Maternal Immune Activation Hypotheses for Human Neurodevelopment: Some Outstanding Questions

  • Thomas G. O’Connor
    Correspondence
    Correspondence concerning this article should be addressed to Tom O’Connor, Wynne Center for Family Research, Department of Psychiatry, University of Rochester, 300 Crittenden Blvd, Rochester, NY 14642; ph: 585 273-1221
    Affiliations
    Department of Psychiatry, University of Rochester

    Department of Psycholog, University of Rochestery

    Department of Neuroscience, University of Rochester

    Department of Obstetrics and Gynecology, University of Rochester

    Wynne Center for Family Research, University of Rochester
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  • Allison A. Ciesla
    Affiliations
    Department of Psychiatry, University of Rochester
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Published:October 21, 2021DOI:https://doi.org/10.1016/j.bpsc.2021.10.006

      Abstract

      The Maternal Immune Activation (MIA) hypothesis is a leading model for understanding prenatal influences on individual differences in, and clinical syndromes of, neurodevelopment. Experimental animal and human research has proliferated in recent years, and there is now a sizable research base. Several meta-analyses demonstrate general support for an association between prenatal immune activation and neurodevelopment in human research. However, questions remain about the nature of the immune activation, the network of underlying mechanisms involved, and the breadth of impact across behavioral phenotypes. Complementing recent reviews of results, the current review places particular emphasis on how advances in understanding mechanisms may be improved with greater attention to addressing the methodological variation and limitations of existing studies, and identifies areas for further clinical research.

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      References

        • Estes M.L.
        • McAllister A.K.
        Maternal immune activation: Implications for neuropsychiatric disorders.
        Science. 2016; 353: 772-777
        • Hantsoo L.
        • Kornfield S.
        • Anguera M.C.
        • Epperson C.N.
        Inflammation: A Proposed Intermediary Between Maternal Stress and Offspring Neuropsychiatric Risk.
        Biol Psychiatry. 2019; 85: 97-106
        • Han V.X.
        • Patel S.
        • Jones H.F.
        • Nielsen T.C.
        • Mohammad S.S.
        • Hofer M.J.
        • et al.
        Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.
        Transl Psychiatry. 2021; 11: 71
        • Careaga M.
        • Murai T.
        • Bauman M.D.
        Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates.
        Biol Psychiatry. 2017; 81: 391-401
        • Jiang N.M.
        • Cowan M.
        • Moonah S.N.
        • Petri Jr., W.A.
        The Impact of Systemic Inflammation on Neurodevelopment.
        Trends Mol Med. 2018; 24: 794-804
        • Brown A.S.
        • Meyer U.
        Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective.
        Am J Psychiatry. 2018; 175: 1073-1083
        • Goldstein J.A.
        • Norris S.A.
        • Aronoff D.M.
        DOHaD at the intersection of maternal immune activation and maternal metabolic stress: a scoping review.
        Journal of developmental origins of health and disease. 2017; 8: 273-283
        • Torrey E.F.
        • Torrey B.B.
        • Peterson M.R.
        Seasonality of schizophrenic births in the United States.
        Arch Gen Psychiatry. 1977; 34: 1065-1070
        • Volk H.E.
        • Park B.
        • Hollingue C.
        • Jones K.L.
        • Ashwood P.
        • Windham G.C.
        • et al.
        Maternal immune response and air pollution exposure during pregnancy: insights from the Early Markers for Autism (EMA) study.
        J Neurodev Disord. 2020; 12: 42
        • Blackmore E.R.
        • Moynihan J.A.
        • Rubinow D.R.
        • Pressman E.K.
        • Gilchrist M.
        • O'Connor T.G.
        Psychiatric symptoms and proinflammatory cytokines in pregnancy.
        Psychosomatic medicine. 2011; 73: 656-663
        • Sanchez C.E.
        • Barry C.
        • Sabhlok A.
        • Russell K.
        • Majors A.
        • Kollins S.H.
        • et al.
        Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta-analysis.
        Obes Rev. 2018; 19: 464-484
        • Hall H.A.
        • Speyer L.G.
        • Murray A.L.
        • Auyeung B.
        Prenatal Maternal Infections and Children's Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD.
        J Atten Disord. 2021; (10870547211015422)
        • Parboosing R.
        • Bao Y.
        • Shen L.
        • Schaefer C.A.
        • Brown A.S.
        Gestational influenza and bipolar disorder in adult offspring.
        JAMA Psychiatry. 2013; 70: 677-685
        • Brown A.S.
