Introduction
- Delahoy MJ
- Whitaker M
- O’Halloran A
- et al.
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- Jering KS
- Claggett BL
- Cunningham JW
- et al.
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- Lokken EM
- Huebner EM
- Gray Taylor G
- et al.
Additionally, SARS-CoV-2 infection has been associated with increased rates of pre-eclampsia.
- Jering KS
- Claggett BL
- Cunningham JW
- et al.
Thus far, studies have been done either with small study populations and greater clinical detail, or with large populations but limited detail (insurance claims or aggregate reporting). It is also well known that minority and low-income communities are disproportionately impacted by COVID-19,
- Little C
- Alsen M
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- et al.
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- Tai DBG
- Shah A
- Doubeni CA
- Sia IG
- Wieland ML
and many risk factors associated with poor birth outcomes are elevated in these populations, which could account for some of the disparity in birth outcomes for pregnant people infected with SARS-CoV-2.
- Goldenberg RL
- Culhane JF
- Iams JD
- Romero R
To the best of our knowledge, as of November, 2021, no primary study has examined the impact of the timing of maternal SARS-CoV-2 infection on birth outcomes in a large, geographically distributed cohort, with analysis across a broad set of biomedical and contextual variables.
- Class QA
- Lichtenstein P
- Långström N
- D’Onofrio BM
Fetuses are most vulnerable to maternal stress during the fifth and sixth month of pregnancy, resulting in higher rates of preterm birth, low birthweight, and small for gestational age (SGA) than exposure during other periods of pregnancy.
- Class QA
- Lichtenstein P
- Långström N
- D’Onofrio BM
Likewise, the effect of maternal influenza infection on birth outcomes depends on the timing of exposure.
Influenza exposure during pregnancy is associated with increased infant and neonatal mortality during the first trimester, decreased birthweight during the second trimester, and increased preterm birth and decreased birthweight during the third trimester. Thus, we expect a difference in birth outcomes based on the gestational age at time of maternal SARS-CoV-2 infection.
Evidence before this study
We searched PubMed for the keywords “SARS-CoV-2” or “COVID-19” combined with “preterm birth” or “trimester,” including all articles published before March 21, 2021. No language restrictions were applied. We found several studies that examined the impact of maternal SARS-CoV-2 infection on pregnancy outcomes using electronic health records (EHRs) or insurance claims. However, these studies were limited by small sample size or narrow scope of the data. Also, most studies did not differentiate between the timing of preterm birth, which has clinically significant implications in terms of neonatal survival, care, and potential lifelong health problems. To our knowledge, as of November, 2021, there has not yet been any primary study that accounts for the trimester of maternal SARS-CoV-2 infection, despite the awareness of the crucial periods during pregnancy when there exists a greater potential for in utero shocks on fetal development.
Added value of this study
We did a retrospective cohort study using EHRs from hospitals and clinics across five states in the USA. We compared pregnancy outcomes of unvaccinated people with a positive SARS-CoV-2 test during pregnancy to a matched control cohort with negative SARS-CoV-2 test results. The positive cohort was substratified by trimester of infection. To our knowledge, our study is the first to modulate birth outcomes by the trimester of maternal infection. Additionally, using propensity score matching, we controlled for several confounding variables known to be associated with negative pregnancy outcomes, which were enriched in the SARS-CoV-2 positive cohort. We evaluated outcomes using delivery events, including preterm birth classifications. There was an increase in preterm birth and stillbirth following SARS-CoV-2 infection, primarily driven by increases following first or second trimester maternal infection. We built supervised learning models that predict gestational age at delivery using demographics, maternal comorbidities, information related to SARS-CoV-2 infection, and fetal characteristics. The single greatest predictor of gestational age at delivery is gestational age at infection, with earlier age at infection associated with earlier age at delivery. There was no correlation between severity of COVID-19 and gestational age at delivery.
Implications of all the available evidence
These results suggest that pregnant people are at increased risk of preterm birth following SARS-CoV-2 infection regardless of COVID-19 severity. We recommend enhanced prenatal care and increased monitoring for pregnant people following a SARS-CoV-2 infection. Due to increased risk of maternal–fetal health of SARS-CoV-2 infection, we propose prioritisation of vaccination of pregnant people in areas where vaccine distribution is scarce.
In this study, we investigated the impact of maternal SARS-CoV-2 infection at each trimester of pregnancy on birth outcomes (preterm birth, stillbirth, birthweight, and SGA) in an unvaccinated population, adjusting for common confounding factors. We also developed models to predict gestational age at delivery for people following a SARS-CoV-2 infection during pregnancy. We evaluate performance and feature importance for each model and discuss the impact of SARS-CoV-2 infection on gestational age at delivery. This research investigates the risk of negative birth outcomes for people exposed to SARS-CoV-2 infection during pregnancy.
