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ORIGINAL RESEARCH |
From the Division of Maternal– Fetal Medicine, Department of Gynecology–Obstetrics, and Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address reprint requests to: Cynthia J. Holcroft, MD, Johns Hopkins Hospital, Department of Gyn-Ob, Phipps 228, 600 North Wolfe Street, Baltimore, MD 21287-1228; E-mail: cholcroft{at}jhmi.edu.
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ABSTRACT |
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METHODS: This is a case–control study of all infants weighing 1500 g or less admitted to a single tertiary neonatal intensive care unit between April 1999 and December 2001. The case group were those neonates with neurologic morbidity including intraventricular hemorrhage, seizures, hydrocephalus, and periventricular leukomalacia. The control group were those without neurologic morbidity. Wilcoxon rank-sum, Fisher exact test, 
2, and univariate and stepwise multiple logistic regression were performed, with P < 0.05 considered significant.
RESULTS: Of 213 VLBW infants, 77 had neurologic morbidity: 61 had intraventricular hemorrhage, eight had seizures, 13 had hydrocephalus, and nine had periventricular leukomalacia. Several infants had more than one morbidity. Gestational age (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.94, 0.96; P < .005), birth weight (OR 0.62; 95% CI 0.49, 0.79; P < .005), and neonatal infection (OR 1.36; 95% CI 1.17, 1.58; P < .005) were highly associated with neurologic morbidity. There was no difference in mean umbilical arterial cord pH (7.25 ± 0.15, 7.28 ± 0.09, P = .45) or base excess (-3.8 ± 4.8 mEq/L, -2.3 ± 3.0, P = .10). Only three of 52 infants (5.8%) in the case group had an umbilical arterial pH of less than 7.
CONCLUSION: Prematurity and neonatal infection were the dominant factors associated with neurologic morbidity in VLBW infants. Intrapartum acidosis occurred in less than 6% of those with neurologic morbidity.
Although brain damage alleged to have risen during the perinatal period is a much publicized cause of medical litigation in modern obstetrics, a great deal of controversy surrounds the extent to which neonatal neurologic injury is related to the birth process.1 Modern obstetric technologies such as electronic fetal heart rate monitoring and, more recently, fetal pulse oximetry have been introduced based on the assumption that predecessors of fetal neurologic impairment could be identified and delivery accomplished before significant injury. Even with the increase in the cesarean delivery rate from 5% to almost 25% and the widespread introduction of electronic fetal heart rate monitoring, the incidence of cerebral palsy has remained unchanged over the past 40 years. It has been difficult to adequately study the impact of technologies such as intrapartum fetal monitoring on the incidence of neonatal neurologic injury because of the low incidence of injury. This study attempted to find intrapartum and neonatal factors that are linked with neurologic injury in the newborn. We chose to study very low birth weight (VLBW) infants because the incidence of cerebral palsy (20 per 1000 live births) is much higher than that seen in term infants (one per 1000 live births).2
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MATERIALS AND METHODS |
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2 analysis, and univariate and stepwise multiple logistic regression were performed, with P < .05 considered significant. Results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Analyses were performed using Excel 2002 (Microsoft Corp., Redmond, WA), Stata 7.0 (Stata Corp., College Station, TX), and SPSS for Windows 10.0 (SPSS Inc., Chicago, IL). |
RESULTS |
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Patient demographics are shown in Table 1
. There was no difference between the groups in terms of maternal age, gravidity, parity, or race. Umbilical artery cord gases were obtained in 137 of the infants: 52 of the cases (67.5%) and 85 of the controls (62.5%). Although it is our practice to obtain arterial cord gas for every delivery, obtaining an arterial sample from the cord of these VLBW infants can be very difficult, and if enough blood is not obtained the machine is unable to read the sample. There was no statistically significant difference in the mean umbilical cord pH between cases and controls. In the case group, three of 52 infants (5.8%) had an umbilical artery cord pH of less than 7; in the control group, one of 85 infants (1.2%) had an umbilical artery cord pH of less than 7 (P = .15). All three case infants with an umbilical arterial pH of less than 7 had a nonreassuring fetal heart tracing noted before delivery. Two of the three infants were delivered by cesarean because of the nonreassuring fetal heart tracing. The first of these was found to have an abruption at the time of delivery. The second case was complicated by chronic hypertension with superimposed preeclampsia; hemolysis, elevated liver enzymes, low platelets syndrome; and immunoglobulin A nephropathy with acute renal failure. The third infant with a nonreassuring fetal heart rate tracing would have been delivered by cesarean if maternal medical status had permitted. This patient had severe pulmonary hypertension and morbid obesity, and it was felt that she was not a candidate for general anesthesia. She delivered vaginally, with an umbilical arterial pH of 6.99 and a base excess of -2.0 mEq/L. Also, an abruption was noted after delivery. The one patient in the control group whose infant had an umbilical arterial pH of less than 7 had an emergent cesarean delivery at 31 weeks for twins with nonreassuring fetal heart rate tracing. One of the twins had an umbilical arterial pH of 6.9 and a base excess of -7.0 mEq/L but did not have any neurologic morbidity before discharge from the NICU.
