Lutinus

Ovarian stimulation was achieved by the long gonadotropin-releasing hormone (GnRH) agonist protocol. Pituitary desensitization with buserelin 0.5 mg (Suprefact®, Sanofi-Aventis, Paris, France) was started on cd 21 in regularly menstruating women and at cd 15 for oligo/amenorrhoeic women starting with ethinylestradiol 30 mg/desogestrel 150 mg daily from the 1^st day of bleeding (Marvelon®, Organon/Microgyn®, Bayer Pharma, Leverkusen, Germany) and until cd 21. Controlled ovarian stimulation with recombinant FSH (rFSH) (Puregon®, Organon, Oss, Netherlands) was started after at least 14 days of desensitization. Follicle growth was monitored by transvaginal ultrasound. Recombinant human chorionic gonadotropin (rhCG) 6500 IU (Ovitrelle®, Modugno, Italy) was administered when at least three follicles reached the size of 17 mm. Oocyte Pick-up (OPU) was performed 36 hours later under transvaginal ultrasound guidance. Luteal phase support (Lutinus®, Ferring©, Copenhagen, Denmark) was given from the day of transfer and until the pregnancy test. We adhered to the Danish National Criteria of elective single transfer for all patients <37 years of age. Transvaginal ultrasound was performed three weeks after a positive hCG blood test to confirm intrauterine clinical pregnancy.

Single fresh cleaved embryo transfer was performed on day 2 after oocyte retrieval, as previously described [18 (link), 22 (link)]. Dydrogesterone (30 mg/day orally) was routinely administered during the early luteal phase after the embryo transfer procedures. If luteal function was inadequate, progesterone was administered intravaginally (Lutinus, Ferring Pharmaceuticals, Saint Prex, Switzerland) until week 9 of pregnancy. Clinical pregnancy was defined by observation of a gestational sac at 5–6 weeks after embryo transfer on an ultrasound scan and ongoing pregnancy by detection of a foetal heartbeat at 7 weeks after embryo transfer. The clinical pregnancy rate, ongoing pregnancy rate, and follow-up data on live births were analysed.

SFCT was performed on day 2 after oocyte retrieval as previously described.²⁰ (link)^,24 (link) Dydrogesterone (30 mg per day orally) was routinely administered during the early luteal phase after embryo transfer. If luteal function was inadequate, progesterone was administered intravaginally (Lutinus; Ferring Pharmaceuticals, Saint-Prex, Switzerland) until week 9 of pregnancy. Clinical pregnancy was defined by observation of a gestational sac at 3 weeks after embryo transfer on an ultrasound scan, and ongoing pregnancy was defined by detection of a fetal heartbeat at 5 weeks after embryo transfer. The clinical pregnancy rate, ongoing pregnancy rate, and live birth follow-up data were analyzed.

During the study period, single embryo transfers were performed exclusively. Fresh or vitrified‐warmed embryo transfers were performed in spontaneous natural or hormonal replacement cycles as previously described.6, 12, 14, 15 Cleaved embryo and blastocyst transfers were performed on days 2‐3 and day 5 after oocyte retrieval or the confirmation of ovulation, respectively. Dydrogesterone (30 mg/d) was routinely orally administered during the early luteal phase after the embryo transfer procedure. In addition, in cases with insufficient luteal function, progesterone was administered intravaginally (Lutinus, Ferring Pharmaceuticals) until the ninth week of pregnancy. The clinical pregnancy rate and ongoing pregnancy rate were defined according to the ultrasonographic observation of a gestational sac at 5‐6 weeks after embryo transfer and observation of fetal heartbeats at 7 weeks after embryo transfer, respectively.

All patients received the same vaginal luteal phase support in a standard regimen using 300 mg micronized P₄ daily (Lutinus®, Ferring Pharmaceuticals). Intramuscular P₄ for luteal support was not used in any of the participating patients. A small fraction of patients (n = 41) had one bolus of GnRH agonist (Gonapeptyl 0.1 mg) on OPU+7 based on an individual clinical assessment. In patients receiving Gonapeptyl®, 30/41 were treated in the long GnRH agonist protocol and 11/41 in the GnRH antagonist protocol. Patients receiving a bolus of GnRH as luteal phase support were distributed equally across the different 17-OH P4 groups (p = 0.35).
In case of a GnRH-agonist trigger, a bolus of hCG on the day of oocyte retrieval (1,500 IU) was given to all patients. Based on the individual ovarian response to stimulation, some patients received an additional bolus of HCG on OPU+5 according to a protocol previously described by Humaidan et al. (17 (link)). Vaginal P₄ administration continued until the day of pregnancy testing (hCG trigger) or until 7 completed weeks of gestation (GnRHa trigger).

All patients were given a registration number on the basis of the order of their referral. Then, a specific researcher generated a computer‐based random allocation table, and all patients were randomly assigned to one of the four study groups.
Those assigned to the first study group received 100 mg of a vaginal P4 tablet three times daily (Lutinus, Ferring Pharmaceuticals); those assigned to the second group received 200 mg of vaginal P4 capsules (Utrogestan, FUJIFILM Pharmaceuticals) three times daily; those assigned to the third group received a 400‐mg vaginal suppository (Luteum, ASKA Pharmaceutical) twice daily; and those in the fourth group received 90 mg of a vaginal gel (Crinone, Merckserono) once daily. The randomization lists were kept on a password‐protected computer.