- Email: [email protected]
Neonatal asphyxia. II. Neonatal mortality and long-term sequelae
May .1980 TheJournalofPED1ATRICS
903
Neonatal asphyxia. II. Neonatal mortality and long, term sequelae Neonatal asphyxia, defined in this study as delay of > 1 minute in onset of spontaneous respiration at birth, occurred in 1% of 13,221 live-born infants of birth weight > 500 gm between 1970 and 19)1. Seventy five (56%) of 133 asphyxiated infants survived the neonatal period. Survival was directly related to gestational age. The 65 survivors of asphyxia available for study were seen at a mean age of 4.8 years to determine the incidence and extent of neurologic and developmental abnormalities. Twelve ~hildren (18.5%) had severe impairment: nine had both neurologic and intellectual handicaps, two had neurologic impairment alone, and one had intellectual impairment alone. The incidence an d severity of impairment were not related to gestational age. Postasphyctic seizures were associated with poor outcome.
John C. Mulligan, M.D., Michael J. Painter, M.D.,* Patricia A. O'Donoghue, P.N.P., Hugh M. MacDonald, M.D., Alexander C. Allen, M.D., and Paul M. Taylor, M.D., Pittsburgh, Pa.
DESPITE RECENT ADVANCES in biophysical and biochemical monitoring of the fetus in labor and delivery, neonatal asphyxia still contributes heavily to neonatal mortality and morbidity. Neonatal asphyxia was experienced by 1.16% of 38,105 liveborn infants weighing > 500 gm consecutively delivered at the Magee-Womens Hospital during 1970-1975, and these asphyxiated infants had an overall mortality rate 88 times greater than nonasphyxiated infants? The adverse effects of asphyxia on the neurologic, respiratory, cardiovascular, endocrine, gastrointestinal, and renal systems of the newborn infant have been described, yet follow-up information is not available on a large group of recent survivors. The present study was undertaken to define the incidence and extent of developmental abnormalities in survivors of neonatal asphyxia and to determine which clinical events were associated with a poor long-term outcome. From the Department of Pediatrics, Division oJ" Neonatology, University of Pittsburgh School of Medicine, Magee- Womens Hospital, and Department of Neurology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh. Reprint address: Department of Neurology, Children's Hospital of Pinsburgh, 125 DeSoto St., Pittsburgh, PA 15213.
0022-3476/80/050903 + 05500.50/0 9 1980 The C. V. Mosby Co.
MATERIALS AND METHODS Infants delivered at Magee-Womens Hospital who survived neonatal asphyxia during 1970-1971 were retrospectively identified and Were evaluated for neurologic and intellectual status during a single clinic visit during 1975-1976. Neonatal records were coded at the time of the
See related article, p. 898.
Abbreviations used BW: birth weight GA: gestational age infant's hospital discharge by staff neonatologists according to standardized diagnoses, factors potentially associated with perinatai asphyxia, and the extent and duration of resuscitation. Infants were considered asphyxiated if positive pressure ventilation was required for > 1 minute prior to the onset of spontaneous respiration. The children were seen in the neonatal follow-up clinic, where physical and neurologic assessments were performed by the authors. We defined major neurologic sequelae as functionally significant motor impairments or sensory,hearing loss. Intellectual development was mea-
Vol. 96, No. 5, pp. 903-907
904
Mulligan et al.
The Journal of Pediatrics May 1980
Table I. Neuroiogic sequelae of asphyxia
'r'hll xam
Weight (gin)
age (wk)
age (yr)
1,280
32
5.25
1,820
33
5.0
2,000 2,020 2,110 2,490 2,65i3 3,280 5,810
37 41 34 38 38 38 42 28 32 40
4.0 4.75 4.50 4.30 5.25 4.25
1,520
1;950 4,025
l
3.6
IQ
Finding
Untestable 79 Untestable Untestable 75 Untestable 65 Untestable Untestable
Spastic hemiplegia, hearing loss Hemiplegia, choreoathetosiS, hydrocephalus Spastic quadriplegia, hydrocephalus, died 18 mo Choreoathetosis, cataracts Spastic diplegia Spastic diplegia Spastic diplegia, choreoathetosis Severe aphasia-language Spastic quadriplegia Spastic diplegia Spastic diplegia, choreoathetosis Delayed speech
91
5.8 4.75
104 73
Table 1I. Prenatal complications and outcome of asphyxia
Following prolonged stress No.
