In a recent study published in the journal BMJ, researchers conducted a registry-based study comprising 343,066 infants across Denmark, Sweden, and Norway to investigate if COVID-19 infections or vaccinations during the first trimester were associated with increased risk of congenital anomalies. Of the 11 anomaly subgroups investigated, 10 had adjusted odds ratios (aORs)

Study: Covid-19 infection and vaccination during first trimester and risk of congenital anomalies: Nordic registry based study. Image Credit: Unai Huizi Photography / Shutterstock

Background

Pregnant women represent a high-risk population, with disease contractions during pregnancy often adversely affecting pregnancy and birth outcomes. Observational accounts and recent research have revealed that Coronavirus disease 2019 (COVID-19) infections during pregnancy comply with this trend, increasing the risk of severe illness and pregnancy complications. Given this knowledge, governments of most nations recommend that pregnant women receive COVID-19 vaccinations.

The first trimester represents a critical period of pregnancy, with most congenital anomalies developing during these first three months. Unfortunately, pregnant women are rarely subjected to randomized controlled trials, preventing robust scientific evidence for the safety of vaccinations in this high-risk group. Encouragingly, observational evidence and registry-based studies conducted across Scotland, Israel, Switzerland, France, and the United States (US) of America failed to find evidence for the increased risk of congenital anomalies following COVID-19 infection or vaccination.

Since these studies suffered from the shared limitations of inadequate sample sizes, a lack of first-trimester focus, or inadequate anomaly subgroup analysis, a study accounting for these limitations is necessary. Furthermore, given differences in race/ethnicity-specific COVID-19 outcomes and a shortage of information for Nordic countries, the present study aims to assess risk associations between COVID-19 infections or vaccinations during the first trimester and congenital anomalies across Sweden, Denmark, and Norway.

About the study

This study compiled data from liveborn singleton infants from the Medical Birth Registry of Norway, the Danish National Patient Register, and the Swedish Pregnancy Register between March 2020 and February 2022. Inclusion criteria comprised mothers and infants who were followed up for at least nine months (275 days) following birth, while preterm births were excluded to avoid confounds.

Data collection included maternal socioeconomic information and COVID-19 infection or vaccination status. The exposures of interest were COVID-19 infections of vaccinations during the first trimester, with each exposure (infection and vaccination) analyzed independently. Notably, combined exposure (vaccination followed by infection) was excluded from the analysis.

The European Surveillance of Congenital Anomalies (EUROCAT guide version 1.5) was used to define major congenital anomalies. This study categorized anomalies into 11 subgroups – 1. any, 2. heart, 3. nervous system, 4. eye, 5. ear, neck, or face, 6. respiratory, 7. oro-facial clefts, 8. abdominal wall defects, 9. kidney or urinary tract, 10. genital, or 11. limb anomalies.

Covariates of interest included maternal age, parity, education level, household income, maternal region of birth, pregnancy start date, smoking status, preexisting chronic disease status, and body mass index (BMI), all of which were used as potential confounders during analysis.

Statistical analysis comprised random effects meta-analysis conducted independently for infections and vaccinations and subgrouped by country (Sweden, Norway, or Denmark). Between-country heterogeneity was assessed using I² tests. Sensitivity analyses were conducted in two stages – 1. Infants with a minimum of 12 months of follow-up were included, and 2. Infants with genetic-associated congenital anomalies were excluded.

Study findings

Of the 343,066 infants included in the study, 17,704 presented at least one major congenital anomaly. Of these, 4.2% (n = 737) presented more than one major congenital anomaly. COVID-19 infections were observed for the mothers of 10,229 (3%) of infants, but analysis revealed no additional risk of congenital anomalies in this group (adjusted Odds Ratios [aORs] = 0.96). On a per-subgroup basis, aORs ranged from 0.84 (eye) to 1.12 (oro-facial clefts), but these results did not indicate increased infection-associated risk statistically.

COVID-19 vaccinations were observed for the mothers of 152,261 infants, of which 29,135 (19%) were vaccinated during the first trimester and hence included in subsequent analysis. Once again, the analysis revealed no additional risk of vaccination-associated anomalies, with aORs ranging from 0.84 (nervous system) to 1.69 (abdominal wall defects). Abdominal wall defects were the only statistically significant subgroup, with the remaining 10 subgroups presenting aORs

Conclusions

The present study represents the largest (n = 343,066) assessment of COVID-19 infection or vaccination-associated congenital anomaly risk, with the most prolonged follow-up period (9-12 months). It is also the first to investigate these associations in Nordic populations.

Study findings support previous literature highlighting no association between COVID-19 infection or vaccination and subsequent congenital anomaly risk. However, COVID-19 infections are known to result in other pregnancy and birth complications, supporting governments’ recommendations for pregnant women to receive vaccinations.