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The Relationship Between Plasma Inflammatory Cytokines and Labor Pain

Rhee, Ka Young MD*; Goetzl, Laura MD; Unal, Ramsey MD; Cierny, Jill MD; Flood, Pamela MD, MA§

doi: 10.1213/ANE.0000000000000837
Obstetric Anesthesiology: Research Report
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BACKGROUND: Proinflammatory cytokines are increased in maternal blood at term pregnancy and are associated with cervical ripening and the initiation of labor. We hypothesize that maternal plasma cytokines also affect the sensitivity to labor pain.

METHODS: By using a previously validated model describing labor pain, we used a deidentified database derived from healthy nulliparous parturients who delivered singleton pregnancies at term. Numerical rating scores for pain were recorded after the onset of regular contractions using an 11-point scale. Maternal blood was drawn for the measurement of interleukin (IL)-1β, IL-4, IL-6, IL-8, and IL-10; interferon-γ; and tumor necrosis factor-α on admission or at the onset of painful contractions, whichever occurred later. Individual demographic, physiognomic, and cytokine variables that significantly affected labor pain at P < 0.05 were reported and included stepwise into a multivariable model.

RESULTS: One hundred sixty parturients provided 411 numerical analog scores for pain that were evaluated with our model. The relationship between numerical analog scores and cervical dilation was significantly affected by the type of membrane rupture, membrane status, induction, oxytocin administration, maternal race, and plasma IL-1β concentration as individual variables. Only the association between the highest IL-1β quartile and slower acceleration of pain during labor remained significant in the multivariate model (P = 0.0003). Women with IL-1β concentration in the highest quartile arrived at the labor room with a more dilated cervix than those with lower plasma concentrations of IL-1β (5.1 ± 3.0 vs 4.1 ± 2.6 cm; P < 0.02) and had faster labor progress.

CONCLUSIONS: Inflammatory cytokines including IL-1β play a role in cervical ripening. High maternal plasma concentrations of IL-1β may serve as a marker of advanced cervical ripening and readiness for labor that proceeds with less pain.

Published ahead of print June 19, 2015

From the *Department of Anesthesiology and Pain Medicine, Konkuk University School of Medicine, Seoul, South Korea; Department of Obstetrics and Gynecology, Temple University, Philadelphia, Pennsylvania; Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South Carolina; and §Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, Stanford, California.

Accepted for publication March 21, 2015.

Published ahead of print June 19, 2015

Funding: Supported by March of Dimes (6-Fy06-311; to LG).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Pamela Flood, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Ave., Palo Alto, Stanford, CA 94140. Address e-mail to pflood@stanford.edu.

The experience of pain during labor varies widely among individual women. In midgestation, under the influence of estrogen, transient receptor potential cation channel subfamily V member 1 expressing C-fibers infiltrate the uterine cervix and lower body at high density.1,2 Proinflammatory cytokines sensitize these peripheral C-fibers and accentuate the activation of transient receptor potential cation channel subfamily V member 1 receptors.

Although associations have been identified between physiognomic, treatment, and genetic differences and reported labor pain,3–5 the role of the inflammatory milieu in labor pain is unknown. Proinflammatory cytokines are increased at term gestation and are believed to affect cervical ripening and labor initiation.6 Cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 are increased in plasma from term laboring parturients who have no signs of infection and are associated with incipient onset of labor. High concentrations of plasma cytokines, including TNF-α and IL-1β and IL-6, have been implicated in sensitization in chronic pain syndromes not related to pregnancy, including chronic pelvic pain, endometriosis, and other types of neuropathic pain.7–10 Therefore, we investigated the hypothesis that a high maternal plasma cytokine concentration may serve to sensitize the parturient to labor pain.

We previously developed and validated a model that describes pain during the course of the first stage of labor.4,5 This model can detect the influence of physiologic and genetic factors with a high statistical significance.3,4 By using mixed effects modeling to consider other relevant covariants, we investigated how maternal cytokine concentration affected the labor pain reported by the parturient.

