key: cord-0758159-ipskteuz
authors: Raschetti, Roberto; Vivanti, Alexandre J.; Vauloup-Fellous, Christelle; Loi, Barbara; Benachi, Alexandra; De Luca, Daniele
title: Synthesis and systematic review of reported neonatal SARS-CoV-2 infections
date: 2020-10-15
journal: Nat Commun
DOI: 10.1038/s41467-020-18982-9
sha: 18619fd3c746571483472059d7dca5c8f419c9ed
doc_id: 758159
cord_uid: ipskteuz

A number of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have been reported in neonates. Here, we aim to clarify the transmission route, clinical features and outcomes of these infections. We present a meta-analysis of 176 published cases of neonatal SARS-CoV-2 infections that were defined by at least one positive nasopharyngeal swab and/or the presence of specific IgM. We report that 70% and 30% of infections are due to environmental and vertical transmission, respectively. Our analysis shows that 55% of infected neonates developed COVID-19; the most common symptoms were fever (44%), gastrointestinal (36%), respiratory (52%) and neurological manifestations (18%), and lung imaging was abnormal in 64% of cases. A lack of mother–neonate separation from birth is associated with late SARS-CoV-2 infection (OR 4.94 (95% CI: 1.98–13.08), p = 0.0002; adjusted OR 6.6 (95% CI: 2.6–16), p < 0.0001), while breastfeeding is not (OR 0.35 (95% CI: 0.09–1.18), p = 0.10; adjusted OR 2.2 (95% CI: 0.7–6.5), p = 0.148). Our findings add to the literature on neonatal SARS-CoV-2 infections.

S ince December 2019, the infection of a novel beta-coronavirus, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread worldwide and caused a potentially lethal illness: the coronavirus disease 2019 . The World Health Organization (WHO) on 11 March 2020 1 declared the outbreak a public health emergency of international concern and, since then, 27 ,000,000 cases have occurred worldwide (https://www.who.int/ docs/default-source/coronaviruse/situation-reports/20200907-weeklyepi-update-4.pdf?sfvrsn=f5f607ee_2). Of these cases~40-45% is reported to be asymptomatic 2,3 , but more than 900,000 infected patients have died (https://www.who.int/docs/default-source/ coronaviruse/situation-reports/20200907-weekly-epi-update-4.pdf? sfvrsn=f5f607ee_2).

COVID-19 may appear with a panoply of clinical manifestations. It usually starts with influenza-like symptoms, eventually progressing toward pneumonia and acute respiratory distress syndrome (ARDS), but cardiovascular, renal, neurological, dermatological, and gastrointestinal manifestations have also been reported 4, 5 . The pathophysiology of COVID-19 includes the direct viral cytopathic effect, but also an exaggerated inflammatory response (the so-called "cytokine storm"), with hypercoagulable state and tissue damage 6 . COVID-19 is more frequent and tends to be more severe with increasing age and in patients with certain characteristics, some of which are represented by comorbidities typical of older adults (such as cardiovascular disorders and diabetes) 7, 8 . These risk factors have a role both in the disease occurrence and in the progression towards greater clinical severity and mortality 7, 8 . Moreover, children might be less prone to develop the chaotic inflammatory host response that contributes to the clinical picture of COVID-19 9 and the disease seems to have a milder clinical course in children than in adults 10 . However, the proportion of asymptomatic infections seems to be lower in children than in adults 11, 12 .

Despite these findings, the knowledge about pediatric SARS-CoV-2 infection is still based on a paucity of data and the maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain. However, with the pandemic spreading around the world, some cases of SARS-CoV-2 infection in the first month of life have been reported in the literature or in the mass media 9 , and it has been hypothesized that neonatal COVID-19 might occasionally become clinically apparent. SARS-CoV-2 has been isolated in placental tissues 13, 14 and, in a few cases, maternal-fetal transmission was suspected 15 . Nonetheless, guidance criteria for the diagnosis of perinatal and neonatal SARS-CoV-2 infections have been released only recently and the cases published so far were not systematically analyzed according to these criteria 16 .

