ARTICLE

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

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 intel-

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 highquality 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:

ligence over time.

Results: Growth in institutionalized children was compromised, particularly in infants weighing less than

NCT00747396 Arch Pediatr Adolesc Med. 2010;164(6):507-516 tutional care settings.4,10-12 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.13-32 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
WWW.ARCHPEDIATRICS.COM

Author Affiliations are listed at the end of this article.

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,2-5 though all share 2 characteristics: otherwise unexplained growth failure occurring in association with socially stressful conditions and significant catch-up when a childs 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,7-9 or placed for adoption from insti-

SYNDROME OF POOR GROWTH

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 507

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

CARE AS USUAL AND FOSTER CARE GROUPS

Enrollment 187 Assessed for eligibility

51 Did not meet inclusion criteria

136 Randomly assigned

Allocation

68 Assigned to institutional care as usual

68 Assigned to foster care

Follow-up

11 Lost to follow-up 7 Adopted/dropped out 2 Reintegrated/dropped out 2 Missing data 6 Found to meet medical/ genetic exclusion criteria

4 Lost to follow-up 3 Adopted/dropped out 1 Reintegrated/dropped out 5 Found to meet medical/ genetic exclusion criteria

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 childrens original group assignments. Thus, our findings represent a conservative estimate of the response to intervention.

Analysis

51 Included in analysis

59 Included in analysis

NEVER-INSTITUTIONALIZED GROUP
Figure 1. Group status at age 54 months in children living in Romanian institutions.

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,33-35 we postulated that catch-up growth in those randomized to foster care would be associated with cognitive abilities at follow-up.
METHODS

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.18,27,38-40 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.

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.

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.

PHYSICAL GROWTH
Supine length (at 24 months) or height (at 24 months), weight, and weight for height were converted to agestandardized scores (z scores) based on 2000 Centers for Disease Control and Prevention data.41 Use of z score measures

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 508

WWW.ARCHPEDIATRICS.COM

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

Table 1. Demographics, Growth, Caregiving Quality, and Cognitive Scores for the Institutionalized and Never-Institutionalized Groups
Mean (SD) Institutionalized Child Characteristic Age, mo Romanian ethnicity, % Roma/other/unknown ethnicity, % Female sex, % Birth weight, g Birth weight 2500 g, % Proportion of life institutionalized Baseline height z score Baseline height z score 2, % Baseline weight z score Baseline weight z score 2, % Baseline head circumference z score Baseline head circumference z score 2, % Baseline weight-for-height z score Baseline weight-for-height z score 2, % Postrandomization results Baseline CQS 30-Month CQS 42-Month CQS 30- and 42-month CQS Cognitive measure Baseline DQ DQ at 42 months WPPSI full-scale IQ at 54 months Institutionalized (n= 125) 21.0 (7.4) 55 a 45 50 2834 (596) a 24 a 62.9 (25.1) a 0.84 (0.86) a 9b 1.23 (1.08) a 25 a 1.10 (0.99) a 17 c 0.67 (1.14) a 16 c Never Institutionalized (n = 72) 19.3 (7.1) 91 9 57 3333 (459) 3 0 0.13 (0.91) 2 0.05 (1.00) 0 0.15 (0.86) 2 0.16 (0.96) 2 2.82 (0.53) 2.86 (0.55) 2.75 (0.59) 2.81 (0.49) 103.8 (11.3) 103.4 (11.8) 109.3 (21.2) e 2.0 (0.62) d 2.46 (0.63) d,e,f 2.53 (0.58) e 2.49 (0.48) d,e,f 72.5 (13.2) d 77.1 (13.3) d,e,f 73.3 (13.1) d,f 2.29 (0.57) d 2.75 (0.52) e 2.79 (0.57) e 2.76 (0.48) e 76.1 d (13.1) 85.7 d,e (14.2) 81.0 d,e (18.5) Care as Usual (n = 62) Foster Care Group (n = 63)

Abbreviations: CQS, caretaking-quality score; DQ, developmental quotient; WPPSI, Wechsler Preschool and Primary Scale of Intelligence. a P .001 vs never institutionalized, t or 2 test. b P .05 vs never institutionalized, t or 2 test. c P .01 vs never institutionalized, t or 2 test. d P .05 vs never institutionalized, 1-way analysis of variance post hoc test. e P .05 vs baseline scores, t test. f P .05 vs foster care, 1-way analysis of variance post hoc test.

