This study demonstrates that the clinical characteristics of pregnant women who deceased and those who survived COVID-19 infection differ significantly. The maternal death group had a higher comorbidities and pregnancy complications compared to the survived group (Cardiac disease, acute kidney injury, co-infection, and anemia). Contrary to many reports, our study did not found an increased prevalence of hypertension/preeclampsia, obesity, and diabetes in maternal death groups [28–34]. Acute kidney injury is the comorbidities with the highest risk to maternal death (OR: 19.14), followed by cardiac disease, co-infection, and anemia. Acute kidney injuries can result from a cytokine storm or microthrombi-mediated destruction and are proportional to the infection's severity [32]. The maternal death group also had a greater prevalence of secondary infections compared to the survived group, in accordance with a study involving 68 maternal deaths conducted in Wuhan [35]. The co-infection in this study consist of HIV, hepatitis B, syphillis, tuberculosis, urinary tract infection, vaginal infections, and dengue haemorrhagic fever. These infectious disease is still a common and main problems in Indonesia. The study of 690 pregnant women in East part of Indonesia showed that the prevalence of HIV, Hepatitis B, and Syphilis was 4.2%, 0.4%, and 3.8% [36]. The prevalence is high although the testing rate of these infections in pregnant women is relatively low (14.1%)[36]. The relatively high prevalence of these infection in community may contribute to the high maternal death numbers in pregnant women with COVID-19 in Indonesia. Anemia is another significant pre-existing illness associated with maternal mortality in COVID-19 pregnant women. In Indonesia, anemia during pregnancy (most commonly caused by iron deficiency) remains a significant issue. According to the Indonesia Family Life Survey, the prevalence of anemia in pregnancy (among women older than 15) in Indonesia is 37.3%. (2008) [37]. Other study reported that Indonesian prevalence of anemia during pregnancy in 2018 was 48.9% [38]. Women with anemia are highly susceptible to pregnancy complications, including the risk to the fetus [39]. Cardiac illness is also one of the significant comorbidities related with COVID-19-associated maternal death during pregnancy. Common cardiac disease/complications found in Indonesian pregnant women including: preipartum cardiomyopathy, pulmonary hypertension, ventricular septal defect, atrial septal defect, and rheumatic heart disease. In a large case control study by Vouga et al, the prevalence of cardiac comorbidities is higher in the severe compared to the no/mild adverse maternal outcomes group (3.3% vs 1.3%) [28]. There are many evidences that maternal mortality is increased during pregnancy with COVID-19. In one of the largest meta-analyses covering 293,152 pregnant women with COVID-19 vs 2.903.149 without COVID-19, those with the condition had a sixfold increased risk of maternal death compared to those without the disease [34]. Any presence of maternal comorbidity is associated with severe COVID-19 (OR: 1.48, 95% CI: 1.19–1.85) [34]. Other meta-analyses involving 13 trials and 154 deceased patients found that the presence of an one severe co-morbidity doubled the chance of mortality (RR: 2.65, 95% CI: 1.77–2.89) [29]. Interestingly, we found that the prevalence of PROM is significantly lower in the maternal death groups. The explanation for this finding is still unclear. PROM may be responsible for an earlier termination of pregnancy, a reduction in the maternal burden associated with pregnancy, and improvement in maternal immunity against COVID-19. Obesity, an other significant risk factor for maternal death, is not elevated in the maternal death group. Meta-analysis reported a double risk of maternal death by COVID-19 in pregnant women with obesity [29]. However in other large case control study involving 926 pregnant women with COVID-19, obesity was not independently associated with an increased risk of severe adverse outcomes [28].
Our study showed that the deceased women had more prominent sign and symptoms compared to the survived women. The highest risk of symptoms related to maternal death is a fever. The prescence of fever increase the risk of maternal death as high as 18.59 fold. In the systematic review of 154 deceased pregnant women by COVID-19, eight studies reported that the most dominant symptoms before hospital admission was fever (87.5%), followed by dyspnea (68.75%), and cough [29]. In the INTERCOVID multinational cohort study involving 706 pregnant women with COVID-19 and 1424 pregnant women without COVID-19, fever and shortness of breath for any duration were linked to an elevated risk of severe maternal and newborn complications [17]. The other symptom related to maternal death is a pneumonia diagnosed from chest x-ray (88.3%). The chest x-rays of all women who died from COVID-19 infection showed severe and extensive pulmonary damage. In contrast, the majority of the survivors exhibit patchy shadowing or ground glass opacity. This pneumonia findings from chest x-ray increased the maternal death risk as high as 7.63 fold. The meta analysis reported that all the deceased women from seven studies had a ground glass opacity from chest CT scans [29]. Due to a lack of resources in Indonesia, chest CT scans were not used to confirm COVID-19 pneumonia. We utilized a chest x-ray as a screening alternative for pneumonia in all pregnant women suspected of having COVID-19 [15, 40]. Other important sign related to maternal death includes vomiting, myalgia, headache, and cough. Contrary to the findings of the majority of studies, we discovered in our investigation that anosmia increases the risk of maternal mortality. In the sub analysis of the HOPE COVID-19 registry (Health Outcome Predictive Evaluation for COVID-19) study, olfactory and gustatory dysfunctions (OGD) involving anosmia have an inverse relation with death (OR: 0.26, 95% CI: 0.15–0.44, p < 0.001) [41].
