14. Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes—2020

Recommendations

• 14.1 Starting at puberty and continuing in all women with diabetes and reproductive potential, preconception counseling should be incorporated into routine diabetes care. A

• 14.2 Family planning should be discussed, and effective contraception (with consideration of long-acting, reversible contraception) should be prescribed and used until a woman’s treatment regimen and A1C are optimized for pregnancy. A

• 14.3 Preconception counseling should address the importance of achieving glucose levels as close to normal as is safely possible, ideally A1C <6.5% (48 mmol/mol), to reduce the risk of congenital anomalies, preeclampsia, macrosomia, and other complications. B

All women of childbearing age with diabetes should be informed about the importance of achieving and maintaining as near euglycemia as safely possible prior to conception and throughout pregnancy. Observational studies show an increased risk of diabetic embryopathy, especially anencephaly, microcephaly, congenital heart disease, renal anomalies, and caudal regression, directly proportional to elevations in A1C during the first 10 weeks of pregnancy (3). Although observational studies are confounded by the association between elevated periconceptional A1C and other poor self-care behavior, the quantity and consistency of data are convincing and support the recommendation to optimize glycemia prior to conception, given that organogenesis occurs primarily at 5–8 weeks of gestation, with an A1C <6.5% (48 mmol/mol) being associated with the lowest risk of congenital anomalies (3–6).

There are opportunities to educate all women and adolescents of reproductive age with diabetes about the risks of unplanned pregnancies and about improved maternal and fetal outcomes with pregnancy planning (7). Effective preconception counseling could avert substantial health and associated cost burdens in offspring (8). Family planning should be discussed, including the benefits of long-acting, reversable contraception, and effective contraception should be prescribed and used until a woman is prepared and ready to become pregnant (9–13).

To minimize the occurrence of complications, beginning at the onset of puberty or at diagnosis, all girls and women with diabetes of childbearing potential should receive education about 1) the risks of malformations associated with unplanned pregnancies and even mild hyperglycemia and 2) the use of effective contraception at all times when preventing a pregnancy. Preconception counseling using developmentally appropriate educational tools enables adolescent girls to make well-informed decisions (7). Preconception counseling resources tailored for adolescents are available at no cost through the American Diabetes Association (ADA) (14).

Recommendations

• 14.4 Women with preexisting diabetes who are planning a pregnancy should ideally be managed beginning in preconception in a multidisciplinary clinic including an endocrinologist, maternal-fetal medicine specialist, registered dietitian nutritionist, and diabetes educator, when available. B

• 14.5 In addition to focused attention on achieving glycemic targets A, standard preconception care should be augmented with extra focus on nutrition, diabetes education, and screening for diabetes comorbidities and complications. E

• 14.6 Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. Dilated eye examinations should occur ideally before pregnancy or in the first trimester, and then patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy and as recommended by the eye care provider. B

The importance of preconception care for all women is highlighted by the American College of Obstetricians and Gynecologists (ACOG) committee opinion 762, Prepregnancy Counseling (15). A key point is the need to incorporate a question about a woman’s plans for pregnancy into routine primary and gynecologic care. The preconception care of women with diabetes should include the standard screenings and care recommended for all women planning pregnancy (15). Prescription of prenatal vitamins (with at least 400 mg of folic acid and 150 μg of potassium iodide [16]) is recommended prior to conception. Review and counseling on the use of nicotine products, alcohol, and recreational drugs, including marijuana, is important. Standard care includes screening for sexually transmitted diseases and thyroid disease, recommended vaccinations, routine genetic screening, a careful review of all prescription and nonprescription medications and supplements used, and a review of travel history and plans with special attention to areas known to have Zika virus, as outlined by ACOG. See Table 14.1 for additional details on elements of preconception care (15,17). Counseling on the specific risks of obesity in pregnancy and lifestyle interventions to prevent and treat obesity, including referral to a registered dietitian nutritionist (RD/RDN), is recommended when indicated.

Diabetes-specific counseling should include an explanation of the risks to mother and fetus related to pregnancy and the ways to reduce risk including glycemic goal setting, lifestyle management, and medical nutrition therapy. The most important diabetes-specific component of preconception care is the attainment of glycemic goals prior to conception. Diabetes-specific testing should include A1C, creatinine, and urinary albumin-to-creatinine ratio. Special attention should be paid to the review of the medication list for potentially harmful drugs (i.e., ACE inhibitors [18], angiotensin receptor blockers [18], and statins [19,20]). A referral for a comprehensive eye exam is recommended. Women with preexisting diabetic retinopathy will need close monitoring during pregnancy to assess for progression of retinopathy and provide treatment if indicated (21). The use of aspirin (81–150 mg) can be considered preconception as it is recommended for all pregnant women with diabetes (if no contraindication) by 16 weeks of gestation to reduce the risk of preeclampsia. Please see preeclampsia and aspirin for more information.