Compared with adult medicine, neonatology suffers from a clear knowledge gap about the SARS-CoV-2 infection. In fact, the main transmission route is unknown, as neonates can be infected antenatally (through the placenta), during the delivery, or postnatally (through environmental exposure) and the clinical features of neonatal SARS-CoV-2 infections are unclear. We performed a systematic review and synthesis of published cases of neonatal SARS-CoV-2 infections, having as primary objective to describe the route of transmission and the clinical characteristics of neonatal SARS-CoV-2 infections. Our secondary objective was to clarify the effect of mother-neonate separation and breastfeeding on the incidence of late-onset neonatal infections.

Workflow of review, synthesis, and meta-analysis. Figure 1 illustrates the project flow chart with included and excluded records (and the reasons for their exclusions). Finally, 74 articles were considered, consisting of 37 case series, 34 case reports, two retrospective cohort studies, and one cross-sectional study .

Only three articles were not peer-reviewed already. The paper characteristics are reported in Table 1 : the methodological quality of case reports and series was estimated as intermediate (median score 5 [2;6] ).

Basic patients' characteristics. These articles described 176 neonates infected by SARS-CoV-2, whose general characteristics are reported in Table 2 . Only two neonatal infections were diagnosed by the presence of IgM in newborn blood 29,82 : these cases qualified as possible congenital and probable postpartum acquired infections, respectively, according to the classification system 16 ; all the other cases had at least one positive RT-PCR. Nine (5.1%) neonates required delivery room resuscitation 19, 20, 38, 41, 44, 69, 77, 87 and 67 (38.3%) needed to be admitted to the NICU 17, 18, 20, 27, 31, 33, 35, 36, 38, 41, 44, 45, [47] [48] [49] [51] [52] [53] [57] [58] [59] 61, 62, [64] [65] [66] [69] [70] [71] [72] [73] 77, [80] [81] [82] [85] [86] [87] [88] . The median NICU stay was 8 [5;18] days (min 1; max 69 days). Of these neonates, five were extremely preterm (of 26, 27 and 28 weeks' gestation; birth weight ranging between 900 and 1410 g, respectively), five were preterm (31 and 32 weeks' gestation; birth weight ranging between 1580 and 2300 g), nine were moderately preterm (33 and 34 weeks' gestation; birth weight ranging between 1839 and 3280 g) and eleven were late preterm (35 and 36 weeks' gestation; birth weight ranging between 2000 and 2540 g); all other NICU-admitted neonates were term infants.

Transmission routes of neonatal SARS-CoV-2 infections. SARS-CoV-2 infection was classified 16 as shown in Fig. 2 : the majority of infections were likely transmitted postpartum, that is, they were due to environmental exposure, although~30% of cases were likely due to vertical transmission, either intrapartum or congenitally. Of these,~9% of cases were confirmed vertical infections (3.3% for intrapartum and 5.7% for congenitally transmitted infections, respectively).

