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Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
1
Neurodevelopmental andHealth Outcomes of Preterm Children
Maureen Hack, M.D.Rainbow Babies and Children’s Hospital
Case Western Reserve UniversityCleveland, OH
Gestation Distribution: United States, 2005
Term (37- 42 weeks)
80.3%
Post term(42 weeks or more)
7%
Preterm
(<37 weeks)
12.7%
<32 weeks = 2.0%
<28 weeks = 0.7%
NVSS 2005
United States 2007
Low birth weight <2.5kg 8%
Very low birth weight <1.5kg 1.5%
Multiple births 3.4%
Pediatrics Jan 2010
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
2
Early
Childhood
Outcomes
Major Impairments
• Global cognitive dysfunction
• Neurosensory disorders
–Cerebral palsy
–Blindness
–Deafness
Cleveland – 20 Month OutcomeBirth Weight < 1Kg
0%
20%
40%
60%
80%
100%
1977-1979 1982-1989 1990-1999 2000-2002 2003-2005
Normal
Impaired
Lost
Death
Year of Birth
Pe
rcen
t o
f P
op
ula
tio
n
Corrected Age
Early Childhood Cognitive Function
From 33 to 27 weeks gestation - deficit of 2.5 points per week of gestation
At 24 weeks gestation –20 point deficit
Robertson 2009
Predictors of Outcome
Social - Proximal- Family functioning, maternal distress
Distal - Sociodemographic
Biologic - Gender
Neonatal risk factorsultrasound abnormalitieschronic lung disease? sepsis, ? jaundice
Subnormal brain growthGenetic -
Probability of Poor 18-Month Outcome(BPD, Severe ROP, Brain Injury)
Number of Neonatal Morbidities
Pro
bability o
f P
oor
Outc
om
e a
t 18 m
onth
s (
%)
100
80
60
40
20
00 1 2 3
Schmidt, JAMA 2003
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
3
Cerebral Ultrasound Prediction of Cerebral Palsy -- Review
Normal
Grade IVH
1-2
3
4
Cystic PVL
Ventricular dilatation
Hydrocephalus
5% (4 - 6%)
9% (4 - 22%)
26% (13 - 45%)
53% (29 - 76%)
74% (42 - 92%)
22% (17 - 28%)
27% (10 - 56%)
Cerebral Palsy
Probability (95% CI)Ultrasound Result
Nongena 2009
MRI Prediction of Cerebral Palsy -- Review
Moderate – Severe
Ventricular dilatation >8mm
Internal capsule abnormality
CognitiveImpairment
CerebralPalsyMRI Abnormality
Nongena 2009
Probability (95% CI)
35% (19-55%)
86% (42-99%)
90% (54-99%)●
52% (36-67%)
---
---
● very wide confidence intervals
“Wise clinicians have always known that
individual tests rarely provide certainty, and
they continue to use neuro-imaging with
circumspection.”
Outcome Measures
• Cerebral palsy– Interobserver reliability
– Functional classification (Palisano)
• IQ–Cultural
– Social class dependent
–Comparison to norms used
Bayley Scales of Infant Development
• Version II (1992)– Mental Developmental Index– Motor Developmental Index
• Version III (2006)– Cognitive– Language– Motor– Social/emotional– Adaptive behavior
Child testing
Parent questionnaireneurological
developmental
Non-neurological:
•Home oxygen
•NGT feeds
•Growth <-3 SD
Epicure 1999
Multiple Impairments
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
4
MDI <70 Neurosensory
Abnormality
Impairment(MDI <70 and/or
Neurosensory
Impairment)* p<0.001
80
60
40
20
0
Present
Absent
Malformation
Perc
en
t
* * *
Effect of Congenital Malformations on VLBW Infants (<1.5 kg BWt) age 2 years
Hack, unpublished
There are many ways to appear
foolish - but the most certain
way is to predict the future.
Bruno Bettelheim
560 Grams Birth Weight
22 Weeks Gestation
Birth: 1981
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
5
Age 16 Years
School Age
Population
Extremely Low Birth Weight (ELBW)Admissions 331 (1992-1995)Survived 238 (72%)8 year follow-up 219 (92%)14 year follow-up 181 (76%)
Normal Birth Weight (NBW)School controls 17614 year follow-up 115 (65%)(matched by race, sex, age within 3 months)
Measures
Categorical
– Specific diagnoses and disabilities
Non-categorical
– QUICCC (Questionnaire for Identifying Children with Chronic
Conditions)
Results adjusted for sex, race and SES defined as average z-
score of maternal education and median family income.
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
6
Asthma and Neurosensory Outcome
0
5
10
15
20
25
Asthma Cerebral palsy Vision <20/200 Hearing loss
ELBW NBW
Pe
rcen
t
School Age Assessment
• IQ
• Academic Achievement
–Reading
–Math
– Spelling
• Neuropsychologic Abnormalities
Subnormal Developmental and Adaptive Functioning
0
10
20
30
40
50
IQ<70 Academic skills <70 Motor skills <30 Poor adaptive
functioning
ELBW NBW
Pe
rcen
t
IQ Equivalent by Birth Weight GroupAge 7 Years
0
5
10
15
20
25
30
35
40
45
<70 70-84 85-99 100-114 115-130
IQ Equivalent
<750 grams
750-1499 grams
Term born
Problems evident even in children with
normal IQ and no overt neurosensory
abnormalities.
