Hum. Reprod. Advance Access originally published online on February 11, 2008
Human Reproduction 2008 23(4):857-862; doi:10.1093/humrep/den012
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Prospective randomized study comparing luteal phase support for ICSI patients up to the first ultrasound compared with an additional three weeks
The Egyptian IVF-ET Centre, 3 St. 161 Hadaek El-Maadi, Maadi, Cairo 11431, Egypt; Department of Obstetrics and Gynaecology, Faculty of Medicine, Cairo University, Cairo, Egypt
1 Correspondence address. Tel: +20-2-25254944; Fax: +20-02-25253532; E-mail: ghar{at}link.net
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Abstract |
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BACKGROUND: There is a consensus that administration of progesterone to women after IVF for luteal phase support (LPS) is associated with a higher ongoing pregnancy rate. However there are few studies, including only one randomized study, which have examined the optimal duration of LPS.
METHODS: A questionnaire concerning details of LPS was returned from 21 leading IVF centres. We then randomized 257 women, who were pregnant after ICSI on day of first ultrasound, into two groups: to continue LPS for three more weeks or to stop on the day of ultrasound.
RESULTS: The duration of LPS in the questionnaire varied from the day of positive pregnancy test up to 12 weeks of pregnancy in different centres. In the randomized sutdy, 132 patients in Group A continued LPS for 3 weeks after first ultrasound, whereas 125 patients in Group B stopped LPS on day of first ultrasound. After confirming pulsations, the miscarriage rate up to 20 weeks of gestation was 4.6% (6/132) in group A and 4.8% (6/125) in group B [odds ratios (OR) = 0.94; 95% confidence intervals (CI) = 0.3–3.1]. Bleeding episodes were 15.9% in Group A compared with 20.8% in group B (OR = 0.72; 95% CI = 0.38–1.36).
CONCLUSIONS: There is no international consensus about the duration of LPS; our single-centre randomized trial did not support extending the LPS beyond the day of first ultrasound demonstrating echoes and pulsations. Trials registry number–ISRCTN: 88722916.
Key words: luteal phase support/progesterone/early pregnancy/miscarriage/bleeding eposodes
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Introduction |
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In the mid-1980s, the incorporation of gonadotropin-releasing hormone agonists (GnRHa) into ovarian stimulation regimens became associated with improved outcomes after in vitro fertilization (Hughes et al., 1992). By 1995,
85% of all IVF practitioners in the world included GnRH agonists in the stimulation protocol (de Mouzon and Lancaster, 1995
). Most infertility specialists use this long protocol for their stimulation cycles in normal responders (Gomel and Cheung, 1997).
However it has been shown that inadequate development of endometrium after ovarian stimulation with GnRHa protocol is due to inadequate corpus luteum function (Smitz et al., 1988; Macklon and Fauser, 2000).
Several meta-analysis have concluded that luteal phase support (LPS) is definitely indicated in IVF treatment cycles (Pritts and Atwood, 2002; Daya and Gunby, 2004; Nosarka et al., 2004).
In a randomized study, it was found that there is no significant difference in the ongoing pregnancy rate between cycles with LPS starting from the day of hCG, the day of oocyte retrieval or the day of embryo transfer (Mochtar et al., 2006).
Throughout the world, clinicians have prescribed progesterone for LPS to women who achieve pregnancy after either IVF or ICSI using the GnRHa protocol (Andersen et al., 2002; Penzias 2000).
The practice of LPS, is universally accepted, yet the duration of progesterone supplementation may be limited to around the day of positive β-hCG (Mochtar et al., 1996; Andersen et al., 2002) or extended to 8 weeks (Polson et al., 1992; Miles et al., 1994) or up to 12 weeks of pregnancy (Smitz et al., 1988; Smitz et al., 1992; van Steirteghem et al., 1998; Sohn et al., 1999; Schoolcraft et al., 2000; Ludwig and Diedrich, 2001).
In our questionnaire, there were great differences in the duration of LPS between different IVF centres. This was an important reason to start this randomized study.
The objective of the present work was two-fold: (i) To send questionnaires via e-mail to 21 leading centres worldwide and ask about the type of LPS used, its dose and its duration in their centre. (ii) To perform a single-centre prospective randomized study (RCT) to investigate the effect of the duration of LPS after ICSI on the outcome of pregnancy.
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Materials and Methods |
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- A questionnaire was sent to 21 leading IVF centres worldwide with questions about the type of LPS, dose and route of administration as well as its duration. There were 13 centres were from Europe, 6 from North America and 2 from the Middle East. The majority of centres were chosen from Europe and North America because the majority of IVF cycles are done in these two continents.
- The practical part of this study included a total of 257 pregnant women after ICSI. They were recruited during the period from 20 December 2006 to the end of July 2007 at the Egyptian IVF Centre, Maadi, Cairo, Egypt. All patients signed an informed consent form before being included in the study.
