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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Pathology, and Graduate School of Health Sciences, New York Medical College, Valhalla, New York.
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Abstract |
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Methods: We studied neonates at our institution who weighed 1750 g or less at birth from January 1990 through December 1997. The population was stratified primarily by presence of histologic chorioamnionitis and secondarily by exposure to antenatal steroids. Subgroups were compared by various perinatal outcomes and confounding variables. Student t test, 
2, Fisher exact test, and logistic regression were used for analysis.
Results: Among 1260 neonates entered, the placentas of 527 had evidence of histologic chorioamnionitis and 733 did not. Those with histologic chorioamnionitis had a lower mean gestational age, lower birth weight, and higher rate of major neonatal morbidities than those without it. After adjusting for confounding variables, histologic chorioamnionitis independently associated with lower gestational age, lower birth weight, and neonatal death. Among neonates exposed to antenatal steroids who had histologic chorioamnionitis, there was a significantly lower incidence of low Apgar scores (18% compared with 33.5%, P < .001), respiratory distress syndrome (RDS) (39.6% compared with 55.9%, P < .001), intraventricular hemorrhage and periventricular leukomalacia (21.9% compared with 36.9%, P < .001), major brain lesions (7.7% compared with 18.4%, P < .001), patent ductus arteriosus (14.8% compared with 23.7%, P = .018), and neonatal death (8.3% compared with 16.2%, P = .02), with no increase in rate of proven neonatal sepsis (18.3% compared with 14%, P = .24).
Conclusion: Histologic chorioamnionitis increases major perinatal morbidity through its association with preterm birth and is independently associated with neonatal death. In the presence of histologic chorioamnionitis, antenatal steroids significantly decreased the incidence of RDS, intraventricular hemorrhage and periventricular leukomalacia, major brain lesions, and neonatal mortality, without increasing neonatal sepsis.
Histologic chorioamnionitis has been associated consistently with preterm birth, low birth weight, preterm premature rupture of membranes (PROM), neonatal sepsis, and death.1 It is a known risk factor for long-term neurologic sequelae in term and preterm fetuses2,3; however, the relationship between histologic chorioamnionitis and preterm neonatal morbidity and mortality is uncertain. Is histologic chorioamnionitis inherently associated with increased neonatal morbidity and mortality, or are they the consequence of preterm birth? The relationship between antenatal steroids and histologic chorioamnionitis also is unknown. Although antenatal steroids are contraindicated for clinical chorioamnionitis, there is paucity of information on the effects of antenatal steroids in the presence of histologic chorioamnionitis.
Our primary objective was to determine the effect of histologic chorioamnionitis on perinatal outcomes of preterm neonates. Our secondary objective was to determine the effectiveness of antenatal steroids for reducing neonatal morbidity and mortality, and elucidate potential adverse effects of antenatal steroids in the presence of histologic chorioamnionitis.
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Materials and Methods |
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Preterm labor with intact membranes was diagnosed with six to eight contractions per hour or four contractions in 20 minutes, associated with cervical changes but with no prelabor rupture of membranes. Preterm PROM included cases in which delivery followed prelabor rupture of membranes, documented by pooling of fluid on sterile speculum examination, ferning, and alkaline pH of fluid collected from the posterior vaginal fornix. Pregnancy-associated hypertension included severe preeclampsia, eclampsia, and chronic hypertension with superimposed severe preeclampsia. Gestational age was estimated by using the last menstrual period (LMP) when reliable or by an ultrasonogram in the first 20 weeks of pregnancy. Fetal growth restriction (FGR) was defined as birth weight below the tenth percentile expected for gestational age when Brenner birth percentile criteria were used.4 Antenatal steroids were two 12-mg intramuscular doses of betamethasone 24 hours apart, with a repeated course 7 days from the first dose if patients were undelivered.
Histologic chorioamnionitis was diagnosed using criteria described by Salafia et al.5 Tissue samples included sections of umbilical cord, chorionic plate, and a roll of membranes that extended from an area of membrane rupture to the margin of the placenta. Tissue blocks were fixed with 10% formalin and embedded in paraffin. Sections of tissue blocks were stained with hematoxylin-eosin and read by a perinatal pathologist who was masked to clinical courses of patients. The presence of five or more polymorphonuclear leukocytes in any tissue qualified as positive for chorioamnionitis.
