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Prenatal inflammation is associated with adverse neonatal outcomes
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OBSTETRICS
Prenatal inflammation is associated with adverse neonatal outcomes Jamie A. Bastek, MD, MSCE; Anita L. Weber, PhD; Meghan A. McShea, BS; Meghan E. Ryan, BA; Michal A. Elovitz, MD OBJECTIVE: The purpose of this study was to determine whether
prenatal inflammation (as assessed by clinical chorioamnionitis, maternal temperature >38 C, or histologic chorioamnionitis) is associated with a composite adverse neonatal outcome. STUDY DESIGN: We performed a prospective cohort study of women
at 22 weeks to 33 weeks 6 days’ gestation with symptoms of labor (April 2009 to March 2012). Relevant maternal and neonatal exposures and outcomes were recorded. Multivariable logistic regression was performed to determine the association between prenatal inflammation and neonatal outcomes that were controlled for potential confounders. RESULTS: We analyzed 871 mother-infant pairs. The preterm birth
rate was 42.0%. When we controlled for infant sex and modified the data by gestational age at delivery, prenatal inflammation remains a significant risk factor for adverse neonatal outcomes, despite
advancing gestational age: clinical chorioamnionitis at 32 weeks’ gestation (odds ratio [OR], 3.12; 95% confidence interval [CI], 1.02e9.52], at 36 weeks’ gestation (OR, 8.88; 95% CI, 4.32e18.25), and at 40 weeks’ gestation (OR, 25.30; 95% CI, 9.25e69.19); maternal temperature >38 C at 32 weeks’ gestation (OR, 3.18; 95% CI, 0.66e15.42), at 36 weeks gestation (OR, 8.40; 95% CI, 3.60e19.61), and at 40 weeks gestation (OR, 22.19; 95% CI, 8.15e60.44); histologic chorioamnionitis at 32 weeks gestation (OR, 1.25; 95% CI, 0.64e2.46), at 36 weeks gestation (OR, 2.56; 95% CI, 1.54e4.23), and at 40 weeks gestation (OR, 5.23; 95% CI, 1.95e13.99). CONCLUSION: The protective association with advancing gestational age is diminished when prenatal inflammation is present.
Key words: adverse neonatal outcome, chorioamnionitis, placenta, prenatal inflammation, preterm birth
Cite this article as: Bastek JA, Weber AL, McShea MA, et al. Prenatal inflammation is associated with adverse neonatal outcomes. Am J Obstet Gynecol 2014;210:450.e1-10.
O
ver the last 20 years, evidence has emerged to suggest that prenatal inflammation and/or intrauterine infection leads to the activation of localized inflammatory pathways, plays a critical role in at least 25-40% of spontaneous preterm births,1-6 and is a significant contributor to the development of adverse neonatal outcomes.7-9 Prenatal inflammation that predisposes to spontaneous preterm birth and adverse neonatal outcomes may occur in the form of either histologic (HCA)10-13
and/or acute clinical14-22 chorioamnionitis (CCA). The association between acute CCA or perinatal infection23 and adverse neonatal outcomes (which includes sepsis,24-27 respiratory compromise,20,25,27-31 necrotizing enterocolitis,20,31-33 intraventricular hemorrhage,20,25,27,34,35 and long-term outcomes such as cerebral palsy21,36-45 and neonatal death18,25) has been wellestablished. However, most of these studies have been small and retrospective and have focused on the prevalence of
From the Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women’s Health (Drs Bastek and Elovitz, Ms McShea, and Ms Ryan), and the Department of Biostatistics and Epidemiology (Dr Weber), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Received July 8, 2013; revised Dec. 6, 2013; accepted Dec. 17, 2013. Supported by a March of Dimes grant (21-FY08-539; principal investigator, M.A.E.). The authors report no conflict of interest. Presented in poster format at the 32nd annual meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Feb. 6-11, 2012. Reprints: Jamie A. Bastek, MD, MSCE, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce St, 585 Dulles Bldg, Philadelphia, PA 19104. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.12.024
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adverse neonatal outcomes in cohorts of preterm infants. As a result, many investigators attribute the risk of adversity to gestational age at delivery rather than prenatal inflammation.46 Furthermore, studies that have examined the risks of inflammation to term neonates have concluded that inflammation poses only minimal risk.47,48 As a result, the relative contributions of preterm birth and prenatal inflammation to adverse neonatal outcomes are yet to be determined. To that end, our primary objective was to determine whether prenatal inflammation that is assessed by acute CCA, maternal temperature >38 C in the 24 hours preceding delivery, or postpartum diagnosis of HCA was associated with a composite adverse neonatal outcome variable (COMP). Secondary objectives were to determine the association between prenatal inflammation and the individual adverse neonatal outcomes sepsis and respiratory compromise. Our hypotheses were that, for all outcomes, prenatal inflammation would be associated with an increased risk for neonatal adversity and that these associations
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TABLE 1
Association between demographic variables and prenatal inflammation (n [ 871) Exposure Demographic characteristics
Present
Not present
P valuea
Clinical chorioamnionitisb Preterm birth <37 wk, n (%) Gestational age at delivery, wk
28 (49)
338 (42)
34.93 5.48
c
36.60 3.38
Race, n (%)
.26 .34 .29
Black
47 (82)
668 (82)
White
4 (7)
94 (12)
Asian
4 (7)
24 (3)
Other
2 (4)
28 (3)
Infant male sex, n (%)
33 (58)
436 (54)
.53
Corticosteroids, n (%)
27 (47)
269 (33)
.03
Maternal age, y
c
Gestational age at enrollment, wkc
24.97 6.08
25.62 6.08
.48
29.35 3.24
30.36 3.66
.03
Temperature >38 Cd Preterm birth <37 wk, n (%) Gestational age at delivery, wk
15 (31)
351 (43)
37.41 3.89
c
36.44 3.55
Race, n (%)
.003 .60
Black
40 (82)
675 (82)
White
4 (8)
94 (11)
Asian
3 (6)
25 (3)
Other
2 (4)
28 (3)
32 (65)
437 (53)
.10
Corticosteroids, n (%)
12 (24)
284 (35)
.15
Maternal age, yc
24.37 5.84
25.65 6.09
.12
30.12 3.19
30.31 3.67
.50
Infant male sex, n (%)
Gestational age at enrollment, wk Histologic chorioamnionitis
c
e
Preterm birth <37 wk, n (%) Gestational age at delivery, wk
160 (72)
206 (32)
33.75 4.72
c
37.44 2.47
Race, n (%)
< .001 < .001 .16
Black
192 (86)
523 (81)
White
16 (7)
82 (13)
Asian
8 (4)
20 (3)
Other
7 (3)
23 (4)
Infant male sex, n (%)
121 (54)
348 (54)
.89
Corticosteroids, n (%)
125 (56)
171 (26)
< .001
25.62 6.18
Maternal age, yc Gestational age at enrollment, wk a
.10
c
29.86 3.77
25.57 6.05
.93
30.45 3.59
.04
Determined by c test (categoric data) and Kruskal-Wallis rank test (continuous data); Present, 57; not present, 814; c Data presented as mean SD; d Present, 49; not present, 822; e Present, 223; not present, 648. 2
b
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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would persist when adjustment was made for gestational age at delivery.
M ATERIALS
AND
M ETHODS
We performed a prospective cohort study at a single, urban tertiary care center. The cohort consisted of women with singleton pregnancies at 22 weeks to 33 week 6 days’ gestational age who came to the labor and delivery triage unit with complaints concerning preterm labor. Patients were excluded for multiple-gestation, major fetal anomaly, intrauterine fetal death, severe preeclampsia before enrollment, chronic steroid or immunosuppressive drug use, active immunologic disease, acute systemic febrile illness, and/or pregestational diabetes mellitus. Patients who either were not delivered at our institution or whose infants were transferred to a different hospital for care were also excluded from these analyses. Patients were enrolled in the study by trained clinical research coordinators who obtained informed consent at the time of enrollment. Once a patient was enrolled in the study, all treatment decisions were made by the treating physician according to the standard of care at our institution. Women were enrolled from April 2009 through March 2012. At our institution, maternal fever is diagnosed as a temperature >38 C. Maternal temperature is recorded on laboring patients every 4 hours while membranes are intact and hourly after membranes are ruptured. A diagnosis of temperature >38 C was obtained from review of the electronic nursing records in the 24 hours preceding each patient’s delivery. Acute CCA is diagnosed in the setting of maternal temperature >38 C and at least 1 of the following occurrences: maternal tachycardia (100 beats per minute), fetal tachycardia (>160 beats per minute), and/or fundal tenderness. Patients who receive a diagnosis of acute CCA who are not in spontaneous labor are induced at the time this diagnosis is made. HCA is a diagnosis that is made by the pathologist after microscopic examination of the placenta and is defined as the presence of neutrophils in the chorion or amnion.