The study protocol was approved by our IRBM.
Inclusion criteria: Patients who were diagnosed as having clinical pregnancy as demonstrated by fetal echoes and pulsations on their first ultrasound examination at 6–7 weeks (i.e. 2–3 weeks after positive β-HCG) were included, provided that they had LPS by IM or vaginal progesterone, were 39 years of age or less, and had undergone ovarian stimulation by a long mid-luteal GnRHa protocol.
Exclusion criteria: Patients with azoospermic husbands, patients who received hCG for LPS, patients who had bleeding episodes before the first ultrasound examination irrespective of ultrasound results (because they are likely to violate the protocol and continue progesterone therapy) and patients with no fetal echoes and pulsations seen at 7 weeks gestation were all excluded from the study.
The protocol of the study was registered at Current Controlled trials under number: ISRCTN88722916 [controlled-trials.com] .
All patients were treated by long GnRH agonist down-regulation protocol which was confirmed by an E2 level below 
50 pg/ml and ultrasound scan of the ovaries (Mansour et al., 2005). Patients started to receive LPS on the day of oocyte retrieval, and stopped on day of the first ultrasound or 3 weeks later.
Randomization
Patients were randomized on the day of the first ultrasound after confirming at least one sac with echoes and pulsations.
Method of randomization
Dark, sealed envelops contained the intervention (continuation or stoppage of LPS) were created by a third party not involved in the allocation process. Randomization was performed by picking one envelope for each patient from sequential numbered envelopes on the day of intervention initiation by a nurse not involved in the study and the patient was informed about the allocated arm.
Power of the study
The sample size of women 220 (110 in each arm) provides 80% power and a two-sided significance level of 0.05 to test whether LPS for 3 weeks after first ultrasound, as compared to stopping LPS on the day of ultrasound examination, in ICSI cycles, can decrease the miscarriage rate from 15 to 5%.
Primary outcome measure: miscarriage rate between the day of first ultrasound up to 20 weeks of gestation.
Secondary outcome measure: attacks of bleeding during first 12 weeks of pregnancy after randomization.
All patients in the study started LPS on day of oocyte retrieval. In patients who continued LPS for 3 weeks, 15 out of 132 (11%) received vaginal progesterone and 117 (89%) received IM progesterone. In patients who stopped LPS on the day of the first ultrasound, 14 out of 125 (11%) received vaginal progesterone and 111 (89%) received IM progesterone.
All patients were asked to report the presence and intensity of any vaginal bleeding after the first ultrasound. No hormones were measured except β-hCG; the study does not contain data on any possible treatment with progesterone given by the patient's obstetrician at a later date.
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Statistical analysis |
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Statistical analysis was performed according to the intention to treat principle. All analyses of significance were two-sided and tested at the 5% level; values of P < 0.05 were considered to indicate significant differences. Continuous variables were tested if they presented normal distribution using the t-test. The results of the two groups were compared using the t-test or Mann–Whitney U-test for parametric or nonparametric data, respectively. Qualitative variables were compared with the use of the chi-squared test with Yates correction or Fisher's exact test, when necessary, and the 95% confidence intervals (95% CI) were calculated using the Woolf (logit) approximation. Odds ratios (OR) and 95% CI were calculated to examine the odds of improving clinical outcomes. Clinical and demographic data are also presented as the mean (and SD) or as the frequency distribution for simplicity. Statistical analysis was performed using the computer statistical package Stats Direct (Stats Direct Ltd, UK).
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Results |
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All 21 centres questioned responded positively to our questionnaire and the results are shown in Table I. LPS by micronized progesterone was used by 17 centres. Vaginal progesterone suppositories were used in 16 centres. One centre used oral micronized progesterone (3 tablets Uterogestan). Three centres used 50 mg IM progesterone daily. One centre used hCG for LPS. All centres started luteal support on the day of retrieval or embryo transfer. LPS was stopped on the day of β-hCG in 8 centres; two weeks after positive βhCG in 4 centres; 2–4 weeks after positive βhCG in 5 centres; at 9, 10 and 11 weeks of pregnancy in 3 centres and at 12 weeks in one centre.
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Study group: Included in the study were 257 patients who were confirmed to have a viable pregnancy by echoes and pulsations at 6–7 weeks gestation. They were divided into two groups after randomization: Group A consisted of 132 patients who continued progesterone in oil 50 mg IM (Prontogest, Nile Company, Cairo, Egypt) or vaginal progesterone 600 mg (Cyclogest, Multipharma, Egypt) for 3 weeks after the first ultrasound examination. Group B consisted of 125 patients who stopped LPS on the day of first ultrasound examination.
Demographic information and clinical data for all randomized patients are shown in Table II. Table III shows data on singleton pregnancies and Table IV shows data on multiple pregnancy.
