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OBESITY IN PREGNANCY

Recent estimates reveal that in the US 18.5-38.3% of pregnant women are obese (289), a 30% increase in the last 10 years. Pregnancy complicated by maternal overweight (BMI 25-30 kg/m2) and obesity (BMI > 30 kg/m2) is associated with an increased risk for diabetes mellitus, hypertensive disorders, urinary tract infections, thrombophlebitis, and operative delivery (289-94). In turn, an operative delivery is associated with increased anesthetic and postoperative complications such as wound infection, dehiscence, and thromboembolic events. Respiratory complications include decreased lung volume related to chest wall and abdominal fat, mild hypoxia (295), and Pickwickian syndrome with hypoventilation and hypercapnia. These respiratory complications may be exacerbated by the expanding abdominal contents in pregnancy. Sleep disordered breathing, with increases in apnea/hypopnea, oxygen desaturation, and snoring times, is also more common in pregnancies complicated by obesity (296). This may predispose to intrauterine fetal growth restriction in the offspring, and hypertensive disorders and increased cardiovascular risk in the mothers.

Maternal overweight and obesity are associated with multiple complications in the offspring. These include macrosomia unrelated to gestational diabetes mellitus (289-91,297-9), intrauterine fetal growth restriction, congenital anomalies, and stillbirth. At one year, infants of obese mothers remain significantly more obese than infants of nonobese mothers (293). There is a clear association between maternal obesity and spina bifida and other neural tube defects in the offspring (289,298). Several studies have also demonstrated an increase in cardiac defects in pregnancies complicated by obesity, with no reduction in rate when supplements are used (289,299). Overall, there is an increase in orofacial clefts, club foot, cardiac septal defects, and abdominal wall defects. Craniofacial and musculoskeletal defects are increased 3-fold when pregnancy is complicated by both obesity and diabetes mellitus. Stillbirth increases 2-fold in the presence of maternal obesity. Other delivery complications include meconium, late decelerations, and shoulder dystocia (294).

Weight gain guidelines have been established by the Institute of Medicine (300) (Table 3), and are discussed in the Diabetes in Pregnancy section below. Obese mothers are able to mobilize nutrients for adequate fetal growth without significant weight gain in pregnancy. Obese mothers who lose weight in pregnancy still deliver offspring with birth weights higher than the birth weights of term infants of normal weight mothers who gain the recommended amount of weight (301). Excessive weight gain in pregnancy has adverse impact on maternal complications, fetal/neonatal complications, and results in higher long-term maternal weight (302).

DIABETES IN PREGNANCY

Insulin is the primary anabolic hormone of pregnancy. Early in gestation, progesterone in concert with estrogen has a direct tropic effect on the pancreatic b cells. Postprandial insulin concentrations rise in the presence of normal glucose tolerance, and contribute to an anabolic process of accretion of maternal subcutaneous fat and adipocyte enlargement. Animal models also demonstrate hepatic glycogen accumulation and an increase in lean body mass.

Insulin sensitivity appears to decline starting after 12-14 weeks of gestation, with progression to severe insulin resistance during the 3rd trimester (303), under the influence of rising placental hormones including human chorionic somatomammotropin, placental growth hormone variant, cortisol, prolactin, and progesterone. Marked hyperinsulinemia creates an anabolic state of maternal fuel storage during the fed state, which is offset by the catabolic effects of these insulin antagonists in the fasted state. Insulin resistance at the skeletal muscle and hepatocyte prolongs the accessibility of nutrients within the plasma compartment after feeding to allow a rapid transfer of stored nutrients to the fetal compartment in the second half of gestation, corresponding with the time of a geometric increase in the fetal-placental mass (304). This system is disturbed when insulin secretion is inadequate, as with diabetes mellitus. All of the plasma substrates are affected, including fasting and postprandial glucose, FFA's, triglycerides, cholesterol, and branched-chain amino acids (305,306). These metabolic disturbances provide increased fuels to the fetal compartment, resulting in fetal hyperinsulinemia which mediates the adverse effects of diabetes mellitus on the offspring (307-10). The timing of the metabolic insult predicts the adverse outcome ("fuel-mediated teratogenesis"), with both perinatal and long-term consequences (307,308).

