Effectiveness of the BNT162b2 mRNA COVID-19 Vaccine in Pregnancy

Effectiveness of the BNT162b2 mRNA COVID-19 Vaccine in Pregnancy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication Effectiveness of the BNT162b2 mRNA COVID-19 Vaccine in Pregnancy Ran Balicer, Noa Dagan, Noam Barda, Tal Biron-Shental, Maya Makov-Assif, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-665725/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Sep, 2021 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract Background: As mass vaccination campaigns against COVID-19 accelerate worldwide, there remains only limited evidence regarding vaccine effectiveness (VE) among pregnant women. Pregnant women have been shown to be at risk for severe COVID-19, resulting in adverse obstetrics outcomes, and their immune system is known to undergo alterations during pregnancy. Phase III clinical trials of the approved mRNA COVID-19 vaccines excluded pregnant women, yet current guidelines encourage offering the vaccine to pregnant women. In this study, we examine data from Israel’s largest healthcare organization to evaluate the effectiveness of the BNT162b2 mRNA vaccine among pregnant women. Methods: We conducted an observational cohort study of pregnant women 16 years or older, with no history of SARS-CoV-2, who were vaccinated between December 20, 2020 and June 3, 2021. Vaccinated subjects were matched to unvaccinated controls according to a set of demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. For each outcome, VE was estimated at several periods following vaccination as one minus the risk ratio using the Kaplan–Meier estimator. Results: 10,861 vaccinated women were matched to an identical number of unvaccinated controls. Estimated VE from 7 through 28 days after the second dose was 97% (95% CI 91%-100%) for any documented infection, 96% (86-100%) for infections with documented symptoms, and 85% (32%-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group, and no deaths were observed in either group -- insufficient incidence for estimating VE for these outcomes. Discussion: The BNT162b2 mRNA vaccine was found to have high VE among pregnant women. Since high VE has been reported as one of the strongest predictors of COVID-19 vaccine acceptance among pregnant women, the high VE estimates found in this study have the potential to increase vaccine acceptance in this group. In addition, the present VE estimates are similar to those reported in the general population for the same variants, suggesting that it may be possible to infer the VE for pregnant women from studies in the general population for both current and future variants. Epidemiology Virology Infectious Diseases Health Economics & Outcomes Research Health Policy COVID-19 vaccination pregnancy vaccine effectiveness Figures Figure 1 Introduction Hundreds of millions of people worldwide have been infected by the SARS-CoV-2 virus, and millions have died from COVID-19 and related complications. COVID-19 vaccines are currently the leading approach for combating the pandemic’s advance. Phase III clinical trials conducted to evaluate the safety and efficacy of mRNA COVID-19 vaccines did not include pregnant women, even though they are at risk for severe COVID-19( 1 ) and potentially for adverse pregnancy outcomes( 2 ). Ongoing trials are limited to late pregnancy vaccination and surrogate efficacy outcomes (i.e., immunogenicity). Despite the current lack of evidence regarding the safety and efficacy of the vaccines for this population( 3 , 4 ), current guidelines state that pregnant women should be offered the vaccines( 5 ). As the number of vaccinated individuals increases worldwide, there is an opportunity to evaluate the real-world effectiveness and safety of the mRNA COVID-19 vaccines using observational data. Initial reports regarding vaccine safety indicate no obvious safety signals among pregnant women( 6 ). However, information regarding vaccine effectiveness (VE) among pregnant women is still limited( 5 ). The immune system is known to undergo alterations during pregnancy. For example, there is evidence that levels of CD4 + and CD8 + lymphocytes decrease during pregnancy, as do the levels of some inflammatory cytokines( 7 ). Since mRNA-based vaccines are a novel technology that has not been widely tested among pregnant women, it is plausible that the immune response triggered by these vaccines in pregnant women may be altered compared to the general population, increasing the need to evaluate VE specifically for this sub-population. In a previous report, confidence in VE among pregnant women was mentioned as one of the strongest predictors of COVID-19 vaccine acceptance in this group( 8 ). The objective of this study is thus to provide real-world VE measures in a large cohort of vaccinated pregnant women. Methods Data Source Clalit Health Services (CHS) is an integrated healthcare payer-provider organization that serves 52% of the Israeli population. The present study is based on CHS data covering patients vaccinated from the start of the vaccination campaign in Israel on December 20, 2020 through June 3, 2021. CHS data systems contain medical and claims data covering all facets of patient care, including primary care, specialist care, imaging, labs, and hospitalizations, with over 20 years of historical depth for most individuals. CHS community care includes dedicated systems for prenatal care, with specific data fields for “date of last menstrual period” and “projected birth date.” These data are integrated daily with data collected centrally by the Israeli Ministry of Health regarding COVID-19 vaccines, SARS-CoV-2 tests, as well as COVID-19 related hospitalizations, disease severity and death. Study Design and Study Population We conducted an observational cohort study that emulates a target trial to estimate the effectiveness of the BNT162b2 mRNA COVID-19 vaccine among pregnant women. We used a similar methodology to previous studies on VE using the same database( 9 ). Eligibility criteria considered at the start of follow-up were being pregnant (as recorded in the CHS data systems), age 16 or older, continuous membership in the CHS health organization for a complete year, no prior positive SARS-CoV-2 PCR test, no prior SARS-CoV-2 vaccination, not residing in long-term care facilities, no home confinement due to medical reasons, not being a healthcare worker, and no interaction with the healthcare system (physician appointment, laboratory test or hospitalization) in the previous 2 days (as this may signal a pre-existing SARS-CoV-2 infection). Individuals with missing data (only relevant for the BMI and living area variables) were excluded, as these are rare