key: cord-0796849-wjqknlg8
authors: Vardhelli, Venkateshwarlu; Pandita, Aakash; Pillai, Anish; Badatya, Susanta Kumar
title: Perinatal COVID-19: review of current evidence and practical approach towards prevention and management
date: 2020-11-12
journal: Eur J Pediatr
DOI: 10.1007/s00431-020-03866-3
sha: 49f7fdb0217f67ca67fdb2ae4189e13d2a562306
doc_id: 796849
cord_uid: wjqknlg8

The clinical spectrum of the perinatal COVID-19 and prospective data on neonatal outcomes remains largely unexplored. Most of the existing literature is in the form of case series or single-centre experience. In this review, we aim to summarize available literature on the clinical spectrum of COVID-19 in neonates and mothers and suggest a practical approach towards management of clinical scenarios. This review explores the clinical characteristics and outcomes of COVID-19 in neonates born to mothers who were detected with the virus during the pregnancy. We conducted a comprehensive search of PubMed, Google Scholar and Cochrane Database of Systematic Review between November 2019 and June 2020 and screened articles related to perinatal COVID-19. This review included 786 mothers, among which 64% (504) were delivered by caesarian section. There were 3 still births and 107 (14%) were delivered preterm. Out of 793 neonates born, 629 neonates (79%) were tested after birth. The commonest symptom in neonates was respiratory distress. Respiratory support was needed in 60 neonates (7.6%), with 14 babies needing mechanical ventilation (1.8%), 25 needing non-invasive ventilation and 21 needing nasal oxygen. Only 35 of the 629 tested neonates (5.5%) were positive for COVID-19. Of the 35 positive neonates, 14 (40%) were symptomatic. The COVID-19 seems to have favourable neonatal outcomes. Majority of neonates are asymptomatic. Respiratory distress is the most common manifestation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00431-020-03866-3.

Coronaviruses are positive sense single strand RNA viruses of zoonotic origin surrounded by an envelope. The Coronaviridae family has Orthocoronavirinae subfamily which is further divided into four genera, namely, Alpha, Beta, Gamma, and Delta coronavirus [1, 2] . So far, seven human coronaviruses (HCoVs) have been identified, all of which fall within the Alpha and Beta coronavirus genera. The severe acute respiratory distress syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS CoV) and novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) belong to the genus Beta coronavirus [2] [3] [4] [5] .

In early December 2019, an outbreak of respiratory illness of unknown origin was reported in Wuhan, Hubei Province, China, which was later isolated and reported as SARS-CoV-2 virus [6, 7] . Since the beginning of this epidemic, SARS-CoV-2 has now spread to all continents and was declared as pandemic by WHO on March 11, 2020 (https://www.who.int/ docs/default-source/coronaviruse/situation-reports/ 20200311-sitrep-51-covid- 19 .pdf?sfvrsn=1ba62e57_10) [8] [9] [10] [11] . SARS-CoV-2 infection has also been reported in pregnant women and neonates, but the data is scattered and limited [12] .

We conducted a comprehensive review of literature describing perinatal SARS-CoV-2 infection which included articles published between November 2019 and June 2020. To identify relevant articles, we systematically searched PubMed, Google Scholar and Cochrane Database of Systematic Review. For searching PubMed, we combined the population terms ("Infant" [Mesh] OR "premature birth"[MeSH Terms] OR newborn OR neonat* OR perinat*) and the outcome terms ("COVID-19" [Supplementary Concept] OR "SARS-CoV" OR "coronavirus" OR "COVID-19" OR "SARS-CoV-2" OR "novel coronavirus" OR "neonatal covid" OR "2019-nCOV"). The initial search yielded 873 articles, of which 824 were in English. We found 6 meta-analyses, of which 3 were related to perinatal COVID-19. No randomized control trials were found. After excluding duplicates, the rest of the articles comprising of observational studies (single and multicentre) and case reports were screened by 2 researchers independently. Similarly, the Cochrane Database of Systematic Review and Google Scholar were searched. All relevant prospective/retrospective studies (including case reports) and review articles were included. Further, a rapid review was conducted to include more recent articles up to August 2020. Guidelines and recommendations of relevant national and international organizations were also reviewed. In this article, we discuss important aspects of perinatal-neonatal COVID-19 infection, systematically summarize current evidence (updated to June 2020) and propose a practical approach towards its management and prevention in neonates.

