Etiological Factors
Oded Langer, MD, PhD
If you always do what you’ve always done, you’ll get what you’ve always gotten.
—Anthony Robbins
We must become the change we want to see in the world.
—Anonymous, sometimes attributed to Mahatma Gandhi
Key Points
• In diabetic women, fetal growth is the result of interaction between the genetic drive to grow and substrate availability.
• Fetal growth during the first and second trimesters accounts for about 20% of fetal weight at delivery; growth drive is primarily genetic.
• Most fetal growth occurs during the third trimester. The growth drive is influenced mainly by environmental and nutritional factors.
• The majority of large and small infants (70%) are constitutional and influenced by genetic factors.
• Fetal insulin clearance occurs mainly in the liver and not through the kidneys and urine.
• Fetal hyperinsulinemia is considered the marker for diabetic fetopathy. The measurement of fetal insulin in amniotic fluid will result in a high false negative rate.
INTRODUCTION
The famous literary and satirical reports of macrosomia were written by the 16th-century monk and physician Francois Rabelais. He told the story of the birth of the “giant” baby Gargantua; many years later, Gargantua’s wife dies giving birth to another “giant,” Pantagruel, “...who was so amazingly large and heavy that he could not come into the world without suffocating his mother.”1 Ortega in 1891 reported the birth of a 24-pound, 13-ounce male infant.2 These examples may be anecdotal, but they are the largest babies reported in the literature. Today, there are numerous institutions worldwide with documented claims for their own “infamous” large babies.
The association between maternal diabetes and the large-for-gestational-age (LGA) infant was first described by Allen.3 In the same year, Koff and Potter4 reported the experience of the Chicago Lying-In Hospital where delivery of an infant weighing more than 4500 g was frequently attended with serious difficulties resulting in high fetal and maternal mortality rates. Farquhar5 in describing the infant of a diabetic mother not only used “gigantism” and “visceromegaly” in his narrative but also used very descriptive nonmedical terms: “.plump, sleek, liberally coated with vernix caseosa, full-faced and plethoric. The umbilical cord and placenta share in the gigantism.”
In the United States, close to 450,000 large infants are born annually. In general, birth weight has shown an incremental rise over time that parallels the progression of obesity and diabetes in the general population. There is ample evidence that fetal macrosomia is associated with increased risk of complications for the mother and the newborn. In current obstetrics, the mac- rosomic fetus represents a frequent clinical challenge. Evidence is emerging that being born macrosomic is also associated with future health risks. The indication is extensive that maternal overweight and associated metabolic changes, including type 2 and gestational diabetes mellitus (GDM), play a central role. This phenomenon may have a “snowball effect” since the likelihood of obstetric complications (shoulder dystocia, trauma, etc.) increases with enhanced weight. Contemporary researchers have reconfirmed that perinatal morbidity and mortality are higher for the macrosomic neonate (weight > 4000 g) than for neonates who are appropriate-for-gestational age (AGA). Antenatal detection of the excessively large fetus may significantly reduce mortality and morbidity rates.6
DEFINITIONS
There are several definitions that characterize the large infant. Many of these definitions, rather than providing a general weight threshold associated with pathophysiology and fetal disease, equate weight thresholds linked to specific complications such as shoulder dystocia and cesarean section.7,8 This narrow perspective precludes the potential morbidity of the macrosomic condition. Macrosomia has also been defined as a birth weight exceeding an arbitrary limit, and different studies have set the cutoff at various weight values (4000 g, 4100 g, 4500 g, 4536 g, and 5000 g).9-14 Using the definition derived mainly from the association between the rate of shoulder dystocia and fetal weight category (4500 g) fails to demonstrate the full magnitude of the diabetic fetopathy. Macrosomia, defined as a weight of 4000 g, is the most common weight category cited in the literature. The use of a higher weight threshold will result in fewer cases of macrosomia but will mask the extent of the complications associated with this condition. These definitions are of historical significance; they bear scant relevance to the understanding and continuing developments in today’s research on deviant fetal growth.
A more contemporary approach is to use the term macroso- mia as a descriptor of fetal disease (e.g., diabetic fetopathy) rather than as a birth weight cutoff. This definition provides the practitioner with an approach to assessing fetal growth and health for clinical decision making rather than the narrower view of fetal weight in isolation. A more inclusive spectrum of diabetic fetopathy would also include measurement of the fetal heart, body composition, and liver size—all of which assist in differentiating between the constitutionally and abnormally large fetuses. In addition, clinical factors such as glycemic profile and obesity need to be included in the overall assessment to maximize a successful delivery (i.e., the whole is equal to the sum of its parts).
Birth percentile using a threshold of >90th percentile for a given gestational age results in the birth of approximately 70% of babies who are healthy but are constitutionally large and 30% who suffer from diabetic fetopathy. Moreover, using weight thresholds limits the identification of fetuses compromised by diabetic fetopathy since only late in gestation do these infants reach weights >4000 g even when the mother is diabetic. For example, a fetus weighing 3860 g at 35 weeks would not be classified macrosomic by the former definition even though its weight would be greater than the 97 th percentile for gestational age. Several standard weight cutoffs are used by obstetricians.15,16 A national reference of fetal growth was generated using the 1991 US Live Birth File of the National Center for Health Statistics based on more than 3.8 million births.17 These and other guidelines identify fetal growth more accurately throughout pregnancy to facilitate timely intervention, but still lack the ability to separate between constitutional and disease-related large infants. Furthermore, growth standards are open to several potential errors. A miscalculation of gestational age, even by a few days, may categorize a diabetic infant as LGA rather than as adequate-for-gestational age. Geographic location15 as well as ethnicity16 affects infant size. Table 7-1 demonstrates the differences in weight thresholds by different growth standard tables.
