Lubchenco and coworkers (1963) 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 neonates as those whose weights were below the 10th percentile for their gestational age. Low-birthweight newborns who are small for gestational age are often designated as having fetal-growth restriction. Such infants were shown to be at increased risk for neonatal death. For example, the mortality rate of SGA neonates born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights.
Importantly, many neonates with birthweights <10th percentile are not pathologically growth restricted, but instead are small simply because of normal biological factors. As many as 70 percent of such SGA infants have normal outcomes and are thought to be appropriately grown when maternal ethnic group, parity, weight, and height are considered (Unterscheider, 2015). These small but normal infants also do not show evidence of the postnatal metabolic derangements commonly associated with deficient fetal growth. Moreover, intrinsically SGA newborns 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. 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 newborns smaller than the 3rd percentile. The importance of this cut-off has been independently confirmed in a prospective study by Unterscheider and colleagues (2013a).
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 decreases.. (Data from Manning, 1995.)
More recently, individual or customized fetal-growth potential is proposed to replace a population-based threshold. In this model, a fetus that deviates from its individual optimal size at a given gestational age is considered either overgrown or growth restricted (Chiossi, 2017). Such optimal projections are based on maternal race or ethnicity. But, the superiority of customized growth curves has not been established (Chiossi, 2017; Costantine, 2013; Grobman, 2013; 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 compared with head growth. The onset or etiology of a particular fetal insult is 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, early global insults such as those 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 later pregnancy insult such as placental insufficiency from hypertension. In this variation, resultant diminished glucose transfer and hepatic storage would primarily affect cell size and not number. Thereby, 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, fetuses with aneuploidy typically have disproportionately large head sizes and thus are asymmetrically growth restricted, which is contrary to contemporaneous thinking (Nicolaides, 1991). Moreover, most preterm neonates with growth restriction due to preeclampsia and associated uteroplacental insufficiency are 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 greater 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.
Other data further challenge the concept of brain sparing. Roza and associates (2008) found that fetuses with circulatory redistribution—brain sparing—had a higher incidence of later behavioral problems. In another study, evidence of brain sparing was found in half of 62 growth-restricted fetuses with birthweights <10th percentile and who showed abnormal middle cerebral artery Doppler flow studies (Figueras, 2011). Compared with controls, these neonates had significantly lower neurobehavioral scores in multiple areas, suggesting profound brain injury. Zhu and coworkers (2016) prospectively compared late-onset growth restriction in 14 fetuses with that in 26 non-growth-restricted fetuses using magnetic resonance imaging to analyze hemodynamic flow. Despite the concept of brain sparing, growth-restricted infants had significantly smaller brains than controls. The complex effects of such insults—with respect to timing and severity—on brain structure, connectivity, and neurobehavioral outcomes have been recently reviewed by Miller and colleagues (2016).
Fetal-growth restriction is one of the “major obstetrical syndromes” associated with defects in early placentation (Brosens, 2015). Rogers and coworkers (1999) concluded that implantation-site disorders may be both a cause and consequence of hypoperfusion at the placental site. This comports with the association of certain placental angiogenic factors with pregnancy hypertensive disorders (Chap. 40, Endothelial Cell Injury). 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. For example, atrial natriuretic peptide converting enzyme, also known as corin, plays a critical role in trophoblastic invasion and remodeling of the uterine spiral arteries (Cui, 2012). These processes are impaired in corin-deficient mice, which also develop evidence of preeclampsia. Moreover, mutations in the gene for corin have been reported in women with preeclampsia (Chen, 2015a).
Several immunological abnormalities are 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. In a study of 10,204 placentas, chronic villitis was associated with placental hypoperfusion, fetal acidemia, and fetal-growth restriction and its sequelae (Greer, 2012). Kim and coworkers (2015) extensively reviewed chronic inflammatory placental lesions and their association with fetal-growth restriction, preeclampsia, and preterm birth.
