CHAPTER 5 PREEXISTING DIABETES AND PREGNANCY John L. Kitzmiller, MD, MS, Assiamira Ferrara MD, PhD, Tiffany Peng, MA, Michelle A. Cissell, PhD, and Catherine Kim, MD, MPH Dr. John L. Kitzmiller retired in 2015 as Consultant in Maternal-Fetal Medicine and Director of the Diabetes and Pregnancy Program at Santa Clara County Medical and Health Centers, San Jose, CA, and previously as Professor of Obstetrics at UCSF, San Francisco, CA. Dr. Assiamira Ferrara is Associate Director of Women’s and Children’s Health, Division of Research, Kaiser Permanente Northern California, Oakland, CA. Ms. Tiffany Peng is Senior Data Consultant, Division of Research, Kaiser Permanente Northern California, Oakland, CA. Dr. Michelle A. Cissell is a science writer and editor, Chicago, IL. Dr. Catherine Kim is Associate Professor of Medicine, Obstetrics & Gynecology, and Epidemiology at the University of Michigan, Ann Arbor, MI. SUMMARY The prevalence of diabetes in adolescents and women of reproductive age has increased since 1995. However, no prospective national population-based data from the United States are available regarding women with preexisting diabetes in pregnancy (pregestational)— that is, type 1 diabetes or type 2 diabetes identified before pregnancy. Knowledge of the true prevalence depends on inclusion of women with early pregnancy losses, which are not available in birth certificate or hospital discharge data. In this chapter, prevalence data are presented from selected populations, including women who have recently given birth to a live infant, women who have used diabetes medications during pregnancy, women who have delivered in hospitals, and women enrolled in specific health plans. These reports, as well as population-based reports from other countries, suggest that diabetes during pregnancy has at least doubled since 1995, with increases in pregnancies affected by type 1 and type 2 diabetes and across all age groups. Surveys of diabetes in female youth show that the prevalence of type 1 diabetes is greater than type 2 diabetes, but by the time in life of pregnancy, the ratio has reversed in population-based analyses of births. The former crude prevalence of preexisting diabetes mellitus in pregnancy of approximately 0.3% has risen to 1.0%–1.9% in major parts of North America, paralleling the diabetes prevalence in repro- ductive-age women, which was approximately 1.85%–3.0% between 2002 and 2009. Preconception care of diabetes has consistently been reported to reduce major congenital malformations and perinatal complications by over 60%, thus rendering such care cost-effective. Utilization of preconception care is suboptimal, in part because of the high frequency of unplanned pregnancy, as well as lack of access to care. No national or regional surveillance systems are in place to prospectively monitor utilization of preconception care of diabetes and outcomes in the United States. Even though the risks of unplanned pregnancy are greater in women with diabetes than in nondiabetic women, women with diabetes are less likely to receive contraception counseling than women without diabetes. Large prospective studies of diabetic women from the preconception period forward are needed in order to obtain reliable data on the prevalence of preconception care of diabetes and the use of contraception, as well as the number of diabetic women becoming and remaining pregnant. This effort might also have the effect of better linkage of general diabetes care to enhanced preconception manage- ment of diabetic women. Severe maternal complications of pregnancy may be rare in the United States, but diabetes increases the relative risks of maternal mortality, ischemic stroke, myocardial infarction, preeclampsia-eclampsia, and possibly sepsis and venous thromboembolism. Prevention of diabetic ketoacidosis and severe maternal hypoglycemia is crucial; their frequencies should be monitored as indicators of quality of care, including self-care by the patient. Population-based systems to monitor these important comorbidities are lacking in the United States. Proliferative retinopathy can progress during pregnancy, but risk of vision loss can be reduced by comprehensive ophthalmologic screening and photocoagulation as necessary. Data from other countries suggest that pregnancy does not exacerbate mild nephropathy in the long term, although the presence of nephropathy can contribute to poorer birth outcomes and worsen prognosis over the long term. Hypertensive disorders affect >10% of diabetic pregnancies, contributing to neonatal morbidity. Prospective data on treatment of hypertension during diabetic pregnancy are lacking. First trimester glycosylated hemoglobin (A1c) levels >7.0% are associated with poorer birth outcomes. The teratogenic effects of hyper- glycemia may be compounded by obesity, smoking, alcohol use, and/or poor nutrition. Fetal complications include a higher frequency of major congenital malformations, the most common of which are cardiovascular. It is controversial whether the use of medications Received in final form January 24, 2018. 