Diabetes Mellitus in Pregnancy

1. Suboptimal control of blood sugars in diabetes during pregnancy has the potential for serious maternal and neonatal adverse effects.

2. Pediatric providers must be sensitive to the association between a newborn’s risk and the mother’s level of glycemic control during pregnancy.

After completing this article, readers should be able to:

1. Understand the impact of maternal gestational and preexisting diabetes mellitus on the neonate.

2. Distinguish between the fetal risks associated with gestational diabetes and those associated with preexisting diabetes mellitus.

3. Become aware about the method of diagnosing gestational diabetes.

4. Review typical maternal care for women with diabetes in pregnancy.

Diabetes is the most common metabolic disorder to affect pregnancy and is associated with increased maternal and neonatal morbidity. (1) Three types of diabetes affect pregnancy: gestational diabetes mellitus (DM), type 2 DM (T2DM), and type 1 DM (T1DM). The latter 2 are referred to as pregestational diabetes because the onset predates the current pregnancy. Depending on the timing of onset, inappropriate glucose homeostasis has been associated with congenital malformations, miscarriage, perinatal mortality, preeclampsia, preterm birth, increased birthweight, neonatal hypoglycemia, and respiratory distress. (1)(2)(3) In addition, increased insulin resistance has been associated with recurrent miscarriage even in women with no known history of diabetes. (4)(5) Fetal exposure to maternal hyperglycemia can lead to hyperinsulinemia, resulting in short- and long-term complications, including childhood obesity and insulin resistance. (6)(7)

The prevalence of diabetes in pregnancy has increased substantially over the last 20 years because of the obesity epidemic and improved DM screening. (8) In particular, the incidence of T2DM is anticipated to continue to rise, with an expected increase of another 165% by 2050. (9) This increase is anticipated because of the association between obesity, sedentary lifestyles, and T2DM. From 1988 to 2010, the mean body mass index (BMI) in the US adult population with DM increased from 30.2 to 32.8 kg/m². (8) In addition, gestational diabetes mellitus (GDM) is associated with a high BMI; a woman’s risk of developing GDM increases from as low as 4% if she is underweight to greater than 15% if she is morbidly obese. (10) Overall, it is estimated that DM complicates 6% to 7% of pregnancies in the United States. (11) GDM accounts for approximately 90% of these cases, with T2DM accounting for most of the remaining 10%. (12)

GDM is defined as carbohydrate intolerance of variable severity that starts or is first recognized in pregnancy. It has been estimated to affect 4% to 6% of pregnancies in the United States. (13) GDM is most prevalent in women of Hispanic, African, Native American, Asian, and Pacific Island descent. (12)(14) Women with GDM are at higher risk for maternal, fetal, and neonatal complications (Fig 1). (15)(16) Up to 50% of women with GDM will go on to develop T2DM over their life course. (16)(17)

GDM represents the maternal system failing to adapt to normal pregnancy physiology. Early gestation is associated with increases in maternal fat stores and decreases in free fatty acid concentration. As gestation advances, insulin sensitivity decreases in both the liver and peripheral tissue. These changes are the physiologic consequence of placental and maternal hormones, specifically human placental lactogen, progesterone, estrogen, cortisol, prolactin, and tumor necrosis factor alpha. This metabolic change is intended to increase glucose levels and allow for the increased energy needs required for fetal growth. (18) Normally, the decreased insulin sensitivity is associated with increased insulin secretion. However, in GDM, the increased secretion is not adequate and manifests as hyperglycemia during pregnancy. Because of this pathophysiology, GDM develops over the course of pregnancy. Most commonly, women with GDM are diagnosed at 24 to 28 weeks of gestation, the time of routine screening.

The International Diabetes Federation estimated that 382 million people worldwide had DM in 2013. The Federation predicts that by 2035, this number will rise to 592 million people. These estimates include individuals with both T1DM and T2DM. In developed countries, it is estimated that T2DM makes up 85% to 95% of all cases of DM. (19)

Although T1DM is less common, the onset is typically in childhood due to autoimmune destruction of the pancreatic islet cells. (20) T1DM usually presents abruptly at a young age with insulinopenia and necessitates lifelong insulin replacement.

