Archives of Disease in Childhood 1994; 71: F136-F141

CURRENT TOPIC

Gastric ontogeny: clinical implications

Eric J Kelly, Simon J Newell

The delivery of a preterm infant offers a uniqueopportunity to look directly upon the processof ontogeny, while at the same time organimmaturity is the basis of the clinical problemswhich challenge neonatal medicine. In recentyears our knowledge of foregut ontogeny hasincreased, together with an increased body ofclinical experience, yet the nutritional manage-ment of the preterm infant remains a con-tentious area, with wide variations in clinicalpractice. The compelling evidence of theimportance of early nutritional managementon neurodevelopmental outcome now focusesthe debate sharply. Closer knowledge of thedevelopment of functional maturity in thegut may allow more rapid and rationaladvances to be made. In this paper we discussthe embryology, the development of secretoryand digestive function, and the maturationof gastro-oesophageal motor activity as abackground to the clinical management ofnutrition in the preterm infant.

General embryologyThe human stomach develops from a fusiformswelling of the foregut at about 4 weeks' gesta-tion. Originating in the neck, this swellingdescends into the abdomen during the nexteight weeks. Differential growth rates resultinitially in the formation of the greater andlesser curvatures, followed by a 900 clockwiserotation of the stomach which occurs at6 weeks' gestation. 1 The stomach isinitially lined by stratified2 or pseudostratified3columnar epithelial cells which are laterreplaced by cuboidal cells. Gastric pitshave developed in the epithelium by 14 weeks'gestation, and develop a mature glandularstructure over the following weeks. Structuralmaturity is reached before the fetus becomesviable, and by 20 weeks' gestation the fetalstomach macroscopically and microscopicallyresembles that of the newborn infant at term.Nerve fibres reach the gastric primordium at

5 weeks' gestation, four weeks before the firstmyoblasts are seen, and by 30 weeks' gestationboth are morphologically and histologicallymature.4 5

Regional NeonatalUnit, St James'sUniversity Hospital,Leeds LS9 7TFE J KellyS J Newell

Correspondence to:Dr Newell.

Acid secretionGastric acid has many important fumctions inthe human, including a role in the luminalimmune system and the initiation of digestion.Hydrogen ions are secreted by the parietal cells

located on the luminal aspect of the gastricmucosa by an energy dependent H±/K+ATPase (proton pump). Acid secretion isunder neural and hormonal control, princi-pally vagal stimulation and local secretion ofgastrin and histamine. These act either directlyon the parietal cell or through entero-chromataffin-like cells.

Differentiated glandular epithelial cells,which are structurally and histochemicallyidentifiable as parietal cells, appear from 11weeks' gestation.6 During early fetal life pari-etal cells are located in the body and antrum ofthe stomach, but by term only 20% ofneonateshave parietal cells in the antrum, similar tothe proportion seen in adults.7 We haveshown that from 13 weeks' gestation theseparietal cells are functionally mature with theH+/K+ ATPase in situ,8 and as early as 1929Lucas-Keene and Hewer found hydrochloricacid in the fetal stomach from 19 weeks' gesta-tion.9 It is not known how much acid thefetus produces in utero but we have recentlydemonstrated the secretion of gastric acid ineven the most immature infants, from 24weeks' gestation. In this study infants receivingintensive care were all found to be capable ofproducing and maintaining a gastric pH <2within the first days of life.10 The principalmechanisms controlling acid secretion in thepreterm infant and the effects of factors such asenteral feeds are not known.

Gastric acid has both beneficial and detri-mental effects in the immature newborn infant.Its presence acts as a barrier to the entry ofmicro-organisms into the small intestine,and one study has shown that infants givencimetidine had a higher incidence of necro-tising enterocolitis than a control group.11Gastric acid may therefore have a role incontrolling gut microflora implicated in theaetiology of necrotising enterocolitis.On the other hand, acid related disease may

occur. Acid and pepsin are both present in thenewborn,'2 and mucosal damage occurs whenthere is imbalance between their harmfuleffects and mucosal protective mechanisms.Protection against acid-peptic damage isprovided by a number of factors. It requiresgood gastric mucosal perfusion from thesplanchnic circulation. Prostaglandins, notablyPGE2 which is present in the gastric juice ofsick preterm infants,'3 have a number ofactions which suggest their central role inmucosal protection. They stimulate mucusproduction and secretion of bicarbonate,

