term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years

TERM INFANTS WITH HVPOXIC-ISCHEMIC ENCEPHALOPATHV: OUTCOME AT 3 8 5 YEARS

Charlene Robertson Neil Finer

Hypoxic-ischemic encephalopathy (HIE) of the term neonate is well recognized as a consequence of perinatal insults. It has been established by Nelson and Ellenberg (1981) that term infants with very low Apgar scores at 10 minutes or later have a high rate of cerebral palsy and mental retardation, although the infants reported had a variety of neonatal disorders. The same authors also reported in 1979 that 15 per cent of surviving infants of 37 weeks or more with evidence of a definite brain abnormality at the time of nursery discharge developed cerebral palsy, and that 38 per cent of this population died within the first year of life. Brown et al. (1974) indicated that persistent hypotonia was associated with a poor prognosis. Sarnat and Sarnat (1976) distinguished three clinical stages of term infants with HIE (stage I , hyperalert; stage 2, lethargic and hypotonic; and stage 3, stuporous and flaccid) and using EEG information, they related outcome at one year to the clinical stage in 21 affected infants. All of the stage 1 infants moved on to stage 2 in that study. Our previous experience (Finer et a/. 198 1, 1983) with term infants with HIE indicated that the most significant factors in predicting poor outcome were the presence of a Sarnat stage 2 or 3 (moderate or severe encephalopathy) and neonatal convulsions unresponsive to a single anticonvulsant.

Others have also noted a strong relationship between intractible neonatal seizures in term infants and a poor neurological outcome (Bergman et al. 1983).

Holden and Willerman (1972) investi- gated neurologically damaged infants from lower and higher social-classes and found that the children were homogeneous in developmental levels at eight months but differed on psychological testing at four years, with the children from the lower social-class group having lower scores. Few studies have looked at the long-term developmental levels of term infants with documented HIE, and have attempted to relate neonatal neurological- clinical syndromes to other neonatal, z obstetrical or social factors. i

This prospective study reviews the 3 outcome at 3.5 years of 167 of an original 226 term infants with HIE, and correlates 3

is

3

d

9 m c d

ri r--

vc 00

$ a both perinatal events and social factors to outcome. The purposes of this study were to determine the extent of term HIE leading to death or severe handicap in this regional perinatal program; to determine the effects of social factors on outcome; to determine the value of prospectively categorizing term neonates with HIE; and to establish

d u .s

2 c .. E -3

whether the HIE categories and other : significant perinatal factors are predictors 6

major childhood handicaps. 4 73 of long-term developmental outcome and

4 74

Material and method Study population The infants studied were term neonates (37 completed weeks gestation or greater by maternal dates and Dubowitz examination; (Dubowitz et al. 1970) with HIE, born between August 1974 and March 1979 and cared for in the tertiary Neonatal Intensive Care Units (NICUS) of a regional perinatal program. The diagnosis of HIE was made on the basis of an abnormal neurological examination completed after one hour of age, and on one or more of the following criteria: (1) intrapartum fetal distress, based on abnormal heart-rate patterns, with or without the passage of meconium; (2) immediate neonatal distress indicated by a low one- or five-minute Apgar score

(3) immediate neonatal resuscitation, including bag and mask ventilation or intubation with ventilation.

The results of the neurological examination were considered abnormal when two of the following were present: alteration in consciousness, alteration in muscle tone, or abnormal primitive reflexes. These examinations were performed by the attending neonatologists, and the encephalopathy was categorized as mild (hyperalert and hyperexcitable), moderate (hypotonia and suppressed primitive reflexes), or severe (stuporous, flaccid and absent primitive reflexes). All infants were examined at least once before discharge by one of the authors (C.R.), who then assigned to the child the most severe HIE category recorded during the first week of life. Seizures included observed single or repetitive tonic or clonic movements, as well as subtle seizures (Volpe 1977). When seizures occurred in a hyperalert infant without suppressed primitive reflexes, this was categorized as mild HIE.

The clinical management of the infants was left to the individual neonatologist. The seizures were treated with a loading dose of 10 to 20mg/kg of phenobarbitol, and with subsequent doses to maintain a serum phenobarbital level of 2 to 3mg %.

All children with known syndromes or malformations affecting the central ner- vous system, or with known major insults such as intracranial hematomas, infections or encephalopathies due to causes other

(a);

than asphyxia diagnosed in the neonatal period were excluded from the study. A total of 229 children were registered with the follow-up program. Subsequently, two children with severe HIE and one with moderate H I E were excluded because of the diagnosis of other underlying conditions- myotonic dystrophy, translocation 12-21 and Prader-Willi syndrome.

General obstetric and neonatal data were collected from medical records, using a medical data-collection form which is part of the standard Data Collection Manual (Robertson 1980) in our follow-up program. Neonatal neurological information was recorded directly onto data- collection forms by one of the authors (C. R.).

Follow-~p The surviving infants were enrolled in the Neonatal Follow-up Clinic, Glenrose School Hospital, and assessments were scheduled for six, 12, 27 months and 3.5, 5 5 and eight years of age. The assessment team included a developmental pediatrician, nurse, occupational therapist, physiotherapist, developmental psychologist, speech pathologist, audiologist, social worker, consultant ophthalmologist and consultant pediatric physiatrist. Developmental information thus obtained was recorded directly by the assessors onto data-collection forms. The language of testing was English. Demographic and social variables included home community size; distance from tertiary care; family income; mother tongue; ethnic background; birth order; guardianship of child; parents’ occupation, schooling, age, marital status and whether or not employed, and the natural father’s socioeconomic index (Blishen 1976). These were collected at the time of the infants’ first visit to the follow-up clinic by means of a parent questionnaire and an interview with the parent(s) by the social worker.

