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Perinatal magnesium administration and the prevention of periventricular leukomalacia (and cerebral palsey)

Perinatal magnesium administration and the prevention of periventricular leukomalacia (and cerebral palsey)



Ross Finesmith MD

Ross Finesmith MD



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    Perinatal magnesium administration and the prevention of periventricular leukomalacia (and cerebral palsey) Perinatal magnesium administration and the prevention of periventricular leukomalacia (and cerebral palsey) Document Transcript

    • AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 14, NUMBER 5 May 1997 EFFECT OF MAGNESIUM SULFATE ON THE DEVELOPMENT OF CYSTIC PERIVENTRICULAR LEUKOMALACIA IN PRETERM INFANTS Ross B. FineSmith, M.D., * Kevin Roche, M.D.,f Paul B. Yellin, M.D.,* Kevin K. Walsh, Ph.D.,§ Calvin Shen, M.D.,# Mark Zeglis, Atiya Kahn, M.D., * and Irving Fish, M.D. * ABSTRACT Downloaded by: NYU. Copyrighted material. To determine if magnesium sulfate has an effect on the development of cystic periventricular leukomalacia in preterm infants, this retrospective case control study was conducted. There were 23,382 infants born at three teaching hospitals in the metropolitan New York area from January 1992 to December 1994. Four hundred ninetytwo infants met our entrance criteria. Criteria included a birth weight <1 750 g, survival to at least 7 days of life and at least one cranial ultrasound after 7 days of life. Infants exposed to magnesium sulfate in utero were less likely to develop periventricular leukomalacia. Two of 18 (11%) infants with periventricular leukomalacia were exposed to magnesium sulfate in-utero compared to 14 of 36 controls (39%) (p = 0.035) (OR = 0.196, 95% Cl = 0.039-0.988). Pre-eclampsia as an independent factor was not associated with a reduced risk (p = 0.251) (OR = 0.294, 95% Cl = 0.033-2.65). Preterm infants exposed to antenatal magnesium sulfate were found to have a reduced risk of developing cystic periventricular leukomalacia. Keywords: Periventricular leukomalacia; preterm infants; neuroprotection; cerebral palsy; magnesium sulfate; preterm labor Each year, more than 50,000 babies with birth weights less than 1500 g are born in the United States.1 These very low-birth-weight infants are being successfully resuscitated and treated as the result of recent advances in obstetric and neonatal care. In fact, neonatal mortality has declined 36% since 1980, and the current survival rate of babies with birth weights less than 1500 g is over 85%.2 Despite such improvements in survival, neurological morbidity remains a major threat to their long-term outcome.3-7 One of the most common neurological sequela in the preterm infant is cerebral palsy (CP). Many different factors appear to contribute to the development of CP but strongly associated factors include preterm birth, hypoxia/ischemia and infection. Naulty et al8 compared recent epidemiological findings on prematurity, low birth weight, and cere- bral palsy to the findings of the National Collaborative Perinatal Project of 1959 to 1966.9 This confirmed that there are now more infants surviving with birth weights less than 1500 g and that these infants have a threefold increase in the incidence of CP when compared to the same weight group in the earlier study. This suggests that advances in cardiopulmonary care that allow these infants to survive have not been met with equal advances in our ability to protect the brain. Cystic periventricular leukomalacia (cPVL) is an ischemic lesion that is a structural antecedent to CP,10 most frequently the spastic diplegic form. cPVL is associated with preterm birth and is attributed in part to the preterm infants metabolically vulnerable white matter,11-13 immature vasculature of the periventricular white matter,14 passive pressure cerebral blood flow, and poor cerebral au- *Department of Neurology, ^Department of Pediatric Radiology, and ^Department of Pediatrics, New York University, New York; developmental Disabilities Center and #Department of Pediatrics, Morristown Memorial Hospital, Morristown, New Jersey Request reprints: Dr. FineSmith, Department of Neurology, NYU School of Medicine, 550 First Avenue, New York, NY 10016 Copyright © 1997 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved. 303
