key: cord-0737103-nb9afhny
authors: La Verde, Marco; Riemma, Gaetano; Torella, Marco; Cianci, Stefano; Savoia, Fabiana; Licciardi, Federico; Scida, Serena; Morlando, Maddalena; Colacurci, Nicola; De Franciscis, Pasquale
title: Maternal death related to COVID‐19: A systematic review and meta‐analysis focused on maternal co‐morbidities and clinical characteristics
date: 2021-05-18
journal: Int J Gynaecol Obstet
DOI: 10.1002/ijgo.13726
sha: 70e4e45679c09d87bb8b8cf6d317f54765eb3509
doc_id: 737103
cord_uid: nb9afhny

BACKGROUND: Besides reducing the quality of obstetric care, the direct impact of COVID‐19 on pregnancy and postpartum is uncertain. OBJECTIVE: To evaluate the characteristics of pregnant women who died due to COVID‐19. SEARCH STRATEGY: Cochrane Library, Embase, MEDLINE, Scopus, and Google Scholar were searched from inception to February 2021. SELECTION CRITERIA: Studies that compared deceased and survived pregnant women with COVID‐19. DATA COLLECTION AND ANALYSIS: Relevant data were extracted and tabulated. The primary outcome was maternal co‐morbidity. MAIN RESULTS: Thirteen studies with 154 deceased patients were included. Obesity doubled the risk of death (relative risk [RR] 2.48, 95% confidence interval [CI] 1.41–4.36, I (2) = 0%). No differences were found for gestational diabetes (RR 5.71; 95% CI 0.77–42.44, I (2) = 94%) or asthma (RR 2.05, 95% CI 0.81–5.15, I (2) = 0%). Overall, at least one severe co‐morbidity showed a twofold increased risk of death (RR 2.26, 95% CI 1.77–2.89, I (2) = 76%). Admission to intensive care was related to a fivefold increased risk of death (RR 5.09, 95% CI 2.00–12.98, I (2) = 56%), with no difference in need for respiratory support (RR 0.53, 95% CI 0.23–1.48, I (2) = 95%) or mechanical ventilation (RR 4.34, 95% CI 0.96–19.60, I (2) = 58%). CONCLUSION: COVID‐19 with at least one co‐morbidity increases risk of intensive care and mortality.

COVID-19 was declared a pandemic by WHO on March 11, 2020, during its 51st situation report. To date, the disease is still causing harmful consequences in almost every country. 1 The clinical course of the disease frequently starts with lowgrade fever, cough, anosmia, ageusia, headache, chest pain, or pneumonia. 2 Specific consequences of the infection on pregnancy and neonatal outcomes are still uncertain since evidence regarding the disease is still ongoing. The severity of the disease ranges from asymptomatic to acute respiratory distress. The reported mortality for SARS-Cov-2 is estimated in the range of 1%-2%, less than other coronaviruses including Middle East Respiratory Syndrome (MERS) and

Severe Acute Respiratory Syndrome (SARS), for which the reported rate of death is estimated at about 35% and 10%, respectively. 3 The morbidity rate of COVID-19 in pregnant women is higher than MERS, SARS, and also influenza and Ebola. 4 Nevertheless, it seems that pregnancies affected by COVID-19 do not develop more severe symptoms compared to the general population and an increased risk for pregnant women, compared to non-pregnant women, has not been demonstrated yet. 5, 6 However, it is ascertained that pregnant women cannot avoid mandatory examinations; therefore, they cannot avoid interactions with healthcare professionals. For this reason, they could be more exposed to contagion than nonpregnant women. 7 On the contrary, women of reproductive age are expected to have 60% less access to intensive care units (ICUs) than postmenopausal women. 3, 8 Moreover, new findings from studies conducted in lowresource countries showed an increased risk of death in obstetric patients who tested positive for SARS-CoV-2. 9 Therefore, evidence concerning the impact of pregnancy as well as its co-morbidities on COVID-19-related maternal mortality is still uncertain.

