NUOVE FORMULE NEI DISORDINI FUNZIONALI GASTROINTESTINALI

1. NUOVE FORMULE NEI DISORDINI FUNZIONALI GASTROINTESTINALI Annamaria StaianoDipartimento di Scienze Mediche TraslazionaliUniversità di Napoli “Federico II”

2. NUOVE FORMULE NEI DISORDINI FUNZIONALI GASTROINTESTINALI (DFGIs) OUTLINE • Epidemiologia DFGIs nel primo anno di vita • Novità in campo di terapia dietetica • Reflusso gastroesofageo • Coliche • Stipsi

3. P.E. Hyman et al GASTROENTEROLOGY 2006;130:1519–1526

4. Prevalence of common gastrointestinal symptoms in infants from birth to 12 months of age and their impact on future health outcomes Y Vandenplas, M Bellaiche, M Benninga, JP Chouraqui, F Ç Çokuðraþ, T Harb, B Hegar, C H Lifschitz, T Ludwig, M Miqdady, M B Morais, S Osatakul, R Shamir, A Staiano, H Szajewska, N Thapar, S Salvatore Average estimated prevalences from worldwide survey JPGN 2015 in press

5. P.E. Hyman et al GASTROENTEROLOGY 2006;130:1519–1526

6. … Si tratta di Disordini Funzionali GI o IPLV/APLV? About one third of infants fed standard formula in USA switch formula before 4 months of age. In Israel 50% of infants switch formulas at least once by 6 months of age (Lasekan JB 2011)

7. Y Vandenplas, C Dupont, P Eigenmann, A Host, M Kuitunen, C Ribes-Koninck, N Shah, R Shamir, A Staiano, H Szajewska, A Von Berg • Depending on the awareness of healthcare professionals, these functional digestive symptoms may or may not be attributed to the ingestion of cow’s milk. • If so, words such as “allergy” or “intolerance” are used interchangeably. However, there is a distinction between the terms. • Intolerance, or hypersensitivity, relates to all reactions to foods, while an allergy indicates that an immune mechanism is involved and atopy is the terminology for immunoglobulin E (IgE) mediated reactions. An allergy to cow’s milk is one of the most common food allergies in young children. Acta Paediatr. 2014 Dec 29

8. Y Vandenplas, C Dupont, P Eigenmann, A Host, M Kuitunen, C Ribes-Koninck, N Shah, R Shamir, A Staiano, H Szajewska, A Von Berg • The Cow's Milk-related Symptom Score (CoMiSS), which considers general manifestations, dermatological, gastrointestinal and respiratory symptoms, was developed as an awareness tool for cow's milk related symptoms. • It can also be used to evaluate and quantify the evolution of symptoms during therapeutic interventions, but does not diagnose cow's milk protein allergy and does not replace a food challenge. • Its usefulness needs to be evaluated by a prospective randomised study. • ConclusionThe CoMiSS provides primary healthcare clinicians with a simple, fast and easy-to-use awareness tool for cow’s milk related symptoms. Acta Paediatr. 2014 Dec 29

9. Symptom-based clinical score Vandenplas Y…Staiano A et al. Acta Paediatr. 2014 Dec 29

10. Y Vandenplas, P Steenhout and D Grathwohl A symptom-based score was developed Range: 0 – 33 Arbitrary: score > 12 was postulated as = CMPA (at least: 2 symptoms “severe” or 2 organ systems involved Predictive of CMPA: A SBS of > 12 : selects infants at risk for CMPA If elimination diet  score < 6 PPV of challenge is 80 % SAGE Open Med 2014; 2: 2050312114523423 10 20-12-2019

11. Infant Regurgitation

12. A consensus report on the management of frequent gastro-intestinal symptoms in infants: regurgitation, colic, constipation, diarrhoea and cow’s milk protein allergy. A Position paper of the ESPGHAN Gastroenterology Committee and additional experts. Vandenplas Y, Broekaert I, Falconer J, Gottrand F, Lionetti P, Orel R, PapadopoulouA, Ribes-Koninck C, Ruemmele FM, Schäppi M, ThaparN, Wilschanski M; Benninga M, Guarino A, LifschitzC, Salvatore S, ShamirR, Staiano A, Szajewska H • Position paper che si propone di offrire semplici algoritmi e raccomandazioni per guidare la pratica quotidiana per la diagnosi e la gestione di alcuni disordini funzionali GI del primo anno di vita. • Queste raccomandazioni sono state sviluppate da un gruppo di esperti, dopo una review aggiornata della letteratura. • In assenza di dati disponibili, le raccomandazioni sono basate su opinioni di esperti. JPGN 2015 Submitted