At each assessment a complete general physical and neurodevelopmental examination was performed, and a conference was held to obtain the child’s developmental profile. The follow-up program gave all families explanations of the neonatal events and counselling for developmental problems. All children with diagnosed handicaps received treatment through the

Glenrose School Hospital, the Pediatric Rehabilitation Center for Northern and Central Alberta, and, where appropriate, outside agencies and preschool programs.

Handicaps were grouped as follows: (1) cerebral palsy (CP) of all types and severity, i.e. chronic disability character- ized by aberrant control of movement or posture without the presence of recognized progressive disease; (2) visual impairment (vision <20/60) or legal blindness (vision <20/200) in the best eye following correction; (3) cognitive delay, i.e. performance in the trainable or profoundly mentally retarded range (>3 SD below the mean of standardized testing); (4) severe, difficult to control convulsive disorders with myoclonic epilepsy or repeated grand ma1 seizures; ( 5 ) neurosensory hearing-loss of >70dB in the better ear.

The Stanford-Binet Intelligence Scale (sB) (Terman and Merrill 1973), administered by a psychologist, was the principal test used for intellectual evaluation. Only two children received the non-verbal Leiter Scale (Leiter 1969). An intelligence quotient (IQ) could not be determined for five extremely delayed children, and as these children were considered to be in the profoundly mentally retarded range by the whole assessment team, a score of 20 was assigned to each child. The Visual-Motor Integration Test (VMI) (Beery 1967) was administered by a psychologist; the results were recorded in months above and below chronological age (CA).

Speech and language were assessed by a speech pathologist. The IQ scores from the Peabody Picture Vocabulary Test (PPVT) (Dunn 1965) were used as a measure of receptive language in general, and of auditory receptive vocabulary in par- ticular. The mean length of utterance (MLU), recorded in morphemes (Brown 1973), was used as a measure of expressive language. The MLU score was expressed in standard deviations: this represented the degree to which a child’s MLU differed from that predicted for chronological age (Miller 1981). No attempt was made to grade those children with non-oral communication skills.

Audiological screening was done by a clinical audiologist. Test procedures and

pass-fail criteria varied according to the developmental level of the child. Thus, hearing sensitivity was determined or inferred from at least one of the following criteria obtained in sound field in a standard autiometric booth: speech aware- ness thresholds (Giolas 1975); warbled pure-tone thresholds, as tested by visual reinforcement audiometry (Liden and Kankkumen 1969, Moore et al. 1977); and startle responses to speech. In addition, impedance audiometry, including tympan- ometry and acoustic reflex testing, was carried out to determine middle-ear function and to further infer hearing sensitivity (Keith 1973, Margolis and Popelka 1975). If hearing impairment was suspected, serial audiometric testing with earphones was undertaken and, after 1978, brainstem evoked response audiometry was performed to determine monaural thresholds (Kileny et al. 1980, Kileny 1981).

Fine motor (FM) and gross motor (GM) skills were assessed by the occupational therapist, physiotherapist and developmental pediatrician (C.R.), and levels of development were assigned by means of charts based on the publications of Gesell et al. (1940), Sheridan (1968) and Egan et al. (1969). Documentation of motor developmental levels is given in Appen- dices A and B.

Statistical analysis Statistical analysis was completed on 167 children, i. e. 83 9 per cent of survivors. For continuous variables, one-way analysis of variance (ANOVA) with Scheffk multiple comparisons were used to examine the significance of the differences in means for various subgroups. xz was employed to test group differences on non-continuous variables. Pearson Product Moment Correlations (r) were used to examine relationships between variables.

Results Over-all outcome As indicated in Table I, of the 226 children originally cared for in the NICUs, outcome information is available for 88 5 per cent at 3 . 5 years of age (including three children seen after five rather than 3.5 years of age). 26 of the 226 children (1 1 a 5

per cent) died as a result of HIE and its complications; 17 died in hospital and nine 47s

x 5 P

01 c d

f w

TABLE 1 Over-all outcome to 3.5 years after hypoxic-ischemic encephalopathy (N = 226)

~ ~~ ~~~ ~

Not FOIIOW-UP FoIIow-UP available < 2 yrs Deaths by mail to Population

Admissions for and lost Available In After 3 . 5 yrs at 3.5 yrs HIE to NIClJs follow-up (NHt) at 3.5 yrs hospital discharge NH H t t NH H

Mild 79 6 4 69 - - 3 - 66 - Moderate I19 7 9 103 3 3 $ 1 2 74 20

7 Severe 28 - - 28 14 7

Total 226 13 13 200 17 10 5 2 140 27 % loo 88.5

- - -

?Not handicapped; ??handicapped; lone death due to motor vehicle accident.

TABLE I1 Handicapped survivors (N = 38)

N % Cognitive delay 22 57.9 Cerebral palsy 20 52.6

Spastic quadriplegia 14 Spastic-athetoid quadriplegia 2 Athetoid quadriplegia I Spastic right hemiplegia 3

Convulsive disorder 13 34 .2 Visual loss 1 1 28.9

Visual impairment <20/60 7 Legal blindness <20/200 4

Deafness >70dB 4 10.5

476

after discharge. The in-hospital mortality rate for moderate HIE was 2.5 per cent and for severe HIE was 50 per cent. One child with moderate HIE in the newborn period, who developed normally, died in a motor vehicle accident at two years of age. Children with mild HIE in the neonatal period did not develop any major handicaps, and there were no deaths in this group.

Of the 226 children (220 singletons), 126 were males and 100 were females. Of the 27 children who died, 13 were males and 14 were females. Of the 29 surviving handicapped children at 3 .5 years (27 from the study population and two from follow- up by mail), 13 were male and 16 were female.

