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Article |

Growth and Associations Between Auxology, Caregiving Environment, and Cognition in Socially Deprived Romanian Children Randomized to Foster vs Ongoing Institutional Care FREE

Dana E. Johnson, MD, PhD; Donald Guthrie, PhD; Anna T. Smyke, PhD; Sebastian F. Koga, MD; Nathan A. Fox, PhD; Charles H. Zeanah, MD; Charles A. Nelson III, PhD
[+] Author Affiliations

Author Affiliations: Department of Pediatrics (Dr Johnson), and Institute of Child Development (Dr Nelson), University of Minnesota, Minneapolis; Semel Institute, University of California–Los Angeles, Los Angeles (Dr Guthrie); Department of Psychiatry and Neurology, Tulane University, New Orleans, Louisiana (Drs Smyke and Zeanah); Department of Neurosurgery, University of Virginia, Charlottesville (Dr Koga); and Department of Human Development, University of Maryland, College Park (Dr Fox). Dr Nelson is now with the Department of Medicine, Children's Hospital Boston/Harvard Medical School, Boston, Massachusetts.


Arch Pediatr Adolesc Med. 2010;164(6):507-516. doi:10.1001/archpediatrics.2010.56.
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Objectives  To determine effects of improved nurturing compared with institutional care on physical growth and to investigate the association between growth and cognitive development.

Design  A randomized controlled trial beginning in infants (mean age, 21.0 months; range, 5-32 months), with follow-up at 30, 42, and 54 months of age.

Setting  Institutionalized and community children in Bucharest, Romania.

Participants  One hundred thirty-six healthy institutionalized children from 6 orphanages and 72 typically developing, never-institutionalized children.

Intervention  Institutionalized children were randomly assigned to receive foster care or institutional care as usual.

Outcome Measures  Auxology and measures of intelligence over time.

Results  Growth in institutionalized children was compromised, particularly in infants weighing less than 2500 g at birth. Mean height and weight, though not head size, increased to near normal within 12 months in foster care. Significant independent predictors for greater catch-up in height and weight included age younger than 12 months at randomization, lower baseline z scores, and higher caregiving quality, particularly caregiver sensitivity and positive regard. Baseline developmental quotient, birth weight, and height catch-up were significant independent predictors of cognitive abilities at follow-up. Each incremental increase of 1 in standardized height scores between baseline and 42 months was associated with a mean increase of 12.6 points (SD, 4.7 points) in verbal IQ (P < .05).

Conclusions  Foster care had a significant effect on growth, particularly with early placement and high-quality care. Growth and IQ in low-birth-weight children are particularly vulnerable to social deprivation. Catch-up growth in height under more nurturing conditions is a useful indicator of caregiving quality and cognitive improvement.

Trial Registration  clinicaltrials.gov Identifier: NCT00747396

Figures in this Article

A syndrome of poor growth in socially deprived children has been recognized since the eponymous Kasper Hauser was discovered with stunted growth and developmental delays outside the gates of Nuremberg, Germany, in 1828.1 Several subtypes have been described,25 though all share 2 characteristics: otherwise unexplained growth failure occurring in association with socially stressful conditions and significant catch-up when a child's caregiving environment improves.3 Understandably, studies to date have relied exclusively on convenience samples of children referred to specialists for evaluation of short stature,2,3,5,6 entering child protection systems,79 or placed for adoption from institutional care settings.4,1012 Under these circumstances, basic social and medical information is lacking, and it has been virtually impossible to ascertain the type, severity, or duration of adversity the child experienced.

The Bucharest Early Intervention Project (BEIP), the first randomized controlled study of foster vs institutional care, offered a unique opportunity to study growth within otherwise healthy institutionalized children with a known duration of social deprivation.1332 As opposed to previous studies reporting on growth under adverse social circumstances, caregiving quality was quantified before and following randomization of those institutionalized to foster vs institutional care as usual. Contrasting these children with matched, never-institutionalized controls, we initially explored biologic and environmental factors that contributed to growth failure within institutional care settings. Because past publications from BEIP documented significant and often age-related improvements in a variety of domains in those randomized to foster care,15,18,24,32 we next investigated whether growth improved and if factors such as enhanced caregiver-child interaction and earlier age at randomization influenced catch-up.

Finally, we explored the association between growth and cognition. Reestablishment of normal kinetics in the growth hormone/insulinlike growth factor-1 [IGF-1] axis has been shown to be important in growth recovery in neglected children placed in more nurturing environments. Based on this fact and on reports correlating improvement in stature with cognitive gains in stunted, intellectually impaired children treated with growth hormone,3335 we postulated that catch-up growth in those randomized to foster care would be associated with cognitive abilities at follow-up.

STUDY DESIGN

Subject selection has been discussed in detail in past publications but will be summarized briefly.18,22,27 Enrollment, group assignments, and follow-up of subjects through 54 months are illustrated in Figure 1.

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Figure 1.

Group status at age 54 months in children living in Romanian institutions.

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CHILDREN IN INSTITUTIONS

All children younger than 32 months living in institutions for infants in all 6 sectors of Bucharest, Romania, other than those scheduled for adoption, were included (n = 187). Children were excluded if they had serious handicapping conditions (n = 51), eg, genetic syndromes, facial features (3 or 4) indicative of a high risk of prenatal alcohol exposure,36,37 severe microcephaly, cerebral palsy, or a high suspicion of bilateral hearing loss. Subjects were recruited from February through June 2001.

CARE AS USUAL AND FOSTER CARE GROUPS

Following identification and baseline assessment of the institutionalized cohort (n = 136), equal numbers of children were randomly assigned to remain within institutional care and receive care as usual or were assigned to a foster care group. Eleven of the children who were originally approved for participation were later determined to have conditions that met exclusion criteria and were eliminated from analyses.22 Because government-sponsored foster care was unavailable when our study commenced, we created our own foster care program.23,27 Children randomized to care as usual were deinstitutionalized at the discretion of child-protection officials. However, irrespective of changes in caregiving environment over the duration of the study, an intent-to-treat approach was followed, whereby all analyses we report are based on children's original group assignments. Thus, our findings represent a conservative estimate of the response to intervention.

NEVER-INSTITUTIONALIZED GROUP

Children (n = 72) were recruited from community pediatric clinics and were born at the same hospitals as the institutionalized children. They were living with their birth family, had no history of institutional care, and were approximately matched on age and sex to those in the care as usual and foster care groups.

