Pregnancy is a complex metabolic state that involves dramatic alterations in the hormonal milieu (increases in estrogen, progesterone, prolactin, cortisol, human chorionic gonadotropin, placental growth hormone, and human placental lactogen), inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], C-reactive protein), and adipokines (leptin and adiponectin) to alter maternal insulin resistance so that the mother can provide the necessary nutrients for the growing fetal-placental unit.

Pregnancy is characterized by profound metabolic changes that promote adipose tissue accretion in early gestation; many women show increased insulin sensitivity between 10 and 20 weeks of pregnancy. Interestingly, a few studies have reported transient increases in insulin resistance prior to 10 weeks, although others describe more frequent episodes of hypoglycemia. Fasting insulin levels and glucose values are lower, and women are prone to nocturnal hypoglycemia and ketogenesis, especially if they suffer from nausea and vomiting during pregnancy. In addition to increased insulin sensitivity and fat storage, the first and early second trimesters are usually characterized by an earlier transition from carbohydrate to fat utilization in the fasting state. Pregnant women deplete their glycogen stores quickly and switch from carbohydrate to fat metabolism within 12 hours, often becoming ketonemic.

The late second and third trimesters, in contrast, are consistently characterized by insulin resistance, with a nearly 50% decrease in insulin-mediated glucose disposal (assessed by the hyperinsulinemic euglycemic clamp technique) and a 200% to 300% increase in insulin secretion in late pregnancy. These changes shunt necessary fuels to meet the metabolic demands of the placenta and growing fetus, which requires 80% of its energy as glucose, while maintaining euglycemia in the mother. Women usually have lower fasting plasma glucose levels and fasting hypoinsulinemia because of continued shunting of carbohydrate to the fetal-placental unit in the unfed state, often resulting in the presence of urinary ketones. Because of the increasing placental-fetal glucose demands, glycogen stores are depleted rapidly, and pregnant women must transition from carbohydrate to fat metabolism earlier in the fasting state, a phenomenon called “accelerated starvation.” There is a dramatic insulin resistance in skeletal muscle and in the liver, resulting in increased hepatic gluconeogenesis to ensure adequate substrate delivery to the fetus. The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy, causing free fatty acid (FFA) levels to increase. However, owing to the placental hormone–mediated increase in insulin resistance with maternal hyperinsulinemia in the fed state, pregnant women demonstrate minimally elevated postprandial glucose excursions. In an extensive review of glycemia patterns in normal pregnancy, mean fasting blood glucose (FBG) levels were 72 mg/dL, 1-hour postprandial values were 109 mg/dL, and 2-hour values were 99 mg/dL, with a 24-hour mean glucose level of 88 mg/dL, all much lower than current therapeutic targets. Immediately after delivery, insulin sensitivity returns, and the early postpartum period is often one of extreme insulin sensitivity, especially if mothers are breastfeeding; a subgroup of postpartum diabetic women requires almost no insulin for several days.

In a study that examined continuous glucose profiles in women in both early (∼16 weeks) and late (∼28 weeks) gestation and used a controlled eucaloric diet with the same macronutrient composition in both groups, obese pregnant women demonstrated 24-hour glycemic profiles that were higher than normal-weight women both early and late in gestation. At 28 weeks of gestation, nearly all fasting and postprandial glycemic values were higher in obese women, as were fasting insulin, triglyceride, and FFA values. Mean 1-hour and 2-hour postprandial glucose levels were 102 and 96 mg/dL, compared with 115 and 107 mg/dL in the normal-weight and obese women, respectively. In late pregnancy, 95% of all glucose values were lower than 116 mg/dL, compared with 133 mg/dL in obese women. Interestingly, although pre-pregnancy body mass index (BMI), late gestation average daytime glucose level, and late gestation fasting insulin correlated with infant percentage body fat, maternal triglyceride and FFA values were stronger predictors of excess newborn fat.