in the CHS data. Each day during the study period, eligible women vaccinated on that day were individually matched to eligible women who had not yet been vaccinated and who were not previously matched as controls. Matching factors included age (in 3 year bins), trimester of pregnancy, geostatistical living area (corresponding to a small town or a single neighborhood within a large city, or city/town of residence when the smaller geostatistical living area was not available), population sector (General Jewish, Arab or Ultraorthodox Jewish), count of influenza vaccinations in the last 5 years (in 2 bins), and existence of a CDC risk factor for severe COVID-19( 10 ). Definitions for all variables used in the study are included in Table S1. The outcomes studied were: Documented SARS-CoV-2 infection - defined as a positive SARS-CoV-2 PCR test; Symptomatic SARS-CoV-2 infection (COVID-19) - defined by an infection accompanied by the documentation of COVID-19 symptoms in dedicated fields in the outpatient health record (or an infection that warranted an hospitalization); COVID-19 related hospitalization; Severe COVID-19 - as defined by the Israeli ministry of health using international criteria( 11 ); and COVID-19 related death. The outcome date was set to the date of the first positive test for the first two outcomes and the date of first occurrence for the latter outcomes. Statistical Analysis Following matching, we used the Kaplan-Meier estimator to construct cumulative incidence curves. We estimated VE at different periods following vaccination: days 14–20 after the first dose, days 21–27 after the first dose and days 7–56 after the second dose. In each period, we restricted the analysis to matched pairs where both members were not censored and had not developed the outcome prior to the beginning of that period. We then calculated the risk ratio and risk difference during that period, with VE defined as one minus the risk ratio. To estimate the analog of a per-protocol effect, we censored both members of the matching pair when either member received a vaccination. Confidence intervals were estimated using the nonparametric percentile bootstrap method with 1,000 repetitions. Analysis was performed using the R programming language, version 4.0.4. Ethics This study was approved by the CHS institutional review board. Results Of 38,836 women in CHS vaccinated during pregnancy, 28,227 met the eligibility requirements, and 10,861 were successfully matched to unvaccinated controls (Figure S1).The full population was similar to the eligible population (Table S2). Matched individuals were also similar to the eligible population, albeit with a lower proportion of existing conditions for some of the risk factors for severe COVID-19 (Table S2). The baseline characteristics of the matched individuals were very similar in the vaccinated and unvaccinated groups (Table S3). The median age was 30 years, with 26%, 48%, and 26% in the first, second and third trimesters, respectively. Of the matched individuals, 18% had at least one risk factor for severe COVID-19 (the most common being obesity). During a median follow-up of 77 days, 131 infections were documented in the vaccination group and 235 infections in the control group. Event counts in each of the analysis periods are included in Table S4. Cumulative incidence curves from the time of the first vaccine dose are shown in Fig. 1 . The curves in the vaccinated and unvaccinated groups are similar until day 14 following the first vaccine dose, when incidence in the vaccinated group begins to decline sharply. The estimated VE for documented infections was 67% (95% CI: 40%-84%) in days 14–20 following the first dose, 71% (33%-94%) in days 21 − 17 following the first dose, and 96% (89%-100%), in days 7–56 following the second dose. The estimated VE for symptomatic infection was 66% (95% CI: 32%-86%) in days 14–20 following the first dose, 76% (30%-100%) in days 21 − 17 following the first dose, and 97% (91%-100%), in days 7–56 following the second dose. VE for COVID-19 related hospitalization was 89% (43%-100%) in days 7–56 following the second dose (Table 1 ). The VE could not be estimated for the other outcomes and periods due to the small number of events. Table 1 Risk ratios and risk differences (per 100,000) of COVID-19 outcomes for vaccination vs. no vaccination at several periods following vaccination, in pregnant women who are members of Clalit Health Services, December 20, 2020 through June 3, 2021. The study population numbered 10,861 individuals in each arm. 1,529 individuals were first included as unvaccinated and then re-recruited as vaccinated. Period Documented Infection Symptomatic Infection Hospitalization Severe Disease 1-RR (95-CI) RD (95-CI) 1-RR (95-CI) RD (95-CI) 1-RR (95-CI) RD (95-CI) 1-RR (95-CI) RD (95-CI) Days 14–20 after 1st dose 67% (40%-84%) 309.22 (145.43-485.69) 66% (32%-86%) 223.59 (82.44-361.63) 3 vs. 0* 2 vs. 0* Days 21–27 after 1st dose 71% (33%-94%) 157.30 (41.42-285.23) 76% (30%-100%) 116.52 (26.92-217.92) 5 vs. 0* 0 vs. 0* Days 7–56 after 2nd dose 96% (89%-100%) 933.40 (685.60-1192.33) 97% (91%-100%) 621.70 (433.68-847.26) 89% (43%-100%) 132.28 (31.67-241.03) 1 vs. 0* *Estimates were only calculated for cells with more than 5 events, otherwise raw counts were reported. Discussion In this study we estimated that the BNT162b2 mRNA COVID-19 vaccine is as effective for pregnant women as previously reported for the general population for the same variant composition: 96% effectiveness against documented infection and 97% effectiveness against symptomatic infection 7–56 days following receipt of the second vaccine dose. Effectiveness against COVID-19-related hospitalization was high, but a paucity of cases prevented precise estimation. These results reflect the VE mainly against the original SARS-CoV-2 reference strain and the B.1.1.7 (Alpha) variant, which were the dominant strains circulating in Israel during the study period. As the original phase III trials did not include pregnant women, data regarding the effectiveness of the novel mRNA COVID-19 vaccines in this population is still scarce in the medical literature. One study confirmed the immunogenicity of these vaccines in pregnant women by confirming cellular and humoral immune responses against SARS-CoV-2( 12 ). To the best of the authors’ knowledge, the present study is the first to directly evaluate VE against infection and symptomatic disease among women vaccinated during pregnancy. The VE of the BNT162b2 mRNA COVID-19 vaccine against documented and symptomatic infections was previously reported for a general population using the data repositories of the same healthcare organization and covering