Duration of luteal support (DOLS) with progesterone pessaries to improve the success rates in assisted conception: study protocol for a randomized controlled trial

Abstract

BackgroundLuteal support with progesterone is necessary for successful implantation of the embryo following egg collection and embryo transfer in an in-vitro fertilization (IVF) cycle. Progesterone has been used for as little as 2 weeks and for as long as 12 weeks of gestation. The optimal length of treatment is unresolved at present and it remains unclear how long to treat women receiving luteal supplementation.DesignThe trial is a prospective, randomized, double-blind, placebo-controlled trial to investigate the effect of the duration of luteal support with progesterone in IVF cycles. Following 2 weeks standard treatment and a positive biochemical pregnancy test, this randomized control trial will allocate women to a supplementary 8 weeks treatment with vaginal progesterone or 8 weeks placebo. Further studies would be required to investigate whether additional supplementation with progesterone is beneficial in early pregnancy.DiscussionCurrently at the Hewitt Centre, approximately 32.5% of women have a positive biochemical pregnancy test 2 weeks after embryo transfer. It is this population that is eligible for trial entry and randomization. Once the patient has confirmed a positive urinary pregnancy test they will be invited to join the trial. Once the consent form has been completed by the patient a trial prescription sheet will be sent to pharmacy with a stated collection time. The patient can then be randomized and the drugs dispensed according to pharmacy protocol. A blood sample will then be drawn for measurement of baseline hormone levels (progesterone, estradiol, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A, Activin A, Inhibin A and Inhibin B). The primary outcome measure is the proportion of all randomized women that continue successfully to a viable pregnancy (at least one fetus with fetal heart rate >100 beats/minute) on transabdominal/transvaginal ultrasound at 10 weeks post embryo transfer/12 weeks gestation (that is at the end of 8 weeks supplementary trial treatment).Trial registrationISRCTN05696887

Duration of luteal support after IVF is important, so why is there no consistency in practice? The results of a dynamic survey of practice in the United Kingdom

“…Whilst we concede that the emerging evidence suggests that early withdrawal of luteal support is safe and would signifi cantly reduce unnecessary treatment burden and drug costs for patients, larger prospective well designed trials are required before this can be adopted as routine practice. At least one randomised placebo-controlled trial studying the effect of luteal support duration is registered with the ISRCTN database (Gazvani et al, 2012). In the meantime, the inconsistencies observed in practice are likely to continue.…”

Short versus extended progesterone supplementation for luteal phase support in fresh IVF cycles: a systematic review and meta-analysis

“…The other described a retrospective analysis and so did not meet inclusion criteria (Schmidt et al, 2001). After literature search and screening, seven articles remained for inclusion in the analysis (Aboulghar et al, 2008;Gazvani et al, 2012;Goudge et al, 2010;Kohls et al, 2012, Kyrou et al, 2011Nyboe Andersen et al, 2002, Prietl et al, 1992.…”

“…Three of the trials were identified as having high-risk allocation concealment (Kohls et al, 2012;Nyboe Andersen et al, 2002;Prietl et al, 1992) indicating concern of possible selection bias due to inadequate concealment of allocations. Only one of the trials adequately blinded participants, personnel and outcome assessors; this was also the only placebo-controlled trial (Gazvani et al, 2012). A summary of Week 4 (day 15 after OR) 55…”

“…Three studies presented data on live birth rate (Gazvani et al, 2012;Goudge et al, 2010;Nyboe Andersen et al, 2002). Overall 672 live births were reported in 830 participants.…”

“…A subgroup analysis was performed due to study differences in timing of early cessation of progesterone supplementation. In five of the studies progesterone was withdrawn on the day of a positive HCG test (Andersen et al, 2002;Gazvani et al, 2012;Goudge et al, 2010;Kyrou et al, 2011;Prietl et al, 1992) and in two studies progesterone was withdrawn on the day that clinical pregnancy was confirmed at 5-7 weeks' gestation (Aboulghar et al, 2008;Kohls et al, 2012). This stratified analysis revealed no significant differences between the studies in which progesterone was stopped on the day of positive HCG (RR 0.93, 95% CI 0.83-1.06; P = 0.27) or on the day that clinical pregnancy was verified (RR 1.01, 95% CI 0.97-1.06; P = 0.55) (FIGURE 2B).…”