In 2018, the World Health Assembly, through resolution WHA71.9 on infant and young child feeding, affirmed that “the protection, promotion and support of breastfeeding contributes substantially to the achievement of the Sustainable Development Goals on nutrition and health and is a core element of quality health care” and recognized that “appropriate, evidence-based and timely support of infant and young child feeding in emergencies saves lives, protects child nutrition, health and development and benefits mothers and families”. The World Health Assembly requested WHO “to continue to update and generate evidence-based recommendations”.
WHO recommends exclusive breastfeeding for infants 0–6 months of age and continued breastfeeding to 2 years and beyond. WHO interim guidance published during the Zika virus outbreak was based on a limited volume of evidence under an emergency process during a Public Health Emergency of International Concern. Subsequent rapid advice and a WHO toolkit for supporting people affected by complications associated with Zika virus recommended that mothers with possible or confirmed Zika virus infection or exposure continue to breastfeed, since the benefits of breastfeeding outweigh any potential risk of Zika virus infection through breast-milk. Concerns about possible Zika virus transmission during breastfeeding remain, since the virus has been detected in breast-milk samples. It is not clear whether breast-milk from women with Zika virus has enough viral load or infectivity to lead to infection among infants. Also, during breastfeeding, other bodily fluids could be exchanged, such as sweat and blood, in addition to breast-milk.
There are also concerns related to the transmission of Zika virus infection from the mother to the fetus during pregnancy. Zika virus infection during pregnancy can result in microcephaly and other congenital anomalies among affected infants, known as congenital Zika syndrome. Zika virus infection is also associated with other complications, including preterm birth and miscarriage. An increased risk of nervous system complications is associated with Zika virus infection among children, including Guillain-Barré syndrome, neuropathy and myelitis.
Infants with congenital Zika syndrome may have a decline in nutritional status owing to hypotonia, abnormal metabolic demands because of spasticity and difficulties feeding. Among the latter, infants with congenital Zika syndrome are especially affected by dysphagia, difficulty feeding, gastroesophageal reflux and delayed gastric emptying. There are certain modifications to feeding depending on the spectrum of manifestations and their severity, which may include postural correction, adjustment of the environment and thickening feeds, among others, as age appropriate.
Support for the caregivers of infants with congenital Zika syndrome may aid the infants in achieving improved growth and nutritional status, attaining developmental milestones and enhancing the quality of life. WHO published guidelines for screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero in 2016.
Although there is no longer an outbreak, Zika virus transmission continues in some areas. As of July 2019, 87 countries and territories across four of the six WHO regions (African Region, Region of the Americas, South-East Asia Region and Western Pacific Region) had evidence of autochthonous mosquito-borne Zika virus transmission. It is important to have a standard guideline as part of efforts to manage infant feeding in areas where there is transmission as the data about long-term outcomes associated with Zika virus infection among infants are becoming available.
Purpose of the guideline
The objective of this guideline is to provide global, science-informed recommendations on infant feeding in areas of Zika virus transmission.1 The primary audience of this guideline is health professionals responsible for developing national and local health protocols, especially those related to infant feeding in infancy and early childhood. The primary audience also includes those directly providing care to infants, such as nurses, general medical practitioners, paediatricians, managers of maternal, newborn and child health programmes and relevant personnel in health ministries, in all settings. Lastly, this guideline is also of interest to pregnant or breastfeeding women living or travelling to areas where Zika virus transmission continues.
This guideline aims to help WHO Member States and their partners to make science-informed decisions on the appropriate actions in their efforts to achieve the Sustainable Development Goals, the resolutions of the World Health Assembly on infant and young child feeding and the global targets put forward in the comprehensive implementation plan on maternal, infant and young child nutrition, the global strategy for infant and young child feeding and the Zika Strategic Response Plan.
