key: cord-0696494-t0mglhqp
authors: Knobel, Roxana; Takemoto, Maíra L. S.; Nakamura‐Pereira, Marcos; Menezes, Mariane O.; Borges, Vicente K.; Katz, Leila; Amorim, Melania M. R.; Andreucci, Carla B.
title: COVID‐19‐related deaths among women of reproductive age in Brazil: The burden of postpartum
date: 2021-07-18
journal: Int J Gynaecol Obstet
DOI: 10.1002/ijgo.13811
sha: 4c66dea2d5361425d51b556746f0c0d8aac5d625
doc_id: 696494
cord_uid: t0mglhqp

OBJECTIVE: To compare risk of death due to COVID‐19 among pregnant, postpartum, and non‐pregnant women of reproductive age in Brazil, using the severe acute respiratory syndrome surveillance system (SARS‐SS). METHODS: A secondary analysis was performed of the Brazilian official SARS‐SS, with data retrieved up to August 17, 2020. Cases were stratified by pregnancy status, risk factors or co‐morbidities, and outcome (death or recovery). Multiple logistic regression was employed to examine associations between independent variables and risk of death. RESULTS: A total of 24 805 cases were included, with 3129 deaths (12.6%), including 271 maternal deaths. Postpartum was associated with increased risk of death, admission to the intensive care unit (ICU), and mechanical ventilation. Co‐morbidities with higher impact on case fatality rate among non‐obstetric cases were cancer and neurological and kidney diseases. Among pregnant women, cancer, diabetes mellitus, obesity, and rheumatology diseases were associated with risk of death. In the postpartum subgroup, age over 35 years and diabetes mellitus were independently associated with higher chance of death. CONCLUSION: Postpartum was associated with worse outcomes among the obstetric population, despite lower risk of dying without accessing ICU care. Non‐pregnant women with cancer, neurological diseases, and kidney diseases have a higher risk of death due to COVID‐19.

Recently gathered evidence suggested that obesity, diabetes, and cardiovascular diseases might increase the risk of death among pregnant and postpartum women, as previously described for the general population. 3, 4 However, further chronic conditions that might pose additional risk for the obstetric population remain to be studied. The same can be said about women of reproductive age, who are usually younger and having fewer co-morbidities when compared to most samples of patients with COVID-19 studied so far. Studies focusing on repercussions of COVID-19 upon women of reproductive age comparing disease evolution throughout different phases of women's lives have shown that pregnancy and/or postpartum status are associated with worse outcomes of COVID-19. 5, 6 Brazil faces the second worst pandemic scenario globally, with more than 190 000 deaths as of late December 2020. 7 Reasons for worse outcomes of coronavirus infection in the country include erratic containment measures, lack of timely guidelines for COVID -19 care, barriers to health access, inequalities among vulnerable populations, and the pandemic burden upon the already overloaded and underfinanced Brazilian public health system. 8, 9 The aims of the present study were to analyze whether the gestational period alone encloses higher risk of death due to COVID-19 on women of reproductive age, and to compare the findings among pregnant, postpartum, and non-pregnant women in Brazil, using data from the severe acute respiratory syndrome (SARS) surveillance system (SARS-SS).

The present study was based on publicly available data from the Brazilian official SARS-SS (SIVEP-Gripe in Portuguese). SARS is a nationally notifiable disease mandatorily reported to the Ministry of Health in Brazil by public and private hospitals. 10 Cases of SARS-SS are defined by flu-like symptoms and at least one of the following severity criteria: dyspnea; respiratory distress; or oxygen saturation below 95%. Information on the methods were also described elsewhere. 3 Over 95% of cases of SARS-SS COVID-19 were diagnosed based on laboratory tests, predominantly the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test.

All female cases within the age group of 10-45 years were included. The final sample was classified by pregnancy status as nonobstetric women, pregnant women, and postpartum women (up to 42 days after childbirth). Unfortunately, the exact time from childbirth until SARS diagnosis was not available. Cases of pregnant and postpartum women were identified using a two-step process. First, the two close-ended fields available in the database were selected: "Pregnancy Trimester" (answer options "first," "second," "third," "unknown gestational age," or "not applicable"); and "Postpartum" (answer options "yes" or "no"). Missing information for those variables were coded as non-pregnant women of reproductive age in the first step. Second, additional hand-searches in the "other co-morbidities" open-ended field were performed, looking for mentions of pregnancy, postpartum, abortion, and childbirth/delivery. Risk factors for death associated with COVID-19 during pregnancy and postpartum were previously reported by the study group. 11 In the present study, non-pregnant women of reproductive age were also included, as well as a thorough analysis of all close-ended co-morbidities and risk factors variables available in the database, including the open-ended "other co-morbidities" variable. A semi-automatic algorithm to classify descriptive data about co-morbidities (reported by the provider at SARS notification) was adopted, using a specifically programmed software, applying the Python language. The software singled-out all unique "other co-morbidities" open-ended field entries and made it possible to classify them into a set of created close-ended categories, subsequently assigning the close-ended category linked to the "other comorbidities" of all individuals in the dataset.

