1. No evidence that formula is an effective intervention: In their introduction, the authors state that the World Health Organization (WHO) recommends immediate and exclusive breastfeeding, and that some exclusively breastfed infants in low- and middle-income countries (LMIC) fail to thrive. They claim that providing additional nutrition to breastfeeding during early infancy, particularly to infants who initially fail to thrive, may have the potential to prevent wasting, and stunting and improve health outcomes. The authors state that formula supports weight gain of at-risk infants in early infancy. We do not agree that formula supplementation is an ethical or logical medical approach to the management of infants at risk for failure to thrive.
It is irrefutable that exclusive breastfeeding is associated with decreased morbidity and mortality in LMIC1. Yes, some exclusively breastfed infants fail to thrive, but this is typically due to reversible breastfeeding problems. Newborn complications that lead to insufficient milk extraction such as tongue tie, submucosal clefts, sleepiness, and low tone can all be managed appropriately by assisting with milk transfer from the breast. Maternal complications of breastfeeding/lactation that contribute to insufficient feeding can often be addressed with evidence-based breastfeeding education for the family. Other problems related to maternal anatomic or physiologic issues, such as large nipples, nipple pain, low milk production, retained placental fragment, maternal hypotension immediately postpartum and high body mass index can all be managed medically. Medical mismanagement is a well-documented reason for complications of lactation, and there is a multitude of professional organizations that advocate for core competences in breastfeeding care and services for all health professionals2.
This protocol does not address root cause analysis for failure to thrive in this population, nor does it explain why formula supplementation is an evidence-based strategy with a favorable benefit/cost ratio. There has never been any evidence that replacing a feeding of breastmilk with formula is advantageous. Formula is not higher in calories, nor is it more nutritious in any way as compared to human milk. There are very few medical indications for formula as outlined by the Academy of Breastfeeding Medicine3. Replacement of breastmilk for the simple purposes of improving growth has never been an evidence-based reason for giving formula, and such advice often comes from uneducated health professionals.
2. Poorly defined study population: It appears from this protocol that the authors are defining the study population as high-risk based on a birth weight <2500 grams. However, they are not determining gestational age associated with the birth weights, such that it is impossible to identify if these infants are truly small for gestational age, appropriate for gestational age, or even possibly large for gestational age.
3. Effect of early formula on breastfeeding: Formula supplementation early postpartum has been shown to be associated with decreased breastfeeding rates at 6 and 12 months. The authors state in their introduction ‘Tested in two randomized controlled trials in the United States, early, daily, small-volume formula supplementation supported growth without interfering with overall breastfeeding duration’.
The larger and most recent of these 2 cited RCTs, Valerie J. Flaherman, MD, MPH, Nicole R. Narayan, PhD, Dennis Hartigan-O'Connor, MD, PhD, Michael D. Cabana, MD, MPH, Charles E. McCulloch, PhD, and Ian M. Paul, MD, MSc ‘The effect of early limited formula on breastfeeding, readmission, and intestinal microbiota: A randomized trial, J of Pediatrics 2018’ included a largely White population where 10 ml of formula vs none was given with each feeding in the first few days after birth for infants with weight loss ≥75% according to the Newborn Weight Loss Tool3, until ‘the milk came in’. The formula was given for an average of 2 days. The risk ratio for the effect of this early limited formula on outcome of breastfeeding cessation at 1 month was 1.21. Further, this supplementation was given via a feeding syringe, not a bottle as proposed in the protocol of concern. The authors from this Flaherman (et al) 2018 study also mentioned that because there were few African Americans in this study and only 15% of mothers were under 25 years old, the results were not generalizable to these aforementioned populations. Nor would they be generalizable to a completely different culture, as Ugandans. Furthermore, 2 days of formula supplementation via syringe for otherwise well White infants in a high-income country is inappropriate evidence to support the administration of daily formula via bottle for 30 days to a low-income population at risk for failure to thrive in Uganda.
Interestingly, the authors of the protocol of concern did not include the results from their 2019 publication, Effect of Early Limited Formula on Breastfeeding Duration in the First Year of Life: A randomized Clinical Trial, JAMA Pediatrics 2019;173(8):729-735, which reported breastfeeding rates at 6 and 12 months from the 2018 study data described above. The 2019 publication states the following: ‘The receipt of formula at 1 week of age was very strongly associated with all subsequent breastfeeding outcomes. At ages 6 and 12 months, respectively, 11 (31.4%) and 2 (5.7%) of 35 infants who had received formula in the past 24 hours at age 1 week were still breastfeeding, compared with 75 (85.2%) and 47 (53.4%) of the 88 who had not received formula in the past 24 hours at age 1 week.’ Yet, this study protocol intends to supplement children in Uganda with formula for an entire month via bottle.
