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The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
Carolyn M. Clancy, M.D.
Director
Agency for Healthcare Research and Quality
Jean Slutsky, P.A., M.S.P.H.
Acting Director, Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.
Objectives. The evidence report provides a systematic review of the scientific evidence to answer the question of whether children, defined by investigators as failing to thrive or grow adequately, have a concurrent ‘disability’, or will have one within 6 months. The population of interest includes children age 18 years or younger, both male and female, of all racial, ethnic and socioeconomic groupings.
Search Strategy. Systematic searches were performed for relevant articles in MEDLINE® from 1966 through December 2000, with updates through September 2001. Additional studies were identified from other databases, reference lists of review and primary articles, and from domain experts. Since disability is not a specific medical condition that can readily be searched for, many studies with related concepts (i.e. medically definable impairments that are related to disability) were reviewed to identify potentially relevant studies. Search terms were textwords: failure to thrive, failure to grow, growth retardation, childhood malnutrition, protein-calorie malnutrition, starvation and psychosocial dwarfism
Selection Criteria. Eligibility criteria for study inclusion included: 1) published articles including at least one disability related outcome; 2) cross-sectional or longitudinal studies; 3) studies with at least two arms, one of which had a non-failure to thrive or healthy control group [added to control for potential confounders for any particular statistically significant outcome or covariate]; 4) studies conducted in either developed or developing countries. Studies of sample size of less than 10 subjects per arm, or those concerned primarily with particular diagnoses and conditions were excluded, as were studies published only as abstracts. Investigators' own definitions of failure to thrive were retained despite their resulting variability in inclusion criteria across studies.
Main Results. Including studies found from other sources, a total of 10,966 English language citations were identified. A total of 275 original studies were retrieved for careful evaluation. Detailed examination of these articles identified 52 publications comprising 43 studies that met inclusion criteria. Detailed data extraction was performed on these 43 studies.
Persistent disorders of growth. Overall these studies comparing children who were thriving with those who were undernourished in both developed and developing countries show that children with FTT have poorer growth in weight, height, and head growth, and that this poorer growth is often long-standing despite appropriate interventions. Earlier intervention leads to potentially better long-term outcome.
Associations of FTT with immunologic/infectious outcomes. The evidence that children with FTT have significantly greater susceptibility to infection is strong, with significant immunologic dysfunction and clinical infectious complications seen consistently across a variety of conditions. The laboratory markers of immunologic dysfunction were apparent in children with moderate severity. Only one study demonstrated improvement following immunologic intervention. Severe complications were most prevalent among the most severely malnourished children.
Disabilities related to child behavior associated with Failure to Thrive. The evidence identified by the search showed that children with failure to thrive concurrently exhibited a variety of behavioral disorders as well as at follow-up. The behavioral problems ranged from eating disorders, increased negative and decreased positive affective expression, to lower scores in communication and mood.
Developmental disorders associated with Failure to Thrive. FTT is associated consistently with depressed developmental test scores. In both clinical and epidemiological samples, FTT is associated on average with roughly 2/3 of a standard deviation decrease in developmental test scores. As a result, a greater proportion of children who are failing to thrive than children in a reference population will score in the supplemental security income (SSI) qualifying range for developmental delay.
Evidence that Failure to Thrive (FTT) is associated with other psychosocial and family factors. Compared to well-nourished peers, children with FTT were more likely to have had neonatal problems (jaundice, possible sepsis, and poor feeding, and family problems). There were no differences however in the incidence of prematurity, LBW, or maternal pregnancy complications.
Conclusions. The findings emphasize the importance of early and intensive intervention for children with poor growth velocity (FTT) so as to prevent permanent growth retardation. The evidence also supports the value of identification of children with growth failure as a marker for chronic and multiple acute infections. Children with a history of FTT were found to have clinically and statistically significant behavioral deficits and consistently depressed scores in cognitive, neurological, and psychomotor development. The increased risks for secondary disability generally persist in spite of intervention.
In summary, there is persuasive evidence that failure to thrive is associated with a range of organic and psychosocial difficulties and significant disability. Primary categories of associations include the child's age, socioeconomic factors (lower income, lower maternal education, less enriched family environment/interactions); neonatal morbidity; acute illnesses and hospitalizations; and neurological/anatomical abnormalities.
The Social Security Administration (SSA) requested that the Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Center (EPC) program, provide a systematic review of the scientific evidence on whether children, defined by investigators as failing to thrive or grow adequately, have a concurrent disability, or will have one within 6 months. The population of interest includes children age 18 years or younger, both male and female, of all racial, ethnic, and socioeconomic groupings.
The evidence report was prepared to assist SSA in updating its Listing of Impairments and revising its disability policy, as may be appropriate.
The underlying cause of failure to thrive (FTT) is always insufficient usable nutrition. This may occur when sufficient nutrients are not available to the child as a result of social or environmental causes that prevent parents from obtaining, preparing, or offering age-appropriate foods to the child. This growth failure often includes concurrent and potentially persistent disability. This syndrome of under-nutrition, previously termed “non-organic FTT” is recognized as a multifaceted disease. Because of this, the world's literature on the disabilities of poorly nourished children in developing as well as developed countries becomes relevant to the discussion of disability arising from FTT even in the United States.
In addition, almost any serious pediatric illness can result in FTT. There are three basic mechanisms for this phenomenon:
(1) insufficient nutrition is available to the child because of the child's inability to feed properly, e.g. severe neurological dysfunction, gastroesophageal reflux, cleft palate; (2) nutrition is adequate but inadequately absorbed and/or utilized (malabsorption syndromes); or (3) the disease process creates added metabolic requirements, e.g. asthma, cardiac failure, thyroiditis. It is not uncommon for FTT to be the first clue to an active disease process which has not yet manifested itself in specific symptomatology.
Whatever its multidimensional causes, FTT affects growing children in many important ways. Severe malnutrition has been shown to cause permanent damage to various parts of the brain and central nervous system, leading to a range of disabilities manifested by aberrant behavioral, cognitive, language, and motor development. In addition, FTT is closely linked with infectious disease. Children who are undernourished (of which FTT is an indicator) consistently have been found to have significant and profound changes in cell-mediated immunity, complement levels, and opsonization that lead to susceptibility to various infections. FTT is associated with disabilities also in cardiac functioning, gastrointestinal conditions, persistently small stature, and other physiological derangements.
The key question posed by SSA was refined by the EPC Evidence Review Team and technical experts to review the association of five categories of disability with failure to thrive.
Key Question: Among children defined by investigators as failing to thrive or grow adequately, what evidence exists that they have, or will have within 6 months, a concurrent disability?
The following associations between FTT and disability were investigated:
Persistent disorders of growth following FTT
Association of FTT with immunologic/infectious outcomes
Child behavior associated with FTT
Developmental disorders associated with FFT
Association of FTT with other psychosocial and family factors
Most clinicians make a diagnosis of FTT when a child's growth in weight and/or in height fails to increase as expected for his or her age. Operationally this is frequently defined as a crossing of two or more standard percentile lines in a standard growth chart. Other clinicians use a definition of FTT that can be assessed without access to growth charts, or that can be assessed at a single point in time. These definitions include children who are persistently at or below the third or fifth percentile for weight, or less than the 80th percentile of median weight-for-height.
