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Prenatal pregnancy-related anxiety predicts boys' ADHD symptoms via placental C-reactive protein
Shanshan Shao1, Jianqing Wang2, Kun Huang1
1Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No. 81 Meishan Road, Hefei, 230032, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, No. 81 Meishan Road, Hefei, 230032, Anhui, China; Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China.
Insights
Pregnancy anxiety increases boys' risk for attention deficit hyperactivity disorder (ADHD), a link mediated by placental inflammation (CRP). This effect was not observed in girls, suggesting a sex-specific mechanism for ADHD development.
Area of Science:
- Neuroscience
- Developmental Psychology
- Immunology
Background:
- Maternal stress during pregnancy is linked to offspring externalizing behaviors, potentially in a sex-specific manner.
- The interplay between maternal stress, immune activation, and offspring neurodevelopment in humans remains under-investigated.
- Pregnancy-related anxiety is a significant stressor with potential implications for child neurodevelopment.
Purpose of the Study:
- To investigate the association between pregnancy-related anxiety and attention deficit hyperactivity disorder (ADHD) symptoms in offspring.
- To explore the mediating role of placental inflammatory markers in the relationship between maternal anxiety and ADHD, examining sex differences.
- To provide direct human evidence on the combined effects of maternal stress, immune activation, and neurodevelopment.
Main Methods:
- Prospective cohort study of 2926 pregnant women followed from pregnancy to 36 months postpartum.
- Assessment of pregnancy-related anxiety using the Pregnancy-Related Anxiety Questionnaire at three time points.
- Measurement of child ADHD symptoms via the Conners' Hyperactivity Index and analysis of nine inflammatory cytokines (including CRP mRNA) in placental tissues.
Main Results:
- Pregnancy-related anxiety in at least two trimesters significantly increased ADHD risk in boys (aOR=3.37) but not in girls (aOR=1.02).
- Structural equation modeling indicated that placental C-reactive protein (CRP) mRNA expression mediated the link between maternal anxiety and ADHD in boys (indirect effect: β=0.025, P=0.022).
- No significant mediation was found for girls (indirect effect: β=0.005, P=0.589), highlighting a sex-specific pathway.
Conclusions:
- Frequent pregnancy-related anxiety is a risk factor for ADHD symptoms in boys, independent of other confounding factors.
- Placental inflammation, specifically elevated CRP mRNA expression, partially explains the sex bias in ADHD development linked to maternal anxiety.
- These findings underscore the importance of maternal mental health during pregnancy for offspring neurodevelopment and suggest targeted interventions may be sex-specific.
Abstract:
Many modes of stress (i.e. life events, catastrophic events) during pregnancy have been found to increase the risk of externalizing behaviors, and probably in a sex-specific way. Maternal immune activation may be the sex-difference mechanism, but direct evidence that assess three factors in conjunction -- maternal stress, maternal immune activation, and offspring neurodevelopment --from human beings is lacking. This prospective study followed 2926 pregnant women from early pregnancy to 36 months after delivery. Pregnancy-related anxiety symptoms assessment was completed three times using the Pregnancy-Related Anxiety Questionnaire; child attention deficit hyperactivity disorder (ADHD) symptoms were assessed by the parent version of the Conners' Hyperactivity Index. More importantly, nine inflammatory cytokines were detected in placental tissues for the sex-difference mechanism investigation. Our results showed that after controlling for confounding factors, pregnancy-related anxiety during at least two trimesters of pregnancy increased the risk of ADHD for boys (adjusted odds ratio (aOR) = 3.37, 95 % confidence interval (95 % CI) = 1.78-6.38), but not for girls (aOR = 1.02, 95 %CI = 0.44-2.38), which confirmed previous findings. Besides, the structural equation models revealed that placental C-reactive protein (CRP) mRNA expression significantly mediated the association between pregnancy-related anxiety and ADHD for boys (indirect effect: β = 0.025, P = 0.022), but not for girls (indirect effect: β = 0.005, P = 0.589). This prospective study suggested that frequent pregnancy-related anxiety during pregnancy and its induced-placental inflammation partially contributed to the sex-bias of ADHD symptoms.
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