Fetal- Growth Disorders
BS. Nguyễn Hồng Anh
Disorders o etal growth occur at both ends o the spectrum, either etal-growth restriction or macrosomia. Each poses concern because o associated morbidities and potential mortality. However, in both categories most o these newborns are ultimately deemed normal and healthy but merely constitutionally small or large. Te clinical challenge thus lies in the evaluation and management o suspected etal-growth disorders.
NORMAL FETAL GROWTH
Fetal growth may be divided into three phases. Te initial phase o hyperplasia occurs in the rst 16 weeks and is characterized by a rapid rise in cell number. Te second phase, which extends up to 32 weeks’ gestation, includes both cellular hyperplasia and hypertrophy. Ater 32 weeks, etal mass accrues by cellular hypertrophy, and it is during this phase that most etal at and glycogen accumulate. Te corresponding etal-growth rates during these three phases approximate 5 g/d at 15 weeks’ gestation, 15 g/d at 24 weeks’, and 30 g/d at 34 weeks’ (Grantz, 2018; Williams, 1982).
In the National Institute o Child Health and Human Development Fetal Growth Studies, serial sonographic evaluations were perormed in 1733 nonobese, low-risk pregnancies at 12 sites across the United States (Grantz, 2018). As shown in Figure 47-1, growth velocity peaked at 35 weeks’ gestation (Grantz, 2018).
Te investigators demonstrated that etal growth varies considerably and that it is not highly correlated with etal birthweight percentile. Some etuses with initial estimated weights below the 5th percentile maintained their growth velocity and ultimately weighed more at birth than other etuses whose weight percentiles were initially higher but whose growth was slower. Such ndings support our understanding that large and small etal weight percentiles reect constitutional size in some but indicate disordered growth in others. Tey urther highlight the importance o serial sonography when abnormal growth is a concern.
■ Normal Birthweight
Accurate gestational age assessment is critical or determining whether birthweight is normal. Current normative data are based on birthweights rom pregnancies in which gestational age is established using an obstetrical estimate that includes sonography and discussed in Chapter 14 (p. 248) (American College o Obstetricians and Gynecologists, 2019b). Te birthweight percentiles shown in Table 47-1 were derived using data rom more than 3 million liveborn singletons delivered across the United States in 2011 (Duryea, 2014). As shown in Figure 47-2, use o a birthweight percentile curve in which gestational age is based on a last menstrual period alone yields signicantly larger weights or a given gestational age, particularly in the preterm period. Te accuracy o a birthweight reerence thus has potential to aect the prevalence o neonates diagnosed as small or large or gestational age.
Te curve by Duryea and associates (2014) is most accurately termed a population reerence, rather than a standard. A population reerence incorporates pregnancies o varying risks, along with the resulting outcomes, both normal and abnormal. In contrast, a standard incorporates normal pregnancies with normal outcomes. Because population reerences include preterm births, which are more likely to be growth restricted, it has been argued that the associated birthweight data overestimate impaired etal growth (Mayer, 2013; Zhang, 2010).
■ Physiology of Fetal Growth
Fetal development is believed to be determined by maternal provision o substrate and its placental transer, whereas etal growth potential is governed by the genome. Te precise cellular and molecular mechanisms leading to normal etal growth are incompletely understood. Considerable evidence supports the role oinsulin and insulin-like growth actors in etal growth and weight gain regulation (Luo, 2012). Tese growth actors are produced by virtually all organs and are potent stimulators o cell division and dierentiation. Other hormones implicated in etal growth include leptin and other adipokines, which are derived rom adipose tissue.
Fetal leptin concentrations rise during gestation, and they correlate both with birthweight and with neonatal at mass (Bria, 2015; Ökdemir, 2018; Simpson, 2017). Both excessive and diminished maternal glucose availability also have the potential to aect etal growth (Chap. 7, p. 135). Tat said, growth-restricted neonates do not typically show pathologically low glucose concentrations in cord blood (Pardi, 2006). Fetal-growth restriction in response to glucose deprivation generally results only ater long-term severe maternal caloric deprivation (Lechtig, 1975). Conversely, hyperglycemia more consistently results in excessive growth. Te Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group (2008) ound that elevated cord C-peptide levels, which reect etal hyperinsulinemia, are associated with greater birthweight. Tis relationship was noted even in women with maternal glucose levels below the threshold or diabetes.
Excessive transer o lipids has similarly been implicated in etal overgrowth (Delhaes, 2018). Free or nonesteried atty acids in maternal plasma may be transerred to the etus via acilitated diusion or ater liberation o atty acids rom triglycerides by trophoblastic lipases (Gil-Sánchez, 2012). Independent o prepregnancy body mass index (BMI), higher maternal ree atty acid levels during the latter hal o pregnancy correlate with birthweight (Crume, 2015). Greater intake o certain atty acids, particularly omega-3, is associated with greater birthweight (Calabuig-Navarro, 2016).
Placental atty acid metabolism and transer may be dysregulated in etal-growth restriction and in maternal conditions associated with etal overgrowth. For example, levels o endothelial lipase are reduced with decient etal growth, and this enzyme is overexpressed in placentas o women with diabetes (Gauster, 2007, 2011). Others have reported that diabetes and obesity are associated with altered placental lipid-transport gene expression (Segura, 2017). Obesity is also linked with greater expression o atty acid binding/transport proteins within the trophoblast (Myatt, 2016). Tese alterations lead to an abnormal accumulation o lipids that can result in pathological placental inammation and dysunction (Calabuig-Navarro, 2016; Myatt, 2016; Yang, 2016).
