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Severe fetal acidemia: Neonatal neurologic features and short-term outcome
Severe Fetal Acidemia: Neonatal Neurologic Features and Short-term Outcome Jeffrey
M. Perlman,
MB*
The objectives of this study were to determine if infants delivered with severe acidemia (cord umbilical arterial p H < 7.0) h a d s h o r t - t e r m neurologic effects and w h e t h e r infants with persistent b r a d y c a r d i a who received c a r d i o p u l m o n a r y resuscitation (CPR) in the delivery r o o m would be at greatest risk for subsequently developing neonatal seizures. Forty-seven infants (39 term, 8 p r e t e r m ) delivered with severe fetal a c i d e m i a were studied. T h e m e a n (+ S.D.) f o r pH, P a c o 2 , a n d base deficit for the 47 infants was 6.86 _+ 0.11, 97 _+22 m m Hg, a n d -17 + 4, respectively. L a b o r complications were c o m m o n and included placental a b r u p t i o n in 8, r u p t u r e d uterus in 4, cord prolapse in 3, fetal h e a r t rate decelerations in 12, a n d other (n = 14). M o s t infants were delivered via e m e r g e n c y cesarean section (n = 29). Delivery r o o m interventions included oxygen and b a g / m a s k ventilation only (n = 20) a n d intubation a n d ventilation (n = 22); 7 of 22 infants received C P R and epinephrine for persistent b r a d y c a r d i a (heart rate < 80 beats/min despite ventilatory support). Five infants required no intervention. Eight infants (17%) had seizures; 6 of these infants received C P R in the delivery room. S h o r t - t e r m outcomes were a b n o r m a l in 7 of 8 infants (i.e., death in 5, a b n o r m a l neurologic examination at discharge in 2). I n 39 infants without seizures, 32 had transient neurologic abnormalities (i.e., irritability, hyperreflexia, proximal hypotonia) which resolved by discharge, a n d 2 h a d a b n o r m a l and 5 n o r m a l examinations. By univariate analysis, adverse outcome was related to 1 min (P < .001) a n d 5 min A p g a r scores (P = .019) a n d C P R in the delivery r o o m (P < .0001). The odds ratio estimate for C P R is 234. These d a t a indicate that C P R a n d epinephrine intervention in the delivery r o o m for persistent b r a d y c a r d i a identifies infants at greatest risk for s h o r t - t e r m adverse o u t c o m e a n d that therapeutic strategies to preserve b r a i n function in severe fetal acidemia should focus on such infants. Perlman JM, Risser R. Severe fetal acidemia: Neonatal neurologic features and short-term outcome. Pediatr Neurol 1993;9:277-82.
From the *Department of Pediatrics and *AcademicComputing Services; University of Texas Southwestern Medical Center; Dallas, Texas.
and Rick Risser, MSt
Introduction Approximately 0.3% of deliveries at our institution are complicated by severe fetal acidemia (i.e., cord umbilical arterial pH < 7.0) [ 1]. Despite enormous potential for neurologic injury, there is limited information regarding neurologic sequelae in such infants [1-3]. Although it may be a marker of asphyxia, low cord umbilical arterial pH provides limited information about the duration of the insult and/or the fetal adaptive mechanisms in response (i.e., redistribution of cardiac output to maintain cerebral perfusion) [4,5]. In the experimental model of asphyxia, cerebral blood flow (CBF) and oxygen delivery is maintained, provided the mean systemic blood pressure is within the normal range, however, when the asphyxial event is associated with a reduction in mean systemic blood pressure, a marked decrease in CBF and oxygen delivery occurs [6]. We postulated that infants delivered with severe acidemia would be at greatest risk for subsequent neuronal injury if associated circulatory collapse with compromise in cerebral peffusion were to occur. We reasoned that the need for cardiopulmonary resuscitation (CPR) in the delivery room for persistent bradycardia would identify such high-risk infants. We conducted this prospective study with the following objectives: (1) To determine the neonatal neurologic manifestations of infants delivered with severe fetal acidemia; and, (2) To determine whether infants with persistent bradycardia who received CPR would be those at greatest risk for neonatal seizures. Methods Forty-seven infants admitted to the Intensive Care Nursery at Parkland Memorial Hospital from December, 1990 to November, 1991 with an umbilical cord arterial pH < 7.0 were evaluated. Umbilical cord arterial blood samples are routinely obtained for blood gas analysis from all live births occurring at this institution [1]. Blood is immediately drawn from a doubly clamped segment of cord into 3 ml plastic syringes flushed with heparin (100 u/ml); the specimens are placed in ice prior to transport to the laboratory for analysis. Each identified infant underwent a detailed neurologic examination [7]. Samat staging was utilized to characterize postanoxic enceph-
Communications should be addressed to: Dr. Pedman; Department of Pediatrics; University of Texas Southwestern Medical Center; 5323 Harry Hines Boulevard; Dallas, TX 75235-9063. Received March 15, 1993; accepted June 9, 1993.
