INTRODUCTION — Growth failure is a common extraintestinal manifestation of inflammatory bowel disease (IBD) in children, particularly among those with Crohn disease [1]. The causes of growth failure are complex and include the inflammatory process itself, undernutrition, pubertal delay, and, in some cases, effects of glucocorticoids. Pubertal delay is also associated with undernutrition and inflammation and has secondary effects on growth.
The pathogenesis, evaluation, and treatment of growth failure or poor weight gain in children and adolescents with IBD will be reviewed here. The assessment and management of micronutrient deficiencies in these patients are discussed separately. (See "Vitamin and mineral deficiencies in inflammatory bowel disease".)
DEFINITIONS
●Growth failure – A variety of anthropometric measures are used to monitor growth in children with IBD. A clinically practical definition of acute growth failure is height velocity <4 cm/year (or <10th percentile for age on standard height velocity charts). Chronic growth failure is reflected by decreasing height percentiles over time and/or predicted height substantially lower than genetic potential. Specific parameters to define growth failure are outlined in the Paris Classification for pediatric IBD; one such parameter is difference between observed height Z-score and pre-illness height Z-score >1.0 [2].
●Pubertal delay – Delayed puberty is defined as pubertal onset >2 to 3 standard deviations above the mean age for the relevant population. In the United States, this corresponds to an upper limit of approximately 12 to 13 years for females and approximately 13 to 14 years for males. Stalled puberty refers to abnormally slow pubertal progression after pubertal onset, eg, no significant pubertal progression for two or more years.
These thresholds are not absolute, and children may warrant additional monitoring and attention to nutrition and IBD management before the above thresholds are reached. (See 'Routine monitoring of growth and puberty' below.)
PATHOGENESIS OF GROWTH FAILURE — A combination of factors contribute to the pathogenesis of growth failure in children with IBD. Different clinical variables are associated with growth in male versus female children with Crohn disease. For example, poorer growth was seen in females with arthralgia at symptom onset and in males with mouth sores [3].
●Inflammation – Inflammation appears to be an important mediator of growth failure in children with IBD [4,5]. This notion is supported by observed improvements in linear growth that occur after a variety of treatments that reduce inflammation in IBD, including exclusive enteral nutrition [6,7], infliximab [8-12], adalimumab [13-15], or surgical resection [16]. The improvement in linear growth can be independent of weight gain or reductions in corticosteroid dose [1,10].
Inflammation probably inhibits linear growth through proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6. TNF-alpha appears to affect growth primarily by suppressing appetite [17], whereas IL-6 exerts direct effects on growth by inhibiting insulin-like growth factor 1 (IGF-1), which modulates the physiologic effects of growth hormone in a pattern suggestive of growth hormone resistance [4,17-19], and stimulating lipolysis [20]. Malnutrition also contributes to this suppression of the growth hormone-IGF-1 axis [17]. Interactions with genetic factors also have been suggested [21-25].
●Malnutrition – Both malnutrition and systemic inflammation reduce circulating IGF-1, a major mediator of growth failure in IBD [26]. Severe acute malnutrition is uncommon but occasionally occurs in children with Crohn disease. Several mechanisms contribute to malnutrition:
•Insufficient nutrient intake – This is the most important contributor to malnutrition in IBD. Children with IBD often ingest less dietary energy compared with healthy children [27]. Nutrient intake may be particularly low during acute exacerbations of IBD. In one report, children with active Crohn disease were found to consume less energy than did those in remission [28].
Several mechanisms contribute to decreased intake, including anorexia (perhaps mediated by TNF-alpha, hypothalamic serotonin, and IL-1), the learned association of food with abdominal pain or diarrhea, and early satiety (possibly related to decreased gastric emptying [29-32]).
Increased rates of disordered eating have been found among adolescents with IBD [33]. Further, a study of adult patients with IBD found that 17 percent were at risk for avoidant restrictive feeding disorder (ARFID), based on a screening questionnaire. Risk factors included active symptoms and inflammation, but 74 percent avoided foods even when in remission [34]. Those at risk for ARFID were more likely to be at risk for malnutrition. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis", section on 'Avoidant/restrictive food intake disorder'.)
In some cases, altered taste (eg, due to concomitant zinc deficiency [35] or medications, such as metronidazole) may decrease food intake [36-39]. In addition, some patients with IBD follow a restricted diet that can reduce caloric intake, although such dietary restrictions are unnecessary for most patients, except when prescribed as part of a specific regimen (eg, a specific exclusion diet). (See "Overview of the management of Crohn disease in children and adolescents", section on 'Other dietary changes'.)
