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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology, Pathology, Center for Statistical Sciences, and Pediatrics, Brown University, Women and Infants’ Hospital, Providence, Rhode Island.
Address reprint requests to: Scott C. Dexter, MD Department of Obstetrics and Gynecology Albany Medical Center 47 New Scotland Avenue, Mail code 133 Albany, NY 12208
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Abstract |
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Methods: Five hundred four maternal charts (97% of all VLBW infants delivered from 1990 to 1994) were reviewed. A historical cohort study of the 330 infants delivered secondary to preterm premature rupture of membranes or preterm labor was performed. Case subjects (71) were delivered of mothers with chorioamnionitis by clinical criteria; control subjects (259) were delivered of mothers without chorioamnionitis. Bayley index scores at 7 months’ corrected age and special care nursery outcomes were compared. One hundred seventy-three subjects were necessary to reject the two-sided null hypothesis with 80% power with a difference in mean Bayley index scores of at least 8.
Results: Neonatal sepsis (8.5% compared with 1.9%; odds ratio [OR] = 4.7, 95% confidence interval [CI] 1.4, 15.9, P = .015) and a low 5-minute Apgar (72% compared with 55%; OR = 2.1, CI 1.2, 3.8, P = .012) occurred more frequently in the chorioamnionitis group. One hundred eighty-seven (68%) of 273 surviving neonates had follow-up. Cases and controls were similar in mean Bayley mental developmental index (91.2 compared with 91.8, P = .84), Bayley psychomotor developmental index (89.8 compared with 89.1, P = .82), and number of infants developmentally delayed. Duration of exposure to chorioamnionitis did not affect neonatal outcome.
Conclusion: Despite higher rates of sepsis and low Apgar scores, no difference in outcome at 7 months of corrected age was detected in VLBW infants exposed to chorioamnionitis. Contemporary neonatal management may reduce the adverse effects of this exposure.
Intrauterine infection is common in preterm deliveries. Garite and Freeman1 reported clinically diagnosed chorioamnionitis in 19% of 251 women with preterm premature rupture of the membranes (PROM) between 28 and 34 weeks. Similarly, Zlatnik et al2 diagnosed clinical chorioamnionitis in 21% of patients delivering before 35 weeks following either preterm PROM or preterm labor. The rate of clinical chorioamnionitis may be higher in deliveries at earlier gestations, particularly in those patients with preterm PROM. Major and Kitz-miller3 diagnosed clinical amnionitis in 43% of pregnancies complicated by second-trimester preterm PROM.
Clinical and microbial evidence of amnionitis has been associated with increased rates of neonatal morbidity. In infants delivered of patients with the clinical diagnosis of intrauterine infection, Morales4 found higher rates of neonatal mortality, respiratory distress syndrome (RDS), intraventricular hemorrhage, and sepsis. Garite and Freeman1 reported higher rates of perinatal death, RDS, and neonatal infection. Hillier et al5 noted that isolation of bacteria from the chorion and amnion was associated with an increased risk of neonatal death.
Two previous studies have examined the effect of chorioamnionitis on outcome in the first year of life. Hardt et al6 evaluated infants with birth weights less than 2000 g and found a lower mental developmental index at 12 months of age in those exposed to chorioamnionitis compared with those delivered after preterm PROM without chorioamnionitis. Although the infants exposed to chorioamnionitis were of earlier mean gestational age (28.8 compared with 30.1 weeks) and lower mean birth weight (1266 compared with 1438 g), the mental developmental index score difference remained after controlling for the effects of gestational age and birth weight. Chorioamnionitis was diagnosed by a scoring system that included parameters accessible only after delivery, including placental histology and postpartum fever. These criteria, therefore, cannot be used for the antepartum diagnosis and management of chorioamnionitis.
In a second study, Morales4 reported on infants delivered after preterm PROM at 26 to 34 weeks and found no difference in mean Bayley scores at 1 year of life between infants exposed to chorioamnionitis and controls. Chorioamnionitis was diagnosed by the presence of maternal fever. Subjects in the control group were selected to match the case group for the presence and severity of RDS and the grade of intraventricular hemorrhage, which may affect long-term neurodevelopment. Matching for these variables may diminish true differences in developmental scores between the groups. This is a particular concern because severe intraventricular hemorrhage occurred more often in infants exposed to chorioamnionitis in the study.
The purpose of this study, therefore, was to determine the relationship between maternal chorioamnionitis and the neonatal and follow-up status at 7 months of corrected age of very low birth weight (VLBW) infants. Our null hypothesis was that with improved perinatal/neonatal care in the 1990s, exposure to in utero chorioamnionitis would be associated with no difference in mean Bayley developmental scores in VLBW infants at 7 months of corrected age.