In general, the weight standard used in a study needs to reflect that of the study population. For purposes of portraying an accurate picture, both LGA and macrosomic infants should be reported since using the macrosomic weight definition alone will not provide an accurate description of study results. When delivery occurs at 37-38 weeks, it artificially decreases the number of macrosomic infants and minimizes the magnitude of the problem.
CONTROL OF HUMAN FETAL GROWTH
Embryonic cell proliferation and weight increase rapidly during organ embryogenesis, yet 95% of the ultimate weight of the fetus is gained during the second half of pregnancy.18 Human placental and fetal weights are comparable until approximately 20 weeks of gestation when the rapid growth phase begins in the fetus. After this, fetal growth continually increases to a maximum rate during the third trimester, while placental weight gain does not parallel this increase, suggesting that factors other than the placental transport functions are involved in controlling fetal growth.
During the early phases of organ embryogenesis, control is exercised primarily by the genome. Beyond this point, however, the ultimate growth of the fetus is controlled by a multitude of factors such as nutrients, environmental considerations, and aberrant metabolic states, that is, diabetes. The growth and development of the fetus are regulated by and dependent on numerous factors. They include the maternal uterine environment, the functioning of the placenta, and the availability of nutrients to mother and fetus. For normal pregnancies, a strong correlation exists between birth weight and gestational age. However, an infant who is small at birth may be chronologically and functionally mature, whereas, in pregnancies complicated by diabetes, a neonate of normal term size may be actually preterm. Fetal growth differs from postnatal growth. Fetal growth appears to be constrained, that is, the fetus does not appear to grow to its maximal potential; the constraining influences are primarily maternal in origin.19
TABLE 7-1 Percentiles for Birth Weight for Gestational Age
|
Birth Weight (g) |
||||||
|
50th Percentile |
90th Percentile |
95th Percentile |
||||
|
Gestational Age (yr) 37 |
Alexander et al. 3117 |
Langer 3033 |
Alexander et al. 3755 |
Langer 3657 |
Alexander et al. 3956 |
Langer 3875 |
|
38 |
3263 |
3147 |
3867 |
3742 |
4027 |
3912 |
|
39 |
3400 |
3260 |
3980 |
3827 |
4107 |
3997 |
|
40 |
3495 |
3317 |
4060 |
3920 |
4185 |
4111 |
|
41 |
3527 |
3430 |
4094 |
4040 |
4217 |
4238 |
|
42 |
3522 |
3473 |
4098 |
4111 |
4213 |
4309 |
FETAL GROWTH: LESSONS FROM THE LABORATORY
Animal models for diabetes and specifically diabetes in pregnancy are continually evolving especially for type 1 diabetes. However, for GDM and type 2 diabetes, designing a model is more difficult because it needs to duplicate insulin resistance and relatively decreased insulin secretion, the hallmarks of GDM and type 2 diabetes. A second limitation in these models is that the human placenta is different than those of sheep, mice, and monkeys and, therefore, the responses are varied and not always comparable.
Maternal diabetes has been produced by streptozotocin injection in the pregnant rhesus (Macaca mulatto) monkey.20 The infants born to these monkeys are macrosomic and exhibit the selective organomegaly characteristics of human infants of diabetic mothers.21 These monkeys appear to be metabolically similar to human infants of diabetic mothers with demonstrable hyperglycemia and hyperinsuline- mia. The rhesus monkey model provides experimental verification of the Pedersen hypothesis yet does not prove a cause-and-effect relationship between fetal hyperinsulinemia and fetal overgrowth. The rhesus monkey fetus is hyperinsulinemic and hyperglycemic, differing from the human fetus who is characteristically hyperinsulinemic and hypoglycemic. Thus, the possibility of hyperglycemia induced by excess substrate on fetal growth cannot be excluded in the monkey. Even with the marked fetal hyperinsulinemia and attendant increase in fetal substrate use, fetal glucose concentrations may be maintained by increased glucose delivery from the mother to the fetus.
Susa et al., in a series of studies, evaluated the effect of hyper- insulinemia on the fetus of primates.22,23 With the use of different concentration levels and, more specifically, in insulin concentrations comparable to those that may be reached in infants of human mothers with poorly controlled diabetes, the authors produced macrosomia and fetal hyperinsulinemia in primates.24,25 In the low- dose insulin-treated primate group, the insulin concentration was comparable to levels reported in human fetuses of diabetic mothers.24-26 In the high-dose insulin-treated primate group, insulin concentrations were higher than those observed in infants of diabetic mothers; the primate fetuses were approximately 100 g heavier than their age-matched controls. The excess weight for these two groups over controls was 23% for the low dose and 27% for the high dose.26
The fetal rhesus monkey gains weight at the approximate rate of 5 g/d.27 In insulin-treated fetuses, there is a doubling of weight gain to 10 g/d. The placental weight also increased with insulin treatment but only in the high-dose treated group.28 Organomegaly, very similar to the human infant of the diabetic mother, was produced in the fetal primates, with significantly increased body, heart, liver, and spleen weight. The lower-dose insulin treatment produced only significant weight gain and cardiomegaly.
