To the best of our knowledge, this is the first comprehensive case-control study in Iran that compares maternal and neonatal outcomes in positive COVID-19 with negative pregnant women. In summary, the most prevalent symptoms related to COVID-19 were fever (69.09%) and cough (58.18%). Less common symptoms included fatigue, diarrhea, shortness of breath, sore throat, and myalgia. Based on the present study’s findings, the laboratory profile of pregnant women with COVID-19 is similar to that of the control group except for C-reactive protein concentration, ALT, and AST. Chen et al. reported the most prevalent symptoms of COVID-19 infection in nine pregnant women were fever and cough [11]. Our results replicate the findings of a previous study in pregnant women with SARS in Hong Kong, which reported that fever was the predominant symptom [2].
One of the most critical concerns of obstetricians during the outbreak of COVID-19 is whether pregnant women will be worse off. Based on our findings, maternal and obstetric outcomes—neonatal in case groups—such as mode of delivery, premature rupture of membrane, postpartum hemorrhage, perineal resection rate, birth weight of neonates, Apgar score, and neonatal asphyxia rate were similar to pregnant women without COVID-19. In a case study with ten pregnant women infected with COVID-19, five underwent emergency cesarean section due to the fetus distress (three, 30%), premature rupture of membrane (one, 10%), and stillbirth (one, 10%) even though the severity of COVID-19 in most of these patients was as mild to moderate classified [3]. Another study was performed on 16 pregnant women with COVID-19 and 45 non-infected pregnant women in the third trimester of pregnancy. The results showed no increased risk of perinatal complications in women infected with COVID-19, including severe preeclampsia, premature rupture of membranes, fetal distress, meconium-stained amniotic fluid, preterm delivery, neonatal asphyxia, and postpartum hemorrhage [4]. These conflicting results may be due to selection bias. This suggests that the effects of COVID-19 in pregnancy require further study. In the last systematic review including seventeen studies comprising 84 live births, adverse outcomes including stillbirth (1.2%), neonatal death (1.2%), preterm birth (21.3%), low birth weight (< 2500 g, 5.3%), fetal distress (10.7%), and neonatal asphyxia (1.2%) were reported. The case-control study showed no significant differences in fetal and neonatal outcomes (fetal distress [p = 0.668], preterm birth [p = 0.686], and neonatal asphyxia [p = 0.441]) between groups [5]. However, available data on fetal and neonatal outcomes to date only include pregnant women infected in their third trimesters, same to our study. We did not follow our mothers who were COVID-19 positive until delivery to determine whether infection in the first or second trimester would increase the risk of adverse fetal and neonatal outcomes. Therefore, future follow-up studies of COVID-19 in pregnant women in early pregnancy to evaluate vertical transmission potential are urgently needed. In our study, all the neonates we tested were negative for COVID-19, consistently with previous reports [1, 6]. However, no conclusion can be drawn from our results about the possibility of intrauterine vertical transmission.
During the COVID-19 outbreak, it is proposed that cesarean delivery under general anesthesia has been the preferred mode of delivery to ensure a controllable delivery process, avoid emergency respiratory problems, and reduce the risk of infection exposure. However, the effects of these measures have not been fully proven. In a retrospective case series of 43 pregnant women with PCR-confirmed COVID-19 infection from two American centers, most women were obese, and 18 had additional co-morbidity. Among these 43 women, 18 gave birth, ten by uncomplicated vaginal deliveries, and eight by cesareans for obstetric reasons unrelated to COVID [7]. For common type COVID-19 patients in our hospital, vaginal delivery can be chosen if the relationship between the fetal head and pelvis is good. It is estimated that vaginal delivery can be performed within a short time. Pregnant women were given nasal catheter oxygen inhalation and wore medical surgical masks in the isolation delivery room. Freedom to move may alleviate pain and promote vaginal delivery during the labor process. If necessary, episiotomy, forceps delivery, and vacuum extraction can be used. Given our study’s small sample size, the possibility of vertical transmission during vaginal delivery still cannot be ruled out. Li et al. [8] confirmed and suspected COVID-19 infection had been included as one indication for cesarean section in their hospital because there was only one negative pressure operation room suitable for airborne precautions. However, two patients had vaginal delivery in positive pressure labor rooms before being diagnosed with COVID-19 pneumonia. No transmission events occurred in the doctors and midwives, wearing a full set of personal protective equipment (N95 respirators, protective gown, coveralls, gloves, and goggles) during the delivery procedure. In the expert consensus (2020), it is recommended that delivery and delivery timing is individualized based on obstetrical indications and maternal-fetal status [10].
Our findings have shown in the case group that preterm delivery was significantly more than pregnant women without COVID-19. Yan and colleagues reported a retrospective series expanded from four previous small case series, totaling 116 pregnant women with COVID-19 pneumonia from 25 hospitals in China [1, 3, 9]. Preterm delivery before 34- and 37-week gestation occurred in 2% and 21.2% of cases: 6.9% (8/116) of the women were admitted to ICU, 5.2% (6/116) required non-invasive and 1.7% (2/116) invasive ventilation, and 0.9% (1/116) ECMO. While these results were consistent with ours, the authors concluded that “there is no evidence that pregnant women with COVID-19 are more prone to develop severe pneumonia, in comparison to nonpregnant patients.” [10]. In Knight et al. (2020) [12], over half of all women admitted with COVID-19 infection have given birth; 12% were delivered preterm solely due to maternal respiratory compromise. Almost 60% of women gave birth by cesarean section; most cesarean deliveries were for indications other than the maternal center due to COVID-19 infection. However, during the COVID-19 study (2021), Danish premature birth rates concluded COVID-19 lockdown has drastically changed their lives by changing our working environment, reducing physical interactions, and increasing our focus on hygiene. This unusual situation is likely to have influenced several risk factors for premature birth [13]. Prematurity is a complex and challenging pathophysiological condition associated with an increased risk of long-term morbidity and mortality. It is the leading cause of death in children under 5 years of age [13]. Prevalence of preterm birth is different among regions and countries. Worldwide, an estimated 11.1% of all live births were born preterm in 2010 [14]. Based on the World Health Organization’s 2011 report, the prevalence of preterm delivery in 184 countries was between 5 and 18%, of which 60% of these deliveries occurred in Africa and South Asia. In low-income countries, on average, 12% of babies are born prematurely; in contrast, this rate is 9% in high-income countries [15]. However, in some high-income countries (such as the USA with 12% and Australia with 10.9%), premature birth is considerable [16]. The overall estimated prevalence of preterm in Iran was 9.2%. Based on some studies in Iran, low general health status, history of disease during pregnancy, family history of prematurity, previous preterm labor, history of last neonatal death, periodontal disease, decreased amniotic fluid, multiple pregnancies, infertility, and cervical incompetence were identified as risk factors of preterm labor [17]. Our regression analysis found that women with COVID-19 had a more than twofold increased odds of preterm labor. History of preterm delivery was also associated with high twofold odds of preterm labor.
Our study has several strengths, including greater sample size and the inclusion in a control group design for comparison. There are some limitations. First, most of the included patients presented as mild to moderate, which limited the interpretation of results. Second, due to the retrospective study’s nature, we could not test samples of the placenta, amniotic fluid, cord blood, and vaginal mucosa, which weakened our conclusion of no vertical transmission potential. Third, we did not take throat swab samples of all the newborns to check for COVID-19 infection. But more case-control studies are needed to ascertain the results. Serological studies and those using prospective data to identify women with either confirmed or presumed mild infection in pregnancy will be essential to fully assess potential impacts such as congenital anomalies, miscarriage, or intrauterine fetal growth restriction.
