Hostname: page-component-78c5997874-xbtfd Total loading time: 0 Render date: 2024-11-17T14:08:35.119Z Has data issue: false hasContentIssue false

Maternal immune-related conditions during pregnancy may be a risk factor for neuropsychiatric problems in offspring throughout childhood and adolescence

Published online by Cambridge University Press:  01 June 2020

Shrujna Patel
Affiliation:
Autism Clinic for Translational Research, Child Neurodevelopment and Mental Health Team, Brain and Mind Centre, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Matthew N. Cooper
Affiliation:
Telethon Kids Institute, University of Western Australia, Perth, Australia
Hannah Jones
Affiliation:
Autism Clinic for Translational Research, Child Neurodevelopment and Mental Health Team, Brain and Mind Centre, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Andrew J.O. Whitehouse
Affiliation:
Telethon Kids Institute, University of Western Australia, Perth, Australia
Russell C. Dale
Affiliation:
Autism Clinic for Translational Research, Child Neurodevelopment and Mental Health Team, Brain and Mind Centre, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Adam J. Guastella*
Affiliation:
Autism Clinic for Translational Research, Child Neurodevelopment and Mental Health Team, Brain and Mind Centre, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
*
Author for correspondence: Adam J. Guastella, E-mail: [email protected]

Abstract

Background

Emerging research suggests that maternal immune activation (MIA) may be associated with an increased risk of adverse neurodevelopmental and mental health outcomes in offspring. Using data from the Raine Study, we investigated whether MIA during pregnancy was associated with increased behavioral and emotional problems in offspring longitudinally across development.

Methods

Mothers (Generation 1; N = 1905) were classified into the following categories: AAAE (Asthma/Allergy/Atopy/Eczema; N = 1267); infection (during pregnancy; N = 1082); no AAAE or infection (N = 301). The Child Behavior Checklist (CBCL) was administered for offspring at ages 5, 8, 10, 14, and 17. Generalized estimating equations were used to investigate the effect of maternal immune status on CBCL scores.

Results

AAAE conditions were associated with significant increases in CBCL Total (β 2.49; CI 1.98–3.00), Externalizing (β 1.54; CI 1.05–2.03), and Internalizing (β 2.28; CI 1.80–2.76) scores. Infection conditions were also associated with increased Total (β 1.27; CI 0.77–1.78), Externalizing (β 1.18; CI 0.70–1.66), and Internalizing (β 0.76; CI 0.28–1.24) scores. Exposure to more than one AAAE and/or infection condition was associated with a greater elevation in CBCL scores than single exposures in males and females. Females showed greater increases on the Internalizing scale from MIA, while males showed similar increases on both Internalizing and Externalizing scales.

Conclusions

MIA was associated with increased behavioral and emotional problems in offspring throughout childhood and adolescence. This highlights the need to understand the relationship between MIA, fetal development, and long-term outcomes, with the potential to advance early identification and intervention strategies.

