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Intrapartum fetal hypoxia: A study of long-term morbidity
Intrapartum fetal hypoxia: A study of long-term morbidity J.
A. LOW
R. S. GALBRAITH D. W. ML'IR H. L. KILLEN E. A. PATER
E. J. KARCHMAR Kingston, Ontario, Canada Reported is the second phase of a prospective follow-up study of 37 children who had episodes of intrapartum fetal hypoxia at defivery indentified by an acid-base assessment and of a control group of 59 children who had no evidence of intrapartum fetal hypoxia. The newborn infants were normally grown and mature at delivery. Follow-up assessments of motor, cognitive, and language development were made between 1 and 6 years of age. There was no significant difference in the pattern of physical growth and the incidences of motor and cognitive handicap or developmental delay, language developmental delay, and tests of vision and hearing in the children of the hypoxia group and the children of the control group. These findings suggest that acid-base measures of metabolic acidosis can be used as a method of assessment of the mature normally grown fetus during labor without compromising the long-term outcome of the child. (AM. J. OesTET. GYNECOL 145:129, 1983.)
PERINATAL HYPOXIA may result in central nervous system injury. The wide spectrum of injury involving the cerebral cortex and brain stem in the human has been demonstrated by neuropathologic examination of the brains from infants who suffered perinatal deaths associated with hypoxia, and from children with sequelae attributed to hypoxia. 1- 3 Although studies in the fetal monkey have provided evidence in this experimental model, 4- 6 the degree and duration of hypoxia in a particular human fetus which will result in central nervous system injury have not been established. Severe intrapartum fetal hypoxia will result in hypoxic-ischemic encephalopathy. 1• 8 Clinical studies of severe birth asphyxia have demonstrated that all chi!-
From the Department of Obstetrics and GJIUllicology, Queen's University. Supported in part by Grant No. 721 from the Ontario Mental Health Foundation. Presented at the Thirty-eighth Annual Meeting of The Society of Obstetricians and Gynaecologists of Canada, Toronto, Ontario, Canada, june 15-19, 1982. Reprint requests:]. A. Low, M.D., Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada K7L 3N6. 0002-9378/83/020129+06$00.60/0 © 1983 The C. V. Mosby Co.
dren who survived with sequelae had clinical signs of encephalopathy during the neonatal period.9- 12 Clinical studies of hypoxic-ischemic encephalopathy in neonates have demonstrated sequelae in approximately 30% of the surviving children. 13- 15 Additionally significant correlations have been demonstrated between central nervous system signs in neonates and subsequent long-term motor and cognitive handicap. 16• 17 Thus, present evidence suggests that perinat11l hypoxia with encephalopathy in the neonate may be associated with subsequent central nervous system handicap. The effect of intrapartum fetal hypoxia without encephalopathy in the neonate requires definition. The present study was undertaken to assess the effect of intrapartum fetal hypoxia without encephalopathy in the neonate in respect to long-term sequelae in the mature, normally grown fetus.
Methods The children studied were all mature at delivery, i.e., equal to or greater than 37 weeks of gestational age, with weights greater than the tenth percentile for gestational age. There were 37 children in the fetal hypoxia group in whom the umbilical artery buffer base at delivery was less than 34 mEq/L (mean, 31.1
129
130 Low et al. Am.
January 15, l9K:l Obstel. Gynecol.
J.
Table I. Criteria for handicap or developmental delay of motor, cognitive, or language development Handicap Major Motor
Cerebral palsy
Cognitive
W.P.P.S.l. full score, <70
I
,\'linor
Developmental delay
Minor abnormal neurological signs W.P.P.S.I. full score, 70-84
Language
mEq/L). There were 59 children in the control group in whom the umbilical artery buffer base at delivery was greater than 36 mEq/L (mean, 39.9 mEq/L). The children of the hypoxia group exhibited newborn depression as expressed by low Apgar scores, however, with three exceptions, with no evidence of encephalopathy in the newborn period. The characteristics of the obstetric patients and their pregnancies and the follow-up observations on these children to 12 months of age have been reported previously. 18 Follow-up observations were obtained at 12, 24, 36, 42, 48, and 60 months and on completion of senior kindergarten. Measures of physical growth (weight, height, head and chest circumference) were obtained at each visit, and a detailed physical examination was done at 12, 24, and 60 months. Measures of motor development included Bayley's Physical Development Index at 12 and 24 months, the motor subscale of the McCarthy Scales of Children's Abilities at 36, 42, 48, and 60 months, and a neurological examination at 12, 24, and 60 months. The Imitation of Gestures Test was carried out in conjunction with the neurological examination at 60 months. Measures of cognitive development included Bayley's Mental Development Index at 12 and 24 months, the Stanford- Binet I.Q. Test at 36 and 48 months, and the Wechsler Pre-school and Primary Scale of Intelligence (W.P.P.S.l.) at 60 months. Language development was assessed by the Reynell Language Development Scales at 42 months. Assessment of hearing was done by history and peripheral audiology tests, including a screening test, tympanometry, and tests of stapedial reflexes at 60 months. Vision was assessed with a screening test at 60 months. School performance was assessed on the completion of senior kindergarten by a teacher interview, with evaluation of cognitive and motor skills. The six items, scored on a rating scale from 1 to 6, were: school performance, vocabulary, concentration, gross and fine motor function, and activity. The final assessment with respect to pass or fail was obtained.
