Introduction

In December 2019, a new severe disease caused by coronavirus 2 (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) emerged in Wuhan, China, creating a global pandemic of unprecedented magnitude.1 By April 2, 2020, >1,000,000 cases of coronavirus disease (COVID-19) have been reported in >200 countries, resulting in >52,000 deaths.2 COVID-19 appears to have the greatest impact on seniors and those with significant co-morbidities.3

SARS-CoV-2 infection in children appears to be less common and less severe compared with adults.4,5,6 Few cases of neonatal COVID-19 have been reported to date, and little is known regarding route of infection, clinical presentation, management, and outcome.7,8 Reassuringly, vertical transmission of SARS-CoV-2 appears rare, consistent with other coronavirus infections.7,9 In the few reported infants with possible vertical transmission, the clinical course was mild.5,8,10 Answers are missing to a number of pressing questions, including the significance of vertical and horizontal transmission for the newborn, route and timing of horizontal transmission, the role of breastfeeding, prediction of infant disease severity, and the effectiveness of preventive measures to protect infants and health care workers (HCW), as well as the potential side effects of such measures. Nonetheless, HCW must act to protect patients and families in the face of uncertainty. The aforementioned questions are of utmost importance for organizing an effective and efficient health system response for mothers and infants, while protecting HCW and limited resources. Yet, in the absence of high-quality evidence, pragmatic solutions need to be found.11

We compare the experiences and practical recommendations from international, national, and local guidelines on the management of newborn infants born to SARS-CoV-2-suspected or SARS-CoV-2-positive mothers. Common to all efforts are the lack of objective data and limited published reports on effective management at the time guidelines were devised. This report reflects possible management options at a specific point in time and future work will supercede the presented guidance. We aim to highlight the state of coordinated guideline-informed approaches to the pandemic while extracting lessons for future pandemic preparedness.

Methods

On March 10, 2020, a core group of experts in neonatal intensive care from Italy, Norway, the United States (US), Ireland, and the United Kingdom (UK), began to share local guidance on the management of babies born to mothers with COVID-19. Initially, protocols from Chinese units were requested from professional contacts, followed by further invitation of key professionals, in the following referred to as collaborators, who were identified via societal databases (European Society for Paediatric Research, Society for Pediatric Research and American Academy of Pediatrics, and personal contacts). We aimed to secure global representation through a wide selection of national backgrounds, including low-and-middle-income countries. Collaborators shared national epidemiological data on disease prevalence and provided national and local guidelines on the management of neonates born to COVID-19-suspected or COVID-19-positive mothers. When local guidelines were provided, they reflected practice at the collaborators’ institution but were not necessarily representative of national guidelines.

A convenience sample of 23 experts from 21 countries was approached via email with a structured questionnaire. Collaborators were surveyed between March 14 and 21, 2020. We focused on the following aspects of management: organization of hospital triaging and centralization of care (sequestering patients in designated hospitals or wards); hygiene management, including use of personal protective equipment (PPE) in the delivery room (DR) and the neonatal intensive care unit (NICU) with a specific focus on aerosol-generating procedures (AGP); clinical pathways for asymptomatic infants, those delivered vaginally or by cesarean section, and those inborn or outborn; approaches to breastfeeding; diagnostic testing; family access to the NICU; and psychological support for families and HCW.

Data were analyzed in Microsoft Excel (Microsoft Redmond, Washington, U.S.).

