ABSTRACT
Background
Clinical chorioamnionitis is a major contributor to preterm birth and neonatal morbidity. Diagnosis in women with intact membranes is challenging, particularly in the subclinical phase where maternal signs are subtle and conventional serum markers are limited in predictive value.
Aims
To evaluate the diagnostic performance of selected novel amniotic fluid biomarkers (interleukin‐6, interleukin‐10, tumour necrosis factor‐ɑ, matrix metalloproteinase‐8), and conventional amniotic and serum biomarkers in predicting delivery for clinical chorioamnionitis within 14 days of amniocentesis in women with suspected subclinical infection and intact membranes.
Materials and Methods
A prospective cohort study was conducted at a single Australian tertiary hospital. Thirty‐two women with singleton pregnancies and suspected subclinical chorioamnionitis underwent amniocentesis. Amniotic fluid and serum were analysed for selected biomarkers. The primary outcome was delivery for clinical chorioamnionitis within 14 days of amniocentesis. ROC curves were constructed to assess biomarker performance.
Results
Delivery for clinical chorioamnionitis occurred in 11 of 31 evaluable cases (35%). Matrix metalloproteinase‐8, lactate dehydrogenase, and glucose were the strongest predictors (area under the curve (AUC) of 0.93 (95% CI 0.85–1.0), 0.93 (95% CI 0.85–1.0), and 0.92 (95% CI 0.8–1.0) respectively). Amniotic fluid biomarkers outperformed serum markers (C‐reactive protein AUC 0.70 (95% CI 0.49–0.91) and white cell count AUC 0.67 (95% CI 0.46–0.86)). Novel amniotic fluid biomarkers did not demonstrate superior diagnostic performance over conventional amniotic fluid biomarkers including lactate dehydrogenase and glucose.
Conclusions
Amniotic fluid biomarkers show promise in identifying women with subclinical chorioamnionitis. These findings support further validation of scalable biomarker‐based testing to guide early intervention and improve perinatal outcomes.
Keywords: amniotic fluid, biomarkers, chorioamnionitis, cytokines, preterm birth
1. Introduction
Clinical chorioamnionitis refers to acute infection and/or inflammation of the chorioamnion, and may lead to adverse maternal and neonatal outcomes. Chorioamnionitis contributes to 40%–70% of preterm births, either through spontaneous preterm labour [1] or via iatrogenic delivery to prevent congenital neonatal sepsis [2]. Affected neonates are at increased risk of multi‐organ dysfunction [3].
Chorioamnionitis most commonly results from uterine migration of cervicovaginal microorganisms following membrane rupture, though cases have also been described in women with intact membranes [4]. The conventional diagnosis relies on clinical features such as maternal fever, purulent vaginal discharge, maternal leucocytosis, and fetal tachycardia [5].
A subclinical state frequently precedes overt clinical chorioamnionitis. This is characterised by the presence of intra‐amniotic inflammation without any clinical features and can present with painless cervical shortening and/or dilatation [6] or with subtle symptoms such as low‐grade fevers, abdominal discomfort or uterine irritability.
The subclinical phase is characterised by elevated intra‐amniotic pro‐inflammatory cytokines such as interleukin‐6 (IL‐6) and matrix metalloproteinase‐8 (MMP‐8), exposure to which has been linked to an increased risk of serious morbidity including cerebral palsy [7].
Early identification of subclinical chorioamnionitis—defined as infection and/or inflammation of the amniotic cavity prior to development of maternal fever, pain, or preterm labour [8]—may reduce neonatal morbidity through timely intervention. Diagnosis of this precursor state could inform targeted or empiric antibiotic therapy to prevent progression to chorioamnionitis and potentially prolong pregnancy. Conversely, confirmation of its absence is particularly important in women with cervical insufficiency, as subclinical chorioamnionitis reduces the effectiveness of cerclage [9].
Multiple amniotic fluid biomarkers have been investigated for detecting intra‐amniotic infection and inflammation. IL‐6, MMP‐8 [10, 11], and tumour necrosis factor‐alpha (TNF‐α) [12] have shown elevated concentrations in affected pregnancies. IL‐6, the most extensively studied marker correlates with both microbial invasion [1, 11, 13, 14] and histologic inflammation [14]. However, heterogeneity in study populations, diagnostic definitions, and testing methods has limited translation into routine clinical practice, highlighting the need for further large‐scale validation.