The aim of the present systematic review and meta-analysis was to investigate the clinical characteristics of pregnant women who died due to COVID-19.

The research protocol was designed a priori, defining methods for searching the literature. The meta-analysis was conducted complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 10 and the Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) statement guidelines. 11 The review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with the ID number CRD42021228455.

Five electronic databases (Cochrane Library at the CENTRAL register, Ovid Embase, MEDLINE, Scopus, and Google Scholar) were searched from inception to February 2021. Eligible studies were identified with a combination of the following keywords and/or Medical Subject Headings (MeSH) terms: "maternal death"; "maternal mortality"; "coronavirus"; "COVID-19"; "COVID 19"; and "SARS-CoV-2". Case reports, case series, prospective cohort studies, and retrospective cohort studies regarding maternal mortality cases due to COVID-19 and neonatal outcomes were considered eligible if they reported at least one maternal death with the clinical characteristics of the adverse events and if they were published in a peer-reviewed journal. No language restrictions were applied. Review articles, letters to the editor, non-peer-reviewed reports, studies with unspecified dates and places of research, suspicion of duplicate reporting and/or unreported data on maternal deaths were excluded from the study. From the selected studies, the references were also evaluated in order to find additional relevant studies.

Titles and abstracts were reviewed separately by two reviewers (MLV and FL) to identify all eligible articles. Full-text articles were retrieved for further consideration for inclusion. Discrepancies were solved by discussion with a third author (SS).

The analyzed data were selected from each relevant study and systematically collected in a database. The following information was obtained: author's name; institution and country; study design; sample size; maternal age; gestational age at admission; symptoms on admission to hospital and the days before; pregnancy co-morbidity; mode of delivery; acute respiratory distress syndrome (ARDS) developed; maternal and neonatal outcomes; chest computed tomography (CT); time between delivery and maternal death; the results of COVID-19 tests performed on the neonatal population; and the perinatal outcomes. Not all studies reported on all evaluated variables and studies that did not report on a specific outcome were recorded as not reported.

The primary outcome was maternal co-morbidities. The secondary outcomes were admission to the intensive care unit (ICU) and the need for respiratory support. When described, additional data regarding the delivery mode, onset of ARDS, chest CT, and the perinatal and neonatal outcome were also collected. All the clinical characteristics reported and information regarding the maternal and perinatal death were recorded, including the clinical manifestations of COVID-19 at admission and the days before.

The methodological quality of the studies was assessed independently by the same two authors using the Joanna Briggs Institute (JBI) tool for case series and case reports, 12 and using the Newcastle-Ottawa Scale (NOS) for observational studies. 13 According to the NOS, every trial is assessed based on three crucial elements: selection of study groups; comparability of the study groups; and ascertainment of the interested outcome. Assessment of the selection of a study requires the following: estimation of the representativeness of the exposed cohort; selection of the non-exposed cohort; checking the exposure; and validation that the evaluated endpoint was not likely to occur spontaneously at the beginning of the study. The comparability of studies is judged, including the assessment of the comparability of cohorts on the design or analysis. In addition, the ascertainment of the outcome of interest is evaluated using the following: determination of the outcome; duration; and adequacy of the follow-up. According to NOS criteria, a study can be awarded a maximum of one star for each of the numbered items within the Selection and Outcome categories.

Risk of bias judgment was independently assessed by three authors (SC, GR, and MM). Any disagreement was resolved by discussion with a fourth reviewer (PDF).