Type
Original Article
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abrahamsson, T. R., Sandberg Abelius, M., Forsberg, A., Bjorksten, B., & Jenmalm, M. C. (2011). A Th1/Th2-associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization. Clinical and Experimental Allergy, 41(12), 17291739. doi: 10.1111/j.1365-2222.2011.03827.x.CrossRefGoogle ScholarPubMed
Achenbach, T. M. (1991). Manual for the child behavior checklist/4-18 and 1991 profile. Burlington, VT: Department of Psychiatry, University of Vermont.Google Scholar
Basil, P., Li, Q., Dempster, E. L., Mill, J., Sham, P. C., Wong, C. C., & McAlonan, G. M. (2014). Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain. Translational Psychiatry, 4(9), e434. doi: 10.1038/tp.2014.80.CrossRefGoogle ScholarPubMed
Bask, M. (2015). Externalising and internalising problem behaviour among Swedish adolescent boys and girls. International Journal of Social Welfare, 24(2), 182192. doi: 10.1111/ijsw.12106.CrossRefGoogle Scholar
Benros, M. E., Mortensen, P. B., & Eaton, W. W. (2012). Autoimmune diseases and infections as risk factors for schizophrenia. Annals of the New York Academy of Sciences, 1262(1), 5666. doi: 10.1111/j.1749-6632.2012.06638.x.CrossRefGoogle Scholar
Berg-Nielsen, T. S., Vika, A., & Dahl, A. A. (2003). When adolescents disagree with their mothers: CBCL-YSR discrepancies related to maternal depression and adolescent self-esteem. Child: Care, Health and Development, 29(3), 207213. doi: 10.1046/j.1365-2214.2003.00332.x.CrossRefGoogle ScholarPubMed
Braun, A. E., Carpentier, P. A., Babineau, B. A., Narayan, A. R., Kielhold, M. L., Moon, H. M., … Palmer, T. D. (2019). ‘Females are not just “protected” males’: Sex-specific vulnerabilities in placenta and brain after prenatal immune disruption. eNeuro, 6(6), 125. doi: 10.1523/ENEURO.0358-19.2019.CrossRefGoogle Scholar
Brown, A. S., & Meyer, U. (2018). Maternal immune activation and neuropsychiatric illness: A translational research perspective. American Journal of Psychiatry, 175(11), 10731083. doi: 10.1176/appi.ajp.2018.17121311.CrossRefGoogle ScholarPubMed
Carey, V. J. (2015). gee: Generalized Estimation Equation Solver. R package version 4.13-19. Retrieved from https://CRAN.R-project.org/package=gee.Google Scholar
Chen, S. W., Zhong, X. S., Jiang, L. N., Zheng, X. Y., Xiong, Y. Q., Ma, S. J., … Chen, Q. (2016). Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: A systematic review and meta-analysis. Behavioural Brain Research, 296, 6169. doi: 10.1016/j.bbr.2015.08.035.CrossRefGoogle ScholarPubMed
Crespi, B. J., & Thiselton, D. L. (2011). Comparative immunogenetics of autism and schizophrenia. Genes, Brain, and Behavior, 10(7), 689701. doi: 10.1111/j.1601-183X.2011.00710.x.CrossRefGoogle Scholar
Croen, L. A., Grether, J. K., Yoshida, C. K., Odouli, R., & Van de Water, J. (2005). Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: A case-control study. Archives of Pediatrics and Adolescent Medicine, 159(2), 151157. doi: 10.1001/archpedi.159.2.151.CrossRefGoogle ScholarPubMed
Darlenski, R., Kazandjieva, J., Hristakieva, E., & Fluhr, J. W. (2014). Atopic dermatitis as a systemic disease. Clinics in Dermatology, 32(3), 409413. doi: 10.1016/j.clindermatol.2013.11.007.CrossRefGoogle ScholarPubMed
Ellman, L. M., Yolken, R. H., Buka, S. L., Torrey, E. F., & Cannon, T. D. (2009). Cognitive functioning prior to the onset of psychosis: The role of fetal exposure to serologically determined influenza infection. Biological Psychiatry, 65(12), 10401047. doi: 10.1016/j.biopsych.2008.12.015.CrossRefGoogle Scholar
Estes, M. L., & McAllister, A. K. (2016). Maternal immune activation: Implications for neuropsychiatric disorders. Science (New York, NY), 353(6301), 772777. doi: 10.1126/science.aag3194.CrossRefGoogle ScholarPubMed
