Over the past 20 years, significant strides have been made toward understanding the pathophysiology of the diabetic pregnancy. This understanding, the development of specialized healthcare centers for pregnant diabetic women, and remarkable improvements in neonatal care have conjointly resulted in a markedly improved prognosis for the infant of the diabetic mother. Despite these optimistic undertones, it is prudent to bear in mind that these unborn infants, developing in the sweet maternal environment, are set out for a bitter struggle against some rather unfavorable odds. This article provides some background for understanding the characteristic morbidity of infants of mothers with diabetes and addresses common questions and dilemmas facing the pediatrician caring for these newborn infants.
Is the infant of a mother with diabetes at increased risk for acquiring diabetes later in life?
One of the issues that often is concerning to the diabetic patient is the risk of transmitting the disease to the offspring. This will depend on the type of diabetes in question. Type I insulin-dependent diabetes mellitus (IDDM, juvenile-onset diabetes) is a chronic, autoimmune disease that occurs in genetically susceptible individuals. Although no genetic marker has been identified yet for IDDM, a major component of genetic susceptibility has been identified within the D region of the HLA complex, on the short arm of chromosome 6. It seems that IDDM is a polygenic disorder with variable forms of expression, possibly requiring the interaction of at least five different susceptibility genes and environmental factors. Several investigators have reported a greater risk of IDDM for offspring of diseased fathers (4-1% to 6.1%) than of mothers (1.3% to 1.7%).1-2 Possible mechanisms to explain these sex differences could be increased fetal wastage of the infant at risk for diabetes born to a diabetic mother and some form of protection acquired by the fetus exposed to maternal diabetes in utero. Additionally, the risk is approximately twofold higher if the parent's diabetes was diagnosed before age 11 than if it was diagnosed later.3 In one study,4 25% of individuals with IDDM had at least one first -degree relative with IDDM; 17% of infants with IDDM had at least one affected sibling, and half of these were affected more than 10 years after onset of diabetes in the first affected sibling.
Type II noninsulin dependent diabetes mellitus (NIDDM, adult-onset) is the most common form of diabetes, and many women with this disorder are in the reproductive age group. Noninsulin dependent diabetes mellitus has no proven genetic markers, but clearly has strong heterogenic genetic associations. Thus, it is extremely difficult to counsel the patient on the risk of the offspring developing NIDDM later in life. Similarly, if the mother was diagnosed during her pregnancy with gestational diabetes (GDM)1 she has approximately a 50% risk of developing overt NIDDM within 20 years, and her infant is therefore subject to an increased risk of diabetes due to the aforementioned genetic susceptibility. However, it is presently impossible to quantify this increased risk.
Is there a specific teratogen related to the embryopathy of diabetic pregnancy?
The developing embryo of the mother with diabetes is exposed to an altered milieu that may exert devastating toxic effects, resulting in a spectrum of pathologic consequences. However, the specific toxic mediators and teratogenic mechanisms in diabetes have yet to be determined. From current data, it is suggested that some aspect of glycémie control, or perhaps a related factor such as ketogenesis, is important. Animal studies have ascribed embryopathy to the effects of glucose, β-hydroxybutyrate, insulin, disruption of arachidonic acid and glycolytic metabolic pathways, decreased fetal zinc uptake, increased fetal manganese uptake, somatomedin inhibitors, hyperosmolarity, and biophysical modifications via nonenzymatic glycosylations. Taken together, these studies indicate that no single parameter of the diabetic state can be viewed in isolation to correlate diabetic embryopathy with maternal diabetic control.
It appears that outcome of the pregnancy is related to the teratogenic effect in a time specific manner. An early insult following fertilization may result in degeneration of the embryo and the appearance of a blighted ovum or in an increased rate of lethal malformations incompatible with intrauterine life. Other possible mechanisms underlying spontaneous abortion in these pregnancies may be abnormal placentation and vascularization, and perhaps an increased incidence of chromosomal abnormalities associated with poor glycemie control. Later in pregnancy, the teratogenic insult may result in disruption of embryogenesis with the development of major congenital malformations. Later on, insults may result in minor congenital malformations. Besides timing, the intensity of the insult also may be important in determining its consequences. In addition, diabetic embryopathy may be conditioned by the interplay between genetic predisposition and environmental triggers.
How significant is the problem of congenital malformations in infants of diabetic mothers?