Other definitions used commonly in the professional literature include height-for-weight <3rd percentile; weight-for-age less than 3rd or 5th percentile or less than 80 percent of mean for age; weight-for-height <10th percentile; and weight-for-age less than 2 standard deviations below the mean for age. Because of inconsistent definitions it is hard to make comparisons among the various investigative approaches to this syndrome.
Current SSA guidelines consider FTT to be present when there is a fall in weight to below the 3rd percentile or to less than 75 percent of median weight-for-height or age in children under 2 years old. There must be no underlying medical disorder, and growth failure should last, or be expected to last, for at least 12 months.
Earlier research attempted to distinguish FTT that resulted from a known organic disease process from the more common circumstance in which the specific cause for the growth failure is unknown. This distinction is no longer considered useful. Instead, current data suggest that organic and non-organic causes and effects are intertwined in most affected children. This review therefore will not use the terms organic or non-organic FTT.
Disability is not a specific medical condition that can readily be searched for. Thus, we had to look at many studies with related concepts (i.e., medically definable impairments that are related to disability) to identify potentially relevant studies.
The main search consisted of a MEDLINE® search from 1966 through December 2000. A broadly sensitive, rather than specific, search strategy was employed to identify relevant studies. The search strategy used the following textwords: failure to thrive, failure to grow, growth retardation, childhood malnutrition, protein-calorie malnutrition, starvation and psychosocial dwarfism. Development of the search strategies was an iterative process that included input from domain experts. Keywords from known relevant studies were used to refine and focus the final search strategies used. Results were limited to studies in age-group under 18 and English language only. Various investigators defined the population of interest differently. We accepted whatever definition the investigator had used to identify children who were not growing as expected. We also inspected references from retrieved primary studies, relevant reviews, and consulted with technical experts and colleagues in order to identify additional studies.
Including studies found from other sources, a total of 10,486 English language citations were identified in the initial search. An updated MEDLINE® search using the same search strategy was conducted in September 2001 which resulted in additional 480 abstracts.
Titles and abstracts were manually screened by physician members of the EPC and pediatricians to identify potentially relevant articles. Inclusion criteria for article selection were as follows: 1) published articles including at least one disability-related outcome; 2) cross-sectional or longitudinal studies; 3) studies with at least two arms, one of which had a non-FTT or healthy control group; and 4) studies conducted in either developed or developing countries. The third inclusion criteria was added to control for potential confounders for any particular statistically significant outcome or covariate. Studies of sample size of less than 10 subjects per arm, or those concerned primarily with particular diagnoses and conditions were excluded, as were studies published only as abstracts.
The mechanisms of undernutrition have been well-studied in developing countries. In addition, the associations of undernutrition and various outcomes such as cognitive and neurological development and infections are clearly delineated in these conditions. Because undernutrition as applied to developed countries may not be understood or studied as extensively, studies in developing countries were included to help correlate associations made.
A total of 275 original studies were retrieved for careful evaluation. Detailed examination of these articles identified 52 publications comprising 43 studies that met the inclusion criteria. Detailed data extraction was performed on these 43 studies. Their overall methodologic quality will be described individually below.
Findings from Industrialized Nations. Seven studies compared anthropometric data of FTT patients with healthy comparison groups in developed countries. Most studies were performed in the United States or the United Kingdom, with one study from Israel. The majority of the studies were prospective-longitudinal, and two of the studies were ambidirectional blinded studies. Six out of seven of these studies show a statistically significant association between FTT and sub-optimal weight-for-height and weight-for-age. This growth retardation for the most part persists despite adequate correction of malnutrition. The clinical significance of this degree of growth retardation is not clear.
Findings From the Developing World. Seven studies compared anthropometric data of FTT patients with well-nourished control groups in developing countries. The studies in developing countries mainly compared children with marasmus and kwashiokor to healthy controls, mostly from outpatient settings, and six of the seven studies found similar associations. One study 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. The addition of more adequate nutritional supplementation to such children would be anticipated to aid in these improvements in outcome. Two other studies also showed significant differences in body fat and arm muscle composition in the FTT groups compared to controls; in one of the studies, the decreased body fat and muscle mass had a negative impact on physical performance.
Overall these studies comparing children who were thriving with those who were undernourished in both developed and developing countries show that children with FTT have poorer growth in weight, height, and head growth, and that this poorer growth is often long-standing despite appropriate interventions. Earlier intervention leads to potentially better long-term outcomes. 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.
A total of 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.
Of the studies, seven were prospective cross-sectional studies and one study was retrospective. Only two studies were longitudinal; all others were cross-sectional. The principal source of potential bias involved the selection of controls. One study included adults as well as children in the controls; additionally, there were only controls (no FTT patients) entered from the children in an urban study center. The FTT and control groups in one study were from different hospitals serving different social-economic status (SES) populations; in another study controls included children with “nutritional growth retardation,” likely comparable to the United States FTT population.
Studies comparing children who ware thriving with those who were undernourished in both developed and developing countries show that children with FTT have such factors as significantly decreased chemotactic response to bacterial endotoxin as well as phagocytosis of zymogen particles; significantly lower percentages of rosette forming cells (a sensitive marker of cellular immune function); and reduced Candida killing ability. Studies comparing the same cohort of children also show that children with FTT have significantly greater evidence both clinically and in the laboratory of susceptibility to infection. These findings emphasize the importance of identifying children who are failing to grow normally since their growth failure may be a marker for a variety of chronic and multiple acute infections that would otherwise be hard to identify. In addition, treatment of FTT provides an opportunity to prevent the far more destructive consequences and costs associated with chronic infectious conditions in children.
Fifteen studies examined the relationship between FTT and behavioral disorders. Evidence will be presented in three areas.
Evidence of Concurrent Feeding-Related Behavior Problems Associated With Failure To Thrive. Four studies noted concurrent feeding disorders in children diagnosed with FTT. Behavior problems were more common in children with FTT, even beyond those children who were known to be failing to grow on the basis of neurological or other organic damage or disease. Children had such factors as 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. Also, parents reported more feeding problems during infancy for the FTT cases, and described their children as uninterested or poor eaters.
Evidence Suggesting Other Concurrent Behavioral Problems. Four studies examined behavior problems that were either diagnosed concurrently with diagnosis or within the ensuing weeks or months. These behavior problems were related to evidence of insecure attachment, and problems with communication and with mood/affect. The FTT groups scored significantly lower than controls on reports describing affect and communication skills, matched for such factors as age, sex, and race.
Evidence Regarding Behavior Problems Detected in Followup After a Diagnosis of Failure To Thrive. Seven studies evaluated children with FTT for behavioral disorders. When compared to the controls, the index groups had significantly more family problems, poor psychological development, or behavioral deficits as measured by a variety of behavioral screening questionnaires or checklists used in the studies.
FTT is consistently associated with evidence of neurologic 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 most rapid 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. In addition, FTT appears to heighten developmental vulnerability to other adverse environmental factors. In addition, subtle neurologic 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. We present data from three domains.
Five prospective, epidemiologic, and observational studies consistently noted increased rates of feeding difficulties in children with FTT with some investigators also noting clinically poorly specified “neurologic” findings other than in feeding skills. Since these studies are often based on parental report, it is difficult to disaggregate true subtle neurologic (either oral motor or sensory) deficits in feeding from parental perceptions and from learned behaviors. However, delays in acquisition of mature feeding skills are a consistent finding in every study where they have been assessed.