Perlman and Risser: Severe Fetal Acidemia 277
alopathy in term infants [81. Briefly, we describe the 3 stages to this classification: Stage 1 is characterized by hyperalertness and exaggerated Mort and stretch reflexes usually lasting < 24 hours; Stage II is marked by obtundation, hypotonia, and seizures: and, Stage IIl is characterized by stupor, flaccidity, and suppression of brainstem and autonomic function. Sarnat staging in the premature infants was modified as lbllows: Stage I is characterized by irritability and exaggerated stretch reflexes; Stage II is marked by hypotonia and seizures; and, Stage Ill is recognized by stupor and flaccidity with suppression of brainstem function. The examinations were performed by one of the authors (JMP) in the first 3 postnatal days, at 7 days, and prior to discharge. An abnormal short-term neurologic outcome was considered when there were neonatal seizures [7] or abnormal examination at discharge (i.e., spasticity, hypotonia, feeding difficulties). Cranial sonography was performed on each infant on the first or second postnatal day or more frequently if abnormal. Abnormalities included periventricular-intraventricular hemorrhage, evolution of cystic changes within periventricular white matter, increased echoes within brain parenchyma, (i.e., of greater intensity than choroid plexus) or changes compatible with cerebral edema (slit-like ventricles and hyperechoic periventricular region) [9]. When cranial sonography was abnormal the infant underwent either computed tomography (CT) or magnetic resonance imaging. Electroencephalography (EEG) was performed in all infants with clinical seizures [7]. We previously evaluated 50 healthy term infants admitted to the regular newborn nursery utilizing cranial sonography to define the occurrence of abnormalities in this population. Abnormalities were observed in 2 infants (4%); both had germinal matrix hemorrhage. The chart of each patient was reviewed to obtain an obstetric history, labor complications, mode of delivery, and delivery room resuscitation. In general, our management of a depres~d infant is influenced by the initial heart rate. When the heart rate is > 100 beats/min, the management is supplementation oxygen administration and stimulation (i.e., drying of the infant). When the heart rate ranges 60-100 beats/rain the initial management is bag and mask ventilation for approximately 60 s. Should the heart rate remain unchanged despite this intervention, the infant would be intubated and positive-pressure ventilation applied. With a heart rate < 60 beats/min the initial treatment is bag and mask ventilation, intubation, CPR, and epinephrine, depending upon the heart rate response to each intervention; therefore, CPR + epinephrine is administered for persistent bradycardia (i.e., heart rate < 60 beats/min). Other observations recorded included the Apgar scores at 1, 5, and 10 min (as noted by the pediatrician in the delivery room), respiratory complications (i.e., radiologic evidence of meconium aspiration syndrome and persistent pulmonary hypertension of the newborn) [10], evidence of renal failure (defined as a urine output < I cc/kg/hr _> 24 hours coupled with a rising BUN and creatinine) and hypoglycemia (serum glucose: < 40 mg/dl). Statistical Methods. Fisher's Exact Test was used to assess the significance of the relationship between delivery room resuscitation and seizures (negative outcome). The odds ratio was used to characterize the relative risk of negative outcome with resuscitation over no resuscitation. Other putative markers of negative outcome were assessed using the Fisher's Exact Test for categorical markers or the exact linear trend test when marker values were placed in (> 2) ordered categories. Markers considered were 1 min Apgar score (< 3 compared to _> 3), 5 min Apgar (< 3 compared to _>3), 10 min Apgar (< 5 compared to -> 5), gestational age (< 37 weeks compared to _> 37 weeks), birth weight (< 2,500 gm, 2,501-3,200 gm, or > 3,200 gm), umbilical cord pH (< 6.9 compared to 6.9-7.0) and base deficit (<_ -14 vs > -14). Markers that relate significantly to outcome were used to stratify the patients and refine the resuscitative risk estimates for negative outcome. For example, resuscitation risk was evaluated separately for strata based on the 1 min Apgar score. Data analysis was performed using SAS [11] and StatXact [12] software. Test results were considered significant when P < .05.
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Results The patient population comprised 39 term infants (82%) with birth weights of 3,182 _+ 492 gin and gestational ages of 39 _+ 1 wk and 8 preterm infants (18%) with birth weights of 1,753 _+ 469 gin, and gestational ages of 32 +_ 2.5 wks. The mean pH, Pact2, and base deficit for the 47 infants was 6.86 + 0.11, 97 _+ 22 mm Hg, and -17 + 4, respectively. The acidosis was respiratory in 3 infants and mixed in 44. Labor and delivery was complicated in 95% of patients. In almost 80% of patients the complication appeared to be of short duration secondary to clinical events, such as placental abruption in 8, ruptured uterus in 4, cord prolapse in 3, and maternal seizures (Table 1). Fetal heart rate abnormalities (i.e., decelerations) occurred in 12 infants, 6 of whom had associated meconium-stained amniotic fluid. Delivery was uncomplicated in 2 patients (4%). The most common route of delivery was via emergency cesarean section (n = 29; 62%). The remaining infants were delivered via vaginal (n = 12; 26%), assisted Ibrceps (n = 3; 6%), or elective cesarean section (n = 3: 6%). The Apgar score was _< 3 in 31 infants (67%) at 1 min, in 10 infants (21%) at 5 rain, and in 1 infant (2%) at 10 min. The Apgar score was _>7 in 7 infants (15%) at I rain, in 15 infants (32%) at 5 min, and in 30 infants (64%) at 10 min. The number of infants with an intermediate Apgar score (i.e., 4-6 at 1, 5, and 10 min) was 9 (19%), 22 (46%), and 16 (34%), respectively. To summarize, the Apgar score increased in all but 1 infant (2%). The delivery room intervention occurred as follows: 20 infants (43%) with initial heart rates between 60-101) beats/min responded favorably to oxygen and/or bag and mask ventilation and were never intubated; and 15 infants (47%) were intubated and ventilated. Seven intubated infants received CPR and epinephrine because of persistent severe bradycardia (heart < 60 beats/rain) unresponsive to bag and mask ventilation or intubation; 5 infants (11%) required no intervention in the delivery room. Table 1. Complications of labor in 47 infants delivered with severe fetal acidemia
Complications During Labor
Number of Patients
Abruptio placentae
8 ~17~
Ruptured uterus
4 ( 9%i
Cord prolapse
3 (6%)
Nuchal cord
4 ( 9%~
Other (e.g., maternal seizures, pregnancy-induced hypertension)
14 (30°A)
Fetal heart rate abnormality
12 (26%)
No complications
2 I 4%)
Table 2.
Outcome in infants with neonatal seizures
Patient Number
Gestational Age
CPR
Sarnat Staging
1
40
+
3
Death
+
Cerebral edema
2
40
+
3
Death
+
Cerebral edema*
3
39
+
3
Death
+
Cerebral edema
4
32
+
3
Death
+
Periventricular leukomalacia
5
32
+
3
Death
NP
Intraparenchymal hemorrhage*
6
39
+
3
Abnormalt
+
Periventricular hyperechoic lesion
7
40
-
2
Abnormal1
+
Cerebral edema
8
41
-
2
Normal
Normal
Normal
Outcome
Neuroimaging
EEG
* Autopsy performed. t Spasticity (see text for details). Abbreviations: + = CPR administered = CPR not administered NP = Not performed
Postnatal Findings
Seizures. Eight infants (17%; 6 term, 2 preterm) had clinical evidence of neonatal seizures. The seizures were categorized as subtle (e.g., horizontal eye deviation, bicycling, lip smacking), clonic, or tonic in nature. The seizures evolved in the first day at a postnatal age of 14 + 8 hrs (range: 2-20 hrs). Antiepileptic drugs (i.e., phenobarbital as the initial agent, phenytoin and, if necessary, lorazepam) were administered to all infants for persistent seizures. Seizure control was achieved in 7 of 8 infants. EEG was confirmatory in 6 of 7 infants evaluated. One infant died prior to the performance of EEG. The degree of postanoxic encephalopathy was moderate to profound in all 8 infants (i.e., 6 infants in stage III and 2 in stage II encephalopathy; Table 2). Cranial sonograms were abnormal in 7 of 8 patients. Four infants (all term) had evidence of cerebral edema (i.e., slit-like ventricles, hyperechoic periventricular region). The sonograms were abnormal in 2 preterm infants: 1 with intraparenchymal hemorrhage confirmed at autopsy and the other with the evolution of cystic periventricular leukomalacia (PVL). A unilateral pinpoint hyperechoic lesion within basal ganglia which resolved prior to discharge was noted in 1 infant. The sonogram was normal in 1 infant. The outcome was unfavorable in 7 of 8 infants with seizures. Five infants (3 term, 2 preterm) died, all of severe brain injury. Four died within the first 4 days of life and 1 infant with cystic PVL died at 158 days of life secondary to aspiration pneumonia. Autopsy was performed in 2 infants. In 1 infant, there was evidence of diffuse, acute changes of hypoxia and ischemia with
pyknotic nuclei and eosinophilic cytoplasm involving neurons within the cerebrum, pons, and cerebellum. The second infant had evidence of intraventricular hemorrhage and a large left frontoparietal intraparenchymal hemorrhage. The neurologic examination was abnormal in 2 of 3 survivors at discharge at 14 and 21 days, respectively. Both infants exhibited generalized hypertonicity and hyperreflexia of the extremities. Six of 7 infants with abnormal outcomes had required CPR in the delivery room. One infant was normal at discharge.
