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Perrin EC, Frank DA, Cole CH, et al. Criteria for Determining Disability in Infants and Children: Failure to Thrive. Rockville (MD): Agency for Healthcare Research and Quality (US); 2003 Mar. (Evidence Reports/Technology Assessments, No. 72.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Criteria for Determining Disability in Infants and Children: Failure to Thrive

Criteria for Determining Disability in Infants and Children: Failure to Thrive.

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3Results

A total of 275 original articles were reviewed, of which 52 publications comprising 43 studies met the criteria outlined in Chapter 2 and were assembled to provide the summary of results that follows. For the purposes of this summary, we will present the findings in categories of disability that were identified. Thus some articles will appear in more than one section if the investigators identified more than one type of disability in their sample. Categories of disability presented include (1) growth; (2) infectious/immunologic disorders; (3) behavioral disorders; (4) disorders of development; and (5) miscellaneous conditions.

Table 1. Outcomes and covariates studied

Table 2. Studies of persistent anthropometric abnormalities following diagnosis of Failure to Thrive in developed countries

Table 3. Studies of persistent anthropometrics abnormalities in malnourished cases in developing countries

Table 4. Studies with associations of immunologic dysfunction or infectious diseases to Failure to Thrive & healthy comparison groups in developed countries

Table 5. Studies with associations of immunologic dysfunction or infectious diseases and malnourished cases compared to well-nourished controls in developing countries

Table 6. Studies with association of behavioral correlates to Failure to Thrive compared to healthy comparison groups in developed and developing countries

Table 7. Studies with association of cognitive & neurological development to Failure to Thrive compared to healthy comparison groups in developed countries

Table 8. Studies with association cognitive & neurological development and malnourished cases compared to well-nourished controls in developing countries

Persistent disorders of growth following diagnosis of Failure to Thrive

Findings from Industrialized Nations

Most studies were performed in the United States, the United Kingdom, with one study from Israel. Six out of seven of these studies show a statistically significant association between failure to thrive and a risk of continued sub-optimal weight-for-height and weight-for-age. Of particular concern is the finding, in the majority of these studies, that this growth retardation persists despite adequate correction of malnutrition (Black and Krishnakumar, 1999; Corbett, Drewett, and Wright, 1996; Drewett, Corbett, and Wright, 1999; Kelleher, Casey, Bradley, et al., 1993; Mitchell, Gorrell, and Greenberg, 1980; Reif, Beler, Villa, et al., 1995).

Mitchell, Gorrell, and Greenberg (1980) showed that weight and head circumference were lower in children with FTT than in healthy controls at least until age 4–5 years (FTT 10–15% below controls for weight, p<0.001) and 10% below controls for head circumference (p<0.05). This was a longitudinal study on a US population in an outpatient clinical setting. The authors found no differences between controls and FTT groups for age, sex, mother's age/marital status, household composition, or maternal employment. Neonatal problems were more common in the FTT group, including evaluations for sepsis, poor sucking ability, mild neonatal jaundice but they were not thought to be a medically significant etiology for the FTT.

In an ambidirectional blinded study from the United Kingdom by Drewett, Corbett, and Wright (1999), children who failed to thrive from 1 to 5 years of age were smaller and had smaller head circumferences than their non-FTT counterparts at school age (median weight for FTT of 23.8 kg, IR 21.5 to 26.8 vs. controls 27.9 kg, IR 15.3 to 17.8). Black and Krishnakumar (1999), in a prospective, longitudinal study in the outpatient setting, demonstrated that despite catch up growth, weight and height for age were of significantly slower velocity in the FTT group compared to non-FTT controls. In another ambidirectional-longitudinal outpatient study by Reif, Beler, Villa, et al. (1995), mother's education level and family issues/living conditions were significant (p<0.05) covariants for long term recovery of weight and height in the FTT group.

Similar findings were shown in the prospective, longitudinal study by Haynes, Cutler, Gray, et al. (1984), where weight, head circumference and length were significantly lower in the FTT group, both on initial evaluation and at 6 month follow-up, despite an outpatient treatment program that included a case worker, visiting nurse, pediatrician and infant stimulation program, with 29/37 children not showing catch up growth in 6 months. Significantly, children diagnosed and treated within the first 6 months of life were more likely to have improved growth outcomes. In their conclusion, the authors emphasized the need for more aggressive identification and more intensive intervention to reverse the altered growth patterns in these children.

Corbett, Drewett, and Wright (1996) extended the association of FTT with poor weight, height and developmental outcome one step further. This study was also an outpatient-based longitudinal 5-year follow up study. They identified a significant difference within the failure to thrive group with the severity of poor growth (weight and height) correlating with poorer developmental outcome.

Findings from the Developing World

In addition to these findings from industrial nations, seven pertinent studies were identified in developing countries. The studies in developing countries mainly compared children with marasmus and kwashiokor to healthy controls, mostly from outpatient settings, (Branko 1979; Evans et al. 1980, Galler et al. 1985). Using ambidirectional/longitudinal and prospective longitudinal research design, the majority of the studies found similar associations between the diagnosis of FTT and long-term disorders of growth (Branko 1997; Galler et al. 1985; Alvear et al. 1986; Grantham-McGregor et al. 1982, 1987; Benefice 1992; Walker et al. 1996). Specifically, in the studies by Grantham-McGregor, Schofield, and Powell (1987) looked primarily at the effect of home visits on Jamaican children with FTT and found that height for age remained low in the FTT group, even with the intervention (p<0.001 for Height/Age 88% FTT, 101% control; Head Circumference/Age 91% FTT, 99% control). The addition of more adequate nutritional supplementation to such children would be anticipated to aid in these improvements in outcome. This is further supported in the study by Evans and colleagues (1980), where height and weight improvements (p<0.01 in treatment vs. control group) seen two years post nutritional intervention did not persist six to seven years after intervention. Two other studies also showed significant differences in body fat and arm muscle composition in the FTT groups compared to controls (p<0.05) (Alvear, Artaza, Vial, et al., 1986, arm fat area 73.5+/-15.3 and 64.5 +/-16.5 in FTT groups and 91+/-24.7 and 95.7 +/-28.5 in control groups) (Benefice, 1992, % body fat of arm muscle area 18.7+/-0.33 in FTT and 21.8 +/-0.47 in controls). In the study by Benefice (1992), the decreased body fat and muscle mass had a negative impact on physical performance.

Summary

Overall these studies comparing children who were thriving with those who were undernourished in both developed and developing countries show that children with FTT are at substantial risk for continued poor growth in weight, height, and head circumference, and that this growth disturbance is difficult to reverse despite appropriate interventions. The data also suggest that earlier diagnosis and intervention lead to potentially better long-term outcome. The fact that children who fail to thrive have poorer head growth is not surprising considering that human brain growth is tremendous in the early childhood years and insults during this time may impact permanently on developmental and intellectual outcome. These findings emphasize the importance of early and intensive intervention for children with or at risk for FTT so as to prevent permanent growth retardation.

Associations of FTT with Immunologic/Infectious Outcomes

Eight controlled studies were identified for review; four of these focused primarily upon aspects of immune function while four examined clinical infections among FTT children. Studies carried out in developing countries have variable generalizability for outcomes and policies in the United States. The studies conducted by Sherrod, O'Connor, Vietze, et al. (1984) in Tennessee, and by Carvalho Neves Forte, Martins Campos, and Carneiro Leao (1984) in Brazil involved infants and children with moderate degrees of malnutrition, similar to the patient population in the USA. Studies by Ferguson, Lawlor, Jr., Neumann, et al. (1974) (Ghana) and Friedland (1992) (South Africa) included only cases of severe malnutrition, i.e., marasmus and kwashiorkor. The studies of Tuck, Burke, Gracey, et al. (1979), Neumann, Lawlor, Jr., Stiehm, et al. (1975), and Pandey and Chakraborty (1996) included more than one group of FTT children, graded by severity. Patients in the moderate malnutrition categories likely represent a reasonable comparison to the US population of FTT patients.