A postmortem study of human infants of diabetic mothers from a Scandinavian population reported total body and heart weight increases.29 These data are evidence that hyperinsulinemia in the absence of elevated growth substrate concentrations stimulates cellular proliferation; when fetal growth substrates are also elevated, both hyperplasia and hypertrophy have been reported. Naeye studied 21 macrosomic infants and demonstrated that body weight was increased 141% relative to controls. His measurements included length, 112%; heart, 174%; liver, 179%; lung and spleen, 127% each; adrenal, 158%; and pancreas, 110%; and the kidneys and brain remained uninvolved. Thus, both hypertrophy and hyperplasia accounted for the organ enlargement.28 We studied 84 stillbirths of diabetic mothers.30 The weight of the principal organs of these fetuses were obtained during autopsy and scored using standard weight autopsy tables. Cases of anomalies, multiple births, and severe macerated fetuses were excluded resulting in 59 diabetic stillbirths compared to 59 nondiabetic stillbirths. Cases were stratified into macrosomic (>4000 g) and nonmacro- somic (<4000 g) in both groups (Table 7-2). The study revealed a significantly larger placenta for the diabetic versus the nondiabetic mothers of macrosomic infants (808 ± 134 compared to 645 ± 156, respectively). In contrast, no significant difference in placental size was found in the mothers of the nonmacrosomic infants. Finally, fetal organomegaly was demonstrated in all insulin-sensitive tissues of diabetic stillbirths when the mother was hyperglycemic. On the other hand, the organ size of nondiabetic macrosomic and nonmacrosomic infants was within the normal range suggesting constitutional macrosomia.
TABLE 7-2 Mean Organ Percentiles in Relation to Standard Postmortem Weight Table (=100%)
|
Naeye28 |
Langer and Kagan-Hallet30 |
|||
|
Diabetes |
Nondiabetes |
|||
|
<4000 |
<4000 |
>4000 |
>4000 |
|
|
Heart |
174% |
167% |
168% |
101% |
|
Lung |
127% |
147% |
152% |
116% |
|
Liver |
179% |
114% |
163% |
97% |
|
Spleen |
127% |
95% |
129% |
105% |
|
Brain |
100% |
90% |
96% |
100% |
|
Placenta (g) |
— |
808 ±134 |
645 ±156 |
581±143 |
Hypertrophy and hyperplasia account for organ enlargement.
Furthermore, fetal hyperinsulinemia causes increased cellular glucose utilization, which promotes hepatic glycogen deposition, decreased mobilization of lipids, and increased protein production. Insulin stimulates incorporation of amino acids into proteins, and, in diabetic pregnancies, increased fetal uptake of amino acids and protein synthesis and decreased protein catabolism. During the last 12 weeks of gestation, the fetus of a diabetic mother deposits 50%-60% more fat than the fetus of a nondiabetic woman. The fat consumption pattern of the pregnant diabetic mother is unrelated to the subsequent infant adiposity.31
GENETIC FACTORS
The preliminary drive to growth is genetic. By mechanisms that remain poorly defined, there is a genetic control of cell growth and differentiation that is the basic determinant of species size at birth. There are two gene mechanisms associated with cellular, tissue, and organism growth. The first involves cellular division leading to tissue hyperplasia, which peaks in human gestation at the beginning of the third trimester.32 Hyperplasia is dependent on growth-promoting factors and apoptosis (programmed cell death) controlling systems. The second mechanism is increase in cellular size and mass leading to tissue hypertrophy, the main contributor to fetal weight in the third trimester.33 The range of birth size determined genetically is large, that is, 2830-3900 g at 40 weeks gestation.34 Regardless of the number of fetuses, uteroplacental constraints appear to become the major factor for growth at approximately 3000-3200 g in normal pregnancy.19 The difference in fetal size becomes apparent in the third trimester rather than in early gestation.35 Early in gestation, genetic factors dominate. Fetal growth in late gestation can be considered the result of the interrelationship between the genetic drive to grow and constraining influences that inhibit growth. Exogenous factors are more important in later gestation when variations in birth size are evident. The balance between genetic and exogenous influences (maternal nutrition, placental factors) is probably controlled by fetal hormones.