Perinatal Morbidity and Mortality
Several short-term and long-term adverse sequelae are linked with fetal-growth restriction. First, perinatal morbidity and mortality rates are substantive (see Fig. 44-3). Rates of stillbirth and adverse neonatal outcomes that include birth asphyxia, meconium aspiration, hypoglycemia, and hypothermia are all increased, as is the prevalence of abnormal neurological development. This is true for both term and preterm growth-restricted newborns. In one analysis of nearly 3000 newborns born before 27 weeks’ gestation, those weighing <10th percentile had a nearly fourfold higher risk of neonatal death or neurodevelopmental impairment and a 2.6-fold increased risk of cerebral palsy compared with non-SGA neonates (De Jesus, 2013). In another analysis of more than 91,000 uncomplicated pregnancies, newborns with weights <5th percentile had a higher risk of low 5-minute Apgar score, respiratory distress, necrotizing enterocolitis, and neonatal sepsis than appropriate-weight neonates. The risks of stillbirth and neonatal death were sixfold and fourfold higher, respectively (Mendez-Figueroa, 2016).
The most severely growth-impaired newborns also have the worst outcomes. In one study of more that 44,561 neonates, only 14 percent of those weighing <1st percentile at birth survived to discharge (Griffin, 2015). For those infants who survive, the risks of adverse neurodevelopmental outcomes are substantial, especially for growth-impaired fetuses with either brain sparing or a major birth defect (Meher, 2015; Nelson, 2015b). Poor motor, cognitive, language and attention, and behavioral outcomes in growth-restricted newborns unfortunately persist into early childhood and adolescence (Baschat, 2014; Levine, 2015; Rogne, 2015).
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, numerous reports describe a relationship between suboptimal fetal nutrition and an increased risk of subsequent adult hypertension, atherosclerosis, type 2 diabetes, and metabolic derangement (Burton, 2016; Jornayvaz, 2016). The degree to which low birthweight mediates adult disease is controversial, as weight gain in early life also appears important (Breij, 2014; Kerkhof, 2012; McCloskey, 2016).
Mounting evidence suggests 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. In one study, 80 infants who were born SGA before 34 weeks’ gestation were compared at 6 months with 80 normally grown children (Cruz-Lemini, 2016). The heart in the SGA children had a more globular ventricle that resulted in systolic and diastolic dysfunction. In another study, echocardiography in 418 adolescents showed that low birthweight was associated with a thicker left ventricular posterior wall (Hietalampi, 2012). In their review, Cohen and colleagues (2016) concluded, however, that these findings have unclear long-term significance.
Deficient fetal growth is also associated with postnatal structural and functional renal changes. In a review by Luyckx and Brenner (2015), birthweight abnormalities were evaluated for linkage with disordered nephrogenesis, renal dysfunction, chronic kidney disease, and hypertension. Both low and high birthweight, as well as maternal obesity and gestational diabetes, affect in-utero development of the kidney and its health into adulthood. However, other variables that include childhood nutrition, acute kidney injury, excessive childhood weight gain, and obesity also worsen long-term renal function.
Particularly in women with diabetes and elevated cord blood levels of IGF-1, fetal overgrowth is associated with greater neonatal fat mass and morphological heart changes. Pedersen (1954) first proposed that hyperglycemia leads to fetal hyperinsulinemia and fetal overgrowth. This has been extended to organ dysmorphia, for example, increased interventricular septal thickness in neonates of mothers with gestational diabetes (Aman, 2011; Garcia-Flores, 2011). The cardiopulmonary vasculature is also adversely affected by diabetes in pregnancy. In 3277 cases of persistent pulmonary hypertension of the newborn (PPHN), maternal obesity, diabetes, and both deficient and excessive fetal growth were independent risk factors (Steurer, 2017). Long-term consequences of fetal overgrowth from obesity and diabetes are discussed in Chapters 48 (Antepartum Management) and 57 (Types of Diabetes).