In this study, we aimed to identify amniotic fluid biomarkers that could predict delivery for clinical chorioamnionitis within 14 days of amniocentesis in women with intact membranes at risk of subclinical intra‐amniotic infection. We evaluated three inflammatory cytokines (IL‐6, MMP‐8, and TNF‐ɑ) and an anti‐inflammatory cytokine (IL‐10).
2. Materials and Methods
This prospective study was conducted a single Australian tertiary hospital between February 2020 and July 2023. The study protocol was approved by the local Research Ethics and Governance Office (2019_ETH00253). The study was supported by a research grant provided by the local Health District, through their PITCH initiative (2017).
Inclusion criteria were women ≥ 18 years and > 15 weeks' gestation with a singleton pregnancy. Women were recruited if there were clinician concerns for subclinical chorioamnionitis in the setting of an asymptomatic shortened cervix with a length less than or equal to 15 mm, open or dilated cervix with or without bulging membranes, or signs/symptoms not meeting criteria for clinical chorioamnionitis (fevers > 37.5°C without another identifiable source, raised inflammatory markers (white cell count [WCC] > 11 × 109/L or C‐reactive protein [CRP] > 5 mg/L) or abdominal pain).
Exclusion criteria included premature prelabour rupture of membranes, clinical chorioamnionitis, presence of major congenital anomalies (as diagnosed on antenatal ultrasound), abnormal fetal karyotype or chromosomal microarray, fetal death at the time of amniocentesis or confirmed congenital infection. Eligible patients were offered an amniocentesis to rule out subclinical chorioamnionitis prior to emergent cervical cerclage and consented for collection of additional amniotic fluid for storage and biomarker testing. Clinical management was at the discretion of the treating obstetric team.
2.1. Collection of Samples and Laboratory Procedures
Transabdominal amniocentesis was performed with aseptic technique to obtain amniotic fluid samples. 40 mL of amniotic fluid was collected in 4 vials, 2 vials were sent for karyotype analysis, one for immediate testing for lactate dehydrogenase (LDH), glucose, Gram stain and culture at RPA Pathology and one vial stored for subsequent batched cytokine testing. The latter was aliquoted, frozen and stored at −80°C until testing.
Measurement of cytokines (IL‐6, IL‐10 and TNF‐ɑ) and MMP‐8 was carried out by multiplex beads assays (MILLIPLEX MAP Human Cytokine/Chemokine/Growth Factor Panel A and MILLIPLEX MAP Human Sepsis Magnetic Bead Panel 2, Millipore, Merck, Germany) on MAGPIX instrument (Luminex XMAP Technology) with xPONENT software and MILLIPLEX Analyst software. Quality controls (low and high) were provided in the kit. The experiments were performed according to the manufacturer's instructions. 25 μL of amniotic fluid sample was added to wells with 25 μL of sample buffer and 25 μL of mixed antibody‐immobilised beads against IL‐6, IL‐10, TNF‐ɑ, and MMP‐8. The plate was sealed, protected from light, and incubated on a plate shaker for 2 h at room temperature. The contents of the plate were removed and washed with a wash buffer using the BioTek ELx50 magnetic plate washer. 25 μL of biotinylated detection antibodies were then added to the plate, sealed, protected from light and incubated on a plate shaker for 1 h at room temperature. Next, 25 μL of Streptavidin‐Phycoerythrin conjugate was added to the plate, sealed, protected from light and incubated on a plate shaker for 30 min at room temperature. The contents of the plate were removed and washed with a wash buffer using the BioTek ELx50 magnetic plate washer. Finally, 100 μL of Drive Fluid PLUS was added to the plate and placed on a plate shaker for 5 min to resuspend the beads. Each assay was validated by high‐ and low‐quality controls against each standard curve.
2.2. Outcomes
The primary outcome was delivery for clinical chorioamnionitis within 14 days of amniocentesis. Secondary outcomes collected included histological chorioamnionitis and neonatal infection defined as either positive neonatal blood cultures, documented clinical impression of infection, or prolonged course of antibiotics.
