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https://orcid.org/0000-0003-1722-3553
Abstract
Abstract
Objective
This is the first comprehensive review to focus on currently available evidence regarding maternal, fetal and neonatal mortality cases associated with Coronavirus Disease 2019 (COVID-19) infection, up to July 2020.
Methods
We systematically searched PubMed, Scopus, Google Scholar and Web of Science databases to identify any reported cases of maternal, fetal or neonatal mortality associated with COVID-19 infection. The references of relevant studies were also hand-searched.
Results
Of 2815 studies screened, 10 studies reporting 37 maternal and 12 perinatal mortality cases (7 fetal demise and 5 neonatal death) were finally eligible for inclusion to this review. All maternal deaths were seen in women with previous co-morbidities, of which the most common were obesity, diabetes, asthma and advanced maternal age. Acute respiratory distress syndrome (ARDS) and severity of pneumonia were considered as the leading causes of all maternal mortalities, except for one case who died of thromboembolism during postpartum period. Fetal and neonatal mortalities were suggested to be a result of the severity of maternal infection or the prematurity, respectively. Interestingly, there was no evidence of vertical transmission or positive COVID-19 test result among expired neonates.
Conclusion
Current available evidence suggested that maternal mortality mostly happened among women with previous co-morbidities and neonatal mortality seems to be a result of prematurity rather than infection. However, further reports are needed so that the magnitude of the maternal and perinatal mortality could be determined more precisely.
1. Introduction
Up to August 2020, it has been estimated that more than 20 million people are infected by coronavirus disease 2019 (COVID-19) worldwide [1]. This pandemic is caused by a pathogen recognized as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has become an urgent global health crisis.
Previous reports on hospitalized patients diagnosed with COVID-19 revealed that up to 32% of severe cases have been admitted to intensive care units and 17–29% of them showed symptoms of acute respiratory distress syndrome (ARDS). Moreover, the mortality rate has been subjected to range from 4 to 15% among general population [2,3]. However, data on impact of COVID-19 on pregnant women and their pregnancy outcome are lacking and there are only some non-conclusive reports with conflicting findings [4]. In a previous review evaluating impact of COVID‐19 on pregnancy outcome, it has been suggested that COVID-19 during pregnancy possibly has a clinical presentation and severity comparable with non-pregnant population and is not associated with poor maternal or neonatal outcomes [5]. However, only one maternal and three neonatal mortality cases have been reported in the latter review and to our knowledge, there is no comprehensive review gathering data on morality cases of COVID-19 among pregnant population.
Maternal mortality statistics and risk factors associated with maternal and neonatal mortality from COVID-19 infection will be reported in the recent future [6]; however, until then, healthcare providers specially obstetricians are faced with a challenging dilemma, are pregnant women and their newborns are at a higher risk of mortality due to COVID-19 infection?
To date, no previous review study has summarized the maternal-fetal and neonatal mortality cases related to COVID-19 infection. Thus, this systematic review aimed to present an overview of mortalities and their related-characteristics among maternal and neonatal population.
2. Methods
2.1. Search strategy
A systematic electronic search was performed up to 20 July 2020 from PubMed, Scopus, Web of Science, and Google scholar databases to retrieve the related studies that have assessed the maternal or perinatal outcome of pregnancies complicated with COVID-19. A combination of the MeSH terms and keywords were applied to perform a comprehensive literature search: (“COVID-19” OR “COVID” OR “coronavirus” OR “sars cov-2” OR “sars cov 2” OR “sars-cov 2” OR “sars-cov-2” OR “2019-nCoV infection” OR “coronavirus disease 2019” OR “COVID-19 pandemic” OR “2019nCoV disease” OR “2019 novel coronavirus disease” OR “COVID19” OR “2019 novel coronavirus infection” OR “coronavirus disease-19” OR “severe acute respiratory syndrome coronavirus 2”) AND (“pregnancy” OR “maternal” OR “gestation” OR “pregnant” OR “maternal mortality” OR “maternal death” OR “prenatal” OR “perinatal” OR “neonatal” OR “perinatal death” OR “perinatal mortality” OR “neonatal mortality” OR “neonatal death” OR “antenatal”). Meanwhile, a manual search was conducted by checking the reference lists of relevant.