the same variant distribution – after the second vaccine dose, VE was and found to be 92% (88%-95%) and 94% (87%-98%), respectively( 9 ). In an updated analysis of the same data over a longer period of time, the confidence intervals were narrower, with estimates of 93% (91%-94%) for documented infection and 96%(94%-97%) for symptomatic infection( 13 ). The VE estimated in the present study suggests that pregnant women have similar VE as the general population, or maybe even slightly higher VE than the general adult population, which is older on average and has a higher burden of comorbidities (some of which were demonstrated to reduce VE). That pregnancy was not found to reduce VE suggests that it may be reasonable to infer VE for pregnant women based on studies in the general population, for both current and future variants. Vaccination of pregnant women may also provide protection for their newborns. A recent study found binding and neutralizing antibodies in the cord blood of infants born to mothers who were vaccinated with mRNA vaccines, and in the mothers’ breast milk( 12 ). Another study found that vaccination of breastfeeding women resulted in a rapid increase of anti–SARS-CoV-2-specific antibodies in their breast milk( 14 ). The duration of the potential protection is still unclear. However, it is plausible that the antibody secretion in breast milk will provide protection to newborns, especially among those women vaccinated during the later stages of pregnancy. The high VE among pregnant women estimated in this study may also contribute to increased vaccination acceptance rates among this group. It was previously reported that high VE is an important factor for encouragement of pregnant women to receive COVID-19 vaccines: If VE of above 90% was achieved, 52% of the pregnant women reported that they would be willing to receive the vaccine. Furthermore, pregnant women indicated higher likelihood of vaccination with higher VE( 8 ). This study has several limitations. First, despite the careful matching between cohorts, there is the lingering possibility of residual confounding. This is particularly true because information regarding pre-natal complications was not available. However, the very similar incidence of documented and symptomatic infections between the study groups during the early period following the first vaccine dose suggests that residual confounding, if present, is minor. Second, due to the low incidence of the more severe outcomes, this study was not able to provide precise VE estimates for them. Third, the strict matching process required to achieve exchangeability between the study groups resulted in a relatively large fraction of the eligible population not being included in the study. As a result, the proportion of women with some chronic conditions was somewhat lower in the final study population. VE for women with chronic conditions may be somewhat lower than the average VE reported in this study, as previously reported for the general population ( 13 ). In conclusion, the results of this study indicate that the BNT162b2 mRNA COVID-19 vaccine is highly effective among pregnant women for the original SARS-CoV-2 strain and the B.1.1.7 (Alpha) variant. The similarity between the VE estimates among pregnant women and those reported for the same variants in the general population suggests that it may be possible to infer VE for pregnant women from studies in the general population for both current and future variants. Further studies are needed to better characterize the dynamics of VE throughout pregnancy, as well as the relationship between vaccination timing and infant protection after birth. Declarations Author Contributions ND, NB, TBS, CK, SHD, BR and RDB conceived and designed the study. ND, NB and MMA participated in data extraction and analysis. ND, NB, ZK, MAH, ML, SHD, BR and RDB wrote the manuscript. TBS and SHD provided clinical guidance. All authors critically reviewed the manuscript and decided to proceed with publication. BR and RDB supervised the study process and vouch for the data and analysis. Funding This research was supported by the Ivan and Francesca Berkowitz Family Precision Medicine Clinic at Clalit Research Institute and the Ivan and Francesca Berkowitz Family Living Laboratory at Harvard Medical School. ML was supported by the Morris-Singer Fund. Competing interests ND, NB, MMA and RDB report institutional grants to Clalit Research Institute from Pfizer outside the submitted work and unrelated to COVID-19, with no direct or indirect personal benefits. ML reports grants from Pfizer, personal fees from Merck, personal fees from Bristol-Meyers Squibb, personal fees from Sanofi Pasteur, personal fees from Janssen, grants from NIH (US), grants from National Institute for Health Research (UK), grants from CDC (US), grants from Open Philanthropy Project, grants from Wellcome Trust, grants from Pfizer outside the submitted work; he has provided unpaid advice on COVID vaccines or vaccine studies to One Day Sooner (nonprofit), Pfizer, Astra-Zeneca, Janssen, and COVAXX (United Biosciences). MAH reports grants from NIH, grants from VA, personal fees from Cytel, personal fees from ProPublica, outside the submitted work; he has provided unpaid advice on COVID vaccine studies to Pfizer. SHD reports consulting fees from Roche and UCB outside the submitted work. BYR reports grants from NIH outside the submitted work. Data availability Due to data privacy regulations, the raw data of this study cannot be shared. Code availability The modeling code used in this study is part of standard R libraries that are freely available. References 1. Zambrano LD, Ellington S, Strid P, Galang RR, Oduyebo T, Tong VT, et al. Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status - United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020 Nov 6;69(44):1641–1647. 2. Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. Can Med Assoc J. 2021 Mar 19; 3. Rubin R. Pregnant People’s Paradox-Excluded From Vaccine Trials Despite Having a Higher Risk of COVID-19 Complications. JAMA. 2021 Mar 16;325(11):1027–1028. 4. Rasmussen SA, Kelley CF, Horton JP, Jamieson DJ. Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy: What Obstetricians Need to Know. Obstet Gynecol. 2021 Mar 1;137(3):408–414. 5. Riley LE, Jamieson DJ. Inclusion of Pregnant and Lactating Persons in COVID-19 Vaccination Efforts. Ann Intern Med. 2021 Jan 26; 6. Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, et al. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. N Engl J Med. 2021 Apr 21; 7. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014 Jun 5;370(23):2211–2218. 