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inhibit acid secretion, and increase mucosalsurface hydrophobicity. Epidermal growthfactor (EGF) may also be cytoprotective. Thisacid stable peptide, present in large amounts inbreast milk,14 produces inhibition of acidsecretion in experimental animals.15 Receptorsfor EGF have now been demonstrated in thegastric mucosa of the fetus and the newborn. 16The preterm neonate is at high risk of

acid-peptic disease. Sick preterm infants havebeen demonstrated to have a lower gastric pHthan other preterm infants, increasing the riskof gastric bleeding.'7 Mucosal resistance toacid peptic digestion may be reduced bypoor gastric blood flow. Dexamethasoneand indomethacin inhibit the production ofcytoprotective prostaglandins, and tolazolineand morphine increase histamine concentra-tions. It is therefore not surprising that studiesusing endoscopy suggest a high incidence ofmucosal lesions.18 Acid-peptic disease is mostfrequently restricted to superficial mucosaldamage, but may produce more significantulceration or haemorrhage. Gastric perforationis a rare but catastrophic event in sick, stressed,preterm infants, and carries a 50% mortality. Ithas been described in the fetus. 19 In theneonate it may occur in association withdexamethasone20 and tolazoline2' treatmentand there is a worrying theoretical risk withmorphine.22What strategy might therefore be adopted

to best protect the preterm infant from acid-peptic disease? Circulatory support to avoidgastric hypoperfusion, and judicious use ofagents likely to reduce mucosal resistance isprudent. When upper gastrointestinal bleedingoccurs, or when the risk is high, as with the useof high dose dexamethasone, therapeutic orprophylactic intervention is justified. Milkfeeds increase gastric pH. In healthy preterminfants receiving three hourly formula feeds,buffering of intragastric pH >4 lasts up to90 minutes after a feed,23 and breast milkcontaining EGF, may confer further benefit.The histamine antagonist, ranitidine, is effec-tive in the preterm infant. Intragastric aciditymay be reduced to pH >4, a value thought toprevent acid-peptic disease, with an intra-venous infusion of ranitidine at 00625mg/kg/hour.24 The efficacy of H2 blockade inthe prevention of mucosal lesions requires acontrolled trial in the intensive care popula-tion. There are no data concerning omeprazolein the preterm infant. Sucralfate, whichadheres to damaged mucous membrane andpromotes local prostaglandin and mucus pro-duction, is effective in stress ulceration inadults, but may retard gastric emptying andhas been reported to cause bezoar formation ina low birthweight infant.25 Misoprostol, aprostaglandin analogue, may have beneficialeffects through reversal of the steroid induceddisruption of cytoprotective mechanisms.Experience with misoprostol in the newbornis small, and long term use of prostaglandinsto maintain patency of the ductus arteriosusin infants with congenital heart disease hasbeen associated with gastric outlet obstruc-tion.26

GASTRINGastrin is produced by G cells found withinthe antrum, pylorus, and duodenum. It is botha trophic hormone and a potent stimulant ofgastric acid secretion. Immunohistochemicalstudies have demonstrated small numbers ofGcells between 12 and 18 weeks' gestation,27becoming more numerous in the antrum asthe density of parietal cells decreases.8 Themechanism linking gastrin and acid productionin newborns is not understood but is thoughtto be different from that in adults. Newborninfants have significantly higher circulatingconcentrations of gastrin than adults, thesehigh concentrations persist until at least 4months of age. Under 3 months of age infantsdo not demonstrate the typical postprandialrise in gastrin seen in adults,28 and administra-tion of the synthetic analogue pentagastrinproduces no increase in gastric acid pro-duction.29 It is likely therefore that in thenewborn, gastrin activity is maintained atmaximal level.

MotilityGastric and oesophageal motility are integrallylinked, and it is worth noting the ontogeniccoincidence of swallowing and mature loweroesophageal sphincter (LOS) function andsmall intestinal motility.