Historically, developmental delay was considered by some authors as one of the criteria necessary for a diagnosis 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 gain alone. Thus many older studies do not include children who are failing to thrive but developing normally. In addition 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 some experimenter effect cannot be ruled out in the studies summarized below.
There are three United States studies, two based on hospitalized children and the other on a sample not hospitalized but drawn from an outpatient inner city clinic (Mackner, Starr, Jr., and Black, 1997). In all three studies, the average Bayley Mental Development (MDI) scores were strikingly and significantly lower in children who had been identified with FTT compared to the control groups.
Two studies from the United Kingdom reported similar findings. Infants with FTT had scores that were significantly lower than controls on both the Bayley MDI (98.2 vs.108.5) and Psychomotor Development Index (PDI) (96.7 vs. 103.6). 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.
Four studies evaluated developmental/cognitive function in later childhood among survivors of early FTT. Three of the four were United Kingdom studies; one, a United States study. Two were ambidirectional longitudinal studies, one prospective longitudinal and the fourth, an ambidirectional cross-sectional study. Two were of high quality, two, of low quality. In one study, children with a history of FTT were found to have clinically and statistically significant cognitive deficits. The remaining three studies found that FTT was associated with decreased cognitive, motor, or neurological measures compared to controls.
At the time of identification, FTT is associated with lower than expected developmental test scores, especially 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 Supplemental Security Income qualifying range of developmental delay than children in a reference population.
Thirteen studies assessed diverse risks associated with FTT. These studies were from developed countries (eight from the United States, four from the United Kingdom and one from Israel) and populations were highly comparable. Five studies were prospective longitudinal, three were prospective cross-sectional, two each were retrospective longitudinal or ambidirectional cross-sectional, and one, ambidirectional longitudinal.
There is persuasive evidence that FTT is associated with a variety of other difficulties that may 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. Clearly these factors may precede the infant's FTT and/or occur subsequent to it. These variables are almost certainly multiply interrelated and the directions of causation impossible to describe in a linear fashion (for example, poverty may be one factor that leads to malnutrition, which increases the risk of illness/disability, which leads to increased poverty).
The studies comprising this report, though insufficient in number and variable in their methodologic quality and their potential biases, were of sufficient validity to provide significant information regarding the association of FTT with disability. The variety and long-term nature of the disabilities associated with FTT have major impact on the child, the family, and society.
Notwithstanding this, it may well be that the most significant finding of this review was the paucity of information available on the subject. Much remains to be learned regarding the extent and specifics of these associations and disabilities. Even more remains to be determined as to the optimal management of these patients.
The following recommendations for future research address specific problematic issues and limitations identified from review of existing research:
One of the central problems in interpreting these studies was the heterogeneity of definitions of FTT. This variability in case definition makes it unclear how well the population at risk is being identified at present. Future research should apply a uniform definition of FTT. This would serve to facilitate comparison and perhaps even allow a meta-analysis of studies. It would also define more clearly the true prevalence of FTT.
Within the definition of FTT, provisions should be made for categorization based upon 1) severity and 2) longevity or duration of growth failure. The data currently available indicate that both of these factors are strong predictors not only for the risk of associated disabilities but for potential response to therapy as well. Refining the classification of the FTT population in this way would facilitate identification of the relative risk of disability for an individual FTT child. It would also help in the evaluation of intervention studies.
Although it is clear that the degree of disability increases with increasing severity of growth failure, this is an imprecise correlation especially in children with mild to moderate FTT. Since the majority of FTT that is seen in the United States tends not to be the most severe forms of marasmus and kwashiorkor, future research should specifically target those children with mild to moderate growth failure.
Similarly, more research needs to be conducted in the United States or in developed countries with comparable social-economic structures and health care systems.
Special emphasis should be given to outcomes focusing on neurodevelopmental and cognitive disorders. The data presented in this report indicate that this is likely one of the areas of strongest impact of FTT and certainly one with the greatest relevance for long-term disability. Specifically, very few studies have focused on the issue of FTT and brain growth during the immediate post-neonatal period and early infancy. This is one of the most critical periods for dendritic arborization, axonal myelination, and the development of cognitive functions. More studies are needed in this area.
Further study is also needed on the association of FTT with general health outcomes because of their potential impact on the health care system. Beyond the risk to the individual child, the data linking FTT to increased risk of infections and poorer general health may have important implications at a broader level. Such data may help us understand the true “cost” of FTT and prove useful in evaluating intervention strategies.
In order to better define the true nature and extent of the disabilities associated with FTT, more studies are needed that prospectively follow children for a sufficient duration to capture the more complex disabilities that may result from FTT.
A consistent finding among the studies reviewed was the ineffectiveness of existing intervention programs. Although strictly beyond the focus of this report, much work still needs to be done on developing effective treatment programs for children with FTT. Unfortunately, the optimal intervention will yet require better definition of the complex physical, medical, cognitive, and psychosocial problems associated with FTT
The Social Security Administration (SSA) of the Department of Health and Human Services requested that the Agency for Healthcare Research and Quality, through its Evidence-based Practice Center (EPC) program produce an evidence report on the failure to thrive (FTT) syndrome. The purpose of this initiative is to assess evidence relating to the relationship between FTT and disability.
This is one of three reports requested by SSA in the broader topic of “Criteria for Determining Disability in Infants and Children.” The evidence reports are prepared to assist the SSA in updating its Listing of Impairments, and revising its disability policy, as may be appropriate.
The syndrome of failure to thrive (FTT) is variously defined but in general terms it describes children who fail to maintain normal age and sex-adjusted growth parameters. FTT is not a diagnosis, but a syndrome that results from many different medical, social, or environmental processes. Children may fail to grow because they receive insufficient nutrients to sustain their caloric needs; because they fail to absorb and/or utilize the nutrients they take in; or because their caloric needs are excessive and thus the usual amount of nutrition is still insufficient for them to grow normally.
FTT sometimes reflects a systemic health condition or it may be a marker for some undiagnosed physiological derangement. In addition, FTT may itself exacerbate other unrelated conditions; and it can cause a variety of new health problems. We will address these various ramifications of growth failure in turn.
Current SSA guidelines consider FTT to be present when there is a fall in weight to below the 3rd percentile or to less than 75% of median weight-for-height or age in children under two years old. There must be no underlying medical disorder, and growth failure should last, or be expected to last, for at least twelve months. These guidelines are to be updated and the purpose of this review of the literature was to generate an evidence base to assist the SSA in revising its disability policy with regard to children who are failing to thrive.
Most clinicians make a diagnosis of FTT when children's growth in weight and/or in height fails to increase as expected for their age. Operationally this is frequently defined as a crossing of two or more standard percentile lines in a standard growth chart. Other clinicians use a definition of FTT that can be assessed without access to growth charts, or that can be assessed at a single point in time. These definitions include children who are persistently at or below the third or fifth percentile for weight, or less than 80 percent of median weight-for-height or weight-for-age.
Other definitions are used commonly in the professional literature such as height-for-weight <3rd percentile; weight-for-age less than 3rd or 5th percentile or less than 80 percent of median for age; weight-for-height <10th percentile; and weight-for-age more than 2 standard deviations below the mean for age. Because of inconsistent definitions it is hard to make comparisons among the various investigative approaches to this syndrome.
