Breastfeeding for children of mothers who are infected with SARS- CoV-2: a systematic scoping review

Ana Paula Vieira Faria Universidade Federal de Minas Gerais Thales Philipe Rodrigues da Silva Universidade Federal de Minas Gerais Camila Kümmel Duarte Univerisdade Federal de Minas Gerais Luana Caroline dos Santos Universidade Federal de Minas Gerais Maria Margarida Leitão Filipe Unidade de Saúde de Matosinhos Nágela Cristine Pinheiro Santos Universidade Federal de Minas Gerais Fernanda Penido Matozinhos (  nandapenido@hotmail.com ) Universidade Federal de Minas Gerais


Introduction
In November 2019, several cases of pneumonia with an unknown cause were identi ed in the city of Wuhan, located in the People's Republic of China. Investigations that were conducted later have found the emergence of a new coronavírus, called SARS-CoV-2 [1].
World wide, until may 8, 2020, 6,931,000cases of the disease were con rmed, with 400,857 deaths, distributed in 200 countries [2]. The spread of this virus has been shown to be rapid in several countries [1,3]. In March 2020, the coronavirus disease  was characterized by the World Health Organization (WHO) as a pandemic [4].
The transmission of SARS-CoV-2 can occur when a person ingests or inhales droplets expelled by coughing or sneezing from people infected by the virus, called droplet transmission; or when an individual touches a contaminated surface or object, known as contact transmission. In addition, it can also occur in closed environments, called aerosol transmission [5].
The main clinical characteristics observed in infected individuals are: cough, fever, dyspnea, myalgia and radiological examination with in ammatory manifestations [6]. The clinical characteristics observed in pregnant women were similar to those observed in other individuals [7]. The clinical condition may vary according to the pro le of the individuals, with the elderly people and patients with chronic diseases who are more likely to develop the severe form of the infection [8].
Evidence shows that pregnant women and newborns are at a particularly high risk for COVID-19 [9] because during pregnancy women experience changes in the immune and physiological systems inherent in this period, which predispose them to greater susceptibility to infections [9][10]. It is noteworthy that, until now, there is little scienti c evidence demonstrating the possibility of vertical transmission of SARS-CoV-2 from the mother to the fetus, especially during breastfeeding [11] and the bene ts on the health of the mother and child in relation to breastfeeding are known and proven [12].
In this context, this study aimed to review the literature in a systematic way, in order to clarify whether breastfeeding is safe for children of mothers infected by SARS-CoV-2.

Methods
We conducted a systematic scope review to synthesize knowledge about breastfeeding safety by infected mothers. This systematic scope review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13] and was conducted following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [14][15].

Search Strategy
The searches were carried out on MEDLINE (via PubMed), EMBASE and related articles, and manual search of reference lists in March 25 and updated in July 5. In addition, governmental organizations and publications were used as a source of information on the subject. No period or language restrictions were used in the search strategy. The keywords were "breastfeeding", "puerperium", "newborn", "SARS-CoV-2", "COVID-19", "vertical transmission" and its synonyms. Pubmed and EMBASE search strategies are presented in supplement 1.

Eligibility criteria
We included all trials, observational studies, letters, editorial sand documents in which the security of breastfeeding after COVID-19 infection was explored. We excluded, a priori, papers without the data or theory about vertical transmission of COVID-19.