OESOPHAGUSInterest here centres on the complex integratedfunction of swallowing and the loweroesophageal sphincter as a barrier againstgastro-oesophageal reflux (GOR). Swallowingis first seen from 12-16 weeks, and has animportant role in the regulation of liquorvolume, as the fetus swallows 2-7 mI/dayinitially, rising to 300-700 ml/day at term.30The role of swallowed liquor in the gastro-intestinal ontogeny is not clear. Liquor isknown to contain proteins, carbohydrates,and triglycerides which may be important asluminal nutrients. It clearly provides volumewhich may encourage the maturation of motil-ity through secretion of enteric hormones,3'and interest recently has focused upon thelarge amount of growth factors present in theamniotic fluid.32 EGF, probably originatingfrom the amniotic membranes, is present inhigh concentrations in liquor.'6 In murinemodels, the administration of EGF antisera tothe newborn is associated with significantretardation of small intestinal growth andmaturity.33

Swallowing is a complex function, integrat-ing the movement of a bolus from the mouth tothe stomach with protection of the airway,inhibition of respiration, and appropriaterelaxation of the oesophageal sphincters andthe gastric fundus. In the newborn, non-nutritive sucking may be seen at a very earlygestation but nutritive sucking and swallowingdoes not occur until 34 weeks' postconcep-tional age, even if infants are born earlier andhave received intragastric milk feeds. This isunlike some other features of gut ontogeny,

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such as small intestinal motility which isincreased when milk feeds are given, althoughmature patterns are not seen before 32weeks.34

Little is known of the function of the upperoesophageal sphincter which may be detectedmanometrically from 32 weeks' gestation, 6-8cm from the nares, and which shows the sameresponse to a dry swallow in low birthweightand term infants.35 Coordinated motor activityin the body of the oesophagus is not presentin the preterm,35 showing some of thefeatures seen in older children with GOR.36Oesophageal peristalsis matures with postnatalage and exposure to milk feeds.35The LOS is the principal antireflux

barrier.37 An effective LOS pressure mustexceed intra-abdominal pressure in the fundusof the stomach. In the adult anatomical studieshave now demonstrated the muscularequivalent of the high pressure zone,38although the mechanisms of neuronal andhormonal control remain elusive. In theopossum, which is very immature at birth, aneffective LOS pressure is present at birth, withcontinued maturation of muscle mass andfunction in the postnatal period.39 Similarobservations have been made in the cat anddog.40

Studies in the human infant require carefulattention to the physics of intraluminalpressure measurement which requires acontinuously perfused, rapid response, lowcompliance manometric system.4' Details ofsystem design were not given in a study whichshowed the absence of any effective sphincterpressure in the first six weeks of life in term orpreterm infants.42 Newborn infants, however,do not reflux continuously, and a study of terminfants at a mean age of 8 hours demonstratedeffective LOS pressure equal or greater thanthose seen in older children.43 In the preterminfant effective LOS pressures rises fromaround 053 kPa (4 mm Hg) before 28 weeksto 2-40 kPa (18 mm Hg) at term. This rise inpressure is most clearly related to gestation atbirth and postconceptional age rather thanpostnatal age or postnatal experience.44

GASTRO-OESOPHAGEAL REFLUXGOR occurs when the LOS fails to prevent it.There is, however, no clear relationshipbetween resting LOS pressure and GOR in theindividual.45 46 This apparent paradox may beexplained by motility studies. Reflux mayoccur in subjects with low sphincter pressure inassociation with a rise in intra-abdominalpressure. Alternatively it is seen duringtransient relaxation of the LOS, appropriatelyafter a swallow, or inappropriately at othertimes.47 Similarly studies relating GOR togastric emptying (see below) are at variance. Itseems likely that the individual with good LOSfunction and rapid gastric emptying will be atlow risk of GOR, while when either of thesemechanisms is deficient, as occurs in thepreterm infant, the risk of GOR will beincreased.

In the preterm infant the combined effect

of a poor antireflux barrier, immatureoesophageal motility, and slow gastricemptying, make the risk ofGOR high. Amongpreterm infants who have no symptoms tosuggest reflux, 85% have a reflux index(percentage exposure time of the oesophagusto a pH <4) greater than 1%, with a meanreflux index of 4. 5%.46 This is higher than seenin healthy term infant.48 Caffeine, whichreduces LOS pressure, and physiotherapy,which increases intra-abdominal pressure, areboth associated with increased reflux,46 whilemechanical ventilation, which maintains apositive intrathoracic pressure, is associatedwith a diminution in the amount of reflux.49 50There is now little doubt that reflux may beimplicated in the pathogenesis of the problemsof recurrent apnoea,46 bronchopulmonarydysplasia,51 aspiration pneumonitis,52 andoesophagitis,53 and these issues have beendiscussed in detail elsewhere.

