Coronavirus Disease 2019 (COVID-19) Perinatal Outcomes Across the Pandemic at an Academic Medical Center in New York City : Obstetrics & Gynecology

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Coronavirus Disease 2019 (COVID-19) Perinatal Outcomes Across the Pandemic at an Academic Medical Center in New York City

Seaton, Christine Leinbach BA; Cohen, Alexa MD; Henninger, Erin M. BA, MPH; Gendlina, Inessa MD, PhD; Hou, Wei PhD; Bernstein, Peter S. MD, MPH; Duong, Tim Q. PhD

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Obstetrics & Gynecology: October 27, 2022 - Volume - Issue - 10.1097/AOG.0000000000004978
doi: 10.1097/AOG.0000000000004978
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Emerging evidence suggests that pregnant individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have higher risks of severe coronavirus disease 2019 (COVID-19) and mortality compared with those without SARS-CoV-2 infection1,2 and nonpregnant adults with SARS-CoV-2 infection,3 but its effect on pregnancy is still uncertain. Several physiologic changes during pregnancy may contribute to more severe COVID-19. Enlargement of the uterus increases intra-abdominal pressure on the diaphragm and reduces functional residual capacity of the lung. Increased estrogen during pregnancy causes airway mucosal hyperemia, edema, and hypersecretion. Placental production of estrogen and progesterone lowers hemoglobin concentrations, which could lead to increased susceptibility to hypoxic injury. Maternal immunologic tolerance toward the fetus could lead to reduced ability to fight SARS-CoV-2 infection. These physiologic changes could also increase susceptibility to adverse perinatal complications (in addition to COVID-19 critical illness and mortality) in patients with SARS-CoV-2 infection, such as preterm birth, low birth weight, stillbirth, and preeclampsia. Additionally, SARS-CoV-2 infection during pregnancy may affect the development of the fetus and placentation, leading to adverse perinatal outcomes.

Current data on COVID-19–related perinatal outcomes are controversial. A few cohort studies have reported that patients with COVID-19 have an increased risk for adverse perinatal outcomes, including preterm birth, low birth weight, stillbirth, and preeclampsia; cesarean birth rates have been modestly increased in some studies, although some have suggested that the risk may be limited to those with severe or critical COVID-19.3–5 Other studies reported that maternal and fetal outcomes have worsened for all pregnant individuals during the COVID-19 pandemic, with an increase in maternal deaths, stillbirths, ruptured ectopic pregnancies, and maternal depression.6 One study found no difference in outcomes between individuals with SARS-CoV-2 infection and those without, though it studied only first-trimester infection.7 Most of these studies reported findings earlier in the pandemic. Evolving SARS-CoV-2 variants, public health polices (such as social distancing and mask mandates), availability of new treatments and vaccines, and overall improved management of COVID-19 may have affected perinatal complications across the pandemic.

The goal of this study was to investigate perinatal outcomes among pregnant individuals with and without SARS-CoV-2 infection during pregnancy across multiple distinct COVID-19 waves. Our health system, a large urban academic health system in the Bronx, New York, is a perinatal referral center that serves a racially and ethnically diverse population, many of whom are of lower socioeconomic status. New York City has experienced four distinct waves during the pandemic, each driven by a different variant of the SARS-CoV-2 virus: the original strain, Alpha (B.1.1.7), Delta (B.1.617. 2), and Omicron (B.1.1.529) (NYC DOHMH, as of April 1, 2022). Analysis was performed with variant groupings based on delivery date and, separately, based on infection date.

METHODS

This retrospective cohort study, with approval by the Einstein-Montefiore IRB (#2021-13658), included all patients who delivered at Montefiore Medical Center at either the Wakefield or Weiler campus in the Bronx, New York, between March 1, 2020, and February 13, 2022. Of note, from April 2, 2020, onward, patients admitted to the labor and delivery unit were universally tested for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-PCR). SARS-CoV-2 positivity was defined as a positive RT-PCR test result at our institution any time during pregnancy through 2 days postpartum, allowing for delayed testing or return of results. Home test results were not considered because their reporting was neither reliable nor consistent.

All data originated from Montefiore Health System and were made available for research after standardization to the Observational Medical Outcomes Partnership Common Data Model version 6. The Observational Medical Outcomes Partnership Common Data Model contains health care data from diverse sources, which are stored in standard vocabulary concepts, allowing systematic analysis of disparate observational databases, including data from the electronic medical record, administrative claims, and disease classification systems (eg, International Classification of Diseases, Tenth Revision; SNOMED; LOINC). ATLAS, a web-based tool developed by the Observational Health Data Sciences and Informatics community that enables navigation of patient-level observational data in the Common Data Model format, was used to search vocabulary concepts and facilitate cohort building. Data were subsequently imported into SQLite 3.37.2 and queried using the DB Browser 3.12.0. In addition, data were electronically abstracted from medical records to supplement data that were not available in ATLAS. We have cross-validated this COVID-19 cohort database by chart review as needed, as described previously.8-13 Data on vaccination status and reason for hospitalization for the subset of patients who tested positive for SARS-CoV-2 infection while hospitalized were obtained from infectious disease specialists, who began collecting this information through expert chart review in November 2020.

