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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology, and Radiology, and the Graduate School of Health Sciences, New York Medical College, Westchester Medical Center, Valhalla, New York.
Address reprint requests to: Joseph C. Canterino, MD Meridian Health System Jersey Shore Medical Arts Building 1944 State Route 33, Suite 203 Neptune, NJ 07753
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Abstract |
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Methods: This retrospective cohort study included 1161 neonates with gestational ages of 24–34 weeks and birth weights of 500–1750 g, divided into two groups on the basis of antenatal steroid treatment. Neonatal neurosonograms were done on days 3 and 7 of life and labeled normal or abnormal. The abnormal outcomes evaluated were periventricular leukomalacia or intraventricular hemorrhage, periventricular leukomalacia with intraventricular hemorrhage, and isolated periventricular leukomalacia. The group treated with antenatal steroids was compared with the untreated group for these outcomes.
Results: Antenatal steroids were associated with significantly less periventricular leukomalacia or intraventricular hemorrhage (23% versus 31%, P = .005), periventricular leukomalacia with intraventricular hemorrhage (5% versus 11%, P = .001), and isolated periventricular leukomalacia (3% versus 7%, P = .009). Logistic regression analysis of antenatal steroid treatment, controlling for confounding maternal and neonatal characteristics, indicated that neonates treated with antenatal steroids had a 56% lower likelihood of periventricular leukomalacia with intraventricular hemorrhage (adjusted odds ratio [OR] 0.44, 95% confidence interval [CI] 0.25, 0.77) and a 58% lower likelihood of isolated periventricular leukomalacia (adjusted OR 0.42, 95% CI 0.20, 0.88).
Conclusion: Antenatal steroid treatment was associated with over 50% reduction in the incidence of periventricular leukomalacia in preterm neonates. Increased use of antenatal steroid therapy might improve long-term neonatal neurologic outcomes.
Recent improvements in neonatal survival partially result from the administration of antenatal steroids, which reduce the risk of respiratory distress syndrome (RDS), intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death.1 However, the effect of antenatal steroids on periventricular leukomalacia is less clear. Since the 1994 consensus report of the National Institutes of Health Development Conference,2 the use of antenatal steroids has increased from approximately 18% to over 60%.3 However, with improving survival of preterm infants, particularly at the lower birth weight ranges, the prevalence of cerebral palsy is increasing.4 Because periventricular leukomalacia is a strong predictor of cerebral palsy,5–7 we hypothesized that antenatal steroid treatment might reduce the risk of periventricular leukomalacia. We designed this study to evaluate the independent effect of antenatal steroid treatment on the incidence of periventricular leukomalacia in preterm neonates.
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Materials and Methods |
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Maternal and neonatal characteristics recorded for each case included maternal age, indication for steroid treatment defined as preterm delivery (preterm labor or premature rupture of membranes [PROM]) or neonates delivered for maternal-fetal indications, gestational age determined by menstrual history and ultrasound measurements, birth weight, the presence of clinical chorioamnionitis defined as maternal pyrexia of over 38C on two occasions 6 hours apart with uterine tenderness or malodorous discharge, histologic chorioamnionitis defined as infiltration of the chorionic plate with polymorphonuclear cells, Apgar score less than 7 at 5 minutes, RDS diagnosed clinically and by the need for mechanical ventilation for at least 48 hours with the confirmatory presence of radiologic findings, and neonatal death.
The outcome analyzed was based on neonatal transfontanelle neurosonograms done on days 3 and 7 of life. Standard coronal and sagittal views were obtained and reviewed by a single radiologist who was unaware of the patients’ obstetric background and classified as normal or abnormal. Abnormal neurosonograms were then classified into the following three categories: any abnormal neurosonograms to include periventricular leukomalacia or intraventricular hemorrhage, periventricular leukomalacia with intraventricular hemorrhage, and isolated periventricular leukomalacia. Periventricular leukomalacia was defined as hyperechoic lesions persisting through day 7 of life or any hypoechoic lesions. Intraventricular hemorrhage was defined by the criteria of Papile et al.8
The groups (antenatal steroid treatment or no treatment) were compared for the primary outcome of any abnormal neurosonograms, periventricular leukomalacia with intraventricular hemorrhage, and isolated periventricular leukomalacia. The secondary outcome variables included maternal age, indication for steroid therapy, gestational age, birth weight, clinical chorioamnionitis, histologic chorioamnionitis, Apgar score less than 7 at 5 minutes, RDS, and neonatal death. At each stage of the analysis, the risk of any abnormal sonograms, periventricular leukomalacia with intraventricular hemorrhage, or isolated periventricular leukomalacia was analyzed with adjustment for the confounding effects of maternal and neonatal variables.