Congenital malformations have emerged as the single most important cause of perinatal mortality among infants of diabetic mothers, accounting for 50% of perinatal deaths compared with 20% to 30% in infants of nondiabetic mothers.5
Women who are insuhn-dependent at the time of conception are at high risk for having a malformed fetus, a fact that has been appreciated for decades. Women with gestational diabetes are probably not at increased risk, but it is unclear what the risk for congenital malformations is in women who are Type II noninsulin dependent diabetics diagnosed prior to or with the onset of pregnancy. Although there are clear genetic linkages with both Type I and Type II diabetes, this does not seem to bear any relationship to the incidence of congenital malformations in diabetic pregnancies because there is no increased risk for infants of fathers with diabetes. Based on data from the World Health Organization, major congenital malformations occur in 1.65% of the general population.6 The rate of major congenital malfromations in infants of diabetic mothers is at least three to five times higher than in the non-diabetic population, and reported in 4% to 11% of pregnancies in IDDM mothers. In this sense, diabetes may be considered a teratogen, but it differs from other known teratogens in generally not having a specific phenotypic expression, such as may often be encountered with other teratogenic agents. A whole range of organ systems may be affected, resulting in defects in the cardiac, central nervous, genitourinary, and skeletal systems. Many of the most common defects in the general population occur at increased rates in infants of diabetic mothers. Certain anomalies, such as sacral dysgenesis or holoprosencephaly, carry an extremely high risk in infants of diabetic mothers, but their actual incidence is very small, and they are extremely rare in the general population. Thus, sacral dysgenesis is approximately 300 times more common in diabetic pregnancies that in the general population, but the actual incidence of this defect among diabetic pregnancies is rather low. Conversely, although the relative risk for cardiac anomalies is only approximately three to four times higher, these malformations constitute the greatest problem in infants of diabetic mothers because of their high frequency in the general population.
Given the known organogenic sequences in the embryo, the most common anomalies in infants of diabetic mothers cannot occur later than 3 to 6 weeks after conception (5 to 8 weeks' gestation). For example, the central nervous system is formed by 4 weeks, the urinary system by 5 weeks, and the cardiac structures by 6 weeks after conception. Thus, the critical period for congenital malformations is usually over by the time pregnancy becomes clinically apparent and the mother seeks prenatal care.
Is there a level of maternal glycemie control that can be considered safe with respect to the risk of congenital malformations in the infant?
Several studies have established the relationship between congenital malformations and poor glycemie control during the first trimester in mothers with IDDM.7,8'9 These studies have shown that higher firsttrimester glycohemoglobin concentrations are associated with an increased risk of malformations. There is some controversy as to whether there is a threshold of poor glycémie control beyond which the risk of embryopathy is increased. Several authors advocate maintaining absolute normogiycemia in the mother during the preconceptional period and throughout pregnancy to optimize pregnancy outcome. Others have found that the risks of spontaneous abortion and congenital malformations increase in a nonlinear fashion beyond certain thresholds of glycohemoglobin or mean glucose concentrations. A recent study has found that the risks of spontaneous abortion and congenital malformations increase when maternal glycohemoglobin concentrations exceed 6 to 7 standard deviations above the mean, or when mean firsttrimester preprandial glucose concentrations exceed 120tol30mg/dL.10
Can congenital malformations in infants of diabetic mothers be prevented?
Prevention of congenital malformations in infants of diabetic mothers focuses on preconceptional and early postconceptional control of diabetes, and early detection of congenital malformations in utero. Clearly, the patient with abnormally high glycohemoglobin levels (for which there is currently no standard definition) is at increased risk for an infant with congenital malformations. However, some authors contend that even with strict and timely glycemie control, infants of women with diabetes have an increased rate of congenital malformations above the background rate of the general, nondiabetic population, and even strict glycemie control initiated in a timely manner may not entirely eliminate the problem of excess malformations in this population.11
Early and thorough sonographic examinations and fetal echocardiography will identify many of the anomalies in these pregnancies. Additionally, screening for maternal serum alpha-fetoprotein levels as currently advocated for all pregnant women will identify the vast majority of fetuses with open neural tube defects. However, it should be noted that these levels may be lower in poorly controlled diabetic women compared with nondiabetic women,12 and results must be standardized and interpreted accordingly.
Is the macrosomic infant of the diabetic mother different from any other macrosomic baby?