GASTRIC EMPTYINGIn the active fetus between 26 weeks' gestationand term, liquor fills and empties from thestomach with a periodicity of around 45minutes.54 In the early postnatal periodadequate gastric emptying is essential for theintroduction of enteral nutrition, and poorgastric emptying is common in the preterminfant, presenting as failure to 'tolerate' milkfeeds. In the very low birthweight infantthis problem may resolve quickly andspontaneously but may be protracted, and yetlittle is known about gastric emptying inthese infants because of the methodologicaldifficulties of studying small volume feeds, ininfants receiving intensive care.55Manometric studies in the preterm infant

have shown poorly organised, non-rhythmicgastric pressure waves following on fromoesophageal peristalsis.35 Pressure in thefundus44 and antrum34 rises with increasingpostconceptional age. Gastric emptying hasbeen measured in the preterm infantestablished on milk feeds. Half emptying timesfor breast milk have been estimated between20 and 40 minutes.55-57 This is slower than theterm infant and follows a biphasic curve, withan initial fast phase which is less obvious whenartificial formula is used.56 A number of factorshave been shown to have an effect upon gastricemptying. The stomach empties less quicklywith increasing energy density,58 higher fat andlong chain triglyceride content,59 and greaterdextrose concentration,60 and is modified byposition and postnatal disease.6' Emptying ismore rapid when breast milk is used ratherthan formula,56 57 glucose polymers ratherthan dextrose, and medium chain ratherthan long chain triglycerides.59 Osmolality,62temperature of the feed, phototherapy,63 andnon-nutritive sucking64 have been studiedwithout an apparent affect upon emptying.

If the relationship between gastric emptyingand gestation or the effects of early intro-duction of milk feeds are to be explored atechnique capable of repeated measurementsof emptying of small volume feeds without

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disturbance of the infant in intensive care isrequired. Radiographic and isotope techniqueshave obvious drawbacks. Measurement ofresidual volume can only be done once duringeach feed and assumes that the stomach can beemptied through an intragastric tube. Dyedilution techniques have been refined andallow accurate repeated measurement ofintragastric volume.64 Dye, however, must beinstilled and mixed with gastric contentsmaking this technique less suitable for thestudy of small volume feeds. We have recentlyused ultrasound to make repeated assessmentsof antral cross sectional area during a feed,55allowing the study of feeds down to 4 mlvolume, with minimal disturbance to theinfant. This method has been used todemonstrate marked difference in gastricemptying of breast milk and formula.57

Future work will need to look at theeffects of maturity, postnatal age, and theeffects of feeding upon gastric emptying.Current knowledge concerning the physio-logical control of the maturation of gastricemptying is poor, and the relationship betweenGOR and gastric emptying needs elucidationas the current evidence in this area is conflict-ing. The modulation of gastric emptyingthrough refinements of the composition ofmilk and timing and method of feed adminis-tration requires exploration. Cisapride, aprokinetic agent, has been used in infants in adose range of 0-1-0-3 mg/kg/dose, eighthourly, to accelerate gastric emptying and forthe control of GOR. One uncontrolled study inpreterm infants has demonstrated improvedgastric emptying,65 but double blind controlledstudies are needed to determine its potentiallybeneficial role.

In the term infant, persistent clinicalproblems as a result of poor gastric emptyingare rare. Infants with congenital gut anomalies,notably gastroschisis, on the other hand mayhave protracted problems. The origin ofthese problems is unclear. It may relate to theabnormal intrauterine environment of thegut, or perinatal and postnatal trauma. Theassociation between chronic intestinal pseudo-obstruction and the persistence of motilitydisorders in infants who have had malrotationmay allow inference of a primary motilitydisorder which may have led to the congenitalabnormality.66