Clinical features of neonatal SARS-CoV-2 infections. Ninetyseven neonates presented with clinical features related to COVID-19: 18, 20, [26] [27] [28] 30, 32, [34] [35] [36] [38] [39] [40] [41] 44, 45, [50] [51] [52] 55, 56, 58, 60, 61, [65] [66] [67] [70] [71] [72] 77, 78, 80, 81, [85] [86] [87] [88] 90 their distribution is shown in Table 3 . Respiratory manifestations mainly consisted of signs of respiratory failure, such as tachypnoea, intercostal retractions, and rhinitis; neonatal ARDS was not diagnosed in any case. Gastrointestinal manifestations were primarily represented by feeding difficulties, diarrhea, and vomiting, while neurological ones consisted of hypertonia and irritability, but also hypotonia and lethargy, as well as apnea. Cardiovascular features were tachycardia and hypotension. Other manifestations included conjunctivitis, hypothermia and cutaneous rash. Laboratory abnormalities were evident in a minority of cases: 14 (14.4%) and 4 (4.1%) out of 97 neonates presented with lymphopenia 20, 41, 53, 55, 59, 64, 69, 72, [79] [80] [81] 88 and raised liver enzymes 35, 72, 79, 88 , respectively. Inflammatory markers (Creactive protein and procalcitonin) were increased in 15 (15.5%) out of 97 neonates 20, 27, 38, 40, 43, 45, 49, 59, 70, 72, [80] [81] [82] 88 . Lung imaging was abnormal in 62 (64%) out of 97 neonates and consisted of an interstitialalveolar pattern at lung ultrasound or chest X-ray and ground-glass opacities at CT-scan 17, 19, 21, 23, 27, 29, 32, 36, 38, 44, 45, 51, 53, 55, 58, 59, [64] [65] [66] [69] [70] [71] 73, [77] [78] [79] [80] 82, 85, 88, 90 . One neonate presenting with neurological manifestations also showed bilateral gliosis of the deep white periventricular and subcortical matter, together with signs of cerebral vasculitis, which was not totally remitted at the hospital discharge 77 . Seven neonates were treated with oral hydroxychloroquine and/or azithromycin, two with intranasal interferon-α1b and one with intravenous remdesivir, oseltamivir and ritonavir/lopinavir, respectively 17 Factors influencing occurrence of late neonatal infection. Fig. 3 shows that the lack of mother-neonate separation from birth was significantly associated with the incidence of late (i.e. occurring after the first 72 h of life) SARS-CoV-2 neonatal infection (OR 4.94 (95% CI: 1.98-13.08), p = 0.0002; adjusted OR 6.6 (95% CI: 2.6-16), p < 0.0001), while breastfeeding was not (OR 0.35 (95% CI: 0.09-1.18), p = 0.10; adjusted OR 2.2 (95% CI: 0.7-6.5), p = 0.148); models goodness of fit was always satisfactory (Hosmer-Lemeshow test p = 0.654 and p = 0.573, for the two regressions, respectively).

Several cases of neonates infected by SARS-CoV-2 are reported in the literature and here we have systematically analyzed and synthesized them. Our findings confirm that SARS-CoV-2 can infect neonates and that the majority of these infections occur For articles reporting both infected and non-infected neonates, only those with proven infection (defined as at least one positive nasopharyngeal swab, and/or the presence of specific IgM) were included in the review. The methodological quality of case reports and case series was evaluated using the Mayo Evidence-Based Practice Center tool 103 , specifically dedicated to the quality evaluation of this type of articles and summarized both as a 0-8 score and as overall qualitative evaluation. The tool was not applied to the retrospective cohort or cross-sectional studies included in the review. postnatally, although vertical transmission may be possible iñ 30% of cases. Neonatal SARS-CoV-2 become clinically evident in half of the patients as they developed features of COVID-19. The clinical appearance of neonatal COVID-19 seems similar to those reported in older patients, both in terms of symptoms and laboratory or imaging abnormalities, and the outcome is generally favorable. Neonates who were not transiently separated from their mothers seem to have a higher incidence of SARS-CoV-2 infections occurring after the first 72 h of life.

These findings are important as they formally describe neonatal SARS-CoV-2 infection and partially fill our aforementioned knowledge gap. There are some interesting points to be highlighted. First, transplacental transmission of SARS-CoV-2 is indeed possible and this is corroborated by a consistent background of laboratory findings, since angiotensin-converting enzyme receptors are expressed in placental tissues 91 , with the expression reaching a peak at the end of gestation 92 , and SARS-CoV-2 may invade the placenta 13,14 potentially causing miscarriage 93 . Second, neonatal COVID-19 manifestations seem similar to those observed in adults, while fever seems to be more frequent in COVID-19 than in common neonatal infections 94 and no cases of neonatal ARDS 95 were evident.