Complication
Sequelae
10 Fetal malnutrition 1 Pre-eclampsia 2 Pre-eclampsia with diabetes 1 Pre-eclampsia with fetal malnutrition 1 Ec]ampsia 6 Chorioamnionitis 2 Prolonged labor 1 Erythroblastosis fetalis (anemia) 2 Hydmps fetalis 1 Maternal hepatitis
3
27
7 (26%)
I
1 1
Following combined acute and prolonged stress
Following acute stress No. I
Complication
2 1 1 3 1 2
Breech with diabetes Breech with second twin Breech with prolapsed cord High or mid forceps Maternal hypotension Second twin (prolonged second stage) 5 Malpresentation 2 Abruptio placenta
Sequelae 1
2
1
17
sured by the Stanford Binet Intelligence Scale, form L - M ? A score of < 80 on the Stanford Bluet was considered to indicate developmental delay. The ages referred to in this paper are corrected for the degree of the infant's prematurity. For example, the corrected age for a 10-month-old child delivered at 32 weeks would be noted as 8 months. RESULTS Asphyxia was documented in 133 of 13,221 live-born infants weighing > 500 gin. Sixty-five of the 74 who survived the neonatal period were available for evaluation. Six children were completely lost to follow-up. The families and physicians of three additional children not examined reported that two were neurologically and
3 08%)
No. [
Complication
I Sequelae
3
Fetal malnutrition, breech 1 Fetal malnutrition, prolapsed cord, high forceps 1 Fetal malnutrition, precipitous delivery i Maternal hypotension, Shoulder dystocia l Chorioamnionitis abruptio placenta 1 Hydrops fetalis, placenta previa l Prolonged labor, breech
9
l (ll%)
developmentally normal; a third was "hyperactive." One additional infant was excluded from follow-up evaluation since he was found to have neurofibromatosis which may have affected development. These ten infants are not included in this report. The birth weight, gestational age, sex, and socioeconomic status of the 65 survivors who were examined and of the nine lost to follow-up were similar. The mean age at the time of examination was 4 years 10 months, ranging from 3 years, 6 months, to 6 years, 3 months. One child died of ventriculitis from an infected shunt at 18 months and is included in our results. Twelve children (18.5%) had major sequelae (Table I). Nine of these infants had both neurologic and intellectual impairment; two had neurologic sequelae without intel-
Volume 96 Number 5
Neonatal asphyxia. II.
905
14
NEUI~
12
ABNC
II IO Z ILl rY r'~ --I T (D LL O tY bJ
8
6
:!:i:!:!:i
:.;.;+:.
4
z
~:2:J;~:2;:
2
:i:!:i:!iii :!:i:i:?:i:
0
ii)iii!~i 60 UNTESTABLE
70
80
90
I00110
INTELLIGENCE
120 130 14.0150
QUOTIENT
Fig. 1. 1Q distribution of survivors of asphyxia as determined by Stanford-Binet Intelligence Scale, form LM? Open blocks indicate infants with normal neurologic findings, closed those with neurologic sequelae.
lectual impairment, and one had intellectual impairment without neurologic sequelae. Five children were very seriously impaired and p r o b a b l y will never function independently. One child with severe Spastic quadriplegia and hydrocephalus died at 18 months. Six children with mild abnormalities (two with very mild spastic paraparesis and four with mild sPeech delay or articulation errors) were functioning normally when examined and felt not to represent problems that would be handicaps to future learning. They therefore were assigned to the "no severe sequelae" group. The median score of all children on the Stanford Binet was 108 (Fig. 1). Ten children (15%) were intellectually impaired. Four scored between 65 and 80, 5 were untestable, and the one who was not tested was profoundly retarded at the time of his death. Scores were not related to birth weight, gestational age, sex, time of onset of respiration, or age at time of examination. Clinical correlations. We attempted to identify perinatal factors associated with subsequent impairment. Survi vors with and without severe sequelae did not differ significantly in birth weight, gestational age, sex, race, or socioeconomic status. Fifty-three (82%) of the 65 survivors wer e product s of complicated pregnancies or deliveries. Ten of the 53 with prenatal complications had severe impairments. We found no relationship between OUtcome
and those prenatal complications associated with acute stress, prolonged stress, or both acute and prolonged stress (Table II). The relationships between outcome and neonatal complications that have been previously reported to be associated with neurologic sequelae (fetal malnutrition, hypothermia, hyperbilirubinernia, hypoglycemia, and seizures) are presented in Table III, We defined fetal malnutrition as a birth weight less than the third percentile for gestational age (growth retardation as defined in the previous report' and including the few infants who had clinical soft tissue wasting but-were not small for gestational age); hypothermia as rectal temperature < 95~ on admission to the nursery; hyperbilirubinemia as an indirect bilirubin concentration > 15 mg/dl; and hypoglycemia as a blood sugar concentration < 30 mg/dl. The incidence of severe sequelae was not significantly different for iaffants who were either fetalIy malnourished, hypothermic, or hypoglycemic than for those who were not. Differences were greater when infants with combinations of complications were compared with those without complications, but the numbers were too small for statistical analysis. Postasphyctic seizures were related to poor outcome. Convulsions occurred in 19 of the 135 asphyxiated infants. In that, group of 19 infants, six died-, six survived impaired,
Mulligan et al.