The SARS-CoV-2 enters the host cell by attaching to the SARS-coronavirus receptor, angiotensin-converting enzyme 2 (ACE-2). The entry is facilitated by the spike (S) protein. ACE-2 is a surface molecule expressed in alveolar type 2 cells of lung, oesophageal upper epithelial cells and absorptive enterocytes from ileum and colon [13] . The novel SARS-CoV-2 transmits between humans through the respiratory droplets and aerosols from coughing and sneezing usually up to 6 ft. It can also be transmitted through direct or indirect contact with mucous membranes of the eyes, mouth or nose [14] . Possibility of infection through gastrointestinal tract has also been reported in a study by invasion of ACE-2 expressing enterocytes [15] . According to the initial available literature, the risk of vertical transmission is 5-30% but may be underreported due to lack of early diagnosis. ACE2 receptors and TMPRSS2 molecules are highly expressed in placenta and the expression peaks at term and the virus often invade the placenta and rarely cause miscarriage [16] [17] [18] [19] . From two different case series, 4 infants had positive nasopharyngeal SARS-CoV-19 RT-PCR within 2 days of life, but cord blood, amniotic fluid and cord blood samples were negative in these infants [20, 21] . Serological testing with SARS-CoV-2specific IgM and IgG showed positive IgM in serum of 3 out of 7 newborns in two different studies with negative nasopharyngeal swab and serum RT-PCR in the same infants [22, 23] . Serum IgM can give both false positive and false negative results depending on the technique used. It is very difficult to differentiate early postnatal transmission/ colonization versus vertical transmission in neonates. There are cases of neonatal detection for SARS-CoV-2 within the first 24 h of life. An infant born to a 41-year-old pregnant woman with severe COVID-19 infection requiring mechanical ventilation tested positive at 16 h age. The patient underwent a caesarean delivery, and the neonate was isolated immediately without delayed cord clamping or skin-to-skin contact. The serology tests IgM and IgG for SARS-CoV-2 were negative [24] . Another recent case by Kirstman et al. reports a term male infant born to a 40-year-old COVID-19positive mother by caesarian section. The infant did not require resuscitation at birth but was admitted to NICU at 37 h for temperature instability, hypoglycaemia and feeding difficulty. The infant had positive RT-PCR from nasopharyngeal swab on day of birth, day 2 and day 7. Also, this is the first report where samples of placenta, maternal vaginal swab and breast milk were positive for the virus [25] . Another study tested multiple breast milk samples in two COVID-19positive mothers. Authors reported positive RT-PCR in one mother on days 10, 12 and 13. Further breast milk samples repeated later were negative. [26] In a case report of preterm infant born to mother with COVID-19, infant had fever after birth and was treated with intravenous antibiotics. Maternal vaginal secretions, umbilical cord blood, neonatal nasal and throat swabs at birth were negative for SARS-CoV-2. But amniotic fluid sample was positive. The second nasal swab test at 24 h was positive for SARS-CoV-2. Third and fourth neonate's PCR test was positive 1 week later. In this case, the neonate was separated from mother at birth and was fed with formula [27] . These findings raise the uncertainty regarding transmission of SARS-CoV-2 by placenta and human milk and highlight the importance of measures to prevent horizontal transmission. Previous case series have not detected COVID-19 virus in breast milk or placenta [28] [29] [30] [31] . Recently there have been few case reports suggestive of secretion of coronavirus in breast milk [32] . However, in a case series of 18 mothers, data suggests that the presence of SARS-CoV-2 RNA in breast milk does not represent replicationcompetent virus and that breast milk may be safe for the infant. Furthermore, pasteurization by Holders technique has shown to completely destroy the viral RNA present in the breast milk [33] . Neonates may also acquire infection postnatally from close contact with other COVID-19-positive people such as healthcare workers and family members.

The mean incubation period of COVID-19 is 5.2 days (95% CI: 4.1-7 days) with over 90% infected individuals developing symptoms within the initial 10 days. Based on these findings, 14-day monitoring period is advised after contact with a COVID-19-confirmed case. The reproduction number (R0), defined as average number of secondary infections caused by one infected person in a naïve population, ranges from 1.4 to 6.49 with the mean of 3.28, which is higher compared to H1N1 influenza (R0 of 1.2-1.6) and SARS-CoV (R0 of 2-5) [34] [35] [36] .

