Diabetes Medications in Preconception and Pregnancy

Educational Objectives

The goal of this program is to improve the management of type 2 diabetes in preconception and pregnancy. After hearing and assimilating this program, the clinician will be better able to:

1. Analyze the effects of elevated maternal hemoglobin A_1C levels during preconception and pregnancy.
2. Appraise the American College of Obstetricians and Gynecologists recommendations for managing gestational diabetes (GD).
3. Evaluate the effectiveness of different diabetes medications in achieving glycemic control in pregnant women with GD.

Summary

Type 2 Diabetes (T2D) During Preconception and Pregnancy

Introduction: T2D during preconception and pregnancy can be managed by identifying and using a suitable effective medication to achieve glycemic control

Preconception counseling for T2D: blood glucose above normal values is a dose-dependent teratogen; elevated hemoglobin A_1C (HbA1C) is associated with increased congenital anomalies; Miller et al (1981) found a significantly higher incidence of congenital anomalies in the offspring of women with elevated HbA_1C values; He et al (2024) — found a linear relationship between increasing HbA_1C and the increasing risk for congenital heart defects; older maternal age is also an independent risk factor for congenital heart defects; the risk for congenital anomalies is ≈2-fold higher with HbA_1C of 9% to 10% compared with HbA_1C of 6% or 7%; it is important to communicate with patients that achieving glycemic control changes pregnancy outcomes

Preconception care (PCC): Wahabi et al (2020) — PCC reduced risk for congenital malformation by ≈70% and perinatal mortality by ≈50%; PCC lowers HbA_1C in early pregnancy by ≈1.3%; <33% of patients with T2D seek prepregnancy counseling; American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin 201 — all health care provider visits should be an opportunity to talk about T2D management during pregnancy

Preconception T2D management: the first line of T2D management is lifestyle modifications, ie, weight loss ≥5%, moderate to intense physical activity 150 min per week, and avoiding prolonged sitting; if these are not effective, metformin can be administered; the American Diabetes Association (ADA) prefers semaglutide (Ozempic; Wegovy) as the effective first-line treatment option over insulin; the ADA recommends prioritizing the patient’s goals of care during decision making for T2D management; although fetal risk cannot be ruled out for any T2D medications, initiating antidiabetes medications is considered to be a better option than uncontrolled T2D

Semaglutide: women often get pregnant while on semaglutide for T2D or obesity management; its implications in pregnancy are largely unknown; it also has a long washout period (5-6 wk); one should stop semaglutide during pregnancy and initiate metformin or insulin; effective contraception is recommended when starting semaglutide

Individualized PCC: ideally, all patients with T2D should use contraception; passive preconception phase — patients who do not use contraception are considered to be in the active preconception phase; they should be managed with an individualized approach, eg, semaglutide, lifestyle modifications, weight loss surgery to reverse T2D, and regular HbA_1C assessment; active preconception phase — frequent HbA_1C checks and exercise are recommended for patients (with a new diagnosis of T2D) actively trying to get pregnant; insulin helps to achieve fast and efficient glycemic control; for patients planning fertility therapies, insulin with or without metformin is recommended for aggressive glycemic control (when oral agents, diet, and exercise are ineffective)

T2D during pregnancy: insulin requirements are significantly higher (4-5 times) during pregnancy to maintain euglycemia; thus, patients with T2D may require additional medications during pregnancy; most patients require insulin; metformin is a useful tool to lower the necessary doses of insulin; oral agents have a limited role during pregnancy

Gestational Diabetes (GD)

Overview: lifestyle modifications, diet, and exercise are first-line management strategies; ≈30% of patients with GD need medication