906
The Journal of Pediatrics May 1980
57
IZ IJJ
I00
--
90
--
80
--
70
--
60
--
0
50--
I.d n
40.--
48
38
/NORMAL
50-20-I0
/EXPIRED
--
0 < 50
30 - 36
GESTATIONAL
AGE-
WEEKS
Fig. 2. Outcome of asphyxiated infants. Numerals above columns indicate total number of infants in that gestational age group, those within boxes the number of intants in outcome groups. Survival was directly related to maturity. Incidence of severe sequelae in survivors was unrelated to maturity: viz., 25% at < 3 0 weeks, 18% at 30 to 36 weeks, and 19% at > 3 6 weeks.
Despite the association of more severe sequelae with a longer delay to onset of respiration, there was no absolute time limit that universally predicted severe sequelae. Five of the 13 survivors had seizures over less than a 48-hour period; four of the five were normal at follow-up. Eight infants had seizures over a period > 48 hours; only three were subsequently normal. Mean delay in onset of respiration was similar for infants who had convulsions for more than or less than 48 hours. The age at which secures began was not related to outcome. Phenobarbital, dilantin, paraldehyde, and diazepam were used alone or in combinations to attempt to control seizures. Outcome was not related to choice of anticonvulsant agents, either singly or in combination. The adequacy of treatment utilizing eithe r plasma anticonvulsant levels or therapeutic response could not be assessed in this population. Survival was directly related to gestational age. Both incidence and severity of impairments, on the other hand, were similar for mature and premature infants (Fig. 2). Severe sequelae occurred in 5 (19%) of 26 preterm infants (GA ~< 36 weeks) and 7 (18%) of 39 term infants (GA > 36 weeks), DISCUSSION
Table IIl. Neonatal complications and incidence of severe sequelae Severe sequelae 4
Complication
N
N
[ %
X2
P
0.16
<0.7
0.0005
<0.99
0.16
<0.7
1.81
<0.2
6.14
<0.02
i
Hypothermia No hypothermia Hyperbilirubinemia No hyperbilirubinemia Fetal malnutrition No fetal malnutrition Hypoglycemia No hypoglycemia SeiZures No seizures
16 49 8 57 16 49 10 46 13 52
4 8 1 11 4 8 4 7 6 6
25 16 13 19 25 16 40 15 46 12
and seven survived intact. Although we arbitrarily define asphyxia as primary apnea at birth > 1 minute, the actual age at onset of respiration ranged from 2 to > 20 minutes, with a mean of 7.8 minutes -+ 0.8 (SE). Mean age at onset o( spontaneous respirati)on was significantly later for infants who had convulsions than for those Who did not, 14.2 minutes _+ 1.7 (SE) versus 6.0 __+0.7, respectively (P < 0.001). The incidence of seizures was significantly less for infants who established respiration within 5 minutes (2 of 41, 5%) than for those who established respiration after 5 minutes (11 or 21, 52%), P < 0.01.