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Pathologists were unaware of whether patients were enrolled in the study and/ or whether their neonates had any adverse outcomes. If the placenta was not sent to pathology, then HCA was assumed to be not present.
TABLE 2
Association between demographic and composite adverse neonatal outcome variables No composite Composite adverse adverse neonatal neonatal outcome outcome variable P valuea variable (n [ 168) (n [ 703)
Demographic characteristic
Data collection After enrollment, each patient was tracked for the remainder of her pregnancy. Relevant maternal information that included pertinent medical, surgical, and gynecologic histories was recorded; relevant delivery information was obtained through chart review. Whether antenatal corticosteroids were administered, whether HCA or CCA was diagnosed, and the highest maternal temperature within 24 hours before delivery were also noted. Relevant neonatal information that included gestational age at delivery, mode of delivery, infant sex, birthweight, and nursery admission were recorded.
Preterm birth <37 wk, n (%)
143 (85)
Gestational age at delivery, wk
223 (32)
32.01 4.59
b
37.57 2.21
Race, n (%)
< .001 < .001 .73
Black
140 (83)
575 (82)
White
16 (10)
82 (12)
Asian
7 (4)
21 (3)
Other
5 (3)
25 (4)
Infant male sex, n (%)
98 (58)
371 (53)
.19
Corticosteroids, n (%)
112 (67)
184 (26)
< .001
b
Maternal age, y
Gestational age at enrollment, wk a
b
26.07 6.12
25.46 6.07
.15
29.13 3.77
30.58 3.56
< .001
Determined by c2 test (categoric data) and Kruskal-Wallis rank test (continuous data); b Data presented as mean SD.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
TABLE 3
Association of composite neonatal outcome with prenatal inflammation (n [ 871) Composite adverse neonatal outcome variable, n (%) Prenatal Inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.0)
Not present 25 (3.6)
Crude
Adjusted
c
Crude/adjusted odds ratio Interaction < .001
6.38 (3.66e11.11)
32
3.12 (1.02e9.52)
< .05
36
8.88 (4.32e18.25) < .001
40
25.30 (9.25e69.19) < .001
Temperature >38 C, wk
20 (11.9)
29 (4.1)
3.18 (0.66e15.42)
.15
36
8.40 (3.60e19.61) < .001
40
22.19 (8.15e60.44) < .001
Histologic chorioamnionitis, wk
101 (60.1) 122 (17.4)
32
1.25 (0.64e2.46)
.51
36
2.56 (1.54e4.23)
< .001
40
5.23 (1.95e13.99) < .001
n ¼ 168; b n ¼ 703; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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.061
< .001
7.18 (4.98e10.34)
CI, confidence interval.
< .01
< .001
3.14 (1.73e5.70)
32
a
P value
Odds ratio (95% CI) b
< .05
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FIGURE 1
100 90 80 70 60 50 40 30 20 10 0
Odds Ratio of Clinical Chorioamnionitis
Odds ratios for composite neonatal outcome by clinical chorioamnionitis exposure
25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
Neonatal chart abstraction was performed, and the presence of key diagnoses was determined by review of the documentation of the attending neonatologist or pediatrician who assessed each infant. Such key diagnoses included presumed (diagnosis by neonatology attending based on clinical presentation for which 7 days of antibiotics were administered) or proved (culture positive) sepsis, respiratory compromise (need for continuous positive airway pressure or mechanical ventilation beyond the delivery room), seizures, necrotizing enterocolitis (diagnosed both clinically and radiographically), intraventricular hemorrhage (grades III-IV), and/or death before discharge. Neonatal information was limited to those events that occurred between delivery and the infant’s discharge home from the hospital. The use of a surrogate composite variable for cases in which individual outcomes were of low prevalence has been performed in previous neonatal studies.49-51 Therefore, a COMP was
created to summarize neonatal outcomes for the primary outcome of this study. A neonate was classified as having the primary composite outcome if at least one of the adverse outcomes listed earlier (sepsis, respiratory compromise, seizures, necrotizing enterocolitis, intraventricular hemorrhage, and/or death) was present. A neonate was classified as having one of the secondary outcomes if either presumed or proven sepsis or respiratory compromise were present, as defined earlier. Preterm birth was defined as delivery at <37 weeks’ gestational age.
Data analyses Associations between categoric variables were examined with chi-squared analyses. Normality for continuous variables was assessed with the Shapiro-Wilk test for normality. Where a normal distribution could be ruled out, the Kruskal Wallis equality-of-populations rank test was used to test differences. Although our choice of 38 C as a cut point for the variable to assess elevated
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maternal temperature was made (38 C represents a fever at our institution) before any analyses were performed, we verified that this cut-point was the most associated with COMP among candidate cut-points of 37, 37.5, 38, and 38.5 C in both raw models of COMP that were associated with a “yes/no” higher temperature and full models that included interaction of temperature with gestational age at delivery and adjustment by male sex (data not shown). Multivariable logistic regression was performed to determine the association between each form of prenatal inflammation (CCA, temperature >38 C [T38], and HCA) and both composite and individual adverse neonatal outcomes (neonatal sepsis and respiratory compromise). To control for potential confounding of the association of composite neonatal outcome and prenatal inflammation, we selected potential confounders for testing based on the association with adverse neonatal outcome found in the literature, which included gestational age at presentation with preterm labor, antenatal corticosteroid treatment, maternal age, and maternal race. Modeling strategy was change-in-estimate of the inflammation variable over a multivariable baseline model of adverse outcome and inflammation that included gestational age at delivery in weeks and infant sex, which were selected because their clinical relevance. Potential confounders were examined individually and, if associated with a 5% change in the regression coefficient of the indicator of prenatal inflammation (ie, the “change in 5% rule”), was retained in the model. Because we believed that gestational age would modify the association between inflammation and adverse neonatal outcomes, we tested the interaction of gestational age at delivery in weeks with inflammation in association with adverse neonatal outcomes. Goodness of fit for the multivariable models was assessed with the use of the HosmerLemeshow c2 test,52 where a large probability value indicates that the model is well-fit. We used a threshold of a probability value of > .05. Areas under the receiver operating characteristic curve
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Sample size A priori sample size calculations were performed to determine how many mother-infant pairs would be needed to detect a 2.5-fold increase in the prevalence of COMP between those infants who were exposed to prenatal inflammation compared with those who were not exposed. Based on previously published data from our institution, we estimated that the prevalence of COMP among infants who were not exposed to prenatal inflammation was 6.0%.50 Assuming 90% power, a type I error of 5%, and an enrollment ratio of 1:4 between those with and without prenatal inflammation exposure, we determined we would require 850 mother-infant pairs. This study was approved by the institutional review board at the University of Pennsylvania (Philadelphia, PA).
R ESULTS Delivery information was available to analyze for 871 women and their infants. The rate of preterm birth in this highrisk cohort was 42.0%. The cohort prevalence of CCA was 6.5% (n ¼ 57), of T38 was 5.6% (n ¼ 49), and of HCA was 25.6% (n ¼ 223). Most patients with CCA or T38 had other inflammatory exposures. Specifically, 87.7% of the women with CCA also had HCA, and
FIGURE 2
10
20
30
40
50
60
70
80
90
100
Odds ratios for composite neonatal outcome by temperature exposure
0
(AUC) for each multivariable model were calculated and compared with the use of a statistical receiver-operator curve area comparison test. Multivariable models with each prenatal inflammation variable were compared with each other variable to determine whether 1 particular prenatal inflammation variable had superior discriminatory ability to the others and to verify that each multivariable model that included a prenatal inflammation variable was significantly more discriminatory than the model that included only gestational age at delivery and infant sex. In all analyses, a probability value of < .05 was considered statistically significant, and probability value of < .10 was the threshold for display of an interaction. Stata software (version 10.1; StataCorp, College Station, TX) was used for all analyses.
