Chorioamnionitis is a common obstetric complication associated with significant maternal and perinatal adverse outcomes.1–3 The clinical definition of chorioamnionitis varies, but usually includes maternal fever with two or more of the following: maternal tachycardia, fetal tachycardia, uterine tenderness, or purulent amniotic fluid drainage.
The long-term effects of chorioamnionitis on neurologic development in exposed fetuses are unclear. It is widely accepted that short-term potential sequelae of chorioamnionitis include neonatal sepsis, respiratory distress syndrome, bronchopulmonary dysplasia, and neonatal meningitis.4,5 Some studies have also suggested a link between chorioamnionitis and intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, and possibly developmental delay.6,7 Furthermore, some studies link chorioamnionitis with perinatal brain injury (specifically white matter brain injury)1,2,8,9; however, it is difficult to determine whether this association is causal, because some studies have found that prematurity rather than chorioamnionitis is the causal link.10,11 To better understand long-term neurodevelopmental outcomes after chorioamnionitis, we assessed whether clinical chorioamnionitis is associated with decreased neurocognitive function as measured by Bayley II scores.
MATERIALS AND METHODS
This is a secondary analysis of the Beneficial Effects of Antenatal Magnesium randomized controlled trial conducted through the Eunice Kennedy Shriver National Institute of Child Health and Development's Maternal-Fetal Medicine Units Network, which enrolled women at 20 centers across the country from December 1997 to May 2004. The purpose of the parent study was to assess whether antenatal magnesium decreased the rate of moderate or severe cerebral palsy or death in children who were at high risk of preterm birth. Women were considered eligible for the parent study if they presented at 24–31 weeks of gestation with a high likelihood of preterm delivery. Data were entered by trained study staff who were specifically credentialed to record the outcomes. Complete details of the study design and methods have been previously reported.12 This data set is publically available and de-identified and was therefore exempt from institutional review board review at our institution.
The current study is an observational cohort study. From the parent trial we included women with singleton gestations in whom exposure to chorioamnionitis was recorded and whose children had Bayley II scores available. Neonates with major malformations were excluded. Our primary exposure was chorioamnionitis, defined as a clinical diagnosis of chorioamnionitis and a temperature greater than 100°F. Culture-proven neonatal sepsis was defined as positive blood, urine, or cerebrospinal fluid cultures with suspicious clinical findings of infection on physical examination, clinical evidence of cardiovascular collapse, or unequivocal radiographic findings confirming infection in a neonate clinically appearing septic.
The Bayley Scales of Infant Development (Bayley scores) are a standardized series of measurements designed to assess for developmental delay in children ages 0–3 years. The current edition of Bayley scores, known as the Bayley III, is a comprehensive scale designed to assess cognitive, language, and motor skills along with social–emotional and adaptive behavior skills. In contrast, the prior editions of Bayley scores, the Bayley I and II, assessed only motor and cognitive skills. During the time of data collection in the parent trial, Bayley III scores had not yet been developed, and thus Bayley II scores were performed to assess both neuromotor and cognitive function at 2 years of age. The standardized mean Bayley II score is 100 with a standard deviation (SD) of 15. Our primary outcome was Bayley II Mental Developmental Index score or Psychomotor Developmental Index score dichotomized as greater or less than 2 SDs below the mean. Our secondary outcome was a Mental Developmental Index score or Psychomotor Developmental Index score dichotomized as greater or less than 1 SD from the mean.
Patient characteristics and other demographic variables were analyzed by χ2 tests for categorical variables and Student's t test for continuous variables. Nonparametric data were analyzed using Wilcoxon rank-sum tests. We then fit a log-linear regression model adjusting for possible confounders to assess factors related to Mental Developmental Index score or Psychomotor Developmental Index score less than 1 or 2 SDs below the mean. Log-linear regression was used to estimate relative risks, because a traditional logistic regression would yield an odds ratio that may overestimate the association of our outcome with our exposure. A P value of <.05 was considered significant. Given our fixed sample size incorporating our exclusions from the parent trial, with power set at 80% and a type I error rate of 5%, we estimated our detectable effect size would be a relative risk of 1.5 or greater.
Of 2,444 pregnancies in the parent study, we excluded 406 twin gestations, 409 gestations for missing Psychomotor Developmental Index scores, 16 gestations for missing Mental Developmental Index scores, and 39 gestations with neonates born with major congenital malformations (Fig. 1), leaving 1,574 women and their offspring eligible for inclusion in our analysis. Of the eligible women, 194 (12%) were diagnosed with chorioamnionitis (Fig. 1).
The majority of patients in the study (87%) had preterm premature rupture of membranes, and the mean gestational age at delivery was 29 3/7 weeks. Analysis of maternal characteristics by exposure showed that the two groups were similar in age, race, body mass index, exposure to antibiotics, diagnosis of ruptured membranes, and duration of ruptured membranes (Table 1). However, those patients diagnosed with chorioamnionitis were more likely to have more years of education and were more likely to be delivered by cesarean (Table 1). Analysis of neonatal characteristics by exposure showed that the children in both exposure groups were similar in rates of magnesium exposure and rates of neonatal sepsis (Table 2). Neonates exposed to chorioamnionitis were more likely to be born at an earlier gestational age and were more likely to have a 5-minute Apgar score less than 7 (Table 2).