    • toregulation.15'16 PVL has been reported to occur in 5-17% of all infants born weighing <1500 g.17~19 Between 66-100% of infants that develop PVL will develop CP.16-19 Hence, the incidence of CP is 30-50 per 1000/live births <1500 g20-23 compared to 3 per 1000 in all births.24"26 The characteristic type of CP preterm infants develop is spastic diplegia.2127 The spastic diplegic form occurs in up to 80% of preterm infants that develop CP28 compared to 16% of all children with CP.29 Nelson and Grether30 recently reported that antenatal exposure to magnesium sulfate (MgSO4) is associated with a reduced risk of developing cerebral palsy in very low-birth-weight infants. It was interesting to note that of the three preterm infants that developed CP in thier MgSO4 exposed group, two had the hemiparetic type that is typically not related to the cPVL lesion and 1 (33%) had the spastic diplegic type. In comparison, 23 of the 39 (59%) infants found to have CP that were not exposed to MgSO4 had the spastic diplegic form. Because there were not cranial ultrasounds reported in Nelson and Grether's study it is not possible to explore the relationship between MgSO4, cPVL, and CP. However, these data are suggestive that MgSO4 may be more specifically protective against spastic diplegia and its antecedent cPVL. In utero, fetal exposure to MgSO4 occurs in the treatment of maternal preeclampsia and when the agent is used as a tocolytic to delay labor. In an effort to determine if antenatal exposure to MgSO4 is associated with any effect on the incidence or relative risk of developing cPVL in the population of preterm infants treated at our institutions, we performed the following retrospective casecontrol study. Periventricular echodensities were not included in this analysis because their significance are not well understood. METHODS The study period covered the years 1992 to 1994. During this period all infants born at three teaching institutions (NYU Medical Center, Morristown Memorial Hospital, and Bellevue Hospital) were reviewed for entrance criteria for the study. Criteria included birth weights less than 1750 g, survival for more than 7 days, at least one cranial ultrasound after 7 days of life and must have had all of the following information in the infant's chart or the labor and delivery room records: gestational age; history of maternal complications and reason for prematurity; length of rupture of membranes; whether antenatal steroids, MgSO4, or other tocolytic agents were administered; mode of delivery; evidence of pre-eclampsia; Apgar scores; and number of days intubated. Birth weights were recorded and categorized as between 500-700, 751-1000, 1001-1250, 1251-1500, or 1501-1750 g. All infants received care in one of the three tertiary level neonatal intensive care units (NICU). 304 Each center was equipped with a portable neonatal May 1997 cranial ultrasound machine with a 7.5-MHz transducer producing transfontanel coronal and sagittal scans. One institution reproduced ultrasound images on paper. Cranial ultrasounds from all infants were collected and re-read by a single pediatric radiologist experienced in newborn diagnostic imaging. Cranial ultrasounds were classified as normal, grade I through III intraventricular hemorrhage, intraparenchymal hemorrhage, and cPVL. The radiologist was blinded to all clinical parameters. Ultrasound quality was judged on a 4-point grading system. A quality grade 1 study was a technically good study and a grade 4 was a poor-quality study. Controls were selected from a pool of infants with a normal cranial ultrasound or grade I intraventricular hemorrhage. Infants in the control pool with birth weights outside the range found in the cPVL group were removed to make the control pool similar to the cPVL group. From this control pool, two controls were randomly selected for each cPVL case. Chi-square analyses were used to compare incidence of cPVL in infants that received MgSO4 in utero with the control group. Odds ratios (OR) were calculated to estimate the relative risk of developing cPVL in the two groups. An OR <1 represents a reduction of a disease outcome related to the intervention. We used a 95% confidence interval (CI) as a measure of statistical precision for each OR. To determine if the cPVL and control groups had a similar demographic make-up, two separate analyses were carried out. First, a multivariate test for group differences was carried out on a number of noncategorical variables. Specifically, a one-way multivariate analysis of variance (MANOVA) by groups (cPVL vs. control) and a univariate analysis