A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone

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1 A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone Paul W. Zarutskie, M.D., a and James A. Phillips, Dr.PH. b a Zarutskie Fertility and Endocrine Institute, Seattle, Washington; and b Sage Statistical Solutions, Inc., Efland, North Carolina Objective: To perform an analysis of data with consideration for the current clinically accepted vaginal progesterone (P) or intramuscular (IM) P dosing regimens and the clinically relevant randomized clinical trials published during the time frame 1992 to Design: Meta-analysis of progesterone luteal support in IVF cycles using odds ratios (OR) and 95% confidence intervals (CI). Setting: Previously conducted randomized clinical trials meeting acceptance criteria. Patient(s): Infertility patients. Intervention(s): Progesterone (50 mg) IM daily or 200 mg P-in-oil capsules three times a day vaginally or 90 mg P in bioadhesive gel daily vaginally. Main Outcome Measure(s): Clinical, ongoing, miscarriage. Result(s): This analysis showed a comparable effect between vaginal progesterone as an oil-in-capsule or as a bioadhesive gel and IM P administration on the endpoints of clinical (OR ¼ 0.91, 95% [CI 0.74, 1.13]) and ongoing (OR ¼ 0.94, 95% [CI 0.71, 1.26]). A nominally significantly lower rate of miscarriage was observed with vaginal P compared with IM P (OR ¼ 0.54, 95% [CI 0.29, 1.02]). Conclusion(s): Administration of vaginal P is comparable to administration of IM P for luteal phase support in assisted reproductive technology. (Fertil Steril Ò 2009;92: Ó2009 by American Society for Reproductive Medicine.) Key Words: Luteal phase support, IVF, ART, vaginal progesterone, meta-analysis, intramuscular progesterone, hormone replacement therapy The need for hormonal support of the luteal phase in assisted reproductive technologies (ART) has historically been an important and debated topic among reproductive specialists (1, 2). In the early days of ART, luteal phase support (LPS) was often provided by the administration of human chorionic gonadotropin (hcg). In recent years, LPS has improved outcomes during ART, with progesterone (P) supplementation being the preferred treatment (3 6). Vaginal and intramuscular (IM) routes of administration have both shown success in promoting embryo implantation and ongoing rates (6, 7). The current standard of P administration for LPS during ART is vaginally as an oil-in-capsule formulation (600 mg/ daily [200 mg three times a day]) or 90 mg daily in a bioadhesive gel or through IM injection (50 mg/day). This standard of care is based upon work performed over the past decade (3, 6, 8) that has shown that these two vaginal formulations provide comparable efficacy outcomes to 50 mg IM P daily. Received September 2, 2008; revised February 2, 2009; accepted February 9, 2009; published online April 10, P.W.Z. is on the Speaker s Board for Organon, the Advisory Board for Columbia Labs, and has a spouse on the Nursing Advisory Board for Columbia Labs. J.A.P. has nothing to disclose. Supported by a grant from Columbia Laboratories. Presented at a meeting at ASRM 2007, October 13 17, Washington, DC (poster). Reprint requests: Paul W. Zarutskie, M.D., Zarutskie Institute, 1916 Pike Place, #12-333, Seattle, WA (FAX: ; pwzlnca@aol.com). In 2004, a meta-analysis was published (9) that sought to evaluate 1 whether LPS in ART improved outcomes, that is, the and miscarriage rates; 2 the optimal hormone administration for LPS, that is, hcg, P, a combination of both, or a combination of P and estrogen; and 3 the optimal route of hormone administration. In this analysis, comparisons were made between hormone support (hcg, vaginal P, IM P) and placebo/no treatment protocols for six endpoints (clinical, ongoing, miscarriage, severe ovarian hyperstimulation syndrome [OHSS], live birth, and multiple ). At the time the individual studies were performed, the optimal dose for LPS was not well established. In the meta-analysis of the primary objective of LPS during ART, the investigators did not need to consider dose because the focus of the review was to compare outcomes following any luteal support versus no luteal support. However, although not recognized in the original analysis of the third objective, at this time in the history of ART, the dose and formulation of P are clinically important. The methodology for the original meta-analysis (9, 10) was rigorous and well-defined. The review concluded that, with respect to the optimal route of P administration,. there was evidence of benefit of IM over the vaginal progesterone administration for the outcomes of ongoing and live birth (9). The current body of evidence on vaginal P administration in support of ART appears to run counter to this conclusion, and therefore, a closer review of /09/$36.00 Fertility and Sterility â Vol. 92, No. 1, July doi: /j.fertnstert Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 this meta-analysis was conducted with an objective of refining the selection of studies to include