in high altitude or with cyanotic heart disease, some fetuses have significant reduction in birthweight. Maternal anemia In most cases, anemia does not cause growth restriction. Exceptions include sickle cell disesase or other inherited anemias associated with serious maternal disease. Conversly, deficient total maternal blood volume early in pregnancy has been linked to fetal growth restriction. Placental and cord abnormalities Chronic partial placental separation, extensive infarction, or chorioangioma are likely to cause restricted fetal growth. A circumvallate placenta or a placenta previa may impair growth, but usually the fetus is not markedly smaller than normal. Marginal insertion of the cord and espedially velamentous insertions are more likely to be accompanied by a growth restricted-fetus, as well as many conditions contributing to placental insuffiency. Multiple fetuses Pregnancy with two or more fetuses is more likely to be complicated by diminished growth of one or both fetuses compared with normal singleton. Antiphospholipid antibody syndrome Two classes of antiphospholipid antibodies have been associated with fetal growth restriction, namely anticardiolipin antibodies and lupus anticoagulant. Pathophysiological mechanism in the fetus appear to be caused maternal platelet aggregation and placental thrombosis. Extrauterine pregnancy The fetus gestated outside the uterus is usually growth restricted. Also, some maternal uterine malformations have been linked to impaired fetal growth. PATHOGENESIS AND CATEGORIES There are standards or averages in weight for unborn babies according to their gestational age in weeks, however, using a fetal growth curve derived from population and applying it to another can result in over- or under estimation of the true incidence of SGA. A population of smaller individuals will have smaller babies, so the difference lies in genetic growth potential.9 The normal intrauterine growth pattern occurs in three stages. In the first stage, four to 20 weeks gestation, rapid cell division and multiplication (hyperplasia) occur as as the embyo grows into a fetus. In the second stage, 20 28 weeks gestation, cell division (hyperplasia) declines and the cells increase in size (hypertrophy). In stage three, 28 40 weeks, there is a rapid increase in cell size, rapid accumulation of fat, muscle, and connective tissu. Ninety-five percent of fetal weight gain occurs during the last 20 weeks of gestation. If the delicate process of development and weight gain is disturbed or interrupted, the baby can suffer from restricted growth.9 There are two distinctive categories of growth restriction, indicating the stage at which the development slowed: symmetrical and asymmetrical growth restriction. Symmetrical IUGR may occur when the unborn baby experiences a problem during early development, and asymmetrical IUGR may occur when it experiences a problem during later development.9 Growth inhibition during the first stage produces an undersized fetus with fewer cells, but normal cell size, causing symmetric IUGR. In symmetrical IUGR, weight, head and length are all below the 10th percentile and the babys head and body are proportionately small. Thus, symmetric growth restriction implies a fetus whose entire body is proportionally small.1 Conditions associated with symmetric IUGR include: genetic (constitutional, chromosomal and single gene defect, and deletion disorders and inborn errors of metabolism), congenital anomalies, intrauterine infections, and therapeutic

iradiation. Substance abuse and cigarette smoking, depending on dose and timing, can cause either symmetrical or asymmetrical IUGR.9 Growth inhibition during stage two and three causes a decrease of cell size and fetal weight with less effect on total cell number and fetal length and fetal head circumfernce, causing asymmetric IUGR.9 Asymmetric growth restriction implies a fetus who is undernourished and is directing most of its energy to maintaining growth of vital organs, such as brain and heart, at the expensive of the liver, muscle and fat. This is the role of brain sparing effect (redistribution mechanism). A fetus with asymmetric IUGR has a normal head dimension but a small abdominal circumference (due to decreased liver size), scrawny limbs (because of decreased muscle mass), and thinned skin (because of decreased fat). If the insult causing asymmetric growth restriction is sustained long enough or is severe enough, the fetus may lose the ability to compensate and will become symmetrically growth-restricted.1 This type of growth restriction is usually the insult of placental insufficiency. Conditions associated with asymmetric IUGR include: uteroplacental insufficiency, which is usually caused by chronic hypertention or preeclampsia; chronic renal disease; cyanotic heart disease; hemoglobinopathies; placental infarcts; abruptio placenta; multiple gestation; velamentous insertion of the umbilical cord and circumvallate placenta; and high altitude. In asymmetrical IUGR, weight is below the tenth percentile, and head and length are preserved. The brain can weigh five or six times more than the liver, whereas in a normal infant, the brain weighs about three times more than liver.9 PERINATAL COMPLICATIONS IUGR causes a spectrum of perinatal complications, including fetal morbidity and mortality, iatrogenic prematurity, fetal compromise in labor, need for induction of labor, and cesarean delivdery.5 They can be classified as antepartum complications and neonatal complications.2 a. Antepartum Complications 1. Stillbirth There is a definite relationship between uterine malnutrition and the incidence of stillbirths. Approximately 20 % of all stillborn infants show signs of growth retardation, and IUGR was associated with and probably responsible for 26 % of stillbirths among infants with a birth weight less than 2500 gram.2 2. Oligohydramnion The most likely caused of oligohydramnions in IUGR babies is decreased fetal urinary output caused by redistribution of the blood flow with preferential shunting to the brain and decrease in renal perfusions.2 3. Intrapartum fetal acidosis Fetal monitoring signs of acidosis such as late decelerations, severe variable decelerations, decreased beat-to-beat varaibility, and episode of bradicardia are more frequent in IUGR.2 b. Neonatal Complications IUGR infants who are also premature are at greater risk for medical problems than full-term IUGR infants. Full-term IUGR infants do not have the complications related to organ system immaturity that premature infants have.10 At birth, IUGR infant shows signs of soft tissue wasting. The skin is loose and thin, and there is little subcutaneous fat. The abdomen is scaphoid, the ribs are protuberant, and the muscle mass of the arms, buttocks, and thighs is reduced. The umbilical cord is limp, thin, and frequently meconium stained. The head circumference is larger than the abdominal circumference. The IUGR infant frequenly develops complication. They are: related to perinatal asphyxia and acidosis, metabolic alterations, and .related to spesific cause of fetal growth retardation.2 1. Meconium aspiration syndrome