8. Skjefte M, Ngirbabul M, Akeju O, Escudero D, Hernandez-Diaz S, Wyszynski DF, et al. COVID-19 vaccine acceptance among pregnant women and mothers of young children: results of a survey in 16 countries. Eur J Epidemiol. 2021 Feb;36(2):197–211. 9. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Apr 15;384(15):1412–1423. 10. Certain Medical Conditions and Risk for Severe COVID-19 Illness | CDC [Internet]. [cited 2020 Dec 9]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html 11. COVID-19 Treatment Guidelines [Internet]. [cited 2021 Jan 9]. Available from: https://www.covid19treatmentguidelines.nih.gov/ 12. Collier A-RY, McMahan K, Yu J, Tostanoski LH, Aguayo R, Ansel J, et al. Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women. JAMA. 2021 May 13; 13. Barda N, Dagan N, Balicer RD. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Reply. N Engl J Med. 2021 Apr 21;384(20). 14. Perl SH, Uzan-Yulzari A, Klainer H, Asiskovich L, Youngster M, Rinott E, et al. SARS-CoV-2-Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women. JAMA. 2021 May 18;325(19):2013–2014. Additional Declarations Yes there is potential Competing Interest. ND, NB, MMA and RDB report institutional grants to Clalit Research Institute from Pfizer outside the submitted work and unrelated to COVID-19, with no direct or indirect personal benefits. ML reports grants from Pfizer, personal fees from Merck, personal fees from Bristol-Meyers Squibb, personal fees from Sanofi Pasteur, personal fees from Janssen, grants from NIH (US), grants from National Institute for Health Research (UK), grants from CDC (US), grants from Open Philanthropy Project, grants from Wellcome Trust, grants from Pfizer outside the submitted work; he has provided unpaid advice on COVID vaccines or vaccine studies to One Day Sooner (nonprofit), Pfizer, Astra-Zeneca, Janssen, and COVAXX (United Biosciences). MAH reports grants from NIH, grants from VA, personal fees from Cytel, personal fees from ProPublica, outside the submitted work; he has provided unpaid advice on COVID vaccine studies to Pfizer. BYR reports grants from NIH outside the submitted work. Supplementary Files PregnancyVESupplementv14.docx Supplemental Material flatBardars.pdf Reporting Summary flatBardaepc.pdf Editorial Policy Checklist Cite Share Download PDF Status: Published Journal Publication published 07 Sep, 2021 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-665725","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Brief Communication","associatedPublications":[],"authors":[{"id":36217959,"identity":"e2905c17-fb59-412d-9ec5-59aa3ed9659a","order_by":0,"name":"Ran 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University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ben","middleName":"","lastName":"Reis","suffix":""}],"badges":[],"createdAt":"2021-06-28 06:00:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-665725/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-665725/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41591-021-01490-8","type":"published","date":"2021-09-07T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":11383104,"identity":"1d97dc1a-483e-47b3-81d9-cc6dd5d0073b","added_by":"auto","created_at":"2021-07-12 16:28:57","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":324011,"visible":true,"origin":"","legend":"Cumulative incidence of outcomes. Cumulative incidence curves of COVID-19 outcomes in pregnant women, Clalit Health Services, December 20, 2020 through June 3, 2021. Shaded areas are 95% confidence intervals. The vertical lines at days 28 and 77 demarcate the period in which an individual is considered “fully vaccinated” in the manuscript (7 through 58 days after receipt of the second dose). The tables below each curve present the number at risk at each time point, along with the cumulative number of events. Each individual was included only once in each study group, but individuals could move from the unvaccinated group to the vaccinated group after receipt of the vaccine.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-665725/v1/58e18e0c19ee317a5f4c8263.jpg"},{"id":15781016,"identity":"187a0a2c-306e-403e-a498-3dbba4e1db51","added_by":"auto","created_at":"2021-11-22 15:42:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":414561,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-665725/v1/79fc7c66-fdf4-450e-8393-cde962396eaa.pdf"},{"id":11383405,"identity":"7090615c-ce6f-46d2-8c36-a99e42e4be5e","added_by":"auto","created_at":"2021-07-12 16:31:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":158277,"visible":true,"origin":"","legend":"Supplemental Material","description":"","filename":"PregnancyVESupplementv14.docx","url":"https://assets-eu.researchsquare.com/files/rs-665725/v1/6afdac5a6648ed2b71c6ab68.docx"},{"id":11383106,"identity":"5c27660b-1ee3-477c-8f8b-b97eb95d33ef","added_by":"auto","created_at":"2021-07-12 16:28:57","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1350645,"visible":true,"origin":"","legend":"Reporting Summary","description":"","filename":"flatBardars.pdf","url":"https://assets-eu.researchsquare.com/files/rs-665725/v1/2d4957cf7fdbf510d789d14c.pdf"},{"id":11383107,"identity":"defed170-dd7f-4470-88e4-6f7058c4ef13","added_by":"auto","created_at":"2021-07-12 16:28:57","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1507902,"visible":true,"origin":"","legend":"Editorial Policy Checklist","description":"","filename":"flatBardaepc.pdf","url":"https://assets-eu.researchsquare.com/files/rs-665725/v1/efd1ac0b0ed55c6ea25f3bf9.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nND, NB, MMA and RDB report institutional grants to Clalit Research Institute from Pfizer outside the submitted work and unrelated to COVID-19, with no direct or indirect personal benefits. ML reports grants from Pfizer, personal fees from Merck, personal fees from Bristol-Meyers Squibb, personal fees from Sanofi Pasteur, personal fees from Janssen, grants from NIH (US), grants from National Institute for Health Research (UK), grants from CDC (US), grants from Open Philanthropy Project, grants from Wellcome Trust, grants from Pfizer outside the submitted work; he has provided unpaid advice on COVID vaccines or vaccine studies to One Day Sooner (nonprofit), Pfizer, Astra-Zeneca, Janssen, and COVAXX (United Biosciences). MAH reports grants from NIH, grants from VA, personal fees from Cytel, personal fees from ProPublica, outside the submitted work; he has provided unpaid advice on COVID vaccine studies to Pfizer. BYR reports grants from NIH outside the submitted work.","formattedTitle":"Effectiveness of the BNT162b2 mRNA COVID-19 Vaccine in Pregnancy","fulltext":[{"header":"Introduction","content":" \u003cp\u003eHundreds of millions of people worldwide have