Several studies have shown improved diabetes and pregnancy outcomes when care has been delivered from preconception through pregnancy by a multidisciplinary group focused on improved glycemic control (22–25). One study showed that care of preexisting diabetes in clinics that included diabetes and obstetric specialists improved care (25). However, there is no consensus on the structure of multidisciplinary team care for diabetes and pregnancy, and there is a lack of evidence on the impact on outcomes of various methods of health care delivery (26).

Recommendations

• 14.7 Fasting and postprandial self-monitoring of blood glucose are recommended in both gestational diabetes mellitus and preexisting diabetes in pregnancy to achieve optimal glucose levels. Glucose targets are fasting plasma glucose <95 mg/dL (5.3 mmol/L) and either 1-h postprandial glucose <140 mg/dL (7.8 mmol/L) or 2-h postprandial glucose <120 mg/dL (6.7 mmol/L). Some women with preexisting diabetes should also test blood glucose preprandially. B

• 14.8 Due to increased red blood cell turnover, A1C is slightly lower in normal pregnancy than in normal nonpregnant women. Ideally, the A1C target in pregnancy is <6% (42 mmol/mol) if this can be achieved without significant hypoglycemia, but the target may be relaxed to <7% (53 mmol/mol) if necessary to prevent hypoglycemia. B

• 14.9 When used in addition to pre- and postprandial self-monitoring of blood glucose, continuous glucose monitoring can help to achieve A1C targets in diabetes and pregnancy. B

• 14.10 When used in addition to self-monitoring of blood glucose targeting traditional pre- and postprandial targets, continuous glucose monitoring can reduce macrosomia and neonatal hypoglycemia in pregnancy complicated by type 1 diabetes. B

• 14.11 Continuous glucose monitoring metrics should not be used as a substitute for self-monitoring of blood glucose to achieve optimal pre- and postprandial glycemic targets. E

• 14.12 Commonly used estimated A1C and glucose management indicator calculations should not be used in pregnancy as estimates of A1C. C

Pregnancy in women with normal glucose metabolism is characterized by fasting levels of blood glucose that are lower than in the nonpregnant state due to insulin-independent glucose uptake by the fetus and placenta and by mild postprandial hyperglycemia and carbohydrate intolerance as a result of diabetogenic placental hormones. In patients with preexisting diabetes, glycemic targets are usually achieved through a combination of insulin administration and medical nutrition therapy. Because glycemic targets in pregnancy are stricter than in nonpregnant individuals, it is important that women with diabetes eat consistent amounts of carbohydrates to match with insulin dosage and to avoid hyperglycemia or hypoglycemia. Referral to a registered dietitian nutritionist is important in order to establish a food plan and insulin-to-carbohydrate ratio and to determine weight gain goals.

Recommendations

• 14.13 Lifestyle behavior change is an essential component of management of gestational diabetes mellitus and may suffice for the treatment of many women. Insulin should be added if needed to achieve glycemic targets. A

• 14.14 Insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus. Metformin and glyburide should not be used as first-line agents, as both cross the placenta to the fetus. A Other oral and noninsulin injectable glucose-lowering medications lack long-term safety data.

• 14.15 Metformin, when used to treat polycystic ovary syndrome and induce ovulation, should be discontinued by the end of the first trimester. A

GDM is characterized by increased risk of macrosomia and birth complications and an increased risk of maternal type 2 diabetes after pregnancy. The association of macrosomia and birth complications with oral glucose tolerance test (OGTT) results is continuous with no clear inflection points (34). In other words, risks increase with progressive hyperglycemia. Therefore, all women should be tested as outlined in Section 2 “Classification and Diagnosis of Diabetes” (https://doi.org/10.2337/dc20-S002). Although there is some heterogeneity, many randomized controlled trials (RCTs) suggest that the risk of GDM may be reduced by diet, exercise, and lifestyle counseling, particularly when interventions are started during the first or early in the second trimester (46–48).

Sulfonylureas

Sulfonylureas are known to cross the placenta and have been associated with increased neonatal hypoglycemia. Concentrations of glyburide in umbilical cord plasma are approximately 50–70% of maternal levels (57,58). Glyburide was associated with a higher rate of neonatal hypoglycemia and macrosomia than insulin or metformin in a 2015 meta-analysis and systematic review (59). More recently, glyburide failed to be found noninferior to insulin based on a composite outcome of neonatal hypoglycemia, macrosomia, and hyperbilirubinemia (60). Long-term safety data for offspring exposed to glyburide are not available (60).

