As the year 2000 approaches, it is assumed that increased experience in the diagnosis and treatment of diabetes, as well as attempts to prevent some of its sequelae, will lessen the frequency and severity of the complications for this condition. Diabetes mellitus is a commonly encountered medical complication of pregnancy that affects more than 100,000 pregnancies annually. Since the discovery of insulin more than 70 years ago, the outcomes of pregnancies complicated by diabetes have continued to improve. However, despite this improvement, women with diabetes and their infants remain at risk for a number of complications.
Pregnancy has frequently been described as having a diabetogenic effect on normal carbohydrate metabolism. It is associated with hyperglycemia and hyperinsulinemia in response to feeding1 and a constellation of events and processes leads to glucose intolerance (or the clinical condition of gestational diabetes) among 3% to 5% of pregnant women. Pregnancy also worsens the metabolic state of patients with pregestational diabetes. Because the availability of nutrients for the fetus is primarily dependent on the maternal metabolic state, these aberrations in maternal fuel metabolism are believed to result in a host of perinatal complications, including abortions, abberant fetal growth, and diabetic embryopathy. The frequency of congenital anomalies is also increased among infants of mothers with diabetes, and these anomalies are responsible for approximately 50% of all perinatal deaths experienced by these women.
Recent evidence suggests that normalization of blood glucose levels with contemporary management strategies can reduce the frequency of congenital anomalies as well as improve maternal and neonatal outcomes.2,3 However, to impact congenital anomalies, euglycemia must begin in the pre-conceptional period and confinue throughout organogenesis. Pre-conception counseling and intensive therapy regimens remain the focus of management targeted at women with pregestational diabetes.
Classification of Diabetes in Pregnancy*
This article outlines the current concepts and theories in the management of pregnancy in women, especially the adolescent and the young adult, with pregestational diabetes mellitus.
Management of pregnancy in women with diabetes is a complex task that should start before conception. In view of the importance of planned pregnancies and of good glycémie control, pregnancy should be discussed with all young women who have diabetes, and contraceptive advice should be offered to such women of childbearing age. This could be described as pre-pregnancy care.4 When a couple decides to have a baby, they should be seen by a perinatologist who specializes in diabetes. The aims of this visit are:
1. To assess the woman's medical status.5
2. To explain the goal for metabolic control.6
3. To discuss the prenatal care and the diagnosis of congenital malformations.
4. To discuss neonatal outcome and care.
Table 1 summarizes the classification of diabetes in pregnancy in order of increasing severity.
ASSESSMENT AND MANAGEMENT OF MICROVASCULAR AND MACROVASCULAR DISEASE
Diabetic retinopathy (class R; Table 1) is the result of retinal arteriolar and capillary endothelial damage, basement membrane thickening, and pericyte damage.7 Diabetic retinopathy can be classified into nonproliferative (background) and proliferative retinopathy.8 The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESODR) found that the prevalence of retinopathy in patients with onset of diabetes before age 30 was 17% after 5 years and was 97.5% at more than 15 years' duration.9
By and large, background retinopathy does not threaten vision until or unless it evolves into the proliferative form. It is characterized by exudates, microaneurysms, and small red dot hemorrhages in the retina, and is usually not clinically apparent with basic ophthalmologic examination. Although almost universal after the existence of diabetes for 20 years, background retinopathy is uncommon in patients who have had diabetes for fewer than 10 years. Not all background retinopathy will progress to proliferative retinopathy.10
The prognosis for vision in proliferative diabetic retinopathy has improved with the advent of panretinal photocoagulation. Reece et al.11 reported the retinal and pregnancy outcomes, in the presence of diabetic proliferative retinopathy, in 20 pregnancies. Photocoagulation therapy was necessary prior to pregnancy in 45%, during pregnancy in 80%, and postpartum in 65%. No pregnancies had to be terminated because of progressive visual changes.
