Congenital, Intrapartum and Postnatal Maternal-Fetal-Neonatal SARS-CoV-2 Infections: A Narrative Review

Background: There is inconclusive evidence regarding congenital, intrapartum, and postnatal maternal-fetal-neonatal SARS-CoV-2 infections during the COVID-19 pandemic. A narrative review was conducted with the aim of guiding clinicians on the management of pregnant women with respect to congenital, intrapartum, and postnatal maternal-fetal-neonatal SARS-CoV-2 infections and breastfeeding during the COVID-19 pandemic. Methods: Searches were conducted in Web of Science, PubMed, Scopus, Dialnet, CUIDEN, Scielo, and Virtual Health Library to identify observational, case series, case reports, and randomized controlled trial studies assessing the transmission of SARS-CoV-2 from mother to baby and/or through breastfeeding during the COVID-19 pandemic. Results: A total of 49 studies was included in this review, comprising 329 pregnant women and 331 neonates (two pregnant women delivered twins). The studies were performed in China (n = 26), USA (n = 7), Italy (n = 3), Iran (n = 2), Switzerland (n = 1), Spain (n = 1), Turkey (n = 1), Australia (n = 1), India (n = 1), Germany (n = 1), France (n = 1), Canada (n = 1), Honduras (n = 1), Brazil (n = 1), and Peru (n = 1). Samples from amniotic fluid, umbilical cord blood, placenta, cervical secretion, and breastmilk were collected and analyzed. A total of 15 placental swabs gave positive results for SARS-CoV-2 ribonucleic acid (RNA) on the fetal side of the placenta. SARS-CoV-2 RNA was found in seven breastmilk samples. One umbilical cord sample was positive for SARS-CoV-2. One amniotic fluid sample tested positive for SARS-CoV-2. Conclusions: This study presents some evidence to support the potential of congenital, intrapartum, and postnatal maternal-fetal-neonatal SARS-CoV-2 infections during the COVID-19 pandemic. Mothers should follow recommendations including wearing a facemask and hand washing before and after breastfeeding.


Introduction
The new coronavirus disease  has rapidly spread around the world since its first identification in Wuhan (China) [1]. COVID-19 is caused by a coronavirus named SARS-CoV-2

Results
A total of 302 studies was selected. The search on WOS provided 25 hits. The search on PubMed offered 162 outcomes, while 86 studies were found through SCOPUS. Twenty-nine results were identified through VHL. No studies were found on Dialnet, CUIDEN, or Scielo. See Figure 1 for a detailed view of the selection and inclusion process.
Forty-nine studies were included in this review after assessing their eligibility . All the studies (n = 49) selected in this review were case studies or case reports published in 2020. A pool of 329 pregnant women and their 331 neonates (two pregnant women delivered twins) was derived from the selected studies. Nevertheless, an overlap in cases might be present. The majority of studies were performed in China (n = 26), and the rest were performed in the USA (n = 7), Italy (n = 3), Iran (n = 2), Switzerland (n = 1), Spain (n = 1), Turkey (n = 1), Australia (n = 1), India (n = 1), Germany (n = 1), France (n = 1), Canada (n = 1), Honduras (n = 1), Brazil (n = 1), and Peru (n = 1).

Congenital, Intrapartum, and Postnatal Maternal-Fetal-Neonatal SARS-CoV-2 Infection
Maternal-fetal-neonatal SARS-CoV-2 infection can occur in utero (following maternal viremia and placental infection), intrapartum (via cervical or vaginal secretions), or after birth via breast milk. The detection of the virus by polymerase chain reaction (PCR) in umbilical cord blood or neonatal blood collected within the first 12 h of birth or amniotic fluid collected prior to the rupture of the membrane gives evidence for a congenital infection [10]. A narrative synthesis is presented below.

Results
A total of 302 studies was selected. The search on WOS provided 25 hits. The search on PubMed offered 162 outcomes, while 86 studies were found through SCOPUS. Twenty-nine results were identified through VHL. No studies were found on Dialnet, CUIDEN, or Scielo. See Figure 1 for a detailed view of the selection and inclusion process.
Forty-nine studies were included in this review after assessing their eligibility . All the studies (n = 49) selected in this review were case studies or case reports published in 2020. A pool of 329 pregnant women and their 331 neonates (two pregnant women delivered twins) was derived from the selected studies. Nevertheless, an overlap in cases might be present. The majority of studies were performed in China (n = 26), and the rest were performed in the USA (n = 7), Italy (n = 3), Iran (n = 2), Switzerland (n = 1), Spain (n = 1), Turkey (n = 1), Australia (n = 1), India (n = 1), Germany (n = 1), France (n = 1), Canada (n = 1), Honduras (n = 1), Brazil (n = 1), and Peru (n = 1).