Odds Ratio of Yes/No Temperature > 38 deg C
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25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
64.9% of the women with CCA had T38; 75.5% of the women with T38 also had CCA, and 79.6% of the women with T38 had HCA. However, only 22.4% of the women with HCA had CCA, and 17.5% of the women with HCA had T38. We compared demographic variables among women with and without exposure to prenatal inflammation. The demographic variables that were associated significantly with HCA exposure (Table 1) were preterm birth, gestational age at delivery, antenatal corticosteroids, and gestational age at enrollment. For CCA, associations were limited to antenatal corticosteroids and gestational age at enrollment, and the associations for T38 were limited further to gestational age at delivery. Preterm birth, gestational age at delivery, antenatal corticosteroids, and gestational age at enrollment were also associated significantly with the primary outcome COMP (Table 2). To address our primary objective, we determined whether prenatal inflammation (measured by CCA, T38, and HCA) was associated with COMP. In bivariate
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analyses, all measures of prenatal inflammation were associated significantly with increased risk. Furthermore, gestational age at delivery significantly modified the association of both CCA (P < .01) and HCA (P < .05) on COMP and trended towards significance of T38 on COMP (P ¼ .061; Table 3). The inclusion of the potential confounders antenatal corticosteroid use, maternal age, or maternal race 1 at a time in the multivariable main-effects models of COMP resulted in changes of <5% of the regression coefficient of any of the indicators of prenatal inflammation and therefore were not included in the final model. To better understand the interaction of gestational age at delivery and prenatal inflammation, we graphed the odds ratio (OR) of prenatal inflammation in association with COMP using CCA (Figure 1), T38 (Figure 2), and HCA (Figure 3) as a function of gestational age at delivery from 25-41 weeks. All models were modified by gestational age at delivery and controlled for infant sex.
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FIGURE 3
20 18 16 14 12 10 8 6 4 2 0
Odds Ratio of Histological Chorioamnionitis
Odds ratios for composite neonatal outcome by histologic chorioamnionitis exposure
25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
The OR of each model is significantly different from 1.0, which is the OR of the group without inflammation exposure, starting at week 32 for CCA, 33 for T38, and 34 for HCA and continues to increase with increasing age. In infants at 32-34 weeks’ gestational age that were not exposed to prenatal inflammation, there was a sharp decrease in COMP. However, in those infants who were exposed, the magnitude of this decrease was not as great, which suggests that the protective association with advancing gestational age is diminished when prenatal inflammation is present (data not shown). To attach numbers to the ORs and 95% confidence intervals (CIs) found in the Figures, we selected 3 gestational ages (32, 36, and 40 weeks; Table 3). The inclusion of the potential confounders antenatal corticosteroid use, maternal age, or maternal race 1 at a time in the multivariable main-effects models of COMP resulted in changes of <5% of the regression coefficient of any of the indicators of prenatal inflammation and
therefore were not included in the final model. Secondary objectives were to determine the association between prenatal inflammation and individual adverse outcomes of neonatal sepsis and respiratory compromise. As with COMP, gestational age at delivery significantly modified the association with both CCA (P < .01) and T38 (P < .05) on neonatal sepsis but was not significant between HCA and neonatal sepsis (P ¼ .59). Through selection of 3 gestational ages at delivery (32, 36, and 40 weeks), we found that the associations between prenatal inflammation and neonatal sepsis continued to be significant when modified by gestational age at delivery and controlling for infant sex, again with relatively larger ORs for neonatal sepsis associated with more advanced gestational ages (CCA at 32 weeks [OR, 2.80; 95% CI, 1.36e5.77], at 36 weeks [OR, 7.23; 95% CI, 3.25e16.10], and at 40 weeks [OR, 18.70; 95% CI, 5.79e60.39]; T38 at
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32 weeks [OR, 3.03; 95% CI, 1.05e8.74], at 36 weeks [OR, 7.09; 95% CI, 3.07e16.35], and at 40 weeks [OR, 16.58; 95% CI, 5.17e53.23]). Because the interaction of HCA and age was not significant, the association of HCA with neonatal sepsis was estimated in a main effect model when controlled for gestational age at delivery and infant sex. It was significant (P < .01) with an OR of 3.18 (95% CI, 1.65e6.13). Similarly, gestational age at delivery modified the association with CCA (P < .05) and T38 (P ¼ .052, with the probability value of a < .10 threshold for reporting results of an interaction) on respiratory compromise but did not modify the effect between respiratory compromise and HCA (P ¼ .18). Through sampling the same 3 gestational ages, we found that the associations between prenatal inflammation and respiratory compromise continued to be significant at older gestational ages when modified by gestational age at delivery and controlling for infant sex (CCA at 32 weeks [OR, 2.24; 95% CI, 0.79e6.33], at 36 weeks [OR, 5.74; 95% CI, 2.60e12.63], and at 40 weeks [OR, 14.69; 95% CI, 4.24e50.91]; T38 at 32 weeks [OR, 1.94; 95% CI, 0.47e7.94], at 36 weeks [OR, 5.27; 95% CI, 2.25e12.35], and at 40 weeks [OR, 14.32; 95% CI, 4.21e48.65]) The association of HCA with respiratory compromise, which was estimated in a main effects model that controlled for gestational age at delivery and infant sex, was not significant (OR, 1.48; 95% CI, 0.87e2.52) in contrast with neonatal sepsis. AUC for each multivariable logistic model to discriminate between those patients who did vs did not experience COMP were calculated and compared. Accounting for effect modification by gestational age at delivery and controlling for infant sex, the discriminatory ability of each prenatal inflammation variable was very strong (CCA AUC, 0.89; T38 AUC, 0.89; HCA AUC, 0.88). Although the multivariable model that included only gestational age at delivery in weeks and infant sex had similar clinical ability to discriminate for COMP (AUC, 0.86), the AUC was significantly smaller than a model that also included
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either CCA (P < .05), T38 (P < .05), or HCA (P < .05). Finally, we performed analyses parallel to those that are reported in Table 3 on subsets of patients without preeclampsia (Table 4) and without induction of labor (Table 5). In both restricted samples, similar results were found to those in the complete cohort. Probability values of the interaction between prenatal inflammation and gestational age at delivery were within 0.10, which was our threshold for display. All indices of prenatal inflammation showed increasing OR in association with COMP with increasing gestational age at delivery (data not shown).
C OMMENT Previous studies have described an association between CCA and HCA and both preterm birth and adverse neonatal outcomes that include sepsis, respiratory distress, necrotizing enterocolitis, intraventricular hemorrhage, cerebral palsy, and death.24-43,53-
57
However, many of these studies have been smaller and retrospective in design and, as a result, are more limited in their ability to describe the relationship between these exposures and relevant outcomes.58 Furthermore, because of the increased risk for chorioamnionitis with decreasing gestational age, most previous studies focused on the role of preterm birth, rather than the role of prenatal inflammation per se, in contributing to such neonatal adversity.53,54,59-63 Although our study found that gestational age does modify the association with prenatal inflammation on neonatal outcomes, the associations of inflammation on the neonatal outcomes are significant from 32-34 weeks’ gestational age of delivery and persist after adjustment for a variety of potential confounders: infant sex, maternal age, maternal race, gestational age at enrollment and antenatal corticosteroids. Thus, in the presence of evidence of inflammation-related exposures, the risk
of adverse outcome increases even after adjustment for potential confounders.
Strengths and limitations Our study had several strengths. Our patients were identified prospectively, thus limiting misclassification bias by ensuring that our cohort consisted of women at high risk for preterm birth because of symptoms of preterm labor. Eligibility criteria for enrollment were determined before the start of the study by the primary and senior authors and not by the treating physician, thereby minimizing potential enrollment biases. Diagnoses of HCA were made by the pathologist without knowledge of neonatal outcomes. Finally, although our choice of 38 C as a cut point for an intrapartum maternal fever was made because 38 C represents a fever at our institution, we also verified that this cut-point was the most associated with COMP in multivariable and bivariable models.