Evidence from two randomized, prospective trials directly implicates the importance of metabolic control on the progression of diabetic retinopathy. The first study was from Sweden where 102 patients with type I diabetes mellitus and background retinopathy were assigned to intensive or standard insulin treatment.12 During the study period, the two groups had a significant difference in proliferative retinopathy requiring photocoagulation (27% versus 52%, respectively).
The second study, the Diabetes Control and Complications Trial (DCCT),13 provided the definitive answer as to the relationship of retinopathy and glucose control in nonpregnant women with diabetes. This trial included 1,441 patients with type I diabetes mellitus randomized into two groups. The intensive care group was maintained at a mean hemoglobin A (HbA1 ) level of 7.2%, whereas the standard care group had a mean HbAJc level of 9%. The first group had a 50% lower prevalence rate of new-onset retinopathy or progression of retinopathy compared with the second group. These two studies strongly suggest that normoglycemia is the treatment goal for patients with diabetes and may prevent the onset, or possibly the progression, of diabetic retinopathy.
Other investigators have reported different findings regarding the effects of pregnancy on diabetic retinopathy. When a women starts her pregnancy with minimal or no retinopathy, there may be minor progression; the risk of progression varies from 0% to 40% and retinopathy that threatens vision rarely occurs. However, for a woman who starts her pregnancy with more severe retinopathy, the likelihood that this will progress increases by as much as 63%. The duration of diabetes is an independent risk factor for the progression of retinopathy during pregnancy. Hypertension has also been linked to the severity of retinopathy. Studies of antihypertensive drugs have also suggested that such therapy may retard the progression of retinopathy.
In summary, the retinal status should not preclude pregnancy, because contemporary methods of management can result in satisfactory retinal and pregnancy outcomes, even in the presence of advanced diabetic retinopathy. Duration of diabetes and the state of the retina at the beginning of the pregnancy influence the rate of acceleration. However, based on available evidence, hyperglycemia and hypertension at the start of pregnancy will accelerate retinopathy.
Diabetic nephropathy (class F; Table 1) is a major complication of type I diabetes mellitus and will eventually occur in 30% to 40% of these patients.14 Following the onset of macroproteinuria (more than 300 mg/d), renal function inexorably deteriorates in all patients to end-stage renal failure, during 3 to 15 years. Because the onset occurs predominantly between 20 and 30 years of age, nephropathy often complicates pregnancy.
An important question is whether pregnancy adversely affects the course of diabetic nephropathy. Several studies exairdning fetal outcome and maternal risks in women with diabetic nephropathy suggest that, during the course of pregnancy, most patients will have increased proteinuria. Reece et al.14 reported that 70% of pregnancies had such an increase that exceeded 3.0 g/d in the third trimester. Kitzmiller et al.15 also found that increasing proteinuria occurred during the third trimester, with almost 60% exceeding 6.0 g/d then.
Miodovnik et al.16 compared the maternal outcomes of pregnant patients with type I diabetes mellitus who either did (n = 46) or did not (n = 136) have nephropathy. They concluded that pregnancy neither increases the risk of development of nephropathy, nor accelerates the progression of renal disease in women with diabetes who have preexisting nephropathy.
Reece et al.14 recently reported the maternal and fetal outcomes of 27 pregnancies complicated by diabetic nephropathy. Chronic hypertension (77%) and preeclampsia (53%) were common maternal complications. Intrauterine growth restriction (IUGR) and major congenital malformations were observed in 9% of neonates, whereas successful pregnancy outcomes were achieved in more than 95%. The English-language literature reveals that eight major studies were published between 1981 and 1998, representing more than 250 pregnancies complicated by diabetic nephropathy. In this group, complications related to growth and development of the fetus were considerable, and included stillbirth (0% to 7.7%), IUGR (15% to 22%), and major congenital malformations (0% to 18%). Preterm delivery occurred in 18% to 30.8% of pregnancies and neonatal death occurred in 0% to 4%. Third-trimester maternal parameters revealed that proteinuria exceded 3 g/d in 36% and 6 g/d in an additional 49% of women. Chronic hypertension was found in 61% to 100% of women and preeclampsia occurred in 19% to 63%, whereas anemia, defined as hemoglobin less than 10 g/dL, was diagnosed in 42% to 63%.