Metformin

Metformin was associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in systematic reviews (59,61,62,65). However, metformin readily crosses the placenta, resulting in umbilical cord blood levels of metformin as high or higher than simultaneous maternal levels (66,67). In the Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU) study’s analyses of 7- to 9-year-old offspring, the 9-year-old offspring exposed to metformin in the Auckland cohort for the treatment of GDM were heavier and had a higher waist-to-height ratio and waist circumference than those exposed to insulin (68). This was not found in the Adelaide cohort. In two RCTs of metformin use in pregnancy for polycystic ovary syndrome, follow-up of 4-year-old offspring demonstrated higher BMI and increased obesity in the offspring exposed to metformin (69,70). A follow-up study at 5–10 years showed that the offspring had higher BMI, weight-to-height ratios, waist circumferences, and a borderline increase in fat mass (70,71). Metformin is being studied in two ongoing trials in type 2 diabetes (Metformin in Women with Type 2 Diabetes in Pregnancy Trial [MiTY] [72] and Medical Optimization of Management of Type 2 Diabetes Complicating Pregnancy [MOMPOD] [73]), but long-term offspring data will not be available for some time. A recent meta-analysis concluded that metformin exposure resulted in smaller neonates with acceleration of postnatal growth resulting in higher BMI in childhood (68,69).

Randomized, double-blind, controlled trials comparing metformin with other therapies for ovulation induction in women with polycystic ovary syndrome have not demonstrated benefit in preventing spontaneous abortion or GDM (74), and there is no evidence-based need to continue metformin in such patients (75–77).

There are some women with GDM requiring medical therapy who, due to cost, language barriers, comprehension, or cultural influences, may not be able to use insulin safely or effectively in pregnancy. Oral agents may be an alternative in these women after a discussion of the known risks and the need for more long-term safety data in offspring. However, due to the potential for growth restriction or acidosis in the setting of placental insufficiency, metformin should not be used in women with hypertension, preeclampsia, or at risk for intrauterine growth restriction (78,79).

Insulin

Insulin use should follow the guidelines below. Both multiple daily insulin injections and continuous subcutaneous insulin infusion are reasonable delivery strategies, and neither has been shown to be superior to the other during pregnancy (80).

Recommendations

• 14.16 Insulin is the preferred agent for management of both type 1 diabetes and type 2 diabetes in pregnancy. E

• 14.17 Either multiple daily injections or insulin pump technology can be used in pregnancy complicated by type 1 diabetes. C

The physiology of pregnancy necessitates frequent titration of insulin to match changing requirements and underscores the importance of daily and frequent self-monitoring of blood glucose. Due to the complexity of insulin management in pregnancy, referral to a specialized center offering team-based care (with team members including maternal-fetal medicine specialist, endocrinologist, or other provider experienced in managing pregnancy in women with preexisting diabetes, dietitian, nurse, and social worker, as needed) is recommended if this resource is available.

None of the currently available human insulin preparations have been demonstrated to cross the placenta (80–86). A recent Cochrane systematic review was not able to recommend any specific insulin regimen over another for the treatment of diabetes in pregnancy (87).

While many providers prefer insulin pumps in pregnancy, it is not clear that they are superior to multiple daily injections (88–90). Closed-loop technology that is U.S. Food and Drug Administration approved outside of pregnancy can only target a glucose of 120 mg/dL at this time, which is likely to be too high for optimal nocturnal control in pregnancy. However, given potential benefits, ongoing work is being done in this area.

Recommendation

• 14.18 Women with type 1 or type 2 diabetes should be prescribed low-dose aspirin 60–150 mg/day (usual dose 81 mg/day) by the end of the first trimester in order to lower the risk of preeclampsia. A

Diabetes in pregnancy is associated with an increased risk of preeclampsia (93). Based upon the results of clinical trials and meta-analyses (94), the U.S. Preventive Services Task Force recommends the use of low-dose aspirin (81 mg/day) as a preventive medication at 12 weeks of gestation in women who are at high risk for preeclampsia (95). A cost-benefit analysis has concluded that this approach would reduce morbidity, save lives, and lower health care costs (96). However, more study is needed to assess the long-term effects of prenatal aspirin exposure on offspring (97).

Recommendations

• 14.19 In pregnant patients with diabetes and hypertension or significant proteinuria, a consistent blood pressure >135/85 mmHg should be treated in the interest of optimizing long-term maternal health. Blood pressure targets should range no lower than 120/80 mmHg, as lower blood pressure targets may impair fetal growth. C

• 14.20 Potentially harmful medications in pregnancy (i.e., ACE inhibitors, angiotensin receptor blockers, statins) should be stopped at conception and avoided in sexually active women of childbearing age who are not using reliable contraception. B

In normal pregnancy, blood pressure is lower than in the nonpregnant state. In a pregnancy complicated by diabetes and chronic hypertension, a target goal blood pressure of <135/85 mmHg is reasonable (98,99). Blood pressure targets lower than 120/80 mmHg may be associated with impaired fetal growth, especially in the setting of placental insufficiency. In a 2015 study targeting diastolic blood pressure of 100 mmHg versus 85 mmHg in pregnant women, only 6% of whom had GDM at enrollment, there was no difference in pregnancy loss, neonatal care, or other neonatal outcomes, although women in the less intensive treatment group had a higher rate of uncontrolled hypertension (100).