Results

The epidemiological burden of COVID-19 differs markedly between countries. By March 21, 2020, Italy and China were the 2 most severely affected countries, while 8 countries reported <10 deaths (for more detail, see Supplementary Table S1). The availability of local and national guidelines for neonatal management varied considerably among collaborators. Half of the institutions adopted national guidelines, and the remainder relied on local guidelines. Reasons for not adopting national guidelines included: unavailable at the time of the survey, difficult application or disagreement with national guidelines, and lack of granularity of national guidelines. Means for triaging actively laboring SARS-CoV-2-positive mothers were considered in all guidelines. Interventions included transfer to specific hospitals or hospital sites, for example, designated isolation rooms on delivery suites. Guidelines regarding centralization of care for symptomatic and/or SARS-CoV-2-positive infants varied widely (Table 1). More consistency was observed with regard to PPE, which was universally recommended during neonatal management in the DR (Table 2). Isolation procedures in the NICU varied, with the majority of respondents suggesting isolation for infants in single rooms. When conducting AGP such as non-invasive respiratory support, most guidelines recommended isolation in closed incubators. However, only a few institutions had an explicit respiratory support plan for infected and/or symptomatic patients. Most national or local guidelines suggested that an asymptomatic infant could stay with the mother to breastfeed, with the exception of China, and, in part, Ireland and the US. Breastfeeding COVID-19-positive mothers were to be supplied with material clearly explaining hygienic precautions. Most guidelines recommend viral testing of all infants born to COVID-19-positive mothers but a few countries restricted testing to symptomatic infants (Table 3). For viral testing, nasopharyngeal swabs (NPSs) were most commonly advised. In Table 4, we present data on infant feeding, visitation arrangements, and considerations for psychological care for parents/caregivers. Guidelines from several countries included detailed descriptions of recommended psychological care; however, the content varied. Very few guidelines mentioned psychological care for parents or HCW affected by COVID-19.

Table 1 Patient triage, care centralization, and national collaborations.
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Table 2 Delivery room and NICU management.
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Table 3 Clinical pathway for asymptomatic infants, inborn/outborn, testing, and follow-up.
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Table 4 Breastfeeding, family access restrictions in NICU, and psychological support.
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Discussion

We performed an analysis of the early, quasi ad hoc process of national and local guidelines developed for managing neonates born to SARS-CoV-2-positive mothers during the month of March 2020. Our pragmatic international survey includes guidance from 20 countries on 6 continents. Many similarities, but also striking differences, became apparent. At the early stage of the pandemic, guidelines from the World Health Organization (WHO) or national authorities may have been difficult to implement in different local contexts or had left several, relevant aspects of newborn care undefined, necessitating the formulation of pragmatic local recommendations. We have observed the constant growth in the evidence base for managing infants born to COVID-19-positive mothers alongside the changing interpretation of the available data. Thus already existing guidelines are being adapted in a non-predictable pattern. Common to all is the likelihood that guidelines will continue to evolve over the coming weeks according to the best available evidence. Until sufficiently evidence-based guidelines are in place, international recommendations and national protocols need to be adapted to the local settings.

The progression of international and national guidance since the writing of this paper illustrates how knowledge gained and shared by reputable institutions worldwide has entered guidelines. On March 13, the WHO published an interim guidance on clinical management of COVID-19, “Caring for infants and mothers.”12 At that time, available evidence suggested no vertical transmission, and in small case series from China, samples from amniotic fluid, genital tract, cord blood, and breast milk from COVID-19-infected mothers were negative for SARS-CoV-2.9,13,14,15 The Royal College of Obstetricians and Gynaecologists (RCOG) in the UK published their first guidance “Coronavirus (COVID-19) infection and pregnancy” even before the WHO on March 9. Since then, there have been regular updates, and the fifth version appeared on the 28th of March, reflecting the rapidly evolving knowledge in this area.16

An issue of primary interest for neonatologists is the DR management of infants born to mothers with suspected or confirmed SARS-CoV-2 infection. The limited literature concerning the risk of vertical transmission of SARS-CoV-2 as well as for related viruses causing severe respiratory illness, SARS-CoV and Middle East respiratory syndrome-CoV, indicates a low risk.6,7 The first reports on postnatal COVID-19 disease in newborns from China have also been reassuring.5,8 Many experts suggest that the contagious potential of the newborn infants themselves immediately after birth is very low. Nevertheless, an anxiety persists as the DR setting represents a contagious area due to maternal COVID-19 disease and due to possible contact with maternal fecal flora containing virus and transmitted to the baby at delivery. Therefore, all international, national, and local guidelines presented in our current report recommended caution during deliveries, including isolation room and the need for PPE, and have made no distinction in managing cesarean and vaginal deliveries.

