Safety of COVID-19 vaccination in early pregnancy: a focus on miscarriage and ectopic pregnancy

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Most women who get SARS-CoV-2 (COVID-19) infection in pregnancy will experience mild symptoms. However, it has been shown that pregnant women are more likely than non-pregnant women to have severe COVID-19 symptoms. Although relatively rare, there can also be serious consequences for their babies, with data showing that babies exposed to maternal COVID-19 infection in pregnancy are more likely than the babies of pregnant women without COVID-19 infection to be born early and die within 28 days of birth. Vaccination is effective in reducing the risk of severe COVID-19 infection in pregnant women, but we are still seeing much lower levels of vaccine uptake in pregnant women compared to vaccine uptake in the rest of the population in Scotland (1). 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, particularly in the early stages of the vaccine programme. As is often the case with clinical trials, pregnant women were excluded from the trials of COVID-19 vaccinations, leading to inconsistent guidance on whether pregnant women should be vaccinated early in the vaccination programme. In Scotland, for example, the vaccination programme started on December 08, 2020 but it was only towards the end of February, 2021 that explicit guidance was given that pregnant women should be vaccinated in line with the risk groups prioritized for vaccination.   

In a joint effort between Public Health Scotland and the University of Edinburgh, we have been linking data from both records of COVID-19 tests and records of COVID-19 vaccination to pregnancy records (Figure 1). The COVID-19 in Pregnancy in Scotland (COPS) database captures almost all pregnancies that have occurred in Scotland since January 01, 2015, and has been an important resource allowing us to track levels of COVID-19 infection and vaccine uptake in pregnant women in Scotland. It has also allowed us to conduct some detailed epidemiological studies, several of which have focused on assessing the safety of COVID-19 vaccination in pregnancy. Our study published in Nature Communications presents the first vaccination safety paper emerging from COPS, with the specific aim of exploring whether there was any evidence of an increased risk of either miscarriage (pregnancy loss prior to 20 weeks gestation) or ectopic pregnancy (fertilized egg implanted outside of uterus) following COVID-19 vaccination in early pregnancy. We also explored whether COVID-19 infection in early pregnancy was associated with increased risk of either miscarriage or ectopic pregnancy.

  

Figure 1: Overview of the creation of the COPS cohort. ICU=intensive care unit (adapted from (2))

We identified a total of 18,780 pregnant women who received any COVID-19 vaccination between six weeks preconception up to 20 weeks gestation (or the end of pregnancy if earlier) in Scotland between December 08, 2020 (start of the vaccination programme) and the end of January 2022. Pfizer-BioNTech BNT162b2 was the most commonly received vaccine type, and around a quarter of the vaccinated women received two or more doses during this pregnancy exposure period. Of these pregnant vaccinated women, 9% had a miscarriage. We compared this risk of miscarriage in women vaccinated in early pregnancy, to the risk of miscarriage in two comparison groups. The first comparison group was pregnant women from before the COVID-19 pandemic started (referred to as “historical controls”), while the second group was pregnant women who were selected from the same period in which women were vaccinated but who did not received vaccination between six weeks conception up to 20 weeks gestation (referred to as “contemporary controls”). After controlling for key socio-demographic characteristics, we found no evidence that any COVID-19 vaccination was associated with increased risk of miscarriage when we compared our vaccinated group to either of our comparison groups (Key results comparing to historical unvaccinated comparison group in Figure 2). A smaller number of women were infected with COVID-19 between six weeks preconception and 20 weeks gestation (N=3,025), and there was no evidence that infection led to an increased risk of miscarriage in these women.

 

Figure 2: Crude and adjusted estimates of the association between vaccination and (1) miscarriage and (2) ectopic pregnancy, when comparing these outcomes between women vaccinated early in pregnancy to unvaccinated women from the pre-pandemic period.

For ectopic pregnancy, our vaccinated group only included women who were vaccinated from six weeks preconception up to three weeks gestation (N=10,570), 1% of whom had an ectopic pregnancy. A narrower exposure window was used compared with miscarriage because implantation has occurred by three weeks gestation and so any vaccination after this gestation could not affect the risk of ectopic pregnancy. We found no evidence for an association between either vaccination or SARS-CoV-2 infection and the risk of ectopic pregnancy but have high levels of uncertainty. For example, when we compared our vaccinated group to historical unvaccinated controls (and accounted for socio-demographic and clinical differences between the groups), we estimated that the vaccinated group had a 13% higher risk of ectopic pregnancy, but our uncertainty intervals suggested that the true population estimate could range from 8% lower risk up to a 38% higher risk (Figure 2).

This study provides important reassurance to women planning to become pregnant or in the early stages of pregnancy, and their healthcare providers, that COVID-19 vaccination (particularly mRNA vaccination that the majority of pregnant women received in Scotland) does not increase the risk of miscarriage. This is in line with studies already published from Norway (3) and the USA (4). We cannot rule out an increased risk of ectopic pregnancy, but we have very high levels of uncertainty due to small numbers. More data are required from other settings to draw robust conclusions on any association between COVID-19 vaccination and ectopic pregnancy. In Scotland, we are now focusing our efforts on looking at the risk of other perinatal and maternal outcomes following COVID-19 vaccinations and COVID-19 infection, and hope to be able to provide further evidence to support pregnant women in their decision-making around COVID-19 vaccination.

References

[1] Public Health Scotland. Public Health Scotland COVID-19 Statistical Report As at 26 September 2022. (Accessed October 21, 2022 at: https://www.publichealthscotland.scot/media/15346/2022-09-28-covid-19-publication_report.pdf) 2022

[2] Stock S. J. et al. Cohort profile: the COVID-19 in pregnancy in Scotland (COPS) dynamic cohort of pregnant women to assess effects of viral and vaccine exposures on pregnancy. International Journal of Epidemiology 2022. https://doi.org/10.1093/ije/dyab243

[3] Magnus MC, Gjessing HK, Eide HN, Wilcox AJ, Fell DB, Håberg SE. Covid-19 Vaccination during Pregnancy and First-Trimester Miscarriage. New England Journal of Medicine 2021; 385(21): 2008-10

[4] Kharbanda EO, Haapala J, DeSilva M, et al. Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. JAMA 2021; 326(16): 1629-31.

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