FETAL-GROWTH RESTRICTION
Fundamental to understanding etal-growth restriction (FGR) is an appreciation o the strengths and limitations o its dening criteria. A diagnosis based on estimated etal weight alone does not indicate disease but rather a etus that is in an atrisk category. Benets o denitions such as the one used by the American College o Obstetricians and Gynecologists are ease o application and promotion o consistency across care settings. However, i applied to an otherwise low-risk population, a 10th-percentile threshold will label nearly 10 percent o etuses as growth restricted, although most are merely constitutionally small rather than compromised. Moreover, a threshold will ail to identiy at-risk etuses with a weight above that threshold but who have not reached their growth potential. Tus, the denition is intended to strike a balance between alse-positive and alse-negative diagnoses.
■ Definition
Various criteria and thresholds have been used to dene FGR. Tese have included estimated etal weights (EFW) below the 3rd, 5th, or 10th percentiles; similar abdominal circumerence (AC) percentiles; a specied decline in the EFW percentile or AC percentile over serial assessments; and various abnormal Doppler ndings (Lees, 2020). All denitions are based solely on prenatal sonography and rely on accurate gestational age assessment. Currently, the American College o Obstetricians and Gynecologists (2021a) and the Society or Maternal-Fetal Medicine (2020) recommend dening FGR as either an EFW <10th percentile or gestational age or an AC <10th percentile or gestational age. Use o the AC threshold may correctly identiy one additional small-or-gestational age (SGA) newborn or every 14 sonograms perormed in the last month o pregnancy (Blue, 2018). Importantly, management recommendations are urther stratied based on lower percentile thresholds and ndings such as oligohydramnios or abnormal umbilical artery Doppler velocimetry, as discussed subsequently (p. 829). o more precisely identiy growth-restricted etuses, investigators have derived customized growth charts that incorporate variables such as maternal height and weight, race or ethnicity, parity, and etal sex. However, customized growth curves do not improve outcomes and thus are not recommended (American College o Obstetricians and Gynecologists, 2021a; Chiossi, 2017; Costantine, 2013; Grobman, 2013; Zhang, 2011). FGR should be dierentiated rom SGA, which is a postnatal designation based on birthweight percentile. When considering FGR detection, investigators study the proportion o SGA neonates identied as FGR during prenatal sonography.
However, FGR oten does not equate to SGA because o the inherent error o sonographic measurement. One populationbased study o routine third-trimester sonography ound that 50 percent o those with suspected FGR had birthweights above the 10th percentile (Monier, 2015). Tose with alse-positive diagnoses o FGR were delivered 2 weeks earlier in gestation, which raises concerns about potential iatrogenic sequelae o routine screening.
Importantly, as many as 70 percent o SGA newborns are not pathologically growth restricted. Indeed, such children have normal outcomes and are thought to be appropriately grown when maternal ethnic group, parity, weight, and height are considered (Unterscheider, 2015). In a Swedish study o 130,000 term births, the maternal and paternal birthweights were estimated to account or 6 and 3 percent o variance in birthweight, respectively (Mattsson, 2013). Additionally, as shown in Figure 47-3, most adverse outcomes occur in newborns smaller than the 3rd percentile (Manning, 1995). In a review o more than 80,000 singleton term births rom Parkland Hospital, McIntire and colleagues (1999) ound that neonatal mortality and most neonatal morbidity rates rose only at birthweights at or below the 3rd percentile.
Small-but-normal neonates do not show evidence o the postnatal metabolic derangements commonly associated with decient etal growth. Moreover, these intrinsically small newborns remain signicantly smaller during surveillance to 2 years compared with appropriate-or-gestational-age sized neonates.
However, they do not show dierences in measures o metabolic risk that included glucose and insulin levels (Milovanovic, 2012). As discussed later, true SGA newborns carry short- and long-term metabolic risks.
■ Detection
Identication o truly impaired etal growth remains a challenge. Ideally, it involves detecting etuses who meet the aorementioned denition and also discerning those at risk or compromise. Tere are three main tenets:
1. Te diagnosis relies on accurate gestational age assessment, optimally conrmed with sonography in the rst or early second trimester (able 14-1, p. 248). I gestational age is uncertain and the diagnosis is suspected, serial sonography is considered.
2. In low-risk pregnancies, the diagnosis is suspected based on clinical abdominal examination ater 24 weeks’ gestation in which the undal height lags by ≥3 cm. Sonography is then perormed.
3. I the pregnancy is at risk or FGR, based on actors reviewed in the next section, sonography is considered to assist with detection. Tis is perormed at approximately 32 weeks’ gestation. Care is individualized, and in some cases sonography may be needed every 4 weeks to assess etal growth. One example o the latter is twin gestations, because undal height cannot evaluate individual twin growth (Chap. 48, p. 851).
Uterine Fundal Height
At each prenatal visit ater 20 weeks’ gestation, undal height is assessed to screen or etal-growth impairment (Chap. 10, p. 182). Te measurement in centimeters approximates the gestational age in weeks. Te uterine size-date discrepancy may be unrelated to etal size. However, i the measurement diers by ≥3 cm in the absence o an obvious explanation, sonography is generally perormed.
Serial undal height measurement is the only routine screening or FGR that is endorsed by the American College o Obstetricians and Gynecologists and Society or MaternalFetal Medicine (2021a). International consensus also indicates that careully perormed serial undal height measurements are a simple, sae, inexpensive, and reasonably accurate method to screen or FGR (McCowan, 2018). Limitations o undal height screening are well documented. Te overall sensitivity o undal height to detect FGR ranges rom 11 to 25 percent (Goetzinger, 2012; Grantz, 2021; Roex, 2012; Sparks, 2011). Detection rates are lower in obese women than in those with normal BMI (Goetzinger, 2012).
Sonographic Assessment
Studies o routine screening or FGR using third-trimester sonography have yielded variable results, and detection o SGA neonates ranges rom <20 percent to >60 percent (Hammad, 2016; Monier, 2015; Sovio, 2015; Wanyonyi, 2021). One reason or poor detection is that sonography perormed at any point in gestation will ail to detect pregnancies in which FGR develops later. Also, it will miss those needing delivery or FGR beore the sonographic examination was perormed. Compounding this is that EFW is an imperect metric. Given that most SGA neonates are constitutionally small, it is not unexpected that the recurrence risk or FGR approximates 20 percent. Many o these cases are merely smaller mothers having smaller healthy children in successive pregnancies.
Routine third-trimester sonography to assess etal growth is not recommended because it has not been demonstrated to improve outcomes (American College o Obstetricians and Gynecologists, 2021a). Indeed, a Cochrane database analysis o 13 trials with 34,980 women ound that routine late-pregnancy ultrasound or a low-risk or an unselected population was not associated with maternal or etal benet (Bricker, 2015).
■ Pathophysiology
Fetal-growth restriction is one o the “major obstetrical syndromes” associated with deects in early placentation (Brosens, 2015). Mechanisms leading to abnormal trophoblastic invasion are likely multiactorial, 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 o the uterine spiral arteries (Cui, 2012). Tese processes are impaired in corin-decient mice, which also develop evidence o preeclampsia. Moreover, mutations in the gene or corin are reported in women with preeclampsia (Chen, 2015).
Several immunological abnormalities are associated with FGR. Tis raises the prospect o maternal rejection o the “paternal semiallograt.” Rudzinski and colleagues (2013) studied C4d, a component o complement that is associated with humoral rejection o transplanted tissues. Tey ound this to be highly associated with chronic villitis—88 percent o cases versus only 5 percent o controls—and with reduced placental weight. In a study o 10,204 placentas, chronic villitis was associated with placental hypoperusion, etal acidemia, and FGR and its sequelae (Greer, 2012). Kim and coworkers (2015) extensively reviewed chronic inammatory placental lesions and their association with etal-growth restriction, preeclampsia, and preterm birth.
■ Risk Factors
Risk actors or impaired etal growth may be divided into three overlapping categories or “compartments”: those in the mother, the etus, or the placenta. Some o these are depicted in Figure 47-4. Many causes o FGR are prospectively considered risk actors, because impaired etal growth is not consistent in all aected women.
Gestational Weight Gain and Nutrition
Maternal weight gain during pregnancy is positively correlated with etal size (Hutcheon, 2019). Among women with gestational diabetes, gestational weight gain is also associated with both neonatal birthweight and adiposity (Blackwell, 2016). In contrast, a gestational weight gain during the second and third trimesters that is less than that recommended by the Institute o Medicine is associated with increased risk o an SGA neonate in women o all weight categories except class II or III obesity (Durie, 2011) (Chap. 10, p. 183). Te best-documented eect o amine on etal growth was in the winter o 1944 in Holland. For 6 months, the German occupation army restricted dietary intake to 500 kcal/d or civilians, including pregnant women. As a result, the average birthweight declined by 250 g (Stein, 1975).
Undernourished women may benet rom micronutrient supplementation. In one study, almost 32,000 Indonesian women were randomly assigned to receive micronutrient supplementation or only iron and olate tablets (Prado, 2012). Ospring o those receiving the supplement had lower risks o early inant mortality and low birthweight and had improved childhood motor and cognitive abilities. A Cochrane review o 20 trials involving 141,849 women concluded that supplementation o micronutrients may lower the risk o low birthweight (Keats, 2019). Te importance o antenatal vitamins and trace metals is discussed in Chapter 10 (p. 185).
Socioeconomic Factors
Te eect o social deprivation on birthweight is interconnected with liestyle actors such as smoking, alcohol or other substance abuse, and poor nutrition. With appropriate modiying interventions, women with psychosocial actors were signicantly less likely to deliver a low-birthweight newborn and also had ewer preterm births and other pregnancy complications (Coker, 2012).
Food insecurity, late entry into prenatal care, and limited access to healthcare are all contributors to etal-growth restriction (Bryant, 2010). Hall (2020) ound that in a military population with equal access to healthcare, racial dierences in late entry to prenatal care and FGR persist. An Australian study showed that the proportion o pregnancies aected by etal-growth restriction increased as levels o social disadvantage rose (Langridge, 2011).
Vascular and Renal Disease
Especially when complicated by superimposed preeclampsia, chronic vascular disease commonly restricts etal growth (Chap. 53, p. 948). Maternal vascular disease as evidenced by abnormal uterine artery Doppler velocimetry early in pregnancy is associated with higher rates o preeclampsia, SGA neonates, and delivery beore 34 weeks (He, 2020; Poon, 2019). Using Washington state birth certicate data, Leary and colleagues (2012) ound that maternal ischemic heart disease was associated with a 16-percent risk o having an SGA newborn. Chronic renal insufciency is requently associated with underlying hypertension and vascular disease. Nephropathies are commonly accompanied by restricted etal growth (Cunningham, 1990; Feng, 2015; Saliem, 2016). Tese relationships are considered urther in Chapter 56 (p. 1004).
Pregestational Diabetes
Fetal-growth restriction in newborns o women with diabetes may be related to congenital malormations or may ollow substrate deprivation rom advanced maternal vascular disease (Chap. 60, p. 1072). Te likelihood o restricted growth increases with worsening White classication, particularly nephropathy (Klemetti, 2016). Tat said, the prevalence o serious vascular disease associated with diabetes in pregnancy is low.
Chronic Hypoxia
Conditions associated with chronic hypoxia include asthma, maternal cyanotic heart disease, other chronic pulmonary disease, cigarette smoking, and living at high altitude. When exposed to a chronically hypoxic environment, some etuses have signicantly reduced birthweight. Smoking causes a dose-dependent reduction in etal growth, resulting in an average birthweight 200 g below that o newborns o nonsmokers (D’Souza, 1981). For each 1000- meter rise in altitude, the birthweight declined 150 g in a study o more than 1.8 million births in Austria (Waldhoer, 2015).
