Two-Year Follow-Up Study on Neurodevelopmental Outcomes After Term Intrapartum Asphyxia Using...

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http://jcn.sagepub.com/Journal of Child Neurology

http://jcn.sagepub.com/content/early/2012/10/18/0883073812461564The online version of this article can be found at:

DOI: 10.1177/0883073812461564

published online 30 October 2012J Child NeurolZarrin Keihani-Doust, Maryam Saeedi, Tahere Esmaeilni, Massoud Habibi and Seyed Saeed Hashemi NazariAge and Stages Questionnaire

o-Year Follow-Up Study on Neurodevelopmental Outcomes After Term Intrapartum Asphyxia Us

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Original Article

Two-Year Follow-Up Study onNeurodevelopmental Outcomes AfterTerm Intrapartum Asphyxia Using Age

and Stages Questionnaire

Zarrin Keihani-Doust, MD1

, Maryam Saeedi, MD, MPH1

,Tahere Esmaeilni, MD1, Massoud Habibi, MD2, and

Seyed Saeed Hashemi Nazari, MD, MPH, PhD3

Abstract

Birth asphyxia is one of the multiple causes of neonatal encephalopathy. The objective of this study was to evaluate neurode-

velopmental outcomes of newborn term infants with definitive asphyxia. Thirty infants met study criteria for asphyxia. The 5-yearincidence of asphyxia was estimated to be 5.5 in 1000. According to the Age and Stage Questionnaire, 10.5% of 6-month-oldinfants, 14.3% of 12- and 18-month-old infants, and 5.3% of 24-month-old infants had neurodevelopmental delay in gross motorfunction in the absence of cerebral palsy. In 7.3% of 18-month-old infants, neurodevelopmental delay in problem-solving abilitywas observed. Higher values of Apgar score and bicarbonate levels were associated with higher Age and Stage Questionnaire

total score. Delivery type, maternal age, gravidity of mother, and existence of mother disease during pregnancy were alsoassociated with lower Age and Stage Questionnaire total score in different stages of life.

Keywords

neurodevelopmental delay, Age and Stage Questionnaire, Apgar, asphyxia, term infant, encephalopathy

Received June 18, 2012. Accepted for publication August 27, 2012.

Encephalopathy is the result of brainmalfunction that can be clas-

sified as acute versus chronic or stable versus progressive. About

80% of full-term infants with encephalopathy have acute injuries,

3% have nonhypoxic ischemia and less than 1% have prenatal

injuries. Different disorders in mother can cause fetal hypoxia,

including low maternal blood pressure, inadequate oxygenation

of maternal blood, inadequate relaxation of uterus caused by

excessive administration of oxytocin, premature separation of

placenta, placental insufficiency, and compression of cord.1

Birth asphyxia is one of the multiple causes of neonatal ence-

phalopathy.2 Although in some studies these 2 terms are consid-

ered the same, in the literature on neonatal encephalopathy, once

infants with major malformations, drugs, metabolic causes, and

infections are excluded, the remaining cases are assumed to be

asphyxia related.3 Hypoxic-ischemic encephalopathy is

classified according to assessment of feeding, alertness, tone,

body posture, tendon reflexes, myoclonus, Moro reflex, cornea

situation, duration of signs, and electroencephalogram (EEG)

abnormalities into 3 stages. The prognosis of stage 1 is good.

Stage 2 has varied prognosis and stage 3 or persistence of stage

2 for more than 7 days or failure of EEG to revert to normal is

associated with neurodevelopmental impairment or death.

Expected outcomes for a term newborn with intrapartum

asphyxia are normality, death, or a neurodevelopmental

disability.4

Hypoxic-ischemic encephalopathy usually occurs in 1 to 2

per 1000 newborn infants.5 Almost, 20% of infants with

hypoxic-ischemic encephalopathy die during infancy and

25% suffer from permanent neurodevelopmental impairment.

To our knowledge, few studies have been done on the neu-

rodevelopmental function of term infant with asphyxia in

developing countries and in our country this study is the first

1 Department of Pediatrics, Imam Hospital, Tehran University of Medical

Sciences, Tehran, Iran2 Iranian center for Breast Cancer, Academic Center for Education, Culture

and Research, Tehran, Iran3 Department of Epidemiology and Biostatistics, Tehran University of Medical

Sciences, School of public Health, Tehran, Iran

Corresponding Author:

Maryam Saeedi, MD, MPH, Department of Pediatrics, Imam Hospital, Tehran

University of Medical Sciences, Gharib Street, Keshavarz Boulevard, Tehran,

Iran

Email: [email protected]

Journal of Child Neurology

00(0) 1-7

The Author(s) 2012

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DOI: 10.1177/0883073812461564

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in this field. The objective of our study was to evaluate neuro-

developmental outcomes of a cohort of newborn term infants

with defined asphyxia. These outcomes were measured by Age

and Stages Questionnaire.

