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. Author manuscript; available in PMC: 2022 Jan 25.
Published in final edited form as: J Perinatol. 2020 Oct 22;41(1):119–125. doi: 10.1038/s41372-020-00866-x

Association of chorioamnionitis and patent ductus arteriosus in a national U.S. cohort

Celeste A Green 1, Daniel Westreich 2, Matthew M Laughon 3, David M Stamilio 4, Robert A Strauss 1, Jeff Reese 5, Elaine L Shelton 5, Kartik K Venkatesh 6
PMCID: PMC8788109  NIHMSID: NIHMS1772363  PMID: 33093626

Abstract

Objective

To estimate the effect of clinical chorioamnionitis on the risk of patent ductus arteriosus (PDA).

Study design

A secondary analysis of all deliveries >23 gestational weeks from the U.S. Consortium on Safe Labor (CSL) study. The primary exposure was a clinical diagnosis of chorioamnionitis, and the outcome was a diagnosis of PDA. Generalized estimating equations with estimated error variance for women with multiple deliveries were utilized. Models adjusted for age, race, region, delivery year, body mass index, infant sex, multiple gestation, mode of delivery, and antenatal corticosteroid exposure.

Results

Among 228,438 deliveries, a diagnosis of PDA was more frequent with chorioamnionitis exposure versus without (9.2% vs. 3.0%; OR: 3.25; 95% CI: 2.92–3.62). Chorioamnionitis was associated with higher adjusted odds of PDA (AOR: 2.18; 95% CI: 1.93–2.45). In sensitivity analyses, the association between chorioamnionitis and PDA held after adjustment for gestational age at delivery (AOR: 1.28; 95% CI: 1.13–1.44).

Conclusions

Chorioamnionitis was associated with increased odds of PDA. Robust exposure and outcome ascertainment with careful assessment of confounding is needed to further investigate this epidemiologic association.

Introduction

Chorioamnionitis, which reflects intrauterine infection and/or inflammation, affects 2–5% of term pregnancies, and progressively increases in frequency with decreasing gestational age [1]. Chorioamnionitis itself is a suspected cause of preterm birth and complicates over 50% of preterm births [2]. Epidemiologic data have shown that chorioamnionitis is associated with both adverse maternal and neonatal outcomes [3–5]. With regards to neonatal outcomes, chorioamnionitis has been implicated as increasing the risk of neonatal brain injury, cerebral palsy, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity [6–9].

Whether chorioamnionitis increases the risk of patent ductus arteriosus (PDA) remains to be fully defined [10]. PDA accounts for nearly 10% of congenital heart disease in term infants, and occurs even more frequently in preterm infants (20–60%) [11]. PDA is associated with a range of adverse clinical outcomes in the neonate, including respiratory distress, heart failure, necrotizing enterocolitis, intraventricular hemorrhage, and poor neonatal nutrition [12]. Beyond the risk posed by chorioamnionitis, gentamycin, an aminoglycoside antibiotic commonly used to treat preterm newborns after chorioamnionitis, is a vasodilator that may relax the ductus arteriosus and increase the risk of PDA [13]; conversely, antenatal corticosteroids have been shown to be protective for PDA [7, 14].

There are significant limitations with the published literature to demonstrate the effect of chorioamnionitis on PDA [15]. First, most studies have been of small cohorts with fewer than a 1000 deliveries. Second, these observational studies have not carefully addressed confounding variables. Third, most studies have been restricted to high risk subpopulations, such as infants of extremely low birthweight [16] or preterm infants who received antenatal corticosteroids [17], which may introduce collider bias [18]. A meta-analysis of 23 studies (4,681 chorioamnionitis cases) reported a higher crude odds of PDA with either histologically or clinically diagnosed chorioamnionitis (1.43; 95% CI 1.19–1.72) [19]. A follow-up meta-analysis of 45 studies (7742 chorioamnionitis cases) provided estimates adjusted for gestational age at delivery, and found a lower adjusted odds of PDA with chorioamnionitis (0.80; 95% CI 0.75–0.95) [10]. To what extent chorioamnionitis may independently increase the risk of PDA after careful consideration of confounding variables remains to be fully evaluated.