Fatemi, S. H., Earle, J., Kanodia, R., Kist, D., Emamian, E. S., Patterson, P. H., … Sidwell, R. (2002). Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: Implications for genesis of autism and schizophrenia. Cellular and Molecular Neurobiology, 22(1), 2533. doi: 10.1023/a:1015337611258.CrossRefGoogle Scholar
Ferdinand, R. F., & Verhulst, F. C. (1995). Psychopathology from adolescence into young adulthood: An 8-year follow-up study. American Journal of Psychiatry, 152(11), 15861594. doi: 10.1176/ajp.152.11.1586.Google Scholar
Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R., … Meyer, U. (2013). Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science (New York, NY), 339(6123), 10951099. doi: 10.1126/science.1228261.CrossRefGoogle ScholarPubMed
Giovanoli, S., Weber, L., & Meyer, U. (2014). Single and combined effects of prenatal immune activation and peripubertal stress on parvalbumin and reelin expression in the hippocampal formation. Brain, Behavior, and Immunity, 40, 4854. doi: 10.1016/j.bbi.2014.04.005.CrossRefGoogle ScholarPubMed
Gong, T., Lundholm, C., Rejno, G., Bolte, S., Larsson, H., D'Onofrio, B. M., … Almqvist, C. (2019). Parental asthma and risk of autism spectrum disorder in offspring: A population and family-based case-control study. Clinical and Experimental Allergy, 49(6), 883891. doi: 10.1111/cea.13353.CrossRefGoogle ScholarPubMed
Gray, R., Mukherjee, R. A., & Rutter, M. (2009). Alcohol consumption during pregnancy and its effects on neurodevelopment: What is known and what remains uncertain. Addiction, 104(8), 12701273. doi: 10.1111/j.1360-0443.2008.02441.x.CrossRefGoogle ScholarPubMed
Gumusoglu, S. B., & Stevens, H. E. (2019). Maternal inflammation and neurodevelopmental programming: A review of preclinical outcomes and implications for translational psychiatry. Biological Psychiatry, 85(2), 107121. doi: 10.1016/j.biopsych.2018.08.008.CrossRefGoogle ScholarPubMed
Guo, C., He, P., Song, X., & Zheng, X. (2019). Long-term effects of prenatal exposure to earthquake on adult schizophrenia. British Journal of Psychiatry, 215(6), 730735. doi: 10.1192/bjp.2019.114.CrossRefGoogle ScholarPubMed
Herrmann, M., King, K., & Weitzman, M. (2008). Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Current Opinion in Pediatrics, 20(2), 184190. doi: 10.1097/MOP.0b013e3282f56165.CrossRefGoogle ScholarPubMed
Ho, D. E., Imai, K., King, G., & Stuart, E. A. (2011). Matchit: Nonparametric preprocessing for parametric causal inference. Journal of Statistical Software, 42(8), 28. doi: 10.18637/jss.v042.i08.CrossRefGoogle Scholar
Hofstra, M. B., Van der Ende, J., & Verhulst, F. C. (2000). Continuity and change of psychopathology from childhood into adulthood: A 14-year follow-up study. Journal of the American Academy of Child and Adolescent Psychiatry, 39(7), 850858. doi: 10.1097/00004583-200007000-00013.CrossRefGoogle ScholarPubMed
Jiang, H. Y., Xu, L. L., Shao, L., Xia, R. M., Yu, Z. H., Ling, Z. X., … Ruan, B. (2016). Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain, Behavior, and Immunity, 58, 165172. doi: 10.1016/j.bbi.2016.06.005.CrossRefGoogle ScholarPubMed
Jones, H. F., Ho, A. C. C., Sharma, S., Mohammad, S. S., Kothur, K., Patel, S., … Group, I.-N. S. (2019). Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring. Developmental Medicine and Child Neurology, 61(8), 984988. doi: 10.1111/dmcn.14167.CrossRefGoogle ScholarPubMed
Khandaker, G. M., Zimbron, J., Lewis, G., & Jones, P. B. (2013). Prenatal maternal infection, neurodevelopment and adult schizophrenia: A systematic review of population-based studies. Psychological Medicine, 43(2), 239257. doi: 10.1017/S0033291712000736.CrossRefGoogle ScholarPubMed
Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., … Prinssen, E. P. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews: Neurology, 10(11), 643660. doi: 10.1038/nrneurol.2014.187.Google ScholarPubMed
Leadbeater, B. J., Kuperminc, G. P., Blatt, S. J., & Hertzog, C. (1999). A multivariate model of gender differences in adolescents’ internalizing and externalizing problems. Developmental Psychology, 35(5), 12681282. doi: 10.1037//0012-1649.35.5.1268.CrossRefGoogle ScholarPubMed