2.3. Data Collection
Patient records and paired baby records were reviewed to collect outcome data retrospectively. Clinical chorioamnionitis was defined as maternal fever (> 38°C) and one or more of the following: maternal leucocytosis (WCC > 11 × 109/L), purulent cervical drainage, or fetal tachycardia. Neonatal infection was defined as positive neonatal blood cultures, documented clinician impression of neonatal infection or prolonged course of antibiotics (non‐prophylactic). When available, serum WCC, serum CRP, ethnicity, body mass index (BMI) and age at time of amniocentesis were collected from the records. All data were reviewed by two investigators independently, and any ambiguous classifications were resolved via consensus of the study group consisting of experienced senior clinicians.
2.4. Statistical Analysis
Continuous variables were expressed as mean ± standard deviation (SD) and compared between groups using the Student's t‐test for independent samples. Categorical variables were summarised as counts, and group differences were assessed using Fisher's exact test, given the low expected cell counts and sample size constraints.
To evaluate the diagnostic performance of selected biomarkers, receiver operating characteristic (ROC) curves were constructed. The area under the curve (AUC) was calculated to quantify discriminative ability, with 95% confidence intervals (CI) reported. All statistical tests were two‐tailed, and a p‐value < 0.05 was considered statistically significant. Analyses were performed using R (version 4.4.2).
3. Results
There were 32 amniocenteses performed on 32 different patients. One case was excluded due to confirmed fetal parvovirus and fetal death in utero at the time of amniocentesis. The primary outcome, delivery for clinical chorioamnionitis within 14 days of amniocentesis, occurred in 11 (35%) cases. There were 20 patients in whom the primary outcome did not occur; these served as controls.
Baseline characteristics for the study group are displayed in Table 1. Women who developed clinical chorioamnionitis and were delivered within 14 days of amniocentesis delivered significantly earlier than controls (24.4 weeks compared to 36.2 weeks). There were no differences in age, gestational age at amniocentesis, ethnicity or BMI.
TABLE 1.
Baseline characteristics of case and controls.
| Cases | Controls | p | |
|---|---|---|---|
| n | 11 | 20 | |
| Age (year), mean ± SD | 34.0 ± 4.7 | 31.4 ± 5.5 | 0.21 a |
| Gestational age at time of amniocentesis | 24.0 ± 4.6 | 22.4 ± 3.1 | 0.29 a |
| Ethnicity | 0.29 b | ||
| African | 0 | 2 | |
| Caucasian | 7 | 4 | |
| East Asian | 0 | 2 | |
| Mediterranean | 0 | 1 | |
| Pacific Islander | 1 | 0 | |
| South Asian | 2 | 4 | |
| Southeast Asian | 0 | 1 | |
| Unknown | 1 | 6 | |
| BMI | 26.4 ± 5.2 | 25.5 ± 5.5 | 0.66 a |
| Gestational age at time of delivery | 24.4 ± 4.5 | 36.2 ± 5.1 | < 0.01 a |
| Indication for amniocentesis c | 0.76 b | ||
| Short cervix < 15 mm | 7 | 13 | |
| Exposed membranes | 4 | 5 | |
| Suspected chorioamnionitis | 5 | 6 |
Calculated with two‐sided Student's t‐test.
Calculated with Fisher's test.
The inclusion criteria were not mutually exclusive, and thus some patients had more than one indication: for example, short cervix < 15 mm and suspected chorioamnionitis.
Among the 11 cases, eight had placental histopathology consistent with chorioamnionitis, histopathology was unavailable for two cases, and one case had negative findings. Amniotic fluid culture was positive in three cases, while no positive cultures were identified in the control group. There were three neonatal infections, of which two occurred among the cases, and one occurred in a control infant who delivered over 60 days after amniocentesis for severe pre‐eclampsia.
