Maternal Diabetes

Type 1 Diabetes

Type 1 diabetes is characterized by insulin deficiency resulting from autoimmune destruction of pancreatic insulin-producing beta cells. Typically, people with type 1 diabetes will develop clinical signs and symptoms of diabetes in childhood. However, immune-mediated diabetes can arise at any time through adulthood. Immune-mediated diabetes in adults is characterized by a slower destruction of beta cells and subsequent progression to insulinopenia. People with type 1 DM are dependent on exogenously administered insulin. The underlying pathophysiology of type 1 diabetes and the physiological changes of pregnancy place pregnant patients at elevated risk for diabetic ketoacidosis (DKA). DKA is associated with a significant impact on perinatal morbidity, contributing to higher rates of fetal demise, preterm birth, and NICU admission.

Type 2 Diabetes

Type 2 diabetes is the most common form, accounting for 95% of cases in the United States. Type 2 diabetes is characterized by insulin resistance and is more significantly associated with obesity. Other risk factors include advancing age, sedentary lifestyle, history of gestational diabetes, and comorbidities including hypertension and dyslipidemia. Historically, type 2 diabetes is associated with adult onset, however, there have been increasing rates of diagnoses of type 2 diabetes among children and adolescents that appear to parallel the rise in obesity rates in these age groups.

Monogenic Diabetes

The etiology of ~1% to 2% of diabetes diagnoses are genetic, also referred to as monogenic diabetes (MODY: maturity-onset diabetes of the young). Multiple types of monogenic diabetes exist; all of the genes involved share the common feature of affecting beta cell development, function, or regulation. Clinical presentations of monogenic diabetes are heterogeneous, with phenotypes varying according to the specific mutation ( Table 8.2 ). Most forms share the following clinical features: affected individuals are typically diagnosed before the age of 25 years and are not insulin dependent. Frequently, pregnant patients with monogenic diabetes may be first identified and diagnosed with diabetes during pregnancy. A notable difference from GDM, they are often found to have continued hyperglycemia postpartum. Genetic testing is prompted by the recognition of a strong family history of diabetes (often two or more consecutive affected generations), as well as an absence of obesity or other clinical features suggestive of insulin resistance.

Neonatal Consequences of MODY

The genetic mutations leading to monogenic diabetes are inherited in an autosomal dominant fashion, so there is a 50% risk of inheritance in the offspring. Fetal MODY mutations may impact intrauterine growth. Macrosomia and neonatal hypoglycemia are associated with HNF4A mutations. In an analysis of siblings discordant to the HNF4A mutation, affected infants had birth weights that were on average 790 >4000 g), as compared with 13% of those who were unaffected. Fifteen percent of affected infants demonstrated evidence of neonatal hypoglycemia.

In contrast, fetuses who have inherited the GCK mutation do not appear to demonstrate the excessive fetal growth that typically results from maternal hyperglycemia; studies have reported that affected fetuses may have a birth weight that may be 500 to 600 g lower than unaffected fetuses of mothers with monogenic diabetes due to GCK mutations. Fetuses inheriting the GCK mutation may demonstrate a decreased insulin response to hyperglycemia. Therefore, they may experience less macrosomia. Unaffected fetuses have a normally functioning glucokinase enzyme, are at risk for hyperinsulinemia in response to maternal hyperglycemia, and have a greater risk of macrosomia. Knowledge of the fetal genotype during pregnancy might theoretically allow providers and patients to tailor diabetes management. Definitive diagnosis of fetal genotype requires invasive testing such as first trimester chorionic villus sampling (CVS) or second trimester amniocentesis, with the associated risks of these procedures.

The management of diabetes during pregnancy may also have long-term effects on fetuses who inherit mutations associated with diabetes. Studies have demonstrated that individuals with maternally-inherited HNF1A mutations often have earlier age at diabetes diagnosis and at initiation of insulin therapy than those paternally-inherited mutations ; this observation may suggest that the intrauterine environment may impact the phenotype associated with these mutations, and further highlights the importance of tight maternal metabolic control during pregnancy in optimizing long-term outcomes.

