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S94 Care Volume 39, Supplement 1, January 2016

12. Management of Diabetes in American Diabetes Association Diabetes Care 2016;39(Suppl. 1):S94–S98 | DOI: 10.2337/dc16-S015

For guidelines related to the diagnosis of gestational diabetes mellitus, please refer to Section 2 “Classification and Diagnosis of Diabetes.”

Recommendations Pregestational Diabetes c Provide preconception counseling that addresses the importance of glycemic control as close to normal as is safely possible, ideally A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies. B c should be discussed and effective contraception should be prescribed and used until a woman is prepared and ready to become pregnant. A c Women with preexisting type 1 or who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic . Eye examinations should occur before pregnancy or in the first trimester and then be monitored every tri- mester and for 1 year postpartum as indicated by degree of retinopathy. B

Gestational Diabetes Mellitus c Lifestyle change is an essential component of management of gestational di- abetes mellitus and may suffice for treatment for many women. Medications should be added if needed to achieve glycemic targets. A 12. MANAGEMENT OF DIABETES IN PREGNANCY c Preferred medications in gestational diabetes mellitus are and ; glyburide may be used but may have a higher rate of neonatal and macrosomia than insulin or metformin. Other agents have not been adequately studied. Most oral agents cross the , and all lack long-term safety data. A

General Principles for Management of Diabetes in Pregnancy c Potentially teratogenic medications (ACE inhibitors, statins, etc.) should be avoided in sexually active women of childbearing age who are not using reli- able contraception. B c Fasting, preprandial, and postprandial self-monitoring of are recommended in both gestational diabetes mellitus and pregestational diabe- tes in pregnancy to achieve glycemic control. B c Due to increased turnover, A1C is lower in normal pregnancy than in normal nonpregnant women. The A1C target in pregnancy is 6–6.5% (42–48 mmol/mol); ,6% (42 mmol/mol) may be optimal 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

DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. The majority is gestational diabetes mellitus (GDM) with the remainder primarily pregestational and type 2 diabetes. The rise in GDM and pregestational type 2 diabetes in parallel with both in the U.S. and worldwide is of particular concern. Both pre- Suggested citation: American Diabetes Associa- gestational type 1 diabetes and type 2 diabetes confer significantly greater maternal and tion. Management of diabetes in pregnancy. Sec. d fetal risk than GDM, with some differences according to type as outlined below. In general, 12. In Standards of Medical Care in Diabetes 2016. Diabetes Care 2016;39(Suppl. 1):S94–S98 specific risks of uncontrolled diabetes in pregnancy include spontaneous , fetal © 2016 by the American Diabetes Association. anomalies, preeclampsia, intrauterine fetal demise, macrosomia, neonatal hypoglyce- Readers may use this article as long as the work mia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in preg- is properly cited, the use is educational and not nancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2). for profit, and the work is not altered. care.diabetesjournals.org Management of Diabetes in Pregnancy S95