Non-Categorical OutcomesQuestionnaire for Identifying Children with Chronic
Conditions (QUICCC)
Functional Limitations
Compensatory Dependence
Services above routine
Stein 1993
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
7
Functional Limitations
0
5
10
15
20
25
30
Physical delay Mental or emotional
delay
Reduces time/effort
in activities
ELBW NBW
Pe
rcen
t
Hack 2005
Functional Limitations
Asthma
Cerebral Palsy
Tires easily
Poor coordination
ADHD
Other*
n=41
14
8
10
2
3
4
Needs to reduce time or effort in activities
* epilepsy, cold sensitivity, deformed fingers, overweight Hack 2005
Severe Functional Limitations
0
2
4
6
8
10
12
14
Unable to walk Unable to dress Unable to wash or
use toilet
ELBW NBW
Pe
rcen
t
Hack 2005
Compensatory Dependence Needs
0
5
10
15
20
25
30
35
40
Regular prescribed medication Help or equipment to dress
ELBW NBW
Pe
rcen
t
Hack 2005
Medication Usage
Asthma
ADHD
Epilepsy
Botox/Baclofen
ELBWn=219
NBWn=176
21%
7%
2%
7%
6%
3%
1%
--
Hack 2005
Services Needed Above Routine
0
10
20
30
40
50
60
Doctor/Specialist Counseling PT/OT Special school
arrangements
ELBW NBW
Pe
rcen
t
Hack 2005
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
8
Behavioral Outcomes
Very Low Birth Weight Children
Correlates of Behavioral Problems
Low IQ
Poor motor skills
Grade repetition
Need for special education
Learning problems
Chronic health problems
Very Low Birth Weight Children
Correlates of Behavioral Problems
Biologic Risk Factors
Male sex
Neonatal white matter lesions
Correlates of Preterm Birth
Maternal infant separation
Infant - Sensory isolation
Painful experiences
Illness, poor growth
Less responsive/interactive
Maladaptive maternal infant interactions
8 Year Old < 800 gm Birth Weight Behavior During Assessment
Attention/distractability
Activity/high Level
Insecure vs Confident
Prefers easy tasks
Needs constant encouragement
33%
37%
33%
49%
18%
4%
1%
1%
8%
0%
0.0001
0.001
0.006
0.0001
0.0001
Birth Weight
<800 gmn=90
Normaln=50
p
Whitfield 1997
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
9
Very Low Birth Weight Children
Social and Adaptive Functioning
Fewer friends
Shy, sad, unhappy
Unassertive
Poor peer acceptance
Behavioral Outcomes ofELBW Children (<1kg Birth Weight)
Methods
• Child Symptom Inventory (CSI) (Gadow 1994)
– Cut-off Scores for DSM-IV Diagnoses
– Symptoms Severity Scores
Hack 2009
Child Symptom InventorySymptom Severity Scores
ADHD
Inattentive
Hyperactive
Combined
Generalized Anxiety
Autistic Disorder
Asperger Disorder
ELBW vs NBWEffect Size
p-value
0.78
0.40
0.62
0.36
0.52
0.40
<0.001
<0.001
<0.001
<0.01
<0.001
<0.01
Hack 2009
Parent Report of Child Symptom InventoryCut-off Scores DSM-IV Diagnoses
ADHD (any)
Inattentive
Hyperactive
Combined
17%
10%
3%
5%
5%
3%
2%
0.6%
<0.001
<0.01
NS
<0.05
ELBWn=219
NBWn=176
p-value
Hack 2009
Pervasive Developmental Disorders
Autistic+
Aspergers
NOS*
ELBWN=219
4(2%)
3(1%)
1(0.5%)
NBWN=176
1(0.6%)
-
-
+ Three ELBW had CP, all severe delay
* Not Otherwise SpecifiedHack 2009
Autism Spectrum Disorder ScreeningTwo year outcomes
Modified Checklist for Autism in Toddlers (M-CHAT)
Positive Screen
Neurosensory intact
Neurocognitive intact
<28 wks
21%
16%
10%
Controls
6%
-
-
Kuban 2009
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
10
Child Symptom InventoryParent Report
Enuresis●
Encopresis
15%
13%
8%
3%
<0.05
<0.001
ELBWn=219
NBWn=176
p-value
● Night time bed wetting, neurologically normal (13% vs 8%)
Hack, unpublished
Adult Outcomes
High School Graduation and Grade Repetition
* Adjusted for sociodemographic status and gender
<0.0126%40%Grade repetition
<0.0583%74%Graduated high school
p*NBW(n=233)
VLBW(n=242)