The diagnostic performance of the various serum and amniotic fluid markers available was compared by constructing ROC (Receiver Operating Characteristic) curves and calculating the AUC (Area Under the Curve) (Table 2). Serum markers (WCC and CRP) were inferior to amniotic fluid markers, with an AUC of 0.67 (95% CI 0.46–0.86) and 0.70 (95% CI 0.49–0.91) respectively. Amniotic fluid MMP‐8, LDH, and glucose demonstrated the strongest diagnostic performance with AUCs of 0.93 (95% CI 0.85–1.0), 0.93 (95% CI 0.85–1.0), and 0.92 (95% CI 0.8–1.0) respectively (as depicted in Figure 1).
TABLE 2.
Diagnostic performance of various biomarkers.
| Biomarker | Area under the curve (95% confidence intervals) |
|---|---|
| Amniotic fluid | |
| LDH | 0.93 (0.85–1.0) |
| MMP‐8 | 0.93 (0.85–1.0) |
| Glucose | 0.92 (0.80–1.0) |
| IL‐10 | 0.87 (0.70–1.0) |
| IL‐6 | 0.83 (0.69–0.98) |
| TNF‐ɑ | 0.79 (0.58–0.99) |
| Serum | |
| CRP | 0.70 (0.49–0.91) |
| WCC | 0.67 (0.46–0.86) |
FIGURE 1.
Receiver‐operating characteristic (ROC) curves for biomarkers to predict delivery for clinical chorioamnionitis within 14 days of amniocentesis.
4. Discussion
This study demonstrates a possible role for amniotic fluid biomarkers in predicting delivery for clinical chorioamnionitis among at‐risk women with intact membranes. The strongest predictive performance was observed for LDH, MMP‐8, and glucose with AUCs > 0.9. Overall, amniotic fluid biomarkers outperformed maternal inflammatory markers (WCC and CRP with AUC 0.67 and 0.70 respectively). The findings, however, do not support preferential use of novel biomarkers such as MMP‐8 and IL‐10 over more established markers such as glucose and LDH, which are cheaper to assay, already validated for clinical use, and are more scalable in practice.
These findings are clinically meaningful because current diagnostic approaches for subclinical chorioamnionitis have limited sensitivity and specificity, relying largely on maternal clinical signs and laboratory indices with suboptimal predictive value. The superior diagnostic performance of amniotic fluid biomarkers (particularly those already validated for clinical use such as glucose and LDH) offers a scalable and potentially cost‐effective alternative for early identification of at‐risk pregnancies.
Our results are broadly consistent with existing literature, which demonstrates that MMP‐8 and IL‐6 outperform maternal biochemistry and clinical features in predicting positive amniotic fluid cultures [1, 10, 11, 13, 14], histological chorioamnionitis [14], and neonatal morbidity [11]. However prior studies vary considerably in design, diagnostic criteria and outcome measures, making direct comparisons challenging. In studies using histological chorioamnionitis as the primary outcome (10 of the 11 cases of our cohort had positive histopathology), the performance of several biomarkers in our analysis was comparable: amniotic IL‐6 (AUC of 0.83 vs. 0.76 [14]), glucose (0.92 vs. 0.86 [15]) and serum CRP (0.70 vs. 0.76–0.85 [14, 16]). Notably, amniotic LDH demonstrated superior performance in our cohort (0.93 vs. 0.76 [10]). To our knowledge, there was no comparable published AUC values for histological chorioamnionitis using amniotic IL‐10, MMP‐8, TNF‐ɑ or serum WCC. A more detailed summary of published literature is provided in Supporting Information 1.
Given its anti‐inflammatory function, it was surprising that IL‐10 was positively associated with delivery for clinical chorioamnionitis with relatively strong discriminatory performance (AUC 0.87). The existing literature regarding IL‐10's potential role in chorioamnionitis is mixed, with some authors reporting elevation of IL‐10 with preterm labour and/or chorioamnionitis [17, 18], whilst others found no association [19]. One proposed explanation is that IL‐10 reflects a counter‐regulatory response whereby the host mounts an anti‐inflammatory reaction to suppress ongoing inflammation, thus elevated IL‐10 may mark a later stage of disease progression [20]. Alternatively, reported inconsistencies may arise from small sample sizes, heterogeneous study methods, or biological variability in immune responses between individuals and across different pathogens [21].