Our objective was to estimate the effect of clinical chorioamnionitis on PDA in a large United States cohort of both preterm and term deliveries. We hypothesized that chorioamnionitis would increase the risk of PDA, and that this association would be attenuated towards the null after adjustment for gestational age at birth, an intermediate variable on the causal pathway between chorioamnionitis and PDA [18].

Methods

We conducted a secondary analysis of all deliveries >23 gestational weeks from the U.S. Consortium on Safe Labor (CSL) study. The current study was designed to assess the effect of a clinical diagnosis of chorioamnionitis on documented PDA at birth. Briefly, the CSL study included infants born at ≥23 weeks’ gestation, between 2002 and 2008 at 19 hospitals across the United States [20]. Data linkage, cleaning, recording, and validation have been previously described [20, 21]. Data extracted from the medical record included patient demographics, prenatal complications, labor and delivery information, and maternal and neonatal outcomes. Data from the neonatal intensive care unit were linked to newborn records.

The CSL included a total of 228,438 deliveries, with 9.5% of women (N = 5,053) contributing >1 birth during the specified time period. Consistent with prior analyses from this dataset, women with multiple deliveries during the study period were included, and all models adjusted for interpersonal correlation (i.e., maternal clusters) as described below [3]. We conducted this analysis using a deidentified dataset under a waiver of informed consent, which was approved by the institutional review board at the University of North Carolina at Chapel Hill.

Consistent with prior analyses assessing chorioamnionitis from this dataset [3, 22], the primary exposure was a clinical diagnosis based on an International Classification of Diseases, Clinical Modification (ICD-9-CM) “infection of the amniotic cavity” code (658.4) and/or documentation of chorioamnionitis in the patient chart at delivery discharge [23]. We secondarily classified the exposure of chorioamnionitis based on the time of diagnosis, antepartum (i.e., before labor) versus intrapartum (i.e., during labor). Other clinical indications that may suggest chorioamnionitis, such as preterm premature rupture of membranes or spontaneous preterm labor, were not classified as chorioamnionitis unless they met the above criteria for a diagnosis.

The primary outcome was a diagnosis of PDA by ICD-9 code (747.0) and/or documentation in the patient chart before hospital discharge including NICU stay. We secondarily assessed the outcome of PDA diagnosis resulting in NICU admission. Given the concern of introducing collider bias by stratifying on gestational age [18], assessing the association between chorioamnionitis and PDA by NICU admission allowed for also assessing the impact of lower gestational age on this association.

We compared characteristics between infants with and without a documented PDA using chi square tests for categorical variables and Student’s t test for continuous variables. We used generalized estimating equations with estimated error variance for women with multiple deliveries during the study time period. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were estimated. Multi-variable models adjusted for maternal age (continuous), race (White, Black, Latina, Other), U.S. region (Northeast, West, Midwest, South), year of delivery (continuous), pre-pregnancy body mass index (continuous), infant sex (male, female), multiple gestation (singleton, two or more), mode of delivery (vaginal, cesarean), and antenatal corticosteroid exposure (yes, no). Confounding variables were assessed by use of a Directed Acyclic Graph before statistical modeling [10, 24]. Gestational age at delivery was not included as a covariate in the primary model given its classification as an intermediate variable [18]. The frequency, risk, and clinical management of both chorioamnionitis and PDA were considered a function of gestational age at birth [15, 25, 26].