Guideline development method
WHO developed the present science-informed recommendations using the procedures outlined in the WHO handbook for guideline development. The steps in this process included: (1) identifying priority questions and outcomes; (2) retrieving the evidence; (3) assessing and synthesizing the evidence; (4) formulating recommendations, including research priorities; and planning for (5) dissemination; (6) implementation, equity and ethical considerations; and (7) impact evaluation and updating the guideline. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was followed for preparing evidence profiles related to preselected topics, based on up-to-date systematic reviews. The Confidence in the Evidence from Reviews of Qualitative Research (CERQual) method was used in assessing the findings from systematic reviews of qualitative evidence. The Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice based on Evidence (DECIDE) framework, an evidence-to-decision tool that includes intervention effects, the certainty (or quality) of the evidence, values and preferences, resources, equity, acceptability and feasibility criteria, was used to guide the formulation of the recommendations by the Guideline Development Group.
WHO convened two Guideline Development Group meetings, one on 11 April 2019 and another on 9 and 10 December 2019. The meetings were held virtually. At the first online meeting, the Guideline Development Group provided input into the scope of the guideline, assisted the WHO Guideline Steering Committee in developing the key questions in PICO format and set priorities for outcomes to guide the evidence reviews and focus the recommendations. On 24 July 2019, the WHO Guideline Steering Committee met to discuss expanding this guideline to include infant feeding recommendations for infants presenting with congenital Zika syndrome or Guillain-Barré syndrome and the support mothers and caregivers of these infants require to feed these infants.
This guideline aimed to address the following questions:
For infants not infected with Zika virus, does breastfeeding (any or exclusive) or feeding of breast-milk from a lactating woman infected with Zika virus, compared with not breastfeeding, increase the risk of Zika virus transmission to the infant? Does a lactating woman vaccinated against Zika virus, compared with not breastfeeding, increase the risk of transmitting Zika virus to the infant or young child?
For infants (0–12 months old) affected by complications associated with Zika virus, what modifications in infant feeding practices compared with no modification or standard of care can improve infant outcomes?
Should the primary caregivers of infants (0–12 months old) affected by complications associated with Zika virus receive additional support to improving infant feeding compared with no additional support or standard of care to improve infant outcomes?
During the second online meeting, the Guideline Development Group members reviewed, deliberated and achieved consensus on the strength and direction of the recommendations presented herein. Through a structured process, the Guideline Development Group reviewed the balance between the desirable and undesirable effects and the overall certainty of supporting evidence, values and preferences of stakeholders, resource requirements and cost–effectiveness, acceptability, feasibility, human rights and equity.
Available evidence
To inform this guideline development process on managing infant feeding in the areas of Zika virus transmission, WHO commissioned three systematic reviews addressing: (1) evidence related to the presence in and transmission of Zika virus through breast-milk; (2) modifications in infant feeding practices and additional primary caregiver support to improve infant outcomes among infants affected by congenital Zika syndrome; and (3) the values and preferences of pregnant women, mothers, family members, health-care practitioners, policy-makers and health-care providers (midwives) concerning feeding when there is a risk of mother-to-child transmission of an infectious disease or when an infant or toddler is affected by congenital Zika syndrome. A literature update was also conducted on Zika vaccines and their current development status. The evidence available as of January 2021 is summarized below. Once the final vaccine products come to market, this section will need to be revised.
