Neurodevelopmental and Health Outcomes of … Hack, M.D. Rainbow Babies and Childrens Hospital Case...

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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



San Antonio 2011

7


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


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.



Cleveland, OH



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


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.



Cleveland, OH



San Antonio 2011

9


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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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.



Cleveland, OH



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

Neurodevelopmental and Health Outcomes of … Hack, M.D. Rainbow Babies and Childrens Hospital Case...

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