Target Plasma Glucose Levels in Pregnancy*
Long-term evaluation was conducted in four studies (n = 92) ranging from 0.3 to 10 years after the index pregnancy: 28% of these women continued to have elevated serum creatinine, whereas 74% had persistent hypertension. Seventeen percent had progressed to end-stage renal disease and 10% had died.
In summary, these data indicate that successful pregnancy outcomes with fetal survival rates greater than 95% are achievable in women with diabetes who have diabetic nephropathy. Although many women experience a temporary decline in renal function during gestation, pregnancy per se does not appear to hasten the natural progression to end-stage renal disease in patients with mild or moderate renal insufficiency.
The cumulative incidence of hypertensive complications during gestation was 21% among class B and class C patients, and 40% among class D or greater patients with diabetes (Table I).17 Greene et al.18 demonstrated a significantly higher incidence of hypertensive complications among women with diabetes who had vascular disease compared with those without vascular disease, and they showed that preterm delivery was significantly more common among hypertensive (risk ratio = 2) than nonhypertensive patients with diabetes. Reece et al.14 recently reported their experience in the management of 288 pregnant women with pregestational diabetes. The only maternal complication with increased incidence among women with microvascular disease (n = 185) was acute hypertensive complications (51% vs 32%; P < .05).
In summary, overall hypertensive complications are increased among women with overt diabetes as compared with women without underlying hypertension. Furthermore, the incidence of this complication is greater in patients with diabetes who have vascular disease.
Ischemic Heart Disease
Myocardial infarction (class H) is infrequent during the childbearing years, with an estimated incidence of 1 per 10,000 among all pregnancies. For women aged 25 to 35 years with type I diabetes mellitus, the yearly incidence of death due to coronary artery disease is 1 per 1,000 for those without nephropathy and 3 to 4 per 1,000 for those with nephropathy.19
In light of these findings, it seems prudent to provide an assessment of coronary artery disease when pre-conception counseling is given to women with long-standing diabetes, especially in the presence of macrovascular disease.
GLUCOSE EVALUATION AND CONTROL
The diabetic state during pregnancy is complicated by perturbations in the hormonal milieu that have effects on overall metabolism. As gestation advances, the diabetogenic effects of pregnancy are brought about by the production of increasing amounts of placental hormones that antagonize insulin action, enzymes within the placenta that degrade maternal insulin, and enhanced production of maternal glucose in the fasting state.
The criteria for satisfactory metabolic control vary widely (Table 2). Jovanovic et al.20 described 10 patients in the first trimester who were maintained in tight glucose control using intensive insulin therapy. These patients performed five to eight blood glucose determinations per day, and their average HbA]c levels fell from 9.4% to approximately 5%. The infants were described as showing no signs of macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, or respiratory distress. The authors concluded that normal glycemia could be achieved in early pregnancy and maintained for long periods in the outpatient setting. Later studies21,22 also support the benefit of normal glucose control before and throughout pregnancy. The goal of normal glycémie control during organogenesis and throughout pregnancy has generally been adopted as part of the standard care. Methods of evaluation include selfmonitoring of blood glucose and measurements of HbA1.
HbAlc was initially met with excitement by clinicians. A single test was finally available to reflect overall glucose control. It is now generally agreed that HbA1 is a "rough gauge" of overall glycémie control. The correlation may not be precise or accurately reflect fluctuations of glucose levels. However, clinical and laboratory studies have shown a relationship between glycémie status during organogenesis, as reflected by HbAlc levels, and the incidence of fetal morbidities, including macrosomia and malformations.
