Clinical, epidemiological and laboratory characteristics of cases of Covid-19-related maternal near miss and death at referral units in northeastern Brazil: a cohort study

Abstract Objective: Covid-19 poses a major risk during pregnancy and postpartum, resulting in an increase in maternal mortality worldwide, including in Brazil; however, little research has been conducted into cases of a near miss. This study aimed to describe the frequency of COVID-19-related near miss and deaths during pregnancy or in the postpartum in referral centers in northeastern Brazil, as well as the clinical, epidemiological, and laboratory characteristics of the women who experienced a severe maternal outcome. Methods: A retrospective and prospective cohort study was performed between April 2020 and June 2021 with hospitalized pregnant and postpartum women with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction (RT-PCR). Data from five tertiary hospitals in northeastern Brazil were evaluated. Descriptive statistical analysis was performed using Epi Info, version 7.2.5.0. Results: A total of 463 patients were included. Of these, 64 (14% of the sample) had a severe maternal outcome, with 42 cases of near miss (9%) and 22 maternal deaths (5%). Patients who had a severe maternal outcome were predominantly young (median age 30 years) and 65.6% were black or brown-skinned. The women had between 6 and 16 years of schooling; 45.3% had a stable partner; 81.3% were pregnant at the time of admission to the study; and 76.6% required a Cesarean section. The great majority (82.8%) had severe acute respiratory syndrome (SARS). Other complications included hypertensive syndromes (40.6%), pneumonia (37.5%), urinary tract infections (29.7%), acute renal failure (25.0%) and postpartum hemorrhage (21.9%). Sepsis developed in 18.8% of cases, neurological dysfunction in 15.6%, and hepatic dysfunction and septic shock in 14.1% of cases each. The relative frequency of admission to an intensive care unit was 87.5%, while 67.2% of the patients required assisted mechanical ventilation, and 54.7% required noninvasive ventilation. Antibiotics were prescribed in 93.8% of cases and corticosteroids in 71.9%, while blood transfusion was required in 25.0% of cases and renal replacement therapy in 15.6%. Therapeutic anticoagulants were administered to 12.5% of the patients. Of the patients who had a severe maternal outcome, the frequency of respiratory dysfunction was 93.8%, with 50.0% developing neurological dysfunction and 37.5% cardiovascular dysfunction. Hematological dysfunction was found in 29.7%, renal dysfunction in 18.8%, and uterine dysfunction in 14.1%. Hepatic dysfunction occurred in 7.8% of the sample. The near-miss ratio for Covid-19 was 1.6/1000 live births and the maternal mortality ratio for Covid-19 was 84.8/100,000 live births, with a mortality index of 34.4% in the sample. Conclusion: This study revealed a low Covid-19-related maternal near miss (MNM) ratio of 1.6/1000 live births and a high Covid-19-related maternal mortality ratio (MMR) of 84.81/100,000 live births. The mortality index was also high. Most of the patients were admitted while pregnant, were young, married and black or brown-skinned, and none had completed university education. The majority had SARS and required admission to an intensive care unit and mechanical ventilation. Most were submitted to a Cesarean section.


