PROTOCOL: Effects of neonatal nutrition interventions on neonatal mortality and child health and development outcomes: A systematic review

The decline in rates of neonatal (age 0–28 days) mortality has been slower than the decline in child mortality between 1990 and 2016 (Alkema, Chao, You, Pedersen, & Sawyer, 2014; Bhutta et al., 2015). Neonatal mortality accounted for 46% of child mortality in 2016 compared to 40% of all under-five mortality rates in 1990 (WHO, 2017a). Globally, the percentage of neonatal mortality is the highest in South Asia and Sub Saharan Africa (Alkema et al., 2014). Optimal nutritional support during neonatal period is vital to the short and long term survival of the newborn (Bhutta et al., 2013; WHO, 2017b). Poor nutritional status of neonates is a major cause of illness and can lead to poor growth, increased risk of infection, bleeding, and neonatal death (Bhutta et al., 2013; WHO, 2017b). The risk of morbidity and mortality during neonatal period is higher in low and middle-income countries (LMICs) where many birth happen at home and the prevalence of maternal malnutrition and incidence of low birth weight (birth weight less than 2500 g) and preterm birth (gestational age <37 weeks) is high (Bhutta et al., 2013; Lee et al., 2017; WHO, 2017b). This review will focus on selective nutritional interventions during neonatal periods in LMICs. The approach to nutritional management of newborn depends on maternal nutritional status, co-morbidities during pregnancy (such as gestational diabetes), pregnancy duration (term vs. preterm birth), events at birth (such as birth asyphaxia), birth weight (low birth weight vs. normal birth weight), and available resources for postpartum care of the mother and the baby (such as skill birth attendant, home vs. facility birth, availability of neonatal intensive care, etc.; Bhutta et al., 2013; WHO, 2015; WHO 2017a; WHO, 2017b). The most important nutritional intervention at birth is breastfeeding and this will be covered in a separate Campbell review of this series. There are number of other nutritional interventions that have been proposed in addition to breastfeeding and it is beyond the scope of this review to comprehensively evaluate all the possible nutritional interventions during the neonatal period. We plan to review the following three interventions: neonatal vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during neonatal period in LMICs. Below in this section and rest of the introduction, we describe the rationale for choosing these interventions and why it is important to do this review. Globally, about 190 million children and 19.1 pregnant women are vitamin A deficient based on serum retinol levels (i.e., serum retinol less than 0.70 μmol/L; WHO, 2009a). Vitamin A deficiency (VAD) is most prevalent in South Asia and Africa (Stevens et al., 2015). VAD is associated with increased risk of blindness, infections, and mortality (Imdad, Mayo-Wilson, Herzer, & Bhutta, 2017). Most of the newborns are vitamin A deficient and rely on supplementation from maternal breast milk (Haider, Sharma, & Bhutta, 2017). High prevalence of maternal VAD in LMICs increases the risk of neonatal VAD. There has been interest in vitamin A supplementation during neonatal period to assess if it reduces risk of illness and death (Haider et al., 2017; WHO, 2009b) as it has been shown to reduce morbidity and mortality in children 6–59 months of age (Imdad et al., 2017). Hypoglycemia is common during immediate neonatal period (Kaiser et al., 2015). Recurrent, severe, and persistent hypoglycaemia might lead to brain damage (Kaiser et al., 2015; McKinlay et al., 2017; Thornton et al. 2015). About 10–15% of otherwise healthy newborns have low blood sugars and the rate is much higher among infants with additional risk factors such as: large for gestational age, small for gestational age, low birth weight, preterm birth, infant of diabetic mother, and newborns with perinatal asyphaxia (Thompson-Branch & Havranek, 2017). Additional risk factors for neonatal hypoglycaemia include neonatal sepsis, prolonged labor, and maternal medication use such as beta agonists