Background
Midtrimester ultrasound is a valuable method for identifying asymptomatic women at risk for spontaneous preterm delivery (PTD). However, response to various treatments (cerclage, progestogen) has been variable in the clinical setting. It remains unclear how other biomarkers may be used to guide intervention strategies.
Objective
We applied an amniotic fluid inflammatory scoring system to determine if the degree of inflammation is associated with intervention efficacy in patients with midtrimester short cervix.
Study Design
Women carrying a singleton fetus between 16-24 weeks’ gestation with a short cervix (≤25 mm) on transvaginal ultrasound underwent amniocentesis and were assigned to McDonald cerclage, no cerclage, or weekly 17-alpha hydroxyprogesterone caproate (17OHP-C). Our previously described inflammatory risk score (comprised of 14 inflammatory markers) was used to classify patients as high (score ≥8) or low (score <8) risk for inflammation. Gestational age at delivery was compared for each intervention and risk score status. Risk of delivering as a function of the remaining gestation was evaluated using modified Cox proportional hazards models with incorporation of methods to account for both left and right truncation bias.
Results
Ninety patients were included: 24 were in the nonintervention control group, 51 received cerclage, and 15 received 17OHP-C. Inflammation status at time of sampling influenced the efficacy of the treatment ( P < .001). Compared to the nonintervention control group, in patients with low inflammation (score < 8), both cerclage (adjusted hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.28–6.37) and 17OHP-C (HR, 3.11; 95% CI, 1.04–9.30) were associated with increased hazard of PTD. In contrast, in patients with high inflammation (score ≥8) both cerclage (HR, 0.22; 95% CI, 0.08–0.65) and 17OHP-C (HR, 0.20; 95% CI, 0.05–0.81) were associated with lower hazard of delivering preterm.
Conclusion
Cerclage placement or administration of 17OHP-C therapy for midtrimester short cervix for PTD prevention appears beneficial only in the subset of patients with high inflammation. Knowledge of the amniotic fluid inflammatory status may aid in guiding the appropriate therapy for women presenting with midtrimester short cervix who are at increased risk of PTD.
Introduction
Midtrimester cervical shortening is considered the best marker for identifying women at risk for spontaneous preterm delivery (sPTD). It is estimated that 8-10% of all pregnant women at midtrimester will present with the traditional diagnosis of short cervix (<25 mm) and 30-50% of these will deliver at <33 weeks’ gestation.
Although multifactorial, the pathogenesis of cervical shortening can be generally divided into inflammation-associated short cervix and noninflammation-associated short cervix. Since inflammation-associated short cervix is linked to progression to sPTD, it is expected that identification of such pathogenesis will identify a subset of women at higher risk of developing sPTD and will have a major diagnostic, prognostic, and therapeutic implications. However, there is a paucity of effective tools to predict sPTD or guide therapy options for pregnant women presenting with midtrimester short cervix. We previously reported an amniotic fluid (AF) inflammatory score based on a comprehensive analysis of inflammatory mediators obtained from patients with midtrimester short cervix. There were 14 mediators included in the inflammatory score ( Table 1 ), allowing the score to range from 0-14. In that observational study, a score ≥8 was highly predictive of delivery at <34 weeks’ gestation, with a sensitivity of 87.5%, a specificity of 100%, positive predictive value of 100%, and a negative predictive value of 87.5%.
| Interleukin |
| -1β |
| -1receptor antagonist (ra) |
| -6 |
| -8 |
| -10 |
| -12 |
| -15 |
| -17 |
| Granulocyte colony-stimulating factor |
| Monocyte chemotactic protein-1 |
| Macrophage inflammatory protein |
| –1a |
| –1b |
| Tumor necrosis factor-alfa |
| Regulated on activation normal T-cell expressed and secreted |
The mechanism(s) by which progestogens (including 17-alpha hydroxyprogesterone caproate [17OHP-C]) reduce preterm birth are not completely understood, but may include prevention of gap junction formation or by reducing inflammation. We hypothesized that women with an inflammation-associated short cervix (as determined by AF inflammatory score) will benefit from 17OHP-C or cerclage, while women with noninflammation-associated short cervix may benefit from expectant (nonintervention) management.