Seven studies were prospective and one study was retrospective. Only three studies (Ballard and Neumann, 1995; Pandey and Chakraborty, 1996; Sherrod, O'Connor, Vietze, et al. 1984) were longitudinal; all others were cross-sectional. The principal source of potential bias involved the selection of controls. Tuck, Burke, Gracey, et al. (1979) included adults as well as children in his controls; additionally, there were only controls (no FTT patients) entered from the children in the urban study center. The FTT and control groups in the study by Carvalho Neves Forte, Martins Campos, and Carneiro Leao (1984) were from different hospitals serving different SES populations. Friedland's (1992) controls included children with “nutritional growth retardation”, likely comparable to the US FTT population; further specifics are not provided.

Evidence of Immunologic Dysfunction in Failure to Thrive

Multiple indicators of immunologic function and dysfunction have been used to try to understand the effects of malnutrition on children's response to infectious insults.

Carvalho Neves Forte, Martins Campos, and Carneiro Leao (1984) examined monocyte chemotaxis and phagocytosis in Brazilian children (6 months to 5 years) with moderate protein calorie malnutrition (PCM). Because these investigators were interested in immunologic functioning of children with moderate PCM rather than severe malnutrition, they recruited a sample of children whose weight for age was between the 25th and 40th percentile of standards for age. Compared to well nourished controls, patients with moderate PCM demonstrated significant decreases in chemotactic response to bacterial endotoxin, as well as phagocytosis of zymogen particles (p< .001). Serum complement levels were not different between groups, and the differences in chemotaxis and phagocytosis persisted whether cells were incubated with simple media, patient serum or pooled normal serum suggesting that the defect existed at the level of the cell receptor.

Ferguson, Lawlor, Jr., Neumann, et al. (1974), studied in vivo cell mediated immunity in 10 infants (ages 12–42 months) with severe PCM in Ghana (3 with marasmus, 7 with kwahiorkor) compared to 10 age matched controls. Although total lymphocyte counts were similar in the two groups, PCM infants had significantly lower percentages of rosette forming cells (RFC), a sensitive marker of cellular immune function; 16.6 percent ± 2.7 vs. 64.5 percent ± 1.0 (p<0.001). PCM infants also manifested a higher incidence of negative skin hypersensitivity responses to monilia and SK/SD; no analysis is provided regarding the significance of this trend. Repeat studies on five of the malnourished infants following nutritional therapy with high protein diet showed reversion to normal for both the skin delayed hypersensitivity response and the percentage of RFC's.

Tuck, Burke, Gracey, et al. (1979) studied candidacidal activity of leukocytes in three groups of children in Indonesia as well as both urban and rural Australia: Controls (>80 percent standard weight for age (SWFA)); moderate under-nutrition (60–80 percent SWFA); and marasmus (<60 percent SWFA). Both under-nourished and marasmic children demonstrated reduced Candida killing ability (17.6 percent and 13.7 percent respectively) compared to controls (44.5 percent; p< .001 for comparison of each malnourished group to controls). The candidacidal activity of leukocytes was not improved by addition of normal serum, suggesting, as does the study by Carvalho Neves Forte, Martins Campos, and Carneiro Leao (1984), that there is a primary cellular defect in leukocyte function. No population demographics are provided, including the age of patients and controls, which makes for some difficulty in interpretation and concern about potential bias. Controls included both adults and children; the authors note that candidacidal activity is known not to be age-related, with no difference between healthy, well nourished children and adults.

Neumann, Lawlor, Jr., Stiehm, et al. (1975), examined markers of immunologic dysfunction along with clinical correlates of infection in children ages 6 months to 6 years in Ghana. Three groups of children were compared: Group I, severe malnutrition (50–60 percent weight for age with low serum albumin); Group 2, moderate malnutrition (61–80 percent weight for age with normal serum albumin); and Group 3, well nourished controls (>81 percent weight for age with normal serum albumin). Delayed hypersensitivity skin test response to PHA, monilia and SK-SD were significantly decreased in both malnourished groups compared to controls. Forty-four percent of children with severe malnutrition and 29 percent of those with moderate malnutrition were non-responders to PHA, compared to only 5 percent for controls. In addition, malnourished responders manifested significantly smaller areas of induration. Lymphocyte response to PHA tested in vitro was significantly less in both malnourished groups and absolute lymphocyte counts were significantly lower in the severely malnourished group (all significance at p<.05). Immunoglobulin and complement levels, as well as antibody response to KLH (keyhole limpit hemocyanin) and PPS (pneumococcal polysaccharide) were similar among all three groups.

Tonsil size was reduced in Group 1 compared to Group 2 and Group 3; with 36 percent demonstrating trace or absent tonsil tissue compared with 5 percent of group 2 and none of the control group 3. Clinical infections, particularly pneumonia and fungal skin infections were more frequent in severely malnourished children.

Clinical Infections in Failure to Thrive

Friedland (1992) conducted a large prospective study of FTT infants (median 11 months, range 2–84 months) in South Africa. One thousand five hundred eighty two FTT children (792 with kwashiorkor, 513 with marasmus, and 277 with marasmic kwashiorkor), all of whom were hospitalized specifically for their malnutrition, were compared to 7282 controls hospitalized for other reasons. Controls included both well nourished and “nutritionally growth retarded”; no specifics are provided regarding the percentage of the controls with nutritional growth retardation or the degree of growth retardation present.

Bacteremia, whether compared as total cases, or by subsets of community acquired and hospital acquired cases, was consistently more common among the FTT population. The overall incidence of bacteremia was 9.9 percent for the FTT children vs. 6.0 percent of controls (p<0.001). Furthermore, the mortality among bacteremic patients was also significantly greater among FTT cases (FTT 31 percent vs. controls 13 percent; p<0.001). Therefore, both the risk of bacteremia and subsequent mortality from bacteremia are significantly associated with FTT.

Sherrod, O'Connor, Vietze, et al. (1984) found a 4-fold increase in “bacterial or viral infections such as URI or mumps” among American infants aged 0 to 3 months with non-organic failure to thrive compared to controls (p<.05, Evidence Table 3). FTT was defined as weight gain falling below two-thirds of the Harvard fiftieth percentile growth curve.

Ballard and Neumann (1995) conducted a prospective cohort study of 200 children in Kenya, age 14–25 months. Children were followed for development of acute lower respiratory infections (ALRI) for up to 12 months. Symptom checklists were completed based on parental report at weekly visits. FTT, either low weight for age or low height for age, was a strong predictor of development of ALRI. Height for age < 90 percent of the median had the strongest correlation, with a relative risk of 4.5 vs. non-FTT (95 percent CI 1.1–17.4). The fact that height for age was a stronger predictor than weight for age suggests that chronicity of malnutrition has a greater impact upon immune function and risk of infection than does acute malnutrition.

Pandey and Chakraborty (1996) followed a cohort of 200 Indian children, documenting episodes of acute respiratory infections (ARI). Malnutrition was graded based on weight for age. The number of ARI episodes per child was significantly greater in FTT children than controls (6.6 episodes/year vs. 4.8 episodes /year; p<0.05). Furthermore, there was a stepwise increase from grade I (mild malnutrition; 5.6 episodes/year) to grade IV (severe malnutrition (7.7 episodes/year; p<.05, chi-square) (Evidence Table 4).

