Normal variation in stool frequency and consistency often leads to over-diagnosis of constipation especially in infants. Two recent studies from the Europe (12,984 healthy children, 1-42 months from UK [5] and 600 healthy infants from Netherlands [2]) have shown that the median stool frequency at 1 month of age was 3 (0-9) per day and it decreased significantly at 3 months of age to 2 (0-6) per day. Moreover, there was a significant difference in stool frequency between breastfed and formula-fed babies at 1 month of age [4 (0-9) vs. 1 (0-5) per day, respectively, P<0.01] but there was no difference at 3 months of age [2 (0-6) vs. 1 (0-5) per day] [5,6]. Another study from Turkey in 911 children aged 0 to 24 months has shown that the median defecation frequency at 1 month of age was 6 per day and by 4-6 months of age it became 1 per day. The most interesting observation of this study is that the stool frequency was <1 per day (once in 2-3 days but soft stool) in 39.3% babies in 2-6 months of age [7]. Hence, while considering constipation we should remember the normal variations of stool frequency and consistency in healthy infants and variations as per their feeding pattern (breast fed versus bottle fed).

Constipation is a common problem in children and an estimated prevalence of functional constipation is 3% worldwide [1,10,11]. Though we do not have any prevalence data from Asia, in a study from our center we reported 138 cases of constipation diagnosed over a period of six years and 85% of them were functional [2]. In next 8 years (2007 to 2014), we managed another set of 330 children with constipation and the proportion of functional constipation was 82% (270 of 330) [unpublished data]. Hence, constipation is not uncommon in the Indian subcontinent. It is commonly seen among toddlers and preschool children, and in 17% to 40% of cases, constipation starts in first year of life [12,13].

The common perception in South Asia is that functional constipation is uncommon as diet in South Asia is rich in fiber. In our study [2], we have shown that this perception is incorrect. Constipation is quite common in India and functional constipation is the commonest cause. Common causes of constipation in children are given in Box I. In fact 95% cases are due to functional and only 5% are due to some organic causes [14]. Among the organic causes, Hirschsprung disease is the most common and important cause [2].

 

Fig. 1 Pathogenesis of functional constipation.

Pathogenesis of functional constipation (Fig. 1)

The initiating event in functional constipation is a painful bowel movement which leads to voluntary withholding of stools by the child who wants to avoid unpleasant defecation [15]. Events that lead to initial painful defecation are change in routine like timing of defecation or diet, stressful events, inter-current illness, non-availability of toilets (travel etc.), child’s postponing defecation because he or she is too busy (morning school), and forceful toilet training (too early). All these events give rise to large, hard stool and passage of such stool leads to stretching of the pain sensitive anal canal, and that frightens the child. As a result of which the child fearfully determines to avoid defecation by all of means. Such children respond to the urge to defecate by contracting their external anal sphincter and gluteal muscles, in an attempt to withhold stool. Withholding of feces leads to prolonged fecal stasis in the rectum, with resultant absorption of fluids and harder stools. Successive retention of stools in rectum make them larger. As the cycle is repeated, successively greater amounts of larger and harder stools are built up in the rectum and passed with even greater pain accompanied by severe "stool with-holding maneuvers". Thus a vicious cycle sets in (Fig. 1). These children develop a "stool-withholding maneuver" or retentive posture which parents erroneously think it as an attempt to defecate. They feel that the child is trying hard (straining) in an attempt to pass stool when the child is actually trying his best to stop it. In response to the urge, they refuse to sit on the toilet, rather rise on their toes, hold their legs and buttocks stiffly and often rock back and forth, holding on to a furniture, scream, turn red until a bowel movement finally takes place. With time, such retentive behavior becomes an automatic reaction. They often perform this while hiding in a corner. Eventually, liquid stool from the proximal colon may percolate around hard retained stool and pass per rectum involuntarily (fecal incontinence). Sometimes this fecal incontinence is mistaken as diarrhea. In fact almost 30% children with functional constipation develop fecal incontinence [12]. Eventually, with more and more stasis, the rectum becomes dilated and redundant, and the sensitivity of the defecation reflex and the effectiveness of peristaltic contractions of rectal muscles decrease. This is the stage when it becomes more difficult to have a normal defecation due to fecal impaction.