Digestive functionsDigestion is initiated within the stomach, withthe secretion ofboth acid and pepsin. A varietyof pepsins are released in response to antraldistension through complex neural andhormonal mechanisms. Pepsinogens have beendemonstrated immunohistochemically, in thechief cells from 19-21 weeks' gestation,67 andpeptic activity is present in the stomach in thevery low birthweight infant.68 Jejunal feeding,however, is associated with normal gastro-intestinal absorption and function,69 and thecontribution of peptic activity to proteindigestion may be small.The initial hydrolysis of dietary triglycerides

begins in the stomach through the action ofacid stable lipase. Gastric lipase appears fromthe 11th week of development and is secretedin the fundal region of the stomach.70 Acidstable lipase activity is of gastric origin,although the part played by lingual and breastmilk lipases in initial digestion is unknown.Amniotic fluid contains triglycerides (120mg/l),71 and gastric digestion of lipids maybegin during fetal life. In a study of 350preterm infants lipolytic activity in gastricaspirates was found to reach peak activity at30-32 weeks' gestation.72

INTRINSIC FACTORIntrinsic factor is a small glycoprotein syn-thesised and secreted by the parietal cellsunder the same neural and hormonalmechanisms involved in modulating acidsecretion. It binds to the cobalamin present invitamin B-12 and is absorbed intact in theterminal ileum. Immunohistochemical8 andautoradiographic73 techniques have noted thatintrinsic factor is present in parietal cells fromthe end of the first trimester. There are noclinical studies looking at the secretion ofintrinsic factor or absorption of vitamin B-12in the immature infant.

ConclusionThe upper gut shows considerable structuraland functional maturity by the end of thesecond trimester, but problems related to itsfunction are common in the very low birth-weight infant. Awareness of prenatal factors,the influence of intrauterine nutrition, and ofelements of postnatal care that may affectgastrointestinal ontogeny is essential for futureadvances in the use of enteral feeding. Theobservation that LOS maturation is notmodified by postnatal factors, while gastricemptying clearly is, is hard to explain. Ourability to induce gut maturity and the use ofmilk feeds, not only as a source of nutrition,but also as a method ofpromoting maturation,needs further exploration.

Gastric acid is produced by the preterminfant and endoscopy is beginning to pro-vide data which suggest that we may havebeen under-recognising acid-peptic disease.However, there is insufficient evidence tosupport the suggestion that all undergoingintensive care should receive acid blockingagents. Currently reduction of gastric acidproduction may be justified in infants athigh risk of acid-peptic mucosal damage.H2 blockade with ranitidine is effective inincreasing gastric pH, but omeprazole orcytoprotective prostaglandin analogues maybe used in the future.

Poor LOS function, slow gastric emptying,and immature patterns of gastro-oesophagealmotility make GOR common. The role ofGOR in the pathogenesis of respiratoryproblems is now well established. GOR hasa natural history of resolution in mostinfants, but when necessary, treatment maybe effective, and will probably increasingly

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include the use of cisapride. Slow gastricemptying may increase reflux, but mostfrequently presents with poor 'toleration' offeeds. Studies involving manipulation of feedcomposition and timing may well be helpful inthese infants, allowing better prediction of ababy's ability to tolerate feeds, and providingguidance in the choice of milk and mode ofadministration. The study of gastric emptyingexemplifies well how research into the naturalhistory of ontogeny, and the effects ofintrauterine and postnatal environment uponthat process, may, in the future, allow theformation of a rational basis for the nutritionalmanagement of the preterm infant.

1 Arey LB. Developmental anatomy. Philadelphia: WBSaunders, 1974: 245-62.

2 Hayward AF. The ultrastructure of the developing gastricparietal cells in the foetal rabbit.3Anat 1967; 101: 69-83.

3 Menzies PL. Observations on the development ofcertain cell types in the fundic region of the rabbitstomach. Quarterly Journal of Microscope Science 1964;105: 449-62.

4 Bremner G. Studies on the pyloric muscle. S Aftr Surg1968; 6: 79-85.

5 Deren JS. Development of structure and function in thefetal and newborn stomach. Am J Clin Nutr 1971; 24:144-59.

6 Normura Y. On the submicroscopic morphogenesis ofparietal cells in the gastric gland of the human foetus.ZeitschriftfiirAnatomie und Entwicklungsgeschichte (Berlin)1966; 125: 316-22.