Serial McCarthy motor scores < 39 Serial borderline scores Bayley Mental Development Index Stanford-Binet l.Q. Test W.P.P.S.L Reynell verbal comprehension and/or expressive language score < -1.0
The profile of follow-up observations for each child was reviewed and classified. The categories in this classification were major or minor handicap, developmental delay, or normal development (Table £). A major motor handicap included severe or moderate cerebral palsy. A minor motor handicap included minor abnormal neurological signs of tone, coordination, or motor function in addition to abnormal McCarthy motor subscale scores. Motor developmental delay was identified by serial McCarthy motor subscale scores less than or equal to 39, i.e., one standard deviation below the mean for a normal population. A major cognitive handicap included severe or mild mental retardation expressed by a W.P.P.S.L full score <70 at 60 months, with supplementary supportive measures in the Bayley Mental Development Index scores at i2 and 24 months, and the Stanford-Binet l.Q. Test at 36 and 48 months. A minor cognitive handicap included borderline intelligence expressed by a W.P.P.S.l. full score between 70 and 84 at 60 months, with supplementary supportive measures in the Bayley Mental Development Index scores at 12 and 24 months and the Stanford-Binet I.Q. Test at 36 and 48 months. A cognitive developmental delay included serial abnormal or borderline scores in the Bayley Mental Development Index at 12 and 24 months and the Stanford-Binet I.Q. Test at 36 and 48 month, and a W.P.P.S.I. full score of 85. A language developmental delay was identified by a verbal comprehension and/or expressive language score less than or equal to - 1.0 in the Reynell Language Development Scale at 42 months. This represented a score less than one standard deviation below the mean for a normal population. School performance was assessed as unsatisfactory on the basis of failure in senior kindergarten. Profile assessments were carried out in 80 of the 96 children, 31 in the fetal hypoxia group, and 49 in the control group. Age of the final assessment of the children with incomplete profiles is outlined in Table II. The children with incomplete profiles did not change
20
Table II. Age of final assessment of the 12mo 124rno 136mo
120
;/
18
children with incomplete profiles 48rno
Total
2 3
3 1
0 3
I
0 (17%) 10 (17%)
3
Kgm
I.
12 I
I.
A 4 A
2 BIRTH
No significant difference was observed in the measures of physical growth, i.e., weight, height, and head and chest circumference, at birth between the babies of the fetal hypoxia group and those of the control group. The growth patterns for the children of the two groups were identical to 60 months of age (Fig. 1). Measures of motor development are outlined in Table II I. There was no significant difference between the fetal hypoxia and control groups with respect to Bayley's Physical Development Index scores, and the motor subscale of the McCarthy Scales of Children's Abilities at 36, 42, 48, and 60 months. Neither severe nor moderate cerebral palsy was observed in either the fetal hypoxia or control group. Minor abnormal neurological signs of coordination and motor function occurred with equal frequency in the two groups. The Imitation of Gestures assessment demonstrated no difference in the scores for hand, arm, or finger movements of the children of the fetal hypoxia and control groups. Measures of cognitive development are outlined in Table III. There was no significant difference between the fetal hypoxia group and the control group with respect to Bayley's Mental Development Index at 24 months, Stanford-Binet I.Q. Test scores at 36 and 48 months, and W.P.P.S.I. full score at 60 months. The distributions of W.P.P.S.I. full scores were essentially the same in the two groups (Table IV). Measures of language development are outlined in Table III. The scores for verbal comprehension and expressive language for the children in the fetal hypoxia group were slightly lower than those for the children in the control group, but the differences were not significant. No significant differences were noted between the fetal hypoxia and contol groups in the screening tests of hearing and vision. Comparison of individual profiles of fetal hypoxia and control groups. The number of children with motor, cognitive, or language deficits are summarized
90
"
80
I
Cm
70
I
"
I.
II
6
HEIGHT
WEIGHT 12
24
36 48
81RTH
60
Months
Results Comparison of fetal hypoxia and control groups.
/
100
,&
10
the characteristics of the initial fetal hypoxia and control groups.
110
'
16
14
Hypoxia Control
131
Intrapartum fetal hypoxia
Volume 145 Number 2
12
24 36 48
GO
Months
60 ;;
;;
50
em
Cm 40
HEAD
CIRCUMFERENCE
CHEST CIRCUMFERENCE
~~--~~--~~~
30 L---'---J.-l...--...1...-.....J
BIRTH
24
12
36 48
60
BIRTH
Control Group o--
12
24
36 48
60
Months
Months -
Fetal Hypoxio Group---..
Fig. I. The measures of physical growth (weight, height, head circumference, and chest circumference) at 12, 24, 36, 48, and 60 months in the hypoxia and control groups.
in Table V. There were seven children in the hypoxia group (23%), and twelve children in the control group (24%) with either a motor, cognitive, or language handicap or developmental delay. There were seven children who had both a motor and cognitive de!1cit, eleven children with motor deficit alone, and one child with a language developmental delay alone. There were no children with cerebral palsy or minor motor handicaps. One child in the hypoxia group had a m~jor motor handicap due to a traumatic intercurrent event during childhood. Seventeen children, six in the hypoxia group (19%) and eleven in the control group 121 o/n) h;ui t>virlt>nc:t> of motor develoomental delav. The motor scores for the children with and without motor developmental delay between ;35 and 60 months are outlined in Fig. 2. There were two children in the hypoxia group (7%) and five children in the control group ( 10%) with a cognitive handicap or developmental delay. The cognitive scores for the children with and without cognitive deficits between 36 and 60 months are outlined in Fig. 2. There were four children in the hypoxia group ,--'~I~
-----
-
--------
-
.l
I
132 Low et al.
January 15, 1983 Am. J. Obstet. GynecoL
Table III. Motor development scores and mental development scores at 12, 24, 36, 42, 48, and 60 months and Reynell Language Development scores at 42 months in the fetal hypoxia and control group Control
Hypo~
No. Motor:
Bayley Physical Development Index 12 mo 24 mo McCarthy motor scale 36 mo 42 mo 48 mo 60mo
I
Mean
Hand Arm Finger
Cognitive:
Bayley Mental Development Index 12 mo 24 mo Stanford-Binet I.Q. Test 36 mo 48 mo
I
SD
No.