Demographic data included age, ethnicity, and race. Chronic comorbidities included obesity, diabetes, congestive heart failure, chronic hypertension, chronic kidney disease, coronary artery disease, and asthma diagnosed before delivery. Data on race and ethnicity were collected to examine whether any populations within our community were disproportionately affected by the pandemic.

The COVID-19 waves were identified by a daily test positivity rate of at least 5% that lasted at least 10 days in the Bronx, New York, using nyc.gov data. For the Delta wave, a threshold of 1% was used, an approximate doubling of baseline because the daily positivity rate never reached 5%. By this definition, the first wave spanned March 8, 2020–May 25, 2020, the Alpha wave spanned December 6, 2020–April 5, 2021, the Delta wave spanned July 6, 2021–December 14, 2021, and the Omicron wave spanned December 15, 2021–January 24, 2022.

Primary outcomes were preterm birth (birth occurring before 37 0/7 weeks of gestation), low birth weight (less than 2,500 g), stillbirth, cesarean delivery, and preeclampsia. In the primary analysis, individuals who tested positive for SARS-CoV-2 infection and those who tested negative were compared, and variant groupings for the SARS-CoV-2–positive cohort were based on delivery date to enable comparison with the SARS-CoV-2–negative cohort. In the secondary analysis, individuals who tested positive for SARS-CoV-2 infection were stratified by predominant variant at time of their infection. Variant assignment was based on the date of their first positive test result, and data were limited to the time period when universal testing was done (April 2, 2020–February 13, 2022). Hospitalization due to COVID-19 was used as a marker of severe illness. Additionally, outcomes were analyzed based on trimester of SARS-CoV-2 infection based on first positive RT-PCR test result. In the primary analysis, group differences in categorical variables in frequency and percentages were tested using χ2 test. In the secondary analysis, column proportions were compared using χ2 tests. P<0.05 was considered statistically significant.

RESULTS

Patient demographics, comorbidities, and mortality are described in Table 1. Of the 8,983 patients who delivered, 638 (7.1%) tested positive for SARS-CoV-2 infection during pregnancy, with the highest rates of infection among those who delivered during the Omicron wave (140/449, 31.2%). Age (30.1±6.0 years vs 30.3±5.9 years, P>.05), race, ethnicity, and major comorbidities were not significantly different between the SARS-CoV-2–positive and SARS-CoV-2–negative cohorts (all P>.05). There were no statistically significant differences in outcomes between the SARS-CoV-2–positive and SARS-CoV-2–negative cohorts (preterm birth: 17.0% vs 14.4%; low birth weight: 15.3% vs 13.2%; stillbirth: 2.0% vs 1.3%; cesarean delivery: 37.5% vs 35.6%; preeclampsia: 9.4% vs 8.5%, respectively; P>.05 for all). Two individuals died within 2 days postpartum, and both were in the SARS-CoV-2–negative group.

T1
Table 1.:
Patient Characteristics (Demographics and Comorbidities) and Outcomes (Pregnancy Complications and Mortality) of Pregnant Patients Who Tested Positive or Negative for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Among patients who tested positive for SARS-CoV-2 infection in the secondary analysis (Table 2), the preterm birth rate during the original wave was higher than during the Omicron wave (20.3% vs 9.9%, P=.015) and the preterm birth rate during the Alpha wave was higher than during the Omicron wave (18.4% vs 9.9%, P=.039). The rate of stillbirth was low (between 1% and 4% during the four waves) and was not significantly different across the different waves (P>.05). Cesarean delivery rates ranged from 34.6% to 38.8% and were not significantly different across different waves (P>.05). Preeclampsia rates ranged from 6.6% to 11.6% and were not significantly different across different waves (P>.05).