4. Adverse outcomes due to premature cessation of breastfeeding: Given the above stated results from Effect of Early Limited Formula on Breastfeeding Duration in the First Year of Life: A randomized Clinical Trial, JAMA Pediatrics 2019;173(8):729-735, the risk of premature weaning is understated in this protocol. There is robust evidence that exclusive breastfeeding for the first 6 months with continued breastfeeding after 6 months strongly protects from childhood malnutrition5,6,7,8. It is paradoxical that the infants enrolled in this study will be at an even higher risk for childhood wasting, disease and death by introducing formula right after birth in order to prevent wasting. The authors do not cite any references demonstrating that early formula introduction in similar populations has ever been shown to be safe and effective for infant survival and reduction in morbidity, while the preponderance of evidence actually proves the opposite. This protocol does not plan to track the effect of its intervention on breastfeeding exclusivity at any point, e.g. 3 or 6 months. Furthermore, this protocol does not outline a strategy to support maternal child health for those subjects who prematurely wean due to the impact of this trial. For example, in the short term, these mothers are at higher risk for an earlier pregnancy, and the infants will be at higher risk for needing medical care and hospitalization.
It is irrefutable that not breastfeeding increases the risk of adverse health outcomes in children and their mothers. Infants who are not breastfed have a higher risk of ear infections8and hospitalization for severe infections such as diarrhea, meningitis, pneumonia8. They have a higher risk of childhood obesity9, lower IQ9, higher cholesterol10, higher blood pressure11, type 2 diabetes9, certain childhood cancers12, sudden unexpected infant death syndrome13, and signs of allergies14including eczema and wheezing. Mothers who wean early or who do not breastfeed have a higher risk of breast cancer9, ovarian cancer9, shortened birth intervals9, visceral fat15, metabolic syndrome15, non-alcoholic fatty liver disease16, type 2 diabetes9, hypertension17, stroke18, coronary artery disease19, and high cholesterol17. Because the 2019 study described above showed a marked decrease in breastfeeding rates at 6 and 12 months for infants who received formula supplementation at 1 week, the mothers and infants in the protocol of concern have an elevated risk of morbidity and mortality. The protocol does not include a plan to support breastfeeding until at least age 2, which is the recommended duration of breastfeeding by the World Health Organization. There is also no plan to provide guaranteed access to sufficient clean water and formula until at least 1 year of age for those dyads who end up prematurely weaning as a result of this trial.
5. Additional risk of bottles: The supplementation strategy in this protocol is to bottle feed. The randomized controlled trials presented as evidence to support this protocol of concern used syringes for supplementation, not bottles. The authors do not discuss the risks of bottle feeding. Bottle feeding has been shown to decrease the likelihood of exclusive breastfeeding over time as compared to cup feeding20. The main risk of bottle feeding is breast refusal due to bottle preference. If infants in this population refuse to breastfeed because they have been given bottles for 30 days, how will these mothers sustain breastfeeding and provide their own milk to their infants after the study is over? They would need access to a breast pump, ideally with electricity or a regular supply of batteries, or would need to manually express their milk on a regular basis in order to feed their infants with a bottle or cup. This increases the risk of illness among these infants even if the mothers can express and feed their milk, since the families would require access to soap and clean water to wash the bottles/nipples and cups. They would need access to refrigeration and storage containers to store their expressed breastmilk. If there is no access to freezer storage, they may need to discard expressed milk 4 days after expression, the longest recommended duration of time that milk is safe in the refrigerator21. Feeding expressed breastmilk is immunologically less protective as compared to direct breastfeeding, as direct breastfeeding allows pathogens from the infant’s mouth to migrate into breastmilk, stimulating immunologic responses in the breastmilk that enhance targeted illness protection to the infant22.
6. Risk of HIV transmission: The prevalence of HIV infection in Uganda is 6.2%23. Although the protocol of concern includes negative HIV screening as an inclusion criterion, HIV testing is not repeated, nor are there steps taken to minimize the risk of acquiring HIV in the study population. Infants receiving mixed feeding (breastmilk and formula) have an increased risk of contracting HIV from a lactating mother living with HIV, as mixed feeding markedly increases the risk of maternal-child transmission of HIV as compared to exclusive breastfeeding, even if she is on anti-retroviral therapy24. Because a mother in this protocol may be giving formula at the time that she contracts HIV, this protocol theoretically increases the risk of HIV among infants enrolled in this study.


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