Li, Y., Missig, G., Finger, B. C., Landino, S. M., Alexander, A. J., Mokler, E. L., … Bolshakov, V. Y. (2018). Maternal and early postnatal immune activation produce dissociable effects on neurotransmission in mPFC-amygdala circuits. Journal of Neuroscience, 38(13), 33583372. doi: 10.1523/JNEUROSCI.3642-17.2018.CrossRefGoogle ScholarPubMed
Lombardo, M. V., Moon, H. M., Su, J., Palmer, T. D., Courchesne, E., & Pramparo, T. (2018). Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Molecular Psychiatry, 23(4), 10011013. doi: 10.1038/mp.2017.15.CrossRefGoogle Scholar
Lydholm, C. N., Kohler-Forsberg, O., Nordentoft, M., Yolken, R. H., Mortensen, P. B., Petersen, L., & Benros, M. E. (2019). Parental infections before, during, and after pregnancy as risk factors for mental disorders in childhood and adolescence: A nationwide Danish study. Biological Psychiatry, 85(4), 317325. doi: 10.1016/j.biopsych.2018.09.013.CrossRefGoogle ScholarPubMed
Mac Giollabhui, N., Breen, E. C., Murphy, S. K., Maxwell, S. D., Cohn, B. A., Krigbaum, N. Y., … Ellman, L. M. (2019). Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter. Journal of Psychiatric Research, 111, 96103. doi: 10.1016/j.jpsychires.2019.01.009.CrossRefGoogle ScholarPubMed
Malan-Muller, S., Valles-Colomer, M., Raes, J., Lowry, C. A., Seedat, S., & Hemmings, S. M. J. (2018). The gut microbiome and mental health: Implications for anxiety- and trauma-related disorders. OMICS: A Journal of Integrative Biology, 22(2), 90107. doi: 10.1089/omi.2017.0077.CrossRefGoogle ScholarPubMed
Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J., & Patterson, P. H. (2012). Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior, and Immunity, 26(4), 607616. doi: 10.1016/j.bbi.2012.01.011.CrossRefGoogle ScholarPubMed
Meltzer, A., & Van de Water, J. (2017). The role of the immune system in autism spectrum disorder. Neuropsychopharmacology, 42(1), 284298. doi: 10.1038/npp.2016.158.CrossRefGoogle ScholarPubMed
Meyer, U., Nyffeler, M., Engler, A., Urwyler, A., Schedlowski, M., Knuesel, I., … Feldon, J. (2006). The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. Journal of Neuroscience, 26(18), 47524762. doi: 10.1523/JNEUROSCI.0099-06.2006.CrossRefGoogle ScholarPubMed
Meyer, U., Nyffeler, M., Yee, B. K., Knuesel, I., & Feldon, J. (2008). Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain, Behavior, and Immunity, 22(4), 469486. doi: 10.1016/j.bbi.2007.09.012.CrossRefGoogle ScholarPubMed
Mosser, C. A., Baptista, S., Arnoux, I., & Audinat, E. (2017). Microglia in CNS development: Shaping the brain for the future. Progress in Neurobiology, 149–150, 120. doi: 10.1016/j.pneurobio.2017.01.002.CrossRefGoogle ScholarPubMed
Opolski, M., & Wilson, I. (2005). Asthma and depression: A pragmatic review of the literature and recommendations for future research. Clinical Practice and Epidemiology in Mental Health, 1(1), 18. doi: 10.1186/1745-0179-1-18.CrossRefGoogle ScholarPubMed
Pandolfi, V., Magyar, C. I., & Dill, C. A. (2009). Confirmatory factor analysis of the child behavior checklist 1.5-5 in a sample of children with autism spectrum disorders. Journal of Autism and Developmental Disorders, 39(7), 986995. doi: 10.1007/s10803-009-0716-5.CrossRefGoogle Scholar
Parker-Athill, E. C., & Tan, J. (2010). Maternal immune activation and autism spectrum disorder: Interleukin-6 signaling as a key mechanistic pathway. Neuro-Signals, 18(2), 113128. doi: 10.1159/000319828.CrossRefGoogle ScholarPubMed
Patel, S., Masi, A., Dale, R. C., Whitehouse, A. J. O., Pokorski, I., Alvares, G. A., … Guastella, A. J. (2018). Social impairments in autism spectrum disorder are related to maternal immune history profile. Molecular Psychiatry, 23(8), 17941797. doi: 10.1038/mp.2017.201.CrossRefGoogle ScholarPubMed
