key: cord-0976506-xu75myii
authors: Theiler, R. N.; Wick, M.; Weaver, A.; Mehta, R.; Virk, A.; Swift, M.
title: Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy
date: 2021-05-18
journal: nan
DOI: 10.1101/2021.05.17.21257337
sha: bdcf07961444de62e309ec44b3ffab47b46eb36c
doc_id: 976506
cord_uid: xu75myii

Background: SARS-CoV-2 infection during pregnancy is associated with significant maternal morbidity and increased rates of preterm birth. For this reason, COVID-19 vaccine administration in pregnancy has been endorsed by multiple professional societies including ACOG and SMFM despite exclusion of pregnant women from initial clinical trials of vaccine safety and efficacy. However, to date little data exists regarding outcomes after COVID-19 vaccination of pregnant patients. Study Design: A comprehensive vaccine registry was combined with a delivery database for an integrated healthcare system to create a delivery cohort including vaccinated patients. Maternal sociodemographic data were examined univariately for factors associated with COVID-19 vaccination. Pregnancy and birth outcomes were analyzed, including a composite measure of maternal and neonatal pregnancy complications, the Adverse Outcome Index. Results: Of 2002 patients in the delivery cohort, 140 (7.0%) received a COVID-19 vaccination during pregnancy and 212 (10.6%) experienced a COVID-19 infection during pregnancy. The median gestational age at first vaccination was 32 weeks (range 13 6/7-40 4/7), and patients vaccinated during pregnancy were less likely than unvaccinated patients to experience COVID-19 infection prior to delivery (1.4% (2/140) vs. 11.3% (210/1862)) P<0.001No maternal COVID-19 infections occurred after vaccination during pregnancy. Factors significantly associated with increased likelihood of vaccination included older age, higher level of maternal education, lower pre-pregnancy BMI, and use of infertility treatment for the current pregnancy. Tobacco or other substance use, Hispanic ethnicity, and higher gravidity were associated with a lower likelihood of vaccination. No significant difference in the composite adverse outcome (5.0% (7/140) vs. 4.9% (91/1862) P=0.95) or other maternal or neonatal complications, including thromboembolic events and preterm birth, was observed in vaccinated mothers compared to unvaccinated patients. Conclusions: Vaccinated pregnant women in this birth cohort were less likely to experience COVID-19 infection compared to unvaccinated pregnant patients, and COVID-19 vaccination during pregnancy was not associated with increased pregnancy or delivery complications. Significant sociodemographic disparities in vaccine uptake and/or access were observed among pregnant patients, and future efforts should focus on outreach to low-uptake populations.

In late 2020, the United States Food and Drug Administration (FDA) approved two mRNA women compared to non-pregnant controls, with increased risk for maternal hospitalization, ICU 92 admission, invasive ventilation, and death 5-7 . Because of the known increased maternal risk of 93 adverse outcomes with COVID-19 infection and the lack of theoretical or proven harm from the 94 available vaccines, many patients have opted for vaccination despite limited safety and efficacy 95 data for the vaccines in pregnant patients. The vaccines are thought to be effective when 96 administered during pregnancy, as antibody production occurs rapidly after administration. 97

However, immune alterations that occur in pregnancy may theoretically decrease the vigor of 98 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. SARS-CoV-2 RT-PCR test documented in the medical record between the dates of conception 126 and delivery, and was stratified by first trimester (2-13 6/7 weeks gestation), second trimester 127 (14 0/7-27 6/7 weeks gestation) and third trimester (≥28 weeks gestation) infection. 128

All COVID infections regardless of temporal relationship to vaccine are included in Table X The composite outcome, the adverse outcome index (AOI) was calculated as a composite of 133 any of the following events during the delivery hospitalization: maternal death, uterine rupture, 134 unplanned maternal ICU admission, return to the operating room within 72 hours of delivery, 135 postpartum hemorrhage with blood transfusion, third or fourth degree laceration, intrapartum 136 fetal or unexpected neonatal death (within 72hrs), hypoxic ischemic encephalopathy, five minute 137 Apgar <7, admission to the NICU with birthweight >2500g, or neonatal birth trauma. All 138 qualifying events were verified by chart review. The AOI for a group of patients was calculated 139 as the number of patients with one or more identified adverse events divided by the total 140 number of deliveries, multiped by 100. A woman with multiple gestations was counted as a 141 single delivery. A modified AOI was also calculated by not considering third-and fourth-degree 142 perineal laceration as an adverse event. Additional outcomes measured included 143 thromboembolism or stroke within 4 weeks before or after delivery, gestational hypertensive 144 disorders diagnosed up to 72 hours after delivery, low and very low birth weight, preterm birth (< 145 37 weeks gestation), length of postpartum maternal stay after delivery, and stillbirth. 146 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The primary outcome in this study was AOI. The AOI was 4.9% within the Mayo Clinic Health 147