13. A consensus report on the management of frequent gastro-intestinal symptoms in infants: regurgitation, colic, constipation, diarrhoea and cow’s milk protein allergy. A Position paper of the ESPGHAN Gastroenterology Committee and additional experts. Vandenplas Y, Broekaert I, Falconer J, Gottrand F, Lionetti P, Orel R, PapadopoulouA, Ribes-Koninck C, Ruemmele FM, Schäppi M, ThaparN, Wilschanski M; Benninga M, Guarino A, LifschitzC, Salvatore S, ShamirR, Staiano A, Szajewska H • In the infant with troublesome and frequent regurgitation (more than four episodes a day), the management of regurgitation starts with reassurance of the parents providing information on the natural history of regurgitation, correct formula preparation if the infant is not breastfed and on how overfeeding may exacerbate the symptoms. • In infantile regurgitation, thickened formula or “anti-regurgitation formula” decreases regurgitation Vandenplas Y. et al JPGN 2015 Submitted

14. A consensus report on the management of frequent gastro-intestinal symptoms in infants: regurgitation, colic, constipation, diarrhoea and cow’s milk protein allergy. A Position paper of the ESPGHAN Gastroenterology Committee and additional experts. • The nutritional management of regurgitation consists of correcting the frequency and volume of the feeds if necessary • The commercialized AR-formulae contain different thickening agents: processed rice, corn or potato starch, guar gum or locust bean gum. • If commercial AR-formula is not available, a thickening product may be added to the standard formula. • “Home thickening” of a regular formula always increases osmolarity, which may induce reflux and regurgitation by increasing the number of lower oesophageal sphincter relaxations, which may induce reflux and regurgitation Vandenplas Y. et al JPGN 2015 Submitted

15. Thickened feedings appear to decrease observed regurgitation rather than the actual number of reflux episodes. • Excessive energy intake may occur with long-term use of feedings thickened with rice cereal or corn. • To this point, it is important to realize that thickening a 20kcal/oz infant formula with 1 tablespoon of rice cereal per ounce increases the energy density to 34 kcal/oz. Lightdale JR et al. Pediatrics 2013;131:e1684–e1695

16. Prevalence and Natural History of Infant Regurgitation Pathophysiology of infant regurgitation A recent review on the relationship between reflux and symptoms supports the concept that, in infants, even symptoms such as excessive crying accompanying prominent regurgitation are often caused by gastric distension (“dyspepsia,” or possibly even “functional heartburn”) rather than esophagitis (“heartburn”). Orenstein SR. Curr Gastroenterol Rep (2013) 15:353

17. Prevalence and Natural History of Infant Regurgitation CMPA GER DYSPHAGIA HAEMATEMESIS MELENA RUMINATION NAUSEA/BELCHING ARCHING BRADYCARDIA HICCUPS SANDIFER’S SYNDROME ASPIRATION LARINGITIS/STRIDOR RESPIRATORY INFECTIONS HOARSENESS IRRITABILITY COLIC PARENTAL ANXIETY FEEDING REFUSAL FAILURE TO THRIVE VOMITING REGURGITATION SIDEROPENIC ANAEMIA WHEEZING APNEA/ALTE/SIDS SLEEP DISTURBANCES DIARRHEA BLOODY STOOLS RHINITIS NASAL CONGESTION ANAPHYLAXIS CONSTIPATION ECZEMA/DERMATITIS ANGIOEDEMA LIP SWELLING URTICARIA/ITCHING Vandenplas Y, et al.Nutrition 29 (2013) 184–194

18. Dietary interventions Because regurgitation is sometimes the sole manifestation of cow’s milk protein allergy in healthy-looking infants, a 2-week trial of protein hydrolysate– or amino acid–based formula or a trial of milk-free diet for the breast-feeding mother is appropriate in infants not responding to previous management. J Pediatr Gastroentoerol Nutr 2009;49:498-547

19. Which formula should we use?

20. Hydrolysed protein accelerates the gastrointestinal transport of formula in preterm infants • The gastrointestinal transit time was shorter when a partially HF, containing an ultra-filtrated mixture of hydrolysedwhey and hydrolysed casein, with a molecular weight 75% <1.5 kD, 15% free amino acids, is used compared with standard preterm formula. • Thepartially whey HF had a markedly shorter gastrointestinal transit time (9.8 h) than standard infant formula (19 h) The hydrolysate protein formula accelerated gastrointestinal transit of milk and stools Mihatsch WA et al. Acta Paediatr. 2001 Feb;90(2):196-8.