PRENATAL CARE AND DIAGNOSIS OF CONGENITAL MALFORMATIONS
Congenital anomalies among infants of mothers with diabetes occur at a rate of 6% to 10%.23 This represents a twofold to fivefold increase over that observed in the normal population. There is great diversity in the type of malformations associated with type I diabetes mellitus. However, the organ systems most commonly affected include the cardiovascular, central nervous, and skeletal systems (Table 3).24
Increased malformations account for approximately 40% of perinatal mortality among infants of mothers with diabetes. Despite extensive human and animal studies, the precise pathogenesis of the congenital malformations remains unknown and many etiologic factors have been proposed. Diabetes is not simply a disorder of carbohydrate metabolism but, rather, involves the impairment of lipid and protein metabolism as well. Studies of diabetes-related teratogenesis by Reece et al.,25 Pinter et al.,26 and others27"35 have focused on the mechanism of teratogenesis. A common finding is that concepii cultured in hyperglycemic media are growth restricted, have poor yolk sac development, and have multiple malformations. The frequency of these malformations is related to the glucose concentration. A number of teratogens have been suggested as inducing congenital malformations during the critical phase of organogenesis. The metabolic derangements related to hyperglycemia include hyperketonemia, zinc deficiency, increased concentration of branched-chain amino acids, and excess oxygen free radical production. Additional potential mechanisms include disturbed metabolism of sorbitol, myo-inositol, arachidonic acid, and prostaglandins.25"27,31"36
Congenital Anomalies in Infants of Mothers Who Have Diabetes*
Successful attempts to prevent diabetesinduced malformations have been reported in vitro and in vivo. Growth restriction and neural tube defects induced by hyperglycemia have been reduced or prevented by supplementation of arachidonic acid36 or myo-inositol37 in vitro and in vivo. In addition, oxygen free radical scavenging enzymes38 and antioxidant compounds, such as vitamin E39 and lipoic acid,40 have also reduced malformation rates.
Clinical evidence has demonstrated that maintaining euglycemia throughout organogenesis obviates the teratogenic effect of hyperglycemia. Participation in a pre-conception care program can reduce the incidence of malformations to the background rate. The use of dietary supplements, which presumably would override the teratogenic effects of aberrant metabolic fuels, also holds some promise.
Fetal abnormalities can be diagnosed prenatalIy. For this reason, the sonographic assessment of fetal development is important in the management of diabetic pregnancies. The need for early gestational dating is obvious because alterations in fetal growth are related to fetal age. Prenatal diagnosis by ultrasound will have no effect on the incidence of anomalies, but it can appreciably affect how a pregnancy is managed. Women with diabetes are generally aware of their increased likelihood of delivering malformed infants, and normal results of an ultrasound examination allay their fear. Furthermore, prenatal diagnosis early in pregnancy provides the opportunity for early termination if a woman chooses that option. Some fetuses with spina bifida, gastrointestinal anomalies, cardiac defects, or obstructive uropathy can benefit because ultrasound will allow alteration in obstetric management to optimize fetal outcome.
In addition, macrosomia is reported in approximately 25% of the offspring of women with diabetes. Fetal macrosomia is believed to be caused by maternal hyperglycemia. This induces fetal hyperglycemia and hyperinsulinemia, leading to an increased caloric intake. Recently, other in utero growth promoters such as insulin-like growth factors41 and leptin42 have been found. Conversely, women with diabetes are also at increased risk of delivering infants who are small for their gestational age. This risk of IUGR increases with the severity of maternal vascular disease. Because most complications are related to maternal hyperglycemia, therapeutic strategies should be directed toward normalization of maternal glucose levels. When this is achieved, both perinatal mortality and morbidity are reduced to near background rates.
The clinical management team for pregnancies complicated by diabetes may include: (1) a perinatologist thoroughly familiar with modern care of patients with diabetes; (2) a nurse who devotes significant time to patients with diabetes; (3) availability of a neonatologist and highly competent neonatal unit; and (4) a dietician and appropriate laboratory backup, including ultrasound facilities (Table 4). Some centers make the patient responsible for day-to-day adjustments of insulin. Results are reported to the center at weekly or greater intervals. The use of frequent monitoring of home glucose, diet, and insulin and this team approach can achieve euglycemia in most mothers with diabetes, and thus reduce perinatal morbidity and mortality.
