Feeding strategies to prevent neonatal SARS‐CoV‐2 infection in term or late preterm babies born to mothers with confirmed COVID‐19

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of feeding practices on the risk of  SARS‐CoV‐2 infection in neonates ≥ 34 weeks' gestation born to mothers with confirmed SARS CoV‐2 infection.

Background

Description of the condition

On 11 March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID‐19), a viral infection caused by the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), to be a global pandemic (Cucinotta 2020; WHO 2020a). By early June, over six million persons around the globe have been infected with COVID‐19, including pregnant women and neonates (Dong 2020; WHO 2020b; Zaigham 2020).

The impact of COVID‐19 on neonates is uncertain. Based on available reports, most neonates with COVID‐19 infection have had asymptomatic or mild to moderate illness (Dumpa 2020; Ma 2020; White 2020). Symptoms reported have been fever, poor feeding, vomiting, lethargy, respiratory distress and pneumonia. However, there have been rare reports of some neonates with COVID‐19 who have been critically ill (Munoz 2020). Notably, previous epidemics of coronavirus infections in neonatal intensive care units (NICUs) have been associated with cases of necrotizing enterocolitis (NEC) (Chany 1982; Resta 1985; Rousset 1984) and a sepsis‐like illness with cardiovascular and respiratory complications in the NICU (Gagneur 2008). It is not yet possible to determine the true proportion of critical illness in neonates including the hyperinflammatory syndrome as described in children (Riphagen 2020; Jones 2020).

The potential for spread of COVID‐19 from mother to child, either through vertical or horizontal transmission is unclear. In particular, the risks of breastfeeding pose a particularly difficult problem. Transmission of maternal viral infection to the newborn infant through the breast milk has been shown for infections such as HIV, cytomegalovirus (CMV) and human T‐cell leukemia virus‐1 (HTLV‐1) (Lawrence 2004). As of early June 2020, there is no clear evidence of transmission of neonatal SARS‐CoV‐2 infection via breast milk and no evidence showing presence of viable virus in the breast milk. There are some reports of SARS‐CoV‐2 detection by reverse transcriptase polymerase chain reaction (RT‐PCR) in breast milk from mothers with COVID‐19 infection (Buonsenso 2020; Groß 2020; Kirstman 2020; Wu 2020). However, the overwhelming majority of samples tested have been RT‐PCR negative (Chen 2020; Elshafeey 2020; Lackey 2020; Yang 2020; Yu 2020). It is important to note that the detection of SARS‐CoV‐2 by RT‐PCR does not indicate the presence of viable, replicating virus that may be infective; this would require demonstration of viral subgenomic mRNA or a positive culture. Additionally, the detection of IgA immune response in the breast milk after SAR‐CoV‐2 infection suggests possible protective antibodies that may be conferred to the neonate (Fox 2020). Gross and colleagues described the time course of an infant with a previous negative SARS‐CoV‐2 RT‐PCR, who had subsequent positive tests after being breastfed (with precautions) with milk that also tested positive (Groß 2020). A separate case series from Italy also reported two infants who developed COVID‐19 infection after being breastfed without precautions by mothers with COVID‐19. Notably, the infants born to mothers who utilized precautions in the same study remained negative (Ferrazzi 2020).

To address these concerns, guidelines have been established by authoritative bodies worldwide to address the care of pregnant women with known or suspect COVID‐19 and their newborn infants. Based on the limited clinical evidence on COVID‐19 and on experiences from previous infections such as Human Immunodeficiency Virus (HIV), SARS and Middle East Respiratory Syndrome (MERS), many of the proposed guidelines have threatened some of the established evidence‐based practices in neonatal‐perinatal medicine. Guidelines from the initial epicentres of the COVID‐19 outbreak discouraged any contact between the infected mother and her infant (Gupta 2020; Ma 2020). These recommendations have included withholding of breastfeeding or provision of any breast milk due to concerns about potential SARS‐CoV‐2 transmission (Gupta 2020; Ma 2020).