Fetal genotype accounts for approximately 15% of variations in birth weight because of certain inherited traits.36 These traits include fetal gender, racial and ethnic characteristics, and paternal and maternal genetic contributions. About 2% of variations in birth weight are attributable to sex chromosomes.36 Male genotype is associated with increased birth weight. Male infants average 150-200 g or more than females at term.37 This increase may be the result of the effect of testicular hormones or because of a more marked antigenic difference between the male fetus and his mother. Placentas from male neonates also weigh more than those of females (2% more at 40 weeks).38 There is a significant maternal influence on fetal size; this contribution has been estimated to be approximately 20%. Maternal height39 and weight40 have been shown to be associated with birth weight, while the father’s size does not appear to contribute significantly to neonatal size at birth. In contrast, others reported that maternal height did not contribute to birth weight.41 Others have shown, too, that race, ethnicity, and body mass index (BMI) contribute to fetal weight.42-44
In general, there is a slower rate of growth after 30 weeks gestation in twins and after 36 weeks in singleton births. Women tend to bear infants with comparable birth weights and the same gestational age across successive pregnancies. The fetal size increases with each pregnancy up to about the fifth pregnancy and then stabilizes.45 Therefore, mothers who deliver constitutionally large or small infants are likely to have similar size infants in subsequent pregnancies. This familial birth weight pattern appears to operate primarily through the mother’s linkage. This linkage was also demonstrated in animal studies.46 In diabetic patients, this maternal linkage to birth weight becomes obscured because of failed glycemic control. Therefore, it is metabolic and environmental factors that influence fetal size in each pregnancy.45
INSULIN
Fetal hormones translate genetic information into the actual growth stimuli. Several hormones were proposed to have an effect on fetal growth. However, the permissive and/or regulatory roles of each in normal fetal growth are yet to be established. The Pederson hypothesis suggested that fetal growth is the result of maternal hyperglycemia, which in turn causes fetal hyper- insulinemia and excessive fetal growth.46 Susa et al. confirmed this hypothesis and demonstrated fetal overgrowth in a primate model creating fetal hyperinsulinemia by implanting an Alzet insulin pump.47 The Pederson theory was further modified after recognition that other nutrients are present in increased concentrations (e.g., amino acids and lipids) that may contribute to fetal hyperinsulinemia.48 It has also been suggested that women who are characterized by “relative hypoglycemia” on the glucose tolerance test will also have relative maternal hypoinsulinemia and fetal hypoinsulinemia that result in growth restriction rather than over growth.49-53
Insulin plays a significant role in postnatal life as an anabolic hormone, mainly in carbohydrate metabolism. In intrauterine fetal life, insulin is the most recognized growth-promoting hormone. However, growth hormone per se does not influence fetal growth during intrauterine life. The fetal pancreas is the only source of insulin in the fetal circulation since the maternal insulin does not pass the human placenta. Insulin is already present at 8-10 weeks gestation but remains relatively inactive until 20 weeks of gestation when the insulin response to glucose becomes evident.54 The insulin response to exogenous glucose is related to the endogenous glucose levels in the fetal circulation, which mandate the sensitivity of the fetal β-cells.55 Thus, chronic fetal hyperglycemia accelerates the development of insulin secretory mechanisms, predisposing infants of diabetic mothers to have a mature insulin response.56 Insulin receptor levels in the human fetal liver become maximal at 19-25 weeks of gestation. However, there is an increased affinity for insulin in late gestation.57 Insulin receptors in some fetal tissues are characterized by increasing binding capacity for insulin and failure to down-regulate the receptor number in the presence of hyperinsulinemia.58 Therefore, an abnormal maternal glycemic level prior to the third trimester will not affect the rate of fetal macrosomia and LGA infants. In contrast, the level of glycemia during the third trimester will directly stimulate fetal hyperinsulinemia and fetal overgrowth. Thus, studies reporting an association between first trimester level of glycemia and fetal macrosomia may be the result of patients in poor control at the onset of pregnancy remaining in poor control throughout.
INSULIN-LIKE GROWTH FACTORS
Insulin-like growth factors (IGFs) are a group of peptides with extensive structural homology to proinsulin. In bioassay systems, they have insulin-like activity as well as growth-promoting effects, mainly by stimulation of cellular proliferation. There are two major forms of IGF in the circulation, which are called IGF I and IGF II. The IGFs are produced by fetal tissues and cannot cross the placenta. They are synthesized at multiple sites and probably act on cells near their site of synthesis.
IGF-I and IGF-II exert their biologic effects via receptor-mediated processes comparable to those of insulin. Low-affinity binding exists between IGFs and insulin receptors.59 Homology also exists between the type I IGF receptor that has a higher affinity for IGF-I than for IGF-II and the insulin receptor with the consequences that cross binding is possible. A second IGF receptor that is not structurally homologous to the insulin or IGF-I receptor binds IGF-II with affinity much higher than for IGF-I and binds insulin very poorly.60 The relative ratio of these receptors is tissue specific; therefore, the relative potencies of IGF-I and IGF-II differ from those of insulin.61
Given the relative insulin-like potency and the 2000- to 3000fold higher plasma concentration of IGFs, most of the plasma IGF activity must exist in an inactive form.59,62-64 Most likely, the growth factors (IGFs) act locally, before they are bound by carrier proteins. Their mechanism of action, therefore, should be autocrine or paracrine processes rather than the classical endocrine mechanism. Thus, the IGF plasma levels do not necessarily reflect their physiologic expression or activity.
Evidence suggests that IGFs influence fetal growth: first, studies demonstrate that IGFs are capable of stimulating the proliferation of fetal cells from various species, including humans. Second, both type I and II IGF receptors have been identified and partially purified from fetal tissues. Third, fetal plasma IGFs are of fetal origin; they are not transported from mother to fetus via the placenta. Studies have demonstrated the direct synthesis of IGFs by fetal fibroblasts in several organs such as intestine, heart, brain, kidney, liver, and lung.65
Hill et al.66 demonstrated that cord blood IGF-I and IGF- binding protein-I (IGFBP-I) are correlated with fetal growth. There were decreased levels of IGF-I and increased IGFBP-I levels in growth-restricted infants in comparison to a control group.67-69 Roth et al.70 confirmed this concept and reported increased IGF-I concentrations in macrosomic infants in comparison with a control group of appropriate-for-gestational-age infants. There was a significant correlation between cord IGF-I concentrations and birth weight (r2 = 0.61). Cord IGF-II concentrations are related to fetal pancreatic Β-cell function. Decreased IGF-II concentrations are related to Β-cell apoptosis, whereas increased IGF-II expression inhibits inducible nitric oxide synthase (iNOS), resulting in decreased Β-cell apoptosis.66
Several studies demonstrated a positive correlation between fetal birth weight and IGF-I. In addition, an association was found between IGFs and placental size.34,71 In a study in which IGF-I and IGF-II and their binding proteins were measured in utero by cord puncture between 20 and 37 weeks gestation or taken at delivery between 38 and 42 weeks, IGF-I levels were significantly increased in fetuses whose weights were higher than the mean weight. In contrast, fetuses with growth restriction had significantly reduced IGF-I levels, whereas IGF-II levels did not correlate with weight.67 Both fetal umbilical IGF-I and insulin concentrations are elevated in infants of diabetic mothers and low in growth-restricted neonates.68
Finally, the linear relationship between fetal birth weight and IGFs is probably consistent with the possibility that IGFs influence normal fetal growth. Excess fetal weight in humans and primates is found even when IGF levels are in the normal range but the fetus is hyperinsulinemic. Thus, increased fetal insulin levels are responsible for the fetal macrosomia in diabetes in pregnancy.