Anemia
In most cases, maternal anemia does not impair etal growth. Exceptions include sickle-cell disease and other inherited anemias (Desai, 2017; Tame, 2016). Importantly, curtailed maternal blood-volume expansion is linked to FGR (de Haas, 2017; Stott, 2017). Tis is urther discussed in Chapter 4 (p. 59).
Antiphospholipid Syndrome
Adverse obstetrical outcomes including etal-growth restriction have been associated with three types o antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-β2 glycoprotein-I antibodies. Mechanistically, a “two-hit” hypothesis suggests that initial endothelial damage is then ollowed by intervillous placental thrombosis. More specically, oxidative damage to certain membrane proteins is ollowed by antiphospholipid antibody binding, which leads to immune-complex ormation and ultimately to thrombosis (Giannakopoulos, 2013). Tis syndrome is considered in detail in Chapters 55 (p. 979) and 62 (p. 1115). Women with more than one type o antiphospholipid antibody are at higher risk or FGR compared with those with only one antibody (Saccone, 2017). Also, anti-β2 glycoprotein-I antibodies may have a stronger association with FGR, particularly early-onset disease.
Placental, Cord, and Uterine Abnormalities
Several placental abnormalities are associated with poor etal growth, which is presumed secondary to uteroplacental insu- ciency. Tese are discussed urther throughout Chapter 6 and include chronic placental abruption, extensive inarction, chorioangioma, velamentous cord insertion, and umbilical artery thrombosis. Abnormal placental implantation leading to endothelial dysunction may also limit etal growth (Brosens, 2015). Tis pathology is implicated in pregnancies complicated by preeclampsia (Chap. 40, p. 694). Last, some uterine malormations are linked to impaired etal growth (Chap. 3, p. 43).
Multifetal Gestation
Pregnancy with two or more etuses is more likely to be complicated by diminished growth o one or more etuses compared with that o singletons (Fig. 47-5). Serial sonography is recommended or this reason. With the understanding that normal twin growth may be less than that o singletons, we use a chorionicity-specic twin nomogram to diagnose FGR at Parkland Hospital. Discordance in estimated etal weight also is considered when evaluating twin growth (Chap. 48, p. 851).
Medications and Other Substances
Fortunately, most medications do not aect etal growth. Selected medications and other substances that have been associated with FGR due to etotoxicity are discussed in Chapter 8. Examples include cyclophosphamide and other antineoplastic drugs, signicant lead exposure, and drugs such as cocaine and methamphetamine. Alcohol and tobacco each have potent eects on etal growth. FGR is included among the diagnostic criteria or etal alcohol syndrome, and cigarette smoking is associated with a two- to threeold increased risk o FGR (Werler, 1997).
Maternal and Fetal Infections
Viral, bacterial, protozoan, and spirochetal inections have been implicated in up to 5 percent o FGR cases and are discussed in Chapters 67 and 68. Te best known o these are rubella and cytomegalovirus inection. Both promote calcications in the etus that are associated with cell death, and inection earlier in pregnancy correlates with worse outcomes. oda and colleagues (2015) described a Vietnamese epidemic in which 39 percent o 292 term newborns with congenital rubella syndrome were low birthweight. In one study o 238 primary cytomegalovirus inections, no severe cases were observed when inection occurred ater 14 weeks’ gestation (Picone, 2013). Tese investigators later identied sonographic ndings in 30 o 69 cases o congenital inection, and growth restriction was noted in 30 percent o these 30 cases (Picone, 2014).
Tuberculosis and syphilis also are associated with poor etal growth. Both extrapulmonary and pulmonary tuberculosis are linked with low birthweight (Chap. 54, p. 965). Sobhy (2017) analyzed 13 studies that included a total o 3384 women with active tuberculosis. Te odds ratio was 1.7 or low birthweight. Te etiology is uncertain, however, the adverse eects on maternal health, compounded by eects o poor nutrition and poverty, are important (Jana, 2012). Congenital syphilis is more common, and paradoxically, the placenta is almost always larger and heavier than normal due to edema and perivascular inammation (Chap. 68, p. 1208). Congenital syphilis is strongly linked with preterm birth and thus low-birthweight newborns (Shefeld, 2002).
Congenital inection with toxoplasma gondii is associated with FGR. Capobiango (2014) described 31 Brazilian pregnancies complicated by congenital toxoplasmosis. Only 13 percent were treated antepartum or toxoplasmosis, and low birthweight complicated nearly 40 percent o all the pregnancies. Congenital malaria may similarly cause low birthweight and poor etal growth. Briand and colleagues (2016) emphasize the importance o prophylaxis early in pregnancy or women at risk.
Congenital Malformations
In a classic review o more than 13,000 etuses with major mal- ormations and chromosomal abnormalities, the rate o growth restriction was double the population prevalence (Khoury, 1988). Te birth deect most strongly linked with FGR is gastroschisis. Nelson (2015) reviewed 111 etuses with gastroschisis and ound that a third had birthweights <10th percentile.
Congenital cardiac abnormalities are also associated with a slight increase in FGR risk. In a recent review o 1789 singleton neonates with isolated congenital cardiac abnormalities, the prevalence o SGA was 13 percent, which was 3 percent higher than the general-population risk (Ghanchi, 2021). With ew exceptions, the identication o growth restriction in the setting o a structural malormation urther increases the risk or an underlying genetic syndrome. I not already perormed, amniocentesis with chromosomal microarray analysis should be oered.