The implications of these recommendations are serious. There is overwhelming evidence supporting the benefits of breastfeeding. Non‐breastfed infants have a 3.6‐fold increased risk of hospitalizations for lower respiratory tract infections in the first year of life. Formula feeding is associated with a 1.6 ‐ 2.1‐fold increased risk of sudden infant death syndrome (SIDS) (Stuebe 2009). Breastfed infants also have a lower risk of otitis media, respiratory tract infections, respiratory syncytial virus (RSV) bronchiolitis, NEC, atopic dermatitis and gastroenteritis. Beyond the neonatal period, breastfed infants have a lower risk of obesity, type 1 and 2 diabetes, asthma, celiac disease and leukemia (Eidelman 2012). Breastfeeding mothers have decreased postpartum blood loss, increased child spacing due to lactation amenorrhea and less postpartum depression. In the long‐term, they have a lower risk of breast and ovarian cancer, type 2 diabetes, metabolic syndrome, rheumatoid arthritis, hyperlipidemia and cardiovascular disease (Eidelman 2012; Stuebe 2009)

As the pandemic has progressed, national and international professional bodies such as the WHO, the Royal College of Paediatrics and Child Health (UK), the Italian Society of Neonatology, the Canadian Paediatric Society and the Royal College of Obstetricians and Gynecologists have supported continuation of breastfeeding with infection control precautions (British Association of Perinatal Medicine 2020; Canadian Paediatric Society; Società Italiana di Neonatologia 2020; WHO 2020c). Other groups, such as the American Academy of Pediatrics and the Japanese Society for Neonatal Health and Development have recommended feeding infants expressed breast milk (American Academy of Pediatrics 2020; Japanese Society for Neonatal Health & Development). Many guidelines have recommended the adoption of infection control and preventions measures such as face masking with surgical masks and hand hygiene with feeding of the infant (American Academy of Pediatrics 2020; Devane 2020). Some case series have reported the utilization of minimum precautions (Ferrazzi 2020). Several of these guidelines were reviewed recently (Lavizzari 2020).

With such varying recommendations, several authors have expressed ethical and medical concerns for the maternal‐infant dyad with regards to the effects of separation and withholding breastfeeding (Teti 2020; Tomori 2020).

Description of the intervention

In view of the strong evidence for short and long‐term benefits of breastfeeding and breast milk feeding for the mother and child, any recommendations for alternatives due to the risk of COVID‐19 transmission would require strong justification and consideration. The risk of SARS‐CoV‐2 transmission to the newborn infant through breastfeeding or feeding of expressed mother's own milk from mothers with COVID‐19 is currently unknown. Different interventions have been recommended or implemented: withholding of any feeding of mother's own milk (MOM) (Yang 2020) and feedings of formula milk or donor breast milk; feeding expressed breast milk (American Academy of Pediatrics 2020; Japanese Society for Neonatal Health & Development); and breastfeeding with precautions, which include face mask (N95, surgical or home‐made) and hand hygiene.

This review will compare the risk of SARS‐CoV‐2 infection in neonates receiving such interventions to the risk in those who are breastfed or fed breast milk. Due to the potential variability of transmission risk attributable to different practices and setup (e.g. infection control practices, separation) in the different reports, this review will use a pragmatic/observational approach to compare the risk of SARS‐CoV‐2 Infection by different feeding types. The different interventions may also have other potential effects not related to the acquisition of SARS‐CoV‐2 infection. Pragmatic studies (Edwards 2020) such as this involve real world situations and bundles of care. This approach, as demonstrated by the initiative undertaken by the Vermont Oxford Network (VON), has the potential to provide guidance which can significantly improve neonatal outcomes, and may ultimately inform future randomized controlled trials.

How the intervention might work

Breastfeeding without precautions is the standard against which comparisons will be made. This may or may not be associated with an increased risk of infection, since most but not all breast milk RT‐PCR testing done has been negative (Buonsenso 2020; Elshafeey 2020; Groß 2020; Yang 2020), and the predominant means of viral transmission is through droplet and contact (WHO 2020d). In situations where the infant does get infected, antibodies against SARS‐CoV‐2 may potentially modulate infection severity (Fox 2020).

Based on the available literature and the international guidelines, there are three possible ways in which the different types of feeding interventions can impact on SARS‐CoV‐2 transmission to the infant. These include (1) the transmission of virus that may be present in unpasteurized mother's own milk with active COVID‐19 infection, (2) the exposure of the infant to infectious droplets from the mother as a result of the close proximity during breastfeeding, and (3) SARS‐CoV‐2 specific antibodies in breast milk.

EXPOSURE TO UNPASTEURIZED MOTHER's OWN BREASTMILK:

It is currently unclear if and how often the mother's own unpasteurized breast milk could infect the neonate. One study assessed viability of the virus in expressed breast milk and found it to be negative (Chambers 2020). Another study showed that pasteurization inactivates viable SARS‐CoV2 added experimentally to breast milk (Unger 2020).

Some guidelines have recommended feeding pasteurized donor milk or, if unavailable, formula.

CONTACT TO SARS‐COV‐2 DROPLETS FROM MOTHER:

As described above, the predominant mode of transmission for SARS‐CoV‐2 is droplet and contact (WHO 2020d). Utilization of precautions during breastfeeding have been shown to be effective against other respiratory viral infections, such as influenza (Jefferson 2011, Cantey 2013). Some recommendations for SARS‐CoV‐2 include mask wearing, and hand hygiene (Ferrazzi 2020). Other guidelines for SARS‐CoV‐2 have recommended feeding expressed breast milk by a different, asymptomatic caregiver (American Academy of Pediatrics 2020).

SARS‐CoV‐2 SPECIFIC ANTIBODIES IN BREAST MILK:

SARS‐CoV‐2 specific IgA and IgG were found in breast milk in one case report (Dong 2020 (2)). Fox and colleagues found the presence of secretory Immunoglobulin A (sIgA)‐dominant SARS‐CoV‐2 in human milk in 80% of individuals who had recovered from SARS‐CoV‐2 (preprint publication: Fox 2020). Additional data are needed to assess whether these antibodies may modulate transmission and infection severity.

Why it is important to do this review

A recent Cochrane rapid review has shown the wide range of approaches to breastfeeding and breast milk to decrease infection with the SARS‐CoV‐2 virus (Devane 2020), in spite of the limited evidence. Several of these guidelines were reviewed recently (Lavizzari 2020). Due to the novel nature of this illness, many reviews are outdated by the time of publishing (Elshafeey 2020; Yang 2020). This is highlighted by a number of international guidelines incorrectly highlighting the fact that SARS‐CoV‐2 has not been found in breast milk (Buonsenso 2020; Devane 2020; Groß 2020; Wu 2020). There are still many questions to be answered including the mitigating effects of IgA antibodies in breast milk (Fox 2020), the maternal factors affecting viral excretion in milk, and the viability and transmissibility of virus found in breast milk. A living systemic review provides the opportunity to review the literature at regular intervals and provide updates to the evidence as indicated. It also provides us the opportunity to continue to understand the outcomes of SARS‐CoV‐2 infection in neonates. Due to the low frequency of neonatal SARS‐CoV‐2 infection, the risk of critical illness in neonates remains to be determined. 

PRAGMATIC REVIEW:

This pragmatic review is borne out of significant uncertainty about the risks of SARS‐CoV‐2 transmission through breast milk or breastfeeding and the discrepancies in advice on breastfeeding given by many national and international organizations. This review will compare outcomes associated with different feeding practices for infants born of mothers with SARS‐CoV‐2 worldwide.

Objectives

To assess the effects of feeding practices on the risk of  SARS‐CoV‐2 infection in neonates ≥ 34 weeks' gestation born to mothers with confirmed SARS CoV‐2 infection.

Methods

Criteria for considering studies for this review

Types of studies

We will include studies (listed in the order of the strength of evidence).

1. Randomized controlled trials (RCTs)

2. Quasi‐randomized trials

3. Cohort studies

4. Case‐control studies

5. Cross‐sectional studies

6. Case series or case reports 

At this stage of the pandemic, we expect that most of what will be available will be case reports, case series and cross‐sectional studies. We will compare these designs narratively. Should RCTs and quasi‐RCTs become available later in the pandemic, we will use them for meta‐analysis.

Types of participants

We will include mothers with confirmed COVID‐19 and their term or late preterm infants (≥ 34 weeks' gestation) from birth to 28 days of life. Diagnosis of COVID‐19 will be made by SARS‐CoV‐2 RT PCR from nasopharynx, oropharynx, stool, saliva, urine, or blood.

Types of interventions

1. Breastfeeding with precautions

2. Feeding with mothers own expressed breast milk by a different asymptomatic caregiver

3. Feeding pasteurized donor breast milk or formula by a different asymptomatic caregiver 

We will make the following comparisons (Table 1).