Inadequate protein intake (or fecal protein losses) may affect muscle mass in growing children. Studies of children with Crohn disease demonstrated that increased protein intake resulted in increased nitrogen retention, increased amino acid incorporation into body protein stores, and decreased amino acid loss via oxidation [40,41]. Low protein intake is less likely to cause reduced muscle mass in adults, unless the deficiency is severe and prolonged (starvation).
•Maldigestion – Maldigestion (impaired processing of nutrients within the lumen of the gastrointestinal tract) is uncommon but occurs in some patients with complicated IBD. In particular, fat maldigestion (and subsequent malabsorption) can occur when there are reduced functional bile acids in the lumen, which can be caused by bacterial overgrowth, disease or resection of the terminal ileum, or use of cholestyramine. Maldigestion also can occur among patients with Crohn disease who have extensive mucosal disease, chronic liver dysfunction (eg, sclerosing cholangitis), extensive small bowel resections, or enteroenteric fistulas. In patients with extensive resections or enteroenteric fistulas, ingested nutrients may have insufficient exposure to digestive secretions and enzymes, leading to maldigestion. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption", section on 'Causes of fat malabsorption'.)
•Fecal nutrient losses
-Carbohydrates – Whether there is a greater incidence of lactose intolerance among children with IBD has not been established. Some studies suggest that the prevalence of lactose malabsorption in individuals with Crohn disease may be somewhat higher than in the general population due to small bowel inflammation and enterocyte damage or due to bacterial overgrowth [42]. However, more recent data suggest that there is no difference when compared with controls [42-45]. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management".)
If lactose intolerance is present, it can contribute to gastrointestinal symptoms but rarely causes clinically important energy loss because a portion of malabsorbed carbohydrates is fermented then usually reabsorbed in the colon (unless concomitant antibiotics or colonic disease interfere with this process).
-Fats – Historically, fat malabsorption was seen in approximately 30 percent of patients with Crohn disease [46-48]. The cause is multifactorial, including maldigestion (discussed above), small bowel inflammation, or decreased bowel length due to surgery. With modern treatment modalities that prevent or reverse these processes, clinically significant fat malabsorption is probably uncommon. When present, fat malabsorption substantially reduces energy absorption and contributes to growth failure.
-Proteins – Capillary leak within inflamed tissue may result in protein loss. This is the main cause of reduced serum albumin concentrations that are commonly seen in active Crohn disease and, to a lesser extent, in ulcerative colitis. Fecal alpha-1 antitrypsin serves as a measure of intestinal protein loss and has been shown to reflect disease activity in IBD [49,50]. (See "Protein-losing gastroenteropathy".)
•Increased energy expenditure – Differences in resting energy expenditure (REE) do not contribute significantly to malnutrition in pediatric IBD. REE in well-nourished children with Crohn disease is not different from values of healthy children [36]. Furthermore, REE in children with Crohn disease does not differ between active or inactive disease, based on clinical activity index scores or inflammatory markers (eg, lactoferrin, erythrocyte sedimentation rate, C-reactive protein) [51,52]. In malnourished children with IBD, older studies reported an apparent increase in REE, but this was likely a spurious finding related to efforts to correct for differences in body composition (ie, expressing REE per unit of lean body mass) [51,53,54].
●Hypogonadism – Hypogonadism and pubertal delay are common in children with active IBD and contribute to their decreased linear growth and delayed accretion of lean body mass compared with healthy children of the same age [17]. (See 'Clinical manifestations' below and "Approach to the patient with delayed puberty".)
Because children with pubertal delay usually have delayed bone age, they may experience some catch-up growth after the onset of puberty, particularly if they have adequate nutrition and well-controlled disease. By contrast, patients with prolonged inflammatory disease, malnutrition, or corticosteroid therapy during puberty may not experience full catch-up growth before the epiphyses close, resulting in compromised adult height [55]. (See 'Impaired growth' below.)
Hypogonadism is probably caused by both inflammatory processes and malnutrition [56]. Proinflammatory cytokines directly reduce gonadal sex steroid production and perhaps also androgen and estrogen receptor expression in peripheral tissues [4,57,58]. In addition, healthy body weight is an important prerequisite for the onset of puberty. Leptin levels, which are proportionate to body fat, must be sufficient for maturation of the gonadotropin-releasing hormone axis. (See "Normal puberty", section on 'Body fat and leptin'.)
●Glucocorticoid effects – Glucocorticoids may contribute to growth failure, particularly when used during puberty [59,60]. Glucocorticoids interfere with endogenous growth hormone secretion and action and disrupt metabolic processes essential for normal growth, including bone formation, nitrogen retention, and collagen formation [17]. (See "Causes of short stature", section on 'Glucocorticoid therapy'.)
CLINICAL MANIFESTATIONS
Impaired growth
●Impaired weight gain – IBD is associated with impaired weight gain, which is often present at diagnosis. As an example, in a series of children with newly diagnosed Crohn disease, weight loss was reported in 58 percent and weight was <10th percentile in 32 percent and <3rd percentile in 27 percent [61]. Among those with ulcerative colitis, weight loss was reported in 31 percent and weight was <10th percentile in 15 percent and <3rd percentile in 9 percent. Similarly, in a large study of North American children with newly diagnosed IBD, low body mass index (BMI; <5th percentile) was found in 22 to 24 percent of children with Crohn disease and 7 to 9 percent of those with ulcerative colitis [62]. However, 10 percent of children with Crohn disease and 20 to 30 percent of those with ulcerative colitis had an elevated BMI at diagnosis, reflecting population trends in childhood obesity.
●Reduced muscle mass – Children with Crohn disease typically have lower lean body mass than height-matched unaffected individuals, particularly in the active phase of disease. In a systematic review including 1479 children with IBD, 93.6 percent of patients with Crohn disease and 47.7 percent of those with ulcerative colitis showed deficits in lean mass when compared with healthy controls [60,63,64]. Patients who have lost between 5 and 10 percent of their lean body mass usually have no clinical sequelae. However, loss of lean body mass beyond this threshold is associated with increased morbidity. Children are particularly susceptible to these effects.
The primary mediators of this effect are inflammation (excessive catabolism, which accelerates protein breakdown), decreased physical activity, corticosteroid treatment [65-67], and, possibly, inadequate protein intake. (See 'Pathogenesis of growth failure' above.)
●Linear growth delay – Linear growth is easily disrupted by inflammation and malnutrition, and growth failure is common in children with Crohn disease:
•Short stature at diagnosis – In population-based studies of children with Crohn disease, 6 to 13 percent present with short stature (height <3rd percentile or Z-score <-2) [5,22,61,68]. In a large multicenter Canadian study of children with Crohn disease, each month of diagnostic delay was associated with progressive decreases in height-for-age Z-score [69]. Among children with ulcerative colitis, approximately 3 percent present with short stature, which is similar to the general population [1,22,61,70].
•Height velocity – Height velocity, determined by serial measures of height, is a particularly sensitive measure of growth failure [71]. Reduced height velocity is present at diagnosis in 60 to 90 percent of children with Crohn disease, and marked growth delays occur in 20 to 30 percent at some time during their illness [22,70,72,73]. Height differences are more pronounced in males [74]. Approximately 5 percent of children presenting with Crohn disease have growth failure as their sole presenting complaint [75], and up to 40 percent have significantly delayed bone age [76,77]. For children with ulcerative colitis, decreased height velocity is present at diagnosis in approximately 10 to 25 percent [1,22,61,70]. (See 'Routine monitoring of growth and puberty' below.)
•Response to treatment – Whether growth failure improves after diagnosis depends upon the degree/extent of disease involvement, the child's stage of skeletal development (eg, bone age or stage of puberty), and timing and type of treatment. The association between timing of disease onset and growth effects are complex: On one hand, early onset of disease that attenuates the pubertal growth spurt is more likely to have effects on growth compared with later disease onset [78]. On the other hand, initiation of effective treatment before epiphyseal closure can permit catch-up growth.
Treatment with enteral nutrition [27,79,80] or biologic agents [9,13,81] is particularly effective in improving linear growth. The mechanisms for these effects may include improvements in nutrition, reduction in inflammation, and avoidance of or reduction in glucocorticoid use. By contrast, in older studies of children with Crohn disease, in which treatment tended to rely on glucocorticoids and immunomodulators, growth failure often persisted [22,68,70]. (See 'Pathogenesis of growth failure' above and 'With active IBD' below.)