Earlier research attempted to distinguish FTT that resulted from a known organic disease process from the more common circumstance in which the specific cause for the growth failure is unknown. This distinction is no longer considered useful. Instead, current data suggest that organic and non-organic causes and effects are intertwined in most affected children. Therefore, this review will not use the terms organic or non-organic FTT. Parenthetically, the SSA definition is a reflection of an outdated conceptual model and should be reconsidered. It does not reflect the current thinking, which is that failure to thrive is a complex interaction of medical, nutritional developmental, and social factors which all can contribute to disability.
Depending on the definition used and demographics of the population sampled, the reported prevalence of FTT ranges from 1.3% to 20. 9% (Reilly and Skuse, 1994). Previous reports have estimated its prevalence among hospitalized children to be from 1 to 5% (Zenel, Jr., 1997). It is difficult to estimate the true prevalence of FTT due to the variety of diagnostic criteria used to identify it, and because most children are not hospitalized.
Cross sectional data from the developing world suggest that weight for age is a potent predictor of mortality, while height for age, which reflects duration of insult, correlates with developmental outcome (Wright, Ashenburg, and Whitaker, 1994). Further research is needed to define which criteria are the best predictors of medical and cognitive sequelae of FTT in the United States.
The underlying cause of FTT is always insufficient usable nutrition. This may occur when sufficient nutrients are not available to the child as a result of social or environmental causes that prevent parents from obtaining, preparing, or offering age-appropriate foods to the child. This growth failure often includes concurrent and potentially persistent disability. This syndrome of under-nutrition, previously termed “non-organic FTT” is recognized as a multifaceted disease. Because of this, the world's literature on the disabilities of poorly nourished children in developing as well as developed countries becomes relevant to the discussion of disability arising from FTT even in the USA.
In addition, almost any serious pediatric illness can result in FTT. There are three basic mechanisms for this phenomenon: (1) insufficient nutrition is available to the child because of the child's inability to feed properly, e.g. severe neurological dysfunction, gastroesophageal reflux; cleft palate; (2) nutrition is adequate but inadequately absorbed and/or utilized (malabsorption syndromes); or (3) the disease process creates added metabolic requirements, e.g. asthma, cardiac failure, thyroiditis. It is not uncommon for FTT to be the first clue to an active disease process, which has not yet manifested itself in specific symptomatology.
Whatever its multidimensional causes, FTT affects growing children in many important ways. Severe malnutrition has been shown to cause permanent structural aberrations in the central nervous system. Even mild malnutrition not sufficient to cause dramatic growth failure has been associated with aberrations in neural transmitters and CNS functions with the detectable impairments reflected in a range of disabilities. In addition, FTT is closely linked with infectious disease. Children who are undernourished (of which FTT is an indicator) consistently have been found to have significant and profound changes in cell-mediated immunity, complement levels, and opsonization (vi) that lead to susceptibility to various infections. FTT is associated with persistently small stature. Severe FTT are associated with multiple physiological derangement in cardiovascular and gastrointestinal functioning.
The review that follows attempts to determine the value of the symptom complex of FTT as a marker for basic physiological derangements that might otherwise be either undetectable or non-existent. That is, we are interested in how often a child's failure to grow occurs prior to or coincident with another potentially disabling childhood condition. We do not consider the co-occurrence of FTT with known chronic health conditions that are already regarded as disabling e.g. cystic fibrosis, congenital heart disease, or celiac disease, although undernutrition is known to exacerbate the severity and course of these and other pediatric health conditions. The question that directed this review is: Among children defined by investigators as failing to thrive or to grow adequately, what evidence exists that they have a concurrent disability, or will have one within six months. The definition of disability used for this investigation is an operational one; “the presence of a medically determinable physical or mental impairment that causes marked and severe functional limitations and that is expected to last for 12 months or more”.
Malnutrition severe enough to produce growth failure also impairs immuno-competence, particularly cell-mediated immunity, and diminishes production of complement and secretory IgA. Recurring otitis media, gastrointestinal and respiratory infections are more common among children who fail to thrive than among well-nourished children of the same age.
Children who are not thriving are often trapped in an infection-malnutrition cycle. With each illness, the child's appetite and nutrient intake decrease while nutrient requirements increase as a result of fever, diarrhea, and vomiting. In settings in which nutrient intake is already marginal, even when the child is well, cumulative nutritional deficits occur, leaving the child increasingly vulnerable to more severe and prolonged infections and even less adequate growth. Even in developed countries, malnourished children succumb more often than thriving children to fulminating infections. The more common syndrome of recurrent low-grade infections interferes with both physiologic and psychological processes of childhood.
Insufficient nutrition is associated with perturbations of neurotransmitters and impaired exploration and learning, even before growth is affected. By the time a child has experienced under-nutrition for a long enough period to be identified as “failing to thrive” there have been many “silent” episodes of impaired learning and interaction which cumulatively produces lasting disabilities in cognition and social behavior. Evidence from developing countries of the dire effects of protein-calorie malnutrition on intelligence and social behavior have shed light on the mechanisms that result in impairments at even far less extreme levels of malnutrition, such as those found in the US with alarmingly high prevalence.
These mechanisms account for the most significant persistent physiological derangement that is associated with FTT, namely that of central nervous system function. The majority of available data documents both delayed development and disordered behavior and affect in children at the time of diagnosis of FTT/malnutrition. This is particularly true of children who come to medical attention because of their growth failure, but also to a lesser extent of children identified only in epidemiologic surveys. The majority of studies of clinically diagnosed cases of FTT show reproducible developmental impairments. Various aspects of school achievement, memory, and attentional functions seem to suffer lasting impairment. The effects on the CNS are both structural with impaired myelinization and dendritic arborization, and functional in terms of altered neurotransmitter synthesis.
Growth failure is the most obvious and persistent symptom and sequelae of FTT. Depending on the age of the child when growth failure occurred and the length of time it existed before it was corrected, short stature almost always persists even after the child is once again adequately nourished.
Elevated lead levels correlate with impaired growth, even in the 5 to 35 mg/dl range. Here too, a negative cycle develops. Nutritional deficiencies of iron and calcium enhance the absorption of lead and other heavy metals. As lead levels rise, constipation, abdominal pain, and anorexia occur, leading to even less adequate dietary intake. In a recent study, 16% of children with FTT had lead levels high enough to warrant chelation.
Some of the disabilities created and/or maintained by malnutrition/FTT are restored with nutritional rehabilitation, such as immune, gastrointestinal, and cardiac function, and weight for height. On the other hand, other disabilities are permanent; there are persistent impairments in stature, cognition, attention, and behavior.
This evidence report is based on a systematic review of the literature. Several teleconferences were held with the science partner representatives from the Social Security Administration (SSA), the American Academy of Pediatrics (AAP), the internal technical experts from the EPC, and a representative of the Disability Law Center to refine and address the key question formulated by SSA. A comprehensive search of the medical literature was conducted to identify the evidence available to address the questions.
Detailed information about each study used in the systematic review was abstracted. The results are presented as detailed evidence tables. Information directly pertinent to answer each aspect of the key question is presented in summary tables with the Results chapter (Chapter 3).
