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Diabetes with Pregnancy Classifying Diabetes Diabetes mellitus is generally classified into the following categories: type 1 or insulin-dependent diabetes mellitus, type 2 or noninsulin-dependent diabetes mellitus, and gestational diabetes mellitus (GDM). Approximately 10% of all individuals with diabetes mellitus have type 1 diabetes. Beta cell destruction, with resulting insulin deficiency, is the hallmark of this disorder. Onset is generally before the age of 30 years, and as a result, this type of diabetes is frequently encountered in women of childbearing age. It is estimated that type 1 diabetes complicates approximately 0.2% of all pregnancies in the United States annually. Type 2 diabetes is the most common form of the disease, affecting nearly 90% of all individuals with diabetes. Type 2 diabetes is characterized by defects in both insulin action and secretion. It typically is seen in individuals over the age of 40 years and therefore in the past was felt to be uncommon in women of childbearing age. However, in recent years, the incidence of type 2 diabetes has been increasing steadily among younger individuals, and data from the National Maternal and Infant Health Survey indicates that type 2 diabetes complicates 0.3% of all pregnancies in the United States. Gestational diabetes mellitus is defined as carbohydrate intolerance of variable severity with onset or first recognition during the index pregnancy. If the abnormality in glucose tolerance persists after pregnancy, the patient's diagnosis is revised to type 1, type 2, or impaired glucose tolerance (IGT). Gestational Diabetes Mellitus GDM is a common problem that complicates approximately 5% of all pregnancies in the United States. The likelihood of developing GDM is significantly increased among certain subgroups, including individuals with a positive family history of type 2 diabetes, advancing maternal age, obesity, and. 1 nonwhite ethnicity. Excess risks for both GDM and IGT have been demonstrated in black, Hispanic, and Native American women as well as in women from the Indian subcontinent and the Middle East. Screening and Diagnosis for Gestational Diabetes Mellitus Screening should be performed between 24 and 28 weeks gestation, although women with significant risk factors may benefit from being screened earlier in pregnancy. A 50-g glucose challenge test is performed without regard to the time of day or interval since the last meal. Venous plasma glucose is measured 1 hour later, with a value of ≥140 mg/dL indicating the need for a 3-hour 100-g oral glucose tolerance test (OGTT). The OGTT is performed after an overnight fast and 3 days of an unrestricted carbohydrate diet. A fasting blood glucose level is drawn, and a 100-g glucose load is then administered. Plasma glucose levels are drawn 1, 2, and 3 hours following ingestion of the glucose solution. Diagnosis requires that at least two of the four glucose levels of the OGTT meet or exceed the upper limits of normal. The evaluation of glucose intolerance during pregnancy may be made by using a one-step approach or 2-hour 75-g OGTT. This approach is considered most applicable in high-risk populations. Women with GDM should be evaluated at the first postpartum visit by a 2-hour OGTT using a 75-g load. Greater than 90% of women will convert to normal glucose tolerance following delivery. However, studies indicate that the risk for overt diabetes may be as high as 20% to 50% in this population. Long-term annual follow-up is therefore indicated. GDM is influenced greatly by body weight, with the highest rate occurring in obese patients. 2 Maternal Complications Despite improvements in pregnancy outcomes, women with both GDM and pre-GDM are at greater risk for a number of pregnancy-related as shown in the table. TABLE 15.1 Pregnancy Complications in Diabetes Maternal Preterm labor Infectious morbidities Hydramnios Hypertensive disorders Worsening of diabetic retinopathy Fetal/Neonatal Stillbirth Congenital malformations Altered fetal growth Metabolic abnormalities Hypoglycemia Hypocalcemia Polycythemia Hyperbilirubinemia Cardiomyopathy RDS Long Term Childhood obesity Neuropsychologic defects Diabetes RDS, respiratory distress syndrome. Current data would seem to indicate that pregnancy is an independent risk factor for diabetic retinopathy. Therefore all women with type 1 diabetes for 5 years or more or type 2 diabetes at diagnosis require a thorough dilated ophthalmologic evaluation. However, diabetic nephropathy is the complication of diabetes that is most likely to affect pregnancy outcomes. There are increased risks for pregnancy-induced hypertension and/or a 3 progression of already existing