ACOG Practice Bulletin 190: GD management begins with nonpharmacologic approaches, dietary modifications, exercise, and glucose monitoring; insulin is the first-line agent when nonpharmacologic approaches are insufficient to achieve glycemic control; metformin may be a reasonable alternative, but patients should be counseled about the lack of superiority when compared with insulin, placental transfer of the drug, and the absence of long-term data in exposed offspring; glyburide should not be recommended as a first-choice pharmacologic treatment because, in most studies, it does not yield equivalent outcomes to insulin or metformin; insulin is preferred because oral agents are not approved by the US Food and Drug Administration (FDA) for the treatment of GD, cross the placenta, and lack long-term neonatal safety data; the current medical literature note that trials are of poor quality and are not designed to assess equivalence or noninferiority when comparing oral agents to insulin

Alternative agents: metformin (and rarely glyburide) is a reasonable alternative choice for women who decline insulin, the obstetricians or obstetric care providers believe are unable to safely administer insulin, or cannot afford insulin; the limitations of safety data and high rate of treatment failure that requires insulin supplementation should be discussed with the patient

Alternative recommendations: Society for Maternal-Fetal Medicine statement on GD — metformin is a reasonable and safe first-line pharmacologic alternative; there are concerns about glyburide; the evidence of benefit of one oral agent over the other remains limited; the difference in guidelines (vs ACOG) is based on the values placed by different experts and providers on the available evidence in the medical literature and is not meant to represent an exclusive course of management; National Institute for Health and Care Excellence (NICE) guidelines — if glucose targets are not met with diet and exercise ≤2 wk, offer metformin; if metformin is contraindicated or unacceptable, offer insulin

Issues with the ACOG guidelines: many medicines used in pregnancy cross the placenta; the data on oral medications are satisfactory; long-term safety data for insulin are also limited; an “insulin-always-first” approach fails to consider patient preference; suggesting that metformin could be the first line for patients who cannot afford insulin creates significant equity concerns; implying that a patient who declines insulin is making an inferior decision can be stigmatizing and create equity concerns

FDA approval: the FDA labeling for insulin lispro and metformin (both historically, category B medications) are similar, ie, no clear association between the medication and major birth defects; the studies cannot establish the absence of associated risk because of methodologic limitations

Studies comparing metformin, glyburide, and insulin for GD: Rowan et al (2008) — found no difference in the primary composite outcome, ie, hypoglycemia, jaundice, birth trauma, low APGAR (appearance, pulse, grimace, activity, respiration) score, and prematurity between metformin and insulin; ≈50% of the patients on metformin did not require supplemental insulin and had good outcomes; Langer et al (2000) — found no difference in neonatal hypoglycemia, preeclampsia, large for gestational age (LGA), and blood glucose level between glyburide and insulin

Guo et al (2019): in this meta-analysis, metformin reduced the risk for preeclampsia by 20%, neonatal intensive care unit (NICU) admission by 25%, and neonatal hypoglycemia by 30% compared with insulin; glyburide had a greater increase in neonatal hypoglycemia compared with insulin

Hedderson et al (2022): 86% of patients taking glyburide during pregnancy as their initial medication continued exclusive glyburide therapy until delivery; 66% of patients with insulin continued exclusive insulin therapy (some switched to glyburide); the risk for neonatal respiratory distress syndrome and NICU admission were lower with glyburide compared with insulin; no significant differences in risk for neonatal hypoglycemia, jaundice, shoulder dystocia, LGA, and cesarean delivery were observed between glyburide and insulin initiation

Long-term outcomes of oral agents: studies on long-term outcomes found no major differences in blood glucose, body morphology, psychosocial or developmental differences in the children born to mothers with GD treated with metformin compared with those treated with insulin (Tertti et al [2015]; Landi et al [2019])

Patient preference: in the study by Rowan et al (2008), more women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76% vs 27%); thus, patients preferred oral agents to injections; Venkatesh et al (2024) — of the 144 patients counseled about GD pharmacotherapy, 60% opted for metformin and 40% opted for insulin; individuals in minority groups were more likely to receive metformin compared with non-Hispanic White individuals (35% vs 17%); individuals who chose metformin prioritized avoiding injections, wanting to take medication ≤2 times per day, and believing that both medications can equally prevent adverse pregnancy outcomes; thus, the study demonstrated that the patients have priorities that influence their decision making