Complications

Disturbances in maternal metabolism at the time of conception increases the risk of congenital anomalies and spontaneous abortion (307,309,311). In patients with fair to good control at conception, the incidence of birth defects is approximately 5% (312,313), two times greater than that in the non-diabetic population. Further worsening of glycemic control is associated with dramatic increases in malformation rates (312). The risk of spontaneous abortion is directly proportional to the glycohemoglobin level in early pregnancy (312). Optimization of control prior to conception may reduce the congenital malformation rate to that of the non-diabetic population (314,315).

Macrosomia (birth weight above the 90th percentile for gestational age) is a frequent complication of both pregestational and gestational diabetes mellitus. Neonates may have almost twice as much adiposity as offspring of normal mothers (316), proportional to maternal metabolic control (317). The truncal obesity and asymmetric fetal growth associated with diabetes mellitus increase the risk of shoulder dystocia, birth trauma, and operative delivery. Fetal islet cell function, with b cell hypertrophy and hyperplasia and amniotic fluid hyperinsulinemia, is associated with maternal metabolic control, particularly that found in the second trimester (318,319). Once b cell hyperplasia occurs, the subsequent fetal hyperinsulinemia may further augment fetal growth in the absence of elevated maternal nutrients (318). Maternal postload glucose peaks may be blunted by exaggerated fetal glucose siphoning, which may cause false negative oral glucose tolerance test results (320). Early diagnosis and intervention are therefore critical to avoid complications in the offspring. Intrauterine fetal growth restriction is now rarely seen except in pregnancies complicated by hypertension or nephropathy (321).

There is an increase in the prevalence of obesity in the offspring of diabetic mothers (322). A direct correlation between maternal metabolic control and the development of childhood and adolescent obesity was seen in the Pima Indian study (323,324). Amniotic fluid insulin levels as a measure of stimulated fetal islet function also correlate positively with childhood obesity.(325).

Both animal and human studies demonstrate that disturbances in islet function during intrauterine life predispose the individual to impaired glucose tolerance (322). Pettitt et al examined offspring born to women from 3 risk groups: those who had diabetes during pregnancy ("diabetic"), those with a genetic predisposition to diabetes who had normal glucose tolerance during pregnancy but developed diabetes subsequently ("prediabetic"), and those who never developed diabetes ("nondiabetic"). Controlling for other confounding variables, Type 2 diabetes mellitus was present in 45.5% of those age 20-24 who were offspring of diabetic pregnancies, 8.6% of offspring of prediabetic mothers, and 1.4% of offspring of nondiabetic mothers.(326). Amniotic fluid insulin levels as a measure of fetal hyperinsulinemia are a strong predictor of impaired glucose tolerance in adolescence (327). These studies demonstrate the profound impact of an adverse metabolic environment on a genetic predisposition.

Diagnosis of Gestational Diabetes Mellitus

According to NHANES III, 2.9-17.3% of nonpregnant women age 20-49 have impaired glucose tolerance or diabetes mellitus (328). Pregestational diabetes mellitus complicates up to 0.5% of pregnancies (329), although the prevalence of diabetes in younger age groups has dramatically increased in the last 10 years. Gestational diabetes mellitus (GDM), defined as "glucose intolerance with onset or first recognition during pregnancy," occurs in approximately 4% of pregnancies, with higher rates in at risk populations (330,331). The diagnosis does not exclude the possibility that unrecognized diabetes predated the pregnancy. Patients with GDM demonstrate features found in patients with Type 2 diabetes mellitus, including attenuated first phase and subsequent insulin release, adjusted for the level of insulin resistance (332,333). Therefore, the progressive insulin resistance of pregnancy reveals women at high risk for the development of Type 2 diabetes mellitus.

