Progesterone Supplementation During Early Pregnancy
Progesterone Supplementation During Early Pregnancy
Background: The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation
Methods: There were 200 patients, with a positive β-hCG test (followed by a doubling in β-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second β-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET
Results: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: −2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446).
Conclusions: After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing β-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.
Exogenous supplemental progesterone (P) is a common practice in IVF-stimulated cycles because of associated luteal phase defects (LPDs) (Kolibianakis et al., 2003). Although the benefit of P administration as luteal phase support has been well documented in IVF (Fatemi et al., 2007), the question regarding the optimal time for its discontinuation remains.
Following ovulation, P, produced by corpus luteum (CL), induces secretory transformations of the endometrium (Bourgain et al., 1990) and allows endometrial receptivity and embryo implantation (Kolibianakis and Devroey, 2002). In the case of conception, trophoblast production of hCG prevents regression of the CL and amplifies steroid secretion that consequently decidualizes the endometrial stroma and supports early embryonic development (Penzias, 2002).
Studies conducted more than three decades ago demonstrated that P secretion by the CL is absolutely essential for the success of early pregnancy. The excision of the CL ('luteectomy') before 7 weeks of gestation leads to a precipitate decrease in serum P concentrations, followed by pregnancy loss, while luteectomy at 8 weeks of gestation or later leads to a transient decrease in P levels without any negative impacts in pregnancy outcome (Csapo et al., 1972). However, external administration of P after early luteectomy (before 7 weeks of gestation) could prevent the inevitable miscarriage (Csapo et al., 1973). On the basis of the results of the above studies, it is obvious that the success of early pregnancy depends on the P produced by the CL before 7 eeks of gestation.
Although it is well accepted that P supplementation is crucial during the time between the disappearance of exogenous hCG administered for final oocyte maturation and the rise in endogenous hCG during early implantation (Andersen et al., 2002), the optimal duration of P supplementation in IVF cycles is still a matter of debate. In the existing literature, which concerned pituitary suppression with GnRH agonists, the duration of P supplementation was suggested to be limited to around the day of positive β-hCG (Mochtar et al., 1996; Schmidt et al., 2001; Andersen et al., 2002) up to the first ultrasound (6–7 weeks) (Aboulghar et al., 2008), up to 8 weeks (Polson et al., 1992; Miles et al., 1994) or, alternatively, up to 12 weeks of pregnancy (Smitz et al., 1988; Smitz et al., 1992; Van Steirteghem, 1998; Ludwig and Diedrich, 2001).
Currently, there is no data regarding the effect of prolongation of luteal support on early pregnancy in patients treated with a GnRH antagonist protocol. The purpose of this randomized controlled trial (RCT) was to assess whether the cessation of P supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation.
Abstract and Introduction
Abstract
Background: The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation
Methods: There were 200 patients, with a positive β-hCG test (followed by a doubling in β-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second β-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET
Results: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: −2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446).
Conclusions: After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing β-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.
Introduction
Exogenous supplemental progesterone (P) is a common practice in IVF-stimulated cycles because of associated luteal phase defects (LPDs) (Kolibianakis et al., 2003). Although the benefit of P administration as luteal phase support has been well documented in IVF (Fatemi et al., 2007), the question regarding the optimal time for its discontinuation remains.
Following ovulation, P, produced by corpus luteum (CL), induces secretory transformations of the endometrium (Bourgain et al., 1990) and allows endometrial receptivity and embryo implantation (Kolibianakis and Devroey, 2002). In the case of conception, trophoblast production of hCG prevents regression of the CL and amplifies steroid secretion that consequently decidualizes the endometrial stroma and supports early embryonic development (Penzias, 2002).
Studies conducted more than three decades ago demonstrated that P secretion by the CL is absolutely essential for the success of early pregnancy. The excision of the CL ('luteectomy') before 7 weeks of gestation leads to a precipitate decrease in serum P concentrations, followed by pregnancy loss, while luteectomy at 8 weeks of gestation or later leads to a transient decrease in P levels without any negative impacts in pregnancy outcome (Csapo et al., 1972). However, external administration of P after early luteectomy (before 7 weeks of gestation) could prevent the inevitable miscarriage (Csapo et al., 1973). On the basis of the results of the above studies, it is obvious that the success of early pregnancy depends on the P produced by the CL before 7 eeks of gestation.
Although it is well accepted that P supplementation is crucial during the time between the disappearance of exogenous hCG administered for final oocyte maturation and the rise in endogenous hCG during early implantation (Andersen et al., 2002), the optimal duration of P supplementation in IVF cycles is still a matter of debate. In the existing literature, which concerned pituitary suppression with GnRH agonists, the duration of P supplementation was suggested to be limited to around the day of positive β-hCG (Mochtar et al., 1996; Schmidt et al., 2001; Andersen et al., 2002) up to the first ultrasound (6–7 weeks) (Aboulghar et al., 2008), up to 8 weeks (Polson et al., 1992; Miles et al., 1994) or, alternatively, up to 12 weeks of pregnancy (Smitz et al., 1988; Smitz et al., 1992; Van Steirteghem, 1998; Ludwig and Diedrich, 2001).
Currently, there is no data regarding the effect of prolongation of luteal support on early pregnancy in patients treated with a GnRH antagonist protocol. The purpose of this randomized controlled trial (RCT) was to assess whether the cessation of P supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation.