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Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 InfectionThe INTERCOVID Multinational Cohort Study

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To identify the key insights or developments described in this article
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Key Points

Question  To what extent does COVID-19 in pregnancy alter the risks of adverse maternal and neonatal outcomes compared with pregnant individuals without COVID-19?

Findings  In this multinational cohort study of 2130 pregnant women in 18 countries, women with COVID-19 diagnosis were at increased risk of a composite maternal morbidity and mortality index. Newborns of women with COVID-19 diagnosis had significantly higher severe neonatal morbidity index and severe perinatal morbidity and mortality index compared with newborns of women without COVID-19 diagnosis.

Meaning  This study indicates a consistent association between pregnant individuals with COVID-19 diagnosis and higher rates of adverse outcomes, including maternal mortality, preeclampsia, and preterm birth compared with pregnant individuals without COVID-19 diagnosis.

Abstract

Importance  Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed.

Objective  To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals.

Design, Setting, and Participants  In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge.

Exposures  COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms.

Main Outcomes and Measures  The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity.

Results  A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity.

Conclusions and Relevance  In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

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Article Information

Corresponding Author: Aris T. Papageorghiou, MD, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom (aris.papageorghiou@wrh.ox.ac.uk).

Accepted for Publication: January 21, 2021.

Published Online: April 22, 2021. doi:10.1001/jamapediatrics.2021.1050

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Villar J et al. JAMA Pediatrics.

Correction: This article was corrected on November 15, 2021, to fix an error in the spelling of an author’s name.

Author Contributions: Drs Villar and Papageorghiou had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kennedy and Papageorghiou contributed equally.

Concept and design: Villar, Thiruvengadam, Arturo Cardona-Perez, Ayede, Bako, Duro, Langer, Kennedy, Papageorghiou.

Acquisition, analysis, or interpretation of data: Villar, Ariff, Gunier, Thiruvengadam, Rauch, Kholin, Roggero, Prefumo, Silva do Vale, Maiz, Cetin, Savasi, Deruelle, Easter, Sichitiu, Soto Conti, Ernawati, Mhatre, Singh Teji, Liu, Capelli, Oberto, Salazar, Gravett, Cavoretto, Bizor Nachinab, Galadanci, Oros, Ayede, Sentilhes, Bako, Savorani, Cena, Garcia-May, Etuk, Casale, Abd-Elsalam, Ikenoue, Baffah Aminu, Vecchiarelli, Usman, John-Akinola, Nieto, Ferrazzi, Bhutta, Papageorghiou.

Drafting of the manuscript: Villar, Gunier, Thiruvengadam, Rauch, Prefumo, Maiz, Singh Teji, Liu, Etuk, Kennedy, Papageorghiou.

Critical revision of the manuscript for important intellectual content: Villar, Ariff, Thiruvengadam, Kholin, Roggero, Prefumo, Silva do Vale, Arturo Cardona-Perez, Cetin, Savasi, Deruelle, Easter, Sichitiu, Soto Conti, Ernawati, Mhatre, Singh Teji, Capelli, Oberto, Salazar, Gravett, Cavoretto, Bizor Nachinab, Galadanci, Oros, Ayede, Sentilhes, Bako, Savorani, Cena, Garcia-May, Casale, Abd-Elsalam, Ikenoue, Baffah Aminu, Vecchiarelli, Duro, Usman, John-Akinola, Nieto, Ferrazzi, Bhutta, Langer, Kennedy, Papageorghiou.

Statistical analysis: Villar, Gunier, Rauch, Papageorghiou.

Obtained funding: Villar, Papageorghiou.

Administrative, technical, or material support: Villar, Ariff, Thiruvengadam, Silva do Vale, Arturo Cardona-Perez, Savasi, Easter, Sichitiu, Ernawati, Singh Teji, Liu, Galadanci, Oros, Ayede, Bako, Savorani, Garcia-May, Etuk, Baffah Aminu, John-Akinola, Papageorghiou.

Supervision: Villar, Thiruvengadam, Kholin, Roggero, Cetin, Savasi, Ayede, Cena, Etuk, Usman, Ferrazzi, Langer, Papageorghiou.

