Clinical characterisation and management outcome of obstetric patients following intensive care unit admission for COVID-19 pneumonia

Abstract This study aims to examine the clinical characteristics and mortality-related factors of obstetric patients, who were taken to the intensive care unit due to Coronavirus Disease 2019 (COVID-19). This study included 31 patients in the peripartum period with COVID-19 pneumonia, followed up in the intensive care unit (ICU) from March 2020 to December 2020. Symptoms, laboratory values, intensive care unit duration of stay, complications, the requirement of non-invasive and invasive mechanical ventilation, and mortality were recorded. The mean age was 30.7 ± 6.2 years and the mean gestational age was 31.1 ± 6.4 weeks. Among the patients, 25.8% had a fever, 87.1% had a cough, 96.8% had dyspnoea and 77.4% had tachypnoea. Seventeen patients (54.8%) had mild, 6 (19.4%) had moderate and 8 (25.8%) had severe pulmonary involvement on computed tomography. Sixteen (51.6%) patients required high-frequency oscillatory ventilation, 6 (19.3%) patients required continuous positive airway pressure, and 5 (16.1%) patients required invasive mechanical ventilation. Sepsis complicated by septic shock and multiorgan failure occurred in 4 patients and all of them died. The ICU duration of stay was 4.9 ± 4.3 days. We have found that older maternal age, obesity, high LDH, AST, ALT, ferritin, leukocyte, CRP, and procalcitonin values, and severe lung involvement were mortality-related factors. Impact statement What is already known on this subject? Pregnant women are in the high-risk group for Covid-19 disease and its complications. Although most pregnant women are asymptomatic, severe infection-related hypoxia can cause serious foetal and maternal problems. What do the results of this study add? When we examined the literature, we found that the number of studies on pregnant women with severe Covid-19 infection was limited. For this reason, with our study results, we aim to contribute to the literature by determining the biochemical parameters and patient-related factors associated with severe infection and mortality in pregnant patients with severe Covid-19 infection. What are the implications of these findings for clinical practice and/or further research? With our study results, predisposing factors for the development of severe Covid-19 infection in the pregnant patient population and biochemical parameters that are early indicators of severe infection were determined. In this way, pregnant women in the high-risk group can be followed closely and the necessary treatments can be started quickly so disease-related complications and mortality can be reduced.

Mortality rates in the intensive care unit (ICU) due to COVID-19 are much higher than previous viral pneumonia outbreaks, including the 2009 H1N1 influenza pandemic, which was reported to be 10-30% (ANZIC _ Influenza Investigators 2009, Nguyen- Van-Tam et al. 2010, Burrell et al. 2021).The main characteristic of those with severe COVID-19 disease is the development of acute hypoxemic respiratory failure characterised by bilateral lung infiltrations.Lung protective ventilation, conservative fluid management, empirical antibiotic selection for co-infections, prone position, and extracorporeal membrane oxygenation for refractory hypoxaemia play a significant role in the management of patients with severe hypoxemic respiratory failure (Fan et al. 2017, Murthy et al. 2020).The development of specific organ failures, such as acute renal failure and septic shock, has been associated with increased mortality (Murthy et al. 2020).
There is an increased risk of developing viral respiratory tract infections and severe pneumonia in pregnant women due to physiological changes in the immune system and cardiopulmonary systems (Jamieson et al. 2009, Naccasha et al. 2001).In two previous coronavirus outbreaks (SARS-CoV and MERS-CoV), pregnant women have been observed to be more susceptible to adverse consequences including the need for intensive care, intubation, renal failure, and mortality (Ksiazek et al. 2003, Wong et al. 2004).It is not clear whether the disease course of pregnant women diagnosed with COVID-19 pneumonia is different from that of non-pregnant women and whether the birth exacerbates the symptoms.There is a limited number of studies on this subject.The determination of COVID-19 rates in pregnant women, identification of risk factors, and analysis of clinical signs and results are key to maternal and newborn care and management.
The purpose of the present study is to examine the clinical characteristics and mortality-related factors of patients in the peripartum period, who are followed up in the ICU due to COVID-19.

