Abstract
Background
Prenatal exposure to environmental adversities, including maternal overweight/obesity,
diabetes/hypertensive disorders, or mood/anxiety disorders, increases the risk for
adverse neurodevelopmental outcomes in children. However, the underlying biological
mechanisms remain elusive. We tested whether maternal antenatal inflammation was associated
with the number of neurodevelopmental delay areas in children and whether it mediated
the association between exposure to any prenatal environmental adversity and child
neurodevelopmental delay.
Methods
Mother-child dyads (N = 418) from the PREDO (Prediction and Prevention of Preeclampsia and Intrauterine
Growth Restriction) study were followed up to 10.8 years. We analyzed maternal plasma
high-sensitivity C-reactive protein and glycoprotein acetyls at 3 consecutive antenatal
time points, measured maternal body mass index in early pregnancy, extracted data
on diabetes/hypertensive disorders in pregnancy from medical records, and extracted
data on mood/anxiety disorders until childbirth from the Care Register for Health
Care. To estimate the number of neurodevelopmental delay areas in children across
cognitive, motor, and social functioning, we pooled data from the Care Register for
Health Care on psychological development disorders with mother-reported Ages and Stages
Questionnaire data on developmental milestones.
Results
Higher levels of maternal high-sensitivity C-reactive protein and glycoprotein acetyls
at and across all 3 antenatal time points were associated with 1.30- to 2.36-fold
(p values < .02) increased relative risk for higher number of areas of child neurodevelopmental
delay. Higher maternal inflammation across the 3 time points also mediated the effect
of any prenatal environmental adversity on child neurodevelopmental delay.
Conclusions
Higher levels of maternal inflammation, especially when persisting throughout pregnancy,
increase a child’s risk of neurodevelopmental delay and mediate the effect of prenatal
environmental adversity on child neurodevelopmental delay.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The origins of the developmental origins theory.J Intern Med. 2007; 261: 412-417
- Maternal early pregnancy obesity and related pregnancy and pre-pregnancy disorders: Associations with child developmental milestones in the prospective PREDO study.Int J Obes (Lond). 2018; 42: 995-1007
- Maternal obesity and excessive gestational weight gain are associated with components of child cognition.J Nutr. 2015; 145: 2562-2569
- Maternal prepregnancy obesity and child neurodevelopment in the Collaborative Perinatal Project.Int J Epidemiol. 2014; 43: 783-792
- Maternal pre-pregnancy obesity and risk for inattention and negative emotionality in children.J Child Psychol Psychiatry. 2010; 51: 134-143
- Parental obesity and early childhood development.Pediatrics. 2017; 139e20161459
- Associations of existing diabetes, gestational diabetes, and glycosuria with offspring IQ and educational attainment: The Avon Longitudinal Study of Parents and Children.Exp Diabetes Res. 2012; 2012: 963735
- Maternal medical conditions during pregnancy and gross motor development up to age 24 months in the Upstate KIDS study.Dev Med Child Neurol. 2016; 58: 728-734
- Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology: A global perspective.Dev Psychopathol. 2018; 30: 843-854
- Maternal depressive symptoms during and after pregnancy and child developmental milestones.Depress Anxiety. 2018; 35: 732-741
- Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation.Obesity. 2011; 19: 476-482
- Inflammation in maternal obesity and gestational diabetes mellitus.Placenta. 2015; 36: 709-715
- Inflammation: A proposed intermediary between maternal stress and offspring neuropsychiatric risk.Biol Psychiatry. 2019; 85: 97-106
- Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: A case-control study.Mol Autism. 2011; 2: 13
- Gestational cytokine concentrations and neurocognitive development at 7 years.Transl Psychiatry. 2018; 8: 64
- Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring.Nat Neurosci. 2018; 21: 765-772
- Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life.NeuroImage. 2019; 185: 825-835