Neurologic Features in Infants without Seizures Thirty-two of 39 infants without seizures exhibited transient neurologic abnormalities, characterized as follows: irritability, exaggerated primitive reflexes (e.g., moro), proximal hypotonia (upper > lower extremities), hyperreflexia with or without clonus, and jitteriness. The duration of disturbances in the neurologic examination ranged 4-96 hours. One of these 32 infants received CPR plus epinephrine for persistent bradycardia in the delivery room. The neurologic examination remained abnormal in 2 of 39 infants at discharge (at 7 and 10 days, respectively); both infants were hypertonic. Five of 39 infants had a normal examination throughout the hospital course.
Neuroimaging Abnormalities Ten of 47 infants (24%) had neurosonographic abnormalities. This prevalence of sonographic abnormality is significantly greater than the 4% in our healthy popula-
Perlman and Risser: SevereFetal Acidemia 279
Table 3. Statistical significance of delivery room resuscitation and putative markers of perinatal distress and negative outcome
Negative Outcome ( % )
Marker Resuscitation No resuscitation
85.7 (6 of 7) 2.5 (I of 40)
1 min Apgar score < 3 >- 3
35.0 (7 of 20) 0 (0 of 27)
5 min Apgar score <3 _>3
60.0 (3 of 5) 9.5 (4 of 42)
10 min Apgar score <5 _>5
40.0 (6 of 15) 3.1 (1 of 32)
Birth weight _<2,500 gm 2,501-3,200 gm _>3,201 gm
13.3 (2 of 15) 11.8 (2 of 17) 20.0 (3 of 15)
Gestational age < 37 weeks _>37 weeks
16.7 (2 of 12) 14.3 (5 of 35)
Cord pH _<6.9 6.91-7.0
20.8 (5 of 24) 8.7 (2 of 23)
Base Deficit _<-14 > -14~
18.2 (4 of 22) 8.7 (2 of 23)
P Value*
Odds Ratio
< .0(X)I
234,0
95% Confidence Limits on Odds Ratio Lower Upper 12.8
4.261.3
.0012
30.6 ~
3.61
257.() t
.0187
14.2
1.8
112.4
.0025
20.7
2.2
194.8
1.2§ 0.6 t
0.1 0.1
9.4 4.3
1.0
1.2
0.2
7.2
0.416
2.8
0.5
16.0
0.414
2.3
0.4
14.3
0.8024;
*Fisher's exact test, unless otherwise noted, + 0.5 added to each cell due to zero cell. ~;Exact linear-by-linear trend test. § Risk estimated for lowest birth weight category compared to other specific categories. Base deficit for 1 infant with adverse outcome was not available.
tion (P < .001). The abnormalities included 4 with signs of cerebral edema (1 survivor with cerebral edema had a CT performed at 21 days which demonstrated multicystic encephalomalacia), 3 with intraparenchymal hemorrhage, and 2 with pinpoint unilateral echogenicity within the basal ganglia (CT in 1 revealed bilateral occipital hypodensity and in the other CT was normal). One infant developed cystic PVL.
Systemic Findings Pulmonary. Twenty-seven infants were already intubated upon admission to the intensive care unit. One infant required ECMO because of failed medical treamaent of persistent pulmonary hypertension; one infant was managed with hyperventilation and muscle paralysis as part of management of pulmonary hypertension and was intubated for 7 days; 1 infant was intubated for 34 days because of chronic lung disease; 7 infants were intubated for 72 hours, 2 infants for 48 hours, and 15 infants for 12-36 hours.
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Other Ten of 47 infants (20%) developed hypoglyce~a. Six of 7 infants who received CPR had evidence of renal failure compared to 13 of 42 infants who did not require CPR (P < .05).
Statistical Analysis Negative outcome (i.e., seizures) was related to delivery room resuscitation (P < .001) with 6 of the 7 resuscitated infants (85%) exhibiting seizures compared to 1 of 40 infants (2.5%) with no resuscitation. The odds ratio estimate is 234 (95% confidence limits extend from 12.85 to 4,261), indicating that negative outcome is 234 times more likely to occur with persistent bradycardia requiring resuscitation than without (Table 3). Among the other putative measures assessed, seizures were also related to the following: (1) A low 1 min Apgar score (P = .0012); 7 of 20 infants (35%) with a 1 min Apgar score < 3 exhibited
seizures compared to 0 of 27 infants with a 1 min Apgar score > 3; (2) A low 5 min Apgar score (P = .019); 3 of 5 infants (60%) with a 5 min Apgar score < 3 exhibited seizures compared to 4 of 42 infants (9.5%) with a 5 min Apgar score _>3; (3) A low 10 min Apgar score (P = .0026); 6 of 15 infants (40%) with a 10 min Apgar score < 5 compared to l of 32 infants (3.1%) with a 1 min Apgar score _>5. Using Apgar score categories to stratify subjects we found that seizures generally related to persistent bradycardia even in the lower Apgar score strata, where most seizures occurred; therefore, using 1 min Apgar scores to stratify patients, persistent bradycardia remained a significant risk factor for seizures (P = .0012) in 20 patients with low 1 min Apgar scores, where persistent bradycardia was associated with a negative outcome in 6 of 7 infants (85%) compared to 1 of 13 infants (7.7%) without persistent bradycardia. Similarly, persistent bradycardia was a significant risk factor for seizures (P = .0014) in 15 patients with low 10 rain Apgar scores, where persistent bradycardia was associated with a negative outcome in 6 of 7 infants (85%) compared to no seizures (i.e., infants without persistent bradycardia). Using 5 rain Apgar scores to stratify patients, persistent bradycardia is a marginally significant risk factor for seizures (P = 0.10) in 5 patients with low 5 min Apgar scores (< 3), where persistent bradycardia was associated with seizures in 3 infants compared to no seizures among the 2 infants without persistent bradycardia. In patients with 5 min Apgar scores greater than 2, persistent bradycardia was associated with a negative outcome in 3 of 4 infants compared to 1 of 38 infants (2.6%) who did not receive resuscitation (P = .0014). A common odds ratio estimate for seizures based on the resuscitation risk controlled for the 5 min Apgar score category is 161.4 (with 95% confidence limits of 18.8 and 1,386.5); the BreslowDay test for homogeneity of the odds ratio of the 2 5-min Apgar score categories is not significant (P = 0.505), suggesting that a common odds ratio estimate is suitable.
