Chorioamnionitis and the Prognosis for TermInfants

JAMES M. ALEXANDER, MD, DONALD M. MCINTIRE, PhD, AND

KENNETH J. LEVENO, MD

Objective: To assess the effects of clinical chorioamnionitisand labor complications on short-term neonatal morbidity,including seizures.

Methods: This was a retrospective cohort study of alllive-born term infants who weighed more than 2500 gdelivered between 1988 and 1997 at Parkland MemorialHospital, Dallas, Texas. Infant outcomes were comparedbetween women with and without clinical diagnoses ofchorioamnionitis. Chorioamnionitis was based on maternalfever of 38C or greater with supporting clinical evidenceincluding fetal tachycardia, uterine tenderness, and mal-odorous 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 of7.0 or less, delivery-room intubation, sepsis, pneumonia,seizures in the first 24 hours, and meconium aspirationsyndrome were all increased in infants exposed to chorio-amnionitis. After adjustment for confounding factors, in-cluding route of delivery and length of labor, chorioamnio-nitis remained significantly associated with intubation inthe delivery room (odds ratio [OR] 2.0; 95% confidenceinterval [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 neurologicmorbidity, manifest as seizures, was not related to maternalinfection during labor, but was significantly related to otherlabor complications.

Conclusion: The main short-term neonatal consequence ofchorioamnionitis is infection. Short-term neurologic mor-bidity in infants is related to labor complications and notchorioamnionitis per se. (Obstet Gynecol 1999;94:274–8.© 1999 by The American College of Obstetricians andGynecologists.)

Chorioamnionitis, or acute intra-amniotic infection, his-torically has been associated with maternal morbidityand mortality. Until recently, the major adverse conse-quence of chorioamnionitis was considered to be puer-

peral infection. However, Eschenbach1 reported that thehazards of amniotic fluid infections might be greater forfetuses and newborns. Such infections are now acceptedas a major source of short- and long-term morbidity inpreterm infants. Group B streptococcus prevention pro-grams have been implemented recently in the UnitedStates to reduce such infections in preterm and terminfants.2

Opinions about chorioamnionitis are changing withreports that cerebral palsy is related to what waspreviously considered an exclusively intrapartum ma-ternal infection. Cerebral palsy was linked to chorioam-nionitis in several reports on preterm infants3–7 andmore recently in term infants.8 Grether and Nelson8

found that intrauterine exposure to maternal infectionmarkedly increased the risk of cerebral palsy in terminfants. Chorioamnionitis was noted as a risk factor forneonatal outcomes commonly attributed to birth as-phyxia.

We sought to determine the immediate effects ofchorioamnionitis on newborn term infants in a cohort ofpregnancies large enough to analyze variables poten-tially influencing infant outcomes independent of intra-uterine infection. We were interested in the relationbetween chorioamnionitis and short-term neurologicmorbidity manifest as seizures. We wanted to knowwhether chorioamnionitis caused complications in in-fants or was a marker of other intrapartum events thatled to fetal compromise.

Materials and Methods

Between January 1, 1988 and December 31, 1997, alllive-born infants who weighed at least 2500 g at Park-land Memorial Hospital, Dallas, Texas, were entered ina computerized database. Delivery events were re-corded by attending nurses, and data sheets werechecked for accuracy by research nurses. Infant out-comes were abstracted from the newborn discharge

From the Department of Obstetrics and Gynecology, University ofTexas Southwestern Medical Center, Dallas, Texas.

274 0029-7844/99/$20.00 Obstetrics & GynecologyPII S0029-7844(99)00256-2

records by research nurses, and the results were linkedelectronically to the maternal outcomes. This study waslimited to women with singleton pregnancies and live,cephalic-presenting fetuses at admission to the laborand delivery unit. Women with diabetes, previouscesarean deliveries, and fetal malformations were ex-cluded.