Our arbitrary classification of asphyxia as the requirement of greater than one minute of positive pressure resuscitation prior to onset of respiration was chosen as a clinically recognizable definition. We assume that the infants reported here were apneic secondary to intrapartum asphyxia, smce infants who were depressed because their mothers had received large doses of analgesia or anesthesia during labor are classified when coded as mildly asphyxiated and would be excluded here. Cord pH values were not regularly available to test this assumption. The largest published series in which the neonate's condition in the first minutes of life was related to subsequent neurologic outcome was reported by Drage et aP' * from the data of the Collaborative Study of Cerebral Palsy carried out in the early 1960s. That series provides the closest available for data comparison. Important dissimilarities between our study and that of Drage et al include their assessing degree of asphyxia by Apgar score. not excluding infants whose depression at birth was probably related to intrapartum medication, examining infants for neurologic status alone at one year of age, and not correcting that age for prematurity. In both series, mortality increased progressively with decreasing maturity. The present series and that ofDrage et al do not agree. however, on the relationship between incidence of sequelae and degree of maturity. Drage et al noted that within given groups of five-minute Apgar scores, the incidence of
Volume 96 Number 5
definite neurologic abnormalties at one year increased with decreasing birth weight. With a five-minute Apgar score _< 6, the incidence of impairment in survivors with birth weight <__2,500 gm was 11.3% (P < 0.005). In the present series, neither incidence of sequelae nor degree of impairment was related to GA: 2l (81%) of 26 asphyxiated preterm infants and 32 (82%) of 39 asphyxiated term infants survived intact. The fact that asphyxiated preterm infants have the same chance for intact survival as asphyxiated term infants in the present study probably reflects the many advances in neonatal care over the decade between these two series. This is supported by the observations of Davies and Tizard, ~ who reported that spastic diplegia, occurred in 6 (10%) of the 58 infants weighing < 1,500 gm at birth born between 1961 and 1964, but that it did not occur in any of 107 infants weighing < 1,500 gm at birth born between 1965 and 1970. The most common neurologic abnormalities in the survivors of asphyxia in this series were spastic diplegia and choreoathetosis, either singly or in combination. Most of the neurologically impaired children had significant intellectual deficits; only one child had an intellectual deficit without neurologic impairment. These data are in general agreement with the findings of Brown et al? The present series confirms the findings of Rose and Lombroso ~ and of McInerny and Schuberts that postasphyctic seizures are associated with a high incidence of severe sequelae. Our data indicate that the degree of perinatal insult as defined by time to onset of spontaneous respiration is related to the incidence of seizures. The incidence of seizures was greater in those infants who had not achieved spontaneous respirations within 5 minutes of age or, viewed another way, infants with convulsions had a significantly later mean time of onset of spontaneous respiration than those who did not. Previous authors have not presented data to test the possibility that the incidence of postasphyctic seizures was related to the severity of perinatal insult. Prolonged neonatal seizures might add an increment of
Neonatal asphyxia. II.
907
brain damage to that incurred during perinatal asphyxia. Wasterlain9. 10 demonstrated a decrease in brain RNA~ DNA, protein, and cholesterol in rats following induced neonatal seizures. The observation from the present data that infants who had seizures for more than 48 hours had a higher incidence of severe sequelae than those who had seizures for less than 48 hours is consistent with this posibility, which is further strengthened by the observation that the degree of perinatal insult (as estimated by age of onset of respiration) was similar in the two groups. Although our data do not answer this question, control or, better still, prevention of seizures would appear to be important goals in the management of postasphyctic infant. REFERENCES
1. MacDonald HM, Mulligan JC, Allen AC, and Taylor PM: Neonatal asphyxia. 1. Relationship of obstetrical and neonatal complications, J PEDIATR96:898, 1980. 2. Terman L, and Merrill M: Stanford Binet Intelligence Scale, Form LM, Boston, 1973, Houghton-Mifflin Company. 3. Drage JS, Kennedy C, and Schwarz BK: The Apgar score as an index Of neonatal mortality, Obstet Gynecol 24:222, 1964. 4. Drage JS, Kennedy C, Berendes H, et al: The Apgar score as an index of infant morbidity, Dev Med Child Neurol 8:141, 1966. 5. Davies PA, and Tizard JP: Very low birth weight and subsequent neurological defect, Dev Med Child Neurol 17:3, 1975. 6. BrownJK, Purvis RJ, Forfar JO, et al: Neurological aspects of perinatal asphyxia, Dev Med Child Neurol 16:567, 1974. 7. Rose AL, and Lombroso CT: A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up, Pediatrics 45:404, 1970. 8. McInerny TK, and Schubert WK: Prognosis of neonatal seizures, Am J Dis Child 117:261, 1969. 9. Wasterlain CG, and Plum F: Vulnerability of developing rat brain to electroconvulsive seizures, Arch Neurol 29:38, 1973. 10. Wasterlain CG: Effects of neonatal status epilepticus on rat brain development, Neurology 26:975, 1976.