Women with GDM are generally asymptomatic, and detection requires an active screening program (Table 4). Low risk individuals, who do not need to be screened, include women with all of the following characteristics: member of a racial/ethnic group with a low prevalence of GDM; age < 25 years; normal weight (BMI < 25 kg/m2); no family history of diabetes; and no personal history of abnormal glucose metabolism or poor obstetric outcome. Those at particularly high risk for developing GDM (marked obesity, strong family history of Type 2 diabetes mellitus, personal history of GDM, glucose intolerance, or glucosuria) should be screened as soon as they present pregnant to allow early intervention (334). If GDM is not found, testing should be repeated at 24-28 weeks or at any time the patient develops symptoms suggestive of hyperglycemia. All others should be screened at 24-28 weeks' gestational age. The current recommendation is a 50 gram oral glucose challenge test without regard to the time of day or time of the last meal (335). Women with a one hour plasma glucose value > 140 mg/dl (7.8 mmol/L) require definitive evaluation with an oral glucose tolerance test. This involves approximately 14-18.5% of pregnant women,(330) with a sensitivity of 79% and a specificity of 87%. Decreasing the screening threshold to 130 mg/dl (7.2 mmol/L), increases the need for oral glucose tolerance tests to 20-25% of all pregnant women, but also increases the sensitivity to more than 90%. Blood glucose meters are inadequate for the screening process as they carry an intratest variability of 10-15% (334,336).

A positive screening test is followed by a 100-gram oral glucose tolerance test. The original O'Sullivan and Mahan criteria for the diagnosis of GDM were developed to identify a population of pregnant women at high risk for the subsequent development of diabetes mellitus (337). Later modifications to the criteria were based on alterations in the glucose assay techniques. The current Carpenter and Coustan criteria (2 values at or above: fasting glucose 95 mg/dl, 1-hour 180 mg/dl, 2-hour 155 mg/dl, 3-hour 140 mg/dl) were adopted by the American Diabetes Association (335) because of evidence of perinatal morbidities similar to those found in pregnancies diagnosed with the earlier NDDG criteria (338-40). An international study funded by the NIH is currently underway to identify criteria using a 2-hour 75 gram glucose tolerance test to diagnose GDM based on perinatal outcome measures.

Maternal Complications of Pregestational Diabetes Mellitus

Diabetes in pregnancy is classified based on the severity of the metabolic disturbance and the presence and severity of maternal microvascular, neurologic, and macrovascular complications. These identify perinatal risk. In addition, pregnancy may alter the progression of these complications. Baseline retinopathic, renal, and neurologic function should be determined. Those identified with complications should be counseled regarding their perinatal risk and undergo intensive monitoring throughout pregnancy and postpartum using a team approach of specialists.

Retinopathy may progress during pregnancy secondary to poor glycemic control prior to pregnancy, rapid improvement in control during pregnancy, and concomitant hypertension (341,342). The Diabetes Control and Complications Trial (DCCT) demontrated that pregnancy itself adds independently to the risk of retinopathy progression (343). Patients with diabetes lack the autoregulation of retinal vessel constriction which normally protects the retina from the hyperdynamic changes of pregnancy (344). In addition, the potent angiogenic factor, fibroblast growth factor-2, is elevated in the second and third trimesters and correlate with glycohemoglobin levels (345). Retinopathy may continue to progress into the postpartum period (343,344,346), before it regresses.

Patients with diabetes mellitus have a four-fold increased risk of pregnancy-induced hypertension or preeclampsia (347), which may accelerate nephropathy. Other factors which increase the risk of nephropathy progression include pregnancy-induced glomerular hyperfiltration, increased transmission of systemic pressure to the glomerulus in the presence of hypertension, increase in urinary tract infections, vesicoureteral reflux and physiological hydronephrosis, and inability to use ACE inhibitor therapy in pregnancy secondary to risk of fetal anephrism. Patients with mild diabetic nephropathy (microalbuminuria, proteinuria, and creatinine <1.4 mg/dl) generally exhibit a transient worsening during pregnancy (348,349). Patients with more severe degrees of nephropathy may have an accelerated decline in renal function with pregnancy (350,351).

