Perinatal management and postnatal care of infants born to mothers with a suspected or confirmed SARS-CoV-2 infection and the clinical characteristics of COVID-19 in newborns, infants and children are highly relevant topics. According to existing literature, neonatal and pediatric cases are principally family cluster cases; most of them have epidemiological links to adult subjects, but show milder clinical manifestations, with a good prognosis [22].
Since the SARS-CoV-2 outbreak began, scientists have been trying to explain why children are much less likely than adults to show severe presentation and develop complications from the infection. Some hypotheses have been made, including mal-adapting immune response in the elderly compared to children, developmental changes in immunity, with a predominant innate response to infectious stimulus in young infants, effects of lung development and ageing, differences in the physiology and anatomy of the respiratory tract and the crucial role of comorbidities on outcomes [23]. Also, according to some researchers, children’s healthier endothelium may protect them from progression to severe/fatal disease [24], on the contrary to what may happen in adults, in whom problems with the endothelium seem to be related with a worse prognosis [25].
In conformity with literature, in our case series affected neonates were asymptomatic or paucisymptomatic [19, 22, 26,27,28]. Differently from other reports on neonatal and pediatric COVID-19, we did not observe fever, nor respiratory symptoms [19, 29, 30]. In our series, the gastrointestinal tract was predominantly interested, in accordance with other reports [31] and one infant presented failure to thrive. On the neonate who was treated with antibiotic therapy from day 2 to day 8 of life due to irritability, feeding difficulties and high levels of inflammatory markers (Neonate 5), blood cultures turned negative, leaving the question open to whether his symptoms could be ascribed to a neonatal early-onset bacterial infection or to a systemic viral disease.
Altered laboratory tests have also been reported [17,18,19]. Only a patient in our case series developed blood tests abnormalities during hospital stay, consisting in mild neutropenia, possibly due to different pathophysiological mechanisms related to systemic viral infection, including inhibition of hematopoiesis, granulocyte sequestration, margination, and peripheral destruction [32]. Neutropenia in neonates affected with COVID-19 was also reported in previous case series and reviews [30, 33, 34]. No leukocytopenia nor lymphocytopenia have been observed among our patients, although described in previous studies [17, 18, 26].
Regarding clinical presentation and outcomes, although the majority of reports and our experience described mild symptoms and good outcomes, a few cases of moderate-to-severe presentation and death of neonates born to mothers with COVID-19 have been observed [19, 28, 33]. Thus, we agree on encouraging caregivers of neonates to adopt preventive measures when coming into contact with neonates, in order to limit community-spread of SARS-CoV-2 to this potentially vulnerable population. Additionally, we agree on closely monitor the neonates with a suspected or confirmed SARS-CoV-2 infection [28, 33].
This pandemic is a rapidly growing challenge for labor and delivery units, as long as for hospital nurseries and neonatal care units. There is still an ongoing debate as to whether neonates should be isolated from mothers suspected or confirmed positive for SARS-CoV-2 infection and whether direct breastfeeding is considered to be safe. Significantly different positions have been adopted by international Health Organizations, so far [4, 9, 18, 35,36,37,38,39,40]. According to the Italian National Institute of Health (Istituto Superiore di Sanità, ISS), the Italian Society of Neonatology (SIN) and the Union of European Neonatal & Perinatal Societies (UENPS), a woman with a suspected or confirmed COVID-19, under favorable clinical conditions and according to her desire, should start and continue to breastfeed, directly to the breast or using non-pasteurized expressed breast milk, applying preventive procedures such as hand hygiene and the use of a face mask during feeds. With regards to whether or not to separate mother and child, the ISS suggests the decision should be made on an individual basis, taking into account the informed consent of the mother, her clinical conditions, the hospital logistics and possibly the local epidemiological situation relating to the spread of SARS-CoV-2 [14, 41,42,43]. In our opinion, this approach opens up to a patient-centered, personalized care, by emphasizing the importance of parental will and participation, which must be supported and guided by an exhaustive set of information from the medical staff. Adopting this criterion, a medical team of Pediatricians and Gynecologists together with Mother 1 decided to manage separately the woman and her newborn and to feed the baby with fresh expressed milk. As previously described, the neonate did well and tested negative for SARS-CoV-2.
Based on current knowledge, the breast milk of a COVID-19 mother cannot be considered a transmission vehicle, similarly to other known respiratory viral infections [13, 44]. In our experience, two mothers, after the diagnosis of COVID-19, personally chose to stop breastfeeding and gave their babies formula. RT-PCR on milk of the breastfeeding mothers tested negative for SARS-CoV-2, in line with previous reports that support breastfeeding [7, 11,12,13, 44,45,46]. Moreover, as suggested by Davanzo et al. [45], specific maternal SARS-CoV-2 antibodies pass via the breast milk from the COVID-19 mother to her child within a few days after the onset of the disease, thus possibly modulating the clinical expression of the infant’s infection. Of note, we report the finding of Kirstman et al., who isolated SARS-CoV-2 RNA on a sample of breast milk, collected from a positive mother two days after childbirth. However, as the Authors themselves point out, the potential for respiratory secretion contamination of breast milk could not be ruled out, even though it was minimized by breast hygiene before specimen collection [34].
