Short-term outcomes of COVID-19 in pregnant women unvaccinated for SARS-CoV-2 in the first, second, and third trimesters: a retrospective study

ABSTRACT BACKGROUND: Coronavirus disease 2019 (COVID-19) may be asymptomatic or symptomatic in pregnant women. Compared to non-pregnant reproductive-aged women, symptomatic individuals appear to have a higher risk of acquiring severe illness sequelae. OBJECTIVES: We assessed the clinical and laboratory characteristics and outcomes of pregnant COVID-19 patients unvaccinated for severe acute respiratory syndrome coronavirus 2 according to the trimester of pregnancy. DESIGN AND SETTING: This was a retrospective observational study conducted in a tertiary-level hospital in Turkey. METHODS: This retrospective study reviewed the clinical and laboratory characteristics and outcomes of 445 pregnant COVID-19 patients hospitalized during the first, second, and third trimesters of pregnancy and 149 other pregnant women as controls in a tertiary center from April 2020 to December 2021. All participants were unvaccinated. RESULTS: Overall, the study groups were comparable in terms of baseline clinical pregnancy characteristics. There was no clear difference among the study participants with COVID-19 in the first, second, and third trimesters of pregnancy. However, a considerably high number of clinical and laboratory findings revealed differences that were consistent with the inflammatory nature of the disease. CONCLUSIONS: The study results reveal the importance of careful follow-up of hospitalized cases as a necessary step by means of regular clinical and laboratory examinations in pregnant COVID-19 patients. With further studies, after implementing vaccination programs for COVID-19 in pregnant women, these data may help determine the impact of vaccination on the outcomes of pregnant COVID-19 patients.


INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a ribonucleic acid virus that causes coronavirus disease 2019 . 1,2 Within three months of the first case of COVID-19 being discovered at the end of 2019, the World Health Organization labeled the disease a pandemic. 3 Although most COVID-19 patients present with mild to moderate symptoms, 4 a small proportion of patients develop severe disease presentations, including respiratory failure, myocarditis, septic shock, and multiorgan failure. 5 Acute respiratory distress syndrome develops in up to one-third of individuals hospitalized with severe pneumonia. 6 Despite maximal cardiac support and invasive mechanical ventilation, mortality remains high in this population. 7,8 Pregnant women comprise a distinct subgroup among those at increased risk of severe COVID-19 as these women are more sensitive to certain viral infections than the general population. 9 The pathogenesis of SARS-CoV-2 infection in pregnancy is yet unknown. 10 Affected pregnant women, like other COVID-19 patients, can be asymptomatic; however, they may also have several complications that worsen the outcome of their pregnancy. This is because during the course of their pregnancy, important pathophysiological deterioration can occur, including the development of increased pro-inflammatory states, cytokine production, and oxidative stress, the illness in pregnant COVID-19 patients, is linked to perinatal risks and pregnancy outcomes. 12,13 Pregnant women with suspected or confirmed COVID-19 should receive comprehensive obstetric management as well as mental health and psychosocial support to avoid complications 14 ; in addition, they should be encouraged to receive regular perinatal care. 15 For

OBJECTIVE
This study aimed to assess the clinical and laboratory characteristics and outcomes of pregnant COVID-19 patients unvaccinated for SARS-CoV-2 during the first, second, and third trimesters of pregnancy.