System for calendar year 2019. This study was designed with 80% power, using a two-sided 148 chi-square test with a type I error rate of 0.05, to detect a difference in AOI of 4.9% vs. at least 149 11.5% between those without versus with a COVID-19 vaccine during pregnancy, based on 150 1862 and 140 patients in the two groups. 151

Data management and statistical analysis was performed using SAS version 9.4 (SAS institute, 152

Cary, NC, USA). Comparisons between groups were evaluated using the chi-square test or 153

Fisher's exact test for non-ordered categorical variables, the Wilcoxon rank sum test for ordinal 154 variables, and the two-sample t-test for continuous variables. A 95% confidence interval (CI) for 155 the difference in the AOI between two groups was calculated based on exact methods for a 156 binomial parameter. All calculated p-values were two-sided and p-values less than 0.05 were 157 considered statistically significant. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. years of age, P<0.0001). Vaccinated patients were also more educated, P trend <0.0001, and a 173 history of infertility treatment was also noted more frequently among vaccinated patients, with Table 2) . The composite pregnancy outcome, AOI, did not differ by maternal vaccination 186 status, with rates of 5.0% (7/140) vs. 4.9% (91/1862) in the vaccinated and unvaccinated groups 187 (95% CI for difference in proportions, -3.6% to 3.6%). No maternal or early neonatal deaths 188 occurred in the cohort. Mode of delivery, gestational age at delivery, neonatal birth weight, 189 thromboembolic events, and rates of gestational hypertensive disorders also did not significantly 190 differ between groups. Additional comparison between COVID-19 infected, non-vaccinated 191 patients (n=210) and vaccinated patients without a history of COVID-19 infection (n=138) did 192 not show any difference among the pregnancy outcomes examined in the cohort, but the study 193

was not sufficiently powered to detect a difference in these outcomes (Appendix Table A2 ). 194

Among the unvaccinated patients, pregnancy and birth outcomes did not significantly differ 195 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table A2 pregnancy. The current study largely represents outcomes after third trimester vaccination, but 210 patients who received the vaccine during the late first through second trimesters and delivered 211 preterm are represented in this data set as well. The absence of an increase in preterm births in 212 the cohort thus suggests that vaccination is unlikely to increase preterm birth rates, but analysis 213 of outcomes from currently ongoing pregnancies will be needed to confirm this finding. 214

This study reveals some sociodemographic factors associated with vaccine access and/or 215 uptake in the pregnant population. Vaccination eligibility during the timeframe analyzed was 216 limited to healthcare workers, the elderly, and teachers or other essential workers. For this 217 reason, we cannot discern whether sociodemographic differences in vaccination status are due 218 to vaccine hesitancy or eligibility for vaccination, but we do observe socioeconomic disparity 219 between those who received vaccination during gestation and those who did not. Outreach to 220 the under-represented populations of pregnant patients should be a focus of future education 221 and vaccination efforts. 222

Strengths of this study include the inclusion of comprehensive population-level vaccine registry 223 data in combination with a validated, all-inclusive delivery database including births at multiple 224 community and teaching hospitals across two states As the data were extracted from the 225 primary medical record it is not subject to recall bias. Limitations of this analysis include the 226 small percentage of non-white subjects in this geographic region, the potential for confounding 227 due to the observational nature of the study, as well as the data currently available being biased 228 toward those vaccinated later in gestation and skewed toward the population in the United 229

States healthcare workforce. Finally, only two COVID-19 infections occurred in the vaccinated 230 group early in pregnancy, so they may be a group who had lower baseline exposure compared 231 to the unvaccinated group. 232

Our findings should give clinicians confidence that COVID-19 vaccination during pregnancy is 233 effective in preventing maternal SARS-CoV-2 infection, and that no pattern of adverse maternal 234 or neonatal outcomes is evident during pregnancy, adding to the growing body of evidence 235 supporting the safety of COVID vaccines in pregnant women. Additional studies will be needed 236 to examine differences in rare adverse birth outcomes, as well as outcomes following (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.17.21257337 doi: medRxiv preprint

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Vaccinating Pregnant and Lactating Patients Against COVID-19Practice Advisory: American 251 College of Obstetrics and Gynecology

Maternal and Neonatal Morbidity and Mortality Among 253 Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort 254 Study

Pregnancy Outcomes Among Women With and Without 256 Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Disease severity, pregnancy outcomes, and maternal 259 deaths among pregnant patients with severe acute respiratory syndrome coronavirus 2 infection 260 in Washington State

Immunogenicity of COVID-19 mRNA Vaccines in Pregnant 262 and Lactating Women

Preliminary Findings of mRNA Covid-19 Vaccine Safety in 264 Pregnant Persons

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