Head Growth and Developmental Outcome in Very Low-Birth-Weight Infants

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70 PEDIATRICS Vol. 71 No. 1 January 1983

Head

Growth

and

Developmental

Outcome

in

Very

Low-Birth-Weight

Infants

Steven J. Gross, MD, Jerri M. Oehler, RN, MS, and

Carol

0. Eckerman,

PhD

From the Department of Pediatrics, Duke University Medical Center, and Department

of Psychology, Duke University, Durham, North Carolina

ABSTRACT. The predictive role of early head growth for subsequent outcome was evaluated in 85 infants with birth weight <1,500 g. On the basis ofhead circumference at birth and head growth between birth and age 6 weeks, infants were divided into four groups: (1) microcephalic at birth with less (<3.5 cm) postnatal head growth (n =

9), (2) microcephalic at birth with more (3.5 cm) post-natal head growth (n = 12), (3) normocephalic at birth

with less head growth (n = 32), and (4) normocephalic at

birth with more head growth (n = 32). At both 6 and 15

months of age the two groups of infants with less post-natal head growth had an increased incidence of growth failure, whereas the two groups with more postnatal head growth had a low incidence, similar to that for a matched full-term group (n = 95). Major neurologic defects

oc-curred significantly more frequently among infants who were microcephalic with less postnatal head growth; two thirds showed evidence of blindness, hydrocephalus, or spastic diplegia. This group also performed more poorly on the Bayley Scales than any of the other groups. Infants who were normocephalic with greater head growth were

free of neurologic defects and had Bayley scores that did not differ from those for the healthy full-term infants. The two groups of infants with only one poor measure of head growth demonstrated intermediate scores at age 6 months. At age 15 months, the group with normocephaly and less postnatal head growth continued to have inter-mediate scores. The group with microcephaly and greater postnatal head growth, however, showed developmental catch-up; their scores did not differ from those of the group that was normocephalic with greater head growth or the full-term group. Less postnatal head growth was associated with an increased requirement for mechanical ventilation, patent ductus arteriosus, sepsis, delayed to!-erance of feeding, and slower weight gain. These data suggest that early postnatal head growth may summarize the adverse effects of many perinatal risk factors and that head circumference at birth and head growth by six weeks

are strong predictors of early developmental outcome in

very low-birth-weight infants. Pediatrics 1983;71:70-75;

Received for publication Dec 16, 1981; accepted April 9, 1982. Reprint requests to (S.J.G.) P0 Box 3967, Duke University Medical Center, Durham, NC 27710.

ry low-birth-weight infants, developmental follow-up, head growth.

Recent follow-up studies of low-birth-weight

in-fants have demonstrated increased survival and

improved outcome for infants with birth weights

<1,500 g.’5 Nevertheless, a wide range of

develop-mental outcomes exists for these infants, and

at-tempts to predict even early outcome from perinatal

assessments have had limited success. Previously,

we demonstrated that low-birth-weight infants with

microcephaly at birth had poorer growth, increased

neurologic defects, and poorer intellectual perform-ance at 5 years of age than low-birth-weight infants who were normocephalic at birth.t’ This association

between head circumference at birth and

develop-mental outcome in low-birth-weight infants has

been confirmed recently.7 The period of most rapid

brain growth extends beyond the time of birth;

hence, brain growth during the early postnatal

pe-nod may also have an important impact upon

sub-sequent outcome. Significant postnatal illness in

preterm infants has been shown to result in

mark-edly decreased head growth.89 but no data exist

relating postnatal head growth to subsequent

de-velopment. The purpose of the present study is to

relate both head circumference at birth and early

postnatal head growth to developmental outcome

in very low-birth-weight infants.

MATERIALS AND METHODS

The patient population consisted of all surviving infants with birth weights <1 ,500 g treated at Duke

University Medical Center from January 1978

through March 1979. Overall, 124 infants with birth

weights between 500 and 1,500 g were admitted to

the intensive care nursery; 87 (70%) survived to

at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news

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discharge. Of these infants 62 (71%) were inborn

and 25 (29%) were transferred after birth.