        • Begg M.D.
        • Gravenstein S.
        • Schaefer C.A.
        • Wyatt R.J.
        • Bresnahan M.
        • et al.
        Serologic evidence of prenatal influenza in the etiology of schizophrenia.
        Archives of general psychiatry. 2004; 61: 774-780
      1. Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman JM, et al. A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biological psychiatry. 2001; 49(6): 473-486.

        • Brown A.S.
        • Hooton J.
        • Schaefer C.A.
        • Zhang H.
        • Petkova E.
        • Babulas V.
        • et al.
        Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.
        The American journal of psychiatry. 2004; 161: 889-895
        • Brown A.S.
        • Schaefer C.A.
        • Wyatt R.J.
        • Goetz R.
        • Begg M.D.
        • Gorman J.M.
        • et al.
        Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study.
        Schizophrenia bulletin. 2000; 26: 287-295
        • Easter S.R.
        • Cantonwine D.E.
        • Zera C.A.
        • Lim K.H.
        • Parry S.I.
        • McElrath T.F.
        Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia.
        Am J Obstet Gynecol. 2016; 214: 387 e1-7
        • Selten J.P.
        • Termorshuizen F.
        The serological evidence for maternal influenza as risk factor for psychosis in offspring is insufficient: critical review and meta-analysis.
        Schizophr Res. 2017; 183: 2-9
        • Scheller J.
        • Chalaris A.
        • Schmidt-Arras D.
        • Rose-John S.
        The pro- and anti-inflammatory properties of the cytokine interleukin-6.
        Biochim Biophys Acta. 2011; 1813: 878-888
        • Richard A.S.
        • Shim B.S.
        • Kwon Y.C.
        • Zhang R.
        • Otsuka Y.
        • Schmitt K.
        • et al.
        AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses.
        Proc Natl Acad Sci U S A. 2017; 114: 2024-2029
        • Adams Waldorf K.M.
        • McAdams R.M.
        Influence of infection during pregnancy on fetal development.
        Reproduction. 2013; 146: R151-R162
        • Saliba E.
        • Henrot A.
        Inflammatory mediators and neonatal brain damage.
        Biol Neonate. 2001; 79: 224-227
        • Rasmussen J.M.
        • Graham A.M.
        • Gyllenhammer L.E.
        • Entringer S.
        • Chow D.S.
        • O'Connor T.G.
        • et al.
        Neuroanatomical Correlates Underlying the Association Between Maternal Interleukin-6 Concentration During Pregnancy and Offspring Fluid Reasoning Performance in Early Childhood.
        Biological psychiatry Cognitive neuroscience and neuroimaging. 2021;
        • Yanni D.
        • Korzeniewski S.J.
        • Allred E.N.
        • Fichorova R.N.
        • O'Shea T.M.
        • Kuban K.
        • et al.
        Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns.
        Pediatr Res. 2017; 82: 691-696
        • Wu W.L.
        • Hsiao E.Y.
        • Yan Z.
        • Mazmanian S.K.
        • Patterson P.H.
        The placental interleukin-6 signaling controls fetal brain development and behavior.
        Brain Behav Immun. 2017; 62: 11-23
        • Rose D.R.
        • Careaga M.
        • Van de Water J.
        • McAllister K.
        • Bauman M.D.
        • Ashwood P.
        Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.
        Brain Behav Immun. 2017; 63: 60-70
        • Christian L.M.
        • Porter K.
        Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: effects of maternal body mass index.
        Cytokine. 2014; 70: 134-140
        • Gumusoglu S.B.
        • Fine R.S.
        • Murray S.J.
        • Bittle J.L.
        • Stevens H.E.
        The role of IL-6 in neurodevelopment after prenatal stress.
        Brain Behav Immun. 2017; 65: 274-283
        • Rudolph M.D.
        • Graham A.M.
        • Feczko E.
        • Miranda-Dominguez O.
        • Rasmussen J.M.
        • Nardos R.
        • et al.
        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
        • Spann M.N.
        • Monk C.
        • Scheinost D.
        • Peterson B.S.
        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
        • Monje M.L.
        • Toda H.
        • Palmer T.D.
        Inflammatory blockade restores adult hippocampal neurogenesis.
        Science. 2003; 302: 1760-1765
        • Kohman R.A.
        • Rhodes J.S.
        Neurogenesis, inflammation and behavior.
        Brain, behavior, and immunity. 2013; 27: 22-32
        • Bilbo S.D.
        • Levkoff L.H.
        • Mahoney J.H.
        • Watkins L.R.