21. UPDATE ON ANTI-REGURGITATION MILK FORMULAS. • A significant difference was observed on gastric emptying between casein-predominant and whey-hydrolysate feedings. • According to data obtained with a 13C-octanoic acid breath test in a randomized controlled cross-over study, extensive hydrolysates have a significant enhanced gastric emptying compared to formulas with partial hydrolyzed and intact proteins. • In a cross-over double-blinded trial, infants significantly reduced regurgitation, crying and gastric emptying time (assessed by 13-C acetate breath test) when fed a partial whey hydrolysate with a combination of thickeners (bean gum and processed tapioca starch) compared to an intact-protein casein-predominant (single) thickened one. • The above studies show that hydrolyzed formulas (more eHF than pHF) accelerates gastric emptying compared to standard formula. JPGN 2015 in press

22. Thickened formulas reduce regurgitation. • Recent studies indicate that thickened partially HF may have an additional benefit, although the data are too limited to result in a recommendation. Y Vandenplas, S Cruchet, C Faure, HC Lee, C Di Lorenzo, A Staiano, XuChundi, MM Aw, P Gutierrez-Castrellon, A Asery, J Spolidoro, RG Heine, M Miqdady, ME Arancibia, P Alarcon Acta Pædiatrica. 2014 103, pp. 689–695

23. Infantile colic

24. Nutritional Management: Cow's milk elimination • For breast-fed infants, clinicians should advise mothers to continue breastfeeding. In some infants however, with excessive irritability and crying a diagnostic elimination diet of the lactating mother excluding dairy products for two to four weeks followed by challenge, may be recommended in order to exclude CMPA. • In formula-fed infants, the elimination of CMP and dietary treatment with an extensively hydrolyzed protein formula (eHF) has been reported as effective

25. Nutritional Management: Other dietary interventions • Experience, but not evidence, has suggested that partially hydrolyzed formulas can be a useful alternative especially when eHF are too expensive or not available and CMPA is not a potential cause of IC. • In some cases, these formulae are lactose-reduced or lactose-free and contain prebiotics or probiotics causing, with varying levels of evidence, a reduction in the number of crying episodes and total crying time. Acta Paediatr 2014; 103: 689-95. J Pediatr Gastroenterol Nutr 2014; 58: 265-81

26. There seems to be a trend that partially HF may be better tolerated. • There are insufficient data to recommend a partially HF as single dietary intervention in colicky infants as most studies included other dietary changes as well. Y Vandenplas, S Cruchet, C Faure, HC Lee, C Di Lorenzo, A Staiano, XuChundi, MM Aw, P Gutierrez-Castrellon, A Asery, J Spolidoro, RG Heine, M Miqdady, ME Arancibia, P Alarcon Acta Pædiatrica. 2014 103, pp. 689–695

27. A consensus report on the management of frequent gastro-intestinal symptoms in infants: regurgitation, colic, constipation, diarrhoea and cow’s milk protein allergy. A Position paper of the ESPGHAN Gastroenterology Committee and additional experts. Vandenplas Y, Broekaert I, Falconer J, Gottrand F, Lionetti P, Orel R, PapadopoulouA, Ribes-Koninck C, Ruemmele FM, Schäppi M, ThaparN, Wilschanski M; Benninga M, Guarino A, LifschitzC, Salvatore S, ShamirR, Staiano A, Szajewska H • There is no evidence that probiotics added to infant formulae have a similar effect, as this has not been studied. • The addition of pre- and probiotics to infant formula has been shown to decrease colic, while the voting did not reach consensus that evidence justifies to recommend such a formula. Vandenplas Y et al JPGN 2015 Submitted

28. Y Vandenplas, S Cruchet, C Faure, HC Lee, C Di Lorenzo, A Staiano, XuChundi, MM Aw, P Gutierrez-Castrellon, A Asery, J Spolidoro, RG Heine, M Miqdady, ME Arancibia, P Alarcon • Lactose-free infant feeding does not adversely affect growth in term infants. • The presence or absence of lactose in infant feeding is an area of debate: while the advantage of lactose-reduced or lactose-free infant feeding is not evidence based, doing so is also not related to any negative effect. Acta Pædiatrica. 2014 103, pp. 689–695 In formula-fed infants, when low lactase activity is suspected and the child has gassiness, diarrhoea and, in some cases, diaper rash due to the evacuation of acidic stools, lactose may be withdrawn temporarily from the diet. Y. Vandenplas et al. Nutrition 29 (2013) 184–194

