Nearly 20 percent of the almost 4 million infants born in the United States are at the low and high extremes of fetal growth. In 2010, 8.2 percent of infants weighed < 2500 g at birth, whereas 7.6 percent weighed > 4000 g. And although most low-birthweight infants are born preterm, approximately 3 percent are term. The proportion of infants with birthweight < 2500 g has increased by more than 20 percent since 1984, and at the same time, the incidence of birthweight > 4000 g continues to decline (Martin, 2012). This shift away from the upper extreme is difficult to explain because it coincides with the epidemic prevalence of obesity (Morisaki, 2013).
Human fetal growth is characterized by sequential patterns of tissue and organ growth, differentiation, and maturation. However, the “obstetrical dilemma” postulates a conflict between the need to walk upright—requiring a narrow pelvis—and the need to think—requiring a large brain, and thus a large head. Some have speculated that there may be evolutionary pressure to restrict growth late in pregnancy (Dunsworth, 2012; Espinoza, 2012). Thus, the ability to growth restrict may be adaptive rather than pathological.
Fetal growth has been divided into three phases. The initial phase of hyperplasia occurs in the first 16 weeks and is characterized by a rapid increase in cell number. The second phase, which extends up to 32 weeks’ gestation, includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetal growth is by cellular hypertrophy, and it is during this phase that most fetal fat and glycogen are accumulated. The corresponding fetal-growth rates during these three phases are 5 g/day at 15 weeks’ gestation, 15 to 20 g/day at 24 weeks, and 30 to 35 g/day at 34 weeks (Williams, 1982). As shown in Figure 44-1, there is considerable biological variation in the velocity of fetal growth.
FIGURE 44-1 Increments in fetal weight gain in grams per day from 24 to 42 weeks’ gestation. The black line represents the mean and the outer blue lines depict ±2 standard deviations. Data from pregnancies managed at Parkland Hospital. (Image courtesy of Dr. Don McIntire.)
Fetal development is determined by maternal provision of substrate, placental transfer of these substrates, and fetal growth potential governed by the genome. However, the precise cellular and molecular mechanisms by which normal fetal growth ensues are incompletely understood. That said, there is considerable evidence that insulin and insulin-like growth factors, particularly insulin-like growth factor-I (IGF-I), have an important role in regulation of fetal growth and weight gain (Luo, 2012; Murray, 2013). These growth factors are produced by virtually all fetal organs and are potent stimulators of cell division and differentiation.
Other hormones implicated in fetal growth have been identified in recent years, particularly hormones derived from adipose tissue. These hormones are known broadly as adipokines and include leptin, the protein product of the obesity gene. Fetal leptin concentrations increase during gestation, and they correlate with birthweight (Forhead, 2009; Karakosta, 2011). This relationship, however, is controversial in growth-restricted fetuses (Kyriakakou, 2008; Mise, 2007). Other adipokines under investigation include adiponectin, ghrelin, follistatin, resistin, visfatin, vaspin, omentin-1, apelin, and chemerin. Data for these adipokines are often conflicting, and their roles in normal and disordered fetal growth are still being elucidated (Chap. 48, p. 961).
Fetal growth is also dependent on an adequate supply of nutrients. As discussed in Chapter 4 (p. 53), glucose transfer has been extensively studied during pregnancy. Both excessive and diminished maternal glucose availability affect fetal growth. Reducing maternal glucose levels may result in a lower birthweight. Still, growth-restricted neonates do not typically show pathologically low glucose concentrations in their cord blood (Pardi, 2006). Fetal-growth restriction in response to glucose deprivation generally results only after long-term severe maternal caloric deprivation (Lechtig, 1975).
Excessive glycemia produces macrosomia. Varying levels of glucose affect fetal growth via insulin and its associated insulin-like growth factors discussed earlier. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) found that elevated cord C-peptide levels, which reflect fetal hyperinsulinemia, have been associated with increased birthweight. This relationship was noted even in women with maternal glucose levels below the threshold for diabetes. Overgrowth does occur in the fetuses of euglycemic women. Its etiology is thus likely more complicated than a paradigm of dysregulated glucose metabolism resulting in fetal hyperinsulinemia (Catalano, 2011).
Excessive transfer of lipids to the fetus has also been postulated to result in fetal overgrowth (Higa, 2013). Free or nonesterified fatty acids in maternal plasma may be transferred to the fetus via facilitated diffusion or after liberation of fatty acids from triglycerides by trophoblastic lipases (Gil-Sánchez, 2012). Generally speaking, lipolytic activity is increased in pregnancy, and fatty acids have been reported to be increased in nonobese women during the third trimester (Diderholm, 2005). In obese women without diabetes who were fed a controlled diet, neonatal adiposity was strongly linked both with fasting triglyceride levels in early pregnancy and with free fatty acid levels at 26 to 28 weeks’ gestation (Harmon, 2011). Other studies have correlated maternal triglyceride levels with birthweight in both early and late pregnancy (Di Cianni, 2005; Vrijkotte, 2011). Overgrown infants have higher placental levels of certain fatty acids, particularly omega-3, and this has been associated with increased trophoblastic lipase expression (Varastehpour, 2006). Conversely, growth restriction in the third trimester has been associated with decreased maternal lipolysis (Diderholm, 2006). This may be related to dysregulation of the triglyceride lipase gene family, which has been reported in placentas from pregnancies complicated by fetal-growth restriction (Gauster, 2007).
Amino acids undergo active transport from maternal blood to the fetus, which explains the normally higher fetal concentrations. This concentration differential is decreased in growth restriction because of lower fetal amino acid levels and higher maternal amino acid concentrations (Cetin, 1996). The etiology of this altered ratio is uncertain, but there are multiple points at which dysregulation can occur. Amino acids that reach the fetus must first cross the microvillus membrane at the maternal interface, traverse the trophoblastic cell, and finally cross the basal membrane into fetal blood (Chap. 5, p. 92). This process is incompletely understood, particularly with respect to trophoblast metabolism of amino acids and export mechanisms from the trophoblast to the fetus. Jansson and colleagues (2013) have linked expression and activity of particular amino-acid transporters at the microvillous membrane with increasing birthweight and maternal body mass index (BMI). Expression of particular amino acid efflux transporters has been positively correlated with multiple measures of fetal and neonatal growth (Cleal, 2011).
Normative data for fetal growth based on birthweight vary with ethnicity and geographic region. For example, infants born to women who reside at high altitudes are smaller than those born at sea level. Term infants average 3400 g at sea level, 3200 g at 5000 feet, and 2900 g at 10,000 feet. Accordingly, researchers have developed fetal-growth curves using various populations and geographic locations throughout the United States (Brenner, 1976; Ott, 1993; Overpeck, 1999; Williams, 1975). Because these curves are based on specific ethnic or regional groups, they are not representative of the entire population.
To address this, data such as those shown in Table 44-1 were derived on a nationwide basis in both the United States and Canada (Alexander, 1996; Kramer, 2001). Data from more than 3.1 million mothers with singleton liveborn infants in the United States during 1991 were used to derive the growth curve by Alexander and colleagues, colored red in Figure 44-2. Also shown, the previously published regional fetal-growth curve data in general underestimated birthweights compared with national data. Importantly, there are significant ethnic and racial variations in neonatal mortality rates within the national neonatal mortality rate and within national birthweight and gestational age categories (Alexander, 1999, 2003).
TABLE 44-1. Smoothed Percentiles of Birthweight (g) for Gestational Age in the United States Based on 3,134,879 Singleton Live Births
FIGURE 44-2 Comparison of fetal-growth curves for infants born in different regions of the United States and compared with those of the nation at large. (Modified from Alexander, 1996.)