        • Rudy J.W.
        • Maier S.F.
        Neonatal infection induces memory impairments following an immune challenge in adulthood.
        Behavioral neuroscience. 2005; 119: 293-301
        • Short S.J.
        • Lubach G.R.
        • Karasin A.I.
        • Olsen C.W.
        • Styner M.
        • Knickmeyer R.C.
        • et al.
        Maternal Influenza Infection During Pregnancy Impacts Postnatal Brain Development in the Rhesus Monkey.
        Biological psychiatry. 2010; 67: 965-973
        • Dammann O.
        • Leviton A.
        Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn.
        Pediatr Res. 1997; 42: 1-8
        • Choi G.B.
        • Yim Y.S.
        • Wong H.
        • Kim S.
        • Kim H.
        • Kim S.V.
        • et al.
        The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.
        Science. 2016; 351: 933-939
        • Akintunde M.E.
        • Rose M.
        • Krakowiak P.
        • Heuer L.
        • Ashwood P.
        • Hansen R.
        • et al.
        Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma.
        J Neuroimmunol. 2015; 286: 33-41
        • Al-Ayadhi L.Y.
        • Mostafa G.A.
        Elevated serum levels of interleukin-17A in children with autism.
        J Neuroinflammation. 2012; 9: 158
        • Suzuki K.
        • Matsuzaki H.
        • Iwata K.
        • Kameno Y.
        • Shimmura C.
        • Kawai S.
        • et al.
        Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders.
        PLoS One. 2011; 6e20470
        • Tissieres P.
        • Ochoda A.
        • Dunn-Siegrist I.
        • Drifte G.
        • Morales M.
        • Pfister R.
        • et al.
        Innate immune deficiency of extremely premature neonates can be reversed by interferon-gamma.
        PLoS One. 2012; 7e32863
        • Collinson A.C.
        • Moore S.E.
        • Cole T.J.
        • Prentice A.M.
        Birth season and environmental influences on patterns of thymic growth in rural Gambian infants.
        Acta Paediatr. 2003; 92: 1014-1020
        • Ahmed S.
        • Mahabbat-e Khoda S.
        • Rekha R.S.
        • Gardner R.M.
        • Ameer S.S.
        • Moore S.
        • et al.
        Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood.
        Environ Health Perspect. 2011; 119: 258-264
        • Ahmed S.
        • Moore S.E.
        • Kippler M.
        • Gardner R.
        • Hawlader M.D.
        • Wagatsuma Y.
        • et al.
        Arsenic exposure and cell-mediated immunity in pre-school children in rural Bangladesh.
        Toxicol Sci. 2014; 141: 166-175
        • Moore S.E.
        • Prentice A.M.
        • Wagatsuma Y.
        • Fulford A.J.
        • Collinson A.C.
        • Raqib R.
        • et al.
        Early-life nutritional and environmental determinants of thymic size in infants born in rural Bangladesh.
        Acta Paediatr. 2009; 98: 1168-1175
        • Raqib R.
        • Alam D.S.
        • Sarker P.
        • Ahmad S.M.
        • Ara G.
        • Yunus M.
        • et al.
        Low birth weight is associated with altered immune function in rural Bangladeshi children: a birth cohort study.
        Am J Clin Nutr. 2007; 85: 845-852
        • Vuolteenaho K.
        • Koskinen A.
        • Kukkonen M.
        • Nieminen R.
        • Paivarinta U.
        • Moilanen T.
        • et al.
        Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production.
        Mediators Inflamm. 2009; 2009: 345838
        • Tang C.H.
        • Lu D.Y.
        • Yang R.S.
        • Tsai H.Y.
        • Kao M.C.
        • Fu W.M.
        • et al.
        Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia.
        J Immunol. 2007; 179: 1292-1302
        • Butovsky O.
        • Jedrychowski M.P.
        • Moore C.S.
        • Cialic R.
        • Lanser A.J.
        • Gabriely G.
        • et al.
        Identification of a unique TGF-beta-dependent molecular and functional signature in microglia.
        Nat Neurosci. 2014; 17: 131-143
        • Umeda-Yano S.
        • Hashimoto R.
        • Yamamori H.
        • Okada T.
        • Yasuda Y.
        • Ohi K.
        • et al.
        The regulation of gene expression involved in TGF-beta signaling by ZNF804A, a risk gene for schizophrenia.
        Schizophr Res. 2013; 146: 273-278
        • Buss C.
        • Entringer S.
        • Davis E.P.
        • Hobel C.J.
        • Swanson J.M.