A careful history and thorough physical examination (including digital rectal examination) are all that is required to diagnose functional constipation provided there are no "red flags" like fever, vomiting, bloody diarrhea, failure to thrive, anal stenosis, and tight empty rectum [16]. Abnormal physical findings, which help to distinguish organic causes of constipation from functional, are failure to thrive, lack of lumbo-sacral curve, sacral agenesis, flat buttock, anteriorly displaced anus, tight and empty rectum, gush of liquid stool and air on withdrawal of finger, absent anal wink and cremasteric reflex. Features which differentiate Hirschsprung disease from functional constipation are given in Table I. The most important features in the history, which help to distinguish Hirschsprung disease from functional consti-pation, are onset in first month of life and delayed passage of meconium beyond 48 hours and the most important examination finding is empty rectum on digital rectal examination. It has been shown that 99% healthy, term neonates and 50% babies with Hirschsprung disease pass meconium in first 48h of life [17,18]. In fact, in a classical case of functional constipation, no investigation is required to make the diagnosis. There is no need to do barium enema in all cases of constipation to rule out Hirschsprung disease. If the clinical suspicion of Hirschsprung disease is strong (based on history of delayed passage of meconium and empty rectum on digital rectal examination) then only one may consider getting barium enema done. However, to diagnose Hirschsprung disease, rectal biopsy is a must. The common mistake that leads to further confusion is delayed film (24 hours) showing retention of barium which is a common finding in functional constipation as well. The interpretation of barium enema should be on the basis of reversal of recto-sigmoid ratio (sigmoid becomes more dilated than rectum) and documentation of transition zone and not on mere presence of barium in rectum after 24 hours (Fig. 2).

TABLE I	Differences Between Functional Constipation and Hirschsprung Disease

Fig. 3 Suggested approach to functional constipation: modified from ESPGHAN recommendations.

Most children with functional constipation get benefited from a precise, well-organized treatment plan, which includes cleaning of fecal retention, prevention of further retention and promotion of regular bowel habits. The general approach includes the following steps: (a) determine whether fecal impaction is present, and treat the impaction if present, (b) initiate maintenance treatment with oral laxative, dietary modification, toilet training, and (c) close follow up and medication adjustment as necessary [16]. Suggested approach to constipation is given in Fig. 3.

Disimpaction

First step in the management of constipation is to decide whether the child has fecal impaction or not. This can be accomplished by abdominal examination (in half of the cases hard fecal mass or fecalith is palpable in the lower abdomen) [19], by digital rectal examination (rectum is usually loaded with hard stools), or rarely by abdominal X-ray. Routinely abdominal X-ray is not required to detect fecal impaction. However, if the child refuses rectal examination, if he/she is obese, or if there is a doubt about the diagnosis of constipation then only an abdominal X-ray is required to document excess fecal matter in the colon.

If there is fecal impaction (most of the children with functional constipation do have), then the first step in the management is disimpaction, means clearing or removal of retention from the rectum. This can be achieved by oral or by rectal route. Oral route is non-invasive, gives a sense of power to the child but compliance is a problem. Polyethylene glycol (PEG) lavage solution is given orally (1-1.5g/kg/day for 3-6 days) or by naso-gastric tube (25mL/kg/hour, reconstituted PEG solution) until clear fluid is excreted through anus. Adequate disimpaction means both output (stool) and input (lavage solution) should be of same color in case of naso-gastric tube disimpaction [16]. Successful disimpaction for home-based regimen (3-6 days) is defined as either empty or a small amount of soft stool on rectal examination and resolution of the left lower quadrant mass if it was there [20, 21].

To prevent re-accumulation after removing impaction maintenance therapy in the form of dietary modification, toilet training and laxatives needs to be started immediately after disimpaction or if there is no impaction, then as a first step.