Materials and methods
This single-centre and retrospective study was approved by the Ministry of Health and the local ethics committee of the hospital.The present study included 31 patients in the peripartum period with radiological and clinical signs of COVID-19 pneumonia, followed up in the ICU between March 2020 and December 2020.The nasopharyngeal and oropharyngeal swab polymerase chain reaction (PCR) tests of patients were positive.The study excluded the patients under 18 years of age, with a negative PCR test, whose treatment has not reached the final result, with missing data, positive PCR test but were admitted to ICU due to reasons other than respiratory failure indication (postpartum haemorrhage, etc.) and a length of hospital stay of <48 hours.The PCR tests were performed within the framework of the protocol determined by the World Health Organisation (WHO).
The patient follow-up forms and electronic medical records were examined.The patient's demographic data, comorbidity, symptoms at the time of admission, length of stay in ICU, length of stay in the hospital, maternal complications, and mortality were recorded.The gestational week of all patients at the time of admission was recorded.The week of delivery, presence of preterm birth (<37 weeks), mode of delivery (vaginal or caesarean section), birth weight, low birth weight (<2500 gr), Apgar score (minutes 1 and 5), neonatal mortality, and foetal complications were recorded.
Leukocyte, lymphocyte, neutrophil, thrombocyte, urea, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), c-reactive protein (CRP), procalcitonin, D-dimer, ferritin, fibrinogen, and arterial blood gas values were reported.The values at the time of admission and the peak values during hospitalisation was recorded.Radiological data, including Xray or computed tomography (CT) analysis, were examined and recorded.Patients were classified as mild/moderate/severe according to CT examination.
Antiviral treatments applied to the patients were recorded.Systemic corticosteroid therapy and other additional treatments were recorded.Patients who have required oxygen support were identified and those who have required high flow oxygen therapy (HFOT), continuous positive airway pressure (CPAP), and invasive mechanical ventilation were determined and recorded.

Statistical analysis
Statistical analyses used the SPSS 22.0 for the Windows program.Numerical data are expressed as mean and standard deviation, while categoric data are given as frequency and percentage.The Kolmogorov-Smirnov test was used to assess whether non-categorical data abided by normal distribution or not.Comparison of data abiding by normal distribution used the Student's t-test, with results given as mean ± standard deviation (SD).Comparison of data not abiding by normal distribution used the Mann-Whitney U test, with results presented as median (minimum-maximum).Comparison of categoric data in the groups used the chi-square test with results given as numbers and percentages (%).All comparisons accepted p < 0.05 as significant.

Results
1681 pregnant women diagnosed with COVID-19 were admitted to our hospital between 15 March 2020 and 31 December 2020.328 pregnant women (19.5%) were hospitalised and 31 pregnant women needed intensive care.1.8% (31/1681) of the pregnant women diagnosed with COVID-19 needed intensive care.This rate was 9.4% (31/328) in the pregnant women who are hospitalised and followed up. 4 patients died and 27 patients were discharged with full recovery (Figure 1).When we examined the PCR results of our patient group, we found that the dominant variant was Delta (B.1.617.2) (64.5%).
In the follow-up period in ICU, 12 (38.7%)patients had still pregnant and 19 (61.3%) patients gave birth.Three of those (9.7%)gave birth by vaginal delivery and 16 (51.6%)by caesarean.14 (45.2%) had preterm birth (<37 weeks). 1 patient was in the first trimester of pregnancy, 5 were in the second trimester, and 25 were in the third trimester.All pregnancies were single.Pregnancy-related complications occurred in 4 patients.Preeclampsia was detected in 1 patient, gestational diabetes mellitus in 2 patients, and abruptio placentae in 1 patient (Table 1).
The examination of newborns revealed that the mean birth weight was 2396 ± 639 gr, the mean Apgar score at minute 1 was 6.2 ± 2.3 and the mean Apgar score at minute 5 was 7.6 ± 2.2.Intrauterine foetal demise developed in one patient (Table 1).
The CT reports of patients interpreted by the radiology unit revealed that 17 (54.8%)had mild pulmonary involvement, 6 (19.4%) had moderate pulmonary involvement and 8 (25.8%) had severe pulmonary involvement (Figures 2, 3).Sixteen (51.6%) patients required HFOT, 6 (19.3%) patients required CPAP, and 5 (16.1%) patients required invasive mechanical ventilation.One intubated patient was extubated, and the others resulted in mortality.Six patients were transferred to the tertiary ICU due to the need for advanced follow-up and treatment.Sepsis complicated by septic shock and multiorgan failure occurred in 4 of those.Renal replacement therapy was performed on two of the patients with acute renal failure.Spontaneous pneumothorax developed in one patient and a left chest tube was inserted.Vasopressor therapy was performed in 3 patients with developed septic shock.The mean length of stay in the ICU and hospital was 4.9 ± 4.3 (1-18) days and 10.4 ± 5.1 (3-21) days, respectively (Table 2).
As a standard therapy, lopinavir, ritonavir, and therapeutic-dose anticoagulant were administered to all patients.The patient had no known thromboembolic event developed.21 (67.7%)patients received dexamethasone, 5 (16.1%) received tocilizumab, and 1 (3.2%) patient received plasma therapy (Table 2).The highest laboratory values of pregnant women at the time of admission and during their hospitalisation are given in Table 3.
Additional analysis was performed to evaluate the patients with mortality.Obesity rates were statistically significantly higher in those with mortality.The CT reports showed that severe lung involvement was statistically significantly higher in patients with mortality.The need for HFOV was not a factor that affects mortality, whereas the need for CPAP and invasive mechanical ventilation was statistically significant in those with mortality.The use of dexamethasone was not associated with mortality.However, the use of interleukin-6 antagonists was found to be significantly higher in those with mortality.The peak leukocyte, ferritin, lactate dehydrogenase (LDH), ALT, AST, CRP, and procalcitonin values were statistically significantly higher in those with mortality compared to those without mortality during their hospitalisation.In the arterial blood gas sampling, the pO 2 value was statistically lower in those with mortality.

