Keywords
COVID-19 - SARS-CoV-2 - coronavirus - pregnancy - acute respiratory distress syndrome
- maternal death - maternal mortality - mortality rate - case-fatality
Palavras-chave
COVID-19 - SARS-CoV-2 - coronavírus - gestação - síndrome respiratória aguda grave
- morte materna - mortalidade materna - taxa de mortalidade
Introduction
Since the first case of COVID-19 was notified in Brazil on February 26, 2020, the
pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
has spread out at an accelerated pace. According to the Brazilian Ministry of Health,
from the beginning of the pandemic up to December 09, 2021, a total of 21,184,824
people were infected by SARS-CoV-2, and 616,691 died in Brazil.[1]
In the face of a viral pandemic of unpredictable and unknown evolution, the primary
concern among obstetricians was whether pregnancy could be a risk factor for severe
COVID-19 outcomes, as was seen for respiratory disease caused by the influenza virus
in the past decades.[2]
[3] The first Brazilian studies using 2020 data from the Acute Respiratory Distress
Syndrome (ARDS) Surveillance System (SIVEP-GRIPE, in the Portuguese acronym) reported
many maternal deaths. However, they did not define whether pregnant women have a higher
risk of severe outcomes than the general female population. Furthermore, early data
on maternal mortality from COVID-19 were scarce and limited.[4]
[5]
[6]
[7]
In 2020, the peak of the Brazilian pandemic occurred in the 30th epidemiological week, when 319,653 new cases of SARS-CoV-2 infections were reported
in one week. After a short period of slowdown of the pandemic in late 2020, Brazil
experienced a rapid acceleration in 2021, reaching 539,903 new cases in the 12th epidemiological week of 2021.[1] Although official obstetric data from the first and second waves have not been fully
consolidated in Brazil, we have seen an increase in COVID-19 serious outcomes in pregnant
women at our healthcare center, a referral hospital for high-risk pregnancy care that
covers a population of > 6 million people in the Southeast of Brazil (unpublished
data).
In the present study, we aim to compare death rates due to ARDS by COVID-19 in pregnant
or postpartum and nonpregnant women during the first and second waves of the Brazilian
pandemic.
Methods
We conducted an exploratory analysis of death rates due to ARDS by COVID-19 in women
aged between15 and 49 years old with SARS-CoV-2 confirmed by real-time polymerase
chain reaction (RT-PCR) or serological antibodies. We compared pregnant and postpartum
(up to 45 days after delivery) women, namely the obstetric group, with nonpregnant
and nonpostpartum women, who composed the nonobstetric group. We collected data from
the SIVEP-GRIPE[8] from the 8th to the 53rd epidemiological weeks of 2020 (February 26, 2020, to January 2, 2021)[9] and from the 1st to the 26th epidemiological weeks of 2021 (January 3 to June 30, 2021).[10]
Outcomes were defined as crude rates of death or cure among persons included in the
SIVEP-GRIPE Brazilian databank. Women were also categorized according to the presence
or absence of the following comorbidities: chronic respiratory disease, cardiovascular
disease, diabetes, pregestational obesity and/or other conditions (immune deficiency,
hematologic disease, hepatopathy, genetic syndrome, kidney chronic pathology, neurology
disorder).
We also determined a maternal mortality ratio (MMR) for each Brazilian state as a
proportion between the number of deaths due to ARDS by COVID-19 in the obstetric group
in the years of 2020 or 2021 and the number of liveborn infants in the year of 2019,
obtained from the Brazilian Information System on Live Births (SINASC, in the Portuguese
acronym).[11] Only births from women aged between 15 and 49 years old were considered.
The detailed database used in the present study is available at the Mendeley Data
repository.[9]
[10] We evaluated public and unidentified data from a national database that did not
require prior ethical committee approval.
We calculated the mean age between the 2 groups and compared it with the Student t-test
and the odds ratio (OR) with a 95% confidence interval (CI) to compare mortality.
We used the software EPI-Info version 7.2.2.16 (Centers for Disease Control and Prevention,
Atlanta, GA, USA).
