There is growing awareness that prenatal adversity may increase the risk of autism spectrum disorder (ASD). Here, we examined the association between hypertensive disorders of pregnancy (HDP) and ASD risk at 7 years of age using the Millennium Cohort Study (MCS), a representative cohort of 13,192 children born in the UK from 2000 to 2001. We also sought to examine cytokine expression in the serum of women with pre-eclampsia, which is the most common HDP, and whether exposure of foetal neurons to this serum could change patterns of neuronal growth. HDP were reported by mothers 9 months post-delivery. ASD was parent reported at age seven, based on a doctor or health care professional’s diagnosis. Weighted logistic regression was used for data analysis, adjusting for several potential confounders including maternal alcohol consumption, education, depression, age, and poverty status. Sensitivity analyses were performed excluding pre-term births, small for gestational age (SGA), and pre-pregnancy hypertension and depression. There was a significant association between HDP and a twofold increased risk of ASD (AOR = 2.10 [95% CI 1.20–3.70]). Excluding preterm births, SGA births, and offspring of women who had pre-pregnancy hypertension or over the age of 40 did not change the results materially. At the cellular level, exposure of foetal cortical neurons to 3% serum isolated from women with an established HDP increased neuronal growth and branching in vitro. These findings indicate that HDP exposure may increase the risk of ASD in the offspring.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383:896–910
Estes ML, McAllister AK (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16:469–486
Spratt EG, Nicholas JS, Brady KT, Carpenter LA, Hatcher CR, Meekins KA, Furlanetto RW, Charles JM (2012) Enhanced cortisol response to stress in children in autism. J Autism Dev Disord 42:75–81
Christensen, D.L., Baio, J., Van Naarden Braun, K., Bilder, D., Charles, J., Constantino, J.N., Daniels, J., Durkin, M.S., Fitzgerald, R.T., Kurzius-Spencer, M., Lee, L.C., Pettygrove, S., Robinson, C., Schulz, E., Wells, C., Wingate, M.S., Zahorodny, W., Yeargin-Allsopp, M., Centers for Disease, C., Prevention, 2016. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2012. Morbidity and mortality weekly report. Surveill Summ 65, 1–23.
Mandy W, Lai MC (2016) Annual research review: the role of the environment in the developmental psychopathology of autism spectrum condition. J Child Psychol Psychiatry Allied Discip 57:271–292
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) The familial risk of autism. JAMA 311:1770–1777
Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA et al (2014) Patches of disorganization in the neocortex of children with autism. N Engl J Med 370:1209–1219
Stiles J, Jernigan TL (2010) The basics of brain development. Neuropsychol Rev 20:327–348
Olson-Chen C, Seligman NS (2016) Hypertensive emergencies in pregnancy. Crit Care Clin 32:29–41
Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I (2015) Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr 169:154–162
Mann JR, McDermott S, Bao H, Hardin J, Gregg A (2010) Pre-eclampsia, birth weight, and autism spectrum disorders. J Autism Dev Disord 40:548–554
Polo-Kantola P, Lampi KM, Hinkka-Yli-Salomaki S, Gissler M, Brown AS, Sourander A (2014) Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr 164:358–365
Ratsep MT, Paolozza A, Hickman AF, Maser B, Kay VR, Mohammad S, Pudwell J, Smith GN et al (2016) Brain structural and vascular anatomy is altered in offspring of pre-eclamptic pregnancies: a pilot study. AJNR. Am J Neuroradiol 37(5):939–945
Connelly R, Platt L (2014) Cohort profile: UK Millennium Cohort Study (MCS). Int J Epidemiol 43:1719–1725
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, Hoeffer CA, Littman DR et al (2016) The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351:933–939
Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M et al (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22(2):273–279
Wu WL, Hsiao EY, Yan Z, Mazmanian SK, Patterson PH (2017) The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun 62:11–23
Plewis I (2007) The millennium cohort study: technical report on sampling. Centre for Longitudinal Studies, University of London. http://www.cls.ioe.ac.uk/library-media/documents/Technical_Report_on_Sampling_4th_Edition.pdf. Accessed 09 Jan 2017