903
Neonatal asphyxia. II. Neonatal mortality and long, term sequelae Neonatal asphyxia, defined in this study as delay of > 1 minute in onset of spontaneous respiration at birth, occurred in 1% of 13,221 live-born infants of birth weight > 500 gm between 1970 and 19)1. Seventy five (56%) of 133 asphyxiated infants survived the neonatal period. Survival was directly related to gestational age. The 65 survivors of asphyxia available for study were seen at a mean age of 4.8 years to determine the incidence and extent of neurologic and developmental abnormalities. Twelve ~hildren (18.5%) had severe impairment: nine had both neurologic and intellectual handicaps, two had neurologic impairment alone, and one had intellectual impairment alone. The incidence an d severity of impairment were not related to gestational age. Postasphyctic seizures were associated with poor outcome.
John C. Mulligan, M.D., Michael J. Painter, M.D.,* Patricia A. O'Donoghue, P.N.P., Hugh M. MacDonald, M.D., Alexander C. Allen, M.D., and Paul M. Taylor, M.D., Pittsburgh, Pa.
DESPITE RECENT ADVANCES in biophysical and biochemical monitoring of the fetus in labor and delivery, neonatal asphyxia still contributes heavily to neonatal mortality and morbidity. Neonatal asphyxia was experienced by 1.16% of 38,105 liveborn infants weighing > 500 gm consecutively delivered at the Magee-Womens Hospital during 1970-1975, and these asphyxiated infants had an overall mortality rate 88 times greater than nonasphyxiated infants? The adverse effects of asphyxia on the neurologic, respiratory, cardiovascular, endocrine, gastrointestinal, and renal systems of the newborn infant have been described, yet follow-up information is not available on a large group of recent survivors. The present study was undertaken to define the incidence and extent of developmental abnormalities in survivors of neonatal asphyxia and to determine which clinical events were associated with a poor long-term outcome. From the Department of Pediatrics, Division oJ" Neonatology, University of Pittsburgh School of Medicine, Magee- Womens Hospital, and Department of Neurology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh. Reprint address: Department of Neurology, Children's Hospital of Pinsburgh, 125 DeSoto St., Pittsburgh, PA 15213.
0022-3476/80/050903 + 05500.50/0 9 1980 The C. V. Mosby Co.
MATERIALS AND METHODS Infants delivered at Magee-Womens Hospital who survived neonatal asphyxia during 1970-1971 were retrospectively identified and Were evaluated for neurologic and intellectual status during a single clinic visit during 1975-1976. Neonatal records were coded at the time of the
See related article, p. 898.
Abbreviations used BW: birth weight GA: gestational age infant's hospital discharge by staff neonatologists according to standardized diagnoses, factors potentially associated with perinatai asphyxia, and the extent and duration of resuscitation. Infants were considered asphyxiated if positive pressure ventilation was required for > 1 minute prior to the onset of spontaneous respiration. The children were seen in the neonatal follow-up clinic, where physical and neurologic assessments were performed by the authors. We defined major neurologic sequelae as functionally significant motor impairments or sensory,hearing loss. Intellectual development was mea-
Vol. 96, No. 5, pp. 903-907
904
Mulligan et al.
The Journal of Pediatrics May 1980
Table I. Neuroiogic sequelae of asphyxia
'r'hll xam
Weight (gin)
age (wk)
age (yr)
1,280
32
5.25
1,820
33
5.0
2,000 2,020 2,110 2,490 2,65i3 3,280 5,810
37 41 34 38 38 38 42 28 32 40
4.0 4.75 4.50 4.30 5.25 4.25
1,520
1;950 4,025
l
3.6
IQ
Finding
Untestable 79 Untestable Untestable 75 Untestable 65 Untestable Untestable
Spastic hemiplegia, hearing loss Hemiplegia, choreoathetosiS, hydrocephalus Spastic quadriplegia, hydrocephalus, died 18 mo Choreoathetosis, cataracts Spastic diplegia Spastic diplegia Spastic diplegia, choreoathetosis Severe aphasia-language Spastic quadriplegia Spastic diplegia Spastic diplegia, choreoathetosis Delayed speech
91
5.8 4.75
104 73
Table 1I. Prenatal complications and outcome of asphyxia
Following prolonged stress No.
