key: cord-0956705-tx2qq21t
authors: Litman, Ethan A.; Yin, Ying; Nelson, Stuart J.; Capbarat, Emily; Kerchner, Daniel; Ahmadzia, Homa K.
title: Adverse Perinatal Outcomes in a Large US Birth Cohort During the COVID-19 Pandemic: Adverse Perinatal Outcomes During COVID-19
date: 2022-02-01
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2022.100577
sha: 417c6f3348d203ea3275f7bb32d1b2ce9429cb2f
doc_id: 956705
cord_uid: tx2qq21t

OBJECTIVE: To investigate whether coronavirus disease 2019 (COVID-19) is associated with adverse perinatal outcomes in a large national dataset and to examine rates of adverse outcomes during the pandemic compared to pre-pandemic period. METHODS: This observational cohort study included 683,905 patients, between the ages of 12-50, hospitalized for childbirth and abortion between January 1, 2019 and May 31, 2021. During the pre-pandemic period, 271,444 women were hospitalized for childbirth. During the pandemic, 308,532 women were hospitalized for childbirth and 2,708 had COVID-19. Associations between COVID-19 and in-hospital adverse perinatal outcomes were examined using propensity score-adjusted logistic regression. RESULTS: Compared to women without COVID-19, women with COVID-19 were more likely to experience both early and late preterm birth (aOR 1.38 [95% CI 1.1-1.7], aOR 1.62 [95% CI 1.3-1.7], respectively), preeclampsia (aOR 1.2 [95% CI 1.0-1.4]), disseminated intravascular coagulopathy (DIC) (aOR 1.57 [95% CI 1.1-2.2]), pulmonary edema (aOR 2.7 [95% CI 1.1- 6.3]), and need for mechanical ventilation (aOR 8.1 [95% CI 3.8-17.3]). There was no significant difference in the prevalence of stillbirth among women with (n= 16 / 2,708) and without (n= 174 / 39,562) COVID-19, p=0.257. There were no differences in adverse outcomes among women who delivered during the pandemic versus pre-pandemic period. Combined in-hospital mortality was significantly higher for women with COVID-19 (147 [95% CI 3.0 -292] vs 2.5 [95% CI 0-7.5] deaths per 100,000 women). Women diagnosed with COVID-19 within 30 days prior to hospitalization were more likely to experience early preterm birth, placental abruption, and mechanical ventilation, compared to women diagnosed with COVID-19 > 30 days prior to hospitalization for childbirth (4.0% vs. 2.4% for early preterm birth, aOR 1.7 [95% CI 1.1-2.7]; 2.2% vs. 1.2% for placental abruption, aOR 1.86 [95% CI 1.0 - 3.4]); 0.9% vs. 0.1% for mechanical ventilation, aOR 13.7 [95% CI 1.8-107.2])). CONCLUSION: Women with COVID-19 had a higher prevalence of adverse perinatal outcomes and increased in-hospital mortality, with highest risk occurring when diagnosis was within 30 days of hospitalization, raising the possibility of a high-risk period.

Scientific consensus has yet to be achieved regarding the clinical impact of coronavirus disease 2019 (COVID-19) infection in pregnancy. A recent meta-analysis of a global population demonstrated worsened maternal and fetal outcomes during the COVID-19 pandemic, with large disparities between high and low resource countries. 1 While some studies 2, 3 support this metaanalysis, other studies [4] [5] [6] [7] have demonstrated a mixed effect of the impact of COVID-19 on pregnancy. One of the largest US study showed a significant difference in mortality rates, ICU admission, and preterm birth among women with COVID-19. 3 However, most US studies were smaller in size and were conducted during the first few months of the pandemic, prior to the largest increase in COVID-19 case numbers and fatalities in the US, during fall and winter 2020. 8 We utilized a large cohort to study the effect of COVID-19 on perinatal outcomes occurring during fall and winter 2020. We investigated the relationship between the timing of COVID-19 diagnosis and childbirth to adverse perinatal outcomes. Additionally, we examined the change in adverse perinatal outcomes by comparing the 14-month pandemic period to the 13 months prior to the pandemic.