Materials and Methods
We performed a secondary analysis of 2 previously reported randomized controlled trials for treatment of short cervix. The first was cerclage vs no cerclage intervention and the second was cerclage vs weekly intramuscular 17OHP-C. The studies were identical with respect to their inclusion and exclusion criteria and differed only in their interventions (no cerclage, cerclage, and weekly intramuscular 17OHP-C). Prior to randomization in both studies, patients underwent amniocentesis to rule out infection (using culture and glucose). When feasible, an aliquot of AF was stored (–80°C) for future analysis.
Inclusion criteria for this study were singleton pregnancies, gestational age (GA) 16-24 weeks at the time of amniocentesis, a transvaginal cervical length of ≤25 mm, and an AF aliquot available for analysis. Exclusion criteria included any known chromosomal or structural anomaly, ruptured membranes, vaginal bleeding, the need for an indicated delivery, evidence of infection (positive culture, AF glucose <14 mg/dL), prolapse of the membranes beyond the external cervical os at presentation, or persistent uterine activity accompanied by cervical change.
AF samples were subsequently analyzed for 14 inflammatory mediators using the Bio-Plex array system (Bio-Rad Laboratories, Hercules, CA). Cytokine analysis was performed after conclusion of the randomized trials and therefore was not available to the managing physicians.
We applied a previously described AF cytokine inflammatory score to each patient. The score ranges from 0-14, and represents an overall summary of the inflammation status based on cytokine levels. Based on our previous study, patients were classified as having high inflammation if their score was ≥8 or low inflammation if their score was <8. We then compared GA at delivery based on the inflammatory status and intervention. We designated our control group to be those patient randomized to no intervention and would otherwise be similar to the cerclage and 17OHP-C intervention patients in regard to their other management, demographic, and clinical characteristics.
This project contained deidentified samples and data and therefore was deemed exempt from institutional review board approval by our local institutional review board.
Statistical analysis
Statistical analysis included χ 2 or Fisher exact probability for categorical variables. Results are presented as means ± SEM for continuous data, and medians and ranges for nonparametric data. The associations between the AF inflammatory score and intervention (cerclage and 17OHP-C), as well as the potential interaction between inflammatory status score and intervention on the risk of delivery at <37 weeks were evaluated based on the Cox proportional hazards regression models adjusted for study. In these models, we considered GA at delivery as the time scale, and considered women delivering at ≥37 weeks as being right censored. Since the lower GA at recruitment to the 2 original randomized trials differed (× weeks for the cerclage-placebo trial and × weeks for the 17OHP-C placebo trial), we accounted for this difference as a left truncation phenomenon, and modified the Cox models to address the left truncation bias. Confounders included in the regression models included those previously described. From these models, we expressed the association based on the hazard ratio (HR) with 95% confidence interval. The log rank test was used to examine if the hazard (survival) curves were different between groups. The proportional hazards assumption was tested by visual inspection in the graphs of the Schoenfeld scaled residuals (reference). These plots did not show evidence of nonproportional hazards. The study in which the patients participated was included in the regression models to adjust for any effects of the individual clinical trial. All analyses were performed using R statistical programing language (R Foundation for Statistical Computing, Vienna, Austria).
Materials and Methods
We performed a secondary analysis of 2 previously reported randomized controlled trials for treatment of short cervix. The first was cerclage vs no cerclage intervention and the second was cerclage vs weekly intramuscular 17OHP-C. The studies were identical with respect to their inclusion and exclusion criteria and differed only in their interventions (no cerclage, cerclage, and weekly intramuscular 17OHP-C). Prior to randomization in both studies, patients underwent amniocentesis to rule out infection (using culture and glucose). When feasible, an aliquot of AF was stored (–80°C) for future analysis.
Inclusion criteria for this study were singleton pregnancies, gestational age (GA) 16-24 weeks at the time of amniocentesis, a transvaginal cervical length of ≤25 mm, and an AF aliquot available for analysis. Exclusion criteria included any known chromosomal or structural anomaly, ruptured membranes, vaginal bleeding, the need for an indicated delivery, evidence of infection (positive culture, AF glucose <14 mg/dL), prolapse of the membranes beyond the external cervical os at presentation, or persistent uterine activity accompanied by cervical change.
AF samples were subsequently analyzed for 14 inflammatory mediators using the Bio-Plex array system (Bio-Rad Laboratories, Hercules, CA). Cytokine analysis was performed after conclusion of the randomized trials and therefore was not available to the managing physicians.
