Risk of attention-deficit hyperactivity disorder in offspring of mothers with infections during pregnancy

Kjersti M Walle; Ragna B Askeland; Kristin Gustavson; Siri Mjaaland; Eivind Ystrom; W Ian Lipkin; Per Magnus; Camilla Stoltenberg; Ezra Susser; Michaeline Bresnahan; Mady Hornig; Ted Reichborn-Kjennerud; Helga Ask

doi:10.1002/jcv2.12070

Risk of attention-deficit hyperactivity disorder in offspring of mothers with infections during pregnancy

JCPP Adv. 2022 Mar 10;2(2):e12070. doi: 10.1002/jcv2.12070. eCollection 2022 Jun.

Authors

Kjersti M Walle¹, Ragna B Askeland^{1

2}, Kristin Gustavson^{1

3}, Siri Mjaaland¹, Eivind Ystrom^{1

4

5}, W Ian Lipkin^{6

7

8}, Per Magnus⁹, Camilla Stoltenberg^{1

10}, Ezra Susser^{6

11}, Michaeline Bresnahan^{6

11}, Mady Hornig⁶, Ted Reichborn-Kjennerud^{1

12}, Helga Ask¹

Affiliations

¹ Norwegian Institute of Public Health Oslo Norway.
² Medical Research Council Integrative Epidemiology Unit University of Bristol Bristol UK.
³ Department of Psychology University of Oslo Oslo Norway.
⁴ Promenta Research Center University of Oslo Oslo Norway.
⁵ School of Pharmacy University of Oslo Oslo Norway.
⁶ Department of Epidemiology Columbia University Mailman School of Public Health New York USA.
⁷ Center for Infection and Immunity Columbia University Mailman School of Public Health New York USA.
⁸ Departments of Neurology and Pathology Columbia University Vagelos College of Physicians and Surgeons New York USA.
⁹ Centre for Fertility and Health Norwegian Institute of Public Health Oslo Norway.
¹⁰ Department of Global Public Health and Primary Care University of Bergen Bergen Norway.
¹¹ New York State Psychiatric Institute New York USA.
¹² Department of Medicine University of Oslo Oslo Norway.

Abstract

Background: Maternal infections during pregnancy are common events that have been suggested to be risk factors for Attention-deficit hyperactivity disorder (ADHD) in offspring. Only a few studies have been conducted to date and results are conflicting. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, considering timing of exposure and the role of fever.

Methods: We used data from the prospective Norwegian Mother, Father and Child Cohort Study (MoBa), including more than 112,000 pregnancies, linked with data from the Medical Birth Registry of Norway and the Norwegian Patient Registry to estimate odds ratios for the likelihood that children develop ADHD after being exposed to maternal infections during gestation.

Results: Children exposed to any maternal infection during pregnancy showed increased risk of receiving an ADHD diagnosis (OR = 1.15, CI = 1.03-1.27). Specifically, increased ADHD risk was observed after exposure to genitourinary infections in second (OR = 1.42, CI = 1.06-1.90) or third trimester (OR = 2.04, CI = 1.19-3.49), and to respiratory infections in second trimester (OR = 1.31, CI = 1.12-1.54), provided these infections were accompanied by episodes of fever. Increased ADHD risk was also observed after exposure to diarrhea without fever in the third trimester (OR = 1.25, CI = 1.07-1.46).

Conclusions: Overall, our results suggest that prenatal exposure to maternal infections, particularly with co-occurring episodes of fever, are risk factors for ADHD. Fever (or severity of the infection) appears to be more important in mid-pregnancy associations. Our results indicate that type of infection and timing of exposure might influence the associations, but small effect sizes require careful interpretations. The association between infection and ADHD should be estimated using discordant siblings or other negative control designs that give better adjustment for unmeasured familial confounding.

Keywords: ADHD; MBRN; MoBa; infections; pregnancy.