TABLE 4
Association of composite neonatal outcome with prenatal inflammation, excluding preeclampsia (n [ 849) Composite adverse neonatal outcome, n (%) Odds ratio (95% CI) Prenatal inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.5)
b
Not present 24 (3.5)
Crude
36
Crude/adjusted odds ratio Interaction < .001
2.98 (0.98e9.07) 9.30 (4.51e19.18)
.055 < .001
20 (12.2)
28 (4.1)
< .001
3.26 (1.79e5.95)
32
3.01 (0.63e14.48)
.17
36
8.75 (3.75e20.41)
< .001
40
25.44 (9.16e70.65)
< .001
Histologic chorioamnionitis, wk
< .01
29.05 (10.41e81.07) < .001
40
100 (61.0) 113 (16.5)
32
1.33 (0.67e2.65)
.41
36
2.63 (1.56e4.42)
< .001
40
5.19 (1.88e14.37)
< .05
n ¼ 164; b n ¼ 685; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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< .05
< .001
7.91 (5.45e11.49)
CI, confidence interval. a
Adjusted
6.68 (3.81e11.70)
32
Temperature >38 C, wk
P value c
.055
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TABLE 5
Association of composite neonatal outcome with prenatal inflammation, excluding inductions (n [ 819) Composite adverse neonatal outcome variable, n (%) Prenatal inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.8)
Not present 20 (3.0)
P value
Odds ratio (95% CI) b
Crude
Adjusted
c
Crude/adjusted odds ratio Interaction < .001
7.84 (4.35e14.14)
32
3.06 (1.02e9.20)
< .05
36
10.72 (5.13e22.38)
< .001
40
37.57 (13.04e108.22) < .001
Temperature >38 C, wk
20 (12.3)
24 (3.6)
< .001
3.71 (2.00e6.91)
32
2.96 (0.63e13.85)
.15
36
9.68 (4.15e22.60)
< .001
40
31.66 (11.14e89.96)
< .001
Histologic chorioamnionitis, wk
100 (61.7) 109 (16.6)
< .01
< .05
< .001
8.11 (5.56e11.83)
32
1.29 (0.65e2.57)
.47
36
2.70 (1.59e4.57)
< .001
40
5.64 (1.99e15.96)
< .05
< .05
CI, confidence interval. a
n ¼ 162; b n ¼ 657; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
Except for very large cohort studies with an investigation of neonatal outcomes, it often becomes necessary to create a composite outcome. In this study because several of our individual adverse outcomes were of low prevalence, we did need to create a composite outcome. Although there are some noted limitations in creating a composite outcome, this approach has been done in several other studies and still can provide meaningful information.49-51 Of note, although we assumed that the relationship between advancing gestational age and adverse neonatal outcomes was linear, it may be possible that this association is nonlinear at the extremes of gestational age. To explore this possibility would require a much more robust population of both early preterm and term infants; therefore, we are underpowered to investigate this relationship with our current sample size. Not all term placentas were reviewed by a pathologist. For statistical purposes, we assumed that those placentas not
sent to pathology were they tested negative for HCA. However, previously published data suggest that CCA and T38 may be poor surrogates for HCA64,65; therefore, many of the placentas that were assumed to have been low risk for HCA (based on lacking clinical suspicion) actually may have been positive for HCA. Therefore, we believe that, through coding this missing data as negative, we may have biased our results to the null. Had these data not been missing, we believe that the strength of the association that we observed between HCA and COMP would be only stronger. Neonatal diagnoses were made by the attending neonatologist or pediatrician who cared for the infant. Because there was not a single provider diagnosing all of the infants, there may have been bias secondary to interpractitioner variability in diagnostic criteria. To what degree this may have introduced unnecessary bias is unclear. Additionally, we did not have access to records of infants who
were transferred to another hospital after birth, to long-term neonatal outcomes, or to hospital readmissions, which limited our ability to assess healthcare use and chronic neonatal adverse outcomes such as lung disease. However, because of the difficulty in obtaining data describing long-term neonatal wellbeing, other obstetric studies have included preterm birth, gestational age at delivery, and immediate postpartum outcomes as surrogate outcomes of interest. Furthermore, there are data to suggest that short-term adverse outcomes may be associated with increased risk of chronic disease with inherent morbidity and with increased risk of long-term disease.60 Consequently, we believe that these findings provide important information about the risk from exposure to prenatal inflammation. This study provides further evidence that exposure to prenatal inflammation alters neonatal risk. Importantly, although prematurity is a known risk factor for adverse neonatal outcomes,
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prenatal inflammation increases the odds of adverse outcomes, and the protective association with advancing gestational age is diminished when prenatal inflammation is present. What must be considered is whether the measured markers of exposure for this study (CCA, T38, and HCA) are late findings of prenatal inflammation and whether fetuses are exposed to prenatal inflammation days, if not weeks, before these clinical findings. If true, then our current treatment of tocolysis for women with preterm labor and/or delaying delivery of patients with preterm premature rupture of membranes to deliver older neonates might not be the most beneficial strategy to decrease neonatal adversity if this tradeoff prolongs fetal exposure to prenatal inflammation. Understanding that prenatal inflammation dramatically increases the likelihood of adverse neonatal outcomes, therapeutic strategies to target women with these exposures should be considered and pursued. -
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9. Romero R, Gomez R, Ghezzi F, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998;179:186-93. 10. Russell P. Inflammatory lesions of the human placenta; III, the histopathology of villitis of unknown aetiology. Placenta 1980;1:227-44. 11. Mueller-Heubach E, Rubinstein DN, Schwarz SS. Histologic chorioamnionitis and preterm delivery in different patient populations. Obstet Gynecol 1990;75:622-6. 12. Yoon BH, Romero R, Park JS, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 2000;183:1124-9. 13. Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 2000;284:1417-24. 14. Sperling RS, Newton E, Gibbs RS. Intraamniotic infection in low-birth-weight infants. J Infect Dis 1988;157:113-7. 15. Gibbs RS, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991;164: 1317-26. 16. Yoder PR, Gibbs RS, Blanco JD, Castaneda YS, St Clair PJ. A prospective, controlled study of maternal and perinatal outcome after intra-amniotic infection at term. Am J Obstet Gynecol 1983;145: 695-701. 17. Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol 1999;94:274-8. 18. Morales WJ, Washington SR 3rd, Lazar AJ. The effect of chorioamnionitis on perinatal outcome in preterm gestation. J Perinatol 1987;7:105-10. 19. Lau J, Magee F, Qiu Z, Hoube J, Von Dadelszen P, Lee SK. Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only. Am J Obstet Gynecol 2005;193:708-13. 20. Aziz N, Cheng YW, Caughey AB. Neonatal outcomes in the setting of preterm premature rupture of membranes complicated by chorioamnionitis. J Matern Fetal Neonatal Med 2009;22:780-4. 21. Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290:2677-84. 22. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy; I, univariate analysis of risks. Am J Dis Child 1985;139:1031-8. 23. Dammann O, Drescher J, Veelken N. Maternal fever at birth and non-verbal intelligence at age 9 years in preterm infants. Dev Med Child Neurol 2003;45:148-51. 24. Wolfs TG, Jellema RK, Turrisi G, Becucci E, Buonocore G, Kramer BW. Inflammationinduced immune suppression of the fetus: a potential link between chorioamnionitis and
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postnatal early onset sepsis. J Matern Fetal Neonatal Med 2012;25(suppl 1):8-11. 25. Morales WJ. The effect of chorioamnionitis on the developmental outcome of preterm infants at one year. Obstet Gynecol 1987;70: 183-6. 26. Yancey MK, Duff P, Kubilis P, Clark P, Frentzen BH. Risk factors for neonatal sepsis. Obstet Gynecol 1996;87:188-94. 27. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;91:725-9. 28. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol 1982;59: 539-45. 29. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210-5. 30. Sato M, Nishimaki S, Yokota S, et al. Severity of chorioamnionitis and neonatal outcome. J Obstet Gynaecol Res 2011;37:1313-9. 31. Seliga-Siwecka JP, Kornacka MK. Neonatal outcome of preterm infants born to mothers with abnormal genital tract colonisation and chorioamnionitis: a cohort study. Early Hum Dev 2013;89:271-5. 32. Martinez-Tallo E, Claure N, Bancalari E. Necrotizing enterocolitis in full-term or near-term infants: risk factors. Biol Neonate 1997;71: 292-8. 33. Been JV, Lievense S, Zimmermann LJ, Kramer BW, Wolfs TG. Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis. J Pediatr 2013;162:236-42. 34. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK, Canadian Neonatal Network. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009;200:372.e1-6. 35. Polam S, Koons A, Anwar M, ShenSchwarz S, Hegyi T. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med 2005;159: 1032-5. 36. Zanardo V, Trevisanuto D, Cosmi E, Chiarelli S. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 2010;116: 1454. 37. Ribiani E, Rosati A, Romanelli M, Cruciani L, Incalza F, Di Renzo GC. Perinatal infections and cerebral palsy. Minerva Ginecol 2007;59: 151-7. 38. Bashiri A, Burstein E, Mazor M. Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med 2006;34: 5-12. 39. Neufeld MD, Frigon C, Graham AS, Mueller BA. Maternal infection and risk of cerebral palsy in term and preterm infants. J Perinatol 2005;25:108-13. 40. Hagberg H, Jacobsson B. [Chorioamnionitiserisk factor of cerebral palsy in fullterm infants]. Lakartidningen 2004;101:2542.
