Systematic review: feeding practices for LBW infants in LMICs Abimbola Akindolire

Background Survival of small and very small babies have improved over the last 20 years. A large majority of preterms at term gestational age are growth restricted The main consequence of this growth restriction is reduced brain growth leading to cognitive delays. To prevent this, adequate nutrition must be started as early as possible. New research into best feeding practices in order to how to achieve the same intrauterine growth rates Most available research/reviews are from the HICs and current guidelines are based on these information Mortality rates for preterm neonates have reduced in the last 20 years, survival of small and very small babies have improved Survival of small and very small babies have improved over the last 20 years. A large majority of preterms at term gestational age are growth restricted because for many reason they have not had enough protein and energy required for their growth. The main consequence of this growth restriction is reduced brain growth leading to cognitive delays. To prevent this, adequate or complete nutrition must be started earlier or age appropriate nutrition given. New research into nutrition and how to achieve the same growth rates as for babies growing in their mother’s uterus.

Literature search A literature search was conducted to see what evidence is available from LMICs to base current feeding practices on The questions we were asking at this time were What to feed How to feed When to start feeding How to advance

Literature search- what to feed Reviews comparing formula milk to human milk Henderson et al in 2007 compared formula milk and maternal breast milk The outcomes of interest were the effects on growth & development and morbidity & mortality No randomized control trials were found Henderson et al in 2007 compared nutrient enriched formula milk and human breast milk post-discharge The outcome of interest were the effects on growth & development, bone mineralization, feed intolerance, BMI and blood pressure on follow up

Literature search- what to feed Review comparing formula milk to donor human milk Quigley 2014 9 studies -Europe 5, USA 3, Europe &USA 1; 5 studies term formula vs donor human milk and 4 studies preterm formula vs human donor milk 1070 babies- <1,800gm/32 weeks Outcomes of interest were effects on Growth & development. Incidence of adverse effects such as death, NEC, invasive infection and feed intolerance. Days to full feed. Quality of evidence was weak Main findings were increased short-term growth with formula but no effect on post-discharge growth or developmental outcomes. There was increased risk of NEC and feed intolerance in the formula fed population Quality of evidence was weak: uncertainty about concealment of allocation methods and lack of blinding Need more studies comparing preterm formula with human milk

Literature search Reviews on breast milk fortification Many reviews in HICs Most show evidence of improvement in weight gain with fortification

Europe 5, N. America 4, Asia 3, South Africa 1071 <2Kg Author, year No. of studies Setting No. of children Comparison Outcomes Quality of evidence Conclusion Brown 20161 14 Europe 5, N. America 4, Asia 3, South Africa 1071 <2Kg Multinutrient fortified human milk vs unfortified human milk Growth & development Weak Limited data Improved in-hospital growth Kuschel 2000 1 Sweden Supplementation of human milk with fat/MCT vs unsupplemented human milk Growth & neurodevt. outcomes at 12-18 months. GI dist., feeding intolerance, diarrhoea, NEC Small numbers Insufficient data Young 20132 2 Canada & Denmark 246 Multinutrient fortification of human milk vs unfortified human milk post-discharge for 3-4 months Growth & devt. Duration of B/feeding. Bone mineralization. Rickets. Feed intolerance. Blood pressure on follow up Good but small numbers Limited data Europe 5, N. America 4, Asia 3(India & Oman), South Africa Limited data – no strong evidence of effect of fortification on important outcomes. Improved in-hospital growth No significant difference in short term growth. Insufficient data to make recommendation Limited data does not provide evidence of effect on important outcomes in infancy.

Literature search Reviews comparing different types of formula feeds Author, year Setting N Comparison Outcomes QOE Conclusion Basuki, 20137 3-USA 2, India 1 102 Dilute vs full strength in exclusively formula fed preterm NEC, wt gain. Feed tolerance, time to full feeds, LOHS Low to moderate quality Less feed intolerance less time to full feeds in the dilute strength. NEC not reported. Fenton 20148 6-USA 3, UK 1, Netherlands 1, Sweden 1 244 Higher (≥3g/kg/day but <4g/kg/day) vs lower (<3g.kg.day) protein in formula fed preterm or LBW infants 5 studies and 1 study with very high (≥4g/kg/day) vs high(≥3g/kg/day but <4g/kg/day Growth, BUN, IQ, abnormal phenylalanine levels, growth failure. Feed intolerance, days to full feed, NEC, sepsis, diarrhoea, metabolic acidosis Weak Higher protein intake accelerates weight gain but limited data on long term outcomes. Insufficient evidence to make recommendations for very high protein formula. Little information on information on allocation method or blinding. Heterogeneity in formulas tested, and characteristics of infants may explain differences in treatment effects

17-Mainly Europe, USA and Canada, multicentre 2, Taiwan 1 2,260 Moon 20169 17-Mainly Europe, USA and Canada, multicentre 2, Taiwan 1 2,260 Longchain PUFA enriched formula vs standard formula Visual development, neurodevelopment, growth Low Pooling of results showed no clear longterm benefits or harms of the intervention Nehra 200210 8-USA 5, Netherlands 2, Canada 1 182 High vs low medium chain triglyceride content formula Short term growth, neurodevelopment, longterm growth Little info on allocation method or blinding No evidence of difference in short term growth. Young 201611 16 Most in Europe, USA. 1 -S. Korea, Israel and Taiwan 1,251 Nutrient enriched vs standard formula post-discharge Growth, devt. Feed tolerance Bone mineralization BMI, Bp. Moderate Limited evidence that use of preterm formula post-discharge may increase growth up to 18 months. 2. No evidence of difference in short term growth. Long term outcomes in growth and neurodevelopment were not reported. No evidence of effect of NEC- larger studies are needed 3. Limited evidence that use of preterm formula post-discharge may increase growth up to 18 months. Not enough evidence to recommend routine

