Article
Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey

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Abstract

This worldwide web-based survey compared the clinical practice for luteal-phase supplementation (LPS) in stimulated IVF cycles to the current evidence-based literature. Eighty-four treatment centres in 35 countries, representing a total of 51,155 IVF cycles/year, responded. Vaginal progesterone alone was used for LPS in 64% of cycles and in another 16% of cycles in combination with either i.m. (15%) or oral progesterone (1%). As a single agent, i.m. progesterone was used in 13% of cycles, oral progesterone in another 2% and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles and in 22% and 12% it was discontinued when fetal heart pulsations are recognized or until βHCG was positive, respectively. In conclusion, in almost two-thirds of the assisted cycles represented in this survey, vaginal administration of progesterone is preferred for LPS. Nevertheless, despite the available literature on the disadvantages of oral progesterone, i.m. progesterone and HCG for LPS, these agents are still used routinely by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks’ gestation, this practice is used in the majority of IVF cycles worldwide.

This worldwide web-based survey assessed the clinical practice for luteal-phase support in stimulated cycles in comparison to the current evidence-based literature. The survey included the following questions: (i) ‘What is the progesterone you use for luteal support?’; and (ii) ‘How long does progesterone needs to be administered in an IVF cycle if the patient becomes pregnant?’. Eighty-four units from 35 countries representing a total of 51,155 treated IVF cycles/year were included. Vaginal progesterone alone was used for luteal-phase supplementation in 64% of cycles. In another 16% of cycles, vaginal progesterone was used in combination with either intramuscular (15%) or oral progesterone (1%). As a single agent, intramuscular progesterone was used in 13% of cycles, oral progesterone in another 2%, and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles, in 22% of cycles it was discontinued when fetal heart pulsations are recognized, and in 12% it was administered until a positive pregnancy test. In conclusion, in agreement with the currently available literature, in almost two-thirds of assisted cycles worldwide, the vaginal route of progesterone administration is preferred for luteal-phase supplementation. Nevertheless, despite the described disadvantages of oral progesterone, intramuscular progesterone and HCG for LPS, these agents are still used routinely in clinical practice by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks of gestation, this practice is used in the majority of IVF cycles worldwide.

Introduction

A normal luteal function is vital for stabilizing the endometrium and preparing it for implantation and pregnancy. If pregnancy is established, following implantation, the developing blastocyst secretes human chorionic gonadotrophin (HCG), which preserves the viability of the corpus luteum (Penzias, 2002) until the luteoplacental shift occurs at around gestation week 7 (about 5 weeks after embryo transfer) (Scott et al., 1991).

In stimulated IVF cycles, however, it is well established that virtually all cycles are characterized by an abnormal luteal phase (Edwards et al., 1980, Kolibianakis et al., 2003, Macklon and Fauser, 2000, Ubaldi et al., 1997), leading to inadequate development of the endometrium and thus asynchrony between the endometrial receptiveness and the embryo transfer (Abate et al., 1999, Devroey et al., 2004, Macklon and Fauser, 2000, Nikas et al., 1999, Smitz et al., 1988). The dis-synchrony is related to the more advanced stroma in comparison with the development of the endometrial glands. Rapid increase in serum progesterone causes rapid development of the endometrial glands while duration of exposure is related to stromal development. In more than 50% of the cases, there is a dis-synchrony and delayed endometrial development of more than 2 days, which sometimes interferes with normal implantation (De Ziegler et al., 1994).

The first meta-analysis of randomized controlled trials (RCT) of luteal-phase supplementation (LPS) was published by Soliman et al. (1994). This meta-analysis included 18 studies and concluded that both HCG and progesterone supplementation improved pregnancy rates in stimulated IVF cycles; however, although HCG was superior to progesterone, its administration resulted in an increased risk for ovarian hyperstimulation syndrome (OHSS) (Soliman et al., 1994). Pritts and Atwood (2002) in a meta-analysis of 30 RCT reported that, compared with progesterone, HCG was superior only to oral progesterone, while there were no differences in outcomes (i.e. clinical pregnancies, ongoing pregnancies, deliveries and miscarriages) when compared with i.m. or vaginal progesterone administration. Nosarka et al. (2005) in another meta-analysis of 18 randomized trials concluded that HCG, i.m. progesterone and vaginal progesterone all significantly improved pregnancy rate per cycle; however, HCG was preferable to progesterone. Daya and Gunby (2004) published a systematic review of LPS that included 59 studies and found that OHSS was more than 3-fold higher when HCG was administered compared with progesterone alone. Recently, Van der Linden et al. (2011) updated the Cochrane Review published by Daya and Gunby (2004), including 69 studies with a total of 16,327 women and concluded that there is a significant effect in favour of progesterone for LPS and that, overall, the addition of other agents such as oestrogen or HCG did not seem to improve outcomes. In addition, there was no evidence favouring a specific route or duration of administration of progesterone.