        • Wadhwa P.D.
        • et al.
        Impaired Executive Function Mediates the Association between Maternal Pre-Pregnancy Body Mass Index and Child ADHD Symptoms.
        PLoS One. 2012; 7e37758
        • Torres-Espinola F.J.
        • Berglund S.K.
        • Garcia-Valdes L.M.
        • Segura M.T.
        • Jerez A.
        • Campos D.
        • et al.
        Maternal Obesity, Overweight and Gestational Diabetes Affect the Offspring Neurodevelopment at 6 and 18 Months of Age--A Follow Up from the PREOBE Cohort.
        PLoS One. 2015; 10e0133010
        • Jo H.
        • Schieve L.A.
        • Sharma A.J.
        • Hinkle S.N.
        • Li R.
        • Lind J.N.
        Maternal prepregnancy body mass index and child psychosocial development at 6 years of age.
        Pediatrics. 2015; 135: e1198-e1209
        • Hinkle S.N.
        • Schieve L.A.
        • Stein A.D.
        • Swan D.W.
        • Ramakrishnan U.
        • Sharma A.J.
        Associations between maternal prepregnancy body mass index and child neurodevelopment at 2 years of age.
        Int J Obes (Lond). 2012; 36: 1312-1319
        • Aye I.L.
        • Lager S.
        • Ramirez V.I.
        • Gaccioli F.
        • Dudley D.J.
        • Jansson T.
        • et al.
        Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways.
        Biol Reprod. 2014; 90: 129
        • Schmatz M.
        • Madan J.
        • Marino T.
        • Davis J.
        Maternal obesity: the interplay between inflammation, mother and fetus.
        J Perinatol. 2010; 30: 441-446
        • Denison F.C.
        • Roberts K.A.
        • Barr S.M.
        • Norman J.E.
        Obesity, pregnancy, inflammation, and vascular function.
        Reproduction. 2010; 140: 373-385
        • Challier J.C.
        • Basu S.
        • Bintein T.
        • Minium J.
        • Hotmire K.
        • Catalano P.M.
        • et al.
        Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta.
        Placenta. 2008; 29: 274-281
        • Scott-Pillai R.
        • Spence D.
        • Cardwell C.R.
        • Hunter A.
        • Holmes V.A.
        The impact of body mass index on maternal and neonatal outcomes: a retrospective study in a UK obstetric population, 2004-2011.
        BJOG. 2013; 120: 932-939
        • Ippoliti F.
        • Canitano N.
        • Businaro R.
        Stress and obesity as risk factors in cardiovascular diseases: a neuroimmune perspective.
        Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2013; 8: 212-226
        • Sullivan E.L.
        • Grayson B.
        • Takahashi D.
        • Robertson N.
        • Maier A.
        • Bethea C.L.
        • et al.
        Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010; 30: 3826-3830
        • Tenenbaum-Gavish K.
        • Hod M.
        Impact of maternal obesity on fetal health.
        Fetal Diagn Ther. 2013; 34: 1-7
        • Leddy M.A.
        • Power M.L.
        • Schulkin J.
        The impact of maternal obesity on maternal and fetal health.
        Reviews in obstetrics & gynecology. 2008; 1: 170-178
        • Dziegielewska K.M.
        • Ek J.
        • Habgood M.D.
        • Saunders N.R.
        Development of the choroid plexus.
        Microsc Res Tech. 2001; 52: 5-20
        • Ek C.J.
        • Dziegielewska K.M.
        • Habgood M.D.
        • Saunders N.R.
        Barriers in the developing brain and Neurotoxicology.
        Neurotoxicology. 2012; 33: 586-604
        • Saunders N.R.
        • Ek C.J.
        • Habgood M.D.
        • Dziegielewska K.M.
        Barriers in the brain: a renaissance?.
        Trends Neurosci. 2008; 31: 279-286
        • Stolp H.B.
        • Dziegielewska K.M.
        • Ek C.J.
        • Habgood M.D.
        • Lane M.A.
        • Potter A.M.
        • et al.
        Breakdown of the blood-brain barrier to proteins in white matter of the developing brain following systemic inflammation.
        Cell Tissue Res. 2005; 320: 369-378
        • Stolp H.B.
        • Ek C.J.
        • Johansson P.A.
        • Dziegielewska K.M.
        • Potter A.M.
        • Habgood M.D.
        • et al.
        Effect of minocycline on inflammation-induced damage to the blood-brain barrier and white matter during development.
        Eur J Neurosci. 2007; 26: 3465-3474
        • Stolp H.B.