Discussion Perinatal asphyxia has long been implicated as a major cause of neurologic morbidity [13]. Markers of asphyxia have included factors such as the Apgar score and umbilical cord pH; however, such putative indicators of asphyxia have been demonstrated to be unreliable predictors of long-term neurologic outcome [14-17]. Even when the acidosis in the umbilical cord is profound, the relationship to subsequent neurologic dysfunction is poor [2]. This discordant relationship may be explained, in part, by the fact that measures, such as severe acidemia, are poor indicators of the fetal adaptive response to asphyxia. This fetal adaptive mechanism includes a redistribution of cardiac output with increased flow to brain, heart, and adrenal gland with concomitant reduction in intestinal, renal,
and skeletal blood flow [4,5]. The ability to maintain this adaptive response will depend, in part, on both the severity and/or duration of the stressful event; therefore, during initial arterial hypoxia the fetal cerebrovascular resistance can decrease by more than 50% to maintain CBF with a minimal decrease in oxygen delivery [18,19], provided that the mean arterial pressure is elevated or normal. With systemic hypotension, cerebrovascular resistance cannot decrease further resulting in a marked reduction in CBF [20,21]. Recent experimental data indicate that severity of neuronal injury in the asphyxiated animal model accompanied by hypotension was worse when the arterial pH was < 7.0 [22]. The reduction in perfusion pressure with asphyxia is in large part related to reduction in cardiac output secondary to direct myocardial effects [4]. We reasoned that in infants delivered with severe acidemia, acute adverse neurologic manifestations (i.e., seizures) would be more likely to occur in those infants with persistent bradycardia who received CPR in the delivery room when compared to infants without this intervention. The data in this report support this hypothesis; therefore, a 234-fold increased risk of seizures occurred in infants with persistent bradycardia who had CPR in the delivery room. Expressed differently, nearly 90% of such infants had unfavorable short-term outcomes. In contrast, < 5% of infants without CPR exhibited an abnormal short-term outcome. Although other indicators of perinatal asphyxia (e.g., extended Apgar score) were related to seizures, the predictive values were low. Additionally, CPR administration related significantly to seizures even among the subset of infants identified at risk by the Apgar score. Clearly, these latter indicators, while markers of stress, provide little insight into cerebral perfusion and oxygen delivery. There is limited, retrospective information about the acute neurologic findings in infants delivered with severe acidemia [1,3]. Seizures that are the most distinctive indicators of neuronal injury in the newborn period occurred in approximately 16% of infants. The outcome of infants with seizures was invariably poor. Thus, almost all either died or were distinctly abnormal at short-term follow-up. In contrast, the outcome of infants without seizures was mostly favorable. Although most exhibited transient neurologic signs (e.g., proximal hypotonia, hyperreflexia) the neurologic examination was nearly normal or normal at discharge in approximately 90% of infants. Neurologic examination at discharge is regarded as one of the most important predictors of subsequent longterm outcome [6,23]. Moreover, the neurologic examination was entirely normal throughout the hospital stay in approximately 10% of all infants. The predominant neurosonographic findings in term infants were suggestive of cerebral edema as previously described [9]. Additional abnormalities were consistent with ischemia and/or reperfusion injury (i.e., PVL and/or hemorrhage within brain substance). None of the infants demonstrated sonographic evidence of chronic ischemia.
Perlman and Risser: SevereFetal Acidemia 281
Newer
t h e r a p i e s i n t e n d e d to p r e v e n t m o r t a l i t y a n d
l o n g - t e r m n e u r o l o g i c d e f i c i t s f r o m b i r t h a s p h y x i a are b e i n g e v a l u a t e d in e x p e r i m e n t a l m o d e l s [24-25]. T h e s e e x c i t i n g t h e r a p i e s h a v e p o t e n t i a l side effects t h a t will req u i r e the ability to i d e n t i f y i n f a n t s w h o s e clinical m a n i f e s t a t i o n s are due to a s p h y x i a a n d thus serious e n o u g h to w a r r a n t s o m e risk in t h e i r t r e a t m e n t . D a t a in this r e p o r t clearly i d e n t i f y a s u b g r o u p f r o m o n e h i g h - r i s k c a t e g o r y of infants, those with persistent bradycardia administered C P R w h o are at g r e a t e s t risk f o r n e u r o l o g i c i n j u r y a n d w h o m a y b e n e f i t f r o m early t h e r a p e u t i c i n t e r v e n t i o n s .