hypertension, intrauterine growth retardation resulting in small-for-gestational-age infants, preterm deliveries secondary to fetal distress, and a 10-fold increase in the incidence of stillbirth over women with diabetes but without nephropathy. Preeclampsia is the most frequent, serious complication of maternal nephropathy, with implications for both mother and fetus. Neonatal Complications The offspring of women with diabetes remain at increased risk for a number of complications, which includes congenital anomalies, fetal macrosomia, respiratory distress syndrome (RDS), and metabolic abnormalities as well as long-term sequelae. Perinatal Mortality The two major causes of perinatal mortality are unexplained fetal death and congenital malformations. The causes of unexpected death are not well understood. In animal models, sustained hyperglycemia has been associated with increased insulin secretion, elevated fetal oxygen consumption, acidosis, and death. It has been postulated that fetal polycythemia and increased platelet aggregation could explain the increased incidence of intravascular thrombosis in infants of diabetic mothers and that thrombotic episodes could be the underlying cause for late unexplained intrauterine deaths. Approximately 40% of perinatal deaths that occur among infants of women with diabetes can be attributed to malformations. Diabetes mellitus is one of the most common maternal conditions that results in anomalous offspring. The frequency of major congenital anomalies is increased two- to threefold over the general population. 4 The most frequent types of malformations involve 1-the central nervous system 2-cardiovascular3-gastrointestinal, 4-genitourinary 5-and skeletal systems, with cardiac malformations being the most common. The defects most often associated with diabetes occur during organogenesis before 7 weeks gestation. As a result, the management goal for diabetic pregnancies has become the establishment and maintenance of near euglycemia beginning with the preconceptual period and continuing throughout gestation. Altered Fetal Growth Macrosomia is a classic hallmark of the pregnancy complicated by diabetes and is reported to occur in 20% to 25% of pregnancies complicated by diabetes. Macrosomia is defined as excessive birth weight (>90%) for gestational age or as a birth weight >4000 g. Increased adiposity is the primary cause of the increased birth weight seen in the offspring of diabetic women. Numerous studies have established a relationship between the level of maternal glucose control and macrosomia. Mothers of macrosomic infants usually have significantly elevated plasma glucose levels at term, indicating increased glucose availability to the fetus, with hyperinsulinemia a likely intermediate step, during the third trimester. Other factors associated with an increased risk for fetal macrosomia include 1-increased maternal weight, 2-increased parity,3- previous delivery of a macrosomic infant, 4-and insulin requirements >80 U per day. Macrosomic fetuses have higher perinatal and neonatal mortality and morbidity rates. Approximately 10% of infants weighing over 4,500 g at birth will require admission to a neonatal intensive care nursery. In addition, the reported perinatal mortality is two to five times higher in this group of children than in average-sized children. Delivery of a 5 macrosomic infant is dangerous because of the risk for birth trauma to the head and neck. Fetal asphyxia and meconium aspiration may occur as a result of prolonged labor secondary to unrecognized cephalopelvic disproportion and shoulder dystocia. At the other extreme, women with type 1 diabetes also are at increased risk for delivering a small-for-gestational-age infant. In general, the risk of growth retardation increases with the severity of the mother's clinical diabetes. Vascular complications, such as retinopathy and nephropathy, are believed to be associated with uteroplacental insufficiency in pregnant women with diabetes. Poor maternal renal function, hypertension, and placental lesions have all been associated with intrauterine growth retardation in the offspring of diabetic mothers. However, more recent evidence suggests that the growth retardation may be related to disturbances in maternal fuels during organogenesis. Metabolic Abnormalities Hypoglycemia occurs when plasma glucose levels fall below 35 mg/dL in the term infant and 25 mg/dL in the preterm infant. The incidence of hypocalcemia also is significantly increased in the infants of women with diabetes. Hypocalcemia generally occurs in association with hyperphosphatemia and occasionally with hypomagnesemia. Neonatal hypocalcemia is defined as a calcium level at or below 7 mg/dL. Serum calcium levels