Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG)

The study investigates the impact of SARS-CoV-2 infection during pregnancy on maternal and perinatal outcomes and identifies risk factors for infection and severe disease. Prior evidence suggests associations of infection with preterm delivery, preeclampsia, cesarean delivery and stillbirth, with varying effect sizes by country, testing strategies, populations, variants and vaccination status. Scandinavian estimates appear smaller than elsewhere, and a previous Danish study with fewer infected pregnancies found limited complications. Additionally, SARS-CoV-2 diagnosis during pregnancy had not been validated by linking register data with medical records. The objective was to evaluate risk factors and outcomes after infection in a universally tested, unvaccinated Danish population, examine the influence of hospital admission (disease severity) on outcomes, and validate registry identification of infection using medical records.

Previous studies and meta-analyses have linked SARS-CoV-2 infection in pregnancy to increased risks of preterm birth, preeclampsia, cesarean delivery and stillbirth, with risk factors for severe disease including higher maternal age, higher BMI, minority ethnicity, comorbidities and later gestational age at infection. Reported risks vary by country and testing strategy, and Scandinavian cohorts generally report smaller effects. A prior Danish study of 418 infected pregnancies during the first 8 months found few complications, likely due to limited sample size and early-pandemic testing patterns. The present study updates and expands these findings and uniquely validates registry-based SARS-CoV-2 diagnoses against medical records for pregnancies.

Design: Nationwide cohort study in Denmark including all women with a pregnancy or birth-related ICD-10 diagnosis/procedure recorded between March 1, 2020 and February 28, 2021 in the Danish National Patient Register (DNPR). Pregnancies were included from the calculated first day of last menstrual period based on gestational age (GA) at delivery or abortion. Women were followed until April 21, 2021. Data sources: DNPR; Danish Microbiology Database (MiBa; all PCR tests and, from December 2020, antigen tests); Civil Registration System; and the Danish COVID-19 in pregnancy database (DCOD) with medical record-validated SARS-CoV-2 cases (PCR/antigen/antibody with symptoms during pregnancy). Linkage used unique personal identification numbers. Exposure: SARS-CoV-2 infection during pregnancy, identified via DCOD and registers. Disease severity stratification: infections with hospital admission within 14 days of a positive test were categorized as (1) admission for any reason with concurrent infection, or (2) admission due to COVID-19 symptoms (admission and discharge on different dates and symptomatic COVID-19). Outcomes and covariates: Maternal characteristics and pregnancy, delivery and neonatal outcomes identified in DNPR (definitions/codes in Appendix S2). For certain outcomes (SGA, intrauterine fetal death, preterm birth) risk time started at GA 22 weeks. Statistical analysis: - Maternal characteristics presented as counts/frequencies or medians (IQR). - Risk factors for infection and for hospital admission analyzed using Poisson regression (gestational diabetes modeled via Cox as time-varying). - Maternal, pregnancy, birth and neonatal outcomes (except mode of delivery) analyzed using Cox models with SARS-CoV-2 as a time-varying exposure; mode of delivery analyzed using Poisson regression. - Continuous outcomes analyzed via linear regression of log-transformed values, presented as median ratios via back-transformation. - Relative risks (RR), hazard ratios (HR), 95% CIs; clustered sandwich estimators used to account for multiple pregnancies per woman; bootstrap CIs for median ratios. Confounding control: Multivariable adjustments for maternal age, date of last menstrual period (seasonality), and preexisting asthma. Delivery/birth/neonatal outcomes further adjusted for pre-pregnancy BMI, smoking in pregnancy and parity; observations with missing data on these (4.4%) were excluded for these analyses. Effect modification was assessed via interaction terms and stratified analyses. Validation: Positive and negative predictive values (PPV, NPV) of identifying SARS-CoV-2 infection during pregnancy in registers were calculated using DCOD (medical records) as reference. Sensitivity analyses: - PPVs for early pregnancy loss, termination, and live birth in DNPR compared with DCOD among women with outcomes in both sources (n=1096). - Analyses restricted to deliveries (enabling adjustment for BMI, smoking, parity). - Extension of exposure period to April 21, 2021 using MiBa definitions for (i) the subsequent 2 months and (ii) the entire period. - Assessment of smoking using DCOD data to address missingness in non-deliveries. Ethics: Approved by Danish Patient Safety Authority and Regional Data Protection Agencies; individual consent not required; reported per STROBE guidelines.

