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Review

Preexisting Diabetes and Pregnancy

John L. Kitzmiller  1 , Assiamira Ferrara  2 , Tiffany Peng  3 , Michelle A. Cissell  4 , Catherine Kim  5
Catherine C. Cowie  1 , Sarah Stark Casagrande  2 , Andy Menke  2 , Michelle A. Cissell  3 , Mark S. Eberhardt  4 , James B. Meigs  5 , Edward W. Gregg  6 , William C. Knowler  7 , Elizabeth Barrett-Connor  8 , Dorothy J. Becker  9 , Frederick L. Brancati  10 , Edward J. Boyko  11 , William H. Herman  12 , Barbara V. Howard  13 , K. M. Venkat Narayan  14 , Marian Rewers  15 , Judith E. Fradkin  16
, editors.
In: Diabetes in America. 3rd edition. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018 Aug. CHAPTER 5.
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Review

Preexisting Diabetes and Pregnancy

John L. Kitzmiller et al.
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Excerpt

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 reproductive-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 management 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 hyperglycemia 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 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 infrequent. 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 development (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 pregnancy 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.

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Conflict of interest statement

DUALITY OF INTEREST

Drs. Kitzmiller, Ferrara, Cissell, and Kim and Ms. Peng reported no conflicts of interest.

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Prevalence of Diabetes in Pregnancy

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Maternal Complications

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Birth Outcomes

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Congenital Malformations

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    2. Of 914,427 live births, stillbirths, and terminated pregnancies, 0.61% were complicated by maternal pregestational diabetes mellitus. In the latter group, the prevalence of offspring with cardiac defects was 3.44% versus 1.14% without diabetes (adjusted RR 2.92, 95% CI 2.54–3.36). The associated risk did not change during the study period. Within the pregestational diabetes mellitus group, the prevalence of congenital heart defects in very macrosomic infants (birth weight >3 SDs above the reference mean) was 5.61% compared to 2.48% in the nonmacrosomic group (adjusted RR 2.23, 95% CI 1.39–3.59).

Neonatal Complications

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    2. U.S. multicenter study of 312 infants of multiethnic mothers using insulin before pregnancy (IBP), delivered at 22–28 weeks and cared for at one of 24 NIH Neonatal Research Network hospitals in 2006–2011; outcomes were compared to 10,245 controls without maternal diabetes. Birth weight extremes for gestational age and sex (Olsen norms) were 10% LGA (NS) and 18% SGA (NS); 5% major birth defects (NS); 15% Apgar score ≤3 at 5 minutes (NS). Rates of morbidities in-hospital in 286 IBP infants surviving >12 hours included 20.6% death before discharge (NS); 99% respiratory distress syndrome (NS); 36% need for supplemental oxygen use at 36 weeks postmenstrual age (NS); 16% severe intraventricular hemorrhage (NS); 3% periventricular leukomalacia (NS); 15% necrotizing enterocolitis (vs. 11%; adjusted RR 1.55, 95% CI 1.17–2.05); and 35% late-onset sepsis after 3 days (vs. 28%; adjusted RR 1.26, 95% CI 1.07–1.48). Of 189 IBP infants eligible for follow-up at age 18–22 months, there were 37% total deaths between birth and age 18–22 months (NS vs. 38% of 6,598 infants eligible for follow-up). Of 109 IBP offspring examined at age 18–22 months, 19% had neurodevelopmental impairment (NS vs. 16% of 3,608 controls). There were no data on maternal glycemic control.

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    2. Population-based study using prospectively collected data on live singleton births of nonmalformed infants from several nationwide Swedish registries for 1997–2011; 5,941 infants of mothers with type 1 diabetes (IDM1), 711 infants of mothers with type 2 diabetes (IDM2), compared to 1,337,099 infants of mothers without any type of diabetes (controls). Maternal characteristics were: BMI ≥30 kg/m2 in 17.5% of women with type 1 diabetes, 55.5% of women with type 2 diabetes, and 10.7% in controls (excluding women with missing data); smoking in 10.2% of type 1 diabetes, 11.7% of type 2 diabetes, and 9.4% of controls; chronic hypertension in 4.2% of type 1 diabetes, 7.5% of type 2 diabetes, and 0.6% of controls; preeclampsia in 14.2% of type 1 diabetes, 7.6% of type 2 diabetes, and 2.7% in controls; delivery by cesarean section in 50.7% of type 1 diabetes, 42.6% of type 2 diabetes, and 15.1% of controls.

      Neonatal characteristics were: delivery at <32 weeks in 1.8% of IDM1, 2.0% of IDM2, and 0.6% of controls; delivery at 32–36 weeks in 17.9% of IDM1, 11.0% of IDM2, and 3.9% of controls; birth weight <third percentile for gestational age in 1.0% of IDM1, 1.3% of IDM2, and 1.5% of controls; birth weight >97th percentile for gestational age in 33.3% of IDM1, 19.8% of IDM2, and 3.4% of controls; Apgar score 0–6 at 5 minutes in 2.6% of IDM1 (adjusted OR 2.67 compared to controls, 95% CI 2.23–3.20), 2.1% of IDM2 (NS), and 0.9% of controls; and combined convulsions/hypoxic-ischemic encephalopathy in 1.0% of IDM1 (adjusted OR 3.40 compared to controls, 95% CI 2.58–4.48), in 1.3% of IDM2 (adjusted OR 2.54 compared to controls, 95% CI 1.13–5.69), and 0.3% of controls. There was some relation of risk of low Apgar score and neonatal convulsions to increasing maternal BMI in IDM1 and certainly in controls, but the increased rates of the complications in IDM1 remained greater than controls at each maternal BMI grouping. There were no data on maternal glycemic control.