Intrauterine infection or chorioamnionitis was diag-nosed in women with fever of 38C or greater andclinical evidence not explained by another source ofinfection, including fetal tachycardia, uterine tender-ness, or foul odor at delivery. Women with chorioam-nionitis received intravenous ampicillin and gentami-cin, or clindamycin if they were allergic to penicillin, atthe time of diagnosis. Neonatal sepsis was diagnosedwhen blood or cerebrospinal fluid cultures were posi-tive.

We analyzed selected infant outcomes applicable toterm pregnancies in women with and without intrapar-tum chorioamnionitis. Respiratory distress was diag-nosed when infants required mechanical ventilationbeginning in the first 24 hours of life. Seizure activityapparent during the first 24 hours of life was selected asan outcome. Meconium aspiration syndrome was diag-nosed in infants with clinical and radiographic evi-dence. All diagnosed infants had dyspnea, tachypnea,need for supplemental oxygen by 6 hours of life, anddiffuse irregular patchy infiltrates on chest radiographs.Infants with meconium below the vocal cords but withno clinical evidence of disease were not diagnosed withaspiration syndrome.

The strength of associations between classificationvariables was measured using the x2 statistic for con-tingency tables or Fisher exact test when small cell sizeswere expected. Student t test was used to compare themeans of measures between groups. A generalizedestimating equation was used to account for infantsdelivered to the same mother (ie, multiparous women).With this statistic, delivery is grouped by mother suchthat within each mother, any variance among deliveriesis adjusted. Any maternal proclivity for specific charac-teristics (eg, chorioamnionitis, prolonged labor) is ac-counted for. The measure of association between neo-natal outcomes, chorioamnionitis, and otherdichotomous outcomes was adjusted by generalizedestimating equations using the logistic link factor. P ,.05 was considered statistically significant. All testswere two-sided.

Results

A total of 101,170 singleton pregnancies with infantswho weighed at least 2500 g met the inclusion criteriafor analysis. Chorioamnionitis was diagnosed in 5144

(5%) of theses pregnancies. Table 1 summarizes selectedmaternal demographic and pregnancy characteristics inwomen with and without chorioamnionitis. Chorioam-nionitis was significantly increased in women who wereyounger, nulliparous, or Hispanic. Similarly, chorioam-nionitis was significantly associated with intrapartumhypertension and post-term pregnancies.

Labor characteristics are summarized in Table 2.Every labor outcome analyzed, including oxytocin stim-ulation, ruptured membranes without labor, prolongedlabor, fetal heart rate (FHR) decelerations, and cesareandelivery for dystocia or nonreassuring FHR, was signif-icantly increased in women with chorioamnionitis. Asshown in Figure 1, the incidence of chorioamnionitisincreased in direct proportion to the duration of laborwhen measured by admission-to-delivery intervals.

Several complications of infants in the delivery roomand the nursery were significantly increased in motherswho had chorioamnionitis (Table 3). Larger infants(birth weight 4000 g or greater) were born more often towomen with chorioamnionitis. For example, 12% of

Table 1. Maternal Demographics and PregnancyComplications

Characteristic

Chorioamnionitis

PYes

(n 5 5144)No

(n 5 96,026)

Maternal age (y)* 22.4 6 5 23.3 6 5 ,.001Nulliparous 3856 (75%) 36,876 (38%) ,.001Race

Hispanic 3547 (69%) 52,139 (54%) ,.002Black 985 (19%) 26,501 (28%)White 490 (10%) 14,504 (15%)Other 122 (2%) 2881 (3%)

Hypertension 728 (14%) 9926 (10%) ,.001Gestation $42 wk 854 (17%) 10,812 (11%) ,.001

* Mean 6 standard deviation.

Table 2. Labor Characteristics

Characteristic

Chorioamnionitis

PYes

(n 5 5144)No

(n 5 96,026)

Oxytocin usedInduction 779 (15%) 8659 (9%) ,.001Augmentation 2883 (56%) 18,165 (19%) ,.001

Ruptured membranes beforeonset of labor

1245 (24%) 8877 (9%) ,.001

Second stage $2 h 740 (14%) 1635 (2%) ,.001Labor time $10 h 3427 (67%) 17,887 (19%) ,.001Cesarean delivery

Total 1449 (28%) 6926 (7%) ,.001Dystocia 1165 (23%) 3716 (4%) ,.001Nonreassuring FHR 229 (4%) 2304 (2%) ,.001

FHR 5 fetal heart rate.