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[111 SAS/STAT User',, Guide. Version 6, 4lh ed.. vt~l i C':ux ,+'.;AS Institute, 1989;I 13-22. [121 Mehta C, Patel N. StatXact-J'urbo User t'VIHnHLtK(iambridgc: CYTEL Software, 1992. [131 Little WJ. On the influence of abnormal parturition, dillicalt labor, premature births and asphyxia neonatorium on the mental and physical condition of the child especially in relation to deformities. Trans Obstet Soc Lond 1861-62;3:293-344. [14] Ruth VJ, Raivio KO. Perinatal brain damage: Predicti,~c value of metabolic acidosis and the Apgar score. BMJ 1988;297:24-7. [15] Grant A, O'Brien N, Joy MT, Hennessy E+ MacDonald I). Cerebral palsy among children born during the Dublin randomized trial of intrapartum monitoring. Lancet 1989;1 : 1233-5. [16] Painter MJ, Scott M, Hirsch RR O'Donoghue R Depp R. Fetal heart rate patterns during labor: Neumlogic and cognitive development at six to nine years of age. Am J Obstet Gynecol 1988;159:854-8. [17] Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. N Engl J Med 1986;315:81-6. [18] Jones MD, Sheldon RE, Peeters LL, Makowski El+. Regulation of cerebral blood flow in the ovine fetus. Am J Physiol 1978:235: H 162-6. [191 Ashwai S, Dale PS, Longo LD. Regional cerebral blood flow studies in the fetal lamb during hypoxia, hypercapnia, acidosis and hypotension. Pediatr Res 1984; 18:1309-16. [20] Johnson GW, Palahniwk RJ, Tweed WA, Jones MV. Regional cerebral blood flow changes during severe fetal asphyxia produced by slow partial umbilical cord compression. Am J Obstet Gynecol 1979; 135:48-52. [211 Lou HC, Lassen NA, Tweed WA, Johnson G+ Jones M, Palahuick R. Pressure passive cerebral blood flow and breakdown of the blood-brain barrier in experimental fetal asphyxia. Acta Pediatr Scand 1979;68:57-63. [22] Gunn AJ, Parer JT, Mallard EC, Williams CE, Gluckman PD. Cerebral histologic and electro-corticographic changes after asphyxia in fetal sheep. Pediatr Res 1992;31:486-91. [23] Nelson KB, Ellenberg JH. The asymptomatic newborn and risk of cerebral palsy. Am J Dis Child 1987;141:1333-5. [24] Varmucci RC. Current and potentially new management strate+ gies for perinatal hypoxic ischemic encephalopathy. Pediatrics 1990;85: 961-8. [25] Espinoza MI, Parer JT. Mechanisms of asphyxial brain damage and possible pharmalogical interventions in the fetus. Am J Obstet Gynecol 1991; 164:1582-91.
M. Perlman,
MB*
The objectives of this study were to determine if infants delivered with severe acidemia (cord umbilical arterial p H < 7.0) h a d s h o r t - t e r m neurologic effects and w h e t h e r infants with persistent b r a d y c a r d i a who received c a r d i o p u l m o n a r y resuscitation (CPR) in the delivery r o o m would be at greatest risk for subsequently developing neonatal seizures. Forty-seven infants (39 term, 8 p r e t e r m ) delivered with severe fetal a c i d e m i a were studied. T h e m e a n (+ S.D.) f o r pH, P a c o 2 , a n d base deficit for the 47 infants was 6.86 _+ 0.11, 97 _+22 m m Hg, a n d -17 + 4, respectively. L a b o r complications were c o m m o n and included placental a b r u p t i o n in 8, r u p t u r e d uterus in 4, cord prolapse in 3, fetal h e a r t rate decelerations in 12, a n d other (n = 14). M o s t infants were delivered via e m e r g e n c y cesarean section (n = 29). Delivery r o o m interventions included oxygen and b a g / m a s k ventilation only (n = 20) a n d intubation a n d ventilation (n = 22); 7 of 22 infants received C P R and epinephrine for persistent b r a d y c a r d i a (heart rate < 80 beats/min despite ventilatory support). Five infants required no intervention. Eight infants (17%) had seizures; 6 of these infants received C P R in the delivery room. S h o r t - t e r m outcomes were a b n o r m a l in 7 of 8 infants (i.e., death in 5, a b n o r m a l neurologic examination at discharge in 2). I n 39 infants without seizures, 32 had transient neurologic abnormalities (i.e., irritability, hyperreflexia, proximal hypotonia) which resolved by discharge, a n d 2 h a d a b n o r m a l and 5 n o r m a l examinations. By univariate analysis, adverse outcome was related to 1 min (P < .001) a n d 5 min A p g a r scores (P = .019) a n d C P R in the delivery r o o m (P < .0001). The odds ratio estimate for C P R is 234. These d a t a indicate that C P R a n d epinephrine intervention in the delivery r o o m for persistent b r a d y c a r d i a identifies infants at greatest risk for s h o r t - t e r m adverse o u t c o m e a n d that therapeutic strategies to preserve b r a i n function in severe fetal acidemia should focus on such infants. Perlman JM, Risser R. Severe fetal acidemia: Neonatal neurologic features and short-term outcome. Pediatr Neurol 1993;9:277-82.
From the *Department of Pediatrics and *AcademicComputing Services; University of Texas Southwestern Medical Center; Dallas, Texas.
and Rick Risser, MSt
Introduction Approximately 0.3% of deliveries at our institution are complicated by severe fetal acidemia (i.e., cord umbilical arterial pH < 7.0) [ 1]. Despite enormous potential for neurologic injury, there is limited information regarding neurologic sequelae in such infants [1-3]. Although it may be a marker of asphyxia, low cord umbilical arterial pH provides limited information about the duration of the insult and/or the fetal adaptive mechanisms in response (i.e., redistribution of cardiac output to maintain cerebral perfusion) [4,5]. In the experimental model of asphyxia, cerebral blood flow (CBF) and oxygen delivery is maintained, provided the mean systemic blood pressure is within the normal range, however, when the asphyxial event is associated with a reduction in mean systemic blood pressure, a marked decrease in CBF and oxygen delivery occurs [6]. We postulated that infants delivered with severe acidemia would be at greatest risk for subsequent neuronal injury if associated circulatory collapse with compromise in cerebral peffusion were to occur. We reasoned that the need for cardiopulmonary resuscitation (CPR) in the delivery room for persistent bradycardia would identify such high-risk infants. We conducted this prospective study with the following objectives: (1) To determine the neonatal neurologic manifestations of infants delivered with severe fetal acidemia; and, (2) To determine whether infants with persistent bradycardia who received CPR would be those at greatest risk for neonatal seizures. Methods Forty-seven infants admitted to the Intensive Care Nursery at Parkland Memorial Hospital from December, 1990 to November, 1991 with an umbilical cord arterial pH < 7.0 were evaluated. Umbilical cord arterial blood samples are routinely obtained for blood gas analysis from all live births occurring at this institution [1]. Blood is immediately drawn from a doubly clamped segment of cord into 3 ml plastic syringes flushed with heparin (100 u/ml); the specimens are placed in ice prior to transport to the laboratory for analysis. Each identified infant underwent a detailed neurologic examination [7]. Samat staging was utilized to characterize postanoxic enceph-
Communications should be addressed to: Dr. Pedman; Department of Pediatrics; University of Texas Southwestern Medical Center; 5323 Harry Hines Boulevard; Dallas, TX 75235-9063. Received March 15, 1993; accepted June 9, 1993.
