On December 27, 2019, three adults (one woman and two men) were admitted to a hospital in Wuhan, China, with severe pneumonia. Patient 2 died, and patients 1 and 3 underwent bronchoalveolar-lavage sampling on December 30, 2019. From these samples, in February 2020, Zhu et al1 described a novel coronavirus, labeled as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infected humans with a respiratory illness called coronavirus disease 2019 (COVID-19). By May 1, 2020, there were more than 3.33 million confirmed cases of SARS-CoV-2 infection globally and more than 237,000 people had died.2
The adverse effects associated with the novel virus vary and are, in part, influenced by the individual's age and comorbidities.3 Annually there are more than 140 million births worldwide, and pregnant women, with putative immunocompromise, are potentially at increased risk for adverse outcomes with the novel coronavirus.4,5 Although there are a multitude of case reports of infection with SARS-CoV-2 during pregnancy, their small sample size precludes nuanced understanding of the potential complications and management schema.
The objective of this systematic review was to ascertain the frequency of maternal and neonatal complications, as well as maternal disease severity, in pregnancies affected by SARS-CoV-2 infection.
We performed this review based on guidelines designed for performing a systematic review and meta-analysis.6–8 This project was registered with PROSPERO before initiation of data extraction. Along with librarian assistance, we searched MEDLINE, Ovid, ClinicalTrials.gov, MedRxiv, and Scopus from their inception through April 29, 2020. Search strategy included the MeSH terms, key words, and word variants for “coronavirus” or “SARS-CoV-2” or “COVID-19,” and “pregnancy.r Reference lists of all identified articles were hand searched for inclusion. Reference lists of relevant articles and reviews were hand searched for additional reports (Fig. 1). Search results were not limited by language. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines were followed.9–11
Inclusion criteria for this study were case series of at least 10 pregnant patients who tested positive for SARS-CoV-2 infection. There was considerable heterogeneity in case definitions, reflecting regional variations between countries and changes in case definitions across time within the same country as the pandemic evolved. We attempted to limit our interpretation to data from laboratory-confirmed cases; however, when this distinction was not discernible, data from all cases presented were incorporated into our analysis. Microbiological diagnosis was preferred but not strictly required for articles that included clinical and microbiological diagnoses but did not separate characteristics or outcomes data between these two groups. Neonatal data were collected when available, but not all women had delivered by the time of publication. Furthermore, these articles did not routinely parse maternal characteristics for women who had delivered from women who were still pregnant. Given the nature of the rapidly evolving pandemic and the anticipated utility of aggregated data, we did not exclude articles with incomplete delivery data. Articles were also not excluded based on country of origin or language. We did exclude publications of smaller cases that were subsequently incorporated into larger case series. In an effort to minimize duplication of data, we compared the names of hospitals from previously published studies.
One of this study's authors (S.P.C.) sent repeated emails to corresponding authors from six prior published studies in China whose patient populations were derived from the same or similarly named hospitals (Li et al,12 Liu et al,13 Chen et al,14 Zeng et al,15 Khan et al,16 and Wu et al17). Three replies were received,12,16,17 and one article12 was removed from our analysis because the data were aggregated into a larger study by Chen et al.18 Similarly, data from Liu et al13 were aggregated into a subsequently published larger study by Yan et al19; hence, the original article was also removed from consideration.
