Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review

Abstract

Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such as autoimmunity, asthma, and infection. Maternal immune activation (MIA), triggered by both acute and systemic chronic inflammation, is hypothesized to be one of the mechanisms implicated in the pathogenesis of neurodevelopmental disorders (NDD). Although there is substantial preclinical evidence to support the MIA hypothesis, the human evidence is disparate. We performed a systematic review on human studies examining associations between maternal inflammatory states and offspring NDDs (autism spectrum disorder- ASD, attention deficit hyperactivity disorder-ADHD, Tourette syndrome-TS). 32 meta-analyses and 26 additional individual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-eclampsia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-eclampsia, smoking, low socioeconomic status (SES), stress, autoimmune disease, and asthma. Maternal states associated with TS include low SES, depression, and autoimmune diseases. Diverse maternal inflammatory states in pregnancy are associated with common offspring NDDs. Given the increased prevalence of NDDs, there is urgent need to explore relative and cumulative maternal risk factors and disease mechanisms. Defining preventable risk factors in high-risk pregnancies could mitigate the expression and severity of NDDs.

Fig. 1. Maternal immune activation, triggered by acute and systemic chronic inflammation, is proposed to affect fetal neurodevelopment, through inflammatory and epigenetic mechanisms.

Common maternal disease and environmental factors including obesity, gestational diabetes, pre-eclampsia, smoking, pollution, low socioeconomic status, depression, psychosocial stress, autoimmune diseases and asthma are implicated in systemic chronic inflammation. In addition, infection is involved in acute inflammation. These maternal inflammatory states play a key role in immune activation during pregnancy through the placenta and immature blood-brain barrier to cause dysfunction in the developing fetal brain and prime the child to be susceptible to future hits through microglia activation and epigenetic alterations, manifesting a spectrum of diverse neurodevelopmental outcomes with varied expression and progression.

Fig. 2. Study selection flow diagram of studies included in review.

Study selection flow diagram of (a) meta analysis and (b) individual studies. No meta-analyses investigated associations between maternal asthma and ASD or ADHD, low socioeconomic status and ASD, or maternal infection and ADHD in offspring. A second search to look for individual states examining these associations was performed and included into the review.

Fig. 3. Epidemiological studies of maternal inflammatory states and autism spectrum disorder (ASD) in offspring.

Maternal inflammatory states included in Y-axis (with columns including author names, year of publication, type of study, number of individual studies included in meta-analysis, effect estimate with 95% confidence interval (CI)). Effect estimate with 95% confidence interval reported in X-axis. In this forest plot, we only included the largest meta-analysis that examined the association of individual maternal inflammatory state and ASD in offspring. For full data see supplementary Fig. 1. SES = socioeconomic status, PM_2.5 = particulate matter (particles with diameter of 2.5 micrometers or less), PM₁₀ = particulate matter (particles with diameter of 10 micrometers or less), NO₂ = nitrogen dioxide, O₃ = ozone, MA = meta-analysis, CC = case-control, CO = cohort, CS = cross sectional, RR = relative risk, OR = odds ratio PR = prevalence ratio.

Fig. 4. Epidemiological studies of maternal inflammatory states and attention deficit hyperactivity disorder (ADHD) in offspring.

Maternal inflammatory states included in Y-axis (with columns including author names, year of publication, type of study, number of individual studies included in meta-analysis, effect estimate with 95% confidence interval (CI)). Effect estimate with 95% confidence interval reported in X-axis. In this forest plot, we only included the largest meta-analysis that examined the association of individual maternal inflammatory state and ADHD in offspring. For full data see Supplementary Fig. 2. SES = socioeconomic status, PM_2.5 = particulate matter (particles with diameter of 2.5 micrometers or less), PM₁₀ = particulate matter (particles with diameter of 10 micrometers or less), NO₂ = nitrogen dioxide, UTI = urinary tract infection, Respi infection= respiratory infection, MA = meta-analysis, CC = case-control, CO = cohort, RR = relative risk, OR = odds ratio, HR = hazard ratio.

Fig. 5. Epidemiological studies of maternal inflammatory states and Tourette syndrome in offspring.

Maternal inflammatory states included in Y-axis (with columns including author names, year of publication, type of study, number of individual studies included in meta-analysis, effect estimate with 95% confidence interval (CI)). Effect estimate with 95% confidence interval reported in X-axis. SES socioeconomic status, Preg pregnancy, CC case-control, CO cohort, RR relative risk, OR odds ratio, HR hazard ratio, IRR incidence risk ratio.