In summary, studies comparing children who are thriving with those who were undernourished in both developed and developing countries show that children with FTT have significant pertubrations in immunologic function, and a corresponding increased susceptibility to clinical infection. These findings emphasize the importance of identifying children who are failing to grow normally since their growth failure may put them at additional risk for a variety of acute and chronic infections that might not necessarily be appreciated. In addition, treatment of FTT provides an opportunity to prevent the additional consequences and costs associated with chronic infectious conditions in children.

Child Behavior Problems Associated with Failure to Thrive

Systematic assessment of children's behavior (usually by parent report) was a part of about one-third of the studies reviewed. The specific aspects of behavior assessed, and the instruments used to quantify these difficulties, are disparate and not easily comparable. Therefore we will present descriptive information summarizing the conclusions of the sixteen investigators who addressed behavioral difficulties as a part of their analyses. Evidence will be presented in three areas:

  • concurrent feeding-related behavior problems associated with FTT
  • other concurrent behavioral problems
  • behavior problems detected in follow-up subsequent to the diagnosis of FTT.

Evidence of Concurrent Feeding-Related Behavior Problems Associated with FTT

Feeding is a critical self help skill that develops during infancy and toddlerhood. Inability to self-feed in toddlers or inability to be cooperative with caretaker feeding during infancy is a functional impairment in caring for oneself and in maintaining health and physical well-being. Depending on degree, disorders of feeding may result in either marked or severe functional limitation, thus contributing to or establishing disability.

Four controlled studies noted concurrent feeding disorders in children diagnosed with FTT. These studies varied in their definitions of eating disorders, and will be reviewed individually. One study grouped feeding behaviors with other behavior disorders, one study observed infant affect during feeding, one observed feeding behavior directly, and the fourth used maternal recall of feeding behavior. Regardless of methodology used, significant feeding-related issues were more frequently in infants with failure-to-thrive than in control infants.

In the first relevant study, 19 FTT children and age/sex-matched controls were evaluated over several weeks to determine incidence of feeding, autoerotic and self-harming behaviors by Pollitt and Eichler (1976). Children with mean age of 33 months were enrolled in an outpatient clinic. Controls were matched for age, sex, and race. Children with already-identified birth complications, physical disability, brain damage or “organic growth retardation” were excluded. Thus the group called “FTT” were those for whom no medical cause for the FTT had been identified. Behavior was assessed by interview and direct observations at home. Of particular interest/attention were the child's response to food, mood while eating, and the presence of polydipsia, pica, and hiding food. Eating behavior was rated by observers on a 4-point scale created by the investigators. Information was collected also about autoerotic and self-harming behaviors. Overall, 10 children with FTT exhibited abnormal eating behavior determined over weekly interviews conducted for 7–11 weeks, compared to matched controls. These data demonstrate that eating behavior is more problematic in children with FTT, than in children growing normally.

Polan, Leon, Kaplan, et al. (1991) reported a small masked study of affective expression in 6–36 month old children born appropriate for gestational age (AGA) at 35 weeks or older in US with (28) and without (14) FTT in feeding and non-feeding situation. The Kiddie Affect Inventory and Assessment, which reports four channels of emotion - facial display pattern, vocalization, gesture, body position and movement was used. FTT was associated with increased negative affect and decreased positive affect during feeding compared to controls, with no difference in non-feeding situations. Severity of malnutrition, but not presence of organic disease, was associated with affective outcomes.

A community-based cohort of children at 15 months of age was identified through medical records from two Israeli communities by Wilensky, Ginsberg, Altman, et al. (1996). A subgroup of 50 diagnosed cases of FTT was assessed along with 50 matched controls. A maternal questionnaire was developed to assess feeding behavior. Feeding problems included both behavioral (e.g. turned head from food, spits out food) and affective items (e.g. shows pleasure at meals). The results demonstrated significantly more feeding problems among FTT children compared with controls.

A population-based study in Newcastle, England utilized a screening program to identify one hundred twenty cases of FTT during the two-year enrollment period. Wright and Birks (2000) reported on ninety-seven FTT cases who had complete data and 28 controls identified from 3 general practices. FTT cases were reported to start solid foods later than controls, 3.89 months versus 3.04 months (p = .003), as well as being delayed in starting finger foods, at 7.15 months versus 6.14 months (p = .005). The clinical importance of these small differences is unclear. However, there were more parent-reported feeding problems during infancy for the FTT cases, 28 percent versus 2 percent for the controls (p = .022). Parents of FTT children more often described their children as uninterested or poor eaters (FTT 11 vs. Controls 0, p = .003).

Evidence Suggesting Concurrent Behavioral Problems Associated with FTT

This section reviews concurrent or nearly-concurrent behavioral problems associated with failure-to thrive. Four controlled studies examined behavior problems that were either diagnosed concurrently with diagnosis or within six months. Because each study established its own definition of behavioral disorder, the studies are reviewed individually rather than combined. Three of the four studies found an increase in attachment disorders or other early childhood behavior disorders in infants and toddlers with diagnosed FTT. These disorders all comprise functional limitations in interacting or relating to others, which may be marked or severe in individual cases, and would contribute to or establish disability.

Hutcheson, Black, and Starr, Jr. (1993) observed the behaviors of thirty-four children with FTT and matched comparison children with their mothers during feeding. The children were divided into two age groups, infants (age 8 – 13.4 months), and toddlers (age 13.5 – 24 months). Controls were matched based on age, sex and race. Parenting functioning, child functioning, and contextual sources of stress and support were assessed, using the Infant Characteristics Questionnaire. Mothers of younger children reported a greater level of difficulty in caretaking. No other age or group differences were found on parenting stress, informal support, life events, and negative affectivity.

Chatoor, Ganiban, Colin, et al. (1998) studied three groups of toddlers from various ethnic and economic classes based on diagnosis of infant anorexia (n=33), picky eaters (n=34), and healthy eaters (n=34). The study examined attachment and security level in the three groups, using the Ainsworth and Cassidy & Marvin attachment classification systems. Most of the children were evaluated as ‘secure’, but the frequency of insecure attachments was significantly related to diagnostic group, χ2 = 8.0, p < .05. There was a greater frequency of insecure attachments in infants with anorexia compared to picky eaters, or compared to healthy eaters χ2 = 6.7, p < .0 and χ2 = 3.9, p < .05, respectively. A nine point Likert scale was used to assess the degree of attachment security. The infants with anorexia obtained the lowest score of 4.9 while picky eaters and healthy eaters scored 6.0 and 6.1 respectively. There was a main effect for the group, F = 5.8, p < .01, and a positive correlation between ideal weight and attachment security, r = 0.31, p < 01 (Evidence Table 5).

Steward, Moser, and Ryan-Wenger (2001) evaluated 14 children with FTT compared to 14 controls matched for age, sex and race. They evaluated behavioral responsiveness of the infant using the Parent-Child Early Relational Assessment Scale. The FTT group scored significantly lower on the communication subscale (FTT 3.19 vs. Control 4.07). During interactions with their mothers, they had less visual contact, more gaze aversion, and vocalized less than controls. They also scored lower than controls on the mood subscale, as they were more irritable and apathetic (FTT 3.65 vs. Control 4.26).

Skuse, Pickles, Wolke, et al. (1994) is a population study in south London of low SES infants. Forty-seven FTT cases identified and matched forty-seven controls were assessed at approximately 15 months of age. Using the Tester's Rating of Infant Behavior instrument, no significant differences were found between the groups for expression of positive affect, task directed behavior, and task persistence.