Genetic Abnormalities
Many genetic syndromes are strongly linked with prenatalgrowth impairment or postnatal ailure to thrive. Among liveborn neonates with autosomal trisomies, trisomy 21 is associated with an SGA prevalence o 15 to 30 percent (Herrera, 2020; Khoury, 1988). With trisomies 13 and 18, the risk o SGA is signicantly greater, 50 percent and >80 percent, respectively (Khoury, 1988). In trisomy 18, the combination o etal abnormalities plus FGR and hydramnios is particularly common. Te crown-rump length in etuses with trisomy 18 and 13, unlike that with trisomy 21, is also typically shorter than expected (Bahado-Singh, 1997; Schemmer, 1997). Poor etal growth similarly complicates urner syndrome, and the severity correlates with increasing haploinsufciency o the short arm o the X chromosome (Fiot, 2016). In contrast, poor growth is not characteristic o an increased number o X chromosomes (Ottesen, 2010; Wigby, 2016). Discussed in Chapter 16 (p. 318), confned placental mosaicism is a recognized cause o FGR.
■ Management
I FGR is detected, eorts are made to assess the etal condition and search or possible causes. Te risk or stillbirth is increased, and early-onset growth restriction is especially problematic. General tenets o management include serial evaluation o etal growth every 3 weeks and at least weekly evaluation o amnionic uid and umbilical artery Doppler velocimetry. A etus with slow but progressing EFW is more reassuring than one that has plateaued growth. Tis is supplemented with antepartum evaluation o etal well-being, which is usually nonstress testing or biophysical prole (American College o Obstetricians and Gynecologists, 2021a) (Chap. 20, p. 387). Consideration is also given to perorming a detailed etal anatomic survey and amniocentesis to assess or underlying genetic abnormalities or inection—particularly with early-onset FGR. A management algorithm is shown in Figure 47-6.
Delivery timing balances the risks o etal death with the hazards o preterm birth. Several multicenter studies address these problems, but unortunately, none has elucidated the optimal timing o delivery. For the preterm etus, the only randomized trial o delivery timing is the Growth Restriction Intervention rial (GRI) (Tornton, 2004). Tis trial involved 548 women between 24 and 36 weeks’ gestation. Women were randomly assigned to immediate delivery or to delayed delivery until the situation worsened. Te primary outcome was perinatal death or disability ater reaching age 2 years. Mortality rates did not dier through 2 years o age. Moreover, children aged 6 to 13 years did not show clinically signicant dierences between the two groups (Walker, 2011). Te Disproportionate Intrauterine Growth Intervention rial at erm (DIGIA) study examined the delivery timing o growth-restricted etuses who were 36 weeks’ gestation or older. Te 321 enrolled women were randomly assigned to labor induction or to expectant management. Composite neonatal morbidity rates did not di- er, except that neonatal admissions were lower ater 38 weeks’ gestation in a secondary analysis (Boers, 2010, 2012). Secondary analyses o DIGIA did not identiy a clear subgroup that beneted rom labor induction, and neurodevelopmental and behavioral outcomes at age 2 were similar in both groups (ajik, 2014; Van Wyk, 2012).
Doppler Velocimetry
Umbilical artery Doppler ow studies are central to the evaluation and management o the etus with growth restriction (Chap. 14, p. 262). Abnormalities represent the negative progression rom etal adaptation to ailure. Specically, initially increased impedance to ow in the umbilical artery may progress to absent end-diastolic ow and then reversed enddiastolic ow (Fig. 47-7). Tis negative progression correlates with hypoxia, acidosis, and etal death. In one prospective series o 1116 etuses with EFW <10th percentile, only 1 percent o those with normal umbilical artery Doppler studies had adverse outcomes compared with 12 percent o etuses with Doppler abnormalities (O’Dwyer, 2014). Te stillbirth risk in the setting o absent and reversed end-diastolic ow is 7 percent and 19 percent, respectively (Caradeux, 2018). Because o these ndings, the American College o Obstetricians and Gynecologists (2021a,b) and Society or Maternal-Fetal Medicine (2020) recommend serial umbilical artery Doppler studies in the management o FGR. Doppler abnormalities in other vessels may convey inormation regarding pathophysiology, but interrogation o these is not recommended or routine management o the pregnancy complicated by FGR (American college o Obstetricians and Gynecologists, 2021a; Society or Maternal-Fetal Medicine, 2020). Doppler abnormalities o the ductus venosus (Fig. 14-12, p. 264) reect increased central venous pressure rom decreased cardiac compliance and higher right ventricular end-diastolic pressure. Fetuses with abnormal ductus venosus Doppler ow have a 20-percent risk or stillbirth, and this increases to 46 percent in cases with a reversed A-wave (Caradeux, 2018). Second, pulsatile ow in the umbilical vein waveorm (Fig. 14-12) indicates cardiac dysunction. Last, cerebral vasodilation is the etal adaptative response to hypoxemia in the setting o growth restriction. Te cerebroplacental ratio (CPR)—dened as middle cerebral artery pulsatility index divided by umbilical artery pulsatility index—is a measure o this adaptation and may be abnormal in severe cases o FGR. An abnormal CPR <1 has been associated with greater risk or earlier delivery, lower birthweight, cesarean delivery, neonatal intensive care unit admission, and perinatal death (DeVore, 2015; Flood, 2014). However, a metaanalysis o 18,731 etuses ound the CPR was not predictive o adverse perinatal outcomes (Vollgra, 2021).
Management of the Near-term Fetus
Delivery o a suspected growth-restricted etus with normal umbilical artery Doppler velocimetry, normal amnionic uid volume, and reassuring etal testing can likely be deerred until 37 to 38 weeks’ gestation (see Fig. 47-6). Expectant management can be guided using antepartum evaluation o etal well-being described in Chapter 20. I oligohydramnios is present, delivery between 360/7 and 376/7 weeks’ gestation is recommended (American College o Obstetricians and Gynecologists, 2021c; Society or Maternal-Fetal Medicine, 2020). With a normal etal heart rate pattern, vaginal delivery is planned. Notably, some o these etuses do not tolerate labor.