ETHICAL CONSIDERATIONS

At the time the study commenced, foster care was exceedingly uncommon in Romania. Given limited governmental resources and the certainty that without the BEIP intervention, all of the children would have likely remained institutionalized, the investigators and their Romanian government and scientific partners concluded that randomization was acceptable. The rationale behind the study, justification and critique of the randomized controlled design, and the approval process and procedures put in place to safeguard these children have been discussed in depth in previous publications.18,27,3840 Approval was obtained from the institutional review boards of the home institutions of the principal investigators (C.A.N., C.H.Z., and N.A.F.).

DATA COLLECTION

Assessments of cognitive level and caregiving environment were obtained at 3 times: baseline (mean age, 21.0 months [SD, 7.4 months ]; range, 5-32 months) and 30 and 42 months of age as previously described.18,22 Birth weight was obtained from medical record review in the institutionalized group (90%) and from parental report in the never-institutionalized group (94%). Information on gestational age at birth for those institutionalized was not available or deemed unreliable, making it impossible to determine whether low-birth-weight (LBW) infants (<2500 g) were appropriate or small for gestational age. In addition to baseline and 30- and 42-month auxology, measurements were scheduled monthly in the care as usual and foster care groups. Cognitive testing was also obtained at 54 months. All reported P values are 2-sided. Data were analyzed using SPSS, version 11.0, and SAS, version 9.1.

PHYSICAL GROWTH

Supine length (at <24 months) or height (at ≥24 months), weight, and weight for height were converted to age-standardized scores (z scores) based on 2000 Centers for Disease Control and Prevention data.41 Use of z score measures standardized sizes, thus making them comparable across age ranges. Occipital-frontal circumference (OFC) z scores were calculated using the standardized data (0-18 years of age) of Roche and colleagues.42

COGNITIVE DEVELOPMENT AND CAREGIVING ENVIRONMENT

Developmental quotients (DQs) at baseline and 30 and 42 months were based on the Bayley Scales of Infant Development II, Mental Developmental Index.22,43 The Wechsler Preschool Primary Scale of Intelligence II was used at 54 months.44

The Observational Record of the Caregiving Environment45 was adapted and used to assess a child's caregiving experience in either institutional or family settings. Children were videotaped with their preferred caregiver for 1½ hours within the environment where they were receiving care at that particular time. The training process for coders, coding protocols, and scale and interrater reliability for this cohort have been previously published.22 The caregiving-quality score was obtained by averaging 5 qualitative scales from the Observational Record of the Caregiving Environment (detachment [reversed], flat affect [reversed], positive regard for child, sensitivity, and stimulation of development), each of which received a rating from 1 (not at all characteristic) to 4 (highly characteristic). Scores ranged from 1 (lowest possible) to 4.

CONTROL ANALYSES

Children in the never-institutionalized group were primarily of Romanian ethnicity (Table 1). Birth weight was lower and the incidence of LBW (<2500 g) was higher in institutionalized children. At baseline, the parameters listed in Table 1 were similar in children randomized into care as usual and foster care groups.

Table Graphic Jump LocationTable 1. Demographics, Growth, Caregiving Quality, and Cognitive Scores for the Institutionalized and Never-Institutionalized Groups
AUXOLOGY AT BASELINE

At baseline, all physical measurements were significantly smaller and z scores less than −2 were more frequent in institutionalized vs never-institutionalized children. Caregiving-quality scores were significantly lower in institutionalized children as well (Table 1) but increased with age (caregiving-quality score = 1.8 + 0.02 [age in months]; F1,114 = 6.00; P = .02; R = 0.05). The prevalence of wasting (weight-for-height z scores <−2) in institutionalized children was high (16%)46 and especially common in infancy (wasting, 30% of infants aged <12 months vs 8% of infants aged ≥24 months, χ21 = 5.83, P = .02; mean weight-for-height z scores, −1.22 [SD, 1.14] in infants <12 months vs −0.40 [SD, 0.14] ≥24 months, t69 = −2.98, P = .004).

Multiple regression models accounted for significant variance in baseline z scores for height, weight, OFC, and weight for height (Table 2). Significant unique predictors of lower z scores at baseline included lower birth weight (height, weight, OFC, and weight for height), older age (height), and non-Romanian ethnicity (OFC). Within those institutionalized, LBW children were significantly more growth impaired than children with birth weights 2.5 kg or heavier in all parameters other than OFC (P = .08) (Table 3). Both birth-weight groups were significantly different from the never-institutionalized group. Institutionalized children of Roma, other, or unknown ethnicity had smaller OFC z scores at baseline than children who were of Romanian ethnicity (mean OFC z score, −1.43 [SD, 0.83] vs −0.83 [SD, 1.03], t118 = 3.43, P = .001). However, birth weight, baseline caregiving-quality score, and baseline DQ did not differ between these 2 ethnic groups, making it more likely that this difference was an inherent auxologic characteristic rather than the result of prenatal or postnatal factors.

Table Graphic Jump LocationTable 2. Multiple Regression of Baseline Measures in the Institutionalized Group
Table Graphic Jump LocationTable 3. Effect of Low Birth Weight on Baseline Growth in the Institutionalized vs Never-Institutionalized Groupsa
POSTRANDOMIZATION GROWTH

Caregiving-quality scores at 30 and 42 months improved in the foster care group and did not differ significantly from the never-institutionalized group (Table 1). In the care as usual group, only 48% and 35% remained institutionalized at 42 months and 54 months of age, respectively. Consequently, caregiving-quality scores improved over time for these children as well.

Catch-up growth was first examined from baseline to 42 months of age, a mean of 19 months (SD, 6.7 months; range, 9.1-31.2 months; the duration between baseline and 42-month follow-up was ≥12 months in 93% of the children) after randomization. Random-effects linear growth models (SAS PROC MIXED) with monthly measurements between baseline and 42 months of age in raw, nonstandardized form indicated that children in the foster care group grew significantly faster in height and weight than those in the care as usual group (Figure 2A). Growth in head circumference did not differ between the foster care group and care as usual. We also conducted a 1-way within-subject analysis of variance within each group with the factor being time (baseline and 30 and 42 months) and the dependent variables being measurements (Figure 2B and C). When corrected for regression to the mean,47 only height (0.50 increase) and weight (0.46 increase) z scores in the foster care group and weight z scores (0.08 increase) in the care as usual group showed improvement.

