Abstract and Introduction
Study Question: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation?
Summary Answer: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage.
What is Known Already: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection.
Study Design, Size, Duration: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment.
Participants/Materials, Setting, Methods: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2.
Main Results and the Role of Chance: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7–9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8–11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2–3]), 295/3041 were in the uncertain group (9.7% [95% CI 9–11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87–89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6–22] versus 15/295 [95% CI 3–8] versus 212/2669 [95% CI 7–9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0–3.0, P = 0.06).
Limitations, Reasons for Caution: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered.
Wider Implications of the Findings: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection
Study Funding/Competing Interest(S): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
Trial Registration Number: N/A.
Despite more than 300 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections worldwide, many important questions remain unanswered on the impact of this infection in pregnancy. There have been numerous publications on SARS-CoV-2 in pregnancy but the focus of research has been on hospitalized pregnant women with severe infections in the late second and third trimesters (Khalil et al., 2020; Knight et al., 2020; Pierce-Williams et al., 2020). Seroprevalence studies and a recent meta-analysis have shown that SARS-CoV-2 is commonly asymptomatic in pregnant women (Allotey et al., 2020; Crovetto et al., 2020); yet little is known about the effect of asymptomatic or mild infections on early pregnancy loss. Vaccine hesitancy amongst young women remains a concern and one of the latest reports from UK Obstetric Surveillance System reveals that 99% of pregnant women admitted to hospital with symptomatic infection are unvaccinated (Vousden et al., 2022). Therefore, information about the potential effect of SARS-COV-2 on pregnancy is pertinent and urgent.
Studies of past outbreaks of viral infections in pregnancy, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and influenza A/H1N1, show conflicting data. The 2002 SARS coronavirus epidemic was associated with severe maternal illness, maternal death, and miscarriage, but there were no cases of vertical transmission (Schwartz and Graham, 2020). There are only a few documented cases of MERS in pregnancy (n = 11) but the maternal and foetal fatality rates were high in both (27%) (Schwartz and Graham, 2020). During the 2009 influenza A/H1N1 pandemic, pregnant women were found to be at an increased risk of becoming severely ill and increased risk of hospitalization, intensive care unit admission and death (Jamieson et al., 2009; Mosby et al., 2011). Infants of affected mothers were rarely affected but they were more likely to be born preterm (Institute of Medicine Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007), whilst vertical transmission was not conclusively established (Mosby et al., 2011).
Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity (Khalil et al., 2020) and stillbirth (Allotey et al., 2020). Infants born to mothers with confirmed SARS-CoV-2 infection were mostly asymptomatic and transmission of the virus was uncommon (Knight et al., 2020; Pierce-Williams et al., 2020) with around 1.9% of infants born to women with confirmed infection testing positive (Khalil et al., 2020). Emerging data show that vertical transmission of the virus is probable (Baud et al., 2020; Farrell et al., 2020; Khalil et al., 2020) but further evidence is still required.
Data on the impact of first trimester infection with SARS-CoV-2 on early pregnancy outcomes are scarce. The majority of published studies are retrospective in design with small sample sizes (Cosma et al., 2021; la Cour Freiesleben et al., 2021; Sacinti et al., 2021). We performed a nationwide prospective cohort study in the United Kingdom (UK) where infection rates are one of the highest in the world and where nasopharyngeal PCR testing was readily available from 28 May 2020 to those with symptoms. We collected prospective data on pregnancy outcomes from women in the community who conceived during the SARS-CoV-2 pandemic. In this paper, we assess the impact of SARS-CoV-2 infection in the first trimester on early miscarriage risk (pregnancy loss before 13 weeks (≤12 + 6) of pregnancy).
Hum Reprod. 2022;37(6):1126-1133. © 2022 Oxford University Press