Abnormalities of Fetal Growth

Definitions

The duration of pregnancy is an integral component of prenatal growth assessment, and all currently prevailing definitions of fetal growth are gestational age specific. Assessing the gestational age accurately, however, can be challenging, and any error in dating will lead to misclassification of the infant, which can have significant clinical implications. In many instances, the method of gestational age determination has contributed to variations in the gestational age specific reference growth curves. For example, some nomograms are based on approximating the gestational age to the nearest week whereas others use completed weeks. The birth weight charts are also affected by other variables that may limit their reliability. Many of these, such as fetal sex, race, parity, birth order, parental size, and altitude, contribute to the normal biologic variations in human fetal growth. There is continuing controversy on whether the reference growth charts should be customized by multiple variables or developed from the whole population. The customized approach predicts the optimal growth in an individual pregnancy and therefore specifically defines suboptimal growth for that pregnancy. However, it has been argued that such an approach may lead to a profusion of standards and may not contribute to improving the outcome of small for gestational age (SGA) infants. In recognition of the utility of a national standard, a population-based reference chart for fetal growth was developed from all the singleton births (over 3 million) in the United States in 1991. More recently, a similar national population-based fetal growth chart, which is also sex specific, has been developed in Italy. In a multicenter cross-sectional study, 8070 ultrasonographic examinations from low-risk singleton pregnancies between 16 and 40 weeks of gestation were used to develop growth curves: biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). Quantile regression was used to examine the impact of fetal sex across the biometric percentiles of the fetal measurements considered together with parents’ height, weight, parity, and race ( Fig. 4.1 ).

There is no universal agreement on the classification of an SGA infant. Various definitions appear in the medical literature, making comparisons between studies difficult. Additionally, investigators have shown that the prevalence of fetal growth restriction varies according to the fetal growth curve used. The most common definition of SGA refers to a weight below the 10th percentile for gestational age or birth weight less than 2 standard deviations (SD) from the mean. Some investigators also use measurements below the third percentile to define SGA. However, these definitions do not make a distinction between infants who are constitutionally small, growth-restricted and small, and those that are not small but growth-restricted relative to their potential. For example, as many as 70% of fetuses who weigh below the 10th percentile for gestational age at birth are small simply because of constitutional factors such as female sex or maternal ethnicity, parity, or body mass index; they are not at high risk of perinatal mortality or morbidity. In contrast, true intrauterine growth restriction (IUGR) is associated with numerous perinatal morbidities. This has clinical relevance to perinatologists and neonatologists, as many of the tiniest premature neonates in the neonatal intensive care units are probably growth restricted.

Increasing intervention for fetal growth restriction (FGR) is changing the definition of SGA as defined by population-derived birthweight centiles. This was recently shown in Victoria, Australia, where improved detection of FGR reduced the proportion of babies with birthweight <3rd centile from 3.1% to 1.9%. Over time, it is projected that this will cause the birthweight cutoff that defines the 3rd centile to increase. In that same Australian population, it has been projected that the birthweight defining the 3rd centile at 40 weeks’ gestation will increase by 150 g over 35 years. The authors of these studies proposed using the INTERGROWTH-21st birthweight charts that are derived from healthy populations specifically selected to demonstrate ideal fetal growth applicable across all countries. This is an active and important area of research, and it is clear that there is not consensus around the world as to which growth charts should be utilized.

Patterns of Altered Growth

Neonates with intrauterine growth retardation can be classified as demonstrating either symmetrical or asymmetrical growth. Infants with symmetric IUGR have reduced weight, length, and head circumference at birth. Weight (and then length) of infants with asymmetric growth retardation is affected, with a relatively normal or “head-sparing” growth pattern. Factors intrinsic to the fetus in general cause symmetrical growth restriction, whereas asymmetric IUGR is often associated with maternal medical conditions such as preeclampsia, chronic hypertension, and uterine anomalies. Asymmetrical patterns generally develop during the third trimester, a period of rapid fetal growth. However, now that fetal surveillance is more common, asymmetrical growth restriction is often diagnosed in the second trimester.