2.2. Inclusion and exclusion criteria
Study was included that met the following inclusion criteria: study design was case-report, case-series or observational study (either cohort, case-control, or cross-sectional design), patients were pregnant women with laboratory confirmed COVID-19 infection, those studies reporting the maternal mortality (defined as death while pregnant or within 42 d of postpartum), fetal deaths in pregnancies >20 weeks of gestation and neonatal mortality (defined as death within 28 d of birth) would be reported in this review. We excluded studies that conducted with other designs such as animal study, in vivo, in vitro and did not the published-full paper. Unpublished papers, studies with suspicion of duplicate reporting, and unreported maternal or perinatal outcomes were also excluded.
2.3. Data extraction
The extracted data included: study characteristics of selected articles (i.e. authors, year, countries), number of mortality events, maternal, gestational or neonatal age, complications leading to maternal mortality, previous co-morbidities and outcome of pregnancy. Due to rapid publication of research papers during COVID-19 pandemic, some of the primary sources might overlap (known as duplicate data). Thus, we have traced the cases through careful data collection and contacting the authors to eliminate the possibility of double counting.
3. Results
3.1. Search results and study characteristics
A total of 2815 articles were primarily identified from the databases search. After an in-depth screening of records, 10 articles were found to be eligible for inclusion in this review. The details of step by step study identification and selection are demonstrated in Figure 1. The most of included studies were designed as case-reports or brief communication [7–13] and only two studies were conducted as case-series [6,14]. Of these, four studies were carried out in China [8–10,14], two in Iran [6], and one in United Kingdom [7], one in United States [12] one in Mexico [11], and one in Brazil [15]. Included studies involved data on a total of 49 mortality cases of whom 37 were maternal cases and 12 were among fetal or neonatal population, respectively.
Published online:
16 August 2020![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ijmf20/0/ijmf20.ahead-of-print/14767058.2020.1806817/20200816/images/medium/ijmf_a_1806817_f0001_c.jpg"})
Figure 1. PRISMA flowchart of study selection.
3.2. Maternal mortality and related demographic and clinical characteristics
As shown in Table 1, maternal age of the reported mortalities due to COVID-19 ranged from 22 to 49 years and all of the cases had laboratory confirmed COVID-19 infection. Twenty-four women died during postpartum period, and 6 cases died during pregnancy and for the other 7 cases it was not precisely determined when mortality happened. The two pregnant women who had died during pregnancy both were at 24 weeks of gestation, one had singleton and the other one had twin pregnancy. The fetuses of both women died while in utero and were not delivered after maternal death.
Table 1. Characteristics of included studies reporting maternal mortalities associated with SARS-CoV-2 positive pregnancies.
Regarding the perinatal outcome of the maternal deaths, four of them had intrauterine fetal demise (one twin), two had neonatal deaths and other cases’ newborns have survived with no serious complication. Only one of the newborns had positive RT-PCR for COVID-19.
All of the maternal deaths happened to women with some types of previous co-morbidities including obesity [6,7,11,15], diabetes [6,7,11], asthma [7,15], hypothyroidism [6,13], advanced maternal age [6,12]. COVID-19 pneumonia and associated ARDS have been proposed as leading cause of maternal mortality in all cases, except for one COVID-19 positive mother reported by Ahmed et al., that developed basilar artery thrombosis due to hypercoagulative state during postpartum period [7].