Perlman and Risser: Severe Fetal Acidemia 277
alopathy in term infants [81. Briefly, we describe the 3 stages to this classification: Stage 1 is characterized by hyperalertness and exaggerated Mort and stretch reflexes usually lasting < 24 hours; Stage II is marked by obtundation, hypotonia, and seizures: and, Stage IIl is characterized by stupor, flaccidity, and suppression of brainstem and autonomic function. Sarnat staging in the premature infants was modified as lbllows: Stage I is characterized by irritability and exaggerated stretch reflexes; Stage II is marked by hypotonia and seizures; and, Stage Ill is recognized by stupor and flaccidity with suppression of brainstem function. The examinations were performed by one of the authors (JMP) in the first 3 postnatal days, at 7 days, and prior to discharge. An abnormal short-term neurologic outcome was considered when there were neonatal seizures [7] or abnormal examination at discharge (i.e., spasticity, hypotonia, feeding difficulties). Cranial sonography was performed on each infant on the first or second postnatal day or more frequently if abnormal. Abnormalities included periventricular-intraventricular hemorrhage, evolution of cystic changes within periventricular white matter, increased echoes within brain parenchyma, (i.e., of greater intensity than choroid plexus) or changes compatible with cerebral edema (slit-like ventricles and hyperechoic periventricular region) [9]. When cranial sonography was abnormal the infant underwent either computed tomography (CT) or magnetic resonance imaging. Electroencephalography (EEG) was performed in all infants with clinical seizures [7]. We previously evaluated 50 healthy term infants admitted to the regular newborn nursery utilizing cranial sonography to define the occurrence of abnormalities in this population. Abnormalities were observed in 2 infants (4%); both had germinal matrix hemorrhage. The chart of each patient was reviewed to obtain an obstetric history, labor complications, mode of delivery, and delivery room resuscitation. In general, our management of a depres~d infant is influenced by the initial heart rate. When the heart rate is > 100 beats/min, the management is supplementation oxygen administration and stimulation (i.e., drying of the infant). When the heart rate ranges 60-100 beats/rain the initial management is bag and mask ventilation for approximately 60 s. Should the heart rate remain unchanged despite this intervention, the infant would be intubated and positive-pressure ventilation applied. With a heart rate < 60 beats/min the initial treatment is bag and mask ventilation, intubation, CPR, and epinephrine, depending upon the heart rate response to each intervention; therefore, CPR + epinephrine is administered for persistent bradycardia (i.e., heart rate < 60 beats/min). Other observations recorded included the Apgar scores at 1, 5, and 10 min (as noted by the pediatrician in the delivery room), respiratory complications (i.e., radiologic evidence of meconium aspiration syndrome and persistent pulmonary hypertension of the newborn) [10], evidence of renal failure (defined as a urine output < I cc/kg/hr _> 24 hours coupled with a rising BUN and creatinine) and hypoglycemia (serum glucose: < 40 mg/dl). Statistical Methods. Fisher's Exact Test was used to assess the significance of the relationship between delivery room resuscitation and seizures (negative outcome). The odds ratio was used to characterize the relative risk of negative outcome with resuscitation over no resuscitation. Other putative markers of negative outcome were assessed using the Fisher's Exact Test for categorical markers or the exact linear trend test when marker values were placed in (> 2) ordered categories. Markers considered were 1 min Apgar score (< 3 compared to _> 3), 5 min Apgar (< 3 compared to _>3), 10 min Apgar (< 5 compared to -> 5), gestational age (< 37 weeks compared to _> 37 weeks), birth weight (< 2,500 gm, 2,501-3,200 gm, or > 3,200 gm), umbilical cord pH (< 6.9 compared to 6.9-7.0) and base deficit (<_ -14 vs > -14). Markers that relate significantly to outcome were used to stratify the patients and refine the resuscitative risk estimates for negative outcome. For example, resuscitation risk was evaluated separately for strata based on the 1 min Apgar score. Data analysis was performed using SAS [11] and StatXact [12] software. Test results were considered significant when P < .05.
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Results The patient population comprised 39 term infants (82%) with birth weights of 3,182 _+ 492 gin and gestational ages of 39 _+ 1 wk and 8 preterm infants (18%) with birth weights of 1,753 _+ 469 gin, and gestational ages of 32 +_ 2.5 wks. The mean pH, Pact2, and base deficit for the 47 infants was 6.86 + 0.11, 97 _+ 22 mm Hg, and -17 + 4, respectively. The acidosis was respiratory in 3 infants and mixed in 44. Labor and delivery was complicated in 95% of patients. In almost 80% of patients the complication appeared to be of short duration secondary to clinical events, such as placental abruption in 8, ruptured uterus in 4, cord prolapse in 3, and maternal seizures (Table 1). Fetal heart rate abnormalities (i.e., decelerations) occurred in 12 infants, 6 of whom had associated meconium-stained amniotic fluid. Delivery was uncomplicated in 2 patients (4%). The most common route of delivery was via emergency cesarean section (n = 29; 62%). The remaining infants were delivered via vaginal (n = 12; 26%), assisted Ibrceps (n = 3; 6%), or elective cesarean section (n = 3: 6%). The Apgar score was _< 3 in 31 infants (67%) at 1 min, in 10 infants (21%) at 5 rain, and in 1 infant (2%) at 10 min. The Apgar score was _>7 in 7 infants (15%) at I rain, in 15 infants (32%) at 5 min, and in 30 infants (64%) at 10 min. The number of infants with an intermediate Apgar score (i.e., 4-6 at 1, 5, and 10 min) was 9 (19%), 22 (46%), and 16 (34%), respectively. To summarize, the Apgar score increased in all but 1 infant (2%). The delivery room intervention occurred as follows: 20 infants (43%) with initial heart rates between 60-101) beats/min responded favorably to oxygen and/or bag and mask ventilation and were never intubated; and 15 infants (47%) were intubated and ventilated. Seven intubated infants received CPR and epinephrine because of persistent severe bradycardia (heart < 60 beats/rain) unresponsive to bag and mask ventilation or intubation; 5 infants (11%) required no intervention in the delivery room. Table 1. Complications of labor in 47 infants delivered with severe fetal acidemia
Complications During Labor
Number of Patients
Abruptio placentae
8 ~17~
Ruptured uterus
4 ( 9%i
Cord prolapse
3 (6%)
Nuchal cord
4 ( 9%~
Other (e.g., maternal seizures, pregnancy-induced hypertension)
14 (30°A)
Fetal heart rate abnormality
12 (26%)
No complications
2 I 4%)
Table 2.