No. Amino acids, triglycerides, cholesterol, and FFAs are also increased; the increase in FFAs may further accentuate the insulin resistance of pregnancy. A growing number of studies support that elevations of maternal triglycerides and FFAs are an important source of excess fuel to the fetus and are predictive of LGA (large-for-gestational-age; > 90th percentile for gestational age) status and increased newborn adiposity. At this time, there are no formal recommendations to target maternal triglycerides in pregnancy as a potential intervention to decrease the risk for newborn adiposity or macrosomia (birth weight > 4000 gm), but trials using high doses of fish oils are ongoing.

Optimally diabetes should be under tight control before conception. During the first trimester, nausea, increased insulin sensitivity, and accelerated starvation may put the mother at risk for severe hypoglycemia, and thus, insulin requirements are the least stable at this time. This risk is especially high at night because of prolonged fasting and continuous fetal-placental glucose utilization. Women with type 1 diabetes must have a bedtime snack and usually need to have the basal insulin decreased or the evening dose of neutral protamine Hagedorn (NPH) insulin lowered and moved from supper to bedtime administration to avoid early-morning hypoglycemia. Severe hypoglycemia occurs in 30% to 40% of pregnant women with type 1 diabetes in the first 20 weeks of pregnancy, most often between midnight and 8:00 am. Diabetic women who have gastroparesis or hyperemesis gravidarum are at the greatest risk for daytime hypoglycemia. During the first trimester, glycemic control just above the normal range (hemoglobin A_1C [HbA_1C] < 7.0%) may thus be safer than “normal” and may decrease the risk of both maternal and fetal hypoglycemia.

After 20 weeks, peripheral insulin resistance increases insulin requirements. It is not unusual for a pregnant woman to require two to three times as much insulin as she did before pregnancy. Fasting hyperglycemia and postprandial hyperglycemia are risk factors for LGA status or macrosomia. Therefore, tight glucose control in women with preexisting diabetes usually requires both basal insulin and rapid-acting insulin at each meal with frequent monitoring to allow appropriate insulin dosage adjustments.

The most important recommendation in preconception counseling is the need for optimal glucose control before conception. Unplanned pregnancies occur in about two thirds of women with diabetes, making it critical that the primary care physician, endocrinologist, or obstetrician-gynecologist address preconception care in women of childbearing age. Providing effective contraception until optimal glycemic control is achieved is the most common error of omission by all health professionals who care for women with diabetes. In a retrospective study, only 25% of women of childbearing age with preexisting diabetes had preconception counseling of any kind. Four times as many fetal and neonatal deaths and congenital abnormalities occurred in a group of women who did not receive prenatal counseling than in those who did. In all series, preconception counseling significantly improved glycemic control, lowered rates of major malformations, and reduced rates of major adverse pregnancy outcomes, including very premature delivery, stillbirth, and neonatal death.

The maintenance of normal glucose control is the key to preventing complications, such as fetal malformations in the first trimester, macrosomia in the second and third trimesters, and neonatal metabolic abnormalities. Hyperglycemia modulates the expression of an apoptosis regulatory gene as early as the preimplantation blastocyst stage in the mouse, resulting in fetal wastage that can be prevented by treating with insulin. This finding may account for the high risk of first-trimester loss in pregnant women with poor glycemic control. In later pregnancy, there is a fourfold to fivefold higher rate of stillbirths and perinatal deaths in diabetic women than in the general population. Glycemic control as indicated by HbA_1C was assessed in the Diabetes and Preeclampsia Intervention Trial; women in whom preeclampsia developed had significantly higher HbA_1C values before and during pregnancy. In comparison with optimal control, an HbA_1C of 8.0% or higher in early pregnancy was associated with an odds ratio of 3.7 for preeclampsia.

