20-year study challenges link between gestational diabetes and ADHD

Gestational diabetes mellitus (GDM) is not associated with attention-deficit/hyperactivity disorder (ADHD) in offspring, a 20-year multinational study has shown.

“The impact of maternal diabetes mellitus [ie, GDM and pregestational DM (PGDM)] on the risk of ADHD in children has been a subject of debate because of inconsistent findings in previous studies,” wrote the researchers.

It was hypothesized that hyperglycaemia may affect the neurodevelopment of offspring by altering the intrauterine environment with increased inflammation, metabolic stress, and lipotoxicity. “[However,] previous studies showing an association between maternal diabetes mellitus and ADHD often overlooked unmeasured confounders such as shared genetics and environmental factors,” pointed out the researchers. [Nat Med 2024;doi:10.1038/s41591-024-02917-8]

To control these potential confounders, the researchers used patient-level electronic health data to conduct a multinational, population-based cohort study with sibling-matched analyses. They included >3.6 million mother-child pairs from Hong Kong, Taiwan, New Zealand, Finland, Iceland, Norway, and Sweden between 2001 and 2014, with follow-up until 2020.

Results showed that children born to mothers with maternal diabetes mellitus had a significantly higher risk of ADHD (pooled hazard ratio [HR], 1.16; 95 percent confidence interval [CI], 1.08–1.24; I², 91 percent; p<0.0001) vs unexposed children. Higher risks of ADHD were observed for both GDM (pooled HR, 1.10; 95 percent CI,1.04–1.17; I², 79 percent; p=0.001) and PGDM (pooled HR, 1.39; 95 percent CI, 1.25–1.55; I², 77 percent; p<0.00001), indicating a small-to-moderate association between maternal diabetes mellitus and ADHD.

“Of note, the association is likely confounded by shared genetic and familial factors, at least in the case of GDM,” pointed out co-lead author Professor Ian Chi-Kei Wong of the Department of Pharmacology and Pharmacy, University of Hong Kong. This is evidenced by sibling-matched analyses showing similar risks of ADHD in siblings with discordant exposure to GDM in pregnancy (pooled HR, 1.05; 95 percent CI, 0.94–1.17; I²,57 percent; p=0.38).

Furthermore, the risk was similar between children born to unmedicated vs medicated mothers with GDM (pooled HR, 1.14; 95 percent CI, 0.92–1.42; I², 81 percent; p=0.22). This finding was contradictory to a previous US study showing a 38 percent increased risk of ADHD in offspring born to mothers requiring vs those not requiring GDM treatment (HR, 1.38; 95 percent CI, 1.20–1.59; p<0.001). [Diabetes Care 2018;41:2502–2508; Nat Med 2024;doi:10.1038/s41591-024-02917-8]

“Combining our results with currently available evidence, it remains unclear whether GDM severity [and resulting use of] antidiabetic medication underlies the association with ADHD,” commented the researchers. “This further poses a question on the role of glycaemic control during pregnancy in mitigating the risk of ADHD in offspring.”

“This implies that women who are planning pregnancy should look at their holistic risk profile rather than focusing solely on GDM,” Wong said. “Future studies should investigate the specific roles of genetic factors and glycaemic control during different developmental stages of human embryonic brain.”