1. Comparison of types of interventions.

Intervention	Control
Breastfeeding with precautions	Breastfeeding without precautions
Feeding mother’s own expressed breast milk by a different asymptomatic caregiver	ANY breastfeeding (breastfeeding with precautions + breastfeeding without precautions)
Feeding pasteurized donor breast milk or formula	ANY breastfeeding (breastfeeding with precautions + breastfeeding without precautions)
Feeding pasteurized donor breast milk or formula	Feeding mother’s own expressed breast milk by a different asymptomatic caregiver

We plan to accept all feeding regimens as stipulated or described including mixed feeding of any of the three feeding regimens, various feed intervals, and all methods of feeding mothers own expressed breast milk, donor breast milk or formula feeding (direct feeding, nasogastric or orogastric tube feeding).

1. Breastfeeding with precautions versus breastfeeding without precautions

2. Feeding mother’s own expressed breast milk by a different asymptomatic caregiver versus breastfeeding (with or without precautions)

3. Feeding pasteurized donor breast milk or formula by a different asymptomatic caregiver versus breastfeeding (with or without precautions)

4. Feeding pasteurized donor breast milk or formula by a different asymptomatic caregiver versus feeding mothers own breast milk by a different asymptomatic caregiver

Types of outcome measures

Primary outcomes

1. Confirmation of neonatal SARS‐CoV‐2 infection by a positive RT‐PCR test (from nasopharynx, oropharynx, saliva, stool, urine,  or blood)

2. Neonatal death

Secondary outcomes

Family psychosocial outcomes

1. Parental and familial satisfaction with birth hospitalization (measured by a validated tool/instrument)

2. Mother‐infant attachment (measured by a validated tool/instrument)

3. Mother‐infant interaction (measured by a validated tool/instrument)

4. Maternal postpartum depression (measured by a validated tool/instrument)

Among COVID‐19 positive neonates: 

see Appendix 1 for definitions

1. Asymptomatic

2. Mild and moderate illness

3. Severe or critical illness

Among all neonates:

1. Hospital readmission during the neonatal period

2. Specific neonatal morbidities    

   1. Upper respiratory tract infections

   2. Late onset neonatal sepsis (> 72 hours and ≤ 28 days of age)

   3. Otitis media

   4. RSV bronchiolitis

   5. Atopic dermatitis

   6. Gastroenteritis

   7. Necrotizing enterocolitis stage 2 or 3

   8. Sudden Infant death Syndrome SIDS

   9. Hospitalization for respiratory infection in the 1st year of life

   10. Other morbidities (other outcomes will be added post hoc if felt to be clinically relevant)

3. Length of birth hospitalization stay (days)

4. Breastfeeding at birth and at discharge

5. Breastfeeding duration 

6. Neurodevelopmental outcomes at 18 months or later

Search methods for identification of studies

Electronic searches

We will conduct a comprehensive search including:

1. Cochrane Central Register of Controlled Trials (CENTRAL 2020, current issue) in the Cochrane Library;

2. Cochrane COVID‐19 Study Register, via CRS Web;

3. Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) (1946 to current);

4. CINAHL (1981 to current);

5. World Health Organization (WHO) COVID‐19 Global Research Database

6. Centers for Disease Control and Prevention COVID‐19 Research Article Database

7. International Standard Randomized Controlled Trial Number (ISRCTN) Registry www.isrctn.com/

We include the MEDLINE search (Appendix 2), which will be translated into the other databases.

We will not apply language restrictions.

We will update the search every six months.

Searching other resources

We will review relevant published articles cited in reviews, systematic reviews and other important studies we identify. We plan to contact experts as indicated to help identify further relevant studies.

Data collection and analysis

We will follow standard Cochrane methods as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). Two authors (KT, KB) will independently screen all titles and abstracts for eligibility using Covidence. We (KT, KB) will independently review the full‐text reports of all potentially eligible records to determine whether these studies should be included in the meta‐analysis. We will resolve any differences, in each of the two stages mentioned above, by discussion leading to a consensus, with the involvement of an arbiter (JMH, LPB), if necessary. 

Selection of studies

Two review authors (KT, KB) will independently screen all titles and abstracts for eligibility. We (KT, KB) will obtain and independently review the full‐text reports of all potentially eligible records in all languages. If non‐English records are identified, we plan to obtain a translation of the full‐text report of the record to assess eligibility.