The work of Alexander and associates (1996) is most accurately termed a population reference, rather than a standard. Iams (2010) emphasizes the problems that result from blending a population reference for fetal growth with a fetal-growth standard. A population reference incorporates pregnancies of varying risks, along with the resulting outcomes, both normal and abnormal. In contrast, a standardincorporates normal pregnancies with normal outcomes. Because population references include preterm births, which are more likely to be growth restricted, it has been argued that the associated birthweight data underestimate deficient fetal growth (Mayer, 2013; Zhang, 2010). That said, there is not a widely accepted standard for the United States.
Fetal Growth versus Birthweight
Most of what is known regarding normal and abnormal human fetal growth is actually based on birthweights that are assembled as references for fetal growth at particular gestational ages. This is problematic, however, because birthweight does not define the rate of fetal growth. Indeed, such birthweight curves reveal compromised growth only at the extreme of impaired growth. Thus, they cannot be used to identify the fetus who fails to achieve an expected size but whose birthweight is above the 10th percentile. For example, a fetus with a birthweight in the 40th percentile may not have achieved its genomic growth potential for a birthweight in the 80th percentile. The rate or velocity of fetal growth can be estimated by serial sonographic anthropometry. For example, Milovanovic (2012) demonstrated that the growth rate of intrinsically small-for-gestational age newborns approximates that of appropriate-for-gestational age neonates. Diminished growth velocity has been linked to perinatal morbidity and adverse postnatal metabolic changes that are independent of birthweight (Beltrand, 2008; Owen, 1997, 1998). Conversely, an excessive fetal-growth velocity, particularly of the abdominal circumference—which may be correlated with increased hepatic blood flow—is associated with an overgrown neonate. This is especially true when detected earlier in pregnancy (Ebbing, 2011; Kessler, 2011; Mulder, 2010).
Low-birthweight newborns who are small for gestational age are often designated as having fetal-growth restriction. In 1963, Lubchenco and coworkers published detailed comparisons of gestational ages with birthweights to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco (1967) then classified small-for-gestational-age (SGA) neonates as those whose weights were below the 10th percentile for their gestational age. Such infants were shown to be at increased risk for neonatal death. For example, the neonatal mortality rate of SGA infants born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights.
Many infants with birthweights < 10th percentile, however, are not pathologically growth restricted, but are small simply because of normal biological factors. As many as 25 to 60 percent of SGA infants are thought to be appropriately grown when maternal ethnic group, parity, weight, and height are considered (Gardosi, 1992; Manning, 1991). These small but normal infants also do not show evidence of the postnatal metabolic derangements commonly associated with deficient fetal growth. Moreover, intrinsically SGA infants remain significantly smaller during surveillance to 2 years compared with appropriate-for-gestational age neonates, but they do not show differences in measures of metabolic risk (Milovanovic, 2012).
Because of these disparities, other classifications have been developed. Seeds (1984) suggested a definition based on birthweight < 5th percentile. Usher and McLean (1969) suggested that fetal-growth standards should be based on mean weights-for-age, with normal limits defined by ±2 standard deviations. This definition would limit SGA infants to 3 percent of births instead of 10 percent. In a population-based analysis of 122,754 births at Parkland Hospital, McIntire and colleagues (1999) showed this definition to be clinically meaningful. Also, as shown in Figure 44-3, most adverse outcomes are in infants < 3rd percentile.
FIGURE 44-3 Relationship between birthweight percentile and perinatal mortality and morbidity rates in 1560 small-for-gestational age fetuses. A progressive increase in both mortality and morbidity rates is observed as birthweight percentile falls. (Data from Manning, 1995.)
More recently, individual or customized fetal-growth potential has been proposed in place of a population-based cutoff. In this model, a fetus that deviates from its individual optimal size at a given gestational age is considered either overgrown or growth restricted (Bukowski, 2008). Such optimal projections are based on maternal race or ethnicity. However, the superiority of customized growth curves has not been established (Hutcheon, 2011a,b; Larkin, 2012; Zhang, 2011).
Symmetrical versus Asymmetrical Growth Restriction
Campbell and Thoms (1977) described the use of the sonographically determined head-to-abdomen circumference ratio (HC/AC) to differentiate growth-restricted fetuses. Those who were symmetrical were proportionately small, and those who were asymmetrical had disproportionately lagging abdominal growth. Furthermore, the onset or etiology of a particular fetal insult has been hypothetically linked to either type of growth restriction. In the instance of symmetrical growth restriction, an early insult could result in a relative decrease in cell number and size. For example, global insults such as from chemical exposure, viral infection, or cellular maldevelopment with aneuploidy may cause a proportionate reduction of both head and body size. Asymmetrical growth restriction might follow a late pregnancy insult such as placental insufficiency from hypertension. Resultant diminished glucose transfer and hepatic storage would primarily affect cell size and not number, and fetal abdominal circumference—which reflects liver size—would be reduced. Such somatic-growth restriction is proposed to result from preferential shunting of oxygen and nutrients to the brain. This allows normal brain and head growth, that is—brain sparing. Accordingly, the ratio of brain weight to liver weight during the last 12 weeks—usually about 3 to 1—may be increased to 5 to 1 or more in severely growth-restricted infants.
Because of brain-sparing effects, asymmetrical fetuses were thought to be preferentially protected from the full effects of growth restriction. Considerable evidence has since accrued that fetal-growth patterns are much more complex. For example, Nicolaides and coworkers (1991) observed that fetuses with aneuploidy typically had disproportionately large head sizes and thus were asymmetrically growth restricted, which was contrary to contemporaneous thinking. Moreover, most preterm infants with growth restriction due to preeclampsia and associated uteroplacental insufficiency were found to have more symmetrical growth impairment—again, a departure from accepted principles (Salafia, 1995).
More evidence of the complexity of growth patterns was presented by Dashe and associates (2000). These investigators analyzed 8722 consecutive liveborn singletons who had undergone sonographic examination within 4 weeks of delivery. Although only 20 percent of growth-restricted fetuses demonstrated sonographic head-to-abdomen asymmetry, these fetuses were at increased risk for intrapartum and neonatal complications. Symmetrically growth-restricted fetuses were not at increased risk for adverse outcomes compared with those appropriately grown. These investigators concluded that asymmetrical fetal-growth restriction represented significantly disordered growth, whereas symmetrical growth restriction more likely represented normal, genetically determined small stature.
Finally, data from Holland further challenge the concept of “brain sparing.” Roza and associates (2008) provided surveillance of 935 Rotterdam toddlers enrolled between 2003 and 2007 in the Generation R Study. Using the Child Behavior Checklist at age 18 months, they found that infants with circulatory redistribution—brain sparing—had a higher incidence of behavioral problems. In another study, evidence of brain sparing was found in half of 62 growth-restricted fetuses with birthweight < 10th percentile and who showed abnormal umbilical artery Doppler flow studies (Figueras, 2011a). Compared with controls, these neonates had significantly lower neurobehavioral scores in multiple areas, suggesting profound brain injury.
Fetal-growth restriction was included by Brosens and colleagues (2011) as one of the “great obstetrical syndromes” associated with defects in early placentation. Rogers and coworkers (1999) had observed that implantation site disorders such as incomplete trophoblastic invasion are associated with both fetal-growth restriction and hypertensive disorders. They concluded that implantation site disorders may be both a cause and consequence of hypoperfusion at the placental site. These disorders ultimately lead to pregnancy complications such as fetal-growth restriction with or without maternal hypertension. This comports with the association of certain placental angiogenic factors with pregnancy hypertensive disorders (Chap. 40, p. 735). Thus, it may be that placentas from pregnancies complicated by hypertension elaborate these angiogenic factors in response to placental site hypoperfusion, whereas pregnancies complicated by fetal-growth restriction without hypertension do not (Jeyabalan, 2008).
Mechanisms leading to abnormal trophoblastic invasion are likely multifactorial, and both vascular and immunological etiologies have been proposed. Recently, atrial natriuretic peptide converting enzyme, also known as corrin, has been shown to play a critical role in trophoblastic invasion and remodeling of the uterine spiral arteries. These processes are impaired in corrin-deficient mice, which also develop evidence of preeclampsia. Moreover, mutations in the gene for corrin have also been reported in women with preeclampsia (Cui, 2012).