Current SSA guidelines consider FTT to be present when there is a fall in weight to below the 3rd percentile or to less than 75% of median weight-for-height or age in children under two years old. There must be no underlying medical disorder, and growth failure should last, or be expected to last, for at least twelve months. Disability is defined as the presence of a ‘medically determinable physical or mental impairment’ that causes ‘marked and severe functional limitations’ and that is expected to last for twelve months or more. In turn, a ‘medically determinable impairment’ is ‘an impairment that results from anatomical, physiological, or psychological abnormalities which can be demonstrated by medical evidence consisting of signs, symptoms and laboratory findings’ (Disability evaluation under Social Security. Social Security Administration, 1999)
SSA Functional limitations may occur in any of six areas of functioning: 1) acquiring and using information; 2) Attending and completing tasks; 3) Interaction with others; 4) Moving about and manipulating objects; 5) caring for oneself; and 6) health and physical well-being. Marked limitation in two areas or extreme limitation in one suffices to establish disability. These guidelines are to be updated and the purpose of this study question was to generate an evidence base to assist the SSA in revising its disability policy.
Following a series of teleconferences, science partners and EPC technical experts arrived at a consensus on the main study question as outlined below:
Among children defined by investigators as failing to thrive or grow adequately, what evidence exists that they have a concurrent disability (or will have one within six months)?
For the purposes of this question, the SSA definition of disability was applied; however, the definition of FTT was expanded to include growth failure in children older than two years, with failure to grow at the expected rate, without reference to specific percentile height and weight cutoffs or underlying medical conditions. Duration of disability was to be at least six months.
Disability is not a specific medical condition that can readily be searched for. Thus, we had to look at many studies with related concepts (i.e. medically definable impairments that are related to disability) to identify potentially relevant studies.
The main search consisted of a MEDLINE® search from 1966 through December 2000. A broadly sensitive, rather than specific search strategy was employed to identify relevant studies. The search strategy used the following textwords: failure to thrive, failure to grow, growth retardation, childhood malnutrition, protein-calorie malnutrition, starvation and psychosocial dwarfism. Results were limited to studies in age group under 18 and English language only. We also inspected references from retrieved primary studies, relevant reviews, and consulted with technical experts and colleagues in order to identify additional studies.
A total of 10,486 abstracts were identified in the initial search. An updated MEDLINE® search using the same search strategy was conducted in September 2001, which resulted in additional 480 abstracts.
Physician members of the EPC and pediatricians manually screened titles and abstracts to identify potentially relevant articles. Inclusion criteria for article selection were as follows: 1) published articles including at least one disability-related outcome; 2) cross-sectional or longitudinal studies; 3) studies with at least two arms, one of which had a non-failure to thrive or healthy control group; 4) studies conducted in either developed or developing countries. Studies of sample size of less than 10 subjects per arm or those concerned primarily with particular diagnoses and conditions were excluded, as were studies published only as abstracts. The third inclusion criterion was added to control for potential confounders for any particular statistically significant outcome or covariate.
The mechanisms of undernutrition have been well studied in developing countries. In addition, the associations of undernutrition and various outcomes such as cognitive and neurological development, and infections are clearly delineated in these conditions. Because undernutrition as applied to developed countries may not be understood or studied as extensively, studies in developing countries were included to help correlate associations made.
Disability-related concepts include mental or physical impairment that results from anatomical, physiological, or psychological abnormalities that can be shown by medically acceptable clinical and laboratory diagnostic techniques. A physical or mental impairment must be established by medical evidence consisting of signs, symptoms, and laboratory findings. The rational is to relate FTT with physical or mental impairment. There are factors that in turn may cause or modify the severity of the impairments. Listed below are factors or correlates explored in this evidence report.
The data abstraction form was developed as part of an iterative process involving the methodologic and domain experts. The form was designed to capture data from primary articles including study setting, demographic data on the study subjects as well as data on the family social-economic status (SES), inclusion/exclusion criteria, number of subjects, study design, funding source, relevant measurements and outcomes evaluated, statistical methodology, results, potential biases, and study quality.
As part of the data abstraction form development, domain experts performed data abstraction after a training period. Each pediatrician tested the form with two different articles and each article was extracted at least twice by different pediatricians. Because of the variation of data reporting by the primary articles, this process also served to validate the forms.
Data abstraction of each study was performed in duplicate, once by the pediatrician and once by an EPC methodologic staff. Discrepancies were resolved in a conference or by a third reviewer.
The evidence we found for the FTT is summarized in two complementary forms. The evidence tables provide detailed information about the feature of study design and results of all the studies reviewed. A narrative and tabular summary of the strength and quality of the evidence of each study are provided for each main outcome. In addition, the country in which the study was conducted was divided between two sets of tables categorized by developed and developing countries. This is for the purpose of generalizability as conditions are more severe in developing countries and may not apply to the FTT populations in the United States. However, the outcomes can provide a parallel comparison to measure the strength of association.
Evidence tables were constructed for five different categories and grouped between developed and developing countries. The categories include cognitive & neurological development, behavioral problems, immunologic response or infectious diseases, anthropometrics, and other correlates/outcomes. They are presented under the Evidence Tables section of this evidence report:
| Table Number | Table Content |
|---|---|
| Evidence Table 1 | Studies associating anthropometrics with Failure to Thrive patientscompared to healthy control subjects in developed countries |
| Evidence Table 2 | Studies associating anthropometrics with malnourished patients compared to well-nourished control subjects in developing countries |
| Evidence Table 3 | Studies associating immunologic response or infectious diseases with Failure to Thrive patients compared to healthy control subjects in developed countries |
| Evidence Table 4 | Studies associating immunologic response or infectious diseases with malnourished patients compared to well-nourished control subjects in developing countries |
| Evidence Table 5 | Studies associating behavioral problems with Failure to Thrive patients compared to healthy control subjects in developed countries |
| Evidence Table 6 | Studies associating behavioral problems with malnourished patients compared to healthy control subjects in developing countries |
| Evidence Table 7 | Studies associating cognitive & neurological development with Failure to Thrive patients compared to healthy control subjects in developed countries |
| Evidence Table 8 | Studies associating cognitive & neurological development with malnourished patients compared to well-nourished control subjects in developing countries |
| Evidence Table 9 | Studies associating other correlates / outcomes with Failure to Thrive patients compared to healthy control subjects in developed countries (miscellaneous) |
| Evidence Table 10 | Studies associating other correlates / outcomes with malnourished patients compared to well-nourished control subjects in developing countries (miscellaneous) |
Summary tables were created to describe studies reviewed for each main topic. The tables describe the strength of the evidence according to six dimensions: study size, age at follow-up, duration of follow-up, study sample applicability, strength of association, and methodological quality. The study data on follow-up duration and age at enrollment were presented in a heterogeneous manner that required reporting of follow-up data to be approximated in some cases. When possible, follow-up time was calculated from the age of diagnoses of FTT or malnutrition. The summary tables are presented in Chapter 3 of this evidence report.
In order to answer the key questions, it was necessary to assess the strength of the available evidence. There is no current standard approach to assess the methodological quality and the reliability of these studies. In this report, we used the evidence-grading scheme described below.
Methodological quality (or internal validity) refers to the design, conduct, and reporting of the clinical study. Because studies with a variety of design types were evaluated, a three-level classification of study quality, used in previous reports, was modified:
Least bias: Results
are valid. A study that mostly adheres to the commonly held concepts of high
quality, including the following: a formal study; prospective design, clear
description of the population and setting; proper measurement techniques;
appropriate statistical and analytic methods; no reporting errors; no
obvious bias.
