[Skip to Content]
[Skip to Content Landing]

Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is COVID-19 exposure in utero associated with increased risk for neurodevelopmental disorders in the first year of life?

Findings  In this cohort study of 7772 infants delivered during the COVID-19 pandemic, those born to the 222 mothers with a positive SARS-CoV-2 polymerase chain reaction test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery.

Meaning  These preliminary findings suggest that COVID-19 exposure may be associated with neurodevelopmental changes and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.

Abstract

Importance  Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.

Objective  To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth.

Design, Setting, and Participants  This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021.

Exposures  Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy.

Main Outcomes and Measures  Neurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record.

Results  The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01).

Conclusions and Relevance  This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: April 6, 2022.

Published: June 9, 2022. doi:10.1001/jamanetworkopen.2022.15787

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Edlow AG et al. JAMA Network Open.

Corresponding Author: Roy H. Perlis, MD, MSc, Center for Quantitative Health and Department of Psychiatry, Massachusetts General Hospital, 185 Cambridge St, Simches Research Building, Boston, MA 02114 (rperlis@mgh.harvard.edu).

Author Contributions: Dr Perlis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Castro, Kaimal, Perlis.

Acquisition, analysis, or interpretation of data: Edlow, Castro, Shook, Perlis.

Drafting of the manuscript: Edlow, Castro, Perlis.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Castro, Perlis.

Administrative, technical, or material support: Edlow, Castro, Kaimal.

Supervision: Perlis.

Conflict of Interest Disclosures: Dr Edlow reported receiving grants from Simons Foundation during the conduct of the study. Dr Perlis reported receiving consulting fees from Burrage Capital, Genomind, RID Ventures, Belle Artificial Intelligence, and Takeda; he reported receiving equity in Psy Therapeutics, Belle Artificial Intelligence, and Circular Genomics; Dr Perlis also reported receiving personal fees from Genomind Scientific Advisory Board and personal fees from Vault Health Scientific Advisory Board outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the National Institute of Mental Health (R01MH116270 and 1R56MH115187; Dr Perlis) and the National Institute of Child Health and Human Development (R01 HD100022-02S2; Dr Edlow).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Dr Perlis is an associate editor for JAMA Network Open but was not involved in the editorial review or decision for this manuscript.