Of the 38 children with diagnosed handicaps after discharge from hospital (Table 11), there were 22 (57.9 per cent) with cognitive delay, including seven who

were thought to be in the trainable to profoundly retarded range but who died before the age of two years; 20 (52.6 per cent) with cerebral palsy, including five who could ambulate without aids at 3.5 years; 13 (34.2 per cent) with poorly controlled convulsive disorders, with daily or weekly seizures; 11 (28.9 per cent) with visual loss; and four (10.5 per cent) with severe to profound deafness. (The specific clinical diagnoses of these 38 children are available from the authors.)

Moderate HIE in the neonatal period resulted in 24 (20.7 per cent) of the discharged children developing one or two handicaps. Two of these children with severe convulsive disorders died. Severe HIE resulted in seven deaths after discharge, leaving only 25 per cent of the original number to survive to 3 * 5 years. Six of the seven children who died had severe convulsive disorders. The seven children with severe HIE surviving to 3 * 5 years had between one and four major handicaps. Four of these seven had severe convulsive disorders, the other three had one to three non-febrile grand ma1 seizures after discharge.

Compared to the study population at 3 * 5 years, the children who died after discharge had severe HIE ( x 2 170.6, p< 0.0001), received a larger number of types of anticonvulsants ( x 2 46.5, p<O.OOOl), required intubation ( x 2 17.9, p =O.OOOl) and mechanical ventilation (x ’ 12.9, p =0.0015), had abnormalities on neurological examination at discharge ( x 2 170.4, p<O.OOOI), had primitive (subtle) seizures in combination with other types of

TABLE I11 Some perinatal and demographic variables of study population at 3 . 5 years

Total Mild HIE Moderate HIE Severe HIE ( N = 167) ( N = 66) (N = 94) ( N = 7)

Dichotomous variables: % Outborn: not born in tertiary hospital Sex: male

* Background: non-Caucasian

Mother tongue: not English Father’s schooling: <grade 9 Mother’s schooling: <grade 9 Type of delivery: caesarean section Presentation at delivery: breech Resuscitation method: intubation and

Admission temperature: 36” and less

* registered Indian

ventilation >5 mins

* Mechanical ventilation: after initial

* Neonatal convulsions **Neurological examination at discharge:

**N of types of anticonvulsant drugs per

resuscitation

not normal

child: 2 or more Available as continuous variables: mean (SD)

Natural father: age at birth of child Natural mother: age at birth of child Apgar at 5 mins Gestation: weeks comoleted

44.3 58.7 14.4 7 . 8

18.0 14.6 8 . 5

29.3 7.2

13.4 18.0

26.9 58.7

55.1

31.7

28.1 ( 6.0) 25.3 ( 5.2) 6 . 4 ( 2.2)

3 9 . 8 ( 1.6)

42.4 54.5 4 . 5 0.0

13.6 12.1 3 . 0

30.3 9 . 1

12.1 21.2

16.7 48.5

30.3

10.6

27.1 ( 5 . 5 ) 2 4 . 9 i 4.6)

45.7 62.8 22.3 13.8 22.3 16.0 12.8 29.8 6 . 4

13.8 14.9

33 .O 63.8

69.1

42.6

28.8 ( 6.4) 5 . 4 1 5 . 5 )

42.9 42.9 0.0 0 . 0 0.0

14.3 0.0

14.3 0 . 0

28.6 28.6

42.9 85.7

100.0

85.7

30.0 ( 5.7) 2 6 . 9 i 5.9)

6 .5 ( 2.3 j 6.3‘( 2.2)

3227.3 (606. i j 3230.3 (601.8) 3236.2 (617.4) 3079.7 i566.2)’ 3 9 . 9 ( 1.7) 3 9 . 9 ( 1.6)

Birthweight: g Birth length: cm 5 1 . 2 ( 3.0) 51.1 ( 3.0) 5 1 . 3 ( 3 .1) 5 0 . 4 ( 1.9) Birth head-circumference: cm 3 4 . 7 ( 1 .7) 3 4 , 7 ( 1.5) 3 4 . 8 ( 1.8) 3 3 . 6 ( 2.6)

* Days in NICU at tertiary centers 1 4 . 4 ( 10.1) l l . 2 ( 6.7) 1 6 . 4 ( 11.7) 1 8 . 6 ( 3.8) Time of onset of seizures (if present): hrs 23.8 ( 27.9) 23.8 ( 23.2) 24.5 ( 1.2) 11.2 ( 9.2)

g 3

Significant differences in HIE categories: *p<0.05; **p<O.OOOl.

neonatal convulsions (x2 14.6,p=0.0234), and subsequently had one or more major handicaps (x2 43.4, p<O.OOOI). Of these handicapped children, more had loss of vision, cognitive delay and postnatal convulsive disorders than those handicapped in the study population. The mean time in a NICU for children who died after discharge was 47.2 f 33.0 days, whereas for assessed survivors it was 14.4 2 10.1 days (ANOVA, F = 15.0, p<O.OOOI). The mean time of onset of seizures in hours was earlier for the children who died after discharge, 1 I * 3 hours of age compared to 23.8 hours in the long-term survivors. However, this difference was not statisti- cally significant. Also, no significant differences were found in social factors.

The children lost to follow-up at two years or less did not differ in perinatal o r social factors from the non-handicapped children at 3 .5 years, except for the possible significance of ‘gravida of

mother’. More mothers of children lost to follow-up were more than gravida one ( ~ = 4 * 0 , p=0.02).

Outcome at 3 . 5 years Of the 167 children with outcome data at 3 .5 years, the mean age at assessment was 43.8 months (SD 4 .6 months). Relevant social and perinatal variables of this study population are presented in Table 111 and the 3 .5 year outcome in Table IV.