Results
Table 2Birth outcomes of people with SARS-CoV-2 infection during their first, second, or third trimester
Data are n (%) or median (IQR), unless stated otherwise. Stillbirth and small for gestational age rates for people with maternal SARS-CoV-2 infections during their first, second, or third trimester compared with the matched negative control group. Median (IQR) of the fetal growth percentile at delivery, gestational age at delivery, and weight at delivery.
Figure 1Earlier 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 2Contribution 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 3The 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.
Table 3Contribution of features towards the predicted gestational age
Pearson’s correlation coefficient and the corresponding p values for the 24 features (two-tailed) used in the predictive models.
Discussion
In this study, we examined the impact of maternal SARS-CoV-2 infection on birth outcomes modulated by gestational age, which resulted in the following key findings. First, more negative birth outcomes were observed when infections occurred earlier in gestation, including increased risk for preterm birth and stillbirth. Second, there were increased rates of SGA infants born to people who had a positive SARS-CoV-2 test result during pregnancy, suggesting that preterm delivery is induced via a mechanism that could impact fetal growth. Third, there appears to be two distinct populations of pregnant people: a subset with a negative correlation between the time of maternal SARS-CoV-2 infection and gestational age at delivery and a second population appearing to be unaffected. Fourth, the difference between mild and moderate severity of the SARS-CoV-2 infection does not appear to play a part in whether a pregnancy is likely to be negatively affected. Taken together, these findings suggest that SARS-CoV-2 infection early in pregnancy is an important risk factor that should be monitored in health systems.
- Delahoy MJ
- Whitaker M
- O’Halloran A
- et al.
,
- Jering KS
- Claggett BL
- Cunningham JW
- et al.
However, these studies did not account for trimester of infection. Cohorts might have been skewed towards people infected during their third trimester due to the state of testing early in the pandemic and studies’ earlier reporting, which would mean a low number of observations of first or second trimester SARS-CoV-2 infection. We showed that gestational timing of infection is the most important factor of birth outcome. Further, COVID-19 disproportionately impacts low-income and minority communities, resulting in many covariates known to increase the risk of preterm birth and other negative birth outcomes.
- Vogel JP
- Chawanpaiboon S
- Moller A-B
- et al.
There were significant differences in the demographics, comorbidities, and birth characteristics of people in the SARS-CoV-2 positive and SARS-CoV-2 negative cohorts, including ethnicity, race, and Medicaid insurance status. Because these variables have previously been associated with differences in birth outcomes in the USA, we control for these cofactors using propensity score matching.
- Lye P
- Dunk CE
- Zhang J
- et al.
The SARS-CoV-2 spike protein interacts with ACE2 for entry into human cells,
- Hoffmann M
- Kleine-Weber H
- Schroeder S
- et al.
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- Wang Q
- Zhang Y
- Wu L
- et al.
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- Zhou P
- Yang X-L
- Wang X-G
- et al.
and ACE2 placental levels are dependent on gestational age, with the highest levels observed early in gestation and near undetectable levels observed near term.
- Lye P
- Dunk CE
- Zhang J
- et al.
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- Zhou P
- Yang X-L
- Wang X-G
- et al.
This difference implicates an increased risk of SARS-CoV-2 infecting the placenta via ACE2 binding. Vertical SARS-CoV-2 transmission has been reported, but remains a rare mode of infection.
- Bloise E
- Zhang J
- Nakpu J
- et al.
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- Wastnedge EAN
- Reynolds RM
- van Boeckel SR
- et al.
However, an intrauterine infection can lead to ACE2-expressing neutrophils and monocytes (macrophage) to invade the placenta, which could result in increased risk for fetal distress.
- Lye P
- Dunk CE
- Zhang J
- et al.
This is a potential mechanism by which increased stress occurs on the placenta during SARS-CoV-2 infection in a gestational age dependent manner. The histological features of SARS-CoV-2 infected placenta remain ill-defined due to scarce placenta histopathological reports. However, given that patients with COVID-19 have an increased risk of thromboembolic events, additional investigations into placental thrombosis, thromboembolic events, and anticoagulation in pregnant patients following maternal SARS-CoV-2 infection are justified.
- Wastnedge EAN
- Reynolds RM
- van Boeckel SR
- et al.
Only 35 people in the SARS-CoV-2 positive cohort received anticoagulants as a treatment for COVID-19 in this study. Because few people in this study received anticoagulation during acute COVID-19 infection, it is not possible to do a rigorous analysis on the association between this treatment and birth outcomes. This remains an important area for future investigation. Future studies examining the impact of SARS-CoV-2 infection on placenta health are needed to provide insight into the mechanism by which maternal SARS-CoV-2 infection might promote negative pregnancy outcomes.