Current Educational Activity at 20 years
0%
20%
40%
60%
80%
100%
Four Year College
Community College
High School/GED
None
VLBW NBW
MALES
n=116 n=118
Current Occupation at 20 years
0%
20%
40%
60%
80%
100%
Post HS Study
Work Only
HS/GED, no work
Unemployed
Incarcerated
Disabled
MALES
n=116 n=118
VLBW NBW
Current Educational Activity at 20 years
0%
20%
40%
60%
80%
100%
Four Year College
Community College
High School/GED
None
VLBW NBW
FEMALES
n=126 n=125
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
11
Substance Use (during last year)
0
20
40
60
80
100VLBW
NBW
Total Population
Smoking Alcohol Marijuana Other
Illicit Drugs
Pe
rcen
t
*
**
* p<0.05
** p<0.001
Dating and Sexual History
0
20
40
60
80
100 VLBW
NBW
Females
Ever
Dated
Current
Relationship
Intercourse
(ever)
Pregnant
(ever)
Live
Birth
Pe
rcen
t
* p<0.05
** p<0.001
*
***
*
*
Dating and Sexual History
0
20
40
60
80
100VLBW
NBW
Males
Steady Relationship
(current)
Pe
rcen
t
Dated
(ever)
Intercourse
(ever)
Pregnancy
(ever)
Internalizing Behaviors Above Clinical Cut-off*Females
* Anxious, Depressed, Withdrawn > 90th percentile
2.4 (1.2,5.0)11%23%Parent report
2.0 (0.9,4.3)10%18%Young adult
O.R.(95% C.I.)
NBW(n=124)
VLBW(n=125)
0
5
10
15
20
25
30
35
40
45
50
Perc
en
t
VLBW
Controls
Patterns of Self-Assessed Health at 20 YearsProfile Types of the CHIP-AE
Healthy/
Average
High
Risk
Low
Resilience
Dissatisfied/
Uncomfortable
Poor Health
on 3-4 Domains
* p<0.05 Hack 2007
**
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
12
Fetal and Early Childhood Effects on Adult Health
Disturbances of growth during critical periods
of development may influence adult
cardiovascular health.
Barker
Method of Study
• Weight and length/height measures
• Usher Norms CDC 2000 Growth Data
Birth 40 wks 8 20 8 20
term months years
Very Low Birth WeightWeight Z Scores from Birth to 20 Years
BIRTH
40 WEEKS
8 MONTHS
2 YEARS
8 YEARS
20 YEARS
4
2
0
-2
-4
MALES
-6
4
2
0
-2
-4
FEMALES
-6
Age
Z S
co
re
Birth 20 Years Birth 20 Years
Very Low Birth WeightHeight Z Scores from Birth to 20 Years
BIRTH
40 WEEKS
8 MONTHS
2 YEARS
8 YEARS
20 YEARS
4
2
0
-2
-4
-6
-8
MALES4
2
0
-2
-4
-6
-8
FEMALES
Age
Z S
co
re
Birth 20 Years Birth 20 Years
Very Low Birth WeightBMI Z Scores at 8 and 20 Years
4
2
0
-2
-4
MALES4
2
0
-2
-4
FEMALES
8 YEARS
20 YEARS
Z S
co
re
8 20
Years
8 20
Years
Comparison of Growth at 20 Years
Males
Weight
Height
BMI
69 kg
174 cm
23
80 kg
177 cm
26
Very Low
Birth Weight
Normal
Birth Weight
p*
Value
<.001
<.01
<.001
* Adjusted for maternal education and race.
Females
Weight
Height
BMI
65 kg
162 cm
25
68 kg
163 cm
25
NS
NS
NS
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
13
WeightHeight
Weight
Height
.8
.6
.4
.2
-.2
-.4
-.6
-.8
Age 8 Teen
Age of Study Subjects
ELBW
CONTROLS
<1000 gm Birth Weight Catch-Up Growth Between 8 and 14 Years
Saigal 2001
z-s
co
re
Intrauterine and
Postnatal Growth Failure
Bwt 1.3 Kgm (z-score –1.85) Gest. Age 32 wks 20 year BMI 29.6
Potential Longer-Term Sequelae
• Obesity ?
• Type II diabetes
• Cardiovascular risk
VLBW (<1.5Kg) Preterm InfantsGlucose Tolerance Tests
• Increase in insulin resistance
• Increase in fasting insulin
• Impaired glucose tolerance
Hovi 2009
Results of Blood PressureStudies to Date
• Preterm children and adults have higher mean
systolic blood pressure
• Not related to intrauterine growth failure
Maureen Hack, M.D.
Rainbow Babies and Childrens Hospital
Case Western Reserve University
Cleveland, OH
Neurodevelopmental and
Health Outcomes of Preterm Children
San Antonio 2011
14
Rapid Catch-up GrowthThe Dilemma
Beneficial for brain growth
But:
May predispose to cardiovascular and metabolic
risks
Thank You
Rainbow Babies& Children’s Hospital