Conflict of Interest Disclosures: Dr Gunier reported grants from Oxford University during the conduct of the study. Dr Sentilhes reported personal, lecture, and consulting fees from Ferring Pharmaceutical and personal and lecture fees from Bayer outside the submitted work. Dr Papageorghiou reported grants from National Institute for Health Research Biomedical Research Centre and other support from Intelligent Ultrasound as director outside the submitted work. No other disclosures were reported.

Funding/Support: The study was supported by the COVID-19 Research Response Fund from the University of Oxford (reference 0009083). Dr Papageorghiou is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the National Institute for Health Research Biomedical Research Centre Biomedical Research Centre funding scheme.

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: The views expressed herein are those of the authors and not necessarily those of the UK National Health System, the US National Institute for Health Research Department of Health, or any of the other funders.

Additional Contributions: We are grateful to the following colleagues for their contributions to the study: Josephine Agyeman-Duah, MSc (Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK), study coordinator, Nkawkaw, Ghana; Eric Baafi, MD (Holy Family Hospital, Nkawkaw, Ghana), data collection, Ghana; Anne Caroline Benski, MD (Hôpitaux Universitaires de Genève, Département de la Femme, de l’Enfant et de l'Adolescent, Geneva, Switzerland), data collection, Geneva, Switzerland; Rachel Craik, BSc (Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK), study coordinator (overall study); Sonia Deantoni, MD (Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK; Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, UK; Neonatal Care Unit, Department of Public Health and Pediatrics, School of Medicine, University of Turin, Italy), data collection, Oxford, UK, and data input (multiple sites); Ken Takahashi, PhD (Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan), data collection, Jikei, Japan; Gabriela Tavchioska, MSc (Department of Pediatrics, General Hospital Borka Taleski, Prilep, Republic of North Macedonia), data collection, Prilep, Republic of North Macedonia; Jim G. Thornton, MD (Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK), literature reviews and study advisor; Albertina Rego, PhD (Departamento de Pediatria, Faculdade Universidade Federal de Minas Gerais, Belo Horizonte, Brazil), study coordinator, Brazil; and Adele Winsey, PhD (Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK), study coordinator (overall study). Dr Winsey and Ms Craik were supported by the COVID-19 Research Response Fund from the University of Oxford. Other contributors did not receive any compensation (eAppendix 1 in the Supplement). We also thank all the contributing institutions and local researchers involved in the study. eAppendix 2 in the Supplement contains their details as well as details of the study committees.