Diabetes Management: Maternal Follow-Up

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    1. Egan AM, Carmody L, Kirwan B, Dunne FP; Atlantic DIP Collaborators: Care of women with diabetes before, during and after pregnancy: time for a new approach? Diabet Med 34:846–850, 2017 - PubMed

    2. In a multicenter study in West Ireland, 247 women with type 1 diabetes and 137 women with type 2 diabetes were evaluated before, during, and after pregnancy; 20% were lost to 1-year follow-up from clinical care. Average A1c had returned to preconception level for both diabetes groups, and there was no improvement in other measures of diabetes control. Attendees for prepregnancy care (44.9% of type 1 diabetes and 27.7% of type 2 diabetes) maintained superior glycemic control throughout the study and were more likely to be receiving specialist care postpartum.

Breastfeeding and Offspring

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    2. Modeled a hypothetical cohort of U.S. women followed from age 15 to 70 years and their children from birth to age 20 years, using Monte Carlo simulations based on current literature on the associations between breastfeeding and health outcomes for nine pediatric and five maternal diseases. For every 597 women who optimally breastfeed, one maternal death (including myocardial infarction, breast cancer, or diabetes) or child death (including sudden infant death syndrome or necrotizing enterocolitis) is prevented.

    1. Nucci AM, Virtanen SM, Sorkio S, Barlund S, Cuthbertson D, Uusitalo U, Lawson ML, Salonen M, Berseth CL, Ormisson A, Lehtonen E, Savilahti E, Becker DJ, Dupre J, Krischer JP, Knip M, Akerblom HK; TRIGR Investigators: Regional differences in milk and complementary feeding patterns in infants participating in an international nutritional type 1 diabetes prevention trial. Matern Child Nutr 13:e12354, 2017. Jul [Epub] doi: 10.1111/mcn.12354 - DOI - PMC - PubMed

    2. Among newborn infants with a first degree relative with type 1 diabetes and increased HLA-conferred susceptibility to type 1 diabetes distributed in four regions of Europe, two of North America, plus Australia, a lower proportion of infants born to mothers with than without type 1 diabetes were breastfed until age 6 months in all regions (range 51%–60% vs. 70%–80%). Maternal diabetes status was associated with breastfeeding and other milk feeding patterns similarly across regions but was unrelated to the introduction of complementary foods, which did vary by region overall, largely inconsistent with guidelines.

    1. Lund-Blix NA, Dydensborg Sander S, Stordal K, Nybo Andersen AM, Ronningen KS, Joner G, Skrivarhaug T, Nijolstad PR, Husby S, Stene LC: Infant feeding and risk of type 1 diabetes in two large Scandinavian birth cohorts. Diabetes Care 40:920–927, 2017 - PMC - PubMed

    2. Analyzed data from 155,392 children participating in Norwegian and Danish studies; parents reported infant dietary practices at ages 6 and 18 months. Children who were never breastfed had a twofold increased risk of type 1 diabetes at follow-up compared with those who were breastfed (HR 2.29, 95% CI 1.14–4.61). The incidence of type 1 diabetes was independent of duration of full or partial breastfeeding.

    1. Uusitalo U, Liu X, Lang J, Aronsson CA, Hummel S, Butterworth M, Lernmark A, Rewers M, Hagopian W, She JX, Simell O, Toppari J, Ziegler AG, Akolkar B, Krischer J, Norris JM, Virtanen SM; TEDDY Study Group: Association of early exposure to probiotics and islet autoimmunity in the TEDDY Study. JAMA Pediatr 170:20–28, 2016 - PMC - PubMed

    2. Ongoing prospective cohort follow-up study of 7,473 infants with high-risk HLA (human leukocyte antigen)-DR genotypes at three U.S. and three European centers to determine persistent islet autoimmunity. In children with the DR3/4 genotype, early (age 0–27 days), but not later, supplementation with varied probiotics by parental report (mainly in Europe; from dietary supplements in Finland and probiotic infant formulas in Germany) was associated with decreased risk of later islet autoimmunity when adjusting for duration of exclusive breastfeeding and many other factors (HR 0.40, 95% CI 0.21–0.74) and strongly associated with diarrhea and antibiotic use in the first year of life.

    1. Krischer JP, Lynch KF, Lernmark A, Hagopian WA, Rewers MJ, She JX, Toppari J, Ziegler AG, Akolkar B; TEDDY Study Group: Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: the TEDDY Study. Diabetes Care 40:1194–1202, 2017 - PMC - PubMed

    2. Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. The persisting GAD (glutamic acid decarboxylase) antibody was associated with only father as the diabetic proband and infant weight at age 12 months; mother as the diabetic proband was not a significant risk factor.

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