PLACENTAL HORMONES AND THE REGULATION OF FETAL GROWTH
Although the molecular mechanism that controls fetal growth remains poorly understood, the placenta, through the delivery of blood, oxygen, and vital nutrients to the fetus and clearance of fetal waste products, remains the controlling agent. During early and mid-gestation, maternal food intake increases 10%—15%, intestinal calcium absorption doubles, and first-phase insulin secretion increases 60%. During the first half of pregnancy, insulin sensitivity is preserved; the increase in insulin secretion promotes lipogenesis and limits fatty acid oxidation and facilitates fat storage.72 During mid-gestation and late gestation, although maternal food intake and fat mass increase, the maternal metabolism is regulated by insulin resistance, thus expediting maternal utilization of free fatty acids as an energy source. Moreover, this facilitates the transport of glucose, amino acids, essential fatty acids, and ketones for fetal growth.
In recent years, the role of several hormones has become evident. Prolactin (PRL) is produced by the mother’s pituitary gland and decidua. It binds with high affinity to human chorionic somatomammotropin (CSH) but with low affinity to human growth hormone (GH) receptors, suggesting that it functions as a lactogen rather than as a somatogen during pregnancy. As a result, the mother in mid-gestation and late gestation is suffused with high levels of lactogenic hormones: PRL, CSH, and virtually pure somatogen, placental growth hormone (PGH). CSH and PRL are also secreted into the fetal circulation; PGH can be detected only in maternal blood.72
Maternal weight and fat storage facilitate vital fetal growth. Small-for-gestational-age (SGA) children’s mothers had lower prepregnancy BMI and less pregnancy weight gain than mothers of AGA children. The mothers of LGA fetuses contributed the opposite effect to their offspring.41 However, when good metabolic control is achieved, there is no difference in arachidonic and docosahexaenoic acid in the blood of a mother and umbilical vein in type 1 diabetic women, suggesting that the lipid effect is secondary to the maternal metabolic status.73
PGH and CSH expression may also modify release of other critical hormones such as insulin or IGF-I, alter the delivery and accessibility of maternal nutrients, and influence the growth of fetal tissues.74 An increase in maternal BMI or gestational weight gain enhances maternal fat stores and reduces maternal insulin sensitivity prompting pregnancy glucose intolerance. This hyperglycemic state increases placental weight and fetal weight through induction of fetal hyperinsulinemia.41 Maternal fat reduces plasma adiponectin. This action may occur because CSH adiponectin suppresses CSH as well as PGH. An increase in CSH in fetal circulation could induce hyperinsulinemia by induction of Β-cell replication, thus increasing fetal weight gain.75 An increase in maternal CSH and stimulation of maternal β-cell replication and insulin production may provide compensation for maternal insulin resistance and preclude the development of GDM.72 In addition, adiponectin seems to determine fetal growth and adipose tissue accretion, and low molecular weight is more specifically implicated in males, whereas the higher molecular weight isoform may be more important in females.76
OTHER HORMONES
Specific growth-promoting factors that directly influence fetal growth have been difficult to identify. Growth hormone of maternal origin appears to have little influence on fetal growth since normal birth weight is obtained after maternal hypophysectomy in a variety of animals77 and in humans.78 A correlation exists between infant birth weight and maternal under nutrition when maternal growth factors are dramatically suppressed; however, newborn birth weight is reduced by up to 20%.79 The role of thyroid hormone and growth hormone in postnatal growth is well established.80,81 In contrast, these hormones play a minimal role in prenatal growth. Adrenal corticosteroids fulfill a critical role in the induction of maturational processes in specific organ systems such as lung and intestine.
MATERNAL AND ENVIRONMENTAL RISK FACTORS
Certain factors have been empirically associated with fetal macrosomia such as history of large babies,82 multiparity, maternal obesity (women who are more than 25% overweight or who have a prepregnant weight/height ratio >2.4), excessive weight gain (more than 35 pounds) during pregnancy, postmature pregnancy (greater than 294 days), and prolonged and/ or difficult labor.83 Chervenak et al.84 studied 317 consecutive postdate patients with well-dated pregnancies and found a 26% incidence of macrosomia. The incidence of cesarean section for arrest-protraction disorders was 22%. Patients with non- macrosomic infants had a significantly lower cesarean section rate (10%).85 Stallone and Ziel82 found that the maternal factor most commonly associated with macrosomia was a history of large babies. Modanlou et al.11 demonstrated that 37% of the mothers of macrosomic infants, excluding diabetics, were obese. These studies substantiate the findings of Chervenak et al.84 that pregravid obesity is a significant etiologic factor in the development of fetal macrosomia. In addition, the rate of oxytocin augmentation of labor has been found to be significantly higher in deliveries of large infants. Prolonged labor, especially in primigravid women, has been reported in mothers of macrosomic babies.
