Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit.

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant KV6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express KV2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing KV6.4-Met419, the voltage dependence of inactivation for KV2.1 is more depolarized compared with neurons overexpressing KV6.4. Finally, KV6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that KV6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.

Effects of antenatal hypnosis on maternal salivary cortisol during childbirth and six weeks postpartum-A randomized controlled trial.

BACKGROUND: Cortisol has been used to capture psychophysiological stress during childbirth and postpartum wellbeing. We explored the effect of a brief antenatal training course in self-hypnosis on salivary cortisol during childbirth and 6 weeks postpartum. METHODS: In a randomized, controlled trial conducted at Aarhus University Hospital Skejby Denmark during the period January 2010 until October 2010, a total of 349 healthy nulliparous women were included. They were randomly allocated to a hypnosis group (n = 136) receiving three one-hour lessons in self-hypnosis with additional audio-recordings, a relaxation group (n = 134) receiving three one-hour lessons in various relaxation methods with audio-recordings for additional training, and a usual care group (n = 79) receiving ordinary antenatal care only. Salivary cortisol samples were collected during childbirth (at the beginning of the pushing state, 30 minutes, and 2 hours after childbirth), and 6 weeks postpartum (at wake up, 30 minutes after wake up, and evening). Cortisol concentrations were compared using a linear mixed-effects model. Correlations between cortisol concentrations and length of birth, experienced pain and calmness during birth were examined by a Spearman rank correlation test. FINDINGS: During childbirth, week correlations were found between cortisol concentrations 30 minutes after childbirth and length of birth. In the beginning of the pushing state and 2 hours after childbirth, we found a tendency towards higher cortisol concentrations in the hypnosis group compared to the other two groups (hypnosis versus relaxation p = 0.02 and 0.03, hypnosis versus usual care p = 0.08 and 0.05). No differences were observed in cortisol concentrations between the groups 30 minutes after childbirth (hypnosis versus relaxation p = 0.08, hypnosis versus usual care 0.10) or 6 weeks postpartum (hypnosis versus relaxation: p = 0.85, 0.51, and 0.68, hypnosis versus usual care: p = 0.85, 0.93, and 0.96). CONCLUSION: Antenatal hypnosis training may increase the release of cortisol during childbirth with no long-term consequences. Further research is needed to help interpret these findings.

Electroacupuncture for pain relief in labour inhibits spinal p38 MAPK-mediated prostaglandin E2 release and uterine prostaglandin E2 receptor expression in rats.

BACKGROUND: p38 mitogen-activated protein kinase (p38 MAPK) activation involves the release of prostaglandin E2 (PGE2) and hyperalgesia. We have previously reported that electroacupuncture (EA) relieves labour pain, but the potential mechanisms remain unclear. OBJECTIVE: To observe the effects of EA on labour pain intensity, serum PGE2 levels and the p38 MAPK signalling pathway in rats during labour. METHODS: Female rats copulated with male rats to induce pregnancy, and then received castor oil to trigger labour. During labour, rats remained untreated (Control group, n=30) or were treated with remifentanil (n=30) or EA at Jiaji (n=30) or SP6+LI4 (n=30), respectively. The warm water tail-flick test was used to assess labour pain. Serum PGE2 levels were measured by ELISA. Protein expression of prostaglandin E2 receptor (PGER2), p38 MAPK and phospholipase A2 (PLA2) were analysed by Western blotting, and mRNA levels were measured by real-time PCR. RESULTS: EA treatment at Jiaji or SP6+LI4 significantly relieved labour pain, decreased serum PGE2 levels and inhibited protein and gene expression of PGER2 in the myometrium. Moreover, EA reduced protein expression of PLA2 and p38 MAPK, and inhibited phosphorylation of p38 MAPK in the lumbar spinal cord but not in the cerebral grey matter. Additionally, EA markedly decreased mRNA levels of p38 MAPK in the lumbar spinal cord and significantly reduced PLA2-IV mRNA levels in both the lumbar spinal cord and cerebral grey matter. CONCLUSIONS: This study indicates that EA relieves labour pain through, at least in part, inhibition of spinal p38 MAPK-mediated PGE2 release and uterine PGER2 expression in rats.