•Adult stature – Because of persistent disruptions of linear growth during childhood, some patients with Crohn disease have reduced adult stature. A study of young adults diagnosed with Crohn disease prior to age 16 calculated a height deficit of 2.4 cm compared with estimated target heights [82]. For almost 20 percent of the subjects, the height deficit was more than 8 cm. In more recent studies, in which treatment often included enteral nutrition or biologic agents, short stature was reported in approximately 6 percent of patients at maximal follow-up and approximately 20 to 30 percent of patients did not reach their target height [5,22,83]. The effect of disease on adult height is somewhat mitigated because they tend to have delayed bone age and thus often continue to grow beyond the time of expected growth plate closure. In one study, 80 percent of pediatric patients with IBD demonstrated continued growth of 1.3 to 1.6 cm beyond the time of expected growth plate closure [84].
Pubertal delay — Pubertal delay is common and depends on the age of onset of IBD. In one series of 11 females with early-onset Crohn disease, 75 percent had menarche at 16 years of age or later [85]. Pubertal delay was much less common in children with ulcerative colitis. Other series report average delays in puberty onset of approximately 1.5 years for females and 0.8 years for males [86,87].
Pubertal delay can contribute to growth failure, psychosocial stress, and reduced bone mineral density. However, it is also associated with delayed epiphyseal closure, which may permit catch-up growth in some cases. Interventions to treat the underlying disease activity and improve nutrition are the first-line therapies and are generally successful. For selected patients, adjunctive treatment with sex steroids may be appropriate. (See 'Management of growth failure and pubertal delay' below and 'Other interventions' below.)
Pubertal delay in IBD is mediated by both malnutrition and inflammation and appears to involve both central (hypogonadotropic) and peripheral hypogonadism [17]. (See 'Pathogenesis of growth failure' above.)
Other comorbidities
●Bone disease – Children and adolescents with IBD tend to have reduced bone mineral density [88,89]. This is more common among those with Crohn disease than those with ulcerative colitis and may be present at diagnosis [90,91]. Bone disease (osteoporosis and/or osteomalacia) is a common problem in adults with IBD, and the rate does not differ among patients with Crohn disease compared with those with ulcerative colitis [92]. Risk factors for bone disease include corticosteroid use, disease activity, pubertal delay, and, possibly, deficiencies of calcium and vitamins D and K [93-96]. (See "Metabolic bone disease in inflammatory bowel disease".)
It is unclear whether modest decreases in bone density predict fracture risk [96], and limited information is available to guide management. Nonetheless, because of the high frequency of bone disease in adult patients with IBD and its effects on quality of life, we recommend close attention to bone health throughout life. Prevention, monitoring, and treatment of bone disease in children and adolescents with IBD are discussed in a separate topic review. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density'.)
●Postoperative morbidity – Malnutrition is a risk factor for complications after surgery for IBD. As examples, among children requiring first-stage surgical therapy for ulcerative colitis, low serum albumin and preoperative corticosteroid use were predictors for postoperative infection, although preoperative BMI was not [97]. Similarly, a study in adults undergoing surgery for Crohn disease found that poor nutritional status was a risk factor for intraabdominal septic complications [98].
●Psychosocial stress – Children with IBD are at increased risk for anxiety and depression, with a prevalence of approximately 22 percent [99]. The causes are multifactorial and often relate to disease activity, but short stature, pubertal delay, and associated body image dissatisfaction may also be contributors in some cases. Screening for psychosocial stress is recommended in children with IBD [100]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Psychological screening and support'.)
EVALUATION — Routine monitoring of growth and puberty is essential for the care of children with IBD. Prompt recognition of impaired growth allows for intervention to optimize nutrition, suppress inflammation, and restore healthy growth and pubertal development.
Routine monitoring of growth and puberty — All children with IBD should have regular measurements of body weight, height, and pubertal status (algorithm 1) [1,71]. In our practice, we perform these measurements at least every four months for patients with quiescent disease and more frequently for those with active disease or evidence of growth failure (table 1). Reduced linear growth is often first noted by a decreasing trend in height percentiles on a standard height-for-age chart.
The child's growth and puberty are then assessed with the following derived measures:
●Height velocity – Height velocity measurements are the most sensitive parameter for detection of growth abnormalities during IBD in children [71,73]. Height velocity can be calculated from two or more serial measurements of height, ideally taken three to six months apart and expressed as growth in cm/year. Any child older than two years whose height velocity is less than 4 cm/year probably has growth failure because at least 95 percent of healthy children grow faster than 4 cm/year [101]. During puberty, peak height velocity is 6 to 12 cm/year in boys and 5 to 10 cm/year in girls. (See "Diagnostic approach to children and adolescents with short stature", section on 'Is the child's height velocity impaired?'.)