was conducted. We also analyzed the data with logistic regression in an effort to identify whether or not the variables in the study could predict cPVL. In particular, we were interested in the nature of MgSO4 in the prediction model. Criteria used for including variables in the prediction model were (a) there was a statistically significant logistic regression, and (b) the variables in the model served to maximize correct prediction of cases in the sample. Because this is a preliminary investigation and there were no clear a priori reasons to identify primacy among variables, hierarchical or stepwise procedures were not used. Second, categorical variables were analyzed by Chi-square analysis. This protocol was approved by the institutional review boards of the participating hospitals. RESULTS During the 2-year study period there were 23,382 infants born at the three institutions. There were 561 (2.4%) infants admitted to one of the three NICUs with a birth weight of less than 1750 g. Of these infants, 492 met the entrance criteria of the study. Seventeen infants died prior to 7 days of life, 23 infants did not receive cranial ultrasounds Downloaded by: NYU. Copyrighted material. AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 14, NUMBER 5
    • MAGNESIUM SULFATE A N D CYSTIC PERIVENTRICULAR LEUKOMALACIA I N PRETERM INFANTS/FineSmith et al not a statistically significant increase in the risk of developing cPVL associated with any of these variables except magnesium. The Chi-square tests were nonsignificant suggesting a general similarity between the experimental and control groups except for magnesium, the variable of interest. See Tables 1 and 2. The results of the logistic regression showed the solution that best satisfied the criteria of statistical significance and maximum predictability included six variables: gestational weight, antenatal exposure to MgSO4, 1- and 5-min Apgar scores, number of days intubated, reason for prematurity, and type of delivery. The logistic solution including these variables was significant (Chi-square = 23.4, df= 12, p = 0.014). Of all the variables in the logistic equation, MgSO4 had the highest value of the R statistic, which in the present analysis is a measure of the partial correlation of the variables. The R statistic for MgSO4 was significant (p < 0.03, df= 1). The logistic regression model was able to correctly predict 67% (12 of 18) of the cPVL cases and 92% (33 of 36) of the controls. When this same logistic solution was calculated without MgSO4, prediction in the cPVL group dropped to 44%, less than chance, and the regression was no longer statistically significant. Therefore, inclusion of MgSO4 resulted in a 22% increment in prediction and increased prediction 17% above chance levels. This bears out the findings in the analyses above that MgSO4 plays a role in the prevention of cPVL. Downloaded by: NYU. Copyrighted material. after 7 days of life, and 29 infants had insufficient data recorded in their charts. There were no cases of cPVL detected in any of the cases excluded from the study. A total of 857 ultrasound studies were reviewed. There were 12 quality grade 2 and 2 quality grade 3 ultrasound studies. The remainder were grade 1 studies. There were 18 cases of cPVL that formed the experimental group. Two infants in this group (11.1%) were exposed to MgSO4 in utero compared to 14 of the 36 (38.8%). Table 1 shows the OR, significance and 95% CI for MgSO4 exposure. Because earlier studies have examined the relationship between preeclampsia and C.P. (see, e.g., Ref. 30), we specifically examined our data from this perspective. Preeclampsia was diagnosed in 5.5% (1 out of 18) of the mothers with children with cPVL compared to 14.7% (6 out of 36) of the controls. To evaluate the possible effect of preeclampsia on cPVL, the number of infants born with cPVL to mothers with preeclampsia were compared between the two groups with results shown in Table 1. We also compared the nonpreeclamptic infants exposed to MgSO4 to the nonpreeclamptic controls. In the cPVL group, 2 of the 17 nonpre-eclamptic infants were exposed and 9 of the 30 nonpre-eclamptics in the control group were exposed (11.8 vs. 30%). The PVL and control group were found to be equal in all variables except magnesium exposure. Analysis was conducted on the continuous and categorical variables. The continuous variables (gestational age, number of days intubated and 1- and 5min Apgar scores) were found to be nonsignificant (p = 0.53) although days of intubation was found to covary with each of the variables tested. In part this is due to the fact that one infant in the cPVL group (mean = 16 days) was intubated for 100 days. Without this one case, the mean for the group would have been 11 days and the group difference would not have been statistically significant (t= 0.53, p = 0.14). Second, several categorical variables were available in the records of the infants. These variables included gestational weight, time of rupture of membranes, reason for prematurity, type of delivery, whether or not the mother received terbutaline, ritodrine, steroids, or magnesium, and the number of infants in each group that survived. There was DISCUSSION In this study of preterm infants with a birth weight of <1750 g, we found that those infants with cPVL were less likely to have been exposed to antenatal MgSO4. The groups were shown to be statistically similar in all other variables recorded. These observations are consistent with those of Nelson and Grether30 who noted a reduction in the risk of developing CP in the group exposed to antenatal MgSO4. Our findings suggest that the reduction in CP may be related to a reduction in cPVL. However, a larger prospective randomized study is needed to substantiate these findings. Table 1 . Maternal and Fetal Variables and Risk of Developing cPVL Condition cPVL cases N=18 No. (%) Controls N=36 No. (%) MgSO 4 exposed Pre-eclampsia Steroid exposed Fetal distress Premature rupture Preterm labor 2 1 6 1 4 10 14 6 17 2 12 19 11.1 5.6 33.3 5.6 22.2 55.6 38.9 16.7 47.2 5.6 33.3 52.8 p Value OR 95% CI >0.035 >0.1 >0.1 >0.1 >.1 >.1 .19 .29 .59 1.0 .57 1.1 .039-.988 .033-2.65 .17-1.8 .08-1.18 .15-2.12 .058-1.65 305
    • AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 14, NUMBER 5 May 1997 Table 2. Comparison of Neonatal Variables in cPVL and Control Group Variables cPVL Cases (mean) (SD) Controls (mean) (SD) # days intu bated Apgar at 1 min Apgar at 5 min Gestational age birthweight (g) 16.1 5.44 7.11 28.06 1105 3.92 6.31 7.97 28.08 1137 27.9 2.68 2.22 2.04 254 6.0 1.82 1.00 1.92 279 t Value 0.08 (ns) 0.23 (ns) 0.13 (ns) 0.92 (ns) 0.80 (ns) Since pre-eclampsia is a common indication for antenatal exposure to MgSO4, it would be important to consider the possibility that preeclampsia itself may confer some neuroprotection. However, when we looked only at those infants born to preeclamptic mothers, we were unable to find any evidence of such a primary protective effect with regard to cPVL. Conversely, the association between antenatal MgSO4 and the reduction in cPVL persisted in infants born to nonpreeclamptic mothers who received MgSO4 solely for tocolysis. This further supports the notion that it is the MgSO4 and not preeclampsia that is protective. There is convincing evidence in studies at the cellular level 31 as well as in ischemic animal models that magnesium has neuroprotective properties.32"35 Magnesium markedly reduces infarct size in perinatal rats. The mechanism of action may be related to the inhibition of the iV-methyl D-aspartate (NMDA) receptor.36 The NMDA receptor is stimulated by excitatory amino acids (EAA) in hypoxic conditions and this results in a massive inflow of calcium ions into the neuron. This has been described as the initial phase in the cascade of neuronal cell death. Magnesium blocks the ion pore in the NMDA receptor in a voltage-dependent manner. Even when the NMDA receptor is stimulated by EAAs, calcium cannot enter the cell until the magnesium ion is extruded, thereby preventing the initiation of the cell death cascade. Other postulated mechanisms may be related to the overall metabolic and functional depressive effects of magnesium on the brain. Magnesium may also act as an antagonist to the presynaptic adenosine a3 receptor and inhibit EAA release. This study is limited by the small number of follow-up ultrasounds in those infants found to have a normal ultrasound early in their course. Also, in this retrospective study we were unable to document the dose of medication, duration of in-utero exposure, and serum levels of magnesium in infants exposed to MgSO4. Additionally, the number of mothers included in the preeclampsia comparisons was small making it difficult to demonstrate a statistical relationship. As noted, the wide discrepancy in the number of days intubated between the cPVL group (0 to 100 days) and the controls (0 to 20 days) made it difficult to determine significance. The