Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy

Abstract

Background Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing. Methods Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design. Results Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks’ gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks’ gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. Conclusions Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

Clinical Course of SARS CoV-2 Infection in Hospitalized Pregnant Patients

“…18 In another systematic review reporting on 41 delivered patients preterm delivery rate was 41%, and perinatal deaths were 07%. 19 In another published series of 43 patients from New York, labour was induced in 50%,44% delivered by cesarean section, and preterm delivery was 5% compared to 2.4% preterm deliveries in our study. 20 Our study found that most pregnant patients were young and in good health, and there were no obstetric complications.…”

Effects of intrauterine exposure to SARS-CoV-2 on infants’ development: A rapid review and meta-analysis

“…The immunological and in ammatory events related to SARS-CoV-2 infection during pregnancy are complex and not completely understood [8]. Many factors, such as the placenta maturity, the developmental stage of the fetus's central nervous system at the moment of maternal infection, the viral load and variants, and the COVID-19 clinical presentation, would theoretically modify the developmental outcomes [8, 49,52,53].…”

“…The timing of infection and the severity of maternal disease are important factors that may be associated with the offspring outcomes in gestational infections [49][50][51]. Most mothers in the included studies were infected in the third gestational trimester, were asymptomatic, or had mild COVID-19 symptoms.…”

Pregnancy outcomes after SARS-CoV-2 infection: the current evidence

“…However, severe infection in late pregnancy significantly increased the risk of preterm delivery (compared with no infection), primarily due to an increase in medically indicated preterm deliveries (including preterm caesarean sections) while the increase in spontaneous preterm delivery was mild. Overall, mild or moderate infection conferred minimal risk, as did severe disease in early pregnancy 44 .…”