To determine if a child's height velocity is appropriate for age, calculate the height velocity (in cm/year) and plot the result on a standard curve (figure 1A-B). Height velocity below the 10th percentile warrants additional assessment of nutrition and IBD management (see 'Additional evaluation for children with growth failure' below). A child's height and height velocity should also be interpreted in the context of their genetic potential, which is usually estimated based on the midparental height. (See "Diagnostic approach to children and adolescents with short stature", section on 'Prediction of adult height'.)
●Body mass index (BMI) – Determine the age-specific percentiles for BMI by plotting on a standard chart (figure 2A-B) or by using a calculator for males (calculator 1) or for females (calculator 2). For children with progressive decreases in BMI percentiles or a BMI below the 10th percentile for age, we perform further evaluation of nutrition and IBD management.
●Pubertal timing and progression
•Sexual maturity rating – At each visit, determine the patient's sexual maturity rating, also known as Tanner staging. In females, the earliest signs of pubertal development in females are the appearance of breast buds (picture 1A-B). In males, the earliest sign is a testicular volume of greater than or equal to 4 mL (picture 2), corresponding to approximately 2.0 to 3.1 cm in testicular length.
Other key milestones are the pubertal growth spurt (normally at approximately 10 to 13 years in females and 12 to 15 years in males) and menarche in females. Growth potential is limited after menarche. (See "Normal puberty".)
•Pubertal progression – Using serial measurements or reported history, determine if puberty is delayed or stalled (see "Approach to the patient with delayed puberty"):
-Delayed puberty is defined as the absence of pubertal onset by an age 2 to 3 standard deviations above the mean age of pubertal onset for the relevant population. In the United States, this corresponds to an upper limit of approximately 12 to 13 years for females and approximately 13 to 14 years for males.
-Stalled puberty refers to abnormally slow pubertal progression after pubertal onset, eg, no significant pubertal progression for two or more years.
Children with pubertal delay may warrant additional attention even before the above thresholds are reached. This may include optimizing nutrition and IBD management, avoiding glucocorticoid therapy, and close monitoring of puberty (eg, through referral to an endocrine or adolescent medicine specialist). (See 'Management of growth failure and pubertal delay' below.)
Additional evaluation for children with growth failure — More detailed evaluation is warranted for children with delayed growth (eg, height velocity or BMI <10th percentile for age) or delayed puberty, including the following measures:
●Bone age determination – For children with growth failure, radiographic determination of bone age is a valuable component of the evaluation because it helps to determine the severity of the growth deficit as well as residual growth potential. Results are abnormal in up to 40 percent of children with IBD [76]. (See "Diagnostic approach to children and adolescents with short stature", section on 'Bone age determination'.)
●Nutritional assessment – In our practice, we perform a structured assessment of dietary intake in children who are not gaining weight appropriately and if the mechanism is unclear. For these children, the assessment can help determine whether the problem is related to inadequate caloric intake versus malabsorption. For other children, we find that formal assessments rarely contribute to clinical decision-making because poor weight gain in IBD is generally mediated by reduced appetite and thus does not readily respond to dietary modification. Despite this limitation, some experts perform periodic structured dietary assessment (eg, twice a year in younger patients and once a year in adolescents), as suggested in a European guideline [102].
When a structured dietary assessment is undertaken, it generally is based on a dietary recall or log for a three- to five-day period, with calculation of total calories, protein, and micronutrients consumed. These estimates are then compared with recommended nutrient intakes for the child's age group, adjusted for physical activity level and catch-up growth. (See "Dietary history and recommended dietary intake in children".)
●Micronutrient deficiencies – Laboratory evaluation for micronutrient deficiencies is appropriate at the initial diagnosis of IBD and also for children with growth failure. The selection of tests depends upon the patient's overall nutritional status and disease activity and location, as outlined in the table (table 2). (See "Vitamin and mineral deficiencies in inflammatory bowel disease".)
●Bone density – There are no widely accepted standards for monitoring bone health in children and adolescents with IBD, and practice varies regarding routine monitoring. However, we suggest obtaining baseline densitometry (dual-energy x-ray absorptiometry [DXA]) in patients with risk factors for bone disease, including those with growth failure, secondary or primary amenorrhea, pubertal delay, refractory IBD, prolonged use of glucocorticoids, or a history of clinically significant fractures. Monitoring and management of bone mineral density in this population are discussed separately. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density'.)