been infected by the SARS-CoV-2 virus, and millions have died from COVID-19 and related complications. COVID-19 vaccines are currently the leading approach for combating the pandemic\u0026rsquo;s advance. Phase III clinical trials conducted to evaluate the safety and efficacy of mRNA COVID-19 vaccines did not include pregnant women, even though they are at risk for severe COVID-19(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and potentially for adverse pregnancy outcomes(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Ongoing trials are limited to late pregnancy vaccination and surrogate efficacy outcomes (i.e., immunogenicity). Despite the current lack of evidence regarding the safety and efficacy of the vaccines for this population(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), current guidelines state that pregnant women should be offered the vaccines(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs the number of vaccinated individuals increases worldwide, there is an opportunity to evaluate the real-world effectiveness and safety of the mRNA COVID-19 vaccines using observational data. Initial reports regarding vaccine safety indicate no obvious safety signals among pregnant women(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, information regarding vaccine effectiveness (VE) among pregnant women is still limited(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe immune system is known to undergo alterations during pregnancy. For example, there is evidence that levels of CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;lymphocytes decrease during pregnancy, as do the levels of some inflammatory cytokines(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Since mRNA-based vaccines are a novel technology that has not been widely tested among pregnant women, it is plausible that the immune response triggered by these vaccines in pregnant women may be altered compared to the general population, increasing the need to evaluate VE specifically for this sub-population. In a previous report, confidence in VE among pregnant women was mentioned as one of the strongest predictors of COVID-19 vaccine acceptance in this group(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The objective of this study is thus to provide real-world VE measures in a large cohort of vaccinated pregnant women.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003cp\u003e\u003cstrong\u003eData Source\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eClalit Health Services (CHS) is an integrated healthcare payer-provider organization that serves 52% of the Israeli population. The present study is based on CHS data covering patients vaccinated from the start of the vaccination campaign in Israel on December 20, 2020 through June 3, 2021. CHS data systems contain medical and claims data covering all facets of patient care, including primary care, specialist care, imaging, labs, and hospitalizations, with over 20 years of historical depth for most individuals. CHS community care includes dedicated systems for prenatal care, with specific data fields for \u0026ldquo;date of last menstrual period\u0026rdquo; and \u0026ldquo;projected birth date.\u0026rdquo; These data are integrated daily with data collected centrally by the Israeli Ministry of Health regarding COVID-19 vaccines, SARS-CoV-2 tests, as well as COVID-19 related hospitalizations, disease severity and death.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec4\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Design and Study Population\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eWe conducted an observational cohort study that emulates a target trial to estimate the effectiveness of the BNT162b2 mRNA COVID-19 vaccine among pregnant women. We used a similar methodology to previous studies on VE using the same database(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). Eligibility criteria considered at the start of follow-up were being pregnant (as recorded in the CHS data systems), age 16 or older, continuous membership in the CHS health organization for a complete year, no prior positive SARS-CoV-2 PCR test, no prior SARS-CoV-2 vaccination, not residing in long-term care facilities, no home confinement due to medical reasons, not being a healthcare worker, and no interaction with the healthcare system (physician appointment, laboratory test or hospitalization) in the previous 2 days (as this may signal a pre-existing SARS-CoV-2 infection). Individuals with missing data (only relevant for the BMI and living area variables) were excluded, as these are rare in the CHS data.\u003c/p\u003e\n \u003cp\u003eEach day during the study period, eligible women vaccinated on that day were individually matched to eligible women who had not yet been vaccinated and who were not previously matched as controls. Matching factors included age (in 3 year bins), trimester of pregnancy, geostatistical living area (corresponding to a small town or a single neighborhood within a large city, or city/town of residence when the smaller geostatistical living area was not available), population sector (General Jewish, Arab or Ultraorthodox Jewish), count of influenza vaccinations in the last 5 years (in 2 bins), and existence of a CDC risk factor for severe COVID-19(\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e). Definitions for all variables used in the study are included in Table S1.\u003c/p\u003e\n \u003cp\u003eThe outcomes studied were: Documented SARS-CoV-2 infection - defined as a positive SARS-CoV-2 PCR test; Symptomatic SARS-CoV-2 infection (COVID-19) - defined by an infection accompanied by the documentation of COVID-19 symptoms in dedicated fields in the outpatient health record (or an infection that warranted an hospitalization); COVID-19 related hospitalization; Severe COVID-19 - as defined by the Israeli ministry of health using international criteria(\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e); and COVID-19 related death. The outcome date was set to the date of the first positive test for the first two outcomes and the date of first occurrence for the latter outcomes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec5\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFollowing matching, we used the Kaplan-Meier estimator to construct cumulative incidence curves. We estimated VE at different periods following vaccination: days 14\u0026ndash;20 after the first dose, days 21\u0026ndash;27 after the first dose and days 7\u0026ndash;56 after the second dose. In each period, we restricted the analysis to matched pairs where both members were not censored and had not developed the outcome prior to the beginning of that period. We then calculated the risk ratio and risk difference during that period, with VE defined as one minus the risk ratio. To estimate the analog of a per-protocol effect, we censored both members of the matching pair when either member received a vaccination. Confidence intervals were estimated using the nonparametric percentile bootstrap method with 1,000 repetitions. Analysis was performed using the R programming language, version 4.0.4.