Safety of COVID-19 vaccination in early pregnancy: a focus on major congenital anomalies

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SARS-CoV-2 infection in pregnancy is associated with severe COVID-19 symptoms and adverse outcomes for both mother and baby. Despite COVID-19 vaccination being shown to reduce the risk of severe illness in pregnancy, uptake remains low in pregnant women compared to the general population. The reasons for these high levels of vaccine hesitancy are driven, at least in part, by the lack of safety data on COVID-19 vaccination in pregnancy, particularly in the early stages of the vaccine programme. There is a growing body of evidence confirming the safety of COVID-19 vaccination in pregnancy with respect to maternal and baby outcomes, including some previous work by our group published in Nature Communications that shows COVID-19 vaccination is not associated with the risk of miscarriage in Scotland. However, there are very few high-quality studies published looking at whether there is any association between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies.

Researchers at Public Health Scotland (PHS) and the University of Edinburgh have linked healthcare records on all pregnancies in Scotland including early pregnancy losses (e.g. miscarriage, ectopic pregnancy), terminations of pregnancy, live and stillbirths and neonatal health records, with COVID-19 test results and COVID-19 vaccine records to create the COVID in Pregnancy in Scotland (COPS) study. The COPS study has been vital in Scotland for tracking levels of SARS-CoV2 infection and COVID-19 vaccine uptake in pregnancy in near real time, as well as conducting a range of more complex epidemiological analyses. In our paper recently published in Nature Communications we present the results of a national, population based, matched cohort study using the COPS cohort in which we estimate the association between any COVID-19 vaccination and, separately, a confirmed SARS-CoV-2 infection just before or in early pregnancy up to 20 weeks gestation (“pregnancy risk period”) and the risk of any major congenital anomaly or the risk of any non-genetic major congenital anomaly. For this study, we linked data from the Congenital Conditions and Rare Diseases Registration & Information Service for Scotland​ (CARDRISS) which is a national register that collects and holds information about babies in Scotland with a major structural or chromosomal condition or recognised syndrome (including terminations of pregnancy for anomalies, as well as live and stillbirths with anomalies) to the COPS database. Most studies to-date looked only at any congenital anomalies, but this include anomalies with a genetic basis that are not caused by environmental exposures such as medicines and vaccines, hence the importance of also looking at non-genetic major congenital anomalies as an outcome.

There were 53,914 babies in the COPS dataset where the mother was in early pregnancy (i.e., at <20 weeks gestation) or conceived after the 8th December 2020 (when the vaccination programme started in Scotland) and conceived before the 2nd June 2021 (so there was sufficient follow-up time for any congenital anomalies to be identified up to 28 days following a term birth in the dataset). After excluding babies where the mother had SARS-CoV-2 infection in the pregnancy risk period  (N=1,939) or where the pregnancy ended before 12 weeks gestation (N=11,412), we had 6,731 babies in our vaccinated cohort and 20,193 matched control babies who were not exposed to vaccination in the pregnancy risk period (matched on maternal age at conception and ensuring that the controls had reached at least the gestational week at which the mother was vaccinated). Most mothers received mRNA vaccination, specifically Pfizer-BioNTech BNT162b2. Of the babies exposed to any vaccination in the pregnancy risk period, the prevalence of major congenital anomalies was 23.1 per 1000 babies and the prevalence of non-genetic major congenital anomaly was 18.6 per 1000 babies; this compares to 22.7 and 17.8, respectively, among the control babies not exposed to vaccination.

After adjusting for key socio-demographic and clinical characteristics, we found no evidence for an association between COVID-19 vaccination and any major congenital anomaly or any non-genetic major congenital anomaly (Figure 1), and these results were robust in sensitivity analyses. In vaccine type subgroup analyses, we found no evidence for an association between mRNA vaccination and either any major congenital anomaly or any non-genetic major congenital anomaly; however, we could not rule out an increased risk of congenital anomalies with the viral vector vaccination Oxford-AstraZeneca ChAdOx1-s/nCoV-19. We urge caution in the interpretation of the  ChAdOx1-s/nCoV-19 subgroup analyses as we have high levels of uncertainty due to small numbers and, because of the nature of the roll-out of the vaccination programme in Scotland, the women who received ChAdOx1-s/nCoV-19 are likely to be different to their controls in a number of ways (e.g. higher clinical risk groups) which we may not have adequately captured in our adjusted analyses.

Figure 1 – COVID-19 vaccination and the risk of major congenital anomalies

Our study also adds to a growing body of epidemiological evidence that maternal SARS-CoV-2 infection is not associated with the risk of congenital anomalies. We found no evidence for an association between SARS-CoV-2 infection and any major congenital anomaly or any non-genetic major congenital anomaly (Figure 2). We do note that a limitation of our study was that we were not able to look at specific types of congenital anomalies. We present descriptive data on the types of anomalies in our infection and control groups and do not note any major differences which is reassuring; however, we encourage continued monitoring and publication of more specific types of congenital anomalies and, where possible, pooling of data across different settings to look at these rarer events.

Figure 2 – SARS-CoV-2 infection and the risk of major congenital anomalies

In summary, this study provides important reassurance to women planning to become pregnant or in the early stages of pregnancy, and their healthcare providers, that mRNA COVID-19 vaccination (received by most pregnant women in Scotland) does not increase the risk of congenital anomalies. This is in line with studies already published from Israel, the UK and the US. More data are required from other settings to draw robust conclusions on any association between ChAdOx1-s/nCoV-19 vaccination and the risk of congenital anomalies. In Scotland, we are now focusing our efforts on looking at the risk of other baby and maternal outcomes following COVID-19 vaccinations and SARS-CoV-2 infection, with the aim of providing further high-quality evidence to support pregnant women in their decision-making around COVID-19 vaccination.

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