Effectiveness of the SARS-CoV-2 mRNA Vaccines in Pregnant Women

Pregnancy may increase the risk of adverse maternal and neonatal outcomes in SARS-CoV-2 infection. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known. Using a test-negative case-control study, we determined the vaccine effectiveness of mRNA vaccines in preventing conrmed SARS-CoV-2 infection in pregnant women at a national referral hospital, which handles > 75% of the deliveries in Qatar. Among 2,020 pregnant women who met the study criteria, 397 had a positive SARS-CoV-2 RT-PCR and 1,623 had a negative test. Vaccine effectiveness ≥ 14 days after the second dose was 67.7% (95%CI 30.5–86.9), while vaccine effectiveness ≥ 14 days after the rst dose but before the second dose was 40.3% (95%CI 0.0-80.4). There were nine severe/critical disease cases, and no deaths in the PCR-positive pregnant women, all among unvaccinated. The mRNA vaccines provide high level of protection against documented SARS-CoV-2 infection, which supports including pregnant women in vaccination campaigns.


Introduction
Several vaccines for the SARS-CoV-2 infection have received emergency use authorization across the globe. The earliest vaccines to obtain such authorization were the BNT-162b2 (P zer) and the mRNA-1273 (Moderna) vaccines. Early randomized clinical trials using these vaccines reported an e cacy of 94-95% in preventing con rmed SARS-CoV-2 infection or symptomatic COVID-19 disease. 1,2 Subsequent effectiveness studies in the real-world settings have reported similarly high rates of effectiveness in preventing con rmed infection and nearly 100% effectiveness in preventing severe disease or death. 3,4 SARS-CoV-2 infection in pregnant women is often asymptomatic, though maternal infection in pregnancy is associated with higher rates of neonatal respiratory distress and hospitalization. 5,6 However, no mortality difference in infants born to mothers with SARS-CoV-2 infection in pregnancy has been observed. 6 When maternal infection occurs >60 days prior to delivery, e cient transfer of maternal SARS-CoV-2 antibodies has been reported with up to 38% of infants demonstrating positive IgG antibodies at 13-28 weeks. 7 Despite being at a potentially high risk of more severe disease and adverse outcomes, pregnant women were excluded from the vaccine e cacy trials. 8 Hence, other than very limited data in women who were inadvertently enrolled in clinical trials, no robust data are available regarding the effectiveness of SARS-CoV-2 vaccines in pregnant women. We undertook this study to determine the effectiveness of SARS-CoV-2 mRNA vaccines in pregnant women at a national level in Qatar.

Results
Between December 20, 2020 and May 30, 2021, we identi ed 4,534 with con rmed pregnancy. We excluded 2,087 without any SARS-CoV-2 testing during the study period and 427 who were tested before pregnancy onset. (Figure) Among the remaining 2,020 pregnant women, 397 had a positive SARS-CoV-2 RT-PCR and 1,623 had a negative test. For 393 RT-PCR positive pregnant women, we found 1,074 matched RT-PCR negative controls using an algorithm to nd up to 3 controls for each case. Our nal study groups consisted of 23 vaccinated and 370 unvaccinated cases ("test-positive" group) and 109 vaccinated and 753 unvaccinated controls ("test-negative" group).
The median age was 31 years for the cases and controls. Age group distribution and nationalities of the cases and controls are presented in table 1. Vaccine effectiveness >14 days after the second dose was 67.7% (95% CI 30.5-86.9), while vaccine effectiveness >14 days after the rst dose but before the second dose was 40.3% (95% CI 0.0-80.4). (Table 2)

Discussion
To our knowledge, this is the rst large scale study of SARS-CoV-2 vaccine effectiveness in pregnant women. We found the vaccine effectiveness to be 68.5% in preventing any documented infection.
Pregnant women with SARS-CoV-2 infection are at a higher risk of adverse maternal and neonatal outcomes. They are more likely to experience premature rupture of membranes, venous thrombotic events, severe pre-eclampsia, pre-term birth, and fetal death. 9 Strengths of our study include a large national population of pregnant women, with robust testing and vaccination data and availability of data on variants of concern. Of all infections diagnosed on these pregnant women, 74 were alpha variant (previously known as the B1. In conclusion, the mRNA vaccines are associated with a 67.7% effectiveness against documented infection >14 days after the second dose. While lower than the effectiveness observed in non-pregnant persons, the extremely low number of more severe outcome events among the vaccinated group provides strong supporting evidence to include pregnant women in SARS-CoV-2 vaccination campaigns.

Study Setting and Participants
The study was carried out at Hamad Medical Corporation in Qatar, which provides approximately 85% of the hospital bed capacity in Qatar. A specialty care hospital for women caters to more than 75% of the deliveries in Qatar. SARS-CoV-2 vaccination campaign began in Qatar in December 2020, prioritizing high risk individuals early in the campaign due to limited global supplies of the vaccine. The earliest persons to be vaccinated included those >70 years old, those with comorbidities, and frontline healthcare workers. Vaccination was rapidly expanded to younger age groups in a stepwise fashion. Pregnancy itself was not a priority condition, though pregnant women were encouraged to get vaccinated based on age and comorbidity criteria.
All women who presented to Hamad Medical Corporation between December 20, 2020 and May 30, 2021 with con rmed pregnancy were eligible to be included for the current study. Pregnant women were identi ed from the centralized hospital electronic medical records. Pregnancy was ascertained by presence of diagnostic codes for pregnancy in women attending antenatal clinics. We excluded those who were tested for SARS-CoV-2 by RT-PCR on a nasopharyngeal swab prior to pregnancy and those who had no SARS-CoV-2 testing done between December 20, 2020 and May 30, 2021. For each woman who tested among the vaccinated group, we identi ed up to 3 RT-PCR negative controls matched on age and reason for testing.

Statistical Analyses
We used test-negative case control design to determine the effectiveness of vaccination against con rmed SARS-CoV-2 infection. This design is a widely accepted standard to determine vaccine effectiveness in a population after the introduction of a vaccine. [13][14][15] Vaccine effectiveness was determined using the following formula: The test-negative design is predicated on negative controls getting tested for symptoms compatible with the outcome of intertest (in this case, SARS-CoV-2 infection). In a real-world setting, those getting tested for a speci c disease or infection approximate this population and the above formula can be applied. 13 We have used the same design to report overall effectiveness of the P zer-BNT162b2 vaccine against the B1.1.7 and B1.351 variants in Qatar. 4 We used STATA SE 16.1 (Stata Corporation, College Station TX) for statistical analyses.

Outcomes
We determined overall vaccine effectiveness >14 days after the second dose of the vaccine as our primary outcome of interest. We also determined vaccine effectiveness >14 days after the rst dose up to the date of the second dose. For all point estimates of vaccine effectiveness, we calculated the corresponding 95% con dence intervals. 16,17 Declarations Data Availability Statement Requests for deidenti ed and aggregate data must be directed to the Ministry of Public Health in the State of Qatar. Any request must ful l all requirements for data sharing according the existing laws, regulations, and policies of the State of Qatar. Any data sharing will be at the sole discretion of the relevant legal authorities in the State of Qatar.

Code Availability
Statistical code can be provided upon request made to the authors. Figure 1 Flowchart of dataset creation.

Supplementary Files
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