Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

IMPORTANCE: Few translational human studies have assessed the association of prenatal maternal immune activation with altered brain development and psychiatric risk in newborn offspring.

OBJECTIVE: To identify the effects of maternal immune activation during the 2 nd and 3 rd trimesters of pregnancy on newborn brain metabolite concentrations, tissue microstructure, and longitudinal motor development.

DESIGN: Prospective longitudinal cohort study conducted from 2012 - 2017.

SETTING: Columbia University Irving Medical Center and Weill Cornell Medical College.

PARTICIPANTS: 76 nulliparous pregnant women, aged 14 to 19 years, were recruited in their 2 nd trimester, and their children were followed through 14 months of age.

EXPOSURE: Maternal immune activation indexed by maternal interleukin-6 and C-reactive protein in the 2 nd and 3 rd trimesters of pregnancy.

MAIN OUTCOMES AND MEASURES: The main outcomes included (1) newborn metabolite concentrations, measured as N-acetylaspartate, creatine, and choline using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity measured using Diffusion Tensor Imaging; and (3) indices of motor development assessed prenatally and postnatally at ages 4- and 14-months.

RESULTS: Maternal interleukin-6 and C-reactive protein levels in the 2 nd or 3 rd trimester were significantly positively associated with the N-acetylaspartate, creatine, and choline concentrations in the putamen, thalamus, insula, and anterior limb of the internal capsule. Maternal interleukin-6 was associated with fractional anisotropy in the putamen, insula, thalamus, precuneus, and caudate, and with mean diffusivity in the inferior parietal and middle temporal gyrus. C-reactive protein was associated with fractional anisotropy in the thalamus, insula, and putamen. Regional commonalities were found across imaging modalities, though the direction of the associations differed by immune marker. In addition, a significant positive association was observed between offspring motor development and both maternal interleukin-6 and C-reactive protein (in both trimesters) prenatally and 4- and 14-months of age.

CONCLUSIONS AND RELEVANCE: Using a healthy sample, these findings demonstrate that levels of maternal immune activation in mid- to late pregnancy associate with tissue characteristics in newborn brain regions primarily supporting motor integration/coordination and behavioral regulation and may lead to alterations in motor development.

KEY POINTS: Question: What are the associations of prenatal maternal immune activation (MIA) with newborn brain microstructure, metabolite concentrations, and longitudinal motor development? Findings: In this longitudinal cohort study we recruited 76 adolescent and young adult pregnant women and assessed maternal interleukin (IL)-6 and C-reactive protein (CRP) levels in the 2 nd and 3 rd trimesters. These pro-inflammatory markers were significantly associated with brain microstructure and metabolite concentrations in newborns, and longitudinal motor development (prenatally, 4- and 14-months of age). Meaning: This study suggests that prenatal exposure to MIA has an influence on brain microstructure, metabolite concentration and motor development in offspring.