Results
The search identi ed 436 citations ( gure-1). After reading the titles and abstracts, 47 references met the eligibility criteria and were selected for review of the full text. At the end, 30 studies were eligible for this review. A search was also carried out on documents published by health organizations and governments as guidelines and statements that could answer the research question, 7 guidelines were identi ed. At the end, 37 citations were included in this review.
We separated the citations into three tables, table 1 shows the characteristics of the 12 studies included in the systematic scope review, most of the selected studies are located in China, among them, cohort studies, cross-sectional studies, case report and cross sectional were found. Table 2 presents the characteristics of 14 guidelines from different regions, including China, Italy, Portugal and London. Table 3, on the other hand, presents other 11 citations included in this study, comments, letters to the editor, protocols and other documents that answered the systematic scope review question. The synthesis of the results was divided into three topics: studies that guide the prevention of breastfeeding, studies that recommend the maintenance of breastfeeding or studies without consensus on guidelines.
It is noteworthy that for the three articles [17][18][19][20][21] of cross-sectional design, cohort and transversal, the risk of bias assessment was performed using the Newcastle-Ottawa scale. In all articles, the nal score obtained by NOS was six.
A Chinese study analyzed the presence of SARS-CoV-2 in breast milk: in two cases of mothers who are infected with SARS-CoV-2 [17] the authors chose to advise avoiding breastfeeding during the disease period, even with negative samples for SARS-CoV-2 in maternal milk, due to the risk of transmission by contact [17]. Additionally, it was recommended to isolate the neonate from the mother for 10 days, until the end of the period of mother's isolation [27].
One study [25] highlighted that vertical transmission cannot be discarded, due to the lack of reliable evidence. In this speci c work, mothers with SARS-CoV-2 infection were advised to avoid breastfeeding and that the newborn should receive breast milk through the donation of other women, requiring pasteurization and screening for SARS-CoV-2 in donated milk [25]. In addition, a study [21] carried out in China, identi ed a sample of breast milk with the presence of SARS-CoV-2, however, other samples collected, presented a negative result, the author reports that the possibility of vertical transmission through breast milk cannot be excluded, and until larger studies demonstrate the safety of breast milk, it is recommended not to offer breast milk until the mother's full recovery from infection [21].

Evidences without consensus on breastfeeding
Fourteen statements [18][19][20][30][31][32][33][34][35][36][37][38][39][40] do not present a consensus on breastfeeding in cases of mothers infected with SARS-CoV-2. Two studies [30][31] report that although there are negative data for the presence of the virus in breast milk, the evidence is insu cient to guide breastfeeding, there is no consensus on the indication. Two researches [19,32] reported cases of a woman with the infection, however, even with negative samples for the virus in breast milk, the authors contraindicate breastfeeding because of the limitation of the sample. Guidelines have been developed [33)]in Europe to cope with SARS-CoV-2, emphasizing that it is not possible, so far, to prove transmission through breast milk. The author stressed that in China, for safety, newborns are separated from mothers con rmed for SARS-CoV-2 for 14 days, it is not advisable to offer breast milk, however, milking should be encouraged to stimulate lactation and to avoid complications resulting from not breast-feeding. The International Society of Gynecology and Obstetrics [34] issued guidelines for case management and the study concluded that there was no consensus on breastfeeding, due to the lack of evidence. According to the College of Specialty of Gynecology/Obstetrics of Portugal, the separation of mother and child after childbirth is a controversial issue, as the bene ts of breastfeeding do not outweigh the risk of contamination of the newborn. However, he stresses that health institutions make individual decisions, taking into account the mother's will, the facilities available in the hospital and the availability of health teams. The recommendations are added when there is a mother-child separation, it is recommended to express the milk with pump and its waste until the mother has two negative tests [36].
In a retrospective cohort study [18] with women in China, the breast milk was collected from mothers diagnosed with SARS-CoV-2 and all samples showed negative results for the infection. The authors concluded that due to the low sample size, there was not enough evidence on the safety of breastfeeding in this period. Also, a case report [35] with a woman with SARS-CoV-2, in which the collection of breast milk was performed after delivery, it showed a negative result for the infection in the sample, however the author reported that even with this result, vertical transmission cannot be discarded, requiring further investigation. Finally, a study carried out with a 40-year-old woman and her 8month-old son, concluded that although two samples of breast milk showed the presence of SARS-CoV-2, the risk of contamination of the sample by the environment or by the mother was not can be discarded; considering the uncertain whether there is a risk of infection with breast milk [40].
A study [44] does not recommend the separation of mother and child, nor contraindicated breastfeeding during the mother's infection period. However, it stressed that transmission prevention measures must be rigorous, such as hand hygiene.