www.AJOG.org 41. Jacobsson B. Infectious and inflammatory mechanisms in preterm birth and cerebral palsy. Eur J Obstet Gynecol Reprod Biol 2004;115: 159-60. 42. Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol 2004;18:425-36. 43. Shatrov JG, Birch SC, Lam LT, Quinlivan JA, McIntyre S, Mendz GL. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol 2010;116:387-92. 44. Yoon BH, Romero R, Park JS, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000;182: 675-81. 45. Yoon BH, Park CW, Chaiworapongsa T. Intrauterine infection and the development of cerebral palsy. BJOG 2003;110(suppl 20):124-7. 46. Ramsey PS, Lieman JM, Brumfield CG, Carlo W. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. Am J Obstet Gynecol 2005;192:1162-6. 47. Ferguson MG, Rhodes PG, Morrison JC, Puckett CM. Clinical amniotic fluid infection and its effect on the neonate. Am J Obstet Gynecol 1985;151:1058-61. 48. Mecredy RL, Wiswell TE, Hume RF. Outcome of term gestation neonates whose mothers received intrapartum antibiotics for suspected chorioamnionitis. Am J Perinatol 1993;10:365-8. 49. Tomashek KM, Shapiro-Mendoza CK, Weiss J, et al. Early discharge among late
Obstetrics preterm and term newborns and risk of neonatal morbidity. Semin Perinatol 2006;30:61-8. 50. Bastek JA, Sammel MD, Pare E, Srinivas SK, Posencheg MA, Elovitz MA. Adverse neonatal outcomes: examining the risks between preterm, late preterm, and term infants. Am J Obstet Gynecol 2008;199:367.e1-8. 51. Bastek JA, Sammel MD, Rebele EC, Srinivas SK, Elovitz MA. The effects of a preterm labor episode prior to 34 weeks are evident in late preterm outcomes, despite the administration of betamethasone. Am J Obstet Gynecol 2010;203:140.e1-7. 52. Hosmer DW, Lemeshow S. Applied logistic regression, 2nd ed. New York: Wiley; 2000. 53. Horvath B, Grasselly M, Bodecs T, Boncz I, Bodis J. Histological chorioamnionitis is associated with cerebral palsy in preterm neonates. Eur J Obstet Gynecol Reprod Biol 2012;163:160-4. 54. Xu LP, Ren RN, Zhu SB, Zhuang HM, Huang ZL, Yang H. [Effect of chorioamnionitis on brain injury in preterm infants]. Zhongguo Dang Dai Er Ke Za Zhi 2012;14:661-3. 55. Plakkal N, Soraisham AS, Trevenen C, Freiheit EA, Sauve R. Histological chorioamnionitis and bronchopulmonary dysplasia: a retrospective cohort study. J Perinatol 2013;33:441-5. 56. Jobe AH. Effects of chorioamnionitis on the fetal lung. Clin Perinatol 2012;39:441-57. 57. Strunk T, Doherty D, Jacques A, et al. Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 2012;129:e134-41. 58. Andrews WW, Cliver SP, Biasini F, et al. Early preterm birth: association between in
Research
utero exposure to acute inflammation and severe neurodevelopmental disability at 6 years of age. Am J Obstet Gynecol 2008;198:466. e1-11. 59. Martinelli P, Sarno L, Maruotti GM, Paludetto R. Chorioamnionitis and prematurity: a critical review. J Matern Fetal Neonatal Med 2012;25(suppl 4):29-31. 60. Nasef N, Shabaan AE, Schurr P, et al. Effect of clinical and histological chorioamnionitis on the outcome of preterm infants. Am J Perinatol 2013;30:59-68. 61. Soraisham AS, Trevenen C, Wood S, Singhal N, Sauve R. Histological chorioamnionitis and neurodevelopmental outcome in preterm infants. J Perinatol 2013;33:70-5. 62. Burd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol 2012;67: 287-94. 63. Xie AL, DI XD, Chen XM, Hu YC, Wang YH. [Factors and neonatal outcomes associated with histologic chorioamnionitis after premature rupture of membranes in the preterms]. Zhonghua Fu Chan Ke Za Zhi 2012;47:105-9. 64. Curtin WM, Katzman PJ, Florescue H, Metlay LA. Accuracy of signs of clinical chorioamnionitis in the term parturient. J Perinatol 2013;33:422-8. 65. Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol 1999;94: 1000-5.
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OBSTETRICS
Prenatal inflammation is associated with adverse neonatal outcomes Jamie A. Bastek, MD, MSCE; Anita L. Weber, PhD; Meghan A. McShea, BS; Meghan E. Ryan, BA; Michal A. Elovitz, MD OBJECTIVE: The purpose of this study was to determine whether
prenatal inflammation (as assessed by clinical chorioamnionitis, maternal temperature >38 C, or histologic chorioamnionitis) is associated with a composite adverse neonatal outcome. STUDY DESIGN: We performed a prospective cohort study of women
at 22 weeks to 33 weeks 6 days’ gestation with symptoms of labor (April 2009 to March 2012). Relevant maternal and neonatal exposures and outcomes were recorded. Multivariable logistic regression was performed to determine the association between prenatal inflammation and neonatal outcomes that were controlled for potential confounders. RESULTS: We analyzed 871 mother-infant pairs. The preterm birth
rate was 42.0%. When we controlled for infant sex and modified the data by gestational age at delivery, prenatal inflammation remains a significant risk factor for adverse neonatal outcomes, despite
advancing gestational age: clinical chorioamnionitis at 32 weeks’ gestation (odds ratio [OR], 3.12; 95% confidence interval [CI], 1.02e9.52], at 36 weeks’ gestation (OR, 8.88; 95% CI, 4.32e18.25), and at 40 weeks’ gestation (OR, 25.30; 95% CI, 9.25e69.19); maternal temperature >38 C at 32 weeks’ gestation (OR, 3.18; 95% CI, 0.66e15.42), at 36 weeks gestation (OR, 8.40; 95% CI, 3.60e19.61), and at 40 weeks gestation (OR, 22.19; 95% CI, 8.15e60.44); histologic chorioamnionitis at 32 weeks gestation (OR, 1.25; 95% CI, 0.64e2.46), at 36 weeks gestation (OR, 2.56; 95% CI, 1.54e4.23), and at 40 weeks gestation (OR, 5.23; 95% CI, 1.95e13.99). CONCLUSION: The protective association with advancing gestational age is diminished when prenatal inflammation is present.
Key words: adverse neonatal outcome, chorioamnionitis, placenta, prenatal inflammation, preterm birth
Cite this article as: Bastek JA, Weber AL, McShea MA, et al. Prenatal inflammation is associated with adverse neonatal outcomes. Am J Obstet Gynecol 2014;210:450.e1-10.
