(219) Exposure to Non-Insulin 2nd-Line Antidiabetic Medications in Early Pregnancy and Risk of Major Congenital Malformations

Friday, August 26, 2022

8:00 AM – 6:00 PM CEST

Location: Hall C

Publication Number: 550

Presenting Author(s)

Carolyn E. Cesta, PhD
– PhD, Karolinska Institutet, Stockholm, Sweden

Co-Author(s)

Ran Rotem
– Harvard T.H. Chan School of Public Health, Boston, MA, USA, United States
Krista Huybrechts, MS, PhD, FISPE
– Harvard Medical School, Boston, Massachusetts, United States
Brian Bateman
– Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA, United States
Gabriel Chodick
– Tel Aviv-Yafo, Tel Aviv, Israel
Ellen W Seely, MD
– Director of Clinical Research, Endocrine Division, Professor of Medicine, Harvard Medical School, Brigham & Women's Hospital, United States
Elisabetta Patorno
– Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, United States
Sonia Hernandez-Diaz, MD, MPH, FISPE
– Professor of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States

Background: Metformin is the 1st line pharmacological treatment for type 2 diabetes (T2DM). The use of 2nd line non-insulin antidiabetic medications (ADM) is increasing overall and in women of reproductive age, which may result in fetal exposure in early pregnancy. However, the teratogenic risk of these drugs is unknown.

Objectives: To evaluate if use of non-insulin 2nd-line ADM exposure in early pregnancy is associated with an increased risk of major congenital malformations (MCM) in the infant compared to pregnancies with no pregestational diabetes and pregnancies with T2DM exposed to insulin, the recommended T2DM treatment in pregnancy.

Methods: We conducted a cohort study of pregnant women with T2DM and their liveborn infants in the IBM MarketScan Research Database in the US (2011-2019) and Maccabi Health Services (MHS) in Israel (2009-2020). Exposure was defined based on ≥1 prescription fills from 90 days before the first day of the last menstrual period (LMP) to LMP+90 of insulin or any non-insulin 2nd line ADM including sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, sodium-glucose co-transporter 2 (SGLT2) inhibitors, or other blood glucose lowering drugs. Crude prevalence ratios (PR) and 95% confidence intervals (CI) were estimated comparing pregnancies exposed to a non-insulin 2nd line ADM to those with no pregestational diabetes (i.e., no Type 1 or T2DM) and those exposed to insulin with or without metformin augmentation. Pregestational diabetes, T2DM, and MCMs were identified using validated algorithms.

Results: Among a total of 1,065,597 pregnancies, we identified 1593 with pregestational T2DM exposed to insulin and 2155 exposed to a non-insulin 2nd line ADM, with sulfonylureas (n=1168) and GLP-1 analogues (n=499) being the most common. The risk of MCM was 4.7% in pregnancies with no pregestational diabetes, 7.7% in those exposed to insulin, and 7.6% in those exposed to a non-insulin 2nd line ADM. The crude PR of MCM for non-insulin 2nd line ADM exposed pregnancies was 1.61 (95%CI 1.39-1.87) compared to pregnancies in women no pregestational diabetes, and 0.99 (95%CI 0.79-1.23) compared to those with T2DM treated with insulin. Results were similar in both cohorts.

Conclusions: Preliminary results show a higher prevalence of MCM in pregnancies exposed to non-insulin 2nd line ADM compared to pregnancies with no pregestational diabetes. However, the PR moves to the null when using a comparison group with the same underlying indication and on the recommended T2DM treatment in pregnancy. Further exploration will focus on individual 2nd-line non-insulin ADM drugs and separate MCM groups (e.g., cardiac) in adjusted analyses accounting for T2DM severity and glycemic control.