3.3. Fetal-neonatal mortality and related demographic and clinical characteristics
As shown in Table 2, among the 12 perinatal deaths related to pregnancies diagnosed with COVID-19, seven cases were intrauterine fetal demise and 5 were neonatal deaths. Gestational age at fetal demise ranged from 24 to 35 weeks. The leading cause of fetal demise was attributed to the severity of maternal COVID-19 infection in 6 cases. In these cases IUFD happened during maternal hospitalization when ARDS [6,8], septic shock [6,8] or multiple organ dysfunction syndrome [8,10] were diagnosed in mothers. In one IUFD case (fetal demise at 36 weeks) preterm premature rupture of membranes and decreased fetal movement were followed by fetal demise despite maternal survival [6].
Table 2. Characteristics of included studies reporting perinatal (fetal-neonatal) mortalities associated with SARS-CoV-2 positive pregnancies.
Among 5 neonatal deaths, three cases of mortality were related to prematurity [6,8], severe neonatal asphyxia [8] and low birthweight [8]. One neonatal death at 9-day old was associated with disseminated intravascular coagulopathy and multiple organ dysfunction with no potential correlation with COVID-19 infection [14]. Another neonate born at 35 weeks of gestation died 2 h after birth which was attributed to rapid deterioration in maternal condition, which eventually led to the death of the neonate [9]. In the latter neonate, laboratory analysis of umbilical cord blood at birth showed a substantial increase in myocardial enzymes, suggesting that the fetal myocardium was significantly damaged due to hypoxemia. However, no positive COVID-19 test result was reported among expired neonates.
4. Discussion
The present systematic review provided comprehensive data on maternal and perinatal mortalities among pregnancies complicated by COVID-19 infection. This review summarizes the main findings of 10 studies addressing COVID-19 related maternal or perinatal mortalities. In summary, there were 37 maternal deaths published in literature, which only 6 of them happened during pregnancy and the others were during postpartum period. All maternal deaths were attributed to COVID-19 pneumonia and the resulting ARDS, except for one patient complicated with pulmonary thromboembolism and basilar artery thrombosis. Among fetal-neonatal outcome of pregnancies diagnosed with SARS-CoV-2, there were 7 IUFD and 5 neonatal deaths, which were suggested to be a result of prematurity rather than vertical transmission of infection. None of expired neonates were reported to have a positive COVID-19 test result.
The current COVID-19 pandemic is the third time that a zoonotic coronavirus has infected human beings during the past two decades [16]. In year 2002, during SARS-CoV-1 outbreak, the mortality rate of general population had been estimated to be around 10.5%, while this rate was up to 25% among pregnant population [17]. However, data on SARS-CoV-2 positive pregnancies and related morbidity and mortality are lacking. A recent meta-analysis evaluating COVID-19 impact on maternal-fetal outcome revealed that there is no documented evidence of vertical transmission at least during the late pregnancy. Furthermore, there seems to be no significant adverse outcome for fetuses or neonates [18]. Another review article assessing clinical presentation and outcomes of 385 pregnant women with COVID-19 infection, reported that most of the women (95.6%) were asymptomatic or had mild features of the disease and 0.8% of them had critical condition and only one maternal mortality has been reported in their review [5].
Pregnant women are generally thought to be more susceptible to severe forms of viral infection, mainly through the shift from cellular to humoral immunity during gestation [19]. However, data on maternal susceptibility to SARS-CoV-2 are contradictory and some authors even suggest less morbidity and mortality among pregnant women due to COVID-19 infection as compared with general population. The previous research showed that human chorionic gonadotropin and progesterone can downregulate the Th-1 proinflammatory activity by decreasing tumor necrosis factor-α [20]. Therefore, this unique and complex immune modulation may have a protective effect for pregnant women against cytokine storm and associated morbidity and mortality from COVID-19 [5].
Although there seems to be a relatively small number of maternal mortalities associated with COVID-19 infection, obstetricians and other healthcare providers caring for pregnant women urgently need more data to understand whether this infection can lead to severe adverse maternal or neonatal outcomes. They should be informed about mortalities and related clinical characteristics of expired patients, mainly because the median time from onset of the symptoms to pneumonia diagnosed by imaging is only 4 d [21] and from onset to death can be as short as two weeks [22]. Hence, earlier diagnosis seems critical for physicians to identify pregnant women who are at a higher risk for severe forms of COVID-19 and apply preventive measures in order to minimize the risk of mortality.