Risk of transmission through breast-milk, breastfeeding or expressed breast-milk in areas of Zika virus transmission
The updated systematic review aimed to assess the available evidence of the possible transmission of Zika virus through breast-milk intake or breastfeeding. This review was an update (data of search 18 June 2020) of a previous systematic review. The search strategy identified 2881 records, of which 1626 titles and abstracts were screened. There were 300 full-text articles assessed for eligibility, of which 14 remained for inclusion. These studies were reports from Brazil, Colombia, France, French Polynesia, New Caledonia, Thailand and the Bolivarian Republic of Venezuela. Collectively, they reported a total of 17 breast-milk samples from 17 women that were positive for Zika virus RNA by reverse transcription–polymerase chain reaction (RT-PCR) detection. Ten of these cases were described in case reports and seven in longitudinal studies. There were 10 cases where a breast-milk sample tested positive for viral RNA, but the infant had no infection. Among these, one newborn who was exclusively breastfed was tested at birth and followed up for seven months, while six other newborns were weaned when breast-milk tested positive. For another 10-month-old infant, breastfeeding was interrupted seven days after the onset of maternal symptoms and restarted four days after symptoms resolved. Of the seven infants who tested positive, five neonates and one five-month-old infant had confirmed Zika virus infection by RT-PCR test and one neonate had undetermined RT-PCR results. Among those with confirmed Zika virus infection by RT-PCR, there was one three-day-old neonate who had been breastfed since birth and a four-day-old-neonate fed both breast-milk and infant formula. One newborn was formula fed and one five-month-old infant was breastfed during the maternal symptomatic phase. Infant feeding practices were not reported in two newborn cases. All in all, evidence indicated Zika virus presence in breast-milk, and although three infants had virus present, no clear evidence of disease or clinical complications among infants could be associated with Zika virus in breast-milk or breastfeeding. The certainty of the evidence obtained in this systematic review was assessed as being very low.
Zika virus vaccine development for women who are breastfeeding
WHO has called for the development of a Zika virus vaccine that adheres to specific characteristics described in a target product profile. More than one vaccine may be required, depending on the needs of various population groups. Inactivated vaccines may be more adequate for women 15–49 years old and those who are pregnant, whereas live attenuated vaccines could be used among children, men and older adults. To date, 16 clinical trials have been registered to evaluate the safety and efficacy of candidate Zika virus vaccines, most of which are Phase 1 trials. The low number of new Zika virus infection cases recorded challenges the feasibility of Phase 3 field trials.
Feeding infants affected by complications associated with Zika virus
No eligible studies assessing modified infant feeding versus no modified infant feeding practices were identified. However, data from eight observational studies conducted in Brazil were examined, since they included important information related to the nutritional status of infants with congenital Zika syndrome or of infants whose mothers live in areas with active transmission of Zika virus, infant feeding practices and the outcomes of infants exposed to Zika virus or diagnosed with congenital Zika syndrome. These studies highlight the need for early nutrition interventions and caregiver support among infants affected by Zika virus or diagnosed with congenital Zika syndrome. They also underscore the importance of early nutrition interventions to reduce the risk of diminished nutritional status over time.
Support for primary caregivers of infants (0–12 months old) affected by complications associated with Zika virus
No eligible studies assessing support for caregivers of infants affected by complications associated with Zika virus were retrieved. Instead, the same eight observational studies mentioned above were examined. In general, family and community values and preferences and economic considerations play a role in the decision-making of pregnant women and mothers on infant feeding. Mothers and the family members of infants affected by congenital Zika syndrome reported frustration, fear, stress, anxiety and additional burden regarding the needs of their infants and the potential complications, such as choking or reflux. In addition, the caregivers of infants exposed to Zika virus or diagnosed with congenital Zika syndrome will most likely require continuing support in various areas of care and well-being.
Recommendations
To ensure that the recommendations are correctly understood and applied in practice, guideline users may want to refer to the remarks and the evidence summary, including the considerations on implementation.
Breastfeeding or expressed breast-milk in areas of Zika virus transmission
Infants born to mothers with suspected, probable or confirmed Zika virus infection or who reside in or have travelled to areas of ongoing Zika virus transmission should be fed according to normal infant feeding guidelines. They should start breastfeeding within one hour of birth, be exclusively breastfed for six months and have timely introduction of adequate, safe and properly fed complementary foods, while continuing breastfeeding up to two years of age or beyond (strong recommendation, very-low certainty of evidence).
Infants fed with expressed breast-milk from mothers with suspected, probable or confirmed Zika virus infection or who reside in or have travelled to areas of ongoing Zika virus transmission should be fed according to normal infant feeding guidelines (strong recommendation, very-low certainty of evidence).
