Objective
To determine whether labor-associated inflammatory markers differ between low-risk, nulliparous women in preactive vs active labor at hospital admission and over time.
Study Design
Prospective comparative study of low-risk, nulliparous women with spontaneous labor onset at term (n = 118) sampled from 2 large Midwestern hospitals. Circulating concentrations of inflammatory markers were measured at admission and again 2 and 4 hours later: namely, neutrophil, and monocyte counts; and serum inflammatory cytokines (interleukin -1β, interleukin-6, tumor necrosis factor-α, interleukin-10) and chemokines (interleukin-8). Biomarker concentrations and their patterns of change over time were compared between preactive (n = 63) and active (n = 55) labor admission groups using Mann-Whitney U tests.
Results
Concentrations of interleukin-6 and interleukin-10 in the active labor admission group were significantly higher than concentrations in the preactive labor admission group at all 3 time points. Neutrophil levels were significantly higher in the active group at 2 and 4 hours after admission. The rate of increase in neutrophils and interleukin-10 between admission and 2 hours later was faster in the active group ( P < .001 and P = .003, respectively).
Conclusion
Circulating concentrations of several inflammatory biomarkers are higher and their rate of change over time since admission is faster among low-risk, nulliparous women admitted to hospitals in active labor, as compared with those admitted in preactive labor. More research is needed to determine if progressive changes in inflammatory biomarkers might be a useful adjunct to improving the assessment of labor progression and determining the optimal timing of labor admission.
Inflammatory events not seen before labor onset can be observed during parturition in the cervix, myometrium, and fetal membranes. Coincident with these events, maternal peripheral leukocytes (primarily neutrophils and monocytes) infiltrate the reproductive tissues, even in the absence of infection. These leukocytes are a major source of proinflammatory peptides in uterine and cervical tissues during labor, although the reproductive tissues also synthesize cytokines/chemokines (eg, interleukin [IL]-8) that may attract additional leukocytes through chemotaxis. The proinflammatory peptides most implicated in labor progression are IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, which contribute to recruitment and activation of additional leukocytes, augmentation of prostaglandin production, cervical ripening and dilation, membrane rupture, and uterine contractions. Thus, a positive feedback loop of cytokine production by activated leukocytes in maternal and fetal tissues is at least permissive, and perhaps essential, to labor onset and progression.
Activation of the inflammatory response likely explains the marked leukocytosis commonly found in the maternal blood during physiologic labor. Serum concentrations of IL-1β, IL-6, IL-8, and TNF-α are also significantly higher during labor than levels found before labor onset. Hebisch and colleagues reported that IL-6 concentrations during latent labor were significantly lower than concentrations associated with established and advanced labor. Moreover, serum IL-6 and IL-8 levels were positively related to cervical dilatation, and IL-6 was significantly higher with stronger and more frequent contractions, which are more likely to occur during active labor. Production of antiinflammatory cytokines such as IL-10 (which is produced by almost every immune cell and within reproductive tissues ) is enhanced by proinflammatory stimuli; thus, increases in serum concentrations of IL-10 are also expected with advancing labor. These findings suggest that women in earlier vs more advanced labor may be at distinctly different points in the inflammatory pathway. A better understanding of the physiologic differences between women in preactive vs active labor is important to improving birth outcomes in light of the higher rates of oxytocin augmentation and cesarean delivery rates seen in nulliparous women admitted to hospitals before active labor begins. Knowledge of the progression of inflammatory processes known to be associated with efficient labor progress will advance our understanding of labor physiology and may eventually inform admission decisions and evaluation of labor progress.
In this study, we examined neutrophil and monocyte counts and serum cytokine/chemokine (IL-1β, IL-6, IL-8, TNF-α, and IL-10) concentrations in low-risk, nulliparous women at term admitted to the hospital following the onset of spontaneous contractions. Our primary aim was to evaluate differences in these biomarkers at admission and at 2 and 4 hours after admission between women later determined to be admitted in preactive or active labor. We hypothesized that women admitted in active labor would have greater concentrations of inflammatory biomarkers than women admitted in preactive labor, indicating a more advanced stage of the inflammatory pathway driving labor progress. Our secondary aim was to evaluate patterns of biomarker changes over time between the preactive and active labor admission groups.