Dietary modification: The diet of most children with functional constipation lacks fiber. Many of them are predominantly on milk with very little complementary food. The children with functional constipation should be encouraged to take more fluids, absorbable and non-absorbable carbohydrate as a method to soften stools. Non-absorbable carbohydrate (sorbitol) is found in some fruit juices like apple, pear and prune juices. A balanced diet that includes whole grains, fruits and vegetables is advised. The recommended daily fiber intake is age (in years) + 5 in g/day. In our practice, where most children are predominantly on milk diet, we counsel the parents to restrict milk so that the child starts eating solid foods. Though cow milk protein allergy (CMPA) was proposed as one the common causes of constipation [24], subsequent studies [16,25] and our experience did not substantiate that claim.

Toilet training: It should be imparted after 2 to 3 years of age. Too early and vigorous toilet training may be detrimental for the child. The child is encouraged to sit on the toilet for 5 to 10 minutes, 3 to 4 times a day immediately after major meals for initial months [26]. The gastro-colic reflex, which goes into effect shortly after a meal, should be used to advantage [27]. Children are encouraged to maintain a daily record (stool diary) of bowel movements, fecal soiling, pain or discomfort, consistency of stool and the laxative dose. This helps to monitor compliance and to make appropriate adjustment in the treatment program. Parents are instructed to follow a reward system. Children should be rewarded for not soiling and for regular sitting on the toilet. This acts as a positive reinforcement for the child.

Laxatives: Table II [28] presents the doses and side effects of various laxatives. It has been shown that lactulose, sorbitol, milk of magnesia (magnesium hydroxide), and mineral oil (castor oil), all are equally effective in children. Milk of magnesia and mineral oil are unpalatable and due to the risk of lipoid pneumonia mineral oil is contraindicated in infants. The commonly used laxative in children so far was lactulose, until the introduction of PEG. The study by Loening-Baucke [26] has shown that low volume (0.5 to 1g/kg/day) polyethylene glycol (PEG) without electrolytes is as effective as milk of magnesia in the long-term treatment of constipation in children. Low volume PEG has been compared with lactulose in the treatment of childhood functional constipation and a meta-analysis of five RCTs comprising of 519 children has shown that PEG was more effective than lactulose with equal tolerability and fewer side effects [29]. Side effects, especially bloating and pain are less with PEG. With long term use, lactulose loses its efficacy due to change in gut flora but PEG does not [30]. The dose of laxative should be adjusted to have one or two soft stools/day without any pain or soiling. Once this target is achieved, the same dose should be continued for at least 3 months to help the distended bowel to regain its function. Point to be remembered here is that laxative needs to be continued for several months and sometimes years at the right dose. Early and rapid withdrawal is the commonest cause for recurrence. Stimulant laxatives (senna, bisacodyl) are not used routinely and are contraindicated in infants. They may be used for a short course in refractory cases as a rescue therapy [16].

TABLE II  Laxatives–dosage and Side Effects (Modified from NASPGHAN Position Statement) [28]

A close and regular follow-up is a key to the success of treatment of functional constipation. Initial follow-up should be monthly till a regular bowel movement is achieved. After that it should be 3 monthly for 2 years and then yearly [26]. On each visit, by reviewing stool records and repeating abdominal and (if required) rectal examination, progress should be assessed. If necessary, dosage adjustment is to be made. Once a regular bowel habit is established, the laxative dosage is to be decreased gradually before stopping.

In a long-term follow up study (mean 6.9 ±2.7 years) on 90 children, who were <4 years at diagnosis, Loening-Baucke [31] showed that 63% had recovery but symptoms of chronic constipation persisted in one third of cases 3 to 12 years after initial evaluation and treatment. In another study, it has been shown that 50% of patients were off laxative at 1 year, another 20% at 2 years and the remaining 30% were on laxative for many years [14]. von Ginkel, et al. [32] in a long-term follow up (mean 5 years) study on 418 cases have also shown that 60% were successfully treated at one year but 30% of cases in the 16 years or older age group continued to have constipation. They found that age at onset of constipation (<4 years) and associated fecal incontinence were poor prognostic factors. In a large study on 300 children, Clayden [33] has shown that 22% required laxative for <6 months, 44% for <12 months and 56% for >12 months. By summarizing all these studies it can be said that half to two thirds of children with functional constipation had successful outcome with laxative therapy for 6 to 12 months but the remaining one thirds require long-term therapy and they may continue to have constipation as an adult. Recurrence of constipation after initial recovery is common (50% may have relapse within a year of stopping therapy) but they respond well to retreatment [12]. Poor prognostic factors are; early onset (<4 years), associated with fecal incontinence, and longer duration of symptoms (>6months) [16].