Discussion
In the patients followed up in ICU due to COVID-19, 51.6% required HFOT, 19.3% required CPAP, and 16.1% required invasive mechanical ventilation.12.9% of the patients died.Age, obesity, severe lung involvement in CT, low pO2 value in arterial blood gas, need for CPAP, and need for invasive mechanical ventilation were determined to be risk factors associated with mortality.The peak leukocyte, ferritin, LDH, ALT, AST, CRP, and procalcitonin values during the hospitalisation were associated with mortality.
The vast majority of COVID-19 infections progress as an asymptomatic or mild systemic disease.However, it causes mortality in severe conditions such as pneumonia and respiratory failure (Savasi et al. 2020).Based on the WHO data, 80% of COVID-19 infections are asymptomatic-mild, 15% need additional oxygen support and 5% need mechanical ventilation (WHO 2020).Large-series studies involving only pregnant patients reported the severe COVID-19 rate as 5--18%, the need for intensive care as 4-8%, the need for invasive mechanical ventilation as 3-3.8%, and the need for ECMO as 0.4% (Allotey et al. 2020, Can et al. 2022, Savasi et al. 2020, Tunc ¸ et al. 2022).A meta-analysis by Juan et al. including 324 pregnant patients has reported that the rate of severe pneumonia development varied between 0-14% and most of them required intensive care (Juan et al. 2020).The study by Blitz et al. PCR (þ) in 462 pregnant patients found the maternal mortality rate in 15% of the patients admitted to intensive care and 25% of patients who required invasive mechanical ventilation (Blitz et al. 2020).Our study found that 9.4% of 328 pregnant patients diagnosed with COVID-19 and followed up in our hospital required intensive care and 1.5% required invasive mechanical ventilation.Only one patient was weaned off the mechanical ventilator and 4 patients died.The mortality rate in pregnant women followed up in our hospital with a diagnosis of COVID-19 was 1.2% (4/328) and it was 12.9% (4/31) in pregnant patients followed up in the ICU.The rate of need for intensive care and overall mortality rate in our study was similar to previous studies and the mortality rate in those who required mechanical ventilation was higher than in other studies.
The meta-analysis by Allotey et al. has reported that age, obesity, chronic hypertension, and the presence of diabetes are risk factors for intensive care admission and mortality, similar to the general population (Allotey et al. 2020).Obesity is an already known risk factor for death due to COVID-19 for both pregnant and non-obstetric patients (Knobel et al. 2021).Obesity is also associated with many co-morbidities such as gestational hypertension, diabetes, and cardiovascular diseases.Moreover, the disease itself is associated with insulin resistance, hyperglycaemia, altered adipokines, and chronic inflammation (Akg€ ol et al. 2022, O� glak et al. 2022, Olmez et al. 2022).It is obvious that there is a high risk for thrombosis in obese patients.Considering that thromboembolic events and abnormal cytokine response, which are common in Covid-19 patients, are correlated with the severity of the disease, the pathophysiological basis of the increase in mortality and morbidity caused by Covid-19 in obese patients will be better understood (Knobel et al. 2021, Sattar et al. 2020).In our study, obesity was found in 42% of pregnant women.In line with the literature, we found that maternal age and obesity were significantly higher in the group with mortality.One patient had gestational diabetes and two patients had obesity.Contrary to the study by Allotey et al, diabetes and chronic hypertension were not risk factors for mortality in our study.This may be due to the younger patient population in our study.