Introduction
At the end of 2019, the world learned of a new ribonucleic acid (RNA) virus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Although respiratory symptoms were the most common, various other systemic repercussions, as well as deaths, were reported.On 11February 2020, the World Health Organization (WHO) officially named this condition coronavirus-19 disease, Covid-19 [1].The pandemic decreed by the WHO on 11 March 2020 [2] continues to inflict significant damage to public health, particularly during pregnancy and postpartum.For several months now, Brazil has had the third-highest number of infected individuals and the second-highest number of Covid-19-related deaths worldwide [3].
Epidemiological evidence prior to the emergence of SARS-CoV-2 already suggested that pregnant women are at a greater risk of severe disease, complications and death from viral infections during pandemics [4].Changes to the body that affect the cardiorespiratory, circulatory blood and immune systems during pregnancy/postpartum, in addition to the anatomical changes, are important biological determinants of this risk [5-7] since severe systemic infections represent "potentially life-threatening" clinical conditions considered relevant in severe maternal outcomes (SMO) (near miss and death) [8].
There is robust evidence of maternal complications and severe outcomes associated with Covid- 19 [9,10].The Centers for Disease Control and Prevention (CDC) showed that the maternal mortality rate in the United States increased steeply in the first year of the Covid-19 pandemic [11].In Brazil, as of the beginning of the Covid-19 pandemic, the increased number of maternal deaths indicated a difference in maternal mortality between low-and middle-income countries that was later confirmed [12,13].In addition to the adverse consequences of hypertensive syndromes, obesity, and metabolic syndrome, social inequalities acted as another risk factor in Covid-19-related maternal deaths in Brazil, with a two-fold risk of death in black compared to white women [14].Barriers to healthcare access reduced attendance for prenatal care, while, in hospital settings, 41% of women who died had not been admitted to an intensive care unit (ICU), 47% had not received mechanical ventilation and 29.0% received no form of respiratory support [15].
The public policies adopted during the pandemic severely affected pregnant and postpartum women in Brazil.Between March 2020 and the eleventh epidemiological week of 2022, 2011 maternal deaths occurred: 461 in 2020, 1513 in 2021, and 37 in 2022, with a mortality rate of 10.3% in the population of pregnant/puerperal women with SARS [16].Covid-19 is currently the major cause of maternal death, surpassing the classic causes affecting pregnancy and the puerperium [16].Unfortunately, for many women safe motherhood is not guaranteed, and maternal mortality remains a critical public health issue and an important marker of quality in the healthcare system.
This study evaluated data from five referral centers in northeastern Brazil to determine the frequency of Covid-19-associated maternal near miss (MNM) and death in pregnant or postpartum women and to analyze their clinical, epidemiological and laboratory characteristics.

Materials and methods
A retrospective-prospective cohort study was conducted to describe the clinical, epidemiological, and laboratory characteristics of cases of Covid-19-associated MNM and maternal death in northeastern Brazil as part of a larger multicenter study ongoing since 2020 and registered at Clinical Trials under reference NCT04462367.The internal review board of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) approved the study protocol (CAAE 39892020.6.0000.5201).The STROBE guidelines for reporting observational studies were followed.
Using a standardized form, data were collected from patients admitted to five tertiary hospitals in northeastern Brazil: The Women's Healthcare Center at IMIP, Recife, Pernambuco; the Dom Malan Hospital, Petrolina, Pernambuco; the Assis Chateaubriand Maternity Hospital (Federal University of Cear� a), Fortaleza, Cear� a; the Elp� ıdio de Almeida Health Institute, Campina Grande, Para� ıba; and the Frei Damião Maternity Hospital, João Pessoa, Para� ıba.All have COVID-19 wards, high-risk pregnancy wards, and mother and baby units, as well as ICUs for severe cases of Covid-19.
The study was conducted between April 2020 and June 2021 following ethical approval.The prospective phase of the study included all data collected from patients admitted from the ethical approval of the project (11 November 2020) to June 2021.In the retrospective arm, data obtained from April 2020, the initial period of the pandemic, to the ethical approval date were included.Pregnant or postpartum women admitted to the referral center with a diagnosis of Covid-19 confirmed by real-time polymerase chain reaction (RT-PCR) were included.A non-probabilistic, consecutive, convenience sample was obtained according to the order of arrival at the hospitals participating in the multicenter project and following the epidemic trends in the country.Since the study included all the patients hospitalized in the defined period and evaluated rare outcomes (MNM and maternal death), sample size was not calculated.
The study variables included: biological and sociodemographic characteristics (maternal age, ethnicity/skin color, schooling, paid employment, marital status); obstetric characteristics (patient's status at inclusion, number of pregnancies, parity, number of prenatal visits, gestational age at delivery and mode of delivery); comorbidities/complications associated with pregnancy/puerperium (SARS, hypertensive syndromes, pneumonia, urinary tract infection, acute renal failure, puerperal hemorrhage, sepsis, neurological dysfunction, hepatic dysfunction, septic shock, cardiopathies, thromboembolic complications, gestational diabetes, multiple pregnancy, bronchial asthma, myocardial dysfunction, premature labor, placental abruption, diabetic ketoacidosis, clinical diabetes, infection at surgical site, peritonitis, placenta previa and premature rupture of membranes); and treatment provided during hospitalization (antibiotics, ICU admission, prophylactic and therapeutic anticoagulant use, corticosteroids, assisted mechanical ventilation, noninvasive ventilation, antivirals, blood derivatives and renal replacement therapy).