●Body composition – BMI measurement alone is usually a sufficient index of body composition for clinical decision-making. While BMI does not directly measure body composition, it is correlated with both adiposity and lean body mass.
Direct measures of body composition are generally not necessary or helpful for clinical practice. These include triceps skinfold thickness measurements (reflecting body fat) and midarm cross-sectional area (reflecting lean body mass). DXA provides an accurate and direct measurement of body composition, but its main clinical use in children with IBD is to measure bone density [71]. (See "Measurement of body composition in children".)
PREVENTION — All individuals with IBD should be given dietary advice to encourage a balanced diet with adequate calories to optimize growth [71]. For patients with active disease or malabsorption, energy intake goals will often be higher than for the general population.
To optimize energy intake, we avoid dietary restrictions for most patients. There is no good evidence that dietary restrictions are beneficial, except as part of carefully supervised nutritional therapy for IBD (eg, exclusive enteral nutrition) or when needed to address specific problems (eg, limiting dairy products in patients with lactose intolerance or limiting fiber in patients with intestinal strictures) [71]. A notable exception is certain specific carbohydrate diets, which show some promise when used with close clinical guidance and, sometimes, in conjunction with partial enteral nutrition. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Other dietary changes'.)
For all patients, we minimize the use of glucocorticoids because of their adverse effects on growth and bone health [1]. These adverse effects of glucocorticoids must be balanced against their potential therapeutic value.
MANAGEMENT OF GROWTH FAILURE AND PUBERTAL DELAY — The goals of treatment include correction of malnutrition and normalization of linear growth and pubertal development [102]. This requires both optimizing nutrition and effectively treating the underlying inflammatory disease process. The intensity of the intervention can be adjusted to the severity of the growth failure. Prompt and comprehensive intervention is particularly important if a child has marked growth failure near the end of puberty (eg, around menarche) because such children have limited time left to grow before epiphyseal closure. (See 'Pathogenesis of growth failure' above.)
Initial steps depend on the severity of growth failure and disease activity (algorithm 1):
Patients with mild growth failure or pubertal delay without active IBD — For patients with mild growth failure (eg, decreased height velocity) and/or pubertal delay, the initial intervention is to provide focused dietary advice to increase energy intake, which may include adding liquid supplements (formulated as shakes or puddings). Children with growth failure also have increased energy requirements for catch-up growth, even if their IBD is inactive. Catch-up growth typically requires 125 to 150 percent of the recommended daily allowance for energy and 2.4 to 3 g/kg per day of protein [71,103]. (See "Dietary history and recommended dietary intake in children" and "Normal growth patterns in infants and prepubertal children", section on 'Ideal body weight'.)
The efficacy of nutritional counseling in IBD has not been carefully studied, and the energy and nutrient increases achieved through dietary counseling are probably modest. Addition of a liquid supplement taken by mouth supplying 35 to 50 percent of estimated energy needs effectively promotes weight gain [104,105].
In addition, the use of cyproheptadine as an appetite stimulant can be considered. While this has not specifically been studied in a group of children with IBD, it has been proven effective in children with cystic fibrosis, growth hormone deficiency, and cancer. The main reported side effect is sedation [106].
Children who do not respond to this intervention, or those with clearly adequate intake, should be reevaluated for the possibility of occult IBD activity and for other causes of growth failure (eg, familial short stature or constitutional delay of growth and puberty, which are variants of normal growth). (See "Diagnostic approach to children and adolescents with short stature".)
Patients with marked growth failure or pubertal delay — Effective treatment of the inflammatory process itself is critical to restoring growth. As a result, children with marked growth failure should undergo a thorough assessment of IBD activity (which may be occult). This may include laboratory testing and endoscopic evaluation.
With active IBD — For patients with marked growth failure and evidence of active IBD (which may be occult), management includes optimizing nutrition and initiating or escalating IBD treatment to address the underlying inflammatory disease process.
For children with Crohn disease, the primary options are (see "Overview of the management of Crohn disease in children and adolescents"):
●Exclusive enteral nutrition – Exclusive enteral nutrition (enteral nutrition with no food taken by mouth) is an important option for primary therapy for Crohn disease and is especially valuable in children with primarily small intestinal disease and growth failure. Small randomized trials indicate that exclusive enteral nutrition suppresses inflammation, promotes mucosal healing, and reverses growth failure in children with IBD. This approach is discussed in a separate topic review. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Exclusive enteral nutrition'.)
