Mark P. Hehir

Uterorelaxant effect of ghrelin on human myometrial contractility

OBJECTIVE Ghrelin is a peptide that regulates maternal appetite and energy expenditure as well as playing a role in fetal nutrition. The purpose of the study was to investigate the effects of ghrelin on human myometrial contractility in vitro. STUDY DESIGN Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 21). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of ghrelin in the concentration range of 1 nmol/L to 1 micromol/L. Control experiments were performed simultaneously. RESULT Ghrelin exerted an inhibitory effect on contractility, compared with control strips. The mean maximal inhibition values were as follows: 33.66% +/- 2.63% for spontaneous contractions (n = 6; P < .05), and 31.55% +/- 4.64% for oxytocin-induced contractions (n = 6; P < .05). CONCLUSION This inhibitory effect of ghrelin on uterine contractions suggests it plays a physiologic role in regulation of myometrial activity and further studies to evaluate the signaling pathways involved may help to define this role. These findings highlight the emerging role of metabolic modulation of myometrium, and particularly at extremes of body mass index measurements.

The adipokine apelin and human uterine contractility

OBJECTIVE Obesity is an increasing problem in obstetric practice. Apelin, secreted by adipocytes, is present in increased serum concentrations in an obese state. Our group has previously highlighted that the adipokines leptin and ghrelin have a potential role in metabolic modulation of uterine contractility in obese women. The aim of this study was to evaluate the effects of apelin on human uterine contractility in vitro. STUDY DESIGN Biopsies of human myometrium were obtained at elective cesarean section. Myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of apelin in the concentration range of 1 nmol/L to 1 μmol/L. Control experiments were performed simultaneously. RESULTS Apelin exerted an inhibitory effect on spontaneous and oxytocin induced contractions in human myometrium. The mean maximal inhibition values were 36.8 ± 6.4% for spontaneous (n = 6; P = .002) and 30.4 ± 4.6% for oxytocin-induced contractions (n = 6; P < .0001). CONCLUSION Apelin inhibits human uterine contractility in vitro, raising the possibility that such metabolic modulation may play a physiological role in obese parturients.

17 alpha-hydroxyprogesterone caproate vehicle, castor oil, enhances the contractile effect of oxytocin in human myometrium in pregnancy.

OBJECTIVE The possibility exists that the vehicle for 17-alpha-hydroxyprogesterone caproate, castor oil, exerts an effect on human uterine contractility. The aim of this study was to evaluate its effects on contractility of myometrial preparations that were obtained during pregnancy. STUDY DESIGN Myometrial strips were suspended under isometric conditions. Contractility was induced with oxytocin. Strips were incubated in castor oil or physiologic salt solution and suspended for a further oxytocin challenge. Contractile integrals were compared between both groups. RESULTS Strips that were exposed to castor oil demonstrated increased contractile activity that was elicited by oxytocin (mean contractility value, 165.53%+/-17.03%; n=8; P=.004), compared with control strips (mean contractility value, 72.57%+/-7.48%; n=8; P=.003). There was a significant increase in contractile activity of the castor oil-exposed strips, compared with those that were exposed to physiologic salt solution (n=8; P<.001). CONCLUSION Exposure of human myometrial preparations to castor oil results in enhanced oxytocin-induced contractility.

Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility

OBJECTIVE This study was undertaken to investigate the effects of 3 histone deacetylase inhibitors on human uterine contractility. STUDY DESIGN Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 histone deacetylase inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 micromol/L) and valproic acid (100 nmol/L--1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. RESULTS All 3 histone deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% (P < .05); valproic acid, 35-36% (P < .05); and suberic bishydroxamate, 53-65% (P < .05). CONCLUSION The histone deacetylase inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of histone deacetylase inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.

Increasing rates of operative vaginal delivery across two decades: accompanying outcomes and instrument preferences

OBJECTIVE To examine rates and outcomes of operative vaginal delivery over a 20-year study period and the changing preference for various instruments during this period. STUDY DESIGN This retrospective analysis of prospectively gathered data was carried out at a large tertiary referral center from 1991 to 2010. All cases of operative vaginal delivery during the study period were recorded. The rates of instrumental delivery, as well as neonatal outcomes and instrument preference, were compared for individual 5-year epochs. RESULTS During the study period there were 156,130 deliveries of which 17,841 were operative vaginal deliveries, an incidence of 11.4/100 deliveries and 13.6/100 vaginal deliveries. There was an increase in the rate of operative vaginal delivery across the 20-year period (P < 0.0001; R(2) = 0.85; Slope = 0.42). When individual 5-year epochs were compared, the incidence of instrumental delivery increased from 7.3% (2340/31,937) in the first five years, 1991-1995, to 13.7% (6179/45,177) in the final five years, 2006-2010 (P < 0.0001; OR 2.34, 95% CI = 2.23-2.47). The perinatal mortality rate in cases of instrumental delivery was decreased when these time periods were compared (7.3/1000 (17/2340) vs. 1.8/1000 (11/6179); P = 0.003, OR 0.24, 95% CI = 0.11-0.52). The choice of instrument also varied, with 68.2% (1596/2340) of instrumental deliveries in 1991-1995 being carried out with forceps compared to 32.9% (2033/6179) in 2006-2010 (P < 0.001). CONCLUSION Rates of operative vaginal delivery have increased over the 20-year study period. The rate of perinatal mortality in infants who had an assisted vaginal delivery was decreased in the 5-year epoch at the end of the study compared with the period at the beginning. The rate of forceps delivery has fallen significantly, with vacuum delivery now being the choice of the majority of clinicians.