A case of constipation is labeled as refractory when there is no response to optimal conventional treatment for at least 3 months [16]. The prevalence of refractory constipation is said to be 20-30% [16, 34] but the prevalence is much higher in India at primary care pediatrician level due to lack of awareness about optimal conventional treatment. At primary care level, disimpaction is hardly practiced and as a result of which the response of laxative therapy is not optimal. The second important reason is early discontinuation of therapy which leads to refractoriness of constipation. The true refractory constipation is extremely uncommon in primary care set up. Even at tertiary care centers, refractory constipation is uncommon [2].

Fig. 4 (a) Colon transit time (CTT) study by radio-opaque markers showing slow transit constipation; 4(b) Functional outlet obstruction.

Besides organic causes of constipation, motility disorders (like slow transit constipation), disorders of stool expulsion like dyssynergic defecation, internal anal sphincter achalasia and sphincter dysfunction in children with Hirschsprung disease which persist after surgery are important causes of refractory constipation [34]. While approaching refractory constipation common organic causes (Fig.2) like Hirschsprung disease, hypothyroidism, celiac disease, hypercalcemia, spinal cord abnormalities should be ruled out first and then motility studies (like colon transit time [CTT], anorectal manometry with balloon expulsion test, colonic manometry) to be done to find out motility disorders [34, 35]. The simplest and the most informative of all these tests is colon transit time (CTT) study which can be done by radio-opaque markers and by radionuclide scintigraphy (NTS or nuclear transit studies) [34]. In radiographic CTT study, a capsule containing 20 radio-opaque markers (different shape in different days) are given daily for 3 days and plain x-ray abdomen is taken on day four and if required on day 7 (when all markers are retained on day 4). From X-ray, markers are counted in right colon, left colon and recto-sigmoid regions and the mean segmental time is calculated. Slow transit constipation is defined as retention of markers for 62 hours or more [36, 37]. As per the CTT study, constipation can be divided into three categories; (i) normal transit constipation, (ii) functional outlet obstruction or dyssynergic defecation (retention of markers in rectosigmoid region) and (iii) slow transit constipation (retained markers are distributed all over) (Fig. 4a and 4b). In a study of 225 children (135 pediatric constipation, 56 non-retentive fecal incontinence and 24 recurrent abdominal pain) Benninga, et al. [36,37] have shown that 56% of constipated children had normal CTT, 24% had functional outlet obstruction and just 20% had slow transit constipation. In another study on 85 children with functional constipation with rectal fecal impaction by Bekkali, et al. [20] have shown that 93% had delayed CTT and as expected majority (83.5%) of them had delayed rectosigmoid segment CTT. As the basic pathophysiology of functional constipation is voluntary withholding of feces, it is expected that most children with functional constipation will have either functional outlet obstruction/dyssynergic defecation or normal transit constipation.

In normal defecation there is synchronized relaxation of puborectalis muscle (makes ano-rectal angle straight) and external anal sphincter along with generation of propulsive force through contraction of colon and increased in intra-abdominal pressure, which propels stools out of rectum. In dyssynergic defecation there is paradoxical contraction or failure of relaxation of external anal sphincter and puborectalis muscle with or without increased rectal pressure (propulsive force) [38]. These features are detected on anorectal manometry. Therapeutic option of refractory constipation due to dyssynergic defecation is biofeedback (to restore the normal pattern of defecation) and for slow transit constipation is to enhance colonic transit with newer drugs like colon-specific prokinetics like prucalopride (5HT4 agonist) [39] and intestinal secretagogue (lubiprostone) [40], which increases intestinal chloride secretion and accelerates small intestinal and colonic transit. Antegrade continence enema helps in refractory slow transit constipation cases [41].