Epidemiologic and prospective studies have shown that the HbA_1C level in the 6 months before conception and during the first trimester correlates with the incidence of major malformations, such as neural tube and cardiac defects. The neural tube is completely formed by 4 weeks and the heart by 6 weeks after conception. This fact underscores the need for preconception counseling to achieve these goals because many women do not even know that they are pregnant this early. Overall, the risk of an adverse outcome is halved with each percentage reduction in HbA_1C level achieved before pregnancy. It has been demonstrated that women with a normal HbA_1C value at conception and during the first trimester have no increased risk, whereas women with an HbA_1C value greater than 12% have up to a 25% risk of major fetal malformations. The International Diabetes Federation recommends a goal pre-pregnancy HbA_1C of less than 7.0%, and other guideline committees recommend less than 6.5% if it can be safely achieved. Excess fetal growth has been associated with an abnormal HbA_1C in the first trimester as well as in the second and third trimesters. Both fasting hyperglycemia and postprandial hyperglycemia are contributors to excess fetal growth and metabolic complications.

The incidence of congenital abnormalities in the offspring of diabetic mothers in the early era of insulin use was 33%. Since the mid-1990s, with the advent of home glucose monitoring and more rigid objectives, this percentage has fallen to less than 10%. The randomized prospective Diabetes Control and Complications Trial (DCCT) has shown that timely institution of intensive therapy for blood glucose prior to conception is associated with rates of spontaneous abortion and congenital malformations that are similar to those in the nondiabetic population. Although the rate of LGA infants has been recognized to be high in women with type 2 diabetes, this rate has also significantly increased in women with type 1 diabetes, likely owing to the growing number of women who are also overweight and insulin resistant.

The fetus has minimal ability for hepatic gluconeogenesis until close to delivery, so profound and sustained maternal hypoglycemia is likely to cause the same in the fetus. Further, the best predictors of severe hypoglycemia during pregnancy are hypoglycemic unawareness and the presence of at least one episode of severe hypoglycemia the year before pregnancy. Severe hypoglycemia is five times more common in pregnancy if present in the year prior to pregnancy and most often occurs in the first trimester, especially between 8 and 16 weeks. The risk is highest during fasting and sleep because the fetal-placental unit continues to extract glucose during these times. Whether severe and prolonged hypoglycemia could have long-term adverse neurologic effects in the offspring has not yet been well studied.

Oral hypoglycemic agents, such as sulfonylureas and metformin, do not appear to be teratogenic. There are very few data on meglitinide use in pregnancy. A retrospective series of 332 women with type 2 diabetes treated with diet, insulin, or oral sulfonylureas during the first 8 weeks of gestation found no significant adverse effects. There are few data on the risk of thiazolidinediones in the first trimester; these agents should definitely be stopped before a woman actively tries to become pregnant. Alpha-glucosidase inhibitors, such as acarbose, have not been associated with any abnormal outcomes. Therapy with an incretin, such as an amylinomimetic, GLP-1-mimetic, or DPP-IV inhibitor, has not been well studied in pregnancy and therefore is not recommended, but it is unlikely that these agents would increase the risk of major malformations if conception occurred during their use. Women who are actively trying to become pregnant should be switched to insulin during the preconception period because it may take some time to determine the ideal insulin dose before the critical time of embryogenesis.

Glyburide crosses the placenta less than all other sulfonylureas and appears to affect fetal insulin levels minimally. In the only large randomized prospective trial, however, it was not given until after 24 weeks of gestation to women with gestational diabetes mellitus (GDM). Since that time, many more studies have utilized glyburide in pregnancy, primarily after 24 weeks of gestation in women with GDM. The International Association of Diabetes in Pregnancy Study Group (IADPSG) approved the use of glyburide as an alternative treatment in a subset of women with GDM.