Outcome in infants with neonatal seizures
Patient Number
Gestational Age
CPR
Sarnat Staging
1
40
+
3
Death
+
Cerebral edema
2
40
+
3
Death
+
Cerebral edema*
3
39
+
3
Death
+
Cerebral edema
4
32
+
3
Death
+
Periventricular leukomalacia
5
32
+
3
Death
NP
Intraparenchymal hemorrhage*
6
39
+
3
Abnormalt
+
Periventricular hyperechoic lesion
7
40
-
2
Abnormal1
+
Cerebral edema
8
41
-
2
Normal
Normal
Normal
Outcome
Neuroimaging
EEG
* Autopsy performed. t Spasticity (see text for details). Abbreviations: + = CPR administered = CPR not administered NP = Not performed
Postnatal Findings
Seizures. Eight infants (17%; 6 term, 2 preterm) had clinical evidence of neonatal seizures. The seizures were categorized as subtle (e.g., horizontal eye deviation, bicycling, lip smacking), clonic, or tonic in nature. The seizures evolved in the first day at a postnatal age of 14 + 8 hrs (range: 2-20 hrs). Antiepileptic drugs (i.e., phenobarbital as the initial agent, phenytoin and, if necessary, lorazepam) were administered to all infants for persistent seizures. Seizure control was achieved in 7 of 8 infants. EEG was confirmatory in 6 of 7 infants evaluated. One infant died prior to the performance of EEG. The degree of postanoxic encephalopathy was moderate to profound in all 8 infants (i.e., 6 infants in stage III and 2 in stage II encephalopathy; Table 2). Cranial sonograms were abnormal in 7 of 8 patients. Four infants (all term) had evidence of cerebral edema (i.e., slit-like ventricles, hyperechoic periventricular region). The sonograms were abnormal in 2 preterm infants: 1 with intraparenchymal hemorrhage confirmed at autopsy and the other with the evolution of cystic periventricular leukomalacia (PVL). A unilateral pinpoint hyperechoic lesion within basal ganglia which resolved prior to discharge was noted in 1 infant. The sonogram was normal in 1 infant. The outcome was unfavorable in 7 of 8 infants with seizures. Five infants (3 term, 2 preterm) died, all of severe brain injury. Four died within the first 4 days of life and 1 infant with cystic PVL died at 158 days of life secondary to aspiration pneumonia. Autopsy was performed in 2 infants. In 1 infant, there was evidence of diffuse, acute changes of hypoxia and ischemia with
pyknotic nuclei and eosinophilic cytoplasm involving neurons within the cerebrum, pons, and cerebellum. The second infant had evidence of intraventricular hemorrhage and a large left frontoparietal intraparenchymal hemorrhage. The neurologic examination was abnormal in 2 of 3 survivors at discharge at 14 and 21 days, respectively. Both infants exhibited generalized hypertonicity and hyperreflexia of the extremities. Six of 7 infants with abnormal outcomes had required CPR in the delivery room. One infant was normal at discharge.
Neurologic Features in Infants without Seizures Thirty-two of 39 infants without seizures exhibited transient neurologic abnormalities, characterized as follows: irritability, exaggerated primitive reflexes (e.g., moro), proximal hypotonia (upper > lower extremities), hyperreflexia with or without clonus, and jitteriness. The duration of disturbances in the neurologic examination ranged 4-96 hours. One of these 32 infants received CPR plus epinephrine for persistent bradycardia in the delivery room. The neurologic examination remained abnormal in 2 of 39 infants at discharge (at 7 and 10 days, respectively); both infants were hypertonic. Five of 39 infants had a normal examination throughout the hospital course.
Neuroimaging Abnormalities Ten of 47 infants (24%) had neurosonographic abnormalities. This prevalence of sonographic abnormality is significantly greater than the 4% in our healthy popula-
Perlman and Risser: SevereFetal Acidemia 279
Table 3. Statistical significance of delivery room resuscitation and putative markers of perinatal distress and negative outcome
Negative Outcome ( % )
Marker Resuscitation No resuscitation
85.7 (6 of 7) 2.5 (I of 40)
1 min Apgar score < 3 >- 3
35.0 (7 of 20) 0 (0 of 27)
5 min Apgar score <3 _>3
60.0 (3 of 5) 9.5 (4 of 42)
10 min Apgar score <5 _>5
40.0 (6 of 15) 3.1 (1 of 32)
Birth weight _<2,500 gm 2,501-3,200 gm _>3,201 gm
13.3 (2 of 15) 11.8 (2 of 17) 20.0 (3 of 15)
Gestational age < 37 weeks _>37 weeks
16.7 (2 of 12) 14.3 (5 of 35)
Cord pH _<6.9 6.91-7.0
20.8 (5 of 24) 8.7 (2 of 23)
Base Deficit _<-14 > -14~
18.2 (4 of 22) 8.7 (2 of 23)
P Value*
Odds Ratio
< .0(X)I
234,0
95% Confidence Limits on Odds Ratio Lower Upper 12.8
4.261.3
.0012
30.6 ~
3.61
257.() t
.0187
14.2
1.8
112.4
.0025
20.7
2.2
194.8
1.2§ 0.6 t
0.1 0.1
9.4 4.3
1.0
1.2
0.2
7.2
0.416
2.8
0.5
16.0
0.414
2.3
0.4
14.3
0.8024;
*Fisher's exact test, unless otherwise noted, + 0.5 added to each cell due to zero cell. ~;Exact linear-by-linear trend test. § Risk estimated for lowest birth weight category compared to other specific categories. Base deficit for 1 infant with adverse outcome was not available.
tion (P < .001). The abnormalities included 4 with signs of cerebral edema (1 survivor with cerebral edema had a CT performed at 21 days which demonstrated multicystic encephalomalacia), 3 with intraparenchymal hemorrhage, and 2 with pinpoint unilateral echogenicity within the basal ganglia (CT in 1 revealed bilateral occipital hypodensity and in the other CT was normal). One infant developed cystic PVL.
Systemic Findings Pulmonary. Twenty-seven infants were already intubated upon admission to the intensive care unit. One infant required ECMO because of failed medical treamaent of persistent pulmonary hypertension; one infant was managed with hyperventilation and muscle paralysis as part of management of pulmonary hypertension and was intubated for 7 days; 1 infant was intubated for 34 days because of chronic lung disease; 7 infants were intubated for 72 hours, 2 infants for 48 hours, and 15 infants for 12-36 hours.
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Other Ten of 47 infants (20%) developed hypoglyce~a. Six of 7 infants who received CPR had evidence of renal failure compared to 13 of 42 infants who did not require CPR (P < .05).