PERINATAL AND NEONATAL CARE
Neonatal morbidity is frequent in gestational and pregestational diabetes, but is much greater in the latter. It includes hypoglycemia, polycythemia, respiratory distress syndrome (RDS), hypocalcemia, and macrosomia. The exact etiology of many of these disorders remains unclear. However, there is evidence to show that neonatal morbidity is related to poor metabolic control during pregnancy. Landon et al.43 studied glycémie control and neonatal morbidity in 75 patients with type I diabetes mellitus and found that patients with mean capillary blood glucose lower than 110 mg/dL during the second and third trimesters had less neonatal morbidity than when mean capillary blood glucose was greater than 110 mg/dL. The latter group had higher rates of macrosomia (34% vs 9.3%), RDS (21% vs 2.3%), neonatal hyr^rbilirubinemia (40% vs 23%), and hypoglycemia (40% vs 18.6%).
Hypoglycemia in infants of mothers with diabetes is probably related to the overproduction of insulin by the fetal pancreas. At birth, the transplacental source of glucose abruptly stops. leading to the increased risk of neonatal hypoglycemia. Clinical signs include tremor, cyanosis, convulsions, apathy, and sweating. Because prolonged and severe hypoglycemia may be associated with neurologic sequelae, initiation of treatment is advised in all neonates of mothers with diabetes who have plasma glucose levels below 40 mg/dL.
RDS is a common neonatal morbidity in infants of mothers with diabetes. Factors contributing to this are preterm delivery, delayed fetal lung maturation, and high rates of elective cesarean section. In patients with poorly controlled diabetes, high fetal insulin levels seem to inhibit surfactant production. Infants of mothers with diabetes should have delivery planned at term whenever possible and assessment of fetal lung maturation prior to delivery. Occasionally, premature delivery may be necessary because of maternal or fetal complications. Under these circumstances, pharmacologic acceleration of lung maturation should be considered before (by maternal steroid administration) or after (by administration of surfactant) delivery.
The precise incidence of polycythemia and hyperviscosity has not been well documented, although it seems fairly common. The mechanism is based on a hypoxia-induced increase in erythropoietin and subsequent erythropoiesis. Fetal hypoxia during labor may increase the possibility of placental transfusion and hypervolemia. The treatment of polycythemia or hyperviscosity consists of a partial exchange transfusion.
The incidence of hypocalcemia, defined as calcium at or below 7 mg/dL, approaches 20%. The etiology is not yet clear. However, there is some evidence that it is related to relative neonatal hypoparathyroidism.44
In summary, current evidence suggests that much of the morbidity in infants of mothers with diabetes is preventable by tight maternal glycémie control during pregnancy.
Since the discovery of insulin more than 70 years ago, the outcomes of pregnancies complicated by diabetes mellitus have continued to improve. It was once common for young women with diabetes to be cautioned against pregnancy. Fortunately, the outlook for most women with diabetes who are considering pregnancy is brighter than it was even as recently as 10 years ago.
Diabetes-irt-Preg nancy Program Protocol*
1. Catalano PM, Tyzbir ED, Wolfe RR, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol. 1993;264:E60-E67.
2. Damm P, Molsten-Pedersen L. Significant decrease in congenital malformations in newborn infants of an unseIected population of diabetic women. Am ] Obstet Gynecol. 1989;161:1163-1167.
3. Gabbe SG. Medical complications of pregnancy management of diabetes in pregnancy: six decades of experience. In: Pitkin RM, Zlatnik FJ, eds. Year Book of Obstetrics and Gynecology: Part I. Obstetrics. Chicago: Year Book Medical Publishers; 1980:37.