We will resolve any discrepancies by consensus or by involving a third author (JMH, LPB). We will include all types of records, including abstracts. We will include published and unpublished studies available in full‐text article or abstract form. We will contact the authors of studies for which additional information is not provided in the available reports, and also for any studies that are available only as abstracts.

Data extraction and management

We will carry out data extraction using a pilot‐tested Microsoft Excel spreadsheet, and each data point will be reviewed twice. We will record the following information:

1. study design;

2. setting of hospital;

3. maternal characteristics;

4. infant characteristics;

5. intervention characteristics;

6. outcomes;

7. numerical data of interest.

We will screen for duplicate data of participants by examining and cross‐referencing individual clinical and demographic information of the mother and child including, but not limited to, the dates of admission, hospital of admission, maternal age and gestational age. If we identify a duplicate study, then we will exclude that study.

We plan to contact study authors for clarification, if necessary. We plan to resolve any differences in our data by discussion, leading to a consensus.

In addition, we will analyze studies with different design separately. Regional case series and national data reports may include patients listed in case reports and local case series.

We will carry out quantitative analyses using R version 4.02 (2020‐06‐22) and RStudio‐1.3.1056  (The R Foundation for Statistical Computing)(R 2020; RStudio 2019).

Assessment of risk of bias in included studies

Two review authors (KT, KB) will independently assess the risk of bias (low, high, or unclear) of all included RCTs using the Cochrane ‘Risk of bias’ tool (Figure 1) for the following domains (Higgins 2011;Higgins 2019). 

1.

1. Sequence generation (selection bias) 

2. Allocation concealment (selection bias) 

3. Blinding of participants and personnel (performance bias) 

4. Blinding of outcome assessment (detection bias) 

5. Incomplete outcome data (attrition bias) 

6. Selective reporting (reporting bias) 

7. Any other bias 

We will assess observational studies by the level of evidence:

1. design of the study: cohort studies > case‐control > cross‐sectional > case series or reports;

2. overall assessment of the study.

We will resolve any disagreements by discussion or by consulting with a third author (JMH, LPB). See Appendix 3 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We will perform the statistical analyzes using Review Manager 5 (Review Manager 2014). We will analyze categorical data using risk ratio (RR) and risk difference (RD). For statistically significant outcomes, we will calculate the number needed to treat for an additional beneficial outcome (NNTB), or the number needed to treat for an additional harmful outcome (NNTH). We will calculate mean differences (MDs) between treatment groups where outcomes are measured in the same way for continuous data. Where outcomes are measured differently, we will report data as standardized mean differences (SMD). We will report 95% confidence intervals (CIs) for all outcomes. 

Unit of analysis issues

The unit of analysis will be the participating infant in individually randomized trials, and an infant will be considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital will be the unit of analysis in cluster‐randomized trials. We will analyze them using an estimate of the intra‐cluster correlation coefficient (ICC) derived from the trial (if possible), or from a similar trial or from a study with a similar population as described in Section 23.1.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019).

If we use ICCs from a similar trial or from a study with a similar population, we will report this and conduct a sensitivity analysis to investigate the effect of variation in the ICC. 

If we identify both cluster‐randomized trials and individually randomized trials, we will only combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of the intervention and the choice of randomization unit is considered to be unlikely. 

We will acknowledge any possible heterogeneity in the randomization unit, and perform a sensitivity analysis to investigate possible effects of the randomization unit. 

Dealing with missing data

If we find a significant missingness of data with no reasonable explanation, we will assign the study as having high risk of bias in the criterion of "incomplete outcome data". If we consider the extent of missing data to be critical to the final estimates in our meta‐analysis, we will contact the authors to request further information. We will perform sensitivity analysis to assess how the overall results are affected with and without the inclusion of studies with high risk of attrition bias from incomplete outcome data.  

Assessment of heterogeneity

Randomized controlled trials

We will estimate the treatment effects of individual trials and examine heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. In accordance with the recommendations of Cochrane Neonatal, we will grade the degree of heterogeneity as: less than 25% no heterogeneity; 25% to 49% low heterogeneity; 50% to 75% moderate heterogeneity; more than 75% substantial heterogeneity. If we note significant statistical heterogeneity (I² > 50%), we will explore the possible causes (e.g. region, precautions, no breastfeeding, etc.).