The prevalence of diabetic neuropathy increases with the duration of diabetes mellitus, with rates up to 50% after 25 years. Autonomic neuropathy may adversely impact on maternal morbidity and pregnancy outcome (352,353). The irregular gastric emptying of gastroparesis causes erratic blood sugar control from a mismatch of insulin administration with the nutrient delivery to the small intestine. Postprandial emesis may be exacerbated by the "morning sickness" of early pregnancy and later by the mechanical compression of the stomach by an enlarging uterus. This can lead to intractable vomiting with maternal and fetal malnutrition, hypoalbuminemia, dehydration, and maternal aspiration. Incomplete bladder emptying may predispose to recurrent urinary tract infections and worsening renal function. Individuals with orthostatic hypotension, an infrequent finding in diabetic pregnancies, may have symptomatic improvement with the volume expansion of pregnancy (354) or may worsen with the normal pregnancy decline in blood pressure.

Macrovascular disease may progress in pregnancy. Cholesterol and triglyceride levels increase during gestation (see below). Diabetes is a risk factor for pregnancy-induced hypertension or preeclampsia (355,356). Microvascular disease may further increase the risk. The marked fluid shifts which occur postpartum increase the risk of myocardial infarction and congestive heart failure in women with coronary artery disease (357). Women who have had diabetes for more than 25 years should undergo stress testing prior to conception to allow intervention at that time if necessary.

Management

Monitoring
The goal of therapy is to maintain normal maternal pre- and postprandial glucose levels to avoid the immediate and long-term risks to the offspring. The trade-off of tight control is an increased risk for hypoglycemia. Hypoglycemia is frequent in patients with Type 1 diabetes mellitus, particularly in the first trimester (358), often during nocturnal hours. Intensive self-glucose monitoring is essential.

Patients with GDM and pregestational diabetes should monitor fasting urinary ketones to assess the adequacy of their nutritional intake and determine potential metabolic decompensation early in its development. Those with GDM on dietary therapy monitor fasting and one- or two-hour postprandial glucose levels to determine adequacy of therapy. Patients requiring insulin therapy may add premeal and bedtime glucose levels to facilitate insulin adjustment. Postmeal glucose levels demonstrate better correlation with birthweight than premeal glucose levels, reflecting fuel delivery to the fetus (359). Ongoing postprandial hyperglycemia despite normal preprandial glucose levels requires adjustment of meal size and frequency.

Diet
Diet is the cornerstone of therapy. Dietary prescriptions are individualized for ethnic and personal preferences, activity level, and prepregnancy BMI. The Institute of Medicine has published optimal weight gain guidelines during pregnancy based on associations between weight gain in pregnancy and perinatal morbidity (300)(Table 3, see above). Recommended weight gain is inversely proportional to maternal adiposity. A diet of 30-32 kcal/kg ideal body weight is prescribed in the first trimester, with an increase to 35-38 kcal/kg ideal body weight in the second trimester, with adjustments to attain the desired weight gain. The calories include 50-55% carbohydrate, <30% fat, and 1.0-1.5 g/kg ideal body weight protein. Intake is spread throughout the day with the addition of a bedtime snack to avoid the predilection for accelerated starvation (360). Carbohydrate intake is limited at breakfast because of the increased insulin resistance at that time. Isocaloric dietary modifications which increase fat to reduce postprandial hyperglycemia (361) have undetermined impact on other maternal fuels, and the impact on the long-term outcome of the offspring has not been assessed. High fat diets are associated with altered vascular reactivity in the offspring of a rat model (362,363). Periconception supplementation with folic acid (0.8 mg/day) is recommended for diabetics, as it is for all women, to reduce the increased risk of neural tube defects.