One of our most pertinent findings concerned the guidance on the controversial topic of mother–infant separation, i.e., whether a COVID-19-positive mother and her asymptomatic infant should be separated right after birth in order to prevent postnatal horizontal disease transmission, through contact or respiratory droplets. In China, this seems to be routine practice and infants are usually fed formula.17 In contrast, both WHO and RCOG recommend that babies may stay with the mother if she is able to care for the infant, and breastfeeding is recommended.12,16 The interim guidance from the Center of Disease Control (CDC) in the US takes an intermediate standpoint on this topic and suggests that “whether and how to start or continue breastfeeding should be determined by the mother in coordination with her family and healthcare providers. A mother with confirmed or suspected COVID-19 should take all possible precautions to avoid spreading the virus to her infant, including washing her hands before touching the infant and wearing a face mask, if possible, while feeding at the breast.”18 In our study, the majority of national or local guidelines allowed the mother to stay with her asymptomatic infant after birth, and supported breastfeeding with hygiene precautions. These countries/hospitals most likely considered that the benefits of breastfeeding and early infant bonding outweigh the potential risks of postnatal transmission and in most cases mild respiratory disease in infants. The exceptions were China where separation was recommended, Ireland where separation was suggested but maternal decision to room-in with precautions was also available, the US where the CDC suggests “consider temporary separation”, and Israel where a COVID-19-positive mother and her COVID-19-negative child should be separated.

Isolation and personal protection practices were quite consistent across countries. Although neonates are not typically considered capable of generating infectious airborne particles, airborne precautions are recommended for AGPs for infants with SARS-CoV-2 infection.19 NICUs from most countries reported the use of PPE for neonatal resuscitation for newborns of mothers who are suspected or confirmed COVID-19 positive. This is to protect HCW from maternal aerosolization in the second stage of labor or from the potential contamination and aerosolization that may occur during neonatal resuscitation. Recommendations for protection did not differ for infants in need of immediate intensive care after vaginal or cesarean delivery. The notable exceptions were Norway and Sweden, who consider infants after vaginal or cesarean delivery not likely or very unlikely to be contagious if immediately separated from the mother, for example, due to preterm delivery or acute asphyxia, owing to the lack of demonstrated vertical transmission. For potentially contagious infants in the NICU, countries were also quite consistent in attempting to care for infants in incubators, in isolation, or, if available, in negative pressure rooms (particularly in those with aerosolizing respiratory support), and HCW wearing PPE. One NICU from Brazil limits non-invasive respiratory support, favoring intubation instead, which is aligned with recommendations for adult management of COVID-19-associated acute respiratory syndrome. Several countries use filters in their equipment to minimize aerosolization. Given the shortage of PPE, equipment, and physical space to isolate infants, many countries employ efforts to limit their use, such as cohorting of patients, limiting staff access, and ending isolation as soon as feasible based on testing. A careful balance must be achieved between protecting HCW and other patients from infection while minimizing PPE wastage in low-risk patients. Continued data collection will reveal the true risk posed by newborns to transmit SARS-CoV-2 infection.

Guidelines in most countries suggest performing viral testing of all neonates born to COVID-19-positive mothers, regardless of symptoms. A few countries recommend testing only symptomatic infants. The purpose of testing may be to explain symptoms in infants with respiratory pathology and to end isolation measures in asymptomatic infants tested negative on two separate occasions. Obtaining NPS on asymptomatic infants may result in false negatives, and the optimal timing of testing is unclear,20 a potential argument for not testing asymptomatic infants. In contrast, it has been suggested that all infants presenting with possible COVID-19 respiratory symptoms should be tested after 72 h of age to avoid potential false-negative results and tested again on day 5 before declaring non-infected.20 However, the timing of testing is still controversial.8

In response to the pandemic, all countries reported a restricted regimen for family access to the NICU.21 The majority of hospitals limited access to the NICU to only one parent at a time, wearing a surgical mask and under strict hygiene precautions. All strictly prohibited the entrance of symptomatic visitors. At the time of the survey, only Australia had not yet limited parental NICU access, possibly reflecting a different disease burden at the time (Fig. 1). In China and Poland, by contrast, the restriction to parental access also extended to mothers. Limitations in parent–infant contact may have significant adverse consequences on infants’ neurobehavioral development and family psychological well-being. Nevertheless, the dire risk of contracting SARS-CoV-2 led to unanimous agreement for prioritizing patients and HCW safety over family-centered care. All countries though recognized the need for psychological support for families. The medical uncertainties related to COVID-19 are amplified in pediatric patients due to the lower rate and severity of cases compared with adult patients and lack of follow-up data. To date, neither the WHO nor other international organizations recommended a specific follow-up for infants developing COVID-19.12 Only a few countries have already put in place a structured follow-up, highlighting the need for more information about the disease course in infancy.