In a sensitivity analysis, we adjusted for gestational age at birth to explore its effect on the observed association between chorioamnionitis and PDA. In secondary analyses, we repeated the primary analysis, excluding both multiple gestations and fetuses with a congenital anomaly (N = 20,595 or 9.0%). We also assessed whether the primary analysis held when restricting the exposure to antepartum versus intrapartum chorioamnionitis to the 86% (N = 6132/7164) of chorioamnionitis cases for which timing of diagnosis was available. Lastly, we assessed whether the primary analysis results were stable when restricting the outcome of PDA to the 94% (N = 3901/4147) of PDA cases that resulted in NICU admission at birth to assess whether chorioamnionitis increased the risk of PDA in the setting of a critically ill infant needing NICU care. Imputation for missing data were performed for the following covariates (n = 30 imputations) and estimates were combined using Rubin’s rule for the following: race (4.0%), body-mass index (33.6%), age (0.1%), infant sex (0.2%), and antenatal corticosteroids (36.1%). All statistical analyses were performed using STATA (STATACORP, version 16.1, College Station, TX).

Results

Among 228,438 deliveries, 7164 (3.1%) were exposed to chorioamnionitis, and 4147 (1.8%) infants had a documented PDA diagnosis prior to discharge. The mean maternal age overall at delivery was 28 years (SD: 6.19), and 52% were of white race. The mean gestational age at delivery was 38 weeks (SD: 2.47), and 13% of deliveries were preterm <37 weeks. More than a quarter of deliveries (29%) were by cesarean.

Deliveries to women with chorioamnionitis were more likely to be of younger maternal age, nulliparous, non-white race, higher maternal BMI, and multiple gestation (p < 0.05 for all) (Table 1). Deliveries affected by chorioamnionitis were also more likely to be by cesarean (47 vs. 28%; p < 0.001) and at a lower mean gestational age at delivery (37 vs. 38 weeks; p < 0.001).

Table 1.

Delivery characteristics by chorioamnionitis and patent ductus arteriosus status.

Characteristics Chorioamnionitis (yes/no) Patent ductus arteriosus (yes/no)
Chorioamnionitis
N = 7164
n (%)		 No Chorioamnionitis
N = 221,274
n (%)		 Patent ductus arteriosus
N = 4147
n (%)		 No Patent ductus arteriosus
N = 224,291
n (%)
Maternal characteristics
Age, mean (SD), yearsa 27.0 (6.48) 27.6 (6.18) 28.2 (6.64) 27.6 (6.18)
Parity, 1 or greater 2100 (29.3) 135,067 (61.0) 2100 (29.3) 135,067 (61.0)
Self-reported racea
 White 2290 (32.9) 110,934 (52.2) 1660 (41.2) 111,564 (51.8)
 Black 2124 (30.6) 49,268 (23.2) 1272 (31.6) 50,120 (23.3)
 Latina 1887 (27.1) 37,829 (17.8) 809 (20.1) 38,907 (18.1)
 Asian 411 (5.9) 8934 (4.2) 148 (3.6) 9197 (4.2)
 Other 232 (3.3) 5168 (2.4) 134 (3.3) 5266 (2.4)
Delivery yeara
 2002–2003 624 (8.7) 16,382 (7.4) 326 (7.8) 16,680 (7.4)
 2004–2005 2452 (34.2) 76,804 (34.7) 1404 (33.8) 77,852 (34.7)
 2006–2008 4088 (57.1) 128,029 (57.8) 2417 (58.2) 129,700 (57.8)
Pre-pregnancy BMI, mean (SD), kg/m2a 25.3 (6.14) 25.4 (6.25) 26.6 (6.98) 25.4 (6.23)
U.S. region
 West 2505 (34.9) 66,207 (29.9) 1085 (26.1) 67,627 (30.1)
 Midwest 1905 (26.6) 32,778 (14.8) 636 (15.3) 34,047 (15.1)
 South 1995 (27.8) 67,273 (30.4) 1629 (39.2) 67,639 (30.1)
 Northeast 759 (10.5) 55,016 (24.8) 797 (19.2) 54,978 (24.5)
Cesarean delivery 3386 (47.2) 62,604 (28.2) 1757 (42.3) 160,691 (71.6)
Infant characteristics
Twins or higher order gestation 246 (3.4) 4807 (2.1) 425 (10.2) 4628 (2.0)
Receipt of antenatal corticosteroidsa 726 (13.2) 5219 (3.7) 712 (32.0) 5233 (3.6)
Gestational age at delivery, weeks 37.4 (4.43) 38.4 (2.34) 33.0 (5.71) 38.5 (2.22)
Female sexa 3654 (51.1) 112,791 (51.0) 2175 (53.4) 114,270 (51.0)
NICU admission at delivery 2415 (33.7) 27,215 (12.3) 3,901 (94.0) 25,729 (11.4)
Infant weight at birth (SD), grams 3018.2 (940.98) 3228.6 (610.98) 2147.7 (1,220,81) 3241.2 (591.63)
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BMI body mass index, SD standard deviation, NICU neonatal intensive care unit.

