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Maternal deaths due to COVID‐19 disease: The cases in a single center pandemic hospital in the south east of Turkey

Abstract Coronavirus‐19 disease is still a pandemic health problem and uncertainty in the management of severe or critically ill pregnant women confuses continually the obstetricians. The nationwide maternal mortality rate due to covid‐19 still has not been presented in any study in Turkey. The study includes four maternal mortality cases in a referral single pandemic center in our country. Case 1, a 34‐year‐old, 34 weeks of gestation with moderate disease. The cesarean section was performed due to nonreassuring nonstress tests. She died on the postpartum seventh day. Case 2, a 37‐year‐old, at 36 weeks of gestation. The symptoms consisted of dry cough, shortness of breath and labor pain, and 3 cm cervical opening. Her second cesarean section was performed and she died at postpartum ninth day. Case 3, 33 years old, 33 weeks of gestation with moderate/severe stage of the disease. A few days after the treatment, CS was performed due to her severe condition and she died at postpartum 15th day. Case 4, 39 years old, 35 weeks of gestation, she was at a severe stage of the disease. On the second day after the treatment, CS was performed due to her severe condition and she died at postpartum seventh day. The postpartum period after cesarean section should be followed cautiously under the appropriate treatment of the COVID‐19 disease. Unfortunately, the reason for this rapid deterioration which we observed in our cases is not well known and appropriate medications and algorithms should be established as soon as possible.


Introduction
The World Health Organization announced a global pandemic caused by COVID-19 disease on March 11, 2020. 1 As of March 2021, the virus has infected over 100 million people. 2 There are some concerns about the effect of COVID-19 on pregnancy. While a report published in May 2020 suggests that overall clinical outcomes in pregnant patients do not differ from nonpregnant patients, 3 the other study published in September 2020 stated that pregnancy worsens the morbidity of COVID-19 and it seems more likely to increase as the pregnancy advances. 4 An exact management algorithm for severe or critically ill pregnant women infected with Covid-19 regarding to timing and mode of delivery and appropriate medication could not be developed up to the date. 5 Some experts suggest delivery if the mother's condition is stable after 32-34 weeks of gestation, while the others decide to give birth only in hypoxemic respiratory failure. 6,7 Moreover, a report demonstrated that critically ill 34 week pregnant women with COVID-19 can be managed and treated successfully even under the mechanical ventilation without performing emergent CS. 8 A nationwide study was not conducted yet about maternal mortality regarding COVID-19 diseases in Turkey. In our institution, 25 000 births occur per year. During the pandemic, 83 symptomatic pregnant women who were Covid-19 PCR positive gave birth between March 2020 and January 2021. Sixteen of those were followed up at the intensive care unit. Fifty-four of 83 pregnant women (asymptomatic and symptomatic) gave birth in cesarean while 29 of them gave birth via vaginal, and 4 maternal deaths occurred only among cesarean births. Maternal mortality rate can be calculated as 4.8% (4/83) in this symptomatic cohort. The study aims to present our four maternal mortality cases in Diyarbakır province in Turkey. The written informed consent was obtained from the relatives of the patients.

Case 1
Our first patient was a 34-year-old, gravida 3 parity 1 (CS) and abortion 1, woman who presented at 34 weeks of gestation with symptoms of subjective fevers, dry cough, and back pain for a few days. Oxygen saturation in room air was 94%, the fever was 37 C. Her body mass index (BMI) was 26.5 kg/m 2 . Fetal evaluation was resulted as well by performing fetal ultrasonography and nonstress test (NST). There was no contact history with a COVID-19 positive person as known and her medical history was unremarkable. She was hospitalized with suspicion of Covid-19 disease (September 2020). PCR for COVID-19 was performed and resulted as a positive test. Computed tomography was interpreted as compatible with COVID-19 pneumonia. First laboratory findings were not remarkable (Table 1). Lopinavir-ritonavir to reduce viral replication, subcutaneous heparin for anticoagulation, and nasal oxygenation were started. After 2 days, oxygen saturation in room air was 92% and she had mild uterine contraction, cervical opening, and effacement were increased (2 cm and 50% respectively), the NST was nonreassuring. The patient was evaluated between a perinatologist, an anesthesiologist, and an obstetrician. Decision of CS was taken according to these consultations. CS was performed without any problems and the newborn was healthy with 1-and 5-min APGAR score 5 and 8. The patient who was going on initial treatment was not bad for 2 days after the operation, but on the third day the patient deteriorated and oxygen saturation started to decrease up to 80%. A follow-up chest tomography showed bilaterally increased consolidations and opacities in the lung (Figure 1). On the postoperative fourth day she had to be intubated in the ICU and hydroxychloroquine, steroids, and vancomycin were added to the treatment. Tocilizumab was given once a day for 2 days. Arterial blood gasses confirmed worsening and severe metabolic acidosis. All laboratory findings can be seen on Table 1. Decision of hemodialysis could not be applied, because we lost the patient without response to the cardiopulmonary resuscitation (CPR) on the postpartum seventh day. The planned autopsy was not accepted by the relatives of the patient, whom we thought to have died as a result of multiorgan failure.