Social variables for the three clinical categories of HIE were compared and no significant differences were found, other than in ethnic background. The majority of non-Caucasian children and all of the registered Indian children were found in the moderate HIE category. Registered North American Indians (excluding Metis) made up only 2 . 1 per cent of the provincial population in the mid-year of this study, 1976 (Indian and Inuit Affairs Program 477

TABLE IV Significant differences at 3 .5 years in relation to HIE category

'd 8 t 2

478

Mild Moderate Severe Statistical Total HIE HIE HIE results

(N = 167) (N = 66) (N = 94) (N= 7)

Available as ordinal and/or continuous variables: % Handicapped 16.2 - 21.3 100.0 x2 50.8 Fine motor skills: >6 mths delay 13.2 1 . 5 14.9 100.0 x' 115.7 Gross motor skills: >6 mths delay 16.2 4 . 5 18.1 100.0 x' 114.3

Available as continuous variables: Mean (SD) ~

VMI (months from CA) -4.01 ( 9.7) -0.74 ( 5 .7 ) -4.7 (10.1) -25.7 ( 3.3) F 28.7 93.6 (23.8) 101.5 (14.0) 92.3 (23.2) 37.1 (26.7) F 32.6 96'4(17.2) 104.1 (13.7) 92.8(17.2) 71.7( 7.2) F 19.1

MLU (in SD) -0.23( 1.9) 0 .99( 1.4) -0.04( 1.9) -3 '32( 0.4) F 2 4 . 4

IQ (SB) IQ ( P P W

All results are significantly different for all HIE categories; p<O.OOI.

1976). However, 7.8 per cent of the HIE study population were Indian. Since there were no Indian children in the mild or severe HIE categories, their proportion in the moderate HIE category was even higher, 13.8 per cent. Of the 27 handicapped children, six (22.2 per cent) were Indian. The group of children with handicaps due to HIE contains a significantly higher proportion of Indians than the provincial population (xz 52.9,

Few significant differences were found in the perinatal variables for the three clinical categories of HIE (Table 111). However, significant differences in the three categories were found in the number of anticonvulsants used per child ( x2 28.1, p<O*OOOl) and the percentage of infants with an abnormal neurological examination at the time of NICU discharge (x' 26.5, p<O*OOOl).

As shown in Table IV, on all 3 - 5-year outcome measures the children with severe HIE had significantly lower scores than the children with moderate and mild HIE, and the children with moderate HIE had significantly lower scores than those with mild HIE. All children with mild HIE were free of handicaps and had average mean scores and standard deviations on standardized measures.

As the three clinical categories of HIE thus were determined to be predictors of long-term developmental outcome, an attempt was made to subdivide the categories using other perinatal factors.

p<o * 00 1).

The presence of neonatal convulsions and the neurological examination at NIcU discharge were studied to determine their usefulness as predictors within the HIE categories. Analysis of variance was performed to compare the mean differences in all developmental outcome tests for children with and without neonatal convulsions. Neonatal convulsions made no difference to outcome of those neonates with mild HIE, but in the moderate HIE group they resulted in significantly more handicapped children (30.0 vs. 5.9 per cent) (x2 6.6, p =0.01). However, neonatal convulsions did not change the outcome within the moderate HIE group for FM or GM skills, or intelligence or language scores. Within the total population, including those with severe HIE, neonatal convulsions resulted in significantly more handicapped children (24.5 vs. 4 .3 per cent)(x2 10.8,p=O.OOl),lowerVMIscores ( -5 .8f9 .9 vs. -1 .5k8 .8 months) ( F = 8.2, p=0.005), poorer FMskills(l8-4per cent vs; 5 . 8 per cent delayed (x2 4.6, p=O*O3), and lower IQ (SB) (89 .7f26 .2 YS. 99 3 _+ 18 - 5 ) (F = 6-9, p = 0.009). Gross motor skills and language scores were not significantly diminished by neonatal convulsions in the total population. Six of the seven children with severe HIE had neonatal convulsions. Thus, the poorer outcome in the total population seems to be due to the inclusion of children with severe HIE, not to the presence of neonatal convulsions as such.

Although the time of onset of neonatal

convulsions in the total population was earlier for the handicapped children (12.3 f 12.1 hours) than the non-handicapped children (27 .1 f 3 0 . 5 ) ( F = 5 - 3 , p = 0.0229), the time of onset of neonatal convulsions in the moderate HIE category for the handicapped children was not significantly earlier than the non- handicapped children. The time of onset did not differ significantly between the mild and moderate categories.

For the mild HIE group, abnormalities on discharge neurological examination in the NICU demonstrated no relationship to developmental outcome. Thus neonates with persistent hyperexcitability and excessive alertness did not have a poorer outcome than those whose symptomatology lasted for less than 24 hours. However, if the neonate had hypotonia with suppressed primitive reflexes, as seen in moderate HIE, then persistent abnormal findings resulted in more handicapped children (29 2 vs. 3.4 per cent) ( ~ ’ 6 . 5 , p=O.OI), poorer FM skills (21.5 per cent delayed vs. 0.0 per cent) (x2 5.7, p=O.O2), poorer GM skills (26.2 per cent delayed vs. 0.0 per cent) (x2 7.6, p =0.006), lower IQ (SB) (88.3 f 2 4 . 8 vs. 101.4f16.1) ( ~ = 6 . 8 , p=O.Ol), and lower language scores (PPVT: F = 7.9, p=0.006; MLU: F=5*3,p=0.02) . Within the total population, including those with severe HIE, an abnormal examination at discharge was associated with significantly poorer outcome in all measured areas: more handicapped children (28.1 vs. 1 3 per cent) (x2 17.1, p<o.0001), poorer FM skills (23.1 per cent delayed vs. 1.3 per cent) (x2 15.3, p<O.OOOl), poorer GM skills (27.5 per cent delayed vs. 2 .6 per cent) (x2 17.1, p<o*ooo1), lower VMI scores (-6 * 3 f 1 1 1 vs. - 1 . 2 f 6.8 months) ( F = 12.3, p =0.0006), lower IQ (SB) (88.1 k26 .9 VS. 100.3+17*1) ( ~ = 1 1 . 8 , p = 0.0007), lower IQ (PPVT) (91.6k17.4 vs. 102.1 f15 .2 ) (F= 16.7, p=O.OOOl), and lower MLU (-0.21 k2 .02 vs. 0 . 7 6 f 1 . 5 ) (F=11.8, p=0.0007).