O
ver the last 20 years, evidence has emerged to suggest that prenatal inflammation and/or intrauterine infection leads to the activation of localized inflammatory pathways, plays a critical role in at least 25-40% of spontaneous preterm births,1-6 and is a significant contributor to the development of adverse neonatal outcomes.7-9 Prenatal inflammation that predisposes to spontaneous preterm birth and adverse neonatal outcomes may occur in the form of either histologic (HCA)10-13
and/or acute clinical14-22 chorioamnionitis (CCA). The association between acute CCA or perinatal infection23 and adverse neonatal outcomes (which includes sepsis,24-27 respiratory compromise,20,25,27-31 necrotizing enterocolitis,20,31-33 intraventricular hemorrhage,20,25,27,34,35 and long-term outcomes such as cerebral palsy21,36-45 and neonatal death18,25) has been wellestablished. However, most of these studies have been small and retrospective and have focused on the prevalence of
From the Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women’s Health (Drs Bastek and Elovitz, Ms McShea, and Ms Ryan), and the Department of Biostatistics and Epidemiology (Dr Weber), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Received July 8, 2013; revised Dec. 6, 2013; accepted Dec. 17, 2013. Supported by a March of Dimes grant (21-FY08-539; principal investigator, M.A.E.). The authors report no conflict of interest. Presented in poster format at the 32nd annual meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Feb. 6-11, 2012. Reprints: Jamie A. Bastek, MD, MSCE, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce St, 585 Dulles Bldg, Philadelphia, PA 19104. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.12.024
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adverse neonatal outcomes in cohorts of preterm infants. As a result, many investigators attribute the risk of adversity to gestational age at delivery rather than prenatal inflammation.46 Furthermore, studies that have examined the risks of inflammation to term neonates have concluded that inflammation poses only minimal risk.47,48 As a result, the relative contributions of preterm birth and prenatal inflammation to adverse neonatal outcomes are yet to be determined. To that end, our primary objective was to determine whether prenatal inflammation that is assessed by acute CCA, maternal temperature >38 C in the 24 hours preceding delivery, or postpartum diagnosis of HCA was associated with a composite adverse neonatal outcome variable (COMP). Secondary objectives were to determine the association between prenatal inflammation and the individual adverse neonatal outcomes sepsis and respiratory compromise. Our hypotheses were that, for all outcomes, prenatal inflammation would be associated with an increased risk for neonatal adversity and that these associations
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TABLE 1
Association between demographic variables and prenatal inflammation (n [ 871) Exposure Demographic characteristics
Present
Not present
P valuea
Clinical chorioamnionitisb Preterm birth <37 wk, n (%) Gestational age at delivery, wk
28 (49)
338 (42)
34.93 5.48
c
36.60 3.38
Race, n (%)
.26 .34 .29
Black
47 (82)
668 (82)
White
4 (7)
94 (12)
Asian
4 (7)
24 (3)
Other
2 (4)
28 (3)
Infant male sex, n (%)
33 (58)
436 (54)
.53
Corticosteroids, n (%)
27 (47)
269 (33)
.03
Maternal age, y
c
Gestational age at enrollment, wkc
24.97 6.08
25.62 6.08
.48
29.35 3.24
30.36 3.66
.03
Temperature >38 Cd Preterm birth <37 wk, n (%) Gestational age at delivery, wk
15 (31)
351 (43)
37.41 3.89
c
36.44 3.55
Race, n (%)
.003 .60
Black
40 (82)
675 (82)
White
4 (8)
94 (11)
Asian
3 (6)
25 (3)
Other
2 (4)
28 (3)
32 (65)
437 (53)
.10
Corticosteroids, n (%)
12 (24)
284 (35)
.15
Maternal age, yc
24.37 5.84
25.65 6.09
.12
30.12 3.19
30.31 3.67
.50
Infant male sex, n (%)
Gestational age at enrollment, wk Histologic chorioamnionitis
c
e
Preterm birth <37 wk, n (%) Gestational age at delivery, wk
160 (72)
206 (32)
33.75 4.72
c
37.44 2.47
Race, n (%)
< .001 < .001 .16
Black
192 (86)
523 (81)
White
16 (7)
82 (13)
Asian
8 (4)
20 (3)
Other
7 (3)
23 (4)
Infant male sex, n (%)
121 (54)
348 (54)
.89
Corticosteroids, n (%)
125 (56)
171 (26)
< .001
25.62 6.18
Maternal age, yc Gestational age at enrollment, wk a
.10
c
29.86 3.77
25.57 6.05
.93
30.45 3.59
.04
Determined by c test (categoric data) and Kruskal-Wallis rank test (continuous data); Present, 57; not present, 814; c Data presented as mean SD; d Present, 49; not present, 822; e Present, 223; not present, 648. 2
b
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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would persist when adjustment was made for gestational age at delivery.
M ATERIALS
AND
M ETHODS
We performed a prospective cohort study at a single, urban tertiary care center. The cohort consisted of women with singleton pregnancies at 22 weeks to 33 week 6 days’ gestational age who came to the labor and delivery triage unit with complaints concerning preterm labor. Patients were excluded for multiple-gestation, major fetal anomaly, intrauterine fetal death, severe preeclampsia before enrollment, chronic steroid or immunosuppressive drug use, active immunologic disease, acute systemic febrile illness, and/or pregestational diabetes mellitus. Patients who either were not delivered at our institution or whose infants were transferred to a different hospital for care were also excluded from these analyses. Patients were enrolled in the study by trained clinical research coordinators who obtained informed consent at the time of enrollment. Once a patient was enrolled in the study, all treatment decisions were made by the treating physician according to the standard of care at our institution. Women were enrolled from April 2009 through March 2012. At our institution, maternal fever is diagnosed as a temperature >38 C. Maternal temperature is recorded on laboring patients every 4 hours while membranes are intact and hourly after membranes are ruptured. A diagnosis of temperature >38 C was obtained from review of the electronic nursing records in the 24 hours preceding each patient’s delivery. Acute CCA is diagnosed in the setting of maternal temperature >38 C and at least 1 of the following occurrences: maternal tachycardia (100 beats per minute), fetal tachycardia (>160 beats per minute), and/or fundal tenderness. Patients who receive a diagnosis of acute CCA who are not in spontaneous labor are induced at the time this diagnosis is made. HCA is a diagnosis that is made by the pathologist after microscopic examination of the placenta and is defined as the presence of neutrophils in the chorion or amnion.
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Pathologists were unaware of whether patients were enrolled in the study and/ or whether their neonates had any adverse outcomes. If the placenta was not sent to pathology, then HCA was assumed to be not present.
TABLE 2
Association between demographic and composite adverse neonatal outcome variables No composite Composite adverse adverse neonatal neonatal outcome outcome variable P valuea variable (n [ 168) (n [ 703)
Demographic characteristic
Data collection After enrollment, each patient was tracked for the remainder of her pregnancy. Relevant maternal information that included pertinent medical, surgical, and gynecologic histories was recorded; relevant delivery information was obtained through chart review. Whether antenatal corticosteroids were administered, whether HCA or CCA was diagnosed, and the highest maternal temperature within 24 hours before delivery were also noted. Relevant neonatal information that included gestational age at delivery, mode of delivery, infant sex, birthweight, and nursery admission were recorded.
Preterm birth <37 wk, n (%)
143 (85)
Gestational age at delivery, wk
223 (32)
32.01 4.59
b
37.57 2.21
Race, n (%)
< .001 < .001 .73
Black
140 (83)
575 (82)
White
16 (10)
82 (12)
Asian
7 (4)
21 (3)
Other
5 (3)
25 (4)
Infant male sex, n (%)
98 (58)
371 (53)
.19
Corticosteroids, n (%)
112 (67)
184 (26)
< .001
b
Maternal age, y
Gestational age at enrollment, wk a
b
26.07 6.12
25.46 6.07
.15
29.13 3.77
30.58 3.56
< .001
Determined by c2 test (categoric data) and Kruskal-Wallis rank test (continuous data); b Data presented as mean SD.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
TABLE 3
Association of composite neonatal outcome with prenatal inflammation (n [ 871) Composite adverse neonatal outcome variable, n (%) Prenatal Inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.0)
Not present 25 (3.6)
Crude
Adjusted
c
Crude/adjusted odds ratio Interaction < .001
6.38 (3.66e11.11)
32
3.12 (1.02e9.52)
< .05
36
8.88 (4.32e18.25) < .001
40
25.30 (9.25e69.19) < .001
Temperature >38 C, wk
20 (11.9)
29 (4.1)
3.18 (0.66e15.42)
.15
36
8.40 (3.60e19.61) < .001
40
22.19 (8.15e60.44) < .001
Histologic chorioamnionitis, wk
101 (60.1) 122 (17.4)
32
1.25 (0.64e2.46)
.51
36
2.56 (1.54e4.23)
< .001
40
5.23 (1.95e13.99) < .001
n ¼ 168; b n ¼ 703; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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.061
< .001
7.18 (4.98e10.34)
CI, confidence interval.
< .01
< .001
3.14 (1.73e5.70)
32
a
P value
Odds ratio (95% CI) b
< .05
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FIGURE 1
100 90 80 70 60 50 40 30 20 10 0
Odds Ratio of Clinical Chorioamnionitis
Odds ratios for composite neonatal outcome by clinical chorioamnionitis exposure
25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
Neonatal chart abstraction was performed, and the presence of key diagnoses was determined by review of the documentation of the attending neonatologist or pediatrician who assessed each infant. Such key diagnoses included presumed (diagnosis by neonatology attending based on clinical presentation for which 7 days of antibiotics were administered) or proved (culture positive) sepsis, respiratory compromise (need for continuous positive airway pressure or mechanical ventilation beyond the delivery room), seizures, necrotizing enterocolitis (diagnosed both clinically and radiographically), intraventricular hemorrhage (grades III-IV), and/or death before discharge. Neonatal information was limited to those events that occurred between delivery and the infant’s discharge home from the hospital. The use of a surrogate composite variable for cases in which individual outcomes were of low prevalence has been performed in previous neonatal studies.49-51 Therefore, a COMP was
created to summarize neonatal outcomes for the primary outcome of this study. A neonate was classified as having the primary composite outcome if at least one of the adverse outcomes listed earlier (sepsis, respiratory compromise, seizures, necrotizing enterocolitis, intraventricular hemorrhage, and/or death) was present. A neonate was classified as having one of the secondary outcomes if either presumed or proven sepsis or respiratory compromise were present, as defined earlier. Preterm birth was defined as delivery at <37 weeks’ gestational age.