Macrosomia has long been recognized as one of the hallmarks of diabetic fetopathy, found in 15% to 40% of diabetic pregnancies. Macrosomia is most commonly defined as birthweight that exceeds the 90th percentile of a reference population, by gestational age, preferably stratified by race and sex. Some define macrosomia as any birthweight >4000 g. Normal infants who are constitutionally large obviously also will be labeled macrosomic. However, the macrosomia characteristic of the diabetic pregnancy is associated with altered body composition with increased body fat and therefore may be considered abnormal. Pedersen's original hypothesis13 suggested that macrosomia in infants of diabetic mothers is related to fetal pancreatic ß cell hypertrophy and hyperinsulinism, secondary to maternal hyperglycemia. There is, indeed, evidence that ß cells in these infants undergo hypertrophy and hyperplasia, and also demonstrate increased insulin content.14 Insulin is a major anabolic growth hormone of the fetus that increases cell size by stimulating protein synthesis and increases glucose uptake and glycogenesis in peripheral tissues. This intrauterine hyperinsulinemic state results in increased tissue fat, liver glycogen content, and total body size. Typically, accelerated abnormal fetal growth occurs in the third trimester, with abnormal adipose deposition and distribution, visceral organ hypertrophy and hyperplasia, and acceleration of skeletal growth. This produces the characteristic macrosomic infant of the diabetic mother, with increased abdominal girth and subcutaneous fat deposition.
Can good glycemic control during pregnancy prevent fetal macrosomia?
Whether strict glycemic control of the pregnant woman with diabetes can prevent macrosomia is a controversial issue. Some investigators have found an association between giucose control and macrosomia.15'16 Specifically, some investigators have found an association between macrosomia and an increased level of maternal postprandial glucose concentrations, suggesting that both preprandial and postprandial glucose concentrations must be controlled to prevent fetal macrosomia.17 However, despite the prevailing trend of maintaining fairly strict glycemic control throughout pregnancy, it seems that the frequency of macrosomia has not decreased over the past decade. Indeed, several investigators have found that women with diabetes continue to have macrosomic infants despite stringent glycemic control during pregnancy.18
It is possible that fetal hyperglycemia, secondary to maternal hyperglycemia, is not the sole etiologic stimulus for endogenous fetal hyperinsulinemia. The roles of insulinogenic amino acids and of insulin-like growth factors in this context have not been established. Furthermore, although it is generally believed that maternal insulin binds to placental receptors, but does not cross the placenta, antibody-bound maternal insulin (primarily animal insulin) may be found in the fetal circulation and may, in theory, exert anabolic effects.19
Thus, it appears that even when excellent glycemic control is maintained throughout pregnancy approximately 20% to 30% of infants of diabetic mothers are bom with excessive weight and size.
What are the potential complications of fetal diabetic macrosomia, and can they be prevented?
Excessive fetal size is the principal factor contributing to the increased risk of birth trauma in infants of diabetic mothers, with such mishaps as shoulder dystocia, asphyxia, brachial plexus injuries, and facial nerve palsies. Macrosomia is also a major factor in the increased rate of cesarean delivery among diabetic women. As mentioned previously, infants of diabetic mothers are characterized by disproportionate or asymmetric macrosomia, with relatively excessive growth of the fatty tissues, abdomen, and visceral organs. This results in a high ponderal index, or in other words, a high ratio of fetal weight to length. This infant is, therefore, at increased risk for shoulder dystocia resulting in birth trauma, and many obstetricians will lower their threshold for electing a cesarean delivery when planning the delivery of infants of diabetic mothers who is large for gestational age. Thus, many obstetricians will use a cutoff of 4500 g estimated fetal weight for electing a cesarean delivery in a nondiabetic mother, but will lower the threshold to 4000 to 4250 g in infants of mothers with diabetes.
Ultrasound is used routinely to identify the macrosomic infant before delivery so that steps may be taken to avoid birth trauma. However, it is important to note that most widely used formula for calculation of fetal weight using ultrasound measurements may underestimate actual weight by 300 to 1000 g.M Various investigators have suggested innovative sonographic methods to identify the macrosomic infants of diabetic mothers, such as measuring the upper arm circumference or the cheek-to-cheek diameter, but none of these methods are sufficiently sensitive or specific for accurate prediction of fetal macrosomia. Additional information can be obtained by examining the sonographic head-abdomen ratio, which may suggest typical asymmetric macrosomia when it falls below the normal range.