An alternate approach with promising preliminary evidence is partial enteral nutrition with a rigorously administered specific exclusion diet. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Partial enteral nutrition with specific exclusion diet'.)
●Biologic agents – Marked growth failure is considered a symptom of moderate or severe Crohn disease and is thus an indication for biologic therapy with infliximab or adalimumab [8,9,13,107]. These therapies have the greatest benefits on growth when initiated at earlier stages of puberty (ie, Tanner stage 1 to 3) [12]. The benefit of these and other biologic therapies on growth is probably due to their antiinflammatory effects rather than to reductions in corticosteroid use. (See "Medical therapies for Crohn disease in children and adolescents", section on 'First-line biologic agents'.)
●Surgery – In children with localized treatment-resistant Crohn disease or refractory colonic IBD, surgical resection of the inflamed bowel segment can be effective in restoring growth [108,109]. These observations further suggest that effective treatment of the inflammatory process is a critical component of treatment for growth failure in IBD. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Surgery'.)
●Immunomodulators – Thiopurines (azathioprine or 6-mercaptopurine) appear to have little or no effect on growth. A randomized trial of early treatment with 6-mercaptopurine did not show beneficial effects on growth compared with conventional treatment with glucocorticoids, but the sample size was small and the subjects had minimal growth retardation at randomization [110]. Moreover, an observational study reported that treatment with thiopurines was negatively associated with several anthropometric measures [111].
Similarly, children with ulcerative colitis complicated by growth failure or pubertal delay require reassessment and optimization of disease management. (See "Management of mild to moderate ulcerative colitis in children and adolescents" and "Management of severe or refractory ulcerative colitis in children and adolescents".)
Without active IBD — Patients with marked growth failure and/or pubertal delay and no evidence of active IBD (after careful reevaluation) should be evaluated for other causes; referral to a pediatric endocrinologist may be appropriate (see "Diagnostic approach to children and adolescents with short stature"). If no specific cause is identified and the child is unable to voluntarily increase their energy intake, we suggest a trial of nocturnal enteral feeding (partial enteral nutrition).
When this approach is used, the child usually eats freely during the day and then passes a nasogastric tube at night to administer formula while sleeping. Nutritional goals for total intake are generally from 100 to 150 percent of the recommended daily allowances for height-age for both energy (85 to 90 kCal/kg per day) and protein (2.4 to 3.0 g/kg per day). This usually translates to 1000 to 1500 kCals of formula nightly, depending on the child's weight and typical daytime food intake. Initially, smaller supplementary caloric goals can be used (500 to 1000 kcals) to judge tolerability. Based on weight gain over time, the calories are adjusted. If volume/rate is a limiting factor, formulas with higher caloric density can be used. If the child is severely malnourished, it may be prudent to initiate therapy in the hospital and monitor for refeeding syndrome, which is characterized by low levels of phosphorus, potassium, and magnesium developing during the first one to two weeks of refeeding.
The easiest and most successful approach is to administer a set amount of formula each night rather than calculating the target volume each night based on the child's observed food intake. Deficiencies in vitamins and minerals should be assessed and replaced by supplementation [112]. The type of formula used (elemental versus polymeric) is not important [71]. This issue has been best examined in the setting of exclusive enteral nutrition, which is discussed below.
Benefits of this approach were seen in a small nonrandomized study of prepubertal children with Crohn disease, in which nocturnal feedings yielded a mean weight gain of 11.75 kg and a mean height gain of 6.98 cm over one year, whereas matched control subjects had no significant change in weight and height [113]. Another observational study reported improved weight gain and height velocity among children treated with intermittent nocturnal supplemental feeds (administered one out of every four months) [114]. A third study, performed retrospectively, suggested that use of supplementary nasogastric feeds during remission of IBD improved linear growth and prolonged remission [115]. Supplemental feeds typically increase intakes of energy, calcium, and vitamin D, which help to prevent and treat bone disease. (See "Vitamin and mineral deficiencies in inflammatory bowel disease" and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density'.)
Partial enteral nutrition has also been used in conjunction with a specific Crohn disease exclusion diet. This is a highly structured approach intended as a primary therapy to induce mucosal healing in Crohn disease (similar to exclusive enteral nutrition). The limited evidence is summarized separately. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Partial enteral nutrition with specific exclusion diet'.)
