Macronutrient Digestion and Absorption in the Preterm Infant Marta Rogido, MD,*†‡ Ian Griffin, MD*†‡ *Goryeb Children’s Hospital, Morristown, NJ †Mid-Atlantic Neonatal Associates, Morristown, NJ ‡Biomedical Research Institute of New Jersey, Cedar Knolls, NJ Education Gap Knowledge of the importance of human milk enzymes in macronutrient digestion has increased greatly over recent years, and provides a further impetus to the use of human milk, especially mother’s own milk, in the nutrition of preterm infants. Abstract The human fetus receives oral nutrition through swallowed amniotic fluid and this makes a significant nutritional contribution to the fetus. Postnatally, macronutrient absorption and digestion appear to function well in the preterm infant. Although pancreatic function is relatively poor, the newborn infant has several mechanisms to overcome this. These include a range of digestive enzymes in human milk, novel digestive enzymes involved in fat and protein digestion that do not appear to be present in the older child or adult, and the presence of a Bifidobacterium-rich colonic microbiome that may “scavenge” AUTHOR DISCLOSURE Drs Rogido and Griffin unabsorbed macronutrients and make them available to the fi have disclosed no nancial relationships infant. relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device. Objectives After completing this article, readers should be able to: ABBREVIATIONS BSDL bile salt–dependent lipase 1. Understand the importance of human milk in macronutrient digestion in BSSL bile salt–stimulated lipase the preterm infant. GLUT2 glucose transporter 2 GLUT5 glucose transporter 5 2. Understand the role of the colonic microbiome of human milk-fed HMO human milk oligosaccharide infants in scavenging unabsorbed nutrient in the preterm infant. IMMC interdigestive migrating motor fi complex 3. Understand the importance of relative pancreatic exocrine insuf ciency in LCPUFA long-chain polyunsaturated fatty preterm infants and the alternative digestive enzymes that serve to acid mitigate its effect. PEPT1 peptide transporter 1 PLRP2 pancreatic lipase-related protein 2 PTL pancreatic triglyceride lipase SGLT1 sodium-glucose linked transporter 1 Vol. 20 No. 1 JANUARY 2019 e25 Downloaded from http://neoreviews.aappublications.org/ at Swets Blackwell Inc. on February 15, 2021 INTRODUCTION Ingestion of amniotic fluid by the fetus has an impor- tant nutritional role. There is good evidence that esopha- Current nutritional recommendations in the preterm infant geal atresia (which prevents fetal swallowing) reduces emphasize that postnatal growth mirrors that of the fetus of birthweight. Birthweight Z score is lower in infants with the same gestational age. Typically, this goal is not met and esophageal atresia than in infants with anorectal malfor- the growth of preterm infants, especially very low-birth- mations. (10) Although infants with proximal intestinal weight infants (birthweight <1,500 g), is often far slower obstructions (both esophageal atresia and duodenal atre- than in utero growth. (1) Although there is evidence of sia) have associated reduced birthweight Z scores, infants some improvement in recent years, (2) these nutritional with a more distal obstruction (jejunal atresia and ileal deficits are associated with poorer long-term neurodevelop- atresia) have appropriate fetal growth. Esophageal liga- mental outcomes. Much of the early growth deficits of tion in fetal rabbits leads to significant reductions in preterm infants are associated with reduced protein and birthweight and birth length compared with sham oper- energy intake, (3) and both poor growth and lower nutrient ations, and these effects are reversed by esophageal intake are associated with poorer outcomes. (2)(3) infusions that restore fetal “swallowing.” (11) Based on Traditionally, neonatologists have some hesitancy when these studies, investigators estimated that swallowed initiating and advancing enteral feedings in very preterm amniotic fluid provides 10% to 14% of nutrition in the infants because of the perceived associated risk of necro- fetal rabbit. (11) tizing enterocolitis. However, there is good evidence that more conservative approaches to feeding, such as prolonged periods of “trophic” feedings, very slow advancement of Amino Acids in Amniotic Fluid enteral feeding volume, and delayed fortification of human Human amniotic fluid contains a broad range of amino milk, are not associated with lower rates of NEC. (4)(5)(6)(7) acids; concentrations of alanine, lysine, and phenylalanine (8) Studies have found that these cautious regimens may be are high, whereas that of cysteine is low. (12) The amount of associated with a number of adverse outcomes such as lower amino acids in amniotic