The effect of maternal SARS-CoV-2 infection timing on birth outcomes: a retrospective multicentre cohort study

Abstract

Background: The impact of maternal SARS-CoV-2 infection remains unclear. In this study, we evaluated the risk of maternal SARS-CoV-2 infection on birth outcomes and how this is modulated by the pregnancy trimester in which the infection occurs. We also developed models to predict gestational age at delivery for people following a SARS-CoV-2 infection during pregnancy.

Methods: We did a retrospective cohort study of the impact of maternal SARS-CoV-2 infection on birth outcomes. We used clinical data from Providence St Joseph Health electronic health records for pregnant people who delivered in the USA at the Providence, Swedish, or Kadlec sites in Alaska, California, Montana, Oregon, or Washington. The SARS-CoV-2 positive cohort included people who had a positive SARS-CoV-2 PCR-based test during pregnancy, subdivided by trimester of infection. No one in this cohort had been vaccinated for COVID-19 at time of infection. The SARS-CoV-2 negative cohort were people with at least one negative SARS-CoV-2 PCR-based test and no positive tests during pregnancy. Cohorts were matched on common covariates impacting birth outcomes, and univariate and multivariate analysis were done to investigate risk factors and predict outcomes. The primary outcome was gestational age at delivery with annotation of preterm birth classification. We trained multiple supervised learning models on 24 features of the SARS-CoV-2 positive cohort to evaluate performance and feature importance for each model and discuss the impact of SARS-CoV-2 infection on gestational age at delivery.

Findings: Between March 5, 2020, and July 4, 2021, 73 666 pregnant people delivered, 18 335 of whom had at least one SARS-CoV-2 test during pregnancy before Feb 14, 2021. We observed 882 people infected with SARS-CoV-2 during their pregnancy (first trimester n=85; second trimester n=226; and third trimester n=571) and 19 769 people who have never tested positive for SARS-CoV-2 and received at least one negative SARS-CoV-2 test during their pregnancy. SARS-CoV-2 infection indicated an increased risk of preterm delivery (p<0·05) and stillbirth (p<0·05), accounted for primarily by first and second trimester SARS-CoV-2 infections. Gestational age at SARS-CoV-2 infection was correlated with gestational age at delivery (p<0·01) and had the greatest impact on predicting gestational age at delivery. The people in this study had mild or moderate SARS-CoV-2 infections and acute COVID-19 severity was not correlated with gestational age at delivery (p=0·31).

Interpretation: These results suggest that pregnant people would benefit from increased monitoring and enhanced prenatal care after first or second trimester SARS-CoV-2 infection, regardless of acute COVID-19 severity.

Funding: US National Institutes of Health.

Figure 1

Earlier maternal SARS-CoV-2 infection and premature delivery First, second, and third trimester maternal SARS-CoV-2 infection compared with matched SARS-CoV-2 negative control. Percentage of births as defined by the Centres for Disease Control and Prevention were term, late preterm, moderate preterm, very preterm, or extremely preterm.

Figure 2

Contribution of features towards the predicted gestational age The contribution of all the features in the random forest model towards the predicted gestational age at delivery as measured by the Shapley algorithm and reported as the SHAP value. This value is the average marginal contribution of a feature value across all permutations of features providing insight into the degree of influence of the feature on an individual's predicted gestational age at delivery. Each line represents a feature, and each dot represents a sample. The dot colour represents the value of the feature for the sample, with red being a high value and blue being a low value for that feature across all samples. SHAP=Shapley additive explanations.

Figure 3

The severity of maternal SARS-CoV-2 infection is not correlated with gestational age at delivery Correlation between gestational age at delivery for all instances of maternal SARS-CoV-2 infection (n=882) and gestational age at maternal SARS-CoV-2 infection, number of unique medications active ingredients prescribed, COVID-19 severity, and number of encounters during an active SARS-CoV-2 infection. The R2 value and trendline equation are displayed.