Maternal periconception hyperglycemia, preconception diabetes, and risk of major  congenital malformations in offspring

Ran S Rotem; Marc G Weisskopf; Brian Bateman; Krista Huybrechts; Sonia Hernández-Diáz

doi:10.1093/humrep/deae233

Maternal periconception hyperglycemia, preconception diabetes, and risk of major congenital malformations in offspring

Rotem RS, Weisskopf MG, Bateman B, Huybrechts K, Hernández-Diáz S

Published December 2024 Human Reproduction (Oxford, England), 39(12), 2816-2829

DOI 10.1093/humrep/deae233 PMID 39406385 PMC PMC11630054

RRM Academy Synopsis

Higher HbA1c at conception is tied to heart defects in Israeli babies

In a cohort of 46 534 Israeli children, higher maternal HbA1c around conception was linked to more congenital heart defects in newborns. HbA1c is a blood test of average blood sugar. Among mothers with type 2 diabetes, about 35 out of 1,000 children had a heart defect, against about 13 out of 1,000 among mothers without diabetes.

Key Findings

Among 46 534 children born in 2001–2020, heart defects occurred in 134 of 5855 (2.3%) whose mothers had an abnormal HbA1c and 566 of 40 679 (1.4%) with a normal one.
The authors' analysis suggested excess risk of congenital heart defects beginning at HbA1c values above the conventional threshold, with a possible plateau at very high levels.
Heart defects affected 48 of 1361 children (3.5%) of mothers with type 2 diabetes and 398 of 30 964 (1.3%) without diabetes (adjusted odds ratio 1.89, 95% CI 1.18, 3.03).
Among 433 children of mothers with type 2 diabetes and a normal HbA1c, 14 (3.2%) had a heart defect (odds ratio 2.06, 95% CI 1.14, 3.74).
Among 186 children of mothers with type 2 diabetes, a normal HbA1c and continuous medication use, 5 (2.7%) had a heart defect (odds ratio 1.63, 95% CI 0.60, 4.46).

Interpretation

This cohort study followed 46 534 children born in Israel between 2001 and 2020, linking maternal HbA1c and diabetes status at conception to congenital heart defects diagnosed in their children. The association with elevated HbA1c held across values above the conventional threshold, with a possible plateau at very high levels. The type 2 diabetes association persisted, modestly attenuated, after adjustment for other heart and metabolic conditions. The authors suggest several explanations, including pathways partly independent of blood sugar. The authors note that HbA1c averages blood sugar over 8 to 12 weeks and may miss short-term swings. The findings support larger studies of preconception glucose control and its role in congenital heart defects.

RRM Context

Restorative reproductive medicine approaches preconception health as a root-cause question, and metabolic health is part of it. The cohort links a mother's HbA1c and diabetes status at conception with heart defects in her baby. Mothers with type 2 diabetes and normal HbA1c values still had a raised risk, and the estimate stayed above 1 among those with consistent medication use. The authors read this as a sign of pathways partly independent of blood sugar control, and they call for research on insulin resistance and high insulin levels.

Our editorial summary of this paper, not the article's abstract.

Abstract

Study Question

What are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring?

Summary Answer

Maternal periconceptional glycated hemoglobin (HbA1c) levels over 5.6% were associated with an increased risk of congenital heart defects (CHD) in the offspring, and maternal preconception diabetes was associated with an increased risk of CHD, including when HbA1c levels were within euglycemic ranges.

What Is Known Already

Maternal preconception diabetes has been linked with MCMs in the offspring. However, evidence concerning associations with specific periconception serum measures of hyperglycemia, and susceptibility of different organ systems, is inconsistent. Moreover, limited evidence exists concerning the effectiveness of antidiabetic medications in mitigating diabetes-related teratogenic risks.

Study Design, Size, Duration

A large Israeli birth cohort of 46 534 children born in 2001-2020.

Participants/Materials, Setting, Methods

Maternal HbA1c test results were obtained from 90 days before conception to mid-pregnancy. Maternal diabetes, other cardiometabolic conditions, and MCMs in newborns were ascertained based on clinical diagnoses, medication dispensing records, and laboratory test results using previously validated algorithms. Associations were modeled using generalized additive logistic regression models with thin plate penalized splines.

Main Results and the Role of Chance

Maternal periconceptional HbA1c value was associated with CHD in newborns, with the risk starting to increase at HbA1c values exceeding 5.6%. The association between HbA1c and CHD was stronger among mothers with type 2 diabetes mellitus (T2DM) compared to the other diabetes groups. Maternal pre-existing T2DM was associated with CHD even after accounting for HbA1C levels and other cardiometabolic comorbidities (odds ratio (OR)=1.89, 95% CI 1.18, 3.03); and the OR was materially unchanged when only mothers with pre-existing T2DM who had high adherence to antidiabetic medications and normal HbA1c levels were considered.

Limitations, Reasons for Caution

The rarity of some specific malformation groups limited the ability to conduct more granular analyses. The use of HbA1c as a time-aggregated measure of glycemic control may miss transient glycemic dysregulation that could be clinically meaningful for teratogenic risks.

Wider Implications of the Findings

The observed association between pre-existing diabetes and the risk of malformations within HbA1c levels suggests underlying causal pathways that are partly independent of maternal glucose control. Therefore, treatments for hyperglycemia might not completely mitigate the teratogenic risk associated with maternal preconception diabetes.

Study Funding/Competing Interests

The work was supported by NIH grants K99ES035433, R01HD097778, and P30ES000002. None of the authors reports competing interests.

Trial Registration

N/A.

Ran S Rotem, Marc G Weisskopf, Brian Bateman, Krista Huybrechts, Sonia Hernández-Diáz

R Rotem, M Weisskopf, B Bateman, K Huybrechts, S Hernández-Diáz

PMID 39406385 39406385 DOI 10.1093/humrep/deae233 10.1093/humrep/deae233 Rotem et al. 2024, Rotem 2024

Keywords

Glycated Hemoglobin, Hemoglobin A1c Protein, Human, Hypoglycemic Agents

Maternal periconception hyperglycemia, preconception diabetes, and risk of major congenital malformations in offspring

Higher HbA1c at conception is tied to heart defects in Israeli babies

Key Findings

Interpretation

RRM Context

Abstract

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