55 35
100.4 90.6
18
28 35
46.7 45.8 40.6 41.5
I
Mean
SD
P value
18.5 12.0
0.6 0.1
5.7 10.0 10.0
0.8 0.5 0.9 0.3
36 23
98.8 96.3
13.1 13.2
7 14 24
47.4 43.9 41.1 44.4
6.6 8.8 8.7 8.5
28 28 28
9.6 9.6 10.9
0.8
1.1 2.2
45 45 45
9.6 9.6 12.0
0.8 0.8 4.9
0.9 0.8 0.3
36 28
108.4 110.8
13.1 16.0
55 40
109.6 112.2
16.1 17.9
0.7 0.7
25 28
97.4 101.5
15.6 15.6
45 42
97.9 103.7
15.4 14.9
0.9 0.6
30
107.4
12.8
45
103.5
16.5
0.3
1.0 1.2
40 35
1.1
0.4 0.6
16
l mitation of Gestures Test:
I
25
8.1
W.P.P.S.I.
60 mo Language: Verbal Expression
28 27
0.4 0.01
0
2
1
4
15 23
l.O
Table V. Motor, cognitive, and language deficits in children in the control group and the hypoxia group at 5 years of age
Table IV. Distribution of W.P.P.S.l. full scores in the fetal hypoxia and control groups at 60 months
Hypoxia Control
0.7 0.14
13 17 Deficit
(13%) and five children in the control group (10%) with
an abnormal score in the Reynell Language Development Scale. Six of these children had an abnormal score in both verbal comprehension and expressive language. Socioeconomic status. At l year of age, the coefficient of correlation between the Blishen Score and the Bayley Physical Development Index (-0.06) and between the Blishen Score and the Bayley Mental Development Index (0.2) was not significant. However, by 5 years of age, there was a very significant correlation between the Blishen Score and measures of motor and cognitive development. The coefficient of correlation between the Blishen Score and the McCarthy motor score was 0.4 (p < 0.001), and that between the Blishen Score and the W.P.P.S.I. full score was 0.5 (p < 0.001). School assessment. There was no significant difference in the mean rating scores for school performance, vocabulary, concentration, gross and fine motor func-
Motor: Major Minor Developmental delay Cognitive: Major Minor Developmental delay Language delay: Verbal Comprehension Both
I
Control
Hyp~
No.
7 I
I
%
No.
%
23
12
24
0
0
0
6
11
0
l
2
3
0
1
1
0
1 2
4
I
tion, and activity between the children of the fetal hypoxia group and those of the control group. Ten children failed in senior kindergarten: two children in the fetal group (6%) and eight children in the control group (16%).
Comment Fetal hypoxia may result in cerebral ischemia and cellular hypoxia leading to necrosis and, if the child survives, central nervous system handicap. The occur-
Intrapartum fetal hypoxia
Volume 145 Number 2
Table VI. Classification of perinatal hypoxia Stage IA. Fetal metabolic acidosis Children with evidence of fetal metabolic acidosis of a significant degree (umbilical artery buffer base <34 mEq/L) and duration as defined by intrapartum acid-base measures. The diagnosis of fetal metabolic acidosis may be supported by evidence of hypoxemia, hypercarbia, and hyperlactatemia with increased lactate-pyruvate ratio Stage lB. Fetal metabolic acidosis plus newborn depression Children with evidence of significant fetal metabolic acidosis with evidence of newborn depression as expressed by an Apgar score at 1 minute <3 and at 5 minutes <7 and/or respiratory delay >5 minutes requiring assisted ventilation Stage I l. Fetal metabolic acidosis plus neonatal encephalopathy Children with evidence of significant fetal metabolic acidosis and neonatal encephalopathy as expressed by abnormal neurological signs in respect to consciousness, tone, seizures, primitive reflexes, and autonomic nervous system function renee of such central nervous system injury depends upon the characteristics of the fetus stressed and the degree and duration of the hypoxia. The relevance of the characteristics of the fetus stressed is emphasized by the different pathologic features and subsequent disability in the premature infant in relationship tO the mature infant. 7 Studies in the fetal monkey have provided some indication of the critical range of hypoxia. These studies suggest that approximately 12 minutes of total anoxia and 2 hours of relative hypoxia may result in central nervous system injury with subsequent handicap. 6 Although the relationship between perinatal hypoxia in the human fetus and subsequent handicap in the surviving children has been assessed in many retrospective and prospective studies, the majority of such clinical studies have lacked a measure of the severity or duration of the hypoxic episode experienced by the fetus and newborn infant. A more precise definition of the hypoxic episode experienced by the human fetus is now available with acid-base assessment of fetal blood during labor and delivery. The duration of the hypoxic episode is expressed by serial measures of metabolic acidosis during labor, and the degree of the hypoxic episode, by the severity of metabolic acidosis at delivery. The immediate effect of the hypoxic episode can be assessed by a measure of newborn depression as expressed by an Apgar score at I and 5 minutes and by the occurrence of newborn hypoxic-ischemic encephalopathy during the neonatal period. Therefore, a clinical classification of hypoxia has been proposed, based upon an objective measure of fetal hypoxia and the subsequent behavior of the newborn infant (Table VI), to provide a more discriminating interpretation of the relationship of hypoxia to subsequent handicap. The children of the hypoxia group in this prospec-
100
100
90
o----<:>
Normal Children Children c Oef,cits
80
70
70
~~~
..
60
60 u
..-----
90
80
<1>
0
133
Q>
50
(/)
40
~
o.............,..,
-......