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

RESULTS

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. 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]; F 1,114 = 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
WWW.ARCHPEDIATRICS.COM

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 childs caregiving experience in either institutional or family settings. Children were videotaped with their preferred caregiver for 112 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.

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 509

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

Table 2. Multiple Regression of Baseline Measures in the Institutionalized Group

Z Score, Characteristic Intercept Sex, M = 1, F = 0 Ethnicity, Romanian=0, other=1 Birth weight, kg Caregiving-quality score Age, mo Height a 1.53 (0.46) e 0.17 (0.15) 0.07 (0.15) 0.67 (0.13) e 0.24 (0.13) 0.03 (0.01) g (Standard Error) by Baseline Measurement OFC c 2.17 (.57) e 0.04 (0.18) 0.50 (0.18) f 0.36 (0.16) g 0.05 (0.15) 0.01 (0.01) Weight for Height d 3.04 (0.70) e 0.08 (0.22) 0.09 (0.23) 0.47 (0.20) g 0.15 (0.19) 0.03 (0.02)

Weight b 3.64 (0.62) e 0.04 (0.20) 0.15 (0.20) 0.79 (0.17) e 0.09 (0.17) 0.02 (0.01)

Abbreviation: OFC, occipital-frontal circumference. a Adjusted R 2 = 0.233, P .001. b Adjusted R 2 = 0.189, P .001. c Adjusted R 2 = 0.084, P .05. d Adjusted R 2 = 0.083, P .05. e P .001. f P .01. g P .05.

Table 3. Effect of Low Birth Weight on Baseline Growth in the Institutionalized vs Never-Institutionalized Groups a
Z Score, Mean (SD) Institutionalized Measure Baseline height Baseline weight Baseline occipital-frontal circumference Baseline weight for height 2.5 kg (n = 27) 1.19 (0.15) b,c 1.80 (0.20) b,c 1.35 (0.17) c 1.12 (0.23) b,c (P 2.5 kg (n = 85) 0.70 (0.10) c 1.04 (0.12) c 0.97 (0.11) c 0.56 (0.13) c .05). Never Institutionalized, 2.5 kg (n = 65) 0.13 (0.12) 0.09 (0.13) 0.15 (0.11) 0.11 (0.13)

a Equal variance was assumed unless the Levine test for equality of variance was significant b P .05 vs the institutionalized group with a 2.5-kg or greater birth weight. c P .001 vs the never-institutionalized group with a 2.5-kg or greater birth weight.

12 months vs 8% of infants aged 24 months, =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 nonRomanian 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.
2 1

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
WWW.ARCHPEDIATRICS.COM

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 510

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

1.0

CAU FCG

0.5

FCG Height Weight

CAU Height Weight

0.5

Mean Growth Rate, /mo

0.8 0.0

0.0

FCG Weight for height OFC

CAU Weight for height OFC

Z Score

Z Score

0.6

0.5

0.5

0.4

1.0

1.0

0.2

1.5

1.5

0.0 Height, cm Weight, kg OFC, cm

2.0 Baseline 30 42

2.0 Baseline 30 42

Time, mo

Time, mo

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 2 = 0.67; and weight z score, F1,50 = 94.0, P .001, partial 2 =0.65; CAU weight z score, F1,50 =10.3, P =.002, partial 2 =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.

(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. 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. 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. Multipleregression 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 cor-

0.5

FCG Height Weight

CAU Height Weight

0.0

FCG Weight for height OFC

CAU Weight for height OFC

Z Score

0.5

1.0

1.5

2.0 0 6 12 18 0 6 12 18

Time Postrandomization, mo

Time Postrandomization, mo

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 2 = 0.57; and weight z score, F1,43 = 63.65, P .001, partial 2 = 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.

related 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). 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
WWW.ARCHPEDIATRICS.COM