        • Johansson P.A.
        • Habgood M.D.
        • Dziegielewska K.M.
        • Saunders N.R.
        • Ek C.J.
        Effects of neonatal systemic inflammation on blood-brain barrier permeability and behaviour in juvenile and adult rats.
        Cardiovascular psychiatry and neurology. 2011; 2011: 469046
        • Reyes T.M.
        • Fabry Z.
        • Coe C.L.
        Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli.
        Brain Res. 1999; 851: 215-220
        • Elovitz M.A.
        • Brown A.G.
        • Breen K.
        • Anton L.
        • Maubert M.
        • Burd I.
        Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury.
        Int J Dev Neurosci. 2011; 29: 663-671
        • Mac Giollabhui N.
        • Breen E.C.
        • Murphy S.K.
        • Maxwell S.D.
        • Cohn B.A.
        • Krigbaum N.Y.
        • et al.
        Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter.
        J Psychiatr Res. 2019; 111: 96-103
        • Benros M.E.
        • Trabjerg B.B.
        • Meier S.
        • Mattheisen M.
        • Mortensen P.B.
        • Mors O.
        • et al.
        Influence of Polygenic Risk Scores on the Association Between Infections and Schizophrenia.
        Biol Psychiatry. 2016; 80: 609-616
        • O'Connor T.G.
        • Moynihan J.A.
        • Caserta M.T.
        Annual Research Review: The neuroinflammation hypothesis for stress and psychopathology in children - developmental psychoneuroimmunology.
        Journal of child psychology and psychiatry, and allied disciplines. 2014; 55: 615-631
        • Jiang N.M.
        • Tofail F.
        • Moonah S.N.
        • Scharf R.J.
        • Taniuchi M.
        • Ma J.Z.
        • et al.
        Febrile illness and pro-inflammatory cytokines are associated with lower neurodevelopmental scores in Bangladeshi infants living in poverty.
        BMC pediatrics. 2014; 14: 50
        • O'Connor T.G.
        • Scheible K.
        • Sefair A.V.
        • Gilchrist M.
        • Blackmore E.R.
        • Winter M.A.
        • et al.
        Immune and neuroendocrine correlates of temperament in infancy.
        Dev Psychopathol. 2017; 29: 1589-1600
        • Varner M.W.
        • Marshall N.E.
        • Rouse D.J.
        • Jablonski K.A.
        • Leveno K.J.
        • Reddy U.M.
        • et al.
        The association of cord serum cytokines with neurodevelopmental outcomes.
        Am J Perinatol. 2015; 30: 115-122
        • Allred E.N.
        • Dammann O.
        • Fichorova R.N.
        • Hooper S.R.
        • Hunter S.J.
        • Joseph R.M.
        • et al.
        Systemic Inflammation during the First Postnatal Month and the Risk of Attention Deficit Hyperactivity Disorder Characteristics among 10 year-old Children Born Extremely Preterm.
        J Neuroimmune Pharmacol. 2017; 12: 531-543
        • Abdallah M.W.
        • Larsen N.
        • Grove J.
        • Bonefeld-Jorgensen E.C.
        • Norgaard-Pedersen B.
        • Hougaard D.M.
        • et al.
        Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study.
        Cytokine. 2013; 61: 370-376
        • Ashwood P.
        • Enstrom A.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.L.
        • Croen L.A.
        • et al.
        Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes.
        J Neuroimmunol. 2008; 204: 149-153
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Pessah I.N.
        • Van de Water J.
        Altered T cell responses in children with autism.
        Brain, behavior, and immunity. 2011; 25: 840-849
        • Na K.S.
        • Jung H.Y.
        • Kim Y.K.
        The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia.
        Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48: 277-286
        • Sekar A.
        • Bialas A.R.
        • de Rivera H.
        • Davis A.
        • Hammond T.R.
        • Kamitaki N.
        • et al.
        Schizophrenia risk from complex variation of complement component 4.
        Nature. 2016; 530: 177-183
        • Paolicelli R.C.
        • Bolasco G.
        • Pagani F.
        • Maggi L.
        • Scianni M.
        • Panzanelli P.
        • et al.
        Synaptic pruning by microglia is necessary for normal brain development.
        Science. 2011; 333: 1456-1458
        • Luo L.
        • O'Leary D.D.
        Axon retraction and degeneration in development and disease.
        Annu Rev Neurosci. 2005; 28: 127-156
        • Bilbo S.D.
        • Frank A.
        Beach award: programming of neuroendocrine function by early-life experience: a critical role for the immune system.