Accelerated Lung Maturation
Numerous reports have described 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 augmenting adrenal glucocorticoid secretion, which leads to accelerated fetal lung maturation (Laatikainen, 1988). Although this concept pervades modern perinatal thinking, evidence to support it is negligible.
To examine this hypothesis, Owen and associates (1990) analyzed perinatal outcomes in 178 women delivered because of hypertension. They compared these with outcomes in newborns 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 described 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, cytomegalovirus infections can affect the fetus directly. In contrast, bacterial infections such as tuberculosis may have significant maternal effects that lead to poor fetal growth. Similarly, malaria, a protozoal infection, is a recognized cause of fetal-growth restriction (Briand, 2016). Importantly, many causes of diminished fetal growth are prospectively considered risk factors, because impaired fetal growth is not consistent in all affected women.
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. 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, Severe Undernutrition). Also, both maternal and paternal size influences birthweight. In a Swedish study of 137,538 term births, it was 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 study by Durie (2011) 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 (Blackwell, 2016).
As perhaps expected, eating disorders are linked with significantly higher risks for low birthweight and preterm birth (Micali, 2016). Marked weight gain restriction after midpregnancy should not be encouraged even in obese women (Chap. 48, Antepartum Management). Even so, it appears that food restriction to <1500 kcal/d 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/d 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 one study, almost 32,000 Indonesian women were randomly assigned to receive micronutrient supplementation or only iron and folate tablets (Prado, 2012). Offspring of those receiving the supplement had lower risks of early infant mortality and low birthweight and had improved childhood motor and cognitive abilities. Conversely, Liu and coworkers (2013) randomly assigned 18,775 nulliparas 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. But, supplementation did not affect other maternal or neonatal outcomes. A Cochrane database review of 19 trials involving 138,538 women concluded that supplementation of iron and folic acid improved birth outcomes, including lower risks of low birthweight and SGA (Haider, 2017). The importance of antenatal vitamins and trace metals is further discussed in Chapter 9 (Minerals).
Exercise in pregnancy may be beneficial for optimal fetal growth. One metaanalysis of 28 studies involving 5322 women concluded that exercise reduces the risk of fetal overgrowth without raising the risk of poor growth (Wiebe, 2015). Another metaanalysis concluded that aerobic exercise did not result in low-birthweight neonates (Di Mascio, 2016).
The effect of social deprivation on birthweight is interconnected with lifestyle factors such as smoking, alcohol or other substance abuse, and poor nutrition. With appropriate modifying interventions, women with psychosocial factors were significantly less likely to deliver a low-birthweight infant and also had fewer preterm births and other pregnancy complications (Coker, 2012).
Women who are immigrants may be at particular risk for poor fetal growth. In one study of 56,443 singleton pregnancies in Rotterdam, social deprivation was associated with adverse perinatal outcomes that included SGA newborns (Poeran, 2013). That said, a similar linkage was not found in socially deprived women of non-Western origin. The effect of immigration, however, is complex and dependent on the population studied (Howell, 2017; Sanchez-Vaznaugh, 2016).
Vascular and Renal Disease
Especially when complicated by superimposed preeclampsia, chronic vascular disease commonly causes growth restriction (Chap. 50, Management During Pregnancy). In a study of more than 2000 women, vascular disease as evidenced by abnormal uterine artery Doppler velocimetry early in pregnancy was associated with higher rates of preeclampsia, SGA neonates, and delivery before 34 weeks (Groom, 2009). Using Washington state birth certificate data, Leary and colleagues (2012) found that maternal ischemic heart disease was linked to SGA infants in 25 percent of 186 births. Roos-Hesselink and coworkers (2013) described similar pregnancy outcomes in 25 women with ischemic heart disease.
Chronic renal insufficiency is frequently associated with underlying hypertension and vascular disease. Nephropathies are commonly accompanied by restricted fetal growth (Cunningham, 1990; Feng, 2015; Saliem, 2016). These relationships are considered further in Chapter 53 (Chronic Kidney Disease).