Perinatal and neonatal mortality and morbidity rates are higher in the macrosomic infant. Modanlou et al.11 reported that of the 66,000 infants weighting 4500 g or more at birth in the United States each year, approximately 10% require admission to an intensive care nursery. The perinatal morbidity rate is at least twice that of normal-sized infants and mortality rates are at least five times higher.86
METABOLIC SUBSTRATE FACTORS
Maternal diabetes is characterized by increased plasma concentrations of glucose, free fatty acids, triglycerides, and some amino acids.48 Maternal plasma concentrations of glucose, triglycerides, and the amino acids alanine, serine, and isoleucine are correlated with the birth weight of the infants of diabetic mothers.54 Similarly, excess of substrate (glucose) will result in fetal hyperinsulinemia; inadequate substrate delivery to the fetus will be reflected in fetal hypoinsulinemia resulting in growth delay and smaller fetuses. In addition, it has been shown that growth-restricted infants are characterized by hypoinsulinemia, hypoglycemia, and low insulin index.87 We demonstrated that in the presence of tight glycemic control (<87 mg/dL), there was more than a 20% incidence of SGA infants.88 This finding may represent fetal nutrition deprivation resulting in growth delay-related abnormalities. Thus, although tight glycemic control is desirable, the care provider must be alert to preventing overtreatment, which could predispose the fetus to growth restriction.
The growth potential of the developing fetus, under normal conditions, is determined by genetic factors and the adequacy of the maternal uterine environment. This includes the proper functioning of the placental supply line. Any conditions that interfere with this potential impose growth constraints. They may include genetic abnormalities and maternal disease, most significantly diabetes in pregnancy.
Since its recognition 150 years ago, macrosomia has been systematically included as one of the outcome measures in the majority of papers on diabetic fetopathy. Hyperglycemia characteristically exists in the poorly controlled diabetic because of relative hypoinsulinemia. Glucose crosses the placenta by facilitated diffusion, and the fetus maintains a level that represents approximately 75% of the maternal concentration. This imposes a carbohydrate surplus on the fetus, which in response, increases insulin secretion resulting in fetal hyperinsulinemia (Figure 7-1).
FETAL GROWTH PATTERNS IN THE DIABETIC NEONATE
The Gaussian distribution of fetal weight even in the nondiabetic population results in 10% LGA (above the 90th percentile) and 10% SGA (below the 10th percentile). Thus, the majority of LGA and SGA fetuses are either constitutionally large or small but healthy. In pregnant diabetic women, the effect (toxic) of glucose will cause accelerated fetal growth. Therefore, the rate of LGA infants is threefold higher in comparison to the general population.
The growth of the fetal head and femur follows a pattern similar to that of “normal” fetuses. It is after 26-28 weeks of gestation that the abnormal growth patterns become evident and are mostly confined to the abdominal circumference (AC). Ogata et al.89 studied 23 women with diabetes in pregnancy and showed ultrasonographically that accelerated abdominal growth can be detected at 28-32 weeks gestation and that it diverges from the predicted curve at this stage. Landon et al.90 studied 31 women with type 1 diabetes mellitus using serial ultrasound examinations in the third trimester and demonstrated a divergent growth pattern (acceleration of AC growth) at week 32 in fetuses destined to be LGA at birth. Langer et al.91 identified two distinct abnormal fetal growth patterns in the infants of pregnant diabetic women by estimated fetal weight and AC growth velocity throughout the third trimester. The reliability of fetal weight estimation was reflected in the overall error of less than 10%. The results of our study support the existence of both early and late accelerated growth patterns in the fetuses of gestational and pregestational diabetic women. These patterns are inherently different from the growth patterns exhibited by macrosomic fetuses of nondiabetic postdate women. Furthermore, our study described the presence of varied types of delayed growth patterns discernible by sonographic measurements among type 1 diabetes, GDM, and control subjects.
The existence of two distinct excessive growth patterns in the LGA infants was revealed by assessment with serial ultrasonography. At 30 weeks gestation, an early accelerated growth pattern was detected in 23% of the LGA infants; in 77% of these fetuses, the late accelerated growth pattern was observed. Growth escalation began at 33 weeks gestation and reached the 90th percentile at 36 weeks gestation. Head circumference (HC), femur length, and corresponding daily growth rates were comparable for LGA and AGA infants of diabetic mothers. The distinctive factors for identification of the macrosomic infant in utero are an enlarged AC and its corresponding daily growth rate. Other organs affected by the diabetic fetopathy leading to restricted or accelerated growth may be used as potential markers for these deviant growth patterns. These may include subcutaneous fat in the cheek, skin fold thickness, and liver size.92
LGA infants of diabetic mothers exhibited a significantly greater daily growth rate in AC than the AGA infants. Within the early accelerated growth pattern, the growth rate for AC remained constant throughout the third trimester. At 30 weeks gestation, the AC was already above the 95th percentile. In infants manifesting the late accelerated growth pattern, acceleration of growth in AC occurred later in the third trimester and reached the 95th percentile at 35 weeks gestation. In this growth pattern, the daily growth rate in AC was significantly greater during the second half of the third trimester (36-40 weeks) than during the first half. Mean blood glucose in the two growth patterns were comparable: 107 ± 16 mg/dL in the early pattern and 116 ± 18 mg/dL in the late pattern. Thus, differences in glycemic profile cannot be attributed to either early or late onset of accelerated growth.91,92
As previously discussed, accelerated fetal growth begins in the third trimester. Identification of fetuses in the first and second trimesters at the 90th percentile will suggest genetic influence and constitutional macrosomia rather than diabetic fetopathy. Further confirmation can be made by evaluating insulin levels in the amniotic fluid prior to unnecessary intervention during the 37th to 38th weeks of gestation. The evidence for the presence of fetal hyperinsulinemia will classify the fetus at risk. We demonstrated in over 700 gestational diabetic women with amniocentesis after 37 weeks gestation that the hyperinsulinemic fetuses were several folds at higher risk for neonatal diabetic complications compared to normoinsulinemic fetuses (Table 7-3 and Figure 7-2). However, it is important to note that measurements of amniotic fluid insulin will not identify all hyper- insulinemic fetuses since insulin metabolizes primarily in the liver.