T2
Table 2.:
Perinatal Outcomes and Hospitalization and Vaccination Data for Individuals Who Tested Positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Pregnancy by SARS-COV-2 Variant

Among patients who were hospitalized at the time they tested positive for SARS-CoV-2 infection (Table 2), the rate of hospitalization due to COVID-19 was significantly lower during the Omicron wave (3.9%) compared with the Alpha (21%, P<.001) and Delta (45.5%, P<.001) waves. Hospitalization status due to COVID-19 was not significantly associated with primary outcomes (P>.05). The vaccination rate was 47.2% in those with Omicron-variant SARS-CoV-2 infection and 2.6% in those with Delta-variant SARS-CoV-2 infection. There were no significant differences in primary outcomes between vaccinated and unvaccinated patients who tested positive for SARS-CoV-2 infection (P>.05).

Twenty-seven (4.3%) individuals acquired SARS-CoV-2 infection in the first trimester, 82 (13.1%) in the second trimester, and 518 (82.6%) in the third trimester (Table 3). When primary outcomes were analyzed by trimester of SARS-CoV-2 infection, significantly more individuals who acquired infection during the second trimester experienced preterm birth, low birth weight, and stillbirth compared with those who acquired infection in the third trimester (P<.05).

T3
Table 3.:
Perinatal Outcomes Among Individuals Who Tested Positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Trimester of Infection

DISCUSSION

This study investigated perinatal outcomes in individuals with COVID-19 during pregnancy in an academic health system in New York City across multiple waves from March 2020 to February 2022. The major findings are: 1) the infection rate during pregnancy was 7.1% for the study period; 2) there were no statistically significant differences in perinatal outcomes between the SARS-CoV-2–positive and SARS-CoV-2–negative cohorts across the entire pandemic; 3) however, in the SARS-CoV-2–positive cohort, the preterm birth rate significantly decreased across the pandemic and low birth weight, cesarean delivery, and preeclampsia trended lower across the pandemic; 4) there was a marked increase in positive SARS-CoV-2 test results in individuals who gave birth during the Omicron wave, but the incidence of pregnancy complications in those with Omicron-variant SARS-CoV-2 infection was low compared with other waves; 5) among individuals hospitalized at the time of SARS-CoV-2 diagnosis, vaccination rates were low before the Omicron wave and rose to 47.2% during the Omicron wave; and 6) second-trimester infection was associated with worse perinatal outcomes compared with third-trimester infection.

We found no statistically significant differences in rates of preterm birth, low birth weight, stillbirth, cesarean delivery, or preeclampsia between our SARS-CoV-2–positive and SARS-CoV-2–negative cohorts. However, there were comparatively higher rates of each of these outcomes among individuals who tested positive for SARS-CoV-2 infection. Other studies reported that SARS-CoV-2 infection was associated with increased pregnancy complications. Metz et al1 found that, among pregnant and postpartum individuals at 17 U.S. hospitals, SARS-CoV-2 infection was associated with an increased risk for a composite outcome of maternal mortality or serious morbidity from obstetric complications. In a multinational study from March 2, 2020, to February 2, 2021, Papageorghiou et al14 found that COVID-19 during pregnancy was strongly associated with preeclampsia, especially among nulliparous individuals. This association was independent of any risk factors and preexisting conditions. In a multinational cohort study from March to October 2020, Villar et al15 found that COVID-19 in pregnancy was associated with substantial increases in severe maternal morbidity and mortality when pregnant individuals with and without a COVID-19 diagnosis were compared. A meta-analysis by Wei et al5 reports an association between SARS-CoV-2 infection and preterm birth, preeclampsia, and stillbirth and low birth weight. It is possible that we did not observe these differences due to the preponderance of testing, which was more likely to pick up asymptomatic cases. We also include cases spanning the pandemic (from March 2020–February 2022), and, as our secondary analysis shows, there has fortunately been a trend toward improvement over time. In a meta-analysis, Chmielewska et al6 compared perinatal outcomes before and during the pandemic, and reported a significant increase in the rate of stillbirth, maternal death, and poor mental health during the pandemic with worse outcomes in low-income and middle-income countries. These findings suggest that all pregnant individuals may have been affected by the pandemic due to difficulty accessing care, particularly among individuals in disadvantaged minority groups. This may have played a role in why we did not detect a difference if both SARS-CoV-2–positive and SARS-CoV-2–negative pregnant individuals were negatively affected by the pandemic.