Statistical Analysis Negative outcome (i.e., seizures) was related to delivery room resuscitation (P < .001) with 6 of the 7 resuscitated infants (85%) exhibiting seizures compared to 1 of 40 infants (2.5%) with no resuscitation. The odds ratio estimate is 234 (95% confidence limits extend from 12.85 to 4,261), indicating that negative outcome is 234 times more likely to occur with persistent bradycardia requiring resuscitation than without (Table 3). Among the other putative measures assessed, seizures were also related to the following: (1) A low 1 min Apgar score (P = .0012); 7 of 20 infants (35%) with a 1 min Apgar score < 3 exhibited
seizures compared to 0 of 27 infants with a 1 min Apgar score > 3; (2) A low 5 min Apgar score (P = .019); 3 of 5 infants (60%) with a 5 min Apgar score < 3 exhibited seizures compared to 4 of 42 infants (9.5%) with a 5 min Apgar score _>3; (3) A low 10 min Apgar score (P = .0026); 6 of 15 infants (40%) with a 10 min Apgar score < 5 compared to l of 32 infants (3.1%) with a 1 min Apgar score _>5. Using Apgar score categories to stratify subjects we found that seizures generally related to persistent bradycardia even in the lower Apgar score strata, where most seizures occurred; therefore, using 1 min Apgar scores to stratify patients, persistent bradycardia remained a significant risk factor for seizures (P = .0012) in 20 patients with low 1 min Apgar scores, where persistent bradycardia was associated with a negative outcome in 6 of 7 infants (85%) compared to 1 of 13 infants (7.7%) without persistent bradycardia. Similarly, persistent bradycardia was a significant risk factor for seizures (P = .0014) in 15 patients with low 10 rain Apgar scores, where persistent bradycardia was associated with a negative outcome in 6 of 7 infants (85%) compared to no seizures (i.e., infants without persistent bradycardia). Using 5 rain Apgar scores to stratify patients, persistent bradycardia is a marginally significant risk factor for seizures (P = 0.10) in 5 patients with low 5 min Apgar scores (< 3), where persistent bradycardia was associated with seizures in 3 infants compared to no seizures among the 2 infants without persistent bradycardia. In patients with 5 min Apgar scores greater than 2, persistent bradycardia was associated with a negative outcome in 3 of 4 infants compared to 1 of 38 infants (2.6%) who did not receive resuscitation (P = .0014). A common odds ratio estimate for seizures based on the resuscitation risk controlled for the 5 min Apgar score category is 161.4 (with 95% confidence limits of 18.8 and 1,386.5); the BreslowDay test for homogeneity of the odds ratio of the 2 5-min Apgar score categories is not significant (P = 0.505), suggesting that a common odds ratio estimate is suitable.
Discussion Perinatal asphyxia has long been implicated as a major cause of neurologic morbidity [13]. Markers of asphyxia have included factors such as the Apgar score and umbilical cord pH; however, such putative indicators of asphyxia have been demonstrated to be unreliable predictors of long-term neurologic outcome [14-17]. Even when the acidosis in the umbilical cord is profound, the relationship to subsequent neurologic dysfunction is poor [2]. This discordant relationship may be explained, in part, by the fact that measures, such as severe acidemia, are poor indicators of the fetal adaptive response to asphyxia. This fetal adaptive mechanism includes a redistribution of cardiac output with increased flow to brain, heart, and adrenal gland with concomitant reduction in intestinal, renal,
and skeletal blood flow [4,5]. The ability to maintain this adaptive response will depend, in part, on both the severity and/or duration of the stressful event; therefore, during initial arterial hypoxia the fetal cerebrovascular resistance can decrease by more than 50% to maintain CBF with a minimal decrease in oxygen delivery [18,19], provided that the mean arterial pressure is elevated or normal. With systemic hypotension, cerebrovascular resistance cannot decrease further resulting in a marked reduction in CBF [20,21]. Recent experimental data indicate that severity of neuronal injury in the asphyxiated animal model accompanied by hypotension was worse when the arterial pH was < 7.0 [22]. The reduction in perfusion pressure with asphyxia is in large part related to reduction in cardiac output secondary to direct myocardial effects [4]. We reasoned that in infants delivered with severe acidemia, acute adverse neurologic manifestations (i.e., seizures) would be more likely to occur in those infants with persistent bradycardia who received CPR in the delivery room when compared to infants without this intervention. The data in this report support this hypothesis; therefore, a 234-fold increased risk of seizures occurred in infants with persistent bradycardia who had CPR in the delivery room. Expressed differently, nearly 90% of such infants had unfavorable short-term outcomes. In contrast, < 5% of infants without CPR exhibited an abnormal short-term outcome. Although other indicators of perinatal asphyxia (e.g., extended Apgar score) were related to seizures, the predictive values were low. Additionally, CPR administration related significantly to seizures even among the subset of infants identified at risk by the Apgar score. Clearly, these latter indicators, while markers of stress, provide little insight into cerebral perfusion and oxygen delivery. There is limited, retrospective information about the acute neurologic findings in infants delivered with severe acidemia [1,3]. Seizures that are the most distinctive indicators of neuronal injury in the newborn period occurred in approximately 16% of infants. The outcome of infants with seizures was invariably poor. Thus, almost all either died or were distinctly abnormal at short-term follow-up. In contrast, the outcome of infants without seizures was mostly favorable. Although most exhibited transient neurologic signs (e.g., proximal hypotonia, hyperreflexia) the neurologic examination was nearly normal or normal at discharge in approximately 90% of infants. Neurologic examination at discharge is regarded as one of the most important predictors of subsequent longterm outcome [6,23]. Moreover, the neurologic examination was entirely normal throughout the hospital stay in approximately 10% of all infants. The predominant neurosonographic findings in term infants were suggestive of cerebral edema as previously described [9]. Additional abnormalities were consistent with ischemia and/or reperfusion injury (i.e., PVL and/or hemorrhage within brain substance). None of the infants demonstrated sonographic evidence of chronic ischemia.
Perlman and Risser: SevereFetal Acidemia 281
Newer
t h e r a p i e s i n t e n d e d to p r e v e n t m o r t a l i t y a n d
l o n g - t e r m n e u r o l o g i c d e f i c i t s f r o m b i r t h a s p h y x i a are b e i n g e v a l u a t e d in e x p e r i m e n t a l m o d e l s [24-25]. T h e s e e x c i t i n g t h e r a p i e s h a v e p o t e n t i a l side effects t h a t will req u i r e the ability to i d e n t i f y i n f a n t s w h o s e clinical m a n i f e s t a t i o n s are due to a s p h y x i a a n d thus serious e n o u g h to w a r r a n t s o m e risk in t h e i r t r e a t m e n t . D a t a in this r e p o r t clearly i d e n t i f y a s u b g r o u p f r o m o n e h i g h - r i s k c a t e g o r y of infants, those with persistent bradycardia administered C P R w h o are at g r e a t e s t risk f o r n e u r o l o g i c i n j u r y a n d w h o m a y b e n e f i t f r o m early t h e r a p e u t i c i n t e r v e n t i o n s .
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