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThis study was approved by the CHS institutional review board.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf 38,836 women in CHS vaccinated during pregnancy, 28,227 met the eligibility requirements, and 10,861 were successfully matched to unvaccinated controls (Figure S1).The full population was similar to the eligible population (Table S2). Matched individuals were also similar to the eligible population, albeit with a lower proportion of existing conditions for some of the risk factors for severe COVID-19 (Table S2).\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of the matched individuals were very similar in the vaccinated and unvaccinated groups (Table S3). The median age was 30 years, with 26%, 48%, and 26% in the first, second and third trimesters, respectively. Of the matched individuals, 18% had at least one risk factor for severe COVID-19 (the most common being obesity).\u003c/p\u003e\n\u003cp\u003eDuring a median follow-up of 77 days, 131 infections were documented in the vaccination group and 235 infections in the control group. Event counts in each of the analysis periods are included in Table S4. Cumulative incidence curves from the time of the first vaccine dose are shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The curves in the vaccinated and unvaccinated groups are similar until day 14 following the first vaccine dose, when incidence in the vaccinated group begins to decline sharply.\u003c/p\u003e\n\u003cp\u003eThe estimated VE for documented infections was 67% (95% CI: 40%-84%) in days 14\u0026ndash;20 following the first dose, 71% (33%-94%) in days 21\u0026thinsp;\u0026minus;\u0026thinsp;17 following the first dose, and 96% (89%-100%), in days 7\u0026ndash;56 following the second dose. The estimated VE for symptomatic infection was 66% (95% CI: 32%-86%) in days 14\u0026ndash;20 following the first dose, 76% (30%-100%) in days 21\u0026thinsp;\u0026minus;\u0026thinsp;17 following the first dose, and 97% (91%-100%), in days 7\u0026ndash;56 following the second dose. VE for COVID-19 related hospitalization was 89% (43%-100%) in days 7\u0026ndash;56 following the second dose (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The VE could not be estimated for the other outcomes and periods due to the small number of events.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk ratios and risk differences (per 100,000) of COVID-19 outcomes for vaccination vs. no vaccination at several periods following vaccination, in pregnant women who are members of Clalit Health Services, December 20, 2020 through June 3, 2021. The study population numbered 10,861 individuals in each arm. 1,529 individuals were first included as unvaccinated and then re-recruited as vaccinated.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePeriod\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDocumented Infection\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSymptomatic Infection\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHospitalization\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSevere Disease\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e1-RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e1-RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e1-RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e1-RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95-CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDays 14\u0026ndash;20\u003c/p\u003e\n \u003cp\u003eafter 1st dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67% (40%-84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e309.22 (145.43-485.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66% (32%-86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e223.59 (82.44-361.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3 vs. 0*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 vs. 0*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDays 21\u0026ndash;27\u003c/p\u003e\n \u003cp\u003eafter 1st dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71% (33%-94%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e157.30 (41.42-285.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76% (30%-100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e116.52 (26.92-217.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 vs. 0*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 vs. 0*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDays 7\u0026ndash;56 after 2nd dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96% (89%-100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e933.40 (685.60-1192.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97% (91%-100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e621.70 (433.68-847.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89% (43%-100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e132.28 (31.67-241.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 vs. 0*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e*Estimates were only calculated for cells with more than 5 events, otherwise raw counts were reported.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eIn this study we estimated that the BNT162b2 mRNA COVID-19 vaccine is as effective for pregnant women as previously reported for the general population for the same variant composition: 96% effectiveness against documented infection and 97% effectiveness against symptomatic infection 7\u0026ndash;56 days following receipt of the second vaccine dose. Effectiveness against COVID-19-related hospitalization was high, but a paucity of cases prevented precise estimation. These results reflect the VE mainly against the original SARS-CoV-2 reference strain and the B.1.1.7 (Alpha) variant, which were the dominant strains circulating in Israel during the study period.\u003c/p\u003e \u003cp\u003eAs the original phase III trials did not include pregnant women, data regarding the effectiveness of the novel mRNA COVID-19 vaccines in this population is still scarce in the medical literature. One study confirmed the immunogenicity of these vaccines in pregnant women by confirming cellular and humoral immune responses against SARS-CoV-2(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). To the best of the authors\u0026rsquo; knowledge, the present study is the first to directly evaluate VE against infection and symptomatic disease among women vaccinated during pregnancy.