VOL. 94, NO. 2, AUGUST 1999 Alexander et al Chorioamnionitis and Term Infants 275

women with chorioamnionitis delivered infants weigh-ing 4000 g or more compared with 8% of womenwithout it (P , .001). Measures of poor infant condition,including 5-minute Apgar scores of 3 or less, severeumbilical artery (UA) blood acidemia (pH 7.0 or less),and need for intubation in the delivery room, were allsignificantly increased with chorioamnionitis. Asshown in Table 3, infants born to women with chorio-amnionitis had increased rates of respiratory distress,meconium aspiration, and neurologic abnormalities inthe first 24 hours of life. Culture-proved sepsis andpneumonia also were increased significantly in womenwith chorioamnionitis, although neonatal deaths werenot increased. A total of three neonates born to womenwith chorioamnionitis died, two from complications

related to sepsis and the third of aspiration followed byrespiratory arrest in the nursery. The cause of aspirationwas not determined, and no autopsy was done.

We ranked the maternal and intrapartum factorssignificantly associated with chorioamnionitis accord-ing to their odds ratios (ORs) (Table 4). Women withprolonged labors, as measured by a second stage of 2hours or longer, labor and delivery times of 10 hours orlonger, need for oxytocin stimulation, and cesareandelivery for dystocia or FHR decelerations, had thehighest ORs for chorioamnionitis. Chorioamnionitisand the risk factors shown in Table 4 were used in astepwise logistic regression analysis for adverse infantoutcomes (Table 5). After adjustment, chorioamnionitisremained significantly associated with the need forintubation of infants in the delivery room, pneumonia,and newborn sepsis. Seizures, Apgar scores of 3 or less

Table 3. Neonatal Outcomes

Outcome

Chorioamnionitis

PYes

(n 5 5144)No

(n 5 96,026)

Birth weight (g)* 3465 6 451 3357 6 439 ,.009$4000 g 616 (12%) 7673 (8%) ,.001

Apgar score #3 at 5 min 27 (0.5%) 250 (0.3%) ,.001Umbilical artery pH , 7.0 23 (0.5%) 268 (0.3%) .04Intubation in delivery room 84 (1.6%) 524 (0.6%) ,.001Sepsis† 69 (1.3%) 206 (0.2%) ,.001Respiratory distress‡ 43 (0.8%) 257 (0.3%) ,.001Pneumonia 98 (1.9%) 605 (0.6%) ,.001Meconium aspiration syndrome 16 (0.3%) 136 (0.1%) .003Seizures in first 24 h 14 (0.3%) 127 (0.1%) .01Fetal death in labor unit 2 (0.04%) 4 (0.00%) .01Neonatal death 3 (0.06%) 36 (0.04%) .46

* Mean 6 standard deviation.† Positive blood or cerebrospinal fluid culture.‡ Requiring mechanical ventilation in first 24 hours of life.

Figure 1. Frequency of chorioamnionitis in relation to elapsed admis-sion-to-delivery times in 101,170 single term pregnancies (vertical barsindicate range).

Table 4. Significant Risk Factors Related toChorioamnionitis

Risk factor OR 95% CI

Second stage $2 h 9.7 8.8, 10.6Labor time $10 h 8.6 8.0, 9.1Cesarean for dystocia 7.3 6.8, 7.8Oxytocin used 6.3 5.9, 6.7Cesarean for FHR decelerations 1.9 1.7, 2.2Gestational age $42 wk 1.6 1.5, 1.7Hypertension 1.4 1.3, 1.6

OR 5 odds ratio; CI 5 confidence interval; FHR 5 fetal heart rate.

