i) A baby is reviewed in clinic and his mother describes episodes of vomiting post feeds and says that he seems uncomfortable. She has tried positioning the baby after feeds but feels this has not made any difference. A friend has said that her baby has gastro-oesophageal reflux and she has been extensively reviewing this subject on the internet. She would like you to discuss the pros and cons of the following investigations for GOR.

ii) Mother elects to have empiric treatment. Which of the following treatments would you suggest?

i) Maternal iron deficiency affects 30–50% of pregnancies

ii) Maternal iron deficiency anaemia is associated with an increased risk of preterm delivery

iii) Maternal smoking can cause perinatal iron deficiency

iv) Maternal diabetes can cause perinatal iron deficiency

v) Iron supplementation prevents early anaemia

vi) Can lead to an increased risk of infection

vii) Should be given at the same time as calcium and phosphorus supplements

viii) Can be started safely at about 4–6 weeks of life

ix) Is only needed in infants fed formula milk

x) Supplements should be started immediately after birth

xi) Iron deficiency can lead to problems with neurodevelopment which are reversed once treatment is started.

i) Early feeds

ii) Indomethacin

iii) Blood transfusion

iv) Fortified feeds

v) Thickened feeds

vi) H2 receptor antagonists.

i) All preterm formula fed infants should receive folic acid

ii) Infants with haemolytic anaemia should always receive folate supplementation

iii) Human milk contains sufficient vitamin A for the preterm infant

iv) Vitamin A supplementation is associated with a reduction in the incidence of chronic lung disease

v) All preterm infants should receive a minimum of 1000 IU vitamin D a day to prevent rickets

vi) Vitamin supplementation should be increased in hepatic failure

vii) Rickets can be prevented by adequate vitamin D supplementation

viii) Increasing calcium intake is usually helpful when there is evidence of poor bone mineralisation

ix) Nucleotide supplementation of formula milk may enhance growth in preterm infants

x) Human milk does not contain nucleotides

xi) Beta-carotene supplementation is of proven benefit in preterm babies

xii) Vitamin E supplementation is essential in infants receiving human milk

xiii) Vitamin E supplementation is useful in the prevention of haemolytic anaemia, ROP, BPD and IVH

xiv) Vitamin C levels in preterm infants are normally satisfactory and supplementation is not recommended

xv) The vitamin content of breast milk is affected by maternal diet.

i) Is this a plausible explanation for the symptoms?

ii) How do you explain the difference between CMA and CMPI?

iii) What is the prognosis for both conditions?

iv) What investigations do you carry out?

v) What do you tell her?

vi) Do you alter your treatment of the baby? If so, what do you do?

i) Long-chain polyunsaturated fatty acids improve retinal sensitivity in preterm infants

ii) LCPUFA enriched formula milk can decrease the incidence of bronchopulmonary dysplasia

iii) LCPUFA enriched formula milk leads to a decrease in the incidence of sepsis

iv) A protein intake of above 3 g/kg/day is needed to support the same rate of growth as in utero for a preterm baby

v) Amino acids in total parenteral nutrition should be started on day 3 after renal function has improved to prevent elevation in blood urea nitrogen (BUN)

vi) The addition of glutamine improves feeding tolerance in ELBW infants

vii) The addition of glutamine may decrease the incidence of infection in ELBW infants.

i)

ii) There is a lack of evidence of efficacy and safety for all medications and none can be recommended routinely in the absence of evidence to suggest that GOR is the cause of symptoms. As several studies have failed to demonstrate such an association an argument could be made that none of these agents are appropriate. There are, however, specific considerations with some of these agents.