We will explore high statistical heterogeneity in the outcomes by visually inspecting the forest plots and by removing the outlying studies in the sensitivity analysis (Higgins 2019). Where statistical heterogeneity is significant, we will interpret the results of the meta‐analyzes accordingly; and we will downgrade the certainty of evidence in the ‘Summary of findings’ tables, according to the GRADE recommendations.

Observational studies

For observational studies we will assess heterogeneity by reporting the information in the tables that are described in the data synthesis.

Assessment of reporting biases

We intend to conduct a comprehensive search for eligible studies and will be alert for duplication of data. If we identify 10 or more trials for meta‐analysis, we will assess possible publication bias by inspection of a funnel plot. If we uncover reporting bias that could, in the opinion of the review authors, introduce serious bias, we will conduct a sensitivity analysis to determine the effect of including and excluding these studies in the analysis. 

Data synthesis

Randomized trials

If we identify multiple studies that we consider to be sufficiently similar, we will perform meta‐analysis using Review Manager 5 (Review Manager 2014). For categorical outcomes, we will calculate the typical estimates of RR and RD, each with its 95% CI; for continuous outcomes, we will calculate the MD or the SMD, each with its 95% CI. We will use a fixed‐effect model to combine data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If we judge meta‐analysis to be inappropriate, we will analyze and interpret individual trials separately. If there is evidence of clinical heterogeneity, we will try to explain this based on the different study characteristics and subgroup analyzes. 

Observational studies

We will assess and mitigate heterogeneity for cohort studies, case‐control studies, cross‐sectional studies, case series or case reports.  We will use the recommended strategies to reduce heterogeneity including 1) duplicate analysis of data and 2) prespecified subgroup analyzes.

We will report data in the tables as shown in Table 2

2. Tables for data reporting.

	Study type
Feeding Strategies	Randomized/quasi‐randomized  controlled trials	Cohort studies	Case‐control studies	Cross‐sectional studies	Case series/case reports
Breastfeeding with precautions
Breastfeeding without precautions
Feeding with mothers own expressed breast milk by a different asymptomatic caregiver
Feeding pasteurized donor breast milk or formula by a different asymptomatic caregiver
Any breastfeeding (with precautions + without precautions)
Feeding any mother's own milk by either breastfeeding with or without precautions or expressed breast milk

We will compare dichotomous outcomes by chi‐square analysis with Bonferroni correction for pairwise comparisons with standard of care. We will compare continuous outcomes by analysis of variance followed by the Tukey test or Dunnetts C test (variables with gaussian distribution with equal variances across groups or equal variance, respectively) or Kruskall‐Wallis test (variables with non‐gaussian distribution).

To minimize heterogeneity regarding variable studies, we will analyze our primary and secondary outcomes by feeding strategy as shown in Table 3.

3. Outcomes by feeding strategy.

Outcome		Intervention			Control
Primary outcomes	Positive SARS‐CoV‐2 PCR in neonate
	Neonatal death
Secondary Outcomes	Family psychosocial outcomes
	Outcomes in SARS‐CoV‐2 positive neonates
	Outcomes in all neonates

Subgroup analysis and investigation of heterogeneity

We will consider the following groups for subgroup analysis where data are available and for the individual objectives.

1. Neonatal factors

i) Term (≥ 37 weeks' gestation)

ii) Late preterm (≥ 34 weeks' and < 37 weeks' gestation)

2. Maternal factors

Severity of maternal infection

i) Asymptomatic

ii) Symptomatic

3. Separation of mother‐neonatal dyad

i) Complete separation

ii) No separation

iii) Intermittent contact with mother and infant dyad

4. Precautions

(i) Unspecified precautions – no specific recommendations

(ii) Type 1 precautions – minimum of homemade mask and hand hygiene

(iii) Type 2 precautions – minimum of hospital grade mask and hand hygiene
 

Sensitivity analysis

Where we identify substantial heterogeneity, we will conduct sensitivity analysis to determine if the findings are affected by inclusion of only those trials considered to have used adequate methodology with a low risk of bias (selection and performance bias). We will report results of sensitivity analyses for primary outcomes only.

Summary of findings and assessment of the certainty of the evidence

Two review authors (KT, KB) will independently assess the certainty of the evidence for each of the outcomes above. We will consider evidence from RCTs as high certainty, downgrading the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We will use GRADEpro GDT Guideline Development Tool to create a ‘Summary of findings’ table to report the certainty of the evidence. 