Table 5. Multivariate Analysis of Maternal and IntrapartumFactors Related to Neonatal Outcome*

Factor OR 95% CI

Intubation in delivery roomCesarean for dystocia 4.1 3.1, 5.5Chorioamnionitis 2.0 1.5, 2.6

PneumoniaChorioamnionitis† 2.2 1.7, 2.8

Newborn sepsisDelivery time $10 h 3.4 2.4, 4.8Chorioamnionitis 2.9 2.1, 4.1

Meconium aspiration syndromeCesarean for dystocia 3.5 1.7, 7.1Chorioamnionitis 2.2 1.2, 4.0

SeizuresCesarean for dystocia 2.8 1.5, 5.2Chorioamnionitis 1.1 0.57, 2.0

Umbilical artery pH , 7.0Cesarean for dystocia 2.4 1.4, 3.9Chorioamnionitis 1.2 0.76, 2.0

5-min Apgar score , 4Oxytocin use 2.3 1.7, 3.05Chorioamnionitis 1.3 0.8, 2.0

OR 5 odds ratio; CI 5 confidence interval.* Most significant association and chorioamnionitis are reported.† Chorioamnionitis was the most significant association.

276 Alexander et al Chorioamnionitis and Term Infants Obstetrics & Gynecology

at 5 minutes, and UA pH of 7.0 or less were no longerassociated with chorioamnionitis. However, these fac-tors were associated significantly with oxytocin stimu-lation of labor, prolonged labor times, and cesareandelivery for dystocia.

Discussion

The results of this analysis of more than 100,000 termpregnancies suggest that chorioamnionitis in mothersduring labor is associated with adverse infant out-comes. Resuscitation at birth, indicated by intubation inthe delivery room, was required in almost 2% of cho-rioamnionitis infants. Nearly every measure of compro-mised infant condition at birth was increased in associ-ation with maternal infection during labor. The infantsalso experienced morbidity after their arrival in thenursery, with significant increases in sepsis, pneumo-nia, meconium aspiration syndrome, and seizures.

The chorioamnionitis story includes more than infantconsequences. Many maternal demographic variablesand labor features were strongly associated with infantoutcomes linked to chorioamnionitis. Nulliparity, race,intrapartum hypertension, post-term pregnancy, oxyto-cin stimulation of labor, prolonged labor, and cesareandelivery were all variables associated with chorioam-nionitis and infant risk. Each of the significant laborfeatures associated with chorioamnionitis was poten-tially related to maternal demographics. For example,nulliparous women more often are younger and havelonger labors, and labor is frequently longer in womenwho have induction for hypertension or post-termpregnancy.

We attempted to adjust for the large number ofinteracting labor variables linked to adverse infantoutcomes using stepwise logistic regression analysis,which found that several maternal variables were morepotent modifiers of infant outcome than chorioamnio-nitis alone. For example, although chorioamnionitisremained associated with the need for infant resuscita-tion in the delivery room (OR 2.0; 95% confidenceinterval [CI] 1.5, 2.6), cesarean delivery for dystocia wasa more powerful predictor (OR 4.1; 95% CI 3.1, 5.5).Indices of neonatal infection were most closely relatedto maternal chorioamnionitis. For example, chorioam-nionitis had strong associations with neonatal pneumo-nia (OR 2.2; 95% CI 1.7, 2.8) and sepsis (OR 2.9; 95% CI2.1, 4.1). One interpretation of these results is thatchorioamnionitis in mothers is most closely related toinfections in infants, whereas other labor events deter-mine fetal condition at birth, such as the need forresuscitation.

The overall incidence of chorioamnionitis in thiscohort analysis is consistent with other reports. Gibbs

and Duff9 reported that clinical chorioamnionitis com-plicated 1–5% of term pregnancies and that this com-plication was a well-recognized risk after rupturedmembranes and prolonged labor at term. We found adirect correlation between the duration of labor andclinical infection in mothers. Such a link between infec-tions and duration of labor implicates dysfunctionallabor, need for oxytocin stimulation, and cesarean de-livery as covariables in adverse infant outcomes associ-ated with maternal chorioamnionitis. Under these cir-cumstances, chorioamnionitis is a marker of abnormallabor.10 This observation does not minimize the delete-rious effects on infants of maternal chorioamnionitis inlabor, but emphasizes that the primary neonatal conse-quence of abnormal labor is infection in newborns.