7 Naik KS, Lagopoulos M, Primrose JN. Distribution ofantral G-cells in relation to the parietal cells of thestomach and anatomical boundaries. Clinical Anatomy1990; 3:17-24.

8 Kelly EJ, Lagopoulos M, Primrose JN. Immuno-cytochemical localisation of parietal cells and G-cellswithin the developing human stomach. Gut 1993; 34:1057-9.

9 Lucas-Keene MF, Hewer EE. Digestive enzymes in thehuman foetus. Lancet 1929; i: 767-9.

10 Kelly EJ, Newell SJ, Brownlee KG, Primrose JN, DearPRF. Gastric acid secretion in preterm infants. Early HumDev 1993; 35: 215-20.

11 Udall JN. Gastrointestinal host defence and necrotizingenterocolitis. JPediatr 1990; 117: S33-44.

12 Agunod M, Yamaguchi N, Lopez R, Luhby AL, Glass GBJ.Correlative study of hydrochloric acid, pepsin and intrin-sic factor secretion in newborns and infants. AmericanJournal of Digestive Diseases 1969; 14: 400-14.

13 MarinoLR, Blumer JL, Halprin TC. Prostaglandin E2 con-centrations in gastric secretions of critically ill, full term,and premature infants. Pediatr Res 1983; 17: 669-71.

14 Reed LC, Upton FM, Francis GL, et al. Changes in thegrowth promoting activity of human milk during lactation.PediatrRes 1984; 18: 133-9.

15 Konturek SJ, Brzozowski T, Konturek PK, Majka J,Dembinski A. Role of salivary glands and epidermalgrowth factor (EGF) in gastric secretion and mucosalintegrity in rats exposed to stress. Regul Pept 1991; 32:203-15.

16 Kelly EJ, Newell SJ, Brownlee KG, Primrose JN. Theontogenic role of EGF and TGF alpha in the developinghuman stomach. Gut 1993; 34 (suppl 4): S31.

17 Sankaman K, Hayton S, Duff E, Waygood B. Time-wisesequential analysis of gastric aspirate for occult blood andpH in sick preterm infants. Clin Invest Med 1984; 7:115-8.

18 Maki M, Ruuska T, Kuusela A-L, et al. High prevalence ofasymptomatic esophageal and gastric lesions in preterminfants in intensive care. Crit Care Med 1993; 21: 1863-7.

19 Wen H, Chen M, Ho M, Hwang K. Fetal gastric ulcer pre-senting with bloody amniotic fluid. J Pediatr GastroenterolNutr 1992; 15: 455-7.

20 Ng PC, Brownlee KG, Dear PRF. Gastroduodenal perfora-tion in preterm babies treated with dexamethasone forbronchopulmonary dysplasia. Arch Dis Child 1992; 66:1164-6.

21 Butt W, Auldist A, McDougall P, Duncan A. Duodenalulceration: a complication of tolazaline therapy. AustralianPaediatricJournal 1986; 22: 221-3.

22 Treuren BC, Galletly DC, Robinson BJ, Short TG, UreRW.Theinfluence of H1 and H2 receptor antagonists,terfenadine and ranitidine, on the hypertensive and gastricpH effects of the histamine releasing drugs morphine andtubocurarine. Anaesthesia 1993; 48: 758-62.

23 Sondheimer JM, Clark DA, Gervaise EP. Continuousgastric pH measurement in young and older preterminfants receiving formula and clear liquid feedings.JPediatr Gastroenterol Nutr 1985; 4: 352-5.

24 Kelly EJ, Chatfield SL, Brownlee KG, PrimroseJN, NewellSJ, Dear PRF. The effect of intravenous ranitidine on theintragastric pH of preterm infants receiving dexametha-some. Arch Dis Child 1993; 69: 37-9.

25 Tang T, Yeung C. Intestinal obstruction and perforationfollowing sucralfate administration in a very low birthweight infant. Jf Perinat Med 1992; 20: 317-21.

26 Peled N, Dagan 0, Babyn P, et al. Gastric-outlet obstruc-tion induced by prostaglandin therapy in neonates. N EnglJMed 1992; 327: 505-10.