It is recommended that oral hypoglycemic agents be avoided during pregnancy, with the possible exception of glyburide and metformin, which have been used to treat GDM in the late second and third trimesters. Although metformin does cross the placenta, there are a fair amount of data using metformin throughout the first trimester of pregnancy in women with polycystic ovarian syndrome (PCOS) without any apparent risk, and a few small studies suggest that it decreases the risk for development of GDM. There are no known adverse effects of glyburide use in the first trimester although the vast experience with glyburide, like that with metformin, is in women with GDM after 24 weeks of gestation. However, a woman taking a sulfonylurea or metformin who is discovered to be pregnant should not stop these agents until she can be effectively switched to insulin, because the risk of teratogenicity from hyperglycemia is much higher than any risk from these agents. Both metformin and glyburide are much less likely than insulin to be effective in pregnancy, especially for women with preexisting diabetes, because of the profound insulin resistance in the second and third trimesters of pregnancy.

Women should be counseled that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are contraindicated in the second and third trimesters of pregnancy because of the risk of fetal anuria. A report in 2006 from a Tennessee Medicaid population described increased cardiac and central nervous system malformations in fetuses exposed in the first trimester. However, a subsequent report of pregnant women in the Kaiser Permanente Northern California region from 1995 to 2008 did not confirm this association, instead showing ACE inhibitors in the first trimester to confer a risk similar to that from other antihypertensives. It is now recommended that women who are actively trying to conceive and who have no history of infertility should probably be switched to a safer agent before pregnancy (calcium channel blocker, methyldopa, or hydralazine). A woman who receives treatment with an ACE inhibitor or ARB for significant diabetic nephropathy and who is not actively trying to conceive should be told to perform home pregnancy tests if she misses a period and to immediately stop her ACE inhibitor or ARB if there is any suspicion of pregnancy. At that time, she can be switched safely to an alternative agent.

The morbidity and mortality rates of coronary artery disease are high in pregnant women with diabetes. Cardiac status should be assessed with functional testing before conception in women older than 35 years who have any additional cardiac risk factors, such as hyperlipidemia, hypertension, smoking, cardiac autonomic neuropathy, or a strong family history and in women with any suggestive symptoms. A resting electrocardiogram (ECG) should be considered for asymptomatic women age 35 or older. Pregnancy causes a 25% increase in cardiac output, a significant decrease in systemic vascular resistance (which can shunt blood away from the coronary arteries), and an increase in oxygen consumption, all of which reduce the ability of maternal coronary blood flow to meet the demands of the myocardium. Myocardial demands are even higher at labor and delivery, and activation of catecholamines can further promote myocardial ischemia.

Women with type 1 diabetes have an increased risk of hypothyroidism due to Hashimoto’s thyroiditis, and it is recommended by both the Endocrine Society and the American Thyroid Association that they be screened. It is less clear that women with type 2 diabetes have an increased risk, but some consensus panels recommend screening for them as well. It is recommended that women with a thyroid-stimulating hormone (TSH) level higher than 2.5 to 3.0 mU/L in the first trimester and higher than 3.0 to 3.5 mU/L in the second and third trimesters be treated, especially if they are shown to have thyroid peroxidase (TPO) antibodies, although the long-term neurologic benefit to the offspring of such treatment has not yet been demonstrated. The American College of Obstetricians and Gynecologists (ACOG) has not made any formal recommendations to screen and treat subclinical hypothyroidism in pregnancy until results of the ongoing Maternal Fetal Medicine Units (MFMU) network trial are available. Screening for TPO antibodies is not recommended in euthyroid women with or without a history of pregnancy loss because of insufficient data that treatment with thyroid hormone is effective.

Data about the safety of statins during human pregnancy are inadequate, but animal data on these agents are concerning. Although statins have been given a classification of “X” by the U.S. Food and Drug Administration (FDA), there are no data in human pregnancy to support their being a major teratogen in a woman who is taking them and does not realize she is pregnant. However, statins should be discontinued in women who are actively trying to conceive and should not be continued during pregnancy. There does not appear to be an increased risk of malformations in women who conceive while taking fibrates. In fact, if a woman has severe hypertriglyceridemia, which puts her at high risk for pancreatitis, it may be necessary to use a fibrate in the second or third trimester of pregnancy if a low-fat diet and use of fish oils are not effective or tolerated. Serum triglyceride levels double to triple in pregnancy and therefore treatment may be indicated, especially if they approach 1000 mg/dL after meals.