All seven children with severe HIE had abnormalities on neurological examination at discharge. Of the 72 children in the moderate and severe HIE categories with abnormal findings on the neurological examination at discharge, 26 (36.1 per cent) had major handicaps. Only one child with a major handicap had normal

TABLE V Category of HIE for non-handicapped children: other developmental problems up to 3.5 years (N = 140)

Mild Moderate HIE HIE

(N = 66) (N = 74)

Esotropia (2 children with repair of strabismus) 1 5

Single afebrile grand ma1 3 convulsions -

Febrile convulsions 1 2 Neurosensory hearing-loss:

I 1

Hydrocephalus:

Bilateral moderate - Unilateral profound -

Communicating-no shunt - 1 Obstructive-shunted - 1

findings on neurological examination at discharge.

Infants with moderate HIE and without subsequent handicaps, as defined in this study, have more developmental problems than neonates with mild HIE, including neurosensory hearing-loss and esotropia (Table V). The only child with shunted hydrocephalus in this study developed meningitis in infancy; this is the only surviving child in the total population with a known CNS insult after the neonatal period, which may have interfered with developmental performance.

Relationships between perinatal and social variables and outcome variables in the total population (N = 167) were studied by means of Pearson Correlation Coef- ficients. The major variable relating to outcome was HIE category (Table VI). A less favourable outcome on all developmental scores also correlated well with a greater number of anticonvulsants per child and an abnormal neurological examination at discharge. Neonatal convulsions correlated significantly with more handicapped children, and with FM, GM and VMI scores. Parent’s schooling (particularly the mother’s) and ‘mother tongue’ correlated significantly with language and intelligence scores, but not with the number of handicapped children or motor scores. As the increased number of days in hospital did not correlate well with handicaps or motor scores, and did correlate significantly with language scores, some of the longer stays in hospital may have been for social rather than medical reasons. No significant cor-

6 9

2 E 2 c d

479

TABLE VI Correlations of perinatal and social variables and outcomes at 3 . 5 yearst (Pearson Correlation Coefficients)

120

100

h

a m c

9 - 3 x w

-

-

480

Handicapped FM GM VMI IQ (SB) IQ(PPVY) MLU

HIE category N types of anticonvulsants Neurological exam at discharge Neonatal convulsions Days in hospital Mother’s schooling Father’s schooling Mother tongue: non-English Background: non-Caucasian

0.48 0.43 0.43 0.41 0.43 0.34 0.35 0.34 0.34 0.34 0.34 0.26 0.27 0.24 0.23 0.22

- - 0.23 -

0.42 0.42 0 .43 0.34 0.29 0.24 0.26 0.30 0.26 - - -

0.24 0.27 0.29 0.23 0.33 0.21 - 0.26 -

0.26 0.37 0.32 0.29 0.30 0.29

tlncludes only variables with r>0.21 (probability for r

T I I

1 l 1 C D MR VL CP D no1 HC

n= 4 14 8 16 4 140

Fig. 1. Inrelligence scores (Sranford Binet) a: 3.5 years of handicapped and non-handicapped survivors of hypoxic-ischemic encephalapathy. CD = convulsive disorder, MR =cognitive delay, VL = visual loss, CP =cerebral palsy. D =deafness, nor HC = non-handicapped.

relations were found with any other social variables, other than non-Caucasian background, where the significant differences were thought to be associated with English as a test language for children whose ‘mother tongue’ was not English.

Although we recognize the difficulty in obtaining and verifying results of standardized intelligence testing of young handicapped children, the mean IQ (SB) scores and standard deviations for the 27 handicapped children are shown in Figure 1. Children with deafness performed at the

=0.22 is 0,004).

highest levels and children with severe convulsive disorders performed at the lowest levels. The mean IQ for handicapped children was 58.9 ( k 2 8 . 9 . The non- handicapped children had an average mean score and standard deviation for the Stanford-Binet Intelligence Scale--100.4 (k 15.4).

Discussion We have attempted to give a total outcome overview of a selected ‘high-risk’ neonatal population of term infants with prospectively clinically categorized hypoxic- ischemic encephalopathy. No attempt has been made to evaulate the r61e of laboratory investigation or treatment of these infants. The discharge and the follow-up neurological examinations, as well as the supervision of the inter- disciplinary assessments of these infants, were done by one of the authors, which has added a greater degree of consistency to the study.

The most important aspect of this study is to underline the previously recognized value of prospectively categorizing term neonates with HIE. As all neonates with mild HIE, with or without clinical convulsions and whether or not the discharge examination was normal, are free from handicaps, have few developmental problems and have average mean scores and standard deviations on standardized testing at 3 * 5 years, the long-term prognosis for these children is good. They should not be considered ‘high-risk’ and perhaps should not be classed as having an

encephalopathy at all. Up to 3.5 years of age they show no evidence of neonatal CNS damage in this study. We suggest that the approach to the parents ofthese children at the time of neonatal illness should be reassuring. This study will continue to follow these children to an age of eight years to determine school-related performance.

In this study all neonates with severe HIE, with or without clinical convulsions, have died or have severe handicaps by 3.5 years of age. The differentiation of neonates with moderate HIE requiring anticonvulsants from those withsevere HIE may be difficult within the first week of life. In general, children with severe HIE have multiple handicaps involving motor development, vision and intelligence. Further- more, the mortality rate is high for those with convulsive disorders and severe convulsive disorders are less common in the long-term survivors. In view of the devastating outcome for newborns with severe HIE, further research to prevent and lessen this problem is needed urgently.