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It has been reported that the rate of preterm birth and caesarean section has increased in pregnant women with COVID-19 (Allotey et al. 2020, Easter et al. 2021, Nie et al. 2020, Savasi et al. 2020).They have reported that 45% of the patients, who had caesarean delivery due to maternal respiratory reasons, required intensive care (Savasi et al. 2020).The study by Williams et al. on 64 pregnant patients reported that the preterm birth and caesarean section rates were 88% and 94%, respectively (Pierce-Williams et al. 2020).The study by Rui et al. reported that 2 of 33 pregnant women had preeclampsia, 22 had gestational diabetes and 3 had pregnancy complications such as premature rupture of membrane (Nie et al. 2020).Similar to the literature, we found that the caesarean section rate (51.6%) and preterm birth rate (45.2%) were high in those who gave birth in our study.We detected preeclampsia in one patient, gestational diabetes in 2 patients, and abruptio placentae in one patient.
The study by Rui et al. reported that the 1-minute Apgar score was between 8-10 and the 5-minute Apgar score was  (Blitz et al. 2020).In our study, similar to the literature, the patients had a cough (87.1%), dyspnoea (96.8%), and fever (25.8%).
In the diagnosis and follow-up of COVID-19 in pregnant women, ground glass areas, consolidations, and patchy infiltrations due to ARDS and pneumonia can be seen in lung CT imaging (Ashokka et al. 2020, Chen R et al. 2020, Liu et al. 2020,).The meta-analysis by Farida et al. in 385 pregnant women reported that 121 patients had lung involvement on CT and 17 patients required intensive care (Elshafeey et al. 2020).In our study, we found that all patients followed in the ICU had pulmonary involvement on CT.Severe lung involvement was more common in patients with mortality.
More severe lymphopenia has been reported in patients with poorer results in terms of prognostic laboratory parameters (Chen J et al. 2020Huang et al. 2020, Wang et al. 2020, Wu et al. 2020, Zhou et al. 2020).Studies are reporting high levels of D-dimer and ferritin among other laboratory markers of severe disease (Can et al. 2022, Wang et al. 2020, Wu et al. 2020,).In adult COVID-19 patients, increased CRP, increased LDH, increased sedimentation, and decreased lymphocytes are among other laboratory abnormalities (Demirel Kaya et al. 2020, G€ okl€ u et al. 2023, Rodriguez-Morales et al. 2020,).The study by Shi et al. found that the most common laboratory abnormalities in pregnant patients with COVID-19 were increased D-dimer (82%), increased neutrophil rates (81%), increased CRP and decreased lymphocyte ratios (59%) (Shi et al. 2020).Our study was similar to previous studies in terms of laboratory values.However, in our additional analysis, we found that pregnant patients with mortality had high serum LDH, AST, ALT, ferritin, leukocyte, CRP, and procalcitonin ratios.

Limitations
Our study has some limitations.First, the study was retrospective and the sample size was limited.Therefore, there is a need for larger and multi-centre studies.Second, the outcomes of patients who did not give birth could not have been determined.Third, the effects of different disease severities on clinical outcomes in pregnant and non-pregnant women have not been compared.

Conclusion
COVID-19 infection progresses with asymptomatic or mild symptoms in most pregnant women.However, current evidence shows that COVID-19 infection may have serious maternal consequences during pregnancy.Our study results have shown that older maternal age and the presence of obesity are associated with increased mortality in pregnant patients.We have found that high serum LDH, AST, ALT, ferritin, leukocyte, CRP, and procalcitonin values and severe lung involvement in CT were mortality-related factors.Therefore, pregnant women with COVID-19 should be followed closely and necessary preparations should be made by determining the risk factors that affect mortality.

Table 1 .
Patient characteristics of Obstetric Patients in ICU care for COVID-19 Pneumonia.

Table 2 .
Clinical Characteristics of Obstetric Patients in ICU care for COVID-19 Pneumonia.
CT: computed tomography; HFOV: high frequency oscillatory ventilation; CPAP: continuous positive airway pressure; ICU: intensive care unit; P values for continuous variables were calculated by Student's t-test or Mann-Whitney U-test, and P values for categorical variables were calculated by the chi-square test, � statistically significant.

Table 3 .
(Pierce-Williams et al. 2020)etric Patients in ICU for COVID-19 Pneumonia.valueatthetime of admission, b peak value during hospitalisation, WBC: white blood cells; LDH: lactate dehydrogenase, ALT: alanine transaminase; AST: aspartate transaminase; CRP: c-reactive protein; p values for continuous variables were calculated by Student's t-test or Mann-Whitney U-test, and p values for categorical variables were calculated by the chi-square test, � statistically significant.9-10,andthelow-birth-weightratewas17.9%.They have reported an intensive care admission in one newborn(Nie et al. 2020).The meta-analysis by Allotey et al. has reported 18 stillbirths and 6 neonatal mortalities(Allotey et al. 2020).In our study, we observed one neonatal mortality among 19 patients due to terminated pregnancy.The study by Williams et al. has reported neonatal birth weight to be 2403 ± 858 g(Pierce-Williams et al. 2020).In our study, we found the neonatal birth weight to be 2396 ± 639 g and we considered that this is due to the increasing rate of preterm birth in critically ill patients.A prospective study by Sahin et al. in 100 pregnant women has reported that the symptoms of patients at the time of admission were cough (58.6%), fever (27.6%), and myalgia (51.7%).In terms of vital signs, tachycardia was reported in 24.1% and tachypnoea in 27.6%(S¸ahin et al.  2020).The study byBlitz et al.reported that the symptoms were cough (100%), dyspnoea (77%), and myalgia (46%) a