Smoking continues to be the leading cause of low-birth-weight infants in patients with and without diabetes and puts the infant at increased risk for respiratory infections, reactive airway disease, and sudden infant death syndrome. Smoking cessation efforts must be intensified before conception. The nicotine patch is believed to be safer than continuing smoking in pregnancy and should be offered to women addicted to nicotine who are already pregnant and unable to quit without its use.

Proteinuria increases in pregnancy, and women with proteinuria often become nephrotic owing to the increased glomerular filtration of protein during pregnancy. In some patients, proteinuria can become massive and result in significant hypoalbuminemia, edema, and a hypercoagulable state, and ultimately, in fetal growth restriction. Although women with mild renal insufficiency are not at an appreciable risk for irreversible progression of nephropathy, those with more severe renal insufficiency (serum creatinine > 2.5 mg/dL or estimated glomerular filtration rate [GFR] < 30 mL/min) have a 30% to 50% risk of a permanent pregnancy-related decline in GFR and may require dialysis in pregnancy.

Preeclampsia complicates approximately 20% of pregnancies in women with preexisting diabetes, and the risk is much higher in women with hypertension or renal disease. The risk for development of preeclampsia in women with nephropathy is greater than 50%. The preeclampsia may be severe, especially in women who are hypertensive and have decreased renal function, particularly those with a serum creatinine level higher than 1.4 mg/dL. Women with significant nephropathy are also at higher risk of having preterm and low-birth-weight infants. Therefore a woman with diabetic nephropathy should be counseled to have children when her diabetes is optimally controlled and preferably early in the course of the nephropathy. Some experts recommend a target blood pressure of less than 135/85 mm Hg in women with diabetic renal disease to reduce the risk of further end-organ damage and, possibly, preeclampsia. However, reducing the blood pressure too aggressively may worsen perfusion pressure in the woman whose placental bed has a high vascular resistance due to preeclampsia, and it may worsen instead of improve fetal growth.

Women who have undergone successful renal transplantation at least 1 to 2 years before pregnancy and who have good renal function, adequate blood pressure control, and a low requirement for antirejection medications have a much more favorable outcome than women with severe renal disease who have not received a transplant. Women with severe renal insufficiency who require dialysis in pregnancy have the highest risk of adverse pregnancy outcomes, including severe growth restriction, prematurity, preeclampsia, and stillbirth.

Retinopathy may progress during pregnancy either from the institution of tight glycemic control or from the increases in growth factors, blood volume, cardiac output, anemia, and the hypercoagulable state of pregnancy. Women with proliferative retinopathy are at the highest risk of progression; in one series, retinopathy worsened in more than 50% of the women. It is therefore imperative that retinopathy be optimally treated with laser therapy before pregnancy, although laser therapy can be instituted during pregnancy. It is less likely that only background retinopathy will progress significantly during pregnancy, but there are reports that as many as 20% of cases do progress. Baseline and follow-up retinal examinations are recommended for all diabetic pregnant women at risk for retinopathy.

Priscilla White at the Joslin Diabetes Center observed that the patient’s age at onset of diabetes, duration of diabetes, and severity of complications, including vascular disease, nephropathy, and retinopathy, significantly influenced maternal and perinatal outcomes. In 1949, she developed a classification scheme based on these parameters. The initial scheme was developed for women with type 1 diabetes; there is no separate classification for type 2 diabetes.