Complication
Sequelae
10 Fetal malnutrition 1 Pre-eclampsia 2 Pre-eclampsia with diabetes 1 Pre-eclampsia with fetal malnutrition 1 Ec]ampsia 6 Chorioamnionitis 2 Prolonged labor 1 Erythroblastosis fetalis (anemia) 2 Hydmps fetalis 1 Maternal hepatitis
3
27
7 (26%)
I
1 1
Following combined acute and prolonged stress
Following acute stress No. I
Complication
2 1 1 3 1 2
Breech with diabetes Breech with second twin Breech with prolapsed cord High or mid forceps Maternal hypotension Second twin (prolonged second stage) 5 Malpresentation 2 Abruptio placenta
Sequelae 1
2
1
17
sured by the Stanford Binet Intelligence Scale, form L - M ? A score of < 80 on the Stanford Bluet was considered to indicate developmental delay. The ages referred to in this paper are corrected for the degree of the infant's prematurity. For example, the corrected age for a 10-month-old child delivered at 32 weeks would be noted as 8 months. RESULTS Asphyxia was documented in 133 of 13,221 live-born infants weighing > 500 gin. Sixty-five of the 74 who survived the neonatal period were available for evaluation. Six children were completely lost to follow-up. The families and physicians of three additional children not examined reported that two were neurologically and
3 08%)
No. [
Complication
I Sequelae
3
Fetal malnutrition, breech 1 Fetal malnutrition, prolapsed cord, high forceps 1 Fetal malnutrition, precipitous delivery i Maternal hypotension, Shoulder dystocia l Chorioamnionitis abruptio placenta 1 Hydrops fetalis, placenta previa l Prolonged labor, breech
9
l (ll%)
developmentally normal; a third was "hyperactive." One additional infant was excluded from follow-up evaluation since he was found to have neurofibromatosis which may have affected development. These ten infants are not included in this report. The birth weight, gestational age, sex, and socioeconomic status of the 65 survivors who were examined and of the nine lost to follow-up were similar. The mean age at the time of examination was 4 years 10 months, ranging from 3 years, 6 months, to 6 years, 3 months. One child died of ventriculitis from an infected shunt at 18 months and is included in our results. Twelve children (18.5%) had major sequelae (Table I). Nine of these infants had both neurologic and intellectual impairment; two had neurologic sequelae without intel-
Volume 96 Number 5
Neonatal asphyxia. II.
905
14
NEUI~
12
ABNC
II IO Z ILl rY r'~ --I T (D LL O tY bJ
8
6
:!:i:!:!:i
:.;.;+:.
4
z
~:2:J;~:2;:
2
:i:!:i:!iii :!:i:i:?:i:
0
ii)iii!~i 60 UNTESTABLE
70
80
90
I00110
INTELLIGENCE
120 130 14.0150
QUOTIENT
Fig. 1. 1Q distribution of survivors of asphyxia as determined by Stanford-Binet Intelligence Scale, form LM? Open blocks indicate infants with normal neurologic findings, closed those with neurologic sequelae.
lectual impairment, and one had intellectual impairment without neurologic sequelae. Five children were very seriously impaired and p r o b a b l y will never function independently. One child with severe Spastic quadriplegia and hydrocephalus died at 18 months. Six children with mild abnormalities (two with very mild spastic paraparesis and four with mild sPeech delay or articulation errors) were functioning normally when examined and felt not to represent problems that would be handicaps to future learning. They therefore were assigned to the "no severe sequelae" group. The median score of all children on the Stanford Binet was 108 (Fig. 1). Ten children (15%) were intellectually impaired. Four scored between 65 and 80, 5 were untestable, and the one who was not tested was profoundly retarded at the time of his death. Scores were not related to birth weight, gestational age, sex, time of onset of respiration, or age at time of examination. Clinical correlations. We attempted to identify perinatal factors associated with subsequent impairment. Survi vors with and without severe sequelae did not differ significantly in birth weight, gestational age, sex, race, or socioeconomic status. Fifty-three (82%) of the 65 survivors wer e product s of complicated pregnancies or deliveries. Ten of the 53 with prenatal complications had severe impairments. We found no relationship between OUtcome
and those prenatal complications associated with acute stress, prolonged stress, or both acute and prolonged stress (Table II). The relationships between outcome and neonatal complications that have been previously reported to be associated with neurologic sequelae (fetal malnutrition, hypothermia, hyperbilirubinernia, hypoglycemia, and seizures) are presented in Table III, We defined fetal malnutrition as a birth weight less than the third percentile for gestational age (growth retardation as defined in the previous report' and including the few infants who had clinical soft tissue wasting but-were not small for gestational age); hypothermia as rectal temperature < 95~ on admission to the nursery; hyperbilirubinemia as an indirect bilirubin concentration > 15 mg/dl; and hypoglycemia as a blood sugar concentration < 30 mg/dl. The incidence of severe sequelae was not significantly different for iaffants who were either fetalIy malnourished, hypothermic, or hypoglycemic than for those who were not. Differences were greater when infants with combinations of complications were compared with those without complications, but the numbers were too small for statistical analysis. Postasphyctic seizures were related to poor outcome. Convulsions occurred in 19 of the 135 asphyxiated infants. In that, group of 19 infants, six died-, six survived impaired,
Mulligan et al.