Gestational age of each infant was determined

from the date of the last menstrual period and

substantiated by clinical examination of the

in-fant.’#{176}Infants were classified as small for

gesta-tional age (SGA) if their birth weights were less

than the tenth percentile for gestational age.’ ‘ The

head circumference of 85 infants (two infants

trans-ferred to outlying hospitals within 2 weeks of

ad-mission were not included) was measured at birth

and weekly for 6 weeks by a single examiner using

a disposable paper tape at the largest

occipitofron-tal diameter. Head circumference at birth was used

to designate infants as either microcephalic (<10th

percentile) or normocephalic (lOth percentile).”

It has been suggested that only infants who have a

disparity between head circumference at birth and

other growth measurements be designated as

mi-crocephalic. We chose to define microcephaly as a

head circumference <10th percentile (irrespective

of other growth values) so we could compare these

results with those published previously. The

me-dian change in head circumference between birth

and 6 weeks of age was used to designate infants as

having either less postnatal head growth (<3.5 cm)

or more postnatal growth (3.5 cm). Based on these

head circumference measurements, infants were

di-vided into four groups: (1) microcephalic at birth

with less postnatal head growth (n = 9), (2)

micro-cephalic at birth with more postnatal head growth

(n = 12), (3) normocephalic at birth with less

post-natal head growth (n = 32), and (4) normocephalic

at birth with more postnatal head growth (n = 32).

Standard care included maintenance of

temper-ature in the neutral thermal range and infusion of

intravenous solutions of dextrose, water, and

elec-trolytes. Determinations of serum glucose,

electro-lytes, and calcium were performed routinely.

Um-bilical artery catheters were placed in infants who

had respiratory distress, and inspired oxygen

con-centration was regulated to maintain Pao2 between

60 and 80 mm Hg. Continuous positive airway

pres-sure was used for infants requiring an oxygen

con-centration >40% and a pressure-cycled ventilator

was used for infants with severe apnea or

respira-tory failure.

Exchange transfusion for hyperbilirubinemia was

performed when the ratio of serum bilirubin to body

weight exceeded 1 mg/100 g and at lower levels in

the sickest infants. Antibiotics were used only for

suspected infection. Nutrition was provided by

or-ogastric tube feedings of human milk or 67 kcal/dL

of formula. Hyperalimentation was not used

rou-tinely; however, 25 infants who were unable to

tolerate adequate enteral feeding by 3 weeks of age

were fed intravenously using glucose, electrolyte,

and amino acid solutions (Freamine, McGaw

Lab-oratories, Irvine, CA) and Intralipid (Cutter

Labo-ratories, Berkley, CA). Routine ophthalmologic

ex-aminations were performed prior to discharge.

Par-ents were allowed unrestricted visiting and were

encouraged to visit their infants as frequently as

possible.

Follow-up evaluations were scheduled at Duke

University for all infants at 6.0 ± 0.5 months and 15.0 ± 0.5 months of age, corrected for prematurity.

In addition, a comparison group of 95 infants born

at term (38 to 42 weeks gestation) following

uncom-plicated pregnancy, labor, and delivery was

matched to the low-birth-weight infants for sex,

race and maternal age, parity, and education, and

this group was similarly evaluated. At each visit a

medical and developmental history was obtained

and a complete physical and neurologic

examina-tion was performed. Measurements of weight,

length, and occipitofrontal head circumference were

plotted on standard growth charts.’2 Developmental

evaluations were performed using the Bayley

Men-tal and Motor Scales of Infant Development” by

examiners blind to the head circumference groups

of the infants.

Head circumference groups of low-birth-weight

infants were compared with each other and to the

full-term infant group to determine to what extent

early head circumference measurements were

pre-dictive of developmental outcome. Medical

compli-cations and other postnatal growth assessments

were summarized to examine correlates of head

circumference classifications. Differences among

the groups in continuous variables were assessed by

one-way analyses of variance followed by Duncan

multiple range tests’4; for categorized data, tests

were employed, followed by Fisher exact tests using

Bonferroni’s method for multiple comparisons.’5

RESULTS

Follow-up Data

Only one very low-birth-weight (VLBW) infant

was lost to follow-up at 6 months and one infant

was lost to follow-up at 15 months. Two infants

died after discharge from the nursery. One infant,

who was normocephalic with greater head growth,

was a victim of sudden infant death syndrome at

age 5 months. Another infant, who was

normoce-phalic with less head growth, died of pneumonia at

age 8 months. He was failing to thrive and had

severe developmental delay. The comparison group

of 95 term infants was recruited at age 6 months

and 87 (92%) were re-evaluated at age 15 months.