- Maternal systemic interleukin-6 during pregnancy is associated with newborn amygdala phenotypes and subsequent behavior at 2 years of age.Biol Psychiatry. 2018; 83: 109-119
- Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter.J Psychiatr Res. 2019; 111: 96-103
- Elevated maternal C-reactive protein and autism in a national birth cohort.Mol Psychiatry. 2014; 19: 259-264
- Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring.J Psychosom Res. 2016; 89: 98-101
- Maternal infections and subsequent psychosis among offspring.Arch Gen Psychiatry. 2001; 58: 1032-1037
- Maternal C-reactive protein and cytokine levels during pregnancy and the risk of selected neuropsychiatric disorders in offspring: A systematic review and meta-analysis.J Psychiatr Res. 2018; 105: 86-94
- Maternal infection and schizophrenia: Implications for prevention.Schizophr Bull. 2011; 37: 284-290
- Prenatal maternal immune disruption and sex-dependent risk for psychoses.Psychol Med. 2014; 44: 3249-3261
- Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort.Am J Psychiatry. 2014; 171: 960-968
- Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.Proc Natl Acad Sci U S A. 2017; 114: 6728-6733
- Maternal immune activation during the third trimester is associated with neonatal functional connectivity of the salience network and fetal to toddler behavior.J Neurosci. 2018; 38: 2877-2886
- Prenatal immune programming of the sex-dependent risk for major depression.Transl Psychiatry. 2016; 6: e822
- Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: The early markers for autism study.Transl Psychiatry. 2016; 6: e783
- Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.Schizophr Res. 2010; 121: 46-54
- Gestational maternal C--reactive protein and risk of bipolar disorder among young individuals in a Nationwide Birth Cohort.J Affect Disord. 2017; 208: 41-46
- Maternal serum cytokine levels and risk of bipolar disorder.Brain Behav Immun. 2017; 63: 108-114
- Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.Mol Psychiatry. 2017; 22: 273-279
- Prenatal stress-immune programming of sex differences in comorbidity of depression and obesity/metabolic syndrome.Dialogues Clin Neurosci. 2016; 18: 425-436
- Metabolic profiling of pregnancy: Cross-sectional and longitudinal evidence.BMC Med. 2016; 14: 205
- Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems.Proc Natl Acad Sci U S A. 2012; 109: E1312-E1319
- The epigenetic clock at birth: Associations with maternal antenatal depression and child psychiatric problems.J Am Acad Child Adolesc Psychiatry. 2018; 57: 321-328.e2
- The biomarker GlycA is associated with chronic inflammation and predicts long-term risk of severe infection.Cell Syst. 2015; 1: 293-301
- Depression and anxiety both associate with serum level of hs-CRP: A gender-stratified analysis in a population-based study.Psychoneuroendocrinology. 2017; 81: 63-69
- The association between C-reactive protein levels and depression: Results from the northern Finland 1966 birth cohort study.Biol Psychiatry. 2006; 60: 825-830
- Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis.Atherosclerosis. 2017; 259: 75-82
- Maternal depression and inflammation during pregnancy [published online ahead of print Aug 23].Psychol Med. 2019;
- Cohort Profile: Prediction and prevention of preeclampsia and intrauterine growth restriction (PREDO) study.Int J Epidemiol. 2017; 46: 1380-1381g
- Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics.Circ Cardiovasc Genet. 2015; 8: 192-206
- Quality of the Finnish Hospital Discharge Register: A systematic review.Scand J Public Health. 2012; 40: 505-515
- The validity, reliability, and cost of a parent-completed questionnaire system to evaluate at-risk infants.J Pediatr Psychol. 1988; 13: 55-68
- Revision of a parent-completed development screening tool: Ages and Stages Questionnaires.J Pediatr Psychol. 1997; 22: 313-328
- Support for the global feasibility of the Ages and Stages Questionnaire as developmental screener.Early Hum Dev. 2009; 85: 443-447
- Effects of tobacco smoke on immunity, inflammation and autoimmunity.J Autoimmun. 2010; 34: J258-J265
- Pathways linking childhood abuse history and current socioeconomic status to inflammation during pregnancy.Brain Behav Immun. 2018; 74: 231-240