27 Grasso S, Buffa R, Martino E, Bartalena L, Curzio M,Salomone E. Gastrin (G) cells are the cellular site of thegastric thyrotropin-releasing hormone in human fetusesand newborns. A chromatographic, radioimmunulogical,and immunocytochemical study. _J Clin Endocninol Metab1992; 74: 1421-6.

28 Moazam F, Kirby WJ, Rogers BM, McGuigan JE.Physiology of serum gastrin production in neonates andinfants. Ann Surg 1984; 199: 389-92.

29 Euler AR, Bryne WJ, Meis PJ, Leake RD, Ament ME. Basaland pentagastrin stimulated acid secretion in newbornhuman infants. PediatrRes 1983; 13: 36-7.

30 Pritchard JA. Fetal swallowing and amniotic fluid volume.Obstet Gynecol 1966; 28: 606-10.

31 Lucas A, Bloom SR, Aynsley-Green A. Metabolic andendocrine events at the time of the first feed of humanmilk in preterm and term infants. Arch Dis Child 1978; 53:731-6.

32 Weaver LT, Walker WA. Epidermal growth factor andthe developing human gut. Gastroenterology 1988; 94:845-7.

33 Zschiesche W. Retardation of growth and epithelial differ-entiation in suckling mice by anti-EGF antisera. BiomedBiochimActa 1989; 48: 103-9.

34 Bisset WM, Watt JB, Rivers RPA, Milla PJ. The ontogenyof small intestinal fasting motor activity in the humaninfant. Gut 1988; 29: 483-8.

35 Gryboski JD. The swallowing mechanism of the neonate I:esophageal and gastric motility. Pediatrics 1965; 35:445-52.

36 Cucchiara S, Staiano A, Di Lorenzo C, et al. Esophagealmotor abnormalities in children with gastroesophagealreflux and peptic disease. J Pediatr 1986; 108: 907-10.

37 Newell SJ. The lower oesophageal sphincter in the preterminfant. In: Milla PJ, ed. Disorders of gastro-intestinal motilityin childhood. Chichester: John Wiley, 1988: 39-50.

38 Liebermann-Meffert D, Allgower M, Schmid P, Blum AL.Muscular equivalent of the lower esophageal sphincter.Gastroenterology 1979; 76: 31-8.

39 Cohen S. Developmental characteristics of loweresophageal sphincter function: a possible mechanism forinfantile chalasia. Gastroenterology 1974; 67: 252-8.

40 Spedale SB, Weisbrodt NW, Morriss JR. Ontogenic studiesof gastro-intestinal function II: lower esophageal sphinctermaturation in neonatal beagle puppies. Pediatr Res 1982;16: 851-5.

41 Weihrauch TR. The physics of intraluminal pressurerecording. Oesophageal manometry: methods and clinicalpractice. Baltimore-Munich: Urban and Schwarzenberg,1981: 20-63.

42 Boix-Ochoa J, Canals J. Maturation of the lower esophagus.JPediatrSurg 1976; 11: 749-56.

43 Moroz SP, Beiko P. Relationship between loweroesophageal sphincter pressure and serum gastrin concen-tration in the newborn infant. J Pediatr 1981; 99: 725-8.

44 Newell SJ, Sarkar PK, Durbin GM, Booth IW, McNeishAS. Maturation of the lower oesophageal sphincter in thepreterm baby. Gut 1988; 29: 167-72.

45 Euler AR, Byrne WJ. Twenty four hour esophageal intra-luminal pH probe testing: a comparative analysis.Gastroenterology 1981; 80: 957-61.

46 Newell SJ, BoothIW, Morgan MEI, Durbin GM, McNeishAS. Gastro-oesophageal reflux in preterm infants. ArchDis Child 1989; 64: 780-6.

47 Brueton MJ, Clarke GS, Sandhu BK. Gastro-esophagealreflux in infancy. In: Milla PJ, ed. Disorders ofgastro-intesti-nal motility in childhood. Chichester: John Wiley, 1988:53-64.

48 Vandenplas Y, Goyvaerts H, Helven R, Sacre L.Gastroesophageal reflux, as measured by 24-hour pHmonitoring, in 509 healthy infants screened for risk ofsudden infant death syndrome. Pediatrics 1991; 88:834-40.

49 Pradeaux L, Boggio V, Gouyon JB. Gastro-oesophagealreflux in mechanically ventilated preterm infants. Arch DisChild 1991; 66: 793-6.