According to the published literature, the clinical characteristics of pregnant women with COVID-19 are similar to nonpregnant COVID-19 adult patients [36] [37] [38] [39] [40] [41] [42] [43] [44] . In our review that included 786 mothers, we found that 64% (504) delivered by caesarian section. There were 3 still births, and 107 (14%) were delivered preterm. The gestation was not specified in 33% of cases, and the rest were term neonates. A recently conducted systematic review and meta-analysis on outcomes of coronavirus spectrum infections in pregnancy included 19 studies with 79 women affected with SARS, MERS and SARS-CoV-2 infections. The authors reported miscarriage in 39.1%, preterm birth (< 37 weeks) in 24.3%, premature pre-labour rupture of membranes (pPROM) in 20.7%, preeclampsia in 16% and foetal growth restriction in 11.7% of COVID-19 mothers [29] . On subgroup analysis consisting of 41 pregnancies with COVID-19 (SARS-CoV-2 infections), the most common adverse pregnancy outcome was preterm birth. It was reported in 56% of patients, of which 15% delivered before 34 weeks. The perinatal mortality was 7%, including one still birth and one neonatal death [29] . Furthermore, pPROM was observed in 18.8% of patients [29] . However, it is important to emphasize these data reflect small numbers in early COVID-19 era, and the perinatal issues may not be directly related to maternal or neonatal infection with coronavirus.

The transmission and symptom profile of COVID-19 in neonates are described in Fig. 1 . As per our compiled data, out of 793 neonates born, 629 neonates (79%) were tested after birth. The commonest symptom in this group was respiratory distress. Respiratory support was needed in 60 neonates, with 14 babies needing mechanical ventilation, 25 needing non-invasive ventilation and 21 needing nasal oxygen. The respiratory symptoms are more likely related to prematurity, transient tachypnoea, and respiratory distress syndrome rather than COVID-19 pneumonia. Only 35 of the 629 tested neonates (5.5%) were positive for COVID-19. However, it is difficult to rule out false negative cases, as the timing and protocol for testing was variable and the optimal protocol is currently unclear. Of the 35 positive neonates, 14 (40%) were symptomatic. The commonly described symptoms were respiratory (tachypnoea, respiratory distress, cough), gastrointestinal (diarrhoea, vomiting, feed intolerance), lethargy and temperature instability. It is also difficult to assume if these symptoms are attributable to COVID-19 disease as few infants who tested negative also developed symptoms. [30] The potential severity of SARS-CoV-2 late onset sepsis has been discussed in the case report by Munoz et al. which describes manifestation of hypotension, need of mechanical ventilation with high settings and occurrence of pneumothorax [45] . Although the extent of disease severity is difficult to describe given the limited literature, majority of neonates have had mild disease. The available case reports and case series on neonates born to COVID-19 pregnant women are summarized in Table 1 .

Detection of viral nucleic acid by reverse transcriptase polymerase chain reaction (RT-PCR) is the current gold standard and confirmatory test for COVID-19 [46] . The sensitivity of RT-PCR depends on the precise RT-PCR assay, the type of specimen obtained, the quality of specimen and the duration of the illness at the time of testing. RT-PCR may be false negative in low viral load states like very early or late phase of disease [47] . Nasopharyngeal swab and oropharyngeal swab are recommended for screening or diagnosis of early infection (https://www.aappublications.org/news/2020/07/ 22/newbornguidance072220). In a study on the sensitivity of RT-PCR for various specimens, positivity rates were 93% for broncho-alveolar lavage,72% for sputum, 63% for nasal swab, 46% for bronchoscopic brush biopsy, 32% for pharyngeal swabs, 29% for faeces, 1% for blood and 0% for urine specimens. Lower respiratory tract specimens have higher positive rates probably due to higher viral loads [17, 47, 48] (https:// w w w . a a p p u b l i c a t i o n s . o r g / n e w s / 2 0 2 0 / 0 7 / 2 2 / newbornguidance072220). American Academy of Paediatrics (AAP) recommends testing with molecular assay on swabs of nasopharynx and throat (oropharynx) [one single swab to sample throat first and then the nasopharynx], initially at 24 h of age and repeat testing at 48 h of age. In mechanically ventilated neonates, tracheal aspirate should be tested. In the neonates with initial positive PCR test, follow-up testing with 48-72-h interval should be done until 2 consecutive negative tests (https://www.aappublications.org/news/2020/07/22/ newbornguidance072220). The Canadian Paediatric Society recommends testing within 2 h of life after cleansing the face to reduce colonization. For positive tests, repeat testing after 24-48 h is recommended. Optimal precautions should be ensured during sample collection and processing to avoid risk of exposure to virus due to aerosol transmission (https://www. cps.ca/en/documents/position/nicu-care-for-infants-born-tomothers-with-suspected-or-proven-covid- 19) .