I t is much more difficult to give an accurate prognosis for the long-term development of children with moderate HIE. The occurrence of clinical convulsions did not independently affect outcome in the mild or severe HIE groups. In contrast, in the moderate HIE group neonatal convulsions were associated with an increase in the number with handicaps and to a slight decrease in visual-motor integration, but did not significantly affect other developmental levels. Convulsive disorders were unusual among long-term survivors in the moderate HIE group.

For the children with moderate HIE, abnormal findings on neurological examination at discharge were related significantly to the number of children with handicaps, decreased motor skills, lower language scores and lower IQS. Thus the discharge examination was more useful than the presence of neonatal convulsions in distinguishing children with developmental delay in the moderate HIE category.

As a control group for the total study was not obtained, perinatal factors other than category of HIE, neurological examination at discharge and neonatal convulsions were of little help in the prognosis of HIE.

As term infants with hypoxic-ischemic encephalopathy can so easily be subdivided by physical examination, and as these categories of HIE relate well to the long- term outcome, it is suggested that these three HIE categories be used as outcome factors in further studies of health care and of perinatal factors predisposing to birth asphyxia.

Of the handicapped survivors with moderate HIE, those with neurosensory deafness performed best on standard intelligence tests and tended to have just this one handicap. This suggests that deafness may result from a different type of insult.

Using a ‘high-risk’ neonatal population for prospective study of the combination of perinatal and social factors as they relate to developmental outcome has been worthwhile. Nevertheless, the study is limited by the young age of the children and the unavailability of suitable standardized tests for a heterogeneous population, including severely mentally and/or physi- cally handicapped children. It has been established by Zigler et a/. (1973) that ‘disadvantaged’ ethnic-minority children have lower PPVT scores than SB scores and that this difference may relate to the method of giving the test, as well as to what the test measures. Thus a less favourable outcome in language development at 3 * 5 years among children from non-English speaking homes was not unexpected. However, the marked increase in handicaps of Indian children remains un- explained.

Handicaps and motor outcome variables correlated significantly with category of HIE, neonatal convulsions and neurological examination at discharge. However, language and intellectual outcome variables correlated significantly with lower parental schooling (particularly the mother’s) and the family language being other than the English language used in testing.

Intellectual testing of younger children does depend on motor-related tasks to a greater extent than for older children. For the non-handicapped, moderate HIE population, our pending 5 * 5-year study may show improved mean IQ (SB) results because of the increased testing of language skills at that age. Although some

d

T m i- d p. N

(A 00

a’

2 3 d

.c c B B 4 P

481

motor-skill difficulties in the non-handicapped children can be expected to continue during the early school years, these may be compensated for by other learning skills developed in a good learning environment.

This study will follow each child to the age of eight years, and it is expected that outcome for the non-handicapped children will depend less on perinatal factors and more on social factors and related learning opportunities. If our educational and psychological assessments confirm this and show improved outcome at an older age, there will be more room for optimism in the prognosis for neonates with moderate HIE.

Appendix B Gross motor developmental levels at 3.5 years ( I ) Advanced for chronological age: stands on one foot with open eyes for 10 seconds, with closed eyes for five seconds, hops consecutively on one foot more than two jumps, adult stance for throwing ball, catches bounced ball with arms flexed at elbows; quality of performance is good. (2) Normal for chronological age: stands on one foot with open eyes for five to nine seconds, with closed eyes for two seconds, hops on one foot once, throws ball without losing balance, catches large ball thrown and tries to catch bounced ball; quality of performance is fairly good. (3) Normal for chronological age, quality poor; stands on one foot with open eyes for three to five seconds, with closed eyes for one to two seconds, tries to hop on one foot, tries to catch bal1,jumps from 12" elevation with some collapsing on landing. (4) Delay of up to six months below chronological age: stands on one foot with open eyes for one to three seconds, cannot maintain balance with closed eyes, no hopping on one foot attempted, poor attempts at catching ball, jumps from 12" elevation with feet together but usually collapses to floor; quality is poor, showing awkwardness and decreased balance ability. ( 5 ) Delay of seven to 18 months below chronological age: momentary standing on one foot with open eyes, unable to stand on one foot with closed eyes, no hopping, steps off rather than jumps from 12" elevation, throws ball erratically and overhand, unable to catch ball; quality is very poor, showing awkwardness; rigidity/stiffness of movement; poor balance ability. (6) Delay of more than 18 months below chronological age: the child could not be tested because of the severity of the handicaps(s). Note: The coding was adjusted when the child's chronological age was below or above 3 . 5 years. Acknowledgement Statistical analysis was compiled by Janis M. Kyle, M.Ed., Consultant in Research and Data Analysis, Winlaw, British Columbia.

Authors' Appointments * C h a r h e M. T. Robertson, M.D., F.R.C.P.(C), Associate Professor, Department of Pediatrics, University of Alberta, Edmonton, Alberta; Director, Neonatal Follow-Up Clinic, Glenrose School Hospital, 10230-1 11 Avenue, Edmonton, Alberta, Canada T5G OB7. Neil N. Finer, M.D., F.R.C.P.(C), Professor of Pediatrics, Department of Pediatrics, University of Alberta, Edmonton, Alberta; Director, Newborn Medicine and Director, Pediatric Intensive Care Unit, Royal Alexandra Hospital, Edmonton, Alberta.