Evidence Regarding Behavior Problems Detected in Follow-up

Galler, Ramsey, Solimano, et al. (1983b) compared 129 Barbadian children with FTT prior to 1 year old with matched controls. Assessments were conducted at age 60–132 months. Behavioral disorders and the presence of ADD were measured using study-specific instruments. Classroom behavior problems were noted more frequently in children with a history of FTT during infancy.

Mitchell, Gorrell, and Greenberg (1980) reviewed the medical records and prospectively followed a cohort of three hundred and twelve children ages two to five years from three rural primary care centers. A majority of families received government insurance; 70 percent were black. Thirty children were defined as FTT based on weight below 80 percent of normal recorded during first 24 months of age. Compared to the remaining controls, the index group had significantly more family problems and neonatal abnormalities such as poor suckling, jaundice, and suspected sepsis, p < .01 and p < .05, respectively. Behavioral evaluation was conducted at a follow-up visit conducted at age 3–6 years, using a behavioral problems questionnaire and the McCarthy Scale of Children's abilities. Children with FTT had more behavioral problems reported and scored lower on intelligence tests (Evidence Table 5).

Drotar and Sturm (1992) evaluated preschool American children with FTT in a comparison trial of three different interventions involving varying degrees of psychosocial support. The scores of the three FTT groups (N= 48) were pooled and compared to healthy controls (N-47). Children were enrolled at age 3 and assessed at age 5. Comparisons were based on use of the California Child Q-set to assess their personality development, the Lock Box to measure organization in problem-solving, and the Child Behavior Checklist (CBCL) to assess problem behaviors. Results showed poor psychosocial development in the five-year-olds who had a history of FTT as infants. Scores in ego resiliency and behavioral organization were lower for the FTT group compared to controls; 376.06 versus 397.37, p < .05, and .95 versus 8.45, p < .01, respectively. The incidence of behavioral problems on the CBCL was also significantly higher for the index group compared to the controls, 58.5 versus 53.2, p < .05. There was no difference in ego control.

A cohort of inner city British white children who were born in 1980 were identified from medical records. Puckering, Pickles, Skuse, et al. (1995) reported on those diagnosed with FTT based on height and weight below 10th percentile compared with control children who were matched on the basis of sex, birth weight, and ethnic origin. Children with a history of FTT were found to have clinically and statistically significant behavioral deficits using the Behaviour Screening Questionnaire, 8.7 versus 6.9 for controls. These observed deficits did not appear to result from parenting practices or other environmental influences.

The study by Kerr, Black, and Krishnakumar (2000) is a follow-up of children 6 years of age from an earlier study (Mackner, Starr, Jr., and Black, 1997) consisting of two initial samples, FTT and adequately nourished children. History of maltreatment was based on at least one report to the Child Protective Services and was not part of the initial recruitment criteria. There was no effort to discern maltreatment in children not reported. Though it was reported that “most children had recovered” from FTT, there were no specific data provided. Three percent of the FTT sample persisted with weight for height below the 5th percentile. The one hundred ninety three, mainly poor, mostly African American inner-city children were divided into four risk factor groups; FTT (n=64), FTT with history of maltreatment (n=28), history of maltreatment alone (n=21), and neither risk factor (n=80). Behavior problems were documented by teacher reports of adaptive functioning at school and the Teacher Report Form; children's behavior at home was measured by the Child Behavior Checklist. Analyses of covariance showed main effects for risk status for all behavioral outcomes, p < 0.01. Analyses revealed statistical significance between the FTT and maltreatment versus the neither risk factor groups for adaptive functioning and school behavior, p < 0.05 (Evidence Table 5).

Corbett, Drewett, and Wright (1996) identified from records from a clinic serving a predominant low income, white population of Newcastle, 52 cases and 52 controls. The five-year follow-up for 48 FTT children and 46 controls found a trend towards behavior problems as measured by Child Behavior Checklist, p < 0.296 (Evidence Table 5).

The Kelleher, Casey, Bradley, et al. (1993) study, which followed a large cohort of low birth weight infants, assessed 180 who developed FTT. Though there were no significant differences between the 180 FTT cases and 591 nonFTT as measured by the Bates Temperamental Scale at 12 months, there was a trend for more behavior problems as measured by the Child Behavior Checklist at 24 months.

Developmental Disorders Associated with Failure to Thrive

FTT is consistently associated with evidence of neurodevelopmental disabilities. Insufficient intake of both macro and micronutrients exerts diverse functional and structural effects on the nervous system, with effects particularly likely to persist if they occur during the vulnerable periods of rapid neural development. Since FTT most often occurs in early life, during the period of most rapid postnatal brain development, developmental concomitants and lasting sequelae are to be expected. Subtle neurological deficits may interfere with the normal progression of feeding skills even in the absence of clinically evident palsies. They contribute to FTT by interfering with the child's ability to take in adequate nutrients. FTT also appears to heighten developmental vulnerability to other adverse environmental factors (Barrett & Frank, 1987).

For the purposes of this review we reported whatever indicators were chosen by particular investigators as indicative of developmental deviations. These heterogeneous indicators range in specificity and in severity. They include, for example, sucking/swallowing difficulties, delays in age of tolerating solid foods, pica, motor delays, and global developmental delays. We attempted to summarize comparisons made by diverse investigators between children failing to thrive and children growing normally. It is important to note that in spite of the highly variable developmental outcomes assessed, the presence of impairment in children who are not growing normally is found consistently across studies and circumstances.

The following discussion is divided by source of subject population (developed versus developing country) and within each category by 3 domains 1) oral motor and other neurological findings; 2) developmental/cognitive functioning concurrent with the identification of FTT; and 3) developmental/cognitive function in later childhood among survivors of early FTT.

Developed Countries

Oral Motor and other Neurological Findings

Prospective, epidemiological, and observational studies consistently note increased rates of feeding difficulties in children with FTT, with some investigators also noting clinically poorly specified “neurological” findings other than in feeding skills. Since these studies are often based on parental report, it is hard to distinguish true subtle neurological (either oral motor or sensory) deficits in feeding from parental perception and from learned behaviors. However, slow feeding and delayed acquisition of age-appropriate feeding skills are a consistent finding in every study where they have been assessed.

Prospectively, in the newborn period, Kelleher, Casey, Bradley, et al. (1993) noted increased rates of abnormal or suspect neurological exams among infants who later failed to thrive, compared to those who did not. Mitchell, Gorrell, and Greenberg (1980) found “suckling difficulties” were more likely to be noted in the newborn records of children who later failed to thrive. Hack, Merkatz, Gordon, et al. (1982) found increased rates of “neurological” abnormalities at 8 months among infants who failed to thrive compared to those who grew well. In a large epidemiological study, Wright and Birks (2000) in Newcastle, England utilized a screening program that identified 120 cases of FTT during the two-year enrollment period. Twenty-eight of the forty controls identified from three general practices that agreed to participate were compared to the 97 FTT cases who had completed data. FTT cases were reported to start solid foods later than controls, 3.89 months versus 3.04 months, p = .003, respectively, as well as starting finger foods later, 7.15 months versus 6.14 months, p = .005. Also reported were more feeding problems during infancy for the FTT cases, 28 percent versus two percent for the controls, p = .022. FTT parents were more likely to describe their children as variable, uninterested, or poor eaters, 11 instances reported for FTT versus none by the control parents, p = .003. In a detailed observational study in the United States, (Pollitt and Eichler, 1976) 19 FTT children and age/sex-matched controls were evaluated over several weeks in open trial. FTT children were found to differ from controls in feeding behaviors as well as in other domains of development.