What is the cause and what are the manifestations of fetal diabetic hypertrophie cardiomyopathy?
Infants of diabetic mothers are at known risk for developing a hypertrophie type of cardiomyopathy with a thickened interventricular septum and thickened ventricular walls. The hypertrophie muscle restricts filling and obstructs outflow, thus decreasing stroke volume and cardiac output. The severity of infants of diabetic mothers cardiomyopathy can vary from incidental echocardiographic findings to severe heart failure. Hypertrophic cardiomyopathy may be considered part of the visceromegaly resulting from hyperinsulinism in these infants, and several studies have noted that the risk of cardiomyopathy is associated with poor maternal glycémie control during pregnancy.21
The spectrum of card ioresp ira tory symptoms in the newborn with cardiomyopathy includes cyanosis, tachypnea, tachycardia, and features of congestive heart failure. The majority of these infants need only supportive care because the cardiorespiratory symptoms usually resolve within the first weeks of life, although the septal and wall hypertrophy may take many months to resolve.
What are the causes of neonatal hypoglycemia in infants of diabetic mothers and can it be prevented?
Neonatal hypoglycemia is a frequent complication in infants of diabetic mothers. The reported incidence of hypoglycemia, occurring in the first 4 hours of life in these infants, ranges from 10% to 50%, with little change in this frequency observed over the last 20 years. The mechanism responsible for the occurrence of hypoglycemia can be explained by Pedersen's classic model, which states that maternal hyperglycemia causes fetal hyperglycemia and islet cell stimulation leading to fetal hypermsulinemia.13 At birth, interruption of the maternal glucose supply to the hyperinsulinemic neonate results in hypoglycemia. Several authors have suggested alternative' Iy that acute hyperglycemia in the diabetic mother at the time of delivery may be the major etiologic determinant in the occurrence of neonatal hypoglycemia rather than chronic hyperglycemia.22 This acute peripartum hyperglycemia results in an acute release of insulin by the fetal pancreas and, following the abrupt termination of transplacental glucose supply, hypoglycemia occurs. Neonatal hypoglycemia tends to be less common and much milder in the infant whose mother is well controlled throughout pregnancy and maintained euglycemic throughout labor and delivery. Close monitoring of the infant's blood glucose concentration and intravenous supplementation when necessary combined with early oral feeding within the first hours of life further decrease the incidence of severe neonatal hypoglycemia.
The long-term prognosis of neonatal hypoglycemia is unknown. Low blood glucose values should be recognized and treated promptly, because prolonged hypoglycemia is clearly associated with central nervous system abnormalities in children and adults.
What other metabolic abnormalities can be expected in newborn infants of diabetic mothers?
The most significant clinical problem of calcium metabolism in the diabetic pregnancy is neonatal hypocalcemia, which may occur in 50% of infants of diabetic mothers during the first 3 days of life. Furthermore, the rate and severity of hypocalcemia are directly related to the severity of maternal diabetes. Hypomagnesemia also occurs frequently in infants of diabetic mothers, reported in up to 38% of newborns and associated with the severity of maternal diabetes and with prematurity.24 The cause of hypomagnesemia and hypocalcemia in infants of diabetic mothers is not fully understood. It has been suggested that the hypomagnesemia in infants of diabetic mothers may develop due to maternal magnesium losses related to diabetes during pregnancy that result in reduced maternal and secondarily reduced fetal serum magnesium concentrations, which causes decreased fetal urinary excretion of magnesium and decreased amniotic fluid magnesium concentrations.25 Magnesium deficiency in the infant may cause a functional hypoparathyroidism that could result in neonatal hypocalcemia when the newborn is no longer provided with calcium of maternal origin through the placenta.
Bone mineral content also is decreased in infants of diabetic mothers, in direct association with maternal bone mineral content at delivery and poor glycemic control, particularly in the first trimester of pregnancy. One speculation that could explain this observation is that increased serum 1,25-(OHHD concentrations in these infants have a potent effect on bone resorption and might be detrimental to bone mineralization. Decreased bone mineral content has not been correlated with neonatal hypocalcemia, possibly due to the large bone reservoir of calcium relative to blood.
Why are the infants of diabetic mothers at increased risk for polycvthemia and hyperbilirubinemia?