30 20
'u-----0
MOTOR DEVELOPMENT
10
0u so
IJ)
40
30 20
COGNITIVE DEVELOPMENT
10
36
48
Months
60
36
48
60
Months
Fig. 2. Left: The McCarthy motor scores at 36. 42, 48, and 60
months in children who were normal and in children with a motor deficit in the hypoxia and control groups. Right: The mental development scores at 36, 48, and 60 months in children who were normal and children with a cog-nitive deficit in the hypoxia and control groups.
tive follow-up study represented principally Stage I fetal hypoxia, in keeping with this classification. The sequelae of intrapartum fetal hypoxia was assessed in normally grown infants who had reached maturity that was equal to or greater than 37 weeks of gestational age at delivery. The children in the hypoxia group and those in the control group were closely matched with respect to maternal, socioeconomic, obstetric, labor, and delivery characteristics. Gestational age and physical measures of the neonates were identical in the two groups, and no major anomalies were identified in these children. The significant variable in the babies of the hypoxia group was an episode of intrapartum fetal hypoxia with metabolic acidosis. The children of the hypoxia group were selected on the basis of the degree of metabolic acidosis at delivery, with a mean umbilical artery buffer base of 31.1 mEq/L. This approximated the criticallevel of the metabolic acidosis observed in the fetal monkeys with central nervous system damage. However, the duration of the hypoxic episode in those cases with appropriate caput data was short, developing during the hour prior to delivery. The newborn infants of the hypoxia group had low Apgar Scores at I and 5 minutes, with an increased requirement for resuscitation with intermittant positive pressure rentilation. Subsequently, during the neonatal period, with the exception of three infants who had mild encephalopathy, these infants did not exhibit the neurological signs of abnormal tone, decreased consciousness, irritability, or seizures of hypoxic-ischemic encephalopathv. The follow-up study was designed to proYide a pro-
134 Low et al.
file of data between I and 5 years of age to identify motor, cognitive, and language deficits. The children in the hypoxia group and those in the control group demonstrated parallel growth characteristics to 60 months of age. The incidence of motor, cognitive, or language deficits or developmental delay was not significantly greater in the children who had experienced an episode of intrapartum fetal hypoxia than that in the children of the control group. Several other observations warrant comment. The constellation of deficits which occur in individual children and the significance of these deficits with respect to subsequent school performance are apparent. Of the 18 children who had a motor or cognitive deficit, 40% had both a motor and cognitive deficit, and 60% had a motor deficit alone. Nine of the 10 children who had a language developmental delay had a motor deficit with or without a cognitive deficit. Eight of the 10 children who failed at school had had one or more deficits. Fi-
January 15. 1983
Am. J. Obstet. Gynecol.
nally, the frequently reported association between socioeconomic status and motor and cognitive development at 5 years of age was apparent. The results of this study imply that mature, normally grown children will not exhibit an increased incidence of neurological sequelae, as assessed by motor, cognitive, and language development, due to an intrapartum Stage I hypoxic episode of short duration. This is reassuring in respect to current clinical practice. An acidbase measure of metabolic acidosis provides a definitive diagnosis of fetal hypoxia. Such a definitive end-point has the advantage of providing an accurate diagnosis upon which to base clinical decisions to intervene in the management of the fetus assessed during labor. The present findings indicate that acid-base measures of metabolic acidosis can be used as a method of assessment of the mature, normally grown fetus without compromising the long-term outcome of the child.
REFERENCES I. Towbin, A.: Central nervous system damage in the human fetus and newborn infant. Mechanical and hypoxic injury incurred in the fetal-neonatal period. Am. J. Dis. Child. 119:259, 1970. 2. Gilles, F. H.: Lesions attributed to perinatal asphyxia in the human, in Gheck, L., editor: Intrauterine Asphyxia and the Developing Fetal Brain, Chicago, 1977, Year Book Medical Publishers, Inc., pp. 99·107. 3. Norman, M.G.: Perinatal brain damage. Perspect. Pediatr. Pathol. 4:41, 1978. 4. Ranck, J. B., and Windle, W. F.: Brain damage in the monkey ma.caca mulatta by asphyxia neonatorium, Exp. Neurol. 1:130, 1959. 5. Sechzer, J. A.: Memory deficit in monkey's brain damaged by asphyxia neonatorum, Exp. Neurol. 24:497, 1969. 6. Meyers, R. S.: Two patterns of perinatal brain damage and their conditions of occurrence, AM. J. OBSTET. GYNECOL. 112:246, 1972. 7. Volpe, J. J.: Perinatal hypoxic-ischemic brain injury, Pediatr. Clin. North Am. 23:383, 1976. 8. Brann, A. W., and Dykes, F. W.: The effect of intrauterine asphyxia on the full term neonate, Clin. Perinatol. 4:149, 1977. 9. Steiner, H., and Neligan, G.: Perinatal cardiac arrest, quality of the survivors, Arch. Dis. Child. 50:696, 1975. 10. Scott, H.: Outcome of very severe birth asphyxia, Arch. Dis. Child. 51:712, 1976.
II. Thomson, A. J., Serle, M., and Russell, G.: Quality of survival after severe birth asphyxia, Arch. Dis. Child. 52:620, 1977. 12. DeSouza, S. W., and Richards, B.: Neurological sequelae in newborn babies after perinatal asphyxia. Arch. Dis. Child. 53:564, 1978. 13. Amiel-Tison, C.: Cerebral damage in full term newborns. Aetiological factors, neonatal status and long term follow-up, Bioi. Neonate. 14:234, 1969. 14. Brown, J. K., Purvis, R. T., Forfar, J. 0., and Cockburn, F.: Neurological aspects of perinatal asphyxia, Dev. Med. Child Neurol. 16:567, 1974. 15. Finer, N. W., Robertson, C. M., Richards, R. T., Pinnell, L. E., and Peters, K. L.: Hypoxic-ischemic encephalopathy in term neonates: Perinatal factors and outcome, J. Pediatr. 98: 112, 1981. 16. Nelson, K. B., and Ellenberg, J. H.: Neonatal signs as predictors of cerebral palsy, Pediatrics 64:225, 1979. 17. Broman, S.: Perinatal anoxia and cognitive development in early childhood, in Field, T., Sostek, A. M., and Goldberg, S., editors: Infants Born at Risk, New York, 1979, Spectrum Books, pp. 25-52. 18. Low, J. A., Galbraith, R. S., Muir, D., Killen, H., Karchmar,J., and Campbell, D.: Intrapartum fetal asphyxia. A preliminary report in regard to long-term morbidity. AM. .J. 0BSTET. GYNECOL. 130:525, 1978.