29. Functional Constipation

30. A consensus report on the management of frequent gastro-intestinal symptoms in infants: regurgitation, colic, constipation, diarrhoea and cow’s milk protein allergy. A Position paper of the ESPGHAN Gastroenterology Committee and additional experts. • Constipation has been shown in some infants to be related to the intake of CMP, although there was no consensus reach that extensive hydrolysates could be indicated in constipated infants. • A few studies have shown that soy formula and eHF might be effective. • Infant formulae containing partially or extensively hydrolysed proteins, fortified with prebiotics and without palm oil as the main source of fat in the oil blend, offer a therapeutic option for those infants with hard stools, but not for infants with infrequent defaecation, although the quality of this evidence is low. Vandenplas Y et al JPGN 2015 Submitted

31. Harder stools are frequent in infants fed formulas containing palm oil as the main source of fat. • Palm oil has a reduced content of fatty acids esterified to glycerol in the sn-2 position and an increase in those esterified in the sn-1 and sn-3 positions. • Fatty acid in positions sn-1 and sn-3 undergoes hydrolysis in the intestine, releasing palmiticacid, which is poorly absorbed and forms calcium soaps responsible for firmer stools. A formula rich in fatty acids in position sn-2 is likely to soften the stools. Fewtrell MS. Br J Nutr. 2013 Sep 28;110(6):1061-7

32. DIFFERENCES IN THE COMPOSITION BETWEEN BREAST- AND FORMULA FEEDING The chemicalstructure of breastmilktriacylglycerolis more favourable to fathydrolisis: In both human milk and infantformulaspalmitic acid is the predominantsaturatedfatty acid In human milk 70-85% of palmitic acid ispositionedat the sn-2 positin of the triacylglycerolmolecule, whereas in regular infantformulas 88-94% of palmitic acid isfoundat the sn-1 and sn-3 position In human milk, palmitic acid esterified at the sn-2 position of the triacylglycerol molecule is well absorbed as 2-monopalmitin, since it readily forms mixed micelles with bile acids Bongers MEJ et al. Nutr J 2007; 6: 1-7

33. POSSIBLE MECHANISMS OF ACTION • Increase in microbial mass • Selective fermentation and production of SCFA • Stimulation of gastrointestinal motility • Direct effects of the provided dietary fibers in the form of scGOS/lcFOS. In several of the studies with scGOS/lcFOS in a ratio of 9:1 in infant milk formulas, positive effects of this mixture on stool characteristics such as stool consistency and stool frequency were observed. World J Gastroenterol 2014 October 7; 20(37): 13446-13452

34. “The clinical effect of a new infant formula in term infants with constipation: a double-blind, randomized cross-over trial” The addition of a high concentration sn-2 palmitic acid, prebiotic oligosaccharides and partially hydrolyzed whey protein resulted in a strong tendency of softer stools in constipated infants, but not in a difference in defecation frequency Bongers MEJ. Nutr J; 2007; 6:8

35. Stool consistency, but not frequency, correlates with total gastrointestinal transit time in children The aims of the study were evaluate: 1) the correlation between stool characteristics (consistency and frequency) and gut transit time in children 2) whether Bristol Stool Form Scale (BSFS) may be considered as a reliable method of assessing intestinal transit rate in children. A significant correlation was found between stool form and whole- gut transit time (WGTT) in both constipatedand non-constipated children, No correlation was found between stool frequency and WGTT and between stool frequency and stool form. Conclusion: In this prospective, observational, case control study we showed that stool form as measured by BSFS rather than stool frequency correlates with whole gut transit time in both constipated and non-constipated children. Russo M. et al. J Pediatr 2012

37. NUOVE FORMULE NEI DISORDINI FUNZIONALI GASTROINTESTINALI Conclusioni Reflusso gastroesofageo funzionale: Latti ispessiti con o senza idrolisi parziale-spinta. Coliche: no studi controllati; se sintomi “molto” severi latti con idrolisi parziale o spinta Stipsi: no studi controllati; se sintomi persistenti latti senza olio di palma, con GOS/FOS; se sintomi “molto” severi latti con idrolisi parziale o spinta

38. Gura T. Science. 2014 Aug 15;345(6198):747-9.