Notably, several immunological abnormalities have been associated with fetal-growth restriction. This raises the prospect of maternal rejection of the “paternal semiallograft.” Rudzinski and colleagues (2013) studied C4d, a component of complement that is associated with humoral rejection of transplanted tissues. They found this to be highly associated with chronic villitis—88 percent of cases versus only 5 percent of controls—and with reduced placental weight. Greer and associates (2012) studied 10,204 placentas and reported that chronic villitis was associated with placental hypoperfusion, fetal acidemia, and fetal-growth restriction and its sequelae. Kovo and coworkers (2010) found that chronic villitis is more strongly associated with fetal-growth restriction than with preeclampsia. Redline (2007) described the findings of activated maternal lymphocytes among fetal trophoblast. However, this author notes uncertainty as to whether these pathological changes represent maternal immunological rejection.
Morbidity and Mortality
As shown in Figure 44-3, fetal-growth restriction is associated with substantive perinatal morbidity and mortality rates. Rates of stillbirth, birth asphyxia, meconium aspiration, and neonatal hypoglycemia and hypothermia are all increased, as is the prevalence of abnormal neurological development (Jacobsson, 2008; Paz, 1995). This is true for both term and preterm growth-restricted infants (McIntire, 1999; Wu, 2006). Smulian and colleagues (2002) reported that SGA infants had a higher 1-year infant mortality rate compared with that of normally grown infants. Boulet and associates (2006) demonstrated that for a fetus at the 10th percentile, the risk of neonatal death is increased but varies with gestational age. Risk is increased threefold at 26 weeks’ gestation compared with only a 1.13-fold increased risk at 40 weeks. More recently, in an analysis of 123,383 nonanomalous singleton live births, Chen and coworkers (2011) reported that SGA infants had a twofold risk for early and late neonatal death but not for postneonatal demise.
Fetal Undergrowth. In his book Fetal and Infant Origins of Adult Disease, Barker (1992) hypothesized that adult mortality and morbidity are related to fetal and infant health. This includes both under- and overgrowth. In the context of fetal-growth restriction, there are numerous reports of a relationship between suboptimal fetal nutrition and an increased risk of subsequent adult hypertension, atherosclerosis, type 2 diabetes, and metabolic derangement (Gluckman, 2008). The degree to which low birthweight mediates adult disease is controversial. For example, it is unclear whether poor health in adulthood is mainly modulated by low birthweight, postnatal compensatory growth, or an interaction of the two (Crowther, 2008; Kerkhof, 2012; Leunissen, 2008; Nobili, 2008; Ong, 2007).
There is increasing evidence that fetal-growth restriction may affect organ development, particularly that of the heart. Individuals with low birthweight demonstrate cardiac structural changes and dysfunction persisting through childhood, adolescence, and adulthood. Crispi and coworkers (2012) studied 50 children aged between 3 and 6 years who were born small-for-gestational age at > 34 weeks and compared them with 100 normally grown children. The heart shape was altered in children born SGA. They had a more globular ventricle that resulted in systolic and diastolic dysfunction. Hietalampi and associates (2012) performed echocardiography in 418 adolescents at a mean age of 15 years and found that low birthweight was associated with increased left ventricular posterior wall thickness. Importantly, current weight and physical activity affected measurements. In another study, 102 adults previously born preterm at a mean gestational age of 30.3 weeks underwent cardiac magnetic resonance (MR) imaging. Their ventricular mass was increased compared with that of 132 adults who were delivered at term (Lewandowski, 2013). Adults previously born preterm also had persistent structural remodeling and had reduced systolic and diastolic function.
Deficient fetal growth is also associated with postnatal structural and functional renal changes. Ritz and colleagues (2011) reviewed the numerous studies associating low birth-weight with disordered nephrogenesis, renal dysfunction, chronic kidney disease, and hypertension. They found that although a low nephron number is associated with hypertension in white individuals, this association does not hold true for blacks.
Fetal Overgrowth. On the other end of the spectrum, fetal overgrowth, particularly in women with diabetes and elevated cord blood levels of IGF-I, is associated with increased neonatal fat mass and morphological heart changes. Aman and coworkers (2011) reported interventricular septal hypertrophy in overgrown neonates of mothers with well-controlled diabetes in pregnancy. Garcia-Flores (2011) also reported increased fetal cardiac intraventricular septal thickness using sonography in women with well-controlled diabetes. Large-for-gestational age infants delivered of women without impaired glucose tolerance show higher insulin levels in childhood (Evagelidou, 2006). Not surprisingly, fetal overgrowth has been associated with development of the metabolic syndrome even in childhood (Boney, 2005).
Accelerated Lung Maturation
Numerous reports describe accelerated fetal pulmonary maturation in complicated pregnancies associated with growth restriction (Perelman, 1985). One possible explanation is that the fetus responds to a stressed environment by increasing adrenal glucocorticoid secretion, which leads to accelerated fetal lung maturation (Laatikainen, 1988). Although this concept pervades modern perinatal thinking, there is negligible evidence to support it.
To examine this hypothesis, Owen and associates (1990) analyzed perinatal outcomes in 178 women delivered because of hypertension. They compared these with outcomes in infants of 159 women delivered because of spontaneous preterm labor or ruptured membranes. They concluded that a “stressed” pregnancy did not confer an appreciable survival advantage. Similar findings were reported by Friedman and colleagues (1995) in women with severe preeclampsia. Two studies from Parkland Hospital also substantiate that the preterm infant accrues no apparent advantages from fetal-growth restriction (McIntire, 1999; Tyson, 1995).
Risk Factors and Etiologies
Risk factors for impaired fetal growth include potential abnormalities in the mother, fetus, and placenta. These three “compartments” are depicted in Figure 44-4. Some of these factors are known causes of fetal-growth restriction and may affect more than one compartment. For instance, infectious causes such as cytomegalovirus may affect the fetus directly. In contrast, bacterial infections such as tuberculosis may have significant maternal effects that lead to poor fetal growth. Malaria, a protozoal infection, possibly creates placental dysfunction (Umbers, 2011). Importantly, many causes of diminished fetal growth are prospectively considered risk factors, because impaired fetal growth is not consistent in all affected women.
FIGURE 44-4 Risk factors and causes of impaired fetal growth centering on the mother, her fetus, and the placenta.
Constitutionally Small Mothers
It is axiomatic that small women typically have smaller newborns. If a woman begins pregnancy weighing less than 100 pounds, the risk of delivering an SGA infant is increased at least twofold (Simpson, 1975). As discussed subsequently, both prepregnancy weight and gestational weight gain modulate this risk. Durie and colleagues (2011) showed that the risk of delivering an SGA neonate was highest among underweight women who gained less weight than recommended by the Institute of Medicine (Chap. 9, p. 177). Also, both maternal and paternal size influences birthweight. In a Swedish study of 137,538 term singleton mother-father-child units, researchers estimated that the maternal and paternal birthweights explained 6 and 3 percent of variance in birthweight, respectively (Mattsson, 2013).
Gestational Weight Gain and Nutrition
In the woman of average or low BMI, poor weight gain throughout pregnancy may be associated with fetal-growth restriction (Rode, 2007). In the study by Durie cited above, gestational weight gain during the second and third trimesters that was less than that recommended by the Institute of Medicine was associated with SGA neonates in women of all weight categories except class II or III obesity. Conversely, excessive gestational weight gain was associated with an overgrown newborn in all weight categories.