There is insufficient evidence to make a recommendation on breastfeeding or expressed milk from a lactating woman vaccinated against Zika virus, since no vaccine is available yet.
Infant feeding among infants affected by complications associated with Zika virus
Among infants (0–12 months) affected by complications associated with Zika virus infection, infant feeding practices should be modified (such as adjusting the environment, postural correction or thickening feeds) to achieve and maintain optimal possible infant growth and development (strong recommendation, very-low certainty of evidence).
Support for primary caregivers of infants (0–12 months old) affected by complications associated with Zika virus
Remarks
All the recommendations in this guideline were considered strong, although the certainty of the evidence was low or very low for the priority critical outcomes. In most of the studies included, the certainty of the indirect or direct evidence was low or very low because of experimental details, especially the type of study, imprecision, publication bias or indirect evidence with viruses similar to Zika virus. Despite the shortcomings of the available evidence, the Guideline Development Group opted to issue recommendations. To achieve this, GRADE guidance on developing science-informed recommendations when there is limited or non-existing published direct evidence is to incorporate indirect evidence and the collective expert evidence approach in the form of a structured and systematic approach to elicit the collective experience of the guideline group members. For this guideline, the Guideline Development Group was presented with the evidence-to-decision frameworks that considered the balance of desirable and undesirable anticipated effects, values and preferences of people affected by the recommendations, among other aspects. This approach is in agreement with the WHO guideline development procedures, specifically with guidance on developing recommendations integrating evidence across multiple domains.
Although Zika virus has been detected in human breast-milk, there is no clear evidence about the origin and a still undefined risk of transmission to the infant. Since Zika virus infection is mild for infants, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding.
The modifications to infant feeding would be similar to that of infants with similar symptoms regardless of whether these symptoms are associated with Zika virus or not.
The recommendation on skilled support from health-care workers is consistent with previous WHO recommendations on protecting, promoting and supporting breastfeeding in facilities providing maternity and newborn services and on counselling women to improve breastfeeding practices.
Research gaps
The Guideline Development Group identified important knowledge gaps that need to be addressed through primary research, which may affect these recommendations. More research is needed related to the resources, feasibility, acceptability and equity of modifying feeding among infants affected by complications associated with Zika virus and on the type of additional support to provide to caregivers of these infants, since no direct evidence was found. The following questions were identified as those that demand urgent priority:
determining the viral load needed to transmit Zika virus through breast-milk;
understanding the views of pregnant women, mothers, family members, health-care practitioners, policy-makers and health-care providers (midwives) concerning infant feeding when there is a risk of potentially transmissible Zika virus;
how breastfeeding or feeding breast-milk to infants from a lactating woman infected with Zika virus affects health equity;
evaluating the acceptability or feasibility of breastfeeding or feeding breast-milk to infants from a lactating woman infected with Zika virus;
how infant feeding modifications affects important infant outcomes among those affected by complications associated with Zika virus and evaluating the resources, feasibility, acceptability and equity of these modifications; and
how providing additional support and follow-up to caregivers for improving infant feeding affects those affected by complications associated with Zika virus and evaluating the resources, feasibility, acceptability, continuity and equity of this support.
Plans for updating the guideline
WHO will continue to follow research developments in infant feeding in areas of Zika virus transmission, including the availability of a Zika virus vaccine in the market. WHO will follow the dynamic system of giving priority to technical products on norms and standards data and research for country impact and will maintain literature surveillance to respond rapidly to any changes in the epidemiology of Zika virus transmission along with any emerging evidence relevant to ensure that accurate, relevant and up-to-date guidance is available to countries and their partners globally.
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These areas are classified according to country, territory or subnational area into 1) Countries and territories with current or previous Zika virus transmission and 2) Countries and territories with established Aedes aegypti mosquito vectors, but no known cases of Zika virus transmission. The most recent classification is available in the latest Zika virus epidemiological update 2019.