Fig. 1: COVID-19 cases and deaths by country and region.
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a Cases by country, b deaths by country, c cases by region, d deaths by region. From Financial Times COVID-19 case and death data, accessed 31 March, 2020. Regions only represent the countries included in this study. *Countries with <5000 total detected cases in descending order—Israel (4695), Norway (4445), Brazil (4371), Australia (4245), Sweden (4028), Ireland (2615), Poland (2055), Mexico (993), Argentina (820), Kenya (50); **countries with <100 deaths in descending order—Canada (67), Ireland (46), Norway (32), Poland (31), Argentina (23), Mexico (20), Australia (18), Israel (16), Kenya (1).

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It is heartening that this sample of guidelines agreed in several domains, but we also found multiple areas in which recommendations diverged between local and national guidance or between countries. The reasons for such inconsistency in practice can generally be grouped into two categories, both of which are more pronounced during the COVID-19 pandemic. First, the interpretation of evidence may differ between organizations conducting literature review. This will be particularly evident when evidence is lacking, of poor quality, or only indirectly applicable, as is the case with a novel viral disease. Standardization of care is still likely to improve outcomes even in such a situation, but the choice of which potentially better practices to implement is much more arbitrary in the absence of high-quality data. Second, countries and institutions develop guidelines with close consideration of the context in which they will be applied. The same intervention may be highly effective in one setting but of less use in another. Relevant context in the case of COVID-19 might include the feasibility of implementation given supply chain disruptions and personnel availability, the background prevalence of disease, and the degree of central control and regionalization of a health care system, which facilitates the dissemination and adoption of recommendations at the frontline.

The scenario of a global viral (influenza) pandemic had been predicted for decades,22 but when it happened with this new coronavirus, the neonatal health care community was relatively unprepared. However, rarely was the need for robust guidelines on disease management so immediately needed as in these times. Likewise, to date, concerted efforts to combat global pandemics have rarely been put to the test at such intensity. Specific efforts are ramping up to better understand this specific pandemic, but the need for a systematic effort to create an international structure for disaster preparedness is evident. Such a structure could provide important epidemiologic and quality of care information, including, for example, disease incidence, and diagnostic and therapeutic approaches. It could also serve as a rapidly mobilized trial network. Existing quality improvement networks, such as the Vermont Oxford Network, have started organizing an audit platform (VON SONPM Covid-19 Impact Audit) to assess and track the impact of COVID-19 in neonatal units around the world (Jeffrey Horbar, April 1, 2020, personal communication).

This study should be viewed in light of its design. We managed to collect granular data on guidelines from 20 countries in 6 continents early in the pandemic. However, not all respondents had available or applied national guidelines, and their responses thus reflected local rather than national practice. COVID-19 guidelines reported in this study reflect a single timepoint early in the pandemic with countries at different stages as illustrated in Fig. 1. Thus variation in response may not reflect different practice but simply different timing, and it is possible that responses centered by pandemic stage would further converge. However, given socio-political, cultural, health system, and resource capacity differences across countries, we think that convergence would remain incomplete. Finally, we did not inquire regarding each institution’s volume of suspected or known COVID-19-positive mothers or infants, which may influence local response readiness. However, given the early pandemic stage in most countries, few respondents had significant patient volume.

Conclusions

This paper establishes both similarities and differences in the management of newborns at the early stage of this pandemic. Guidelines and evidence are rapidly evolving with rapid generation of new knowledge.23 However, many aspects of COVID-19 still lack clarifying evidence, particularly for the population of newborn infants. Generous and high-level international collaboration across the specialty of neonatology will promote best practice guidelines for the care of infants and offers a path forward beyond the immediate needs during this pandemic.