ALEXANDER, JAMES M. MD; MCINTIRE, DONALD M. PhD; LEVENO, KENNETH J. MD
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
Address reprint requests to: James M. Alexander, MD, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9032; E-mail: email@example.com
Received June 23, 1998. Received in revised form December 22, 1998. Accepted January 28, 1999.
Objective: To assess the effects of clinical chorioamnionitis and labor complications on short-term neonatal morbidity, including seizures.
Methods: This was a retrospective cohort study of all live-born term infants who weighed more than 2500 g delivered between 1988 and 1997 at Parkland Memorial Hospital, Dallas, Texas. Infant outcomes were compared between women with and without clinical diagnoses of chorioamnionitis. Chorioamnionitis was based on maternal fever of 38C or greater with supporting clinical evidence including fetal tachycardia, uterine tenderness, and malodorous infant.
Results: A total of 101,170 term infants were analyzed, 5144 (5%) of whom were born to women with chorioamnionitis. Apgar scores of 3 or less at 5 minutes, umbilical artery pH of 7.0 or less, delivery-room intubation, sepsis, pneumonia, seizures in the first 24 hours, and meconium aspiration syndrome were all increased in infants exposed to chorioamnionitis. After adjustment for confounding factors, including route of delivery and length of labor, chorioamnionitis remained significantly associated with intubation in the delivery room (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.5, 2.6), pneumonia (OR 2.2; 95% CI 1.7, 2.8), and sepsis (OR 2.9; 95% CI 2.1, 4.1). Short-term neurologic morbidity, manifest as seizures, was not related to maternal infection during labor, but was significantly related to other labor complications.
Conclusion: The main short-term neonatal consequence of chorioamnionitis is infection. Short-term neurologic morbidity in infants is related to labor complications and not chorioamnionitis per se.
Chorioamnionitis, or acute intra-amniotic infection, historically has been associated with maternal morbidity and mortality. Until recently, the major adverse consequence of chorioamnionitis was considered to be puerperal infection. However, Eschenbach 1 reported that the hazards of amniotic fluid infections might be greater for fetuses and newborns. Such infections are now accepted as a major source of short- and long-term morbidity in preterm infants. Group B streptococcus prevention programs have been implemented recently in the United States to reduce such infections in preterm and term infants. 2
Opinions about chorioamnionitis are changing with reports that cerebral palsy is related to what was previously considered an exclusively intrapartum maternal infection. Cerebral palsy was linked to chorioamnionitis in several reports on preterm infants 3–7 and more recently in term infants. 8 Grether and Nelson 8 found that intrauterine exposure to maternal infection markedly increased the risk of cerebral palsy in term infants. Chorioamnionitis was noted as a risk factor for neonatal outcomes commonly attributed to birth asphyxia.
We sought to determine the immediate effects of chorioamnionitis on newborn term infants in a cohort of pregnancies large enough to analyze variables potentially influencing infant outcomes independent of intrauterine infection. We were interested in the relation between chorioamnionitis and short-term neurologic morbidity manifest as seizures. We wanted to know whether chorioamnionitis caused complications in infants or was a marker of other intrapartum events that led to fetal compromise.
Materials and Methods
Between January 1, 1988 and December 31, 1997, all live-born infants who weighed at least 2500 g at Parkland Memorial Hospital, Dallas, Texas, were entered in a computerized database. Delivery events were recorded by attending nurses, and data sheets were checked for accuracy by research nurses. Infant outcomes were abstracted from the newborn discharge records by research nurses, and the results were linked electronically to the maternal outcomes. This study was limited to women with singleton pregnancies and live, cephalic-presenting fetuses at admission to the labor and delivery unit. Women with diabetes, previous cesarean deliveries, and fetal malformations were excluded.
Intrauterine infection or chorioamnionitis was diagnosed in women with fever of 38C or greater and clinical evidence not explained by another source of infection, including fetal tachycardia, uterine tenderness, or foul odor at delivery. Women with chorioamnionitis received intravenous ampicillin and gentamicin, or clindamycin if they were allergic to penicillin, at the time of diagnosis. Neonatal sepsis was diagnosed when blood or cerebrospinal fluid cultures were positive.