5–1 DIABETES IN AMERICA, 3rd Edition common among women with diabetes contributes to the malformation risk, although insulin, antihyperglycemic medications, and oral contraceptives do not appear to do so. Stillbirths occur more frequently among women with poorer glucose control, and degree of risk increases with degree of A1c elevation. The prevalences of major malformations and stillbirths in surveys depend on the inclusion of terminations of pregnancy or late fetal losses at 20–23 weeks gestation, respectively. Women with diabetes also have a 30%–60% higher risk of infants affected by preterm delivery and macrosomia with concomitant birth trauma events, such as shoulder dystocia with vaginal delivery. In 2009, approximately 56.5% of births to women with pregestational diabetes mellitus were by cesarean section, and 16%–27% of births resulted in birth weights >4,000 g. Other adverse events among infants of mothers with diabetes include infant mortality and neonatal hypoxic-ischemic encephalopathy, although such events are infre- quent. Infants of diabetic mothers can experience a higher frequency of respiratory distress, polycythemia, hypoglycemia, hypocalcemia, and hyperbilirubinemia compared to infants of mothers without diabetes. In rare cases, these complications also can contribute to neonatal encephalopathy. The increasing frequency of type 1 and type 2 diabetes in young women and increasing maternal age at conception are likely to further increase the risk of adverse maternal, birth, and infant outcomes. Population-based data are needed to track conception, miscarriage, major malformations, and livebirth and stillbirth frequencies among women with diabetes. Such data would guide the optimal timing and tailoring of preconception interventions. Interventions are needed that quantify the optimal amount of surveillance during fetal develop- ment (balancing costs and benefits), along with interventions that examine long-term risk to mothers and offspring. The subject matter in this chapter is necessarily broad, as it not only discusses prevalence of pregestational diabetes mellitus in preg- nancy but also prevalence of diabetes in reproductive-age women; preconception care and contraception; complications in the mother, fetus, infant, and developing offspring; and methodologic issues related to assessment of outcomes in the mother, fetus, and infant. The beauty and the devil is in the details. The definitions and management of pregnancy-related conditions can vary considerably among studies and, in many cases, are controversial. INTRODUCTION OBJECTIVE HISTORICAL CONTEXT obesity and type 2 diabetes. The latter is This chapter presents population-based or Prior to the application of (a) medical too often unrecognized until pregnancy multicenter data on: (1) the growing preva- nutrition therapy, self-monitoring of is well established. Regional or national lence of type 1 and type 2 diabetes before maternal blood glucose, and individualized surveillance of diabetes and pregnancy and during pregnancy in North America, insulin regimens, (b) technologies of fetal outcomes at the community level in the (2) preconception care and contraception assessment, and (c) intensive neonatal United States has not kept pace with among those with diabetes, (3) maternal care, pregnancy in women with type 1 achievements at centers of excellence. complications of preexisting diabetes in diabetes (then defined as child-onset, These problems gain even more impor- pregnancy, and (4) fetal, neonatal, and insulin-dependent) was a frightening affair tance with the recognition of the lifelong offspring outcomes among women with (1). Maternal risks included diabetic keto- influences of preconception, fetal, and diabetes. Information on diabetes with acidosis (DKA), hypoglycemic coma, and neonatal processes on many features of onset or recognition during pregnancy is progression of vascular disease, including health or disease. provided in Chapter 4 Gestational Diabetes. superimposed preeclampsia. Excess rates This chapter focuses on data published in of early fetal loss, major congenital malfor- In the 1980s–1990s, two national peer-reviewed journals since 2000. If ample mations, fetal growth restriction, stillbirth, prospective studies included a focus U.S. data are not available on the different birth trauma, and neonatal death from on type 1 diabetes and pregnancy. The topics, relevant international popula- hyaline membrane