Background: An increasing proportion of women are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study was to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy.
Methods: In this prospective cohort study, the neurodevelopmental status of infants (N = 298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post-discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff scores ≤ 2 standard deviations (SDs) below the population mean) and no delays (scores > 2 SDs above the population mean).
Results: The majority (90%) of the infants born to mothers with SARS-CoV-2 infections during pregnancy had favorable outcomes and only 10% showed developmental delays. Two of the 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infections during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P = 0.039) and second trimesters (P = 0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester.
Conclusion: The neurodevelopmental outcomes of infants born to mothers with SARS-CoV-2 infections seem favorable. However, more studies with larger sample sizes and longer follow-up periods are required.
Keywords: Coronavirus 2019 (SARS-CoV-2); Neurodevelopment of infants; Perinatal transmission; Pregnancy.
Conflict of interest statement
The authors declare that they have no competing interests.
Mulkey SB, Williams ME, Jadeed N, Zhang A, Israel S, DeBiasi RL.Early Hum Dev. 2022 Dec;175:105694. doi: 10.1016/j.earlhumdev.2022.105694. Epub 2022 Nov 12.PMID: 36402122
Richter LL, Ho MSP, Zhang Q, Bone JN, Portales-Casamar E, Yang CL, Roberts A, Kang K, Kieran E, Lam C, Lisonkova S, Ting JY.Can J Infect Dis Med Microbiol. 2023 May 5;2023:9968774. doi: 10.1155/2023/9968774. eCollection 2023.PMID: 37188258 Free PMC article.
Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020;370:m3320. doi: 10.1136/bmj.m3320. - DOI - PMC - PubMed
la Cour Freiesleben N, Egerup P, Hviid KVR, Severinsen ER, Kolte AM, Westergaard D.SARS-CoV-2 in first trimester pregnancy: a cohort study. Hum Reprod. 2021; 10.1093/humrep/deaa311. - PMC - PubMed
Marodi L. Neonatal innate immunity to infectious agents. Infect Immun. 1999–2006. 10.1128/IAI.74.4.1999-2006.2006. - PMC - PubMed
van Well GTJ, Daalderop LA, Wolfs T, Kramer BW. Human perinatal immunity in physiological conditions and during infection. Mol Cell Pediatr. 2017 doi: 10.1186/s40348-017-0070-1. - DOI - PMC - PubMed
Kotlyar AM, Grechukhina O, Chen A, Popkhadze S, Grimshaw A, Tal O, et al. Vertical transmission of coronavirus disease 2019 a systematic review and meta-analysis. Am J Obstet Gynecol. 2021 doi: 10.1016/j.ajog.2020.07.049. - DOI - PMC - PubMed
Vergara-Merino L, Meza N, Couve-Perez C, Carrasco C, Ortiz-Munoz L, Madrid E, Bohorquez-Blanco S, Preze-Bracchiglinoe J. Maternal and perinatal outcomes related to COVID-19 and pregnancy: An overview of systematic of systematic reviews. Acta Obstet Gynecol Scand. 2021 doi: 10.1111/aogs.14118. - DOI - PMC - PubMed
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 doi: 10.1056/NEJMoa2002032. - DOI - PMC - PubMed
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 doi: 10.1016/S0140-6736(20)30566-3. - DOI - PMC - PubMed
Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, et al. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol. 2020;75:2352–2371. doi: 10.1016/j.jacc.2020.03.031. - DOI - PMC - PubMed
Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2020 doi: 10.1182/blood-2018-11-882993. - DOI - PubMed
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID- 19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020 doi: 10.1016/S0140-6736(20)30628-0. - DOI - PMC - PubMed
Mor G, Aldo P, Alvero AB. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. 2017 doi: 10.1038/nri.2017.64. - DOI - PubMed
Shi L, Tu N, Patterson PH. Maternal influenza infection is likely to alter fetal brain development indirectly: the virus is not detected in the fetus. Int J Dev Neurosci. 2005 doi: 10.1016/j.ijdevneu.2004.05.005. - DOI - PubMed
Patterson HP. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009 doi: 10.1016/j.bbr.2008.12.016. - DOI - PubMed
Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014 doi: 10.1038/nrneurol.2014.187. - DOI - PubMed
Meyer U. Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2014;75:307–315. doi: 10.1016/j.biopsych.2013.07.011. - DOI - PubMed
Ayed A, Embaireeg A, Benawadh A, Al-Fouzan W, Hammoud M, Al-Hathal M, Alzaydai A, et al. Maternal and perinatal characteristics and outcomes of pregnancies complicated with COVID-19 in Kuwait. BMC Pregnancy Childbirth. 2020 doi: 10.1186/s12884-020-03461-2. - DOI - PMC - PubMed
Squire J, Twombly E, Bricker D, Potter L. ASQ-3: User’s guide. Baltimore: Paul H. Brookes Publishing Co; 2009.
Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020 doi: 10.1016/j.ajogmf.2020.100107. - DOI - PMC - PubMed
Maheshwari B, Sharma P, Panwar K, Goswami KG. Evaluation of maternal and fetal outcome in corona positive pregnant women. Int J Reprod Contra Obstet Gynecol. 2020 doi: 10.18203/2320-1770.ijrcog20205244. - DOI
Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, Xia S. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr. 2020;9:51–60. doi: 10.21037/tp.2020.02.06. - DOI - PMC - PubMed
Adams Waldorf KM, McAdams RM. Influence of infection during pregnancy on fetal development. Reproduction. 2013 doi: 10.1530/REP-13-0232. - DOI - PMC - PubMed
Halai UM, Nielsen-Saines K, Moreira ML, Sequeira PC, Pereira Junior JS, Zin AA, et al. Maternal Zika virus disease severity, virus load, prior dengue antibodies, and their relationship to birth outcomes. Clin Infect Dis. 2017 doi: 10.1093/cid/cix472. - DOI - PMC - PubMed
Dodd KC, Michael BD, Ziso B, Williams B, Borrow R, Krishnan A. Herpes simplex virus encephalitis in pregnancy-a case report and review of reported patients in the literature. BMC Res Notes. 2015 doi: 10.1186/s13104-015-1071-6. - DOI - PMC - PubMed
Huddy CLJ, A Johnson A, Hope PL. Educational and behavioral problems in babies of 32–35 weeks gestation. Arch Dis Child Fetal Neonatal Ed. 2001; 10.1136/fn.85.1.F23. - PMC - PubMed
Ellman LM, Yolken RH, Buka SL, Torrey EF, Cannon TD. Cognitive functioning prior to the onset of psychosis: the role of fetal exposure to serologically determined influenza infection. Biol Psychiatry. 2009 doi: 10.1016/j.biopsych.2008.12.015. - DOI - PMC - PubMed
Charafeddine L, Dani A, Badr LK, Sinno D, Tamim H, Khoury J, Nasser F, Makki M. The psychometric properties of the Ages and Stages Questionnaires-3 in Arabic: Cross-sectional observational study. Early Hum Dev. 2019;136:33–38. doi: 10.1016/j.earlhumdev.2019.06.010. - DOI - PubMed
Shuffrey LC, Firestein MR, Kyle MH, et al. Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection. JAMA Pediatr. Published online January 04, 2022. 10.1001/jamapediatrics.2021.5563 - PMC - PubMed
Buonsenso, Danilo et al. “Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: preliminary findings.” European journal of pediatrics, 1–14. 11 Jan. 2022, 10.1007/s00431-021-04319-1 - PMC - PubMed
Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020 doi: 10.1016/S0140-6736(20)30360-3. - DOI - PMC - PubMed
Smith V, Seo D, Warty R, Payne O, Salih M, Chin KL, et al. Maternal and neonatal outcomes associated with COVID-19 infection: A systematic review. PLoS ONE. 2021 doi: 10.1371/journal.pone.0234187. - DOI - PMC - PubMed
Cordeiro CN, Tsimis M, Burd I. Infections and brain development. Obstet Gynecol Surv. 2015 doi: 10.1097/OGX.0000000000000236. - DOI - PMC - PubMed
Hassan N, Muzamil M, Banday D. COVID-19 infection during pregnancy - maternal and perinatal outcomes: a tertiary care center study. Int J Reprod Contracept Obstet Gynecol. 2020 doi: 10.18203/2320-1770.ijrcog20203853. - DOI
Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020 doi: 10.1542/peds.2020-0702. - DOI - PubMed
Lu X, Zhang L, Du H. SARS-CoV-2 infection in children. N Engl J Med. 2020 doi: 10.1056/NEJMc2005073. - DOI - PMC - PubMed
ShekerdemianLS MNR, Wolfe KK, Riggs BJ, Ross CE, McKiernan CA, et al. Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units. JAMA Pediatr. 2020 doi: 10.1001/jamapediatrics.2020.1948. - DOI - PMC - PubMed
Alzamora MC, Paredes T, Caceres D, Webb C, Valdez LM, La Rosa M. Severe COVID-19 during Pregnancy and Possible Vertical Transmission. Am J Perinatol. 2020 doi: 10.1055/s-0040-1710050. - DOI - PMC - PubMed
Peng Z, Wang J, Mo Y, Duan W, Xiang G, Yi M, et al. Unlikely SARS-CoV-2 vertical transmission from mother to child: A case report. J Infect Public Health. 2020 doi: 10.1016/j.jiph.2020.04.004. - DOI - PMC - PubMed
WHO . Middle East respiratory syndrome coronavirus (MERS-CoV) 2019.
Faure-Bardon V, Magny JF, Parodi M, Couderc S, Garcia P, Maillotte AM, et al. Sequelae of congenital cytomegalovirus following maternal primary infections are limited to those acquired in the first trimester of pregnancy. Clin Infect Dis. 2019 doi: 10.1093/cid/ciy1128. - DOI - PubMed
Parboosing R, Bao Y, Shen L, Schaefer CA, Brown AS. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry. 2013;70(7):677–85. doi: 10.1001/jamapsychiatry.2013.896. - DOI - PubMed
Salemi JL, Whiteman VE, August EM, Chandler K, Mbah AK, Salihu HM. Maternal hepatitis B and hepatitis C infection and neonatal neurological outcomes. J Viral Hepat. 2014. 10.1111/jvh.12250. - PubMed
Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep. 2007;56:1–40. - PubMed
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 doi: 10.1001/jamaneurol.2020.1127. - DOI - PMC - PubMed
Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, et al. Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr Res. 2010 doi: 10.1016/j.schres.2010.05.014. - DOI - PMC - PubMed
Rudolph MD, Graham AM, Feczko E, Miranda-Dominguez O, Rasmussen JM, 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 doi: 10.1038/s41593-018-0128-y. - DOI - PMC - PubMed
Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007 doi: 10.1097/GRF.0b013e31811ebef6. - DOI - PubMed
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH. Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun. 2001;15:411–420. doi: 10.1006/brbi.2001.0644. - DOI - PubMed
Wang Y, Chen L, Wu T, Shi H, Qin Li, Jiang H, et al. Impact of Covid-19 in pregnancy on mother’s psychological status and infant’s neurobehavioral development: a longitudinal cohort study in China. BMC Medicine.2020; doi: 10.1186/s12916-020-01825-1. - PMC - PubMed
Kerstjens JM, Nijhuis A, Hulzebos CV, van Imhoff DE, van Wassenaer-Leemhuis AG, van Haastert IC, Lopriore E, Katgert T, Swarte RM, van Lingen RA, Mulder TL, Laarman CR, Steiner K, Dijk PH. The Ages and Stages Questionnaire and Neurodevelopmental Impairment in Two-Year-Old Preterm-Born Children. PLoS ONE. 2015;10(7):e0133087. doi: 10.1371/journal.pone.0133087. - DOI - PMC - PubMed