A. LOW
R. S. GALBRAITH D. W. ML'IR H. L. KILLEN E. A. PATER
E. J. KARCHMAR Kingston, Ontario, Canada Reported is the second phase of a prospective follow-up study of 37 children who had episodes of intrapartum fetal hypoxia at defivery indentified by an acid-base assessment and of a control group of 59 children who had no evidence of intrapartum fetal hypoxia. The newborn infants were normally grown and mature at delivery. Follow-up assessments of motor, cognitive, and language development were made between 1 and 6 years of age. There was no significant difference in the pattern of physical growth and the incidences of motor and cognitive handicap or developmental delay, language developmental delay, and tests of vision and hearing in the children of the hypoxia group and the children of the control group. These findings suggest that acid-base measures of metabolic acidosis can be used as a method of assessment of the mature normally grown fetus during labor without compromising the long-term outcome of the child. (AM. J. OesTET. GYNECOL 145:129, 1983.)
PERINATAL HYPOXIA may result in central nervous system injury. The wide spectrum of injury involving the cerebral cortex and brain stem in the human has been demonstrated by neuropathologic examination of the brains from infants who suffered perinatal deaths associated with hypoxia, and from children with sequelae attributed to hypoxia. 1- 3 Although studies in the fetal monkey have provided evidence in this experimental model, 4- 6 the degree and duration of hypoxia in a particular human fetus which will result in central nervous system injury have not been established. Severe intrapartum fetal hypoxia will result in hypoxic-ischemic encephalopathy. 1• 8 Clinical studies of severe birth asphyxia have demonstrated that all chi!-
From the Department of Obstetrics and GJIUllicology, Queen's University. Supported in part by Grant No. 721 from the Ontario Mental Health Foundation. Presented at the Thirty-eighth Annual Meeting of The Society of Obstetricians and Gynaecologists of Canada, Toronto, Ontario, Canada, june 15-19, 1982. Reprint requests:]. A. Low, M.D., Department of Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada K7L 3N6. 0002-9378/83/020129+06$00.60/0 © 1983 The C. V. Mosby Co.
dren who survived with sequelae had clinical signs of encephalopathy during the neonatal period.9- 12 Clinical studies of hypoxic-ischemic encephalopathy in neonates have demonstrated sequelae in approximately 30% of the surviving children. 13- 15 Additionally significant correlations have been demonstrated between central nervous system signs in neonates and subsequent long-term motor and cognitive handicap. 16• 17 Thus, present evidence suggests that perinat11l hypoxia with encephalopathy in the neonate may be associated with subsequent central nervous system handicap. The effect of intrapartum fetal hypoxia without encephalopathy in the neonate requires definition. The present study was undertaken to assess the effect of intrapartum fetal hypoxia without encephalopathy in the neonate in respect to long-term sequelae in the mature, normally grown fetus.
Methods The children studied were all mature at delivery, i.e., equal to or greater than 37 weeks of gestational age, with weights greater than the tenth percentile for gestational age. There were 37 children in the fetal hypoxia group in whom the umbilical artery buffer base at delivery was less than 34 mEq/L (mean, 31.1
129
130 Low et al. Am.
January 15, l9K:l Obstel. Gynecol.
J.
Table I. Criteria for handicap or developmental delay of motor, cognitive, or language development Handicap Major Motor
Cerebral palsy
Cognitive
W.P.P.S.l. full score, <70
I
,\'linor
Developmental delay
Minor abnormal neurological signs W.P.P.S.I. full score, 70-84
Language
mEq/L). There were 59 children in the control group in whom the umbilical artery buffer base at delivery was greater than 36 mEq/L (mean, 39.9 mEq/L). The children of the hypoxia group exhibited newborn depression as expressed by low Apgar scores, however, with three exceptions, with no evidence of encephalopathy in the newborn period. The characteristics of the obstetric patients and their pregnancies and the follow-up observations on these children to 12 months of age have been reported previously. 18 Follow-up observations were obtained at 12, 24, 36, 42, 48, and 60 months and on completion of senior kindergarten. Measures of physical growth (weight, height, head and chest circumference) were obtained at each visit, and a detailed physical examination was done at 12, 24, and 60 months. Measures of motor development included Bayley's Physical Development Index at 12 and 24 months, the motor subscale of the McCarthy Scales of Children's Abilities at 36, 42, 48, and 60 months, and a neurological examination at 12, 24, and 60 months. The Imitation of Gestures Test was carried out in conjunction with the neurological examination at 60 months. Measures of cognitive development included Bayley's Mental Development Index at 12 and 24 months, the Stanford- Binet I.Q. Test at 36 and 48 months, and the Wechsler Pre-school and Primary Scale of Intelligence (W.P.P.S.l.) at 60 months. Language development was assessed by the Reynell Language Development Scales at 42 months. Assessment of hearing was done by history and peripheral audiology tests, including a screening test, tympanometry, and tests of stapedial reflexes at 60 months. Vision was assessed with a screening test at 60 months. School performance was assessed on the completion of senior kindergarten by a teacher interview, with evaluation of cognitive and motor skills. The six items, scored on a rating scale from 1 to 6, were: school performance, vocabulary, concentration, gross and fine motor function, and activity. The final assessment with respect to pass or fail was obtained.