Management of the Fetus Remote from Term
I growth restriction is identied in a etus beore 34 weeks, and amnionic uid volume and etal surveillance ndings are normal, observation is recommended. As long as interval etal growth and etal surveillance test results are normal, pregnancy is allowed to continue (see Fig. 47-6). Reassessment o etal growth is typically made no sooner than 3 weeks later. Weekly outpatient assessment o umbilical artery Doppler velocimetry and amnionic uid volume is combined with etal well-being testing. I umbilical artery Doppler studies indicate absent or reversed end-diastolic ow, inpatient surveillance is undertaken.
During hospitalization, more requent sonographic evaluations and antenatal testing o etal well-being and close proximity to labor and delivery are advantages. With growth restriction remote rom term, no specic treatment ameliorates the condition. Evidence does not support diminished activity or bed rest to accelerate growth or improve outcomes. Nutrient supplementation, attempts at plasma volume expansion, oxygen therapy, antihypertensive drugs, heparin, and aspirin are all ineective (American College o Obstetricians and Gynecologists, 2021a).
Management decisions hinge on assessment o the relative risks o etal death during expectant management versus the risks rom preterm delivery. Reassuring results rom etal wellbeing tests may allow observation with continued maturation. However, long-term neurological outcome, which theoretically may suer rom additional weeks in an inhospitable intrauterine environment, is a concern (Baschat, 2014; Lees, 2015; Tornton, 2004). Baschat and associates (2009) showed that neurodevelopmental outcome at 2 years in growth-restricted etuses was best predicted by birthweight and gestational age. Doppler abnormalities are generally not associated with poor childhood cognitive developmental scores among low-birthweight etuses delivered in the third trimester (Llurba, 2013). Tese ndings emphasize that adverse neurodevelopmental outcomes cannot always be predicted.
■ Intrapartum Management
When lagging etal growth is the result o placental insufciency due to poor maternal perusion or reduction o unctional placenta, the etal condition may be aggravated by labor. Equally important, oligohydramnios raises the likelihood o cord compression during labor. For these and other reasons, the requency o cesarean delivery is increased. Te risk o neonatal hypoxia or meconium aspiration is also greater. Tus, care or the newborn should be provided immediately by an attendant who can skillully clear the airway and ventilate a neonate as needed (Chap. 32, p. 586). Te severely growth-restricted newborn is particularly susceptible to hypothermia and may also develop other metabolic derangements such as hypoglycemia, polycythemia, and hyperviscosity. Risk is greatest at the lowest extremes o birthweight (Baschat, 2009, 2014; Llurba, 2013).
■ Outcomes
Lessons learned rom SGA neonates inorm concerns about FGR. More than 50 years ago, Battaglia and Lubchenco (1967) classied SGA neonates as those whose weights were below the 10th percentile or their gestational age. Te mortality rate o SGA neonates born at 38 weeks was 1 percent compared with 0.2 percent in those with larger birthweights. More recent data also indicate that the overall stillbirth rate among SGA neonates approximates 1 percent, which is twice as high as the population prevalence (Getahun, 2007).
Te risk or abnormal neurological development also is greater in SGA neonates. In an analysis o nearly 3000 newborns born beore 27 weeks’ gestation, those weighing <10th percentile had a nearly ourold higher risk o neonatal death or neurodevelopmental impairment and a nearly threeold greater risk o cerebral palsy compared with non-SGA neonates (De Jesus, 2013). In another analysis o more than 91,000 otherwise uncomplicated pregnancies, newborns with birthweights <5th percentile had a higher risk o low 5-minute Apgar score, respiratory distress, necrotizing enterocolitis, and neonatal sepsis than appropriate-weight neonates. Te risks o stillbirth and neonatal death were sixold and ourold higher, respectively (Mendez-Figueroa, 2016).
Newborns at the lowest birthweight percentiles are at greatest risk or adverse outcome. In one study o more than 44,561 neonates, only 14 percent o those weighing <1st percentile at birth survived to discharge (Grifn, 2015). Poor motor, cognitive, language and attention, and behavioral outcomes in growth-restricted newborns unortunately persist into early childhood and adolescence (Baschat, 2014; Levine, 2015; Rogne, 2015).
Early-onset Growth Restriction
Perinatal morbidities are urther increased in the 30 percent o FGR pregnancies diagnosed prior to 32 weeks’ gestation (Savchev, 2014). Tus, this gestational age is used to demarcate early-onset rom late-onset growth restriction (Society or Maternal-Fetal Medicine, 2020). Early-onset FGR is typically more severe and more commonly associated with placental dysunction and maternal hypertension than late-onset growth restriction (Aviram, 2019; Dall’Asta, 2017). Pregnancies with early-onset FGR have greater rates o umbilical artery Doppler abnormalities compared with those with late onset. Similar to pregnancies complicated by preeclampsia, increased maternal serum levels o antiangiogenic actors that include soluble vascular endothelial growth actor receptor 1 (sVEGFR-1) and soluble ms-like tyrosine kinase 1 (sFlt-1) are reported in pregnancies complicated by early-onset growth restriction (Kingdom, 2018; Korzeniewski, 2016) (Chap. 40, p. 694).