and beta blockers (Thompson-Branch & Havranek, 2017). The definition of hypoglycaemia is controversial and there is limited evidence to show that blood sugars below a certain level leads to long term brain damage. The American Academy of Pediatrics consider hypoglycaemia as blood sugar below 47 mg/dL (2.61 mmol/L); however, other societies such as Pediatric Endocrine Society consider hypoglycemia as blood sugars levels less than 50 mg/dL (2.77 mmol/L; Thompson-Branch & Havranek, 2017; Thornton et al., 2015). The initial recommended intervention to treat early neonatal hypoglycaemia is to offer feeding in the form of breastfeeding followed by formula feeding if breastfeeding is unsuccessful. Persistent hypoglycaemia may require IV dextrose supplementation and admission to neonatal intensive care unit (Thompson-Branch & Havranek, 2017; Thornton et al., 2015). In LMICs, where a significant proportion of births happen at home and incidence of low birth weight and preterm birth is high, prevention and treatment of hypoglycaemia might be challenging (Singhal et al., 1991; Singhal, Singh, & Paul, 1992; WHO, 2017b; Williams, 1997). The instruments to test blood sugars might not be available in low resource settings and in case blood testing is available, IV dextrose and facility of intensive care unit might not be available to treat persistent and severe hypoglycemia. Recent studies have tested simple interventions such as oral dextrose gel to prevent hypoglycaemia in his risk newborns and treat known hypoglycaemia (Hegarty et al., 2016; Weston et al., 2016). Neonatal sepsis and necrotizing enterocolitis (NEC) are neonatal morbidities that can be fatal (Oza, Lawn, Hogan, Mathers, & Cousens, 2015; WHO, 2017b). Neonatal sepsis is the presence of an infectious agent leading to systemic illness. Bacterial sepsis is common in LMICs and is a significant risk factors of morbidity and mortality (WHO, 2017aa). NEC is a condition that occurs in newborns and can lead to injury to bowel. The extent of injury may vary from mucosal injury to full thickness bowel wall injury. It happens most commonly in preterm babies especially extremely preterm babies (AlFaleh & Anabrees, 2014; Patel & Denning, 2015). Multiple factors lead to development of NEC in preterm infants including altered bacterial gut flora affecting the protective intestinal barrier, decreased intestinal motility and the increased susceptibility for inflammation and infections in preterm infants (Patel & Denning, 2015). Recent studies have shown that imbalance between commensal bacteria and pathogenic bacteria (dysbiosis) makes the babies vulnerable to pathogenic bacterial growth in the intestine causing inflammation that might lead to neonatal sepsis and/or NEC (Arrieta, Stiemsma, Amenyogbe, Brown, & Finlay, 2014; Deshmukh et al., 2014; Gewolb, Schwalbe, Taciak, Harrison & Panigrahi, 1999; Panigrahi et al., 2017). There is an increasing interest in correction of dysbiosis by probiotics to prevent NEC and neonatal sepsis and data from early studies from developed countries is encouraging (AlFaleh & Anabrees, 2014; Panigrahi et al., 2017). Vitamin A is a term used for a subclass of the family of fat soluble compounds: retinoic acids. It is found in nature in two forms: provitamin A carotenoids and preformed vitamin A essential. Plant based foods are the source of provitamin A carotenoids (Beta-carotene is the most commonly known) and animal based foods are the sources of preformed vitamin A (Bates, 1995; Haider & Bhutta, 2011). Plant based foods may not be an adequate source of vitamin A as the gastrointestinal conversion ratio from carotenoid-to-retinol varies from 6:1 to 26:1. VAD may therefore exist in areas even when there is high consumption of plant based foods such as in South Asia and Africa (Imdad et al., 2017; Stevens et al., 2015). Vitamin A from animal sources (retinol, retinal, retinoic acid, and retinyl esters) is the most active form and synthetic vitamin A retinol has been used in most of intervention trials in the past (Haider & Bhutta, 2011; Imdad et al., 2017). Dextrose gel is a thickened aqueous solution that contains concentrated simple