Serological tests are less likely to be reactive in the first several days of infection so are less useful in diagnosis of acute infection. Sensitivity of ELISA is 87% compared to 82% by immunochromatographic card test [49] . Similarities in genetic sequence with other viruses cause cross-reactivity and high false positive rates for serological tests. In a recent study, the positive detection rate was significantly increased (98.6%) when IgM ELISA assay was combined with PCR for each patient compared to qPCR test alone (51.9%) [50] (Fig. 2) . Serological surveys can aid in investigation of an ongoing outbreak and in retrospective assessment of the attack rate or extent of an outbreak (https://www.who.int/newsroom/commentaries/detail/advice-on-the-use-of-point-ofcare-immunodiagnostic-tests-for-covid- 19) . A recent report on placental pathology in 16 women with SARS-CoV-2 infection showed features of decidual arteriopathy and maternal vascular malperfusion [51] . These findings are also seen in neonates had APGAR score < 7 at 5 min. In 10 cases, breast feeding was allowed with mask. Two neonates, in whom mother's COVID-19 was diagnosed postnatally, breast feeding and skin-to-skin contact were allowed without mask initially. In these neonates, SARS-CoV-2 was positive on day 1 and 3, respectively. Neonatal findings Nasal swabs RT-PCR for SARS-Cov-2 at admission was positive and was treated with azithromycin and hydroxychloroquine.

Recovered gradually and discharged on day 9 of admission 8 Salvatori G et al. [66] Bambino Gesu`" Children's Hospital, Rome, Italy 2 mother and infant pairs Postnatally two mother, and term infants pairs were admitted on day 18, day 10, respectively. Both mother and neonate were probably infected by a third person. Mothers were asymptomatic

First neonate was asymptomatic and the second neonate had cough, diarrhoea and poor feeding and needed intravenous fluids for 5 days

None of them required respiratory support. Neonatal nasopharyngeal swabs -positive on admission Both mothers breast milk samples -negative 9 Zamaniyan M et al. [27] Mazandaran University Infants with negative testing and had non-specific clinical features (may not be attributable to SARS-CoV-2 infection) 19 Chen Y et al. [43] Tongji medical college, Wuhan, China

Three -caesarean section, one -vaginal delivery One mother required respiratory support

All had normal APGAR scores Three neonate's throat swab was negative

One infant had facial ulcerations; two had rashes of unknown aetiology at birth One infant had respiratory distress (TTNB) 20 Xu L et al. [72] Tongji medical college, Wuhan 5 mother and neonate pairs All five mothers had pneumonia Four mothers: caesarean delivery (two due to COVID-19 and two due to obstetric causes) One mother: vaginal delivery hypertensive disorders of pregnancy and may reflect an inflammatory state affecting placental physiology. Complete blood count may show normal or low total while cell counts, decreased lymphocyte count and low platelet count. Various enzymes levels including creatinine kinase, lactate dehydrogenase, alanine aminotransferase and inflammatory markers (CRP, ferritin) have shown non-specific elevation [20, 23, 30, 52] . Chest X-ray findings can vary from normal in the initial phases to unilateral or bilateral patchy or ground glass involvement [53] . There are no characteristic Xray and CT features of neonatal COVID-19 till date because of limited data. USG chest could emerge to be a useful tool as it can be done at bedside and does not cause radiation exposure.

Based on resource availability, it may be useful to promote a general SARS-CoV-2 screening for pregnant women admitted to the hospital in order to prevent NICU outbreak. Universal screening of neonates, parents and healthcare workers can prevent spread of SARS-CoV-2 infection among the neonates admitted to a NICU even in an area with a high incidence of SARS-CoV-2 [54] .

Many centres currently practise universal testing approach for pregnant women to determine optimal hospital isolation practices, use of personal protective equipment and neonatal care. However, the application of this strategy may not possible in resource limited settings or in cases of emergency delivery [55] . All pregnant women with clinical features attributable to COVID-19 should be tested by sending nasopharyngeal and/or oropharyngeal swab for RT-PCR testing. If symptoms persist and test reports are negative, ongoing isolation and repeat testing after 2-5 days is recommended. No emergency procedure or delivery should be delayed pending test results. All such cases should be considered suspect cases.