Materials and Methods
We performed a prospective comparative study at 2 large Midwestern hospitals in the United States. Institutional Review Board approval was granted, and written informed consents were obtained from all participants. Recruitment took place from March 2011 to December 2012 and was conducted by research team members in the labor and delivery triage unit or in the labor room soon after admission. All eligible women were approached for participation when a research team member was present on the unit. Approximately 70% of approached women accepted participation; we confirmed that study acceptance rates did not differ between those admitted in preactive vs active labor. The predominant rationale for declining participation was to avoid blood draws required by the study protocol.
Participants (n = 118) were nulliparous women carrying a single, cephalic presenting fetus at term (37-42 weeks’ gestation) admitted by their providers for spontaneous labor onset and an anticipated vaginal delivery. Eligible women were experiencing 2 or more uterine contractions every 10 minutes as objectively determined by external monitoring or palpation at admission, were dilated no more than 6 cm at admission, and had fetal membranes that were either intact or ruptured for not more than 4 hours before admission. Additional eligibility criteria included maternal age of 18-39 years, no significant medical history, absence of major pregnancy complications (eg, preeclampsia, diabetes, oligohydramnios), absence of identified fetal complications (eg, anomalies, nonreassuring status, intrauterine growth restriction), afebrile at study entry, lack of antibiotic or antiinflammatory medication use in the past 6 weeks, and ability to read and speak English. Women with preexisting conditions known to be associated with chronic, low-grade inflammation were excluded (eg, asthma, autoimmune diseases, cardiovascular disease, metabolic syndrome, type 2 diabetes, atherosclerosis, acid reflux, chronic obstructive pulmonary disease, chronic pain). Women undergoing inductions of labor were not eligible. Care during labor was at the discretion of the providers.
All digital cervical examinations by labor care providers during the course of labor were retrieved from the labor record, and the average dilation slope for the first 4 hours postadmission was determined. Because cervical examinations are rarely performed at exactly 4 hours after the admission examination, slope calculations based on the examinations immediately before and after the 4-hour time point were used to approximate dilatation at the 4-hour postadmission time point. The average dilation slope (cm/hour) for the first 4 hours postadmission was then calculated. Finally, each participant’s labor admission was retrospectively classified as either preactive labor or active labor based on the rate of cervical change during the first 4 hours after admission using a priori criteria: a labor admission was classified as preactive when average dilation was <0.5 cm/hour for the first 4 hours postadmission or as active when average dilation was ≥0.5 cm/hour. This differentiation cut point was based on contemporary labor progression research, which is now formally supported by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine in their joint obstetric care consensus on the safe prevention of the primary cesarean delivery. Demographic data were collected from each participant via interview; labor process, and outcome data were extracted from electronic health care records following birth.
Maternal blood was drawn at admission and 2 and 4 hours later. Blood at admission was sampled within 90 minutes of the cervical examination on which the labor admission was based; the median time to initial blood sampling was 33 minutes. Blood for neutrophil and monocyte counts was collected into ethylenediaminetetraacetic acid–containing tubes and quantified using a Sysmex XE-2100 within 30 minutes of blood collection (Sysmex America, Inc., Lincolnshire, IL). Blood for serum cytokine/chemokine determinations was collected into serum separator tubes. These samples were allowed to clot for up to 30 minutes followed by centrifugation at 4° C for 10 minutes at 3000 rpm. Serum was then stored as 1.5 mL aliquots at −70° C. All serum samples from a single participant were analyzed simultaneously in duplicate. Cytokines/chemokines were assayed using Human Proinflammatory 7-Plex II Ultra-Sensitive kits measuring IL-1β, IL-6, IL-8, TNF-α, and IL-10 (Meso Scale Discovery, Rockville, MD) according to manufacturer’s instructions. Assay sensitivity varies by cytokine: IL-1β = 0.58 pg/mL; IL-6 = 0.18 pg/mL; IL-8 = 0.10 pg/mL; TNF-α = 0.28 pg/mL; and IL-10 = 0.57 pg/mL.