The choice between rooming-in or mother-infant separation is an important one and the synthesis of available cases shows that the avoidance of separation might be associated with a higher risk of late-onset neonatal SARS-CoV-2 infections. This is potentially important since neonatal SARS-CoV-2 infections are Classification is based on a system including several virological tests (on placental tissues, amniotic fluid, cord and newborn blood or nasopharyngeal swabs), as well as the presence of clinical manifestations 16 . Cases are divided into: (1) congenital infections, (2) intrapartum acquired infections, or (3) postpartum acquired infections and into five mutually exclusive categories of the likelihood of infection: "confirmed", "probable", "possible", "unlikely", and "not infected". Classification was applied to 122 cases (for 54 neonates, data needed to classify the infection were missing despite repeated requests to the authors of the articles). Areas in blue depict the infections confirmed or supposed to be environmentally acquired (i.e.: postpartum), while areas in brown depict confirmed or supposed to be vertically (either intrapartum or congenitally) transmitted infections; numbers represent the %. 97 . Thus, we believe that a correct and complete counselling should be given to families in order to allow a well-informed choice. This should factor in the benefits of mother-neonate bonding, the risk of neonatal infection, their usually (but not exclusively) benign outcome and the higher maternal contagiousness during the symptomatic period 98 . If rooming-in is chosen, appropriate hygiene advice and personal protective equipment should be given, as these may significantly reduce the risk of transmission 99 . Hygiene measures during mother-neonate contact were described inconsistently and only in a minority of articles 23, 24, 34, 39, 64, 67, 75 , and, given the differences in guidelines worldwide 97 , dedicated studies are warranted to understand what would be the ideal equipment and policy to be applied.

Breastfeeding does not seem to be associated with SARS-CoV-2 infections and this suggests that viral transmission through the milk, if any, should be rare. These findings seem to support the safety of expressed breast milk even when the mother is symptomatic and during mother-neonate separation. However, since few studies have investigated this matter and have yielded conflicting results 39,100 , larger studies are needed to clarify this issue 15 .

The results of this synthesis of neonatal SARS-CoV-2 infections are also consistent with a review performed in older children and adolescents from Asia. This review showed that SARS-CoV-2 infection seems mild in pediatric patients while presenting with the same clinical features or laboratory and imaging abnormalities 10 . Conversely, the analyzed neonates had a quite more frequent need for NICU hospitalization compared to neonates of similar gestational age 101 and to older children 10 . However, not all these NICU-admitted babies may have actually needed critical care and this is not possible to be extrapolated with this type of analysis. The NICU-admission may be influenced by many factors such as local setting, logistics, and isolation policy, since the NICU could represent the only area to isolate infected babies and guidelines are extremely dissimilar between different countries and settings 97 . This should be avoided if NICU care is not actually needed, in order to avoid the shortage of NICU beds during the pandemic 102 .

Since a significant proportion of infections are asymptomatic, it has so far been hard to ascertain the disease burden on neonates and the possibility of transmission to healthcare providers. We shed some light on this, although our findings may change as soon as the pandemic progresses and new experience is accumulated. Meanwhile, it is suggested that evidence derived from case reports and series is currently the best available and should be used to inform decision making until higher level of evidence is available 103 .

This work has limitations. Although the quality of the reviewed reports is intermediate, we should remember that uncontrolled case descriptions and their synthesis are at the bottom of the evidence pyramid 103 . As this is a meta-analysis of mainly case series, the rating of the quality of evidence is 4, according to the Oxford Centre for Evidence-based Medicine classification (https://www.cebm.net/2009/06/oxford-centre-evidence-basedmedicine-levels-evidence-march-2009/). However, the Grading of Recommendations, Assessment, Development, and Evaluation guidelines admit the decision-making process based on lowquality evidence in some particular circumstances 104 and the pandemic surely represents an extraordinary situation. The classification system for diagnosing maternal, fetal, and neonatal SARS-CoV-2 infections may be cumbersome, as it requires consideration of clinical data and of the results of several virological tests 16 : the relatively low number of confirmed infections may be due to the difficulty in obtaining the virological tests in various samples (placenta, amniotic fluid, blood, swabs). However, this represents the best way so far to correctly identify these infections for epidemiological and clinical purposes and it should be promoted. Furthermore, the classification may be adjusted, and a case can be re-classified, if its likelihood of infection changes, as more information becomes available. Similarly, the availability of new diagnostic tests may lead to changes in the diagnostic criteria. Only one case was diagnosed based on positive IgM and negative RT-PCR 29 , thus this is not likely to change the global results of our synthesis. We cannot exclude that some of the clinical features presented by the analyzed cases were due to other concomitant disorders, as this level of detail is not attainable with a synthesis of published reports; however, the analyzed data are coherent and consistent with those from older COVID-19 patients. We have almost no information on neonatal COVID-19 therapies, as these will require more experience and it is unclear if the neonatal SARS-CoV-2 infection may have longterm consequences, as no follow-up studies have been performed so far. Finally, we also enrolled manuscripts posted on preprint server while waiting for peer review and final publication. This might introduce a bias as the quality and reliability of these papers can be suboptimal. However, we provided our own peer review applying rigorous criteria and a specific quality evaluation tool to every and each article 105,103 and we actually have only three reports as preprint. Moreover, the role of preprints during pandemics has been widely recognized as they facilitate the spread of vital information and a recent analysis focused on COVID-19 found the quality of preprint similar to that of final publications 106 .