Respiratory distress syndrome (RDS) was diagnosed clinically by need for mechanical ventilation and oxygen for at least 48 hours, and radiologic chest findings. Each neonate had transfontanelle neurosonography on days 3 and 7 of life. Neurosonograms were evaluated by an experienced sonographer who was unaware of the antenatal steroid exposure statuses of parturients. Intraventricular hemorrhage was graded as described by Papile et al.6 Periventricular leukomalacia was diagnosed by echolucent areas or persistent echogenicity in periventricular areas on coronal and sagittal views. Major brain lesions included intraventricular hemorrhage grades 3 and 4, intraventricular hemorrhage with periventricular leukomalacia, and periventricular leukomalacia. Patent ductus arteriosus included cases that required medical or surgical intervention. Necrotizing enterocolitis was diagnosed clinically and radiologically, and confirmed by surgery or autopsy. Proven neonatal sepsis included cases with positive blood or cerebrospinal fluid cultures.
The study population was stratified primarily according to histologic chorioamnionitis and secondarily on exposure to antenatal steroids. Subgroups were compared for RDS, intraventricular hemorrhage and periventricular leukomalacia, incidence of major brain lesions, necrotizing enterocolitis, proven neonatal sepsis, patent ductus arteriosus, and neonatal death. Subgroups also were compared for confounding variables including gestational age at delivery, birth weight, birth weight percentile, Apgar scores, postnatal surfactant exposure, and clinical group of origin.
Distributional characteristics of variables were examined. Continuous data were normally distributed. As such, differences between groups defined by presence or absence of histologic chorioamnionitis and exposure to antenatal steroids were examined using Student t test for continuous variables and 2 for categoric variables. Fisher exact test was used when expected cell frequencies were less than five. Logistic regression was used to examine influence of histologic chorioamnionitis on selected outcomes, adjusting for confounding factors. For sample computations, we assumed that approximately 30% of women were exposed to antenatal steroids. For conditions with an incidence of 50% (eg, RDS), a sample of 200 neonates (60 exposed compared with 140 unexposed) would provide more than 80% power to detect a 50% reduction in incidence for a two-sided test of significance, at a critical level of .05. For conditions with 25% incidence, such as intraventricular hemorrhage-periventricular leukomalacia, a sample of 280 neonates (80 exposed compared with 200 unexposed) would provide 80% power to detect a 70% reduction in incidence of the condition.
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Results |
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).
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). After we adjusted for confounding variables, histologic chorioamnionitis independently associated with lower gestational ages, birth weight at or below 750 g, and neonatal death (Table 3).
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). The steroid-exposed group also had significantly lower incidence of 5-minute Apgar scores less than 7 (18% compared with 33.5%, P = .001) and patent ductus arteriosus (14.8% compared with 23.7%, P = .018), with no difference in the rate of proved neonatal sepsis (18.3% compared with 14%, P = .24), when compared with the steroid-unexposed group.
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Discussion |
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Antenatal steroids are contraindicated in the setting of clinical chorioamnionitis.10 Studies11–13 have found high recovery rates of microorganisms from preterm placentas with histologic chorioamnionitis, so there are reasonable concerns about the effect of antenatal steroids in the presence of histologic chorioamnionitis. However, our experience indicates that antenatal steroids significantly decrease incidence of RDS, incidence and severity of intraventricular hemorrhage and periventricular leukomalacia, and neonatal mortality in histologic chorioamnionitis, with no apparent increase in rate of proved neonatal sepsis. Those are important findings in view of efforts to detect subclinical infection with markers such as C-reactive protein in maternal serum and amniotic fluid glucose, lactase dehydrogenase, leukocyte count, complement C3, and cytokines. Our study suggests that there should be no reluctance to use antenatal steroids in the presence of subclinical infections.
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Footnotes |
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Received December 22, 1999. Received in revised form March 30, 2000. Accepted April 20, 2000.
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References |
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2. Nelson KB, Ellenberg JH. Predictors of very low birth weight and the relation of these to cerebral palsy. JAMA 1985;254:1473–9.[Abstract]
3. Murphy DJ, Sellers S, Mackenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346: 1449–54.[Medline]
4. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126:555–64.[Medline]
5. Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol 1989;73:383–9.
6. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92: 529–34.[Medline]
7. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi J, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1ß, and tumor necrosis factor-
), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177:19–26.[Medline]
8. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi J, et al. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960–70.[Medline]
9. Russell P. Inflammatory lesions of the human placenta. 1. Clinical significance of acute chorioamnionitis. Am J Diagn Gynecol Obstet 1979;1:127–37.
10. National Institutes of Health. Report of the Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. NIH publication no. 95-3784. Bethesda, MD: National Institute of Child Health and Human Development, 1994.
11. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319: 972–8.[Abstract]
12. Zlatnik FJ, Gellhaus TM, Benda JA, Koontz FP, Burmcister LF. Histologic chorioamnionitis, microbial infection, and prematurity. Obstet Gynecol 1990;76:355–9.
13. Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, et al. Microbial invasion of the amniotic cavity with ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254–60.[Medline]
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