Maternal Coronavirus Infections and Neonates Born to Mothers with SARS-CoV-2: A Systematic Review

The coronavirus disease 2019 (COVID-19) pandemic is continuously affecting the lives of all people. Understanding the impact of COVID-19 on pregnancy in terms of morbidity, mortality, and perinatal maternal and fetal outcomes is essential to propose strategies for prevention and infection control. Here, we conducted a systematic review to investigate pregnant women infected with COVID-19 in terms of signs and symptoms, type of delivery, comorbidities, maternal and neonatal outcomes, and the possibility of vertical transmission. A search on Embase and PubMed databases was performed on 31 October 2020. Observational studies and case reports on pregnant women infected with COVID-19 were included without language restrictions. The 70 selected studies included a total of 1457 pregnant women diagnosed with COVID-19 in the first, second, and third trimesters of pregnancy. The most common signs and symptoms were fever, cough, and nausea. The most frequent comorbidities were obesity, hypertensive disorders, and gestational diabetes. Among maternal and fetal outcomes, premature birth (n = 64), maternal death (n = 15), intrauterine fetal death or neonatal death (n = 16), cases of intrauterine fetal distress (n = 28), miscarriage (n = 7), decreased fetal movements (n = 19), and severe neonatal asphyxia (n = 5) were the most frequent. Thirty-nine newborns tested positive for SARS-CoV-2. Additionally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in the placenta (n = 13) and breast milk (n = 6). This review indicates that COVID-19 during pregnancy can result in maternal, fetal, and neonatal complications. In addition, SARS-CoV-2 viral exposure of neonates during pregnancy and delivery cannot be ruled out. Thus, we highlight the need for long-term follow-up of newborns from mothers diagnosed with COVID-19 to establish the full implications of SARS-CoV-2 infection in these children.


Introduction
Coronavirus disease 2019 (COVID- 19) is an infectious condition caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first reported in December 2019 after an outbreak of pneumonia of unknown etiology was identified in Wuhan, China [1,2]. Currently, the virus continues to spread to different regions of the world, including several countries in Europe and the United States, which reported the highest number of confirmed cases and deaths in March and April [2]. disagreements about the articles were discussed by the research team to make a consensus decision. The data extracted from the studies were as follows: (1) Signs and symptoms of the mother and fetus, (2) gestational age and pregnancy results (maternal or fetal death), (3) type of delivery (natural, emergency or elective cesarean section, abortion, or complications), and (4) possibility of SARS-CoV-2 vertical transmission. The quality of the studies was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) [16,17]. The quality of the evidence from the studies was classified into four categories: High, moderate, low, or very low [16,17].

Results
A flow diagram based on the PRISMA guideline was created to represent the different stages of article selection (Figure 1).

Study Selection
From the 1720 studies retrieved, 1708 were identified in Embase and PubMed while 12 were taken from other sources. After exclusion of duplicate studies, a total of 1035 titles and abstracts were collected. Among these, 218 manuscripts were retrieved for full reading by the three authors (C.R.M., C.L.M., and J.T.A.) independently. A total of 70 studies met the inclusion criteria [5,7,9,. The main findings of the selected studies are shown in Table 1.
A total of 1457 pregnant women diagnosed with COVID-19 and 1042 newborns from infected mothers were included. Maternal SARS-CoV-2 infection was diagnosed by reverse transcriptase-polymerase chain reaction (RT-PCR or PCR) of nasopharyngeal swabs and sputum samples [9].

Gestational Age
Twenty-one (1.4%) of the pregnant women were in the first trimester, 97 (6.6%) in the second trimester, and 1339 (91.9%) in the third trimester of pregnancy.

Type of Delivery
In terms of the type of delivery, 597 (57.3%) underwent elective cesarean section, 36 (3.4%) received emergency cesarean sections, and 364 (34.9%) went through spontaneous vaginal delivery.