Case 2
The second patient who was admitted to our referral hospital was 37 years old, gravida 4 parity 3 (one vaginal and two cesarean delivery), she was at 36 weeks of gestation. Besides the labor pain, shortening of breath and dry cough were main complaints. Her body temperature was 38 C and her BMI was measured as 28 kg/m 2 . She was diagnosed with COVID-19 on her admission and the antiviral therapy was started. Three centimeter cervical opening was detected during the physical examination and oligohydramnios was detected during the sonographic examination and then CS was performed after consultations between the department of perinatology, infectious disease, and anesthesiology on the same day of her admission (August 2020). A healthy baby boy was born with 1and 5-min APGAR scores were 6 and 8, respectively with the negative result of the COVID-19 PCR. Gradually, she worsened despite the treatment (lopinavirritonavir, anticoagulant, corticosteroids). Continuous positive airway pressure (CPAP) was started on day 3 of admission in the ICU and the computed tomography scan demonstrated that bilateral lung airspace densities were common ( Figure 2). Mechanical ventilation had to be performed on day 5 of admission. Tocilizumab was added to her treatment with two dosages. Prone position was admitted twice in a day for 3 h. But, even with all supportive and intense interventions, she died because of cardiopulmonary arrest secondary to the septic shock at postpartum ninth day. The relatives of the patient did not accept the offered autopsy.

Case 3
Our third case was 33 years old gravida 4 parity 3 (vaginal birth) and when she came to the emergency service which separated the area for COVID-19 patients who suspected or known. Thirty-three weeks of gestation was measured and she was hospitalized (October 2020). Her medical history was not remarkable and body mass index was 33 kg/m 2 . It was accepted as a moderate COVID-19 disease due to complaints of mild cough and shortness of breath and a 93% O 2 saturation with capillary measurement.
The fetal well-being was uneventful. The initial laboratory findings were not remarkable. Lopinavirritonavir, the corticosteroid, low molecular weight heparin, and nasal O 2 support were started by using nasal cannula. Gradually, the patient's O 2 requirement was increased the next day and in spite of CPAP therapy, O 2 saturation could only reach up to the 90 s. CS was performed after consultations between the department of perinatology, infectious disease, and anesthesiology on day 5 of admission. The common opacities were observed on the CT scan at postpartum on the first day ( Figure 3). The patient's condition worsened after CS, despite of the changing antiviral therapy (lopinavir-ritonavir to favipiravir), antibiotics (klaritromisin to karbapenem), and starting to the high flow O 2 therapy and she was had to be intubated on  October, 2020. The Tocilizumab [interleukin-6 (IL-6) inhibitor] was started on same day of intubation while IL-6 level was 45 pg/mL on admission and 10 pg/mL (normal range 0-5.9 pg/mL) on day 2 of admission. Postpartum fifth day, the unconscious patient underwent hemodialysis due to low urine output (150 cc urine/24 h). Postpartum 13th day, the patient had to be taken to the prone position for increasing her O 2 saturation. The patient, who was hypotensive despite the maximum norepinephrine and dopamine doses, was arrested at postpartum 15th day and did not respond to the cardiopulmonary resuscitation. Her husband refused the autopsy procedure.

Case 4
The patient was 39 years old, gravida 7 parity 6 (vaginal births). She was at 35 weeks of gestation. COVID-19 PCR positivity was known for 5 days. Her main complaints were shortening of breath and dry cough when she arrived at the emergency service on November 2020. O 2 saturation increased with O 2 mask (3 L/min) up to the 95. Fetal sonographic examination was uneventful. She was hospitalized and low molecular weight heparin, lopinavir-ritonavir, and steroids were ordered. The lung CT findings were evaluated to be compatible with COVID-19 disease on the admission day, but it was not common (Figure 4). During the courses, the need of O 2 support was increased and on day 2 of admission, CS was performed due to low O 2 saturation (88% with CPAP). The newborn was seen as healthy. After Postoperative eighth hour, she underwent mechanical ventilation. On day 4 of admission, the lopinavir-ritonavir was changed with the favipiravir, and 0.6 mL subcutaneous low molecular weight heparin dosage was increased to twice in a day. Tocilizumab was added to the treatments for 2 days. Piperacillintazobactam and teicoplanin were started. Hemodialysis was required at postpartum third and sixth day. It was thought that severe acute respiratory disease syndrome developed and she died at postpartum seventh day without responding to CPR. The relatives of the patient refused the autopsy procedure.