Insulin
Patients with Type 1 diabetes mellitus lack endogenous insulin are deficient in some of the counterregulatory hormones and are predisposed to wide glucose excursions. As noted previously, intensive insulin therapy should be instituted prior to conception to reduce neonatal malformations and other morbidity. If patients with pregestational diabetes not undergoing intensive insulin therapy and under poor control are found to be pregnant, they should be hospitalized immediately for institution of intensive insulin therapy. Details of intensive therapy are beyond the scope of this discussion. This type of treatment generally involves giving basal insulin and premeal boluses of short-acting insulin either as multiple daily injections or using the insulin pump, with adjustments of insulin doses based upon pre- and post-meal glucose levels, meal size, and activity levels. Intensive insulin therapy must be closely monitored. Women with optimal glucose control at conception demonstrate little change in insulin requirement in the first trimester, with a modest decline at 10-14 weeks' gestation. Insulin requirements subsequently increase substantially to plateau late in the third trimester at total daily doses up to 3-fold above prepregnancy levels, and may decline modestly near term. A marked decline in insulin requirements suggests placental or renal dysfunction and warrants intensive maternal and fetal assessments. Patients with Type 2 diabetes mellitus should be treated with insulin prior to conception or at the first prenatal visit in an unplanned pregnancy.

There is no consensus regarding the level at which insulin therapy should be instituted in patients with GDM. Patients with fasting glucose > 105 mg/dl should receive insulin therapy. Rates of macrosomia have been reduced in settings where most of the patients with fasting glucose level < 105 mg/dl have received insulin therapy.(364) Attempts to use fetal ultrasound measurements of macrosomia to target patients for insulin intervention have resulted in a reduction in neonatal macrosomia (365-7), but may not reduce the long-term risks of obesity and glucose intolerance as these may occur in offspring with normal birth weights (324). Generally accepted targets of therapy are a fasting glucose <90-94 mg/dl, 1-hour postprandial glucose < 140 mg/dl, and 2-hour postprandial glucose < 120 mg/dl. Insulin doses of 0.5-2.0 units/kg are generally required to attain these goals.

Exercise
Exercise improves insulin sensitivity and peripheral glucose uptake. Moderate exercise has been used safely to improve glycemic control,(368,369) although previously inactive individuals may have an increased risk for uterine contractility, prematurity, fetal growth restriction, and fetal bradycardia (370).

Oral Agents
Oral agents have not been approved for use in pregnancy, as their safety has not been established during organogenesis (371,372). Adequacy of glycemic control to avoid short- and long-term complications must also be established. Studies are now underway to examine the use of oral agents in patients with GDM who fail dietary therapy (373).

Peripartum
The goal of therapy in the peripartum period is to maintain glucoses in the 70-120 mg/dl range. Oral carbohydrate is restricted, and intravenous dextrose is administered at rates of 5-8 g/hour. Glucose is monitored every 1 to 4 hours, and insulin is administered as necessary either as an intravenous infusion (0.01-0.04 U/kg actual body weight/hour)(374) or by subcutaneous injection of short-acting insulin every 3-6 hours (375). Labor may enhance glucose utilization (376), which may be modulated by the use of an epidural anesthetic. Insulin therapy to maintain euglycemia in labor is rarely required in GDM and may not be needed in many individuals with Type 2 diabetes mellitus.

Insulin requirements decline dramatically postpartum by up to 50-90%. Over the next few weeks, insulin requirements generally return to prepregnancy levels.

Breastfeeding

Breastfeeding increases the caloric requirements by 400-500 kcal/day. The benefits of breastfeeding are similar for the offspring of nondiabetic and diabetic women and should be encouraged. In addition, the epidemiologic study in the Pima Indians suggests additional long-term benefit in reducing the risk of developing Type 2 diabetes in this population (377). A recent study suggests that maternal hyperglycemia during breastfeeding may increase the risk of obesity in the offspring (378). Glycemic control therefore should not be neglected. Women with Type 2 diabetes who wish to breastfeed but require pharmacologic intervention postpartum are continued on insulin therapy until the child is weaned. Sulfonylureas may be secreted in breast milk and can cause hypoglycemia in the infant. The effects of other oral agents given to the mother during lactation on the neonate have not been determined and therefore should be avoided.