4. Steel JM, Parboosingh J, Cole RA, Duncan LJP. Prepregnancy counseling: a logical prelude to the management of the pregnant diabetic woman. Diabetes Care. 1980;3:371-373.
5. Goldman JA, Dicker D, Feldberg D, et al. Pregnancy outcome in patients with insulin-dependent diabetes mellitus with preconceptional diabetic control: a comparative study. Am J Obstet Gynecol. 1986;155:293-297.
6. Ylinen K, Raivo K, Termano K. Haemoglobin Alc predicts the perinatal outcome in insulin-dependent diabetic pregnancies. Br J Obstet Gynaecol. 1981;88:961-967.
7. Sharma NK, Archer DB, Hadden DR, et al. Morbidity and mortality in patients with diabetic retinopathy. Trans Ophthalmol Soc UK. 1980;100:83-89.
8. Cassar J, Kohner EM, Hamilton AM, et al. Diabetic retinopathy and pregnancy. Diabetologia. 1978;15:105-11.
9. Klein R, Klein BEK, Moss S, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: III. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than thirty years. Arch Ophthalmol. 1984;102:520-526.
10. Cunha-Vaz JG, Fonseca JR, Faria De Abreu JR, et al. Detection of early retinal changes in diabetes by vitreous fluorophotomehy. Diabetes. 1979;28:16-19.
11. Reece ER, Homko CJ, Hagay Z. Diabetic retinopathy in pregnancy. Obstet Gynecol Clin North Am. 1996;23:161-171.
12. Pirart J. Diabetes et coplications degeneratives: presentation d'une e'tude prospective portant sur 4400 cas observes entre 1947 et 1973. Diabetes Metab. 1977;3:173182.
13. The Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993,29:977-986.
14. Reece EA, Leguizamon G, Homko C. Pregnancy performance and outcomes associated with diabetic nephropathy. Am ] Perinatal. 1998;15:413-421.
15. Kitzmiller JL, Brown ER, Phillippe M, et al. Diabetic nephropathy and perinatal outcome. Am J Obstet Gynecol. 1981;141:741-751.
16. Miodovnik M, Rosenn BM, Khoury JC, et al. Does pregnancy increase the risk for development and progression of diabetic nephropathy? Am J Obstet Gynecol. 1996;174:1180-1190.
17. Diamond MP, Shah DM, Hester RA, et al. Complication of insulin-dependent diabetic pregnancy by preeclampsia and /or chronic hypertension: analysis of outcome. Am ] Perinatal. 1985;2:263-267.
18. Greene MF, Hare JW, Krache M, et al. Prematurity among insulin-requiring diabetic gravid women. Am J Obstet Gynecol. 1989;161:106-111.
19. Brown FM, Hars JW. Diabetic nephropathy and coronary hypertension. In: Reece EA, Coustan DR, eds. Diabetes Mellitus in Pregnancy. New York: Churchill Livingston; 1995:345-351.
20. Jovanovic L, Peterson CM, Saxena BB, et al. Feasibility of maintaining normal glucose profiles in insulin-dependent pregnant diabetic women. Am J Med. 1980;68:105-112.
21. Landon MB, Gabbe SG. Glucose monitoring and insulin administration in the pregnant diabetic patient. Clin Obstet Gynecol. 1985;28:496-506.
22. Reece EA, Homko CJ. Diabetic nephropathy and coronary hypertension. In: Reece EA, Coustan DR, eds. Diabetes Mellitus in Pregnancy. New York: Churchill Livingston; 1995:155-169.
23. Karlsson K, Kjellmer I. The outcome of diabetic pregnancy in relation to the mother's blood sugar level. Am } Obstet Gynecol. 1972,112:213-220.
24. Fuhrmann K, Reiher H, Semmler K, et al. Prevention of congenital malformations in infants of insulin-dependent diabetic mothers. Diabetes Care. 1983;6:219-223.