Maternal comorbidities, symptoms, and obstetric complications were abstracted. Eight maternal comorbidities of interest were identified by the coauthors at the onset of this systematic review, and additional unique, clinically relevant comorbidities were systematically tallied. The neonatal outcomes we compared were 5-minute Apgar score less than 7, admission to the neonatal intensive care unit (NICU), and death within 28 days. Reports were also searched for data regarding maternal disease severity. Before SARS-CoV-2 became a global pandemic, it was an epidemic in China. We used a three-tiered disease severity category, as defined by Wu and McGoogan20 as follows: mild (“nonpneumonia and mild pneumonia”), severe (“dyspnea, respiratory frequency ≥30/min, blood oxygen saturation ≤93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or lung infiltrates >50% within 24 to 48 hours”), and critical (“respiratory failure, septic shock, and/or multiple organ dysfunction or failure”). Owing to the lack of an internationally agreed on clinical definition of tiered disease severity, as well as regional policy differences during an evolving pandemic, not all publications reported disease severity according to the Wu and McGoogan20 classification. We did not infer that a patient who met definitions for critical disease was necessarily admitted to the intensive care unit (ICU); conversely, neither did we infer that patients admitted to the ICU necessarily met criteria for critical disease as defined by Wu and McGoogan.20
Lastly, we examined the rate of vertical transmission, defined as a positive test result for SARS-CoV-2 infection by neonatal nasal swab immediately (eg, within 5 minutes) after birth or a positive immunoglobulin M result for SARS-CoV-2 infection in cord blood (because vertical transmission of SARS-CoV-2 infection has not been formally defined in the literature yet).
Two authors (B.J.F.H., E.S.H.) reviewed all abstracts independently. Agreement regarding potential relevance or inconsistencies was reached by consensus or resolved by discussion with a third reviewer (S.P.C.). Full-text copies of applicable articles were obtained, and the same reviewers independently extracted relevant data regarding study characteristics and pregnancy outcome. If more than one study was published on the same cohort with identical endpoints, the report containing the most comprehensive information on the population was included to avoid overlapping populations. Most publications reported maternal characteristics for all women who tested positive SARS-CoV-2 infection separately from neonatal outcomes for deliveries that occurred during the study window. Based on published tables, it was not possible to decipher differences in maternal characteristics between women who completed their pregnancies and those who were still pregnant at the conclusion of the original study windows. Thus, the sample sizes for maternal and neonatal outcomes differ.
Overall, we evaluated the prevalence of each of the explored outcomes in pregnancies affected by SARS-CoV-2 infection. Continuous variables were expressed as mean±SD. Categorical variables were expressed as number of cases with percentages and 95% CIs. All proportions were carried out by using StatsDirect 2.7.9.
Quality assessment of the included studies was performed using the methodologic quality and synthesis of case series and case reports described by Murad et al.21 According to this tool, each study is judged on four broad perspectives: the selection of the study groups, the ascertainment and the causality of the outcome observed, and the reporting of the case. A study can be awarded a maximum of one star for each numbered item within the selection and reporting categories, two stars for ascertainment, and four stars for causality21 (Appendix 1, available online at https://links.lww.com/AOG/B946).
Of the 99 articles identified, 13 were eligible for inclusion and were included in this systematic review. These 13 studies14–19,22–28 included 538 pregnancies affected by SARS-CoV-2 infection (420 from China, 76 from the United States, 42 from Italy), with reported outcomes on 435 (80.9%) deliveries (342 from China, 51 from the United States, 42 from Italy). Comorbidity was described variably in the reports, but approximately one in three women with SARS-CoV-2 infection had a comorbid condition. The mean maternal age was 30.2 years (Table 1).
Infection with SARS-CoV-2 was diagnosed by reverse-transcription polymerase chain reaction in a nasopharyngeal swab specimen, which is currently the gold standard for diagnosis. There is notable heterogeneity in case selection among obstetric publications, with some studies reporting results based on universal screening and others leveraging varying clinical parameters to guide selective-screening decisions. Where possible, data included in this review were restricted to laboratory-confirmed cases of SARS-CoV-2 infection, which included both symptomatic and asymptomatic patients. Some women were, however, identified based on clinical examinations and radiologic studies.14,16–18,23,28 Where discernible, we evaluated only patients who had laboratory-confirmed positive test results. Of the data assessed, 462 of 538 (85.9%, 95% CI 82.7–88.6) patients included in our analysis had laboratory-confirmed SARS-CoV-2 infection. The distinction between clinically diagnosed and microbiologically diagnosed patients was indiscernible for 33 of 538 (6.1%) patients. Of the patients included in our analysis, 43 of 538 (8.0%) were diagnosed on clinical grounds but were included nonetheless, because the maternal and neonatal outcomes data for laboratory-confirmed and clinically diagnosed mothers were not independently reported. Women were mostly identified through selective-screening policies. Having a sick contact (ie, with COVID-19) was reported by almost half of the women who had SARS-CoV-2 infection (Table 2). Of the 75.3% (274/364, 95% CI 70.6–79.4) of women who were symptomatic, the two most common symptoms were fever and cough. Laboratory result reporting varied widely, precluding useful analysis. In reporting cases, lymphopenia was found in 110 of 232 women (47.4%, CI 41.1–53.8) (Table 3).
