Abstract

Objective

In this study, maternal and neonatal outcomes of pregnant women with positive severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) RNA tests were evaluated according to their symptomatic status. The clinical progression of SARS-CoV-2-positive pregnant women and the effect of coronavirus disease-2019 (COVID-19) on newborns was investigated.

Material and Methods

This retrospective cohort study was conducted at a tertiary pandemic hospital specializing in caring for pregnant women infected with SARS-CoV-2. We included patients with a positive SARS-CoV-2 polymerase chain reaction test at delivery, subdividing them into symptomatic and asymptomatic groups.

Results

Two hundred and forty-nine patients were included in the study. The mean age of the pregnant women in the symptomatic group was higher than those in the asymptomatic group (p=0.001). The iatrogenic preterm birth rates in the symptomatic and asymptomatic groups were 43.37% and 8.43%, respectively (p<0.001). Cesarean section rate was higher in symptomatic group (p=0.01). Maternal death was significantly higher in symptomatic pregnant women (p<0.001). The neonatal intensive care unit admission rate was higher in symptomatic pregnant women (p<0.001).

Conclusion

The maternal and fetal outcomes for mothers with symptomatic infections tend to be worse, highlighting the importance of careful management, good follow-up and the advisability of closer monitoring.

Introduction

In December 2019, pneumonia cases of unknown origin were reported in the city of Wuhan, China (1). The virus isolated from respiratory tract samples taken from these cases was named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) (2). The virus resulted in the coronavirus disease-2019 (COVID-19) global pandemic (3). Due to the physiological adaptation mechanisms induced by pregnancy, it was predicted that COVID-19 may progress more severely in pregnant women. Many researchers have attempted to define the clinical course of COVID-19 in pregnant women, how the disease affects pregnancy and delivery results, which factors affect the severity of the disease and how much it worsens these results (4). In this study, maternal and neonatal outcomes of pregnant women with positive SARS-CoV-2 RNA tests at delivery were evaluated according to their symptomatic status. Anticipating the complications that may occur in the management of symptomatic COVID-19-positive pregnant women, it was planned to implement necessary medical interventions earlier in the study population. Whether there was a difference between the postpartum clinical course of symptomatic COVID-19-infected pregnant women and the clinical course of their newborns and asymptomatic COVID-19 pregnant women was investigated.

Material and Methods

This retrospective cohort study was conducted at a tertiary pandemic hospital specializing in caring for pregnant women infected with SARS-CoV-2. The data of patients who were confirmed to have COVID-19 by reverse transcription polymerase chain reaction (PCR) test from the nasopharyngeal swab and who gave birth between March 1, 2020, and December 31, 2022, were analysed retrospectively from electronic health records. The collected data were anonymized. The procedures followed were approved by the ethical standards of the responsible committee on human experimentation and in keeping with the Helsinki Declaration of 1975, revised in 2013. COVID-19-positive patients with other reasons for elevated serum liver transaminases, C-reactive protein (CRP), leukocytes, and chronic illness were excluded from the study. Lung ultrasonography (LUS) before delivery and thorax computed tomography (CT) after delivery were performed in all pregnant women. Patients with a positive SARS-CoV-2 PCR test at delivery were included, subdivided into symptomatic and asymptomatic groups. Demographic characteristics, obstetric outcomes, newborn outcomes, maternal laboratory results, maternal intensive care unit (ICU) admission, maternal mortality, and clinical features were compared between the two groups. The University of Health Sciences Turkey, Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital Institutional Ethics Committee approval was granted (approval number: 165, date: 14.12.2022).

Statistical analysis

Data were statistically analysed using the SPSS, v.21.0 (IBM Inc., Armonk, NY, USA). The Shapiro-Wilk test was used to check whether data were normally distributed. Continuous variables are expressed as mean and standard deviation or median and range, as appropriate. Categorical variables were expressed as frequency and percentage. The Independent t-test was used to compare continuous variables, as appropriate. The Pearson’s chi-squared test or Fisher’s exact test were used to compare qualitative data. A logistic regression analysis was performed. A p-value <0.05 was considered statistically significant.

Results

The study included 249 pregnant women, of whom 166 (66.66%) were asymptomatic and 83 (33.34%) were symptomatic. Of the symptomatic patients, 57 (68.7%) had shortness of breath, 22 (26.5%) had cough, and 4 (4.8%) had fever.