Most reports of slow transit constipation in children are from Australia and the clinical presentations of this subset of patients are different from functional constipation (Box 2). In a study of 100 children with slow transit constipation, Hutson, et al. [42,43] have shown that a history of delayed passage of meconium was seen in 30% of cases, onset of severe constipation in infancy in 63% and half (52%) of those presenting after 2 years of age had history of soiling (fecal incontinence) and failure of toilet training, and the majority (90%) had no hard fecal mass in rectosigmoid area. The management of slow transit constipation is quite difficult as they do not respond to conventional laxative therapy and the main concern is soiling. Fiber therapy is contraindicated (as the motility is slow), the newer drugs like colon specific prokinetics like prucalopride [39] and chloride channel activator (lubiprostone) [40] are still investigational drugs in children. The only effective therapy for this subset of patients is antegrade continence enema. Here, appendix is used as conduit to insert cecostomy button (Chait trapdoor button) to give enema [44,45]. It has minimal scar and just a button at right iliac fossa which is used in the morning to give antegrade enema and the whole day patient remains dry (no soiling). In a recent study on 203 cases (median age 10 years, follow up 5.5 years, 62% due to refractory chronic idiopathic constipation) of this modality, Randall, et al. [41] showed good result in 93%, soiling prevented in 75% and symptoms resolved (no longer on antegrade continence enema) in 26% (81% of them were chronic idiopathic constipation).

Colonic manometry plays an important role in guiding both medical and surgical treatment in refractory constipation. In fact it has been shown that the success of antegrade continence enema procedure depends on colonic manometry results [46]. If there is generalized colonic dysmotility (absence of high-amplitude propagating contraction [HAPC] in the entire colon) then there is no point in putting cecostomy catheter. Similarly, colonic manometry results can dictate the type of surgery following colonic diversion; subtotal colectomy if small bowel motility is normal but whole colonic motility is abnormal, left hemicolectomy if only left colonic motility is abnormal and reanastomosis if colonic motility is normal [47].

A relatively less common but important cause of refractory constipation is internal anal sphincter achalasia. In a study of 332 patients with severe constipation, De Caluwe, et al. [48] have reported this as a cause in just 4.5% of cases. This subset of patients usually present with severe constipation (99.7%) which often associated with fecal incontinence (46%) and are diagnosed by absence of anorectal inhibitory reflex (ARIR) on anorectal manometry along with presence of ganglion cell on rectal biopsy [49]. The treatment options for internal anal sphincter achalasia are posterior anal sphincter myectomy and intrasphincteric botulinum toxin injection. In a recent meta-analysis, it has been shown that former is better [49].

Constipation is quite common in Asia, and most often of functional origin. Detailed history and proper physical examination, including digital rectal examination, can easily differentiate functional from organic constipation. There is no need to do any investigation before starting treatment in functional constipation. Disimpaction with oral polyethylene glycol is the main step in the management and skipping this step leads to refractoriness of constipation. Polyethylene glycol is shown to be superior to lactulose in the management of constipation. In most cases, prolonged (months to years) laxative therapy is required and early withdrawal leads to recurrence. Radiological colon transit time study plays an important role in the management of refractory constipation. Slow transit constipation is altogether a different entity and antegrade continence enema helps in this subset of patients.

Funding: None; Competing interests: None stated.

1. Van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review. Am J Gastroenterol 2006;101:2401-9.

2. Khanna V, Poddar U, Yachha SK. Constipation in Indian children: need for knowledge not the knife. Indian Pediatr. 2010;47:1025-30.

3. Rajindrajith S, Devanaryana NM, Adhikari C, Pannala W, Benninga MA. Constipation in children: an epidemiological study in Sri Lanka using Rome III criteria. Arch Dis Child. 2012;97:43-5.

4. Aziz S, Fakih HAM, Di Lorenzo C. Bowel habits and toilet training in rural and urban dwelling children in a developing country. J Pediatr. 2011;158:784-8.