As perhaps expected, eating disorders are associated with significantly increased risks of low birthweight and preterm birth (Pasternak, 2012). This is discussed further in Chapter 61 (p. 1211). Marked weight gain restriction after midpregnancy should not be encouraged even in obese women (Chap. 9, p. 177). Even so, it appears that food restriction to < 1500 kcal/day adversely affects fetal growth minimally (Lechtig, 1975). The best documented effect of famine on fetal growth was in the Hunger Winter of 1944 in Holland. For 6 months, the German Occupation army restricted dietary intake to 500 kcal/day for civilians, including pregnant women. This resulted in an average birthweight decline of only 250 g (Stein, 1975).
It is unclear whether undernourished women may benefit from micronutrient supplementation. In the study by the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group (2008), almost 32,000 Indonesian women were randomized to receive micronutrient supplementation or only iron and folate tablets. Infants of those receiving the supplement had lower risks of early infant mortality and low birthweight and had improved childhood motor and cognitive abilities (Prado, 2012). Conversely, Liu and coworkers (2013) randomized 18,775 nulliparous pregnant women to folic acid alone; folic acid and iron; or folic acid, iron, and 13 other micronutrients. Folic acid and iron with or without the additional micronutrients resulted in a 30-percent reduction in risk of third-trimester anemia. However, it did not affect other maternal or neonatal outcomes. The importance of antenatal vitamins and trace metals is further discussed in Chapter 9 (p. 179).
The effect of social deprivation on birthweight is interconnected to the influence of associated lifestyle factors such as smoking, alcohol or other substance abuse, and poor nutrition. Importantly, Coker and associates (2012) found that women screened during pregnancy for psychosocial risk factors had more appropriate interventions. These women were significantly less likely to deliver a low-birthweight infant and also had fewer preterm births and other pregnancy complications.
Women who are immigrants may be at particular risk in pregnancy. Poeran and colleagues (2013) studied 56,443 singleton pregnancies in Rotterdam between 2000 and 2007 and found that social deprivation was associated with adverse perinatal outcomes that included SGA infants among socially deprived women. However, a similar linkage was not noted in socially deprived women of non-Western origin. The effect of immigration, however, is complex and dependent on the population studied. A paradoxical relationship between pregnancy outcomes in foreign-born Latina women delivering in the United States compared with Latina women born in the United States has been described (Flores, 2012). In particular, foreign-born Latina women appear to have lower risks of preterm birth and SGA neonates.
Especially when complicated by superimposed preeclampsia, chronic vascular disease commonly causes growth restriction (Chap. 50, p. 1004). Preeclampsia may cause fetal-growth failure, which can be an indicator of its severity (Backes, 2011). In a study of more than 2000 women, vascular disease as evidenced by abnormal uterine artery Doppler velocimetry early in pregnancy was associated with increased rates of preeclampsia, SGA neonates, and delivery before 34 weeks (Groom, 2009). Roos-Hesselink and coworkers (2013) described pregnancy outcomes in women with heart disease, and only 25 of the 1321 women had ischemic heart disease, emphasizing its rareness. But these women had the worst outcomes, with significantly lower neonatal birthweights and the highest rates of preterm birth and perinatal mortality.
Chronic renal insufficiency is frequently associated with underlying hypertension and vascular disease. Nephropathies are commonly accompanied by restricted fetal growth (Bramham, 2011; Cunningham, 1990; Vidaeff, 2008). These relationships are considered further in Chapter 53 (p. 1059).
Fetal-growth restriction in women with diabetes may be related to congenital malformations or may follow substrate deprivation from advanced maternal vascular disease (Chap. 57, p. 1128). Also, the likelihood of restricted growth increases with development of nephropathy and proliferative retinopathy—especially in combination (Haeri, 2008). That said, the prevalence of serious vascular disease associated with diabetes in pregnancy is low, and the primary effect of overt diabetes, especially type 1, is fetal overgrowth. For example, Murphy and coworkers (2011) performed a prospective study of 682 consecutive pregnancies complicated by diabetes. Women with type 1 diabetes had significantly fewer of the traditional risk factors for fetal overgrowth, such as increased age, multiparity, and obesity. Yet, they were significantly more likely than women with type 2 diabetes to have a neonate weighing > 90th and 97.7th percentiles. Additionally, women with type 1 diabetes were significantly less likely to deliver an SGA newborn. Similarly, in a smaller study by Cyganek and colleagues (2011), the rate of macrosomia was higher among pregnancies complicated by type 1 diabetes. However, the rates of low birthweight were similar for those with type 1 and type 2 diabetes.
Conditions associated with chronic uteroplacental hypoxia include preeclampsia, chronic hypertension, asthma, smoking, and high altitude. When exposed to a chronically hypoxic environment, some fetuses have significantly reduced birthweight. Gonzales and Tapia (2009) constructed growth charts based on 63,620 Peruvian live births between 26 and 42 weeks’ gestation. They reported that mean birthweight was significantly decreased at higher altitudes compared with lower altitudes—3065 ± 475 g versus 3280 ± 525 grams. At low altitude, the rate of birthweight < 2500 g was 6.2 percent, and it was 9.2 percent at high altitude. In contrast, the rate of birthweight > 4000 g was 6.3 percent at low altitude and 1.6 percent at high altitude. As discussed in Chapter 49 (p. 985), severe hypoxia from maternal cyanotic heart disease frequently is associated with severely growth-restricted fetuses (Patton, 1990).
In most cases, maternal anemia does not cause restricted fetal growth. Exceptions include sickle-cell disease and some other inherited anemias (Chakravarty, 2008; Tongsong, 2009). Conversely, curtailed maternal blood-volume expansion has been linked to fetal-growth restriction (Duvekot, 1995; Scholten, 2011). This is further discussed in Chapter 40 (p. 737).
Antiphospholipid Antibody Syndrome
Adverse obstetrical outcomes including fetal-growth restriction have been associated with three species of antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and antibodies against beta-2-glycoprotein-I. Mechanistically, a “two-hit” hypothesis suggests that initial endothelial damage is then followed by intervillous placental thrombosis. More specifically, oxidative damage to certain membrane proteins such as beta-2-glycoprotein I is followed by antiphospholipid antibody binding, which leads to immune complex formation and ultimately to thrombosis (Giannakopoulos, 2013). This syndrome is considered in detail in Chapters 52 (p. 1033) and 59 (p. 1173). Pregnancy outcomes in women with these antibodies may be poor and include early-onset preeclampsia and fetal demise (Levine, 2002). The primary autoantibody that predicts obstetrical antiphospholipid syndrome appears to be lupus anticoagulant (Lockshin, 2012).
Numerous investigators have evaluated the role of genetic polymorphisms in the mother or fetus and their relationship to growth restriction (Lockwood, 2002; Stonek, 2007). Most suggest that inherited thrombophilias are not a significant factor in fetal-growth restriction (Infante-Rivard, 2002; Rodger, 2008). Facco and colleagues (2009) attribute positive associations primarily to publication bias.
Pregnancies in women with prior infertility with or without infertility treatment have an increased risk of SGA newborns (Zhu, 2007). Kondapalli and Perales-Puchalt (2013) have recently reviewed possible links between low birthweight and infertility with its various interventions. They concluded that the association remains unexplained.
Placental and Cord Abnormalities
Several placental abnormalities may cause poor fetal growth. These are discussed further throughout Chapter 6 and include chronic placental abruption, extensive infarction, chorioangioma, marginal or velamentous cord insertion, placenta previa, and umbilical artery thrombosis. Growth failure in these cases is presumed secondary to uteroplacental insufficiency.
Abnormal placental implantation leading to endothelial dysfunction may also result in limited fetal growth (Brosens, 2011). This pathology has been implicated in pregnancies complicated by preeclampsia as discussed in Chapter 40 (p. 732).
If the placenta is implanted outside the uterus, the fetus is usually growth restricted (Chap. 19, p. 388). Also, some uterine malformations have been linked to impaired fetal growth (Chap. 3, p. 40).
As shown in Figure 44-5, pregnancy with two or more fetuses is more likely to be complicated by diminished growth of one or more fetuses compared with that with normal singletons (Chap. 45, p. 899).