Statistical analyses were performed using SPSS Statistics 21 (IBM Corporation, Armonk, NY) and SAS version 9.3 (SAS Institute Inc., Cary, NC). Maternal demographic characteristics and labor outcomes were compared by Mann-Whitney U tests for continuous variables and Fisher exact tests for categorical variables. Median neutrophil, monocyte, and cytokine/chemokine concentrations and their patterns of change over time (slope) were compared between the preactive and active labor admission groups using Mann-Whitney U tests with Holm’s sequential Bonferroni correction. Alpha level was set at .05; with Holm’s approach, P values considered significant were sequentially determined to account for multiple testing.
Results
Maternal demographic characteristics and labor outcomes are summarized in Table 1 . Of the 118 low-risk nulliparous women, 63 (53.4%) were admitted in preactive labor and 55 (46.6%) in active labor. Women in the preactive group were more racially diverse. Groups had similar dilatations at admission, although women in the preactive group had less cervical effacement. Women admitted in preactive labor received oxytocin more often than the active labor admission group (88.9% vs 43.6%, P < .001) and had a higher cesarean rate (17.5% vs 5.5%, P = .040). In-hospital labor duration was longer in the preactive admission group (12.3 vs 8.0 hours, P < .001).
| Description | Preactive labor (n = 63) | Active labor (n = 55) | P value |
|---|---|---|---|
| Maternal age, y | 26.0 (20.4–32.6) | 28.0 (21.0–33.4) | .243 |
| Gestational age at admission, wk | 39.6 (37.9–40.6) | 39.6 (38.2–40.6) | .413 |
| Race | |||
| White | 47 (74.6%) | 49 (89.1%) | < .05 |
| Black | 13 (20.6%) | 2 (3.6%) | |
| Other | 6 (4.8%) | 4 (7.3%) | |
| Body mass index at admission, kg/m 2 | 30.7 (25.0–38.2) | 28.9 (24.1–36.8) | .109 |
| Cervical dilatation at admission, cm | 3.0 (1.0–4.5) | 3.0 (1.5–4.7) | .123 |
| Cervical effacement at admission c | |||
| 50-75% | 19 (30.2%) | 1 (1.8%) | < .001 |
| ≥80% | 44 (69.8%) | 54 (98.2%) | |
| Fetal station at admission | −2 (−2 to −1) | −2 (−2 to −0.6) | .227 |
| Membrane status at admission | |||
| Intact | 36 (57.1%) | 39 (70.9%) | .130 |
| Ruptured | 27 (42.9%) | 16 (29.1%) | |
| Number of cervical examinations during labor | 8 (5–11) | 6 (3.6–9) | < .001 |
| Rupture of membranes | |||
| Spontaneous | 30 (47.6%) | 25 (45.5%) | .480 b |
| Amniotomy | 33 (52.4%) | 30 (54.5%) | |
| Oxytocin augmentation | |||
| No | 7 (11.1%) | 31 (56.4%) | < .001 b |
| Yes | 56 (88.9%) | 24 (43.6%) | |
| Narcotic analgesia used | 13 (20.6%) | 5 (9.1%) | .123 |
| Epidural analgesia used | 62 (98.4%) | 51 (92.7%) | .183 |
| Mode of birth | |||
| Vaginal d | 52 (82.5%) | 52 (94.5%) | .040 b |
| Cesarean | 11 (17.5%) | 3 (5.5%) | |
| Indication for cesarean, n | |||
| Dystocia (1st stage) | 6 | 0 | < .05 |
| Arrest of fetal descent (2nd stage) | 1 | 1 | > .999 |
| Nonreassuring fetal well-being | 4 | 2 | .684 |
| Time from admission to complete dilation, h | 10.9 (7.3–17.2) | 6.0 (3.7–10.8) | < .001 |
| Second stage duration, min | 79 (30–167) | 83 (30–198) | .859 |
| In-hospital labor duration, h | 12.3 (8.3–19.3) | 8.0 (4.6–12.1) | < .001 |
| Maximum temperature during labor >100.4° F | 5 (7.9%) | 3 (5.5%) | .722 |
| Infant sex | |||
| Female | 31 (49.2%) | 33 (60.0%) | .270 |
| Male | 32 (50.8%) | 22 (40.0%) | |
| Weight (infant), g | 3404 (2749–3909) | 3386 (2807–3812) | .285 |
| Apgar scores | |||
| <8 at 1 min | 9 (14.3%) | 3 (5.5%) | .134 |
| <8 at 5 min | 1 (1.6%) | 2 (3.6%) | .600 |
| Neonatal admission to NICU | 3 (4.8%) | 1 (1.8%) | .622 |
a Data are n (%) and median (10th, 90th percentile). Mann-Whitney U tests performed for continuous level data comparisons because of violations of normality. Fisher exact tests (2-tailed) performed for categorical level data comparisons, unless otherwise specified
b Fisher exact test (1-tailed) performed as test of directional hypothesis that women admitted in preactive labor are more prone to the intervention, as compared with women admitted in active labor
c Although percent effacement was not an inclusion/exclusion criterion, no woman was <50% effaced at admission
d Includes assisted vaginal births (ie, vacuum or forceps), of which there were 6 and 3, respectively, in the preactive and active labor admission groups.