5. Steer CD, Emond AM, Golding J, Sandhu B. The variation in stool patterns from 1 to 42 months: a population bases observational study. Arch Dis Child. 2009;94:231-4.

6. den Hertog J, van Leengoed E, Kolk F, van den Broek L, Kramer E, Bakker E, et al. The defecation pattern of healthy term infants up to the age of 3 months. Arch Dis Child Fetal Neonatal Ed. 2012;97:F465-F470.

7. Tunc VT, Camurdan AD, Ilhan MN, Sahin F, Beyazova U. Factors associated with defecation patterns in 0 to 24 months old children. Eur J Pediatr. 2008;167:1357-62.

8. Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: neonate/ toddler. Gastroenterology. 2006;130:1519-26.

9. Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A. Childhood functional gastrointestinal disorders: child/adolescents. Gastroenterol. 2006; 130:1527-37.

10. Levine MD. Children with encopresis: a descriptive analysis. Pediatrics. 1975;56:412-6.

11. Taitz LS, Water JKH, Urwin OM, Molnar D. Factors associated with outcome in management of defecation disorders. Arch Dis Child. 1986;61:472-7.

12. Amendola S, De-Angelis P, Dall’Oglio L, Di Abriola GF, Di Lorenzo M. Combined approach to functional constipation in children. J Pediatr Surg. 2003;38:819-23.

13. Loening-Baucke V. Constipation in early childhood: Patient characteristics, treatment and long-term follow up. Gut. 1993;34:1400-4.

14. Loening-Baucke V. Chronic constipation in children. Gastroenterol. 1993;105:1557-64.

15. Partin JC, Hamill SK, Fischel JE, Partin JS. Painful defecation and fecal soiling in children. Pediatrics. 1992;89:1007-9.

16. Tabbers MM, Di Lorenzo C, Berger MY, Faure C, Langendam MW, Nurko S, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr. 2014;58:258-74.

17. Metaj M, Laroia N, Lawrence RA, Ryan RM. Comparison of breast- and formula-fed normal new born in time to first stool and urine. J Perinatol. 2003;23 624-8.

18. Jung PM. Hirschsprung’s disease: one surgeon’s experience in one institution. J Pediatr Surg. 1995;30:646-51.

19. Loening-Baucke V. Factors determining outcome in children with chronic constipation and fecal soiling. Gut. 1989;30 999-1006.

20. Bekkali N, van den Berg MM, Dijkgraaf MGW, van Wijk MP, Bongers MEJ, Liem D, et al. Rectal fecal impaction treatment in childhood constipation: enemas versus high doses oral PEG. Pediatric. 2009;124:e1108-e15.

21. Youssef NN, Peters JM, Henderson W, Shultz-Peters S, Lockhart DK, Di Lorenzo C. Dose response of PEG 3350 for the treatment of childhood fecal impaction. J Pediatr. 2002;141: 410-4.

22. Guest JF, Candy DC, Clegg JP, Edwards D, Helter MT, Dale AK, et al. Clinical and economical impact of using macrogol 3350 plus electrolytes in an outpatient setting compared to enemas and suppositories and manual evacuation to treat pediatric fecal impaction based on actual clinical practice in England and Wales. Curr Med Res Opin. 2007;23:2213-25.

23. Freedman SB, Thull-Freedman J, Rumantir M, Eltorki M, Schuh S. Pediatric constipation in the emergency department: evaluation, treatment and outcomes. J Pediatr Gastroenterol Nutr. 2014;59:327-33.

24. Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, et al. Intolerance of cow’s milk and chronic constipation in children. N Engl J Med. 1998;339:1100-4.

25. Simeone D, Miele E, Boccia G, Marino A, Troncone R, Staiano A. Prevalence of atopy in children with chronic constipation. Arch Dis Child. 2008;93:1044-7.

26. Loening-Baucke V. Polyethylene glycol without electrolytes for children with constipation and encopresis. J Pediatr Gastroenterol Nutr. 2002;34:372-7.