The mean ages of the pregnant women in the symptomatic group were higher than those in the asymptomatic group (p=0.001) (Table 1). The nationalities of the pregnant women were evaluated and 155 (93.37%) in the asymptomatic group were Turkish and 11 (6.63%) were ethnically Arabic, while in the symptomatic group 80 (96.38%) were Turkish and 3 (3.62%) were Arabic. There was no significant difference between the nationalities of the pregnant women in the two groups (p=0.333). There was no significant difference between blood groups (p=0.403) or rhesus (Rh) factor status (p=0.894) between the groups. The two groups did not differ for gravida (p=0.091), parity (p=0.133) or history of abortion (p=0.196).

Gestational weeks of pregnancies in the symptomatic group were lower than in the asymptomatic group (p<0.001) (Table 2). The preterm birth rate in the symptomatic group was 48.2% (n=40), significantly higher than the asymptomatic group where it was 14.5% (n=24) (p<0.001). Premature rupture of membranes (PROM) developed more frequently in asymptomatic pregnant women (p<0.001). The vaginal delivery rate was higher in asymptomatic pregnant women, while the cesarean section rate was higher in symptomatic pregnant women (p=0.01). Both maternal ICU admission and maternal death were significantly higher in symptomatic pregnant women (p<0.001). All of the pregnant women in the symptomatic group were diagnosed with COVID-19 pneumonia by thorax CT and 78 (94%) by LUS (p<0.001).

Symptomatic women had a higher rate of leukocytosis (p<0.001) and lymphopenia (p<0.001) than asymptomatic patients. Other laboratory parameters, such as CRP (p<0.001), alanine aminotransferase (ALT) levels (p=0.018), aspartate aminotransferase (AST) levels (p=0.01), blood urea nitrogen (BUN) (p<0.001), creatinine (CR) levels (p=0.029), and international normalized ratio values (p=0.013) were also significantly higher in symptomatic pregnant women (Table 3).

When the results of newborn parameters were evaluated, birth weight (p<0.001), newborn length (p=0.001), newborn head circumference (HC) (p<0.001), 1 minute Activity pulse grimace appearance respiration (APGAR) score (p=0.016), and 5 minute APGAR score (p=0.012) was lower in symptomatic women. The neonatal intensive care unit (NICU) admission rate was higher in symptomatic pregnant women (p<0.001). The rates of indications for NICU admission, including respiratory distress (p=0.009) and prematurity (p=0.012), were higher in the symptomatic group (Table 4).

The delivery rate due to the indication of maternal general condition disorder was higher in the symptomatic group (p<0.001). The birth rate due to PROM (p=0.002), elective cesarean section (p=0.007), and pregnant in term action (p=0.002) was higher in the asymptomatic group (Table 5).

A logistic regression model was developed to assess risk factors in women within the symptomatic group. This showed that symptomatic infection was associated with an increased risk of iatrogenic preterm birth [odds ratio (OR): 8.31, 95% confidence interval (CI): 4.13-16.72; p<0.001] cesarean section (OR: 2.04, 95% CI: 1.15-3.62; p=0.013), maternal death (OR: 1.27, 95% CI: 1.14-1.43; p<0.001), and NICU admission (OR: 4.81, 95% CI: 2.26-8.69; p<0.001) (Table 6).

Discussion

The first COVID-19 case was seen in Turkey on March 11, 2020. On the same date, the World Health Organization declared the coronavirus a pandemic (5). During the course of the pandemic, 102,174 (0.12%) people died due to COVID-19 in Turkey in three years (6). In the present study, the clinical progression of SARS-CoV-2 positive pregnant women according to their symptomatic status was investigated. We found a relatively high rate of asymptomatic pregnant women (n=166, 66.6%). In the study of Vousden et al. (7), the rate of asymptomatic women was 66% and in the systematic review by Allotey et al. (4), the rate of asymptomatic pregnant women was 54-77%. The high rate of asymptomatic patients has been associated to the vaccines developed against COVID-19. The severity of the disease decreased with increasing use of the vaccine. We found the mean age of symptomatic women to be significantly higher than asymptomatic women, a finding also reported by Minisha et al. (8). In the present study, it was also shown that the risk of severe diseases rises with advancing age. The escalation in disease severity correlates with the rise in age-related comorbidities, heightened susceptibility to diseases, and the age-associated diminishing of immunocompetence (9). This heightened risk of severe diseases contributes to symptomatic manifestations in patients.