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Meconium aspiration was a major cause of mortality and morbidity in the IUGR baby. The use of amnioinfusion before birth and proper resuscitative techniques after birth has significantly decreased the severity of this problem.2 Persistent fetal circulation Persistent fetal circulation is a common sequelae of perinatal hypoxia and acidosis. The pathophysiology is characterized by severe pulmonary vasoconstriction with persistent blood flow through the ductus arteriosus. The main signs are hypoxia with moderate hypercarbia, righ-to-left shunting without evidence of intrinsic heart desease, and cardiomegaly.2 Hypoxic-ischemic encephalopathy Hypoxic-ischemic encephalopathy is a nonspesific diagnosis used to describe a variety of neurologic signs and symptoms occuring after episodes of severe perinatal asphyxia. The injury to the brain may range from cerebral edema to diverse forms of intracranial bleeding to nonspecific asphyxial injuries. The symptoms include seizures, irritability, twitching, and apnea.2 Hypoglycemia This condition is caused by lack of adequate glycogen stores in liver and muscle and decreased subcutaneous fat. Another important component is a relative deficiency of hepatic gluconeogenic enzymes. The symptoms are nonspecific: jitteriness, twitching, apnea, tachypnea, and occasionally seizures.2 Hypocalcemia Hypocalcemia, particularly during the first day of life, is common in IUGR babies. Relative hypoparathyroidism, increased calcitonin level caused by chronic asphyxia, and increased phophorus level resulting from increased tissue catabolism seem to be responsible for this problem. Symptoms are nearly identical to those of hypoglycemia.2 Hyperviscosity syndrome The main manifestation is polycythemia, defined as a central hematocrit in excess of 65 % or hemoglobin concentration above 22 g/dl. Polycythemia is probably caused by chronic hypoxic stimulation of the fetal hematopoietic system. Hyperviscosity slows the blood flow in the microcirculation with production of pulmonary infarcts and necrotizing enterocolitis. The destruction of a large number of red cells results in hyperbilirubinemia. Volume overload may lead to pulmonary edema and congestive heart failure.2 Deficient temperature controle The IUGR fetus has poor temperature control and a tendency toward hypothermia resulting from deficient energy stores and the small size of the subcutaneous fat layer.2

CONCLUSIONS 1. IUGR is a part of SGA which occurs due to pathological process that prevents expression of normal growth potential 2. Growth restricted fetuses have a great chance to suffer from many prenatal and/or neonatal complications. 3. There so many risk factors should be recognized in attemp to caring IUGR 4. Pathophysiologically, all insults impairing substrates supply to the fetus may reduce cellular hyperplastic or cellular hypertrphic process resulting in symmetrical or asymmetrical IUGR respectively. Takehome message: The most important thing in efforts to comprehensively overcome IUGR issues is the early detection of its risk factor(s), -- eg. premarital, preconception, or as early as possible in pregnancy.

REFERENCES 1. Peleg, D, Kennedy, C.M, and Hunter, S.K. Intrauterine Growth Restriction: Identification and Management. Iowa: University of Iowa Hospitals and Clinics. 2. Arias, F. Practical Guide ti High-risk Pregnancy and Delivery. 2nd ed.1993;301-318. Baltimore: Mosby Year Book. 3. Newman, C.H and Carrol, B.A. Fetal Biometry and Intrauterin Growth Retardation: Current Concepts. West J Med 1984; 140:414-420. 4. Cunningham, F.G, et al. Williams Obstetrics 21st ed. 2003.Boston: McGraw-Hill. 5. Ross, M.G. Intrauterine Growth Restriction. Medscape. 2011. (online). http://emedicine.medscape.com/article/ Retrieved on May, 20th, 2011 6. Vandenbosche, R.C. and Kirchner, J.T. Intrauterine Growth Retardation. American Family Physician. 1998.(online). http://www.aafp.org/afp/981015ap/. Retrieved on May, 20th, 2011. 7. Reece, E.A, and Hagay, Z. Prenatal Diagnosis of Deviant Fetal Growth. In: Reece, E.A, et al. Medicine of the Fetus & Mother. 1993. Philadelphia: J.B Lippincott Company. 8. Willacy, H. Intrauterine Growth Restriction. Patient.co.uk. 2010. (online). http://www.patent.co.uk/doctor/Intrauterin-Growth-Retardation.htm. Retrieved on May, 20th, 2011. 9. Bennington, L.K. Intrauterine Growth Retardation. Childrens Health. (online). http://www.healthofchildren.com/I-K/Intrauterin-Growth-Retardation.html. Retrieved on May, 20th, 2011. 10. Kendig, J.W. Small-for-Gestational-Age Infant (SGA) (Dysmaturity; Intrauterine Growth Restriction). Merck. 2007. (online). http://www.merckmanuals.com/. Retrieved on May, 20th, 2011.