We analyzed selected infant outcomes applicable to term pregnancies in women with and without intrapartum chorioamnionitis. Respiratory distress was diagnosed when infants required mechanical ventilation beginning in the first 24 hours of life. Seizure activity apparent during the first 24 hours of life was selected as an outcome. Meconium aspiration syndrome was diagnosed in infants with clinical and radiographic evidence. All diagnosed infants had dyspnea, tachypnea, need for supplemental oxygen by 6 hours of life, and diffuse irregular patchy infiltrates on chest radiographs. Infants with meconium below the vocal cords but with no clinical evidence of disease were not diagnosed with aspiration syndrome.
The strength of associations between classification variables was measured using the χ2 statistic for contingency tables or Fisher exact test when small cell sizes were expected. Student t test was used to compare the means of measures between groups. A generalized estimating equation was used to account for infants delivered to the same mother (ie, multiparous women). With this statistic, delivery is grouped by mother such that within each mother, any variance among deliveries is adjusted. Any maternal proclivity for specific characteristics (eg, chorioamnionitis, prolonged labor) is accounted for. The measure of association between neonatal outcomes, chorioamnionitis, and other dichotomous outcomes was adjusted by generalized estimating equations using the logistic link factor. P < .05 was considered statistically significant. All tests were two-sided.
A total of 101,170 singleton pregnancies with infants who weighed at least 2500 g met the inclusion criteria for analysis. Chorioamnionitis was diagnosed in 5144 (5%) of theses pregnancies. Table 1 summarizes selected maternal demographic and pregnancy characteristics in women with and without chorioamnionitis. Chorioamnionitis was significantly increased in women who were younger, nulliparous, or Hispanic. Similarly, chorioamnionitis was significantly associated with intrapartum hypertension and postterm pregnancies.
Labor characteristics are summarized in Table 2. Every labor outcome analyzed, including oxytocin stimulation, ruptured membranes without labor, prolonged labor, fetal heart rate (FHR) decelerations, and cesarean delivery for dystocia or nonreassuring FHR, was significantly increased in women with chorioamnionitis. As shown in Figure 1, the incidence of chorioamnionitis increased in direct proportion to the duration of labor when measured by admission-to-delivery intervals.
Several complications of infants in the delivery room and the nursery were significantly increased in mothers who had chorioamnionitis (Table 3). Larger infants (birth weight 4000 g or greater) were born more often to women with chorioamnionitis. For example, 12% of women with chorioamnionitis delivered infants weighing 4000 g or more compared with 8% of women without it (P < .001). Measures of poor infant condition, including 5-minute Apgar scores of 3 or less, severe umbilical artery (UA) blood acidemia (pH 7.0 or less), and need for intubation in the delivery room, were all significantly increased with chorioamnionitis. As shown in Table 3, infants born to women with chorioamnionitis had increased rates of respiratory distress, meconium aspiration, and neurologic abnormalities in the first 24 hours of life. Culture-proved sepsis and pneumonia also were increased significantly in women with chorioamnionitis, although neonatal deaths were not increased. A total of three neonates born to women with chorioamnionitis died, two from complications related to sepsis and the third of aspiration followed by respiratory arrest in the nursery. The cause of aspiration was not determined, and no autopsy was done.
We ranked the maternal and intrapartum factors significantly associated with chorioamnionitis according to their odds ratios (ORs) (Table 4). Women with prolonged labors, as measured by a second stage of 2 hours or longer, labor and delivery times of 10 hours or longer, need for oxytocin stimulation, and cesarean delivery for dystocia or FHR decelerations, had the highest ORs for chorioamnionitis. Chorioamnionitis and the risk factors shown in Table 4 were used in a stepwise logistic regression analysis for adverse infant outcomes (Table 5). After adjustment, chorioamnionitis remained significantly associated with the need for intubation of infants in the delivery room, pneumonia, and newborn sepsis. Seizures, Apgar scores of 3 or less at 5 minutes, and UA pH of 7.0 or less were no longer associated with chorioamnionitis. However, these factors were associated significantly with oxytocin stimulation of labor, prolonged labor times, and cesarean delivery for dystocia.