References
1.
Shook  LL , Sullivan  EL , Lo  JO , Perlis  RH , Edlow  AG .  COVID-19 in pregnancy: implications for fetal brain development.   Trends Mol Med. 2022;28(4):319-330. doi:10.1016/j.molmed.2022.02.004PubMedGoogle ScholarCrossref
2.
Cai  Z , Pan  ZL , Pang  Y , Evans  OB , Rhodes  PG .  Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration.   Pediatr Res. 2000;47(1):64-72. doi:10.1203/00006450-200001000-00013Google ScholarCrossref
3.
Meyer  U .  Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems.   Biol Psychiatry. 2014;75(4):307-15. doi:10.1016/j.biopsych.2013.07.011Google ScholarCrossref
4.
Meyer  U , Yee  BK , Feldon  J .  The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse?   Neuroscientist. 2007;13(3):241-56. doi:10.1177/1073858406296401Google ScholarCrossref
5.
Urakubo  A , Jarskog  LF , Lieberman  JA , Gilmore  JH .  Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain.   Schizophr Res. 2001;47(1):27-36. doi:10.1016/s0920-9964(00)00032-3Google ScholarCrossref
6.
Al-Haddad  BJS , Jacobsson  B , Chabra  S ,  et al.  Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero.   JAMA Psychiatry. 2019;76(6):594-602. doi:10.1001/jamapsychiatry.2019.0029Google ScholarCrossref
7.
Cordeiro  CN , Tsimis  M , Burd  I .  Infections and Brain Development.   Obstet Gynecol Surv. 2015;70(10):644-55. doi:10.1097/OGX.0000000000000236Google ScholarCrossref
8.
Adams Waldorf  KM , McAdams  RM .  Influence of infection during pregnancy on fetal development.   Reproduction. 2013;146(5):R151-62. doi:10.1530/REP-13-0232Google ScholarCrossref
9.
Al-Haddad  BJS , Oler  E , Armistead  B ,  et al.  The fetal origins of mental illness.   Am J Obstet Gynecol. 2019;221(6):549-562. doi:10.1016/j.ajog.2019.06.013Google ScholarCrossref
10.
Rogers  JP , Watson  CJ , Badenoch  J ,  et al.  Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives.   J Neurol Neurosurg Psychiatry. 2021;92(9):932-941. doi:10.1136/jnnp-2021-326405PubMedGoogle ScholarCrossref
11.
Nalbandian  A , Sehgal  K , Gupta  A ,  et al.  Post-acute COVID-19 syndrome.   Nat Med. 2021;27(4):601-615. doi:10.1038/s41591-021-01283-zPubMedGoogle ScholarCrossref
12.
Castro  VM , Rosand  J , Giacino  JT , McCoy  TH , Perlis  RH .  Case-control study of neuropsychiatric symptoms following COVID-19 hospitalization in 2 academic health systems.   medRxiv. Preprint posted online July 14, 2021. doi:10.1101/2021.07.09.21252353Google Scholar
13.
Taquet  M , Geddes  JR , Husain  M , Luciano  S , Harrison  PJ .  6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records.   Lancet Psychiatry. 2021;8(5):416-427. doi:10.1016/S2215-0366(21)00084-5PubMedGoogle ScholarCrossref
14.
Castro  VM , Gunning  FM , Perlis  RH .  Persistence of neuropsychiatric symptoms associated with SARS-CoV-2 positivity among a cohort of children and adolescents.   medRxiv. Preprint posted online September 29, 2021. doi:10.1101/2021.09.28.21264259Google Scholar
15.
Douaud  G , Lee  S , Alfaro-Almagro  F ,  et al.  Brain imaging before and after COVID-19 in UK Biobank.   medRxiv. Preprint posted online August 18, 2021. doi:10.1101/2021.06.11.21258690Google Scholar
16.
Metz  TD , Clifton  RG , Hughes  BL ,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network.  Disease severity and perinatal outcomes of pregnant patients with coronavirus disease 2019 (COVID-19).   Obstet Gynecol. 2021;137(4):571-580. doi:10.1097/AOG.0000000000004339PubMedGoogle ScholarCrossref
17.
Ding  P , VanderWeele  TJ .  Sensitivity analysis without assumptions.   Epidemiology. 2016;27(3):368-377. doi:10.1097/EDE.0000000000000457PubMedGoogle ScholarCrossref
18.
Mathur  MB , Ding  P , Riddell  CA , VanderWeele  TJ .  Web site and R package for computing e-values.   Epidemiology. 2018;29(5):e45-e47. doi:10.1097/EDE.0000000000000864PubMedGoogle ScholarCrossref
19.
Poole  C .  Commentary: continuing the e-value’s post-publication peer review.   Int J Epidemiol. 2020;49(5):1497-1500. doi:10.1093/ije/dyaa097PubMedGoogle ScholarCrossref
20.
Woodworth  KR , Olsen  EO , Neelam  V ,  et al; CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team; COVID-19 Pregnancy and Infant Linked Outcomes Team (PILOT).  Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy - SET-NET, 16 jurisdictions, March 29-October 14, 2020.   MMWR Morb Mortal Wkly Rep. 2020;69(44):1635-1640. doi:10.15585/mmwr.mm6944e2PubMedGoogle ScholarCrossref
21.
Norman  M , Navér  L , Söderling  J ,  et al.  Association of maternal SARS-CoV-2 infection in pregnancy with neonatal outcomes.   JAMA. 2021;325(20):2076-2086. doi:10.1001/jama.2021.5775PubMedGoogle ScholarCrossref
22.
Wang  Y , Chen  L , Wu  T ,  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 Med. 2020;18(1):347. doi:10.1186/s12916-020-01825-1PubMedGoogle ScholarCrossref
23.
Shuffrey  LC , Firestein  MR , Kyle  M ,  et al.  Birth during the COVID-19 Pandemic, but not maternal SARS-CoV-2 infection during pregnancy, is associated with lower neurodevelopmental scores at 6-months.   JAMA Pediatr. Published online January 4, 2022. doi:10.1001/jamapediatrics.2021.5563Google ScholarCrossref
24.
Boulanger-Bertolus  J , Pancaro  C , Mashour  GA .  Increasing role of maternal immune activation in neurodevelopmental disorders.   Front Behav Neurosci. 2018;12:230. doi:10.3389/fnbeh.2018.00230PubMedGoogle ScholarCrossref
25.
Griffith  GJ , Morris  TT , Tudball  MJ ,  et al.  Collider bias undermines our understanding of COVID-19 disease risk and severity.   Nat Commun. 2020;11(1):5749. doi:10.1038/s41467-020-19478-2PubMedGoogle ScholarCrossref
26.
Sutton  D , Fuchs  K , D’Alton  M , Goffman  D .  Universal screening for SARS-CoV-2 in women admitted for delivery.   N Engl J Med. 2020;382(22):2163-2164. doi:10.1056/NEJMc2009316PubMedGoogle ScholarCrossref
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close