FIGURE 44-5 Birthweight and gestational age relationships in multifetal gestations delivered at Parkland Hospital without malformations. (Data courtesy of Dr. Don McIntire.)
Drugs with Teratogenic and Fetal Effects
Several drugs and chemicals are capable of limiting fetal growth. Some are teratogenic and affect the fetus before organogenesis is complete. Some exert—or continue to exert—fetal effects after embryogenesis ends at 8 weeks. Many of these are considered in detail in Chapter 12, and some examples include anticonvulsants and antineoplastic agents. Some immunosuppressive drugs used for organ transplantation maintenance are also implicated in poor fetal growth (Mastrobattista, 2008). In addition, cigarette smoking, opiates and related drugs, alcohol, and cocaine may cause growth restriction, either primarily or by decreasing maternal food intake. There is a possible link with caffeine use throughout pregnancy and fetal-growth restriction (CARE Study Group, 2008). According to the American College of Obstetricians and Gynecologists (2013c), however, this relationship remains speculative (Chap. 9, p. 187).
Maternal and Fetal Infections
Viral, bacterial, protozoan, and spirochetal infections have been implicated in up to 5 percent of fetal-growth restriction cases and are discussed throughout Chapters 64 and 65. The best known of these are rubella and cytomegalovirus infection. Both promote calcifications in the fetus that are associated with cell death, and infection earlier in pregnancy correlates with worse outcomes. Picone and associates (2013) described 238 primary cytomegalovirus infections and reported that no severe cases were observed when infection occurred after 14 weeks’ gestation.
Tuberculosis and syphilis have both been associated with poor fetal growth. As discussed in Chapter 51 (p. 1020), both extrapulmonary and pulmonary tuberculosis have been linked with low birthweight (Jana, 1994, 1999). The etiology is uncertain. However, the adverse effect of tuberculosis on maternal health, compounded by effects of poor nutrition and poverty, is important (Jana, 2012). Congenital or transplacental tuberculosis is rare, whereas congenital syphilis is more common. Paradoxically, with syphilis, the placenta is almost always larger and heavier due to edema and perivascular inflammation. Congenital syphilis is also strongly linked with preterm birth and thus low-birthweight infants (Sheffield, 2002).
Toxoplasma gondii can also cause congenital infection, and Paquet and Yudin (2013) describe its classic association with fetal-growth restriction. Despite this, an analysis of 386 women who seroconverted during pregnancy from toxoplasma infection found no connection with low birthweight (Freeman, 2005). Congenital malaria has also been implicated, and malaria prophylaxis is associated with a decreased risk of low birth-weight in Sub-Saharan Africa (Kayentao, 2013).
In a study of more than 13,000 fetuses with major structural anomalies, 22 percent had accompanying growth restriction (Khoury, 1988). In their study of 115 pregnancies complicated by fetal gastroschisis, Tam Tam and coworkers (2011) identified low birthweights in 63 percent and fetal-growth restriction in 45 percent of affected newborns. As a general rule, the more severe the malformation, the more likely the fetus is to be SGA. This is especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations.
Depending on which chromosome is redundant, there may be associated poor growth in fetuses with autosomal trisomies. For example, in trisomy 21, fetal-growth restriction is generally mild. By contrast, fetal growth in trisomy 18is virtually always significantly limited. Growth failure has been documented as early as the first trimester using crown-rump length (Baken, 2013). Bahado-Singh (1997) and Schemmer (1997) and their associates found that crown-rump length in fetuses with trisomy 18 and 13, unlike that with trisomy 21, was shorter than expected. By the second trimester, long-bone measurements typically are < 3rd percentile.
As discussed in Chapter 13 (p. 269), aneuploidic patches in the placenta—confined placental mosaicism—can cause placental insufficiency that may account for many previously unexplained growth-restricted fetuses (Wilkins-Haug, 2006). Although addition of an X chromosome in confined placental mosaicism can be associated with diminished fetal growth, this is not so with Klinefelter syndrome (47,XXY). Conversely, monosomy X or Turner syndrome has been associated with a low embryo volume during first-trimester sonography (Baken, 2013). This early finding manifests as growth restriction at delivery. Hagman and colleagues (2010) compared 494 children with monosomy X with normal girls and found a 6.6-fold increased risk for SGA in newborns with Turner syndrome.
First-trimester prenatal screening programs to identify women at risk for aneuploidy may incidentally identify pregnancies at risk for fetal-growth restriction unrelated to karyotype. In their analysis of 8012 women, Krantz and associates (2004) identified an increased risk for growth restriction in eukaryotic fetuses with extremely low free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels. From her review, Dugoff (2010) concluded that although most studies have found that a low PAPP-A level is strongly associated with poor fetal growth, studies of free β-hCG are conflicting. Second-trimester analytes, including elevated alpha-fetoprotein and inhibin A levels and low unconjugated serum estriol concentrations, are significantly associated with birthweight < 5th percentile. An even greater risk of poor growth has been associated with certain combinations of these analytes. Still, these markers are poor screening tools for complications such as fetal-growth restriction due to low sensitivity and positive predictive values (Dugoff, 2010). Nuchal translucency has also not been shown to be predictive of fetal-growth restriction. These markers are discussed further in Chapter 14(p. 289).
Recognition of Fetal-Growth Restriction
Early establishment of gestational age, ascertainment of maternal weight gain, and careful measurement of uterine fundal growth throughout pregnancy will identify many cases of abnormal fetal growth in low-risk women. Risk factors, including a previous growth-restricted fetus, have an increased risk for recurrence of nearly 20 percent (Berghella, 2007). In women with risks, serial sonographic evaluation is considered. Although examination frequency varies depending on indications, an initial early dating examination followed by an examination at 32 to 34 weeks, or when otherwise clinically indicated, will identify many growth-restricted fetuses. Even so, definitive diagnosisfrequently cannot be made until delivery.
Identification of the inappropriately growing fetus remains a challenge. There are, however, both simple clinical techniques and more complex technologies that may prove useful.
Uterine Fundal Height
According to a recent systematic review, insufficient evidence supports the utility of fundal height measurement to detect fetal-growth restriction (Robert Peter, 2012). Nonetheless, carefully performed serial fundal height measurements are recommended as a simple, safe, inexpensive, and reasonably accurate screening method to detect growth-restricted fetuses (Figueras, 2011b). As a screening tool, its principal drawback is imprecision (Jelks, 2007). For example, Sparks and coworkers (2011) reported sensitivities < 35 percent for detecting excessive or deficient fetal growth. Specificity, however, was reported to be > 90 percent.
The method used by most for fundal height measurement is described in Chapter 9 (p. 176). Between 18 and 30 weeks’ gestation, the uterine fundal height in centimeters coincides within 2 weeks of gestational age. Thus, if the measurement is more than 2 to 3 cm from the expected height, inappropriate fetal growth is suspected.
Sonographic Measurements of Fetal Size
One argument in the debate regarding routine sonographic evaluation of all pregnancies is the potential for diagnosis of growth restriction. Typically, such routine screening incorporates an early initial sonographic examination—usually at 16 to 20 weeks’ gestation, but increasingly in the first trimester—to establish gestational age and identify anomalies. Proponents of this view then repeat sonographic evaluation at 32 to 34 weeks to evaluate fetal growth (Chap. 10, p. 198). Although fetal-growth restriction can be detected during the first trimester, its detection using an initial sonogram from the second trimester is more likely to correspond to a birthweight that is small-for-gestational age (Baken, 2013; Mook-Kanamori, 2010; Tuuli, 2011). At Parkland Hospital, we provide midpregnancy sonographic screening examination of all pregnancies. Additional sonographic evaluations of fetal growth are performed as clinically indicated.