Developmental/Cognitive Impairments Concurrent with Identification of FTT

From developed countries there are relatively few controlled papers that document the developmental status of children with FTT at the time the condition is diagnosed either clinically or epidemiologically. The focus has been on follow-up studies, which are therefore described below. The issue is complicated further because developmental delay historically was considered by some authors (Coleman and Provence, 1957) as one of the criteria of FTT in addition to growth failure. It is only in recent decades that children have been labeled as FTT on the basis of weight alone. Moreover, except as noted, most of the studies of FTT children at the time of identification do not use masked testers (and indeed it is difficult to mask testers to the differences in size between acutely underweight FTT children and normally growing comparison children of the same age). Therefore an experimenter effect cannot be ruled out in the studies summarized below. Most, although not all, of the samples in these studies also contribute to long term outcome studies.

There are three US studies, two based on hospitalized samples (Haynes, Cutler, Gray, et al., 1984; Singer and Fagan, III, 1984) and the other on a sample not hospitalized but drawn from an outpatient inner city clinic (Mackner, Starr, Jr., and Black, 1997). In the Singer and Fagan, III (1984) study, 8 month old infants with FTT showed on average a large deficit (30–40 points) on the Bayley Mental Development Index compared to controls, and among some FTT children, a difference also in visual recognition memory. As a baseline for an intervention study, Haynes, Cutler, Gray, et al. (1984) compared 50 FTT children with 25 “thriving” children on the Bayley Scales of Infant Development and found that 62 percent of the FTT sample were either delayed or retarded (22 percent with an MDI less than 70) compared to only 19 percent of controls who were delayed, with none retarded.

Mackner, Starr, Jr., and Black (1997) performed a cross sectional study controlled for maternal IQ and child age on a large sample of 177 inner city toddlers, 3–30 months old who were predominantly African American. Ninety-seven children had FTT defined as weight for age less than 5th percent before age 2. Of these, 27 were also characterized as “neglected,” defined as the lowest tercile on a Home Observation for Measurement of the Environment (HOME) score obtained by a masked examiner. It is not clear if the psychometrician who performed the Bayley tests was masked to FTT status. Children with both FTT and low HOME scores attained Bayley Mental Development Index scores one standard deviation lower than children with neither. Children with FTT with HOME scores above the lowest tercile scored on average 3 points lower than children with neither on Bayley MDI.

Skuse, Pickles, Wolke, et al. (1994) reports on a population survey of low SES infants in south London born in the year 1986. Forty-seven infants with FTT and matched forty-seven controls were identified. They were assessed at approximately 15 months of age, using the Bayley MDI and PDI scores. Infants with FTT had scores which were significantly lower than controls on both the MDI (98.2 vs.108.5) and the PDI (96.7 vs. 103.6). In addition, there was a negative correlation between the FTT children's oral motor skills and their MDI scores (r= -0.38, p = .008). Modeling predicted a correlation between the standardized weight falling during the first 6 months to a 10-point loss in mental and psychomotor development during the second postnatal year. The prediction included weight loss commencing after the first 4 months would have a 3 point loss in development whereas a weight loss after 8 months which would have no effect on development.

Kelleher, Casey, Bradley, et al. (1993) followed a large cohort of babies who had been born with low birth weight of 2500 grams or less and with gestational age up to 37 weeks. Of the 4,551 infants born at the eight Infant Health and Development Program sites, 842 met the inclusion criteria for this study and of those, 180 developed FTT. At 12 and 24 months, Bayley Mental and Psychomotor Development Indexes were lower for children with FTT than children without FTT (p < 0.005) (Evidence Table 7). At 36 months, the Stanford-Binet IQ scores were lower for children with FTT, 84.7 vs. 89.9 for non-FTT, p < 0.007.

Corbett, Drewett, and Wright (1996) reviewed records from the “most economically deprived wards in Newcastle” to identify children with FTT. Diagnosis of FTT required at least 6 recorded weights during their first 18 months. The controls were also from the same clinic serving a predominant low income, white population of Newcastle. The children were assessed at school entry using the CBCL and the Wechsler Pre-School and Primary Scale of Intelligence - Revised. The severity of FTT was significantly associated with full-scale IQ, though no overall group differences were noted between children with a history of FTT and normal controls.

Drewett, Corbett, and Wright (1999) enrolled 136 children with a thrive index < 5 percent, and 136 controls, matched for age and residential area. Follow-up occurred at ages 5.5 to 7.5 years. Assessment was conducted by interviews and testing using the WISC-III and WORD tests. Lower IQ scores were noted in children with a history of FTT compared to controls (mean IQ, FTT 87.6 vs. 90.6).

A cohort of inner city British white children who were born in 1980 were identified from medical records. Puckering, Pickles, Skuse, et al. (1995) reported on those diagnosed with FTT based on height and weight below 10 percentile compared with control children who were matched on the basis of sex, birth weight, and ethnic origin. Using the McCarthy Scales of Children's Abilities, children with a history of FTT were found to have clinically and statistically significant cognitive deficits (FTT 77.1 vs. Control 97.7).

Kerr, Black, and Krishnakumar (2000) followed children 6 years of age from an earlier study (Mackner, Starr, Jr., and Black, 1997). Children with FTT and adequately nourished children were compared. Developmental assessment included cognitive performance measured by Wechsler Preschool and Primary Scale of Intelligence-Revised Edition, and showed that children with FTT consistently had lower cognitive test scores than nutritionally adequate children (FTT 81.98/FTT with maltreatment 77.98 vs. Controls 83.95).

In summary, at the time of identification, FTT is associated with depressed developmental test scores, with most profound depression seen in clinically identified hospitalized children. However, even in samples identified epidemiologically rather than by clinicians, FTT is associated on average with roughly two-thirds of a standard deviation decrease in developmental test scores, so that many more FTT children will score in the SSI qualifying range of developmental delay than children in a reference population.

Developmental/Cognitive Functions in Childhood Among Survivors of FTT in Early Childhood

Duration of follow-up of children with FTT varies widely between studies, as does the setting in which FTT was initially identified (hospital, outpatient clinic, or epidemiological survey). There is often ambiguity in these studies as to whether the deficits identified are attributable to FTT in early life or to concurrent undernutrition and environmental stressors at the time the outcome is measured. Nevertheless, there is a consistent trend for children with a history of FTT to score lower than their social class peers on developmental/cognitive test scores. In contrast to the studies of developmental status of children with FTT at the time of diagnosis, many of the follow-up studies (Corbett, Drewett, and Wright, 1996; Drewett, Corbett, and Wright, 1999; Mitchell, Gorrell, and Greenberg, 1980; Puckering, Pickles, Skuse, et al., 1995; Wilensky, Ginsberg, Altman, et al., 1996) specify that psychometric examiners were masked to the children's early growth history.

The Haynes, Cutler, Gray, et al. (1984) and Singer and Fagan, III (1984) studies which followed small cohorts of hospitalized children for six months after diagnosis and up to age 3 years respectively found persistent and profound decrements in scores on the Bayley Scales of Infant Development compared to the scores of controls. In contrast, Drotar and Sturm (1992) reported in passing that previously hospitalized FTT and not hospitalized comparison children retained until age 4 for a behavioral outcome study did not differ at age 3 in their Stanford-Binet Scores, which were roughly one standard deviation below the mean in both groups (86 vs. 88).