References
1.
Wu  Y , Zhang  C , Liu  H ,  et al.  Perinatal depressive and anxiety symptoms of pregnant women during the coronavirus disease 2019 outbreak in China.   Am J Obstet Gynecol. 2020;223(2):240.e1-240.e9. doi:10.1016/j.ajog.2020.05.009Google ScholarCrossref
2.
Davenport  MH , Meyer  S , Meah  VL , Strynadka  MC , Khurana  R .  Moms are not OK: COVID-19 and maternal mental health.   Front Glob Womens Health. Published online June 19, 2020. doi:10.3389/fgwh.2020.00001Google Scholar
3.
Yap  M , Debenham  L , Kew  T ,  et al; PregCOV-19 Consortium.  Clinical manifestations, prevalence, risk factors, outcomes, transmission, diagnosis and treatment of COVID-19 in pregnancy and postpartum: a living systematic review protocol.   BMJ Open. 2020;10(12):e041868. doi:10.1136/bmjopen-2020-041868PubMedGoogle Scholar
4.
Campbell  KH , Tornatore  JM , Lawrence  KE ,  et al.  Prevalence of SARS-CoV-2 among patients admitted for childbirth in southern Connecticut.   JAMA. 2020;323(24):2520-2522. doi:10.1001/jama.2020.8904PubMedGoogle ScholarCrossref
5.
Knight  M , Bunch  K , Vousden  N ,  et al; UK Obstetric Surveillance System SARS-CoV-2 Infection in Pregnancy Collaborative Group.  Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study.   BMJ. 2020;369:m2107. doi:10.1136/bmj.m2107PubMedGoogle Scholar
6.
Li  N , Han  L , Peng  M ,  et al.  Maternal and neonatal outcomes of pregnant women with coronavirus disease 2019 (COVID-19) pneumonia: a case-control study.   Clin Infect Dis. 2020;71(16):2035-2041. doi:10.1093/cid/ciaa352PubMedGoogle ScholarCrossref
7.
Liao  J , He  X , Gong  Q , Yang  L , Zhou  C , Li  J .  Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic.   Int J Gynaecol Obstet. 2020;150(1):53-57. doi:10.1002/ijgo.13188PubMedGoogle ScholarCrossref
8.
Alfaraj  SH , Al-Tawfiq  JA , Memish  ZA .  Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection during pregnancy: report of two cases & review of the literature.   J Microbiol Immunol Infect. 2019;52(3):501-503. doi:10.1016/j.jmii.2018.04.005PubMedGoogle ScholarCrossref
9.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053Google ScholarCrossref
10.
The Global Health Network. INTERCOVID. Accessed April 5, 2021. https://intergrowth21.tghn.org/intercovid/
11.
Shi  H , Han  X , Jiang  N ,  et al.  Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.   Lancet Infect Dis. 2020;20(4):425-434. doi:10.1016/S1473-3099(20)30086-4PubMedGoogle ScholarCrossref
12.
Bauchner  H , Golub  RM , Zylke  J .  Editorial concern-possible reporting of the same patients with COVID-19 in different reports.   JAMA. 2020;323(13):1256. doi:10.1001/jama.2020.3980PubMedGoogle ScholarCrossref
13.
Kayem  G , Lecarpentier  E , Deruelle  P ,  et al.  A snapshot of the Covid-19 pandemic among pregnant women in France.   J Gynecol Obstet Hum Reprod. 2020;49(7):101826. doi:10.1016/j.jogoh.2020.101826PubMedGoogle Scholar
14.
Sentilhes  L , De Marcillac  F , Jouffrieau  C ,  et al.  Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth.   Am J Obstet Gynecol. 2020;223(6):914.e1-914.e15. doi:10.1016/j.ajog.2020.06.022Google ScholarCrossref
15.
Maraschini  A , Corsi  E , Salvatore  MA , Donati  S , It  OSSC-WG ; ItOSS COVID-19 Working Group.  Coronavirus and birth in Italy: results of a national population-based cohort study.   Ann Ist Super Sanita. 2020;56(3):378-389.PubMedGoogle Scholar
16.
Ferrazzi  E , Beretta  P , Bianchi  S ,  et al.  SARS-CoV-2 infection testing at delivery: a clinical and epidemiological priority.   J Matern Fetal Neonatal Med. 2020;1-3. doi:10.1080/14767058.2020.1788532PubMedGoogle Scholar
17.
Collaborative  CO ; COVIDSurg Collaborative.  Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study.   Lancet. 2020;396(10243):27-38. doi:10.1016/S0140-6736(20)31182-XPubMedGoogle Scholar
18.
Ochiai  D , Kasuga  Y , Iida  M , Ikenoue  S , Tanaka  M .  Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan.   Int J Gynaecol Obstet. 2020;150(2):268-269. doi:10.1002/ijgo.13252PubMedGoogle ScholarCrossref
19.
Mendoza  M , Garcia-Ruiz  I , Maiz  N ,  et al.  Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.   BJOG. 2020;127(11):1374-1380. doi:10.1111/1471-0528.16339PubMedGoogle ScholarCrossref
20.
Lokken  EM , Walker  CL , Delaney  S ,  et al.  Clinical characteristics of 46 pregnant women with a severe acute respiratory syndrome coronavirus 2 infection in Washington State.   Am J Obstet Gynecol. 2020;223(6):911.e1-911.e14. doi:10.1016/j.ajog.2020.05.031Google ScholarCrossref
21.
Onwuzurike  C , Diouf  K , Meadows  AR , Nour  NM .  Racial and ethnic disparities in severity of COVID-19 disease in pregnancy in the United States.   Int J Gynaecol Obstet. 2020;151(2):293-295. doi:10.1002/ijgo.13333PubMedGoogle ScholarCrossref
22.
Goldfarb  IT , Diouf  K , Barth  WH ,  et al.  Universal SARS-CoV-2 testing on admission to the labor and delivery unit: Low prevalence among asymptomatic obstetric patients.   Infect Control Hosp Epidemiol. 2020;41(9):1095-1096. doi:10.1017/ice.2020.255PubMedGoogle ScholarCrossref
23.
Docherty  AB , Harrison  EM , Green  CA ,  et al; ISARIC4C investigators.  Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.   BMJ. 2020;369:m1985. doi:10.1136/bmj.m1985PubMedGoogle Scholar
24.
Villar  J , Valladares  E , Wojdyla  D ,  et al; WHO 2005 global survey on maternal and perinatal health research group.  Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global survey on maternal and perinatal health in Latin America.   Lancet. 2006;367(9525):1819-1829. doi:10.1016/S0140-6736(06)68704-7PubMedGoogle ScholarCrossref
25.
Papageorghiou  AT , Kennedy  SH , Salomon  LJ ,  et al; International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st).  International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy.   Ultrasound Obstet Gynecol. 2014;44(6):641-648. doi:10.1002/uog.13448PubMedGoogle ScholarCrossref
26.
Villar  J , Cheikh Ismail  L , Victora  CG ,  et al; International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st).  International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.   Lancet. 2014;384(9946):857-868. doi:10.1016/S0140-6736(14)60932-6PubMedGoogle ScholarCrossref
27.
Ohuma  EO , Hoch  L , Cosgrove  C ,  et al; International Fetal and Newborn Growth Consortium for the 21st Century.  Managing data for the international, multicentre INTERGROWTH-21st Project.   BJOG. 2013;120(suppl 2):64-70, v. doi:10.1111/1471-0528.12080PubMedGoogle ScholarCrossref
28.
Savasi  VM , Parisi  F , Patanè  L ,  et al.  Clinical findings and disease severity in hospitalized pregnant women with coronavirus disease 2019 (COVID-19).   Obstet Gynecol. 2020;136(2):252-258. doi:10.1097/AOG.0000000000003979PubMedGoogle ScholarCrossref
29.
Ronco  C , Reis  T , Husain-Syed  F .  Management of acute kidney injury in patients with COVID-19.   Lancet Respir Med. 2020;8(7):738-742. doi:10.1016/S2213-2600(20)30229-0PubMedGoogle ScholarCrossref
30.
Di Mascio  D , Khalil  A , Saccone  G ,  et al.  Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis.   Am J Obstet Gynecol MFM. 2020;2(2):100107. doi:10.1016/j.ajogmf.2020.100107PubMedGoogle Scholar
31.
Shanes  ED , Mithal  LB , Otero  S , Azad  HA , Miller  ES , Goldstein  JA .  Placental pathology in COVID-19.   Am J Clin Pathol. 2020;154(1):23-32. doi:10.1093/ajcp/aqaa089PubMedGoogle ScholarCrossref
32.
Narang  K , Enninga  EAL , Gunaratne  MDSK ,  et al.  SARS-CoV-2 infection and COVID-19 during pregnancy: a multidisciplinary review.   Mayo Clin Proc. 2020;95(8):1750-1765. doi:10.1016/j.mayocp.2020.05.011PubMedGoogle ScholarCrossref
33.
Sudre  CH , Lee  KA , Ni Lochlainn  M ,  et al.  Symptom clusters in Covid19: a potential clinical prediction tool from the COVID Symptom study app.   medRxiv. Preprint posted online June 16, 2020. doi:10.1101/2020.06.12.20129056Google Scholar
34.
Walker  KF , O’Donoghue  K , Grace  N ,  et al.  Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis.   BJOG. 2020;127(11):1324-1336. doi:10.1111/1471-0528.16362PubMedGoogle ScholarCrossref
35.
Chambers  C , Krogstad  P , Bertrand  K ,  et al.  Evaluation for SARS-CoV-2 in breast milk from 18 infected women.   JAMA. 2020;324(13):1347-1348. doi:10.1001/jama.2020.15580PubMedGoogle ScholarCrossref
36.
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
37.
Fassett  MJ , Lurvey  LD , Yasumura  L ,  et al.  Universal SARS-Cov-2 screening in women admitted for delivery in a large managed care organization.   Am J Perinatol. 2020;37(11):1110-1114. doi:10.1055/s-0040-1714060PubMedGoogle Scholar
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