The distribution of all variables was examined. Normality was established using histograms, normal probability, and quantile plots. Because the distributions of continuous variables were approximately normal, bivariable comparisons of maternal antenatal steroid exposure were assessed using the Student t test, and 
2 tests were used for categorical variables. Initial evaluation of the risk of any abnormal neurosonograms, periventricular leukomalacia with intraventricular hemorrhage, or isolated periventricular leukomalacia in the steroid exposed group was done using unconditional logistic regression based on the multivariable analysis. Logistic regression models were built by including covariates identified as potentially important from the bivariable analyses. Model fit characteristics were evaluated using a goodness-of-fit test and other methods described by Hosmer and Lemeshow.9 Final logistic regression models were designed to address model fit requirements and to facilitate clinical interpretation. Significance of the variables in the models was based on the Wald 2 test and verified using likelihood ratio tests. All risk estimates are reported as odds ratios (OR) with 95% confidence intervals (CI).
To estimate the degree to which cases of periventricular leukomalacia in the United States could be reduced by expanding the use of steroids in preterm births, we computed the population etiologic fraction according to methods of Kelsey et al.10 This estimate is based on the adjusted risk estimates derived from the logistic regression model for the occurrence of any periventricular leukomalacia. The etiologic fraction is interpreted as the proportion of periventricular leukomalacia cases that are potentially preventable by administration of antenatal steroids.
We anticipated that approximately one third of our sample would be exposed to antenatal steroid therapy and that the incidence of periventricular leukomalacia among the group not exposed to antenatal steroid therapy would be about 10%. Under these assumptions, a sample size of 1100 neonates would provide over 80% power to detect at least a 50% reduction in risk due to antenatal steroid exposure for a two-sided test of significance at a critical level of P = .05. All statistical analyses were done using Stata Statistical Software version 6.0 (Stata Corporation, College Station, TX).
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Results |
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). The secondary outcome variables between the groups showed no differences in maternal age, indication for steroid treatment, gestational age, birth weight, histologic chorioamnionitis, and neonatal death. Neonates exposed to steroids had significantly less clinical chorioamnionitis, Apgar scores less than 7 at 5 minutes, and RDS. Logistic regression analyses of the association between antenatal steroid exposure and any abnormal neurosonograms, periventricular leukomalacia with intraventricular hemorrhage, and isolated periventricular leukomalacia are presented in Table 2. These models adjust for gestational age, birth weight, clinical chorioamnionitis, Apgar score less than 7 at 5 minutes, RDS, and neonatal death. Antenatal steroid exposure resulted in a significant reduction in the incidence of periventricular leukomalacia with intraventricular hemorrhage and in isolated periventricular leukomalacia. Although a reduction was seen in the occurrence of any abnormal sonogram with steroid exposure, this did not reach statistical significance.
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Discussion |
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We found antenatal steroid treatment associated with a 56% reduction in risk of periventricular leukomalacia with intraventricular hemorrhage and a 58% reduction in risk of isolated periventricular leukomalacia. Assuming a causal relationship, increased use of antenatal steroids could lower the incidence of periventricular leukomalacia significantly. In 1995 there were approximately 350,000 preterm deliveries at or before 34 weeks in the United States.13 Assuming that about 40% did not receive antenatal steroid therapy and that the incidence of periventricular leukomalacia is about 8%, we estimate that about 9500 preterm neonatal periventricular leukomalacia lesions could be prevented annually if all eligible women received antenatal steroid therapy (ie, 34% reduction in the number of cases nationally).
Previous work by us and others has addressed the benefits of antenatal steroid therapy.1,2,14 Etiologic factors concerning the development of these lesions are complex and not yet fully understood. The intrinsic vulnerability of cerebral white matter in the preterm infant increases its susceptibility to ischemic events.15 Cerebral white matter is an area of rapidly dividing cells that have high metabolic requirements. These cells are also vulnerable to attack by free radicals that occurs with ischemic-reperfusion conditions.16 Ischemia in the periventricular regions is a result of three major processes. First, periventricular vascular anatomy results in watershed regions of perfusion to the anterior and posterior periventricular regions of the premature developing cortex. Second, these lesions are caused by the immaturity of the cerebral microvasculature and auto-regulatory mechanisms of the preterm neonate. Because neonatal cerebral circulation cannot yet adapt to blood pressure variations, alterations in blood pressure can result in variations in cerebral blood flow with resultant ischemia and hyperperfusion. The inflammatory response and its resultant cytokine cascade, which has been studied in some cases of premature delivery,17 is also involved with the development of periventricular leukomalacia.18–20
Our findings clearly demonstrate that antenatal steroids significantly reduced the incidence of periventricular leukomalacia. We postulate that antenatal steroid exposure has a multifaceted beneficial effect in the reduction of these lesions. Clinical effects of antenatal steroid exposure include accelerated cytodifferentiation and precocious changes in neonatal tissue.21 These effects can lead to more short and long penetrating vessels supplying the periventricular regions and fewer watershed regions in the periventricular white matter. This enhanced differentiation could lead to accelerated maturation of the endothelial cells of the cerebral vasculature22 and the autoregulatory mechanisms of cerebral perfusion. Steroids also stimulate increased activity of antioxidant enzymes21 which can further reduce neurologic cell damage. Finally, antenatal steroids reduce the severity and effects of the systemic inflammatory response23 that is associated with the development of periventricular leukomalacia.19,20 This evidence supports a plausible physiologic mechanism for the role of antenatal steroid therapy in the reduction of periventricular leukomalacia in preterm neonates.