usually are lowest on the second or third day of life. Polycythemia is defined as a venous hematocrit that exceeds 65% and is reported to occur in one third of neonates born to diabetic women. Polycythemia is believed to occur as a result of chronic intrauterine hypoxia, which leads to an increase in erythropoietin and consequently results in an increase in red cell production. Neonates born to women with diabetes also have a higher incidence of hyperbilirubinemia as compared with 6 nondiabetic controls. Neonatal hyperbilirubinemia develops in approximately 20% to 25% of cases. Other Infant Morbidities Offspring born to women with diabetes mellitus also are at increased risk of developing various hypertrophic types of cardiomyopathies and congestive heart failure. RDS is another common complication associated with diabetes. Preconception Care Care of women with type 1 or type 2 diabetes ideally begins before conception. Although numerous clinical trials have demonstrated that strict glycemic control prior to and during early gestation can reduce the rate of structural defects, the vast majority of women with diabetes still seek medical care only after they learn they are pregnant. Consequently, the rate of congenital malformations in infants of mothers with diabetes has continued to remain significantly higher than that of the general population. Diabetes Management The main goal of management for pregnancies complicated by either gestational diabetes or pre-GDM is to achieve and/or maintain euglycemia throughout gestation. The treatment approach requires a combination of diet, exercise, intensive insulin regimens, oral medications, and daily multiple blood glucose determinations. Diet Diet therapy is the cornerstone of diabetes management in pregnancy, just as it is in the nonpregnant state.. Most experts advocate an additional intake of 300 to 400 kcal per day to meet the needs of pregnancy. Recommendations regarding total 7 caloric intake often are based on the mother's pregravid weight—30 kcal/kg of body weight per day for normal weight women with diabetes, 40 kcal/kg per day for underweight women, and 24 kcal/kg per day for overweight women. Exercise Although exercise has been demonstrated to be beneficial in nopregnant individuals, evidence regarding the risk and/or benefits of either periodic or regular exercise in pregnant women with diabetes is limited. Pharmacologic Therapy The goal of insulin therapy is to achieve blood glucose levels that are nearly identical to those observed in healthy pregnant women. Therefore, multiple injections of insulin usually are required in women with preexisting diabetes. Human insulin is the least immunogenic of all insulins and is exclusively recommended in pregnancy. Insulin requirements may change dramatically throughout the various stages of gestation. In the first trimester, the maternal insulin requirement is approximately 0.7 U/kg of body weight per day. This is increased in the third trimester to 1.0 U/kg per day. Monitoring Metabolic Status Self-Monitoring of Blood Glucose Self-monitoring of blood glucose by has become the mainstay of management for pregnancies complicated by diabetes mellitus. Blood glucose measurements should be obtained at least 4 times a day (fasting and 1 to 2 hours after meals) in women with GDM and 5 to 7 times a day in women with preexisting diabetes. In addition to this regular monitoring, patients also 8 should test whenever they feel symptoms of either hyperglycemia or hypoglycemia. Detailed record keeping is useful to help identify glucose patterns. Daily urine ketone testing should be performed to ensure early identification of the development of starvation ketosis or ketoacidosis. Ketone testing also should be performed any time the blood glucose level exceeds 200 mg/dL, during illness, or when the patient is unable to eat. TABLE 15.3 Monitoring the Diabetic Pregnancy Maternal Surveillance Self blood glucose monitoring four to seven times daily A1C Urinary ketones Blood pressure Retinal and renal status (for women with preexisting diabetes) Fetal Surveillance Level II ultrasound and fetal echocardiogram (for women with preexisting diabetes) Serial assessment (4–6 wk) of fetal growth Daily fetal movement counting Weekly NST or BPP NST, nonstress test; BPP, biophysical profile. Blood glucose levels are measured in both the fasted and postprandial states. Current recommendations are that whole blood glucose levels should not exceed 95 mg/dL in the fasted state and 120 mg/dL after meals. Fetal Assessment All pregnancies that are complicated by diabetes require additional fetal evaluation and assessment, Ultrasonography provides the clinician with essential information about the fetus and its