- The complex interaction between home environment, socioeconomic status, maternal IQ and early child neurocognitive development: A multivariate analysis of data collected in a newborn cohort study.PLoS One. 2015; 10e0127052
- IQ at age 4 in relation to maternal alcohol use and smoking during pregnancy.Dev Psychol. 1989; 25: 3-11
- Latent class analysis in health research.J Physiother. 2017; 63: 55-58
- Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation.Behav Res Ther. 2017; 98: 39-57
- Infections and exposure to anti-infective agents and the risk of severe mental disorders: A nationwide study.Acta Psychiatr Scand. 2017; 135: 97-105
- A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide.JAMA Psychiatry. 2016; 73: 912-919
- Iron deficiency anemia: Pregnancy outcomes with or without iron supplementation.Nutrition. 2011; 27: 65-72
- Polyunsaturated fatty acids in perinatal depression: A systematic review and meta-analysis.Biol Psychiatry. 2017; 82: 560-569
- Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders.Rev Neurosci. 2017; 28: 739-749
- Maternal vitamin D prevents abnormal dopaminergic development and function in a mouse model of prenatal immune activation.Sci Rep. 2018; 8: 9741
- Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation.Mol Autism. 2017; 8: 9
- Fatty-acid-mediated hypothalamic inflammation and epigenetic programming.J Nutr Biochem. 2017; 42: 1-6
- Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation.Proc Natl Acad Sci U S A. 2019; 116: 7083-7088
- Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial.Nutrition. 2016; 32: 315-320
- Host remodeling of the gut microbiome and metabolic changes during pregnancy.Cell. 2012; 150: 470-480
- Omega-3 fatty acids and depression: Scientific evidence and biological mechanisms.Oxidat Med Cell Longev. 2014; 2014: 313570
- Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling.Cell Metab. 2015; 22: 658-668
- Interleukin-6: A potential inflammatory marker after total joint replacement.Int Orthop. 2000; 24: 194-196
- Childhood psychiatric disorders as anomalies in neurodevelopmental trajectories.Hum Brain Mapp. 2010; 31: 917-925
- Developmental trajectories of child to adolescent externalizing behavior and adult DSM-IV disorder: Results of a 24-year longitudinal study.Soc Psychiatry Psychiatr Epidemiol. 2011; 46: 1233-1241
- Childhood origins of adult health: A basis for life-course health policy.Health Aff (Millwood). 2004; 23: 155-164
- Trajectory of development in adolescents and adults with autism.Ment Retard Dev Disabil Res Rev. 2004; 10: 234-247
- Long-term risk of neuropsychiatric disease after exposure to infection in utero.JAMA Psychiatry. 2019; 76: 594-602
- Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.J Autism Dev Disord. 2010; 40: 1423-1430
- Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.Brain Behav Immun. 2015; 44: 100-105
- Maternal inflammation and neurodevelopmental programming: A review of preclinical outcomes and implications for translational psychiatry.Biol Psychiatry. 2019; 85: 107-121
- Synaptic pruning by microglia is necessary for normal brain development.Science. 2011; 333: 1456-1458
- Microglial dysregulation in psychiatric disease.Clin Dev Immunol. 2013; 2013: 608654
- Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders.Brain Behav Immun. 2015; 50: 249-258
Article info
Publication history
Published online: December 13, 2019
Accepted:
December 2,
2019
Received in revised form:
November 29,
2019
Received:
June 10,
2019
Identification
Copyright
© 2019 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- The Maternal Immunome as a Potential Biomarker for the Child’s Neurodevelopmental TrajectoryBiological PsychiatryVol. 87Issue 10
- PreviewEnvironmental influences in pregnancy shape the neurodevelopmental trajectory of the child. This process is known as fetal programming and was first introduced by Barker (1), who posed the hypothesis that any stimulus during the critical period of embryonic and fetal development, such as insufficient nutrition, can lead to permanent structural, physiological, or metabolic changes in the offspring and thus might predispose the fetus for postnatal disease (2).
- Full-Text
- Preview