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 511

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

Table 4. Multiple Regression of Change in Z Scores in the Foster Care Group After Randomization
Change in Z Score, Characteristic Intercept Sex, M = 1, F = 0 Ethnicity, Romanian=0, other=1 Birth weight, kg Postplacement caregiving, mean caregiving quality scores at 30 and 42 months Duration of intervention, age at 42-month testing placement age Age, 12 months=0, 12 months=1 Baseline z score Abbreviation: OFC, occipital-frontal circumference. a Adjusted R 2 = 0.271, P .01. b Adjusted R 2 = 0.391, P .001. c Adjusted R 2 = 0.359, P .001. d Adjusted R 2 = 0.295, P .01. e P .01. f P .05. g P .001. Height a 0.04 (1.18) 0.01 (0.20) 0.32 (0.20) 0.10 (0.19) 0.62 (0.19) e 0.01 (0.02) 1.13 (0.49) f 0.36 (0.14) f Weight b 0.44 (1.39) 0.39 (0.23) 0.17 (0.24) 0.08 (0.21) 0.76 (0.24) e 0.01 (0.03) 1.79 (0.57) e 0.37 (0.12) e (Standard Error) OFC c 1.09 (1.12) 0.24 (0.18) 0.15 (0.19) 0.11 (0.17) 0.05 (0.18) 0.02 (0.02) 1.16 (0.46) g 0.29 (0.09) e Weight for Height d 1.47 (1.70) 0.55 (0.28) 0.09 (0.29) 0.20 (0.24) 0.56 (30) 0.03 (0.03) 2.29 (0.71) e 0.26 (0.14)

Table 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
Change in Z Scores, Baseline to 42 Months (n = 53) Qualitative Ratings of Caregiver Interactions a Height Weight OFC Weight for Height 0.009 0.123 0.208 0.163 0.175 0.160

Detachment, b caregiver is emotionally uninvolved, disengaged, and unaware of infants needs 0.410 c 0.149 0.016 0.124 0.188 0.05 Flat affect, b caregiver expresses no emotion or animation Positive regard for the child, caregiver expresses positive feelings in interactions with the child 0.453 d 0.329 e 0.125 Sensitivity, caregiver responds to the infants social gestures and is attuned to the infants needs and moods 0.412 c 0.291 e 0.054 Stimulation of cognitive development, caregiver engages in activities that can facilitate the infants learning 0.201 0.236 0.062 Total caregiving-quality score 0.398 c 0.289 e 0.016 Abbreviation: OFC, occipital-frontal circumference. a Scores range from 0 (not at all characteristic) to 4 (highly characteristic). b Item was reverse scored when calculating the total caregiving-quality score. c P .01. d P .001. e P .05.

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).
COMMENT

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 imWWW.ARCHPEDIATRICS.COM

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 512

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

Table 6. Effect of Low Birth Weight and Sex on Growth and Cognitive Measures Following Randomization to Foster Care a
Z Score, Mean (Standard Error) Sex Measure Height at 42 months Weight at 42 months OFC at 42 months Weight for height at 42 months Change in height at 42 months Change in weight at 42 months Change in OFC at 42 months Change in weight for height at 42 months Baseline CQS Mean CQS at 30 and 42 months Male (n = 31) 0.10 (0.16) 0.35 (0.20) 1.28 (0.21) 0.54 (0.22) 0.92 (0.16) 1.15 (23) 0.06 (0.14) 0.41 (0.23) 2.23 (0.11) 2.70 (0.07) Female (n = 32) 0.22 (0.20) 0.28 (0.24) 1.12 (0.21) 0.63 (0.29) 0.94 (0.13) 1.04 (0.15) 0.13 (0.15) 0.23 (0.21) 2.35 (0.10) 2.81 (0.10) 2.5 (n = 17) 0.26 (0.22) 0.59 (0.21) 1.67 (0.25) 0.70 (0.27) 0.87 (0.18) 1.06 (18) 0.11 (0.15) 0.30 (0.21) 2.34 (0.15) 2.82 (0.12) Birth Weight, kg 2.5 (n =40) 0.19 (0.17) 0.25 (0.22) 0.93 (0.17) b 0.61 (0.26) 0.99 (0.14) 1.10 (0.19) 0.02 (0.14) 0.29 (0.21) 2.23 (0.10) 2.73 (0.08)

Abbreviations: CQS, caregiving-quality score; OFC, occipital-frontal circumference. a Equal variance was assumed unless the Levine test for equality of variance was significant (P b P .05.

.05).