Discussion
Based on the studies selected in this review, no original research has demonstrated the possibility of vertical transmission of SARS-CoV-2 through breast milk. However, recommendations to avoid maintaining breastfeeding take into account the potential risk of transmission through contact.
Currently, organizations such as WHO, CDC, NHS e Royal College of Obstetricians & Gynaecologists [6,10,[42][43] issue guidelines on encouraging breastfeeding in cases of mothers con rmed by SARS-CoV-2, highlighting the effectiveness of breastfeeding against infectious diseases and bene ts for the child -mainly for the improvement of their immune system. These publications emphasize that mothers with positive diagnoses for SARS-CoV-2 should be encouraged to continue offering breast milk, if they wish, and to further strengthen hygiene measures, such as: washing hands frequently and wearing masks if the mother is not in a position to breastfeed, due to the worsening of the signs of infection [6,10,[42][43], milking breast milk and offering it by other means should be encouraged, always providing guidance in relation to adequate care in relation to preventing disease transmission [51].
Among the studies selected in this review, those ones that contraindicate breastfeeding from mothers con rmed with SARS-CoV-2 are mainly based on the possibility of transmissibility of the virus from mother to baby due to the close contact inherent in breastfeeding and reinforce that they should be isolated from their children. It should be noted that this guidance should be carefully considered, since the physical separation of mother and child is a primary factor for early weaning, and there may be an early introduction of formula [52][53]. A study advises that mothers con rmed for SARS-CoV-2 should avoid breastfeeding and that their child should be fed breast milk from a milk bank, however, the need to perform the examination for SARS-CoV-2 in the milk offered is emphasized for screening the infection associated with milk pasteurization [26].
Some studies that contraindicate breastfeeding suggest that infants born to suspected or con rmed mothers for SARS-CoV-2 should be isolated until they complete the recommended isolation period [23,25,27]. Maternal separation in mothers con rmed or suspected for SARS-CoV-2 may cause anxiety for the family, especially the mother. Therefore, if this recommendation is followed, the presence of psychological support is advised [54] and strengthening the maternal support network.
Among the studies without consensus on breastfeeding, a retrospective study [18] with women in China collected breast milk from mothers infected with SARS-CoV-2 and all samples showed a negative result for the infection. Even so, the author concludes that, due to the low sample size, there is not enough evidence about the safety of breastfeeding in this period. A case report [35] performed with a woman with SARS-CoV-2, in which the collection of breast milk was performed after delivery, showed a negative result for the infection in the sample; however the author reports that even in the face of this result, vertical transmission cannot be ruled out, and further studies are needed.
There are studies in the literature on the potential for intrauterine vertical transmission of SARS-CoV-2 [18], but newborns from mothers infected with SARS-CoV-2 were negative [9, 17-18, 30, 32], demonstrating that vertical transmission is still uncertain. Although in a study [32] a positive sample for SARS-CoV-2 was found in the neonate pharyngeal via swab after 36 hours of birth. The author reports that the mother was positive for the infection and during delivery preventive actions were taken to reduce the risk of infection. The newborn had no contact with the mother after delivery, being transferred to isolation and breastfeeding was not performed. As it was not possible to perform the swab collection shortly after birth, transmission by contact during this interval cannot be ruled out. In addition, it is reinforced that among the studies found in this review, none of them identi ed the presence of the SARS-CoV-2 in breast milk [17-18, 30, 32-33].
As much as the evidence in this review demonstrates that there is no transmission of the SARS-CoV-2 through breast milk, it is emphasized that there is the possibility of contamination of the newborn through the respiratory tract and, both mother and child, must adopt measures of social distance to mitigate the expansion of the SARS-CoV-2 [55] in addition to strict transmission prevention measures [6,[42][43]. A study [32] emphasized the importance of implementing preventive measures during childbirth, such as, for example, the use of a negative pressure delivery room, aiming at reducing the risk of transmission to the newborn, and considering that the main forms of virus transmission are by droplets and aerosols.
Despite the caution during the process of study selection, data extraction and writing according to the standards of the Cochrane Collaboration [14], this study has some limitations. The rst one is related to the small number of studies published so far; in addition to the lack of prospective studies on vertical transmission through breast milk in mothers suspected or con rmed case of SARS-CoV-2. Furthermore, the studies presented have a limited sample size. On the other hand, although this infection is recent, the detailed search in different databases made it possible to include studies from different continents.

