Diabetes in pregnancy is associated with increased risks of fetal, neonatal, and lifelong complications in the offspring. Although the adverse effects of diabetes and hyperglycemia in pregnancy have been noted for hundreds of years, the modern history of classification of diabetes in pregnancy began in 1949 with Priscilla White’s classification of maternal diabetes, ranging from gestational diabetes to long-standing insulin-dependent diabetes with systemic complications (Table 62.1
). Most importantly, White highlighted the relationship between maternal end-organ disease and poor perinatal outcomes. In 1952, Jorgen Pedersen advanced the study of diabetes in pregnant women and their offspring by proposing a mechanism of maternal hyperglycemia leading to fetal hyperinsulinism, explaining many of the neonatal complications. Efforts since have led to improved prenatal monitoring and management of diabetes in pregnancy, reducing the incidence of adverse perinatal outcomes. However, as the incidence of obesity and type 2 diabetes climbs, and as we grow to further understand the long-term metabolic impact of exposure to obesity and diabetes in the developing fetus, we are entering a new era that will require vigilance for both mothers and their offspring.
II. CLASSIFICATION OF DIABETES IN PREGNANCY.
Pregnancy itself is characterized by increased insulin resistance as gestation progresses with peak insulin resistance during the third trimester. A state of relative insulin resistance
occurs during pregnancy as a result of the actions of various placental hormones including human placental lactogen, progesterone, prolactin, placental growth hormone, and cortisol. Whereas hormones of pregnancy allow an environment for normal development of the fetus, the pregnant state leaves a narrower margin of error in which women’s propensity for carbohydrate intolerance can become apparent. This chapter will review the effects of both diabetes mellitus (DM) diagnosed before conception (pregestational diabetes) and diabetes
diagnosed during pregnancy, most specifically diagnosed in the second to third trimester (gestational diabetes mellitus [GDM]).
Table 62.1. White Classification of Maternal Diabetes
Gestational diabetes (GD):
Diabetes not known to be present before pregnancy
Abnormal glucose tolerance test in pregnancy
Euglycemia maintained by diet alone
Diet alone insufficient; insulin required
Chemical diabetes; glucose intolerance before pregnancy; treated by diet alone; rarely seen
Prediabetes; history of large babies >4 kg or unexplained stillbirths after 28 weeks
Insulin-dependent; onset after 20 years of age; duration <10 years
C1: Onset at 10-19 years of age
C2: Duration 10-19 years
D1: Onset before 10 years of age
D2: Duration 20 years
D3: Calcification of vessels of the leg (macrovascular disease)
D4: Benign retinopathy (microvascular disease)
D5: Hypertension (not preeclampsia)
Nephropathy with >500 mg/day of proteinuria
Proliferative retinopathy or vitreous hemorrhage
Criteria for both classes R and F coexist
Many reproductive failures
Clinical evidence of arteriosclerotic heart disease
Prior renal transplantation
Note: All classes below A require insulin. Classes R, F, RF, H, and T have no criteria for age of onset or duration of disease but usually occur in long-term diabetes.
Source: Modified from Hare JW. Gestational diabetes. In: Diabetes Complicating Pregnancy: The Joslin Clinic Method. New York, NY: Alan R. Liss; 1989.
A. Pregestational diabetes. Pregestational diabetes is present in 1% to 2% of all pregnancies and 13% to 21% of diabetes in pregnancy. This includes women with type 1 diabetes and type 2 diabetes that have been diagnosed and treated prior to conception. Type 2 pregestational diabetes mellitus (PGDM) is now more common than type 1 as obesity prevalence and its associations climb. Type 1 DM is typically diagnosed early in life and is characterized by relative or absolute insulin deficiency. Type 2 DM is typically diagnosed later in life and is associated with obesity and peripheral insulin resistance.
Poor early glycemic control correlates with adverse maternal and neonatal outcomes including preeclampsia, macrosomia, fetal congenital anomalies, prematurity, and perinatal mortality. Monitoring glucose control and glycosylated hemoglobin (Hgb A1C) levels is very important to improve maternal and neonatal outcomes. Therefore, preconception counseling should be an important part of maternal management for all women with preexisting DM. Unfortunately, less than one-third of women with type 1 or 2 DM actively seek preconceptual counseling. The impacts of PGDM should be discussed during routine gynecologic or primary care visits.
Obstetrical management of women with PGDM includes controlling blood glucoses with a goal of near-normal glucose control (fasting glucose ≤95 mg/dL, 1-hour postprandial glucose ≤140 mg/dL, and 2-hour postprandial glucose ≤120 mg/dL). Most women with PGDM will already be receiving insulin therapy, and insulin requirements will increase from the first to third trimester.