The results of this analysis of more than 100,000 term pregnancies suggest that chorioamnionitis in mothers during labor is associated with adverse infant outcomes. Resuscitation at birth, indicated by intubation in the delivery room, was required in almost 2% of chorioamnionitis infants. Nearly every measure of compromised infant condition at birth was increased in association with maternal infection during labor. The infants also experienced morbidity after their arrival in the nursery, with significant increases in sepsis, pneumonia, meconium aspiration syndrome, and seizures.
The chorioamnionitis story includes more than infant consequences. Many maternal demographic variables and labor features were strongly associated with infant outcomes linked to chorioamnionitis. Nulliparity, race, intrapartum hypertension, post-term pregnancy, oxytocin stimulation of labor, prolonged labor, and cesarean delivery were all variables associated with chorioamnionitis and infant risk. Each of the significant labor features associated with chorioamnionitis was potentially related to maternal demographics. For example, nulliparous women more often are younger and have longer labors, and labor is frequently longer in women who have induction for hypertension or post-term pregnancy.
We attempted to adjust for the large number of interacting labor variables linked to adverse infant outcomes using stepwise logistic regression analysis, which found that several maternal variables were more potent modifiers of infant outcome than chorioamnionitis alone. For example, although chorioamnionitis remained associated with the need for infant resuscitation in the delivery room (OR 2.0; 95% confidence interval [CI] 1.5, 2.6), cesarean delivery for dystocia was a more powerful predictor (OR 4.1; 95% CI 3.1, 5.5). Indices of neonatal infection were most closely related to maternal chorioamnionitis. For example, chorioamnionitis had strong associations with neonatal pneumonia (OR 2.2; 95% CI 1.7, 2.8) and sepsis (OR 2.9; 95% CI 2.1, 4.1). One interpretation of these results is that chorioamnionitis in mothers is most closely related to infections in infants, whereas other labor events determine fetal condition at birth, such as the need for resuscitation.
The overall incidence of chorioamnionitis in this cohort analysis is consistent with other reports. Gibbs and Duff 9 reported that clinical chorioamnionitis complicated 1–5% of term pregnancies and that this complication was a well-recognized risk after ruptured membranes and prolonged labor at term. We found a direct correlation between the duration of labor and clinical infection in mothers. Such a link between infections and duration of labor implicates dysfunctional labor, need for oxytocin stimulation, and cesarean delivery as covariables in adverse infant outcomes associated with maternal chorioamnionitis. Under these circumstances, chorioamnionitis is a marker of abnormal labor. 10 This observation does not minimize the deleterious effects on infants of maternal chorioamnionitis in labor, but emphasizes that the primary neonatal consequence of abnormal labor is infection in newborns.
Other investigators have concluded recently that maternal infection during labor at term has short- and long-term consequences for infants, but that there are many interacting, confounding variables implicated in infant outcomes. Adamson et al 11 analyzed 89 full-term infants who suffered neonatal seizures and found that maternal infection in labor was just one of 15 antepartum or intrapartum factors associated with brain injury in infants. Grether and Nelson 8 reported that intrauterine exposure to maternal infection was associated with a marked increase in cerebral palsy in infants delivered at term. Similar to our results, their newborns exposed to chorioamnionitis were more often depressed at birth and suffered seizures. Grether and Nelson 8 concur with our finding that the link between maternal infection and cerebral palsy is confounded by several maternal characteristics besides intrapartum infection. They computed adjusted ORs for factors individually found to influence the link between maternal infection and cerebral palsy. In their analysis, none of the many factors remained significant for cerebral palsy after regression analysis; however, they did not adjust for duration of labor, which we found to be the most powerful predictor of immediate newborn morbidity attributed to chorioamnionitis. Our results, unlike those of Grether and Nelson, 8 suggest that short-term abnormal neurologic outcomes (seizures in the first 24 hours of life) are not causally related to maternal infections, but to abnormal labors.
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