In vivo controlled release of PGE2 from a vaginal insert (0.8 mm, 10 mg) during induction of labour

Objective To measure the release rate of prostaglandin E-2 (PGE(2)) in vitro from a controlled-release vaginal insert used for cervical ripening and induction of labour at term in women with intact membranes or pre-labour rupture of membranes (PROM). Design Open-label, single centre study. Population Women at term (greater than or equal to 37 gestational weeks) with unripe cervices (Bishop score less than or equal to6) scheduled for labour induction for mainly medical reasons. Methods sixty-eight women 47 with intact membranes and 21 with PROM) had the PGE(2) vaginal insert placed in the posterior fornix of the vagina. Each insert was removed from the women at a predetermined time interval between 0.5 h and 24 h, or earlier if labour was induced, fetal distress was detected or maternal complications occurred. After removal, the vaginal insert was frozen and stored for subsequent assay of residual PGE(2). Blood samples were collected immediately before insertion and at 4-hour intervals until removal of the vaginal insert to determine plasma concentrations of PGE(2) and the major PGE metabolite, 15-Keto-13, 14-dihydro-PGF(2 alpha) (PGE(m)). Vaginal pH was measured immediately before insertion and directly after removal of the vaginal insert. Bishop score was assessed before induction, after 8 h, 12 h and immediately after removal of the vaginal insert. Results There was a positive linear relationship between the amount of PGE(2) released from the insert and the duration of treatment in women with intact membranes (r(p) = 0.95, P = 0.0001). with a calculated PGE(2) release rate of 0.52 +/- 0.33 mg/h over 24 h. The PGE(2) release rate in women with FROM was not linear. The PGE(2) release rate was dependent on vaginal FH, with a faster release rate at higher vaginal pH. Forty-seven women (69.1%) had the insert removed due to the successful induction of labour and consequently discontinued study treatment before their allocated time period. At vaginal delivery, the released amount of PGE(2) at onset of labour was 4.0 +/-3.0 mg and 2.4 +/-2.1 mg for nulliparous women with FROM and intact membranes, respectively (P = 0.1). In multiparous women, the equivalent mean released mount was 3.2 +/-2.6 mg and 1.9 +/-1.4 mg. respectively (P 0.14). In women with intact membranes, the mean plasma concentrations of PGE(2) and PGE(2), after treatment were not statistically different to those women with FROM (P = 0.27 and 0.64, respectively). In women who were delivered vaginally, the median induction to delivery time interval was 17.0 h (range 4-42) in nulliparous women and 8.7 h (range 5-19) in multiparous women (P = 0.003). Ten (14.7%) women, who were all nulliparous, were delivered by caesarean section. Conclusions In women with intact membranes, the PGE(2) release rate was linear over 24 hours. There was a positive linear relationship between vaginal pH and PdE2 release rate. The metabolite analysis revealed no evidence of dose dumping neither in women with intact membranes or in women with PROM.