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Histologic Chorioamnionitis, Antenatal Steroids, and Perinatal Outcomes

From the Departments of Obstetrics and Gynecology and Pathology, and Graduate School of Health Sciences, New York Medical College, Valhalla, New York.

	Abstract

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Objective: To determine the perinatal effects of histologic chorioamnionitis on preterm neonates and the effectiveness of antenatal steroids in the presence of histologic chorioamnionitis.

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 fetuses^2,3; 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.

	Materials and Methods

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We evaluated perinatal outcomes of neonates at our institution who weighed between 500 and 1750 g at birth between January 1990 and December 1997. Clinical backgrounds of the women included preterm labor with intact membranes, PROM, pregnancy-associated hypertension, and other maternal indications. We excluded cases diagnosed with clinical chorioamnionitis.

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.

	Results

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One thousand two hundred sixty neonates who weighed 1750 g or less were born during the study. Four hundred eighty-two were born after preterm labor with intact membranes, and 456 after preterm PROM. Two hundred sixty-eight were born to mothers with pregnancy-associated hypertension, and 54 were delivered for other maternal indications. One thousand twenty-two neonates were appropriate for gestational age, and 238 were growth-restricted. The highest rates of histologic chorioamnionitis were with PROM, preterm labor with intact membranes, and appropriate for gestational age, whereas lower rates prevailed in those with pregnancy-associated hypertension and small for gestational age fetuses (Table 1).

	Discussion

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Antenatal steroids are contraindicated in the setting of clinical chorioamnionitis.¹⁰ Studies^11–13 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.

	Footnotes

 
PII S0029-7844(00)00928-5

Received December 22, 1999. Received in revised form March 30, 2000. Accepted April 20, 2000.

	References

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