Abstract

OBJECTIVE: To investigate the association between maternal glycemic control and the risk of congenital malformations in offspring of women with type 1 diabetes and to examine whether there is a hemoglobin A 1C (Hb A 1C ) threshold value at which the risk for malformations increases significantly. METHODS: Analyses were performed on data from a multinational, observational cohort of 1,908 liveborn offspring of women with type 1 diabetes recruited in early pregnancy from 17 countries between 2013 and 2018. Offspring with malformations were identified according to European Surveillance of Congenital Anomalies version 1.4 and categorized as having one or more major malformations or minor malformations exclusively. The association between first-trimester Hb A 1C levels and the risk of congenital malformations was investigated with splines in crude and adjusted logistic regression models. RESULTS: In total, 11.9% of the offspring (n=227) of women with type 1 diabetes had congenital malformations, including 2.1% (n=40) with at least one severe malformation. Women giving birth to offspring with malformations had a higher prevalence of psychiatric disorders (13.2% vs 7.2%, P <.01), thyroid disorders (33.0% vs 26.7%, P <.05), and folic acid supplementation (87.1% vs 77.7%, P <.01). The Hb A 1C levels in the first trimester were similar (median 6.8% [interquartile range 6.3–7.6%] vs 6.7% [6.2–7.6%], P =.13) compared with women giving birth to offspring without malformations. The spline analysis illustrated a curvilinear association between Hb A 1C levels and the risk of malformations with no clear threshold values. Higher first-trimester Hb A 1C levels were associated with an increased risk of malformations (crude odds ratio [OR] 1.13, 95% CI, 1.01–1.27, adjusted odds ratio [aOR] 1.29, 95% CI, 1.10–1.51) and major malformations (crude OR 1.49, 95% CI, 1.23–1.81, aOR 1.57, 95% CI, 1.15–2.09). CONCLUSION: An increased risk for congenital malformations was curvilinearly associated with higher Hb A 1C levels in early pregnancy among women with type 1 diabetes without any threshold values identified. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01892319.