Barker Hypothesis
Tirty years ago, Barker (1992) hypothesized that adult mortality and morbidity are related to etal and inant health. Tis includes both under- and overgrowth. In the context o FGR, numerous reports describe a relationship between suboptimal etal nutrition and a higher risk o subsequent adult hypertension, atherosclerosis, type 2 diabetes, and metabolic derangement (Colella, 2018; Jornayvaz, 2016). Te degree to which low birthweight mediates adult disease is controversial, as weight gain in early lie also appears important (Breij, 2014; Kerkho, 2012; McCloskey, 2016).
Evidence suggests that FGR may aect organ development, particularly that o the heart. Individuals with low birthweight demonstrate cardiac structural changes and dysunction that persist through childhood, adolescence, and adulthood (Crispi, 2018). In one study, 80 inants who were born SGA beore 34 weeks’ gestation were compared at 6 months with 80 normally grown inants (Cruz-Lemini, 2016). Te ventricle in SGA inants was more globular, resulting in systolic and diastolic dys- unction. In another study, echocardiography in 418 adolescents showed that low birthweight was associated with a thicker let ventricular posterior wall (Hietalampi, 2012). However, these ndings have unclear long-term signicance (Cohen, 2016).
Growth restriction is also associated with postnatal structural and unctional renal changes. Luyckx and Brenner (2015) concluded that both low and high birthweight, maternal obesity, and gestational diabetes adversely aect in-utero development o 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 longterm renal unction.
■ Prevention
Ideally, prevention begins beore conception. Maternal medical conditions are treated, and medications are modied to help lower FGR risks. Smoking cessation is critical. Other risk actors are tailored to the maternal condition, such as antimalarial prophylaxis or women living in endemic areas and correction o nutritional deciencies. reatment o mild to moderate hypertension does not reduce the incidence o SGA newborns (Chap. 53, p. 950).
Currently, no pharmacologic therapies prevent growth restriction. Considerable study o low-dose aspirin therapy has not demonstrated consistent benet in low-risk pregnancies. Daily aspirin therapy did not reduce the risk or SGA neonates in a randomized trial o 1700 women (Rolnik, 2017). wo large metaanalyses involving more than 20,000 women did nd that low-dose aspirin was associated with a signicantly lower risk o FGR, whether initiated prior to or ater 16 weeks’ gestation (Meher, 2017; Roberge, 2017). A Cochrane database analysis showed a small reduction in the risk o SGA neonates with maternal aspirin therapy (Duley, 2019). However, these studies included women at risk or preeclampsia, and the modest decrease in the risk or growth restriction was a secondary nding. Because evidence in women without risk actors or preeclampsia is lacking, aspirin therapy or the prevention o FGR is not recommended (American College o Obstetricians and Gynecologists, 2020a, 2021a; Society or Maternal-Fetal Medicine, 2020)
FETAL MACROSOMIA
■ Definition
Te term macrosomia is used rather imprecisely to describe a etus whose estimated weight exceeds a threshold—typically 4000 g, 4500 g, or even 5000 g (American College o Obstetricians and Gynecologists, 2019a). Although obstetricians generally agree that neonates weighing <4000 g are not excessively large, a similar consensus has not been reached or the denition o macrosomia.
Large or gestational age (LGA) denotes a etus or newborn whose weight exceeds the 90th percentile or gestational age. Similar to SGA, the term LGA does not imply that growth is necessarily abnormal. Indeed, most such neonates are simply constitutionally larger than their peers. Te 90th percentile or birthweight at 39 weeks’ gestation approximates 3900 g (Duryea, 2014). Tus, most LGA neonates would not meet any o the common denitions o macrosomia.
In the United States in 2019, 6.4 percent o all newborns weighed 4000 to 4499 g; 0.9 percent weighed 4500 to 4999 g; and 0.1 percent were born weighing ≥5000 g (Martin, 2021). Similarly, during a 30-year period at Parkland Hospital, during which more than 350,000 singletons were born, only 1.4 percent o neonates weighed ≥4500 g (Table 47-2). We are o the view that the upper limit o etal growth, above which growth can be deemed abnormal, is likely to be two standard deviations above the mean. Tis represents perhaps 3 percent o births. At 40 weeks, such a threshold would correspond to approximately 4500 g.
■ Detection
Because current methods ail to accurately estimate excessive etal size, macrosomia cannot be denitively diagnosed until delivery (American College o Obstetricians and Gynecologists, 2019a). Inaccuracy in estimates o etal weight, by either undal height measurement or sonography, are oten attributable to maternal obesity. In one study o 502 patients with sonographic estimated etal weights >4000 g within 2 weeks o delivery, the risk o birthweight overestimation was >50 percent (Zaman, 2020). O those who underwent cesarean delivery or suspected LGA, almost 30 percent delivered a neonate weighing <4000 g.
■ Pathophysiology
Particularly in women with diabetes and elevated cord blood levels o insulin-like growth actor 1, etal macrosomia is asso ciated with greater neonatal at mass and morphological heart changes. Pedersen (1954) rst proposed that hyperglycemia leads to etal hyperinsulinemia and etal overgrowth. Tis has been extended to organ dysmorphia, or example, increased interventricular septal thickness in neonates o mothers with gestational diabetes (Aman, 2011; Garcia-Flores, 2011). Te cardiopulmonary vasculature also is adversely aected by diabetes in pregnancy. In 3277 cases o persistent pulmonary hypertension o the newborn, maternal obesity, diabetes, and both decient and excessive etal growth were independent risk actors (Steurer, 2017). Long-term metabolic consequences o etal macrosomia in the setting o maternal obesity are discussed in Chapter 51 (p. 907).