Congenital, Intrapartum, and Postnatal Maternal-Fetal-Neonatal SARS-CoV-2 Infection
Maternal-fetal-neonatal SARS-CoV-2 infection can occur in utero (following maternal viremia and placental infection), intrapartum (via cervical or vaginal secretions), or after birth via breast milk. The detection of the virus by polymerase chain reaction (PCR) in umbilical cord blood or neonatal blood collected within the first 12 h of birth or amniotic fluid collected prior to the rupture of the membrane gives evidence for a congenital infection [10]. A narrative synthesis is presented below.

Cervical Secretion
Maternal cervical secretion was only assessed in three case report studies [14,17,21]. One study assessing maternal cervical secretion reported a positive test for SARS-CoV-2 [21]. The neonate in this study had a positive test for SARS-CoV-2 [21].
The main results of the included studies are described in Table 1. Table 1 displays information on the city and country where a certain study was performed, the study design, number of pregnant women participating in each study, maternal age, number of fetuses participating in each study, trimester of pregnancy when the COVID-19 diagnosis was performed, number of pregnant women having a positive test for SARS-CoV-2, gestational age at birth, neonates having a positive throat swab for SARS-CoV-2 (yes = 1; no = 0), potential and confirmed maternal source of neonatal SARS-CoV-2 infection, neonatal feeding method (breast milk versus formula), and number of vaginally born neonates.

Discussion
There is limited evidence on the detrimental impact that COVID-19 may have on pregnancy [1,7]. Inconsistencies exist regarding congenital, intrapartum, and postnatal maternal-fetal-neonatal SARS-CoV-2 infections [8]. Although the benefits that breast milk can have on neonatal health have been reported [60], women are recommended not to breastfeed their neonates during the COVID-19 pandemic [13,16,20,21,26,27,31,47,49,55,59]. The aim of this study was to gather the most up-to-date evidence on the congenital and intrapartum transmission of SARS-CoV-2 from mother-to-child and to extract integrated conclusions from the existing literature. Potential postnatal transmission through breast milk was also considered.
Studies included in this review were all case reports and case series assessing the congenital, intrapartum, and postnatal maternal-fetal-neonatal transmission of SARS-CoV-2. All pregnant women included in the studies had a positive throat swab test for SARS-CoV-2 infection.

Amniotic Fluid
Studies assessing amniotic fluid comprised of 10 studies. Most of the neonates among these 10 studies were delivered by C-section in a negative-pressure room [11][12][13][14][16][17][18][19][20][21]. The amniotic fluid samples assessed in those studies were collected after the rupture of membranes in an operating room at the time of a C-section in eight studies [11,12,14,16,[18][19][20][21]. These studies reported and guaranteed that the amniotic fluid samples were not contaminated and represented fetal intrauterine conditions [11,12,14,16,[18][19][20][21]. The bulk of the studies reported a negative test for SARS-CoV-2 in amniotic fluid specimens. This finding is in line with previous studies concluding that the transmission of SARS-CoV-2 through amniotic fluid during the COVID-19 pandemic was unlikely to occur [1,3]. Unfortunately, those studies were based on samples collected during the early stages of the COVID-19 outbreak [1,3]. In the present review, one study reported a positive test for SARS-CoV-2 inflection in amniotic fluid from a pregnant woman [20]. Due to her severe health state, the pregnant woman in this case report had a C-section and a preterm neonate was born at 33 weeks of gestation. This neonate had a positive result for SARS-CoV-2 but with no respiratory distress. The neonate was fed with formula. Due to respiratory complications, the mother died 16 days after the C-section. An absence of viral RNA was determined from amniotic fluid specimens tested by reverse transcriptase-polymerase chain reaction (RT-PCR) among pregnant women who were positive for previous coronavirus diseases (SARS or MERS) [61]. The findings from studies assessing amniotic fluid suggest that the transmission of SARS-CoV-2 through the amniotic fluid is unlikely to occur. Only one study in this review informed of a positive result for SARS-CoV-2 in amniotic fluid [61]. This finding might have been due to the contamination of the amniotic fluid sample.
In this review, we included a single study reporting a positive result for SARS-CoV-2 in the umbilical stump from a neonate who tested positive for SARS-CoV-2 [26]. This same study reported a positive result for SARS-CoV-2 in the placenta [26]. Delayed cord clamping was not performed in this case study [26]. The mother's nasopharyngeal aspirate was negative for SARS-CoV-2 on the day of admission and at day five. However, the mother tested positive for antibodies 10 days after delivery [26]. None of the studies included in this review reported the presence of SARS-CoV-2 in umbilical cord blood [11][12][13][14]16,18,20,[23][24][25].
Only one study found SARS-CoV-2 in the umbilical cord; this finding was gathered from the umbilical cord stump but not from umbilical cord blood [26]. This finding suggests that SARS-CoV-2 might not cross the placenta barrier through the umbilical cord. Extreme caution should be maintained when manipulating biological measures. It is recommended that protocols are strictly followed to obtain the most accurate results.