The co-morbidity categories were created by the authors.

Obvious predefined reclassifications were solved by the semiautomatic algorithm, and the remaining cases were manually and independently reviewed by two authors. The open-ended "Other co-morbidities" field comprised over 5300 different terms due to diverse description of the same condition ("asthma," "severe asthma,"

"asthmatic bronchitis"), as well as typos. The initial 40 categories were then regrouped, using clinical criteria defined by the authors, resulting in 14 main co-morbidity categories: cancer; cardiovascular diseases; diabetes mellitus; gastrointestinal diseases; hematological diseases; immunosuppression or HIV/AIDS; kidney diseases; liver diseases; neurological diseases or stroke; obesity; respiratory diseases (including asthma); rheumatological diseases; thrombotic events or vascular diseases; and thyroid diseases. Co-morbidity data derived from these procedures were grouped with data from the original SARS-SS close-ended co-morbidity fields to provide a single set of co-morbidities or risk factor data.

Independent variables were included in the risk of death analysis: age; ethnicity; and pregnancy status (non-obstetric, pregnant, or postpartum women). Age was dichotomized as under 20 years, 20-34 years, and 35 years and above. A descriptive secondary analysis of adverse outcomes by pregnancy status was performed, with individual outcomes as follows: admission to the intensive care unit (ICU); mechanical ventilation; and death without intensive care (defined as a death event without a record of being admitted to the ICU or having received mechanical ventilation). Missing data on comorbidities and use of intensive care resources (admission to the ICU and mechanical ventilation) were treated as absence of the condition. Missingness on SARS-SS was previously described. 11, 12 All eligible records documented in the SARS-SS until August 17, 2020, with an outcome (death or recovery) were included in the analysis. Univariate association between independent variables and death was assessed using hypothesis tests, and P values were calculated. Stepwise multiple logistic regression was employed to examine the association between independent variables and risk of death, providing adjusted odds ratio (OR) and corresponding 95% confidence interval. Statistical significance was defined at the 0.05 level, and P values were two-tailed. Analyses were conducted using STATA 12. STROBE reporting guidelines for observational studies were | 103 KNOBEL Et aL.

followed. In accordance with Brazilian regulatory requirements, a secondary analysis of publicly available anonymized data does not require approval from an institutional ethics review board. Table 1 shows sample characteristics by pregnancy status (n = 24 805 cases). There were 3129 fatality cases (case fatality rate of 12.6%),

including 271 maternal deaths. The three subgroups were significantly different in most characteristics, with the exception of diabetes mellitus and three co-morbidity groups with markedly reduced sample sizes (gastrointestinal diseases, hematological diseases, and thrombotic events or vascular diseases). Absence of any comorbidity or risk factor was found in 74.3% of all pregnant women, in 69.8% of all postpartum cases, and in 63.4% of non-obstetric cases. Cardiovascular disease was the most prevalent co-morbidity among all groups (range 9.5%-15.1%), followed by obesity (range 7.9%-8.9%).

All independent variables were significantly associated with risk of death, except for two (gastrointestinal diseases and thrombotic events or vascular diseases) ( Table 2 ). Figure 1 illustrates adverse outcomes of COVID-19 among the three subgroups. Postpartum was associated with increased risk of death, admission to the ICU, and mechanical ventilation, but not with dying without ICU care. The risk of dying without access to the ICU or mechanical ventilation was significantly higher among non-obstetric cases. Figure with any risk factor, followed by non-obstetric cases with any risk factor ( Figure 2 ).

Multiple logistic regression models ( 

In the present sample, the postpartum period was associated with worse outcomes in the obstetric population. When stratified by therapeutic measure. Accordingly, this may also contribute to the more frequent occurrence of death in the postpartum period.

Obstetric patients with SARS often need to be transferred to tertiary health units located away from their place of residence, contributing to worse outcomes. 9 Usually, Brazilian facilities dedicated to COVID-19 are not equipped with midwifery or obstetrics infrastructure; therefore, delivery may be anticipated before the In the present sample, diabetes was a risk factor for death.