No. 355-Physiologic Basis of Pain in Labour and Delivery: An Evidence-Based Approach to its Management.

OBJECTIVE: To review the evidence relating to nonpharmacological approaches in the management of pain during labour and delivery. To formulate recommendations for the usage of nonpharmacological approaches to pain management. OPTIONS: Nonpharmacological methods available for pain management during labour and delivery exist. These should be included in the counselling and care of women. EVIDENCE: PubMed and Medline were searched for articles in French and English on subjects related to "breastfeeding," "pain," "epidural," "anaesthesia," "analgesia," "labour," "labor," and combined with "gate control theory," "alternative therapies," "massage," "position," "mobility," "TENS," "bathing," "DNIC," "acupuncture," "acupressure," "sterile water injection," "higher center," "control mind," "cognitive structuring," "holistic health," "complementary therapy(ies)," "breathing," "relaxation," "mental imagery," "visualization," "mind focusing," "hypnosis," "auto-hypnosis," "sophrology," "mind and body interventions," "music," "odors," "biofeedback," "Lamaze," "Bonapace," "prenatal training," "gymnastic," "chanting," "haptonomy," "environment," "transcutaneous electrical stimulus-stimulation," "antenatal education," "support," "continuous support," "psychosocial support," "psychosomatic medicine," "supportive care," "companion," "intrapartum care," "nurse," "midwife(ves)," "father," "doula," "caregiver," " hormones," "oxytocin," "endorphin," "prolactin," "catecholamine," "adrenaline," and "noradrenaline" from 1990 to December 2015. Additional studies were identified by screening reference lists from selected studies and from expert suggestions. No language restrictions were applied. VALIDATION METHODS: The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report. BENEFITS, RISKS, AND COST: The nonpharmacological method encourages an incremental approach to pain management that contributes to reduced interventions through optimal use of the woman's neurophysiologic and endocrine resources and a better understanding of the physiology of stress and pain during labour. GUIDELINE UPDATE: The guideline will be reviewed 5 years after publication to decide whether all of part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycles, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by The Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: RECOMMENDATIONS.

The effect of labour pain in caesarean delivery on neonatal and maternal outcomes in a term low-risk obstetric population.

Planned caesarean delivery (CD) frequency is increasing in many countries, and elective CD accounts for 50% of preventable causes of neonatal respiratory morbidity. The clearing of fluid in the lungs is important for the establishment of normal gas exchange with inspired air. A defect in this clearance can result in respiratory problems in neonate, but on the other hand patients waiting for the onset of spontaneous labour pain, the increase in emergency CD, together with severe mortality and morbidity are causes of concern and cause anxiety and distrust of obstetricians. In the current study, it was observed that foetal respiratory morbidity was reduced in the group with labour pain. The caesarean applied after the onset of labour pain could be a reason for the significant increase in foetal cord cortisol values in term low-risk neonates. A major advantage of this study was the inclusion of a low-risk patient group, and the increase in foetal cortisol secondary to pain in term neonates was shown objectively. Impact statement What is already known on this subject: The timing of CD is reported to be critical for neonatal morbidity, and elective CD accounts for 50% of preventable causes of neonatal respiratory morbidity. The clearing of fluid in the lungs is important for the establishment of normal gas exchange with inspired air. Cortisol secretion from the foetal adrenal gland is stimulated by stress. What do the results of this study add: Labour pain-related stress in the foetus might be a cause for elevated physiological cortisol, and secondary to that, lower respiratory morbidity. Caesarean delivery commenced after the onset of labour pain could be a reason for the significant increase in foetal cord cortisol values in term neonates. A major advantage of this study was the inclusion of a low-risk patient group, and the increase in foetal cortisol secondary to pain in term neonates was shown objectively. What are the implications of these findings for clinical practice and/or further research: Although it would seem to be rational to perform a caesarean section after the onset of labour pain in cases with a planned caesarean and a history of C-section delivery, with respect to maternal complications, especially in those with a history of more than one caesarean or those who have started active labour; there is a need for further prospective studies.