Infatrini – gluten free

Nutramigen – gluten, sucrose and lactose free

Neocate – milk protein, soy and lactose free

Infasoy – lactose intolerance, galactosaemia

Peptijunior – disaccharide/whole protein intolerance with medium-chain triglycerides.

i) Yes⁴– it is the commonest cause of perinatal iron deficiency worldwide.

ii) Yes – iron deficiency anaemia, when detected early in pregnancy, is associated with a more than two-fold increase for the risk of preterm delivery. ⁴

iii) Yes – maternal smoking can cause perinatal iron deficiency. Smoking leads to increased carbon monoxide and decreased utero-placental blood flow. This in turn leads to erythropoiesis which depletes the iron stores. ⁵

iv) Yes – poorly controlled maternal diabetes can cause perinatal iron deficiency by increased fetal metabolic rate and oxygen consumption. The relative hypoxia again causes increased erythropoiesis and the additional iron required cannot be met by increasing maternal–fetal transport. ⁶

v) No – does prevent late anaemia. Use of erythropoietin and iron can result in a better response to iron

vi) Yes – iron supplements have a high osmolality if given undiluted and if mixed with breast milk can cause disruption of anti-infective properties. Parenteral iron is more likely to do so.

vii) No – insoluble compounds may be formed which would decrease bioavailability.

viii) Yes – most preterm babies have received multiple blood transfusions while in the neonatal unit, and have thus received intravenous iron. They are likely to have extremely high ferritin levels and thus iron supplements can be delayed.

ix) No – human milk has inadequate supplies of iron and preterm infants fed human milk are more likely to suffer from iron deficiency.

x) No – it is generally recommended that iron supplements should not be given in the first 4 weeks after birth when enteral feeds have only just begun as it may be associated with an increased risk of gastrointestinal disturbance.

xi) No – iron deficiency between 6 months and 2 years can lead to long-term neurodevelopmental problems that are not reversed despite adequate treatment. ⁷ Iron is needed for neurotransmission, myelination and brain growth. Areas such as the hippocampus and striatum are particularly vulnerable to iron deficiency. Studies have shown both short- and long-term effects due to perinatal iron deficiency. ⁸

i) Several studies have shown that it is safe to use small feeding volumes early in life, even in selected circumstances, such as feeding during the use of indomethacin to treat symptomatic patent ductus arteriosus. Prolonging small feeding volumes, sometimes called trophic feeding, has been shown to be associated with a marginally significant reduction in necrotising enterocolitis in very low birth weight infants. Cochrane Review concluded that, comparing trophic feeds with no enteral nutrient intake, there was no significant difference in necrotising enterocolitis, infants required more days to reach full enteral feeding and tended to have a longer hospital stay. ^{9.10. and 11.}

ii) Patent ductus arteriosus is a risk factor for the development of necrotising enterocolitis. The use of indomethacin to treat patent ductus arteriosus in preterm infants may either decrease the incidence of necrotising enterocolitis by stabilising or closing the ductus arteriosus or increase its incidence by a direct constricting effect on mesenteric blood vessels. Although some small studies have suggested that indomethacin does increase the risk of NEC, recent papers have concluded that PDA is an independent risk factor for the development of necrotising enterocolitis in very low birth weight infants and therapy with indomethacin did not have a significant effect on the risk for necrotising enterocolitis. ^{12. and 13.}

iii) While anecdotal reports suggest that NEC has developed quickly after a blood transfusion, this information is not reflected in published studies. However, neonatal exchange transfusion and intrauterine transfusion have been shown to be associated with an increased incidence of NEC. Blood transfusions may unmask latent NEC, and apnoeas and desaturations could potentially be an early symptom of NEC. It may be that the anaemia for which a blood transfusion is requested is an independent risk factor for NEC, or an early manifestation of NEC still developing, which then becomes recognised several hours later (during or after the transfusion). Some units omit feeds for the duration of a blood transfusion. There are several reports of blood transfusion causing acute haemolysis in babies with established NEC and red cell T antigen activation although the use of low anti-T titre plasma products has not been shown to reduce mortality and the current neonatal transfusion guidelines remain non-committal about the importance of T activation.