Women who gave birth between January 1, 2019 and May 31, 2021 were identified by

(ICD-10) codes from Cerner Real-World Database TM , which is extracted from the electronic health records of hospitals with which Cerner TM has a data-use agreement. Childbirth during the pandemic period was defined as occurring between March 1, 2020 to May 31, 2021, while childbirth prior to the pandemic (pre-pandemic period), was defined as occurring between January 1, 2019 to February 28, 2020. Race and ethnicity were self-reported, body mass index was calculated using measured height and weight, COVID-19 status was determined using the COVID-19 polymerase-chain (PCR) test result, and comorbidities and in-hospital outcomes were identified using ICD-10 and billing codes (Appendix 1 The Institutional Review Board approved the study protocol and waived the requirement for patient informed consent. Multivariable logistic regression was used to derive a propensity score of COVID-19 infection based on baseline conditions to estimate the probability of developing COVID-19 as a function of 17 baseline covariates, including age, ethnicity, race, single digit zip code, trimester, asthma, autoimmune disease, chronic hypertension, chronic kidney disease, gestational hypertension, gestational diabetes, major mental illness, morbid obesity, obesity, pregestational diabetes, pulmonary disease, and tobacco use. Associations between COVID-19 and in-hospital outcomes were examined using propensity score-adjusted regression. Subgroup analyses were performed to detect differences in adverse perinatal outcomes by racial category. Analyses were conducted using SciKit-Learn 9 and Statsmodels 10 Python Library, with a two-tailed p-value less than .05 considered significant. Categorical variables such as demographics, pre-existing conditions, and outcomes were compared using the Chi-squared test. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. 11

During the pandemic period, 308, 532 women were hospitalized for childbirth; of those tested, 39,562 had a negative COVID-19 PCR result, 2,708 (6.4%) had COVID-19, and of those who tested positive, 1342 (49.5%) were diagnosed with COVID-19 within 30 days prior to hospitalization for childbirth. Compared to women without COVID-19, women with COVID-19

were younger, more likely to identify as Hispanic, and more likely to have comorbid asthma, pulmonary disease, hypertension, gestational hypertension, diabetes, gestational diabetes, obesity, or morbid obesity ( There was no significant difference in the prevalence of stillbirth between women with and without COVID-19 (0.6% vs. 0.5%; aOR 1.46 [95% CI, 0.8-2.4], Table 2 ). However, the prevalence of stillbirths occurring in women diagnosed with COVID-19 within the previous 30 days was significantly greater compared to women diagnosed with COVID-19 31-60 days, 60-120 days, or greater than 120 days prior to hospitalization (11/16 (68.8%), 0/16 (0 %), 3/16 (18.7%), 2/16(12.5%) respectively, p < 0.001) (Appendix 2). A similar pattern was observed for the prevalence of placental abruption, DIC, premature prelabor rupture of membranes (PPROM), and need for mechanical ventilation (Appendix 2).

During the pre-pandemic period, 271,444 women were hospitalized for childbirth.

Compared to the pre-pandemic period, women hospitalized for childbirth during the pandemic period were more likely to have comorbid gestational diabetes, gestational hypertension, hypertension, obesity, morbid obesity, and major mental illness (Appendix 3). Compared to the pre-pandemic period, there was no significant difference in the number of stillbirths, the prevalence of early or late preterm birth, or in-hospital mortality among women who delivered during the pandemic period (Table 3 ).

In a large cohort of US women hospitalized for childbirth, we found that in-hospital mortality, preterm birth, preeclampsia, placental abruption, and DIC were statistically significantly higher among COVID-19 positive women compared to COVID-19 negative women. Women with COVID-19 who were diagnosed within 30 days of hospitalization had the highest prevalence of in-hospital mortality, stillbirth, placental abruption, PPROM, DIC, early and late preterm birth, and need for mechanical ventilation.

To date, this is the third largest US cohort of pregnancies during the COVID-19 pandemic and the second largest US cohort of COVID-19 positive patients. The utilization of a large childbirth cohort enabled us to detect statistically significant differences in mortality and adverse outcomes, even while absolute rates of death and adverse perinatal outcomes were low overall. [12] [13] [14] We were also able to demonstrate a temporal effect of COVID-19 on adverse perinatal outcomes, suggesting a high-risk period.

Our findings of increased risk of preterm birth, preterm labor, and development of preeclampsia among women found to have COVID-19 who were hospitalized for childbirth have not been consistently reported in previous US studies 1, 5 , which may be due to a longer study period, larger sample size in the current study, and the development of novel variants during the study period. Interestingly, in the largest reported US cohort to date, Chinn et al. 3 demonstrated a greater degree of risk of preterm birth among women diagnosed with COVID-19 and hospitalized for childbirth, than the current study. However, unlike Chinn et al., our study accounted for differences in pre-existing comorbid conditions in the cohort, which may account for the variation.

This study did not demonstrate a difference between the prevalence of adverse perinatal outcomes in the year preceding the pandemic and the first 16 months of the pandemic, which was surprising, given the disruptive nature of the COVID-19 pandemic. Some studies have reported decreased premature birth rates during the pandemic, however smaller sample sizes and shorter study period may have biased results. 15, 16 Compared to the pre-pandemic period, women hospitalized for childbirth during the pandemic period were more likely to have comorbid asthma, gestational diabetes, gestational hypertension, hypertension, obesity, and major mental illness, which may be related to non-infectious, environmental disruptive effects of the pandemic. However, any relationship of these findings to the absence of differences in perinatal adverse outcomes between pre-pandemic and pandemic periods is speculative and not adequately addressed by our study design.