Its predictive value allows identification of patients at greatest risk for obstetric complications during pregnancy so that physicians can intensify management and fetal surveillance. In the updated classification (Table 5-1), women with pregestational diabetes are designated by the letters B, C, D, F, R, T, and H according to duration of diabetes and complications. Class A1 or A2 is used to classify women with GDM that is controlled with diet alone or with medications, respectively. It is unclear whether the White classification is better at predicting adverse pregnancy outcomes than categorizing the patients with respect to the absence or presence of vascular disease. However, it is still used by obstetricians to classify the duration and complications of women with diabetes.

The goals of glucose control during pregnancy are rigorous. Optimally, the premeal glucose level should be less than 90 to 95 mg/dL, the 1-hour postprandial glucose level less than 130 to 140 mg/dL, and the 2-hour postprandial glucose level less than 120 mg/dL. More intensive goals have not been tested in an adequately powered randomized controlled trial (RCT) to determine whether they can achieve a reduction in macrosomia without increasing the risk of small-for-gestational-age (SGA) status. The results from the multicenter HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) trial, which studied 25,000 pregnant women in nine countries, suggest that abnormal fetal growth occurs along a continuum and at lower glucose values than previously recognized. They calculated that a 1.75-fold risk of LGA infants occurs at an FBG level of 92 mg/dL or higher. Because macrosomia is related to both fasting and postprandial blood glucose excursions, pregnant diabetic women need to monitor premeal and postprandial glucose values regularly. Patients with type 1 and type 2 diabetes usually require three or four insulin injections per day or an insulin pump to achieve adequate control during pregnancy.

A continuous glucose monitoring system (CGMS) can be helpful, especially in patients with type 1 diabetes who are having frequent hypoglycemic episodes and have hypoglycemic unawareness, allowing better delineation of glucose patterns so that basal and/or bolus insulin can be appropriately adjusted. A CGMS can also reveal postprandial hyperglycemia that might be otherwise unrecognized and that is strongly associated with excess fetal growth. In one series, a mother had to check her glucose levels a minimum of 10 times per day to give an indication of the glucose patterns obtained during CGMS. Another study showed that utilizing CGMSs in pregnant women with preexisting diabetes may not be an effective tool to decrease LGA rates. However, CGMSs have been shown to be very useful in women with type 1 diabetes who may have hypoglycemic unawareness, wide glycemic swings, or difficulty reaching an optimal HbA_1C level despite checking their blood glucose values many times each day.

Experience with the insulin pump in the treatment of type 1 diabetes in pregnancy is increasing. Most trials have found that continuous subcutaneous insulin infusion is equivalent to multiple daily injections using basal and bolus insulin. The pump may be advantageous in women with recurrent hypoglycemia, especially at night, because different basal rates can be programmed. However, there are reports of women who began using the pump in pregnancy in ketoacidosis developed from pump failure. Therefore it may be optimal to begin pump therapy before pregnancy, given the steep learning curve involved in its use and the continuous changes that must be made in dosing basal and bolus insulin because of the changing insulin resistance throughout pregnancy.

Insulin detemir (Levemir) has been approved by the FDA for use in pregnancy and may result in less nocturnal hypoglycemia than NPH insulin. For women with severe hepatic insulin resistance, NPH insulin before bedtime may also be required to achieve sufficient fasting glucose control, although its peak can be variable. Experience with insulin glargine (Lantus) in pregnancy is fairly extensive, and although not yet approved by the FDA, such use has been approved by the European Medicine Agency. However, there are still some concerns about glargine’s potential mitogenic effects and higher affinity for the insulin-like growth factor-1 (IGF-1) receptor, especially in women with proliferative retinopathy. Insulin glargine does not cross the placenta, and no evidence indicates reproductive toxicity or embryotoxicity. Similar pregnancy outcomes have been reported in women taking glargine and women taking NPH. If a patient without proliferative retinopathy is doing well on insulin glargine, it is probably not necessary to switch her to another insulin during pregnancy. Either glargine or detemir insulin may be useful in women who experience recurrent hypoglycemia with NPH insulin therapy.