4.1. Strengths and limitations
The mortality cases presented in this review are based solely on published literature, which is not representative of the actual death rate. Determination of the exact morbidity and mortality indices regarding COVID-19 during pregnancy will require rigorous nationwide surveillance data from all over the World. However, the mortality cases we reported in this review showed that COVID-19 maternal mortality is not zero and further studies reporting details of maternal and perinatal deaths associated with COVID-19 seems necessary in order to reach a more conclusive evidence on COVID-19 and pregnancy. Moreover, we did not evaluate the quality of included studies. It seems reasonable that during a pandemic, because of the intention to share data more rapidly might negatively affect the quality of published reports.
5. Conclusion
In conclusion, pregnant women and their fetuses and newborns do not seem to have an increased risk of mortality as compared with general population. Furthermore, maternal mortality mostly happened to those with previous co-morbidities and neonatal mortality seems to be a result of prematurity rather than infection. However, despite the increasing number of published studies, there are insufficient good-quality reports to draw firm conclusions with regard to the maternal and perinatal mortality during COVID-19 outbreak.
| Study | Country | Number of mortality cases | Maternal age, years | Gestational age at termination of pregnancy or maternal death, weeks | Previous co-morbidities | Attributable complication leading to mortality | Expired while pregnant/postpartum | Neonatal outcome |
|---|---|---|---|---|---|---|---|---|
| Ahmed et al. [7] | United Kingdom | 1 | 29 | 31 | Obesity, diabetes, asthma | Pulmonary embolism, basilar artery thrombosis | postpartum | Survived |
| Hantoushzadeh et al. [6] | Iran | 7 | 25–49 | 24–38 | Obesity, Subclinical hypothyroid, advanced maternal age, gestational diabetes | ARDS–related | 5 cases while postpartum, 2 while pregnant | 4 cases had fetal demise (1 twin), 3 cases survived, 2 cases of neonatal death (1 twin) |
| Lumbreras-Marquez et al. [11] | Mexico | 7 | 26–39 | NR | Obesity, diabetes | NR | NR | NR |
| Takemoto et al. [15] | Brazil | 20 | 20–43 | NR | 9 pregnant women had no co–morbidities, 11 had at least one comorbidity with asthma being the most common | NR | 16 cases while postpartum and 4 while pregnant | NR |
| Vallejo et al. [12] | United states | 1 | 36 | 37 | Advanced maternal age | ARDS–related, multiple organ failure | postpartum | Survived |
| Zamaniyan et al. [13] | Iran | 1 | 22 | 32 | hypothyroidism | ARDS–related | postpartum | Survived |
| Total number of maternal deaths | 37 | |||||||
ARDS acute respiratory distress syndrome, NR not reported.
| Study | Country | Number of mortality cases | Maternal age, years | Fetal demise | Gestational age at fetal demise, weeks | Neonatal death | Gestational age at birth, weeks | Neonatal age at neonatal death, days | Maternal outcome | |
|---|---|---|---|---|---|---|---|---|---|---|
| Hantoushzadeh et al. [6] | Iran | 7 | 25–49 | 5 (2 twins) | 24 and 30 | 2 (1 twin) | 28 | 3 | 1 mother survived and 4 have died | |
| Huang et al. [8] | China | 2 | 29–32 | 1 | 35 | 1 | 31 | 18 | survived | |
| Li et al. [9] | China | 1 | 31 | 0 | NA | 1 | 35 | 1 | survived | |
| Liu et al. [10] | China | 1 | 31 | 1 | 34 | 0 | NA | NA | survived | |
| Zhu et al. [14] | China | 1 | 30 | 0 | NA | 1 | 34 | 9 | survived | |
| Total number of perinatal deaths | 12 (7 fetal demise and 5 neonatal death) | |||||||||
NA: not applicable; NR: not reported.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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