        Hormones and behavior. 2013; 63: 684-691
        • Cunningham C.L.
        • Martinez-Cerdeno V.
        • Noctor S.C.
        Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013; 33: 4216-4233
        • Stevens B.
        • Allen N.J.
        • Vazquez L.E.
        • Howell G.R.
        • Christopherson K.S.
        • Nouri N.
        • et al.
        The classical complement cascade mediates CNS synapse elimination.
        Cell. 2007; 131: 1164-1178
        • Suzuki K.
        • Sugihara G.
        • Ouchi Y.
        • Nakamura K.
        • Futatsubashi M.
        • Takebayashi K.
        • et al.
        Microglial activation in young adults with autism spectrum disorder.
        JAMA Psychiatry. 2013; 70: 49-58
        • Sheridan S.D.
        • Thanos J.M.
        • De Guzman R.M.
        • McCrea L.T.
        • Horng J.E.
        • Fu T.
        • et al.
        Umbilical cord blood-derived microglia-like cells to model COVID-19 exposure.
        Transl Psychiatry. 2021; 11: 179
        • Filiano A.J.
        • Gadani S.P.
        • Kipnis J.
        Interactions of innate and adaptive immunity in brain development and function.
        Brain Res. 2015; 1617: 18-27
        • Ellwardt E.
        • Walsh J.T.
        • Kipnis J.
        • Zipp F.
        Understanding the Role of T Cells in CNS Homeostasis.
        Trends Immunol. 2016; 37: 154-165
        • Mead J.
        • Ashwood P.
        Evidence supporting an altered immune response in ASD.
        Immunol Lett. 2015; 163: 49-55
        • Kentner A.C.
        • Bilbo S.D.
        • Brown A.S.
        • Hsiao E.Y.
        • McAllister A.K.
        • Meyer U.
        • et al.
        Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model.
        Neuropsychopharmacology. 2019; 44: 245-258
        • Hill A.B.
        The Environment and Disease: Association or Causation?.
        Proc R Soc Med. 1965; 58: 295-300
        • Hulshoff Pol H.E.
        • Hoek H.W.
        • Susser E.
        • Brown A.S.
        • Dingemans A.
        • Schnack H.G.
        • et al.
        Prenatal exposure to famine and brain morphology in schizophrenia.
        The American journal of psychiatry. 2000; 157: 1170-1172
        • Brown A.S.
        • van Os J.
        • Driessens C.
        • Hoek H.W.
        • Susser E.S.
        Further evidence of relation between prenatal famine and major affective disorder.
        The American journal of psychiatry. 2000; 157: 190-195
        • Brown A.S.
        • Susser E.S.
        • Lin S.P.
        • Neugebauer R.
        • Gorman J.M.
        Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944-45.
        The British journal of psychiatry : the journal of mental science. 1995; 166: 601-606
        • Huang L.
        • Liu J.
        • Feng L.
        • Chen Y.
        • Zhang J.
        • Wang W.
        Maternal prepregnancy obesity is associated with higher risk of placental pathological lesions.
        Placenta. 2014; 35: 563-569
        • Wylie A.
        • Sundaram R.
        • Kus C.
        • Ghassabian A.
        • Yeung E.H.
        Maternal prepregnancy obesity and achievement of infant motor developmental milestones in the upstate KIDS study.
        Obesity (Silver Spring). 2015; 23: 907-913
        • Huang L.
        • Yu X.
        • Keim S.
        • Li L.
        • Zhang L.
        • Zhang J.
        Maternal prepregnancy obesity and child neurodevelopment in the Collaborative Perinatal Project.
        Int J Epidemiol. 2014; 43: 783-792
        • Panagos P.G.
        • Vishwanathan R.
        • Penfield-Cyr A.
        • Matthan N.R.
        • Shivappa N.
        • Wirth M.D.
        • et al.
        Breastmilk from obese mothers has pro-inflammatory properties and decreased neuroprotective factors.
        J Perinatol. 2016; 36: 284-290
        • Sims C.R.
        • Lipsmeyer M.E.
        • Turner D.E.
        • Andres A.
        Human milk composition differs by maternal BMI in the first 9 months postpartum.
        Am J Clin Nutr. 2020; 112: 548-557
        • Whitaker K.M.
        • Marino R.C.
        • Haapala J.L.
        • Foster L.
        • Smith K.D.
        • Teague A.M.
        • et al.
        Associations of Maternal Weight Status Before, During, and After Pregnancy with Inflammatory Markers in Breast Milk.