Gestational Diabetes

The reported incidence of diabetes in pregnancy is up to 9.2% with 80% to 90% of cases due to gestational diabetes (GDM). GDM is defined by the presence of elevated blood sugars, resulting from insulin resistance diagnosed for the first time during pregnancy. The physiologic changes of pregnancy are associated with hyperglycemia in pregnant patients with GDM, prediabetes and diabetes. In pregnancy, insulin resistance increases with advancing gestation in response to increasing levels of human placental lactogen, progesterone, cortisol, and prolactin. Human placental lactogen and prolactin antagonize the effects of insulin at the cellular level. Progesterone decreases gastrointestinal motility, which may enhance carbohydrate absorption. It is believed that insulin resistance in pregnancy is likely a physiologic adaptation to maintain a steady supply of nutrients to the growing fetus.

Given the underlying pathophysiology of insulin resistance, there is likely some overlap between pregnant patients with type 2 diabetes and those diagnosed with GDM. Because of the likelihood that underlying type 2 diabetes may be first diagnosed in pregnancy (and therefore mistaken for GDM), early screening in pregnancy is recommended for pregnant patients with risk factors for type 2 diabetes ( Table 8.3 ). Risk factors that merit early diabetes testing include the following: a previous history of GDM, history of impaired glucose tolerance, and obesity (body mass index [BMI] ≥30 kg/m ² ). In conjunction with American Diabetes Association recommendations, to facilitate early diagnosis, diabetic screening is recommended for patients with BMI ≥25 kg/m ² and have one of the following additional risk factors: physical inactivity, a first-degree relative with diabetes, history of delivery of a macrosomic infant (defined as birth weight ≥4 kg), or history of polycystic ovarian syndrome or chronic hypertension. A negative early screen for diabetes should be retested later in pregnancy at the recommended universal testing window: 24 to 28 weeks.

Currently in most of the United States, two-step testing is recommended with a 50-g glucose challenge test as the initial screen, followed by definitive diagnostic testing with a 100-g three-hour oral glucose tolerance test; this testing approach is endorsed by the American College of Obstetricians and Gynecologists (ACOG). The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends a one-step testing strategy utilizing a 75-g 2-hour oral glucose tolerance test; the diagnostic thresholds were selected based on odds ratio for various adverse outcomes evaluated in the Hyperglycemia and Adverse Pregnancy Outcome study. Using a one-step approach may diagnose GDM in as many as 18% of pregnant patients. A recent randomized control trial evaluated the one- vs. two-step approach to diagnosis. The one-step approach did diagnose 16.5% of participants with GDM, as compared to 9.2% using the two-step. However, there were no significant between-group differences in primary outcomes related to perinatal and maternal complications. In light of these findings, choice of screening test is left to each provider and/or practice based on the needs and adherence of their unique patient population.

Maternal Obesity

The obesity epidemic is contributing to the global rise in type 2 diabetes and GDM, thus resulting in an increased risk of the perinatal complications attributable to diabetes. Importantly, maternal obesity, even in the absence of diabetes, has been found to be an independent risk factor for adverse obstetric, fetal, and neonatal outcomes. Specifically, maternal prepregnancy obesity has been associated with an increased risk of congenital anomalies, stillbirth, macrosomia, hypertensive disorders of pregnancy (e.g., preeclampsia), stillbirth, cesarean delivery, as well as pediatric obesity.

Pregnancies complicated by obesity are associated with increased odds of fetal open neural tube defects, hydrocephalus, cardiovascular anomalies, cleft lip and/or palate, and limb reduction anomalies. The elevated risk of congenital malformation is likely compounded by the presence of suboptimal control of pregestational diabetes. There is an elevated risk of congenital malformations in offspring of obese pregnant patients with diabetes, and the detection of anomalies by ultrasound evaluation for fetal anomalies is more challenging in this population; studies estimate a 20% lower detection rate for anomalies.

In several studies, the risk of perinatal mortality, including stillbirth, was shown to increase with increasing severity of maternal obesity. Maternal prepregnancy obesity, as defined by a BMI of greater than or equal to 30 kg/m ² , has been identified as an independent risk factor for macrosomia and LGA birth weight. In a cohort of singleton pregnancies, both maternal diabetes and maternal obesity were identified as independent risk factors for LGA birth weight; in the case of maternal obesity, the adjusted odds ratio for delivering an LGA infant is 1.6, while for pregestational diabetes, the adjusted odds ratio is 4.4. Given the greater prevalence of obesity as compared with pregestational diabetes, it is likely that the proportion of LGA infants delivered by obese pregnant patients will exceed that of diabetic pregnant patients. Similar to what is observed in macrosomic infants of diabetic mothers (IDMs), LGA infants born to pregnant patients with obesity appear to have increased adiposity as compared with infants of patients without associated obesity; these children may go on to have an increased risk of childhood obesity and metabolic abnormalities.