a

N for variable: age (n = 228,115), race (n = 219,077), delivery year (n = 228,379), prepregnancy BMI (n = 151,620), infant sex (n = 227,926), antenatal corticosteroids (n = 145,931), and birth weight (n = 225,877).

Deliveries of an infant with a PDA were more likely to be in women of older maternal age, nulliparous, non-white race, higher maternal BMI, and multiple gestation (p < 0.05 for all) (Table 1). Deliveries with an infant with a PDA were less likely to be by cesarean (42.3 vs. 71.6% p < 0.001), and were of lower mean gestational age at delivery (33 weeks vs. 39 weeks; p < 0.001). Almost all cases of PDA (94%, 3901/4147) occurred in infants that were admitted to the neonatal intensive care unit at birth.

PDA was over three times more frequent among infants exposed to chorioamnionitis compared to those without the exposure (9.2 vs. 3.0%; odds ratio, OR: 3.25; 95% CI: 2.92–3.62). In adjusted analyses, chorioamnionitis was associated with over a twofold higher odds of PDA (adjusted odds ratio, AOR: 2.18; 95% CI: 1.93–2.45) (Table 2).

Table 2.

Unadjusted and adjusted analysis of the association between chorioamnionitis and patent ductus arteriosus (PDA).

PDA status Unadjusted and adjusted models
Yes N = 4147
N (%)		 No N = 224,291
N (%)		 Unadjusted analysis OR (95% CI)a Adjusted analysis AOR (95% CI)a,b,c
Chorioamnionitis
 Yes 382 (9.2) 6782 (3.0) 3.25 (2.92–3.62) 2.18 (1.93–2.45)
 No 3765 (90.7) 217,509 (96.9) 1.00 1.00
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a

Generalized estimating equations clustered on women who had multiple deliveries during the study period were used.

b

Multiple imputation was performed for the following covariates (n = 30 imputations); estimates were combined using Rubin’s rule: race (4.0%), body mass index (33.6%), age (0.1%), infant sex (0.2%), and antenatal corticosteroids (36.1%).

c

Adjusted models included: maternal age, race, region/site, year of delivery, prepregnancy body mass index, infant sex, multiple gestation, mode of delivery, and antenatal corticosteroid exposure, but not gestational age at delivery given this was a mediating variable between chorioamnionitis and PDA.

In sensitivity analyses, we adjusted for gestational age at delivery given that this variable was in the causal pathway of chorioamnionitis and PDA (i.e., a mediator rather than a confounder). The above association between chorioamnionitis and PDA persisted after this analysis, but was attenuated toward the null similar to prior meta-analyses that adjusted for gestational age at delivery (AOR: 1.28; 95% CI: 1.13 to 1.44).

In secondary analyses, after excluding deliveries of multiple gestations and those with congenital anomalies, the association between chorioamnionitis and PDA persisted (AOR: 2.30, 95% CI: 1.78–2.94). When stratifying exposure by the timing of chorioamnionitis onset relative to labor, a diagnosis of intrapartum chorioamnionitis was associated with significantly higher odds of PDA (AOR: 1.82, 95% CI: 1.34–2.45), but antepartum chorioamnionitis was not (AOR: 1.56, 95% CI: 0.90 to 2.74). Finally, chorioamnionitis was associated with higher odds of PDA when restricted to a PDA diagnosis resulting in NICU admission (AOR: 2.24, 95% CI: 1.99–2.53).