Fetal-growth restriction in the newborns of women with diabetes may be related to congenital malformations or may follow substrate deprivation from advanced maternal vascular disease (Chap. 57, Preterm Delivery). Also, the likelihood of restricted growth increases with worsening White classification, particularly nephropathy (Klemetti, 2016). 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, in a prospective study of 682 consecutive pregnancies complicated by diabetes, women with type 1 diabetes were significantly more likely than women with type 2 diabetes to have a neonate weighing above the 90th and 97.7th percentiles (Murphy, 2011). Additionally, women with type 1 diabetes were significantly less likely to deliver an SGA newborn. In a recent study of 375 term singleton pregnancies complicated by type 1 diabetes, the risk of fetal overgrowth correlated with rising third-trimester glycemic values (Cyganek, 2017). Nearly a fourth of neonates were macrosomic. And, third-trimester hemoglobin A1c and fasting glucose values were independent predictors for the risk of macrosomia.
Conditions associated with chronic uteroplacental hypoxia include preeclampsia, chronic hypertension, asthma, maternal cyanotic heart disease, smoking, and high altitude. When exposed to a chronically hypoxic environment, some fetuses have significantly reduced birthweight. In more than 1.8 million births in Austria, the birthweight declined 150 g for each 1000-meter rise in altitude (Waldhoer, 2015). In 63,620 Peruvian live births, the mean birthweight was significantly decreased at higher compared with lower altitudes—3065 g ± 475 g versus 3280 g ± 525 g (Gonzales, 2009). In this study, the rate of birthweights <2500 g was 6.2 percent at low altitudes, and it was 9.2 percent at high altitudes. In contrast, the rate of birthweights >4000 g was 6.3 percent at low altitudes and 1.6 percent at high altitudes.
In most cases, maternal anemia does not restrict fetal growth. Exceptions include sickle-cell disease and some other inherited anemias (Desai, 2017; Thame, 2016). Importantly, curtailed maternal blood-volume expansion is linked to fetal-growth restriction (de Haas, 2017; Stott, 2017). This is further discussed in Chapter 40 (Blood Volume).
Adverse obstetrical outcomes including fetal-growth restriction have been associated with three species of antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-β2 glycoprotein-I antibodies. 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 β2 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 (Acquired Thrombophilias) and 59 (Antiphospholipid Syndrome). Pregnancy outcomes in women with these antibodies may be poor and include fetal-growth restriction and fetal demise (Cervera, 2015). The primary autoantibody that predicts obstetrical antiphospholipid syndrome appears to be lupus anticoagulant (Yelnik, 2016).
It is controversial whether pregnancies in women with prior infertility with or without treatment have an increased risk of SGA newborns (Zhu, 2007). Dickey and colleagues (2016) compared birthweight curves for singletons conceived by in vitro fertilization to the birthweight curves of Duryea (2014), described in Fetal Growth versus Birthweight. They found no reduction in fetal growth. Kondapalli and Perales-Puchalt (2013) reviewed possible links between low birthweight and infertility with its various interventions and concluded that any association remains unexplained for singletons.
Placental, Cord, and Uterine Abnormalities
Several placental abnormalities may cause poor fetal growth. These are discussed further throughout Chapter 6 and include chronic placental abruption, extensive infarction, chorioangioma, 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 limit fetal growth (Brosens, 2015). This pathology is implicated in pregnancies complicated by preeclampsia (Chap. 40, Etiology). If the placenta is implanted outside the uterus, the fetus is usually growth restricted (Chap. 19, Abdominal Pregnancy). Finally, some uterine malformations have been linked to impaired fetal growth (Chap. 3, Unicornuate Uterus (Class II)).
Pregnancy with two or more fetuses is more likely to be complicated by diminished growth of one or more fetuses compared with that of normal singletons. This is illustrated in Figure 44-5 and discussed in Chapter 45 (Low Birthweight).