Susceptible to some
bias, but not sufficient to invalidate the results. A study that does not
meet all the criteria of category A. It has some deficiencies but none
likely to cause major bias.
Significant bias that
may invalidate the results. A study with serious errors in design or
reporting. These studies may have large amounts of missing information or
discrepancies in reporting.
Applicability (also known as generalizability or external validity) addresses the issue of whether the study population is sufficiently broad so that the results can be generalized to the population of interest at large. The study population is typically defined by the inclusion and exclusion criteria. The target population was defined to include patients with non-organic failure to thrive, except for studies that included a small subset of FTT deriving from possible or definite organic etiology. A designation for applicability was assigned to each article, according to a three-level scale.
Patients enrolled in
the trial represent a broad spectrum of the population (high degree of
applicability). Typically this would be a large study, although a large
study in itself does not guarantee a high degree of generalizability.
The study included
only a narrow/restricted study population, but the result is relevant to
similar types of patient population (restricted applicability). Typically
this would be a small study, but may also be a large study of a very
homogeneous population.
Studied outlier
population that is not immediately relevant to the study question (very
limited direct applicability or not applicable), or where the study reported
only limited information.
Results are represented by proportions (percents), categorical variables, mean levels for continuous variables, and associations between study measures and children with FTT compared to children without FTT. Symbols indicate the type and significance of associations between study measures.
or
Statistically significant association, (p <
.05)
Positive association
No association
Negative association
or inverse relationship
The study size is used as a measure of the weight of the evidence. Some studies have a high drop out rate due to lost to follow-up; we provide both the enrolled and evaluable number of patients, when these data are reported. A large study provides a more precise estimation of the treatment effect but does not automatically confer broad applicability unless the study included a broad spectrum of patients. Very small studies, taken individually, cannot achieve broad applicability. But several small studies that enrolled diverse populations, taken together, may have broad applicability. The study size is included as a separate dimension used to assist the assessment of applicability. For summarizing all studies, this would be the number of studies and the total number of patients in these studies.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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).
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.
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.
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).
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).
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).
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.
This research has produced an evidence base that the SSA can use to help update its disability guidelines and to revise its disability policy. The review was designed to address the following question: Among children defined by investigators as failing to thrive (FTT) or grow adequately, what evidence exists that they have a concurrent disability (or will have one within six months)?
We reviewed 275 articles and used 52 articles encompassing 43 studies to produce this evidence report. It should be stressed that the single most common reason for exclusion was the lack of a non-FTT comparison group, as we thought that no valid associations could be drawn from descriptive reports or interventional studies that lacked an appropriate control. The quality of the studies we were able to use was variable. While the study question regarding FTT is clear, most of the studies were not designed to specifically address issues relating to disability as defined by the U.S. Congress and interpreted by SSA. Despite this, the evidence extracted from the articles we reviewed clearly suggests a relationship between FTT and concurrent disability, disability within 6 months, and disability beyond 6 months. We described this evidence with respect to specific disabilities in Chapter 3, and in this section we review the implications of those findings as well as some limitations of the studies.
There are a number of potential confounders that need to be considered. The studies from developed countries looked at FTT mainly in lower social-economic status (SES) groups. Several potential risk factors for developing FTT are prevalent among lower SES populations, such as lower family income and maternal level of education, higher incidence of abuse or neglect, family dysfunction and negative maternal interaction. Such factors may exert independent and potentially stronger negative influences on childhood health, well-being and development than those of growth failure, thereby masking the specific deleterious impact of the failure to thrive. Alternatively, the diagnosis of FTT may inherently create bias by increasing clinicians' suspicion and subsequent investigation for potential covariates such as disturbances in family dynamics, or maternal interaction, abuse and neglect.
Studies from developing countries were generally examining the effects of severe malnutrition, often marasmus or kwashiorkor. The extrapolation of their results to the FTT population in the US must be approached with some caution. Lastly, even within developed countries, where the population of FTT children was generally well matched to those in the US, the available studies still demonstrated significant variation, both in specific FTT inclusion criteria, and exclusion criteria (e.g., LBW/SGA).
There is substantial evidence that long term growth in all parameters (weight, height, and head circumference) of children with FTT compares unfavorably with thriving children and that this disparity persists even with appropriate attempts at intervention. This pattern of a persistent growth deficit is seen in both developed and developing countries and across a wide spectrum of severity of FTT.
The effect on head growth is especially concerning, since increasing head circumference reflects brain growth, and therefore any impairment in head growth impacts neurodevelopmental outcomes. There is also evidence that the longer the growth failure continues, the less likely it becomes that treatment will be effective in reversing the negative long-term outcomes. These findings highlight the importance of early identification and intensive nutritional intervention for children with FTT syndrome to improve efficacy of the therapy and to minimize long-term damage.
The evidence that children with FTT have significantly greater susceptibility to infection is strong, and includes both markers of immunologic dysfunction at the cellular level and clinical correlates seen consistently across a variety of conditions. The laboratory indices of cellular immunologic dysfunction were apparent in children with moderate severity and, at least in such moderate cases, may be amenable to nutritional intervention. As expected, the more severe complications were most prevalent among the most severely malnourished children. The evidence is supportive of identifying children with growth failure as being at risk for multiple acute and chronic infections, especially as this may be an area where intervention may effectively reverse the associated risk.
The evidence identified by the search showed that children with FTT exhibited a variety of behavioral disorders, both concurrently at diagnosis as well as at follow-up. All except one of the relevant studies were conducted in developed countries, on a population of children with moderate degrees of FTT, representing a strong match to the case mix of FTT children in the US.
Studies involving concurrent behavioral abnormalities in FTT cases examined children up to 3 years of age. The behavioral problems exhibited by the children diagnosed with FTT included various eating disorders, such as delayed introduction of solid foods, spitting, disinterest, and food aversions. Other behavioral disorders that were noted involve increased negative and decreased positive affective expressiveness, and lower scores on measures of communication and mood. These behavioral difficulties do not in themselves constitute disabilities using the SSA definition, but may contribute to functional deficits noted in neurologic and cognitive/social development.
Studies examining behavior problems in children diagnosed with FTT at follow-up focused on social situations such as classroom behavior. School-related behavioral problems such as attention deficit disorder (ADD) were found in one study to be more common among FTT children than controls. In addition, one investigator found interference with problem-solving skills more often in FTT children than in well-nourished controls.
The evidence identified by the search showed that children with FTT exhibited consistently poorer scores in a variety of tests of cognitive, neurological, and psychomotor development. Indeed, the deleterious effect of growth failure and malnutrition on neurodevelopment is among the strongest and most important associations found. This trend toward poor neurodevelopmental performance was consistent for all fourteen of the studies conducted in developed countries, and five of the six studies conducted in the developing countries.
Despite exclusion of children with overt neurodevelopmental abnormalities from the case definition of FTT, at the time of identification, FTT is still strongly associated with poorer developmental test scores. Again, not unexpectedly, the most severe developmental delays are found among the most severely malnourished, often hospitalized children. However, even in larger epidemiological studies, the effect of FTT on neurodevelopmental outcome is apparent. Such studies indicate that the diagnosis of FTT is associated with an average decrease in developmental test scores of roughly two-thirds of a standard deviation. This means that children with failure to thrive are also more likely to meet criteria for the SSA qualifying range of developmental delay than are children in the general population. Adding to the concern of such cases is the fact that these lower neurodevelopmental testing scores persisted regardless of intervention.