Among samples selected from outpatient clinics the trend is similar across diverse settings Mitchell, Gorrell, and Greenberg (1980) in rural North Carolina measured McCarthy Scores between 3 and 6 years among 12/30 children who had failed to thrive in earlier life and 16/282 comparison cases. On average the children with FTT scored 5 points lower than the comparisons (87.5 vs. 92.5) but the difference was not significant in the sample overall, although girls with a history of FTT scored significantly lower than those without.

Kerr, Black, and Krishnakumar (2000) conducted a follow-up of children at 6 years of age from an earlier study (Mackner, Starr, Jr., and Black, 1997) of one hundred ninety-three, mainly poor, predominantly African American inner-city children divided into four risk factor groups; FTT (n=64), FTT with history of “maltreatment” (n=28), history of “maltreatment” alone (n=21), and neither risk factors (n=80). History of “maltreatment” was based on at least one report to the Child Protective Services (primarily for neglect, but some also for suspected physical or sexual abuse) and was not part of the initial recruitment criteria. There was no effort to discern maltreatment in children not reported. Developmental assessment measured by an abbreviated version of the Wechsler Preschool and Primary Scale of Intelligence-Revised Edition revealed statistically significance differences (78 vs. 84) between the FTT and maltreatment versus the neither risk factor group, with a non-significant trend toward depressed scores among children with FTT but without “maltreatment” (82 vs. 84). There are two urban Israeli studies, one from Jerusalem (Wilensky, Ginsberg, Altman, et al., 1996) and one from Tel Aviv (Reif, Beler, Villa, et al., 1995). Wilensky, Ginsberg, Altman, et al. (1996) found statistically significant differences in average Bayley Mental Development Scores (99.7 vs. 107) and a higher incidence of MDI below 80 (11.5 vs. 4.6%) in 50 children with a history of FTT compared to 50 matched controls. Reif, Beler, Villa, et al. (1995) in a five year follow-up study found almost identical statistically significant rates of developmental delay (not precisely defined) (11.5% vs. 0%) and “learning difficulties” (18% vs. 3%) among 61 children with a history of FTT compared to 65 controls.

The epidemiological studies fall into two main categories -- American studies which follow prospectively low birthweight cohorts and English studies which evaluate term birth cohorts in defined urban neighborhoods. Hack, Merkatz, Gordon, et al. (1982), examined very low birth weight infants' mental, in relation to catch-up growth, at 8 months. One hundred and ninety two infants less than 1,500 grams were divided into two groups, thirty-eight SGA and one hundred fifty-four AGA. At eight months, eight tertiary subgroups were created and measurements were taken again along with the Bayley performance assessment. The developmental scores at eight months for all five normal weight subgroups were above 100, significantly different from those of the subnormal weight groups; SGA (n=19) at 99, AGA (n=30) at 93, and AGA at eight months only (n=13) at 89, p < .005.

The more recent Kelleher, Casey, Bradley, et al. (1993) study incorporates the Infant Health and Development Program which follows a large cohort of low birth weight of 2500 grams or less and with gestation age up to 37 weeks. One hundred eighty of 842 children in the cohort developed FTT. Bayley Mental and Psychomotor Development Indexes were lower for children with FTT than children without FTT for assessments at 12 and 24 months, p < 0.005. At 36 months, the Stanford-Binet IQ scores were lower for children with FTT, 84.7 vs. 89.9 for non-FTT, p < 0.007.

In contrast, the English epidemiologic studies are restricted to infants born at term. Puckering, Pickles, Skuse, et al. (1995) identified from medical records, a cohort of inner city British white children born in 1980. The twenty-three diagnosed with FTT compared to demographically matched controls were found to have strikingly lower developmental quotients on average (77 vs. 97) with deficits of similar magnitude in all the sub-scales of the McCarthy Scales of Children's Abilities. When FTT is defined by slower weight gain, but not by attained weight percentile at any given age, two studies (Corbett, Drewett, and Wright, 1996; Drewett, Corbett, and Wright, 1999) from the same Newcastle research group, but with independent cohorts, at age 6–7 years found on average a three point decrement in WPPSI full scale IQ (84 vs. 87) in one (Corbett, Drewett, and Wright, 1996) and on the Wechsler Intelligence Scale for Children (WISC)-III at 7–9 years (88 vs. 91), but the differences were not statistically significant.

In summary, there is a consistent association between FTT in early life and depressed developmental test scores in the pre and primary school years. While the studies are methodologically disparate and therefore difficult to compare, the direction of the effect is consistent across multiple study designs with samples of diverse ethnicities and gestational age. The magnitude of these effects is quite variable, ranging from 3 to 20 point deficits on standardized cognitive test scores compared to controls. From the perspective of the SSA, the research literature from developed countries suggests that FTT is associated with persistent deficits in cognitive development both at presentation and in follow-up, even if the child's growth has improved. The precise degree of developmental delay that would constitute “disability” from the perspective of the SSA cannot be determined. Most investigators describe developmental scores that are ≥ 1 standard deviation lower than the standard mean score for the test.

Developing Countries

Oral, Motor, and Other Neurologic Findings

In contrast to the data from developed countries which look at neurological findings preceding or concurrent with FTT, studies from the developing world focus on neurological outcomes months to years after the initial diagnosis. Bartel, Griesel, Burnett, et al. (1978) studied the long-term effects of kwashiorkor in 6–12 year old black African children, five to ten years after their hospitalization during infancy. The thirty-one in the index group were compared to siblings and yardmates in the area of psychomotor development. The Lincoln-Oseretsky motor development scale, Smedley hand dynamometer, Reitan Indiana and Halstead neuropsychological test batteries measured motor development, grip strength, and finger-tapping/fine motor speed, but showed no group effects. Two of the ninety-three items involving tapping with feet and fingers were lower for the index group and yardmates compared to the sibling group by Scheffé's multiple comparison, p < 0.10 (Evidence Table 10). In contrast, Galler, Ramsey, and Solimano (1985) reported that children who had been hospitalized for malnutrition in the first year of life showed more neurologic soft signs at ages 5–11 years and impaired scores on the Purdue Pegboard Test between 8 and 15 years, although the latter effect seems to be mediated by IQ. Evans, Hansen, Moodie, et al. (1980) found no impact of early nutritional growth failure on Bender-Gestalt scores between 8 and 9 using sibling controls of children with kwashiokhor.

Bartel, Griesel, Freiman, et al. (1979) in the cohort described above also examined the effect of kwashiorkor on the electroencephalogram using the same study design and comparison groups, but also adding a large control of ninety white children of a higher SES. EEG frequency results were significant for group effect for both hemispheres. There was group effect for the incidence of alpha and delta bands in the right and alpha, delta, and omega in the left hemisphere, p < 0.01. The kwashiorkor consistently scored higher in the delta and lower in the alpha bands compared to the other groups (Evidence Table 10).

Developmental/Cognitive Functions Concurrent with Identification of FTT

A hospitalized Jamaican cohort (Grantham-McGregor, Stewart, and Schofield, 1980; Grantham-McGregor, Stewart, and Desai, 1978) and an epidemiologic out patient cohort from India (Agarwal, Awasthy, Upadhyay, et al., 1992) provide some information about the developmental function of children from developing countries concurrent with acute malnutrition. Grantham-McGregor, Stewart, and Desai (1978, 1980) compared two cohorts of children with third degree malnutrition (one of which later received developmental intervention) with a hospitalized control group at the time of admission and found that the two malnourished groups scored nearly 20 points lower than controls on the Griffith's Mean Development Quotient (61,64, vs. 86), with similar differences in each of the sub-scales of the Griffith's Test. Agarwal, Awasthy, Upadhyay, et al. (1992) looked at Gesell Developmental quotient scores concurrent with the severity of malnutrition at 18,24, and 30 months. At every age there was an inverse relationship between the mean scores on the Gesell and degree of malnutrition. At 3 years of age, the Binet Kulshrestha Intelligence Scale, an Indian adaptation of the Stanford-Binet test, was administered to assess IQ. For overall cognitive development, or IQ, there was a main effect by group; normal group 95.5, Grade I 91.9, Grade II/III 86.8, F = 13.27, p < 001. This result was parallel for measures of motor development, language, and reasoning, p < 001, and concept formation at the level of p < .01. None of the normally nourished children, 23 % of the Grade I malnourished children, and 51% of the Grade II–III children attained scores at age 36 months below 85 (more than 1 std. below the mean).

