Objective
Various tocolytics are used to suppress uterine contractility in patients in preterm labor. Progesterone (P4) is used in patients at high risk for preterm delivery. In this study, we evaluated the effects of various tocolytics with and without P4 to examine effects on uterine contractility.
Study Design
Uterine tissues (n = 280) from women undergoing cesarean at term were exposed in vitro to various agents (vehicle, magnesium sulfate [MgSO 4 ], nifedipine, indomethacin, or pinacidil–all with and without P4). Contractility was measured before and after addition of the various agents.
Results
P4 alone at 10 –5 mol/L concentration has little effect to inhibit contractility ( P ≥ .05). MgSO 4 (2-8 × 10 –3 mol/L) inhibits uterine contractility ( P < .05) but there is no change when combined with P4 ( P > .05). Nifedipine (10 –8 mol/L) and indomethacin (10 –5 mol/L) inhibit contractions alone ( P < .05) and to a greater extent when combined with P4 ( P < .05). P4 significantly ( P < .05) reduced the effects of pinacidil (10 –6.5 mol/L).
Conclusion
Combinations of P4 with nifedipine or indomethacin, but not MgSO 4 , might be used to effectively suppress preterm labor.
Preterm delivery is a major medical problem in the United States and worldwide with an increasing incidence. Worldwide preterm deliveries account for >9% of all births. Prematurity is the direct cause of 28% of all neonatal deaths, accounting for >1 million neonatal deaths in 2004. Preterm labor is the most common reason for antenatal hospitalizations in the United States. There are many risk factors for and causes of preterm labor and delivery. However, the majority of preterm deliveries occur in women without any known or identifiable risk factors. Currently, there are no accurate scoring systems in use to predict preterm birth outside of a woman’s obstetric history.
Several medications, typically beta-mimetics, calcium channel blockers, prostaglandin inhibitors, or magnesium sulfate (MgSO 4 ), are regularly used to treat acute preterm labor. These are administered to decrease the probability of delivery within 24-48 hours allowing for time to administer corticosteroids for fetal benefit. These tocolytics have not been shown to reliably extend pregnancy beyond 1-2 days.
Progesterone (P4) plays an important role in pregnancy. It helps to maintain uterine quiescence during the pregnancy, suppresses uterine contractility, and may also control cervical function. In addition, P4 therapy has also been used as prophylaxis in the prevention of preterm delivery but its use in the setting of acute preterm labor has not been proven.
Progestins (vaginal P4 or 17 alpha hydroxy-P4 caproate [17P]) are thought to be effective therapies to reduce the incidence of recurrent preterm delivery and preterm delivery in high-risk groups. Recently, a multicenter study conducted by the National Institutes of Health confirmed that vaginal P4 may reduce the incidence of preterm delivery. However, there are a number of unanswered questions including who are candidates for preventive therapy, use in acute preterm labor, and whether certain preparations of progestins (P4 vs 17P) are better than others. The object of this study was to examine the effects of P4 alone, various tocolytics alone, and combinations of P4 with various tocolytics on uterine contractions to determine if there are added advantages to using P4 with any tocolytics.
Materials and Methods
After obtaining institutional review board approval at Maricopa Integrated Health System, Phoenix, AZ, patient recruitment began. Women undergoing elective, term cesarean deliveries in the Labor and Delivery Department of Maricopa Integrated Health System were recruited. Informed, written consent was obtained from each woman. After the baby was delivered via cesarean, a 2- × 2- × 1-cm segment of tissue was excised from the lower uterine segment and placed in Krebs solution. Patients recruited for this study were all undergoing elective cesarean delivery at term. The patients had the following characteristics: age 30.4 ± 4.92 (SD) years and parity range of 1–5 (mean = 2.64). During the study period, 37 women were recruited and enrolled. The tissue contraction studies were performed within 24 hours of collection. The methods used in this study were similar to those used previously.
Each of the 37 tissue samples were then cut into 0.2- × 0.2- × 1-cm myometrial strips (8 strips/tissue sample) resulting in 280 tissue samples. The myometrial strips were mounted in an organ chamber system in a bath (10-mL volume) of Krebs solution at 37°C and bubbled with 5% CO2 in air to maintain pH at 7.4. The bottom ends of the uterine tissues were fixed within the organ chamber while the top end was connected to a force transducer and to an online computer. The myometrial strips were equilibrated and spontaneous contractility was stabilized. Comparisons of drug effects with and without P4 were made between data obtained in strips from the same patient.
Crystalline P4 dissolved in ethanol (absolute ethanol [EtOH]) was added to the tissue bath as were MgSO 4 (vehicle = water), indomethacin (vehicle = 0.1 mol/L Na 2 CO 3 ), nifedipine (vehicle = EtOH), and pinacidil (vehicle = EtOH). Nifedipine-containing solutions were also protected from light. All chemicals and drugs used in this study were from Sigma-Aldrich, St Louis, MO.
Solutions of vehicles (run in parallel) and dissolved agents were added to the 10-mL muscle baths in 10-μL volumes. Control experiments were performed by adding only 10 μL of any of the vehicles to the 10-mL muscle bath of Krebs solution. The addition of the vehicle alone did not affect contractility over the recording periods ( Figures 1-4 ) . P4 was used at a fixed concentration (10 –5 mol/L) and concentrations of each tocolytic (various concentrations, based upon previous studies) were also used in combination with P4. Contractile activity was registered for a 6-hour recording period and stored using a data acquisition system. Following each 6-hour recording period, the viability of the muscle strips were confirmed by measuring the contractility effect when KCl was added to each muscle bath.