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Materials and Methods |
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Obstetric management of study subjects was based on the judgment of individual obstetricians independent of the investigation. In patients with preterm PROM, tocolytics and digital vaginal examinations were routinely avoided. Mothers with preterm labor were offered tocolytic therapy. Prophylactic antibiotic use and corticosteroid use were variable, and their frequency was noted. Surveillance for chorioamnionitis, based on individual obstetrician judgment, included serial fetal heart rate tracings, leukocyte counts, daily maternal vital signs, and examinations for fundal tenderness. Amniocentesis was performed in 27 of 358 cases (8%) for a presumptive diagnosis of chorioamnionitis. Cesarean delivery was performed for standard obstetric indications.
The subjects available for the study were all VLBW (less than 1250 g) infants born at Women and Infants’ Hospital of Rhode Island after preterm labor or preterm PROM and admitted to the special care nursery between January 1990 and December 1994. We chose VLBW infants as an appropriate group to study for the adverse effects of chorioamnionitis because they are particularly susceptible to exposure to an adverse intra-uterine environment and they were being followed developmentally in an established follow-up program at our center. The time period examined included a therapeutic intervention for neonates, surfactant, which improved neonatal outcome. All infants were free of known major congenital anomalies. Gestational age was determined by maternal menstrual history and antenatal fetal ultrasound. If satisfactory dating criteria were not available, the Ballard neonatal assessment score was used.8 Fetal growth restriction (FGR) was defined as a birth weight at less than the tenth percentile for gestational age, plotted on the Colorado Intra-uterine Growth Grid.9
Maternal charts were reviewed without knowledge of neonatal outcomes. Data were extracted from all cases of preterm labor and preterm PROM. These data included presence or absence of chorioamnionitis, duration of chorioamnionitis prior to delivery, duration of ruptured membranes, and route of delivery. Mothers were considered to have had preterm PROM if spontaneous rupture of membranes occurred before the onset of labor. Rupture of membranes was diagnosed in most cases by the presence on sterile speculum examination of vaginal pooling, ferning, and alkaline pH. Mothers were considered to have had preterm labor if delivery occurred after idiopathic preterm labor in the absence of preterm PROM. If appropriate classification was not apparent, charts were examined by a second reviewer and a consensus was reached.
The infants were evaluated prospectively in the neonatal follow-up clinic at 7 months’ corrected age (7 months from the estimated date of confinement) using the Bayley Scales of Infant Development.10,11 The Bayley Scales of Infant Development is a well standardized and frequently used research tool for the evaluation of developmental function in children in the first 30 months of life. The motor scale measures fine motor skills, muscle coordination, and degree of body control. Test results are expressed as a standard score, the psychomotor developmental index. The mental scale assesses such abilities as memory, problem solving, communication, and sensory-perceptual acuity. Test results are expressed as a standard score, the mental developmental index.
A power analysis indicated that 110 study subjects were needed to reject the two-sided null hypothesis with 80% power for a difference in mean Bayley scores of at least 8, which represents one-half standard deviation in the Bayley score. Based on a predicted prevalence of chorioamnionitis of 20%, 173 study subjects would be required. Specifically, a 20% prevalence corresponds to 35 case subjects and 138 control subjects required at 7-month follow-up. This was exceeded with 47 case subjects and 140 control subjects available. Statistical analyses were done using the two-tailed Student t test and Wilcoxon rank sum test for continuous variables and two-sided Fisher exact test for categoric data. Spearman rank correlation coefficients were calculated to evaluate the association between the Bayley developmental index scores and the interval of time from the diagnosis of chorioamnionitis until delivery. The study was approved by Women and Infants’ Hospital Institutional Review Board.
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Results |
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depicts the derivation of the study population. There were 519 liveborn deliveries of VLBW infants at Women and Infants’ Hospital between January 1, 1990, and December 31, 1994. Fifteen maternal charts (3%) were not available resulting in 504 charts reviewed. Of the 504 charts reviewed, 90 (18%) were delivered for maternal hypertension, and 52 (10%) were delivered for other conditions: bleeding (11), nonreassuring fetal testing (33), FGR (8). Four patients with preterm labor were excluded from the study group because of secondary complicating maternal conditions: two with human immunodeficiency virus positivity and one each with thyroid storm and asthma-induced adult RDS. The remaining 358 (71%) were delivered after preterm labor or preterm PROM. Twenty-eight subjects were excluded for not meeting Gibbs’ criteria but having a fever (26) or a positive AF Gram stain (2), leaving 330 study subjects. Of these 330 deliveries, 55 were multiple gestations (50 twins, five triplets). Only the firstborn of multiple gestations were included in the study.