Data analyses Associations between categoric variables were examined with chi-squared analyses. Normality for continuous variables was assessed with the Shapiro-Wilk test for normality. Where a normal distribution could be ruled out, the Kruskal Wallis equality-of-populations rank test was used to test differences. Although our choice of 38 C as a cut point for the variable to assess elevated
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maternal temperature was made (38 C represents a fever at our institution) before any analyses were performed, we verified that this cut-point was the most associated with COMP among candidate cut-points of 37, 37.5, 38, and 38.5 C in both raw models of COMP that were associated with a “yes/no” higher temperature and full models that included interaction of temperature with gestational age at delivery and adjustment by male sex (data not shown). Multivariable logistic regression was performed to determine the association between each form of prenatal inflammation (CCA, temperature >38 C [T38], and HCA) and both composite and individual adverse neonatal outcomes (neonatal sepsis and respiratory compromise). To control for potential confounding of the association of composite neonatal outcome and prenatal inflammation, we selected potential confounders for testing based on the association with adverse neonatal outcome found in the literature, which included gestational age at presentation with preterm labor, antenatal corticosteroid treatment, maternal age, and maternal race. Modeling strategy was change-in-estimate of the inflammation variable over a multivariable baseline model of adverse outcome and inflammation that included gestational age at delivery in weeks and infant sex, which were selected because their clinical relevance. Potential confounders were examined individually and, if associated with a 5% change in the regression coefficient of the indicator of prenatal inflammation (ie, the “change in 5% rule”), was retained in the model. Because we believed that gestational age would modify the association between inflammation and adverse neonatal outcomes, we tested the interaction of gestational age at delivery in weeks with inflammation in association with adverse neonatal outcomes. Goodness of fit for the multivariable models was assessed with the use of the HosmerLemeshow c2 test,52 where a large probability value indicates that the model is well-fit. We used a threshold of a probability value of > .05. Areas under the receiver operating characteristic curve
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Sample size A priori sample size calculations were performed to determine how many mother-infant pairs would be needed to detect a 2.5-fold increase in the prevalence of COMP between those infants who were exposed to prenatal inflammation compared with those who were not exposed. Based on previously published data from our institution, we estimated that the prevalence of COMP among infants who were not exposed to prenatal inflammation was 6.0%.50 Assuming 90% power, a type I error of 5%, and an enrollment ratio of 1:4 between those with and without prenatal inflammation exposure, we determined we would require 850 mother-infant pairs. This study was approved by the institutional review board at the University of Pennsylvania (Philadelphia, PA).
R ESULTS Delivery information was available to analyze for 871 women and their infants. The rate of preterm birth in this highrisk cohort was 42.0%. The cohort prevalence of CCA was 6.5% (n ¼ 57), of T38 was 5.6% (n ¼ 49), and of HCA was 25.6% (n ¼ 223). Most patients with CCA or T38 had other inflammatory exposures. Specifically, 87.7% of the women with CCA also had HCA, and
FIGURE 2
10
20
30
40
50
60
70
80
90
100
Odds ratios for composite neonatal outcome by temperature exposure
0
(AUC) for each multivariable model were calculated and compared with the use of a statistical receiver-operator curve area comparison test. Multivariable models with each prenatal inflammation variable were compared with each other variable to determine whether 1 particular prenatal inflammation variable had superior discriminatory ability to the others and to verify that each multivariable model that included a prenatal inflammation variable was significantly more discriminatory than the model that included only gestational age at delivery and infant sex. In all analyses, a probability value of < .05 was considered statistically significant, and probability value of < .10 was the threshold for display of an interaction. Stata software (version 10.1; StataCorp, College Station, TX) was used for all analyses.
Odds Ratio of Yes/No Temperature > 38 deg C
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25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
64.9% of the women with CCA had T38; 75.5% of the women with T38 also had CCA, and 79.6% of the women with T38 had HCA. However, only 22.4% of the women with HCA had CCA, and 17.5% of the women with HCA had T38. We compared demographic variables among women with and without exposure to prenatal inflammation. The demographic variables that were associated significantly with HCA exposure (Table 1) were preterm birth, gestational age at delivery, antenatal corticosteroids, and gestational age at enrollment. For CCA, associations were limited to antenatal corticosteroids and gestational age at enrollment, and the associations for T38 were limited further to gestational age at delivery. Preterm birth, gestational age at delivery, antenatal corticosteroids, and gestational age at enrollment were also associated significantly with the primary outcome COMP (Table 2). To address our primary objective, we determined whether prenatal inflammation (measured by CCA, T38, and HCA) was associated with COMP. In bivariate
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analyses, all measures of prenatal inflammation were associated significantly with increased risk. Furthermore, gestational age at delivery significantly modified the association of both CCA (P < .01) and HCA (P < .05) on COMP and trended towards significance of T38 on COMP (P ¼ .061; Table 3). The inclusion of the potential confounders antenatal corticosteroid use, maternal age, or maternal race 1 at a time in the multivariable main-effects models of COMP resulted in changes of <5% of the regression coefficient of any of the indicators of prenatal inflammation and therefore were not included in the final model. To better understand the interaction of gestational age at delivery and prenatal inflammation, we graphed the odds ratio (OR) of prenatal inflammation in association with COMP using CCA (Figure 1), T38 (Figure 2), and HCA (Figure 3) as a function of gestational age at delivery from 25-41 weeks. All models were modified by gestational age at delivery and controlled for infant sex.
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FIGURE 3
20 18 16 14 12 10 8 6 4 2 0
Odds Ratio of Histological Chorioamnionitis
Odds ratios for composite neonatal outcome by histologic chorioamnionitis exposure
25
27
29
31 33 35 37 Gestational Age at Delivery (wks)
Odds Ratio
39
41
95% Confidence Interval
Estimates have been adjusted for infant sex. CI, confidence interval. Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
The OR of each model is significantly different from 1.0, which is the OR of the group without inflammation exposure, starting at week 32 for CCA, 33 for T38, and 34 for HCA and continues to increase with increasing age. In infants at 32-34 weeks’ gestational age that were not exposed to prenatal inflammation, there was a sharp decrease in COMP. However, in those infants who were exposed, the magnitude of this decrease was not as great, which suggests that the protective association with advancing gestational age is diminished when prenatal inflammation is present (data not shown). To attach numbers to the ORs and 95% confidence intervals (CIs) found in the Figures, we selected 3 gestational ages (32, 36, and 40 weeks; Table 3). The inclusion of the potential confounders antenatal corticosteroid use, maternal age, or maternal race 1 at a time in the multivariable main-effects models of COMP resulted in changes of <5% of the regression coefficient of any of the indicators of prenatal inflammation and
therefore were not included in the final model. Secondary objectives were to determine the association between prenatal inflammation and individual adverse outcomes of neonatal sepsis and respiratory compromise. As with COMP, gestational age at delivery significantly modified the association with both CCA (P < .01) and T38 (P < .05) on neonatal sepsis but was not significant between HCA and neonatal sepsis (P ¼ .59). Through selection of 3 gestational ages at delivery (32, 36, and 40 weeks), we found that the associations between prenatal inflammation and neonatal sepsis continued to be significant when modified by gestational age at delivery and controlling for infant sex, again with relatively larger ORs for neonatal sepsis associated with more advanced gestational ages (CCA at 32 weeks [OR, 2.80; 95% CI, 1.36e5.77], at 36 weeks [OR, 7.23; 95% CI, 3.25e16.10], and at 40 weeks [OR, 18.70; 95% CI, 5.79e60.39]; T38 at
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32 weeks [OR, 3.03; 95% CI, 1.05e8.74], at 36 weeks [OR, 7.09; 95% CI, 3.07e16.35], and at 40 weeks [OR, 16.58; 95% CI, 5.17e53.23]). Because the interaction of HCA and age was not significant, the association of HCA with neonatal sepsis was estimated in a main effect model when controlled for gestational age at delivery and infant sex. It was significant (P < .01) with an OR of 3.18 (95% CI, 1.65e6.13). Similarly, gestational age at delivery modified the association with CCA (P < .05) and T38 (P ¼ .052, with the probability value of a < .10 threshold for reporting results of an interaction) on respiratory compromise but did not modify the effect between respiratory compromise and HCA (P ¼ .18). Through sampling the same 3 gestational ages, we found that the associations between prenatal inflammation and respiratory compromise continued to be significant at older gestational ages when modified by gestational age at delivery and controlling for infant sex (CCA at 32 weeks [OR, 2.24; 95% CI, 0.79e6.33], at 36 weeks [OR, 5.74; 95% CI, 2.60e12.63], and at 40 weeks [OR, 14.69; 95% CI, 4.24e50.91]; T38 at 32 weeks [OR, 1.94; 95% CI, 0.47e7.94], at 36 weeks [OR, 5.27; 95% CI, 2.25e12.35], and at 40 weeks [OR, 14.32; 95% CI, 4.21e48.65]) The association of HCA with respiratory compromise, which was estimated in a main effects model that controlled for gestational age at delivery and infant sex, was not significant (OR, 1.48; 95% CI, 0.87e2.52) in contrast with neonatal sepsis. AUC for each multivariable logistic model to discriminate between those patients who did vs did not experience COMP were calculated and compared. Accounting for effect modification by gestational age at delivery and controlling for infant sex, the discriminatory ability of each prenatal inflammation variable was very strong (CCA AUC, 0.89; T38 AUC, 0.89; HCA AUC, 0.88). Although the multivariable model that included only gestational age at delivery in weeks and infant sex had similar clinical ability to discriminate for COMP (AUC, 0.86), the AUC was significantly smaller than a model that also included
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either CCA (P < .05), T38 (P < .05), or HCA (P < .05). Finally, we performed analyses parallel to those that are reported in Table 3 on subsets of patients without preeclampsia (Table 4) and without induction of labor (Table 5). In both restricted samples, similar results were found to those in the complete cohort. Probability values of the interaction between prenatal inflammation and gestational age at delivery were within 0.10, which was our threshold for display. All indices of prenatal inflammation showed increasing OR in association with COMP with increasing gestational age at delivery (data not shown).