Effects of noninvasive electroacupuncture on labor pain, adrenocorticotropic hormone, and cortisol.

CONTEXT: Labor pain is the most painful experience in a mother's life. Acupuncture has been reported to be useful for pain relief during labor. OBJECTIVE: The study was designed to assess the effects of noninvasive electroacupuncture at Hegu (LI4) on labor pain and on adrenocorticotropic hormone (ACTH) and cortisol levels. DESIGN: The study was randomized, with an experimental acupuncture group (AG) and a control group (CG). SETTING: The study was conducted at the Kayseri Maternity Hospital in Turkey, over a period of 6 months in 2010. PARTICIPANTS: Participants were women in the active phase of labor. INTERVENTION: For the acupuncture group (AG), bilateral, Hegu acupuncture points were stimulated using a transcutaneous electrical nerve stimulation (TENS) acupuncture pen for 20 min in total. The control group did not receive acupuncture. All women received routine and standard nursing care and treatments. PRIMARY OUTCOME MEASURES: Blood ACTH and cortisol levels and visual analogue scale (VAS) scores were compared between the AG and CG to evaluate the efficacy of acupuncture treatment. RESULTS: Blood ACTH and cortisol levels and VAS scores were lower in the AG than in the CG; however, these differences did not reach a statistically significant level. CONCLUSION: In this study, blood ACTH and cortisol levels and VAS scores were affected by electroacupuncture intervention on Hegu (LI4), although the result was not statistically significant.

Optimising endorphins.

The interactions of the hormones of pregnancy, labour and birth are complex and subtle and their effects are far reaching. Within these complex interactions beta endorphin (beta-end) has a key balancing function, being a hormone of relationship and a stress hormone. As well as helping the mother cope with labour, beta-end enhances relationships with the newborn and the initiation of breastfeeding. Both too much endorphin and too little can create problems in labour. Optimising endorphin levels is therefore more complex than simply enhancing them and calls for midwifery skills to relieve fear so that women feel safe.

Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia.

It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE). Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon), in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35%) or xenon (35%) were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND) 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic) neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be tested in clinical trials in the future.

The effects of labor on differential gene expression in parturient women, placentas, and fetuses at term pregnancy.

Labor and its associated pain are thought to have unique impacts on parturient women. The goal of this study was to investigate the effects of labor and associated pain on differential gene expression profiles in the maternal, fetal, and placental compartments. We used microarrays to analyze maternal blood (MB), fetal cord blood (CB), and placental tissue samples in pregnant women after term vaginal deliveries (laboring group) and in term pregnant women after scheduled Ceasarean sections (nonlaboring group). The upregulated genes in the MB of the laboring group are involved in cytokine and nuclear factor-kappa B signaling pathways, regulation of the networks of toll-like receptor 4, and suppressor of cytokine signaling 3. Upregulated genes in the CB of the laboring group are involved in responding to stress and stimuli by regulating the network genes of the T-cell receptor beta locus and the FK506 binding protein 8. Differentially expressed genes in the placenta of the laboring group are involved in nitric oxide transport, gas transport, response to hydrostatic pressure, oxygen transport, acute phase responses, and the tumor necrosis factor-mediated signaling pathway, which are important during the transient hypoxemia and hypoperfusion that occur in the placenta during uterine contractions. Interestingly, few of the genes exhibited simultaneous changes in all three compartments, indicating that different pathways and complex interactions may be involved in human labor. In conclusion, human labor and its associated pain elicit unique gene regulatory changes in MB, placenta, and CB.