\u003c/p\u003e \u003cp\u003eThe VE of the BNT162b2 mRNA COVID-19 vaccine against documented and symptomatic infections was previously reported for a general population using the data repositories of the same healthcare organization and covering the same variant distribution \u0026ndash; after the second vaccine dose, VE was and found to be 92% (88%-95%) and 94% (87%-98%), respectively(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In an updated analysis of the same data over a longer period of time, the confidence intervals were narrower, with estimates of 93% (91%-94%) for documented infection and 96%(94%-97%) for symptomatic infection(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The VE estimated in the present study suggests that pregnant women have similar VE as the general population, or maybe even slightly higher VE than the general adult population, which is older on average and has a higher burden of comorbidities (some of which were demonstrated to reduce VE). That pregnancy was not found to reduce VE suggests that it may be reasonable to infer VE for pregnant women based on studies in the general population, for both current and future variants.\u003c/p\u003e \u003cp\u003eVaccination of pregnant women may also provide protection for their newborns. A recent study found binding and neutralizing antibodies in the cord blood of infants born to mothers who were vaccinated with mRNA vaccines, and in the mothers\u0026rsquo; breast milk(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Another study found that vaccination of breastfeeding women resulted in a rapid increase of anti\u0026ndash;SARS-CoV-2-specific antibodies in their breast milk(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The duration of the potential protection is still unclear. However, it is plausible that the antibody secretion in breast milk will provide protection to newborns, especially among those women vaccinated during the later stages of pregnancy.\u003c/p\u003e \u003cp\u003eThe high VE among pregnant women estimated in this study may also contribute to increased vaccination acceptance rates among this group. It was previously reported that high VE is an important factor for encouragement of pregnant women to receive COVID-19 vaccines: If VE of above 90% was achieved, 52% of the pregnant women reported that they would be willing to receive the vaccine. Furthermore, pregnant women indicated higher likelihood of vaccination with higher VE(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, despite the careful matching between cohorts, there is the lingering possibility of residual confounding. This is particularly true because information regarding pre-natal complications was not available. However, the very similar incidence of documented and symptomatic infections between the study groups during the early period following the first vaccine dose suggests that residual confounding, if present, is minor. Second, due to the low incidence of the more severe outcomes, this study was not able to provide precise VE estimates for them. Third, the strict matching process required to achieve exchangeability between the study groups resulted in a relatively large fraction of the eligible population not being included in the study. As a result, the proportion of women with some chronic conditions was somewhat lower in the final study population. VE for women with chronic conditions may be somewhat lower than the average VE reported in this study, as previously reported for the general population (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn conclusion, the results of this study indicate that the BNT162b2 mRNA COVID-19 vaccine is highly effective among pregnant women for the original SARS-CoV-2 strain and the B.1.1.7 (Alpha) variant. The similarity between the VE estimates among pregnant women and those reported for the same variants in the general population suggests that it may be possible to infer VE for pregnant women from studies in the general population for both current and future variants. Further studies are needed to better characterize the dynamics of VE throughout pregnancy, as well as the relationship between vaccination timing and infant protection after birth.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eND, NB, TBS, CK, SHD, BR and RDB conceived and designed the study. ND, NB and MMA participated in data extraction and analysis. ND, NB, ZK, MAH, ML, SHD, BR and RDB wrote the manuscript. TBS and SHD provided clinical guidance. All authors critically reviewed the manuscript and decided to proceed with publication. BR and RDB supervised the study process and vouch for the data and analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Ivan and Francesca Berkowitz Family Precision Medicine Clinic at Clalit Research Institute and the Ivan and Francesca Berkowitz Family Living Laboratory at Harvard Medical School. ML was supported by the Morris-Singer Fund. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eND, NB, MMA and RDB report institutional grants to Clalit Research Institute from Pfizer outside the submitted work and unrelated to COVID-19, with no direct or indirect personal benefits. ML reports grants from Pfizer, personal fees from Merck, personal fees from Bristol-Meyers Squibb, personal fees from Sanofi Pasteur, personal fees from Janssen, grants from NIH (US), grants from National Institute for Health Research (UK), grants from CDC (US), grants from Open Philanthropy Project, grants from Wellcome Trust, grants from Pfizer outside the submitted work; he has provided unpaid advice on COVID vaccines or vaccine studies to One Day Sooner (nonprofit), Pfizer, Astra-Zeneca, Janssen, and COVAXX (United Biosciences). MAH reports grants from NIH, grants from VA, personal fees from Cytel, personal fees from ProPublica, outside the submitted work; he has provided unpaid advice on COVID vaccine studies to Pfizer. SHD reports consulting fees from Roche and UCB outside the submitted work. BYR reports grants from NIH outside the submitted work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to data privacy regulations, the raw data of this study cannot be shared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe modeling code used in this study is part of standard R libraries that are freely available.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. \u0026nbsp; \u0026nbsp; \u0026nbsp;Zambrano LD, Ellington S, Strid P, Galang RR, Oduyebo T, Tong VT, et al. Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status - United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020 Nov 6;69(44):1641\u0026ndash;1647.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; \u0026nbsp;Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. Can Med Assoc J. 2021 Mar 19;\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp; \u0026nbsp;Rubin R. Pregnant People\u0026rsquo;s Paradox-Excluded From Vaccine Trials Despite Having a Higher Risk of COVID-19 Complications. JAMA. 2021 Mar 16;325(11):1027\u0026ndash;1028.\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp; \u0026nbsp;Rasmussen SA, Kelley CF, Horton JP, Jamieson DJ. Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy: What Obstetricians Need to Know. Obstet Gynecol. 2021 Mar 1;137(3):408\u0026ndash;414.\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; \u0026nbsp; \u0026nbsp;Riley LE, Jamieson DJ. Inclusion of Pregnant and Lactating Persons in COVID-19 Vaccination Efforts. Ann Intern Med. 2021 Jan 26;\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp; \u0026nbsp;Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, et al. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. N Engl J Med. 2021 Apr 21;\u003c/p\u003e\n\u003cp\u003e7. \u0026nbsp; \u0026nbsp; \u0026nbsp;Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014 Jun 5;370(23):2211\u0026ndash;2218.\u003c/p\u003e\n\u003cp\u003e8. \u0026nbsp; \u0026nbsp; \u0026nbsp;Skjefte M, Ngirbabul M, Akeju O, Escudero D, Hernandez-Diaz S, Wyszynski DF, et al.\u0026nbsp;COVID-19 vaccine acceptance among pregnant women and mothers of young children: results of a survey in 16 countries. Eur J Epidemiol. 2021 Feb;36(2):197\u0026ndash;211.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e9. \u0026nbsp; \u0026nbsp; \u0026nbsp;Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al.\u0026nbsp;BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Apr 15;384(15):1412\u0026ndash;1423.\u003c/p\u003e\n\u003cp\u003e10. \u0026nbsp; \u0026nbsp;Certain Medical Conditions and Risk for Severe COVID-19 Illness | CDC [Internet]. [cited 2020 Dec 9]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html\u003c/p\u003e\n\u003cp\u003e11. \u0026nbsp; \u0026nbsp;COVID-19 Treatment Guidelines [Internet]. [cited 2021 Jan 9]. Available from: https://www.covid19treatmentguidelines.nih.gov/\u003c/p\u003e\n\u003cp\u003e12. \u0026nbsp; \u0026nbsp;Collier A-RY, McMahan K, Yu J, Tostanoski LH, Aguayo R, Ansel J, et al. Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women. JAMA. 2021 May 13;\u003c/p\u003e\n\u003cp\u003e13. \u0026nbsp; \u0026nbsp;Barda N, Dagan N, Balicer RD. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Reply. N Engl J Med. 2021 Apr 21;384(20).\u003c/p\u003e\n\u003cp\u003e14. \u0026nbsp; \u0026nbsp;Perl SH, Uzan-Yulzari A, Klainer H, Asiskovich L, Youngster M, Rinott E, et al. SARS-CoV-2-Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women. JAMA. 2021 May 18;325(19):2013\u0026ndash;2014.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"COVID-19, vaccination, pregnancy, vaccine effectiveness","lastPublishedDoi":"10.21203/rs.3.rs-665725/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-665725/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e As mass vaccination campaigns against COVID-19 accelerate worldwide, there remains only limited evidence regarding vaccine effectiveness (VE) among pregnant women. Pregnant women have been shown to be at risk for severe COVID-19, resulting in adverse obstetrics outcomes, and their immune system is known to undergo alterations during pregnancy. Phase III clinical trials of the approved mRNA COVID-19 vaccines excluded pregnant women, yet current guidelines encourage offering the vaccine to pregnant women. In this study, we examine data from Israel’s largest healthcare organization to evaluate the effectiveness of the BNT162b2 mRNA vaccine among pregnant women.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted an observational cohort study of pregnant women 16 years or older, with no history of SARS-CoV-2, who were vaccinated between December 20, 2020 and June 3, 2021. Vaccinated subjects were matched to unvaccinated controls according to a set of demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. For each outcome, VE was estimated at several periods following vaccination as one minus the risk ratio using the Kaplan–Meier estimator.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e10,861 vaccinated women were matched to an identical number of unvaccinated controls. Estimated VE from 7 through 28 days after the second dose was 97% (95% CI 91%-100%) for any documented infection, 96% (86-100%) for infections with documented symptoms, and 85% (32%-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group, and no deaths were observed in either group -- insufficient incidence for estimating VE for these outcomes.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThe BNT162b2 mRNA vaccine was found to have high VE among pregnant women. Since high VE has been reported as one of the strongest predictors of COVID-19 vaccine acceptance among pregnant women, the high VE estimates found in this study have the potential to increase vaccine acceptance in this group. In addition, the present VE estimates are similar to those reported in the general population for the same variants, suggesting that it may be possible to infer the VE for pregnant women from studies in the general population for both current and future variants. \u003c/p\u003e","manuscriptTitle":"Effectiveness of the BNT162b2 mRNA COVID-19 Vaccine in Pregnancy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-12 16:28:55","doi":"10.21203/rs.3.rs-665725/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0ba5aa53-3253-4589-ac8b-eec70a9957b6","owner":[],"postedDate":"July 12th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":5654137,"name":"Epidemiology"},{"id":5654138,"name":"Virology"},{"id":5654139,"name":"Infectious Diseases"},{"id":5654140,"name":"Health Economics \u0026 Outcomes Research"},{"id":5654141,"name":"Health Policy"}],"tags":[],"updatedAt":"2021-11-22T15:37:56+00:00","versionOfRecord":{"articleIdentity":"rs-665725","link":"https://doi.org/10.1038/s41591-021-01490-8","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2021-09-07 04:00:00","publishedOnDateReadable":"September 7th, 2021"},"versionCreatedAt":"2021-07-12 16:28:55","video":"","vorDoi":"10.1038/s41591-021-01490-8","vorDoiUrl":"https://doi.org/10.1038/s41591-021-01490-8","workflowStages":[]},"version":"v1","identity":"rs-665725","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-665725","identity":"rs-665725","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}