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Figure 2.

Growth in the foster care group (FCG) vs care as usual group (CAU) at baseline and at 30 and 42 months of age. A, Mean growth rates from random-effects linear growth models for height, weight, and occipital-frontal circumference (OFC). B, Comparison of height and weight z scores from baseline to 42 months of age (analysis of variance of FCG height z score, F1,50 = 100.6, P < .001, partial η2 = 0.67; and weight z score, F1,50 = 94.0, P ≤.001, partial η2 = 0.65; CAU weight z score, F1,50 = 10.3, P = .002, partial η2 = 0.17; at 42 months, mean height z score in FCG vs CAU, respectively, 0.06 [SD, 0.97] vs −0.62 [SD, 0.99], t1,108 = −3.65; and weight z score, −0.31 [SD, 1.05] vs −0.75 [SD, 1.17], t1,108 = −1.98). C, Comparison of weight for height and OFC z scores. Error bars indicate standard error. *P < .001. †P = .05.

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To study the effect of intervention duration, we plotted growth at 6-month intervals during the 18 months following randomization. Measurements were included in the analyses if obtained within ±1 month of the target intervals (6, 12, and 18 months). The foster care group showed rapid increases in height and weight (Figure 3A) but no change in OFC or weight-for-height z scores (Figure 3B) during the first 12 months, while the care as usual group showed no improvement. When corrected for regression to the mean, height (0.30 increase) and weight z scores (0.48 increase) changed significantly. By 12 months, 100% of the foster care group was in the normal range (z score ≥−2) for height, 90% for weight, and 94% for weight for height. No significant change in any parameter occurred between 12 and 18 months postplacement.

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Figure 3.

Growth in the foster care group (FCG) vs the care as usual group (CAU) at baseline and at 6, 12, and 18 months postrandomization. A, Comparison of height and weight z scores in CAU and FCG, respectively, from baseline (n = 51, n = 54), and at 6 (n = 46, n = 57), 12 (n = 42, n = 51), and 18 (n = 21, n = 50) months postrandomization (analysis of variance for FCG height z score, F1,43 = 57.32, P < .001, partial η2 = 0.57; and weight z score, F1,43 = 63.65, P ≤.001, partial η2 = 0.60). B, Comparison of weight for height and occipital-frontal circumference (OFC) z scores from baseline to 18 months postrandomization. Error bars indicate standard error. *P ≤ .001. †P < .05.

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FACTORS ASSOCIATED WITH GROWTH RECOVERY

We next examined factors influencing z-score changes in the foster care group. To determine whether there were sensitive periods for catch-up growth, as previously reported from BEIP for cognitive outcomes,18 attachment,24 and certain measures of electroencephalogram power and coherence,15 5 dichotomized ages of entry into foster care (12, 15, 18, 21, and 24 months) were tested. Multiple-regression models accounted for significant variance in z score changes for all 4 measures (Table 4). Significant unique predictors of greater change included lower baseline z scores (height, weight, and OFC) and age of randomization younger than 12 months (height, weight, OFC, and weight for height). Higher postplacement caregiving quality was also a significant unique predictor of catch-up in height and weight. Individual components of the caregiving-quality score that positively correlated with catch-up in height and weight included positive regard for the child and sensitivity. Caregiver detachment was negatively correlated with catch-up in height (Table 5). Significant sex differences in z scores at 42 months or change in z scores from baseline to 42 months were not observed in the foster care group. While LBW infants tended to be smaller at 42 months of age, the difference was significant for head size alone (Table 6).

Table Graphic Jump LocationTable 4. Multiple Regression of Change in Z Scores in the Foster Care Group After Randomization
Table Graphic Jump LocationTable 5. Pearson Correlations Between Mean Caregiver Interaction Scale Ratings From the Caregiving-Quality Score and Change in Z Scores Postrandomization in the Foster Care Group
Table Graphic Jump LocationTable 6. Effect of Low Birth Weight and Sex on Growth and Cognitive Measures Following Randomization to Foster Carea
GROWTH AND COGNITIVE IMPROVEMENT IN THE FOSTER CARE GROUP

Finally, we investigated whether growth in the foster care group was a significant independent predictor of cognitive abilities at 42 months and, if so, whether the effects would persist at 54 months. In addition to child characteristics and changes in z scores between baseline and 42 months, a binary age variable was incorporated into models based on our previous finding that placement into foster care prior to the age of 24 months led to better cognitive recovery.18 Duration of intervention was not included, as this parameter was previously shown not to affect cognitive outcome in BEIP.18 Multiple regression models accounted for significant variance in all cognitive measures (Table 7). Baseline DQ was a significant unique predictor of all DQ and IQ measures other than performance IQ at 54 months, and change in height z score was a significant unique predictor of DQ at 42 months and verbal IQ at 54 months. Birth weight was a significant unique predictor of full IQ at 54 months and performance IQ at 54 months. Changes in DQ and IQ between baseline and 42 and 54 months were inversely related to initial DQ. The extreme cognitive vulnerability of LBW infants is highlighted when the risk factors of birth weight and delayed placement into foster care are both taken into account. Children with birth weights of 2.5 kg or greater who are placed in foster care prior to 24 months of age had a mean IQ score of 91.1 (SD, 4) vs 67.7 (SD, 6.2) in LBW infants placed after 24 months of age (Figure 4).

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Figure 4.

Full-scale IQ at 54 months by age of randomization and birth weight in children randomized to foster care. The error bars indicate standard error; *P < .001 vs children with a 2.5-kg or heavier birth weight who were randomized at younger than 24 months of age (mean, 66.6 [SE, 6.2], vs 91.1 [SE, 3.9], t21 = 3.84).

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Table Graphic Jump LocationTable 7. Multiple Regression of Cognitive Variables in Institutionalized Children Randomized to Foster Care

Children raised in institutions had globally suppressed growth followed by recovery of height and weight but not OFC in those removed and then placed in foster care. These observations mirror the findings of suppressed growth within institutional care settings and recovery within adoptive families reported in a meta-analysis by Van Ijzendoorn and colleagues.11 Both the current data and the meta-analysis showed that height catch-up improved if placement occurred prior to 12 months of age. Data from BEIP confirmed the same sensitive period for weight, OFC, and weight for height. In the foster care group, catch-up growth for height and weight were robust and essentially complete by 12 months after randomization when both height and weight z scores were close to 0. Children with the most significant growth impairments at baseline exhibited greater catch-up, but neither sex nor LBW had an effect.