Neonates born to mothers with COVID-19 infection within 14 days of delivery or up to 28 days after birth and neonates exposed to close contacts with COVID-19 infection should be tested [48] . If symptomatic, specimens should be collected as soon as possible. Asymptomatic neonates born to mothers with confirmed COVID-19 infection should be tested between 2 and 12 h after cleansing the face (https://www.cps.ca/en/ documents/position/nicu-care-for-infants-born-to-motherswith-suspected-or-proven-covid-19). Repeat testing after 2-3 days for positive cases and after 3-5 days for negative cases is recommended. If testing is not readily available, clinical monitoring should be done (https://www.aappublications. org/news/2020/07/22/newbornguidance072220). For diagnosing vertical transmission, it is important to follow a universally accepted definition for comparison and collation of data. One such classification system and case definition for SARS-CoV infection in pregnant women, foetuses and neonates has been proposed recently [49] (Table 2) .

Guidelines from Chinese expert consensus, AAP/ American College of Obstetricians and Gynaecologists (ACOG)/Society for Maternal and Fetal Medicine (SMFM)/ Centers for Disease Control and Prevention (CDC) and RCOG/RCPCH are compared in Supplementary Table 1 .

Standardized testing protocol, prevention of spread from mother to child and providing optimal treatment to symptomatic neonates are the key areas in perinatal management of neonates with suspect/positive for COVID-19. It is advisable to cohort pregnant women who are positive for SARS-CoV-2 or as person under investigation (PUI) with ILI (influenza-like illness) (https://www.aappublications.org/news/2020/07/22/ newbornguidance072220, https://www.cps.ca/en/documents/ position/nicu-care-for-infants-born-to-mothers-withsuspected-or-proven-covid-19, https://www.rcog.org.uk/ globalassets/documents/guidelines/2020-04-17-coronaviruscovid-19-infection-in-pregnancy.pdf, https://www.cdc.gov/ coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcareguidance.html, https://www.acog.org/clinical/clinicalguidance/practice-advisory/articles/2020/03/novelcoronavirus-2019) [48, 55, 56] . Ideally this should be done prior to hospital admission through telephonic or video consultation or at hospital entry. Antenatal steroids and magnesium sulphate for neuroprotection should be administered as per current guidelines. The pregnant women should wear mask to prevent the spread through droplet transmission. Neonatology team should discuss with the parents prior to delivery regarding delayed cord clamping, separation of the neonate from mother versus rooming-in and feeding options using a shared decision-making approach. The practices of rooming-in, PPE and mother-neonate separation are extremely variable according to different countries/ setting and guidelines from scientific societies or institutions. Thus, choices must be adapted to the local needs and situation. What is more important is to have a complete, open information to the family and a shared choice post-counselling. In real life, 'zero risk' does not exist, and decision should be based after evaluating the risk-benefit ratio, resource availability, feasibility and parental preference [55, 56] .

Precautions and PPE In the current context of pandemic, triaging pregnant women as suspect, positive or negative cases will optimize utilization of resources. Contact and droplet precautions are recommended for routine encounters with confirmed or suspect neonates with COVID-19 infection. These include gown, gloves, standard procedural mask and eye protection (face shield or goggles). Airborne, contact and droplet precautions are recommended for procedures including bag and mask ventilation, intubation, suctioning and neonates on any form of respiratory support. The PPE includes gown, gloves, N95 respiratory mask with eye protection or air-purifying respirator (powered airpurifying respiratory (PAPR) (https://www.aappublications. org/news/2020/07/22/newbornguidance072220).