Adopting the Wu and McGoogan criteria,20 4 of the 13 publications categorized the women as having mild, moderate, or critical disease.18,22,23,26 Of these patients, 87.2% had mild disease and 1.3% were critically ill (Table 4).
The average gestational age among women who delivered was 38.1 weeks (Table 5). The rate of preterm birth was 20.1% (55/57 preterm births were from Chinese publications, and 2/57 were from Italy; preterm birth data were not discernible in publications from the United States). Eighty-five percent of women underwent cesarean delivery (306/332 cesarean deliveries were from Chinese publications, 18/332 were from Italy, and 8/332 were from the United States). Maternal admission rate to the ICU was 3.0% (8/263), and no maternal deaths secondary to COVID-19 were reported in the studies included. The NICU admission rate was largely influenced by Chinese reports: 134 of 137 newborns admitted to the NICU were identified in Chinese reports, and three were from the United States. Neonatal intensive care unit admission data were not discernible in the publication from Italy. The overall NICU admission rate was 64.9%. Despite this NICU admission rate, the rate of 5-minute Apgar scores less than 7 was 0.5%. Neonatal mortality occurred in 0.3% of cases (Table 6). There were no cases of vertical transmission among 310 deliveries for which reverse-transcription polymerase chain reaction data were made available.
This systematic review of case series with 10 or more pregnant women with SARS-CoV-2 infection includes cases reported in the first 4 months after the disease was identified in late December 2019. Information is accumulating rapidly, and this review is intended to provide early information to help inform counseling and care of pregnant women with SARS-CoV-2 infection. We acknowledge from the outset that the data are incomplete and accept that our current knowledge is limited to case series and case reports. We also acknowledge that the practice of obstetrics differs among the three countries from which these cases were reported and that these baseline differences likely contribute to some of the findings. Nonetheless, there are significant findings.
Among 538 pregnant women with SARS-CoV-2 infection assessed in this systematic review, the primary outcomes of maternal ICU admission occurred in 3.0% of women, maternal critical disease in 1.3% of women, and maternal death in 0.0% of women. The secondary outcome of preterm birth rate was 20.1%, the cesarean delivery rate was 84.7%, the vertical transmission rate was 0.0%, and the neonatal death rate was 0.3%.
Data available at time of publication should be interpreted with caution, because they were disproportionately weighted for publications from China and included outcomes for both selectively screened symptomatic patients and a smaller number of universally screened, test-positive asymptomatic patients (Table 2). Variations in screening methods may well influence pooled proportions of comorbidities and clinical outcomes. The proportion of mild disease (Table 4) is heavily weighted by a selective-screening process wherein asymptomatic women are likely under-represented. Notably high rates of pregnancy-specific complications may be secondary to local practice patterns and novelty of the virus, with lack of evidence to guide management.
The 20% preterm birth rate includes both iatrogenic and spontaneous preterm birth, although only 4 of 13 included reports clearly distinguish between these. Multiple studies from China18,19,22 mention iatrogenic preterm birth, with one citing the indication for preterm cesarean delivery being, “the belief that antiviral treatment was needed as early as possible in the disease course”.