Although growth has shown improvement within cohorts of neglected and or abused children once removed from an adverse environment,9,11,48,49 BEIP is the first study to test the hypothesis that caregiving quality is directly related to catch-up growth. Results showed that child-caregiver interaction is a significant independent predictor of catch-up growth in height and weight. Components of the caregiving-quality score positively correlated with catch-up included sensitivity (child-centered, contingent responses) and positive regard for the child (acceptance, respect, and warmth, including expressions of physical affection).

Following the initial report of Talbot and colleagues,50 investigators have described 4 syndromes of impaired growth associated with adversity based on several factors, including age, nutrition, behavioral or emotional comorbidities, and status of the growth hormone/IGF-1 axis.26 All share the diagnostic features of suppressed growth within the context of adversity followed by catch-up growth after improvement in caregiving environment, a central finding observed in the foster care group. Caloric deprivation has been reported to play a central role in growth failure during infancy (type I growth failure), while changes in the growth hormone/IGF-1 axis (types IIA, IIB, and III) becomes more important in growth suppression and recovery in children beyond the first 18 to 24 months of life.26 Both nutrition and production of endogenous growth factors are likely to be affected by an institutional environment.

Nutritional requirements in children vary depending on growth rates and whether preexisting deficits exist. During the rapid-growth phase between birth and 18 months, the effects of even modest nutritional deficits become magnified. Both LBW infants and children with orofacial malformations or neuromotor problems are overrepresented within institutional care settings and may have difficulty obtaining and/or consuming sufficient calories to grow.10,12,22,51 With the time and fiscal constraints virtually all orphanages worldwide experience, it is highly unlikely that the nutritional needs of individual children both in quantity and quality can be accommodated within an environment where children have no access to breast milk; dietary plans and feeding protocols are strictly regimented; and caregiver actions are based on efficiency and expediency rather than being responsive to child-based cues.52

Considering that neglected infants are highly susceptible to insufficient intake, it is not surprising that malnutrition is felt to be the principal cause of deprivation-associated growth failure within this age group.2,53 Two observations in BEIP underscore the importance of malnutrition as a factor in psychosocial growth failure during infancy: lower caregiving-quality scores during infancy and the significantly more common finding of wasting during infancy (30%). Outside of the first years of life, there is less evidence that caloric deprivation is a primary factor responsible for growth failure in socially deprived children, as weight for height has been reported to be essentially normal.2,3,6 Consistent with past studies, weight for height in institutionalized children at baseline was greater in older children, and only 8% of children older than 24 months were experiencing wasting.

In older children, alterations in the growth homone/IGF-1 axis have been documented to play a key role in growth failure and catch-up.26,48 In a cohort of postinstitutionalized Eastern European children of a similar age as those in BEIP (mean, 20.4 months; range, 7.3-59.9 months), level of IGF-binding protein 3 shortly after placement was an independent predictor of height z score.12 As would be expected with suppressed growth homone/IGF-1 axis function, height in BEIP was lower at baseline in older institutionalized children but not weight, head circumference, or weight for height.

It was impossible for us to measure serum growth factors given constraints imposed by local authorities. In addition, the labor-intensive process of determining nutritional quality and intake could not be conducted with the resources that were available. However, auxology in BEIP is consistent with previous work in this area, which implicates both malnutrition and alterations in the growth hormone/IGF-1 axis in growth suppression. The relative importance of these 2 factors and the consequent clinical presentations almost certainly is age dependent. Malnutrition likely contributes more during periods of rapid growth and utter dependency. Depression of the growth hormone/IGF-1 axis then becomes more important as growth rates slow, as children are more able to regulate their dietary intake, and as linear growth becomes more growth hormone dependent.54,55

With the likelihood that recovery of suppressed growth hormone/IGF-1 axis function played a role in growth recovery in the foster care group, the observation that catch-up growth in height was the only significant independent auxologic predictor of cognitive abilities at 42 and 54 months supports previous work that implicated the growth hormone/IGF-1 axis in cognitive recovery as well. The role of this system in cognitive development is supported by substantial experimental56,57 and clinical evidence. In normal 8- to 9-year-old children, IGF-1 levels were shown to be positively related to IQ.58 Children with 18q deletions,33 Prader-Willi syndrome,34 or who were born small for gestational age,35 conditions characterized by both short stature and cognitive delays, have shown significant improvement in height, IQ, and brain structure following treatment with growth hormones. Finally, children with defects in the growth hormone receptor have IQs and brain structural abnormalities that differ depending on which exon contains the point mutation or deletion.59

From this study, several significant themes emerge with relevance to policies for care of children in out-of-home placement during early life. While these data were developed within institutional care settings, they are applicable to conventional foster care settings as well. This study conclusively demonstrated that LBW infants are particularly vulnerable in terms of growth and cognitive development and should be quickly moved into family care. The unique nutritional needs of LBW infants are unlikely to be appreciated, and dependence on conformity in orphanages makes it unlikely that nutritional interventions that are needed to optimize growth would be offered. The impaired growth at baseline as well as cognitive compromise and smaller head size at 42 months in our institutionalized LBW infants are consistent with the global growth failure, low IQs, and smaller head sizes described in other groups of LBW infants who experienced social deprivation in early life.12,6063

The sensitive period for growth recovery (<12 months) is even earlier than the sensitive period (<24 months) described in previous BEIP publications for cognitive recovery,18 attachment behavior,24 and improvement in electroencephalography results.15 This strengthens the argument for placement within family care as early as possible. Although a family is clearly preferable to institutional care, establishing higher-quality child-caregiver interactions with appropriate screening, training in emotional engagement, and contingent caregiving and monitoring ensures the best outcomes in terms of growth. Finally, whether or not there are direct causal relationships, improvement in stature is not only a useful biologic measure of caregiving environment, but also an informative indicator of cognitive improvement in at-risk children who live in institutions, foster care, or within impoverished families. Under these circumstances, a measuring tape and growth chart become sophisticated and inexpensive tools for assessing quality of care and child well-being, particularly where social services remain underdeveloped and underfunded.