Discussion

Clinical chorioamnionitis was associated with a twofold higher likelihood of PDA. The current study, conducted among over 200,000 births across the United States inclusive of both preterm and term infants, further clarifies the epidemiologic association between an intraamniotic infection and the risk of neonatal morbidity. These results further highlight the importance of efforts aimed at the prevention and treatment of chorioamnionitis.

The epidemiologic association between chorioamnionitis and an increased risk of PDA has clinical implications. From a neonatal perspective, knowledge of chorioamnionitis exposure may increase the clinician’s decision for more detailed surveillance for PDA postnatally. It remains to be studied whether chorioamnionitis may be associated with a PDA that is more difficult to treat, and some data do suggest that PDA in the setting of perinatal infection is less likely to respond to pharmacological closure and require surgery or a second course of treatment [27]. In addition, it remains to be studied to what extent chorioamnionitis may increase the risk of larger PDA, which may be more amenable to earlier prophylaxis 6–12 h after birth [28]. Regarding obstetric implications, these findings highlight yet again the impact of chorioamnionitis on neonatal morbidity, and the importance of its prevention, diagnosis, and treatment. A clinical implication requiring further research is the role of gentamicin, which is commonly used to treat chorioamnionitis, but is also a known vasodilator. Recent data suggests that gentamicin may increase the risk of PDA [29], and if so, may require modifying current first line antibiotic coverage for chorioamnionitis.

The current analysis with >7000 chorioamnionitis cases expands on the findings in the two most recent meta-analyses to assess whether there is an increased risk of PDA with chorioamnionitis. Park et al. with 4681 chorioamnionitis cases, showed that both a clinical and histologic diagnosis of chorioamnionitis increased the risk of PDA, but did not provide an adjusted analysis [19]. Behbodi et al. with 7742 chorioamnionitis cases among preterm infants demonstrated an increased risk of PDA in an unadjusted analysis, but then a decreased risk in adjusted analysis [10]. Meta-regression showed that differences in gestational age and birthweight between infants exposed and unexposed to chorioamnionitis were significantly correlated with the effect size of the association between chorioamnionitis and PDA. The largest study to date that investigated the association between chorioamnionitis and PDA included 8330 very low birthweight infants born <32 weeks’ gestation in Spain (1480 chorioamnionitis cases), and found a lower adjusted odds of PDA with clinical chorioamnionitis (OR: 0.83; PF% CI: 0.71–0.97, p = 0.019) [15]. This study adjusted for gestational age at delivery and was limited to very preterm, low birthweight infants, both of which likely introduced bias (i.e., adjustment for a variable on the causal pathway and conditioning on a collider variable, respectively) [18]. In the current study, we found that the association between chorioamnionitis and PDA remained, but was attenuated towards the null following adjustment for gestational age at birth, and we did not restrict our study population based on gestational age at birth nor birthweight. We were concerned about introducing collider bias by stratifying on a variable on the causal pathway, gestational age at birth, which could occur if comparing the association between chorioamnionitis and PDA between preterm to term infants [18]. Further research in causal inference are needed to reconcile this clinical situation with appropriate epidemiologic methods [30]. Taken together, these data highlight the importance of careful assessment for confounding and identification of mediators when assessing for an epidemiologic association between chorioamnionitis and PDA.

The apparent effect of chorioamnionitis on the risk of PDA is biologically plausible and clinically relevant. It has been proposed that inflammation can affect the developing fetus’ endothelium [11]. Typically within 72 h of birth, the increased oxygen tension of postnatal life results in decreased circulating prostaglandins and altered smooth muscle voltage-gated channels, both of which lead to closure of the ductus [11, 31]. But, in the setting of higher-than-normal prostaglandin exposure due to chorioamnionitis and the resulting intrauterine inflammation, the threshold for ductus closure may be higher. A well-recognized phenomenon is ductal re-opening in the setting of late-onset neonatal sepsis in preterm infants [32], and also provides a biological mechanism based on underlying inflammation and infection for our observed epidemiologic association.