The pathophysiology of T2DM is less clearly understood and involves metabolic, genetic, and environmental factors, which lead to a combination of insulin resistance and deficiency. Up to 17 genetic sequences that affect insulin secretion, function, and receptor production have been associated with an increased risk for T2DM. (21) Adipose tissue has also been shown to secrete cytokines and proteins that contribute toward an increased risk for T2DM. (2)

The risk of developing neonatal complications due to diabetes in pregnancy likely varies with:

1. Time of onset of DM

2. Degree of maternal hyperglycemia/hyperinsulinemia

3. Length of fetal exposure to hyperglycemia (GDM resulting in a shorter exposure than pregestational DM)

4. Severity of maternal disease, because comorbidities (cardiac and renal) have significant neonatal and obstetric effects (1)(12)(22)(23)

We now describe the neonatal complications most often associated with T1DM, T2DM, and/or GDM.

Major congenital malformations occur in up to 6% to 12% of the fetuses of women with T1DM or T2DM and are the leading cause of perinatal mortality among women with DM. (24) The initial injury that leads to malformations tends to occur by the seventh week of gestation. GDM is not associated with an increased risk for anomalies because the condition does not occur until later in pregnancy after organogenesis. (25) Most common defects for women with T1DM and T2DM include cardiac followed by central nervous system and skeletal malformations (Fig 2). Ventricular septal defects and transposition of the great vessels are increased fivefold in insulin-dependent diabetes. Sacral agenesis or caudal dysplasia, although not pathognomonic, should always prompt evaluation of the mother for DM, because it is one of the classic diabetic embryopathies. (1)(22)

The risk for congenital malformations varies with maternal glycosylated hemoglobin level. Women with optimal glucose control and a hemoglobin A1c of 5% to 6% have fetal malformation rates similar to those of the general population (2%–3%). In contrast, women with poor glucose control and hemoglobin A1c levels in excess of 10% have a 10% to 25% risk of having a fetus with congenital malformations. (22)(24)(26) For women with T1DM or T2DM, the focus should be on achieving a hemoglobin A1c level less than 7% to reduce the risk of congenital anomalies. (24)(27) Daily prenatal vitamin supplementation that provides at least 1 mg of folic acid should also be prescribed for a minimum of 3 months to reduce congenital neural tube defects. The mechanism by which DM leads to fetal anomalies is multifactorial (Fig 3). (25)

The American College of Obstetricians and Gynecologists (ACOG) defines macrosomia as birthweight exceeding 4,500 g for neonates of women with DM or GDM. It has been associated with birth trauma and need for cesarean delivery. (1)(16) Studies have shown that insulin is the primary driving force in fetal growth, with growth restriction noted in instances of beta cell dysfunction. (28) Typically, fetuses of women with GDM or DM have normal growth of lean body mass, but higher deposits of fat in the subcutaneous tissues of the abdomen and shoulder. The difference between the chest-to-head and shoulder-to-head ratios, both difficult to quantify antenatally, likely contributes to rates of shoulder dystocia and birth trauma observed in infants of diabetic mothers. (1)(25)(28)(29)

Shoulder dystocia represents an obstetric emergency because of the risk of hypoxia, hypoperfusion, and birth injury. The risk is proportional to fetal weight, with a risk of 5% to 7% if the neonate weighs more than 4,000 g. Maternal diabetes and use of operative delivery compounds this risk. (29)(30) The vast majority of shoulder dystocias do not result in birth injury, but when they do, brachial plexus injury is the most common, followed by clavicle or humerus fracture and cephalhematoma. (31)

Women with T1DM or long-standing T2DM complicated by vascular disease or renal disease are at high risk for fetal growth restriction (FGR), especially asymmetrical FGR, thought to be secondary to uteroplacental vasculopathy. Diabetic ketoacidosis (DKA), maternal hypertension, preeclampsia, and structural anomalies, all of which are more common in women with T1DM and T2DM, are also known risk factors for FGR. (1)(27)

Neonatal hypoglycemia is more common in neonates born to women with GDM or DM. It is particularly frequent among macrosomic newborns of diabetic mothers, affecting 15% to 25% of neonates. (32) The neonatal hypoglycemia seen in infants born to women with GDM and DM is due to fetal/neonatal hyperinsulinemia. Chronic maternal hyperglycemia can cause fetal beta cell hyperplasia and exaggerated insulin responses. Thus, the severity of the hypoglycemia is thought to vary with maternal glucose control in the latter half of pregnancy and during labor. Therefore, all neonates born to women with GDM or DM should have postnatal glucose monitoring until metabolic stability is achieved. (1)(27)(31)

As many as 25% of infants born to women with insulin-dependent GDM or DM will be diagnosed with hyperbilirubinemia and up to 5% will develop polycythemia. (33) Some of the increased risk for hyperbilirubinemia in DM-exposed neonates can be attributed to preterm birth, which is more common in GDM and DM. However, even among term pregnancies, the risk is increased. One possible explanation is fetal exposure to oxidative stress and excess insulin and insulin growth factors. Increased red cell mass due to polycythemia contributes to hyperbilirubinemia, but increased bilirubin production as measured by carbon monoxide production has been documented independent of polycythemia.