There is persuasive evidence that FTT is associated with a range of organic and psychosocial difficulties. Some of these associations may be potential causal factors for the growth failure, such as low socioeconomic status and maternal education level, family dysfunction and the presence of neonatal morbidities. Others, such as the frequency of hospitalization, general health status, and specific neurologic abnormalities are more likely the result of the malnutrition. Furthermore, several of these factors may also independently predict or place a child at risk for significant disability. The possible interrelation of such factors complicates the delineation of the true nature of their association with FTT; nonetheless, they provide further insight into the complexities of the risks inherent in the diagnosis of growth failure.
Overall, the results are generally consistent across a broad spectrum of growth failure severity, and the majority of the studies are readily and creditably generalizable to the population of children with FTT as defined by SSA. Additionally, the study results further highlight the severity and potential long-term impact of these associations in their consistent finding that these psychosocial and family difficulties are not readily amenable to current interventions.
The implications of FTT on long-term morbidity and disability can vary depending upon the severity of FTT, its cause, and most importantly the chronological age at which FTT occurred. Thus, in spite of an appropriate review of literature, we may still be not be able to assess the full magnitude of FTT on developing children because of the wide age range of subjects in the reported studies. One thing we can certainly conclude is that a major FTT event in a child's life occurring particularly at a critical phase of the growth curve (which varies among body systems; brain, skeleton etc.) has a high likelihood of causing major disability. The age of the child and the magnitude of FTT thus may have differing effects on different body systems. This is an important area in which to target intervention programs as well as further probe molecular and genetic bases for such impairments.
The studies comprising this report, though insufficient in number and variable in their methodologic quality and their potential biases, were of sufficient validity to provide significant information regarding the association of FTT with disability. The variety and long-term nature of the disabilities associated with FTT have major impact on the child, the family, and society.
Notwithstanding this, it may well be that the most significant finding of this review was the paucity of information available on the subject. Much remains to be learned regarding the extent and specifics of these associations and disabilities. Even more remains to be determined as to the optimal management of these patients.
Similarly, whatever limitations may have been found in these studies, they have also served to better define relevant outcomes for further study. With this in mind, we offer the following recommendations for future research addressing specific problematic issues and limitationsidentified from review of existing research.
One of the central problems in interpreting these studies was the heterogeneity of definitions of FTT. This variability in case definition makes it unclear how well the population at risk is being identified at present. Future research should apply a uniform definition of FTT. This would serve to facilitate comparison and perhaps even allow a meta-analysis of studies. It would also define more clearly the true prevalence of FTT.
Within the definition of FTT, provisions should be made for categorization based upon 1) severity and 2) longevity or duration of growth failure. The data currently available indicate that both of these factors are strong predictors not only for the risk of associated disabilities but for potential response to therapy as well. Refining the classification of the FTT population in this way would facilitate identification of the relative risk of disability for an individual FTT child. It would also help in the evaluation of intervention studies.
Although it is clear that the degree of disability increases with increasing severity of growth failure, this is an imprecise correlation especially in regards to children with mild to moderate FTT. Since the majority of FTT that is seen in the US tends not to be the most severe forms of marasmus and kwashiorkor, future research should specifically target those children with mild to moderate growth failure.
Similarly, more research needs to be conducted in the US, or in developed countries with comparable social-economic structures and health care systems.
Special emphasis should be given to outcomes focusing on neurodevelopmental and cognitive disorders. The data presented in this report indicate that this is likely one of the areas of strongest impact of FTT and certainly one with the greatest relevance for long term disability. Specifically, very few studies have focused on the issue of FTT and brain growth during the immediate post-neonatal period and early infancy. This is one of the most critical periods for dendritic arborization, axonal myelination, and the development of cognitive functions. More studies are needed in this area.
Further study is also needed on the association of FTT with general health outcomes because of their potential impact on the healthcare system. Beyond the risk to the individual child, the data linking FTT to increased risk of infections and poorer general health may have important implications at a broader level. Such data may help us understand the true “cost” of FTT and prove useful in evaluating intervention strategies.
In order to better define the true nature and extent of the disabilities associated with FTT, more studies are needed that prospectively follow children for a sufficient duration to capture the more complex disabilities that may result from FTT.
A consistent finding among these studies reviewed was the ineffectiveness of existingintervention programs. Although strictly beyond the focus of this report, much work still needs to be done on developing effective treatment programs for children with FTT. Unfortunately, the optimal intervention will yet require better definition of the complex physical, medical, cognitive, and psychosocial problems associated with failure to thrive.
follow-up studies/
follow-up.tw.
exp Case-Control Studies/
case-control.tw.
exp Longitudinal Studies/
longitudinal.tw.
exp Cohort Studies/
cohort.tw.
(random$ or rct).tw.
exp Randomized Controlled Trials/
exp random allocation/
exp Double-Blind Method/
exp Single-Blind Method/
randomized controlled trial.pt.
clinical trial.pt.
(clin$ adj trial$).tw.
((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.
exp PLACEBOS/
placebo$.tw.
exp Research Design/
Comparative Study/
exp Evaluation Studies/
exp Prospective Studies/
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23
disab$.af.
limitation$.af.
handicap$.af.
impair$.af.
25 or 26 or 27 or 28
exp growth disorders/ or failure to thrive/
exp Nutrition Disorders/
failure to thrive.af.
30 or 31
24 and 29 and 33
limit 34 to human
limit 35 to english language
limit 36 to (newborn infant or infant <1 to 23 months> or preschool child <2 to 5 years> or child <6 to 12 years> or adolescence <13 to 18 years>)
36 not 37
limit 38 to (adult <19 to 44 years> or middle age <45 to 64 years> or “aged <65 and over>” or “aged, <80 and over>”)
36 not 39
24 and 32
limit 41 to (newborn infant or infant <1 to 23 months> or preschool child <2 to 5 years> or child <6 to 12 years> or adolescence <13 to 18 years>)
41 not 42
limit 43 to (adult <19 to 44 years> or middle age <45 to 64 years> or “aged <65 and over>” or “aged, <80 and over>”)
41 not 44
limit 45 to human
limit 46 to english language
40 not 47
47 or 48
exp Body Weight/
24 and 29 and 50
limit 51 to human
limit 52 to (newborn infant or infant <1 to 23 months> or preschool child <2 to 5 years> or child <6 to 12 years> or adolescence <13 to 18 years>)
52 not 53
limit 54 to (adult <19 to 44 years> or middle age <45 to 64 years> or “aged <65 and over>” or “aged, <80 and over>”)
52 not 55
limit 56 to english language
49 or 57
exp Failure to thrive/
exp Infant nutrition disorders/
exp Nutrition disorders/
exp failure to thrive/ or exp growth/
exp Growth/
exp Growth disorders/
exp Nutrition disorders/
exp Protein-energy malnutrition/
exp Child nutrition disorders/
exp Child nutrition/
exp Infant nutrition disorders/
exp Body weight/
exp Growth/
exp Protein-energy malnutrition/
exp Growth disorders/
exp Body height/
exp Dwarfism, pituitary/
exp Dwarfism, pituitary/
exp Psychosocial deprivation/
exp Dwarfism/
exp Stress, psychological/
exp Stress, psychological/
exp Psychophysiologic disorders/
exp Hyperphagia/
exp Child behavior/
exp Child abuse/
FAILURE TO THRIVE.mp.
childhood malnutriton.mp. [mp=title, abstract, registry number word, mesh subject heading]
failure to thrive.mp. [mp=title, abstract, registry number word, mesh subject heading]
protein energy malnutrition.mp. [mp=title, abstract, registry number word, mesh subject heading]
growht failure.mp. [mp=title, abstract, registry number word, mesh subject heading]
growth failure.mp. [mp=title, abstract, registry number word, mesh subject heading]
failure to grow.mp. [mp=title, abstract, registry number word, mesh subject heading]
pshchosocial dwarfism.mp. [mp=title, abstract, registry number word, mesh subject heading]
psychosocial dwarfism.mp. [mp=title, abstract, registry number word, mesh subject heading]
hyperphagic short stature.mp. [mp=title, abstract, registry number word, mesh subject heading]
childhood neglect.mp. [mp=title, abstract, registry number word, mesh subject heading]
childhood neglect.mp. [mp=title, abstract, registry number word, mesh subject heading]
thriv$.af.
follow-up studies/
follow-up.tw.