Delivery room Resuscitation of neonates born to mothers with confirm or suspected COVID-19 disease should be in accordance with the latest NRP guidelines (https://www.aappublications.org/ news/2020/07/22/newbornguidance072220). Delayed cord clamping (DCC) has significant benefits in term and preterm neonates, but the small risk of viral transmission through cord blood does exist. As per existing practice, DCC may be considered unless contraindicated, after discussion with families [48] . Resuscitation should be in a separate room and overcrowding should be avoided. If separate room is not available, the neonatal resuscitation corner should be at least 6 ft away from the delivery cot. Resuscitation may involve suctioning, providing PPV or intubation; hence, the providers should don airborne, contact and droplet level-PPE [48] . DR resuscitative manoeuvres are at high risk of aerosolization; also there is risk of transmission from maternal blood, amniotic fluid and other body fluids. Noninvasive ventilation provided during resuscitation may significantly increase this risk like in the NICU as neonatal CPAP and NIV are almost always invariably associated with 40-50% leaks through the mouth [57] . Therefore, PPE should be a norm in DR in the present pandemic era for all the personnel attending to the mother and her neonate. Based on adult data, the risk of acquiring a viral infection is higher during endotracheal intubation compared with manual ventilation (bag-mask ventilation) [58] . The use of bacterial/viral filters in the exhalation limb of T-piece may be effective in reducing viral dispersion and is recommended by many scientific societies. With close monitoring, it may be reasonable to use smaller filters (approximately 10 mL of dead space) in neonates with birth weight > 2 kg.

The neonates born to positive mothers should be nursed in an incubator and transported to the NICU by a dedicated team wearing PPE. Ideally, the neonate should be kept in negative pressure isolation rooms or in rooms with high efficiency particulate air filters (HEPA). Staff should handle the baby with isolation precautions and PPE, and such staff should not move to other sections of the NICU. If the NICU does not have a single-room design, open-bay NICU's should have at least 3 sections, first room for babies born to COVID-19 positive/ suspect mothers, second for babies who are born to COVID-19 negative asymptomatic mothers and third room for babies who were in room one but have tested negative twice. The staff and workforce should also follow the same flow, with dedicated team of healthcare workers (HCW) for each section. It is important to remember that NICU should be reserved only for those neonates needing intensive care. A general NICU admission policy due to positive/suspect COVID status may lead to shortage of beds and will also contribute to false epidemiological data and overestimation of the disease severity in neonatal population [59] .

Testing of the neonate should be performed between 2 and 12 h after birth. If negative, a repeat test should be performed after 3-5 days. If the neonate is requiring prolonged NICU stay and both tests are negative, the neonate can be shifted to a separate room to prevent ongoing risk of transmission from other babies. Symptomatic and supportive therapy are the main principles of management as no specific antiviral agent is approved for use in neonates.

Although neonatal COVID can present with varied symptoms involving cardiovascular, GIT or CNS systems, respiratory distress is the commonest system. However, neonates are more likely to need respiratory support due to other conditions such as prematurity, sepsis, respiratory distress syndrome, and transient tachypnoea of newborn rather than due to COVID-19 pneumonia. Epidemiologically, the priority should be to diagnose neonatal ARDS according to Montreux definition and use it to classify disease severity [60] .

Respiratory management practices should be evidence based for providing optimal support to the neonate and also protecting HCW from the virus. The main concern related to respiratory support in neonates with suspected or confirmed COVID-19 infection is the generation of aerosol-containing particles that can lead to disease spread. The data related to respiratory management of neonates with COVID-19 infection is limited, as majority of neonates have tested negative or have been asymptomatic. Thus, it seems reasonable to have a practical, physiology-based approach for these neonates as we await more evidence.

Non-invasive support CPAP remains the standard therapy in managing neonates with respiratory distress in the NICU including those with COVID-19. Heated humidified high flow nasal cannula (HHHFNC) may lead to higher dispersion of virus due to the presence of higher leak around the nose and should be avoided. A study by Simonds et al. showed that air dispersion during NIPPV generates droplets of > 10 μm in size, which are more likely to deposit on local surfaces within a short distance [61] . CPAP with a close circuit provided by the ventilator may be safer as it has lesser degree of aerosol generation, and the same machine and circuit can be used for mechanical ventilation if the patient deteriorates. However infant flow driver, variable flow CPAP should be avoided as one limb is open to the exterior and may be a source of spread. Precautions during use of CPAP for neonates include proper PPE measures for HCW (airborne, droplet and contact-level PPE), optimal fitting of the interface, adequate spacing/ ventilation in room and regular disinfection of surfaces/baby environment. The CPAP tubing and water reservoir should be replaced every week and discarded appropriately. Disposable circuits should be preferred, and one should use filters on the expiratory limb (at least) of circuits as is stated by many scientific societies.

Invasive support Endotracheal intubation is an aerosol generating procedure and should be performed by skilled person wearing adequate PPE. Both cuffed and uncuffed tube may be used for intubation. Low cuff pressure has been demonstrated to be safe in various studies [88, 89] . Video laryngoscope should be preferred as it allows easy access to the airway and avoids close contact. If available, closed in-line suctioning and use of hydrophobic filter at the exhalation port is recommended both during non-invasive and invasive respiratory support. Use of appropriately sized, endotracheal tube is recommended to minimize leak, and oral intubation should be preferred over nasal intubation [90] . Mode of ventilation and strategy for weaning should be based on disease process and current practice.