Neonatal polycythemia, defined as a venous hematocrit 5=65%, occurs in 3% to 5% of all newboms, but has been observed in up to 29% of infants of diabetic mothers. Neonatal polycythemia and its related increased viscosity may be associated with a spectrum of clinical sequelae, including cardiopulmonary failure, decreased renal function, renal vein thrombosis, necrotizing enterocolitis, and central nervous system damage.
In the pregnant mother with diabetes, hyperglycemia and hyper insulinemia lead to reduced fetal arterial oxygen content, which, in turn, stimulates erythropoiesis. Elevated concentrations of erythropoietin have, indeed, been demonstrated in cord blood of infants of diabetic mothers.26 Furthermore, acute maternal hypoxia in nondiabetic pregnancies results in acute fetal hypoxia and a significant shift of placental blood volume into the fetal compartment. A similar pathophysiologic placental "transfusion" may occur under hyperglycemic and hypoxic conditions in the diabetic pregnancy.
The risk of hyperbilirubinemia in infants of diabetic mothers is higher than in normal infants and has been associated with maternal glycemic control.27 The risk is highest among infants of diabetic mothers who manifest asymmetric macrosomia with a high ponderal index.28 It is tempting to assume that hyperbilirubinemia in infants of diabetic mothers is related to the increased incidence of polycythemia; however, this is not necessarily the case. In infants of nondiabetic mothers, the incidence of hyperbilirubinemia is comparable in polycythemic and control groups. Furthermore, partial exchange transfusion for the treatment of polycythemia in newborns of diabetic mothers does not prevent hyperbilirubinemia in these infants.
There is an increased production rate of bilirubin in infants of diabetic mothers compared with normal controls (up to 30% higher), which is unrelated to the hemoglobin concentration and may be an important contributing factor to the propensity for severe hyperbilirubinemia. Infants of diabetic mothers also may be subject to impairment of hepatocyte function, namely uptake of bilirubin, conjugation or excretion, resulting in delayed clearance of bilirubin. Another plausible mechanism is ineffective erythropoiesis with mild compensated hemolysis, supported by the finding of elevated erythropoietin concentrations in as many as a third of all infants of diabetic mothers29 and an association between blood erythropoietin concentrations and bilirubin production that has been obserted in these infants.30 Thus, it appears that there may be multiple causes of hyperbilirubinemia in infants of diabetic mothers, and because infants of diabetic mothers often are born prematurely, this is often a contributing factor. Treatment for prevention of kernicterus is usually by phototherapy, but "exchange" blood transfusions may be necessary if serum bilirubin concentrations are exceedingly high.
Are infants of diabetic mothers still at increased risk for perinatal asphyxia?
Perinatal mortality in diabetic pregnancies has decreased dramatically over the past 60 years. Currently, reported perinatal mortality rates of infants of diabetic mothers are approximately twice those observed in the general obstetric population. In tertiary centers with special programs for diabetic pregnancies, the rates are comparable to those of nondiabetic mothers. The reduced risk of intrauterine fetal death in infants of diabetic mothers has been associated with improvement in glycemic control during pregnancy, development of methods for fetal surveillance, and advances in neonatology. However, even recent studies have shown that 25% to 28% of infants of diabetic mothers may have evidence of intrapartum asphyxia.31,32
Studies in fetal sheep have demonstrated that maternal hyperketonemia may lead to fetal hypoxemia within hours, whereas hyperglycemia causes a slow and progressive fall in fetal oxygenation over the course of more than a week.33,34 Additionally, diabetes-associated vasculopathy may affect placental vessels and their oxygen diffusion capacity. In human pregnancy, fetal activity decreases during maternal hyperglycemia and fetal acidemta, and fetal heart rate variability is reduced during periods of maternal hyperglycemia.35
How can antepartum asphyxia be prevented?
Various techniques of antenatal surveillance have been used and studied over the past 15 years to provide a rational basis for the management of diabetic pregnancies during the final 6 weeks of gestation, the period of greatest risk for fetal asphyxia and intrauterine demise. As a rule, these techniques have few false-negative results and therefore permit safe prolongation of pregnancy and allow the fetus to benefit from further maturation in utero. The nonstress test that evaluates basal fetal heart rate and the presence of heart rate accelerations is a simple, noninvasive test that has become the preferred test for antenatal screening of fetal condition in pregnancies complicated by diabetes. This test appears abnormal in 10% of cases, has a false-negative rate of <1%, but a rather high rate of 75% to 90% false -positive results. When the nonstress test is abnormal, further evaluation of fetal status may be obtained by performing a contraction stress test which involves evaluation of the fetal heart rate while provoking uterine contractions (10% abnormal tests and 50% false-positive results), or by obtaining a biophysical profile, which involves a combination of a nonstress test with four parameters assessed by real-time ultrasonography (2% abnormal tests and 20% false-positive results).