Birthweight and gestational age relationships in multifetal gestations without malformations delivered at Parkland Hospital.
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 examples include anticonvulsants and antineoplastic agents. Cigarette smoking, opiates and related drugs, alcohol, and cocaine may also cause growth restriction, either primarily or by decreasing maternal food intake. The link with caffeine use and fetal-growth restriction remains speculative (American College of Obstetricians and Gynecologists, 2016b). In contrast, Cyganek and colleagues (2014) studied growth restriction in pregnancies complicated by renal and liver transplants and concluded that common immunosuppressive drugs—prednisone, azathioprine, cyclosporine A, and tacrolimus—did not significantly affect fetal-growth rates.
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. Toda and colleagues (2015) described a Vietnamese epidemic in which 39 percent of 292 term newborns with congenital rubella syndrome were low birthweight. In one study of 238 primary cytomegalovirus infections, no severe cases were observed when infection occurred after 14 weeks’ gestation (Picone, 2013). These investigators later identified sonographic findings in 30 of 69 cases of congenital infection, and growth restriction was noted in 30 percent of these 30 cases (Picone, 2014).
Tuberculosis and syphilis have also both been associated with poor fetal growth. Both extrapulmonary and pulmonary tuberculosis are linked with low birthweight (Chap. 51, Tuberculosis). Sobhy (2017) analyzed 13 studies that included a total of 3384 women with active tuberculosis. The odds ratio was 1.7 for low birthweight. The etiology is uncertain, however, the adverse effects on maternal health, compounded by effects of poor nutrition and poverty, are important (Jana, 2012). Congenital syphilis is more common, and paradoxically, the placenta is almost always larger and heavier due to edema and perivascular inflammation (Chap. 65, Diagnosis). Congenital syphilis is strongly linked with preterm birth and thus low-birthweight newborns (Sheffield, 2002).
Toxoplasma gondii can also cause congenital infection, and Paquet and Yudin (2013) describe its classic association with fetal-growth restriction. Capobiango (2014) described 31 Brazilian pregnancies complicated by congenital toxoplasmosis. Only 13 percent were treated antepartum for toxoplasmosis, and low birthweight complicated nearly 40 percent of all the pregnancies. Congenital malaria also causes low birthweight and poor fetal growth. Briand and colleagues (2016) emphasize the importance of prophylaxis early in pregnancy for women at risk.
In a study of more than 13,000 fetuses with major structural anomalies, 22 percent had accompanying growth restriction (Khoury, 1988). In one study of 111 pregnancies complicated by fetal gastroschisis, a third had birthweights <10th percentile (Nelson, 2015a). As a general rule, the more severe the malformation, the more likely it is that the fetus will be SGA. This is especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations.
Depending on which chromosome is redundant, fetuses with autosomal trisomies may display poor fetal growth. For example, in trisomy 21, fetal-growth restriction is generally mild. By contrast, fetal growth in trisomy 18 is virtually always significantly limited. The crown-rump length in fetuses with trisomy 18 and 13, unlike that with trisomy 21, is typically shorter than expected (Bahado-Singh, 1997; Schemmer, 1997). By the second trimester, long-bone measurements usually are below the 3rd percentile. In one group of 174 children with trisomy 13, the mean birthweight with trisomy 13 was 2500 g, and in 254 children with trisomy 18, it was 1800 g (Nelson, 2016).
Poor fetal growth also complicates Turner syndrome, and the severity correlates with increasing haploinsufficiency of the short arm of the X chromosome (Fiot, 2016). In contrast, poor growth is not characteristic of an increased number of X chromosomes (Ottesen, 2010; Wigby, 2016). As discussed in Chapter 13 (Chromosomal Mosaicism), aneuploidic patches in the placenta—confined placental mosaicism (CPM)—is a recognized cause of fetal-growth restriction. Evidence suggests that aneuploidy affecting both the cytotrophoblast and mesenchymal core of the placenta, which is type 3 CPM, is associated with fetal-growth restriction (Toutain, 2010).