iv) Fortified feeds – many neonatal units are routinely using milk fortifier to enhance the nutrition and growth of preterm infants. It is thought that breast milk fortifier may increase the incidence of NEC stage I–III. ¹⁴

v) Thickened feeds – although descriptive case reports have linked some feeding interventions such as thickened feedings to NEC, there is no evidence to establish a causal relation. There are however several anecdotal reports of infants being fed with thickened feeds and later developing NEC. The theory is that thickened feeds may have led to NEC as a result of bowel obstruction with subsequent bacterial overgrowth or following direct mucosal injury by calorifie dense milk. ^{16. and 17.}

vi) A recent case-control study of NEC of Bell stage II or greater showed a higher incidence if treated with ranitidine. This may support the hypothesis that gastric pH level may be a factor in the pathogenesis of NEC. ¹⁸

i) Although this remains common practice and is recommended in certain textbooks, the composition of current formula milk is sufficient for adequate supplementation. Human breast milk contains approximately twice the minimum folate supplementation in formula milk.

ii) Although this practice has been recommended, this is based upon old studies when folate levels in milk were almost certainly inadequate. Evidence to suggest that this practice should be continued is conflicting and the composition of current formula milk and breast milk is sufficient for adequate supplementation.

iii) Human milk does not supply enough vitamin A for the preterm infant and this situation is compounded by the fact that most preterm infants are born with low stores. Supplementation is recommended but the exact dose is uncertain.

iv) Systematic review has suggested that vitamin A supplementation may lead to a reduction in both supplementary oxygen requirements and death. Treatment regimes have involved intramuscular injection and the treatment has not gained widespread acceptance. Some studies have not shown evidence of benefit.

v) There is good evidence that supplementation of 400 IU vitamin D a day is adequate and higher doses are not required.

vi) Infants with liver failure should be on higher vitamin supplementations including vitamin K.

vii) Radiological rickets may be found in infants with normal vitamin D levels. Hypophosphataemia is now recognised as a more important contributory factor than vitamin D.

viii) Calcium supplementation may be beneficial if intake is poor, but is unlikely to be effective if intake is already adequate. High calcium intake may decrease fat absorption and can lead to calcium soap intestinal bolus obstruction.

ix) There is evidence that babies can utilise preformed nucleotides in supplemented formula milks and that utilisation increases at times of deficiency. Studies in term infants have shown improved growth and reduced gastrointestinal disturbance but this benefit has not been shown in preterm infants.

x) Breast milk contains at least 15 different nucleotides which represent a significant proportion of the non-protein nitrogen. It is for this reason that supplementation of formula feeds has been suggested.

xi) Beta-carotene supplementation of milk is now common. This is almost certainly because of an absence of carotenoids in formula milk which are present in human milk. Beta-carotene is only one of these. Although supplementation is now common, there is no clear information as to what it is supposed to do and currently no evidence of benefit from randomised controlled trials exists.

xii) Human milk contains adequate levels of vitamin E and there is no evidence that supplementation is of additional benefit.

xiii) Vitamin E supplementation may be useful in the prevention of haemolytic anaemia in preterm infants but there is no consistent advice on this. Although it has been suggested and given to prevent ROP, BPD and IVH, there is no evidence of benefit from randomised trials and supplementation with high doses has risks of potential toxicity. A Cochrane Review in 2003 concluded that vitamin E supplementation in preterm infants reduced the risk of IVH but increased the risk of sepsis including NEC. The evidence does not support the routine use of vitamin E supplementation by intravenous route at high doses. ¹⁹

xiv) Vitamin C levels are usually low and supplementation is recommended. Standard multivitamin preparations contain vitamins A, B, C and D.

xv) Levels of water-soluble vitamins in breast milk are influence by dietary changes and breast feeding mothers should be encouraged to eat fruit and vegetables. Routine supplementation with proprietary vitamin preparations is not normally necessary for the mother.

i) This is a plausible explanation. It is thought that up to half the cases of gastro-oesophageal reflux in infants under a year of age may be associated with cows’ milk allergy. It is also thought that the reflux may be induced by the allergy. ²¹ The association has been well described by several groups, one quoting it in up to 42% of infants who previously had received a diagnosis of reflux. ²² The symptoms and age of presentation are similar in both conditions. One group treated a group of infants with reflux who had not responded to pharmacological treatment with a cows’ milk free diet – 20% improved. ²³ The overlapping symptoms include crying, irritability, vomiting, failure to thrive, apnoeas, ALTEs and colic.A recent paper has said that umbilical erythema can be a sign of food intolerance and a useful diagnostic tool for CMPI. ²⁴

ii) Many people use the terms cows’ milk allergy (CMA) and cows’ milk protein intolerance (CMPI) interchangeably.CMA is an immunologically mediated reaction to cows’ milk proteins that can involve the gut, skin, respiratory tract, or cause systemic anaphylaxis. prevalence is about 1–3%, being most common in infants.CMPI, however, should refer to a non-immunological reaction to cows’ milk. The most common cause is lactase deficiency, which is mostly acquired during late childhood or adulthood. It has marked racial variation with lowest incidence in northern Europeans.