Factors that are well-recognized to limit the growth of both the fetal brain and body include chromosomal anomalies (e.g., trisomies), congenital infections (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex [TORCH], malaria, human immunodeficiency virus [HIV], and parvovirus), dwarf syndromes, and some inborn errors of metabolism. Cardiac and renal structural anomalies are common conditions associated with SGA. These conditions retard fetal growth primarily by impaired cell proliferation. Recognized causes of IUGR are listed in Table 4.1 .

Fetal Causes of Growth Restriction

Fetal factors affecting growth include fetal gender, familial genetic inheritance, and chromosomal abnormalities or dysmorphic syndromes. In one large population-based study, the frequency of IUGR among infants with congenital malformations was 22%. The majority of the infants affected had genetic abnormalities including chromosomal, submicroscopic single gene disorders and imprinting defects, such as Russell Silver. Triploidies are the most common anomaly in fetuses below 26 weeks, and trisomy 18 above 26 weeks. Sometimes, the chromosomal anomaly can be confined to the placenta, and cause growth restriction in a chromosomally normal fetus. Mosaicism is defined as the presence of two or more different chromosomal complements in the fetoplacental unit developed from a single zygote. It is caused by a viable somatic postmitotic error occurring in an initially normal conceptus, or a meiotic error resulting in trisomy with subsequent postzygotic trisomic rescue.

Fetal gender also influences size, with male infants showing greater intrauterine growth than female infants.

Placental Causes of Growth Restriction

In mammals, the major determinant of intrauterine growth is the placental supply of nutrients to the fetus. Indeed, in many species, fetal weight near term is positively correlated to placental weight as a proxy measure of the surface area for materno-fetal transport of nutrients. The nutrient transfer capacity of the placenta depends on its size, morphology, blood flow, and transporter abundance. In addition, placental synthesis and metabolism of key nutrients and hormones influences the rate of fetal growth. Changes in any of these placental factors can therefore affect intrauterine growth. However, the fetus is not just a passive recipient of nutrients from the placenta. The fetal genome exerts a significant acquisitive drive for maternal nutrients through adaptations in the placenta, particularly when the potential for fetoplacental growth is compromised.

Placental maturation at the end of pregnancy is associated with an increase in substrate transfer, a slowing (but not cessation) of placental growth, and a plateau in fetal growth near term. Fetal size and placental growth are directly related, and placentas from pregnancies yielding growth-restricted infants demonstrate a higher incidence of smallness and abnormality than those from pregnancies with appropriately grown infants. The difference in size is seen even in a comparison of placentas associated with growth-restricted infants and those associated with appropriate for gestational age (AGA) infants of the same birth weight. Clinical conditions associated with reduced placental size (and subsequent reduced fetal weight) include maternal vascular disease (preeclampsia, eclampsia, and chronic maternal hypertension), uterine anomalies (fibroids, abnormal uterine anatomy), placental infarctions, unusual cord insertions, and abnormalities of placentation.

Multiple gestations are associated with greater risk for fetal growth restriction. The higher risk stems from crowding and abnormalities with placentation, vascular communications, and umbilical cord insertions. Divergence in fetal growth appears from about 30 to 32 weeks in twin gestation compared with singleton pregnancies, although this may occur earlier in gestation. Abnormalities in placentation are also more common with multiple gestations. Monochorionic twins can share placental vascular communication (twin-twin transfusion), leading to fetal growth restriction during gestation. Fetal “competition” for placental transfer of nutrients raises the incidence of growth restriction and discordance in growth between fetuses. The rate of birth weights less than the fifth percentile is higher in monochorionic twins. Placental growth is restricted in utero because of limitation in space, leading to a higher incidence of placenta previa in multiple-gestation pregnancies. Additionally, abnormalities in cord insertions (marginal and velamentous cord insertions) and occurrence of a single umbilical artery are more frequently found in multiple gestations.