Neonatal and Fetal Outcomes
Among neonates born to infected mothers, 187 (17.9%) required admission to neonatal ICUs [18,26,33,41,50,55,56,63,65,66,85]. There were 16 (1.5%) total cases of neonatal death and fetal intrauterine death [20,36,39,41,42,48,49,63,70]. Karami et al. reported a case of an infected pregnant woman who vaginally delivered a cyanotic fetus in the third trimester [39]. In the study by Zhu et al. [67], a newborn delivered at 34 + 5 weeks of gestation from a 30-year-old mother with COVID-19 experienced refractory shock, gastric bleeding, multiple organ failure, and disseminated intravascular coagulation. There were four total cases of fetal demise: One at 17 weeks [49] and three at the third trimester of pregnancy [42,48,63]. Lookken et al. [48] reported one case of stillbirth at 38.7 weeks in which the qualitative PCR tests of placental and fetal tissue were negative for SARS-CoV-2 and cytomegalovirus. However, the delay between fetal death and sample extraction for PCR analysis may have led to inaccurate results.
In the study by Li et al. [42], biochemical examination of umbilical cord blood at birth revealed a marked increase in myocardial enzymes, suggesting severe damage of the fetal myocardium. Considering severe hypoxia, the possibility of immunologic damage cannot be ruled out. This may have led to difficulties in resuscitation and eventually neonatal death. Maternal hypoxia and unstable circulation secondary to COVID-19 can endanger the fetus and cause intrauterine fetal death [42].
In one study, the presence of SARS-CoV-2 was investigated in vaginal discharge and amniotic fluid in four pregnant women with mild acute symptoms of COVID-19 who underwent amniocentesis during the second trimester of pregnancy [72]. In addition, in another study, a case of vaginal delivery without complications was described in a mother with COVID-19 [47]. The test for neonatal COVID-19 24 h after delivery was still negative despite the fact that the infant was breastfed and not separated from the mother [71]. RT-PCR Placental swabs (both maternal and fetal sides) were obtained Placental tissue was sent for PCR and histopathologic examination Nasopharyngeal swabs were obtained from the neonate on the day of birth, day 2, and day 7, after thorough cleansing of the baby and before contact with the mother Cesarean section (n = 1) All 3 of the neonate's nasopharyngeal swabs were positive for SARS-CoV-2 gene targets via RT-PCR testing; neonatal plasma tested positive on day 4, and stool was positive on day 7 (1) The newborn had positive NP swabs immediately at birth, after 24 h, and after 7 days; he remained asymptomatic (2) Neonatal NP swab was 60 negative at birth and turned positive on day 7, with no contact between mother and neonate during that period    Histological, immunohistochemical, in situ SARS-CoV-2 RNA, RNA in situ hybridization and electron microscopy