25. Reece EA, Pinter E, Leranth CZ, et al. Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology. 1985;32:363-373.
26. Pinter E, Reece EA, Leranth C, et al. Arachidonic acid prevents hyperglycemia-associated yolk sac damage and embryopathy. Am J Obstet Gynecol. 1986;155:691-702.
27. Samuelsson B, Dahlen S-E, Lindgren JA, et al. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171-1176.
28. Ramwell PW, Foegh M, Loeb R, et al. Synthesis and metabolism of prostaglandins, prostacyclin, and thromboxanes: the arachidonic acid cascade. Semin Perinatol. 1980;4:3-13.
29. Casey ML, MacDonald PC. The initiation of labor in women: regulation of phospholipid and arachidonic acid metabolism and of prostaglandin production. Semin Perinatol. 1986;10:270-275.
30. Olson DM, Zakart T. Intrauterine tissue prostaglandin synthesis: regulatory mechanisms. Semin Reprod Endocrinol. 1993;11:234.
31. Baker L, Piddington R, Goldman AS, et al. Myo-inositol and prostaglandins reverse the glucose inhibition of neural tube fusion in cultured mouse embryos. Diabetologia. 1990;33:593-596.
32. Hod M, Star S, Passoneau J, et al. Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis. Biochem Biophys Res Commun. 1986;140:974-980.
33. Sussman I, Matschinsky FM. Diabetes affects sorbitol and myo-inositol levels of neuroectodermal tissue during embryogenesis in rat. Diabetes. 1988;37:974-981.
34. Hashimoto M, Akazawa S, Akasawa M, et al. Effects of hyperglycemia on sorbitol and myo-inositol contents of cultured embryos: treatment with aldose reductase inhibitor and myo-inositol supplementation. Diabetologia. 1990;33:597-602.
35. Weigensberg MJ, Garda-Palmer FJ, Freincel N. Uptake of myo-inositol by early-somite rat eonceptus: transport kinetics and effect of hyperglycemia. Diabetes. 1990,39575-582.
36. Reece EA, Wu K-Y, Wiznitzer A, et al. Dietary polyunsaturated fatty acids prevent malformation in offspring of diabetic rat Am } Obstet Gynecol. 1996;175:818-822.
37. Reece EA, Khandelwal M, Wu Y-K, et al. Dietary intake of myo-inositol and neural-tube defects in offspring of diabetic rats. Am J Obstet Gynecol. 1997;176:536-539.
38. Eriksson UJ, Borg LAH. Protection by free oxygen radical scavenging enzymes against glucose induced malformations in vitro. Diabetologia. 199134:325-333.
39. Sivan E, Reece EA, Wu YK, et al. Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol. 1996;1 75:793799.
40. Wiznitzer A, Aylon N, Hershkovitz R, et al. Lipoic acid prevention of neural tube defects in offspring of rats with streptozocin-induced diabetes. Am J Obstet Gynecol. 1999;180:188-193.
41. Wiznitzer A, Reece EA, Homko CJ, et al. Insulin-like growth factors, their binding proteins, and fetal macrosomia in offspring of nondiabetic pregnant women. Am } Perinatol. 1988;151:23-28.
42. Wiznitzer A, Furman B, Hackmon R, et al. Leptin and fetal growth: a new piece in the puzzle of fetal macrosomia. Am J Obstet Gynecol. 1999;180:6.
43. Landon MB, Gabbe SG, Piana R, et al. Neonatal morbidity in pregnancy complicated by diabetes mellitus: predictive value of maternal glycémie profiles. Am J Obstet Gynecol. 1987;156:1089-1095.
44. William OH. Neonatal outcome and care. In: Reece EA, Coustan DR, eds. Diabetes Mellitus in Pregnancy. New York: Churchill Livingston; 1995:369-378.
Classification of Diabetes in Pregnancy*
Target Plasma Glucose Levels in Pregnancy*
Congenital Anomalies in Infants of Mothers Who Have Diabetes*
Diabetes-irt-Preg nancy Program Protocol*