Developmental/Cognitive Functions in Childhood Among Survivors of FTT in Childhood and Early Adolescence

Two investigators, Evans, Hansen, Moodie, et al. (1980) and Drewett, Wolke, Asefa, et al. (2001) reported on South African and Ethiopian cohorts respectively. To account for possible genetic influences on outcome, Evans, Hansen, Moodie, et al. (1980) performed a longitudinal study in South Africa looking at the long-term effects of early infant food supplements on the development of a group of newborns from fourteen families with older children with a history of undernutrition. The siblings constituted one control group. Fourteen children with kwashiorkor, who at one time were hospitalized, and their closest in age siblings, formed two more comparison groups. Height and weight data was taken at 4 years of age, 2 years after supplementation for the intervention group. The children who had food supplements during infancy were statistically greater in weight than the other groups at age 4 years, indicating less malnutrition. At 7 years post intervention, height and weight data was collected again, at which time, all children were tested with the New South African Individual Intelligence scale. At testing time the advantage in height and weight by the intervention group were gone. Results of the intelligence scale for full scale score showed an overall significance for the intervention group 82.0 over the other 3 groups; 71.9, 70.0, 72.0, p < 0.05. For verbal, the trend was higher for the intervention group, with significant difference over their siblings, 81.3 vs. 70.6, p < 0.05. Their performance score for the intervention group was also higher, 86.3 vs. 71.3 for the kwashiorkor, p < 0.01, and 74.4 for the kwashiorkor's siblings, p < 0.05. In a group of normal birthweight Ethiopian children, Drewett, Wolke, Asefa, et al. (2001) compared children with nutritional growth faltering to weight below the third percentile before 4 months of age to those whose growth faltered between 10 and 12 months of age and those who maintained weights above the third percentile throughout the first year. When evaluated by masked assessors at 24 months of age on an Ethiopian adaptation of the Bayley Scales of Infant Development, both groups of growth falterers scored below the controls, and those who faltered early scored below those who faltered late. Mean PDI scores were 6.6 for the early falterers, 8.5 for the late, and 10.2 for controls. Similarly for the MDI mean scores were 22.6 for the early falterers, 26.6 for the late and 28.9 for controls. All differences were significant at p < .001. However, in this cohort malnutrition was untreated and enduring, and the effects were not attributable to early growth faltering after weight at time of testing was controlled statistically.

There are multiple reports from two prospectively followed West Indian cohorts -- one from Jamaica (Grantham-McGregor, Schofield, and Harris, 1983; Grantham-McGregor, Schofield, and Powell, 1987; Grantham-McGregor, Stewart, and Schofield, 1980; Grantham-McGregor, Powell, Stewart, et al., 1982; Grantham-McGregor, Stewart, and Desai, 1978) and the other from Barbados (Galler, Ramsey, Solimano, et al., 1983a; Galler, Ramsey, Solimano, et al., 1983b). Grantham-McGregor, Schofield, and Harris (1983), Grantham-McGregor, Schofield, and Powell (1987), Grantham-McGregor, Stewart, and Schofield (1980), Grantham-McGregor, Powell, Stewart, et al. (1982), and Grantham-McGregor, Stewart, and Desai (1978) studied the short- and long-term effects of a psychosocial intervention on the mental development of Jamaican children hospitalized with severe malnutrition. The study consisted of three arms: the intervention FTT group, a nonintervention FTT group, and a comparison group hospitalized for reasons unrelated to malnutrition. The later two groups received standard care. Intervention consisted of structured daily play during hospitalization. After discharge the sessions were weekly over 2 years and once every 2 weeks for the third year. Using the Griffith's Mental Development Scales, the Development Quotient (DQ) scores were determined for the three groups at various intervals. When scores at admission were compared with those 6 months later, there were increases for all groups; the intervention group's DQs increased from 86 to 96 compared to 98 to 105 for the control group, p < 0.1 at both intervals. The nonintervention group was statistically behind compared to both intervention and control groups. At 60 months after discharge, the relative positions remained unchanged, with the nonintervention group's DQ score less than the intervention group's DQ score, which was lower than the control group's, 78 vs. 86 vs. 93, respectively, p < 0.01. All groups improved over time with respect to anthropomorphic measures. Samples sizes were small for the intervention, nonintervention, and control groups, 18, 16, and 20, respectively.

Galler, Ramsey, Solimano, et al. (1983a, 1983b) examined the intellectual and behavioral development of 5 to 11 year old Barbadian children hospitalized in their first year of life with Grades II and III malnutrition. The Wechsler Intelligence Scale for Children was administered to 119 index children who had a mean IQ score 12 points lower than the 127 controls, with 50 percent of the index group scoring below 90 compared to 14 percent for the later group. One percent of the comparison and nine percent of the index groups had scores below 70. The sex, age, or socioeconomic status of the child had no significant effect on the Full IQ scores.

In summary, while cohorts in the developing world tend to contain a higher proportion of more severely malnourished children than those in the developed world, there is considerable overlap between the distribution of anthropometric measurements in the two settings. Malnutrition with edema (kwashiokhor) is rare in developed countries, but appears to have similar sequelae to malnutrition without edema which is widely prevalent in both settings.

The evidence from developing countries is mixed with regard to persistent non-cognitive neurological findings after early undernutrition. However, in the developing world children malnourished in the first three years of life, who in developed countries would be diagnosed as “FTT,” consistently show concurrent and persistent developmental/cognitive delay compared to their ethnic and SES peers, with an apparent dose response such that children with the most severe degree and the earliest onset of malnutrition show the greatest magnitude of effect. While controlled follow-up data from the developed world do not extend beyond age 9 years, data from the developing world provide evidence of the persistence of effect into later elementary school and early adolescent age groups.

Evidence that Failure to Thrive (FTT) is Associated with Other Clinical, Psychosocial and Family Factors

Fourteen studies assessed diverse risks associated with FTT. These studies were from developed countries (9 from the US, 4 from the UK and 1 from Israel) and were highly comparable to the FTT population in the US. Some of the associated factors are assumed to precede the development of the clinical syndrome of FTT while others are likely to have followed. We make no attempt to discern direction of causality but describe the associations that have been found to be correlated with the development of FTT.

Among studies from the United States, Pollitt and Eichler (1976) reported that children with FTT demonstrated lower maternal education level (p< .05) and per capita income (p<.01) than their matched controls (N=19). Mitchell, Gorrell, and Greenberg (1980) examined a cohort of children from a rural US health center, of whom 30 (9.6 percent) met criteria for FTT (weight for age <80 percent of the Harvard 50 percentile). Compared to their well-nourished controls (282 cases; 90.4 percent of cohort), FTT cases demonstrated a higher incidence of neonatal problems (jaundice, possible sepsis, and poor feeding, 15% vs. 30%, p<.05). There were no differences in the incidence of prematurity, LBW, or maternal pregnancy complications. Family problems, assessed by Coddington scale, were more common for the FTT group (FTT 36.7% vs. Controls 11%, p< .01). The fact that the diagnosis of FTT generated increased inquiry into home situations presents a potential bias. No SES differences were noted, although the clinic population was 70 percent black and of low SES overall (49–53 percent Medicaid). Evidence of concurrent disability was not sought or described.