The GRADE approach results in an assessment of the quality of a body of evidence in one of the following four grades. 

1. High: we are very confident that the true effect lies close to that of the estimate of the effect. 

2. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. 

3. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. 

4. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. 

Discussion

Overall completeness and applicability of evidence

We will assess whether the included studies sufficiently address the objectives of the review; and whether all relevant participants, interventions and outcomes have been evaluated (highlighting any important gaps).

We will highlight the absence of data for any of the comparisons that had been planned. This will include highlighting any outcomes that were looked for, but were not reported by included studies. This section should lead to an overall assessment of the generalizability of the results of the review.

Quality of the evidence:

We will acknowledge lack of strong evidence due to lack of RCTs. We will consider how the risk of bias and GRADE ratings of quality (certainty) of the evidence might impact on the results of the review. We will assess whether the included studies address the review objectives according to the PICO question. We will assess whether the results are consistent across studies. We will assess whether there are enough participants or events in the studies. We will assess the possibility that some studies are missing or were not published, in particular, studies with negative or inconclusive results. We will assess areas where the GRADE tool was included, studies downgraded, and what these mean for the results. We will attempt to provide an overall assessment of the quality of the evidence reviewed.

Potential biases in the review process:

This section will include a description and critical evaluation of the assumptions made when analyzing the data/conducting the review. We will acknowledge limitations in the approaches used; and any effects that this may have had on the results. We will analyze discrepancies and/or uncertainties identified in the results of the included studies, such as how differences in findings between studies were dealt with or explored.

Safety of water may be a concern in some countries or geographic areas. Selection of breastfeeding versus bottle feeding depends on whether there are affordable, feasible, acceptable, sustainable and safe (AFASS) alternatives available (WHO 2016). 

History

Protocol first published: Issue 7, 2020

Appendices

Appendix 1. Clinical status definitions for COVID‐19‐positive neonates

Dong 2020 (3) described the clinical characteristics of more than 2000 pediatric patients and divided the clinical status into asymptomatic, mild, moderate, severe and critical:

Asymptomatic: without clinical signs and symptoms and the chest imaging is normal

Mild: symptoms of acute upper respiratory tract infection, including fever, fatigue, myalgia, cough, sore throat, runny nose, and sneezing.  Physical examination shows congestion of the pharynx without auscultory abnormalities. Some may present with digestive symptoms such as nausea, vomiting, abdominal pain, and diarrhea.  

Moderate: diagnosed with pneumonia, with fever and cough, wheezing, and upper respiratory congestion without hypoxaemia. Some cases may be asymptomatic but will have chest CT or X‐ray showing subclinical lung lesions.

Severe: hypoxia with other previously described symptoms with or without imaging findings

Critical: Multi‐organ dysfunction with respiratory failure, shock, encephalopathy, myocardial impairment, coagulation dysfunction or kidney injury​

Appendix 2. MEDLINE search strategy

The neonatal filters were created and tested by the Cochrane Neonatal Information Specialist. The terms for Covid‐19 were adapted from the PubMed search used for the Cochrane COVID‐19 Study Register (https://community.cochrane.org/about-covid-19-study-register).

OVID Medline

1. 2019 nCoV.ti,ab.

2. 2019nCoV.ti,ab.

3. 2019 novel coronavirus.ti,ab.

4. 2019‐novel CoV.ti,ab.

5. ((coronavirus or "corona virus") and (Huanan or Hubei or Wuhan)).ti,ab.

6. coronavirus‐19.ti,ab.

7. coronavirus disease‐19.ti,ab.

8. coronavirus disease‐2019.ti,ab.

9. ((coronavirus or "corona virus") adj3 "2019").ti,ab.

10. COVID 19.ti,ab.

11. COVID19.ti,ab.

12. COVID 2019.ti,ab.

13. nCov 2019.ti,ab.

14. ncov19.ti,ab.

15. ncov‐19.ti,ab.

16. new coronavirus.ti,ab.

17. new coronaviruses.ti,ab.

18. novel coronavirus.ti,ab.

19. novel coronaviruses.ti,ab.

20. novel corona virus.ti,ab.