27. Lowery SP, Srour JW, Whitehead WE, Schuster MM. Habit training as treatment of encopresis secondary to chronic constipation. J Pediatr Gastroenterol Nutr. 1985;4:397-401.

28. Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo C, Ector W, et al. Clinical practice guideline: Evaluation and treatment of constipation in infants and children: recommendations of the North American Society of Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:e1-e13.

29. Candy D, Belsey J. Macrogol (polyethylene glycol) laxatives in children with functional constipation and fecal impaction: a systematic review. Arch Dis Child. 2009;94:156-60.

30. Candelli M, Nista EC, Zocco MA, Gasbarrini A. Idiopathic chronic constipation; pathophysiology, diagnosis and treatment. Hepatogastroenterol. 2001;48:1050-7.

31. Loening-Baucke V. Constipation in early childhood: patient characteristics, treatment and long-term follow-up. Gut. 1993;34:1400-4.

32. van Ginkel R, Reitsma JB, Buller HA, van Wijk MP, Taminiau JA, Benninga MA. Childhood constipation: longitudinal follow-up beyond puberty. Gastroenterology 2003;125:357-63.

33. Clayden GS. Management of chronic constipation. Arch Dis Child. 1992;67:340-4.

34. Southwell BR, King SK, Hutson JM. Chronic constipation in children: organic disorders are a major cause. J Pediatr Child Health. 2005;41:1-15.

35. Kwshtgar A, Ward HC, Clayden GS. Diagnosis and management of children with intractable constipation. Semin Pediatr Surg. 2004;13:300-9.

36. Benninga MA, Voskuijl WP, Akkerhuis GW, Taminiau JA, Buller HA. Colonic transit times and behavior profiles in children with defecation disorders. Arch Dis Child. 2004;89: 13-6.

37. Benninga MA, Buller HA, Staalman CR, Gubler FM, Bossuyt PM, van der Plas RN, et al. Defecation disorders in children, colonic transit times versus the Barr-score. Eur J Pediatr. 1995;154:277-84.

38. Rao SS. Dyssynergic defecation and biofeedback therapy. Gastroenterol Clin North Am. 2008;37:569-86.

39. Winter HS, Di Lorenzo C, Benninga MA, Gilger MA, Kearns GL, Hyman PE, et al. Oral prucalopride in children with functional constipation. J Pediatr Gastroenterol Nutr. 2013;57:197-203.

40. Hyman PE, Di Lorenzo C, Prestridge LL, Youssef NN, Ueno R. Lubiprostone for the treatment of functional constipation in children. J Pediatr Gastroenterol Nutr. 2014;58:283-91.

41. Randall J, Coyne P, Jaffray B. Follow up of children undergoing antegrade continent enema: experience of over two hundred cases. J Pediatr Surg. 2014;49:1405-8.

42. Hutson JM, McNamara J, Gibb S, Shin YM. Slow transit constipation in children. J Pediatr Child Health. 2001;37:426-30.

43. Wheatley JM, Hutson JM, Chow CW, Oliver M, Hurley MR. Slow transit constipation in childhood. J Pediatr Surg. 1999;34:829-33.

44. Malone PS, Ransley PG, Kiely EM. Preliminary report: the antegrade continence enema. Lancet. 1990;336:1217-8.

45. Chait PG, Shandling B, Richards HF. The cecostomy button. J Pediatr Surg. 1997;32;849-51.

46. Van den Berg MM, Hogan M, Caniano DA, Di Lorenzo C, Benninga MA, Mousa HM. Colonic manometry as predictor of cecostomy success in children with defecation disorders. J Pediatr Surg. 2006;41:730-6.

47. Villarreal J, Sood M, Zangen T, Flores A, Michel R, Reddy N, et al. Colonic diversion for intractable constipation in children: colonic manometry helps guide clinical decisions. J Pediatr Gastroenterol Nutr. 2001;33:588-91.

48. De Caluwe D, Yoneda A, Akl U, Puri P. Internal anal sphincter achalasia: outcome after internal sphincter myectomy. J Pediatr Surg. 2001;36:736-8.