Serial McCarthy motor scores < 39 Serial borderline scores Bayley Mental Development Index Stanford-Binet l.Q. Test W.P.P.S.L Reynell verbal comprehension and/or expressive language score < -1.0
The profile of follow-up observations for each child was reviewed and classified. The categories in this classification were major or minor handicap, developmental delay, or normal development (Table £). A major motor handicap included severe or moderate cerebral palsy. A minor motor handicap included minor abnormal neurological signs of tone, coordination, or motor function in addition to abnormal McCarthy motor subscale scores. Motor developmental delay was identified by serial McCarthy motor subscale scores less than or equal to 39, i.e., one standard deviation below the mean for a normal population. A major cognitive handicap included severe or mild mental retardation expressed by a W.P.P.S.L full score <70 at 60 months, with supplementary supportive measures in the Bayley Mental Development Index scores at i2 and 24 months, and the Stanford-Binet l.Q. Test at 36 and 48 months. A minor cognitive handicap included borderline intelligence expressed by a W.P.P.S.l. full score between 70 and 84 at 60 months, with supplementary supportive measures in the Bayley Mental Development Index scores at 12 and 24 months and the Stanford-Binet I.Q. Test at 36 and 48 months. A cognitive developmental delay included serial abnormal or borderline scores in the Bayley Mental Development Index at 12 and 24 months and the Stanford-Binet I.Q. Test at 36 and 48 month, and a W.P.P.S.I. full score of 85. A language developmental delay was identified by a verbal comprehension and/or expressive language score less than or equal to - 1.0 in the Reynell Language Development Scale at 42 months. This represented a score less than one standard deviation below the mean for a normal population. School performance was assessed as unsatisfactory on the basis of failure in senior kindergarten. Profile assessments were carried out in 80 of the 96 children, 31 in the fetal hypoxia group, and 49 in the control group. Age of the final assessment of the children with incomplete profiles is outlined in Table II. The children with incomplete profiles did not change
20
Table II. Age of final assessment of the 12mo 124rno 136mo
120
;/
18
children with incomplete profiles 48rno
Total
2 3
3 1
0 3
I
0 (17%) 10 (17%)
3
Kgm
I.
12 I
I.
A 4 A
2 BIRTH
No significant difference was observed in the measures of physical growth, i.e., weight, height, and head and chest circumference, at birth between the babies of the fetal hypoxia group and those of the control group. The growth patterns for the children of the two groups were identical to 60 months of age (Fig. 1). Measures of motor development are outlined in Table II I. There was no significant difference between the fetal hypoxia and control groups with respect to Bayley's Physical Development Index scores, and the motor subscale of the McCarthy Scales of Children's Abilities at 36, 42, 48, and 60 months. Neither severe nor moderate cerebral palsy was observed in either the fetal hypoxia or control group. Minor abnormal neurological signs of coordination and motor function occurred with equal frequency in the two groups. The Imitation of Gestures assessment demonstrated no difference in the scores for hand, arm, or finger movements of the children of the fetal hypoxia and control groups. Measures of cognitive development are outlined in Table III. There was no significant difference between the fetal hypoxia group and the control group with respect to Bayley's Mental Development Index at 24 months, Stanford-Binet I.Q. Test scores at 36 and 48 months, and W.P.P.S.I. full score at 60 months. The distributions of W.P.P.S.I. full scores were essentially the same in the two groups (Table IV). Measures of language development are outlined in Table III. The scores for verbal comprehension and expressive language for the children in the fetal hypoxia group were slightly lower than those for the children in the control group, but the differences were not significant. No significant differences were noted between the fetal hypoxia and contol groups in the screening tests of hearing and vision. Comparison of individual profiles of fetal hypoxia and control groups. The number of children with motor, cognitive, or language deficits are summarized
90
"
80
I
Cm
70
I
"
I.
II
6
HEIGHT
WEIGHT 12
24
36 48
81RTH
60
Months
Results Comparison of fetal hypoxia and control groups.
/
100
,&
10
the characteristics of the initial fetal hypoxia and control groups.
110
'
16
14
Hypoxia Control
131
Intrapartum fetal hypoxia
Volume 145 Number 2
12
24 36 48
GO
Months
60 ;;
;;
50
em
Cm 40
HEAD
CIRCUMFERENCE
CHEST CIRCUMFERENCE
~~--~~--~~~
30 L---'---J.-l...--...1...-.....J
BIRTH
24
12
36 48
60
BIRTH
Control Group o--
12
24
36 48
60
Months
Months -
Fetal Hypoxio Group---..
Fig. I. The measures of physical growth (weight, height, head circumference, and chest circumference) at 12, 24, 36, 48, and 60 months in the hypoxia and control groups.
in Table V. There were seven children in the hypoxia group (23%), and twelve children in the control group (24%) with either a motor, cognitive, or language handicap or developmental delay. There were seven children who had both a motor and cognitive de!1cit, eleven children with motor deficit alone, and one child with a language developmental delay alone. There were no children with cerebral palsy or minor motor handicaps. One child in the hypoxia group had a m~jor motor handicap due to a traumatic intercurrent event during childhood. Seventeen children, six in the hypoxia group (19%) and eleven in the control group 121 o/n) h;ui t>virlt>nc:t> of motor develoomental delav. The motor scores for the children with and without motor developmental delay between ;35 and 60 months are outlined in Fig. 2. There were two children in the hypoxia group (7%) and five children in the control group ( 10%) with a cognitive handicap or developmental delay. The cognitive scores for the children with and without cognitive deficits between 36 and 60 months are outlined in Fig. 2. There were four children in the hypoxia group ,--'~I~
-----
-
--------
-
.l
I
132 Low et al.
January 15, 1983 Am. J. Obstet. GynecoL
Table III. Motor development scores and mental development scores at 12, 24, 36, 42, 48, and 60 months and Reynell Language Development scores at 42 months in the fetal hypoxia and control group Control
Hypo~
No. Motor:
Bayley Physical Development Index 12 mo 24 mo McCarthy motor scale 36 mo 42 mo 48 mo 60mo
I
Mean
Hand Arm Finger
Cognitive:
Bayley Mental Development Index 12 mo 24 mo Stanford-Binet I.Q. Test 36 mo 48 mo
I
SD
No.