Fat mass accounts for approximately 14% of the birth weight, but explains 46% of the variance in birth weight.93 In fact infants of mothers with GDM have increased fat mass and percentage body fat (12%-14% compared with 10%-12% in normal infants).94 The fetal overgrowth, seen in pregnancies complicated by GDM, is the result of many different factors and may lead to overt macroso- mia. Several studies have demonstrated that adiposity is higher in infants of diabetic mothers.95-97 Modanlou et al.98 described larger shoulder circumference in macrosomic infants of diabetic mothers in comparison to nondiabetic control subjects. Extra fat may be concentrated in the upper body of these infants, and this weight disproportion may increase their risk of shoulder dystocia.
TABLE 7-3 Comparison between Cord Insulin in Diabetic Patients
|
<13 μU |
>13 μU |
RR |
95% CI |
|
|
Small for gestational age |
3.4% |
9.0% |
2.1 |
0.8-5.8 |
|
Large for gestational age |
9.8% |
31.8% |
4.3 |
1.7-10.9 |
|
Macrosomia |
5.2% |
17.9% |
2.9 |
1.2-8.6 |
|
Polycythemia |
7.1% |
14.6% |
2.2 |
1.1-3.5 |
|
Hyperbilirubinemia |
7.7% |
12.5% |
1.7 |
0.9-3.5 |
|
Hypocalcemia |
5.9% |
12.4% |
2.2 |
1.3-4.6 |
|
Hypoglycemia |
7.2% |
22.5% |
3.7 |
2.0-7.0 |
|
Intravenous glucose |
11.5% |
22.6% |
5.6 |
3.7-6.3 |
|
NICU |
14.2% |
23.0% |
1.8 |
1.2-3.1 |
|
Number of patients (n) |
167 |
262 |
— |
— |
Macrosomic infants of diabetic mothers may have different anthropometric and body composition characteristics than those of nondiabetic patients. Osler95 described a higher body fat percentile in 12 infants of diabetic mothers but did not indicate whether they were macrosomic. Modanlou et al.98 showed that the mean weight of macrosomic infants of diabetic mothers was higher than that of control infants and that shoulder circumference was significantly larger. In a study by Ballard et al.99 infants of diabetic mothers displayed “disproportional macrosomia” defined by increased Ponderal Index more often than infants of nondiabetic mothers.
Brans et al.97 described thicker skin folds in macrosomic infants of type 1 diabetic mothers in comparison to infants of nondiabetic and type 2 diabetic mothers. Vohr and McGarvey96 found that LGA infants of diabetic mothers had significantly thicker skin folds than LGA control infants. Although these studies addressed adiposity, they did not describe anthropometric and body composition characteristics in the same macrosomic infants of diabetic mothers. In our study,100 we described the characteristics that can potentially contribute to shoulder dystocia in macrosomic infants of diabetic mothers: body composition and anthropometric characteristics on the same macrosomic infants.
DETERMINANTS OF NONDIABETIC ABNORMAL FETAL GROWTH
Several conditions associated with fetal macrosomia are found without any relation to diabetes in pregnancy. These conditions are rare and are classified as nondiabetic primary abnormal growth excess of prenatal onset. It is a characteristic of a number of identifiable syndromes, including transposition of the great vessels,101 Soto’s syndrome (cerebral gigantism), Weaver’s syndrome, and Beckwith-Wiedemann syndrome (exomphalos-macroglossia-gigantism). The pathogenesis associated with abnormal secondary growth excess of prenatal onset is more widely known than that of primary growth excess. This is mainly due to the presence of diabetes in pregnancy. The most common consequence for infants of diabetic mothers is macrosomia. Early detection of the maternal risk factors associated with fetal macrosomia may alert the physician to the possibility of its occurrence. Beckwith-Wiedemann syndrome is of unknown etiology. Approximately 200 cases have been reported since Beckwith and Wiedemann reported this distinct clinical entity.102
Neonates are characterized by macrosomia, macroglossia, linear creases in the external ear lobes and higher than expected incidence of omphalocele. Hydramnios is common and, in spite of a relatively high incidence of prematurity, the birth weight and length average 4 kg and 52.6 cm, respectively. Macrosomia is apparent with large muscle mass and thick subcutaneous tissue. There is accelerated bone maturation and occasional hepatomegaly. Affected fetuses have adrenocortical and pancreatic cell hyperplasia, including an excess of islet cells, primary abnormal growth excess and are born with hyperinsulinemia. Some experience profound neonatal hypoglycemia (about 33%-50% of the neonates) with seizures, apnea, and cyanosis.