Cesarean delivery in the United States 2005 through 2014: a population-based analysis using the Robson 10-Group Classification System

BACKGROUND: Cesarean delivery has increased steadily in the United States over recent decades with significant downstream health consequences. The World Health Organization has endorsed the Robson 10‐Group Classification System as a global standard to facilitate analysis and comparison of cesarean delivery rates. OBJECTIVE: Our objective was to apply the Robson 10‐Group Classification System to a nationwide cohort in the United States over a 10‐year period. STUDY DESIGN: This population‐based analysis applied the Robson 10‐Group Classification System to all births in the United States from 2005 through 2014, recorded in the 2003 revised birth certificate format. Over the study 10‐year period, 27,044,217 deliveries met inclusion criteria. Five parameters (parity including previous cesarean, gestational age, labor onset, fetal presentation, and plurality), identifiable on presentation for delivery, were used to classify all women included into 1 of 10 groups. RESULTS: The overall cesarean rate was 31.6%. Group‐3 births (singleton, term, cephalic multiparas in spontaneous labor) were most common, while group‐5 births (those with a previous cesarean) accounted for the most cesarean deliveries increasing from 27% of all cesareans in 2005 through 2006 to >34% in 2013 through 2014. Breech pregnancies (groups 6 and 7) had cesarean rates >90%. Primiparous and multiparous women who had a prelabor cesarean (groups 2b and 4b) accounted for over one quarter of all cesarean deliveries. CONCLUSION: Women with a previous cesarean delivery represent an increasing proportion of cesarean deliveries. Use of the Robson criteria allows standardized comparisons of data and identifies clinical scenarios driving changes in cesarean rates. Hospitals and health organizations can use the Robson 10‐Group Classification System to evaluate quality and processes associated with cesarean delivery.

Mode of delivery and outcomes by birth weight among spontaneous and induced singleton cephalic nulliparous labors

To assess the effect of birth weight on mode of delivery among nulliparous women in a setting with no policy of elective induction for suspected macrosomia.

Early and late preterm delivery rates - a comparison of differing tocolytic policies in a single urban population.

Objective: Preterm delivery results in neonatal morbidity and mortality. We set out to estimate the difference in rates of preterm delivery in two institutions, serving a single population, with differing policies regarding use of tocolytic drugs for the prevention of preterm delivery. Study design: A retrospective study comparing preterm delivery rates between 2002 and 2007 in two large tertiary hospitals serving a single urban population with similar risk factor profile located less than 2 miles from each other. During the study period Hospital A routinely used tocolytic therapy, Hospital B operates a policy of never using any tocolytic drugs. Rates of delivery prior to 26, 30, 34 and 37 weeks were compared for each hospital. Results: During the study period there were 90,843 deliveries between the two hospitals. The overall rates of preterm delivery at less than 37 weeks gestation were comparable with 6.62% (2794/42,232) in Hospital A and 6.15% (2989/48,611) in Hospital B (p = 0.99). There was no significant difference in the numbers delivering at less than 34 weeks, 995/42,232 (2.36%) versus 1134/48,611 (2.33%), p = 0.59, less than 30 weeks, 403/42,232 (0.95%) versus 429/48,611 (0.88%), p = 0.87 or prior to 26 weeks, 126/42,232 (0.29%) versus 121/48,611 (0.25%), p= 0.08. Conclusion: In this large population routine use of tocolytic drugs in the treatment of threatened preterm labor does not alter rates of early or late preterm delivery. While this study is limited by its retrospective nature, it calls into question the practice of tocolysis.

Relaxant effect of Levosimendan on human uterine contractility in vitro

OBJECTIVE Levosimendan, a compound that exerts effects on calcium sensitivity and intracellular free calcium, in addition to opening ATP-sensitive K-channels, is widely used in the treatment of heart failure. Because of its dual mechanism of action, we hypothesized that it would modulate human uterine contractility. STUDY DESIGN Biopsies of human myometrium were obtained at elective cesarean section (n = 16). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of levosimendan in the concentration range of 1 nmol/L to 100 mmol/L. In separate experiments, the effects of prior exposure to the K-ATP antagonist glibenclmide (100 mmol) on the effects of levosimendan on myometrial contractility were evaluated. Simultaneous controls were performed for all experiments. RESULTS Levosimendan exerted an inhibitory effect on spontaneous and agonist induced contractions, when compared with control strips. The mean maximal inhibition (MMI) values were as follows: 45.34% +/- 5.92% for spontaneous contractions (n = 6; P < .05), and 41.88% +/- 5.40% for oxytocin-induced contractions (n = 6; P < .05). The inhibitory effect of levosimendan was significantly antagonized by glibenclamide, resulting in the mean maximal inhibition for levosimendan reduced to 19.04% +/- 3.61% for spontaneous contractions (n = 6; P < .05), and 16.53% +/- 4.08% for oxytocin induced contractions (n = 6; P < .05). CONCLUSION Levosimendan exerted a potent relaxant effect on spontaneous and agonist-induced human uterine contractility in vitro. This effect was reduced in the presence of K-ATP blockade. Because of the putative role of levosimendan in inflammatory conditions, the findings here may have implications for its future use as therapy for preterm labor.

Extreme macrosomia – Obstetric outcomes and complications in birthweights >5000 g

Management of extremely large birthweight infants presents challenges during the period of labour and delivery. We sought to examine outcomes in infants with extreme macrosomia (birthweight > 5000 g), at an institution where the management of labour is standardised.