In conclusion, the synthesis of uncontrolled cases of neonatal SARS-CoV-2 infection shows that infections mainly occur postnatally through environmental exposure, although nearly 30% of infections may be acquired vertically. Approximately half of the infected neonates develop clinically apparent COVID-19, which is often characterized by febrile status, features similar to those of older patients and favorable outcomes. Mother-neonate roomingin is associated with a higher incidence of SARS-CoV-2 infections occurring after the first 72 h of life.

Protocol. Prior to commencing the search, a detailed protocol was agreed to determine the databases to be searched, search modalities, eligibility criteria, and all methodological details. Several virtual meetings between the authors were organized and a dedicated online archive was created to share the data of the reviewed papers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed throughout the whole project 107 . The French Ethical Committee for the Research in Obstetrics and Gynecology reviewed the work and confirmed that the institutional review board approval was unnecessary. The case studies were performed in agreement with principles of the Declaration of Helsinki and all analyzed data were anonymous and respecting local and European privacy regulations.

Eligibility and exclusion criteria. We looked for cohort, cross-sectional and casecontrol studies, as well as case series or case reports published as articles or letters to the editors describing neonates (i.e.: infants within the first 30 days of life) infected by SARS-CoV-2, as demonstrated by: (1) at least one positive real-time reverse transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs, and/or (2) positive serology with detection of specific IgM. These laboratory tests had to be performed according to World Health Organization technical guidance principles or appropriate national guidelines 108 . Moreover, articles had to be published between 1 December 2019 and 30 August 2020. No language restriction was applied: non-English publications were translated personally by the investigators or using the Google translation service. We excluded conference abstracts, any report of neonates exposed to but not infected by SARS-CoV-2 (according to the aforementioned criteria), articles describing only stillbirths or children aged more than 30 days and paper reporting hypotheses or opinions without any clinical data. Duplicate reports and "grey" literature were also excluded.

Information sources and search strategy. We conducted an extensive search of the following databases: PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), The Cochrane Library (https://www.cochranelibrary.com), Web of Science (https:// clarivate.com/webofsciencegroup/solutions/web-of-science/), as well as BioXRiv (https://www.biorxiv.org) and MedXRiv (https://www.medrxiv.org) preprint archives. We used the following keywords or MeSH terms: "Coronavirus", "COVID-19", "SARS-CoV-2", "newborn", "preterm" and "neonates". We also hand-searched references cited in the eligible manuscripts or in review articles on the subject and the authors' personal archives. We used the following Boolean string: (COVID-19 AND neonates) OR (coronavirus AND newborn)) OR (coronavirus AND preterm)) OR (coronavirus AND neonates)) OR (SARS-CoV-2 AND newborn)) OR (SARS-CoV-2 AND preterm)) OR (SARS-CoV-2 AND neonates)) OR (COVID-19 AND preterm)) OR (COVID-19 AND newborn)) AND (("2019/12/01"[Date -Create]: "2020/08/30"[Date -Create])).

Study selection. Articles were assessed by two independent researchers (RR and AJV), as recommended by the quality standards issued by the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group 109 . Investigators evaluated abstracts and (where necessary) the full text of each article, excluding those not meeting the eligibility criteria and removing duplicates. The CARE (Consensus-based Clinical Case Reporting Guideline Development) recommendations, specifically dedicated to case reports and series, were followed during the evaluation process 105 . If an article was eligible but reported data on neonates mixed with those of older children (beyond the first month of life), neonatal data were directly extracted or the authors were contacted to provide the needed data. Authors were also contacted when more information was needed and at least two emails were sent to the corresponding author, 1 week apart, asking for additional data. If discrepancies or uncertainties persisted, they were resolved by discussion between the two independent researchers and, if no agreement was reached, with a third researcher (DDL). All articles finally deemed eligible were collected using Zotero (5.0.87, Roy Rosenzweig Centre for History and New Media, Fairfax, VI -USA) and used for the review.