The maternal death group had higher levels of maternal blood leukocytes, neutrophil, ALT, AST, CRP, and procalcitonin, as determined by laboratory analysis. Contrary to expectations, the levels of BUN and creatinine in the blood of deceased mothers are much lower than in those who survived. In the deceased group, the higher levels of maternal serum leukocyte, CRP, and procalcitonin indicate a more severe infection and inflammatory process. Elevated pro-inflammatory markers like as CRP and procalcitonin indicate a cytokine storm in COVID-19, which is associated with severe clinical manifestations such as acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and even maternal death [32, 42, 43]. The white blood count (leukocyte), neutrophil count, and neutrophil-to-lymphocyte ratio were higher in non pregnant individual with severe or critical ilness than in those with mild or moderate ilness caused by COVID-19 [44–46]. However in pregnant women with COVID-19, leukocyte count was commonly decreased compared to non pregnant women with COVID-19 [47–49]. Our findings demonstrate the opposite, with a greater leukocyte count in the maternal death group than in the survival group. Possible explanation might be an increase in secondary bacterial coinfections, resulting in a higher leukocyte count. In a case report from Surabaya, viral (COVID-19) and bacterial pneumonia co-infections in severely ill pregnant women were reported [50]. Due to the fact that D-dimer and other coagulation variables are not regularly evaluated in the care of COVID-19-infected pregnancies, we do not have data on them in our study. The D-dimer may be an indication of thromboembolism associated with severe COVID-19 infection [51–53].
As expected, the maternal-perinatal outcomes in the maternal death group is worse compared to the survived group. Infected women admitted to the ICU have an 86-fold greater risk of maternal death than infected women treated in an isolation room. The admission rate to the intensive care unit is particularly high in the group of mothers who deceased because of the need for mechanical ventilation due to severe COVID-19-induced acute respiratory distress syndrome. Acute respiratory failure is the primary cause of death in COVID-19, particularly in patients with comorbidities such as chronic obstructive pulmonary disease, advanced age, obesity, and smoking [32, 35]. The maternal death group have a significantly higher risk of stillbirth. In COVID-19-infected women, acute hypoxia during respiratory distress may cause severe uteroplacental insufficiency, resulting in intrauterine fetal death [11, 16, 54–57]. Due to social and cultural restrictions, Indonesia does not perform perimortem cesarean sections, which also contributes to the stillbirth rate. Therefore, doctors will choose to take no action to save the fetus in pregnant women who are close to death. The rate of cesarean section also higher in maternal death groups. Pregnant women with severe/critical COVID-19 may face life-threatening complications including respiratory failure, multiple organ malfunction, and loss of consciousness, necessitating cesarean delivery. Predictably, the length of hospital stay in the maternal death group is double that of the survival groups. Similar to the findings of a large multicenter cohort study, the risk of cesarean section, ICU admission, preterm birth, and neonatal admission to the NICU increased significantly in maternal death groups [28]. The maternal death group also has a worse perinatal outcomes in form of lower birthweight, fetal height, and Apgar scores. These findings is closely related to the higher preterm birth rate, small for gestational age, and low birth weight in maternal death group. In a many large cohort and meta-analysis study, COVID-19 increased the risk of preterm birth, small gestational ages, and low birth weight significantly [17, 28, 29, 34]. These data demonstrate that the degree of maternal illness influences obstetrical and neonatal outcomes substantially.
Ultimately, based on the logistic regression analysis, we concluded that the independent risk factors for maternal death are fever, pneumonia from chest x-ray, and ICU admission. These three events can be used to predict maternal mortality in COVID-19-infected pregnant women. In contrast to Vouga et al., who identified that pulmonary comorbidities, hypertensive disorders, and diabetes are a significant risk factors for catastrophic maternal outcomes [28, 35]. Ruan et al. investigated the mortality of 68 maternal deaths versus 82 survived cases and discovered that age, the presence of underlying disease, the presence of secondary infection, and higher inflammatory markers in the blood were predictors of a fatal outcome in COVID-19 cases [35]. In the largest meta-analysis of COVID-19 in pregnancy, conducted by Allotey et al, older maternal age, a higher body mass index, chronic hypertension, and a history of diabetes were associated with severe COVID-19 in pregnancy [34]. On the basis of all these research, we can conclude that the risk of maternal death in COVID-19-infected pregnant women is increased by fever, pneumonia, underlying disease, secondary co-infection, elevated inflammatory serum markers, and older maternal ages.
Limitation Of Study
Our research has a number of limitations. First, as a control group of negative patients was not included in this study, only observational conclusions can be derived about the absolute risks of severe illness and bad obstetric/neonatal outcomes. This was, however, outside the range of the current investigation, whose primary objective was to identify clinical risk factors associated with maternal death.
Second, there are variations in the screening of pregnant women for COVID-19 between participating centers. While some centers performed routine universal screening on all hospitalized women, others only tested pregnant women with symptoms. This may have resulted to a selection bias of COVID-19 cases with more severe symptoms. This selection bias may have led to an exageration of the absolute risk of adverse outcomes in symptomatic SARS-CoV-2 infection.
Third, we have no information regarding the vaccination status of the participants. Vaccination has been demonstrated to reduce the incidence of maternal mortality and morbidity in COVID-19-infected people [58–65]. This is because the vaccination of pregnant women in Indonesia did not begin until August 2021. As the national vaccination program had not yet launched when the study began, we did not include this as a data point to be recorded. This study collected the majority of cases during the first half of 2021, when the Delta variation predominated. After the immunization program began, the rate of new COVID-19 cases among pregnant women reduced dramatically, and very few women are hospitalized owing to severe COVID-19. Therefore, this study was conducted primarily on pregnant women who were not immunized.