Our study has other limitations that may affect the veracity of our findings. This was an observational study with data abstracted from medical records, which are subject to potential misclassification or information bias. Due to the development of readily accessible COVID-19 testing and routine screening of all hospitalized patients, women who appeared clinically ill may have experienced selection bias towards more frequent testing. Furthermore, this study is unable to provide information about the severity of COVID-19 disease among patients who tested positive. This study is unable to differentiate iatrogenic preterm birth from spontaneous preterm birth, which may be an important driver of preterm birth. Lastly, low case rates and residual confounding may further impact the clinical significance of the results.

Despite these limitations, our study, which focused on a longer peak period of COVID-19 infection, demonstrates that women hospitalized for childbirth with a history of COVID-19 have a higher prevalence of adverse perinatal outcomes and increased in-hospital mortality, consistent with previously reported global results. Future investigation is warranted and should include the delineation of a high-risk period for adverse perinatal outcomes after COVID-19 diagnosis, as enhanced antenatal surveillance may be warranted for women recently diagnosed with COVID-

Women with COVID-19 had a higher incidence of adverse perinatal outcomes, with the highest risk occurring in women diagnosed within 30 days of hospitalization.

A. To investigate whether coronavirus disease 2019 (COVID-19) is associated with adverse perinatal outcomes using a nationally representative dataset of 683,905 pregnancies, including 2,708 COVID positive patients.

B. Compared to women without COVID-19, women with COVID-19 were more likely to experience both early and late preterm birth, preeclampsia, and venous thromboembolism. Combined in-hospital mortality was significantly higher for women with COVID-19. Women diagnosed with COVID-19 within 30 days prior to hospitalization were more likely to experience adverse pregnancy outcomes compared to women diagnosed with COVID-19 > 30 days prior to hospitalization for childbirth.

C. Women with COVID-19 had a higher prevalence of adverse perinatal outcomes and increased in-hospital mortality, with highest risk occurring when diagnosis was within of 30 days of hospitalization, raising the possibility of a high-risk period.

Additional Article Information: Cerner Real World Data TM encounters may include pharmacy, clinical and microbiology laboratory, admission, and billing information from affiliated patient care locations. All admissions, medication orders and dispensing, laboratory orders and specimens are date and time stamped, providing a temporal relationship between treatment patters and clinical information. Cerner Corporation has established Health Insurance Portability and Accountability Act-compliant operating policies to establish de-identification for Cerner Real-World.

The work was not funded Declaration of Competing Interest EAL, YY, SN, EC, DK, HKA have no conflict of interests to disclose Abbreviations: PPROM, preterm prelabor rupture of membranes; DIC, disseminated intravascular coagulopathy; HELLP, hemolysis, elevated liver enzymes, low platelets; ARDS, acute respiratory distress syndrome; VTE, venous thromboembolism; OR, odds ratio. * Trimester-specific information was missing for 10.4% of COVID-19 positive patients. † Adjusted for propensity score, which estimates the probability of developing COVID-19 as a function of 17 baseline covariates, including age, race, ethnicity, single digit zip code, trimester, chronic kidney disease, asthma, pulmonary disease, autoimmune disease, chronic hypertension, gestational, pregestational diabetes, gestational diabetes, major mental illness, morbid obesity, obesity, and tobacco use. The propensity score was defined as the logistic regression of the predicted probability of COVID-19 status. Statically significant outcomes, p< 0.05, in boldface ‡ Birth weight in grams, reported as median, [IQR]. § Myocardial infarction was defined as the composite of myocardial infarction and cardiac arrest. || Length of stay in days, reported as median, [IQR]. 

Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis

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Giving Birth at US Academic Centers During the COVID-19 Pandemic

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Changes in Preterm Birth Phenotypes and Stillbirth at 2 Philadelphia Hospitals During the SARS-CoV-2 Pandemic

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Variation in COVID-19 Hospitalizations and Deaths Across New York City Boroughs

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A marked decrease in preterm deliveries during the coronavirus disease 2019 pandemic

Outcome Pre-Pandemic * (n = 271,444)

Abbreviations: PPROM, preterm prelabor rupture of membranes

* The pre-pandemic period includes hospitalizations between 01/01/2019-02/28/2020; The pandemic period includes hospitalizations between 03/01/2020-05/31/2021. † Birth weight in grams

‡ Myocardial infarction was defined as the composite of myocardial infarction and cardiac arrest. § Length of stay in days