        Obesity (Silver Spring). 2017; 25: 2092-2099
        • Chau V.
        • McFadden D.E.
        • Poskitt K.J.
        • Miller S.P.
        Chorioamnionitis in the pathogenesis of brain injury in preterm infants.
        Clin Perinatol. 2014; 41: 83-103
        • Freeman J.M.
        Chorioamnionitis, cytokines, and brain injury.
        Pediatrics. 2003; 112 (author reply -7): 206-207
        • Patrick L.A.
        • Smith G.N.
        Proinflammatory cytokines: a link between chorioamnionitis and fetal brain injury.
        J Obstet Gynaecol Can. 2002; 24: 705-709
        • Katzman P.J.
        Chronic inflammatory lesions of the placenta.
        Semin Perinatol. 2015; 39: 20-26
        • Kim C.J.
        • Romero R.
        • Chaemsaithong P.
        • Kim J.S.
        Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
        Am J Obstet Gynecol. 2015; 213: S53-69
        • Burd I.
        • Brown A.
        • Gonzalez J.M.
        • Chai J.
        • Elovitz M.A.
        A mouse model of term chorioamnionitis: unraveling causes of adverse neurological outcomes.
        Reprod Sci. 2011; 18: 900-907
        • Chau V.
        • Poskitt K.J.
        • McFadden D.E.
        • Bowen-Roberts T.
        • Synnes A.
        • Brant R.
        • et al.
        Effect of chorioamnionitis on brain development and injury in premature newborns.
        Ann Neurol. 2009; 66: 155-164
        • Walker C.K.
        • Krakowiak P.
        • Baker A.
        • Hansen R.L.
        • Ozonoff S.
        • Hertz-Picciotto I.
        Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay.
        JAMA pediatrics. 2015; 169: 154-162
        • Myatt L.
        • Maloyan A.
        Obesity and Placental Function.
        Semin Reprod Med. 2016; 34: 42-49
        • Aaltonen R.
        • Heikkinen T.
        • Hakala K.
        • Laine K.
        • Alanen A.
        Transfer of proinflammatory cytokines across term placenta.
        Obstet Gynecol. 2005; 106: 802-807
        • Bonnin A.
        • Goeden N.
        • Chen K.
        • Wilson M.L.
        • King J.
        • Shih J.C.
        • et al.
        A transient placental source of serotonin for the fetal forebrain.
        Nature. 2011; 472: 347-350
        • Harris J.W.
        Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases.
        JAMA. 1919; 72: 978-980
        • Wegmann T.G.
        • Lin H.
        • Guilbert L.
        • Mosmann T.R.
        Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?.
        Immunol Today. 1993; 14: 353-356
        • Hill J.A.
        • Polgar K.
        • Anderson D.J.
        T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.
        JAMA : the journal of the American Medical Association. 1995; 273: 1933-1936
        • Kalu E.
        • Bhaskaran S.
        • Thum M.Y.
        • Vishwanatha R.
        • Croucher C.
        • Sherriff E.
        • et al.
        Serial estimation of Th1:th2 cytokines profile in women undergoing in-vitro fertilization-embryo transfer.
        Am J Reprod Immunol. 2008; 59: 206-211
        • Piccinni M.P.
        • Giudizi M.G.
        • Biagiotti R.
        • Beloni L.
        • Giannarini L.
        • Sampognaro S.
        • et al.
        Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones.
        J Immunol. 1995; 155: 128-133
        • Shah N.M.
        • Imami N.
        • Johnson M.R.
        Progesterone Modulation of Pregnancy-Related Immune Responses.
        Frontiers in immunology. 2018; 9: 1293
        • Huber S.A.
        • Kupperman J.
        • Newell M.K.
        Hormonal regulation of CD4(+) T-cell responses in coxsackievirus B3-induced myocarditis in mice.
        J Virol. 1999; 73: 4689-4695
        • Aluvihare V.R.
        • Kallikourdis M.
        • Betz A.G.
        Regulatory T cells mediate maternal tolerance to the fetus.
        Nat Immunol. 2004; 5: 266-271
        • Erlebacher A.
        Mechanisms of T cell tolerance towards the allogeneic fetus.
        Nat Rev Immunol. 2013; 13: 23-33
        • Kraus T.A.
        • Engel S.M.
        • Sperling R.S.
        • Kellerman L.
        • Lo Y.
        • Wallenstein S.
        • et al.
        Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study.
        J Clin Immunol. 2012; 32: 300-311
        • Kinder J.M.
        • Stelzer I.A.
        • Arck P.C.
        • Way S.S.