Investigators have shown an effect of altitude on placenta function, thereby impairing fetal growth, with infants born at high altitudes having lower birth weights. Differences in fetal growth are detected from about 25 weeks with pregnancies at 4000 m. In these high-altitude pregnancies, the abdominal circumference is most affected. Interestingly, investigators have shown that adaptation to high altitude during pregnancy is also possible. Tibetan infants have higher birth weights than infants of more recent immigrants of ethnic Chinese origin living at the same high-altitude (2700 to 4700 m) region of Tibet. Tibetan infants also have less IUGR than infants born to more recent immigrants to the area.

Maternal Causes of Growth Restriction

Maternal health conditions associated with chronic decreases in uteroplacental blood flow (maternal vascular diseases, preeclampsia, hypertension, maternal smoking) are associated with poor fetal growth and nutrition. Infants born to women with preeclampsia are at substantial risk for IUGR. Investigators have shown that the extent of growth restriction correlates with the severity and the onset during pregnancy of the preeclampsia. Ødegård et al. showed that fetuses exposed to preeclampsia from early in pregnancy had the most serious growth restriction, and more than half of these infants were born SGA. Chronic maternal diseases (cardiac, renal) may decrease the normal uteroplacental blood flow to the fetus, and thus may also be associated with poor fetal growth.

Maternal constitutional factors have a significant effect on fetal growth. Maternal weight (prepregnancy), maternal stature, and maternal weight gain during pregnancy are directly associated with maternal nutrition, and correlate with fetal growth. Numerous studies show that these findings are often confounded by highly associated cultural and socioeconomic factors. The woman with a previous SGA infant has a higher risk of a subsequent small infant. Investigators have shown a higher incidence of SGA infants to be associated with lower levels of maternal education. Parity of the mother also affects fetal size, nulliparous women having a higher incidence of SGA infants. A large population-based study in Sweden found that women who were older than 30 years and were nulliparous or had hypertensive disease were at increased risk of preterm and term growth-restricted infants.

Studies have shown differential fetal growth for women of diverse ethnicities, with Latina and white women having higher rates of large for gestational age (LGA) infants, and African-American and South Asian women having a higher incidence of small for gestational age (SGA) infants. These gender and ethnic differences in birth weight become pronounced after 30 weeks of gestation. Investigators in California have shown that US-born Black women have higher rates of prematurity and LBW infants than foreign-born Black women. Other researchers have found that even among women with very low risk of LBW infants (married, age 20 to 34 years, 13 or more years of education, adequate prenatal care, and absence of maternal health risk factors and tobacco or alcohol use), the risk of delivering an SGA infant is still higher for African-American women than for white women. It is unclear whether these differences in fetal growth are due to inherent differences or differential exposure to environmental factors, including stress.

Maternal nutrition significantly impacts fetal growth, primarily in developing countries. Although numerous factors interact with and affect fetal development, maternal malnutrition is assumed to be a major cause of IUGR in developing countries.

Teen pregnancy represents a special condition in which fetal weight is highly influenced by maternal nutrition. Teen mothers (<15 years) have been shown to have a higher risk for delivering a growth-restricted infant. Teen pregnancies are complicated by the additional nutritional needs of a pregnant mother who is still actively growing, as well as by the socioeconomic status of pregnant teens in developed countries.

The effects of micronutrients on pregnancy outcomes and fetal growth have been less well studied. Maternal intake of certain micronutrients has also been found to affect fetal growth. Zinc deficiency has been associated with fetal growth restriction as well as other abnormalities, such as infertility and spontaneous abortion. Additionally, dietary intake of vitamin C during early pregnancy has been shown to be associated with an increase in birth weight. Others have shown strong associations between maternal intake of folate and iron and infant and placental weights. In developing countries, the effects of nutritional deficiencies during pregnancy are more prevalent and easier to detect. Rao and colleagues estimated that one third of infants in India are born weighing less than 2500 g, mainly because of maternal malnutrition. These investigators have shown significant associations between infant birth weight and maternal intake of milk, leafy greens, fruits, and folate during pregnancy. However, many of these studies have not been replicated, and thus, the possible role of nutrient supplementation on fetal growth remains to be determined.