Term definitions [8]
Maternal near miss/MNM: a woman who almost dies but survives a severe complication occurring during pregnancy, childbirth or within 42 days of the delivery, according to WHO criteria.
Maternal death: the death of a woman during pregnancy or within 42 days of termination of pregnancy from pregnancy-related complications, underlying conditions worsened by the pregnancy, or management of these conditions, but not due to accidental or incidental causes.
Severe maternal outcome/SMO: a life-threatening condition (i.e.organ dysfunction); includes all cases of maternal death and MNM.

Statistical analysis
Data were entered into the Redcap platform.Statistical analysis was performed using Epi Info, version 7.2.5.0.The frequencies of SMO, MNM and maternal death were calculated, as well as the MNM ratio, maternal mortality ratio (MMR), SMO ratio, and mortality index [8].
For the descriptive variables (biological, sociodemographic, obstetric, and clinical characteristics, associated comorbidities/complications, and treatment provided), tables of frequency and distribution were constructed, with measures of central tendency and dispersion.For the continuous numerical variables with normal distribution, means and standard deviations were calculated.For non-normal distribution variables, medians and interquartile ranges were obtained.
A total of 25,940 live births were registered, with the Covid-19-related MNM ratio being 1.6/1000 live births and the MMR 84.8/100,000 live births.The mortality index was 34.4% (Table 5).