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METHODS

Six hundred and seven healthy nulliparous women with singleton gestations were enrolled in an observational cohort study of plasma cytokines and labor outcome from 2005 to 2009. A subset of this cohort was investigated here. One hundred sixty women, who had vaginal deliveries of singleton pregnancies at term and provided at least 1 pain score before neuraxial anesthesia, were evaluated. This study was approved by the IRB of the Medical University of South Carolina, and written informed consent was given by all participants. A part of this cohort has been previously reported in a case control study of the role of plasma cytokines on the timing of labor onset.6 The effect of cytokines on labor performance in this cohort was also reported.11

Pain scores were assessed after the onset of regular painful contractions using an 11-point rating scale (numerical rating scores [NRS]) with 0 for no pain and 10 for the worst pain imaginable. During the first stage of labor, cervical dilation (CD) measurements were reported in 1-cm increments from 0 (closed cervix) to 10 cm (fully dilated cervix). In general, the cervix was examined every 4 hours in latent labor and every 2 hours in active labor, or when the clinical situation required intervention. Nalbuphine 5 mg IV or IM was offered before, but not after, initiation of epidural analgesia. Pain scores were not considered after the initiation of neuraxial analgesia.

Demographic characteristics (maternal weight, height, age, race, gestational age, and newborn weight), labor interventions (induction of labor, oxytocin administration, artificial rupture of membranes, and analgesia administration), and labor characteristics (spontaneous rupture of membrane) were recorded and assessed for association with labor pain. Maternal blood was drawn once for serum cytokine measurement at admission or in the setting of induction, measured at the onset of painful contractions associated with cervical change. The purpose was to assess the inflammatory milieu at the onset of labor. Inflammatory cytokines may change as a result of multiple physiologic changes and pharmacologic interventions. However, the interaction between continuous change in cytokine expression and reported labor pain was not assessed in this study. The cytokines, IL-1β, IL-4, IL-6, IL-8, and IL-10; interferon (IFN)-γ; and TNF-α were measured as a multiplex assay on a Luminex 200 (Luminex Corporation, Austin, TX) platform as reported previously.6,11 The lower limit of detection was 0.8 pg/mL for IL-1β, 0.5 pg/mL for IL-4, 1.1 pg/mL for IL-6, 0.5 pg/mL for IL-8, 0.9 pg/mL for IL-10, 19.3 pg/mL for IFN-γ, and 3.0 pg/mL for TNF-α. Cytokine concentration was evaluated as quartiles, as the distribution was not normal. The highest and lowest quartile of each cytokine was compared with all others.

Labor pain was analyzed as a function of CD with NONMEM (nonlinear mixed-effects modeling; Globomax, Ellicott City, MD) using PLT Tools (PLT Soft, San Francisco, CA) as described previously.3–5 A naive pooled data analysis was conducted, and no intraindividual variability was assessed. Variables that significantly affected labor individually at P < 0.05 were reported and included stepwise into a model designed to report the most parsimonious explanation of our findings. Fitted variables are expressed with 95% confidence interval derived from likelihood profiles.

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RESULTS

Demographic information about the cohort is shown in Table 1. Clinical variables are shown in Table 2. Plasma cytokine concentrations were measured in all parturients and are reported in Table 3 as quartiles.

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

The relationship between NRS and CD was modeled as a function: NRS = NRSMIN + (NRSMAX − NRSMIN) × CDγ/(CDγ + CD50γ) to evaluate pain across the progress of labor as described previously and validated.4,5 In women who were not treated with epidural analgesia, the relationship between pain and CD was significantly affected by the induction of labor, use of oxytocin, maternal race, plasma IL-1β, and IFN-γ quartile as individual variables.

Medically induced labor was associated with a lower NRS report in early labor, 2.8 (1.5–4.0) less compared with spontaneous labor (P = 6 E−5). However, treatment with oxytocin for induction or augmentation was associated with a higher pain score in early labor of (E0 2.3 [0.3–3.8] greater, P < 0.03), suggesting that methods of induction other than oxytocin are less painful. Caucasian women reported 3.1 (1.3–5.0) NRS points less in early labor compared with women of other races (E0, P < 0.0004).

Among plasma cytokines tested, plasma IL-1β concentration in the lowest quartile was associated with faster augmentation of labor pain compared with patients with more plasma IL-1β (Fig. 1, quartile 1, difference in slope [γ], 6.0 [1.2−∞], P < 0.0003). Subjects whose IL-1β was in quartile 1 had almost no detectable IL-1β in their plasma (Table 3). Women whose plasma IFN level was in the lowest quartile reported less pain in early labor but then developed pain more quickly when compared with women with higher IFN (E0, 1.8 [0.1–3.4] NRS points lower, γ, P < 0.02).