PRECONCEPTION COUNSELING Insulin Physiology early in gestation (4,9–11). Clinical tri- All women of childbearing age with di- Early pregnancy is a time of insulin sen- als have not evaluated the risks and abetes should be counseled about the sitivity, lower glucose levels, and lower benefits of achieving these targets, and importance of near-normal glycemic con- insulin requirements in women with type 1 treatment goals should account for the trol prior to conception. Observational diabetes. The situation rapidly reverses risk of maternal hypoglycemia in set- studies show an increased risk of diabetic as increases exponen- ting an individualized target of ,6% embryopathy, especially anencephaly, tially during the second and early third (42 mmol/mol) to ,7% (53 mmol/mol). , congenital heart disease, trimesters and levels off toward the end Due to physiological increases in red and caudal regression directly propor- of the third trimester. In women with blood cell turnover, A1C levels fall during tional to elevations in A1C during the first normal pancreatic function, insulin pro- normal pregnancy (12). Additionally, as fi 10 weeks of pregnancy. Although obser- duction is suf cient to meet the challenge A1C represents an integrated measure of vational studies are confounded by the of this physiological insulin resistance glucose, it may not fully capture post- association between elevated periconcep- and to maintain normal glucose levels. prandial , which drives tional A1C and other poor self-care behav- However, in women with GDM and pre- macrosomia. Thus, while A1C may be iors, the quantity and consistency of data gestational type 2 diabetes, hyperglyce- useful, it should be used as a secondary are convincing and support the rec- mia occurs if treatment is not adjusted measure, after self-monitoring of blood ommendation to optimize glycemic con- appropriately. glucose. trol prior to conception, with A1C ,6.5% In the second and third trimester, A1C (48 mmol/mol) associated with the low- Glucose Monitoring ,6% (42 mmol/mol) has the lowest risk fl est risk of congenital anomalies (3,4). Re ecting this physiology, preprandial of large-for-gestational-age infants, There are opportunities to educate all and postprandial monitoring of blood glu- whereas other adverse outcomes in- women and adolescents of reproductive cose is recommended to achieve meta- crease with A1C $6.5% (48 mmol/mol). age with diabetes about the risks of un- bolic control in pregnant women with Taking all of this into account, a target of planned and the opportu- diabetes. Postprandial monitoring is as- 6–6.5% (42–48 mmol/mol) is recom- nities for improved maternal and fetal sociated with better glycemic control mended but ,6% (42 mmol/mol) may outcomes with pregnancy planning (5). and lower risk of preeclampsia (7). There be optimal as pregnancy progresses. Effective preconception counseling are no adequately powered randomized These levels should be achieved without could avert substantial health and asso- trials comparing different fasting and hypoglycemia, which, in addition to the ciated cost burden in offspring (6). Fam- postmeal glycemic targets in diabetes usual adverse sequelae, may increase ily planning should be discussed, and in pregnancy. the risk of low birth weight. Given the effective contraception should be pre- Nevertheless, the American College of alteration in red blood cell kinetics dur- scribed and used, until a woman is pre- Obstetricians and Gynecologists (ACOG) ing pregnancy and physiological pared and ready to become pregnant. (8) recommends the following targets changes in glycemic parameters, A1C for women with pregestational type 1 or levels may need to be monitored Preconception Testing type 2 diabetes: more frequently than usual (e.g., Preconception counseling visits should monthly). address rubella, rapid plasma reagin, hep- ○ Fasting #90 mg/dL (5.0 mmol/L) ○ # – atitis B virus, and HIV testing as well as One-hour postprandial 130 140 MANAGEMENT OF GESTATIONAL – Pap smear, cervical cultures, blood typ- mg/dL (7.2 7.8 mmol/L) DIABETES MELLITUS ○ Two-hour postprandial #120 mg/dL ing, prescription of prenatal vitamins GDM is characterized by increased risk m (6.7 mmol/L) (with at least 400 g of folic acid), and of macrosomia and birth complications cessation counseling, if indi- and an increased risk of maternal diabe- fi These values represent optimal control cated. Diabetes-speci c testing should tes after pregnancy. The association of if they can be achieved safely. In practice, include A1C, thyroid-stimulating hor- macrosomia and birth complications – it may be challenging for women with mone, creatinine, and urinary albumin with oral (OGTT) – type 1 diabetes to achieve these targets to creatinine ratio testing; review of the results is continuous, with no clear in- without hypoglycemia, particularly women medication list for potentially teratogenic flection points (13). In other words, risks with a history of severe hypoglycemia or drugs (i.e., ACE inhibitors, statins); and increase with progressive hyperglyce- hypoglycemia unawareness. referral for a comprehensive eye exam. mia. Therefore, all women should be If women cannot achieve these tar- screened as outlined in Section 2 “Clas- GLYCEMIC TARGETS IN gets without significant hypoglycemia, sification and Diagnosis of Diabetes.” Al- PREGNANCY the American Diabetes Association though there is some heterogeneity, (ADA) suggests less stringent targets Pregnancy in women with normal glucose many randomized controlled trials sug- based on clinical experience and individ- metabolism is characterized by fasting lev- gestthattheriskofGDMmaybere- ualization of care. els of blood glucose that are lower than in duced by diet, exercise, and lifestyle the nonpregnant state due to insulin- counseling (14,15). independent glucose uptake by the pla- A1C in Pregnancy centa and by postprandial hyperglycemia Observational studies show the lowest Lifestyle Management and intolerance as a result rates of adverse fetal outcomes in associa- After diagnosis, treatment starts with of diabetogenic placental . tion with A1C ,6–6.5% (42–48 mmol/mol) medical nutrition therapy, physical S96 Management of Diabetes in Pregnancy Diabetes Care Volume 39, Supplement 1, January 2016