C OMMENT Previous studies have described an association between CCA and HCA and both preterm birth and adverse neonatal outcomes that include sepsis, respiratory distress, necrotizing enterocolitis, intraventricular hemorrhage, cerebral palsy, and death.24-43,53-
57
However, many of these studies have been smaller and retrospective in design and, as a result, are more limited in their ability to describe the relationship between these exposures and relevant outcomes.58 Furthermore, because of the increased risk for chorioamnionitis with decreasing gestational age, most previous studies focused on the role of preterm birth, rather than the role of prenatal inflammation per se, in contributing to such neonatal adversity.53,54,59-63 Although our study found that gestational age does modify the association with prenatal inflammation on neonatal outcomes, the associations of inflammation on the neonatal outcomes are significant from 32-34 weeks’ gestational age of delivery and persist after adjustment for a variety of potential confounders: infant sex, maternal age, maternal race, gestational age at enrollment and antenatal corticosteroids. Thus, in the presence of evidence of inflammation-related exposures, the risk
of adverse outcome increases even after adjustment for potential confounders.
Strengths and limitations Our study had several strengths. Our patients were identified prospectively, thus limiting misclassification bias by ensuring that our cohort consisted of women at high risk for preterm birth because of symptoms of preterm labor. Eligibility criteria for enrollment were determined before the start of the study by the primary and senior authors and not by the treating physician, thereby minimizing potential enrollment biases. Diagnoses of HCA were made by the pathologist without knowledge of neonatal outcomes. Finally, although our choice of 38 C as a cut point for an intrapartum maternal fever was made because 38 C represents a fever at our institution, we also verified that this cut-point was the most associated with COMP in multivariable and bivariable models.
TABLE 4
Association of composite neonatal outcome with prenatal inflammation, excluding preeclampsia (n [ 849) Composite adverse neonatal outcome, n (%) Odds ratio (95% CI) Prenatal inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.5)
b
Not present 24 (3.5)
Crude
36
Crude/adjusted odds ratio Interaction < .001
2.98 (0.98e9.07) 9.30 (4.51e19.18)
.055 < .001
20 (12.2)
28 (4.1)
< .001
3.26 (1.79e5.95)
32
3.01 (0.63e14.48)
.17
36
8.75 (3.75e20.41)
< .001
40
25.44 (9.16e70.65)
< .001
Histologic chorioamnionitis, wk
< .01
29.05 (10.41e81.07) < .001
40
100 (61.0) 113 (16.5)
32
1.33 (0.67e2.65)
.41
36
2.63 (1.56e4.42)
< .001
40
5.19 (1.88e14.37)
< .05
n ¼ 164; b n ¼ 685; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
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< .05
< .001
7.91 (5.45e11.49)
CI, confidence interval. a
Adjusted
6.68 (3.81e11.70)
32
Temperature >38 C, wk
P value c
.055
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TABLE 5
Association of composite neonatal outcome with prenatal inflammation, excluding inductions (n [ 819) Composite adverse neonatal outcome variable, n (%) Prenatal inflammation Clinical chorioamnionitis, wk
Present
a
32 (19.8)
Not present 20 (3.0)
P value
Odds ratio (95% CI) b
Crude
Adjusted
c
Crude/adjusted odds ratio Interaction < .001
7.84 (4.35e14.14)
32
3.06 (1.02e9.20)
< .05
36
10.72 (5.13e22.38)
< .001
40
37.57 (13.04e108.22) < .001
Temperature >38 C, wk
20 (12.3)
24 (3.6)
< .001
3.71 (2.00e6.91)
32
2.96 (0.63e13.85)
.15
36
9.68 (4.15e22.60)
< .001
40
31.66 (11.14e89.96)
< .001
Histologic chorioamnionitis, wk
100 (61.7) 109 (16.6)
< .01
< .05
< .001
8.11 (5.56e11.83)
32
1.29 (0.65e2.57)
.47
36
2.70 (1.59e4.57)
< .001
40
5.64 (1.99e15.96)
< .05
< .05
CI, confidence interval. a
n ¼ 162; b n ¼ 657; c Adjusted for infant sex.
Bastek. Prenatal inflammation and adverse neonatal outcomes. Am J Obstet Gynecol 2014.
Except for very large cohort studies with an investigation of neonatal outcomes, it often becomes necessary to create a composite outcome. In this study because several of our individual adverse outcomes were of low prevalence, we did need to create a composite outcome. Although there are some noted limitations in creating a composite outcome, this approach has been done in several other studies and still can provide meaningful information.49-51 Of note, although we assumed that the relationship between advancing gestational age and adverse neonatal outcomes was linear, it may be possible that this association is nonlinear at the extremes of gestational age. To explore this possibility would require a much more robust population of both early preterm and term infants; therefore, we are underpowered to investigate this relationship with our current sample size. Not all term placentas were reviewed by a pathologist. For statistical purposes, we assumed that those placentas not
sent to pathology were they tested negative for HCA. However, previously published data suggest that CCA and T38 may be poor surrogates for HCA64,65; therefore, many of the placentas that were assumed to have been low risk for HCA (based on lacking clinical suspicion) actually may have been positive for HCA. Therefore, we believe that, through coding this missing data as negative, we may have biased our results to the null. Had these data not been missing, we believe that the strength of the association that we observed between HCA and COMP would be only stronger. Neonatal diagnoses were made by the attending neonatologist or pediatrician who cared for the infant. Because there was not a single provider diagnosing all of the infants, there may have been bias secondary to interpractitioner variability in diagnostic criteria. To what degree this may have introduced unnecessary bias is unclear. Additionally, we did not have access to records of infants who
were transferred to another hospital after birth, to long-term neonatal outcomes, or to hospital readmissions, which limited our ability to assess healthcare use and chronic neonatal adverse outcomes such as lung disease. However, because of the difficulty in obtaining data describing long-term neonatal wellbeing, other obstetric studies have included preterm birth, gestational age at delivery, and immediate postpartum outcomes as surrogate outcomes of interest. Furthermore, there are data to suggest that short-term adverse outcomes may be associated with increased risk of chronic disease with inherent morbidity and with increased risk of long-term disease.60 Consequently, we believe that these findings provide important information about the risk from exposure to prenatal inflammation. This study provides further evidence that exposure to prenatal inflammation alters neonatal risk. Importantly, although prematurity is a known risk factor for adverse neonatal outcomes,
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prenatal inflammation increases the odds of adverse outcomes, and the protective association with advancing gestational age is diminished when prenatal inflammation is present. What must be considered is whether the measured markers of exposure for this study (CCA, T38, and HCA) are late findings of prenatal inflammation and whether fetuses are exposed to prenatal inflammation days, if not weeks, before these clinical findings. If true, then our current treatment of tocolysis for women with preterm labor and/or delaying delivery of patients with preterm premature rupture of membranes to deliver older neonates might not be the most beneficial strategy to decrease neonatal adversity if this tradeoff prolongs fetal exposure to prenatal inflammation. Understanding that prenatal inflammation dramatically increases the likelihood of adverse neonatal outcomes, therapeutic strategies to target women with these exposures should be considered and pursued. -
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