the currently accepted dose regimens of vaginal P. Closer scrutiny of the studies included in the analysis (9) revealed that, of the studies used in the comparison for clinical and ongoing outcomes between vaginal and IM P, several (11 13) used vaginal doses of P ( mg/day) in cream or suppository formulations that are, today, not generally recognized as clinically effective because of the initial studies of lower dosages and the results of the initial analysis and published reports of experience with the higher dosages. Additionally, a literature search was performed to identify more recent studies warranting inclusion in the analysis. Therefore, a new analysis of the data was performed, which focused on including studies that were published between the years 1992 to 2008, which fit the methodology criteria as outlined in the original meta-analysis (9, 10) and compared standard vaginal and IM routes of P administration with comparable dosing regimens that are currently clinically accepted standards of care for LPS in ART (3, 6, 8). MATERIALS AND METHODS The search methods for the identification of most of the studies in this analysis have been previously described (9, 10). For the search up to 2003 that supported the Daya publication, which identified most of the studies, the Menstrual Disorder and Subfertility Group s trials register was searched; the Cochrane Central Register of Controlled Trials was searched; MEDLINE was searched from 1971 to December 2003, and EMBASE from 1985 to 2003; and bibliographies of relevant publication and review articles, and abstracts of major scientific meetings was searched from 1978 to 2003 (9).The studies selected for the Daya review included randomized clinical trials that were either completed, had a planned interim analysis, or were stopped before full enrollment (9). The search was updated by the investigators though a MED- LINE search to December 2008, and two additional studies were identified for inclusion in the new analysis: Yanushpolsky 2008 (14) and Dal Prato (15) Three additional studies found in the search from 2003 to 2008 but not meeting the criteria for the meta-analysis are discussed in the Discussion section of this manuscript. This meta-analysis did not involve any individual patient data, so institutional review board approval of the analysis was not obtained. All of the studies included in this new analysis reported results in publications between 1992 and The criteria for this analysis included one of two vaginal LPS regimens compared with 50 mg IM P daily. The daily vaginal regimens were either 600 mg P (200 mg three times a day) as an oil-in-capsule formulation (Prometrium); or a daily 90-mg vaginal P polymer gel (Crinone 8%). These two vaginal regimens are the most commonly used (3, 6, 8), and have data comparing them to IM in randomized clinical trials (RCTs). Studies were excluded from the new analysis if they did not use one of these vaginal regimens versus IM P in an RCT. In total, nine studies (14 22) were included in the new analysis of clinical rates; six (15 19, 21) were included in a new analysis of ongoing and miscarriage (Table 1). Three studies (11 13) were not included in this analysis because they did not include one of the two vaginal regimens specified. The planned interim analysis by Yanushpolsky et al. (14) that was published as a manuscript in 2008 compared P vaginal gel and IM P use for LPS during IVF-ET, warranted inclusion in the analysis, as did the recent publication of Dal Prato (15). Aside from Yanushpolsky and Dal Prato, the literature search did not identify any other relevant studies appropriate for inclusion in this analysis. There were not enough studies reporting on live birth to conduct a meta-analysis of that endpoint. For the analysis, the homogeneity of treatment effect among trials was tested using the Breslow-Day chi-square test. The odds ratio (OR), with a 95% confidence interval (CI), was calculated for each study and across studies using Logit estimators. The overall effect was tested using the Cochran-Mantel-Haenszel procedure adjusted for study. In addition, 95% CIs on the overall difference in rates were also constructed. RESULTS In total, 1,620 and 1,019 subjects comprised the datasets used for analysis of clinical rates and ongoing rates, respectively. For the miscarriage rate analysis, 320 positive test cases were available. Seven of the nine studies included in the analysis used a daily 90 mg P bioadhesive gel dose (14, 15, 17 21) and two (16, 22) used 600 mg (200 mg three times a day) P oil-in-capsule formulation. All of the IM regimens used were 50 mg daily. Overall, this analysis showed comparable effects of vaginal P and IM P administration on the endpoints of clinical (overall OR ¼ 0.91; Fig. 1) and ongoing (overall OR ¼ 0.94; Fig. 2). Individually, there was variability in odds ratios between studies with ORs ranging from 0.45 to 1.47 in the clinical analysis and 0.32 to 2.63 in the ongoing analysis. However, the overall ORs in the analysis indicated a more comparable effect between the two routes of administration than the ORs previously calculated for clinical (Fig. 1) and ongoing outcomes (Fig. 2). This analysis showed a nominally significantly lower rate of miscarriage with vaginal P than with IM P, and the effect was greater than previously seen in the original analysis (Fig. 3). Because the clinical and ongoing rates between the vaginal and IM P groups were shown to be so close in this analysis, we considered that the difference between the rates for these two routes of P administration may be of clinical interest. To further evaluate the comparability of the 164 Zarutskie and Phillips Vaginal versus IM progesterone for ART LPS Vol. 92, No. 1, July 2009