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weeks gestational age; two of these infants had sepsis, and the third had respiratory distress syndrome with pulmonary hemorrhage and pnuemothorax. The control infant died of complications of herpes simplex virus II infection.
Results of univariate analysis of the risk factors for neurologic morbidity are shown in Table 2. Gestational age, birth weight, 5-minute Apgar score less than 7, and culture-proven neonatal infection were found to be statistically significant. Table 3 shows the results of multiple logistic regression analysis in cases and controls. Culture-proven neonatal infection, umbilical artery base excess, and lower gestational age were found to be statistically significant risk factors for neonatal neurologic morbidity. Multiple gestations were found to have a protective association for neurologic morbidity. In the multiple logistic regression model, neither umbilical artery cord pH nor 5-minute Apgar score less than 7 were significantly associated with neurologic morbidity.
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DISCUSSION |
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A landmark study by Hayakawa et al6 performed serial electroencephalogram recordings on 172 preterm infants (gestational age less than 33 weeks, weight less than 2000 g) to determine the timing of injury in infants with periventricular leukomalacia. Of 26 infants with cystic periventricular leukomalacia, five were determined to have been injured during the antepartum period, 14 just before or around birth, and six during the late postpartum period.6 This study shows that when periventricular leukomalacia is identified in a neonate it may not necessarily be related to intrapartum injury.
Our results agree with the bulk of evidence that seems to point to intrapartum hypoxia–ischemia as an uncommon cause of neonatal neurologic injury. Blair and Stanley7 obtained data on all children with spastic cerebral palsy born in Western Australia between 1975 and 1980 (183 cases) and found that in only 8% (15 of 183) was intrapartum asphyxia the possible cause of their brain damage. They concluded that the contribution of intrapartum events and obstetric mismanagement to overall cerebral palsy rates is probably less than was previously thought. In 1987 Luthy et al8 evaluated 246 low birth weight infants (600–1750 g) and found that grades 3 to 4 intraventricular hemorrhage were a strong risk factor for the later development of cerebral palsy, but that only 15% of their cases of cerebral palsy were associated with any acidosis or preacidosis at birth (pH less than 7.20). The American College of Obstetricians and Gynecologists (ACOG) states that to show a relationship between perinatal asphyxia and neurologic morbidity, there must be a profound umbilical artery metabolic or mixed acidemia with pH less than 7 as well as the persistence of an Apgar score of 3 or less for 5 or more minutes and multiorgan system dysfunction.9,10 Of the 52 infants with neonatal neurologic morbidity in our study in whom cord gas was obtained, only three cases (5.8%) had this degree of acidosis, and though all three cases had evidence of other organ dysfunction, none had an Apgar score of 3 or less at 5 minutes and so would not have satisfied the ACOG criteria for a link between perinatal asphyxia and neurologic deficit. Furthermore, after stepwise multiple regression was performed, there were no statistically significant differences between the cases and controls in terms of 5-minute Apgar scores less than 7 or mean umbilical artery cord pH. This evidence shows that intrapartum compromise, as measured by umbilical arterial acidosis or Apgar score, did not differ among VLBW infants with and without neurologic injury. Although the umbilical arterial pH did not significantly differ between case and control infants, the base excess did, and this agrees with the findings of others that the base excess is more useful than pH because base excess does not change significantly with respiratory acidosis and demonstrates a linear rather than logarithmic correlation to the degree of metabolic acidosis.11 Because base buffer must be consumed before the pH drops, the base excess may be an earlier indicator of the fetus developing metabolic acidosis.