We applied a previously described AF cytokine inflammatory score to each patient. The score ranges from 0-14, and represents an overall summary of the inflammation status based on cytokine levels. Based on our previous study, patients were classified as having high inflammation if their score was ≥8 or low inflammation if their score was <8. We then compared GA at delivery based on the inflammatory status and intervention. We designated our control group to be those patient randomized to no intervention and would otherwise be similar to the cerclage and 17OHP-C intervention patients in regard to their other management, demographic, and clinical characteristics.
This project contained deidentified samples and data and therefore was deemed exempt from institutional review board approval by our local institutional review board.
Statistical analysis
Statistical analysis included χ 2 or Fisher exact probability for categorical variables. Results are presented as means ± SEM for continuous data, and medians and ranges for nonparametric data. The associations between the AF inflammatory score and intervention (cerclage and 17OHP-C), as well as the potential interaction between inflammatory status score and intervention on the risk of delivery at <37 weeks were evaluated based on the Cox proportional hazards regression models adjusted for study. In these models, we considered GA at delivery as the time scale, and considered women delivering at ≥37 weeks as being right censored. Since the lower GA at recruitment to the 2 original randomized trials differed (× weeks for the cerclage-placebo trial and × weeks for the 17OHP-C placebo trial), we accounted for this difference as a left truncation phenomenon, and modified the Cox models to address the left truncation bias. Confounders included in the regression models included those previously described. From these models, we expressed the association based on the hazard ratio (HR) with 95% confidence interval. The log rank test was used to examine if the hazard (survival) curves were different between groups. The proportional hazards assumption was tested by visual inspection in the graphs of the Schoenfeld scaled residuals (reference). These plots did not show evidence of nonproportional hazards. The study in which the patients participated was included in the regression models to adjust for any effects of the individual clinical trial. All analyses were performed using R statistical programing language (R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 90 patients were included in this study: 24 patients were in the nonintervention control group, 51 patients received cerclage, and 15 received 17OHP-C therapy. It is notable that there were more patients in the cerclage group since both of the original randomized trials included a cerclage arm. The 17OHP-C randomized trial compared 17OHP-C to cerclage and did not include a no cerclage arm. In addition, not all of the patients who were in the 17OHP-C trial had AF samples available for analysis. Some differences in demographic or clinical characteristics among the 3 groups were seen ( Table 2 ). A greater proportion of patients in the cerclage group had cervical lengths <5 mm ( P = .039) than women in the no cerclage group. Patient’s in the 17OHP-C group tended to be of lower parity ( P = .014) and with fewer having a prior preterm birth ( P = .013) than those in the nonintervention group. “Study” was included as a covariate in all models to adjust for study-specific effects.
| Variable | Control (N = 24) | Cerclage (N = 51) | 17OHP-C (N = 15) | P value |
|---|---|---|---|---|
| Demographic characteristics | ||||
| Maternal age, y | 29.6 ± 1.4 | 26.2 ± 1.27 | 23.5 ± 2.6 | .100 a |
| Ethnicity | .192 b | |||
| Caucasian | 16 (66.7) | 24 (47.1) | 4 (26.7) | |
| Hispanic | 6 (25.0) | 17 (33.3) | 7 (46.7) | |
| African American | 2 (8.3) | 6 (11.8) | 3 (20.0) | |
| Other | 0 | 4 (7.8) | 1 (6.7) | |
| Gestational age on admission, wk | 20 ± 0.4 | 20 ± 0.4 | 21 ± 0.8 | .486 a |
| Prior PTD | 10 (41.7) | 25 (49.0) | 5 (33.3) | .027 b |
| Parity | 1 (0–3) | 1 (0–7) | 0 (0–2) | .007 c |
| Clinical characteristics | ||||
| Cervical length, mm | 12.8 ± 1.4 | 16.2 ± 1.5 | 15.9 ± 2.9 | .146 a |
| Proportion with cervical length ≤5 mm | 1 (4.2) | 13 (25.5) | 1 (6.7) | .015 b |
| AF glucose, mg/dL | 39 ± 2.4 | 37 ± 2 | 35 ± 4.1 | .748 a |
| AF WBC count | 15 (0–228) | 24 (0–1150) | 27 (0–950) | .220 a |
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