Discussion
In general population, according to the severity of disease, COVID-19 was stratified as being mild (symptomatic or mild pneumonia), severe (tachypnea ≧30 breaths/min, or oxygen saturation ≤93% at rest, or PaO 2 /FiO 2 < 300 mmHg), and critical (respiratory failure requiring endotracheal intubation, shock, or other organ failure that requires intensive care), accounting for 81%, 14%, and 5% of cases, respectively. 9 However, in pregnant population, severely and critically ill rates were reported as 8% and 1%, respectively. 10 These different rates may indicate the preventative feature of pregnancy against the worsening of the disease. During pregnancy human chorionic gonadotropin and progesterone can downregulate the Th-1 proinflammatory activity by decreasing tumor necrosis factor-alpha. Therefore, this immune modulation can have a protective effect on pregnant women, so that, the cytokine storm that aggravates the COVID-19 disease may not occur if pregnancy goes on. 11 On the other hand, data showed that pregnant women are more likely to be hospitalized, admitted to the intensive care unit, and require the mechanical ventilation. 12 The pathogenesis of the worsening of the disease in pregnancy cannot be fully explained.
There is a balance between Treg and Th17 immune responses, these are critical for embryonic implantation and healthy pregnancy. 13 The reduced levels of Treg cells (regulatory T cells) and increased levels of Th17 cells are associated with obstetric complications, such as miscarriage, preeclampsia, preterm birth, and deterioration of maternal condition. 14 However, it is not clear in which patient these changes will occur. In cytokine storm, we know that IL-1 and IL-6 levels increase, anakinra and tocilizumab block these interleukins receptors and may have potential protective and therapeutic effects for severe or critical ill patients. 15 However, accessibility to these drugs is not possible for everywhere. For instance, we had some difficulties reaching these agents at the appropriate time. Among our 83 delivered pregnant women, only four deaths occurred at the postpartum period after cesarean section and death was not seen during pregnancy and after vaginal birth in our pandemic hospital which is unique in our region. Takemoto et al. found that the postpartum period should be considered as a risky situation for the mothers infected by COVID-19, the data about mode of delivery is missing in their study that included 124 maternal deaths versus 854 maternal cures. Thus, according to the Brazilian data of Takemoto et al., the rate of maternal death due to covid-19 was found to be 12% at a dramatic level. 16 On the other hand, Elshafeey et al. published a review article included 385 pregnant infected with COVID-19 disease, only one maternal death reported. 11 Centers for Disease Control in US reported 16 cases (0.2% maternal mortality) of maternal death between 8000 pregnant women with COVID-19 including the asymptomatic persons, this report identified an increased risk of hospital admission, admission to the ICU and mechanical ventilation in pregnant women, although there was no higher rate of death than the nonpregnant population. 12 Tug et al. evaluated 188 pregnant women with COVID-19 in their multicenter study in Turkey, only 6 patients admitted to the intensive care unit and the death was not occurred. 4 There is another publication by Sahin et al. in Turkey, this single center's study stated that maternal mortality rate is 0.4%. 17 Hessami et al. assessed 37 maternal deaths, 24 of them were at postpartum period and mode of deliveries were not clear in their study too. 18 The rate of CS among pregnant women infected with COVID-19 was exceed up to 80% in Huntley et al.'s study but the outcome of the mothers was not clarified exactly and maternal death was not occurred. 19 Cesarean section may be considered as a surgical burden that leads to worsening of the disease. In addition, Lei et al. pointed out those patients who underwent surgery have an increased risk of negative consequences of COVID-19 disease. 20 Our experiences make us think that, surgical procedure may trigger the inflammatory cascade. Similar to what we observed, Vallejo et al. experienced a patient who died with rapid deterioration after cesarean section. 21 Zheng et al. also had to struggle with two worsening patient especially after cesarean section and the death was not occurred. 22 8,23 As effective treatments continue to be developed for COVID-19 disease, the basis and of the treatment is supportive therapy. In addition to the supportive therapy, we used only hydroxychloroquine and lopinavirritonavir for our mild-severe ill pregnants on admission and kept on postpartum period according to the ongoing investigational trials for use in severe or critical COVID-19 infections such as anakinra for anticytokine effect, hydroxychloroquine to reduce acute tissue injury and antiviral medications, such as remdesivir or lopinavir-ritonavir, to inhibit SARS-CoV-2 viral replication. 24 However, after a randomized controlled trial and meta-analysis that did not recommend the use of hydroxychloroquine, we did not use it in our second, third, and fourth patients. 25 These changing response to the drugs and intensity of the occurrence of the infection in different time period may point to the viral mutations. As a matter of fact, the increased cases in the United Kingdom in the last days of 2020 explain this viral mutation. 26 Moreover, a drug whose efficacy on pregnant women has been definitely accepted has not been determined yet. In a study published in early October 2020, it seems that the antiviral drug remdesivir which has been firstly evaluated in pregnant and puerperant women may have good results. 25 In that study, among 86 pregnant and postpartum women with severe COVID-19 who received remdesivir, recovery rates were high and maternal death did not occurred. At December 2020, in a network meta-analysis, anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and intravenous immunoglobulin), convalescent plasma, and remdesivir were found to contribute to improved outcomes in hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin. 27 However, WHO expressed the opposing view of the organization for the use of remdesivir. 28 In conclusion, maternal deaths have devastating consequences and more appropriate management guidelines for pregnant women infected with covid-19 should be prepared immediately. Postpartum period after cesarean section should be followed cautiously under the appropriate treatment of COVID-19 disease.