We did not suggest precautionary measures for the breastfeeding mothers, nor isolation measures, considering that both the mothers and their children were positive on admission.
On mother-to-child transmission modalities, the issue is still controversial. Literature with supporting evidence for vertical transmission and studies on transplacental transmission correlations are still limited [44, 47]. Cases of suspected perinatal infection have been reported [34, 47,48,49]. Two different research teams in China described 3 neonates, born to mothers with COVID-19, whose IgM antibodies for SARS-CoV-2 following birth were elevated [48, 49]. However, none of these babies had a positive RT-PCR test result, thus not supporting the serologic suggestion of in utero transmission. Also, IgM assays are subject to false-positive and false-negative results, along with cross-reactivity. Kirtsman et al. reported a case of probable congenital SARS-CoV-2 infection, with a positive maternal nasopharyngeal swab two days before childbirth and placental swabs (on both the maternal and fetal side), a vaginal swab and a neonatal rhinopharyngeal swab showing a positive result for SARS-CoV-2 on the day of birth [34]. Recently, Patanè et al. described the presence of SARS-CoV-2 RNA on the fetal side of the placenta in 2 cases of mothers who were diagnosed with COVID-19 and whose neonates had positive test results for SARS-CoV-2 at birth [47]. Even though these findings support the possibility of vertical transmission of SARS-CoV-2, further studies are required to confirm these results [45, 47, 50].
Pediatric cases, as long as older patients, usually have a history of epidemiological exposure [22, 30]. Considering the timing of domiciliary testing and the fact that family clusters or epidemiological links to other infected adults cannot be completely excluded, we could not derive conclusions on transmission modalities in four out of five patients in our series. Moreover, we are not able to demonstrate whether the infection was transmitted from the mother to her child or vice versa. In our case, if we assume that a healthy mother could be infected by her child, considering the greater disease severity described in adults, preventive measures such as mother and child isolation should be also promoted to protect mothers during puerperium.
Testing for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) should be reserved to neonates born to mothers with suspected or confirmed COVID-19 and to those presenting with signs of infection suggestive of COVID-19, without neglecting the possibility of alternative diagnoses [51]. Additionally, we of course suggest testing neonates who came into contact with infectious health care professionals. Time for testing ranges from approximately 24 h of life for both symptomatic and asymptomatic neonates born to mothers with suspected or confirmed COVID-19, to the day of onset of signs. Neonates who meet clinical criteria for discharge do not require the results of SARS-CoV-2 testing for leaving the nursery [51]; home isolation and precautions to prevent transmission should continue until the communication of a negative result. According to the last dispositions of the Italian Ministry of Health, discontinuation of home isolation occurs at least 10 days from the first positive result, with a final negative test before isolation is ended, for asymptomatic cases and at least 10 days from the onset of symptoms (the last 3 days in the absence of symptoms), with a final negative test before isolation is ended, for symptomatic cases [52].
The period of time from the onset of symptoms to the first negative RT-PCR test result is defined as nucleic acid conversion time and it has been showed that some COVID-19 adult patients experienced a prolonged nucleic acid conversion time, regardless of the presence of clinical symptoms [53,54,55]. In our cohort we observed a mean time to negative rhino-pharyngeal swab from the first positive result of 6.75 days (range 2–16), with a median of 4.5 [IQR 3.5; 7.75]. Overall, the median age at the 1st negative result was 12 days [IQR 9.75;18.5]. Notably, we cannot derive conclusions on the period of infectiousness, because neonates were tested at different ages and possibly at a different time course of the disease progression, on account of the exposure history. Most of the patients (75%) had negative SARS-CoV-2 rhinopharyngeal PCR samples within a few days from the diagnosis and persistently negative rectal swabs. Only Neonate 2 showed a prolonged viral shedding, with persistent positive RT-PCR test results on both rhino-pharyngeal and rectal swabs, collected every 72 h during hospital stay. These findings are in line with previous reports that taken together show a considerable variability of viral shedding, among different patients and when examining different routes [53,54,55,56,57,58].
For those neonates who tested negative on rhino-pharyngeal swabs on admission, at first, we might have expected a positive rectal swab, due to the described extensive persistence of the virus in the gastrointestinal tract [58]. Due to the low probability of false positive nucleic acid detection tests [59], we speculated that not necessarily the SARS-CoV-2 infection in newborns has to involve the respiratory and gastrointestinal tract simultaneously, as proved by daily clinical experience for other viral illnesses (e.g. Adenovirus gastroenteritis and/or respiratory tract infection). Moreover, a study on 20 serial COVID-19 patients showed that infectious virus was not isolated from stool samples, in spite of high virus RNA concentration. The correlation of RT-PCR positivity in stool with retrieval of live virus from the same samples remains to be further investigated [60].
Our study encompasses some limitations, mainly due to its retrospective, observational nature and to the small sample size.
Although from our data, in line with previous studies, it seems that the disease has a milder presentation in neonates, we believe further standardized, larger studies are needed for a better and comprehensive understanding of the characteristics of COVID-19 in the neonatal population.