Although toxins such as cigarette smoke and alcohol have a direct effect on placental function, they may also affect fetal growth through an associated compromise in maternal nutrition. Other environmental toxins (lead, arsenic, mercury) are associated with IUGR and believed to affect fetal growth by entering the food chain and depleting body stores of iron, vitamin C, and possibly other nutrients.

Numerous studies have shown associations between birth weight and maternal intake of macronutrients and micronutrients, but the effects of nutritional supplements used during pregnancy on fetal growth are equivocal. This is underscored by the results of a large double-blind, randomized controlled trial including 1426 pregnancies that was carried out in rural Burkina Faso. Pregnant women were randomly assigned to receive either iron and folic acid (IFA) or the United Nations International Children’s Emergency Fund (UNICEF)/World Health Organization (WHO)/United Nations University (UNU) international multiple micronutrient preparation (UNIMMAP) daily until 3 months after delivery. Birthweight was only increased by 52 g and birth length by 3.6 mm. Unexpectedly, the risk of perinatal death was marginally but significantly increased in the UNIMMAP group (OR: 1.78; 95% CI: 0.95, 3.32; P = .07). However, another more recent study found that the effects of iron-containing supplements on birth weight depended on baseline hemoglobin concentrations. The iron-containing supplements improved birth weight in women with very high hemoglobin levels before 20 weeks of gestation in a large Chinese cohort.

Maternal socioeconomic status and ethnicity have also been identified as risk factors for IUGR and poor health outcomes in infants in both developing and developed countries. In the United States, low levels of maternal and paternal education, certain maternal and paternal occupations, and low family income are associated with lower birth weights in children of African-American, Hispanic, and white women. In large population-based studies from Sweden, Brazil, France, and Denmark, investigators have similarly shown a higher incidence of fetal growth restriction in association with low maternal education. ^, The incidence of IUGR is also higher in women without medical insurance. Interestingly, Mexican-born immigrants in California have better perinatal outcomes (including birth weight) than both African-Americans and US-born women of Mexican descent. The reasons for this apparent paradox are unclear, but one postulate is the tendency of recent immigrants to maintain the favorable nutritional and behavioral characteristics of their country of origin. These studies support the speculation that the differences in fetal growth between groups do not reflect inherent differences in fetal growth but rather stem from inequalities in nutrition, health care, and other environmental factors.

Smoking

Maternal smoking during pregnancy is associated with a reduction in birth weight of approximately 250 g. In developed countries, cigarette smoking is the single most important cause of poor fetal growth. However, the literature describing associations between maternal smoking and reduced fetal measurements is inconsistent. For example, maternal smoking is associated with reduced second trimester growth in some studies but not all. Abdominal and proximal muscle growth restriction has been linked to maternal smoking in one population but to peripheral fetal growth (i.e., femur length) in others. To address some of these inconsistencies, a recent meta-analysis was conducted of 16 studies from 8 populations. They found that maternal smoking during pregnancy was associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects were attenuated if mothers quit or reduced cigarette consumption during pregnancy. Kataoka and associates report that cigarette smoking also appears to have a dose-dependent effect on the incidence of IUGR, with this effect being seen especially with heavy smoking and smoking during the third trimester. These investigators have shown that if women stop smoking during the third trimester, their infants’ birth weights are indistinguishable from those of infants born to the normal population. Other researchers have shown that even a reduction in smoking is associated with improved fetal growth. Numerous potential causes of the effects of smoking on fetal growth have been suggested, including direct effects of nicotine on placental vasoconstriction, decreased uterine blood flow, higher levels of fetal carboxyhemoglobin, fetal hypoxia, adverse maternal nutritional intake, and altered maternal and placental metabolism.