In a conservative approach, the random-effects model was calculated using the DerSimonian and Laird method. Results were reported as mean differences (MD) or relative risk (RR) with 95% confidence intervals (CI). We quantified heterogeneity using the Higgins (I 2 ) statistics, in which 25%, 50%, and 75% were cutoffs for low, medium, and high heterogeneity, respectively. Statistical analysis was conducted using the software STATA version 14.1 (StataCorp., College Station, TX, USA). In case of descriptive studies or trials without a control group, a narrative synthesis was selected. 14 3 | RE SULTS Figure 1 illustrates the selection of studies for inclusion in the meta-analysis. Out of a total of 13 600 initial records, 13 studies (including 154 women deceased due to COVID-19) that summarized co-morbidities fulfilled the inclusion criteria and were considered for the review. These included four case reports [15] [16] [17] [18] and three case series, 9, 19, 20 two prospective 21, 22 and four retrospectives cohort studies 23,24 ( Table 1) .

Two studies conducted in Brazil and Mexico compared the maternal death group and the survival group and were eligible for the meta-analysis. 25, 26 For the remaining 11 studies, 9,15-17,19-24 a qualitative synthesis was performed.

Nine studies described the maternal co-morbidity at the time 

Publication bias was considered to be high since the vast majority of the included studies were either case series or case reports. The inclusion of two prospective cohort studies slightly decreased the paper's bias due to the vast number of included case reports and case series. A detailed quality assessment of the included studies is reported in Tables S1 and S2.

In the pooled data from the nine studies, [15] [16] [17] [18] [20] [21] [22] [23] [24] (Table S3) . Seven studies 9, 15, 17, 18, [21] [22] [23] reported the results of the chest CT scans and all the patients had a positive CT result (11/11, 100%) with a finding of a bilateral patchy Table 1) . The time taken to develop ARDS, after admission to hospital, was 36 hours (95% CI 24-72). 9, 15, 16, 21 In the seven studies that reported the outcome, 9, [15] [16] [17] [18] 20 

Nine studies reported the pregnancy co-morbidities on admission to hospital, 9, [15] [16] [17] [18] [19] [20] 22 ,23 with a total of 18 patients. With regard to these 18 patients, 5 (27%) did not manifest any pregnancy complications ( Table 2) . Gestational diabetes and obesity were the most frequent co-morbidity (22%, 4/20 for each patient). The second most frequent co-morbidities were maternal hypothyroidism, pre-eclampsia, and twin gestation (11%, 2/18 each). The less common were: obstructive sleep apnea, asthma, renal disease, hepatitis, cardiovascular disease, and HELLP syndrome (5.5%, 1/18 each). Two patients in this series had a twin pregnancy obtained after assisted reproduction. 9 Lumbreras-Marquez et al. 25 for the viral infection, 9, 15, 16, 18, 20, 21 and 2 (25%) fetuses tested positive (Table S5 ). 9

Data regarding maternal diabetes, obesity, asthma, the presence of one co-morbidity or one risk factor, admission to the ICU, and respiratory support were used for the meta-analysis. Overall, maternal obesity increased the risk of maternal death by 2.48 (95% CI Figure 3 ).

The present qualitative and quantitative synthesis showed the clini- In summary, the present review showed that in the case of COVID-19 infection in pregnant women, while the majority of the admissions to hospital occurred during pregnancy, death occurred in the postpartum period. Moreover, at least one maternal comorbidity or one risk factor elevated the possibility of death; maternal diabetes and maternal obesity, in particular, had a negative impact on admission to the ICU. A rapid progression of disease with a short time between delivery and death was noted.

Evidence reporting the characteristics of maternal mortality and morbidity with COVID-19 is still limited and of very low quality.

Therefore, it is necessary to obtain more knowledge to pursue the earlier identification of pregnant women at a higher risk for severe COVID-19 disease.

Open Access Funding provided by Universita degli Studi della Campania Luigi Vanvitelli.

[Correction added on 07-May-2022, after first online publication:

CRUI-CARE funding statement has been added.]

The authors have no conflicts of interest.

Study design: MLV and GR. Acquisition of data: FL, SS, and SC. 

All data generated or analyzed during the present study are included in the published article and its supplementary material file.

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