Data collection process. We developed a dedicated online data extraction sheet (Excel 16; Microsoft Corporation, Redmond, WA-USA), pilot-tested it on three randomly selected manuscripts, and refined it accordingly. Data from included records were extracted independently by two investigators (RR and AJV) using the data extraction sheet and then cross-verified. If some data were lacking, at least two emails were sent to the corresponding authors one week apart to ask them for the missing data. If discrepancies or uncertainties persisted, they were resolved by discussion between the two independent researchers and, if no agreement was reached, with a third researcher (DDL).

Data items. Data collected included article type and details, number of enrolled patients, and their basic characteristics, as mean gestational age, birth weight, sex, mode of delivery, Apgar score, postnatal age at the diagnosis and comorbidities. We also recorded all clinical signs and symptoms, imaging and laboratory findings, use of antiviral therapies, isolation and feeding policies, need for neonatal intensive care unit (NICU) admission and mortality. According to postnatal age at the diagnosis, the SARS-CoV-2 infection was classified as early-or late-onset (i.e. occurring ≤72 or >72 h of life, respectively), as commonly done for neonatal sepsis. We recorded any RT-PCR result in placental tissue, amniotic fluid, cord or newborn blood, urine, stool, and swabs. We also recorded the presence of SARS-CoV-2-IgM, and classified the cases according to the classification system defining maternal, fetal and neonatal SARS-CoV-2 infections 16 . In detail, cases were divided into: (1) congenital infections, (2) intrapartum acquired infections, or (3) postpartum acquired (i.e. environmentally acquired) infections and into five mutually exclusive categories of the likelihood of infection: (a) confirmed (strong evidence of infection with confirmatory microbiology), (b) probable (strong evidence of infection but confirmatory microbiology lacking), (c) possible (evidence suggestive of infection but incomplete), (d) unlikely (little support for diagnosis but infection cannot be ruled out), and (e) not infected (no evidence of infection) 16 . Criteria defining the likelihood of infection were published earlier and are available as Supplementary Material 16 .

We considered outcome data, respectively for our primary and secondary objective: (1) the identified transmission route and all clinical features 16 , and (2) the occurrence of late neonatal infection (that is, those diagnosed after the first 72 h and within the first 30 days of life).

Assessment of risk of bias. Since we expected the majority of analyzed articles to be case reports or case series, we decided to evaluate their methodological quality according to four domains (selection, ascertainment, causality, and reporting). To perform this evaluation, we used the Mayo Evidence-Based Practice Centre tool, which is specifically dedicated to the evaluation of case report/series quality 103 . Two investigators (RR and AJV) independently summarized the results of this evaluation by aggregating the eight binary responses into a 0-8 score. Evaluation results were also qualitatively summarized, as recommended by the tool creators 103 . If discrepancies or uncertainties persisted, they were resolved by discussion NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18982-9 ARTICLE between two researchers (RR and AJV) and, if no agreement was reached, with a third researcher (DDL).

Summary measures and synthesis of results. Cumulative estimates of event rates (frequency) were reported as a percentage for the need of neonatal resuscitation or NICU admission, transmission route, isolation and feeding policies, and for each clinical manifestation, imaging and laboratory findings or therapy. Continuous data were described as mean (standard deviation) or median [interquartile range], as appropriate; minimum and maximum values were also reported: this was the case of basic clinical data (such as birth weight or postnatal age at the diagnosis) and length of NICU stay.

The effect of mother-neonate separation and breastfeeding on the incidence of late-onset neonatal infections was studied with two-sided Fisher's exact test and association between variables was expressed by means of the odds ratio (OR) and 95% confidence interval (CI). Calculations and statistics were performed with Excel 16 (Microsoft Corporation, Redmond, WA-USA) and MedCalc 13.3 (MedCalc, Ostend, Belgium). p-values < 0.05 were considered statistically significant.