First-trimester prenatal programs that screen for fetal aneuploidy may incidentally identify pregnancies at risk for fetal-growth restriction unrelated to karyotype. In their analysis of 8012 women, the risk for growth restriction was higher in eukaryotic fetuses with extremely low free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels (Krantz, 2004). From her review, Dugoff (2010) concluded that a low PAPP-A level is strongly associated with poor fetal growth, but 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 below the 5th percentile. An even greater risk of poor growth is linked 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 is also not predictive of fetal-growth restriction. The role of all these markers in aneuploidy screening is discussed in Chapter 14 (Traditional Aneuploidy Screening Tests).
Fetal-Growth Restriction Recognition
Identification of the inappropriately growing fetus remains a challenge. 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 prior growth-restricted fetus, raise the recurrence risk to nearly 20 percent (American College of Obstetricians and Gynecologists, 2015). In women with risk factors, 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 diagnosis frequently cannot be made until delivery.
According to one systematic review, insufficient evidence supports the utility of fundal height measurement to detect fetal-growth restriction (Robert Peter, 2015). Nonetheless, carefully performed serial fundal height measurements are recommended as a simple, safe, inexpensive, and reasonably accurate screening method to detect growth-restricted fetuses. As a screening tool, its principal drawback is imprecision. Haragan and coworkers (2015) reported sensitivities of 71 and 43 percent for detecting excessive or deficient fetal growth. Specificities were 85 and 66 percent, respectively.
The method used by most for fundal height measurement is described in Chapter 9 (Subsequent Prenatal Visits). 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 and sonography is considered.
One supporting point for routine sonographic evaluation of all pregnancies is the opportunity to diagnose growth restriction. Typically, such routine screening incorporates an early initial sonographic examination—usually at 16 to 20 weeks’ gestation. Increasingly, a first-trimester examination is added to establish gestational age and identify anomalies. Some then recommend repeat sonographic evaluation at 32 to 34 weeks to evaluate fetal growth.
First-trimester sonography has limited accuracy to predict SGA newborns. For example, Crovetto and associates (2017) reported detection rates of 35 and 42 percent with false-positive rates of 5 and 10 percent, respectively. From nearly 9000 screened pregnancies, Tuuli and colleagues (2011) concluded that second-trimester sonography is superior to first-trimester scans for predicting SGA neonates. 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 biometrical measurements. Combining head, abdomen, and femur dimensions provides optimum accuracy, whereas little incremental improvement is gained by adding other biometrical 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.
Correlation of sonographic fetal weight estimation using abdominal circumference (AC) and actual birthweight. (Data from pregnancies managed at Parkland Hospital.
A 36-week newborn with severe fetal-growth restriction. (Used with permission from Dr. Roxane Holt.)
Some studies have reported a significant predictive value for small abdominal circumference with respect to lagging fetal growth. One study screened nearly 4000 pregnancies using either clinically indicated or universal sonography in the third trimester (Sovio, 2015). Universal sonography raised the rate of detection of SGA from 20 percent to 57 percent. Importantly, however, the neonatal morbidity rate was increased only if the abdominal circumference growth velocity was in the lowest decile.
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 2586 women with low-risk pregnancies randomly assigned to sonography at 32 or 36 weeks’ gestation, sensitivity to identify grow restriction was improved at the later gestational age (Roma, 2015). Still, nearly 40 percent of cases of growth restriction defined as birthweight <3rd percentile were missed. A Cochrane database analysis of 13 trials with 34,980 women concluded that routine late pregnancy ultrasound for a low-risk or an unselected population is not associated with maternal or fetal benefit (Bricker, 2015).