Literature review- When to start feeds Morgan, 2013, Trophic feeds vs fasting Primary outcomes Feed intolerance: days to establish full enteral feeding independently of parenteral nutrition. Necrotising enterocolitis Secondary outcomes  All-cause mortality prior to hospital discharge. Growth Neurodevelopment Incidence of invasive infection Duration of phototherapy for hyperbilirubinaemia (days). Duration of hospital stay Delayed introduction or notM Trophic feeding (also referred to as minimal enteral nutrition, gut priming and hypocaloric feeding) was developed and adopted into clinical practice as an alternative to complete enteral fasting for very preterm or VLBW infants during the early neonatal period (Klingenberg 2012). Early trophic feeding is conventionally defined as giving small volumes of milk (typically 12 to 24 ml/kg/day) intragastrically starting within the first few days after birth, without advancing the feed volumes during the first week postnatally (McClure 2001). The primary aim of trophic feeding is to accelerate gastrointestinal physiological, endocrine and metabolic maturity and so allow infants to transition to full enteral feeding independent of parenteral nutrition more quickly. However, any beneficial effects may be negated if early trophic feeding increases the risk of necrotising enterocolitis in very preterm or VLBW infants.

Author Year N, Type of babies Country Intervention Ostertag 1986 North America >day4- day 7 Khayata 1987 12, <1500g Day 10 after birth Davey 1994 62, <2000g >Day4- day 7 Karagiami 2010 84, <35 weeks Greece Pevez 2011 239, <1500g Colombia Abdulma aboud 2012 125, <1500g Qatar Leaf 54, <35weeks UK/Ireland Armanian 2013 82, <1500g Iran Arnon 60, SGA Preterms Israel 754 infants, VLBW or <32 weeks No significant risk of NEC, No significant reduction in time to full enteral feeds

Literature search- How to advance Recommended is 30ml/kg/day What do we practice? Intuition or recommendation? Oddie, 2017 looked at if daily increments of 15 to 20 mL/kg (compared with 30 to 40 mL/kg) reduces the risk of NEC or death in very preterm or VLBW infants, extremely preterm or ELBW infants, SGA or growth-restricted infants, or infants with antenatal AREDFV A total of 3753 infants from 10 studies

Authors Year weight Setting Intervention Rayyis 1999 <1500 N. America 15 vs 35 Caple 2004 1000-2000 20 vs 35 Salhotra <1250 India 15 vs 30 Krishnamurthy 2010 1000-1500 20 vs 30 Karagol 2013 750-1250 Turkey Raban 2014a <1001g S Africa 24 vs 36 2014b <1001 Modi 2015 15- 20 vs 30- 40 SIFT 2016 <1500g UK/Ireland 18 vs 30 Jaih 1000- 1249 s 30 SIFT had 75% of the participants

Literature search- How to advance Slow advancement does not reduce the risk of NEC on All and all the subgroups Formula fed - Rayyis 185 infants, 1 study Infants who were at least partially fed with human milk- 9 studies, 3557 infants Extremely preterm/ELBW- 5 studies, 1299 infants Infants with IUGR- 2 studies 639 infants Infants with absent/ reversed end diastolic flow velocity- 2 studies, 465 infants. Mortality- no effect on risk of mortality on all infants and all subgroups Infants who had fast advancement achieved full enteral feeds and regained birth weight faster than those in the slow group Incidence of LOS was higher in the slow advancement group No conclusive evidence on length of hospital stay Quality of evidence was moderate downgraded from high because of lack of blinding

Literature search- How to feed Continuos vs bolus Push vs gravity NG vs OG Bottles??

How to feed-Nasal versus oral route for placing feeding tube Watson et al, 2013 -3 studies Van someren 1984, 42 babies, 30 to 34weeks Apnoea, Weight gain- no difference Dsilna, 2005 46 <30 weeks/<1200 time to full enteral feeds and regain birth weight and incidence of adverse events Bohnhurst 2010, 35 No significant differences in adverse events time to independence from supplemental oxygen,  time to full enteral feeds time to full oral feeds not reported Statistical significant difference in weight gain in NG 0.6vs OG 8.3g/kg/day in 1st week none after Data not sufficient for policy Decision based on clinicians preference A large RCT needed to compare

How to feed- Continuous versus bolus Shahirose 2011, 7 RCTs, 511 preterm infants less than 1500gmi No significant difference in growth and incidence of NEC but earlier discharge in ELBW fed by continuous nasogastric feeding Quality of evidence is weak

How to feed- Push versus gravity Dawson 2013, looked at the evidence that gravity feeding results in a more rapid establishment of full gavage feeds without increasing adverse events in preterm or low birth weight, or both, infants who require intermittent bolus tube feeding Only one small trial- N 31,<32 weeks No significant difference in heart rate at completion of feeds Difficult to conclude Nurses, what’s the experience

WHO Recommendations on optimal feeding of very low- birth- weight infants What to feed? Choice of milk Mother’s milk*, Donor human milk** Standard formula but if they fail to gain weight -Preterm formula No routine human milk fortifiers except they fail to gain weight Supplements ALL- Vitamin D On human milk-Calcium, phosphorus- unclear for how long; iron from 2 weeks-6 months

WHO Recommendations on optimal feeding of very low- birth- weight infants Daily vitamin A is not recommended due to lack of evidence When and how to initiate feeding 1st day of life 10ml/kg the remaining fluid requirement should be by IV Fluid How to feed? Not clearly how to feed just that in VLBW who need intragastric tube it should be by oral/nasal route How to advance Up to 30ml/kg/day careful monitoring for feed intolerance

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