carbohydrate. It can be administered by direct application to oral, buccal, or sublingual mucosa and can increase blood sugars rapidly by absorption from highly vascularized and thin mucus membranes of oral mucosa (Hegarty et al., 2016). Dextrose gel is a low cost, non-proprietary intervention and can be prepared in hospital pharmacies. The typical ingredients include water, glucose, a gelling agent, and preservatives (Hegarty et al., 2016). The decision to use dextrose gel in a neonate should be taken on individual basis and should be avoided in neonates with compromised mental status (Hegarty et al., 2016; Weston et al., 2016). Prebiotics are supplements that promote the growth of commensal bacteria (AlFaleh & Anabrees, 2014; Panigrahi et al., 2017). Probiotics contain live bacteria that enrich pool of commensal bacteria (AlFaleh & Anabrees, 2014; Millar, Wilks, & Costeloe, 2003; Panigrahi et al., 2017). Synbiotics are a combination of prebiotics and probiotics and might have synergistic effect (Johnson-Henry, Abrahamsson, Wu, & Sherman, 2016; Panigrahi et al., 2017). These supplements are meant to optimize gut health and their hypothesized mechanisms of actions include enhanced gut barrier function, inhibition of gut colonization with pathogenic bacteria, improvement in colonization with healthy commensals bacteria that protect the infant from enteropathogenic infection through production of acetate, enhance innate immunity, and increase maturation of the & 2016). Recent data have shown that probiotic supplements can prevent incidence of NEC in preterm babies (AlFaleh & Anabrees, 2014; et al., 2003; Patel & Denning, 2015; & There are data on use of for prevention of neonatal sepsis et al., 2017; et al., 2016). The most commonly used in probiotics include and et al., 2016). Vitamin A has an effect on and normal of (Bates, 1995; Bhutta et al., 2013; Haider & Bhutta, 2011). It is it to the protective barrier of the and mucosa the from Vitamin A in the of the therefore the of the of infections in newborns & 1999; vitamin A supplementation has been shown to reduce morbidity and mortality in children to months of age (Imdad et al., 2017). The of synthetic vitamin A supplementation include and (Haider & Bhutta, 2011; Haider et al., 2017; Imdad et al., 2017; & Bhutta, 2016). vitamin A supplementation can cause that in the form of a in children of and (Haider et al., 2017; Imdad et al., 2017). The absorption of dextrose gel from oral mucosa leads to of and to the the past effect of from the absorption immediate of to in and dextrose gel can the of and of baby from mother (Hegarty et al., 2016; Weston et al., 2016). The intervention is simple that it not require (such as IV and can be administered by health and mother The include and of treatment for severe hypoglycaemia (Hegarty et al., 2016; Weston et al., 2016). and preterm babies have of normal commensal bacteria and are to NEC and sepsis to growth of pathogenic bacteria in the (AlFaleh & Anabrees, 2014; Patel & Denning, 2015; et al., 2016). Probiotics are used to the with bacteria are known to be et al., 2003; Patel & Denning, 2015). Probiotics therefore reduce the growth of pathogenic bacteria leads to NEC and It increases gut by increasing levels with the of normal flora the mucosal barrier as (Patel & Denning, 2015). These protective mechanisms reduce intestinal a protective mucosal barrier bacteria and increase the production of & 2017; et al., Probiotics are especially protective in preterm babies with and neonates on the normal flora of the for colonization by pathogenic bacteria causing Prebiotics and probiotics can be in the form of a to the gut flora and it can reduce neonatal mortality et al., 2016; Panigrahi et al., 2017). Probiotics are however, there are probiotic supplementation in extremely neonates and of neonatal sepsis have been that to be by probiotics et al., 2016). The trials on neonatal vitamin A supplementation have with studies from South a mortality major in other studies from (Haider et al., and studies even an increased risk of infant mortality in certain et al., 2016). 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