Neonatal infection, but not antenatally diagnosed chorioamnionitis, was found to be a statistically significant risk factor associated with neurologic morbidity. That fetal or neonatal infection may be related to brain injury is supported by several previous studies. In a study of 123 preterm singleton newborns born at 35 weeks or less who underwent amniocentesis and were followed for 3 or more years,12 it was found that antenatal exposure to intraamniotic inflammation and evidence of a systemic fetal inflammatory response (funisitis) were strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years. Wu and Colford13 performed a meta-analysis of full-term infants and found an association between chorioamnionitis and cystic periventricular leukomalacia as well as between chorioamnionitis and cerebral palsy.
In conclusion, our study found that prematurity and culture-documented neonatal infection were statistically significant risk factors associated with neonatal neurologic morbidity in VLBW infants. Intrapartum hypoxia–asphyxia did not play a large role in the neurologic injury seen in these VLBW infants in that less than 6% had an umbilical arterial pH of less than 7. We did find that umbilical arterial base excess is an earlier indicator of metabolic acidosis than pH.
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Footnotes |
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Received May 28, 2002. Received in revised form December 20, 2002. Accepted January 8, 2003.
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REFERENCES |
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2. Goldenberg RL, Nelson KG. Cerebral palsy. In: Creasy RK, Resnik R, eds. Maternal-fetal medicine. 4th ed. Philadelphia: W.B. Saunders Co, 1999:1199.
3. Spinillo A, Capuzzo E, Stronati M, Omerto A, De Santolo A, Acciano S. Obstetric risk factors for periventricular leukomalacia among preterm infants. Br J Obstet Gynaecol 1998;105:865–71.[Medline]
4. Helwig JT, Parer JT, Kilpatrick SJ, Laros RK. Umbilical cord blood acid-base state: What is normal? Am J Obstet Gynecol 196;174:1807–14.
5. Goldaber KG, Gilstrap LC, Leveno KJ, Dax JS, McIntire DD. Pathologic fetal acidemia. Obstet Gynecol 1991;78: 1103–6.
6. Hayakawa F, Okumura A, Kato T, Kuno K, Watanabe K. Determination of timing of brain injury in preterm infants with periventricular leukomalacia with serial neonatal electroencephalography. Pediatrics 1999;104:1077–81.
7. Blair E, Stanley FJ. Intrapartum asphyxia: A rare cause of cerebral palsy. J Pediatr 1988;112:515–9.[Medline]
8. Luthy DA, Shy KK, Strickland D, Wilson J, Bennett FC, Brown ZA, et al. Status of infants at birth and risk for adverse neonatal events and long-term sequelae: A study in low birth weight infants. Am J Obstet Gynecol 1987; 157:676–9.[Medline]
9. American College of Obstetricians and Gynecologists. Fetal and neonatal neurologic injury. ACOG technical bulletin no. 163. Washington: American College of Obstetricians and Gynecologists, 1992.
10. Nelson KB. Perspective on the role of perinatal asphyxia in neurologic outcome: Its role in developmental deficits in children. CMAJ 1989;141(Suppl):3–10.
11. Ross MG, Gala R. Use of umbilical artery base excess: Algorithm for the timing of hypoxic injury. Am J Obstet Gynecol 2002;187:1–9.[Medline]
12. Yoon BH, Romero R, Park JS, Kim CJ, Kim S, Choi JH, et al. Fetal exposure to intra-amniotic inflammation and the develpment of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000;182:675–81.[Medline]
13. Wu Y, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy. JAMA 2000;284:1417–24.
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