*Correspondence to first author.

ti c

Appendix A Fine motor developmental levels at 3.5 years (1) Advanced for chronological age: the child displays adequate abilities at the four-year+ level of development, such as lacing shoes, mature pencil- grasp, pencil skills (drawing diagonals, crosses or squares), cutting out basic shapes with scissors. (2) Normal for chronological age: the child displays appropriate abilities at the mid-three to four-year level of development, such as developing pencil grasp in a tripod fashion, basic pencil skills (drawing circles, vertical and horizontal lines, crosses), block building ( I " cubes), stringing all sizes of DLM beads, wrist pronation/supination and/or ulnarhadial deviation used in 'screw-together' toys. (3) Normal for chronobgical age, quality poor: the child displays the ability to perform the tasks of level two, but the quality is decreased because of tremor, slightly immature grasp/release/placement abilities. (4) Delay of up to six months below chronological age: the child can perform only some of the tasks of level two; the quality is rather poor. ( 5 ) Delay of seven to 18 months below chronological age: the child displays inadequate performances in block building (1" cubes), and stringing beads (even the large size), fisted pencil grasp, scribbling pencil skills, awkward grasp/release/placement skills. (6) Delay of more than 18 months below chronological age: the child could not be tested because of the severity of the handicap(s). Note: The coding was adjusted when the child's chronological age was below or above 3 . 5 years.

SUMMARY A total of 167 term neonates with a diagnosis of hypoxic-ischemic encephalopathy (HIE) had detailed neurodevelopmental follow-up at 3 . 5 years of age. All 66 children with mild HIE were free from handicap; all seven with severe HIE were severely handicapped; and of the 94 with moderate HIE at birth, 2 1 . 3 per cent were handicapped. Mean IQ was significantly related to the category of HIE. Within the moderate HIE category, the neurological examination at discharge from the Neonatal Intensive Care Unit was more useful than the presence of neonatal convulsions in identifying children with subsequent developmental delay. Abnormalities on this examination related significantly to an increased number of handicapped children, decreased motor and language skills, and lower IQs. Although neonatal convulsions were associated with an increased number of handicapped children, they did not significantly affect most other developmental outcome measures. In term infants with documented HIE at birth, major neurodevelopmental dysfunction at 3 . 5 years depended more on prospectively established category of HIE than on other perinatal or social

482 factors.

R ~ S U M ~ Nourrissons nis 6 terme avec enckphalopathie hypoxique ischimique: devenir a trois ans et demi Un total de 167 nouveax-nts A terme chez que avait t t t por t t un diagnostic d’enctphalopathie hypoxique ischtmique (HIE) ont btntficit d’un suivi neurodtvelopmental dttaillt a trois ans et demi. Aucun handicap n’a t t t constatt chez les 70 enfants ayant prtsentt une HIE Itgtre; les sept avec HIE stvtre ttaient gravement handicapts; 21.3 pour cent des 94 enfants ayant prtsentt une HIE modtrte A la naissance ttaient handicapts. Le QI moyen ttait relit significativement a la cattgorie &HIE. Dans la cattgorie de I’HIE modtree, I’examen neurologique ti la sortie de I’unitt de soins ntonataux intensifs avait une valeur prtdictive meilleure que la prtsence de convulsions ntonatales pour caracttriser ceux des enfants ayant prtsentt par la suite un retard de dtveloppement. Les anomalies a cet examen ttaient relites significativement a un nombre accru d‘enfants handicapts, une efficience diminute pour la motricitt et le langage et un QI plus bas. Bien que les convulsions ntonatales aient contribut a donner un nombre accru d’enfants handicapts, les convulsions n’affectaient pas significativement la plupart des mesures du devenir de dtveloppement. Chez les enfants nts a terme, avec une HIE a la naissance bien dtcrite, les dysfonctions majeures neurodevelopmentales ans et demi dtpendaient davantage de la cattgorie ttablie prospectivement de HIE que d’autres facteurs ptrinataux ou sociaux.

trois

ZUS AMMENFASSUNG Zum Termin geborene Kinder mil hypoxisch-ischamischer Encephalopathie: Ergebnis im Alter von 3 . 5 Jahren Insgesamt 167 reife Neugeborenen mit der Diagnose einer hypoxisch-ischamischen Encephalopathie (HIE) wurden im Alter von 3 . 5 Jahren griindlich neurologisch untersucht. Alle 66 Kinder mit einer milden HIE waren unauffallig, die sieben mit einer schweren HIE waren schwerbehindert und von den 94 mit einer mittelschweren HIE waren 21.3 Prozent behindert. Der mittlere IQ zeigte eine signifikante Relation zur Kategorie der HIE. Bei der Gruppe mit mittelschwerer HIE hatte die neurolgische Untersuchung bei der Entlassung von der Neugeborenenstation einen hoheren prognostischen Wert als das Auftreten von Neugeborenenkrampfen, um die Kinder mit einer Entwicklungsverzogerung herauszufinden. Pathologische. Befunde bei dieser Untersuchung korrelierten signifikant mit einer erohten Anzahl behinderter Kinder, mit verminderten motorischen und sprachlichen Fahigkeiten und mit niedrigeren IQ-Werten. Obwohl durch die Neugeborenenkrampfe die Anzahl der behinderten Kinder erhoht wurde, beeinfluoten die Krampfe die meisten anderen Entwicklungsparameter nicht. Bei reifen Neugeborenen mit nachgewiesener HIE waren die wichtigsten neurologischen Entwicklungsstorungen im Alter von 3 . 5 Jahren mehr von der Kategorie der HIE abhangig als von anderen perinatalen oder sozialen Faktoren.

r-- hl

RESUMEN Lactantes a tirmino con isqukmia hipodxica. Situacidn a 10s 3.5 arios Un total de 167 recitn nacidos a ttrmino con diagnbstico de encefalopatia isqutmica hipobxica fueron examinados detalladamente en su desarrollo neurolbgico a 10s 3,5 ailos de edad. Todos 10s 66 nidos con EIH moderada estaban libres de minusvalencia, 10s siete con EIH tenian una minusvalencia grave, y de 10s 94 casos con EIH al nacer el 21,3 por ciento eran minusvalidos. El CI promedio estaba significativamente relacionado con la categoria de la EIH. Dentro de 10s de categoria moderada, el examen neurol6gico al ser dados de aka de la UVI Neonatal era mas util que la presencia de convulsiones neonatales para la identificacidn de niiios con un subsiguiente retraso del desarrollo. Las anomalias en este examen estaban en relacibn significativa con un aumento de nidos minusvilidos, una disminucibn en la habilidad motora y del lenguaje y un CI mas bajo. Aunque las convulsiones neonatales contribuian a aumentar el numero de niilos minusvalidos, la convulsibn no afectaba significativamente la mayoria de 10s otros items de desarrollo. En 10s lactantes a ttrmino, con una EIH documentada al nacer una disfuncion mas de la categoria prospectivamente establecida de la EIH que de otros factores perinatales o sociales.