Curran EA, Cryan JF, Kenny LC, Dinan TG, Kearney PM, Khashan AS (2016) Obstetrical mode of delivery and childhood behavior and psychological development in a British cohort. J Autism Dev Disord 46:603–614
Russell G, Rodgers LR, Ukoumunne OC, Ford T (2014) Prevalence of parent-reported ASD and ADHD in the UK: findings from the Millennium Cohort Study. J Autism Dev Disord 44:31–40
Gardosi J, Francis A (2013) Customised weight centile calculator. In: GROW (Ed.), v6.7 (UK). Gestation Network
Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN, McCowan LM, Simpson NA et al (2014) Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension 64:644–652
Hegarty SV, Collins LM, Gavin AM, Roche SL, Wyatt SL, Sullivan AM, O'Keeffe GW (2014) Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons. NeuroMolecular Med 16:473–489
Gutierrez H, Davies AM (2007) A fast and accurate procedure for deriving the Sholl profile in quantitative studies of neuronal morphology. J Neurosci Methods 163:24–30
O'Keeffe GW, Gutierrez H, Howard L, Laurie CW, Osorio C, Gavalda N, Wyatt SL, Davies AM (2016) Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation. Neural Dev 11:4
Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ (2015) Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 20:440–446
Buchmayer S, Johansson S, Johansson A, Hultman CM, Sparen P, Cnattingius S (2009) Can association between preterm birth and autism be explained by maternal or neonatal morbidity? Pediatrics 124:e817–e825
Burstyn I, Sithole F, Zwaigenbaum L (2010) Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. Chronic Dis Can 30:125–134
Hultman CM, Sparen P, Cnattingius S (2002) Perinatal risk factors for infantile autism. Epidemiology 13:417–423
Langridge AT, Glasson EJ, Nassar N, Jacoby P, Pennell C, Hagan R, Bourke J, Leonard H et al (2013) Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability. PLoS One 8:e50963
Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF (2004) Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry 61:618–627
Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, Schendel D, Thorsen P et al (2005) Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 161:916–925 discussion 926-918
Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, Hertz-Picciotto I (2012) Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 129:e1121–e1128
Lyall K, Pauls DL, Spiegelman D, Ascherio A, Santangelo SL (2012) Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses’ Health Study II. Autism Res 5:21–30
Bilder D, Pinborough-Zimmerman J, Miller J, McMahon W (2009) Prenatal, perinatal, and neonatal factors associated with autism spectrum disorders. Pediatrics 123:1293–1300
Dodds L, Fell DB, Shea S, Armson BA, Allen AC, Bryson S (2011) The role of prenatal, obstetric and neonatal factors in the development of autism. J Autism Dev Disord 41:891–902
Maher GM, O'Keeffe GW, Kenny LC, Kearney PM, Dinan TG, Khashan AS (2017) Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol. BMJ Open in press
Darmochwal-Kolarz D, Kludka-Sternik M, Tabarkiewicz J, Kolarz B, Rolinski J, Leszczynska-Gorzelak B, Oleszczuk J (2012) The predominance of Th17 lymphocytes and decreased number and function of Treg cells in preeclampsia. J Reprod Immunol 93:75–81
Toldi G, Rigo J Jr, Stenczer B, Vasarhelyi B, Molvarec A (2011) Increased prevalence of IL-17-producing peripheral blood lymphocytes in pre-eclampsia. Am J Reprod Immunol 66:223–229
Falkegard M, Schirmer H, Lochen ML, Oian P, Acharya G (2015) The validity of self-reported information about hypertensive disorders of pregnancy in a population-based survey: the Tromso study. Acta Obstet Gynecol Scand 94:28–34
Bohm S, Curran EA, Kenny LC, O'Keeffe GW, Murray D, Khashan AS (2017) The effect of hypertensive disorders of pregnancy on the risk of ADHD in the offspring. J Atten Disord 1:1087054717690230
This study was funded by a research centre’s grant (Grant#: INFANT-12/RC/2272) (L.K.) from Science Foundation Ireland. This study has also emanated from research supported in part by a research grant from SFI under the grant number 15/CDA/3498 (G.OK).
Conflict of Interest
The authors declare that they have no conflict of interest.
Eileen A. Curran and Gerard W. O’Keeffe have joint contribution
About this article
Cite this article
Curran, E.A., O’Keeffe, G.W., Looney, A.M. et al. Exposure to Hypertensive Disorders of Pregnancy Increases the Risk of Autism Spectrum Disorder in Affected Offspring. Mol Neurobiol 55, 5557–5564 (2018). https://doi.org/10.1007/s12035-017-0794-x
- Autism spectrum disorder
- Hypertensive disorders