Additional analyses. The effect of mother-neonate separation and breastfeeding on the incidence of late-onset neonatal infections was also investigated using multivariate logistic regressions, with enter method, adjusting for the quality of reviewed article (evaluated by the specific tool 103 see above). Results were expressed as adjusted OR and 95% CI; model goodness-of-fit was evaluated with Hosmer-Lemeshow test.

Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

All summary data generated during this study are included in this published article. Raw data used for the analyses are available upon request or presented in the original reviewed articles which have been retrieved from the following publicly available databases: PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), The Cochrane Library (https://www. cochranelibrary.com), Web of Science (https://clarivate.com/webofsciencegroup/ solutions/web-of-science/), BioXRiv (https://www.biorxiv.org), and MedXRiv (https:// www.medrxiv.org).

Received: 23 July 2020; Accepted: 23 September 2020;

WHO Director-General's opening remarks at the media briefing on COVID-19: 11

Imperial College COVID-19 Response Team et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo'

Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review

Clinical characteristics of coronavirus disease 2019 in China

The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): a systematic review and meta-analysis of 148 studies from 9 countries

The four horsemen of a viral Apocalypse: the pathogenesis of SARS-CoV-2 infection (COVID-19)

Predictive symptoms and comorbidities for severe COVID-19 and intensive care unit admission: a systematic review and metaanalysis

Factors associated with COVID-19-related death using OpenSAFELY

The EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) initiative: background and protocol for the international SARS-CoV-2 infections registry

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

SARS-CoV-2 infection in children

Visualization of SARS-CoV-2 virus invading the human placenta using electron microscopy

SARS-CoV-2 infection of the placenta

Evidence and possible mechanisms of rare maternal-fetal transmission of SARS-CoV-2

Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates

Neonatal COVID-19 Pneumonia: report of the first case in a preterm neonate in Mayotte, an Overseas Department of France

Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report

Primer caso de infección neonatal por SARS-CoV-2 en España

Severe COVID-19 during pregnancy and possible vertical transmission

Maternal and perinatal characteristics and outcomes of pregnancies complicated with COVID-19 in Kuwait

A preliminary report of COVID-19 in children in India

SARS-CoV-2 in pregnancy: characteristics and outcomes of hospitalized and non-hospitalized women due to COVID-19

Neonatal late onset infection with Severe Acute Respiratory Syndrome Coronavirus 2

Pre-labor anorectal swab for SARS-CoV-2 in COVID-19 pregnant patients: is it time to think about it?

COVID-19: fever syndrome and neurological symptoms in a neonate

Late-onset neonatal sepsis in a patient with Covid-19

Probable vertical transmission of SARS-CoV-2 Infection

Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn

COVID-19) infection: a case report and review of literature

COVID-19 virus in a 6-day-old girl neonate: a case report

Application of pulmonary ultrasound in the diagnosis of COVID-19 pneumonia in neonates

In-utero mother-to-child SARS−CoV−2 transmission: viral detection and fetal immune response

executive management summary and short report of outcome

Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10

Rapid systematic review of neonatal COVID-19 including a case of presumed vertical transmission

Point-of-care lung ultrasound in three neonates with COVID-19

Detection of SARS-CoV-2 in human breastmilk

Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2

Maternal death due to COVID-19 disease

Outcome of COVID-19 with co-existing surgical emergencies in children: our initial experiences and recommendations

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vertical transmission in neonates born to mothers with Coronavirus Disease 2019 (COVID-19) Pneumonia

Lung ultrasound and neonatal COVID-19 pneumonia: a case report

The challenges of contact tracing in a case of early neonatal sepsis with COVID-19

A snapshot of the Covid-19 pandemic among pregnant women in France

Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection

Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV-2 infection in the UK: a national cohort study using the UK Obstetric Surveillance System (UKOSS)

Early-onset symptomatic neonatal COVID-19 infection with high probability of vertical transmission

Shedding of infectious SARS-CoV-2 in symptomatic neonates, children and adolescents

Neonatal early-onset infection with SARS-CoV-2 in a Newborn presenting with encephalitic symptoms

Association between mode of delivery among pregnant women with COVID-19 and maternal and neonatal outcomes in Spain