Conclusion
There is insu cient evidence to conclude the occurrence of vertical transmission of SARS-CoV-2 through breast milk, and further investigations are needed. Therefore, it is essential that health professionals strictly carry out infection prevention from the delivery room, according to current recommendations, in addition to promoting health education in groups at risk, especially pregnant women.
Through the evidence found so far, it is emphasized that the mother/child separation in the neonatal period is discouraged, as it impairs the maternal bond, in addition to interfering considerably in breastfeeding. Therefore, due to the low quality of the evidence found, we cannot recommend, avoid or even guarantee that there will be no infection, but we recommend maintaining breastfeeding, considering that all arguments and bene ts of breastfeeding are recognized, as long as the mother wants to breastfeed and is breastfed under suitable conditions for this. Therefore, strict measures to prevent the transmission of infection must be carried out by the mother. Declarations CKD: Conceptualised and designed overall study, prepared and ran searches, cross-checked shortlisted articles and extracted data, analysed extracted data, interpreted results, co-authored rst draft, critically revised all subsequent drafts and approved nal draft before submission.
LCS: Interpreted results, co-authored rst draft, critically revised all subsequent drafts and approved nal draft before submission.
MMLF: Interpreted results, co-authored rst draft, critically revised all subsequent drafts and approved nal draft before submission.
NCPS: Interpreted results, co-authored rst draft, critically revised all subsequent drafts and approved nal draft before submission.
FPM: Conceptualised and designed overall study, prepared and ran searches, cross-checked shortlisted articles and extracted data, analysed extracted data, interpreted results, co-authored rst draft, critically revised all subsequent drafts and approved nal draft before submission.

Compliance with Ethical Statements
Con ict of Interest: The authors declare that they have no con ict of interest.
Funding: There is no funding source.
Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.  Laishuan [25] China Guideline It is recommended not to breastfeed, as transmission through breast milk cannot be ruled out.
Liona [34] China, London Guideline Due to the lack of evidence to date, mothers who are sick, the separation of mother and child should be performed, and it is recommended to express breast milk to maintain milk production. However, mothers who are able to breastfeed should follow hygiene measures to prevent transmission.

Guideline
There is no consensus on the recommendation of breastfeeding in con rmed or suspected mothers of the infection. Singapore Guidelines Evidence shows that there is no vertical transmission during pregnancy, however, skin-toskin contact between mothers and newborns is not recommended, and considerations can be made to allow the use of donated breast milk from COVID-19-free mothers.
Giuliani, 2020 [49] Italy Suggestions It is recommended that mothers suspected of or con rmed by infection should be encouraged to breastfeed, following transmission prevention measures. China Comment Based on the evidence found, it is recommended that newborns be isolated for at least 14 days after birth, avoiding breastfeeding while the mother is suspected or con rmed by COVID-19.
Shaoshuai, 2020 [28] China Expert opinion It is recommended not to breastfeed the children of mothers suspected or infected by the disease, as drugs used such as Lopinavir / ritonavir can be secreted in breast milk.

Expert opinion
In view of the scarcity of available evidence, it is recommended that breastfeeding may be instituted after the mother's infection period.
Feng, 2020 [24] China Letter Breastfeeding should be avoided in mothers con rmed by the infection, until their recovery.
David, 2020 [27] Canada Expert opinion It is recommended to isolate the newborn born to mothers with the infection, for 10 days or more, avoiding breastfeeding during the isolation period. There is a shortage of data to support the transmission of infection through breast milk. Peyronnet, 2020 [44] France Protocol It has not been possible to prove transmission until now by breast milk, therefore, breastfeeding is recommended respecting the hygiene measures Kathleen, 2020 [46] Estados Unidos

Expert opinion
Due to a lack of data on the transmission of infection through breast milk, suspected or con rmed mothers should be encouraged to offer breast Milk.
Liona, 2020 [42] China Guidance Due to the lack of evidence demonstrating the transmission of infection through breast milk, mothers who are able to breastfeed should perform it, following strict hygiene measures.
Pradip, 2020 [48] Singapore Narrative Breastfeeding should not be contraindicated, based on the guidelines, mothers who wish to breastfeed should follow strict hygiene control.