Postpartum Management

Postpartum reclassification of women with GDM is essential. An oral glucose tolerance test is performed at approximately 6 weeks' postpartum for reclassification, followed by postpartum counseling. Those with a family history of diabetes mellitus, non-Caucasian racial origin, obesity, early gestational age at diagnosis, and more marked hyperglycemia at diagnosis are at highest risk for progression to diabetes mellitus postpartum (379-81). A number of interventions have now been shown to reduce the risk of progression to diabetes in high-risk populations, especially those with impaired glucose tolerance. The Diabetes Prevention Program (DPP) demonstrated a 58% reduction in the progression to diabetes with diet, exercise, and a 7-10% weight loss (382). Pharmacologic therapy with metformin in the DPP provides a 31% reduction in diabetes (382), while troglitazone therapy demonstrated a 70% reduction in diabetes in a placebo-controlled trial in women with impaired glucose tolerance with prior GDM (383). Patients also may exhibit other features of the insulin resistance syndrome, such as hypertension, elevated triglycerides, and low HDL-C (384). These individuals may be at increased risk for premature vascular disease and should be monitored regularly and treated aggressively.

Patients should receive continuing follow-up with annual glucose testing and re-evaluation prior to any future pregnancies. Therapy should be initiated prior to conception to avoid the increased risk of congenital anomalies. Those with normal glucose tolerance before pregnancy should also be evaluated early in gestation, and if normal, again at the usual time of 24-28 weeks gestation. GDM recurs in more than half of subsequent pregnancies (385,386), though the risk of recurrence might be reduced by interpregnancy intervention (386).

Adequate contraception is vital to facilitate pregnancy planning. Low-dose oral contraceptives provide acceptable protection and do not exacerbate hyperlipidemia or glucose intolerance (387). Preparations containing the progestins norethindrone or desogestrel have also shown minimal metabolic effect. Patients treated with the thiazolidinedione derivatives such as pioglitazone need to be aware of possible loss of efficacy of contraception from low dose oral contraceptives.

LIPID DISORDERS IN PREGNANCY

Alterations in lipid metabolism in pregnancy favor fuel production for the developing fetus. Adipose tissue lipolysis increases, elevating the substrates for triglyceride synthesis, while lipoprotein lipase activity declines during the third trimester, reducing triglyceride clearance (388). The triglyceride:cholesterol ratio increases in all of the lipoprotein fractions with the first trimester decline in hepatic lipase (388). There is a consequent increase in triglycerides from the end of the first trimester, approaching levels 3 times greater than prepregnancy levels by term. This increase correlates with the rise in estrogen levels in pregnancy. This fat mobilization provides fuel for fetal development, and midtrimester triglyceride levels correlate with neonatal weight, independent of maternal glucose levels and obesity (389).

Lipoprotein apoB levels increase through gestation (390), and total and LDL cholesterol levels rise during the first trimester to peak at 150% above prepregnancy levels (391). HDL cholesterol increases 25-45% in the first trimester, then declines to near prepregnancy levels by term (391). The increase is secondary to elevations in HDL2b, with a decline in the HDL3a and HDL3b subfractions. The increase in triglycerides and fall in HDL are exaggerated when diabetes complicates pregnancy (391-3).

Postpartum, it generally takes months for the lipids to reach their prepregnancy levels, despite an initial fall in the triglycerides and cholesterol (391).

Patients with preexisting lipid abnormalities must discontinue pharmacologic therapy for pregnancy. HMG Co-A reductase inhibitors are contraindicated in pregnancy as they may impair fetal neural lipid synthesis. Niacin may cause hepatic toxicity and worsen insulin resistance, and its safety in pregnancy has not been studied. The fibrates have not been studied in pregnancy, although gemfibrozil is tumorigenic in rats. Bile acid binding resins are not absorbed. They may be used in pregnancy, but care should be taken to avoid fat-soluble vitamin deficiency.

Severe hypertriglyceridemia may occur in gestation in patients with lipoprotein lipase deficiency (394). Eruptive xanthomas have been seen in one patient during pregnancy (395). Of greater concern is the risk for pancreatitis and ARDS, with a 20% maternal mortality rate (394). Prevention requires drastic dietary fat restrictions. Total parenteral nutrition with no lipid component, or plasma exchange or lipoprotein apheresis may be used (394,396-8).