Results
We identified 47,768 women with ARDS by COVID-19 in 2020, of which 4,853 were from
the obstetric group and 42,915 were nonobstetric. In the first 6 months of 2021, we
identified a total of 66,689 female patients, of which 5,208 were from the obstetric
group and 61,481 were from the nonobstetric group ([Table 1]).
Table 1
Association between acute respiratory distress syndrome by COVID-19 and final outcomes
in the obstetric and nonobstetric groups, with or without comorbidities
|
Group
|
ARDS/COVID-19 in 2020 (8th to 53rd weeks)
|
ARDS/COVID-19 in 2021 (1st to 26th weeks)
|
Death rate 2020–2021
|
|
Deaths (%)
|
Cure (%)
|
OR (95%CI)
|
n
|
Deaths (%)
|
Cure (%)
|
OR (95% CI)
|
n
|
|
All Women
|
|
Obstetric
|
377 (7.7)
|
4476 (92.2)
|
0.52 (0.47–0.58)
|
4853
|
804 (15.4)
|
4404 (84.6)
|
0.61 (0.56–0.66)
|
5208
|
2.0
|
|
Nonobstetric
|
5946 (13.9)
|
36969 (86.1)
|
|
42915
|
14073 (22.9)
|
47408 (77.1)
|
|
61481
|
1.6
|
|
Women with comorbidity
|
|
Obstetric
|
190 (13.3)
|
1239 (86.7)
|
0.52 (0.44–0.61)
|
1429
|
487 (23.3)
|
1598 (76.6)
|
0.66 (0.59–0.73)
|
2085
|
1.7
|
|
Nonobstetric
|
4376 (22.8)
|
14804 (77.2)
|
|
19180
|
8824 (31.4)
|
19280 (68.6)
|
|
28104
|
1.4
|
|
Women without comorbidity
|
|
Obstetric
|
187 (5.5%)
|
3237 (94.5%)
|
0.81&&(0.69–0.95)
|
3424
|
317 (10.1%)
|
2806 (89.9%)
|
0.60&&(0.53–0.68)
|
3123
|
1.8
|
|
NonoObstetric
|
1570 (6.6)
|
22165 (93.4)
|
|
23735
|
5249 (15.7)
|
28128 (84.3)
|
|
33377
|
2.4
|
Abbreviations: ARDS, acute respiratory distress syndrome; CI, confidence interval;
OR, odds ratio.
In the 10 pandemic months of 2020, we identified 377 (7.7%) deaths of pregnant or
postpartum women (OR: 0.52; 95%CI: 0.47–0.58), whereas, in the first 6 months of 2021,
this number increased to 804 (15.4%; OR: 0.61; 95%CI: 0.56–0.66), as shown in [Table 1]. Overall, we observed an increase in women deaths from 2020 to 2021: from 7.7 to
15.4% (2.0-fold) in the obstetric group, and from 13.9 to 22.9% (1.6-fold) in the
nonobstetric group ([Table 1]).
Considering the concurrent medical conditions, we observed an OR increase from 0.52
(95%CI: 0.44–0.61) in 2020 to 0.66 (95%CI: 0.59–0.66) in 2021, which not happened
with the group of women with no comorbidities. We observed that the increase in deaths
was more pronounced in the obstetric group (1.7-fold; from 13.3 in 2020 to 23.3% in
2021) than in the nonobstetric group (1.4-fold; from 22.8 to 31.4%). However, the
inverse was observed for women without comorbidities, in whom the increase in the
number of deaths was more expressive in the nonobstetric group (2.4-fold; from 6.6%
in 2020 to 15.7% in 2021) compared with the obstetric group (1.8-fold; from 5.5% in
2020 to 10.1% in 2021).
As illustrated in [Figure 1], there was an expressive increase in MMR by COVID-19 in 2021 in almost all Brazilian
states. Nonetheless, this increase was most prominent in the North of Brazil, specifically
in the states of Amazonas and Roraima, the epicenter of the P.1 emergence.
Fig. 1 Maternal mortality ratio (MMR) by acute respiratory distress syndrome (ARDS) by COVID-19
in each Brazilian state for the years of 2020 (February to December) and 2021(January
to June).