21. SARS‐CoV2.ti,ab.

22. SARS CoV‐2.ti,ab.

23. SARSCoV2.ti,ab.

24. SARSCoV‐2.ti,ab.

25. SARS‐coronavirus‐2.ti,ab.

26. SARS‐like coronavirus.ti,ab.

27. Severe Acute Respiratory Syndrome Coronavirus‐2.ti,ab.

28. COVID‐19.rs.

29. COVID‐19.rx.

30. COVID‐19.kw.

31. COVID‐19.kf.

32. coronavirus disease 2019.kw.

33. coronavirus disease 2019.kf.

34. coronavirus disease 19.kw.

35. coronavirus disease 19.kf.

36. corona virus disease 2019.kw.

37. corona virus disease 2019.kf.

38. severe acute respiratory syndrome coronavirus 2.os,ox.

39. severe acute respiratory syndrome coronavirus 2.kw.

40. severe acute respiratory syndrome coronavirus 2.kf.

41. SARS‐CoV‐2.kw.

42. SARS‐CoV‐2.kf.

43. COVID‐19 drug treatment.ps.

44. COVID‐19 drug treatment.px.

45. spike protein, SARS‐CoV‐2.nm.

46. spike protein, SARS‐CoV‐2.rn.

47. or/1‐46

48. exp infant, newborn/

49. (newborn* or new born or new borns or newly born or baby* or babies or premature or prematurity or preterm or pre term or low birth weight or low birthweight or VLBW or LBW or infant or infants or 'infant s' or infant's or infantile or infancy or neonat*).ti,ab.

50. exp Breast Feeding/

51. exp Colostrum/

52. exp Milk, Human/

53. (breastfeed* or breast feed* or breast fed or breastfed or breast milk or breastmilk* or colostrum or expressed breast milk or EBM or DBM or foremilk or hindmilk or ((human or breast* or mother* or MOM or expressed or maternal or donor*) adj3 (milk* or breastmilk*))).mp.

54. exp Infant Formula/

55. (formula* adj3 (milk* or feed* or infant*)).mp.

56. (artificial milk or synthetic milk or milk substitute*).mp.

57. or/48‐56

58. 47 and 57

59. exp Animals/

60. exp Humans/

61. 59 not 60

62. (editorial or comment or letter or newspaper article).pt.

63. 61 or 62

64. 58 not 63

65. limit 64 to yr="2019 ‐Current"

Appendix 3. Risk of bias tool

We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of the trials. For each trial, we will seek information regarding the method of randomization, blinding, and reporting of all outcomes of all the infants enrolled in the trial. We will assess each criterion as being at a low, high, or unclear risk of bias. Two review authors will separately assess each study. We will resolve any disagreements by discussion. We will add this information to the 'Characteristics of included studies' table. We will evaluate the following issues and enter the findings into the 'Risk of bias' table.

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we will categorize the method used to generate the allocation sequence as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we will categorize the method used to conceal the allocation sequence as:

• low risk (e.g. telephone or central randomization; consecutively numbered, sealed, opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk, high risk, or unclear risk for participants; and

• low risk, high risk, or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we will categorize the methods used to blind outcome assessment. We will assess blinding separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re‐include missing data in the analyzes. We will categorize the methods as:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data); or

• unclear risk.

6. Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we will compare prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we will contact study authors to gain access to the study protocol. We will assess the methods as:

• low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; the study fails to include results of a key outcome that would have been expected to have been reported); or

• unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we will describe any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk;

• unclear risk.

If needed, we plan to explore the impact of the level of bias by undertaking sensitivity analyzes.

Contributions of authors

Dr. Kikelomo Babata and Dr. Kee Thai Yeo wrote the first draft of the protocol. All the authors have contributed to and approved the current version of the protocol.

Sources of support

Internal sources

• New Source of support, USA

  UT Southwestern Medical Center, Dept Pediatrics, Div Neonatal‐Perinatal Medicine

External sources

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

Declarations of interest

KTY has no interests to declare.

KLB has no interests to declare.

CSC has no interests to declare. 

KM has no interests to declare.

EHA has no interests to declare.

JYK has no interests to declare.

J‐MH has received compensation as a neonatology board member of AbbVie France; fees from Nestec SA (Switzerland), and Nutricia Research (Holland) for consulting service on clinical trials; and from Baxter (USA) as a speaker in an international education program on advanced nutrition; all were outside and unrelated to the submitted work.

LPB has received funding from the NIH (NICHD), the Gerber Foundation and the Children's Medical Center at Dallas for unrelated research.

These authors contributed equally to this work.

These authors contributed equally to this work.

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