Stable neonates born to confirm/suspect COVID-19 mothers who are stable can be roomed-in together in a negative pressure isolation room. The potential benefit of temporary maternal and newborn separation in decreasing neonatal infection versus the issues related to infant separation should be discussed with the family prior to delivery. If mother and baby are roomed-in, an additional caregiver who is non COVID-19 exposed and asymptomatic could be permitted to care for the baby. The mother should wear N-95 mask and practice meticulous hand hygiene. The infant should be placed at least 6 ft from the mother. Breast milk has numerous benefits, and there is little data to suggest that virus transmission occurs via breast milk [25, 26] . Expressed breast milk can be safely fed to the neonate by the designated caregiver after boiling. The breast pump components and paladai/feeding bottles should be thoroughly disinfected after each use. Skin-to-skin contact should be avoided due to risk of transmission of virus. In case the mother wishes to directly breast feed the infant, she should follow strict hand hygiene and wear mask at all times. The neonate should be monitored regularly for vitals and respiratory symptoms. The neonate can be discharged as per routine discharge criteria if asymptomatic and after 2 consecutive negative tests for COVID-19. A comprehensive approach for the perinatal and postnatal management, discharge and follow-up of neonates has been summarized in Fig. 2 .

Transport of a sick infant involves meticulous planning and should be efficient, safe and timely. Data reported by the Neonatal Transport Study Group of the Italian Society of Neonatology showed a significant increase in the median time to complete transport from 120 min previously to 240 min in the current COVID-19 period. The common reasons attributable for this delay include donning and doffing of PPE protocols, disinfection of ambulance, devices and delays in obtaining necessary documentation [91] .

It is important to have a clear communication with the referring unit prior to transport regarding the infant's or mother's recent COVID status. The shortest route of transport and transit modifications inside referring hospitals should be established (e.g. alternative passage or lifts for transfer of suspect/confirmed cases). The ambulance should be equipped with adequate PPE, and number of team members should be restricted depending on the situation. Members of the transport team must wear protective gear including N95 respirator, disposable gown, visor/goggles, face-shield and shoe cover. The equipment used for stabilization should be placed in airtight plastic containers for reuse during the transport. The infant must be transported in an incubator, and unnecessary opening of portholes should be avoided. On arriving at the destination, another team from the tertiary hospital can receive the infant from the ambulance (after donning PPE) and escort to the NICU. Once the neonate is safely transferred to the NICU, cleaning of the transport incubator, monitors, syringe pumps and ventilator must be done with disinfectant wipes or paper cloth soaked in 70% ethyl alcohol or other appropriate disinfectant. Other equipment (i.e. masks, laryngoscope, selfinflating bag) should be sterilized according to standard institutional policy. Lastly, the vehicle should be sanitized prior to the next transport. Road transports should be preferred if possible, and the ambulance should not have any open passage/ windows between the health compartment and driver. Having a clear institution-based standard operating procedure will minimize delays and ensure safe transport for the infant and the crew [92] .

Thus, the overall prognosis of neonates born to COVID-19-positive mothers is favourable. Risk of transmission is low, and most neonates are asymptomatic. Possible protective mechanisms include lower ACE2 expression (SARS-CoV-2 receptor), less robust proinflammatory cytokine response and stronger innate immune system [93, 94] .

Limitations This review is based on mostly retrospective reports, reviews and consensus guidelines whose quality may be suboptimal due to fast-tracked publications considering the unexpected nature of pandemic. These recommendations may change at a later stage, once more robust evidence is available.

Future research considerations There is a need for large prospective multi-centre international registries of neonatal SARS-CoV-2 infections to better understand the epidemiology, the detail and the possibility of interventions for neonatal cases such as registries by AAP and EPICENTRE Registry [95] .