906
The Journal of Pediatrics May 1980
57
IZ IJJ
I00
--
90
--
80
--
70
--
60
--
0
50--
I.d n
40.--
48
38
/NORMAL
50-20-I0
/EXPIRED
--
0 < 50
30 - 36
GESTATIONAL
AGE-
WEEKS
Fig. 2. Outcome of asphyxiated infants. Numerals above columns indicate total number of infants in that gestational age group, those within boxes the number of intants in outcome groups. Survival was directly related to maturity. Incidence of severe sequelae in survivors was unrelated to maturity: viz., 25% at < 3 0 weeks, 18% at 30 to 36 weeks, and 19% at > 3 6 weeks.
Despite the association of more severe sequelae with a longer delay to onset of respiration, there was no absolute time limit that universally predicted severe sequelae. Five of the 13 survivors had seizures over less than a 48-hour period; four of the five were normal at follow-up. Eight infants had seizures over a period > 48 hours; only three were subsequently normal. Mean delay in onset of respiration was similar for infants who had convulsions for more than or less than 48 hours. The age at which secures began was not related to outcome. Phenobarbital, dilantin, paraldehyde, and diazepam were used alone or in combinations to attempt to control seizures. Outcome was not related to choice of anticonvulsant agents, either singly or in combination. The adequacy of treatment utilizing eithe r plasma anticonvulsant levels or therapeutic response could not be assessed in this population. Survival was directly related to gestational age. Both incidence and severity of impairments, on the other hand, were similar for mature and premature infants (Fig. 2). Severe sequelae occurred in 5 (19%) of 26 preterm infants (GA ~< 36 weeks) and 7 (18%) of 39 term infants (GA > 36 weeks), DISCUSSION
Table IIl. Neonatal complications and incidence of severe sequelae Severe sequelae 4
Complication
N
N
[ %
X2
P
0.16
<0.7
0.0005
<0.99
0.16
<0.7
1.81
<0.2
6.14
<0.02
i
Hypothermia No hypothermia Hyperbilirubinemia No hyperbilirubinemia Fetal malnutrition No fetal malnutrition Hypoglycemia No hypoglycemia SeiZures No seizures
16 49 8 57 16 49 10 46 13 52
4 8 1 11 4 8 4 7 6 6
25 16 13 19 25 16 40 15 46 12
and seven survived intact. Although we arbitrarily define asphyxia as primary apnea at birth > 1 minute, the actual age at onset of respiration ranged from 2 to > 20 minutes, with a mean of 7.8 minutes -+ 0.8 (SE). Mean age at onset o( spontaneous respirati)on was significantly later for infants who had convulsions than for those Who did not, 14.2 minutes _+ 1.7 (SE) versus 6.0 __+0.7, respectively (P < 0.001). The incidence of seizures was significantly less for infants who established respiration within 5 minutes (2 of 41, 5%) than for those who established respiration after 5 minutes (11 or 21, 52%), P < 0.01.