References Beery, K. E. (1967) Developmental Test of Visual-

Motor Integration. Chicago: Follett Educational Corn.

Bergrnin, I., Painter, M. J., Hirsch, R. P., Crumrine, P. K., David, R. (1983) ‘Outcome of neonates wit! convulsions treated in an intensive care unit. Annals of Neurology, 14, 642-647.

Blishen, B. R. (1976) ‘A revised Socioeconomic Index for Occupations in Canada.’ Canadian Review of Sociology and Anthropology. 13, 7 1-73.

Brown, J. K., Purvis, R. J . , Forfar, J . 0.. Cockburn, F. (1974) ‘Neurological aspects of perinatal asphyxia.’ Developmental Medicine and Child Neurology, 16, 567-580.

Brown, R. W. (1973) A First Language: The Early Stages. Cambridge, Mass.: Harvard University Press.

Dubowitz, L. M. S., Dubowitz, V., Goldberg, C. (1970) ‘Clinical assessment of gestational age in the newborn infant.’ Journal of Pediatrics, 77,

1-10. Dunn, L. M. (1965) Peabody Picture Vocabulary Tesr.

Circle Pines, Minnesota: American Guidance Service.

Egan, D., Illingworth, R., Mac Keith, R. (1969) Developmental Screening 0-5 Years. Clinics in Developmental Medicine, No. 30. London: S.I.M.P. with Heinemann Medical. pp. 53-60.

Finer, N. N., Robertson, C. M., Peters, K. L., Coward, J . H. (1983) ‘Factors affecting outcome in hypoxic-ischemic encephalopathy in term infants.’ American Journal of Diseases of Children,

- - Richards, R. T., Pinnell, L. E., Peters, K. L. (1981) ‘Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome.’ Journal of Pediatrics, 98, 1 12- 1 17.

Gesell, A. and others (1940) ‘Motor development.’ In Gesell, A. The First Five Years of Life, a Guide in the Study of the Preschool Child, 9th edn. New

37, 21-25.

York: Harper & Row. 483

t 5

i YI z

b

b,

5:

Giolas, T. G. (1975) ‘Speech audiometry.’ In Fulton, R. T., Lloyd, L. L. (Eds.) Auditory Assessment of the Difficult-to-test. Baltimore: Williams & Wilkins.

Holden, R. H., Willerman, L. (1972) ‘Neurological abnormality in infancy, intelligence and social class.’ In Trapp, E. P., Himelstein, P. (Eds.) Readings on the Exceptional Child, 2nd edn. New York: Appleton-Century-Crofts.

Indian and Inuit Affairs Program (1976) ‘Registered Indian Population by Sex and Residence.’ In: Indian and Northern Affairs Canada. Ottawa: Government of Canada.

Keith, R. W. (1973) ‘Impedance audiometry with neonates.’ Archives of Otolaryngology, 91,465-467.

Kileny, P. (198 1) ‘The frequency specificity of tone- pip evoked auditory brain stem responses.’ Ear and Hearing, 2, 270-275. - Connelly, C., Robertson, C. (1980) ‘Auditory brainstem respones in perinatal asphyxia.’ Inter- national Journal of Pediatric Otorhinolarynology,

Leiter, R. G. (1969) General Instructions for the Leiter International Performance Scale. Chicago: Stoelting Company.

Liden, G., Kankkumen, A. (1969) ‘Visual reinforcement audiometry.’ Archives of Otolaryngology.

Margolis, R. H., Popelka, G. R. (1975) ‘Static and dynamic acoustic impedance measurement in infant ears.’ Journal of Speech and Hearing Research, 18,435-439.

Miller, J . F. (1981) Assessing Language Production in Children-Experimental Procedures. Baltimore:

2, 147-159.

89, 865-872.

University Park Press. Moore, J. M., Wilson, W. R., Thompson, G. (1977)

‘Visual reinforcement of head turn response in infants under 12 months of age.’ Journal of Speech and Hearing Disorders, 42, 328-334.

Nelson, K. B., Ellenberg, J. H. (1979) ‘Neonatal signs as predictors of cerebral palsy.’ Pediatrics.

- - (1981) ‘Apgar scores as predictors of chronic neurologic disability.’ Pediatrics. 68, 36-44.

Robertson, C. (1980) Neonatal Follow-up Study- Data Collection and Coding Manual. Edmonton: Glenrose School Hospital.

Sarnat, H. B., Sarnat, M. S. (1976) ‘Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study.’ Archives of Neurology, 33,696-705.

Sheridan, M. (1968) The Developmental Progress of Infants and Young Children, 2nd edn. London: H.M.S.O.

Terman, L. M., Merrill, M. A. (1973) Stanford-Binet Intelligence Scale (Form L-M). Manual for the 3rd Revision, 1972 Norms Edition. Boston: Houghton Mifflin.

Volpe, J. J. (1977) ‘Observing the infant in the early hours after asphyxia.’ In Cluck, L. (Ed.) Intra- uterine Asphyxia and the Developing Fetal Brain. Chicago: Year Book Medical Publishers.

Zigler, E., Abelson, W. D., Seitz, V. (1973) ‘Motivational factors in the performance of economically disadvantaged children on the Peabody Picture Vocabulary Test.’ Child Develop- ment. 44, 294-303.

64,225-232.

484

term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years

Documents