■ Risk Factors
Some actors associated with etal macrosomia are listed in Table 47-3. Many are interrelated. Advancing age usually correlates with multiparity and risk or diabetes, and obesity is similarly associated with diabetes. In one study, the birth prevalence o macrosomia exceeded 24 percent among obese women in China, and macrosomia rates were approximately 2.5-old higher or prolonged pregnancy and gestational diabetes (Wang, 2017). As shown in able 47-2, maternal diabetes is strongly associated with neonates weighing >4000 g. In a prospective study o 682 consecutive pregnancies complicated by diabetes, women with type 1 diabetes were signicantly more likely than women with type 2 diabetes to have a neonate weighing above the 90th and 97.7th percentiles (Murphy, 2011). Higher third-trimester glucose concentration correlates with etal macrosomia, and hemoglobin A1c and asting glucose values are independent predictors o macrosomia risk (Cyganek, 2017). Notably, maternal diabetes is associated with only a small percentage o the total number o LGA newborns.
■ Management
Several interventions have been proposed to interdict suspected or “impending” etal overgrowth. Exercise in pregnancy is benecial to the mother, does not increase the risk or growth impairment, and decreases macrosomia risk. One metaanalysis o 28 studies involving 5322 women concluded that exercise reduces the risk o an LGA newborn or birthweight >4000 g without raising the risk o an SGA neonate or birthweight <2500 g (Wiebe, 2015). Similarly, others have concluded that aerobic exercise increases the likelihood o a normal weight neonate (Di Mascio, 2016; Perales, 2016).
For women with diabetes, insulin therapy and glycemic control may lower the prevalence o neonatal macrosomia but have not consistently translated into reduced cesarean delivery rates. Fetal macrosomia, irrespective o the diagnosis o diabetes mellitus, is strongly associated with maternal obesity and excessive gestational weight gain (Durie, 2011; Durst, 2016; Harper, 2015). Currently recommended weight gains or pregnancy according to maternal BMI are described in Chapter 10 (p. 183).
“Prophylactic” Labor Induction Some clinicians have induced labor when etal macrosomia was suspected in nondiabetic women. Te rationale or this approach was to obviate urther etal growth and, in theory, reduce the risk o delivery complications or cesarean delivery. In a systematic review o 11 studies o expectant management compared with labor induction or suspected macrosomia, labor induction signicantly increased cesarean delivery rates without improving perinatal outcomes (Sanchez-Ramos, 2002). In contrast, Magro-Malosso and colleagues (2017) perormed a metaanalysis o our randomized trials involving 1190 women and concluded that labor induction at ≥38 weeks’ gestation or suspected macrosomia signicantly reduces the requency o etal overgrowth and ractures. In one o these studies, 822 women with suspected LGA etuses were randomly assigned either to early-term delivery or to expectant management (Boulvain, 2015). Tere was a higher rate o vaginal delivery that was marginally signicant and a lower composite measure o morbidity. Te authors cautioned that any benets should be balanced with the risks o early-term labor induction and delivery. Namely, a review o early-term births indicates that elective delivery beore 39 weeks’ gestation does not improve maternal outcomes and is associated with worse neonatal outcomes (ita, 2016). We agree with the American College o Obstetricians and Gynecologists (2019a, 2020b) that current evidence does not support a policy or early labor induction or delivery beore 39 weeks’ gestation.
Elective Cesarean Delivery
With the delivery o macrosomic neonates, shoulder dystocia and its attendant risks described in Chapter 27 (p. 501) are major concerns. Tat said, 9 percent o these injuries still ollow cesarean delivery (Johnson, 2020). Tereore, planned cesarean delivery on the basis o suspected macrosomia to prevent brachial plexopathy is an unreasonable strategy in the general population (Chauhan, 2005). Ecker and coworkers (1997) analyzed 80 cases o brachial plexus injury in 77,616 consecutive newborns at Brigham and Women’s Hospital. Tey concluded that an excessive number o otherwise unnecessary cesarean deliveries would be needed to prevent a single brachial plexus injury in neonates born to women without diabetes. Others echoed these sentiments in their analysis o nondiabetic mothers (Rouse, 1996; Van der Looven, 2020).
Conversely, planned cesarean delivery may be a reasonable strategy or diabetic women with an estimated etal weight >4250 or >4500 g. Conway and Langer (1998) described a protocol o routine cesarean delivery or sonographic estimates o ≥4250 g in diabetic women. Tis management signicantly lowered the shoulder dystocia rate rom 2.4 to 1.1 percent In summary, we agree with the American College o Obstetricians and Gynecologists that elective delivery or the etus that is suspected to be overgrown is inadvisable, particularly beore 39 weeks’ gestation. Last, we also conclude that elective cesarean delivery is not indicated when estimated etal weight is <5000 g among women without diabetes and <4500 g among women with diabetes (American College o Obstetricians and Gynecologists, 2019a, 2020b).
■ Outcomes
Te adverse consequences o excessive etal growth are considerable. Neonates with a birthweight o at least 4000 g have cesarean delivery rates exceeding 50 percent. Tis is particularly true with maternal obesity or diabetes or with birthweights >5000 g (Cordero, 2015; Crosby, 2017; Hehir, 2015). Neonatal morbidity is higher in LGA neonates compared with those with lower birthweights. Macrosomic newborns have higher rates o shoulder dystocia, obstetrical brachial plexus injuries, and birth ractures (Beta, 2019; Chauhan, 2017). Rates o shoulder dystocia vary greatly and can reach nearly 30 percent or macrosomic neonates when maternal diabetes is comorbid (Cordero, 2015).
In general obstetrical populations that include diabetic mothers, dystocia rates are at least 5 percent or neonates with birthweights ≥5000 g (Crosby, 2017; Hehir, 2015). Te risk or stillbirth is greater with macrosomia, and this risk rises with increasing birth weight (Salihu, 2020). Rates o postpartum hemorrhage, perineal laceration, and maternal inection, which are related complications, also are higher in mothers delivering overgrown newborns.
Table 47-4 shows maternal and neonatal outcomes by birthweight or neonates >4000 g delivered at Parkland Hospital
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