Moreover, nonpregnant women enrolled in the present study had a significantly higher
mean age than pregnant and postpartum women (p < 0.0001, t-test; data not shown in tables). This difference was observed both in
the 2020 (32 versus 29 years old) and 2021 study periods (38 versus 29 years old).
Discussion
Main Findings
The main findings of the present study were: 1) maternal death rates more than doubled
in the second pandemic wave in 2021 (n = 804), even considering a shorter period that corresponded to nearly half of the
one analyzed in the first wave in 2020 (n = 377); 2) there was a remarkable increase in maternal mortality ratio by COVID-19
in 2021 in almost all Brazilian states, after the emergence of the P.1 variant; 3)
this increase in mortality was prominent in pregnant or postpartum women with comorbidities;
4) in both periods, deaths were higher in nonpregnant women than in pregnant or postpartum
women.
Results in Context with the Scientific Literature So Far
When interpreting any evidence of the impact of COVID-19 on pregnancy, some considerations
should be made. Studies focusing on the effects of COVID-19 on pregnant women are
often based on symptomatic patients, thus underestimating the rates of unfavorable
outcomes in women without COVID-19. Equally scant is the evidence from studies comparing
pregnant with nonpregnant women with severe forms of COVID-19.[12]
[13]
[14]
Our results are in agreement with data from the literature showing that COVID-19 is
a sufficient factor for serious clinical outcomes in pregnant/postpartum women and
for worse neonatal outcomes.[15] A prospective cross-sectional study conducted at the beginning of the pandemic with
a smaller sample size showed an increase in adverse neonatal outcomes in pregnant
women with COVID-19 compared with pregnant women without COVID-19, especially in pregnant
women with comorbidities.[16] Although the database we used does not provide information on pregnant women without
COVID-19, we show a significant rate of maternal deaths by COVID-19, especially in
patients with some comorbidity.
A meta-analysis conducted by Khalil et al.[17] showed that maternal intensive care admission due COVID-19 was higher in cohorts
with higher comorbidity rates. A small cohort of pregnant patients with initial asymptomatic
COVID-19 showed that the development of severity appears similar to that found for
nonpregnant women.[14] In our study, the mortality rates of nonpregnant women were higher than those of
the obstetric groups in all conditions analyzed. Even so, the increase in maternal
mortality from 2020 to 2021 that we found is an important factor, since pregnant women
constitute a vulnerable group with restricted access to medications and generally
do not participate in clinical research to combat COVID-19, such as vaccine trials.
Comorbidity appeared to be a more significant risk factor for COVID-19 in the nonobstetric
group than in its counterpart. Moreover, nonpregnant women enrolled in the present
study had a significantly higher mean age than pregnant and postpartum women. We observed
this difference in the 2020 (32 versus 29 years old) and 2021 study periods (38 versus
29 years old). It is well-known that aging is associated with worse COVID-19 clinical
outcomes, as was demonstrated by Khalil et al.,[17] who indicated that maternal intensive care admission was higher in cohorts with
maternal age > 35 years. In our study, the average age difference between the obstetric
and nonobstetric groups may be a confounding factor on the influence of comorbidities
in older women from the obstetric group. An extension of the present study, adjusting
the effect of age and comorbidities in the analyzed groups, is currently being outlined
by our research team.
Recently, the world has followed with concern the healthcare system collapsing in
the city of Manaus, the capital of the state of Amazonas, due to the upsurge of the
COVID-19 pandemic. The raised hypothesis of the emergence of a more transmissible
variant was confirmed by Faria et al.,[18] who identified a novel SARS-CoV-2 variant of concern in samples collected in November
and December 2020 in Manaus. The so-called P.1 lineage acquired 17 mutations, including
a trio in the spike protein (K417T, E484K, and N501Y). These researchers also estimated
that the P.1 lineage may be more transmissible and more likely to evade protective
immunity elicited by previous infection with non-P.1 lineages.