Our study found that preterm birth rates were significantly higher in the original and Alpha waves than in the Omicron wave. The decrease in preterm birth rates might be due to differences in SARS-CoV-2 virulence among the variants, clearer guidelines regarding COVID-19 management during pregnancy, improved COVID-19 treatments, availability of vaccines, and greater prevalence of immunity due to prior infection in our study population. Other studies on perinatal outcomes in patients who tested positive for SARS-CoV-2 infection have also found an association between COVID-19 and preterm birth, particularly in individuals with severe COVID-19.3–5 It is possible that the reason we observed a greater effect during the first two waves was because, during this time period, people who had COVID-19 were having more severe illness. At the beginning of the pandemic, little was known about how to manage SARS-CoV-2 infection, there were no known effective therapies, and COVID-19 vaccine was not yet available. A possible mechanism of increased risk of preterm birth could be hyperinflammatory systemic response to SARS-CoV-2 infection, which may make the uterus less hospitable for fetal growth and development. Patberg et al16 found that COVID-19 was associated with placental abnormalities, including fetal vascular malperfusion. Iatrogenic delivery to improve respiratory status in moderate-to-severe COVID-19 illness may also explain the surge in preterm delivery at the beginning of the pandemic, although we did not have data to test this hypothesis. Hospitalization for COVID-19, a surrogate marker for severe illness, was not significantly associated with preterm birth or any other perinatal outcome. This finding should be interpreted with caution because the sample size was small.

We did not observe a spike in preterm births during the Delta wave, whereas a study from Turkey and the United Kingdom17 reports higher preterm birth rates associated with the Delta wave compared with pre-Delta. New York was among the first COVID-19 epicenters, and there may have been more postinfectious immunity that protected individuals in New York from the Delta variant. It is also possible that higher vaccination rates in the community might have reduced cross-infection to pregnant individuals. The differences in outcomes are likely multifactorial and may also include differences in management of pregnancies during the pandemic in different centers, regions, and countries.

The mortality rate was very low in our study in both the SARS-CoV-2–positive and SARS-CoV-2–negative cohorts and was not statistically different. This was expected because our cohort consisted only of individuals who must have delivered.

Vaccination data were reliably documented only for hospitalized patients in our cohort. For those who had vaccination data, almost none of these patients had been vaccinated before the Omicron wave. When compared with data form the New York State Department of Health (nyc.gov data), the vaccination rate among pregnant people in our cohort significantly lagged those among the general population in the Bronx. This is likely due to their exclusion from clinical trials early in the pandemic; thus, pregnant individuals were among the last groups to receive clear guidance on the risks and benefits of vaccination, which may explain the slow uptake in our cohort. It is welcome news that this group (Omicron wave) had a lower preterm birth rate, but the available data could not prove that vaccination was the cause given that the vaccine was not available throughout the pandemic. The improved outcomes across the pandemic could also be associated with general improvement in public health awareness, population-wide vaccination, treatments, and management of SARS-CoV-2 infection. Our study was not powered to separate the cause of improved outcomes.

Most patients in our study tested positive for SARS-CoV-2 infection in the third trimester, likely due to the preponderance of tests at the time of admission for delivery. Note that we could not conclude that the SARS-CoV-2 positivity rate or susceptibility to SARS-CoV-2 infection is higher in any of the trimesters because universal testing across the entire pregnancy (all trimesters) was not performed. Lower rates of the adverse perinatal outcomes observed in the third trimester may be related to universal screening that likely captured those with mild COVID-19 illness and asymptomatic SARS-CoV-2 infection. Second-trimester SARS-CoV-2 infection was significantly associated with worse perinatal outcomes compared with third-trimester infection, which could be because infection then affects a pregnancy for a longer period of time or at a more critical period. Additional studies are needed to understand the effect of timing on perinatal outcomes.

Strengths of this study include that pregnancy complications were tracked by wave across the pandemic, that this study consisted of a large cohort of racially and ethnically diverse individuals, and that outcomes were stratified by trimester of SARS-CoV-2 infection. This study had some limitations. Patients with miscarriages, terminations, and ectopic pregnancies were not analyzed. Hospitalization data during the original SARS-CoV-2 wave were not collected. Given that universal testing was performed during admission for delivery, our study was more likely to detect cases at the end of pregnancy; thus, it was underpowered to detect differences in the effect of timing. Although the Omicron wave returned to baseline by mid-January 2020 in our health system, some outcomes associated with the Omicron wave were not yet known. Given our sample size, retrospective nature of the study, and the evolving treatment options across the pandemic, this study is underpowered to test the effects of different therapies. As with any retrospective study, there could be unintentional confounders and bias. Although our data came from multiple hospitals within our health system, studies from additional health systems and hospitals are needed to improve the generalizability of our findings.

Among individuals who tested positive for SARS-CoV-2 infection, the preterm birth rate significantly decreased across the pandemic and low birth weight, cesarean delivery, and preeclampsia trended lower across the pandemic. Despite a higher infection rate during the Omicron wave, the preterm birth rate was lower compared with during the original wave and during the Alpha wave among those with SARS-CoV-2 infection. Vaccination rates of pregnant individuals were low in our study population. Improved understanding of perinatal outcomes across the pandemic could help to inform COVID-19 management and health policy for pregnant individuals.

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