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Maternal and delivery demographics are summarized in Table 1. Maternal age, parity, and gravidity were similar between groups. Antepartum antibiotic use was more common in mothers diagnosed with chorioamnionitis, but antepartum steroid use was similar. The median duration of ruptured membranes was longer. Infants in the chorioamnionitis group were also significantly more likely to have been delivered after preterm PROM. The frequency of nonvertex presentation was higher in the control group, but this difference did not reach statistical significance. The cesarean delivery rate was significantly higher in the control group.
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summarizes the indications for cesarean delivery for all infants delivered by cesarean. The frequency of cesarean for nonvertex presentation was higher in the control group. The frequencies of cesarean for other indications were similar between groups. Table 3 summarizes the route of delivery and cesarean indication for infants with nonvertex presentation. No statistically significant differences were detected between groups in the frequency of vaginal delivery or in the frequency of cesarean delivery for nonvertex presentation, nonreassuring fetal heart tracing, cord pro-lapse, or refusal of attempt of vaginal birth after cesarean.
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. The two study groups had similar gestational ages, birth weights, small for gestational age status, male sex, and surfactant use.
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depicts the neonatal morbidities. Survival for the chorioamnionitis and control groups did not differ (80.2% compared with 83.4%, respectively). Neonatal sepsis (positive blood culture in the first 48 hours of life) occurred significantly more often in the neonates exposed to chorioamnionitis (8.5% compared with 1.9%). Organisms responsible were coagulase-negative staphylococcus (four), group B streptococcus (two), Escherichia coli (two), Staphylococcus aureus, Streptococcus viridans, and Cedecea davisae (one each). The data were used to calculate the rate of sepsis per 1000 infants as shown in Table 5. A low 5-minute Apgar also occurred more often in the chorioamnionitis group. The rates of seizures, RDS, bronchopulmonary dysplasia, and intraventricular hemorrhage were similar for both groups, as were median peak serum bilirubin and median number of days of oxygenation, ventilation, and hospitalization.
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summarizes the Bayley development data at 7 months of corrected age. As depicted in the table, no difference in median mental developmental index or psychomotor developmental index scores was detected between the two groups. Furthermore, the frequency of both suspected (Bayley score less than 85 = one standard deviation [SD] below the mean) and of diagnosed developmental delay (Bayley score less than 70 = two SD below the mean) were similar. Although there were no statistically significant differences, almost twice as many infants in the chorioamnionitis group had mental developmental index scores in the abnormal range (13.0% compared with 7.2%).
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Table 7 depicts analyses assessing the effects of duration of exposure to chorioamnionitis. There were no differences in the frequency of sepsis, intraventricular hemorrhage, seizures, survival, low Apgar scores, RDS, or bronchopulmonary dysplasia between those infants exposed to chorioamnionitis at less than or greater than 6 hours. Median Bayley mental developmental index and psychomotor developmental index scores were similar, as were the mean days of ventilation, hospitalization, and oxygen use. Correlation between the length of in utero exposure to chorioamnionitis and mental developmental index score (coefficient = .027, P = .86) or psychomotor developmental index score (coefficient = .160, P = .29) at 7 months of corrected age were not significant.
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Discussion |
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Apgar scores at 5 minutes were significantly lower for the chorioamnionitis group, suggesting these infants were experiencing increased intrauterine stress. The importance of the increased (8.5%) prevalence of neonatal sepsis is confirmed as an important neonatal morbidity when it is viewed as a rate of 85 per 1000 infants. The finding of an increased frequency of neonatal sepsis in the chorioamnionitis group is supportive of prior studies showing chorioamnionitis associated with adverse outcomes in the special care nursery.1,4,5 In our series, both infants with group B streptococcal sepsis were in the chorioamnionitis group and both had grade III intraventricular hemorrhage. One died at 90 days of life, and one tested developmentally normal at 7 months of corrected age.
For the total study population, we did not identify a significant group difference of 7-month Bayley scores, supporting our null hypothesis. In that respect, our findings are more consistent with those of Morales4 than with those of Hardt et al.6 The present study differs from those of Hardt et al6 and Morales4 by studying infants delivered at a lower mean gestational age (26 weeks) and birth weight (895 g). Another difference is that we chose the criteria for clinical chorioamnionitis set forth by Gibbs et al.7 Gibbs’ criteria have been associated with microbiologic evidence of intrauterine infection, based on amniotic fluid showing bacteria and leukocytes, more frequent isolation of microbes from the AF at greater than 100 colony-forming units/mL, and higher rates of AF cultures positive for high-virulence organisms.7
Despite higher rates of sepsis and low Apgar scores, 7-month mental developmental index and physical developmental index scores were not different in these VLBW infants delivered after exposure to chorioamnionitis, perhaps as a function of improved special care nursery care in the 1990s. Since the publications of Hardt et al6 and Morales4 in the 1980s, changes in perinatal and neonatal care have occurred, including the use of surfactant. We cannot rule out the possibility that an improved level of neonatal care reduced the adverse effect of exposure to chorioamnionitis and contributed to similar long-term outcomes in the chorioamnionitis and control groups.