55 35
100.4 90.6
18
28 35
46.7 45.8 40.6 41.5
I
Mean
SD
P value
18.5 12.0
0.6 0.1
5.7 10.0 10.0
0.8 0.5 0.9 0.3
36 23
98.8 96.3
13.1 13.2
7 14 24
47.4 43.9 41.1 44.4
6.6 8.8 8.7 8.5
28 28 28
9.6 9.6 10.9
0.8
1.1 2.2
45 45 45
9.6 9.6 12.0
0.8 0.8 4.9
0.9 0.8 0.3
36 28
108.4 110.8
13.1 16.0
55 40
109.6 112.2
16.1 17.9
0.7 0.7
25 28
97.4 101.5
15.6 15.6
45 42
97.9 103.7
15.4 14.9
0.9 0.6
30
107.4
12.8
45
103.5
16.5
0.3
1.0 1.2
40 35
1.1
0.4 0.6
16
l mitation of Gestures Test:
I
25
8.1
W.P.P.S.I.
60 mo Language: Verbal Expression
28 27
0.4 0.01
0
2
1
4
15 23
l.O
Table V. Motor, cognitive, and language deficits in children in the control group and the hypoxia group at 5 years of age
Table IV. Distribution of W.P.P.S.l. full scores in the fetal hypoxia and control groups at 60 months
Hypoxia Control
0.7 0.14
13 17 Deficit
(13%) and five children in the control group (10%) with
an abnormal score in the Reynell Language Development Scale. Six of these children had an abnormal score in both verbal comprehension and expressive language. Socioeconomic status. At l year of age, the coefficient of correlation between the Blishen Score and the Bayley Physical Development Index (-0.06) and between the Blishen Score and the Bayley Mental Development Index (0.2) was not significant. However, by 5 years of age, there was a very significant correlation between the Blishen Score and measures of motor and cognitive development. The coefficient of correlation between the Blishen Score and the McCarthy motor score was 0.4 (p < 0.001), and that between the Blishen Score and the W.P.P.S.I. full score was 0.5 (p < 0.001). School assessment. There was no significant difference in the mean rating scores for school performance, vocabulary, concentration, gross and fine motor func-
Motor: Major Minor Developmental delay Cognitive: Major Minor Developmental delay Language delay: Verbal Comprehension Both
I
Control
Hyp~
No.
7 I
I
%
No.
%
23
12
24
0
0
0
6
11
0
l
2
3
0
1
1
0
1 2
4
I
tion, and activity between the children of the fetal hypoxia group and those of the control group. Ten children failed in senior kindergarten: two children in the fetal group (6%) and eight children in the control group (16%).
Comment Fetal hypoxia may result in cerebral ischemia and cellular hypoxia leading to necrosis and, if the child survives, central nervous system handicap. The occur-
Intrapartum fetal hypoxia
Volume 145 Number 2
Table VI. Classification of perinatal hypoxia Stage IA. Fetal metabolic acidosis Children with evidence of fetal metabolic acidosis of a significant degree (umbilical artery buffer base <34 mEq/L) and duration as defined by intrapartum acid-base measures. The diagnosis of fetal metabolic acidosis may be supported by evidence of hypoxemia, hypercarbia, and hyperlactatemia with increased lactate-pyruvate ratio Stage lB. Fetal metabolic acidosis plus newborn depression Children with evidence of significant fetal metabolic acidosis with evidence of newborn depression as expressed by an Apgar score at 1 minute <3 and at 5 minutes <7 and/or respiratory delay >5 minutes requiring assisted ventilation Stage I l. Fetal metabolic acidosis plus neonatal encephalopathy Children with evidence of significant fetal metabolic acidosis and neonatal encephalopathy as expressed by abnormal neurological signs in respect to consciousness, tone, seizures, primitive reflexes, and autonomic nervous system function renee of such central nervous system injury depends upon the characteristics of the fetus stressed and the degree and duration of the hypoxia. The relevance of the characteristics of the fetus stressed is emphasized by the different pathologic features and subsequent disability in the premature infant in relationship tO the mature infant. 7 Studies in the fetal monkey have provided some indication of the critical range of hypoxia. These studies suggest that approximately 12 minutes of total anoxia and 2 hours of relative hypoxia may result in central nervous system injury with subsequent handicap. 6 Although the relationship between perinatal hypoxia in the human fetus and subsequent handicap in the surviving children has been assessed in many retrospective and prospective studies, the majority of such clinical studies have lacked a measure of the severity or duration of the hypoxic episode experienced by the fetus and newborn infant. A more precise definition of the hypoxic episode experienced by the human fetus is now available with acid-base assessment of fetal blood during labor and delivery. The duration of the hypoxic episode is expressed by serial measures of metabolic acidosis during labor, and the degree of the hypoxic episode, by the severity of metabolic acidosis at delivery. The immediate effect of the hypoxic episode can be assessed by a measure of newborn depression as expressed by an Apgar score at I and 5 minutes and by the occurrence of newborn hypoxic-ischemic encephalopathy during the neonatal period. Therefore, a clinical classification of hypoxia has been proposed, based upon an objective measure of fetal hypoxia and the subsequent behavior of the newborn infant (Table VI), to provide a more discriminating interpretation of the relationship of hypoxia to subsequent handicap. The children of the hypoxia group in this prospec-
100
100
90
o----<:>
Normal Children Children c Oef,cits
80
70
70
~~~
..
60
60 u
..-----
90
80
<1>
0
133
Q>
50
(/)
40
~
o.............,..,
-......