The significance of these findings extends beyond the millions of children worldwide within institutional or conventional foster care to the hundreds of millions of impoverished children who have stunted growth and/or do not meet their developmental potential and are living within families. The interdependence of nutrition and social environment on child outcomes has recently received attention in regards to achieving United Nations Millennium Development Goals.64 This study of growth in institutionalized children adds strong experimental support to the conclusion of Black and colleagues64 that strategies that fail to address nurture along with health and nutrition will likely fail to achieve significant improvements in overall child well-being. Psychosocial deprivation within any caregiving environment during early life is as detrimental as malnutrition and must be viewed with as much concern as any severely debilitating childhood disease.

Correspondence: Dana E. Johnson, MD, PhD, Department of Pediatrics, Division of Neonatology, Mayo Mail Code 211, 420 Delaware St SE, Minneapolis, MN 55455 (johns008@umn.edu).

Accepted for Publication: January 6, 2010.

Published Online: April 5, 2010 (doi:10.1001/archpediatrics.2010.5).

Author Contributions: Dr Johnson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Johnson, Guthrie, Koga, Fox, Zeanah, and Nelson. Acquisition of data: Smyke, Koga, Fox, Zeanah, and Nelson. Analysis and interpretation of data: Johnson, Guthrie, Koga, Fox, Zeanah, and Nelson. Drafting of the manuscript: Johnson, Guthrie, Fox, and Nelson. Critical revision of the manuscript for important intellectual content: Johnson, Guthrie, Smyke, Koga, Fox, Zeanah, and Nelson. Statistical analysis: Johnson, Guthrie, and Fox. Obtained funding: Koga, Nelson, Zeanah, and Nelson. Administrative, technical, and material support: Koga. Study supervision: Smyke, Koga, Nelson, and Fox.

Financial Disclosure: None reported.

Funding/Support: The work reported in this manuscript was supported by funds from the John D. and Catherine T. MacArthur Foundation. Dr Nelson was supported by the Richard David Scott endowment and the Binder Family Foundation.

Role of the Sponsors: The study sponsors had no role in the design or conduct of the study; in the collection, analysis, management, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank Hermi R. Woodward and the MacArthur Foundation Research Network on Early Experience and Brain Development for input regarding the conceptualization, design, and implementation of this project; Gwen Gordon, BA, for assistance in data management; Elizabeth Furtado, BA, for ongoing project coordination; and the caregivers and children who participated in this project.