Hypocalcemia is one of the most common metabolic abnormalities in neonates of diabetic mothers. The pathophysiology has not been fully delineated, but a breakdown in magnesium-calcium economy, hypoxia, and preterm birth are all thought to contribute to the increased risk. The risk of developing hypocalcemia is thought to vary directly with glucose control. One randomized, controlled trial demonstrated that suboptimal glucose control correlated with a higher incidence of hypocalcemia compared with tighter glycemic control (18).

Cardiomyopathy has been observed commonly, especially in macrosomic infants of women with poorly controlled DM and GDM. Fetal hyperinsulinemia causes asymmetric septal hypertrophy and potentially left ventricular outflow obstruction, ultimately leading to congestive heart failure in severe cases. The prevalence of clinical and subclinical forms of septal hypertrophy has been estimated to be as high as 30% in poorly controlled pregestational DM. However, this form of cardiomyopathy is usually transient and resolves by 6 months to 1 year of age. (14)(34)

A retrospective cohort study of more than 800 infants born to women with T1DM and T2DM found that they were 20 times more likely to develop respiratory distress syndrome. Among infants of diabetic mothers with poor glycemic control, lung maturation may be delayed by 10 days on average. (35) Because of maternal complications associated with GDM and DM, such as preeclampsia, women with GDM and DM often deliver before 39 weeks’ gestation. The delay in lung maturation common in DM further complicates these iatrogenically early deliveries.

Before the use of insulin became common, intrauterine fetal demise (IUFD) or stillbirth occurred in up to 30% of pregnancies complicated by T1DM. Although much less frequent since the advent of insulin and reliable glucose monitoring methods, women with all types of diabetes and poor glucose control still have stillbirths. The greatest risk is among women with vascular disease, hypoglycemia, DKA, macrosomia, polyhydramnios, and preeclampsia. The main cause of stillbirth is hypothesized to be chronic intrauterine hypoxia. One proposed mechanism involves fetal hyperinsulinemia, which causes an increase in oxygen consumption and decrease in arterial oxygen content. Maternal uterine blood flow does not increase enough to allow for enhanced oxygen delivery to the increased metabolic demands of the fetus. This hypoxic hypothesis is supported by both pathologic findings of extramedullary hematopoiesis and cord blood of newborns of women with T1DM showing lactic acidosis and fetal erythema. (1)

Prenatal care should begin months before attempting pregnancy. For women without T1DM or T2DM, preconception care involves assessing and attempting to reverse their risk for future GDM. Women with a significant family history of DM or a history of GDM in a prior pregnancy should be tested for DM and prediabetes before conception. For women with T1DM and T2DM, as discussed previously, the risk for congenital anomalies varies directly with glucose control. Thus, women should work closely with their physician to optimize their glucose control and achieve a glycosylated hemoglobin concentration less than 7%. All women should started taking folic acid (prenatal vitamins contain 400 μg of additional folic acid), which has been shown to reduce the risk for neural tube defects in developing fetuses.

Once pregnant, women with risk factors for GDM (ie, previous pregnancy complicated by GDM, known impaired glucose metabolism, or obesity with BMI >30) should undergo early glucose screening around 16 weeks’ gestation (Fig 4). (16)(36) All other women undergo universal GDM screening at 24 to 28 weeks of gestation. The commonly used approach to screening in the United States is a maternal serum glucose level drawn 1 hour after a 50-g oral glucose load. The screening cutoff varies center to center but is typically between 130 and 140 mg/dL (between 7.2 and 7.7 mmol/L). Those exceeding the screening threshold undergo a 100-g 3-hour diagnostic oral glucose tolerance test. (16) Currently, ACOG recommends the use of this 2-step approach because it has proven clinical benefit.

For women with pregestational DM, glucose control in early pregnancy is vital to a normal organogenesis, necessitating early prenatal care; thereafter patients should see a clinician approximately every 2 weeks to optimize their glucose control (Fig 5). Low-dose aspirin should also be discussed with all women with T1DM or T2DM as a means of decreasing their risk of preeclampsia. (37) Given the risk of fetal macrosomia, preterm delivery, and FGR for these women, early ultrasonography is also important to determine the most accurate due date for a pregnancy. At approximately 18 weeks, all women with T1DM or T2DM should undergo a level II, detailed anatomy ultrasonography. Most major congenital anomalies can be detected with such specialized ultrasonography. Between 18 and 22 weeks of gestation, the fetal heart increases from approximately a dime-sized structure to a quarter-sized structure. Given the risk of cardiac defects for fetuses of women with T1DM or T2DM, all women with DM should undergo fetal echocardiography at approximately 22 weeks of pregnancy. Thereafter, fetal growth is evaluated every 4 weeks on average, using ultrasonography, to aid in delivery planning.