Although women with type 2 DM tend to have milder disturbances in glucose, in general, neonatal outcomes are similar to those with type 1 DM, whereas women with type 1 DM are more likely to have pregestational microvascular complications, increased risk of hyper- and hypoglycemia, as well as diabetic ketoacidosis, which is more likely to lead to fetal growth restriction.
1. Maternal complications. Obstetric complications of pregestational diabetes include miscarriage, preeclampsia, gestational hypertension, polyhydramnios, preterm delivery, and increased risk of requiring a cesarean section. Preterm delivery is not typically associated with preterm labor but rather with signs of fetal distress such as growth restriction or maternal hypertension necessitating preterm delivery.
2. Congenital malformations.
Congenital malformations occur two- to fourfold higher in pregestational diabetes, with incidence for type 1 DM 2.9% to 7.5% of offspring and for type 2 DM 2.1% to 12.3% of offspring. Hyperglycemia during organogenesis (weeks 5 to 8 of gestation) reflected by an increase in Hgb A1C levels correlates directly with frequency of anomalies. The rate of congenital anomalies in nondiabetic women with Hgb A1C of 5.5% is 2%; this number rises to 2.7% at Hgb A1C 6.2%, 4% with Hgb A1C 7.6%, and up to 20% with Hgb A1C ≥14%. With good glycemic control, the rate of congenital malformations in pregestational diabetes can fall to approximate levels
of nondiabetic mothers, and a 30% reduction in risk can occur for every 1% lowering of Hgb A1C.
Congenital anomalies in order of prevalence include congenital heart disease, central nervous system (CNS) defects, urogenital defects, limb defects, orofacial clefts, and rarely, yet highly associated with DM, sacral agenesis/caudal dysplasia (15% to 25% of all cases result from DM). Most prevalent cardiac defects include tetralogy of Fallot, transposition of the great arteries, septal defects, and anomalous pulmonary venous return. CNS defects include anencephaly, spina bifida, encephalocele, hydrocephaly, and anotia/microtia.
3. Intrauterine growth restriction (IUGR). Although macrosomia is a risk of DM, a poor intrauterine environment can also lead to growth restriction. In pregnant women with pregestational diabetes plus preexisting hypertension or microvascular complications, there is a 6- to 10-fold higher risk relative to those without vascular disease of having a fetus with growth restriction.
4. Further complications. The earlier discussed complications are much more specifically associated with pregestational diabetes. Other complications that overlap with diabetic fetopathy that occurs due to glycemic derangements later in the pregnancy will be addressed later in this chapter.
B. GDM. GDM is defined as any carbohydrate intolerance first diagnosed during pregnancy. This does not exclude the possibility of some undiagnosed pregestational diabetes. GDM prevalence has been increasing in association with societal increase in obesity and is directly related to the prevalence of type 2 DM in a given population. GDM currently complicates up to 14% of all pregnancies and accounts for the vast majority of all cases of diabetes in pregnancy. Furthermore, 15% to 50% of women diagnosed with GDM will go on to be diagnosed with type 2 DM later in life. Thus, all women with GDM will be screened postpartum for persistent glucose intolerance.
1. Screening and diagnosis.
Appropriate screening and diagnosis are crucial first steps to minimize the risks of GDM to the mother and infant. Risk factors for GDM should be screened at the first prenatal visit (Table 62.2
). Women at risk for undiagnosed type 2 DM typically warrant screening on the first prenatal visit for potential preexisting glucose intolerance. Screening for all women is by glucose challenge at 24 to 28 weeks. Such screening was first developed by O’Sullivan and Mahan in 1950 with criteria established in 1964. Subsequent modifications have been made to the initial criteria, and controversies exist in the determination of exact thresholds for diabetic screening and diagnosis.
Currently, in the United States, most women are screened using a two-step method. The first step is a nonfasting 50-g oral glucose load with a 1-hour postprandial cutoff of either ≤140 mg/dL or ≤130 mg/dL. The cutoffs based on work by Carpenter and Coustan between 130 and 140 mg/dL demonstrate improved sensitivity compared to using the 130-mg/dL limit. It is most important to know your local obstetrical practices in interpreting the prenatal evaluation. For those above the cutoff, the second step is a 100-g oral glucose load after a 12-hour fast, with 1-, 2-, and 3-hour postload glucoses.
Table 62.2. Risk Factors for Gestational Diabetes Mellitus
Advanced maternal age
Previous delivery of a macrosomic infant
Family history of type 2 DM
Maternal short stature
Polycystic ovarian syndrome
Prior neonatal death
Prior cesarean section
Previous stillbirth or congenital malformations
High blood pressure during pregnancy
DM, diabetes mellitus; GDM, gestational diabetes mellitus.
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