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Ghera  MMMarshall  PJFox  NA  et al.  The effects of foster care intervention on socially deprived institutionalized children's attention and positive affect: results from the BEIP study. J Child Psychol Psychiatry 2009;50 (3) 246- 253
PubMed Link to Article
Marshall  PJFox  NABucharest Early Intervention Project Core Group, A comparison of the electroencephalogram between institutionalized and community children in Romania. J Cogn Neurosci 2004;16 (8) 1327- 1338
PubMed Link to Article
Marshall  PJReeb  BCFox  NANelson  CA  IIIZeanah  CH Effects of early intervention on EEG power and coherence in previously institutionalized children in Romania. Dev Psychopathol 2008;20 (3) 861- 880
PubMed Link to Article
Nelson  CA  IIIFurtado  EAFox  NAZeanah  CH The deprived human brain. Am Sci 2009;97 (3) 222- 229
Link to Article
Nelson  CAParker  SWGuthrie  DBucharest Early Intervention Project Core Group, The discrimination of facial expressions by typically developing infants and toddlers and those experiencing early institutional care. Infant Behav Dev 2006;29 (2) 210- 219
PubMed Link to Article
Nelson  CA  IIIZeanah  CHFox  NAMarshall  PJSmyke  ATGuthrie  D Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science 2007;318 (5858) 1937- 1940
PubMed Link to Article
Parker  SWNelson  CABucharest Early Intervention Project Core Group, An event-related potential study of the impact of institutional rearing on face recognition. Dev Psychopathol 2005;17 (3) 621- 639
PubMed Link to Article
Parker  SWNelson  CABucharest Early Intervention Project Core Group, The impact of early institutional rearing on the ability to discriminate facial expressions of emotion: an event-related potential study. Child Dev 2005;76 (1) 54- 72
PubMed Link to Article
Smyke  ATDumitrescu  AZeanah  CH Attachment disturbances in young children, I: the continuum of caretaking casualty. J Am Acad Child Adolesc Psychiatry 2002;41 (8) 972- 982
PubMed Link to Article
Smyke  ATKoga  SFJohnson  DE  et al. BEIP Core Group, The caregiving context in institution-reared and family-reared infants and toddlers in Romania. J Child Psychol Psychiatry 2007;48 (2) 210- 218
PubMed Link to Article
Smyke  ATZeanah  CH  JrFox  NANelson  CA  III A new model of foster care for young children: the Bucharest early intervention project. Child Adolesc Psychiatr Clin N Am 2009;18 (3) 721- 734
PubMed Link to Article
Smyke  ATZeanah  CHFox  NANelson  CAGuthrie  D Placement in foster care enhances quality of attachment among young institutionalized children. Child Dev 2010;81 (1) 212- 223
Link to Article
Windsor  JGlaze  LEKoga  SFBucharest Early Intervention Project Core Group, Language acquisition with limited input: Romanian institution and foster care. J Speech Lang Hear Res 2007;50 (5) 1365- 1381
PubMed Link to Article
Zeanah  CHEgger  HLSmyke  AT  et al.  Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry 2009;166 (7) 777- 785
PubMed Link to Article
Zeanah  CHNelson  CAFox  NA  et al.  Designing research to study the effects of institutionalization on brain and behavioral development: the Bucharest Early Intervention Project. Dev Psychopathol 2003;15 (4) 885- 907
PubMed Link to Article
Zeanah  CHSmyke  ATDumitrescu  A Attachment disturbances in young children, II: indiscriminate behavior and institutional care. J Am Acad Child Adolesc Psychiatry 2002;41 (8) 983- 989
PubMed Link to Article
Zeanah  CHSmyke  ATKoga  SFCarlson  EBucharest Early Intervention Project Core Group, Attachment in institutionalized and community children in Romania. Child Dev 2005;76 (5) 1015- 1028
PubMed Link to Article
Moulson  MCFox  NAZeanah  CHNelson  CA Early adverse experiences and the neurobiology of facial emotion processing. Dev Psychol 2009;45 (1) 17- 30
PubMed Link to Article
Moulson  MCWesterlund  AFox  NAZeanah  CHNelson  CA The effects of early experience on face recognition: an event-related potential study of institutionalized children in Romania. Child Dev 2009;80 (4) 1039- 1056
PubMed Link to Article
Zeanah  CHEgger  HLSmyke  AT  et al.  Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry 2009;166 (7) 777- 785
PubMed Link to Article
Cody  JDSemrud-Clikeman  MHardies  LJ  et al.  Growth hormone benefits children with 18q deletions. Am J Med Genet A 2005;137 (1) 9- 15
PubMed Link to Article
Myers  SEWhitman  BYCarrel  ALMoerchen  VBekx  MTAllen  DB Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A 2007;143 (5) 443- 448
PubMed Link to Article
van Pareren  YKDuivenvoorden  HJSlijper  FSKoot  HMHokken-Koelega  AC Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. J Clin Endocrinol Metab 2004;89 (11) 5295- 5302
PubMed Link to Article
Astley  SJClarren  SK A fetal alcohol syndrome screening tool. Alcohol Clin Exp Res 1995;19 (6) 1565- 1571
PubMed Link to Article
Astley  SJClarren  SK Measuring the facial phenotype of individuals with prenatal alcohol exposure: correlations with brain dysfunction. Alcohol Alcohol 2001;36 (2) 147- 159
PubMed Link to Article
Miller  FG The randomized controlled trial as a demonstration project: an ethical perspective. Am J Psychiatry 2009;166 (7) 743- 745
PubMed Link to Article
Millum  JEmanuel  EJ Ethics: the ethics of international research with abandoned children. Science 2007;318 (5858) 1874- 1875
PubMed Link to Article
Zeanah  CHKoga  SFSimion  B  et al.  Response to commentary: ethical dimensions of the BEIP. Infant Ment Health J 2006;27 (6) 581- 583
Link to Article
Kuczarski  RJOgden  CLGrummer-Strawn  LM  et al.  CDC growth charts: United States. Adv Data June2000; (341) 1- 27
Roche  AFMukherjee  DGuo  SMMoore  WM Head circumference reference data: birth to 18 years. Pediatrics 1987;79 (5) 706- 712
PubMed
Bayley  N Bayley Scales of Infant Development. 2nd ed. New York, NY Psychological Corporation1993;
Wechsler  D Wechsler Preschool and Primary Scale of Intelligence.  San Antonio, TX Harcourt Assessment2000;
NICHD Early Child Care Research Network, Characteristics of infant child care: factors contributing to positive caregiving. Early Child Res Q 1996;11269- 306
Link to Article
Fernandez  IDHimes  JHde Onis  M Prevalence of nutritional wasting in populations: building explanatory models using secondary data. Bull World Health Organ 2002;80 (4) 282- 291
PubMed
Cameron  NPreece  MACole  TJ Catch-up growth or regression to the mean? recovery from stunting revisited. Am J Hum Biol 2005;17 (4) 412- 417
PubMed Link to Article
Gohlke  BCFrazer  FLStanhope  R Growth hormone secretion and long-term growth data in children with psychosocial short stature treated by different changes in environment. J Pediatr Endocrinol Metab 2004;17 (4) 637- 643
PubMed Link to Article
King  JMTaitz  LS Catch up growth following abuse. Arch Dis Child 1985;60 (12) 1152- 1154
PubMed Link to Article
Talbot  NBSobel  EHBurk  BSLindemann  EKaufman  SB Dwarfism in healthy children: its possible relation to emotional, nutritional and endocrine disturbances. N Engl J Med 1947;236783- 793
Link to Article
Landgren  MAndersson Gronlund  MElfstrand  POSimonsson  JESvensson  LStromland  K Health before and after adoption from Eastern Europe. Acta Paediatr 2006;95 (6) 720- 725
PubMed Link to Article
Muhamedrahimov  RJ New attitudes: infant care facilities in St. Petersburg, Russia. Osofsky  JDFitzgerald  HEWAIMH Handbook of Infant Mental Health. Vol 1. New York, NY Wiley1999;245- 294
Whitten  CFPettit  MGFischhoff  J Evidence that growth failure from maternal deprivation is secondary to undereating. JAMA 1969;209 (11) 1675- 1682
PubMed Link to Article
Hochberg  ZAlbertsson-Wikland  K Evo-devo of infantile and childhood growth. Pediatr Res 2008;64 (1) 2- 7
PubMed Link to Article
Rosenfeld  RG Insulin-like growth factors and the basis of growth. N Engl J Med 2003;349 (23) 2184- 2186
PubMed Link to Article
Rodriguez  SGaunt  TRDay  IN Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease. Hum Genet 2007;122 (1) 1- 21
PubMed Link to Article
Scheepens  AModerscheim  TAGluckman  PD The role of growth hormone in neural development. Horm Res 2005;64 ((suppl 3)) 66- 72
PubMed Link to Article
Gunnell  DMiller  LLRogers  IHolly  JMALSPAC Study Team, Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children. Pediatrics 2005;116 (5) e681- e686
PubMed Link to Article
Shevah  OKornreich  LGalatzer  ALaron  Z The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene: correlation with CNS abnormalities. Horm Metab Res 2005;37 (12) 757- 760
PubMed Link to Article
Elgen  IJohansson  KAMarkestad  TSommerfelt  K A non-handicapped cohort of low-birthweight children: growth and general health status at 11 years of age. Acta Paediatr 2005;94 (9) 1203- 1207
PubMed Link to Article
Emond  AMLira  PILima  MCGrantham-McGregor  SMAshworth  A Development and behaviour of low-birthweight term infants at 8 years in northeast Brazil: a longitudinal study. Acta Paediatr 2006;95 (10) 1249- 1257
PubMed Link to Article
Kelleher  KJCasey  PHBradley  RH  et al.  Risk factors and outcomes for failure to thrive in low birth weight preterm infants. Pediatrics 1993;91 (5) 941- 948
PubMed
Escalona  SK Babies at double hazard: early development of infants at biologic and social risk. Pediatrics 1982;70 (5) 670- 676
PubMed
Black  MMWalker  SPWachs  TD  et al.  Policies to reduce undernutrition include child development. Lancet 2008;371 (9611) 454- 455
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 4.