fluid is equivalent to a protein nutrient intakes, (8) prolonged use of central lines, delayed content of approximately 0.4 g/dL (4 g/L). Although this establishment of full enteral feedings, (5)(6)(7) increased amount is less than that found in human milk (typical risk of infection, (7) poorer growth, (6) and increased length estimate 1 g/dL [10 g/L]), it could be nutritionally significant of stay. (5) if sufficient amniotic fluid is ingested. Empirically, most preterm infants seem able to adapt well Methionine in amniotic fluid is of particular interest. to enteral feedings. Nevertheless, many neonatologists con- In rodent models, maternal malnutrition leads to reduced tinue to remain apprehensive about feeding very preterm amniotic fluid methionine (and phenylalanine) levels, and infants as a result of unfounded concerns about NEC and amniotic methionine is correlated with fetal birthweight. are reluctant to be the initiator of feedings. However, this (13) Similar data are reported in humans. In a study of 625 misconception—that the fetus is entirely parenterally fed healthy pregnancies, amniotic fluid methionine concentra- (via the umbilical vein) and that newborn infants (term or tions between 13 and 17 weeks’ gestation were positively preterm) receive their first enteral feeding after birth—is associated with birthweight, and amniotic fluid cysteine actually incorrect. concentration was negatively associated with birthweight. (14) ENTERAL NUTRITION OF THE FETUS Adaptation of Amniotic Fluid Absorption Fetal swallowing is first seen at 18 to 20 weeks of gestation Absorption of amniotic fluid components by the fetus seems and plays an important role in the regulation of amniotic to be adaptable. In one study, pregnant rabbits received fluid volume. The volume ingested in human fetuses is hard intrauterine infusions of galactose or an inert control for 6 to assess. In fetal sheep, fluid flow along the esophagus is days. Exposure of the fetuses to galactose in the amniotic bidirectional, but net inward amniotic fluid flow averages fluid led to increased galactose and glucose uptake in the 175 mL/kg per day at 75% of term gestation (30 weeks’ proximal and distal small intestine. (15) This suggests that gestation in humans) increasing to 274 mL/kg per day at the fetus (and by extension, the preterm infant) may be able 85% of term gestation (34 weeks’ gestation in humans). (9) to adapt to new dietary components by upregulating the Both are far higher than the fluid intake of an adult sheep enzymes and transporters required to digest and absorb (40-60 mL/kg per day). them. e26 NeoReviews Downloaded from http://neoreviews.aappublications.org/ at Swets Blackwell Inc. on February 15, 2021 Absorption of Macromolecules by the Fetal inactivated by pasteurization of human milk. (19) This Gastrointestinal Tract may be a possible explanation for fat absorption being The fate of proteins in amniotic fluid has been studied in 17% lower in preterm infants receiving pasteurized moth- rhesus monkeys. (16) The authors injected an intact protein, er’s own milk compared with those receiving unpasteurized labeled with 35S-methionine, into the amniotic fluid of mother’s own milk. (20) Human BSSL is commercially pregnant rhesus monkeys. The clearance of the protein available as a recombinant protein (rhBSSL). Although was largely determined by the rate of fetal swallowing, one small study suggested that addition of rhBSSL to and evidence of proteolysis of the labeled protein was pasteurized human milk or formula improved growth observed along the length of the small intestine. Amino and long-chain polyunsaturated fatty acid (LCPUFA) sta- acids released by proteolysis of the labeled protein were tus, (21) this has not been borne out in a larger trial. (19) incorporated into gut proteins and released into the fetal Although that larger study found that rhBSSL had no ef- plasma as amino acids, where they equilibrated rapidly with fect on growth of preterm infants (n¼415, gestational age maternal amino acids and entered the amniotic fluid amino £32 weeks), significant improvements in growth were acid pool. One day after peak 35S-methionine enrichment of found in small-for–gestational age preterm infants in a the amniotic amino acid pool occurred, 35S-methionine- plannedsubgroupanalysis(n¼62). (19) labeled amino acids were detected in the fetal plasma, fl indicating that amniotic uid amino acids were being used Other Enzymes in Human Milk for protein synthesis. Labeled proteins were also recovered Various other enzymes are present in human milk that may from the fetal lung, liver, skeletal muscle, and brain. The potentially play a role in the digestion of lipids, carbohy- authors estimated that amniotic fluid amino