- Cohort: 111,185 pregnancies among 107,020 women; 1,819 infections (cumulative incidence 1.6%); monthly incidence ranged from 0.2 per 1000 (June) to 13.7 per 1000 (December). - Hospitalization: 208/1,819 (11.4%) infected pregnancies admitted within 14 days; 51 (2.8%) admitted due to COVID-19 symptoms. - Risk factors for infection: Preexisting asthma associated with infection (RR 1.63, 95% CI 1.28-2.07); smokers were less frequent among infected than non-infected (RR 0.70, 95% CI 0.56-0.87). - Risk factors for severe disease (hospital admission due to COVID-19): Higher BMI (median ratio 1.06, 95% CI 1.04-1.09), preexisting asthma (RR 7.47, 95% CI 3.51-15.90), and later GA at infection (GA 28–36 vs <22 weeks: RR 3.53, 95% CI 1.75-7.10). - Maternal and pregnancy outcomes associated with infection: Hypertensive disorders of pregnancy (aHR 1.31, 95% CI 1.04-1.64); early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88); extremely preterm delivery <GA 28 weeks (aHR 2.31, 95% CI 1.01-5.26); iatrogenic preterm delivery <GA 37 weeks (aHR 1.49, 95% CI 1.01-2.19). - Fetal/Neonatal: SGA <10th percentile (aHR 1.28, 95% CI 1.05-1.54); SGA <2.3rd percentile aHR 1.24 (95% CI 0.89-1.72; not statistically significant). - Disease severity and outcomes: Infected women admitted for any reason had higher risks than non-infected women of hypertensive disorders (aHR 4.38, 95% CI 2.66-7.21), SGA <10th percentile (aHR 2.96, 95% CI 1.76-4.97) and <2.3rd percentile (aHR 2.75, 95% CI 1.21-6.24), preterm delivery <37 weeks (aHR 5.16, 95% CI 2.90-9.20), induction of labor (aHR 2.45, 95% CI 1.71-3.52), and ICU admission (aHR 15.96, 95% CI 6.45-39.48). Admission due to COVID-19 showed non-significant associations with induction of labor (aHR 1.65, 95% CI 0.82-3.31), cesarean delivery (aHR 1.50, 95% CI 0.98-2.30), and neonatal ICU admission (aHR 1.66, 95% CI 0.94-2.92). - Timing: Risk of admission due to symptoms increased with higher GA at infection; admissions were associated with higher likelihood of delivery within 14 days. - Validation: Registry identification of SARS-CoV-2 during pregnancy had PPV 82.1% (95% CI 80.4-83.7) and NPV 99.9% (95% CI 99.9-100.0). For outcomes validation, PPV was very high for births (99.9%, 95% CI 99.5-100.0) and terminations (100.0%, 95% CI 89.4-100.0), lower for early pregnancy loss (82.9%, 95% CI 67.9-92.9). - Sensitivity analyses and extended exposure periods did not materially change associations.

This nationwide cohort found that SARS-CoV-2 infection during pregnancy is associated with increased risks of hypertensive disorders, early pregnancy loss, preterm birth (especially iatrogenic and extremely preterm), and SGA. Severity of maternal COVID-19, proxied by hospital admission, was linked to markedly higher risks of adverse obstetric outcomes. The increased risk of hypertensive disorders aligns with prior studies; biological mechanisms may include SARS-CoV-2-associated hepatic dysfunction, thrombocytopenia, hypercoagulability and placental vascular involvement, potentially mimicking or precipitating preeclampsia and compromising fetal growth, which could explain higher SGA and iatrogenic preterm deliveries. Compared with international data, absolute risks were generally lower, possibly reflecting the overall low-risk Danish obstetric population and universal, free healthcare. Analyses highlighted that restricting cohorts to hospitalized cases inflates risk estimates by excluding milder infections, underscoring the need for population-based designs. Differences between pandemic waves likely reflect evolving testing strategies. Validation showed that Danish registers are acceptable for identifying SARS-CoV-2 during pregnancy, supporting register-based surveillance and research.

Women infected with SARS-CoV-2 during pregnancy had increased risks of hypertensive disorders of pregnancy, early pregnancy loss, preterm delivery and giving birth to SGA infants. Registry-based identification of SARS-CoV-2 infection during pregnancy in Denmark demonstrated acceptable validity. Future research should assess impacts across virus variants and vaccination eras, refine understanding of pathophysiology (including placental effects), and evaluate targeted prevention and management strategies for high-risk subgroups.

- Multiple comparisons may have yielded chance findings (risk of type I error). - Lack of data on ethnicity/country of birth, known to be associated with COVID-19 severity. - Key covariates (BMI, smoking) are only recorded for deliveries in registers, leading to missingness for early pregnancy outcomes and potential residual confounding; supplemental DCOD smoking data were used in sensitivity analyses. - Possible under-ascertainment of infections early in the study period due to lack of universal testing before May 2020, although misclassification would likely be non-differential and bias toward null; DCOD was regularly validated against registers. - Study period limited to the first pandemic year, prior to vaccination and subsequent variants, which may limit generalizability to later periods.