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The miscarriage rate after confirmed pulsation and up to 20 weeks gestation was 4.6% in Group A and 4.8% in Group B (OR = 0.94; 95% CI = 0.3–3.01). Bleeding episodes were 15.9% in Group A as compared to 20.8% in Group B (OR = 0.72; 95% CI = 0.38–1.36). There was no significant difference in the bleeding episodes or miscarriage rate between the two groups.
Although there was a higher percentage of bleeding episodes in patients who stopped LPS, the difference was not significant. This difference was also present in the subgroup analysis of singleton and twin pregnancies, but it did not reach significance.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsStatistical analysisResultsDiscussionReferences |
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Although there is universal agreement regarding the support of the luteal phase for both the GnRHa protocol as well as the antagonist protocols (Friedler et al., 2006), there is, as yet, no agreement on the duration of LPS and when to stop.
LPS was considered essential to counter any luteal insufficiency that may have a negative impact on any early pregnancy (Smitz et al., 1992; La Sala et al., 2004; Ulug et al., 2006).
Without proper progesterone or estrogen stimulation, endometrial receptivity may be compromised, leading to decreased implantation and decreased pregnancy rates (Pritts and Atwood, 2002).
In an attempt to compensate for this abnormality, practitioners have employed luteal supplementation with either single or combined agents. Hormonal supplementation has consisted of progesterone, estrogen or hCG, and has been used during the luteal phase and beyond for patients undergoing IVF cycles. Different doses, durations and types of treatments are used, but the best dose, duration or type of treatment remains controversial (Herman et al., 1990; MacDougall et al., 1992; McClure et al., 1992; Pritts and Atwood, 2002).
It has been reported in the literature that the duration of LPS varies widely up to 8 weeks (Miles et al., 1994) or even longer up to 12 weeks (Smitz et al., 1992; van Steirteghem et al., 1998; Schoolcraft et al., 2000).
According to the results of our questionnaire, which covered 21 large and well respected centres, covering a worldwide area and performed during the year 2007, it was clear that there is no agreement on the duration which varied from stopping LPS on the day of positive hCG or continuation for up to 12 weeks of pregnancy.
A recent meta-analysis of Pritts and Atwood (2002) concluded that the optimal length of LPS remains unsolved and it is unclear how long to treat women receiving luteal supplementation, and that further trials will be needed before clear recommendations can be made.
A review of the literature has shown that there are many studies which compared different drugs for LPS, but very few have studied its optimal duration.
Schmidt et al. (2001) did a retrospective study on 400 patients who became pregnant after IVF/ICSI; 200 women received progesterone during early pregnancy and 200 did not. The study showed that withdrawal of vaginal progesterone at the time of a positive pregnancy test has no influence on the miscarriage rate.
Andersen et al. (2002) in a dual centre study including 303 women who achieved pregnancy and received 600 mg vaginal progesterone following long GnRHa protocol; they were randomized to no further LPS or to continue the same dose of progesterone for three weeks more. They found that prolongation of progesterone supplementation in early pregnancy has no influence on the miscarriage rate, and the authors suggested that progesterone can safely be withdrawn at the time of a positive β-hCG. The percentage of patients with at least one episode of bleeding in the study group was 22.2% as compared to 8.4% in the control group. However this difference was not statistically significant.
The Andersen et al. (2002) study has now been published for over 5 years, and our questionnaire which was sent in 2007 showed that only 8 out of 21 centres stopped LPS with the positive β-hCG result. It seems that the majority of IVF centres believe that extended LPS may yield less bleeding episodes, lower miscarriage rates and a higher take home baby rate. But investigations of the effect of prolongation of LPS up to 10 weeks pregnancy or more on bleeding episodes and the outcome of pregnancy were never carried out.
In the current study patients were randomized from the day of first ultrasound to extend LPS for 3 weeks more (9–10 weeks pregnancy), or to receive no further LPS, to find out if extended progesterone support has an effect on the bleeding episodes and the miscarriage rate. Our aim was to find out whether there is a benefit from the practice of extending the LPS to 10 weeks or more, which the majority of IVF centres in our questionnaire perform routinely. Other results have shown that although the bleeding episodes are more common in the absence of extended LPS, the difference was not significant and did not affect the miscarriage rate in the whole study and in the subgroup analysis of singletons and twin pregnancy. The same observation was noticed in Andersen et al. (2002) study in the arm which stopped LPS at a positive β-hCG. Irrespective of any possible explanation and so long as the difference is not significant and it does not affect miscarriage rate, it should be ignored and patients who develop these episodes of bleeding should be reassured.
We may conclude from this prospective study that there was no advantage for those who continue LPS beyond the day of the first ultrasound over those who did not. As it is advisable to minimize medication during early pregnancy, larger randomized studies should be done to investigate stopping LPS sooner.
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Submitted on October 11, 2007; resubmitted on December 16, 2007; accepted on January 9, 2008.
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