        Immunological implications of pregnancy-induced microchimerism.
        Nat Rev Immunol. 2017; 17: 483-494
        • Brown A.S.
        • Susser E.S.
        • Lin S.P.
        • Gorman J.M.
        Affective disorders in Holland after prenatal exposure to the 1957 A2 influenza epidemic.
        Biological psychiatry. 1995; 38: 270-273
        • Lyall K.
        • Ames J.L.
        • Pearl M.
        • Traglia M.
        • Weiss L.A.
        • Windham G.C.
        • et al.
        A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California.
        Mol Autism. 2021; 12: 24
        • Atladottir H.O.
        • Henriksen T.B.
        • Schendel D.E.
        • Parner E.T.
        Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study.
        Pediatrics. 2012; 130: e1447-e1454
        • Ghassabian A.
        • Albert P.S.
        • Hornig M.
        • Yeung E.
        • Cherkerzian S.
        • Goldstein R.B.
        • et al.
        Gestational cytokine concentrations and neurocognitive development at 7 years.
        Transl Psychiatry. 2018; 8: 64
        • Lee Y.H.
        • Papandonatos G.D.
        • Savitz D.A.
        • Heindel W.C.
        • Buka S.L.
        Effects of prenatal bacterial infection on cognitive performance in early childhood.
        Paediatr Perinat Epidemiol. 2020; 34: 70-79
      2. O'Connor TG, Cielsa AA, Sefair AV, Thorbnburg LL, Brown AS, Glover V, et al. Maternal Prenatal Infection and Anxiety Predict Neurodevelopmental Outcomes in Middle Childhood. Journal of Abnormal Psychology. in press.

        • Bergdolt L.
        • Dunaevsky A.
        Brain changes in a maternal immune activation model of neurodevelopmental brain disorders.
        Prog Neurobiol. 2019; 175: 1-19
        • Weir R.K.
        • Forghany R.
        • Smith S.E.
        • Patterson P.H.
        • McAllister A.K.
        • Schumann C.M.
        • et al.
        Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation.
        Brain Behav Immun. 2015; 48: 139-146
        • Graham A.M.
        • Rasmussen J.M.
        • Rudolph M.D.
        • Heim C.M.
        • Gilmore J.H.
        • Styner M.
        • et al.
        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
        • Croen L.A.
        • Qian Y.
        • Ashwood P.
        • Zerbo O.
        • Schendel D.
        • Pinto-Martin J.
        • et al.
        Infection and Fever in Pregnancy and Autism Spectrum Disorders: Findings from the Study to Explore Early Development.
        Autism Res. 2019; 12: 1551-1561
        • Dimidjian S.
        • Goodman S.H.
        • Sherwood N.E.
        • Simon G.E.
        • Ludman E.
        • Gallop R.
        • et al.
        A pragmatic randomized clinical trial of behavioral activation for depressed pregnant women.
        J Consult Clin Psychol. 2017; 85: 26-36
        • Sanchez-Polan M.
        • Franco E.
        • Silva-Jose C.
        • Gil-Ares J.
        • Perez-Tejero J.
        • Barakat R.
        • et al.
        Exercise During Pregnancy and Prenatal Depression: A Systematic Review and Meta-Analysis.
        Frontiers in physiology. 2021; 12: 640024
        • Grivell R.M.
        • Yelland L.N.
        • Deussen A.
        • Crowther C.A.
        • Dodd J.M.
        Antenatal dietary and lifestyle advice for women who are overweight or obese and the effect on fetal growth and adiposity: the LIMIT randomised trial.
        BJOG. 2016; 123: 233-243
        • Bauer A.Z.
        • Kriebel D.
        • Herbert M.R.
        • Bornehag C.G.
        • Swan S.H.
        Prenatal paracetamol exposure and child neurodevelopment: A review.
        Horm Behav. 2018; 101: 125-147
        • Dathe K.
        • Fietz A.K.
        • Pritchard L.W.
        • Padberg S.
        • Hultzsch S.
        • Meixner K.
        • et al.
        No evidence of adverse pregnancy outcome after exposure to ibuprofen in the first trimester - Evaluation of the national Embryotox cohort.
        Reprod Toxicol. 2018; 79: 32-38
        • Mehrabadi A.
        • Dodds L.
        • MacDonald N.E.
        • Top K.A.
        • Benchimol E.I.
        • Kwong J.C.
        • et al.
        Association of Maternal Influenza Vaccination During Pregnancy With Early Childhood Health Outcomes.
        JAMA. 2021; 325: 2285-2293