Progestin treatment for the prevention of preterm birth

Abstract

Progestin supplementation appears to be a promising approach to both preventing initiation of preterm labor and treating it once it is already established, given the role of progesterone in maintaining pregnancy, as well as support from basic and clinical research. Progesterone and 17α-hydroxyprogesterone acetate slow the process of cervical ripening, and this is the rationale for prophylactic long-term progestin supplementation mostly studied so far. However, progesterone (but not 17α-hydroxyprogesterone acetate) also inhibits myometrial activity even after the cervix has already ripened. Moreover, these effects depend greatly on the vehicle used and the route of administration. Understanding different mechanisms of action, as well as the importance of progestin formulation, vehicle and route of administration, is the key to finding the optimal progestin treatment for prevention of preterm birth.

Figure 1

Bar graphs showing means ± SD of cervical light-induced fluorescence (LIF) obtained in vivo from pregnant rats at different days of pregnancy and postpartum treated with progesterone (P4), 17-OH P, or vehicle. A) Daily treatment with vehicle (controls) or P4 (4 mg, s.c.). Note that delivery is inhibited in the treatment group. B) Treatment daily with vehicle (controls) or 17-OH P (10 mg, s.c.). Note that significant differences are only observed until day 19 of gestation. From Kuon et. al. Am J Obstet Gynecol. 2010;202:455 e1–9.

Figure 2

Treatment with onapristone (ZK-98299) on day 16 of pregnancy induces preterm delivery and an increase the EMG PS Peak frequency in rats. From modification of figures in Shi et. al. Am J. Obstet Gynecol. 2008;198:235 e1–235.e4.

Figure 3

The effects of progesterone (P4) (top 3 traces) and 17-OH P (traces 4 to 6 from top) on myometrial contractility. KCl was added to the baths just prior to termination of the experiment. Note the inhibition of myometrial contractility with P4, but not with 17-OH P. From Ruddock et al. Am J Obstet Gynecol 2008;199:391.e1–391.e7.

Figure 4

Shown is the time of delivery (= hours after 8 a.m. of day 22 of gestation) of pregnant rats treated with vehicles (controls) and progestins by different routes of administration – injections (s.c.; daily): vehicle: sesame oil; progesterone (P4) (4 mg); 17-OH P (10 mg); vaginal (bid): vehicle: Replens^®; P4 (15 mg, Crinone^®); oral (bid): vehicle: sesame oil or H₂O; P4 (15 mg); transdermal (bid): vehicle: Replens^® or fish oil; P4 (15 mg). Rats with delayed parturition were sacrificed on day 25. Asterisks indicate P <0.05 compared with controls. From Kuon et. al. Am J Obstet Gynecol. 2010;202:455 e1–9.

Figure 5

Plasma progesterone (P4) levels in pregnant rats on day 18 and 21 without any treatment (controls) and on day 21 after treatment from day 18 until delivery with vaginal P4 (15 mg, bid), s.c. injections of P4 (4 mg), topical P4 in fish oil (15 mg, bid). Asterisks indicate P <0.05 compared with controls. Note the physiological P4 withdrawal from day 18 to day 21 in non-treated rats, that is prevented by s.c. and topical P4, but not by vaginal P4. From Kuon et. al. Am J Obstet Gynecol. 2010;202:455 e1–9.