Interestingly, it was observed that pregnant women who contracted COVID-19 exhibited a higher rate of symptomatic cases in 2021 and, conversely, a higher rate of asymptomatic cases in 2022 (p=0.015 and p=0.028, respectively). We attribute this reduction in symptomatic infections among pregnant women in 2022 to the widespread adoption of vaccines. Citizen vaccination programmes against the coronavirus commenced in Turkey in January 2021, with a firm recommendation for pregnant women to receive the vaccine published in June 2021 (10). Despite this recommendation, vaccine hesitancy persisted among pregnant women, resulting in an increase in coronavirus vaccination rates among this demographic in the last half of 2021.

In the present study gestational age at birth was significantly lower and the number of iatrogenic preterm births was significantly higher amongst symptomatic patients compared to asymptomatic women. In a systematic review by Khan et al. (11), the rate of preterm birth was also reported to be higher in symptomatic patients. We distinguished between iatrogenic and spontaneous preterm births. We found that symptomatic COVID-19 infection did not affect the spontaneous preterm birth rate (p=0.689), but significantly increased the iatrogenic preterm birth rate (p<0.001). For women in the symptomatic group, the prominence of vital sign deterioration was attributed to the severity of the disease. To avert fatal consequences in fetuses of mothers with compromised vital functions and to alleviate the physiological burden of pregnancy on the mother, the decision to induce labor was made following the administration of necessary agents for fetal lung maturity. The risk of iatrogenic preterm birth was 8.31 times higher in the symptomatic group in the present study and we believe that the higher rates of iatrogenic preterm birth in the symptomatic group stem from the impairment of the maternal general condition. Many studies in the literature have not distinguished between spontaneous and iatrogenic preterm births.

We found higher cesarean rates in symptomatic women (p=0.01). In the study conducted by Şahin et al. (12), the cesarean delivery rate in pregnant women with COVID-19 was reported to be 66.4%. Metz et al. (13) found that cesarean section rates were higher in severe COVID-19 patients than in asymptomatic patients. During pregnancy, changes in the immune system, diaphragmatic elevation, edema in the respiratory tract and increased oxygen consumption occur. These physiological adaptation mechanisms increase the susceptibility of pregnant women to respiratory tract infections (14). Attempting normal birth in mothers with compromised vital functions is somewhat risky, so in cases where the decision for emergency delivery was taken, a cesarean section was performed. This decision was influenced by an increeased oxygen requirement, worsening respiratory failure, worsening clinical condition, and loss of consciousness. The risk of caesarean section was 2.04 times higher in the symptomatic group in the present study and we attribute this higher cesarean delivery rate in women in the symptomatic group to the development of potentially fatal complications arising from COVID-19 infection.

We found high rates of maternal ICU admission (48.2%) and maternal mortality (21.7%) in the symptomatic group. Similarly, Metz et al. (13), reported maternal ICU admission at 35.5% but lower maternal mortality (4.3%) rates in women with severe COVID-19 infection (10). Hantoushzadeh et al. (15) reported that 77.77% of pregnant women with critical COVID-19 died. Tunç et al. (16), demonstrated that all maternal deaths from COVID-19 infection involved reported symptoms of shortness of breath and cough upon initial hospital admission. The risk of maternal death was 1.27 times higher in the symptomatic group in our cohort. Pregnancy adversely affects COVID-19 progression, maternal ICU requirement and maternal mortality rates increase compared to non-pregnant women (17).

In symptomatic women, COVID-19 pneumonia findings detected by radiological methods were more prevalent than in the asymptomatic group (p<0.001) and were present in 78 (94%) of the pregnant women in the symptomatic group with LUS examination before delivery. The finding of COVID-19 pneumonia was confirmed in all women in the symptomatic group with thorax CT after delivery. The diagnostic efficacy of LUS in detecting radiological manifestations of COVID-19 pneumonia appears to be comparable to that of thoracic CT. Lu et al. (18) reported that the sensitivity of LUS was higher in severe disease. In the study by Karacaer et al. (19), the detection rates for confirmed COVID-19 cases were similar at 74% for thoracic CT and 70% for LUS. We performed LUS on admission in all patients because LUS is easy to apply, does not contain radiation, and allows us to obtain radiological findings at the beginning of the hospitalization. The LUS findings were evaluated without the need for a radiologist. Moreover, the treatment of patients with suspicious LUS findings was started at an early stage of admission.