Regarding heightened rates of cesarean delivery, the pooled portions subanalysis of cesarean delivery rates by country represented in this systematic review are 42.9% from Italy (18/42), 44.4% from the United States (8/18), and 92.2% from China (306/332). It is noteworthy that at least three articles from China15,18,19 cite SARS-CoV-2 infection as an indication for cesarean delivery. Similarly, the NICU admission rates are likely highly influenced by local management protocols: two articles from China14,24 report admitting all neonates born to mothers who tested positive for SARS-CoV-2 infection to the NICU. Other measures of neonatal morbidity must be included in future reports to overcome protocol-driven NICU admission, which is a poor proxy for neonatal well-being. Unlike other viral infections,29,30 vertical transmission of SARS-CoV-2 infection to the newborn appears to be uncommon. In distinction from other perinatal viral infections such as influenza, the disease course may be less severe in pregnant women compared with older, nonpregnant adults.31
Fever and cough occur in nearly half of symptomatic maternal cases, whereas myalgias, dyspnea, and fatigue occur in only approximately one sixth of symptomatic pregnant women (Table 3). These data should be interpreted cautiously, however, because testing protocols varied widely and there is significant heterogeneity in the publication of laboratory data.
One strength of our analysis is that, by using a minimum threshold of 10 pregnant patients as inclusion criteria, publication bias of rare adverse outcomes limited to case reports was likely lessened. A second strength is that the review included reports from three countries (China, Italy, and the United States) so as to make the findings more generalizable. Additionally, we restricted the analysis to laboratory-confirmed positive cases if that delineation was possible, avoiding subjective diagnoses based on evolving policies regarding clinical diagnoses, which varied across time and location. A fourth strength is that corresponding authors of prior articles were contacted in an effort to deduplicate data.
There are significant limitations to our study. We included data from retrospective case series from different countries, where the obstetric management decisions at baseline differ even without an evolving pandemic. Regarding maternal characteristics, laboratory findings, methods for screening, and reported outcomes, significant heterogeneity existed not only in what data were reported, but also in how they were reported, making the data difficult to aggregate. Lack of an international standard for publication of data in obstetrics during this pandemic hindered this analysis.
A second limitation is the possibility for data duplication. Although we did not receive replies from all corresponding authors, we were able to remove many studies from consideration because their data were subsequently published in a larger aggregation. However, we chose to include primary data from two studies14,15 that reported on 17 and 33 pregnancies, respectively, despite not receiving replies from these corresponding authors.
A third limitation is that disease severity classifications varied between articles and that proportions of mild, severe, and critical disease represent patients predominately identified by selective-screening methods; hence, asymptomatic patients are likely under-represented. Similarly, the quality of early publications varied significantly. Commonly, there was incomplete information and varied ways of reporting similar information, making it difficult to compare data from one source with data from another. For instance, we were unable to ascertain the adequacy of neonatal testing to be confident of our finding of a negligible vertical transmission rate.
With the release of guidelines on how to manage pregnant women with SARS-CoV-2 infection,5,32 peripartum outcomes should improve.33 Based on phenomenologic modeling with generalized logistic growth models, Putra et al have forecasted 3,308 severe and 681 critical COVID-19 cases in pregnant patients, with 52 COVID-19–related maternal mortalities during delivery hospitalization in the United States alone from March 1, 2020 to December 31, 2020.34 This pandemic will continue to threaten maternal health for the foreseeable future. Thus, there is a continued need to update the systematic review, especially when the results of multiple registries are publicly available.35
In conclusion, although the quality of published data for larger case series on SARS-CoV-2 infection in pregnancy is poor on account of heterogeneity, our systematic review of pregnant patients with SARS-CoV-2 infection indicates that the majority of the adverse outcomes may be limited to increased preterm birth and cesarean delivery rates, both of which may be iatrogenically inflated and will likely decrease. Admittedly, the pooled portions outcomes are disproportionately weighted by a small number of studies that aggregated a large number of deliveries from the same geographic region (the three largest studies all came from China and accounted for 50.6% [272/538] of the total pregnancies assessed in this review). More data from a greater breadth of countries are needed to further assess these outcomes at a global level. Implementation of best-practice suggestions as data are collected to inform evidence-based guidelines will likely alter some of the future outcome results. Fortunately, vertical transmission and both maternal and neonatal mortality appear to be uncommon with SARS-CoV-2 infection. An international publication standard for obstetric data would greatly aid in ongoing data aggregation and subsequent analyses, which would conceivably affect future clinical management decisions and health policy changes for the betterment of pregnant women worldwide. Considering the rapid evolution of the novel virus and our response to it, there is continued need to synthesize available reports to guide patients, clinicians, and policy makers.
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