logistic regression analysis in this study, while 306 significant and showing improved predictability, contained more variables than may be practical to use in clinical settings. When we removed some of these variables from the regression equation, however, predictability suffered, thus leading us to the conclusion that there are complex interactions in these variables that we may not fully understand. Such interactions should be the focus of future research. Further, the number of subjects in this study is limited and it may be that a larger sample, with more stable parameters, may yield more parsimonious regression solutions. Finally, in this preliminary analysis, the method of the regression was simply to enter all the variables into the equation at the same time. Hierarchical and stepwise methods may be able to refine models in future studies. Neonatal resuscitation has been greatly improved resulting in more timely restoration of cerebral oxygenation and perfusion in preterm infants with evidence of hypoxic-ischemic disease (HID). Unfortunately, HID may occur pre- or perinatally when the neonate is not accessible to resuscitation. However, the fetus is accessible to in-utero pharmacological therapy. The occurrence of the HID is much greater in the lower birth-weight and gestational age infants.37 Many of these infants have transient respiratory and cardiac complications that either resolve or are amenable to medical management. However, these nonpermanent cardiorespiratory deficiencies may result in permanent brain damage. The outcome and quality of life of these infants is often dramatically altered. The etiology of CP is clearly heterogeneous, but two prominently identifiable and frequently associated risk factors are preterm birth and HID.38 It is therefore pertinent that the first step in prevention be aimed at the treatment of those infants that are either at greatest risk of, or that have already suffered HID. Comprehensive prenatal care, fetal monitoring, and improved neonatal resuscitation are currently utilized but this has not been enough to improve the incidence of CP in the preterm infant. Therefore, the next frontier is to learn to protect the neonates brain against cell death and injury in the face of the HID. With appropriate treatment, and ultimately prophylactic treatment of preterm neonates, the occurrence of neurological sequela and the quality of life of many thousands of individuals could be vastly improved. Downloaded by: NYU. Copyrighted material. NS-not statistically significant.
    • MAGNESIUM SULFATE AND CYSTIC PERIVENTRICULAR LEUKOMALACIA IN PRETERM INFANTS/FineSmith et al Cerebral palsy of cystic periventricular leukomalacia in lowbirth-weight infants. Acta Paediatrica 1994;83:397-401 20. Pidcock FS, Graziani LJ, Stanley C, Mitchell DG, Merton P. 1. Guyer B, Strobino DM, Venttura SJ, Singh GK. Annual sumNeurosonographic features of periventricular echodensities mary of vital statistics—1994. Pediatrics 1995;96:1029-39 associated with cerebral palsy in preterm infants. J Pediatr 2. Wagner ME. Annual summary of statistics—1993. Pediatrics 1990;116:417-22 1995;94:792-803 21. Powell TG, Pharoah PD, Cooke RI, Rosenbloom L. Cerebral 3. Horbar JD, McHuliffe TL, Adler SM, Albersheim S, Cassady palsy in low-birthweight infants. II. Spastic diplegia: AssociaG, Edwards W, Jones R, Kaftwinkel J, Kraybill EN, Krishnan tions with intrapartum stress. Dev Med Child Neurol 1988; V, Raschko P, Wilkinson AR. Variability in 28 day outcomes 30:19-25 for very low birthweight infants: An analysis of 11 neonatal 22. Powell TG, Pharoah PD, Cooke, RI, Rosenbloom L. Cerebral intensive care units. Pediatrics 1988;82:554-59 palsy in low-birthweight infants. I. Spastic hemiplegia: Asso4. Hagberg B, Hagberg G, Olow I. The changing panorama of ciations with intrapartum stress. Dev Med Child Neurol cerebral palsy in Sweden. Acta Paediatr Scand 1984;73: 1988;30:ll-18 433-400 23. Nelson KB, Ellenberg JH. Neonatal signs as predictors of 5. Pharoah PD, Cooke T, Rosenbloom I, Cooke RI. Trends in cerebral palsy. Pediatrics 1979;64:225-32 birth prevalence of cerebral palsy. Arch Dis Child 1987;2: 24. Naeye RL, Peters EC, Bartholomew M, Landis B. Origins of 379-84 cerebral palsy. AmJ Dis Child 1989; 143:1154-61 6. Hagberg B, Hagberg G, Zetterstrom R. Decreasing perinatal 25. Boyle CA, Decoufle P, Yeargin-Allsopp M. Prevalence and mortality—Increase in cerebral palsy morbidity. 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