Possible coronavirus disease 2019 pandemic and pregnancy: vertical transmission is not excluded

Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study

Coronavirus disease 2019 in newborns and very young infants: a series of six patients in France

SARS-CoV-2 infection in infants less than 90 days old

COVID-19-associated apnea and circumoral cyanosis in a 3-week-old

COVID-19 in neonates and infants: progression and recovery

A multicenter study on epidemiological and clinical characteristics of 125 newborns born to women infected with COVID-19 by Turkish Neonatal Society

SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress

Vertical transmission of coronavirus disease 2019: severe acute respiratory syndrome coronavirus 2 RNA on the fetal side of the placenta in pregnancies with coronavirus disease 2019-positive mothers and neonates at birth

Newborns of COVID-19 mothers: short-term outcomes of colocating and breastfeeding from the pandemic's epicenter

Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study

COVID-19 in a 26-week preterm neonate

A case report of neonatal acute respiratory failure due to Severe Acute Respiratory Syndrome Coronavirus-2

Tetralogy of Fallot palliation in a COVID-19 positive neonate

Managing COVID-19-positive maternal-infant dyads: an Italian experience

Clinical findings and disease severity in hospitalized pregnant women with Coronavirus Disease 2019 (COVID-19)

Spectrum of neonatal COVID-19 in Iran: 19 infants with SARS-CoV-2 perinatal infections with varying test results, clinical findings and outcomes

COVID-19 in a preterm-leading to remodelling of care

Early neonatal SARS-CoV-2 Infection manifesting with hypoxemia requiring respiratory support

Intrauterine transmission of SARS-CoV-2 infection in a preterm infant

COVID-19 perinatal en América Latina

Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study

Evidence of mother-to-newborn infection with COVID-19

Outcomes of maternal-newborn dyads after maternal SARS-CoV-2

Transplacental transmission of SARS-CoV-2 infection

A case of 2019 Novel Coronavirus in a pregnant woman with preterm delivery

SARS-CoV-2 infection in febrile neonates

Neonates hospitalized with community-acquired SARS-CoV-2 in a

Neonatal outcome in 29 pregnant women with COVID-19: A retrospective study in Wuhan, China

Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults

Children with SARS-CoV-2 infection during an epidemic in China (outside of Hubei province)

Transport, diagnosis and treatment of a newborn with severe SARS-CoV-2 infection: a case report

Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission

Antibodies in infants born to mothers with COVID-19 Pneumonia

Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China

Novel Coronavirus Infection in newborn babies under 28 days in China

Distribution of Angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies

The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study

Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection

Neonatal sepsis: an old problem with new insights

The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity

Chinese expert consensus on the perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19

Temporal dynamics in viral shedding and transmissibility of COVID-19

Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Epidemiologic Trends in Neonatal Intensive Care

Managing neonates with respiratory failure due to SARS-CoV-2

Methodological quality and synthesis of case series and case reports

GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction and strength

The CARE guidelines: consensus-based clinical case report guideline development

Early in the epidemic: impact of preprints on global discourse about COVID-19 transmissibility

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

World Health Organization. Coronavirus disease (COVID-19) technical guidance: laboratory testing for 2019-nCoV in humans

Meta-analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in epidemiology (MOOSE) group

We are grateful to the authors of reviewed papers who provided details needed for the synthesis. We also thank the "Emergencia Obstetrica España" Group for the kind collaboration.

Acquisition, analysis, or interpretation of data: R.R., A.V., A.B., C.V.F., and B.L.; drafting of the paper: R.R.; calculations and statistical analysis: A.V. and D.D.L.; administrative, technical, or material support: A.B., C.V.F., and B.L.; study concept, design, and supervision: D.D.L. Critical revision of the paper for important intellectual content: all authors. R.R. and A.V. contributed equally and should be considered co-first authors. All authors take full responsibility for the content of the paper.

The authors declare no competing interests.

Supplementary information is available for this paper at https://doi.org/10.1038/s41467-020-18982-9.Correspondence and requests for materials should be addressed to D.D.L.Peer review information Nature Communications thanks Mohammad Alwardat and the other, anonymous, reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.Reprints and permission information is available at http://www.nature.com/reprintsPublisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.