Other interventions — Optimization of nutrition and control of the underlying IBD using intensive therapies are imperative prior to considering any endocrine therapy [17].
A few reports describe treatment of children with IBD and severe growth delay with recombinant human growth hormone [116-121], but there is insufficient information to recommend for or against this approach in this population.
For children with marked pubertal delay, judicious adjunctive treatment with sex steroids may be appropriate but must be balanced against the risk of growth attenuation by accelerating epiphysial closure. Small case series have described the use of testosterone supplementation in boys with IBD and pubertal delay; however, this is not a mainstay of treatment [122]. The use of estrogen to induce menarche has not been reported in this population. (See "Approach to the patient with delayed puberty", section on 'Hormonal therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inflammatory bowel disease in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Ulcerative colitis in children (The Basics)" and "Patient education: Crohn disease in children (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations
•Impaired growth – Disruption of linear growth is common in children with inflammatory bowel disease (IBD) and particularly those with Crohn disease. Marked growth delays occur in 20 to 30 percent of children with Crohn disease. Linear growth is highly sensitive to disease activity. (See 'Impaired growth' above.)
•Pubertal delay – Crohn disease can interfere with pubertal onset (causing delayed puberty) and/or progression (causing stalled puberty). (See 'Pubertal delay' above.)
●Pathogenesis – A combination of factors contributes to the pathogenesis of growth failure in IBD, including inadequate dietary intake, inflammation, malabsorption, glucocorticoids, and hypogonadism. The hypogonadism is, in turn, mediated by both malnutrition and inflammation. (See 'Pathogenesis of growth failure' above.)
●Evaluation
•Routine monitoring – All children with IBD should have regular measurements of body weight, height, and pubertal status. Body mass index (BMI) and height velocity should be calculated (table 1). (See 'Routine monitoring of growth and puberty' above.)
•Additional evaluation for those with growth failure – Children with IBD whose height velocity (figure 1A-B) or BMI (figure 2A-B) is below the 10th percentile for age are probably experiencing growth failure due to their disease. Similarly, delayed or stalled puberty in this population is likely caused by the underlying disease. (See 'Definitions' above.)
These children should be further assessed for nutritional deficits and IBD activity (which may be occult). Radiographic determination of bone age is a valuable component of the evaluation because it helps to determine the severity of the growth deficit as well as residual growth potential. These children should also undergo laboratory evaluation for micronutrient deficiencies (table 2). (See 'Additional evaluation for children with growth failure' above.)
●Prevention – All children with IBD should be counseled to ensure a balanced diet with adequate dietary energy and nutrients to optimize growth. For patients with active disease, malabsorption, or growth failure, energy and nutrient goals will often be higher than for the general population. (See 'Prevention' above.)
●Management – Management depends upon the severity of growth failure and IBD activity (algorithm 1):
•Mild growth failure without active IBD – Nutritional counseling to increase energy and nutrient intake is generally sufficient for these patients. Interventions may include adding liquid supplements (formulated as shakes or puddings) to the diet. Those who do not respond, or those with clearly adequate intake, should be reevaluated for the possibility of occult IBD activity and for other causes of growth failure. (See 'Patients with mild growth failure or pubertal delay without active IBD' above.)
•Marked growth failure – Patients with marked growth failure should undergo a thorough assessment of IBD activity, which may be occult.
-With active IBD – For patients in this category, management includes optimizing nutrition and initiating or escalating treatment to address the underlying inflammatory process (see 'With active IBD' above):
For patients with Crohn disease, this generally consists of a biologic agent (infliximab or adalimumab) or exclusive enteral nutrition. Surgical treatment may be required for those with localized treatment-resistant disease. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Moderate or severe'.)
For patients with ulcerative colitis, the choice of treatment depends upon the extent of disease, severity of symptoms, and response to initial treatment. Details of initiating and escalating therapy for patients with ulcerative colitis are provided separately. (See "Management of mild to moderate ulcerative colitis in children and adolescents" and "Management of severe or refractory ulcerative colitis in children and adolescents".)
-Without active IBD – Patients in this category should be evaluated for other causes of growth failure. If no specific cause is identified and the child is unable to voluntarily increase their energy intake, we suggest a trial of nocturnal enteral feeding (partial enteral nutrition) rather than other interventions (Grade 2C). (See 'Without active IBD' above.)
