Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs

Abstract

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

Fig. 1. Illustration of cohort inclusion and pregnancy periods.

^aThe earliest date of mothers’ health data in each data source. ^bBaseline conditions included: demographics, maternal conditions and medication use. For HK analysis, maternal age at delivery and birth year were assessed at the date of delivery, body mass index (BMI) was assessed from LMP − 365 days to LMP − 1 day and all other covariates were assessed before LMP; for analysis in Nordic countries and New Zealand, medication use was assessed from LMP − 365 days to LMP − 1 day, and diagnoses were assessed from LMP − 365 days to delivery date; for Taiwan analysis, all covariates were assessed within 2 years before the date of delivery. ^cExposure window: (1) Period before pregnancy, (2) first trimester: LMP to LMP + 90 days, (3) second trimester: LMP + 91 days to LMP + 180 days, and (4) third trimester: LMP + 181 days to delivery date. ^dEarliest of: date of ADHD diagnosis, date of first ADHD medication prescription, date of death, end of database catchment period.

Fig. 2. Flowchart of cohort identification.

^aNot applicable to Finland data, where residence/migration data are not available. ^bIndividuals could fulfill more than one exclusion criteria.

Fig. 3. Meta-analyses of maternal diabetes and the risk of ADHD in offspring.

Data are presented as HRs and 95% CIs, which were adjusted for demographics, socioeconomic status, birth year, multifetal pregnancies, maternal conditions and use of relevant medications using Cox proportional hazard regression, with a significance level of 5% for a two-sided test. No adjustments were made for multiple comparisons. df, degrees of freedom; IV, inverse variance; s.e., standard error; T1DM, type 1 pregestational diabetes; T2DM, type 2 pregestational diabetes.

Fig. 4. Meta-analyses of discordant GDM exposure in siblings and the risk of ADHD.

Data are presented as HRs and 95% CIs, which were adjusted for demographics, socioeconomic status, birth year, multifetal pregnancies, maternal conditions and use of relevant medications using Cox proportional hazard regression, with a significance level of 5% for a two-sided test.

Extended Data Fig. 1. Sample size and power considerations.

Notes: Results are rounded up to the nearest integer. Abbreviations: CC, continuity correction.

Extended Data Fig. 2. General definition of exposure groups.

Abbreviations: GDM, gestational diabetes mellitus; MDM, maternal diabetes mellitus; PGDM, pregestational diabetes mellitus.

Extended Data Fig. 3. Cumulative incidence of ADHD in different comparison groups from the main analyses.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; MDM, maternal diabetes mellitus.

Extended Data Fig. 4. Results of comparisons between different MDM types.

Notes: Data are presented as hazard ratios and 95% CIs, which were adjusted for demographics, socioeconomic status, birth year, multifoetal pregnancies, maternal conditions and use of relevant medications using Cox proportional hazard regression, with a significance level of 5% for a two-sided test. No adjustments were made for multiple comparisons. Abbreviations: CI, confidence interval; df, degrees of freedom; GDM, gestational diabetes mellitus; IV, inverse variance; MDM, maternal diabetes mellitus; PGDM, pregestational diabetes mellitus; T1DM, type 1 pregestational diabetes mellitus; T2DM, type 2 pregestational diabetes mellitus; SE, standard error.

Extended Data Fig. 5. Directed acyclic graph related to the analyses.

Notes: * including diagnosis or medication prescription; psychiatric and neurological conditions: including ASD, anxiety disorders, bipolar disorders, depression, disorders of psychological development, epilepsy, illicit drug use, intellectual disability, personality disorders, schizophrenia, sleep disorders; other chronic medical conditions: including cluster headache, crohn’s disease and ulcerative colitis, hypertension, migraine or other headaches, polycystic ovary syndrome, renal disease, rheumatoid arthritis and other inflammatory polyarthropathies, thyroid disorders; Medications for psychiatric and neurological conditions: including antihypertensives, antipsychotics, antidepressants, antiepileptics, antiparkinson drugs, anxiolytics, sedatives, opioids, triptans; socioeconomic status: defined by income level, birth institution or maternal education according to each data source.