Discussion
This systematic review gathered evidence available on pregnancy and SARS-CoV-2 infection from the international literature to investigate signs and symptoms, type of delivery, comorbidities, clinical outcomes (maternal and neonatal), and vertical transmission risk of COVID-19. This study included a significant number of newborns and pregnant women diagnosed with COVID-19 in the first, second, and third trimesters of pregnancy. Although most studies which were included were case reports or case series that have low levels of evidence quality, these are still important in the current context due to the need for information to support public health policies.
In terms of signs and symptoms of COVID-19, fever above 37.0 • C was the most frequent symptom reported by pregnant women, followed by cough and nausea in the prenatal period. In the postpartum period, subjects were reported to experience fever (37.8-39.33 • C) and a general worsening of the condition, especially in those who were initially asymptomatic. Among symptomatic pregnant women, 4.99% were admitted in the ICU. The results in our study are consistent with those of studies in the general population, where fever and coughing were the most reported symptoms [87].
Obesity and hypertensive disorders were the most reported comorbidities in pregnant women with COVID-19. It is noted that the majority of the pregnant women did not have serious complications, with a low occurrence of maternal death (1.0%) and premature rupture of the membrane (2.5%). However, pregnancy complications, including gestational diabetes and gestational hypertension, were reported. Many pregnant women presented with worsening of the general condition that required an induced delivery or emergency cesarean section. However, we found that the maternal risk in pregnant women diagnosed with COVID-19 was relatively low.
In contrast, 17.9% of newborns were admitted in the neonatal ICU. Fetal and neonatal complications including premature delivery (6.1%), fetal distress (2.7%), decreased fetal movements (1.8%), and fetal and neonatal death (1.5%) were identified. There were also cases of miscarriage and severe neonatal asphyxia. Therefore, we hypothesize that there is a greater risk of fetal and neonatal complications in the first and second trimesters of pregnancy.
This systematic review included cases where SARS-CoV-2 RNA was detected in the placenta (n = 13), breast milk (n = 6), and neonates (n = 39). It is important to note that only five studies confirmed a diagnosis within the first 12 h of birth. In other studies, SARS-CoV-2 was detected 12 h after birth, hinting at the possibility of late-onset neonatal infection. Nevertheless, we highlight that 92% of newborns from mothers infected with COVID-19 did not acquire the infection during birth.
Although there is a theoretical risk of vertical transmission, it seems to be low and, so far, remains poorly understood. It has been reported that the placental barrier does not allow for the passage of SARS-CoV-2 [88]. However, there is evidence of histopathologic placental changes in women infected with COVID-19, showing poor maternal vascular perfusion and inflammation [89]. It is not clear whether this can disrupt the maternal-placental interface to allow the transplacental transmission of SARS-CoV-2 [89]. Furthermore, its role in the occurrence of premature births and other fetal complications remains unknown. Thus, more robust studies, preferably longitudinal studies, involving a large sample size with long-term follow-up are crucial to establish the full implications of COVID-19 on pregnancy and early development. It is unclear whether maternal and newborn COVID-19 infection will cause any sequelae in childhood. Nevertheless, it is essential to formulate guidelines for the management of pregnant women infected with SARS-CoV-2 as a way to minimize viral exposure and transmission [7]. These protocols also play important roles in protecting the medical team and providing a suitable hospital environment (e.g., respiratory precautions, use of personal protective equipment, and negative pressure rooms) [90].
The Lancet Infectious Diseases has published guidelines on the management of pregnant women exposed to COVID-19. For asymptomatic cases, home isolation for 14 days is recommended. In symptomatic cases, key recommendations include prioritization of vaginal delivery when possible, late fixation of the umbilical cord, without early cleaning of the newborn, and isolated neonatal surveillance. In both cases, mother-child separation and breastfeeding are discussed individually by an interdisciplinary team [19]. In addition, a recent guideline published in June recommends that for cases where separation is not applicable, other measures to reduce risk of infection (e.g., physical barriers and face mask) must be adopted. For those who choose to breastfeed, mothers must wear face masks and practice good hygiene (hand and breast) before each feeding. Newborns from mothers with confirmed or suspected COVID-19 at the time of the delivery should be tested 24 h after birth. If negative, another test at approximately 48 h must be done if testing capacity is available [91].

Strengths and Limitations
This review was completed after an extensive bibliographic search using two databases, reference lists, and Google Scholar. We included a large number of pregnant women diagnosed with COVID-19 from 16 countries and data on the first, second, and third trimesters of pregnancy. However, our study has some limitations: First, our findings are mostly limited to case reports and retrospective studies with a small number of cases analyzed. Second, there was a lack of methodological criteria in the conduction of many included studies, which can contribute to erroneous results. However, it is important to highlight that we have gathered all the evidence available in the literature to date and that this information is important to guide health and management policies for pregnant women affected by COVID-19 in the first, second, and third trimesters of pregnancy. In addition, the justification for conducting our study is the need to quickly assess and discuss the evidence that has been generated. Finally, some relevant publications may have been released during the submission or publication process of this paper.

Future Recommendations
With the worsening of the COVID-19 global situation, new well-designed research is needed to clarify the risk of vertical transmission (via placenta or hematogenous routes, birth canal, and lactation) of SARS-CoV-2. In addition, further studies are necessary to investigate potential therapeutic interventions that prevent maternal and neonatal morbidity and possible sequelae resulting from COVID-19 infection. In addition, it is important that future studies assess complications arising from COVID-19 in pregnant women in the first and second trimester. These studies are important to improve clinical and preventive strategies for managing COVID-19 in pregnant women and their newborns.

Conclusions
This review revealed that pregnant women with COVID-19 usually present with fever, cough, and nausea. Among various comorbidities, obesity and hypertensive disorders are the most common. It is important to highlight the prevalence of premature birth, maternal death, premature rupture of the membrane, intrauterine fetal death, neonatal death, miscarriage, decreased fetal movements, and severe neonatal asphyxia among cases of infected mothers. Although we found only 27 cases of newborns infected with COVID-19, viral exposure of SARS-CoV-2 during pregnancy and intrapartum period cannot be ruled out and should be further investigated in future studies. Thus, it is important to follow-up all newborns from mothers diagnosed with COVID-19. Funding: This work was carried out with its own financing.