Full-scale IQ at 54 months by age of randomization and birth weight in children randomized to foster care. The error bars indicate standard error; *P < .001 vs children with a 2.5-kg or heavier birth weight who were randomized at younger than 24 months of age (mean, 66.6 [SE, 6.2], vs 91.1 [SE, 3.9], t21 = 3.84).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Growth in the foster care group (FCG) vs the care as usual group (CAU) at baseline and at 6, 12, and 18 months postrandomization. A, Comparison of height and weight z scores in CAU and FCG, respectively, from baseline (n = 51, n = 54), and at 6 (n = 46, n = 57), 12 (n = 42, n = 51), and 18 (n = 21, n = 50) months postrandomization (analysis of variance for FCG height z score, F1,43 = 57.32, P < .001, partial η2 = 0.57; and weight z score, F1,43 = 63.65, P ≤.001, partial η2 = 0.60). B, Comparison of weight for height and occipital-frontal circumference (OFC) z scores from baseline to 18 months postrandomization. Error bars indicate standard error. *P ≤ .001. †P < .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Growth in the foster care group (FCG) vs care as usual group (CAU) at baseline and at 30 and 42 months of age. A, Mean growth rates from random-effects linear growth models for height, weight, and occipital-frontal circumference (OFC). B, Comparison of height and weight z scores from baseline to 42 months of age (analysis of variance of FCG height z score, F1,50 = 100.6, P < .001, partial η2 = 0.67; and weight z score, F1,50 = 94.0, P ≤.001, partial η2 = 0.65; CAU weight z score, F1,50 = 10.3, P = .002, partial η2 = 0.17; at 42 months, mean height z score in FCG vs CAU, respectively, 0.06 [SD, 0.97] vs −0.62 [SD, 0.99], t1,108 = −3.65; and weight z score, −0.31 [SD, 1.05] vs −0.75 [SD, 1.17], t1,108 = −1.98). C, Comparison of weight for height and OFC z scores. Error bars indicate standard error. *P < .001. †P = .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Group status at age 54 months in children living in Romanian institutions.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 6. Effect of Low Birth Weight and Sex on Growth and Cognitive Measures Following Randomization to Foster Carea
Table Graphic Jump LocationTable 7. Multiple Regression of Cognitive Variables in Institutionalized Children Randomized to Foster Care
Table Graphic Jump LocationTable 5. Pearson Correlations Between Mean Caregiver Interaction Scale Ratings From the Caregiving-Quality Score and Change in Z Scores Postrandomization in the Foster Care Group
Table Graphic Jump LocationTable 4. Multiple Regression of Change in Z Scores in the Foster Care Group After Randomization
Table Graphic Jump LocationTable 3. Effect of Low Birth Weight on Baseline Growth in the Institutionalized vs Never-Institutionalized Groupsa
Table Graphic Jump LocationTable 2. Multiple Regression of Baseline Measures in the Institutionalized Group
Table Graphic Jump LocationTable 1. Demographics, Growth, Caregiving Quality, and Cognitive Scores for the Institutionalized and Never-Institutionalized Groups