Table 7. Multiple Regression of Cognitive Variables in Institutionalized Children Randomized to Foster Care
(Standard Error) At 42 Months DQ (n = 47) a 41.25 (17.31) 4.60 (3.24) 5.00 (3.26) 0.25 (2.70) 0.45 (0.13) h 5.49 (3.47) At 54 Months Verbal IQ (n =45) f 19.11 (27.00) 6.06 (5.05) 2.80 (5.04) 7.04 (4.30) 0.45 (0.20) g 4.47 (5.45) 5.14 (5.92) 12.36 (4.68) g 7.32 (3.80) 1.61 (3.34)

Variable Intercept Sex, M = 1, F = 0 Ethnicity, Romanian=0, other=1 Birth weight, kg Baseline DQ Postplacement caregiving, mean caregiving quality score at 30 and 42 months Age, 24 months=0, 24 months=1 Change in height z score from baseline to 42 months Change in weight z score from baseline to 42 months Change in OFC z score from baseline to 42 months

Change in DQ Change in DQ/IQ From Baseline Full-scale IQ From Baseline Performance IQ (n = 47) b (n = 45) c (n = 45) d (n = 45) e 41.25 (17.31) 15.38 (27.18) 4.60 (3.24) 8.09 (5.09) 5.00 (3.26) 2.04 (5.07) 0.25 (2.70) 9.22 (4.33) g 0.55 (0.13) i 0.46 (0.20) g 5.49 (3.47) 2.48 (5.49) 15.38 (27.18) 8.09 (5.09) 2.04 (5.07) 9.22 (4.33) g 0.54 (0.20) i 2.48 (5.49) 2.73 (5.96) 9.28 (4.71) j 3.35 (3.83) 2.50 (3.40) 29.49 (25.67) 8.61 (4.81) 7.45 (4.79) 9.49 (4.09) g 0.38 (0.19) j 0.28 (5.18) 1.68 (5.64) 3.31 (4.45) 1.78 (3.62) 4.32 (3.21)

3.85 (3.89) 3.85 (3.89) 2.73 (5.96) 8.14 (3.61) g 8.14 (3.61) g 9.28 (4.71) j 4.19 (2.44) 4.19 (2.44) 3.35 (3.83) 0.78 (2.27) 0.78 (2.27) 2.50 (3.40)

Abbreviations: DQ, developmental quotient; OFC, occipital-frontal circumference. a Adjusted R 2 = 0.545, P .001. b Adjusted R 2 = 0.566, P .001. c Adjusted R 2 = 0.404, P .05. d Adjusted R 2 = 0.418, P .05. e Adjusted R 2 = 0.379, P .05. f Adjusted R 2 = 0.403, P .05. g P .05. h P .01. i P .001. j P .06.

pairments 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 (childcentered, 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. 2-6 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
WWW.ARCHPEDIATRICS.COM

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 513

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

100

Birth weight, kg 2.5 <2.5

Full-scale IQ at 54 Months

90

80

70

60

50

<24

24

Age at Randomization, mo

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).

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.2-6 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 deprivationassociated 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.2-6,48 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
WWW.ARCHPEDIATRICS.COM

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 514

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

the global growth failure, low IQs, and smaller head sizes described in other groups of LBW infants who experienced social deprivation in early life.12,60-63 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 wellbeing, 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. Accepted for Publication: January 6, 2010. Published Online: April 5, 2010 (doi:10.1001 /archpediatrics.2010.56). Author Affiliations: Department of Pediatrics (Dr Johnson), and Institute of Child Development (Dr Nelson), University of Minnesota, Minneapolis; Semel Institute, University of CaliforniaLos 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, Childrens Hospital Boston/ Harvard Medical School, Boston, Massachusetts. 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).

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.
REFERENCES
1. Money J. The Kaspar Hauser Syndrome of Psychosocial Dwarfism. Amherst, NY: Prometheus Books; 1992. 2. Blizzard RM, Bulatovic A. Syndromes of psychosocial short stature. In: Lifshitz F, ed. Pediatric Endocrinology. 3rd ed. New York, NY: Marcel Dekker; 1996:83-93. 3. Gohlke BC, Frazer FL, Stanhope R. Body mass index and segmental proportion in children with different subtypes of psychosocial short stature. Eur J Pediatr. 2002;161(5):250-254. 4. Mason P, Narad C. Long-term growth and puberty concerns in international adoptees. Pediatr Clin North Am. 2005;52(5):1351-1368, vii. 5. Skuse D, Albanese A, Stanhope R, Gilmour J, Voss L. A new stress-related syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency. Lancet. 1996;348(9024):353-358. 6. Gohlke BC, Khadilkar VV, Skuse D, Stanhope R. Recognition of children with psychosocial short stature: a spectrum of presentation. J Pediatr Endocrinol Metab. 1998;11(4):509-517. 7. Olivan G. Catch-up growth assessment in long-term physically neglected and emotionally abused preschool age male children. Child Abuse Negl. 2003;27 (1):103-108. 8. Taitz LS, King JM. Growth patterns in child abuse. Acta Paediatr Scand Suppl. 1988;343:62-72. 9. Wyatt DT, Simms MD, Horwitz SM. Widespread growth retardation and variable growth recovery in foster children in the first year after initial placement. Arch Pediatr Adolesc Med. 1997;151(8):813-816. 10. Johnson DE. Medical and developmental sequelae of early childhood institutionalization in Eastern European adoptees. In: Nelson CA, ed. The Effects of Early Adversity on Neurobehavioral Development: The Minnesota Symposia on Child Psychology. Mahwaw, NJ: Lawrence Erlbaum Associates; 2000:113-162. 11. Van Ijzendoorn MH, Bakermans-Kranenburg MJ, Juffer F. Plasticity of growth in height, weight, and head circumference: meta-analytic evidence of massive catch-up after international adoption. J Dev Behav Pediatr. 2007;28(4):334-343.