Figure 1

Figure 1

The aforementioned variables that significantly affected the relationship between labor pain and labor progress were placed into a multivariate model in a stepwise manner with the most significant covariate first and were removed in the opposite order. The most parsimonious model for the effect of the above covariates on labor pain included only IL-1β quartile (Fig. 1). This factor significantly improved the model (P < 0.0003). Plasma IFN was no longer a significant predictor of pain after consideration of plasma IL-1β. Plasma concentration of IL-1β and IFN was significantly correlated (Pearson correlation coefficient, 0.40 [0.32–0.48]). Mean predicted error (MPE) as a measure of bias for the population is 11%, and MPE post hoc is 8%. Mean absolute predicted error (MAPE) as a measure of accuracy for the population is 31%, and MAPE post hoc is 16%. After consideration of IL-1β quartile, MPE is unchanged at 11% and MAPE is reduced to 30%. Parturients whose plasma IL-1β concentration was in the highest quartile arrived to the labor room with a more dilated cervix than those with lower plasma concentrations of IL-1β (5.1 ± 3.0 vs 4.1 ± 2.6 cm; P < 0.02) and had faster labor progress.11

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DISCUSSION

Women whose plasma IL-1β level decreased within the lowest quartile had more labor pain at a smaller CD. These findings suggest a relationship between inflammatory cytokines and pain unique to the puerperium. In other settings, increased IL-1β is associated with hyperalgesia in the peripheral nervous system.7,12,13 However, the findings in labor may differ, because higher plasma IL-1β concentration has also been associated with a more rapid subsequent onset of spontaneous labor.6 Therefore, higher IL-1β may be a marker for efficient/functional labor in the setting of a prepared, softened cervix. In support of this concept, higher concentrations of IL-1β, IL-6, and TNF-α were found in amniotic fluid between 16 and 24 weeks in women who delivered at <34 weeks gestation compared with those delivered at ≥34 weeks gestation.14 Although it is not known whether increased amniotic cytokine levels correlate with increased maternal serum levels, this finding still suggests that maternal proinflammatory cytokines may act as either a marker for cervical ripening or labor initiation. Women whose plasma contained highest quartile IL-1β had shorter latency to spontaneous labor in a previous report on this cohort6 and more efficient labor.11 IL-4 and IFN-γ did not significantly improve a multivariate model, likely because of collinearity with IL-1β.

Preparation of the uterine cervix for childbirth is, at least in part, mediated by inflammation involving the mediators studied.15–17 The results of our study might suggest that women who had higher concentrations of plasma IL1-β when they began their labor may have begun with a more advanced degree of ripening of the uterine cervix that required less force for dilation and thus experienced less pain. Their cervices were in fact more dilated at arrival to the hospital. However, it is not possible to interpret a causal relationship from an association detected in an observational cohort trial. Despite a potential mechanistic interpretation, it is possible that IL-1β is simply a marker for the actual mediator of the labor pain. Low plasma IL-1β might be correlated with high concentrations of another factor that causes sensitization. The inflammatory milieu in which labor occurs should be considered as a potential factor mediating variability in the experience of pain in labor. Ultimately, however, it is reassuring that the increased concentrations of inflammatory factors that may be required for successful labor do not translate into hyperalgesia for mothers but are associated with less painful labor. The mechanisms through which the usual relationship between inflammation and pain is altered in the puerperium deserve further study.

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DISCLOSURES

Name: Ka Young Rhee, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Ka Young Rhee approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Laura Goetzl, MD.

Contribution: This author helped design the study, conduct the study, and prepare the manuscript.

Attestation: Laura Goetzl approved the final manuscript and attests to the integrity of the original data.

Name: Ramsey Unal, MD.

Contribution: This author helped conduct the study.

Attestation: Ramsey Unal approved the final manuscript and attests to integrity of the data.

Name: Jill Cierny, MD.

Contribution: This author helped conduct study.

Attestation: Jill Cierny approved the final manuscript and attests to integrity of the data.

Name: Pamela Flood, MD, MA.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Pamela Flood approved the final manuscript and attests to integrity of the data and analysis.

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RECUSE NOTE

Dr. Pamela Flood is the wife of Dr. Steven Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James G. Bovill, Guest Editor-in-Chief, and Dr. Shafer was not involved in any way with the editorial process or decision.

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