Growth. Growth failure, defined as weight,

length, or head circumference less than the fifth

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72 DEVELOPMENTAL OUTCOME IN VERY LOW-BIRTH-WEIGHT INFANTS

6 and 15 months of age in the two groups of VLBW

infants with less postnatal head growth than in the

full-term infants (Table 1). Growth failure was most

striking for the infants who were also microcephalic

at birth. At age 6 months, more than half of these

infants had growth measurements <5th percentile.

Even by 15 months of age, 38% had weight <5%,

50% had length <5%, and 25% were still

microce-phalic. Low-birth-weight infants with greater

post-natal head growth, whether or not they had been

microcephalic at birth, had low rates of growth

failure that did not differ at either age from those

of the full-term infants.

Neurologic Function. The four groups of VLBW

infants demonstrated significant differences in the

incidence of major neurologic defects (Table 2). At

age 6 months, 5/9 infants with microcephaly and

less postnatal head growth demonstrated major neurologic defects: three children had spastic

diple-gia (two of whom were also blind secondary to

retrolental fibroplasia), one child had

hydrocepha-lus, and one child had severe hypotonia. At 15

months of age, six of these nine children showed

major neurologic defects. Major neurologic defects

were infrequent in the other groups of VLBW

in-fants; by 15 months of age, the only other group

with any such defects was the group with

normo-cephaly and less head growth: five of these 31

infants (16%) showed either spastic diplegia, severe

hypotonia, or hydrocephalus. Major defects did not

occur at either age in any of the 32 children who

were normocephalic with greater head growth or in

any of the full-term infants.

Developmental Evaluations. Results for the

Bay-ley Mental and Motor Scales demonstrated

signif-icant differences among the four groups of VLBW

infants. Those infants who were microcephalic with

less head growth had mean mental developmental

indices (MDIs) and psychomotor developmental

indices (PDIs) that were lower than those of the

other groups at both 6 and 15 months of age (Table

2). At age 6 months, 88% had MDI <80 and 50%

TABLE 1. Relationship Betw een Head Circumf erence (HC) Cia ssifications and Gr owth Failure at F ollow-up

Microceph aly at Birth Normoceph aly at Birth Full-Term

Infants

n =95

Less HC More HC Less HC More HC

Growth Growth Growth Growth

n=9 n=12 n=32 n=32

Age 6 mo

Weight <5th percentile 5/9 (56%)* 1/12 (8%) 12/31 (39%)* 3/31 (10%) 2/95 (2%)

Length <5th percentile 7/9 (78%)* 2/12 (17%) 13/31 (42%)* 2/31 (6%) 1/95 (1%)

HC <5th percentile 5/9 (56%)* 1/12 (8%) 5/31 (16%)* 0/31 (0%) 0/95 (0%)

Agel5mo

Weight <5th percentile 3/8 (38%)* 1/12 (8%) 14/31 (45%)* 4/30 (13%) 3/87 (3%) Length <5th percentile 4/8 (5#{216}%)* 2/12 (17%) 9/31 (29%)* 2/30 (7%) 3/87 (3%)

HC <5th percentile 2/8 (25%)* 0/12 (0%) 7/31 (23%)* 0/30 (0%) 1/87 (1%)

* Incidences of growth failure that differ significantly from those of full-term infants (P < .01).

TABLE 2. Relationship Between Head Circumference (HC) Classifications and Neurodevelopmental Outcome*

Microceph aly at Birth Normoceph aly at Birth Full-Term Infants n =95

Less HC More HC Less HC More HC

Growth Growth Growth Growth

n=9 n= 12 n=32 n=32

Age 6 mo

Major neuro!ogic defect 5/9 (56%)” 1/12 (8%)” 3/31 (10%)” 0/31 (0%)” 0/95 (0%)”

Bayley Scales

MDI (mean ± 1 SD)f 63 ± 14” 85 ± 16” 79 ± 16” 100 ± 15’ 103 ± 15

MDI <80 7/8 (88%) 5/11 (45%) 13/30 (43%) 2/30 (7%) 2/95 (2%)

