# Maternal infections during pregnancy and offspring cognitive outcome: A nationwide full-sibling cohort study

## TL;DR

A study in Denmark found no strong link between maternal infections during pregnancy and cognitive outcomes in children, suggesting these infections likely don't harm long-term brain development.

## Contribution

The study used a nationwide sibling cohort to account for shared family factors, offering a novel approach to reduce confounding in assessing maternal infection effects.

## Key findings

- No consistent difference in school grades or IQ was found in children exposed to maternal infections during pregnancy.
- Findings suggest no critical time windows for fetal brain development sensitive to common maternal infections.
- Results support the safety of commonly prescribed antimicrobials during pregnancy regarding offspring cognitive outcomes.

## Abstract

Maternal infections are common during pregnancy, but it is unclear how they impact the cognitive outcome of the offspring, with many studies suggesting adverse effects. Using long-term follow-up of a nationwide sibling cohort in Denmark with information on maternal antimicrobial prescriptions in community pharmacies and in-patient hospitalizations for infection, we aimed to estimate the effect of maternal infections during pregnancy on offspring school grades and intelligence test results in adolescence.

From population-based national registries we defined a cohort of all full-siblings, born from January 1, 1996 to December 31, 2,003 in Denmark, and linked them to maternal filled prescription for antimicrobial pharmaceuticals and maternal hospitalizations for infection during pregnancy. Standardized examination grades in language and mathematics at the final year of compulsory schooling, in addition to intelligence test scores (calculated as IQ) for a nested sub-cohort of full brothers, were used as outcomes. Among 274,166 children in the full-sibling cohort, 80,817 (29.5%) had a mother who during her pregnancy filled a prescription for a systemic antimicrobial, while 5,628 (2.1%) had a mother who during her pregnancy was hospitalized due to an infection. We found no consistent difference in school grades in language (z-score difference, 0.0, 95% confidence interval [CI] [−0.0,0.0]; p = 0.920) and mathematics (z-score difference, −0.0, 95% CI [−0.0,−0.0]; p = 0.042), and in IQ (IQ-difference, 0.3, 95% CI [−0.2,0.7]; p = 0.217), in children whose mother filled one antimicrobial prescription compared with children whose mother did not fill any, when taking shared family factors into account, while many associations were consistently significant when not taking shared family factors into account. Furthermore, we found no indication of an impact of maternal in-patient hospitalizations for infections during pregnancy on school grades (z-score difference for language, −0.0, 95% CI [−0.1,0.0]; p = 0.103; z-score difference for mathematics, 0.0, 95% CI [−0.0,0.0]; p = 0.809) or IQ (IQ-difference, 0.4, 95% CI [−0.8,1.6]; p = 0.545), when also taking shared family factors into account. Similar findings were found when considering infections in bi-weekly exposure periods during gestation. The main limitations of the study were lacking information on within hospital pharmaceutical prescriptions and the underlying pathogenic microorganisms.

Our study does not support major effects of common maternal infections during pregnancy on offspring cognitive outcomes, and support the safety of commonly prescribed antimicrobials during pregnancy with respect to the long-term cognitive outcomes of the offspring.

Common maternal infections during pregnancy have been associated with offspring cognitive outcomes, but previous findings are conflicting.

Only few of the previous studies investigating the association between maternal infections during pregnancy and cognitive outcomes used a sibling design to account for unmeasured familial confounding.

Furthermore, previous studies investigated the influence of infections only in very broad exposure periods (i.e., during the whole pregnancy or during a trimester), potentially missing strong effects during short and critical developmental windows during gestation.

Using a nationwide full-sibling cohort of children born in Denmark between 1996 and 2003, we investigated the association between maternal infections during pregnancy (identified by antimicrobial prescriptions or hospitalization for infection) and subsequent school grades in language and mathematics.

For a nested full-brother cohort we additionally investigated the association between maternal infection during pregnancy and offspring IQ using results from an intelligence test conducted during evaluation for mandatory military service.

The study found no consistent association between common maternal infections during pregnancy and offspring school grades or intelligence.

The findings support a minimal impact of common maternal infections during pregnancy on cognitive abilities of the offspring.

The findings indicate that there does not exist critical time windows for fetal brain development that are sensitive to common maternal infections during pregnancy.

Future studies on the association between maternal infections and cognitive outcomes will benefit from using a sibling design to diminish unmeasured familial confounding.

The main limitations of the study were lacking information on antimicrobials used during hospitalization and the underlying microorganisms responsible for the maternal infections.

Anders Husby and colleagues investigate the effect of maternal infections during pregnancy on offspring school grades and intelligence test results in adolescence.