Covid-19 vaccine safety in pregnancy, a nested case-control study in births from April 2021 to March 2022, England

Introduction Vaccine safety in pregnancy is always of paramount importance. Current evidence of COVID-19 vaccine safety in pregnancy has been reassuring with no association found with negative maternal and neonatal outcomes. However, very few safety studies are conducted on a national level and investigate dosage, timing of vaccination as well as vaccine manufacturer. To fill this knowledge gap, we conducted a population based COVID-19 vaccine safety evaluation in England, including timing of vaccination by trimester, dosage and vaccine manufacturer received in pregnancy. Method A matched case control study nested in a retrospective cohort where adverse maternal and neonatal pregnancy outcomes were compared across several COVID-19 vaccine exposures using conditional multivariable logistic regression, adjusting for a range of demographic and health characteristics. Eligible participants were identified from the national maternity services dataset (MSDS) and records were linked to hospital admission, national COVID-19 vaccine and COVID-19 testing databases. Matching criteria differed by outcome but included participant’s age and estimated week of conception. Results 514,013 pregnant individuals aged between 18 and 50 years were identified during the study period (births from 16th of April 2021-31st March 2022). Receiving at least one dose of COVID-19 vaccine during pregnancy conferred lower odds of giving birth to a baby who was low birthweight (aOR=0.86, 95% CI: 0.79 – 0.93), preterm (aOR=0.89, 95% CI: 0.85 - 0.92) or who had an Apgar score less than 7 at five mins of age (aOR=0.89, 95% CI: 0.80 - 0.98). There was no association between vaccination in pregnancy and stillbirth (aOR=0.90, 95% CI: 0.76 - 1.07), neonatal death (aOR=1.27, 95% CI: 0.91 - 1.77) perinatal death (aOR=0.98, 95% CI: 0.83 - 1.16), and maternal venous thromboembolism in pregnancy (aOR=0.82, 95% CI: 0.43 - 1.56). The odds of maternal admission to intensive care unit were lower in vaccinated pregnant women (aOR=0.85, 95% CI: 0.76 - 0.95). Conclusion COVID-19 vaccines are safe to use in pregnancy and they confer protection against SARS-CoV-2 infection which can lead to adverse outcomes for both the mother and the infant. Our findings generated important information to communicate to pregnant women and health professionals to support COVID-19 maternal vaccination programmes. What is already known on this topic Current evidence shows that COVID-19 vaccines are safe to use in pregnancy. However, few studies investigate the timing of vaccination in pregnancy including the first trimester for late pregnancy outcomes. Most studies are geographically limited, and few are population based allowing inclusion of participants representative of the country’s inhabitants. What this study adds This is the first population-based study in England investigating COVID-19 vaccine safety in pregnancy. We used the national maternity services dataset and national English health services data enabling inclusion of a huge numbers of participants across the country. As such, we were able to investigate relevant safety research questions such as the timing of vaccine administration in pregnancy by trimester and before pregnancy, the number of doses received and vaccine manufacturer. How this study might affect research, practice or policy This national study adds to further existing evidence demonstrating that all COVID-19 vaccines are safe to use in pregnancy at any point in time and gives pregnant individuals confidence in the COVID-19 maternal vaccine programme. We demonstrated that receiving multiple doses of COVID-19 vaccine in pregnancy is not associated with adverse pregnancy outcomes and additionally it was reassuring that there was no evidence of an increased risk by vaccine type. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement There was no external funding for this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Surveillance of COVID-19 testing and vaccination is undertaken under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002 to collect confidential patient information ([www.legislation.gov.uk/uksi/2002/1438/regulation/3/made][1]) under Sections 3(i) (a) to (c), 3(i)(d) (i) and (ii) and 3(3). The study protocol was subject to an internal review by the UK Health Security Agency Research Ethics and Governance Group and was found to be fully compliant with all regulatory requirements. As no regulatory issues were identified, and ethical review is not a requirement for this type of work, it was decided that a full ethical review would not be necessary. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This work is carried out under Regulation 3 of The Health Service (Control of Patient Information; Secretary of State for Health, 2002) using patient identification information without individual patient consent as part of the UKHSA legal requirement for public health surveillance and monitoring of vaccines. As such, authors cannot make the underlying dataset publicly available for ethical and legal reasons. However, all the data used for this analysis is included as aggregated data in the manuscript tables and appendix. Applications for relevant anonymised data should be submitted to the UKHSA Office for Data Release at . [1]: http://www.legislation.gov.uk/uksi/2002/1438/regulation/3/made