References

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Ghera  MMMarshall  PJFox  NA  et al.  The effects of foster care intervention on socially deprived institutionalized children's attention and positive affect: results from the BEIP study. J Child Psychol Psychiatry 2009;50 (3) 246- 253
PubMed Link to Article
Marshall  PJFox  NABucharest Early Intervention Project Core Group, A comparison of the electroencephalogram between institutionalized and community children in Romania. J Cogn Neurosci 2004;16 (8) 1327- 1338
PubMed Link to Article
Marshall  PJReeb  BCFox  NANelson  CA  IIIZeanah  CH Effects of early intervention on EEG power and coherence in previously institutionalized children in Romania. Dev Psychopathol 2008;20 (3) 861- 880
PubMed Link to Article
Nelson  CA  IIIFurtado  EAFox  NAZeanah  CH The deprived human brain. Am Sci 2009;97 (3) 222- 229
Link to Article
Nelson  CAParker  SWGuthrie  DBucharest Early Intervention Project Core Group, The discrimination of facial expressions by typically developing infants and toddlers and those experiencing early institutional care. Infant Behav Dev 2006;29 (2) 210- 219
PubMed Link to Article
Nelson  CA  IIIZeanah  CHFox  NAMarshall  PJSmyke  ATGuthrie  D Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science 2007;318 (5858) 1937- 1940
PubMed Link to Article
Parker  SWNelson  CABucharest Early Intervention Project Core Group, An event-related potential study of the impact of institutional rearing on face recognition. Dev Psychopathol 2005;17 (3) 621- 639
PubMed Link to Article
Parker  SWNelson  CABucharest Early Intervention Project Core Group, The impact of early institutional rearing on the ability to discriminate facial expressions of emotion: an event-related potential study. Child Dev 2005;76 (1) 54- 72
PubMed Link to Article
Smyke  ATDumitrescu  AZeanah  CH Attachment disturbances in young children, I: the continuum of caretaking casualty. J Am Acad Child Adolesc Psychiatry 2002;41 (8) 972- 982
PubMed Link to Article
Smyke  ATKoga  SFJohnson  DE  et al. BEIP Core Group, The caregiving context in institution-reared and family-reared infants and toddlers in Romania. J Child Psychol Psychiatry 2007;48 (2) 210- 218
PubMed Link to Article
Smyke  ATZeanah  CH  JrFox  NANelson  CA  III A new model of foster care for young children: the Bucharest early intervention project. Child Adolesc Psychiatr Clin N Am 2009;18 (3) 721- 734
PubMed Link to Article
Smyke  ATZeanah  CHFox  NANelson  CAGuthrie  D Placement in foster care enhances quality of attachment among young institutionalized children. Child Dev 2010;81 (1) 212- 223
Link to Article
Windsor  JGlaze  LEKoga  SFBucharest Early Intervention Project Core Group, Language acquisition with limited input: Romanian institution and foster care. J Speech Lang Hear Res 2007;50 (5) 1365- 1381
PubMed Link to Article
Zeanah  CHEgger  HLSmyke  AT  et al.  Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry 2009;166 (7) 777- 785
PubMed Link to Article
Zeanah  CHNelson  CAFox  NA  et al.  Designing research to study the effects of institutionalization on brain and behavioral development: the Bucharest Early Intervention Project. Dev Psychopathol 2003;15 (4) 885- 907
PubMed Link to Article
Zeanah  CHSmyke  ATDumitrescu  A Attachment disturbances in young children, II: indiscriminate behavior and institutional care. J Am Acad Child Adolesc Psychiatry 2002;41 (8) 983- 989
PubMed Link to Article
Zeanah  CHSmyke  ATKoga  SFCarlson  EBucharest Early Intervention Project Core Group, Attachment in institutionalized and community children in Romania. Child Dev 2005;76 (5) 1015- 1028
PubMed Link to Article
Moulson  MCFox  NAZeanah  CHNelson  CA Early adverse experiences and the neurobiology of facial emotion processing. Dev Psychol 2009;45 (1) 17- 30
PubMed Link to Article
Moulson  MCWesterlund  AFox  NAZeanah  CHNelson  CA The effects of early experience on face recognition: an event-related potential study of institutionalized children in Romania. Child Dev 2009;80 (4) 1039- 1056
PubMed Link to Article
Zeanah  CHEgger  HLSmyke  AT  et al.  Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry 2009;166 (7) 777- 785
PubMed Link to Article
Cody  JDSemrud-Clikeman  MHardies  LJ  et al.  Growth hormone benefits children with 18q deletions. Am J Med Genet A 2005;137 (1) 9- 15
PubMed Link to Article
Myers  SEWhitman  BYCarrel  ALMoerchen  VBekx  MTAllen  DB Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A 2007;143 (5) 443- 448
PubMed Link to Article
van Pareren  YKDuivenvoorden  HJSlijper  FSKoot  HMHokken-Koelega  AC Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. J Clin Endocrinol Metab 2004;89 (11) 5295- 5302
PubMed Link to Article
Astley  SJClarren  SK A fetal alcohol syndrome screening tool. Alcohol Clin Exp Res 1995;19 (6) 1565- 1571
PubMed Link to Article
Astley  SJClarren  SK Measuring the facial phenotype of individuals with prenatal alcohol exposure: correlations with brain dysfunction. Alcohol Alcohol 2001;36 (2) 147- 159
PubMed Link to Article
Miller  FG The randomized controlled trial as a demonstration project: an ethical perspective. Am J Psychiatry 2009;166 (7) 743- 745
PubMed Link to Article
Millum  JEmanuel  EJ Ethics: the ethics of international research with abandoned children. Science 2007;318 (5858) 1874- 1875
PubMed Link to Article
Zeanah  CHKoga  SFSimion  B  et al.  Response to commentary: ethical dimensions of the BEIP. Infant Ment Health J 2006;27 (6) 581- 583
Link to Article
Kuczarski  RJOgden  CLGrummer-Strawn  LM  et al.  CDC growth charts: United States. Adv Data June2000; (341) 1- 27
Roche  AFMukherjee  DGuo  SMMoore  WM Head circumference reference data: birth to 18 years. Pediatrics 1987;79 (5) 706- 712
PubMed
Bayley  N Bayley Scales of Infant Development. 2nd ed. New York, NY Psychological Corporation1993;
Wechsler  D Wechsler Preschool and Primary Scale of Intelligence.  San Antonio, TX Harcourt Assessment2000;
NICHD Early Child Care Research Network, Characteristics of infant child care: factors contributing to positive caregiving. Early Child Res Q 1996;11269- 306
Link to Article
Fernandez  IDHimes  JHde Onis  M Prevalence of nutritional wasting in populations: building explanatory models using secondary data. Bull World Health Organ 2002;80 (4) 282- 291
PubMed
Cameron  NPreece  MACole  TJ Catch-up growth or regression to the mean? recovery from stunting revisited. Am J Hum Biol 2005;17 (4) 412- 417
PubMed Link to Article
Gohlke  BCFrazer  FLStanhope  R Growth hormone secretion and long-term growth data in children with psychosocial short stature treated by different changes in environment. J Pediatr Endocrinol Metab 2004;17 (4) 637- 643
PubMed Link to Article
King  JMTaitz  LS Catch up growth following abuse. Arch Dis Child 1985;60 (12) 1152- 1154
PubMed Link to Article
Talbot  NBSobel  EHBurk  BSLindemann  EKaufman  SB Dwarfism in healthy children: its possible relation to emotional, nutritional and endocrine disturbances. N Engl J Med 1947;236783- 793
Link to Article
Landgren  MAndersson Gronlund  MElfstrand  POSimonsson  JESvensson  LStromland  K Health before and after adoption from Eastern Europe. Acta Paediatr 2006;95 (6) 720- 725
PubMed Link to Article
Muhamedrahimov  RJ New attitudes: infant care facilities in St. Petersburg, Russia. Osofsky  JDFitzgerald  HEWAIMH Handbook of Infant Mental Health. Vol 1. New York, NY Wiley1999;245- 294
Whitten  CFPettit  MGFischhoff  J Evidence that growth failure from maternal deprivation is secondary to undereating. JAMA 1969;209 (11) 1675- 1682
PubMed Link to Article
Hochberg  ZAlbertsson-Wikland  K Evo-devo of infantile and childhood growth. Pediatr Res 2008;64 (1) 2- 7
PubMed Link to Article
Rosenfeld  RG Insulin-like growth factors and the basis of growth. N Engl J Med 2003;349 (23) 2184- 2186
PubMed Link to Article
Rodriguez  SGaunt  TRDay  IN Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease. Hum Genet 2007;122 (1) 1- 21
PubMed Link to Article
Scheepens  AModerscheim  TAGluckman  PD The role of growth hormone in neural development. Horm Res 2005;64 ((suppl 3)) 66- 72
PubMed Link to Article
Gunnell  DMiller  LLRogers  IHolly  JMALSPAC Study Team, Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children. Pediatrics 2005;116 (5) e681- e686
PubMed Link to Article
Shevah  OKornreich  LGalatzer  ALaron  Z The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene: correlation with CNS abnormalities. Horm Metab Res 2005;37 (12) 757- 760
PubMed Link to Article
Elgen  IJohansson  KAMarkestad  TSommerfelt  K A non-handicapped cohort of low-birthweight children: growth and general health status at 11 years of age. Acta Paediatr 2005;94 (9) 1203- 1207
PubMed Link to Article
Emond  AMLira  PILima  MCGrantham-McGregor  SMAshworth  A Development and behaviour of low-birthweight term infants at 8 years in northeast Brazil: a longitudinal study. Acta Paediatr 2006;95 (10) 1249- 1257
PubMed Link to Article
Kelleher  KJCasey  PHBradley  RH  et al.  Risk factors and outcomes for failure to thrive in low birth weight preterm infants. Pediatrics 1993;91 (5) 941- 948
PubMed
Escalona  SK Babies at double hazard: early development of infants at biologic and social risk. Pediatrics 1982;70 (5) 670- 676
PubMed
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