When we examined the laboratory parameters of the pregnant women, leukocytosis, lymphopenia, and elevated CRP were prevalent in the symptomatic group (p<0.001). In the study of Grgić et al. (20), lymphocyte levels were lower and leukocyte and CRP values were higher in symptomatic women. London et al. (21) found lower lymphocyte levels in the symptomatic group. In the study of Grechukhina et al. (22), CRP values were found to be useful parameters in predicting the severity of the disease at the time of admission to the hospital. The coronavirus viral genome and antigenic determinants damage the lymphocyte cell skeleton, leading to disintegration. Infection-induced factors, such as soluble Fas Ligand and vascular cell adhesion molecule-1 and the occurrence of cytokine storm exacerbate lymphopenia by inducing programmed death in lymphocytes. In cases of severe pneumonia, lymphocyte counts decrease even further (23). CRP, an acute-phase reactant, serves as a reliable and well-known biomarker of inflammation. It is typically unmeasureable in healthy individuals, with levels rising in response to viral or bacterial infections, concurrently with leukocytes, as part of the reaction of the immune system to inflammatory stimuli (24).

In the present study, prenatal hemoglobin values were significantly lower in the symptomatic group. A meta-analysis conducted by Taneri et al. (25) also found that hemoglobin levels were lower in patients with severe COVID-19 compared to those with moderate severity. Moreover, it has been observed that clinical conditions necessitating intensive care admission due to COVID-19 are associated with even lower hemoglobin levels (25). The mechanism explaining the association between low hemoglobin and COVID-19 infection focuses on iron metabolism and compromised iron utilization in the body. The increased viral load in COVID-19 prevents iron use in erythrocyte biochemical pathways. In addition, iron is crucial for viral particle biogenesis and virus replication. While the host’s natural immunity attempts to restrict the virus from using iron, it can exacerbate the anemia (26). Consequently, hemoglobin levels tend to decrease during viral infections.

There were elevated levels of ALT, AST, BUN, and CR in symptomatic women. Severe COVID-19 is known to increase liver and kidney function biomarkers due to multiple organ involvement. The involvement of these organs is linked to the expression of the angiotensin-converting enzyme 2 (ACE2) receptor. The ACE2 receptor facilitates the entry of SARS-CoV-2 into cells, and its presence in the liver and kidneys leads to viral uptake and organ damage (27). Enzymes surge due to organ damage, and their elevation correlates with the severity of COVID-19. A study, excluding chronic liver patients, demonstrated that liver damage intensifies with the severity of COVID-19 and the emergence of the need for intensive care (28).

In the present study, newborns born to the symptomatic group of women had lower birth weight, length and HC. Jenabi et al. (29) also showed the number of low birth weight newborns to be higher in the symptomatic group. The higher rates of preterm birth in the symptomatic group resulted in lower neonatal anthropometric measurements. Furthermore, NICU requirement was higher in the symptomatic group. In the study conducted by Çelik et al. (30), it was reported that the risk of low birth weight, NICU admission, and prematurity increased in babies of mothers with severe COVID-19. In the present study the risk of NICU admission was 4.81 times higher in the symptomatic group. We also believe that the adverse in-utero environment in symptomatic pregnant women with COVID-19 and iatrogenic preterm births contribute to increased NICU rates (31).

COVID-19 was detected in two (1.2%) newborns in the asymptomatic group of our cohort. No infected newborns were detected in the symptomatic group. Two tests were performed to detect SARS-CoV-2 transmission to newborns in the hospital. The first test was done in the first hour after birth, and the second test was performed 24 hours after birth using the nasopharyngeal swab RT-PCR method. The overall congenital infection rate was 0.81% (n=2). In a systematic review by Allotey et al. (32), the rate of congenital infection was <2%. Vertical transmission was detected at a rate of 1.8% (33). In addition, we think that SARS-CoV-2 is transmitted to the newborn by the fecal-oral route during delivery, droplets during breastfeeding, and may be of nosocomial origin too.

Study limitations

We did not follow up involved women after discharge to monitor possible long-term adverse outcomes. We did not obtain data on the coronavirus variant types and vaccination status of all women. However, we did distinguished between iatrogenic and spontaneous preterm births and found that symptomatic COVID-19 infection did not affect the spontaneous preterm birth rate, but increased the iatrogenic preterm birth rate.

Conclusion

The severity of COVID-19 increased with age. Iatrogenic preterm births and cesarean sections were more common in symptomatic COVID-19 patients because maternal general condition disorder was more prevalent. NICU admission, maternal ICU admission, and maternal mortality rates were higher amongst women with symptomatic COVID-19 infection. We recommend that clinical follow-up is important and closer follow-up is necessary in these women.