3 Fertility and Sterility â 165 TABLE 1 Studies included and excluded in analysis of endpoints. Study Progesterone regimen (vaginal) Progesterone regimen (IM) Subjects (vaginal/im) Clinical Analysis endpoints Ongoing Miscarriage Smitz b micronized progesterone 50 mg daily 131/131 X X X mg daily Abate b 90 mg daily (vaginal gel) 50 mg daily 52/52 X X X Yanushpolsky a,c 90 mg daily (vaginal gel) 50 mg daily 105/110 X NA NA Dal Prato mg daily (vaginal gel) 50 mg daily 137/138 X X X Propst b,c 90 mg daily (vaginal gel) 50 mg daily 102/99 X X X Saucedo b,c 90 mg daily (vaginal gel) 50 mg daily 37/40 X X X Geusa b 90 mg daily (vaginal gel) 50 mg daily 150/150 X NA NA Saucedo b 90 mg daily (vaginal gel) 50 mg daily 50/50 X X X Sumita b micronized progesterone 50 mg daily 50/50 X NA NA 600 mg daily Perino b micronized progesterone 50 mg daily 150/150 excluded excluded excluded 200 mg daily Artini b 100 mg daily (vaginal cream) 50 mg daily 44/44 excluded excluded excluded Porcu b micronized progesterone 200 mg daily 50 mg daily 112/112 excluded excluded excluded Note: NA ¼ not analyzed; IM ¼ intramuscular. a Not included in original meta-analysis. 8 b Included in original meta-analysis. 8 c This study data was part of an interim analysis.

4 FIGURE 1 Intramuscular versus vaginal P administration: clinical per ET. treatments, the additional statistic for the 95% CI on the difference between these two groups was calculated for these two rates (Table 2). For the comparison of vaginal versus IM routes of P administration, the 95% CI was ( 6.9%, 2.6%) for the clinical endpoint and ( 6.7%, 4.4%) for the ongoing rate. DISCUSSION This analysis shows that, based on commonly used P luteal support regimens, vaginal P and IM P are comparable in promoting clinical and ongoing. To better evaluate differences among dosing regimens that are routinely used in current clinical practice, this analysis 1 focused on comparing two routes of LPS of ART (vaginal vs. IM), 2 focused on two vaginal regimens (200 mg P in oil capsules/three times a day; or 90 mg P bioadhesive gel daily), and 3 updated the previous analysis of Daya (9) with two additional studies (14, 15) published since their analysis and identified in the literature update as qualifying for inclusion. These criteria were designed to reflect the vaginal dosing regimens currently used in clinical practice (3, 6, 8). By focusing on two commonly used vaginal regimens (200 mg P in oil capsules three times a day or 90 mg P bioadhesive gel every day), three studies (11, 12, 13) that were included in the previous analysis of Daya (9) were removed. A metaanalysis of clinical for these three underdosed vaginal P regimens resulted in an OR of 0.67 (95% CI: 0.47, 0.97) and an overall adjusted P value of.029. Contrary to the present results with accepted vaginal dose regimens, the inclusion of underdosed vaginal preparations (vaginal cream doses of %200 mg daily) were likely to have contributed to the conclusion in the original meta-analysis that IM P was superior to vaginal P (9). The usually accepted interval for noninferiority in the field of LPS for ART cycles is 10% (23, 24), and the values of 6.9% and 4.4% (Table 2) encompassing the maximum lower and upper bounds of the observed CIs between vaginal and IM P for clinical and ongoing rates in this meta-analysis are well within this interval. Differences between the two vaginal dosing formulations were not evaluated in this analysis, although most of the studies (seven out of the nine) included in this analysis used the vaginal gel. Vaginal P dosing also nominally significantly lowered the likelihood of miscarriage over IM P dosing. Several recent reviews in the literature (6, 25) of LPS during ART, including the Practice Committee Report published within the past year by the American Society of Reproductive Medicine (ASRM) (3), outline vaginal P and IM P dosing regimens most often used and support the chosen dosing regimens included in the analysis. The ASRM Practice Committee Report recommends that. In IVF cycles involving down-regulation with a long-acting GnRH agonist, P supplementation (50 mg/day administered IM or mg/day administered vaginally) yields significantly higher PRs [ rates], compared with treatment with placebo or no treatment (3). Our analysis also included only studies that employed down-regulation with a GnRH agonist. Our analysis supports the conclusion that only 200 mg P in oil 166 Zarutskie and Phillips Vaginal versus IM progesterone for ART LPS Vol. 92, No. 1, July 2009