The higher rate of cesarean in the control group raises the issue of delivery management differences between groups. The higher cesarean frequency is accounted for largely by a higher cesarean rate due to fetal malpresentation. However, this different in cesarean rate for malpresentation appears to reflect a higher frequency of malpresentation in the control group rather than a difference in obstetric decision making. In examining cases of malpresentation (Table 3
), no difference was detected between groups in the frequency of cesarean for this indication. The diagnosis of preterm malpresentation appeared to prompt operative delivery, independent of suspicion for chorioamnionitis.
Infants in the chorioamnionitis group were more likely to be seen in the follow-up clinic compared with controls. It is possible that differences in the characteristics of the neonates account for the difference in the follow-up rate. For example, infants having more difficulty may be more likely to return for follow-up. However, no differences were detected in morbidity in the special care nursery between those presenting for follow-up compared with those who did not for both the cases and controls.
Another important issue addressed in our study is that of a critical interval, or interval of time following the diagnosis of intrauterine infection after which the neonatal risk of adverse outcome increases. At least four previous studies have examined this question, and were unable to identify an interval after which neonatal complications rose.1,4,15,16 Garite and Freeman did note that although neonatal outcome was not affected adversely by increasing duration of maternal fever, neonatal outcome was affected adversely if fever developed antepartum rather than intrapartum. Morales4 used greater and less than 6 hours as a breakpoint for analyses, similar to our approach. We also did not detect differences in outcome when comparing those exposed to chorioamnionitis for greater than or less than 6 hours. Whether such a critical interval exists continues to be an important unanswered question. For this reason and others, cesarean delivery generally is not carried out to hasten delivery for the solitary presumptive diagnosis of chorioamnionitis.
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Footnotes |
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Received October 19, 1998. Received in revised form February 8, 1999. Accepted February 10, 1999.
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References |
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2. Zlatnik FJ, Gellhaus TM, Benda JA, Koontz FP, Burmeister LF. Histologic chorioamnionitis, microbial infection, and prematurity. Obstet Gynecol 1990;76:355–9.
3. Major CA, Kitzmiller JL. Perinatal survival with expectant management of midtrimester rupture of membranes. Am J Obstet Gynecol 1990;163:838–44.[Medline]
4. Morales WJ. The effect of chorioamnionitis on the developmental outcome of preterm infants at one year. Obstet Gynecol 1987;70: 183–6.
5. Hillier SL, Krohn MA, Kiviat NB, Watts DH, Eschenbach DA. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol 1991;955–61.
6. Hardt NS, Kostenbauder M, Ogburn M, Behnke M, Resnick M, Cruz A. Influence of chorioamnionitis on long-term prognosis in low birth weight infants. Obstet Gynecol 1985;65:5–10.
7. Gibbs RS, Blanco JD, St. Clair PJ, Castaneda YS. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis 1982;145:1–8.[Medline]
8. Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard score, expanded to include extremely premature infants. J Pediatr 1991;119:417–23.[Medline]
9. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793–800.
10. Bayley N. Bayley scales of infant development. New York: Psychological Corp., 1969.
11. Bayley N. Bayley scales of infant development II. San Antonio, Texas: Psychological Corp., 1993.
12. Soper DE, Mayhall CG, Dalton HP. Risk factors for intraamniotic infection: A prospective epidemiologic study. Am J Obstet Gynecol 1989;161:592–6.
13. Dinsmoor MJ, Gibbs RS. Previous intraamniotic infection as a risk factor for subsequent peripartal uterine infections. Obstet Gynecol 1989;74:299–301.
14. Newton ER, Prihoda TJ, Gibbs RS. Logistic regression analysis of risk factors for intraamniotic infection. Obstet Gynecol 1989;73: 571–5.
15. Gibbs RS, Castillo MS, Rodgers PJ. Management of acute chorioamnionitis. Am J Obstet Gynecol;136:709–13.
16. Hauth JC, Gilstrap LC, Hankins GDV, Connor KD. Term maternal and neonatal complications of acute chorioamnionitis. Obstet Gynecol 1985;66:59–62.
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