Diabetes can increase respiratory infections due to altered innate immunity and elevate levels of pro-inflammatory cytokine. A metaanalysis of 6452 patients found that SARS-CoV-2 infection in patients with diabetes increased mortality and SARS by two and four times, respectively. 25 However, body mass index was the only risk factor for death or tracheal intubation in an observational study with diabetic patients infected with Obesity is an already known risk factor for death due to COVID-19

for both pregnant and non-obstetric patients, though not for postpartum women. [27] [28] [29] A meta-analysis exploring the relationship between COVID-19 and obesity showed that obese individuals had a 74% higher risk of admission to the ICU, and a 48% increased risk of death. 27 Obesity seems to be an independent risk factor, despite its association with several co-morbidities (diabetes, hypertension, cardiovascular disease). 29 Obesity is a metabolic disease marked by insulin resistance, hyperglycemia, altered adipokines, and chronic inflammation, 27 and the production of abnormal cytokines is also observed in SARS. The disease increases the risk of thrombosis, and severe COVID-19 is associated with prothrombotic disseminated intravascular coagulation and high rates of venous thromboembolism. 30 Two meta-analyses showed that the prevalence of thromboembolic events in hospitalized patients with SARS-CoV-2 surpasses 30%. 31, 32 In the present sample, rheumatological diseases increased the risk of death by seven times in pregnancy, and by three times in the general female population with COVID-19. This group of conditions includes a diverse spectrum of diseases, and SARS-SS does not provide detailed information. However, connective tissue disorders are associated with worse prognoses for SARS-CoV-2 infection. Despite these limitations, the present study was able to provide useful information about the interaction between pregnancy status and co-morbidities as risk factors for death due to COVID-19, using a large dataset with nationwide coverage. The present data adds to the still preliminary knowledge about risk factors for COVID-19related maternal deaths, given the fact that Brazil has overwhelming figures of cases of COVID-19 and deaths, both in the general population and in pregnant and postpartum women.

The findings of the present study highlight the relevance of the postpartum period as a risk factor for COVID-19 adverse outcomes, particularly when in association with co-morbidities. Further prospective studies might clarify the identified risk factors associated with a worsening prognosis of COVID-19 among women.

Postpartum women must be considered a special population within these studies.

The authors thank all members of the Brazilian Group for Studies of COVID-19 and Pregnancy for all their efforts in supporting this work and in improving maternal health.

The authors have no conflicts of interest.

All authors contributed equally for study conception and study de- 

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Clinical characteristics and risk factors for mortality in obstetric patients with severe COVID-19 in Brazil: a surveillance database analysis

Excess maternal deaths associated with Coronavirus Disease 2019 (COVID-19) in Mexico

Pregnant women with severe or critical coronavirus disease 2019 have increased composite morbidity compared with nonpregnant matched controls

Update: characteristics of symptomatic women of reproductive age with laboratoryconfirmed SARS-CoV-2 infection by pregnancy status -United States

Coronavirus Cases

Editorial COVID-19 in Brazil

Risk factors for adverse outcomes among pregnant and postpartum women with acute respiratory distress syndrome due to COVID-19 in Brazil

Secretaria de Vigilância em Saúde. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Influenza

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Delays in receiving obstetric care and poor maternal outcomes: results from a national multicentre cross-sectional study

COVID-19) infection in pregnancy

SARS-CoV-2 in Pregnancy: A Comprehensive Summary of Current Guidelines

Protocolo de Manejo Clínico da Covid-19 na Atenção Especializada

Hazardous postoperative outcomes of unexpected COVID-19 infected patients: a call for global consideration of sampling all asymptomatic patients before surgical treatment

COVID-19 outbreak and surgical practice: unexpected fatality in perioperative period

Association of comorbidities with pneumonia and death among COVID-19 patients in Mexico: a Nationwide Cross-sectional Study

Chemotherapy and COVID-19 Outcomes in Patients with Cancer

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -a systematic review, meta-analysis, and meta-regression

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study

Individuals with obesity and COVID-19: a global perspective on the epidemiology and biological relationships

Factors associated with COVID-19-related death using OpenSAFELY

Obesity and COVID-19 in Latin America: a tragedy of two pandemics-Official document of the Latin American Federation of Obesity Societies

Obesity is a risk factor for severe COVID-19 infection: multiple potential mechanisms

Prevalence and risk factors of thromboembolism among patients with Coronavirus Disease-19: a systematic review and meta-analysis

COVID-19 and venous thromboembolism: a meta-analysis of literature studies

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry

Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study

Inflammation and thrombosis in patients with COVID-19: a prothrombotic and inflammatory disease caused by SARS coronavirus-2

Coronavirus disease 2019 (COVID-19) in autoimmune and inflammatory conditions: clinical characteristics of poor outcomes

Assessment of clinical criteria for sepsis for the third international consensus definitions for sepsis and septic shock (sepsis-3)

SARS-CoV-2 infection and COVID-19 during pregnancy: a multidisciplinary review

Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis

Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: a comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients

How to cite this article

COVID-19-related deaths among women of reproductive age in Brazil: The burden of postpartum