Discussion
In this sample, most of the women with an SMO were young, black or brown-skinned, pregnant and submitted to a Cesarean section.The majority had SARS and required ICU admission, mechanical ventilation, antibiotics and corticosteroids.Common findings included severe hypoxemia, the need for intubation and ventilation unrelated to anesthesia, severe tachypnea, and prolonged loss of consciousness.
Median age (30 years) was similar to that found in two systematic reviews that analyzed Covid-19-related maternal deaths [17,18], with one reporting a mean age of 29 years and the other an age range of 21-42 years.The Brazilian Obstetrics Observatory showed that SARS-related deaths in northeastern Brazil affected predominantly the 20-34-year age group [16].
Women in this sample had 6-16 years of schooling.Although education has improved in recent decades, no patient in this study had completed university.The North and Northeast regions concentrate the lowest socioeconomic status and rates of schooling.Data for Brazil showed that most patients who died from SARS had only high school education [16], with similar findings for northeastern Brazil.
Overall, 65.6% of the pregnant/puerperal women were black or brown-skinned, with only a small percentage being white.These findings corroborate those of the Brazilian Study Group on Covid-19 and Pregnancy [14,15] considering that almost 56% of Brazilian population are black/brow skinned according to Instituto Brasileiro de Geografia e Estat� ıstica (IBGE) releases in 2022.The fact that Covid-19-related SMOs affected the different ethnic groups disproportionally alerted to a possible association with factors originating in the pre-hospital setting such as restricted access to healthcare services and structural determinants that result in poorer life/work conditions [14].This alarm was raised as early as 2020 in a US publication [19] and later corroborated by a CDC report in February 2022 [20].Nevertheless, controlled studies are required  to confirm the magnitude of these findings and quantify risks.In this study, 81.3% of the women were pregnant at diagnosis.Mean gestational age at delivery was 24-41 weeks.Although the risk of Covid-19-related complications and death increases postpartum [16,21], most SMO cases involve pregnant women [19,21,22].In Brazil, around 33% of SARS-related deaths occurred postpartum, while 58% occurred in women in the second or third trimesters [16].A systematic review of Covid-19-related maternal deaths reported a mean gestational age of 32 weeks [17].In this sample, most deaths occurred during pregnancy.
The high frequency of Cesarean delivery (76.6%) found here is in agreement with current data on this high-risk population group [23,24].Brazil has one of the highest Cesarean rates worldwide, further contributing toward increasing the risk of postoperative morbidity and mortality in Covid-19 patients [13].However, most of the hospitalized patients in this study were in severe or critical condition before termination of pregnancy, with a Cesarean section being indicated as a function of the severity of the patient's condition.Of note, Covid-19 per se is not an indication for a Cesarean section.
Before the Covid-19 pandemic, hypertensive disorders, obstetric hemorrhages and infections were the principal causes of maternal mortality [25][26][27], with severe cases resulting from respiratory problems being less common.In middle-income countries, coagulation/hematological dysfunction was the most common abnormality, followed by cardiovascular dysfunction [28], while in Brazil gestational hypertension was the major cause of maternal death/MNM [29].In the present study, in addition to the clear predomination of SARS (81.8%) in the women who had an SMO, other comorbidities/complications included ARDS, hypertensive syndromes, acute renal failure, and postpartum hemorrhage.
As expected, an association between Covid-19 and hypertensive syndromes was also detected in the cases of SMO recorded here.Due to this study methodology, however, it remains undetermined whether hypertension preceded Covid-19, hence representing a risk factor, or whether it developed as a complication of Covid-19.This important discussion has already been raised in previous studies [30].
In Brazil, the factors most associated with Covid-19related maternal deaths are obesity, cardiovascular abnormalities and diabetes [16].A Mexican cohort study confirmed the risk of death associated with obesity, hypertension and diabetes, but included socioeconomic vulnerability as an additional risk factor [22].A systematic review that included cases of death registered in Brazil identified gestational diabetes and obesity as the most common comorbidities [17], while Knobel et al. added that cancer and rheumatic diseases were also associated with an increased risk of death in pregnant women [21].
Other Brazilian investigators have also confirmed the increased demand for ICU admission and respiratory support due to SARS, with a warning regarding the percentage of patients who died but who had not been admitted to hospital, or an ICU, and had not received mechanical ventilation [15,31].Data accumulated up to the eleventh epidemiological week of 2022 show that 25.7% of pregnant/puerperal women with Covid-19-related SARS were admitted to an ICU, while 42.9% required invasive or non-invasive noninvasive mechanical ventilation [16].Although admission to an ICU is not part of the WHO criteria defining an MNM and the figures from the present study are high compared to Brazil as a whole, these data are important since admission to an ICU was associated with 87.5% of SMOs and 100% of deaths.The fact that this study involved only tertiary referral hospitals, all with an obstetric ICU, may explain this finding.
Antibiotics and corticosteroids were the most commonly used drugs, since the number of cases of infection, particularly respiratory infections, was high.
Likewise, clinical practice guidelines recommend corticosteroids to treat critical Covid-19 patients, including those on mechanical ventilation, as shown in several systematic reviews substantiating the use of dexamethasone, in particular, or methylprednisolone, in hospitalized patients requiring oxygen therapy [32,33].Anticoagulants were administered prophylactically to 68.8% and therapeutically to 12.5% of those who had an SMO, probably in view of current evidence that a high dose may be beneficial in patients with severe non-critical disease, and prejudicial in patients with critical disease [33].
Evaluating MNM is part of a WHO strategy to identify failures in obstetric care within the healthcare system [34].Recognizing negative impacts on pregnant/postpartum women could help establish priorities in promoting maternal health and reducing mortality, since almost two-thirds of maternal deaths are avoidable [11].The criteria used here to define an MNM were those standardized by the WHO [8], taking seven types of organ dysfunction and their clinical, laboratory and/or management approaches into consideration.
The predominant cause of an SMO was respiratory dysfunction, affecting 93.8% of the sample.Other complications included severe hypoxemia, a need for intubation and ventilation unrelated to anesthesia, and severe tachypnea.Half the women developed neurological  dysfunction, particularly prolonged loss of consciousness, which occurred in 67.2% of the sample.Covid-19 clearly aggravated the health status of pregnant/postpartum patients.Indeed, SARS affected 82.8% of cases, resulting in an increased need for mechanical ventilation.A 2020 Brazilian report on 124 maternal deaths revealed similar findings, which were later corroborated by the same group and the Obstetric Observatory [15,16].
More than one-third of patients presented with cardiovascular dysfunction, developing some form of shock, severe acidosis and/or required vasoactive drugs.Treatment approaches included blood transfusion and dialysis.Postpartum hysterectomy was required in 15-23% of cases.An increased risk of Covid-19-associated postpartum hemorrhage has already been reported [35].
This study revealed a discrepancy, with a low Covid-19-related MNM ratio of 1.6/1000 live births and a high Covid-19-related MMR of 84.81/100,000 live births.A possible explanation is that these patients had been referred to tertiary units providing care in severe cases of Covid-19; therefore, the likelihood of death was greater.In fact, maternal death is always a tragedy that must be avoided, and certainly, a good part of the deaths would have been avoided by preventive, social, and basic assistance measures, as demonstrated in other Brazilian studies [13,15].
Data from 2017, prior to the pandemic, showed a global MMR of 210/100,000 live births [36].In Brazil, this ratio was 60/100,000 live births, fulfilling goal 3.1 of the United Nations' Sustainable Development Goals to reduce the global MMR to <70/100,000 live births by 2030.With the pandemic and the increase in the number of maternal deaths worldwide, the MMR in Brazil in the first quarter of 2021 was 73.1/100,000, reaching the mark of 110 at the end of the year [16].A recent Brazilian cohort that analyzed data from de the general obstetric population obtained through the Information System for the Epidemiological Surveillance of Influenza (Sistema de Informac¸ão da Vigilância Epidemiol� ogica da Gripe, SIVEP-Gripe) showed a maternal mortality ratio varying between 30 and 60/100,000 among the states in northeastern Brazil, where our study was conducted [37].
The mortality index found here was 34.8%, with 22 deaths within patients admitted to tertiary hospitals.In mid-2021, data from Brazil showed a mortality rate of 13.3% for cases of Covid-19-related SARS in the pregnant/postpartum population [16], making mortality in the present sample higher than that for Brazil as a whole.Within the scope of measures to face the public health emergency arising from COVID-19, many professionals with different levels of medical training were called around the world to work in critical areas, including ICU [38].This fact could have had an impact on the outcomes of the disease.In June 2020, a publication from Brazil showed a clear increase in maternal deaths, with the number of deaths being around 3.4 times higher than the total number of Covid-19-related maternal deaths in the entire rest of the world [13].US data published by the CDC in February 2022 also confirmed the increase in the maternal mortality rate in the United States in 2020 compared to 2019 [39].Currently, up to November 2022, 2049 maternal deaths have occurred in Brazil: 462 in 2020, 1524 in 2021, and 63 up to the 46 th epidemiological week of 2022, with a fatality rate of 1.7% [16].