Amnionic Fluid Volume Measurement
An association between pathological fetal-growth restriction and oligohydramnios has long been recognized. 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. Also, from a recent metaanalysis of 15 studies involving more than 35,000 pregnancies, high-risk pregnancies with oligohydramnios were more likely to be complicated by low birthweight compared with low-risk pregnancies with oligohydramnios (Rabie, 2017). Hypoxia and diminished renal blood flow are proposed explanations for oligohydramnios.
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 reversal of umbilical artery flow and by abnormal flow in the ductus venosus and fetal aortic and pulmonary outflow tracts.
Of these, abnormal umbilical artery Doppler velocimetry findings—characterized by absent or reversed end-diastolic flow—are uniquely linked with fetal-growth restriction (Chap. 10, Doppler). These abnormalities highlight early versus severe growth restriction and represent the transition from fetal adaptation to failure. Thus, persistently absent or reversed end-diastolic flow, such as that shown in Figure 44-8, has long been correlated with hypoxia, acidosis, and fetal death. In one prospective sonographic examination of 1116 fetuses with estimated fetal weights <10th percentile, only 1.3 percent of fetuses with normal umbilical artery Doppler studies had adverse outcomes compared with 11.5 percent of those with Doppler abnormalities (O’Dwyer, 2014). Unterscheider and associates (2013a) reported that abnormal umbilical artery Doppler velocimetry combined with an estimated fetal weight <3rd percentile is most strongly associated with poor obstetrical outcome.
Doppler velocity waveforms. A. Normal waveform with normal S/D ratio. B. Increased impedance to flow with abnormally elevated S/D ratio. C. Absent end-diastolic flow. D. Reversed end-diastolic flow.
Because of these findings, umbilical artery Doppler velocimetry is considered standard in the evaluation and management of the growth-restricted fetus. The American College of Obstetricians and Gynecologists (2015) has concluded that umbilical-artery Doppler velocimetry improves 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.
Other Doppler assessments are still investigational. Interrogation of the ductus venosus was evaluated in a series of 604 fetuses <33 weeks’ gestation who had an abdominal circumference <5th percentile (Baschat, 2007). 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 another study of 46 growth-restricted fetuses, Doppler flow abnormalities of the aortic valve isthmus preceded those in the ductus venosus by 1 week (Figueras, 2009). In their evaluation of several fetal vessels, Turan and associates (2008) described the sequence of changes characteristic of mild placental dysfunction, progressive placental dysfunction, and severe, early-onset placental dysfunction. However, Unterscheider and colleagues (2013b) questioned whether a predictable progression of Doppler indices actually exists in fetal-growth restriction.
Fetal-growth restriction prevention ideally begins before conception. Maternal medical conditions, medications, and nutrition are optimized, and smoking cessation is critical. Other risk factors are tailored to the maternal condition, such as antimalarial prophylaxis for women living in endemic areas and correction of nutritional deficiencies. Of note, treatment of mild-to-moderate hypertension does not reduce the incidence of growth-restricted newborns (Chap. 50, Antihypertensive Treatment in Pregnancy).
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 prior SGA newborn is associated with other adverse outcomes in a subsequent pregnancy, particularly stillbirth and preterm birth, surveillance during a subsequent pregnancy may be beneficial (Mendez-Figueroa, 2016; Spong, 2012). The American College of Obstetricians and Gynecologists (2015) notes that if growth is normal during a pregnancy following a prior pregnancy complicated by fetal-growth restriction, then Doppler velocimetry and fetal surveillance are not indicated. A recent metaanalysis of 45 trials involving 20,909 women reported that low-dose aspirin initiated prior to 16 weeks’ gestation was associated with a significantly lower risk of fetal-growth restriction (Roberge, 2017). Moreover, they described a dose-response effect. The American College of Obstetricians and Gynecologists (2015) has not endorsed prophylaxis with low-dose aspirin for women with a prior growth-restricted fetus.
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 especially problematic. In pregnancies in which fetal anomalies are suspected, patient counseling and prenatal diagnostic testing are indicated (American College of Obstetricians and Gynecologists, 2015).