Other investigators have concluded recently that ma-ternal infection during labor at term has short- andlong-term consequences for infants, but that there aremany interacting, confounding variables implicated ininfant outcomes. Adamson et al11 analyzed 89 full-terminfants who suffered neonatal seizures and found thatmaternal infection in labor was just one of 15 antepar-tum or intrapartum factors associated with brain injuryin infants. Grether and Nelson8 reported that intrauter-ine exposure to maternal infection was associated witha marked increase in cerebral palsy in infants deliveredat term. Similar to our results, their newborns exposedto chorioamnionitis were more often depressed at birthand suffered seizures. Grether and Nelson8 concur withour finding that the link between maternal infection andcerebral palsy is confounded by several maternal char-acteristics besides intrapartum infection. They com-puted adjusted ORs for factors individually found toinfluence the link between maternal infection and cere-bral palsy. In their analysis, none of the many factorsremained significant for cerebral palsy after regressionanalysis; however, they did not adjust for duration oflabor, which we found to be the most powerful predic-tor of immediate newborn morbidity attributed to cho-rioamnionitis. Our results, unlike those of Grether andNelson,8 suggest that short-term abnormal neurologicoutcomes (seizures in the first 24 hours of life) are notcausally related to maternal infections, but to abnormallabors.

References1. Eschenbach DA. Amniotic fluid infection and cerebral palsy. Focus

on the fetus. JAMA 1997;278:247–8.2. Centers for Disease Control and Prevention. Prevention of perina-

tal group B streptococcal disease: A public health perspective.MMWR 1996;45:1–24.

3. Morales WJ, Washington SR 3d, Lazar AJ. The effect of chorioam-nionitis on perinatal outcome in preterm gestation. J Perinatal1987;7:105–10.

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4. Bejar R, Wozniak P, Allard M, Benirschke K, Baucher Y, Coen R, etal. Antenatal origin of neurologic damage in newborn infants.Am J Obstet Gynecol 1988;159:357–63.

5. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R, et al.Obstetric antecedents of intraventricular hemorrhage and periven-tricular leukomalacia in the low-birth-weight neonate. Am J ObstetGynecol 1997;176:275–81.

6. Murphy DJ, Sellers S, Mackenzie IZ, Yudkin PL, Johnson AM.Case-control study of antenatal and intrapartum risk factors forcerebral palsy in very preterm singleton babies. Lancet 1995;8988:1449–54.

7. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, LevenoKJ. Clinical chorioamnionitis and the prognosis for very low birthweight infants. Obstet Gynecol 1998;91:725–9.

8. Grether JK, Nelson KB. Maternal infection and cerebral palsy ininfants of normal birth weight. JAMA 1997;278:207–11.

9. Gibbs RS, Duff P. Progress in pathogenesis and management ofclinical intra-amniotic infection. Am J Obstet Gynecol 1991;164:1317–26.

10. Satin AJ, Maberry M, Leveno KJ, Sherman ML, Kline DM. Chorio-amnionitis: A harbinger of dystocia. Obstet Gynecol 1992;79:913–5.

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Address reprint requests to:James M. Alexander, MDDepartment of Obstetrics and GynecologyUniversity of Texas Southwestern Medical Center at Dallas5323 Harry Hines BoulevardDallas, TX 75235-9032E-mail: jalexa@mednet.swmed.edu

Received June 23, 1998.Received in revised form December 22, 1998.Accepted January 28, 1999.

Copyright © 1999 by The American College of Obstetricians andGynecologists. Published by Elsevier Science Inc.

278 Alexander et al Chorioamnionitis and Term Infants Obstetrics & Gynecology