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 515

WWW.ARCHPEDIATRICS.COM

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.

12. Miller BS, Kroupina MG, Iverson SL, et al. Auxological evaluation and determinants of growth failure at the time of adoption in Eastern European adoptees. J Pediatr Endocrinol Metab. 2009;22(1):31-39. 13. Ghera MM, Marshall PJ, Fox NA, et al. The effects of foster care intervention on socially deprived institutionalized childrens attention and positive affect: results from the BEIP study. J Child Psychol Psychiatry. 2009;50(3):246-253. 14. Marshall PJ, Fox NA; Bucharest 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. 15. Marshall PJ, Reeb BC, Fox NA, Nelson CA III, Zeanah CH. Effects of early intervention on EEG power and coherence in previously institutionalized children in Romania. Dev Psychopathol. 2008;20(3):861-880. 16. Nelson CA III, Furtado EA, Fox NA, Zeanah CH. The deprived human brain. Am Sci. 2009;97(3):222-229. 17. Nelson CA, Parker SW, Guthrie D; Bucharest 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. 18. Nelson CA III, Zeanah CH, Fox NA, Marshall PJ, Smyke AT, Guthrie D. Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science. 2007;318(5858):1937-1940. 19. Parker SW, Nelson CA; Bucharest Early Intervention Project Core Group. An eventrelated potential study of the impact of institutional rearing on face recognition. Dev Psychopathol. 2005;17(3):621-639. 20. Parker SW, Nelson CA; Bucharest 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. 21. Smyke AT, Dumitrescu A, Zeanah CH. Attachment disturbances in young children, I: the continuum of caretaking casualty. J Am Acad Child Adolesc Psychiatry. 2002;41(8):972-982. 22. Smyke AT, Koga SF, Johnson 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. 23. Smyke AT, Zeanah CH Jr, Fox NA, Nelson 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. 24. Smyke AT, Zeanah CH, Fox NA, Nelson CA, Guthrie D. Placement in foster care enhances quality of attachment among young institutionalized children. Child Dev. 2010;81(1):212-223. 25. Windsor J, Glaze LE, Koga SF; Bucharest 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. 26. Zeanah CH, Egger HL, Smyke AT, et al. Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry. 2009;166(7):777785. 27. Zeanah CH, Nelson CA, Fox 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. 28. Zeanah CH, Smyke AT, Dumitrescu A. Attachment disturbances in young children, II: indiscriminate behavior and institutional care. J Am Acad Child Adolesc Psychiatry. 2002;41(8):983-989. 29. Zeanah CH, Smyke AT, Koga SF, Carlson E; Bucharest Early Intervention Project Core Group. Attachment in institutionalized and community children in Romania. Child Dev. 2005;76(5):1015-1028. 30. Moulson MC, Fox NA, Zeanah CH, Nelson CA. Early adverse experiences and the neurobiology of facial emotion processing. Dev Psychol. 2009;45(1):17-30. 31. Moulson MC, Westerlund A, Fox NA, Zeanah CH, Nelson 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. 32. Zeanah CH, Egger HL, Smyke AT, et al. Institutional rearing and psychiatric disorders in Romanian preschool children. Am J Psychiatry. 2009;166(7):777785. 33. Cody JD, Semrud-Clikeman M, Hardies LJ, et al. Growth hormone benefits children with 18q deletions. Am J Med Genet A. 2005;137(1):9-15. 34. Myers SE, Whitman BY, Carrel AL, Moerchen V, Bekx MT, Allen 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):443448. 35. van Pareren YK, Duivenvoorden HJ, Slijper FS, Koot HM, Hokken-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.