Prins, J. R., Eskandar, S., Eggen, B. J. L., & Scherjon, S. A. (2018). Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment? Journal of Reproductive Immunology, 126, 1822. doi: 10.1016/j.jri.2018.01.004.CrossRefGoogle Scholar
Rahman, T., Zavitsanou, K., Purves-Tyson, T., Harms, L. R., Meehan, C., Schall, U., … Weickert, C. S. (2017). Effects of immune activation during early or late gestation on N-methyl-d-aspartate receptor measures in adult rat offspring. Frontiers in Psychiatry, 8, 77. doi: 10.3389/fpsyt.2017.00077.CrossRefGoogle ScholarPubMed
Rana, S. A., Aavani, T., & Pittman, Q. J. (2012). Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life. Hormones and Behavior, 62(3), 228236. doi: 10.1016/j.yhbeh.2012.03.015.CrossRefGoogle ScholarPubMed
Rescorla, L. A., Ginzburg, S., Achenbach, T. M., Ivanova, M. Y., Almqvist, F., Begovac, I., … Verhulst, F. C. (2013). Cross-informant agreement between parent-reported and adolescent self-reported problems in 25 societies. Journal of Clinical Child and Adolescent Psychology, 42(2), 262273. doi: 10.1080/15374416.2012.717870.CrossRefGoogle ScholarPubMed
Sandin, S., Hultman, C. M., Kolevzon, A., Gross, R., MacCabe, J. H., & Reichenberg, A. (2012). Advancing maternal age is associated with increasing risk for autism: A review and meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 51(5), 477486 e471. doi: 10.1016/j.jaac.2012.02.018.CrossRefGoogle ScholarPubMed
Schmeck, K., Poustka, F., Dopfner, M., Pluck, J., Berner, W., Lehmkuhl, G., … Lehmkuhl, U. (2001). Discriminant validity of the child behaviour checklist CBCL-4/18 in German samples. European Child and Adolescent Psychiatry, 10(4), 240247. doi: 10.1007/s007870170013.CrossRefGoogle ScholarPubMed
Schnorr, S. L., & Bachner, H. A. (2016). Integrative therapies in anxiety treatment with special emphasis on the gut microbiome. Yale Journal of Biology and Medicine, 89(3), 397422.Google ScholarPubMed
Scott, O., Shi, D., Andriashek, D., Clark, B., & Goez, H. R. (2017). Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression. Developmental Medicine and Child Neurology, 59(9), 947951. doi: 10.1111/dmcn.13432.CrossRefGoogle ScholarPubMed
Thapar, A., Rice, F., Hay, D., Boivin, J., Langley, K., van den Bree, M., … Harold, G. (2009). Prenatal smoking might not cause attention-deficit/hyperactivity disorder: Evidence from a novel design. Biological Psychiatry, 66(8), 722727. doi: 10.1016/j.biopsych.2009.05.032.CrossRefGoogle Scholar
Timonen, M., Jokelainen, J., Hakko, H., Silvennoinen-Kassinen, S., Meyer-Rochow, V. B., Herva, A., & Rasanen, P. (2003). Atopy and depression: Results from the Northern Finland 1966 Birth Cohort Study. Molecular Psychiatry, 8(8), 738744. doi: 10.1038/sj.mp.4001274.CrossRefGoogle ScholarPubMed
Vandenbulcke, L., Bachert, C., Van Cauwenberge, P., & Claeys, S. (2006). The innate immune system and its role in allergic disorders. International Archives of Allergy and Immunology, 139(2), 159165. doi: 10.1159/000090393.CrossRefGoogle ScholarPubMed
Van den Eynde, K., Missault, S., Fransen, E., Raeymaekers, L., Willems, R., Drinkenburg, W., … Dedeurwaerdere, S. (2014). Hypolocomotive behaviour associated with increased microglia in a prenatal immune activation model with relevance to schizophrenia. Behavioural Brain Research, 258, 179186. doi: 10.1016/j.bbr.2013.10.005.CrossRefGoogle Scholar
Welham, J., Scott, J., Williams, G., Najman, J., Bor, W., O'Callaghan, M., & McGrath, J. (2009). Emotional and behavioural antecedents of young adults who screen positive for non-affective psychosis: A 21-year birth cohort study. Psychological Medicine, 39(4), 625634. doi: 10.1017/S0033291708003760.CrossRefGoogle ScholarPubMed
Wickham, H. (2016). Ggplot2: Elegant graphics for data analysis. New York: Springer-Verlag.CrossRefGoogle Scholar
Supplementary material: File

Patel et al. supplementary material

Tables S1-S8

Download Patel et al. supplementary material(File)
File 51.2 KB