Analysis of our primary outcome showed that 270 (17%) children had Mental Developmental Index scores less than 70, and 224 (14%) had Psychomotor Developmental Index scores less than 70. There was no difference in mean Psychomotor Developmental Index or Mental Developmental Index score between those with or without chorioamnionitis and no difference in the frequency of Psychomotor Developmental Index or Mental Developmental Index scores less than 70 between exposure groups (Table 2). There was a significant difference in the frequency of Psychomotor Developmental Index score less than 85 (76 [39%] compared with 433 [31%] P=.03) in those with or without chorioamnionitis; however, no difference was seen for Mental Developmental Index score less than 85 (Table 2).
We then fit a log-linear regression model adjusting for possible confounders to assess factors related to Mental Developmental Index or Psychomotor Developmental Index score less than 1 or 2 SDs below the mean. In our regression model, we adjusted for maternal age, race, body mass index, gestational age, days of membrane rupture (using less than 7 days as our reference group and categorizing days as less than 7, 7 to less than 14, and 14 or greater), magnesium exposure, delivery route, 5-minute Apgar score less than 7, neonatal sepsis, and maternal antibiotic exposure. We found that chorioamnionitis was not associated with a Mental Developmental Index score less than 85 or less than 70 (Table 3). In this model, proven neonatal sepsis was found to be independently associated with a Mental Developmental Index score less than 70 (adjusted relative risk 1.36, confidence interval 1.04–1.78); but sepsis was not associated with abnormal Psychomotor Developmental Index scores. Similarly, chorioamnionitis was not associated with a Psychomotor Developmental Index score less than 85 or less than 70 (Table 3). Of the neonates born to women diagnosed with chorioamnionitis, 19% (n=36) were noted to have sepsis (Table 2).
In our study, clinical chorioamnionitis was not associated with decreased mental or psychomotor developmental scores in children at age 2 years. However, a diagnosis of neonatal sepsis was associated with a decreased Mental Developmental Index. Thus, only neonatal sepsis was associated with significant long-term neurocognitive deficits as measured by Bayley II scores at age 2 years.
Our study has several strengths. First, this is a secondary analysis and a retrospective observational cohort study based on data from a large randomized controlled trial with both a large sample size and a large number of variables helping to strengthen our overall results. Moreover, our findings are based on standardized neurodevelopmental scales, the Bayley II scales, which are more substantive than the standard screening tests performed in most children at 24 months, making our conclusions regarding neurodevelopmental outcomes more compelling. It is important to note that the children in the primary study were evaluated using the Bayley II developmental scales, which are known to consistently overestimate neurologic impairment as compared with the Bayley III developmental scales.13 However, given that both scales are standardized, we would expect testing results to be proportionately lower across exposure groups (as compared with Bayley III scores); thus, we would not expect changes in the overall differences between exposure groups.
There are also several important limitations to this study. First, the patient cohort in this study comprised patients at high risk for preterm delivery, making it difficult to generalize these results to neonates delivered at term. Second, we only had sufficient statistical power to detect relative risks greater than 1.5. Third, the definition of chorioamnionitis used in this study was broad, based on a temperature of 100°F and a clinical diagnosis of chorioamnionitis by the documenting physician. It is possible that more severe forms of chorioamnionitis are associated with subsequent childhood neurologic impairment.
Only a few studies have looked at long-term neurodevelopmental outcomes in children exposed to chorioamnionitis. Even fewer studies have looked at rigorous markers of neurocognitive development such as the Bayley Scales of Infant Development. Furthermore, the majority of the studies with Bayley score data have looked at neurodevelopmental outcomes in only extremely preterm (less than 28 weeks of gestation) or low birth weight neonates, making it difficult to generalize the results to the general obstetric population.14–16 The effect of prematurity on neurodevelopmental outcome also further confuses the picture, because some studies have found that prematurity alone is associated with lowered Bayley scores,17 whereas others note prematurity, rather than chorioamnionitis, as the likely causal factor in poor neurodevelopmental outcomes.10,11 However, in our study, we adjusted for gestational age, and our findings are based on a larger cohort of children, which includes extremely preterm, late preterm, and term neonates, making them more applicable to the general population. Other studies such as those by Pappas et al18 and Salas et al,19 both of which found poor neurodevelopmental outcomes to be associated with a diagnosis of chorioamnionitis, based their conclusions on histologic chorioamnionitis, making it difficult to utilize their results for practice in a clinical setting.
Given our finding of a significant association between proven neonatal sepsis and decreased mental developmental scores at age 2 years, it is reasonable to presume that there is indeed some link between exposure to an inflammatory environment and poor neurologic development. This may indicate that, although chorioamnionitis is not associated with poor neurodevelopmental outcomes, one of its sequelae, namely sepsis, may place neonates at risk for future neurocognitive dysfunction. The broad definition of clinical chorioamnionitis used in our study as well as in current clinical practice may be a reason for the lack of correlation between chorioamnionitis and sepsis and demonstrates the need for an improved definition for chorioamnionitis.
In conclusion, we could not demonstrate an association between clinical chorioamnionitis and poor neurocognitive function as measured by Bayley scores. The poor correlation between clinical chorioamnionitis and sepsis suggests the need for an alternative approach to identify neonates at risk for sepsis, which may guide antenatal management strategies.
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© 2016 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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