Polyerythrocythemia, hyperviscosity, and respiratory difficulty, generally because of macroglossia, are common. There is an unknown incidence of mild to moderate mental deficiency. When the condition is detected and adequately treated in the neonatal period, the mental capacity is apparently normal. Macroglossia becomes less of a problem when growth of the oral cavity enlarges its space relative to the size of the tongue. The excessive rate of growth usually slows after the first few years of life. Beckwith- Wiedemann syndrome should be suspected in any pregnancy in which macrosomia exists without maternal diabetes. Neonatal complications are similar in many respects to those seen in infants of diabetic mothers. Although hyperinsulinemia is not a constant finding in this syndrome, it has been reported that there is an increase in insulin receptor number and affinity in erythrocytes and it has been suggested that the overgrowth may be a consequence of increased tissue responsiveness to normal circulating concentrations of insulin.103,104 Hypoglycemia in the newborn is usually profound and unrelenting, often resulting in seizures, but is responsive to hydrocortisone analogue therapy. Steroid treatment is usually required for only the first four or five months of life.
An ultrasound examination should be performed to confirm large fetal size and to evaluate for hydramnios in any pregnancy in which macrosomia is suspected. Review of a series of newborns with omphalocele revealed that 11.7% had Beckwith-Wiedemann syndrome.105 Macroglossia and omphalocele may be detectable by ultrasound, which lends credence to the antenatal diagnosis of Beckwith-Wiedemann syndrome. Although data are not available, it is anticipated that in the fetuses with omphalocele, a hint of the process would be provided early in pregnancy by elevation of the maternal serum a-fetoprotein concentration. Fetal cells in amniotic fluid obtained by amniocentesis should be karyotyped because of the possibility of aneuploidy, and the fluid should also be evaluated for insulin concentration, as outlined earlier, for diagnostic purposes only. There is no evidence that additional insulin provided to the mother would be of any benefit to the fetus.
The growth excess may involve hamartomatous or tumor overgrowth within some of the tissues, such as hemangiomata Wilms’ tumor, adrenocortical tumor, or hepatic tumor. Wilms’ tumor occurs in 6.5% of the children with Beckwith-Wiedemann syndrome and may also be responsible for elevated a-fetoprotein concentrations. Serial ultrasound examinations and a-fetoprotein concentration determinations are recommended at 6-month intervals for the first 6 years of life to achieve early detection of tumor development.106
Nesidioblastosis refers to a diffuse or disseminated proliferation of pancreatic islet cells. These infants have persistent hyper- insulinemia and hypoglycemia and have disorganized islets with a relative increase in P-cells. It has been postulated that the primary abnormality may be disordered islet organization that prevents the usual paracrine regulation in insulin secretion by other hormones, in particular, by somatostatin, the normal product of the delta cells, present in the islet.103,107 Without the close relationship of alpha and delta cells, the internal islet control mechanisms are not present and insulin is secreted in unabated fashion. Surgical ablation of up to 95% of the pancreas is the only long-term treatment of nesidioblastosis. The etiology of nesidioblastosis is unclear, but it appears to represent an autosomal recessive disorder of pancreatic development. These infants are phenotypically similar to the infants of the diabetic mother, with macrosomia particularly of adipose and muscle tissue. The condition has been described in five children of both sexes from two families.
Nesidioblastosis should be considered in the differential diagnosis when evaluating a macrosomic fetus. There are no specific ultrasonic criteria for prenatal diagnosis of this entity. One has to proceed in the same way as with the diabetic pregnancy, using ultrasound to confirm macrosomia, amniocentesis for amni- otic fluid insulin concentration, and preparation for the delivery of a large fetus. There are no data to indicate a beneficial effect of additional exogenous insulin given to the mother.
Soto’s syndrome is sporadic in occurrence, but five families are known in which both parents and offspring are affected. If this means that it is inherited as an autosomal dominant, then the majority of the reported individuals with Soto’s syndrome would represent new mutations. The fetus is macrocephalic and dolichocephalic and on close inspection has prognathism with a narrow anterior mandible. Although the fetus is large, the mean term birth weight is only 3.9 kg. Moderate to severe mental retardation is present in 83% of these individuals. There are no reported endocrine abnormalities in Soto’s syndrome with the expectation that 14% of neonates have abnormal glucose tolerance tests.108 Therefore, amniotic fluid insulin concentrations would be expected to be normal or low. Ultrasonic evaluation reveals a large fetus with a greater than normal HC/AC ratio (much like an asymmetrically growth-retarded fetus, but with a higher than expected estimated fetal weight). Prognathism and narrow mandibular development may or may not be detectable by ultrasound.
Weaver’s syndrome is a rare syndrome marked by accelerated skeletal growth, camptodactyly, and unusual facies.
SUMMARY
Fetal growth can be considered the outcome of the interaction between the genetic drive to grow and constraints provided by limitations on substrate availability (selected amino acids, free fatty acids, and mainly glucose). Fetal growth restriction may then be viewed as the appropriate adaptation to limited substrate availability to conserve metabolic fuels. In contrast, macrosomia is the result of excess substrate availability, which results in facilitated anabolism leading to increased cell size. The regulation of fetal growth remains poorly understood, and continued research efforts are indicated.
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