Take-home messages: the “insulin-always-first” approach for GD negates the role of shared decision-making; one should check HbA_1C for all patients with risk factors for T2D who may conceive and offer interventions; patients with T2D should aspire to maintain an HbA_1C <6.5%; there are no major outcome differences between insulin, metformin, and glyburide for GD management; the speaker prefers personalized treatment approach with shared decision making for GD management

Readings

ACOG practice bulletin no. 190: gestational diabetes mellitus. Obstet Gynecol. 2018;131(2):e49-e64. doi:10.1097/AOG.0000000000002501; American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins — Obstetrics. ACOG practice bulletin no. 201: pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi:10.1097/AOG.0000000000002960; Guo L, Ma J, Tang J, Hu D, et al. Comparative efficacy and safety of metformin, glyburide, and insulin in treating gestational diabetes mellitus: a meta-analysis. J Diabetes Res. 2019;2019:9804708. Published 2019 Nov 4. doi:10.1155/2019/9804708; He R, Hornberger LK, Kaur A, et al. Risk of major congenital heart disease in pregestational maternal diabetes is modified by hemoglobin A1c. Ultrasound Obstet Gynecol. 2024;63(3):378-384. doi:10.1002/uog.27456; Hedderson MM, Badon SE, Pimentel N, et al. Association of glyburide and subcutaneous insulin with perinatal complications among women with gestational diabetes [published correction appears in JAMA Netw Open. 2022 Apr 1;5(4):e2212571. doi: 10.1001/jamanetworkopen.2022.12571.]. JAMA Netw Open. 2022;5(3):e225026. Published 2022 Mar 1. doi:10.1001/jamanetworkopen.2022.5026; Landi SN, Radke S, Engel SM, et al. Association of long-term child growth and developmental outcomes with metformin vs insulin treatment for gestational diabetes [published correction appears in JAMA Pediatr. 2019 Feb 1;173(2):199. doi: 10.1001/jamapediatrics.2018.5190.]. JAMA Pediatr. 2019;173(2):160-168. doi:10.1001/jamapediatrics.2018.4214; Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343(16):1134-1138. doi:10.1056/NEJM200010193431601; Miller E, Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med. 1981;304(22):1331-1334. doi:10.1056/NEJM198105283042204; Ogunyemi D, Jesse M, Davidson M. Comparison of glyburide versus insulin in management of gestational diabetes mellitus. Endocr Pract. 2007;13(4):427-428. doi:10.4158/EP.13.4.427; Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes [published correction appears in N Engl J Med. 2008 Jul 3;359(1):106]. N Engl J Med. 2008;358(19):2003-2015. doi:10.1056/NEJMoa0707193; Skov K, Mandic IN, Nyborg KM. Semaglutide and pregnancy. Int J Gynaecol Obstet. 2023;163(2):699-700. doi:10.1002/ijgo.15092; Tertti K, Eskola E, Rönnemaa T, et al. Neurodevelopment of two-year-old children exposed to metformin and insulin in gestational diabetes mellitus. J Dev Behav Pediatr. 2015;36(9):752-757. doi:10.1097/DBP.0000000000000230; Venkatesh KK, Wu J, Trinh A, et al. Patient priorities, decisional comfort, and satisfaction with metformin versus insulin for the treatment of gestational diabetes mellitus. Am J Perinatol. 2024;41(S 01):e3170-e3182. doi:10.1055/s-0043-1777334; Wahabi HA, Fayed A, Esmaeil S, et al. Systematic review and meta-analysis of the effectiveness of pre-pregnancy care for women with diabetes for improving maternal and perinatal outcomes. PLoS One. 2020;15(8):e0237571. Published 2020 Aug 18. doi:10.1371/journal.pone.0237571.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Salmeen was recorded at the Obstetrics and Gynecology Update: What Does the Evidence Tell Us?, held September 25-27, 2024, in San Francisco, CA, and presented by University of California, San Francisco (UCSF). For information on upcoming CME activities from this presenter, please visit ObGynUpdate.ucsf.edu. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

OB720701

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Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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