Maintaining maternal normoglycemia throughout pregnancy reduces the risk of fetal hyperglycemia and hyperinsulinemia, and reduces the risk of fetal hypoxemia and the need for intervention. Given the current standards of management and the availability of specialized programs for diabetic pregnancies, the overall rate of intervention for abnormal fetal testing in these pregnancies is now less than 5%.36'37 Nonstress testing in diabetic pregnancies is routinely performed twice weekly from the 34th week of gestation, and the frequency of intrauterine fetal demise with such protocols is in the range of 5 per 1000 pregnancies (excluding congenital anomalies).
Is the risk of respiratory distress syndrome increased in infants of mothers with diabetes?
Maternal diabetes traditionally has been considered a predisposing factor for respiratory distress syndrome of the newborn. Indeed, hyperglycemia and hyperinsulinemia are associated with a delay of pulmonary maturation, but the precise mechanism by which this occurs remains to be elucidated. More recent studies have shown that the risk of respiratory distress syndrome decreases with improved glycémie control of the diabetic mother38 and that the incidence of respiratory distress syndrome in the infants of well-controlled diabetic mothers delivered at term is similar to that of the general population.39
Measurement of the lecithin/sphingomyelin ratio in amniotic fluid has been used for many years to predict fetal lung maturity, and a value >2 is highly predictive of fetal lung maturity in normal pregnancies. However, there is evidence that this test is less useful in diabetic pregnancies, following observations that infants of diabetic mothers have been bom with respiratory distress syndrome despite "mature" lecithin/sphingomyelin ratios in amniotic fluid.40 Data regarding the reliability of this test in diabetic pregnancies are conflicting, but reliability appears to be enhanced in women who had good glycemic control during pregnancy.41 Prediction of fetal lung maturity can be improved by documenting the presence of phosphatidyl glycerol in amniotic fluid, and a combination of both these methods may be used to obtain accurate prediction of respiratory distress syndrome, transient tachypnea, symptomatic pneumothorax, and persistent fetal circulation.42
Given the current practice of delivering women with diabetes at term and the availability of specialized prenatal care for these patients, the incidence of respiratory distress syndrome in their infants may be expected to be comparable with that of the general population.
Can maternal diabetes during pregnancy affect long-term growth and development of the infant?
There is evidence that the intrauterine exposure to a diabetic milieu may have long-term implications on the physical developmont of the infant. In one study, physical growth of infants of diabetic mothers was similar to that of the general population by 12 months of age, despite the high incidence of macrosomia at birth. However, the weight of these infants increased dramatically after 5 years of age, and by age 8 years, half of them were obese with weights over the 90th percemile.43 This childhood obesity appeared to be affected by maternal glycemic control, as it correlated with third-trimester amniotic fluid insulin concentrations.
Conflicting data exist regarding the effect of maternal diabetes on the mental development of their offspring. While some investigators have found no developmental abnormalities in these infants,44 others have identified cognitive impairment and developmental delay.43,45,46 Poor intellectual performance in these studies was associated with matemal ketonuria, serum-free fatty acids, and β hydroxybutyrate. Thus, improved metabolic control during pregnancy may be important not only for the short-term outcome of pregnancy, but also for the long-term physical and mental development of the infant.
Even though perinatal mortality of infants of diabetic mothers has decreased remarkably in recent years and now approaches that of the general population, these infants still face a multitude of potential complications and the propensity for increased morbidity, both in utero and postnatally. Many of these complications are clearly related to the metabolic status of the diabetic mother. Increasing awareness among insulin-dependent diabetic patients and health providers of the need for glycemic control and the ever-growing understanding of the peculiarities of diabetic pregnancies eventually should combine to provide the best possible outcome for these infants.
1. Tillil H. Kohberling J. Age-corrected-empirical genetic risk estimates for first-degree relatives of IDDM patients. Diabetes. 1987:30:93-99.