Our arbitrary classification of asphyxia as the requirement of greater than one minute of positive pressure resuscitation prior to onset of respiration was chosen as a clinically recognizable definition. We assume that the infants reported here were apneic secondary to intrapartum asphyxia, smce infants who were depressed because their mothers had received large doses of analgesia or anesthesia during labor are classified when coded as mildly asphyxiated and would be excluded here. Cord pH values were not regularly available to test this assumption. The largest published series in which the neonate's condition in the first minutes of life was related to subsequent neurologic outcome was reported by Drage et aP' * from the data of the Collaborative Study of Cerebral Palsy carried out in the early 1960s. That series provides the closest available for data comparison. Important dissimilarities between our study and that of Drage et al include their assessing degree of asphyxia by Apgar score. not excluding infants whose depression at birth was probably related to intrapartum medication, examining infants for neurologic status alone at one year of age, and not correcting that age for prematurity. In both series, mortality increased progressively with decreasing maturity. The present series and that ofDrage et al do not agree. however, on the relationship between incidence of sequelae and degree of maturity. Drage et al noted that within given groups of five-minute Apgar scores, the incidence of
Volume 96 Number 5
definite neurologic abnormalties at one year increased with decreasing birth weight. With a five-minute Apgar score _< 6, the incidence of impairment in survivors with birth weight <__2,500 gm was 11.3% (P < 0.005). In the present series, neither incidence of sequelae nor degree of impairment was related to GA: 2l (81%) of 26 asphyxiated preterm infants and 32 (82%) of 39 asphyxiated term infants survived intact. The fact that asphyxiated preterm infants have the same chance for intact survival as asphyxiated term infants in the present study probably reflects the many advances in neonatal care over the decade between these two series. This is supported by the observations of Davies and Tizard, ~ who reported that spastic diplegia, occurred in 6 (10%) of the 58 infants weighing < 1,500 gm at birth born between 1961 and 1964, but that it did not occur in any of 107 infants weighing < 1,500 gm at birth born between 1965 and 1970. The most common neurologic abnormalities in the survivors of asphyxia in this series were spastic diplegia and choreoathetosis, either singly or in combination. Most of the neurologically impaired children had significant intellectual deficits; only one child had an intellectual deficit without neurologic impairment. These data are in general agreement with the findings of Brown et al? The present series confirms the findings of Rose and Lombroso ~ and of McInerny and Schuberts that postasphyctic seizures are associated with a high incidence of severe sequelae. Our data indicate that the degree of perinatal insult as defined by time to onset of spontaneous respiration is related to the incidence of seizures. The incidence of seizures was greater in those infants who had not achieved spontaneous respirations within 5 minutes of age or, viewed another way, infants with convulsions had a significantly later mean time of onset of spontaneous respiration than those who did not. Previous authors have not presented data to test the possibility that the incidence of postasphyctic seizures was related to the severity of perinatal insult. Prolonged neonatal seizures might add an increment of
Neonatal asphyxia. II.
907
brain damage to that incurred during perinatal asphyxia. Wasterlain9. 10 demonstrated a decrease in brain RNA~ DNA, protein, and cholesterol in rats following induced neonatal seizures. The observation from the present data that infants who had seizures for more than 48 hours had a higher incidence of severe sequelae than those who had seizures for less than 48 hours is consistent with this posibility, which is further strengthened by the observation that the degree of perinatal insult (as estimated by age of onset of respiration) was similar in the two groups. Although our data do not answer this question, control or, better still, prevention of seizures would appear to be important goals in the management of postasphyctic infant. REFERENCES
1. MacDonald HM, Mulligan JC, Allen AC, and Taylor PM: Neonatal asphyxia. 1. Relationship of obstetrical and neonatal complications, J PEDIATR96:898, 1980. 2. Terman L, and Merrill M: Stanford Binet Intelligence Scale, Form LM, Boston, 1973, Houghton-Mifflin Company. 3. Drage JS, Kennedy C, and Schwarz BK: The Apgar score as an index Of neonatal mortality, Obstet Gynecol 24:222, 1964. 4. Drage JS, Kennedy C, Berendes H, et al: The Apgar score as an index of infant morbidity, Dev Med Child Neurol 8:141, 1966. 5. Davies PA, and Tizard JP: Very low birth weight and subsequent neurological defect, Dev Med Child Neurol 17:3, 1975. 6. BrownJK, Purvis RJ, Forfar JO, et al: Neurological aspects of perinatal asphyxia, Dev Med Child Neurol 16:567, 1974. 7. Rose AL, and Lombroso CT: A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up, Pediatrics 45:404, 1970. 8. McInerny TK, and Schubert WK: Prognosis of neonatal seizures, Am J Dis Child 117:261, 1969. 9. Wasterlain CG, and Plum F: Vulnerability of developing rat brain to electroconvulsive seizures, Arch Neurol 29:38, 1973. 10. Wasterlain CG: Effects of neonatal status epilepticus on rat brain development, Neurology 26:975, 1976.