Objective
The purpose of this study was to examine the association between peripheral markers of maternal inflammation and the onset of term labor.
Study Design
A nested case-control study was performed with serum that had been collected at routine visits from a cohort of 607 term nulliparous women. Cases (n = 20) labored spontaneously within 48 hours of enrollment, and control subjects (n = 80) labored spontaneously ≥14 days after enrollment. Maternal serum cytokines were determined with the use of standard multiplex protocols. Median levels of interleukin-1, -4, -6, -8, and -10, interferon-γ, and tumor necrosis factor–α were compared with the use of the Mann-Whitney U test. Correlations between cytokine levels and maternal factors were performed (Spearman’s rho).
Results
Median interleukin-1 and -6 and tumor necrosis factor–α levels were significantly higher in cases vs control subjects (0.76 vs 0.31 pg/mL [ P < .01]; 2.05 vs 0.95 pg/mL [ P = .03]; 0.81 vs 0.51 pg/mL [ P = .02], respectively). Latency until delivery was inversely correlated with interleukin-1 and tumor necrosis factor–α (−0.28 [ P < .01]; −0.246 [ P = .01]), but not with interleukin-6.
Conclusion
Maternal proinflammatory markers increase before spontaneous term labor.
The underlying mechanisms that initiate normal term labor are incompletely understood, but inflammatory pathways are likely integral. Increasing evidence supports the association between inflammation and normal term labor. Amniotic fluid levels of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α are reported to be higher in term laboring women, compared with term nonlaboring women. Increased levels of IL-1, -6, and -8 have been detected in amniotic tissues of women who delivered after spontaneous labor at term, compared with those women who delivered at term without labor ; IL-1 and -6 and TNF-α have been shown to be higher in gestational tissues after both preterm and term labor, compared with pregnancies that delivered at like gestational ages without labor. Evidence also suggests significant systemic maternal inflammation after the onset of normal term labor. Specifically, maternal serum IL-6 levels have been demonstrated to be elevated after the onset of labor, compared with before labor.
Despite this evidence, the temporal relationship between inflammation and the onset of term labor remains unclear. Inflammation may precede the onset of labor or represent a secondary event. Our objective was to examine the association between peripheral markers of maternal inflammation and the clinical onset of labor at term.
Materials and Methods
We performed a nested case-control study. The initial cohort consisted of 607 nulliparous women at >37 weeks’ gestation who were candidates for a trial of labor and had a fetus in vertex presentation. Patients were enrolled during routine prenatal visits; a blood sample was collected at that time. Exclusion criteria were multiple gestation, autoimmune diseases, active infection, and treatment with antiinflammatory agents during the pregnancy (eg, progesterone, corticosteroids, or indomethacin). Cases consisted of all those women within the cohort who were admitted for spontaneous labor within 48 hours of enrollment (n = 20). Women with painful or regular contractions or any other signs of latent labor were excluded. Control subjects were matched to cases 4:1 (n = 80) and were selected at random from all patients within the cohort who experienced spontaneous labor at ≥14 days after enrollment. Maternal data on gestational age at enrollment, height, weight, and ethnicity were collected prospectively. Intrapartum and neonatal data were collected from detailed chart review and from a research quality perinatal database. The study was approved by the Institutional Review Board at the Medical University of South Carolina.
Multiplex analysis was performed in batches to assess cytokine levels. IL-1β, -4, -6, -8, and -10, TNF-α, and interferon-γ levels were assayed with the use of custom kits and standard protocols (Biorad, Hercules, CA) on the Luminex 200 platform (Luminex Corporation, Austin, TX). The assay sensitivities are IL-1ß at 0.8 pg/mL, IL-4 at 0.5 pg/mL, IL-6 at 1.1 pg/mL, IL-8 at 0.5 pg/mL, IL-10 at 0.9 pg/mL, interferon-γ at 19.3 pg/mL, and TNF-α at 3.0 pg/mL.
Statistical analysis was performed with SAS software (version 9.2; SAS Institute, Cary NC) and SPSS software (version 12.0; SPSS, Inc, Chicago IL). Median cytokine levels between cases and control subjects were compared by the Mann-Whitney U test. Correlation between variables was assessed by the Spearman R test. Maternal and neonatal characteristics were compared by the Mann-Whitney U test for continuous variables and χ 2 or Fisher’s exact test for categoric variables. Receiver operating characteristic curves for the prediction of term labor were constructed. Sensitivities, specificities, and positive and negative predictive values were calculated for each individual cytokine and for combinations of cytokines.
Results
Maternal and neonatal characteristics for cases and control subjects are shown in Tables 1 and 2 . There were no statistically significant differences in maternal characteristics or neonatal outcomes, with the exception of some anticipated variables. Cases were enrolled at later gestational ages (39.2 vs 37.3 weeks; P < .0001), delivered at earlier gestational ages (39.2 vs 40.4 weeks; P < .0001), and had a lower median birthweight than control subjects (3205 vs 3485 g; P = .03). Median cervical dilation at enrollment was also more advanced in cases, compared with control subjects (2 vs 1 cm; P = .01).
| Characteristic | Cases (n = 20) | Control subject (n = 80) | P value |
|---|---|---|---|
| Maternal age, y a | 21.5 (16–40) | 23.0 (17–38) | .21 |
| Maternal body mass index, kg/m 2 a | 30.2 (20.9–42.6) | 30.4 (20.1–49.9) | .97 |
| Maternal ethnicity, % | .36 | ||
| White | 25 | 33 | |
| Black | 15 | 28 | |
| Hispanic | 60 | 39 | |
| Gestational age, wk a | 39.2 (37.3–40.3) | 37.3 (36.7–40.0) | < .0001 |
| GBS positivity, % | 15.8 | 28.6 | .38 |
| Dilation, cm a | 2 (0–3) | 1 (0–3) | .01 |
| Prenatal infection: first and second trimester only, % b | 35 | 22.5 | .26 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