As an example of potential future utilisation, we developed a post hoc decision‐tree incorporating amniotic glucose and LDH to accurately identify cases (Figure 2). Given the small sample size, this model is exploratory and requires prospective validation in a large cohort before any clinical relevance can be inferred. The test was considered positive if amniotic glucose was < 1.3 mmol/L, or if LDH > 141 IU/L and glucose < 1.7 mmol/L. This test identified 10 of the 11 cases with no false positives, which equates to sensitivity of 91% and specificity of 100%. For comparison, using combined cut‐offs of LDH > 400 and glucose < 1.04 would identify 4 of 11 cases with no false positives, which equates to sensitivity of 36% and specificity of 100%. We did not report individual sensitivities and specificities for each biomarker, as the selection of optimal thresholds would depend on the intended clinical application for example, provision of antibiotics compared to preterm delivery for suspected chorioamnionitis.
FIGURE 2.
Decision‐tree to predict delivery for clinical chorioamnionitis within 14 days. The proposed decision‐tree divides patients by sequential amniotic glucose (aGlucose) and amniotic LDH (aLDH) thresholds, with the two left groups considered test positive. Cases which were delivered for clinical chorioamnionitis within 14 days are depicted as light grey, and controls which did not are depicted as dark grey. Only one control was misclassified (second group from the left). This decision‐tree was constructed post hoc with quite small numbers and would need prospective validation in a larger patient group before it has any validity clinically.
A key strength of this study was the use of a clinically meaningful primary outcome, namely delivery for clinical chorioamnionitis within 14 days of amniocentesis. This timeframe was adapted from studies investigating biomarkers for PPROM (preterm prelabour rupture of membranes) that considered delivery and histological chorioamnionitis within 7 days as likely related, whereas delivery more than 7 days is indicative of a subsequent or unrelated pathological event [22]. We expanded this to 14 days as our cohort recruited patients with suspected intraamniotic infection with intact membranes, which is potentially an earlier disease state to PPROM. However, this broader window limits direct comparability with existing literature, where microbial invasion of the amniotic cavity (MIAC) is more commonly used as the primary outcome. Of note, only three of the 11 cases in our group had positive amniotic fluid cultures.
Limitations of our study include the relatively small sample size, potential misclassification bias and lack of long‐term neonatal outcome data. Recruitment occurred over several years and proved challenging, and a multi‐centre approach may have bolstered the numbers significantly. To enhance recruitment, we adopted relatively broad inclusion criteria (asymptomatic shortened cervix, exposed membranes and clinician suspicion), which may have resulted in a heterogenous study population.
The wide confidence intervals observed for several biomarkers reflect this limited sample size and mean that the study is not powered to definitively rule out the utility of individual markers. Moreover, the use of clinical chorioamnionitis as part of our primary outcome, while clinically meaningful introduces the possibility of misclassification of cases and controls, given the variability in clinical diagnostic criteria. Notably, only one of the 11 cases, deemed to be clinically chorioamnionitis by the treating clinicians and by the study group, was found to have negative placental histopathology.
If findings from our study can be validated in larger prospective cohorts, amniocentesis with biomarker analysis could be used to identify a cohort of women with subclinical chorioamnionitis who may benefit from early intervention to reduce perinatal morbidity and mortality. Such an approach may also refine the efficacy of other pre‐term birth interventions, such as cervical cerclage, by identifying those cases who are likely to be poor responders to the intervention.
5. Conclusion
Amniocentesis appears to be a useful tool for assessing the likelihood of subclinical chorioamnionitis. However, current evidence remains insufficient to support the routine use of novel biomarkers over more established biomarkers such as LDH or glucose.
Funding
This project was supported by a $30 000 grant provided by Sydney Local Health District through The Pitch competition, which was used to fund consumables and specimen testing.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting Information: 1. Biomarkers investigated to predict chorioamnionitis.
Acknowledgements
This project was supported by a $30 000 grant provided by Sydney Local Health District through The Pitch competition, which was used to fund consumables and specimen testing. The authors would like to acknowledge the considerable efforts of Cecelia O'Brien, Tanya McKenny, and Aparna Ramachandran, who assisted with formulation, recruitment, and data collection.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information: 1. Biomarkers investigated to predict chorioamnionitis.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.