iii) The prognosis for true cows’ milk allergy is worse than for CMPI. It can cause severe morbidity and even fatality if not recognised and treated. Dietary elimination is associated with good prognosis.CMPI, commonly due to a lactase deficiency, is generally a benign condition, with symptoms limited to the gastro-intestinal tract. ²⁵

iv) There are no definitive investigations for cows’ milk protein intolerance or allergy because in general the immunological basis of the involved mechanisms is commonly undetermined. Some tests, however, may reinforce clinical suspicions. Cavataio et al found that IgG anti-beta-lactoglobulin assay was the most useful test for making a diagnosis of both gastro-oesophageal reflux and cows’ milk allergy. The test was positive in 27/30 subjects with GER and CMA and in 4/42 patients with GER only. ²⁶ Generally a diagnosis is made if there is resolution of symptoms with elimination.

v) Concerns have recently been raised regarding potential risks with soy protein. Most recent advice is to use soy protein formulae only in certain cases. They should not be used in preterm infants or infants with food allergy before the age of 6 months.Soy protein formulae can be used for feeding term infants, but they have no nutritional advantage over cows’ milk protein formulae and contain high concentrations of phytate, aluminium and phytoestrogens (isoflavones), which may have side effects.There is no evidence supporting the use of soy protein formulae for the prevention or management of infantile colic, regurgitation, or prolonged crying. ^{27. and 28.}

vi) As this baby is not responding to your usual treatment of reflux, it may well be worth trying a cows’ milk free diet due to the overlap of symptoms in these conditions.The baby should be started on an extensively hydrolysed formula milk of which there are many on the market, such as Peptijunior, Nutramigen, Neocate or Progestamil. A 6–8-week course should be tried as a minimum for resolution of symptoms. These milks can also be thickened if regurgitation symptoms persist.

i) True – LCPUFA are concentrated at synapses within the retina and there is improved retinal sensitivity and visual acuity with LCPUFA added to formula milk.

ii) False – although one study did show that infants fed with an enriched formula had longer duration of ventilation, ²⁹ there has been no difference shown in the rates of BPD in this group of babies compared to controls. ³⁰

iii) False – many trials have reported no difference in sepsis in babies fed with LCPUFA enriched formula milk. ²⁹

iv) True – the most commonly applied standard is that of intra-uterine growth. The protein accretion rate between 24 and 32 weeks’ gestation is approximately 2 g/kg/day, and the estimated rate of obligate protein loss is 1.1–1.5 g/kg/day.

v) False – generally TPN and amino acid solutions are started later in the most sick and preterm infants who are in greatest need of nutrition. Concerns usually raised are problems with acid–base balance and an increase in BUN and ammonia levels. However, studies have shown that there is no difference in plasma levels of cholesterol, triglycerides, bicarbonate, blood urea nitrogen, creatinine and pH in infants with early TPN compared to late (after 48 hours). ³¹ In early life BUN reflects fluid status rather than amino acid intake.

vi) False – glutamine is one of the most abundant amino acids in plasma and in breast milk, but is unstable in aqueous solutions, hence generally not included in amino acid solutions. Glutamine depletion has negative effects on the functional integrity of the gut and leads to immunosuppression. Glutamine-enriched enteral nutrition does not improve feeding tolerance in VLBW infants. ³²

vii) True – studies in adults have shown that glutamine-supplemented amino acid solution decreased the incidence of infections. One study has suggested that the use of glutamine-enriched enteral nutrition in VLBW infants should be seriously considered. ³²