MethodsStudy Population

All deliveries were scanned in a university-based pediatric hospital

between 2007 and 2011 in the capital city of Iran, Tehran. Infants who

met our criteria for definition of intrapartum hypoxia and were born at

term (ie, greater than 36 weeks gestation) were enrolled in a prospec-

tive cohort study with a 24-month follow-up. Infants who suffered

from metabolic diseases or congenital abnormalities were excluded

from this study.

Asphyxia Definition

There is not any global agreement on definition of asphyxia. Our

review literature showed that 3 sets of criteria are used mostly fordiagnosis of asphyxia. According to the American Academy of

Pediatrics and the American College of Obstetrics and Gynecology

in 1996,6

intrapartum hypoxia was defined by profound acidosis (cord

pH


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38.7 weeks; 26.7% had 37 weeks, 23.3% had 38 weeks, 16.7%

had 39 weeks, 20% had 40 weeks, and 13.3% had more than 40

weeks. Twenty-five infants (83.3%) received positive-pressure

ventilation at the time of delivery, 20% received cardiac resusci-

tation, and for 20% intratracheal intubation was performed. From

these infants, 23.3% had seizures within 3 days following the

delivery. Imaging studies wereperformed on the neonate who had

clinical signs of hypoxia. Brain ultrasonography was performed

on 24 infants and brain computed tomography was performed

on 7 infants. Acute asphyxia changes including intraventricular

hemorrhage, periventricular leukomalacia, choroid plexus cyst

and ventriculomegaly were observed in 5 ultrasonographic and

3 computed tomographic scans.

Of 30 infants with asphyxia, 3 (10%) died (2 on the first day

and 1 on the 19th day of life). There was a statistically

significant association between seizure (P .009), intubation

(P .005), and abnormal finding in brain ultrasonography

(P .022) and death outcome. We could not find any signifi-

cant differences in the pH level, base deficit, and the Apgar

score of infants who died in comparison to other infants.

Age and Stage Questionnaire Scores in 6-Month-OldInfants

All the infants received higher than the cut-off score in commu-

nication, fine motor function, problem-solving ability, and

personal-social area. In 10.5% of infants, gross motor function

was lower than the cut-off score. To define the predictors of

neurodevelopmental outcomes, the association of the total

score of the Age and Stage Questionnaire and the score in each

of the 5 neurodevelopmental areas and maternal and neonatal

variables were evaluated in separate univariate regression

models. From maternal and neonatal variables, Apgar score and

bicarbonate levels in blood were associated positively with the

total Age and Stage Questionnaire Score and the base deficit was

associated negatively with the total Age and Stage Questionnaire

score. The results of fitted models are presented in Table 2. Age

and Stage Questionnaire scores of each of the 5 neurodevelop-

ment areas were also regressed on maternal and neonatal

variables.

The communication score was not associated with any of the

defined maternal and neonatal variables. The gross motor score

was associated positively with the Apgar score. The fine motor

score was associated negatively with delivery type (cesarean

section vs normal vaginal delivery), gravidity of mother, and

mother disease during pregnancy. The problem-solving ability

score was associated negatively with the base deficit and

positively with the bicarbonate level. The personal-social score

was associated positively with the Apgar score and the bicarbo-nate level and negatively with the base deficit. The results of

fitted models are presented in Table 3.

Age and Stage Questionnaire Scores in 12-Month-Old

Infants

All the infants received higher than the cut-off score in commu-

nication, fine motor function, problem-solving ability, and

personal-social area. In 14.3% of infants, gross motor function

was lower than the cut-off score. Again, separate univariate

models were fitted to define the maternal and neonatal vari-ables that affect the Age and Stage Questionnaire score. From

the maternal and neonatal variables, the mean bicarbonate level

of the blood samples was associated positively with the total

Age and Stage Questionnaire score and the base deficit was

negatively associated. The results of fitted models are

presented in Table 2.

The communication score was associated positively with

positive-pressure ventilation. The gross and fine motor scores

were associated negatively with base deficit and positively with

the bicarbonate level. The problem-solving ability score and

the personal-social score were associated negatively with birth

weight. The results of fitted models are presented in Table 3.


Infants

In this age, only the gross motor function and problem-solving

abilities were abnormal in 14.3% and 7.1% of infants respec-

tively. Univariate analysis of the neonatal and maternal factors

showed a positive effect for Apgar score on the Age and Stage

Questionnaire score. The maternal age and the mothers disease

during pregnancy demonstrated a negative effect. For a 5-year

increment in mothers age, the Age and Stage Questionnaire

score decreased by 4.25 points. The infants of mothers who had

a disease during pregnancy, had, on average, an Age and Stage

Questionnaire Score that was 14 points less than other infants.