Median concentrations of IL-6 and IL-10 were significantly higher among women admitted in active labor at all 3 sampling points while neutrophil concentrations were higher at 2 and 4 hours after admission with a trend toward significance at the admission time point ( Table 2 ). There were no between group differences in monocyte, IL-1β, IL-8, or TNF-α concentrations at any time point.
| Descriptions | Variable | Preactive labor (n = 63) | Active labor (n = 55) | P value | ||
|---|---|---|---|---|---|---|
| n | Median (range) | n | Median (range) | |||
| Neutrophils | Admission | 61 | 9.28 (4.07–19.51) | 55 | 10.76 (6.02–20.04) | .030 |
| +2 hr | 54 | 9.63 (3.83–22.73) | 51 | 12.00 (7.23–23.11) | < .001 a | |
| +4 hr | 49 | 10.54 (4.69–23.15) | 46 | 12.91 (7.82–23.31) | < .001 a | |
| Monocytes | Admission | 61 | 0.75 (0.30–2.31) | 55 | 0.72 (0.38–1.82) | .866 |
| +2 hr | 54 | 0.71 (0.12–1.35) | 51 | 0.69 (0.22–1.63) | .850 | |
| +4 hr | 49 | 0.70 (0.34–1.26) | 46 | 0.64 (0.34–1.38) | .826 | |
| IL-1β | Admission | 63 | 0.51 (0.00–10.61) | 55 | 0.58 (0.00–3.32) | .352 |
| +2 hr | 58 | 0.49 (0.00–4.01) | 53 | 0.50 (0.00–3.10) | .906 | |
| +4 hr | 56 | 0.48 (0.00–4.50) | 49 | 0.50 (0.00–2.87) | .916 | |
| IL-6 | Admission | 63 | 2.9 (0.8–63.9) | 55 | 5.1 (1.4–30.8) | .002 a |
| +2 hr | 58 | 3.6 (1.3–26.7) | 53 | 6.9 (1.9–39.4) | < .001 a | |
| +4 hr | 56 | 5.2 (1.7–86.2) | 49 | 9.9 (2.3–46.8) | < .001 a | |
| IL-8 | Admission | 63 | 5.7 (1.2–16.6) | 55 | 5.5 (1.8–96.5) | .728 |
| +2 hr | 58 | 5.8 (2.1–17.2) | 53 | 5.7 (2.1–27.7) | .468 | |
| +4 hr | 56 | 6.3 (1.9–14.6) | 49 | 5.3 (1.9–16.3) | .318 | |
| TNF-α | Admission | 63 | 6.8 (1.9–34.7) | 55 | 6.8 (1.9–25.8) | .861 |
| +2 hr | 58 | 7.2 (2.4–33.3) | 53 | 6.5 (1.8–25.2) | .189 | |
| +4 hr | 56 | 7.7 (2.6–33.4) | 49 | 6.1 (1.6–27.1) | .191 | |
| IL-10 | Admission | 63 | 3.6 (0.4–78.5) | 55 | 5.2 (0.6–70.5) | .003 a |
| +2 hr | 57 | 3.6 (0.7–27.9) | 53 | 7.3 (1.6–132.8) | < .001 a | |
| +4 hr | 55 | 3.4 (0.7–28.6) | 49 | 6.8 (0.7–70.5) | .001 a | |
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