50 Newell SJ, Morgan MEI, Durbin GM, Booth IW, McNeishAS. Does mechanical ventilation precipitate gastro-oesophageal reflux during enteral feeding? Arch Dis Child1989; 64: 1352-5.

51 Hrabovsky EE, MullettMD. Gastroesophageal reflux in thepremature infant. JPediatr Surg 1986; 21: 583-7.

52 Wharton BA, Bower BD. Immediate or later feeding forpremature babies? A controlled trial. Lancet 1965; ii:969-72.

53 Anand KJS. Gastric lesions in neonates: effects of stress?Crit Care Med 1993; 21: 1817-9.

54 Devane SP, Soothill PW, Candy DCA. Temporal changesin gastric volume in the human fetus in late pregnancy.Earl Hum Dev 1993;33: 109-16.

55 Newell SJ, Chapman 5, BoothIW. Ultrasonic assessment ofgastric emptying in the preterm infant. Arch Dis Child1993; 69: 32-6.

56 Cavell B. Reservoir and emptying function in the stomachof the premature infant. Acta Paediatrica Scandinavica1982; 296: 60-1.

57 Ewer AK, Durbin GM, Morgan MEI, BoothIW. Gastricemptying in preterm infants: a comparison of breast milkand formula. Arch Dis Child 1994; 71: F24-7.

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58 Siegel M, Lebebthal E, Krantz B. Effect of caloric densityon gastric emptying in premature infants. Pediatr 1984;104: 118-22.

59 Siegel M, Krantz B, Lebenthal E. Effect of fat and carbohy-drate composition on the gastric emptying of isocaloricfeedings in premature infants. Gastroenterology 1985; 89:785-90.

60 Husband J, Husband P. Gastric emptying of waterand glucose solutions in the newborn. Lancet 1969; ii:409-11.

61 Yu VYH. Effect of body position on gastric emptying in theneonate. Arch Dis Child 1975; 50: 500-4.

62 Siegel M, Lebenthal E, Topper W. Gastric emptying in pre-matures of isocaloric feedings with different osmolalities.Pediatr Res 1982; 16: 141-7.

63 Blumenthal I, Lealman GT. Effect of feed temperature andphototherapy on gastric emptying in the neonate. Arch DisChild 1980; 55: 562-74.

64 Szabo JS, Hillemeier AC, Oh W. Effect of non-nutritive andnutritive suck on gastric emptying in premature infants.Pediatr Gastroenterol Nutr 1985; 4: 348-51.

65 Melis K, Janssens G. Long-term use of cisapride (Prepulsid)in premature neonates. Acta Gastroenterol Beig 1990; 53:372-5.

66 Devane SP, Coombs RC, Smith W, et al. Persistent gastro-

intestinal symptoms after correction of malrotation. ArchDis Child 1992; 67: 218-21.

67 Reid WA, McGechaen K, Branch T, Gray HDA,Thompson WD, Kay J. Immunolocalisation of asparticproteinases in the developing human stomach. J7 DevPhysiol 1989; 11: 299-303.

68 Adamson I, Esangbedo A, Okolo AA, Omene JA. Pepsinand its multiple forms in early life. Biol Neonate 1988; 53:267-73.

69 Macdonald PD, Skeoch CH, Carse H, et al. Randomisedtrial of continuous nasogastric, bolus nasogastric, andtranspyloric feeding in infants of birth weight under1400 g. Arch Dis Child 1992; 67: 429-31.

70 Sarles J, Moreau H, Verger B. Human gastric lipase:ontogeny and variations in children. Acta Paediatr 1992;81: 511-3.

71 Codaccioni X, Lecountour X, Delecour M, Biserta G.Physiologie du liquide amniotique. Encyclopedie Midicaleet Chirugicale (Paris) Obstetrique 1985; 5006 A10,6.

72 Lee PC, Borysewicz R, Sturve M, Raab K, Werlin SL.Development of lipolytic activity in gastric aspirates frompremature infants. Pediatr Gastroenterol Nutr 1993; 17:291-7.

73 Hoedemaker PJ, Abels J, Watchers Ji, Arends A, Nieweg H.Further investigations about the site of production ofgastric intrinsic factor. Lab Invest 1966; 15: 1163-73.

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