The results of fitted models are presented in Table 2.

The communication score was associated negatively with the

existence of a disease inside the mother during pregnancy. The

gross motor score was associated positively with bicarbonate

levels. The fine motor score was not associated with any of the

defined maternal and neonatal variables. The problem-solving

ability score was associated negatively with base deficit and posi-

tively with bicarbonate levels. The personal-social score was not

associated with any of the defined maternal and neonatal

variables. The results of fitted models are presented in Table 3.

Table 1. Numbers of Infants With Each of the Inclusion Criteria

Inclusion criteria n (%)

Range

AverageMin Max

Cord blood pH 12 13 (43.3) 21 4.7 12.25-minute Apgar scores


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Infants

At this stage, just the gross motor function was under the

cut-off limit in 5.3% of infants and all other neurodevelopmen-

tal areas were normal. Univariate analysis showed a positive

association between Age and Stage Questionnaire Score and

bicarbonate levels and a negative weak association between

base deficit and the Age and Stage Questionnaire Score. The

results of fitted models are presented in Table 2. The commu-

nication score was associated negatively with the mother

disease during pregnancy and positively with positive pressure

ventilation. The gross motor score was associated positively

with the Apgar score and negatively with maternal age and

maternal disease. The fine motor score was not associated with

any of the defined maternal and neonatal variables. The

problem-solving ability score was associated negatively with

the base deficit and the mothers disease and positively with the

Apgar score and seizure occurrence in infants. The personal-

social score was associated negatively with the childs birth

weight. The results of fitted models are presented in Table 3.

Discussion

Intrapartum asphyxia is only one of the many possible causes

of neonatal encephalopathy.12 Approximately 15% to 20% of

infants with neonatal encephalopathy will die during the new-

born period, and 25% of the survivors will sustain permanent

clinical deficits.5 Only 10% of infants with evidence of hypoxic

ischemic encephalopathy develop cerebral palsy.13 In our

study, 3 of 30 infants with asphyxia (10%) died. The lack of

an objective marker of term intrapartum asphyxia has clouded

efforts to clinically diagnose intrapartum asphyxia and to

understand its potential range of adverse outcomes.

Some studies have shown that in the absence of cerebral

palsy, a neurodevelopmental disability is a relatively common

consequence of term intrapartum asphyxia, which occurs in

approximately 41.5% of patients.12

Some other studies have documented much lower

prevalence for a variety of adverse neurologic outcomes,

including motor, cognitive, memory, language, learning, and

behavioral deficits and limitations that may reach the threshold

for the diagnosis of a specific neurodevelopmental disability(including global developmental delay, mental retardation or

intellectual disability, attention deficit hyperactivity disorder,

learning disabilities, developmental language impairment,

autistic spectrum disorders, epilepsy, and secondary microce-

phaly) in absence of cerebral palsy in term intrapartum

asphyxia.4,5

In the current study, 10.5% of 6-month-old infants, 14.3% of

12- and 18-month-old infants and 5.3% of 24-month-old

infants had neurodevelopmental delay in gross motor function

in the absence of cerebral palsy. In 7.3% of 18-month-old

infants, neurodevelopmental delay in problem solving ability

was observed. These findings are in accordance with other

studies in this field.5,12

Prior studies have shown that clinical and biochemical

variables, such as umbilical artery blood gases or Apgar scores,

are of limitedvalue in predicting neurodevelopmental outcomes.5

In our study, a higher value of Apgar score was a predictor of

higher Age and Stage Questionnaire total score and also better

gross motor and personal-social function and problem-solving

ability. Higher level of bicarbonate was also a predictor of higher

total Age and Stage Questionnaire score and better gross and fine

motor function, problem-solving ability, and personal-social

function. Base deficit was associated negatively with Age and

Stage Questionnaire total score and also gross motor, personal-

social function and problem solving ability.

Table 2. Regression of Age and Stage Questionnaire Total Scores on Maternal and Neonatal Factors in 6-, 12-, 18-, and 24-Month-Old Infants

6th month 12th month 18th month 24th monthCoeff. (95% CI) Coeff. (95% CI) Coeff. (95% CI) Coeff. (95% CI)

Sex 1.6 (5.7, 8.8) 3.7 (6.3, 13.6) 4.2 (6.7, 15.0) 0.7 (5.4, 4.1)Maternal age 0.3 (0.9, 0.2) 0.5 (1.3, 0.3) 0.9 (1.6, 0.1)* 0.0 (0.4, 0.4)