During pregnancy, treatment with ACE inhibitors and angiotensin receptor blockers is contraindicated because they may cause fetal renal dysplasia, oligohydramnios, pulmonary hypoplasia, and intrauterine growth restriction (18). Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, nifedipine, labetalol, diltiazem, clonidine, and prazosin. Atenolol is not recommended, but other β-blockers may be used, if necessary. Chronic diuretic use during pregnancy is not recommended as it has been associated with restricted maternal plasma volume, which may reduce uteroplacental perfusion (101). On the basis of available evidence, statins should also be avoided in pregnancy (102).

See pregnancy and antihypertensive medications in Section 10 “Cardiovascular Disease and Risk Management” (https://doi.org/10.2337/dc20-s010) for more information on managing blood pressure in pregnancy.

Recommendations

• 14.21 Insulin resistance decreases dramatically immediately postpartum, and insulin requirements need to be evaluated and adjusted as they are often roughly half the prepregnancy requirements for the initial few days postpartum. C

• 14.22 A contraceptive plan should be discussed and implemented with all women with diabetes of reproductive potential. C

• 14.23 Screen women with a recent history of gestational diabetes mellitus at 4–12 weeks postpartum, using the 75-g oral glucose tolerance test and clinically appropriate nonpregnancy diagnostic criteria. B

• 14.24 Women with a history of gestational diabetes mellitus found to have prediabetes should receive intensive lifestyle interventions and/or metformin to prevent diabetes. A

• 14.25 Women with a history of gestational diabetes mellitus should have lifelong screening for the development of type 2 diabetes or prediabetes at least every 3 years. B

• 14.26 Women with a history of gestational diabetes mellitus should seek preconception screening for diabetes and preconception care to identify and treat hyperglycemia and prevent congenital malformations. E

• 14.27 Postpartum care should include psychosocial assessment and support for self-care. E

Initial Testing

Because GDM often represents previously undiagnosed prediabetes, type 2 diabetes, maturity-onset diabetes of the young, or even developing type 1 diabetes, women with GDM should be tested for persistent diabetes or prediabetes at 4–12 weeks postpartum with a 75-g OGTT using nonpregnancy criteria as outlined in Section 2 “Classification and Diagnosis of Diabetes” (https://doi.org/10.2334/dc20-S002).

Postpartum Follow-up

The OGTT is recommended over A1C at 4–12 weeks postpartum because A1C may be persistently impacted (lowered) by the increased red blood cell turnover related to pregnancy, by blood loss at delivery, or by the preceding 3-month glucose profile. The OGTT is more sensitive at detecting glucose intolerance, including both prediabetes and diabetes. Women of reproductive age with prediabetes may develop type 2 diabetes by the time of their next pregnancy and will need preconception evaluation. Because GDM is associated with an increased lifetime maternal risk for diabetes estimated at 50–70% after 15–25 years (103,104), women should also be tested every 1–3 years thereafter if the 4–12 weeks postpartum 75-g OGTT is normal. Ongoing evaluation may be performed with any recommended glycemic test (e.g., annual A1C, annual fasting plasma glucose, or triennial 75-g OGTT using nonpregnant thresholds).

Gestational Diabetes Mellitus and Type 2 Diabetes

Women with a history of GDM have a greatly increased risk of conversion to type 2 diabetes over time (103). In the prospective Nurses’ Health Study II (NHS II), subsequent diabetes risk after a history of GDM was significantly lower in women who followed healthy eating patterns (105). Adjusting for BMI moderately, but not completely, attenuated this association. Interpregnancy or postpartum weight gain is associated with increased risk of adverse pregnancy outcomes in subsequent pregnancies (106) and earlier progression to type 2 diabetes.

Both metformin and intensive lifestyle intervention prevent or delay progression to diabetes in women with prediabetes and a history of GDM. Of women with a history of GDM and prediabetes, only 5–6 women need to be treated with either intervention to prevent one case of diabetes over 3 years (107). In these women, lifestyle intervention and metformin reduced progression to diabetes by 35% and 40%, respectively, over 10 years compared with placebo (108). If the pregnancy has motivated the adoption of a healthier diet, building on these gains to support weight loss is recommended in the postpartum period.