activity, and weight management de- insulin for if it suffices to pregnancy that may decrease hypoglyce- pending on pregestational weight, as control hyperglycemia (23–25); how- mia awareness. Hypoglycemia education outlined in the section on pregestational ever, metformin may slightly increase for patients and family members is impor- type 2 diabetes below, and glucose mon- the risk of prematurity. None of these tant before and during early pregnancy itoring aiming for the targets recom- studies or meta-analyses evaluated and throughout pregnancy to help to pre- mended by the Fifth International long-term outcomes in the offspring. vent and manage the risks of hypoglyce- Workshop-Conference on Gestational Thus, patients treated with oral agents mia. Insulin resistance drops rapidly with Diabetes Mellitus (16): should be informed that they cross the delivery of the placenta. Women become placenta and, while no adverse effects very insulin sensitive immediately follow- ○ Fasting #95 mg/dL (5.3 mmol/L) and on the have been demonstrated, ing delivery and may initially require either long-term studies are lacking. much less insulin than in the prepartum ○ One-hour postprandial #140 mg/dL Insulin period. (7.8 mmol/L) or Insulin may be required to treat hyper- Pregnancy is a ketogenic state, and ○ # Two-hour postprandial 120 mg/dL glycemia, and its use should follow the women with type 1 diabetes, and to a (6.7 mmol/L) guidelines below. lesser extent those with type 2 diabetes, are at risk for at Depending on the population, studies MANAGEMENT OF lower blood glucose levels than in the suggestthat70–85% of women diag- PREGESTATIONAL TYPE 1 nonpregnant state. All insulin-deficient nosed with GDM under Carpenter- DIABETES AND TYPE 2 DIABETES women need ketone strips at home and Coustan or National Diabetes Data IN PREGNANCY education on diabetic ketoacidosis pre- Group (NDDG) criteria can control Insulin Use vention and detection. In addition, rapid GDM with lifestyle modification alone; Insulin is the preferred agent for man- implementation of tight glycemic control it is anticipated that this proportion agement of pregestational type 1 diabe- in the setting of retinopathy is associated will increase using the lower Interna- tes and type 2 diabetes that are not with worsening of retinopathy (26). tional Association of the Diabetes and adequately controlled with diet, exer- Pregnancy Study Groups (IADPSG) (17) cise, and metformin. Type 2 Diabetes Pregestational type 2 diabetes is often diagnostic thresholds. The physiology of pregnancy requires associated with obesity. Recommended frequent titration of insulin to match Pharmacological Therapy weight gain during pregnancy for over- changing requirements. In the first tri- Women with greater initial degrees of weight women is 15–25 lb and for obese mester, there is often a decrease in total hyperglycemia may require early initia- women is 10–20 lb. Glycemic control is daily insulin requirements, and women, tion of pharmacological therapy. Treat- often easier to achieve in type 2 diabe- particularly those with type 1 diabetes, ment has been demonstrated to tes than in type 1 diabetes but can re- may experience increased hypoglyce- improve perinatal outcomes in two quire much higher doses of insulin, mia. In the second trimester, rapidly large randomized studies as summa- sometimes necessitating concentrated increasing insulin resistance requires rized in a U.S. Preventive Services Task insulin formulations. As in type 1 diabetes, weekly or biweekly increases in insulin Force review (18). Insulin is the first-line insulin requirements drop dramatically af- dose to achieve glycemic targets. In agent recommended for treatment of ter delivery. Associated hypertension and general, a smaller proportion of the total GDM in the U.S. Individual randomized other comorbidities often render preges- daily dose should be given as basal in- controlled trials support the efficacy tational type 2 diabetes as high or higher sulin (,50%) and a greater proportion and short-term safety of metformin risk than pregestational type 1 diabetes, (.50%) as prandial insulin. In the late (19,20) (pregnancy category B) and gly- even if the diabetes is better controlled third trimester, there is often a leveling buride (21) (pregnancy category B) for and of shorter duration, with pregnancy off or small decrease in insulin require- the treatment of GDM. However, both loss appearing to be more prevalent in ments. Due to the complexity of insulin agents cross the placenta, and long- the third trimester in type 2 in pregnancy, referral to a term safety data are not available for compared with the first trimester in specialized center offering team-based either agent (22). type 1 diabetes (27,28). care (with team members including Sulfonylureas high-risk obstetrician, endocrinologist, More recently, several meta-analyses dietitian, nurse, and social worker, as Postpartum care should include psychoso- and large observational studies examin- needed) is recommended if this resource cial assessment and support for self-care. ing maternal and fetal outcomes have is available. suggested that sulfonylureas, such as gly- All are pregnancy category B Lactation buride, may be inferior to insulin and except for glargine, glulisine, and de- In light of the immediate nutritional and metformin due to increased risk of neo- gludec, which are labeled category C. immunological benefits of breastfeed- natal hypoglycemia and macrosomia with ing for the baby, all women including this class. Type 1 Diabetes those with diabetes should be sup- Metformin Women with type 1 diabetes have an ported in attempts to breastfeed. Metformin, which is associated with a increased risk of hypoglycemia in the may also confer longer- lower risk of hypoglycemia and potential first trimester and, like all women, have term metabolic benefits to both mother lower weight gain, may be preferable to altered counterregulatory response in (29) and offspring (30). care.diabetesjournals.org Management of Diabetes in Pregnancy S97