PDI (mean ± 1 SD)t 75 ± iT’ 90 ± 12” 87 ± 18” 108 ± 15’ 109 ± 13

PDI <80 4/8 (50%) 1/11 (9%) 8/30 (27%) 0/30 (0%) 1/95 (1%)

Age 15 mo

Major neurologic defect 6/9 (67%)U 0/12 (0%) 5/31 (16%)” 0/30 (0%) 0/87 (0%) Bayley Scales

MDI (mean ± 1 SD) 74 ± 25” 98 ± 11” 85 ± 22” 102 ± 10” 104 ± 12”

MDI <80 5/8 (63%) 1/12 (8%) 10/31 (32%) 1/30 (3%) 3/87 (3%)

PDI (mean ± 1 SD) 68 ± 16’ 105 ± 14 94 ± 23” 110 ± 9(

PDI <80 7/8 (88%) 1/11 (9%) 10/31 (32%) 0/30 (0%) 1/87 (1%)

* Groups with same superscript do not differ from each other; groups with different superscripts differ at P < .01.

t Scores on the mental developmental indices (MDIs) and psychomotor developmental indices (PDIs) 50 were scored 50.

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had PDI <80. At 15 months of age, 63% had MDI <80 and 88% had PDI <80.

At the other extreme, infants who were

normo-cephalic with greater head growth had MDIs and

PDIs that did not differ from those for the healthy

full-term infants at both 6 and 15 months of age

(Table 2). MDI <80 occurred in only 7% of these

low-birth-weight infants at 6 months of age and in

3% at 15 months of age. There were no scores <80

for the PDI.

The two groups of infants with only one poor

measure of head growth, ie, those infants who were

microcephalic but with more postnatal head growth

and those infants who were normocephalic but with

less postnatal head growth, demonstrated

interme-diate scores at age 6 months. The mean MDI and

PDI scores for these two groups were similar and

lower than those of the normocephalic, greater head

growth group and higher than those of the

micro-cephalic, less head growth group. More than 40% of

these infants with one poor measure of head growth

had MDIs or PDIs <80. At age 15 months, the

group with normocephaly and less head growth

continued to have intermediate scores (32% with

MDI and PD! <80), but the group with

microceph-aly and greater postnatal head growth now scored

reliably higher, with <10% demonstrating scores

<80. At 15 months of age, their scores were not

different from those of the normocephalic, greater

head growth group or the full-term group.

As a means of summary, a developmental

hand-icap was defined as a major neurologic defect and/

or a MDI or PD! <80 (corresponding roughly to the

lower tenth percentile). At one extreme, the group

with microcephaly and less postnatal growth had a

100% incidence ofhandicap at both 6 and 15 months

of age. At the other extreme, the group with

nor-mocephaly and greater postnatal head growth had

incidences of handicap at 6 months (7%) and 15

months of age (3%) which were similar to those for

the healthy full-term group (2% to 3%). A third

group, normocephalic infants with less postnatal

head growth, showed an incidence of handicap of

43% and 44% at both 6 and 15 months of age. The

final group, microcephalic infants with greater head

growth, showed “catch-up” development. At age 6

months, the incidence of handicap was 42%, but by

15 months it was reduced to 8%, an incidence similar to that for the full-term infants.

To understand further why the head

circumfer-ence classifications were able to predict

develop-mental outcome, we examined the associations

be-tween the head circumference categories and

pen-natal factors thought to put the infant at risk (Table

3). As would be expected, a significantly greater

number of infants who were microcephalic at birth

were SGA. Infants who were microcephalic with

less head growth had a lower mean birth weight,

whereas infants who were microcephalic with

greater head growth had a greater mean gestational

TABLE 3. Relationship between Head Circumference (HC) Classifications and Other Perinatal Data*

Microceph aly at Birth Normoceph aly at Birth

Less HC Growth More HC Growth Less HC Growth More HC Growth

n=9 n=12 n=32 n=32

Mean birth weight ± 1 SD (g)

Meangestationalage ± 1 SD (wk) Small for gestational age

996 ± 220 30.0 ± 2.6’

5 (56%)”

1,287 ± 135b

33.0 ± l.7’ 7 (58%)”

4 ± 211b

29.4 ± 2.2’

2 (fi%)b

1,280 ± 135”

30.2 ± 1.2” 2 (6%)”