2. Warram JH, Krolewtki AS. Gottlieb MS. el al. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med. 1984:311:149-152.
3. Hashlmy M. Angelico MC, Martin BC. Krolewskl AS. Warram JH. Factors modifying the risk of IDDM in offspring of an IDDM parent. Diabetes. 1995;44: 295-299.
4. Lorenjen T, Poclot F, Hougaard P. Nerup J. Long-term risk of IDDM in firat-degree relatives of patients with IDDM. Diabetologia. 199437:321-317.
5. Kalter H. Perinatal mortality and congenital malformations in infants born to women with insulin-dependent diabetes mellitus: United States. Canada and Europe, 1940-1988, MMWR, 1990;39:363-365.
6. Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971;7:61-70.
7. Creene MF, Hire JW. Ooheny JP, et al. First-trimester hemoglobin A^sub 1^ and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology. 1989:39:225-231.
8. Miller E. Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A|C in early pregnancy and major congenital anomalies in infants of diabetic mochen. N Engl J Med. 1981:304:1331-1334.
9. Miodovnlk M, Mi mount F, Dignan PSJ, et al. Major malformattoni in Infants of IDDM women: vatculupathy and early first-trimester poor glycemic control. Diabetes Care. 1988;11:713-718.
10. Rosenn B. Miodovnik M, Combs CA. Khoury J, Siddiqi TA. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol. 1994:84:515-520.
11. Mills JL, Knopp RH, Slmpton JL, et al. Lack of relation of Increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N Engl J Med 1988:318:671-676.
12. Miluniky A, Alpen E, Kitzmtller J, et al. Prenatal diagnosis of neural tube detecta, Vili: the importance of scmm alpha-fetoprotein screening In diabetic pregnant women, Am J Obstet Gynecol. 1982;142:1030-1034.
13. Pedenen J. Weight and length at birth of Infanti of diabetic mothers. Acta EndortmoL 19 54; 16: 330- 342.
14. Cardili BS. Hypertrophy and hyperplasia In the pancreatic islets in newborn infanti. J Pathol Bacterial. 1953;6:335-343.
15. Berk MA, Mimouni F, Miodovnik M, et al. Macroeomia in Infantici Insulin-dependent diabetic mothers. Pediatria. 1989:83:1029-1034.
16. Willman SP, Levenc KJ. Guzick DS. et al. Glucose threshold for macroaomia in pregnancy complicated by diabetes. Am J Obstet Gynecol. 1986:154:470-475.
17. Jovanovk-Petenon L, Petenon CM, Reed Of, et al. Maternal postprandial glucose levels and infant blrthwcight: the diabetes in early pregnancy study. Am J Obstet Gynecol. 1991:164:103-111.
18. Dandona P, Besterman HS, Freedman DB, et al. Macroeomia despite well-controlled diabetic pregnancy. Lancet. 1964:1:737. Letter.
19. Menon RK, Cohen RM, Sperling MA1 et al. Transplaccntal passage of insulin in pregnant women with insulin-dependent diabetes mellitus: iti fole in fetal macrosomia. N Engl J Mea. I990i323:309-315.
20. Tamura RK, Sabbegha RE, Dooley SL, et al. Real-time uÌmuound estimations of weight in fetuses of diabetic gravid women. Am J Obstet Gynecol. 1985;153:57-60.
21. Outgesell HP, Speer ME Rosenburg HS. Characterization of the card tomyopa thy in Infants of diabetic mothers. Circulation. 1980;61:441-450.
22. Andefsen O, Hertel JL. Schroolkcr L, et al. Influence of the maternal pUsma glucose concentration at delivery on the risk of hypoglycemic in infants of insulin-dependent diabetic mothers. Acta Paediatr Scand. 1985:74:268-273.
23. Tsang RC, Kleinman U, Sutherland JM. et al. Hypocalcemic in Infants of diabetic mothers. J Pediatr. 1972;80:384-395.
24. Mitnouni F, Tsang RC, Hertzbefg VS, et al. Polycythemia, hypomagnesemia, and hypocalcemic in infants of diabetic mothers. Am J Dis Child. 1986:140:798-800.