30 20
'u-----0
MOTOR DEVELOPMENT
10
0u so
IJ)
40
30 20
COGNITIVE DEVELOPMENT
10
36
48
Months
60
36
48
60
Months
Fig. 2. Left: The McCarthy motor scores at 36. 42, 48, and 60
months in children who were normal and in children with a motor deficit in the hypoxia and control groups. Right: The mental development scores at 36, 48, and 60 months in children who were normal and children with a cog-nitive deficit in the hypoxia and control groups.
tive follow-up study represented principally Stage I fetal hypoxia, in keeping with this classification. The sequelae of intrapartum fetal hypoxia was assessed in normally grown infants who had reached maturity that was equal to or greater than 37 weeks of gestational age at delivery. The children in the hypoxia group and those in the control group were closely matched with respect to maternal, socioeconomic, obstetric, labor, and delivery characteristics. Gestational age and physical measures of the neonates were identical in the two groups, and no major anomalies were identified in these children. The significant variable in the babies of the hypoxia group was an episode of intrapartum fetal hypoxia with metabolic acidosis. The children of the hypoxia group were selected on the basis of the degree of metabolic acidosis at delivery, with a mean umbilical artery buffer base of 31.1 mEq/L. This approximated the criticallevel of the metabolic acidosis observed in the fetal monkeys with central nervous system damage. However, the duration of the hypoxic episode in those cases with appropriate caput data was short, developing during the hour prior to delivery. The newborn infants of the hypoxia group had low Apgar Scores at I and 5 minutes, with an increased requirement for resuscitation with intermittant positive pressure rentilation. Subsequently, during the neonatal period, with the exception of three infants who had mild encephalopathy, these infants did not exhibit the neurological signs of abnormal tone, decreased consciousness, irritability, or seizures of hypoxic-ischemic encephalopathv. The follow-up study was designed to proYide a pro-
134 Low et al.
file of data between I and 5 years of age to identify motor, cognitive, and language deficits. The children in the hypoxia group and those in the control group demonstrated parallel growth characteristics to 60 months of age. The incidence of motor, cognitive, or language deficits or developmental delay was not significantly greater in the children who had experienced an episode of intrapartum fetal hypoxia than that in the children of the control group. Several other observations warrant comment. The constellation of deficits which occur in individual children and the significance of these deficits with respect to subsequent school performance are apparent. Of the 18 children who had a motor or cognitive deficit, 40% had both a motor and cognitive deficit, and 60% had a motor deficit alone. Nine of the 10 children who had a language developmental delay had a motor deficit with or without a cognitive deficit. Eight of the 10 children who failed at school had had one or more deficits. Fi-
January 15. 1983
Am. J. Obstet. Gynecol.
nally, the frequently reported association between socioeconomic status and motor and cognitive development at 5 years of age was apparent. The results of this study imply that mature, normally grown children will not exhibit an increased incidence of neurological sequelae, as assessed by motor, cognitive, and language development, due to an intrapartum Stage I hypoxic episode of short duration. This is reassuring in respect to current clinical practice. An acidbase measure of metabolic acidosis provides a definitive diagnosis of fetal hypoxia. Such a definitive end-point has the advantage of providing an accurate diagnosis upon which to base clinical decisions to intervene in the management of the fetus assessed during labor. The present findings indicate that acid-base measures of metabolic acidosis can be used as a method of assessment of the mature, normally grown fetus without compromising the long-term outcome of the child.
REFERENCES I. Towbin, A.: Central nervous system damage in the human fetus and newborn infant. Mechanical and hypoxic injury incurred in the fetal-neonatal period. Am. J. Dis. Child. 119:259, 1970. 2. Gilles, F. H.: Lesions attributed to perinatal asphyxia in the human, in Gheck, L., editor: Intrauterine Asphyxia and the Developing Fetal Brain, Chicago, 1977, Year Book Medical Publishers, Inc., pp. 99·107. 3. Norman, M.G.: Perinatal brain damage. Perspect. Pediatr. Pathol. 4:41, 1978. 4. Ranck, J. B., and Windle, W. F.: Brain damage in the monkey ma.caca mulatta by asphyxia neonatorium, Exp. Neurol. 1:130, 1959. 5. Sechzer, J. A.: Memory deficit in monkey's brain damaged by asphyxia neonatorum, Exp. Neurol. 24:497, 1969. 6. Meyers, R. S.: Two patterns of perinatal brain damage and their conditions of occurrence, AM. J. OBSTET. GYNECOL. 112:246, 1972. 7. Volpe, J. J.: Perinatal hypoxic-ischemic brain injury, Pediatr. Clin. North Am. 23:383, 1976. 8. Brann, A. W., and Dykes, F. W.: The effect of intrauterine asphyxia on the full term neonate, Clin. Perinatol. 4:149, 1977. 9. Steiner, H., and Neligan, G.: Perinatal cardiac arrest, quality of the survivors, Arch. Dis. Child. 50:696, 1975. 10. Scott, H.: Outcome of very severe birth asphyxia, Arch. Dis. Child. 51:712, 1976.
II. Thomson, A. J., Serle, M., and Russell, G.: Quality of survival after severe birth asphyxia, Arch. Dis. Child. 52:620, 1977. 12. DeSouza, S. W., and Richards, B.: Neurological sequelae in newborn babies after perinatal asphyxia. Arch. Dis. Child. 53:564, 1978. 13. Amiel-Tison, C.: Cerebral damage in full term newborns. Aetiological factors, neonatal status and long term follow-up, Bioi. Neonate. 14:234, 1969. 14. Brown, J. K., Purvis, R. T., Forfar, J. 0., and Cockburn, F.: Neurological aspects of perinatal asphyxia, Dev. Med. Child Neurol. 16:567, 1974. 15. Finer, N. W., Robertson, C. M., Richards, R. T., Pinnell, L. E., and Peters, K. L.: Hypoxic-ischemic encephalopathy in term neonates: Perinatal factors and outcome, J. Pediatr. 98: 112, 1981. 16. Nelson, K. B., and Ellenberg, J. H.: Neonatal signs as predictors of cerebral palsy, Pediatrics 64:225, 1979. 17. Broman, S.: Perinatal anoxia and cognitive development in early childhood, in Field, T., Sostek, A. M., and Goldberg, S., editors: Infants Born at Risk, New York, 1979, Spectrum Books, pp. 25-52. 18. Low, J. A., Galbraith, R. S., Muir, D., Killen, H., Karchmar,J., and Campbell, D.: Intrapartum fetal asphyxia. A preliminary report in regard to long-term morbidity. AM. .J. 0BSTET. GYNECOL. 130:525, 1978.