Placenta
A total of 11 studies reported a positive test for SARS-CoV-2 RNA in placental tissues [21,25,26,29,[32][33][34][35][36][37][38]. It has been reported that SARS-CoV-2 can bind to the angiotensin-converting enzyme 2 (ACE2) receptors in the placenta for cell entry [64]. The fact that SARS-CoV-2 may cross the placental barrier by means of binding to the ACE2 receptor supports the potential risk of the mother-to-infant transmission of SARS-CoV-2 [38]. A study in this review reported a second-trimester miscarriage in a pregnant woman who was positive for SARS-CoV-2 [25]. The miscarriage in this study appeared to be related to a placental infection with SARS-CoV-2. Nevertheless, fetal samples from the anus, liver, thymus, and lung tested negative for SARS-CoV-2 [25]. On the contrary, a previous study presented some evidence on the unlikelihood of SARS-CoV-2 infecting the placenta, despite ACE2 being minimally expressed in the placenta during pregnancy [65]. Certain viruses such as the Zika virus were found to evade the protection that the placenta barrier confers. Due to the effects that a congenital Zika infection can have, thousands of microcephalic neonates were reported in 2016 [66]. Six studies analyzing the placenta samples in this review gave a negative result for SARS-CoV-2 [12,14,16,17,30,31]. These results are in line with studies on SARS that were unable to find coronavirus in placentas [60][61][62]. Although no SARS was found in some of the placenta specimens, these placentas were reported to present increased subchorionic, intervillous fibrin, thrombotic vasculopathy, and areas of avascular chorionic villi, which are associated with fetal vascular malperfusion and fetal intrauterine growth restriction [62].

Breastfeeding
The United Nations Children's Fund has asserted that breastfeeding provides neonates with a range of micronutrients that may protect them against infections [67]. The WHO has stated that every neonate in the world should be breastfed for at least 6 months [68]. However, only eight studies included in this review reported that neonates were breastfed [29,33,35,[39][40][41][42]45]. Breast milk samples had a positive result for SARS-CoV-2 infection in seven studies that evaluated human milk from mothers infected with the same virus [33,[39][40][41][42][43][44] Five studies in this review reported a positive neonatal case for SARS-CoV-2 among mothers with a positive result for SARS-CoV-2 in breast milk [33,[39][40][41][42]. It should be clarified whether those neonates were positive for SARS-CoV-2 before or after they were breastfed. Future studies should take into consideration the potential contamination of breast milk from neonates' saliva while breastfeeding. None of the studies in this review attempted to culture the SARS-CoV-2 from breast milk samples. Although SARS-CoV-2 RNA has been isolated from breast milk samples, it is still unclear whether breast milk has a potential infectious capacity [69].
Additionally, two studies reported the presence of SARS-CoV-2 IgG in breast milk samples from SARS-CoV-2 positive mothers [45,46]. SARS-CoV-2 IgG was only identified very early after birth (up to 1.5 months later) [46]. Due to the presence of SARS-CoV-2 IgG in two studies, the potential protective role of breast milk against SARS-CoV-2 should be considered [45,46]. The Chinese expert consensus group for managing mothers and neonates with COVID-19 announced that breastfeeding is not recommended [69]. According to the articles reviewed, there is some probability that SARS-CoV-2 infection can be transmitted through breast milk. Due to the SARS-CoV-2 virus being transmitted through respiratory droplets during breastfeeding [4,70], certain recommendations should be taken into consideration if an infected mother decides to breastfeed her neonate. These recommendations have been provided by the Center for Disease Control and Prevention and include wearing a facemask and hand washing before and after breastfeeding [71]. Besides, it has been reported that holder pasteurization, but not freezing, can inactivate the SARS-CoV-2 virus [72].
In summary, in this review, some studies reported that SARS-CoV-2 RNA was found in amniotic fluid, placenta, umbilical cord, and breast milk. Besides, it was found in this review that mothers transmitted SARS-CoV-2 to some neonates through amniotic fluid (n = 1 neonate), cervical secretion (n = 1), placenta (n = 6 neonates), breast milk (n = 5 neonates). Findings from this review support the transplacental infection of COVID-19 in certain cases. Nevertheless, it is not yet clear that SARS-CoV-2 can always be transmitted from mother to infant. Future studies assessing the potential transmission of SARS-CoV-2 from mother to infant should clarify this issue. Prospective studies should also address the circumstances that facilitate or prevent SARS-CoV-2 from crossing the placenta barrier.
Limitations of this study include the fact that all the studies included were case reports or case series. An overlapping of participants among studies might be present. Some studies in this review did not perform analyses for amniotic fluid, cord blood, placenta, or breast milk. Future studies should test as many samples as possible in order to find potential sources of transmission of SARS-CoV-2 from mother to child, especially in those cases in which both the mother and the child had a positive test for SARS-CoV-2.