With sonography, the most common method for identifying poor fetal growth is estimation of weight using multiple fetal biometric measurements. Combining head, abdomen, and femur dimensions has been shown to optimize accuracy, whereas little incremental improvement is gained by adding other biometric measurements (Platz, 2008). Of the dimensions, femur length measurement is technically the easiest and the most reproducible. Biparietal diameter and head circumference measurements are dependent on the plane of section and may also be affected by deformative pressures on the skull. Last, abdominal circumference measurements are more variable. However, these are most frequently abnormal with fetal-growth restriction because soft tissue predominates in this dimension (Fig. 44-6). Shown in Figure 44-7 is an example of a severely growth-restricted newborn.
FIGURE 44-6 Correlation of sonographic fetal weight estimation using abdominal circumference (AC) and actual birthweight. Data from pregnancies managed at Parkland Hospital. (Image courtesy of Dr. Don McIntire.)
FIGURE 44-7 A 36-week newborn with severe fetal-growth restriction. (Photograph contributed by Dr. Roxane Holt.)
Some studies have reported a significant predictive value for small abdominal circumference with respect to lagging fetal growth. However, newer data indicate that abnormal Doppler velocimetry of the umbilical arteries and a combined estimated fetal weight < 3rd percentile are most strongly associated with poor obstetrical outcome (Unterscheider, 2013).
Importantly, sonographic estimates of fetal weight and actual weight may be discordant by 20 percent or more, leading to both false-positive and false-negative findings. Dashe and associates (2000) studied 8400 live births at Parkland Hospital in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They reported that 30 percent of growth-restricted fetuses were not detected. In a study of 1000 high-risk fetuses, Larsen and coworkers (1992) performed serial sonographic examinations beginning at 28 weeks and then every 3 weeks subsequently. Reporting results compared with withholding results from clinicians significantly increased the diagnosis of SGA fetuses. Elective delivery rates were increased in the group whose providers received sonographic reports, but there was no overall improvement in neonatal outcomes.
Amnionic Fluid Volume Measurement
An association between pathological fetal-growth restriction and oligohydramnios has long been recognized (Chap. 11, p. 236). Chauhan and colleagues (2007) found oligohydramnios in nearly 10 percent of pregnancies suspected of growth restriction. This group of women was two times more likely to undergo cesarean delivery for nonreassuring fetal heart rate patterns. Petrozella and associates (2011) reported that decreased amnionic fluid volume between 24 and 34 weeks’ gestation was significantly associated with malformations. In the absence of malformations, a birthweight < 3rd percentile was seen in 37 percent of pregnancies with oligohydramnios, in 21 percent with borderline amnionic fluid volume, but in only 4 percent with normal volumes. Hypoxia and diminished renal blood flow has been hypothesized as an explanation for oligohydramnios. However, Magann and coworkers (2011) reviewed the literature and determined that the etiology of oligohydramnios is likely more complex and possibly involves altered intramembranous absorption as well.
With this technique, early changes in placenta-based growth restriction are detected in peripheral vessels such as the umbilical and middle cerebral arteries. Late changes are characterized by abnormal flow in the ductus venosus and fetal aortic and pulmonary outflow tracts and by reversal of umbilical artery flow.
Of these, abnormal umbilical artery Doppler velocimetry findings—characterized by absent or reversed end-diastolic flow—have been uniquely linked with fetal-growth restriction (Chap. 10, p. 220). These abnormalities highlight early versus severe fetal-growth restriction and represent the transition from fetal adaptation to failure. Thus, persistently absent or reversed end-diastolic flow has long been correlated with hypoxia, acidosis, and fetal death (Pardi, 1993; Woo, 1987). Umbilical artery Doppler velocimetry is considered standard in the evaluation and management of the growth-restricted fetus (Fig. 44-8). The American College of Obstetricians and Gynecologists (2013a) notes that umbilical-artery Doppler velocimetry has been shown to improve clinical outcomes. It is recommended in the management of fetal-growth restriction as an adjunct to standard surveillance techniques such as nonstress testing and biophysical profile.
FIGURE 44-8 Umbilical arterial Doppler velocimetry studies, ranging from normal to markedly abnormal. A. Normal velocimetry pattern with a systolic to diastolic (S/D) ratio of < 3. B. The diastolic velocity approaching zero reflects increased placental vascular resistance. C. During diastole, arterial flow is reversed (negative S/D ratio), which is an ominous sign that may precede fetal demise.
As noted earlier, other Doppler assessments have been proposed but are still investigational. The ductus venosus was evaluated in a series of 604 neonates < 33 weeks who had an abdominal circumference < 5th percentile (Baschat, 2007). Investigators found that the ductus venosus Doppler parameters were the primary cardiovascular factor in predicting neonatal outcome. These late changes are felt to reflect myocardial deterioration and acidemia, which are major contributors to adverse perinatal and neurological outcome. In their longitudinal evaluation of 46 growth-restricted fetuses, Figueras and coworkers (2009) determined that Doppler flow abnormalities at the aortic valve isthmus preceded those in the ductus venosus by 1 week. Turan and associates (2008), in their evaluation of several fetal vessels, described the sequence of changes characteristic of mild placental dysfunction, progressive placental dysfunction, and severe early-onset placental dysfunction.
Prevention of fetal-growth restriction ideally begins before conception, with optimization of maternal medical conditions, medications, and nutrition as discussed throughout Chapter 8. Smoking cessation is critical. Other risk factors should be tailored to the maternal condition, such as antimalarial prophylaxis for women living in endemic areas and correction of nutritional deficiencies. Studies have shown that treatment of mild to moderate hypertension does not reduce the incidence of growth-restricted infants (Chap. 50, p. 1005).
Accurate dating is essential during early pregnancy. Serial sonographic evaluations are typically used, but the best interval between assessments has not been clearly established. Given that a history of SGA is associated with other adverse outcomes in a subsequent pregnancy, particularly stillbirth and preterm birth, surveillance during a subsequent pregnancy may be beneficial (Gordon, 2012; Spong, 2012). According to the American College of Obstetricians and Gynecologists (2013a), if growth is normal during a pregnancy following a prior pregnancy complicated by fetal-growth restriction, Doppler velocimetry and fetal surveillance are not indicated. Prophylaxis with low-dose aspirin beginning early in gestation is not recommended because of its poor efficacy to reduce growth restriction (American College of Obstetricians and Gynecologists, 2013a; Berghella, 2007).
If fetal-growth restriction is suspected, then efforts are made to confirm the diagnosis, assess fetal condition, and search for possible causes. Early-onset growth restriction is easier to recognize but presents challenging issues of management (Miller, 2008). In pregnancies in which there is a strong suspicion of fetal anomalies, patient counseling and prenatal diagnostic testing are indicated (American College of Obstetricians and Gynecologists, 2013a).
One algorithm for management is shown in Figure 44-9. In pregnancies with suspected fetal-growth restriction, antepartum fetal surveillance should include periodic Doppler velocimetry of the umbilical arteries in addition to more frequent fetal testing. At Parkland Hospital, if fetal viability has been reached, we hospitalize these women. Daily fetal heart rate tracings, weekly Doppler velocimetry, and sonographic assessment of fetal growth every 3 to 4 weeks are initiated. Other modalities of Doppler velocimetry, such as middle cerebral arteries or ductus venosus assessment, are considered experimental. The American College of Obstetricians and Gynecologists (2013a) recommends that pregnancies complicated by fetal-growth restriction and at risk for birth before 34 weeks receive antenatal corticosteroids for pulmonary maturation. According to Vidaeff and Blackwell (2011), growth-restricted fetuses may not tolerate the metabolic effects of corticosteroids in the same way as an unstressed fetus. They suggest increased surveillance during administration.
FIGURE 44-9 Algorithm for management of fetal-growth restriction at Parkland Hospital. BPP = biophysical profile; NST = nonstress test.