Gestational age 2.0 (0.1, 4.1) 2.2 (-1.0, 5.4) 1.8 (1.9, 5.4) 0.2 (1.3, 1.6)Birth weight 1.2 (6.3, 4.0) 4.5 (10.8, 1.9) 2.0 (9.4, 5.5) 0.5 (2.3, 3.3)Delivery type 4.1 (9.9, 1.7) 3.7 (11.9, 4.4) 6.0 (14.4, 2.5) 0.3 (4.1, 4.6)Gravidity 0.4 (5.4, 4.5) 0.2 (10.4, 10.1) 3.5 (14.4, 7.4) 0.2 (2.6, 3.0)Mother disease during pregnancy 4.1 (10.5, 2.4) 5.0 (16.6, 6.6) 14.1 (23.7, 4.5)** 8.1 (16.5, 0.3)Meconium-stained liquor 1.7 (8.0, 11.3) 0.8 (17.1, 15.4) 1.0 (16.8, 18.8) 1.6 (7.3, 4.1)Apgar score in fifth minute 1.9 (0.2, 3.7)* 2.0 (0.5, 4.4) 2.8 (0.4, 5.2)* 0.4 (2.7, 1.8)pH 16.5 (9.9, 43.0) 29.8 (12.3, 71.9) 15.9 (33.3, 65.2) 11.3 (37.4, 14.8)Base deficit 0.7 (0.1, 1.3)* 1.0 (0.2, 1.9)* 0.7 (0.4, 1.8) 0.6 (0.0, 1.2)*Bicarbonate level 0.7 (0.2, 1.3)* 1.2 (0.3, 2.1)* 0.8 (0.4, 2.0) 0.6 (0.0, 1.2)*Positive pressure ventilation 2.4 (9.1, 4.2) 0.7 (10.9, 9.5) 2.2 (8.9, 13.3) 1.2 (4.5, 6.9)Chest compression 4.8 (12.5, 3.0) 2.7 (14.5, 9.2) 3.6 (16.5, 9.3) 0.3 (9.0, 9.7)Intubation 3.2 (4.8, 11.2) 6.7 (9.0, 22.4) 5.3 (12.1, 22.8) 0.3 (9.0, 9.7)Seizure 2.0 (10.1, 6.1) 3.1 (13.2, 6.9) 5.6 (16.2, 5.0) 0.0 (5.8, 5.7)

*P < .05, **P < .01, ***P < .001.

4 Journal of Child Neurology 00(0)


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T

able3.RegressionofAgeandStageQuestionnaireScoreinEachof5Neurode

velopmentalAreasonMaternalandNe

onatalFactorsat6-,12-,18-,and24-Mo

nth-OldInfants

N

eurodevelopmental

ar

eas

6thm

onth

12thmo

nth

18thmo

nth

24thm

onth

Variable

Coeff.

(95%CI)

Variable

Coeff.

(95%CI)

Variable

Coeff.

(95%CI)

Variable

Coeff.

(95%CI)

C

ommunication

Positivepressure

ventilation

3

9.2

(2.1,

16.4

)*

Motherdisease

22.9(38.7,7.2

)**

Motherdisease

49.4

(54.6,44.3

)***

Positivepressure

ventilation

3

16.0

(2.5,

29.5

)*

G

rossmotor

Apgarscore

5.3

(1.4,

9.3

)*

Apgarscore

7.3

(0.9,

13.7

)*

Motherage

1.7

(3.1,0.3

)*

Bicarbonatelevel

1.0

(0.2,

1.9

)*

BaseDeficit

2.8

(0.2,5.4

)*

Motherdisease

21.3

(42.5,0.0

02)*

Bicarbonatelevel

3.1

(0.3,

5.9

)*

Apgarscore

6.6(2.6,

10.5

)**

Fi

nemotor

Delivery

7.7

(14.1,1.4

)*

BaseDeficit

1.4

(0.5,2.3

)**

Gravidity

6.4

(11.5,1.3

)*

Bicarbonatelevel

1.2

(0.0,

2.4

)*

Motherdisease

7.7

(14.9,0.5

)*

Problem

solving

BaseDeficit

0.9

(0.1,1.7

)*

Birthweight

5.3

(8.8,1.8

)**

BaseDeficit

1.6

(0.2,2.9

)*

Bicarbonatelevel

1.0

(0.3,

1.8

)**

Motherdisease

17.1

(32.1,2.1

)*

BaseDeficit

1.4

(0.5,

2.2

)**

Apgarscore

4.6

(1.5,

7.6

)**

Bicarbonatelevel

1.1

(0.2,

2.1

)*

Seizure

14.4

(27.3,1.5

)*

Personal-social

Apgarscore

3.2

(1.0,

5.4

)**

Birthweight

5.2

(9.0,1.4

)*

Birthweight

4.0

(7.9,0.1

)*

BaseDeficit

1.1

(0.3,1.8

)*

Bicarbonatelevel

1.2

(0.5,

1.9

)**

*P

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