Second, antibiotics may maintain ductal patency after birth. Aminoglycoside antibiotics, such as gentamicin, can lead to vasodilation [33, 34]. Empiric first-line treatment for preterm infants born to mothers with chorioamnionitis includes gentamicin [1]. Some data from animal models suggest that inflammatory mediators (interleukins, lipopolysaccharides, etc.) do not lead to ductal relaxation, but rather concentration-dependent use of aminoglycosides results in vasodilation of the ductus [35]; and ductus relaxation is not countered by indomethacin use [34]. If gentamicin use plays a causative role in PDA, rather than chorioamnionitis itself, it is possible that the association between chorioamnionitis and PDA may not persist when using a histopathologic diagnosis as the primary exposure, presumably because many of these cases would not have received intrapartum gentamicin therapy.

There are some study limitations to note. First, our exposure of chorioamnionitis was based on a clinical diagnosis in the patient medical record rather than a histopathologic diagnosis or based on confirmed clinical criteria (i.e., maternal fever, white blood cell count, receipt of antibiotics). This is a limitation of many larger studies using diagnostic codes from an electronic health record as high-lighted in the most recent meta-analysis of the association between chorioamnionitis and PDA [10], and could have resulted in misclassification bias. Second, the current cohort did not have data on clinical outcomes of PDA, including medical and surgical management, and further study is needed to understand whether the clinical outcome of PDA varied by chorioamnionitis status. There remains a paucity of long-term data, but in clinical practice, most children with symptomatic PDAs are closed later by cardiologists [36]. Third, we were unable to assess the role antibiotic treatment of chorioamnionitis played in the development of PDA. As described above, we did not have adequate data on antibiotic receipt and type. During the time period of the current study, it was standard of care to initiate antibiotic therapy upon diagnosis of chorioamnionitis, and gentamicin has and continues to be used as first-line therapy [1]. During this time, protocols for the clinical management and echocardiographic screening for PDA likely evolved, which we did not address in this analysis. Fourth, our outcome of PDA was based on a documented diagnosis prior to discharge, rather than a definition based on sonographic findings, medical therapy, and/or surgical intervention [37]. Previous studies have used a range of definitions for this outcome, from pediatric echocardiographic evidence with or without clinical symptoms [8], to only those requiring treatment [38]. Nevertheless, both exposure and outcome misclassification are possible, and further studies are needed that utilize more rigorous exposure and outcome ascertainment. Last, while we were attempting to estimate a causal effect, the possibility of unmeasured or poorly-controlled confounding persists; however, we note that since we could not ethically or practically conduct a trial in which we assigned chorioamnionitis to individuals at random, the gold standard of evidence for this question is a well-conducted observational study.

In summary, we found that chorioamnionitis was associated with a twofold increased odds of PDA in a large sample of U.S. births. This study helps to better characterize the neonatal risks associated with chorioamnionitis for both preterm and term infants. These data provide further evidence to guide both obstetric and pediatric providers in the prompt, accurate diagnosis and management of chorioamnionitis, and understand its impact on neonatal health.

Acknowledgements

Institutions involved in the Consortium include, in alphabetical order: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH.; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville MD (Data Coordinating Center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Houston, Houston, Texas.

Acknowledgement of financial support

Supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The Consortium on Safe Labor was funded by the Intramural Research Program of the NICHD, through Contract No. HHSN267200603425C. The study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Intramural investigators designed the study and data was collected by clinical site investigators. The corresponding author has full access to the data and final responsibility for preparation and submission of the paper for publication. Additional funding support for MML was received from NIH K24 HL143283.

Footnotes

This manuscript was presented as an oral presentation at the Infectious Diseases for Obstetrics and Gynecology (IDSOG) Annual Meeting, August 15, 2020.

Conflict of interest The authors declare that they have no conflict of interest.

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