We believe our study has the strength to support our conclusions and to support the findings of Kari et al11 and Baud et al.12 The statistical analysis incorporates many confounders for the development of these lesions, and our conclusions are physiologically plausible. The weakness of this study is the retrospective design. We did not evaluate the effects of single- and multiple-dose antenatal steroid therapy or interval of treatment to delivery. Further studies to address these important issues are needed.
We recognize that the development of cerebral palsy is multifactorial and that periventricular leukomalacia accounts for a small percentage of cases. However, with increased use of antenatal steroid therapy in the recommended manner,24 a significant number of periventricular leukomalacia lesions, and therefore cases of cerebral palsy, are potentially preventable.
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Footnotes |
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Received May 25, 2000. Received in revised form September 22, 2000. Accepted October 12, 2000.
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References |
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2. National Institute of Health. Report of the Consensus Development Conference on the effect of corticosteroids for fetal maturation on perinatal outcomes. National Institute of Child Health and Human Development. NIH publication no. 95-3784. Bethesda, Maryland: National Institute of Health, November 1994.
3. Gardner MO, Papile LA, Wright LL. Antenatal corticosteroids in pregnancies complicated by preterm premature rupture of membranes. Obstet Gynecol 1997;90:851–3.[Abstract]
4. Bhush V, Paneth N, Kiely J. Impact of improved survival of very low birth weight infants on recent secular trends in the prevalence of cerebral palsy. Pediatrics 1993;91:1094–100.
5. Graziani LF, Pasto M, Stanley C, Pidcock F, Desai H, Desai S, et al. Neonatal neurosonographic correlates of cerebral palsy in preterm neonates. Pediatrics 1986;78:88–95.
6. Smith YF. Incidence and outcome: Periventricular leukomalacia. In: Grant EG, ed, Neurosonography of the preterm neonate. New York: Springer Verlag, 1986:91–3.
7. Graham M, Trocince JQ, Levene MI, Rutter N. Prediction of cerebral palsy in very low birth weight infants: Prospective ultrasound study. Lancet 1987;2:593–6.[Medline]
8. Papile LA, Burnstein R, Koffier H. Incidence and evolution of the subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm. J Pediatr 1978;92:529–34.[Medline]
9. Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley, 1984:82–175.
10. Kelsey JL, Whittemore AF, Evans AS, Thompson WD. Methods in observational epidemiology. New York: Oxford University Press, 1992:37–40.
11. Kari MA, Hallman M, Eronen M, Teramo K, Virtanen M, Kovisto M, et al. Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: A randomized placebo-controlled multicenter study. Pediarics 1994;93:730–6.
12. Baud O, Foix-L’Helias L, Kaminski M, Audibert F, Jarreau P, Papiernik E, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999;341:1190–6.
13. Crowley PA. Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972–1994. Am J Obstet Gynecol 1995;173: 322–35.[Medline]
14. Cooke RW. Trends in incidence of cranial ultrasound lesions and cerebral palsy in very low birthweight infants 1982–93. Arch Dis Child Fetal Neonatal Ed 1999;80:115–7.
15. Volpe J. Brain injury in the premature infant. In: du Plessis AJ ed. Clinics in perinatalogy. Philadelphia: WB Saunders, 1997:567–87.
16. Hirsch E, Blanchard R, Mehta S. Differential fetal and maternal contributions to the cytokine milieu in the murine model of infection-induced preterm birth. Am J Obstet Gynecol 1999;180: 429–34.[Medline]
17. Romero R, Avial C, Santhanan U, Sehgal PB. Amniotic fluid interleukin-6 in preterm labor, association with infection. J Clin Invest 1990;85:1392–400.
18. Yoon BH, Romero R, Kim LJ, Koo JN, Choe G, Syss HC, et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997;177:406–11.[Medline]
19. Martinez E, Fiqueroa R, Garry D, Visintainer P, Patel K, Verma U, et al. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage. J Matern Fetal Invest 1998;8:101–7.[Medline]
20. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173: 254–62.[Medline]
21. Kitchens CS, Pendergast JF. Human thrombocytopenia is associated with structural abnormalities of the endothelium that are ameliorated by glucocorticosteroid administration. Blood 1986;67: 203–6.
22. Tassani P, Richter JA, Barankay A, Braun SL, Haehnel C, Spaeth P, et al. Does high-dose methylprednisone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedure? J Cardiothorac Vasc Arrest 1999;13:165–72.
23. Ruzek MC, Pearce BD, Miller AH, Bicon CA. Endogenous glucocorticoids protect against cytokine-medicated lethality during viral infection. J Immunol 1999;162:3527–33.
24. Antenatal corticosteroids revisited: Repeat courses. NIH Consens Statement Online. 2000 August 17–18;17:1–10.
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