Transported 3 (33%) 3 (25%) 14 (44%) 5 (16%)

Male sex 6 (67%) 7 (58%) 21 (66%) 16 (50%)

Black 6 (67%) 10 (83%) 21 (66%) 24 (75%)

Mean 5-mm Apgar score ± 1 SD

Abnormal neonatal

neuro-6.0 ± 2.7

6 (67%)”

7.9 ± 1.1

0 (0%)b

7.0 ± 2.1 3 (9%)b

7.3 ± 2.0 0 (0%)”

logic examination Mechanical ventilation

Sepsis

Symptomatic patent ductus

6 (67%)ac 6 (67%)” 3 (33%)” 1 (8%)bc 1 (8%)”-” 0 (0%)”-” 20 (62%)” 14 (44%)” 12 (38%)” 4 (12%)” 3 (9%)” 0 (0%)” arteriosus

Serum biirubin >10 mg/dL

Mean no. of days to regain

6 (67%) 22.7 ± 6.9”

6 (50%)

16.1 ± 8.5’

17 (53%)

25.9 ± 10.2”

17 (53%) 17.0 ± 7.0”

birth weight ± 1 SD

Mean no. of days to adequate 55.8 ± 26.7” 14.0 ± 75C 35.8 ± 21.0” 13.3 ± 5.2c

energy intake ± 1 SD

Mean days to 1,800 g ± 1 SD 87.0 ± 24.1” 40.4 ± 10.7c 67.0 ± 25.0” 40.3 ± 10.0

Mean maternal age ± 1 SD (yr) 21.9 ± 7.0 20.8 ± 3.6 22.5 ± 4.6 21.1 ± 3.6

Mean maternal education ± 11.6 ± 1.9 11.0 ± 2.2 12.2 ± 1.7 11.6 ± 2.3

1 SD (yr)

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74 DEVELOPMENTAL OUTCOME IN VERY LOW-BIRTH-WEIGHT INFANTS

age. Less postnatal head growth was associated

with an increased incidence of requirement for

me-chanical ventilation, patent ductus arteriosus with

congestive heart failure, and documented bacterial

sepsis. In addition, these groups with less postnatal

head growth took significantly longer to tolerate

adequate enteral energy intakes (120 kcal/kg/d)

and to attain a weight of 1,800 g. The combination

of microcephaly at birth and less postnatal head

growth was associated with a significantly higher

incidence of abnormal neurologic examination in

the neonatal period (including hypotonia,

hyper-tonia, seizures, and hydrocephalus), and an even

longer time to tolerate adequate enteral energy

intake and to attain a weight of 1,800 g.

There were no differences among head

circum-ference groups for number of infants transported,

Apgar scores, admission measurements of blood

pressure, temperature or pH, or peak serum

biliru-bin levels. Cytomegalovirus was cultured from the

urine of one microcephalic infant and one

normo-cephalic infant. Only one infant had a recognized

congenital anomaly. This infant, born to a diabetic

mother, had caudal regression syndrome and was

normocephalic at birth but with less postnatal head

growth. He demonstrated growth failure and a

ma-jor neurologic defect and performed poorly on the

Bayley Scales at both 6 and 15 months of age. Head

circumference groups were comparable for sex, race,

maternal age, parity, and education.

A stepwise discriminant analysis was utilized to

determine whether any of the other perinatal

van-ables recorded added to the ability of our head

circumference classifications to predict outcome.

The head circumference classifications alone were

able to separate accurately low-birth-weight infants

with developmental handicap from those without

such handicap in 61% of the infants at 6 months

and in 76% of the infants at 15 months of age. Only

one additional variable, number of days to reach

adequate enteral intake, added significantly to this

predictive power, increasing the predictability to

75% at 6 months and 84% at 15 months.

DISCUSSION

Head circumference at birth and postnatal head

growth, when taken together, were strong

predic-tors of early developmental outcome in VLBW

in-fants. The combination of microcephaly at birth

and head circumference increase <3.5 cm by age 6

weeks resulted in uniform poor outcome at 6 and

15 months of age. On the other hand, normocephaly

at birth an(l head circumference increase 3.5 cm

by age 6 weeks resulted in good outcome which was

indistinguishable from that for healthy full-term

infants at both ages. Infants with only poor

intra-uterine head growth or less postnatal head growth

demonstrated intermediate incidences of

develop-mental handicap at 6 months of age. A similar

picture was seen at 15 months for normocephalic

infants with less postnatal head growth, but infants

who were microcephalic at birth with greater

post-natal head growth demonstrated significant

devel-opmental catch-up at age 15 months. Although the

cause of poor intrauterine growth was not apparent,

less postnatal head growth was associated with a

wide range of peninatal complications including

dif-ficulty in achieving adequate enteral nutrition and resultant poor weight gain.

