Objective To estimate vaccine effectiveness (VE) of COVID-19 mRNA vaccines administered during pregnancy. Primary (2-dose) vaccination was compared with unvaccinated women; and 1st booster (3rd dose) with primary (2-dose) vaccination.

Design Target trial emulation cohort study.

Setting Routinely collected health data from UK, Sweden, Spain, and Norway. All had complete vaccine exposure data and were mapped to the OMOP common data model.

Participants Pregnant women (aged 12-55) with ≤34 weeks of gestation, no history of COVID-19 in the 90 days prior and ≥1 year of data visibility. Women were matched 1:1 to those with no dose and 2-dose vaccination, respectively, using weekly sequential matching from vaccination roll-out to 2023 (Swedish data: 2024).

Main outcome measures The main outcomes were COVID-19 infection, hospitalisation and Intensive Care Unit (ICU) admission (COVID-related, excluding delivery-related care). Hazard ratios (HR) were estimated with Cox regression from 15 days post-vaccination, and VE was reported as 100 x (1-HR). Analyses were stratified by pregnancy trimester and vaccine brand. Database-specific results were pooled using a random-effects meta-analysis.

Results We included 62,061 and 41,096 pregnant women at date of vaccination with a first and third dose, respectively. Median follow-up across databases ranged from 42 to 55 days for primary vaccination and 73 to 116 days for boosters. For primary vaccination, the meta-analysis showed a VE of 26.2% (16.2 to 35.1; I2 =0.7) against infection and 55.6% (44.1 to 64.8; I2 =0) against hospitalisation. For boosters, corresponding figures were 33.6% (-1.6 to 56.6; I2=1) and 34.1% (0.6 to 56.4; I2 =0.5). Event counts were insufficient to analyse VE against ICU admission. Results were consistent across pregnancy trimesters and vaccine brands.

Conclusions Vaccination with a primary (2-dose) or a 1st booster (3rd dose) during pregnancy was effective in preventing COVID-19 hospitalisation, with modest and heterogeneous VE against infection across 4 European countries.

What is already known on this topic

- Pregnant women are at increased risk of severe complications from COVID-19, which can affect both mothers and their infants.

- Vaccination during pregnancy has been shown to be safe and effective, with benefits of vaccination outweighing any potential risks.

- Studies examining the effectiveness of COVID-19 vaccines during pregnancy have primarily focused on primary vaccination with BNT162b2, with limited follow-up, sample size and representativeness.

What this study adds

- This study provides evidence on the effectiveness of COVID-19 mRNA vaccines administered during pregnancy using routinely collected data of over 124,122 pregnancies from 4 European countries.

- Primary (2-dose) vaccination against COVID-19 during pregnancy was effective in preventing infection during pregnancy with a vaccine effectiveness of 26%, and 55% for preventing COVID-19 related hospitalisations.

- A 1st booster (3rd dose) had a vaccine effectiveness of 30-35% against COVID-19 infection and COVID-19-related hospitalisation compared to primary (2-dose) vaccination.

BR and TD-S work for a research group that receives/received unconditional research grants from UCB, and Johnson and Johnson, Innovative Medicines Initiative, European Medicines Agency, none of which relate the content of this manuscript. DPA's research group from the University of Oxford has received research grants from the European Medicines Agency, from the Innovative Medicines Initiative, from Gilead Science, and from UCB Biopharma, none of which related to this manuscript. FN has funding for this research from SciLifeLab / the Knut and Alice Wallenberg Foundation (KAW 2021-0010/ VC2021.0018 and KAW 2020.0299/VC 2022.0008) and the Swedish Research Council (2021-05045 and 2021-05450). The overarching SCIFI-PEARL study (contributing Swedish data to the current analysis) through P.I. FN also has core funding from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (Avtal om Lakarutbildning och Forskning/Medical Training and Research Agreement), grants ALFGBG-938453, ALFGBG-971130, ALFGBG-978954, ALFGBG-1006729, a grant from FORTE (Research Council for Health, Working Life, and Welfare), grant 2024-01711, and previously from a joint grant from FORTE and FORMAS (Research Council for Environment, Agricultural Sciences and Spatial Planning), grant 2020-02828. Data acquisition of the Norwegian data in this study was funded by Professor Nordeng's EU-COVID-19 project, funded by the Norwegian Research Council's COVID-19 Emergency Call (project no. 31270).

This study did not receive any funding

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This project was approved by the Clinical Research Ethics Committee of the Primary Health Care Research Jordi Gol i Gurina (IDIAPJGol) (project code: 23/023-EOm), the Clinical Practice Research Datalink (CPRD) Research Data Governance Process (Protocol No 21_000557), the Regional Committee for Research Ethics (approval number: 155294 /REK Nord), the Data Protection Officer at the University of Oslo (approval number: 523275) and the Swedish Ethical Review Authority (EPM 2020-01800 with subsequent amendments).

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