development. A first-trimester scan should be performed to date the pregnancy and establish viability. Evaluation 9 includes a targeted ultrasound to survey general fetal anatomy and fetal echocardiography at approximately 20 to 22 weeks gestation. In addition, the maternal serum alpha-fetoprotein screening test should be performed between 16 and 18 weeks gestation because of the increased risk of neural tube defects. Since women with diabetes are at risk for fetal growth aberrations, frequent ultrasound scans are recommended to identify states of altered growth. Ultrasound examinations should be performed at 4- to 6-week intervals during the second and third trimesters of pregnancy to assess not only fetal growth but amniotic fluid volume as well. Fetal death is more common in pregnancies complicated by diabetes than in the general population. The goal of antepartum surveillance is avoidance of intrauterine death by early detection of fetal compromise. The nonstress test (NST) has become the preferred antepartum fetal heart rate test for screening the fetal condition in pregnancies complicated by diabetes. The NST evaluates the presence of accelerations from the baseline fetal heart rate. An alternative fetal test is the fetal biophysical profile (BPP), which also is utilized to evaluate the significance of a nonreactive NST. Because the BPP employs ultrasound, it permits evaluation of amniotic fluid volume and may detect major fetal malformations in patients who have not been studied earlier in pregnancy. Maternal evaluation of fetal movement counts also should be integrated into the surveillance program. Women with diabetes are instructed to count fetal movements beginning as early as 28 weeks gestation. Although the falsepositive rate is high, the technique is inexpensive and simple and augments the total antepartum surveillance program. Most perinatal centers institute a program of weekly fetal monitoring beginning at 32 to 34 weeks gestation. Since fetal death is more common in women with poor glycemic control, hydramnios, fetal macrosomia, hypertension, or vasculopathy, these women receive twice weekly NST testing. Patients with diet-controlled GDM who maintain normal fasting and postprandial glucose levels are probably at low risk for an intrauterine death and are not tested as early or frequently. 10 However, women with GDM and chronic hypertension, a previous history of stillbirth, and preeclampsia and those who require insulin therapy receive more intense surveillance. Timing and Mode of Delivery It is generally accepted that if a pregnant diabetic patient is in good metabolic control and is receiving fetal surveillance on a regular basis, delivery may be safely delayed until term or the onset of spontaneous labor. Women with poor metabolic control, worsening hypertensive disorders, fetal macrosomia, growth retardation, or polyhydramnios may be electively delivered after fetal lung maturity has been confirmed. If an elective delivery is planned before 38 weeks gestation, amniocentesis should be performed for confirmation of fetal lung maturity. Fetal lung maturation is better predicted by the amniotic fluid phosphatidylglycerol content than by the lecithin:sphingomyelin ratio. Cesarean section should be performed on most diabetic patients with an estimated fetal weight of greater than 4,500 g to prevent shoulder dystocia and birth trauma. Management should be individualized for patients with an estimated fetal weight between 4,000 and 4,500 g. The decision is based on the size of the pelvis and progress of labor as well as the patient's obstetric history. A history of shoulder dystocia often is an indication for repeat cesarean section. During labor and delivery, good blood glucose control should be maintained to prevent neonatal hypoglycemia. Blood glucose levels should be maintained at a level below 100 mg/dL with the use of an insulin infusion. After delivery, insulin requirements tend to dramatically fall as a result of the significant decrease in level of placental hormones. Once the patient is able to eat regular meals, she should receive subcutaneous insulin at approximately one half of her prepregnancy dose. Conclusion The diagnosis of diabetes mellitus during pregnancy has certain implications for the well-being of both the mother and the fetus. 11 Advances in medical and obstetric care have dramatically improved the outlook for women with diabetes and their offspring. However, both mother and child remain at increased risk for a number of complications. Research indicates that the majority of these complications are associated with hyperglycemia. The achievement and maintenance of euglyemia has therefore become the major focus of management. Dr. Naser Malas. 12