25. Mirnouni F, Miodovnik M, Tsang RC, et al. Decreased amniotk fluid magnesium concentration in diabetic pregnancy. Obstet GynecoL 1987;69: 12-14
26. Karlsson R, Kjellmer I, The outcome of diabetic pregnancies in relation to the mother's blood sugar level. Am J Obstet Gynecol. 1972:112:213-220.
27. Johnson JD, Trissel S, Angelus P, et al. Hyperbiliruhinemia in human infants of diabetic mother: (IDM): studies of bilirubin product ion and glycosylated hemoglobin. Pediatr Res. 1986;20:412A.
28. Ballard JL. Rosenn B, Rhoury JC, Miodovnik M. Diabetic fetal macrosomia: significance of disproportionate growth. J Pediacr. 1993:43:21-28.
29. Stevenson DK. Bilirubin metabolism in the infant of the diabetic mother, an overview. In. Gabbe SG, Oh W, eds. Infant of the Diabetic Mother, Report of the Ninety-Third Ross Conference on Pediatric Research. Columbus, Ohio: Ross Laboratories; 1987:109-115.
30. Bucalo LR, Cohen RS, Ostrander CR, et al. Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production: Ik. Evidence for the possible association of cord blood erythropoietin levels and postnatal bilirubin production in infants of mothers with abnormalities of gestationa I glucose metabolism. Am J Permani 1984;1:177-181.
31. Kioroillet JL, Cloherty JP, Younger MD, et al. Diabetic pregnancy and perinatal morbidity. Am J Obstet Gynencol. 1978;131:560-580.
32. Mimouni F, Miodovnik M, Siddlqi TA, et al. Perinatal asphyxia in infants of insulin-dependent diabetic mothers. J Pediatr. 1988;113:345-353.
33. Miodovnik M, Sklllman C, Harrington W, et al. Effects of maternal hyperglycemic and ketceciderma on the pregnant ewe and fetus. Am J Obstet Gynecol 1986;154:394-401.
34. Phillips AF, Rosenkranti TS. Raye J. Consequences of perturbations of fetal fuels in ovine pregnancy. Diobeus. 1985:34:32-35.
35. Kariniemi V, Forss M, Siegberg R. Reduced short-term variability of fetal heart rate in association with maternal hypetglycemia during pregnancy in insulin-dependent diabetic women. Am J Obstet Gyencol. 1983;147:793-794.
36. Diamond MP, Vaughn WK, Salyct SL, et al. Antepartum fetal monitoring in insulin-dependent diabetic pregnancies. Am J Obstet Gynecol 1985:153:528-533.
37. Landen MB, Gabbe SG. Ant epattum fetal surveillance in gestational diabetes meilitus. Dubeuf. 1985;34:50-54.
38. Mimouni F, Miodovnik M, Whitsett JA, et al. Respiratory distress syndrome in infants of diabetic mothers in the 1980s: no direct adverse effect of maternal diabetes with modern management. Obstet Gynecol. 1987;69:191-195.
39. Dudley KLK. Black DM. Reliability of lecithin/sphingomyelin ratios in diabetic pregnancy. Obstet Gynecol 1985;66:521-524.
40. Cruz AC, Buhi WC, Birk SA, et al. Respiratory distress syndrome with mature lecithin/sphyngomyelin ratios: diabetes meillitus and low Apgar scores. Am J Obstet Gynecol 1976;126:78-82.
41. Curet LB, Olson RW, Schneider JM, et al. Effect of diabetes mellitus on amniotic fluid lecithin/spingomyelin ratio and respiratory distress syndrome. Am J Obstet Gynecol. 1979;135:10-13.
42. Hallman M, Teramo K. Amniotic fluid phospholipid profile as a predictor of fetal maturity in diabetic pregnancies. Obstet Gynecol. 1979;54:703-707.
43. Silverman BL, Rizzo T, Green OC, et al. Long-term prospective evaluation of off-spring of diabetic mothers. Diabetes. 1991:40:121-125.
44. Persson B. Gentz J. Follow-up of children of insulin-dependent and gestational diabetic mothers. Acta Paediatr Scand. 1984;73:349-358.
45. Stebhens JA, Baker GL, Kitchell M. Outcome at ages 1, 3 and 5 of children born to diabetic women. Am J Obstet Gynecol. 1977;127:408-413.
46. Rizzo T, Metzger BE, Bums WJ, Burns K. Correlations between antepartum maternal metabolism and child intelligence. N Engl J Med. 1991;325:911-916.