Women with any type of DM who need medications to control their blood glucose levels are at particularly high risk for placental insufficiency, preeclampsia, and stillbirth. Thus, antepartum testing is recommended for these women in the third trimester. The exact timing to initiate such screening varies considerably by practice, but is most commonly conducted at 28 to 34 weeks of gestation. Antepartum fetal monitoring may involve nonstress testing, amniotic fluid index assessment, biophysical profiles, and/or contraction stress testing. Historical reports have shown that the risk of stillbirth is still increased within 1 week of a reactive nonstress test for patients with DM. Therefore, most patients with DM and GDM requiring medication will require twice-weekly testing. (1)(22)

Unlike nonpregnant women, pregnant women are encouraged to check their blood glucose 4 times daily: fasting in the morning and 1 to 2 hours after every meal. (16) Postprandial blood glucose values are particularly important because normal values are associated with a lower incidence of large-for-gestational age infants and lower rates of cesarean delivery due to cephalopelvic disproportion. (38) Both the American Diabetes Association and ACOG recommend a threshold of 140 mg/dL (7.7 mmol/L) at 1 hour or 120 mg/dL at 2 hours after meals. (39)

For all women with T1DM and nearly all with T2DM, insulin is necessary throughout pregnancy. Dosages need to be monitored closely and adjusted every week because insulin requirements often increase dramatically during pregnancy. For women with GDM, initial treatment involves diet therapy. When goal glucose levels cannot be achieved consistently via nutrition and exercise, pharmacologic therapy is recommended. Current evidence does not favor the use of either insulin or oral antidiabetic agents for treatment of GDM with regard to short-term outcomes. However, the literature is still lacking in data on long-term outcomes in diabetic pregnant women treated with oral medications.

The timing of delivery for patients with GDM and DM is guided by the risk of IUFD and macrosomia versus the risk of neonatal complications due to prematurity. Patients with fasting blood glucose levels less than 95 mg/dL (5.2 mmol/L) and postprandial blood glucose levels less than 140 mg/dL (7.7 mmol/L) 1 hour after meals or less than 120 mg/dL (6.6 mmol/L) 2 hours after meals are usually considered “well controlled.” These cases can be managed expectantly until at least 39 weeks of gestation. (22)(39) Women with “poorly controlled” glycemic levels can be offered delivery in the late preterm or early term period. (22)(40) New data suggest that women with GDM who will deliver before 37 weeks of gestation should receive antenatal corticosteroids to reduce the risk of respiratory distress and prolonged neonatal hospitalization. (41) Unfortunately, for women with pregestational DM, the data available thus far support antenatal corticosteroids only if the delivery is to occur before 34 weeks. This is because the risks and benefits of corticosteroids in this population between 34 and 37 weeks’ gestation have not been investigated. Induction of labor to avoid macrosomia has not been shown to prevent birth trauma. (22)(42)(43) Furthermore, cesarean delivery should be reserved for cases in which the estimated fetal weight is greater than 4,500 g. (16)(44)

Diabetes in pregnancy (GDM, T2DM, and T1DM) affects the care of the mother but also has major implications for her offspring. During pregnancy, the fetus is at increased risk for congenital anomalies, growth abnormalities, prematurity, and stillbirth. At birth, injury, respiratory complications, and metabolic derangements occur with regularity in suboptimal glucose control. Furthermore, long after birth, children born to women with GDM or DM are at increased risk for childhood obesity and metabolic syndrome. (45) To completely assess a newborn’s risk, pediatric providers must be aware of the mother’s level of glycemic control as well as the severity of her disease. Only with a complete maternal history can they completely identify infants at highest risk of morbidity and mortality related to diabetes in pregnancy.

ACOG

American College of Obstetricians and Gynecologists

BMI

body mass index

DKA

diabetic ketoacidosis

DM

diabetes mellitus

FGR

fetal growth restriction

GDM

gestational diabetes mellitus

IUFD

intrauterine fetal demise

T1DM

type 1 diabetes mellitus

T2DM

type 2 diabetes mellitus