Gestational Diabetes Mellitus by 35% and 40%, respectively, over 10 years restriction. Antihypertensive drugs Initial Testing compared with placebo (35). known to be effective and safe in preg- Because GDM may represent preexist- nancy include methyldopa, labetalol, ing undiagnosed type 2 or even type 1 Pregestational Type 1 and Type 2 diltiazem, clonidine, and prazosin. diabetes, women with GDM should be Diabetes Chronic diuretic use during pregnancy tested for persistent diabetes or predia- Insulin sensitivity increases with delivery is not recommended as it has been as- betes at 6–12 weeks postpartum with a of the placenta and then returns to pre- sociated with restricted maternal plasma – 75-g OGTT using nonpregnancy criteria pregnancy levels over the following 1 2 volume, which may reduce uteroplacental as outlined in Section 2 “Classification weeks. In women taking insulin, particu- perfusion (37). and Diagnosis of Diabetes.” lar attention is needed to hypoglycemia prevention in the setting of erratic sleep References Postpartum Follow-up and eating schedules. If the pregnancy 1. Holmes VA, Young IS, Patterson CC, et al.; The OGTT is recommended over A1C has motivated the adoption of a healthier Diabetes and Pre- Intervention Trial at the 6- to 12-week postpartum visit diet, building on these gains to support Study Group. Optimal glycemic control, pre- because A1C may be persistently im- weight loss is recommended in the post- eclampsia, and in womenwithtype1diabetesinthediabetes pacted (lowered) by the increased red partum period. and pre-eclampsia intervention trial. Diabetes blood cell turnover related to pregnancy Care 2011;34:1683–1688 or blood loss at delivery. Because GDM Contraception 2. Dabelea D, Hanson RL, Lindsay RS, et al. 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Peri- insulin or oral glucose-lowering medica- all women with diabetes of childbearing age should have family planning options conceptional A1C and risk of serious adverse tion during pregnancy. Ongoing screening pregnancy outcome in 933 women with type 1 may be performed with any recommended reviewed at regular intervals. This ap- diabetes. Diabetes Care 2009;32:1046–1048 glycemic test (e.g., hemoglobin A1C, fast- plies to women in the immediate post- 5. Charron-Prochownik D, Sereika SM, Becker D, ing plasma glucose, or 75-g OGTT using partum period. Women with diabetes et al. Long-term effects of the booster-enhanced READY-Girls preconception counseling program nonpregnant thresholds). have the same contraception options and recommendations as those without on intentions and behaviors for family planning in teens with diabetes. Diabetes Care 2013;36: Gestational Diabetes Mellitus and Type 2 diabetes. 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Suhonen L, Hiilesmaa V, Teramo K. Glycae- Both metformin and intensive life- GDM at enrollment, there was no differ- mic control during early pregnancy and fetal style intervention prevent or delay pro- ence in pregnancy loss, neonatal care, or malformations in women with type I diabetes – gression to diabetes in women with other neonatal outcomes, although mellitus. Diabetologia 2000;43:79 82 11. Maresh MJA, Holmes VA, Patterson CC, et al.; and a history of GDM. Of women in the less intensive treatment Diabetes and Pre-eclampsia Intervention Trial women with a history of GDM and im- group had a higher rate of uncontrolled Study Group. Glycemic targets in the second and paired glucose tolerance, only 5–6indi- hypertension (36). third trimester of pregnancy for women with viduals need to be treated with either During pregnancy, treatment with type 1 diabetes. Diabetes Care 2015;38:34–42 intervention to prevent one case of di- ACE inhibitors and angiotensin receptor 12. 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