We demonstrated previously that head

circum-ference at birth was predictive of developmental

outcome at age 5 years in low-birth-weight infants.

Growth failure, neurologic abnormality, and poor

cognitive function were all significantly associated

with microcephaly (head circumference <10th per-centile) at birth.6 Recently Lipper et a!7 confirmed

this association between head circumference at

birth and developmental outcome in 127

low-birth-weight infants. Of 35 infants who were

microce-phalic at birth (head circumference <10th

percent-ile) 34% had MDI <80, 34% had PD! <80, and 20%

had severe neurologic deficits at age 7 months. In

contrast, of 92 infants who were normocephalic at

birth, only 16% had MDI <80, 18% had PD! <80,

and 5.5% had severe neurologic deficits. No

mea-surements of postnatal head growth were made in

these earlier studies. The results of the present

study demonstrate that early postnatal head growth

moderates the predictive implications of head

cm-cumference at birth. Microcephaly at birth was not

necessarily associated with poor postnatal head

growth. More than half of the infants who were

microcephalic at birth demonstrated postnatal head

growth greater than the median score for all the

VLBW infants and these infants, with greater

post-natal head growth, showed catch-up development.

By 15 months, they did not differ in outcome from

the healthy full-term infants. Therefore, early

post-natal head growth is a stronger predictor of outcome

than head circumference at birth.

Our data suggest that early head circumference

growth may summarize the effects of numerous

potentially adverse conditions affecting brain

de-velopment in VLBW infants. The head

circumfer-ence assessments occur during the period of known

rapid brain growth in the human.” This period is

marked by glial cell multiplication, myelination,

growth of dendrites, and the establishment of

syn-aptic connections. Permanent structural and

corn-positional deficits result from growth restriction

imposed at this stage of development. Winick and

1 7 demonstrated significant reductions in

brain weight, protein, and DNA content in infants

who died of severe malnutrition during the first

(6)

year of life. Infants who were <2,000 g birth weight

were the most severely affected. Moreover, it has

been demonstrated that the increase in head

cir-cumference correlates well with the cellular growth

of the brain in normal infants; in infants who died

of severe malnutrition during the first year of life,

brain weight and protein content were found to be

reduced proportionately to head

The effect of intrauterine growth retardation on

subsequent developmental outcome in

low-birth-weight infants has been investigated previously.

Although some investigators have found that

pre-term SGA infants demonstrate poorer

neurodevel-opmental outcome,’9’#{176} others have not.21’22 These

discrepancies probably relate to the heterogeneity of this group of infants. In the present study, as well

as in previous work in which intrauterine body

growth and head growth have been well

sepa-rated,67 the results indicate that only those preterm

SGA infants who are symmetrically undergrown, ie,

microcephalic, are at increased risk for developmen-tal handicap.

The duration of follow-up is short, but the

mci-dence of major neurologic defects is not likely to

change in subsequent years.2’ Although we could

not measure any relationship between

socioeco-nomic factors and developmental test scores during

the first 15 months of life, we would expect such

associations to be increasingly demonstrable at

later ages. Further follow-up of these VLBW infants

and the full-term comparison group is necessary to

determine to what extent the strong association

between early head growth and developmental

out-come is modified by environment.

ACKNOWLEDGMENTS

This work was supported by grants RR-30 from the Genera! Clinical Research Centers Program of the Divi-sion of Research Resources, National Institutes of Health,

The Hearst Foundation, and Duke University Biomedical Research Support Grant.

The authors thank Lockie McGehee, PhD, Margaret

Wheeler, PhD, Lynne Sturm, BA, Blanche Paul, BA, and Lisa Lannom, BA, for their help in data collection and

analyses.

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Pediatrics

Steven J. Gross, Jerri M. Oehler and Carol O. Eckerman