Hack, Merkatz, Gordon, et al. (1982) reported on the development of FTT in a population of VLBW infants, both SGA infants who failed to catch up and AGA infants who subsequently fell off in growth. FTT was defined as weight for age more than 2 SD below the mean. Assessment of FTT was at term and again at 8 months corrected age. The diagnosis of FTT at 8 month corrected age correlated with neonatal risk score, an index of severity of the neonatal course, as well as the duration of initial hospitalization (r= 0.28, 0.30, 0.32, p< .005). The incidence of rehospitalization after the neonatal period was also significantly greater in children who failed to thrive (p< .001, Evidence Table 9).

Sherrod, O'Connor, Vietze, et al. (1984) reported on 31 cases of FTT within a study examining abused, neglected, and FTT children with a comparison group. FTT was defined as weight for age less than 2/3 of Harvard 50 percentile weight for age. FTT cases revealed more “anatomical abnormalities” (chi-square=5.44, p< .025) and more family dysfunction (chi square 5.32, p< .025) accounting for or identified at clinic visits over the first three years of life compared to controls (N=24) (Evidence Table 9).

Casey, Bradley, and Wortham (1984) compared 23 FTT cases (<3 percentile weight for age or > 3 SD fall off over time) to 23 appropriate weight controls, all of whom had been referred to a Growth and Development Clinic. Despite close matching for SES, the FTT cases scored lower on the HOME inventory for both total score (p< .04) as well as subsets for maternal responsivity (7.7 vs. 8.9, p< .03), maternal acceptance (5.1 vs. 6.2, p< .01), and organization of home environment (4.7 vs. 5.3, p< .02).

Hutcheson, Black, and Starr, Jr. (1993) presented findings of an observational study examining maternal-infant interactions during feedings in 31 FTT cases (weight <5 percent NCHS) and 39 well nourished controls. No differences were found between FTT and controls for parenting stress, “informal supports”, negative “life events” or negative affect. Age-related differences were found--i.e., maternal affect was rated less positive towards FTT toddlers than FTT infants (p< .05). They noted that as all study subjects were drawn from similar low SES, this may account for the lack of distinction between children with FTT and controls; i.e., poverty may prove a stronger marker for negative maternal interactions than FTT (Evidence Table 9).

Kelleher, Casey, Bradley, et al. (1993) reported on 180 FTT cases, all of whom were preterm/LBW. In comparison to 591 well-nourished preterm/LBW controls, the FTT group manifested a significantly higher incidence of SGA (p< .05) and more suspect or abnormal neurological exams (4.6 vs. 8.9, respectively, p< .005). These children also scored lower on the Rand General Health Rating (p< .05), but not the Stein Total Health Scores. FTT also scored lower on the HOME inventory (32.6 vs. 33.9, p< .03).

Drotar, Pallotta, and Eckerle (1994) studying 31 FTT infants (weight < 5th percentile), found them to have lower composite Family Relationship Index (FRI) scores than 39 controls (p< .01), both at intake (1–9 mos of age) as well as at follow-up at 4 years of age, despite the fact that total scores did show improvement over time (Evidence Table 9).

Four studies were from the United Kingdom (Evidence Table 9). Skuse, Gill, Reilly, et al. (1995) found a four-fold increase in the risk of abuse or neglect among 47 FTT cases (weight for age <3rd percentile) compared to 47 non-FTT controls (RR 4.43; p< .01).

Puckering, Pickles, Skuse, et al. (1995) described fewer positive maternal interactions and a higher incidence of negative interactions among FTT cases (weight <10 percent for age; N=23) compared to controls (N=23; p=. 01). In a matched paired comparison (136 FTT; 136 Control), Drewett, Corbett, and Wright (1999) reported that for those infants noted as failing to thrive during the first 18 months of life (at least 2 weights <5 percent), subsequent follow-up at approximately 8 years of age revealed a significantly greater likelihood for hospital admission, or visit to hospital outpatient clinic compared to controls (p=.033).

Wright and Birks (2000) using a definition of FTT related to fall off in weight gain rather than absolute weight percentiles, found a higher incidence of abuse, neglect, or involvement with social services, although it did not prove statistically significant. FTT infants were found to experience a later onset for solid food feedings (p< .03).

Wilensky, Ginsberg, Altman, et al. (1996) reported that Israeli children with FTT (weight <3 percent for age) were twice as likely to be admitted to hospital in the first year compared to controls (N=50 each group; p< .05). They were also noted to have less stimulating home environments (0.84 vs. 0.92, p< .05).

Studies from developing countries again presented much more severe cases of protein energy malnutrition (PEM), and are therefore less directly comparable to the US FTT population. These studies noted a variety of outcomes associated with FTT. Ghosh, Vaid, Mohan, et al. (1979), in a study from India, compared two groups of children with FTT; mild-moderate PEM (weight 71–80 percent of Harvard 50th percentile for age; N=28) and severe PEM (weight for age <60 percent of Harvard 50 percentile; N=39) to well nourished controls (N=60). Lower nerve conduction was observed in severe PEM cases compared to controls (p< .001); no difference was found between controls and the mild-moderate PEM group. Further significant difference was found between those cases whose PEM had its onset before 12 months compared to those with onset after 12 months (p<.001) (Evidence Table 10).

Bartel, Griesel, Burnett, et al. (1978) published two studies from South Africa; the first study examined psychomotor development among 31 patients identified by hospitalization for kwashiorkor during the first 27 months of life. These cases were studied 5–10 years after identification and treatment to consider the potential long-term effects of early severe PEM. Comparison was made to two control groups; well nourished siblings (N=31) and age matched “yardmates”(N=31). There were no significant differences noted between groups for a variety of psychomotor tasks. Subsequently, these same three groups, with an additional control group of age-matched, well-nourished white children (N=90) were studied by EEG monitoring. Findings included significantly lower mean frequency for both hemispheres in kwashiorkor cases compared to white and sibling controls (p<.05). No difference was found among groups for mean EEG amplitude. There was a higher incidence of delta and theta waves, as well as a lower incidence of alpha waves for kwashiorkor cases than for either sibling or white controls (p<.05). The differences between groups, however, fell within range normal variation and thus the biologic significance of these findings is not clear (Evidence Table 10).

Kothari, Patel, Shetalwad, et al. (1992) studied cardiac mass and function by doppler ultrasound in 25 cases of FTT in India, all of whom had severe marasmus or marasmic kwashiorkor. Left ventricular mass was less in FTT cases than controls (N=26; p<.05), but the LV mass/body weight ratio was higher (p<.001); this represents a poor prognostic factor. Ejection fraction was not different between the groups, but cardiac index was higher (p<.05) in FTT cases. The severity of these cases of malnutrition is underscored by the fact that 2 of the 25 FTT cases died within 3 weeks of study.

Benefice (1992) found that Senegalese children with moderate chronic FTT (N=64) scored lower in physical activity (p<.05); lower work capacity and pulmonary function (FVC) than controls (N=34; p<.001).

In summary, there is persuasive evidence that failure to thrive is associated with a range of organic and psychosocial difficulties that may in themselves secondarily predict or cause significant disability. Categories of associations include socioeconomic factors (lower income, lower maternal education, less enriched family environment/interactions); neonatal morbidity; acute illnesses and hospitalizations; neurological/anatomical abnormalities; family dysfunction; and abuse/neglect.

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