36. Astley SJ, Clarren SK. A fetal alcohol syndrome screening tool. Alcohol Clin Exp Res. 1995;19(6):1565-1571. 37. Astley SJ, Clarren SK. Measuring the facial phenotype of individuals with prenatal alcohol exposure: correlations with brain dysfunction. Alcohol Alcohol. 2001; 36(2):147-159. 38. Miller FG. The randomized controlled trial as a demonstration project: an ethical perspective. Am J Psychiatry. 2009;166(7):743-745. 39. Millum J, Emanuel EJ. Ethics: the ethics of international research with abandoned children. Science. 2007;318(5858):1874-1875. 40. Zeanah CH, Koga SF, Simion B, et al. Response to commentary: ethical dimensions of the BEIP. Infant Ment Health J. 2006;27(6):581-583. 41. Kuczarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. June 2000;(341):1-27. 42. Roche AF, Mukherjee D, Guo SM, Moore WM. Head circumference reference data: birth to 18 years. Pediatrics. 1987;79(5):706-712. 43. Bayley N. Bayley Scales of Infant Development. 2nd ed. New York, NY: Psychological Corporation; 1993. 44. Wechsler D. Wechsler Preschool and Primary Scale of Intelligence. San Antonio, TX: Harcourt Assessment; 2000. 45. NICHD Early Child Care Research Network. Characteristics of infant child care: factors contributing to positive caregiving. Early Child Res Q. 1996;11:269306. 46. Fernandez ID, Himes JH, de Onis M. Prevalence of nutritional wasting in populations: building explanatory models using secondary data. Bull World Health Organ. 2002;80(4):282-291. 47. Cameron N, Preece MA, Cole TJ. Catch-up growth or regression to the mean? recovery from stunting revisited. Am J Hum Biol. 2005;17(4):412-417. 48. Gohlke BC, Frazer FL, Stanhope 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. 49. King JM, Taitz LS. Catch up growth following abuse. Arch Dis Child. 1985;60(12): 1152-1154. 50. Talbot NB, Sobel EH, Burk BS, Lindemann E, Kaufman SB. Dwarfism in healthy children: its possible relation to emotional, nutritional and endocrine disturbances. N Engl J Med. 1947;236:783-793. 51. Landgren M, Andersson Gronlund M, Elfstrand PO, Simonsson JE, Svensson L, Stromland K. Health before and after adoption from Eastern Europe. Acta Paediatr. 2006;95(6):720-725. 52. Muhamedrahimov RJ. New attitudes: infant care facilities in St. Petersburg, Russia. In: Osofsky JD, Fitzgerald HE, eds. WAIMH Handbook of Infant Mental Health. Vol 1. New York, NY: Wiley; 1999:245-294. 53. Whitten CF, Pettit MG, Fischhoff J. Evidence that growth failure from maternal deprivation is secondary to undereating. JAMA. 1969;209(11):1675-1682. 54. Hochberg Z, Albertsson-Wikland K. Evo-devo of infantile and childhood growth. Pediatr Res. 2008;64(1):2-7. 55. Rosenfeld RG. Insulin-like growth factors and the basis of growth. N Engl J Med. 2003;349(23):2184-2186. 56. Rodriguez S, Gaunt TR, Day IN. Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease. Hum Genet. 2007;122(1):1-21. 57. Scheepens A, Moderscheim TA, Gluckman PD. The role of growth hormone in neural development. Horm Res. 2005;64(suppl 3):66-72. 58. Gunnell D, Miller LL, Rogers I, Holly JM; ALSPAC 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. 59. Shevah O, Kornreich L, Galatzer A, Laron 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. 60. Elgen I, Johansson KA, Markestad T, Sommerfelt 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. 61. Emond AM, Lira PI, Lima MC, Grantham-McGregor SM, Ashworth 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. 62. Kelleher KJ, Casey PH, Bradley RH, et al. Risk factors and outcomes for failure to thrive in low birth weight preterm infants. Pediatrics. 1993;91(5):941-948. 63. Escalona SK. Babies at double hazard: early development of infants at biologic and social risk. Pediatrics. 1982;70(5):670-676. 64. Black MM, Walker SP, Wachs TD, et al. Policies to reduce undernutrition include child development. Lancet. 2008;371(9611):454-455.

(REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 164 (NO. 6), JUNE 2010 516

WWW.ARCHPEDIATRICS.COM

Downloaded from www.archpediatrics.com on January 30, 2012 2010 American Medical Association. All rights reserved.