One management algorithm is shown in Figure 44-9. In pregnancies with suspected fetal-growth restriction, antepartum fetal surveillance includes periodic Doppler velocimetry of the umbilical arteries in addition to more frequent fetal testing. At Parkland Hospital, for women whose fetus measures ≤3rd percentile and has reached a viable age, we encourage hospitalization on our High-Risk Pregnancy Unit. 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 (2015) recommends that antenatal corticosteroids for pulmonary maturation be given to pregnancies complicated by fetal-growth restriction and at risk for birth before 34 weeks’ gestation.
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 birth must be considered. Several multicenter studies address these problems, but unfortunately, none 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) (Thornton, 2004). This trial 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. Mortality rates did not differ through 2 years of age. Moreover, children aged 6 to 13 years did not show clinically significant differences between the two groups (Walker, 2011).
In the Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE), ductus venosus Doppler evaluation was compared with fetal heart rate monitoring. There were 310 pregnancies between 26 and 32 weeks’ gestation with fetuses displaying an abdominal circumference <10th percentile and an umbilical artery pulsatility index >95th percentile (Lees, 2015). Delivery timing was determined by the results of three differing antenatal fetal assessment arms that were: short-term fetal heart rate variability, early ductus venosus Doppler velocimetry changes, or late ductus changes. The proportion of children with neuroimpairment at 2 years of age was not different among the groups. Of note, only 32 percent of the newborns overall were delivered according to this randomization. Safety net criteria and other maternal/fetal indications prompted these protocol deviations (Visser, 2016). In a post-hoc analysis, these authors concluded that before 32 weeks, delaying delivery until ductus venosus Doppler or fetal heat rate abnormalities occur is likely safe and possibly benefits long-term outcome (Ganzevoort, 2017).
The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) study examined the delivery timing of growth-restricted fetuses who were 36 weeks’ gestation or older. In these 321 women who were randomized to induction or to expectant management, composite neonatal morbidity did not differ, except that neonatal admissions were lower after 38 weeks in a secondary analysis (Boers, 2010, 2012). Another secondary analysis of DIGITAT did not identify a clear subgroup that benefited from labor induction (Tajik, 2014). Other secondary analyses included assessment of neurodevelopmental and behavioral outcomes at age 2, and these also were similar between the randomized groups (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 for Maternal-Fetal Medicine (Spong, 2011) and the American College of Obstetricians and Gynecologists (2017a) are similar. These recommend delivery between 34 and 37 weeks when there are comorbid conditions such as oligohydramnios. With a reassuring fetal heart rate pattern, vaginal delivery is planned. Notably, some of these fetuses do not tolerate labor.
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, 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 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 home and seen intermittently for outpatient surveillance.
With growth restriction remote from term, no specific treatment ameliorates the condition. For example, evidence does not support diminished activity or bed rest to accelerate growth or improve 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 are all ineffective (American College of Obstetricians and Gynecologists, 2015).
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, 2014; Lees, 2015; 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 childhood cognitive developmental scores among low-birthweight fetuses delivered in the third trimester (Llurba, 2013). These findings emphasize that adverse neurodevelopmental outcomes cannot always be predicted.
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 raises the likelihood of cord compression during labor. For these and other reasons, the frequency of cesarean delivery is increased. Accordingly, a woman with a suspected growth-restricted fetus should undergo “high-risk” intrapartum monitoring (Chap. 24, Intrapartum Surveillance of Uterine Activity).
The risk of neonatal hypoxia or meconium aspiration is also greater. Thus, care for the newborn should be provided immediately by an attendant who can skillfully clear the airway and ventilate a neonate as needed (Chap. 32, Resuscitation Protocol). 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 newborns are at higher risk for motor and other neurological disabilities. Risk is greatest at the lowest extremes of birthweight (Baschat, 2009, 2014; Llurba, 2013).