Study limitations
This study was not controlled; therefore, the factors associated with the risk of an MNM or maternal death cannot be established.Since data collection was partially retrospective, some information is missing, including data on weight, body mass index and family income.Another limitation refers to the impossibility of obtaining data on 5 of the 25 variables comprising the WHO criteria for MNM.
Although providing a broad overall view, regional variations in the availability of health resources and difficulties regarding the healthcare teams' compliance with the MNM criteria at the hospitals could have compromised the comparability of data.This limitation has already been discussed, particularly in sub-Saharan Africa, India, and Brazil [29,34,40].In Brazil, the WHO criteria were validated in a multicenter cross-sectional study involving 27 referral maternity hospitals, with the objective of contributing toward evaluating and improving healthcare [41].
Notwithstanding, the substantial number of SMOs evaluated here constituted a study strongpoint.The present results describe the profile of the women who became more severely ill from the disease, requiring a greater complexity of hospital care, more clinical diagnoses, laboratory tests, and therapeutic procedures.The continued analysis of data from the multicenter project will enable future comparison of patients who develop an SMO with those who do not and better analyze the possible detrimental confounders such as black/brow skinned women, low education, low social status, and lower access to healthcare services, that could have overestimated the incidence of SMO.In addition to permitting risk factors to be evaluated, vulnerabilities in the provision of women's healthcare will be identified, contributing toward reducing the alarming numbers of maternal deaths.
Until this date, there are no similar studies conducted in the Northeastern or at the national level with this approach of considering both maternal mortality and near-miss maternal mortality.Using the terms "near miss maternal mortality" OR "near miss" AND "pregnancy" and "COVID-19" we didn't find any published article in PubMed, Scopus, and Lilacs/Scielo.

Figure 1 .
Figure 1.Flowchart of the admission and follow-up of participants in the study.

Table 1 .
Characteristics of the women who had a severe maternal outcome (near miss or death) due to Covid-19 while pregnant or in the postpartum in healthcare institutes in northeastern Brazil.

Table 2 .
Comorbidities/complications in the women who had a severe maternal outcome (near miss or death) from Covid-19 while pregnant or in the postpartum in healthcare institutes in northeastern Brazil.

Table 3 .
Treatment was provided to the women who had a severe maternal outcome (near miss or death) from Covid-19 while pregnant or in the postpartum in healthcare institutes in northeastern Brazil.
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Table 4 .
Frequency of severe maternal outcomes (SMO) as defined by the World Health Organization and the Latin American Center for perinatology (CLAP) in cases of Covid-19-related near miss or death during pregnancy/postpartum in healthcare institutes in northeastern Brazil.

Table 5 .
Indicators of near miss and maternal death in the women who had a Covid-19-related severe maternal outcome during pregnancy/postpartum in healthcare institutes in northeastern Brazil.