The impact of SARS-CoV-2 infection during pregnancy has been extensively studied, revealing associations with adverse pregnancy outcomes like preterm delivery, preeclampsia, and stillbirth. However, risk estimates vary across studies due to differences in testing strategies, populations, and virus variants. Previous research in Scandinavian populations has suggested lower risk estimates compared to other regions. This study aimed to update previous findings using a larger dataset from Denmark, a country with universal testing and well-established, validated registers. The research also aimed to validate the accuracy of SARS-CoV-2 diagnoses in national registers by comparing them to medical record data. This is crucial to ensure the reliability of population-based studies on COVID-19 during pregnancy. The investigation of the influence of hospital admission on pregnancy outcomes adds another layer of understanding to the disease's severity and potential impact.

Existing literature demonstrates a link between SARS-CoV-2 infection during pregnancy and adverse maternal and fetal outcomes. Risk factors for severe COVID-19 in pregnant women include advanced maternal age, high BMI, minority ethnicity, comorbidities, and infection late in pregnancy. Studies have reported varying associations with preterm delivery, preeclampsia, cesarean delivery, and stillbirth, with the Scandinavian region showing potentially lower risks compared to other geographical locations. A previous smaller Danish study revealed limited associated complications, potentially due to sample size constraints. The current study aims to address these limitations by using comprehensive nationwide data and validating the register information.

This national cohort study utilized data from several Danish national registers, including the Danish National Patient Register (DNPR), Danish Microbiology Database (MiBa), and Civil Registration System. The Danish COVID-19 in pregnancy database (DCOD), containing information from medical records, served as a reference standard for validating register data. The study population included all women with pregnancy-related diagnoses or procedures between March 1, 2020, and February 28, 2021. SARS-CoV-2 positive cases were identified through DCOD, including PCR and antigen tests. Pregnancies were followed until April 21, 2021. Women with a concurrent SARS-CoV-2 infection and hospital admission were stratified according to admission reasons (COVID-19 symptoms or other). Statistical analyses included Poisson and Cox regression models, adjusted for confounders such as maternal age, BMI, smoking, and parity. Positive and negative predictive values were calculated to assess the validity of SARS-CoV-2 diagnoses in the national registers. Several sensitivity analyses were also performed to assess the robustness of the findings, considering the extension of the exposure period and handling missing data. Ethical approvals were obtained, and the study followed STROBE guidelines.

The study included 107,020 women with 111,185 pregnancies, with 1819 (1.6%) having confirmed SARS-CoV-2 infection. Asthma was significantly associated with infection (RR 1.63, 95% CI 1.28-2.07). Severe COVID-19, requiring hospital admission, was associated with high BMI, asthma, and gestational age at infection. SARS-CoV-2 infection was associated with increased risks of: hypertensive disorders in pregnancy (aHR 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery (aHR 2.31, 95% CI 1.01-5.26 for <28 weeks; aHR 1.49, 95% CI 1.01-2.19 for <37 weeks), and small-for-gestational-age infants (aHR 1.28, 95% CI 1.05-1.54). These associations were stronger among hospitalized women. Hospital admission due to COVID-19 symptoms increased with gestational age at infection. Validity analysis showed a negative predictive value of 99.9% (95% CI 99.9-100.0) and a positive predictive value of 82.1% (95% CI 80.4-83.7) for SARS-CoV-2 diagnosis in the registers compared to medical records. The risk of SGA was not found to be dependent on GA at the time of infection.

This study confirms the increased risk of several adverse pregnancy outcomes associated with SARS-CoV-2 infection during pregnancy. The lower absolute risks observed compared to other studies may reflect the generally low-risk Danish pregnant population and universal access to healthcare. The stronger associations among hospitalized women highlight the importance of considering disease severity when interpreting results. The findings on hypertensive disorders may be related to the virus's potential effects on the placenta and increased risks of thromboembolism. The increased risk of iatrogenic preterm delivery supports the hypothesis of placental compromise. The results are consistent with previous findings but extend them by using a larger, validated dataset and examining the influence of hospital admission. The observed differences in prevalence, incidence of asthma, and gestational age at infection between the first and second pandemic waves likely reflect changes in testing strategies.

SARS-CoV-2 infection during pregnancy increases the risk of hypertensive disorders, early pregnancy loss, preterm delivery, and small-for-gestational-age infants. The study validates the use of Danish national registers for identifying SARS-CoV-2 infection in pregnancy. Future research should investigate the long-term effects of maternal SARS-CoV-2 infection on both mother and child, considering the influence of vaccination and emerging virus variants.

The large number of analyses performed might increase the risk of false positive findings. Lack of information on ethnicity may limit the generalizability of the findings. Missing data on BMI and smoking before delivery might introduce bias, although this was partially addressed using data from DCOD. The study only included data from the first year of the pandemic, before widespread vaccination and the emergence of new virus variants, limiting the applicability of the findings to the current context.