Case-Control Studies/
case-control.tw.
exp Longitudinal Studies/
longitudinal.tw.
exp Cohort Studies/
cohort.tw.
(random$ or rct).tw.
exp Randomized Controlled Trials/
exp random allocation/
exp Double-Blind Method/
exp Single-Blind Method/
randomized controlled trial.pt.
clinical trial.pt.
(clin$ adj trial$).tw.
((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.
exp PLACEBOS/
placebo$.tw.
exp Research Design/
Comparative Study/
exp Evaluation Studies/
exp Prospective Studies/
2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24
1 and 25
limit 26 to human
limit 27 to english language
The Evidence-based Practice Center staff acknowledges the collaboration of the clinical experts who served on the EPC Technical Expert Panel. The EPC also acknowledges the contributions by those who acted as peer reviewers for the evidence report.
Joseph Lau, MD; EPC/Project Director
Ethan Balk, MD, MPH, Assistant Project Director and Project Leader, Short Stature
Cynthia Cole, MD, MPH, Coordinating Team Leader
Deirdre DeVine, M Litt, Project Manager
Priscilla Chew, MPH, Project Leader, Failure to Thrive
Kimberly Miller, BA, Research Assistant
Chenchen Wang, MD, MSc, Project Leader, Low Birth Weight
Very Low Birth Weight
Dr. Cynthia Cole, Project Coordinator and Team Leader
Drs. Geoffrey Binney, John Fiascone, James Hagadorn, and Chiwan Kim
Patricia Casey, NNP
Short Stature
Dr. Patricia Wheeler, Team Leader
Drs. Barbara Shephard and Karen Bresnahan
Failure To Thrive
Dr. Ellen Perrin, Team Leader
Drs. Stephan Glicken, Nicholas Guerina, Kevin Petit, Robert Sege, MaryAnn Volpe, and Deborah Frank
James Perrin, MD, Pediatric Consultant to the EPC
Social Security Administration
Science Partner: Dr. Paul Burgan, MD, PhD; Regina Connell, MS
Agency for Healthcare Research and Quality (AHRQ)
Marian James, PhD, Task Order Officer
American Academy of Pediatrics
Marilee Allen, MD (Very Low Birth Weight)
Professor
Neonatology, Department of Pediatrics
Johns Hopkins University
Baltimore, Maryland
Joseph Hersh, MD (Short Stature)
Louisville, Kentucky
Michael Farrell, MD (Failure to Thrive)
Chief of Staff
Childrens' Hospital Medical Center
Cincinnati, Ohio
Carla Herrerias, BS, MPH
Senior Health Policy Analyst
Department of Practice and Research
American Academy of Pediatrics
Elk Grove Village, Illinois
Disability Law Center, Inc.
Linda Landry, Esq.
Very Low Birth Weight
Deborah Campbell, MD
Hartsdale, New York
Warren N. Rosenfeld, MD
Department of Pediatrics
Winthrop University Hospital
Mineola, New York
Short Stature
Susan Rose, MD
Department of Endocrinology
Childrens' Hospital Medical Center of Cincinnati
Cincinnati, Ohio
Failure to Thrive
William Cochran, MD
Department of Pediatric GI/Nutrition
Geisinger Health System
Danville, Pennsylvania
A. Jay Cohen, MD
The Endocrine Clinic, PC
Memphis, Tennessee
David M. Brown, MD
Professor of Pediatrics
University of Minnesota
Minneapolis, Minnesota
Gilman Grave, MD
Chief, Endocrinology, Nutrition and Growth Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Catherine Y. Spong, MD (for VLBW and Failure to Thrive)
Chief, Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Tonse Raju, MD (for VLBW and Failure to Thrive)
Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Denis Drotar, MD
Professor and Chief
Division of Behavioral Pediatrics and Psychology
Rainbow Babies and Childrens' Hospital
Cleveland, Ohio
Daniel Kessler, MD
Phoenix, Arizona
| ADHD | Attention deficit hyperactivity disorders |
| ADL | Activities of daily living |
| AFDC | Aid to Families with Dependent Children |
| AGA | appropriate for gestational age |
| ALRI | acute lower respiratory infections |
| ANCOVA | analyses of covariance |
| ARI | acute respiratory infections |
| BGS | Boston Growth Standard |
| BMI | body mass index |
| CBCL | Child Behavior Checklist |
| Ctrl | control |
| D | day(s) |
| D/C | discharge |
| FU | follow-up |
| FVC | forced vital capacity |
| GCI | general cognitive index |
| GA | gestational age |
| Gp | group |
| HC | head circumference |
| HOME | Home Observation for Measurement of the Environment |
| HR | heart rate |
| HS | high school |
| Ht | height |
| Hx | history |
| Incr | increase(d) |
| LBW | low birth weight |
| LOMDS | Lincoln-Oseretsky motor development scale |
| MANCOVA | multivariate of analyses of covariance |
| Mo | month(s) |
| MDI | mental development index |
| ND | no data |
| Nl | normal |
| NOFTT | non-organic failure to thrive |
| NS | not significant |
| NCHS | National Center for Health Statistics |
| Nonsignf | nonsignificant |
| OFTT | organic failure to thrive |
| PCERA | Parent-Child Early Relational Assessment scale |
| PCM | protein-calorie malnutrition |
| PDI | psychomotor development index |
| PEM | protein-energy malnutrition |
| PHA | phytohemagglutinin |
| PPVT | Peabody Picture Vocabulary Test |
| RFC | rosette forming cells |
| RR | relative risk |
| SD | standard deviation |
| SDS | standard deviation score |
| SES | social-economic status |
| SGA | small for gestational age |
| Signf | significant |
| SK-SD | streptokinase-streptodornase |
| Std | standard |
| SOMA | Schedule for Oral Motor Assessment |
| SWFA | standard weight for age |
| THE | tetrahydrocortisol |
| THF | tetrahydrocortisone |
| TRIB | Tester's Rating of Infant Behaviour |
| UI | Medline unique indentifer |
| WAIS | Wechsler Adult Intelligence Scale |
| WD | withdrawn |
| WPPSI / WPPSI-R | Wechsler Pre-school and Primary Scale of Intelligence |
| WISC | Wechsler Intelligence Scale for Children |
| WORD test | Wechsler Objective Reading Dimensions manual |
| Wt | weight |
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