This retrospective study included 445 pregnant COVID-19
patients and 149 healthy pregnant women as controls. Table 1 shows the clinical characteristics of pregnant women with and without COVID-19. Pregnant COVID-19 patients were divided into three groups according to the time of diagnosis in the first, second, and third trimesters. The rate of Arab immigrants in the control group was significantly higher than in the other groups (P < 0.05). In addition, the gestational age at delivery was significantly higher in the control group compared to the second-trimester participants (P < 0.05). There were no significant differences among the study groups regarding maternal age, gravidity, parity, pre-pregnancy body mass index, smoking status, use of assisted reproductive technology, mode of delivery, or maternal comorbidities (P > 0.05). Table 2 shows the laboratory parameters of pregnant women with and without COVID-19. The median lymphocyte, platelet count, and blood urea nitrogen values were significantly higher in the controls and in the first-trimester participants compared to the second-and third-trimester participants (P < 0.05). The median ART = assisted reproductive technology; BMI = body mass index; DM = diabetes mellitus; HT = hypertension; NS = non-significant. Data are presented as medians with minimum and maximum values or as counts with percentages and were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons or the chi-square test as appropriate. Results of the pairwise comparisons were denoted with a letter ( a or b ). There was no significant difference between/among the study groups if they are marked with the same letter (P > 0.05), and there was a significant difference between/among the study groups if they are marked with different letters (P < 0.05).
platelet counts were significantly lower in the first-, second-, and third-trimester participants than that in the controls (P < 0.05).
The median values of aspartate aminotransferase were significantly higher in the first-, second-, and third-trimester participants than that in the controls (P < 0.05). The mean values of hemoglobin and hematocrit were significantly higher in the first-trimester participants than those in the other groups (P < 0.05). The median white blood cell count was significantly higher in the control group than those in the other groups (P < 0.05). The median white blood cell counts were significantly higher in the third-trimester participants than those of the first-and second-trimester participants (P < 0.05). The median neutrophil count was significantly higher in the control group than those in the other groups (P < 0.05).
The median neutrophil counts were significantly higher in the second-and third-trimester participants than that in the first-trimester participants (P < 0.05). The median C-reactive protein level was significantly lower in the control group than those in the other groups (P < 0.05). The median C-reactive protein values were significantly lower in the first-trimester participants than those of the second-and third-trimester participants (P < 0.05).
The median ferritin values were significantly higher in the firstand second-trimester participants than that of the third-trimester participants (P < 0.05). Compared to the values of the other groups, the median creatinine values were significantly lower in the second-trimester participants (P < 0.05). The median alanine aminotransferase value was significantly lower in the control group than those in the other groups (P < 0.05). The median alanine aminotransferase values were significantly lower in the third-trimester participants than those of the first-and second-trimester participants (P < 0.05). The median lactate dehydrogenase values were significantly higher in the controls and in the third-trimester participants than those of the first-and second-trimester participants (P < 0.05). The median D-dimer levels were significantly higher in the third-trimester participants than those of the firstand second-trimester participants (P < 0.05). There were no significant differences in the monocyte and fibrinogen levels among the study groups (P > 0.05). There were no significant differences among the first-, second-, and third-trimester participants regard- ing the values of direct, indirect, and total bilirubin, maternal pH, and bicarbonate (P > 0.05).
The clinical presentations of pregnant women with and without COVID-19 are presented in Table 3. The rates of intrahepatic cholestasis of pregnancy and intrauterine growth restriction were significantly lower in the controls and third-trimester participants than those in the first-and second-trimester participants (P < 0.05). The rate of preeclampsia was significantly lower in the control group than those in the other groups (P < 0.05). The rates of preterm birth and preterm prelabor rupture of membranes were significantly lower in the controls and first-trimester participants than those in the second-and third-trimester participants (P < 0.05). The rate of placental abruption was significantly higher in the third-trimester participants than those in the other groups (P < 0.05). The rates of oligohydramnios were significantly higher in the first-and second-trimester participants than those in the third-trimester participants (P < 0.05). The median length of hospitalization was significantly higher in the COVID-19 participants than that in the controls (P < 0.05). The median lengths of hospitalization were significantly higher in the second-and third-trimester participants than those in the first-trimester participants (P < 0.05). The proportion of second-trimester COVID-19 participants without drug use was significantly higher than those of the firstand third-trimester participants (P < 0.05). More second-trimester participants were using antiviral drugs compared to the first-and third-trimester participants (P < 0.05). The proportions of COVID-19 participants with no computed tomography imaging data and who presented with pneumonia findings in their computed tomography imaging were significantly higher in those in their secondand third-trimesters than in those in their first-trimester (P < 0.05).  Parametric data are presented as means with standard deviations and were analyzed using an analysis of variance (ANOVA) test followed by Tukey's test for pairwise comparisons as appropriate. Non-parametric data are presented as medians with minimum and maximum values and were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons as appropriate. The results of the pairwise comparisons were denoted with letters ( a , b , or c ). There was no significant difference between/among the study groups if they are marked with the same letter (P > 0.05), and there was a significant difference between/among the study groups if they are marked with different letters (P < 0.05). Admission to the ICU, n (%) 0 (0%) 8 (6.7%) 18 (6.5%) -NS  There was no significant difference between/among the study groups if they are marked with the same letter (P > 0.05), and there was a significant difference between/among the study groups if they are marked with different letters (P < 0.05).

Length of stay in the ICU (days)
The proportions of the controls and COVID-19 participants in their third-trimester requiring admission to neonatal ICUs were significantly higher than those of the COVID-19 participants in their first-and second-trimesters (P < 0.05). There were no significant differences among the study groups in terms of stillbirth rates, birth weights, Apgar scores at 1 and 5 min, and cord blood pH values (P > 0.05). There were no significant differences among the In a recent study evaluating the clinical and laboratory data of pregnant COVID-19 patients who did not have any comorbid conditions, some severe clinical symptoms were observed in the third-trimester patients. Additionally, the need for intensive care, the rates of cesarean section delivery, and the rates of preterm delivery were all elevated among pregnant women. 16 In our study, participants with comorbidities were also included, and we found no significant difference among the pregnant COVID-19 patients in the first, second, and third trimesters in terms of rates of disease severity, admission to the ICU, and mode of delivery. However, in our study, the preterm birth rate was significantly higher in the first-trimester participants than in those diagnosed in the second and third trimesters.
Many studies have examined the laboratory characteristics of COVID-19 patients. 17 It has been suggested that pregnant COVID-19 patients' blood parameters be closely monitored, and variations in these inflammatory indices have been linked to patient prognoses. 21 Thrombocytopenia occurs in 5-40% of non-pregnant COVID-19 patients. 23 The virus may directly infect bone marrow cells, or the immune system may aggregate and destroy platelets, thereby increasing platelet consumption via microthrombi production. 24 In a study that included 21 COVID-19 patients in the second and third trimesters of pregnancy and 48 patients without COVID- According to some studies, individuals may also exhibit signs and symptoms associated with effects on other organs.