- Crump C
- Winkleby MA
- Sundquist J
- Sundquist K
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- Zambrano LD
- Ellington S
- Strid P
- et al.
Furthermore, extremely preterm infants require substantial resources for care, with costs nearly 100 times that of care for full-term infant in the first 6 months of life.
- Beam AL
- Fried I
- Palmer N
- et al.
In addition to increased risk of negative pregnancy outcomes following SARS-CoV-2 infection, pregnant people have higher infection rates and are more likely to develop severe COVID-19·
- Delahoy MJ
- Whitaker M
- O’Halloran A
- et al.
,
- Jering KS
- Claggett BL
- Cunningham JW
- et al.
,
- Zambrano LD
- Ellington S
- Strid P
- et al.
,
- Lokken EM
- Gray Taylor G
- Huebner EM
- et al.
Taken together, both maternal and fetal health are at increased risk following maternal SARS-CoV-2 infection. It might, therefore, be prudent to consider pregnant people as a prioritised population for SARS-CoV-2 vaccination in areas where vaccine dissemination is scarce. There is also evidence that vaccine antibodies can pass through the umbilical cord to the fetus in utero, meaning that maternal vaccination can have the additional benefit of protecting the subsequent neonate.
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The results suggest that additional monitoring of birth outcomes following first or second trimester maternal SARS-CoV-2 infection is warranted. The pregnant people who tested positive for SARS-CoV-2 in this study were unvaccinated against COVID-19; therefore, it would be interesting to examine in future studies whether vaccination helps to prevent negative birth outcomes in breakthrough cases. Also, modifiable features that are predictive of premature delivery can suggest hypotheses for clinical interventions, and additional features can be added to improve model accuracy and explore additional potential risk factors. The impact of in utero SARS-CoV-2 exposure on neonatal outcomes, including meeting developmental milestones, also needs further investigation. Finally, the impact of COVID-19 on subsequent pregnancy outcomes should be studied by examining the birth outcomes of non-pregnant women who had COVID-19 and later went on to become pregnant. Such studies are needed to assess the long-term impact of COVID-19 and the effect of post-acute sequelae of SARS-CoV-2 on pregnancy.
Here we examine outcomes of pregnancies that reached at least 20 weeks of gestation. It is possible that first trimester SARS-CoV-2 infection increases the risk of miscarriage, an outcome that we do not evaluate in this study. People in our study cohort had mild or moderate SARS-CoV-2 infections, so our findings might not extrapolate to a pregnant person with severe COVID-19, which remains rare in pregnant people. We have identified features that are predictive of gestational age at delivery, but they are not necessarily risk factors for premature delivery. Furthermore, this study was done at PSJH without validation at an independent health-care system. However, concerns regarding generalisability of this study are mitigated by the size and diversity of PSJH, which serves patients at 51 hospitals and 1085 clinics across five western US states.
- Wastnedge EAN
- Reynolds RM
- van Boeckel SR
- et al.
However, it is too early to observe the impact of in utero SARS-CoV-2 exposure on subsequent neonate and early development. Previously, in utero exposure to viruses have been shown to increase later risk of developing autism or other neuropsychiatric diseases.
- Al-Haddad BJS
- Jacobsson B
- Chabra S
- et al.
Furthermore, in utero exposure to infection is associated with the development of subsequent autoimmune diseases, including asthma and type 1 diabetes.
- Algert CS
- Bowen JR
- Lain SL
- Allen HD
- Vivian-Taylor JM
- Roberts CL
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- Adams Waldorf KM
- McAdams RM
Therefore, it is important to follow children exposed to SARS-CoV-2 in utero to determine if this leads to increase risk of the development of long-term outcomes, especially neuropsychiatric or autoimmune diseases.
This cohort study found that first and second trimester maternal SARS-CoV-2 infection was a risk factor for preterm birth and stillbirth. The greatest predictor of gestational age at delivery following a maternal SARS-CoV-2 infection was the gestational age at infection. In this cohort of patients with mild or moderate COVID-19, there was no correlation between COVID-19 severity and gestational age at delivery. These findings suggest that increased monitoring and enhanced prenatal care could be appropriate for pregnant people who have had a SARS-CoV-2 infection during the first or second trimester of pregnancy, regardless of infection severity.
SNP, NDP, LH, and JJH conceptualised the study. LH and JJH supervised the study implementation. Funding was provided by NDP and JJH. Administrative and material support was provided by LH. SNP and RTR did the data cleaning and transformation. SNP did the data analyses, including statistical analysis and machine learning. SNP, YMH, and TS were involved in data interpretation. SNP prepared the manuscript with critical revision of the manuscript for important intellectual content provided by NDP, LH, and JJH. All authors reviewed and approved the final version of the manuscript. SNP, RTR, YMH, TS, and JJH had full access to the data in the study. All authors had final responsibility for the decision to submit for publication.