Although the SIVEP-GRIPE database does not provide information on the virus variant,
the acceleration of the Brazilian pandemic observed in late 2020 and early 2021 coincides
with the identification of the P.1 lineage. The spread of the newly mutated virus
throughout the Brazilian population, consequently infecting more younger women, probably
reflected in the observed increase in maternal deaths. As illustrated in [Figure 1], there was an expressive increase in MMR by COVID-19 in 2021 in almost all Brazilian
states. Nonetheless, this increase was most prominent in the North of Brazil, specifically
in the states of Amazonas and Roraima, the epicenter of the P.1 emergence. As a comment,
in our hospital, there were no deaths in pregnant women in 2020 and, in 2021, 5 deaths
in until April. These five cases were positive for SARS-CoV-2; RNA sequencing identified
four of them as the P.1 variant and one was identified as a British variant (unpublished
data).
Implications for Clinicians and Public Health Managers
The national pandemic scenario presented herein highlights the need for coordinated
strategies to contain the pandemic and avoid further spreading of other potentially
dangerous variants. Brazil is a continental country, with ethnic, social, cultural
and economic disparities that impact access to the health system in different regions.
The irregular distribution of the number of deaths throughout the Brazilian states
is probably related to different patterns of population exposure and to the deficient
infrastructure available to assist severe cases.
Pregnant women represent a unique and vulnerable group. In this context, our study
provides crucial epidemiological information for the scientific community and public
health managers about the impact of the COVID-19 pandemic on pregnant women. We analyzed
data from an extended period, allowing the evaluation of the Brazilian pandemic evolution
from its onset in 2020 to its worsening in 2021, the latter coinciding with the emergence
of the P.1 variant in Manaus.
Knowledge about the benefits of vaccination in mitigating the pandemic is a consensus
all over the world. In Brazil, 63,276,223 people received all the doses prescribed
by the vaccination protocol until September 7, 2021.[19] Although there is no consolidated information on the efficacy and safety of COVID-19
vaccines in pregnant women, current guidelines recommend their administration even
during pregnancy, as the risks of COVID-19 outweigh the hypothetical risks of the
vaccines.[20] Vaccination against SARS-Cov-2 in Brazil started on January 17, 2021, in the priority
groups defined by the National Immunization Program of the Ministry of Health.[21] In May 2021, pregnant and postpartum women with comorbidities were included in this
priority group, which is consistent with the concerns raised by our results on maternal
mortality.
The present study is based on a comprehensive public database that provides information
on large numbers of women. Epidemiological information about the deaths of pregnant
women is particularly important for the scientific community and public policy managers
to fight this pandemic in Brazil.
The present study shows findings that raise the need for actions to protect the health
of all women during the pandemic, since COVID-19 is an important cause of women deaths
in Brazil, especially in second wave after the emergence of the P.1 variant of SARS-Cov-2.
The increase in maternal deaths in 2021 fosters the debate on the expansion of coverage
and acceleration of the vaccination in pregnant women before more dangerous SARS-CoV-2
variants emerge.
Strengths and Weaknesses of the Study
The present study is based on a comprehensive public database on COVID-19, which allowed
us to include a large sample size comprising pregnant and postpartum women and compared
them with nonpregnant women, all hospitalized with the severe form of COVID-19 confirmed
by laboratory and clinical tests.
Although notification of COVID-19 is mandatory in Brazil, we cannot guarantee that
the databank covers all women hospitalized due to COVID-19. Data entry is done manually
by health professionals throughout the national territory; therefore, there is probably
a significant amount of data gaps.
The present study is a comparative analysis of the number of deaths due to COVID-19
between obstetric and nonobstetric women in the years of 2020 and 2021, in the presence
or absence of comorbidities. The inclusion of a postpartum group could bias the data
analysis, as there is the possibility that some pregnant women with viable fetuses
could have been hospitalized with ARDS and underwent childbirth due to the worsening
of the clinical condition. Eventual deaths are registered as having occurred in the
postpartum period when they resulted from the evolution of the disease since pregnancy.
The public database on which the present study is based did not have the necessary
data for this evaluation.
Conclusion
There was an increase in maternal deaths from COVID-19 in 2021 compared with 2020,
especially in patients with comorbidities. Death rates were even higher in nonpregnant
women, with or without comorbidities.