These reports led to the consensus for the use of progesterone as the main hormonal supplementation for LPS in assisted reproduction treatment. Regardless of the latter meta-analyses however, in clinical practice, there is still a great deal of variation in the supplementation protocol used. The main debates that still need to be addressed to achieve agreement on the optimal supplementation protocol are: What is the better route of progesterone administration? What preparation is best? When should treatment be initiated and stopped? Is there a need for an additional agent (i.e. HCG or oestrogen)? Indeed, Aboulghar et al. (2008), using a questionnaire sent to 21 IVF centres worldwide during 2007, reported that clearly there is no agreement on the duration of LPS, which varied from stopping supplementation on the day of positive HCG to continuing it for 12 weeks of pregnancy.

IVF-Worldwide (www.IVF-Worldwide.com) is a comprehensive IVF-focused website for doctors, embryologists, nurses and social workers, providing its members with the ability to locate IVF units anywhere in the world and to communicate directly with the unit. It links doctors and specialists in IVF centres around the world in order to encourage dialogue and to discuss special treatments and medications. The website is non-commercial and has an advisory board of 52 key leaders in the field, who reviewed this survey’s questions and its results. The aim of this web-based survey posted on IVF-Worlwide.com was to investigate the current clinical practice for LPS in stimulated cycles and to compare the results to the current evidence-based literature.

Section snippets

Materials and methods

The web-based questionnaire entitled ‘Progesterone support in IVF’ was posted on the IVF-Worldwide website on 20 August 2009 and was open for data entry until 5 September 2009. The survey contained demographic questions including the name of the unit’s medical director, the name of the IVF unit, email address, country and number of IVF cycles in the unit in the most recent year.

Two specific questions addressed progesterone support in IVF: (i) ‘What is the progesterone you use for luteal

Quality assurance methods

During the study period, the website had an average of about 1000 entries per month (discrimination between ‘professional’ and ‘non-professional’ entries was not possible). In order to minimize duplicate reports from a unit and possible false data, a computerized software assessed the consistency of four parameters in the self-reported data of the unit surveyed with existing data of units registered on the IVF-Worldwide website. These parameters included the name of the unit, the name of the

Results

Between 20 August and 5 September 2009, 97 IVF units from 35 countries responded to the survey. Of those, 84 units passed the computerized system’s quality assurance test. In total, this report analysed 51,155 treated IVF cycles.

Table 1 displays the country of origin of the 84 participating units and the total number of cycles per country that these units performed in a year. Overall, the average number of treatment cycles per participating centre was below about 600 cycles per year. Only nine

Progesterone used for luteal support

In almost two-thirds of reported cycles, vaginal progesterone alone is used for LPS, 35% of cycles with vaginal cream or gel and 30% with capsules. In another 16% of cycles, vaginal progesterone is used in combination with either i.m. progesterone (15%) or oral progesterone (1%). As a single agent, i.m. progesterone is used in 13% of cycles and oral progesterone in another 2% of cycles. HCG for LPS is still used in almost 5% of cycles, as the only agent in 4% and in combination with

Length of progesterone administration if pregnancy is achieved

Table 3 displays the length of LPS in clinical practice, both overall and by geographic region. In 67% of the reported cycles, progesterone is administered until 10–12 weeks of pregnancy. In 22%, progesterone is discontinued when fetal heart beat is recognized, while in 12%, it is administered only until beta HCG is positive.

Discussion

As far as is known, this is the largest survey to date that addresses the clinical practice of progesterone administration for LPS in IVF cycles.

Regarding the type of progesterone administered, a vaginal progesterone compound (i.e. cream, gel, capsules) as the single agent was used in less than two-thirds of IVF cycles included in this study. i.m. progesterone, alone or in combination with vaginal progesterone, was used in 27% of the cycles and oral progesterone, alone or in combination with

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    Edi Vaisbuch obtained his medical degree in 1999 at the Hebrew University and Hadassah School of Medicine, Jerusalem, Israel. In 2005 he completed his obstetrics and gynaecology residency at the Kaplan Medical Centre, Rehovot, Israel. In 2007 he joined the Perinatology Research Branch of NICHH/NIH/DHHS in Detroit, Michigan, USA as a research associate and in 2008 was appointed as an Assistant Professor at the Wayne State University, Detroit. He received the ‘Academic Excellence Award’ from the Perinatology Research Branch in 2009 and 2010. He is currently working as a senior physician at the high-risk pregnancy unit at the Kaplan Medical Centre. His special interest is pregnancy complications and outcomes.

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