The timing of delivery is crucial, and the risks of fetal death versus the hazards of preterm delivery must be considered. Unfortunately, there are no studies that have elucidated the optimal timing of delivery. For the preterm fetus, the only randomized trial of delivery timing is the Growth Restriction Intervention Trial (GRIT) reported by Thornton and colleagues (2004). This trial was carried out in 13 European countries and involved 548 women between 24 and 36 weeks’ gestation with clinical uncertainty regarding delivery timing. Women were randomly assigned to immediate delivery or to delayed delivery until the situation worsened. The primary outcome was perinatal death or disability after reaching age 2 years. There were no differences in mortality rates through 2 years of age. Moreover, children aged 6 to 13 years did not show clinically significant differences between the two groups (Walker, 2011).
The DIGITAT—Disproportionate Intrauterine Growth Intervention Trial at Term—was designed to study delivery timing of growth-restricted fetuses who were 36 weeks’ gestation or older. There were no differences in composite neonatal morbidity in 321 women with fetal-growth restriction and a gestational age of at least 360/7 weeks who were randomly assigned to induction or to expectant management (Boers, 2010). Secondary analyses included assessment of neurodevelopmental and behavioral outcomes that did not differ at age 2 years (Van Wyk, 2012).
Management of the Near-Term Fetus
As shown in Figure 44-9, delivery of a suspected growth-restricted fetus with normal umbilical artery Doppler velocimetry, normal amnionic fluid volume, and reassuring fetal heart rate testing can likely be deferred until 38 weeks’ gestation. Said another way, uncertainty regarding the diagnosis should preclude intervention until fetal lung maturity is assured. Expectant management can be guided using antepartum fetal surveillance techniques described in Chapter 17. Most clinicians, however, recommend delivery at 34 weeks or beyond if there is clinically significant oligohydramnios. Consensus statements by the Society of Maternal-Fetal Medicine (Spong, 2011) and the American College of Obstetricians and Gynecologists (2013d) are similar. These recommend delivery between 34 and 37 weeks when there are concurrent conditions such as oligohydramnios. With a reassuring fetal heart rate pattern, vaginal delivery is planned. However, some of these fetuses do not tolerate labor, necessitating cesarean delivery.
Management of the Fetus Remote from Term
If growth restriction is identified in an anatomically normal fetus before 34 weeks, and amnionic fluid volume and fetal surveillance findings are normal, then observation is recommended. Screening for toxoplasmosis, cytomegalovirus infection, rubella, herpes, and other infections is recommended by some. However, we and others have not found this to be productive (Yamamoto, 2013).
As long as there is interval fetal growth and fetal surveillance test results are normal, pregnancy is allowed to continue until fetal lung maturity is reached (see Fig. 44-9). Reassessment of fetal growth is typically made no sooner than 3 to 4 weeks. Weekly assessment of umbilical artery Doppler velocimetry and amnionic fluid volume is combined with periodic nonstress testing, although the optimal frequency has not been determined. As mentioned, we hospitalize these women in our High-Risk Pregnancy Unit and monitor their fetuses daily. If interval growth, amnionic fluid volume, and umbilical artery Doppler velocimetry are normal, then the mother is discharged with intermittent outpatient surveillance.
With growth restriction remote from term, no specific treatment ameliorates the condition. For example, there is no evidence that diminished activity and bed rest result in accelerated growth or improved outcomes. Despite this, many clinicians intuitively advise a program of modified rest. Nutrient supplementation, attempts at plasma volume expansion, oxygen therapy, antihypertensive drugs, heparin, and aspirin have all been shown to be ineffective (American College of Obstetricians and Gynecologists, 2013a).
In most cases diagnosed before term, neither a precise etiology nor a specific therapy is apparent. Management decisions hinge on assessment of the relative risks of fetal death during expectant management versus the risks from preterm delivery. Although reassuring fetal testing may allow observation with continued maturation, long-term neurological outcome is a concern (Baschat, 2011; Thornton, 2004). Baschat and associates (2009) showed that neurodevelopmental outcome at 2 years in growth-restricted fetuses was best predicted by birthweight and gestational age. Doppler abnormalities are generally not associated with poor cognitive development scores among low-birthweight children delivered in the third trimester (Llurba, 2013). These findings emphasize that adverse neurodevelopmental outcomes cannot always be predicted.
Labor and Delivery
Fetal-growth restriction is commonly the result of placental insufficiency due to faulty maternal perfusion, reduction of functional placenta, or both. If present, these conditions are likely aggravated by labor. Equally important, diminished amnionic fluid volume increases the likelihood of cord compression during labor. For these reasons, a woman with a suspected growth-restricted fetus should undergo “high-risk” intrapartum monitoring (Chap. 22, p. 450). For these and other reasons, the frequency of cesarean delivery is increased.
The risk of neonatal hypoxia or meconium aspiration is also increased. Thus, care for the newborn should be provided immediately by an attendant who can skillfully clear the airway and ventilate an infant as needed (Chap. 32, p. 625). The severely growth-restricted newborn is particularly susceptible to hypothermia and may also develop other metabolic derangements such as hypoglycemia, polycythemia, and hyperviscosity. In addition, low-birthweight infants are at increased risk for motor and other neurological disabilities. Risk is greatest at the lowest extremes of birthweight (Baschat, 2007, 2009, 2011; Llurba, 2013).
The term macrosomia is used rather imprecisely to describe a very large fetus or neonate. Although there is general agreement among obstetricians that newborns weighing < 4000 g are not excessively large, a similar consensus has not been reached for the definition of macrosomia.
Newborn weight rarely exceeds 11 pounds (5000 g), and excessively large infants are a curiosity. The largest newborn cited in the Guinness Book of World Records was a 23-lb 12-oz (10,800 g) infant boy born to a Canadian woman, Anna Bates, in 1879 (Barnes, 1957). In the United States in 2010, of more than 4 million births, 6.6 percent weighed 4000 to 4499 g; 1 percent weighed 4500 to 4999 g; and 0.1 percent were born weighing 5000 g or more (Martin, 2012). To be sure, the incidence of excessively large infants increased during the 20th century. According to Williams (1903), at the beginning of the 20th century, the incidence of birthweight > 5000 g was 1 to 2 per 10,000 births. This compares with 16 per 10,000 at Parkland Hospital from 1988 through 2008 and 11 per 10,000 in the United States in 2010.
The influence of increasing maternal obesity is overwhelming, and its association with diabetes is well known. Of Parkland mothers with infants born weighing > 5000 g, more than 15 percent were diabetic. Henriksen (2008) searched the Cochrane Database and reported that the rapid increase in the prevalence of large infants was due to maternal obesity and type 2 diabetes. Importantly however, review of data from the National Center for Health Statistics indicates that the rate of birthweight ≥ 4000 g has steadily declined more than 30 percent since 1990—from 10.9 percent to 7.6 percent in 2010 (Martin, 2012). This is discussed further in Chapters 48 (p. 967) and 57 (p. 1140).
Because there are no widely accepted and precise definitions of pathological fetal overgrowth, several terms are currently used clinically. The most common of these—macrosomia—is defined by birthweights that exceed certain percentiles for a given population. Another commonly used scheme is to define macrosomia by an empirical birthweight threshold.
Frequently, macrosomia is defined based on mathematical distributions of birthweight. Those infants exceeding the 90th percentile for a given gestational week are usually used as the threshold for macrosomia or large-for-gestational age (LGA) birthweight. For example, the 90th percentile at 39 weeks is 4000 g. If, however, birthweights that are 2 standard deviations above the mean are used, then thresholds lie at the 97th percentile. Thus, substantially larger infants are considered macrosomic compared with those at the 90th percentile. Specifically, the birthweight threshold at 39 weeks to be macrosomic would be approximately 4500 g for the 97th percentile rather than 4000 g for the 90th percentile.
Newborn weight exceeding 4000 g—8 lb 13 oz—is also a frequently used threshold to define macrosomia. Others use 4250 g or even 4500 g—10 lb. As shown in Table 44-2, birthweights of 4500 g or more are uncommon. During a 30-year period at Parkland Hospital, during which there were more than 350,000 singleton births, only 1.4 percent of newborns weighed 4500 g or more. We are of the view that the upper limit of fetal growth, above which growth can be deemed abnormal, is likely two standard deviations above the mean, representing perhaps 3 percent of births. At 40 weeks, such a threshold would correspond to approximately 4500 g. The American College of Obstetricians and Gynecologists (2013b) concluded that the term macrosomia was an appropriate appellation for newborns who weigh 4500 g or more at birth.
TABLE 44-2. Birthweight Distribution of 354,509 Liveborn Infants at Parkland Hospital between 1988 and 2012
Some factors associated with fetal overgrowth are listed in Table 44-3. Many are interrelated and thus likely are additive. For example, advancing age is usually related to multiparity and diabetes, and obesity is obviously related to diabetes. Koyanagi and coworkers (2013) reported that the incidence of macrosomia exceeds 15 to 20 percent in Africa, Asia, and Latin America when women have diabetes, are obese, or have a postterm pregnancy. Of these, maternal diabetes is an important risk factor for fetal overgrowth (Chap. 57, p. 1129). As shown in Table 44-2, the incidence of maternal diabetes increases as birthweight > 4000 g increases. It should be emphasized, however, that maternal diabetes is associated with only a small percentage of the total number of such large infants.
TABLE 44-3. Risk Factors for Fetal Overgrowth
Diabetes—gestational and type 2
Large size of parents
Advancing maternal age
Previous macrosomic infant
Racial and ethnic factors
Maternal and Perinatal Morbidity
The adverse consequences of excessive fetal growth are considerable. Neonates with a birthweight of at least 4500 g have been reported to have cesarean delivery rates exceeding 50 percent (Das, 2009; Gyurkovits, 2011; Weissmann-Brenner, 2012). The rate of shoulder dystocia has been reported to be as high as 17 percent for neonates with birthweights of at least 4500 g, and 23 percent for neonates with birthweights of at least 5000 g (Stotland, 2004). Rates of postpartum hemorrhage, perineal laceration, and maternal infection, which are related complications, are also increased in mothers delivering overgrown neonates. Maternal and neonatal outcomes by birthweight for large babies > 4000 g and delivered at Parkland Hospital are shown in Table 44-4.
TABLE 44-4. Maternal and Fetal Outcomes for 176,844 Pregnancies Delivered at Parkland Hospital from 1998 Through 2012
Because there are no current methods to estimate excessive fetal size accurately, macrosomia cannot be definitively diagnosed until delivery. Inaccuracy in clinical estimates of fetal weight by physical examination is often attributable, at least in part, to maternal obesity. Numerous attempts have been made to improve the accuracy of sonographic fetal-weight estimation. Several formulas have been proposed to calculate fetal weight using measurements of the head, femur, and abdomen. Estimates provided by these computations, although reasonably accurate for predicting the weight of small, preterm fetuses, are less valid in predicting the weight of large fetuses. Rouse and coworkers (1996) reviewed 13 studies completed between 1985 and 1995 to assess the accuracy of sonographic prediction for suspected fetal macrosomia. They found only fair sensitivity—60 percent—in the accurate diagnosis of macrosomia, but higher specificity—90 percent—in excluding excessive fetal size. Thus, sonographic estimation of fetal weight is unreliable, and its routine use to identify macrosomia is not recommended. Indeed, the findings of several studies indicate that clinical fetal-weight estimates are as reliable as, or even superior to, those made from sonographic measurements (Mattsson, 2007; Noumi, 2005; O’Reilly-Green, 2000).
Several interventions have been proposed to interdict fetal overgrowth. Some include prophylactic labor induction for poorly defined indications such as “impending macrosomia,” or elective cesarean delivery to avoid difficult delivery and shoulder dystocia. For women with diabetes in pregnancy, insulin therapy and close attention to good glycemic control reduces birthweight, but this has not consistently translated into reduced cesarean delivery rates (Crowther, 2005; Naylor, 1996). Irrespective of diabetes mellitus, fetal overgrowth among women is strongly associated with maternal obesity and excessive gestational weight gain (Durie, 2011; Johnson, 2013; Vesco, 2011). Dietary intervention to limit fetal overgrowth by curbing gestational weight gain is an active area of research. However, data to safely guide efforts to limit fetal overgrowth among at-risk women are lacking.
“Prophylactic” Labor Induction
Some clinicians have proposed labor induction when fetal macrosomia is suspected in nondiabetic women. This approach is suggested to obviate further fetal growth and thereby reduce potential delivery complications. Such prophylactic induction should theoretically reduce the risk of shoulder dystocia and cesarean delivery. Gonen and colleagues (1997) randomly assigned 273 nondiabetic women with sonographic fetal weight estimates of 4000 to 4500 g to either induction or expectant management. Labor induction did not decrease the rate of cesarean delivery or shoulder dystocia. Similar results were reported by Leaphart and associates (1997), who found that induction unnecessarily increased the cesarean delivery rate. In their systematic review of 11 studies of expectant management versus labor induction for suspected macrosomia, Sanchez-Ramos and coworkers (2002) found that labor induction results in increased cesarean delivery rates without improved perinatal outcomes.
A review of early term births indicates that elective delivery before 39 weeks’ gestation does not improve maternal outcomes and is associated with worse neonatal outcomes (Wetta, 2012). We agree with the American College of Obstetricians and Gynecologists (2013b,d) that current evidence does not support a policy for early labor induction before 39 weeks’ gestation or delivery for suspected macrosomia. Moreover, delivery or induction for suspected macrosomia at term is likewise not indicated.
Elective Cesarean Delivery
Rouse and colleagues (1996, 1999) analyzed the potential effects of a policy of elective cesarean delivery for sonographically diagnosed fetal macrosomia compared with standard obstetrical management. They concluded that for women who are not diabetic, a policy of elective cesarean delivery was medically and economically unsound. The American College of Obstetricians and Gynecologists (2013b) does not recommend routine cesarean delivery in women without diabetes when the estimated fetal weight is < 5000 g. Conversely, in diabetic women with overgrown fetuses, such a policy of elective cesarean delivery seems tenable. Conway and Langer (1998) described a protocol of routine cesarean delivery for sonographic estimates of 4250 g or greater in diabetic women. This management significantly reduced the shoulder dystocia rate from 2.4 to 1.1 percent.
Prevention of Shoulder Dystocia
With the delivery of macrosomic infants, shoulder dystocia and its attendant risks described in Chapter 27 (p. 541) are major concerns. That said, the American College of Obstetricians and Gynecologists (2012) notes that fewer than 10 percent of all shoulder dystocia cases result in a persistent brachial plexus injury, and 4 percent of these follow cesarean delivery.
It appears that planned cesarean delivery on the basis of suspected macrosomia to prevent brachial plexopathy is an unreasonable strategy in the general population (Chauhan, 2005). Ecker and coworkers (1997) analyzed 80 cases of brachial plexus injury in 77,616 consecutive infants born at Brigham and Women’s Hospital. They concluded that an excessive number of otherwise unnecessary cesarean deliveries would be needed to prevent a single brachial plexus injury in neonates born to women without diabetes. Conversely, planned cesarean delivery may be a reasonable strategy for diabetic women with an estimated fetal weight > 4250 or > 4500 g.
In summary, when fetal overgrowth is suspected, the obstetrician naturally seeks to balance the risks to the fetus with maternal risks. Although interventions to prevent shoulder dystocia may someday prove beneficial, eliminating shoulder dystocia will likely remain an impossible goal. We agree with the American College of Obstetricians and Gynecologists that elective delivery for the fetus that is suspected to be overgrown is inadvisable, particularly before 39 weeks’ gestation. Finally, we agree that elective cesarean delivery is not indicated when estimated fetal weight is < 5000 g among women without diabetes and < 4500 g among women with diabetes (American College of Obstetricians and Gynecologists, 2013b).
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