The following key points summarize practical considerations for perinatal COVID- 19 

Bats and coronaviruses

Emerging coronaviruses: genome structure, replication, and pathogenesis

Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection

Middle East respiratory syndrome

Interspecies transmission and emergence of novel viruses: lessons from bats and birds

A novel coronavirus from patients with pneumonia in China

Severe acute respiratory syndrome-related coronavirus-the species and its viruses, a statement of the coronavirus study group

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in

Xing X (2020) Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

2019-nCoV transmission through the ocular surface must not be ignored

The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes

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

An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes

Synthesis and systematic review of reported neonatal SARS-CoV-2 infections

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

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study

Antibodies in infants born to mothers with COVID-19 pneumonia

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

Severe COVID-19 during pregnancy and possible vertical transmission

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

Detection of SARS-CoV-2 in human breastmilk

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

Outcome of coronavirus spectrum infections (SARS, MERS, COVID 1-19) during pregnancy: a systematic review and metaanalysis

Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia

Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Excretion of SARS-CoV-2 in human breast milk

Evaluation for SARS-CoV-2 in Breast Milk From 18 Infected Women

The reproductive number of COVID-19 is higher compared to SARS coronavirus

Pathogenicity and transmissibility of 2019-nCoV-a quick overview and comparison with other emerging viruses

COVID-19 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals

Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis

Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy

Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases. Zhonghua bing li xue za zhi=

Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province

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

Coronavirus disease 2019 (COVID-19) during pregnancy: a case series

Infants born to mothers with a new coronavirus (COVID-19)

Perinatal aspects on the covid-19 pandemic: a practical resource for perinatal-neonatal specialists

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

Interim guidelines for collecting, handling, and testing clinical specimens from persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19)

World Health Organization. Laboratory testing for coronavirus disease ( COVID-19) in suspected human cases: interim guidance

Neonatal resuscitation where the mother has a suspected or confirmed novel coronavirus (SARS-CoV-2) infection: suggestion for a pragmatic action plan

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

Profiling early humoral response to diagnose novel coronavirus disease (COVID-19)

A case report of neonatal COVID-19 infection in China

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Universal screening of high-risk neonates, parents, and staff at a neonatal intensive care unit during the SARS-CoV-2 pandemic

Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection

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

Mechanics of nasal mask-delivered HFOV in neonates: a physiologic study

Exhaled air dispersion during bag-mask ventilation and sputum suctioning-implications for infection control

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

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

Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and chest physiotherapy in clinical practice: implications for management of pandemic influenza and other airborne infections

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

First case of neonatal infection due to COVID 19 in Spain

Novel coronavirus infection in newborn babies under 28 days in China

Mode of delivery and clinical findings in COVID-19

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

Clinical features and the maternal and neonatal outcomes of pregnant women with coronavirus disease 2019

Association of COVID-19 infection with pregnancy outcomes in healthcare workers and general women

Maternal death due to COVID-19 disease

Coronavirus disease 2019 (COVID-19) in pregnant women: a report based on 116 cases

Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry?

Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection during late pregnancy: a report of 18 patients from Wuhan, China

Clinical characteristics and risk assessment of newborns born to mothers with COVID-19

Early release-lack of vertical transmission of severe acute respiratory syndrome coronavirus 2

Emergency caesarean section on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed patient

COVID-19 in pregnan-cy with comorbidities: more liberal testing strategy is needed

COVID-19 vaginal delivery-a case report

Anesthetic management for emergent cesarean delivery in a parturient with recent diagnosis of coronavirus disease 2019 (COVID-19): a case report

Clinical analysis of pregnant women with 2019 novel coronavirus pneumonia

Management of the first patient with confirmed COVID-19 in pregnancy in India: from guidelines to frontlines

Impact of COVID-19 infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during natural birth

The first Jordanian newborn delivered to COVID-19 infected mother with no evidence of vertical transmission: A case report

Cesarean section in a pregnant woman with COVID-19: first case in Portugal

Lung ultrasound and computed tomographic findings in pregnant woman with COVID-19

Vaginal delivery report of a healthy neonate born to a convalescent mother with COVID19

National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection: NPC-19 registry

The incidence of postoperative respiratory complications: a retrospective analysis of cuffed vs uncuffed tracheal tubes in children 0-7 years of age

Cuffed endotracheal tubes in infants less than 3 kg: a retrospective cohort study

Respiratory support in preterm infants at birth

COVID-19 outbreak impact on neonatal emergency transport

Neonatal emergency transport system during COVID-19 pandemic in the Veneto region: proposal for standard operating procedures

Nasal gene expression of angiotensin-converting enzyme 2 in children and adults

Effects of ageing on the immune system: infants to elderly

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

We are grateful to Shivani Bhan for infographics and other technical help.