5 FIGURE 2 Intramuscular versus vaginal P administration: ongoing per ET. capsules/three times a day; or 90 mg P bioadhesive gel daily administered vaginally is comparable to 50 mg/day IM. We believe that this analysis provides the ART practitioner with data that are more easily interpretable and clinically relevant for clinical decision making based on current clinical trends. A number of studies were identified in the updated literature review that, although not meeting criteria for inclusion in this meta-analysis, nevertheless provide support for the vaginal route of administration. One study (26) was a small matched control study that included the 90 mg bioadhesive gel every day regimen as well as two regimens of the vaginal tablet (Endometrin; Ferring Pharmaceuticals, Parsippany, NJ), which were combined as vaginal P and compared with a matched control group of IM P. The reported outcomes were comparable between the vaginal and IM routes of LPS (26). In a retrospective study, IVF and intracytoplasmic sperm injection patients receiving 90 mg bioadhesive gel administered two times a day was compared with patients receiving IM P (27). In that study the outcomes were significantly higher for the vaginal bioadhesive gel FIGURE 3 Intramuscular versus vaginal P administration: miscarriage per clinical. Fertility and Sterility â 167

6 TABLE 2 Comparability and noninferiority of vaginal to IM progesterone on clinical and ongoing endpoints. 95% CI on the difference in overall proportion Overall proportion progesterone IM OR with (95% CI) Overall proportion progesterone vaginal Number of studies bioadhesive gel versus capsule Analysis 7 versus 2 276/808 (34.2%) 295/812 (36.3%) 0.91 (0.74, 1.13) 2.2% ( 6.9%, 2.6%) Clinical 5 versus 1 129/509 (25.3%) 135/510 (26.5%) 0.94 (0.71, 1.26) 1.1% ( 6.7%, 4.4%) Ongoing Note: CI ¼ confidence interval; OR ¼ odds ratio; IM ¼ intramuscular. two times a day compared with IM P. Studies of outcomes in donor oocyte cycles (donor) and frozen embryo transfer cycles (FET) comparing vaginal P dosing to IM P dosing have most frequently compared the 90 mg bioadhesive gel two times a day to IM P. Four studies confirm that vaginal dosing is comparable to IM dosing (28 31). Although one study of the usual IVF dose for P supplementation in donor cycles suggested that the 90 mg bioadhesive gel every day is as effective as IM P (32), another study of 200 mg oil capsules three times a day was not as effective as IM P in FET cycles (33). Overall, theses additional studies support the concept that outcomes with vaginal dosing of P for LPS is equivalent to the outcomes from IM dosing for LPS for specific vaginal dosing regimens. Among the routes of P administration for LPS in ART, vaginal and IM routes are currently the most commonly used. Oral dosing has the disadvantage of variable plasma concentrations of P as well as side effect issues because of metabolites generated via first-pass metabolism. In past years, pharmacy-prepared vaginal preparations were the alternative to IM dosing, but were messy and not U.S. Food and Drug Administration approved. Furthermore, the inconsistent nature of individually compounded vaginal suppositories may affect quality (34). Vaginally dosed formulations have become more consistent and practical, and the bioadhesive gel formulation, in particular, because of its controlled and sustained-released properties, limits the need for application to once daily (35). Although serum P levels following IM dosing are typically supraphysiologic and easily maintained, serum levels do not predict subsequent P levels in endometrial tissue, as vaginal dosing provides significantly higher levels in the endometrium than IM dosing, despite affording lower plasma concentrations (first uterine pass effect) (36). In addition, serum P levels in IVF cycles have been shown not to correlate with outcome in several trials (28, 30, 36). The lower serum P levels can also result in more favorable side effect profiles. In fact, vaginal delivery of P has consistently been shown to be preferred to IM P preparations when studied as determined by improved patient satisfaction scores, indicating that it is easier to use, less painful, less time consuming, and associated with fewer discomforts (7, 14, 37 39). In conclusion, daily administration of vaginal P (90 mg P bioadhesive gel or 600 mg [200 mg three times a day] P oil in capsule) is comparable to daily administration of 50 mg IM P for LPS of ART based on this meta-analysis of ongoing and clinical, and is associated with a nominally significantly lower rate of miscarriage than IM P. In the current literature, there are not enough studies reporting on live birth to conduct a meta-analysis of that endpoint. The vaginal delivery of P compared with IM injections is favored by many patients and practitioners as an easier and better tolerated route of administration. Studies have shown that the vaginal route of P delivery is preferred over IM injections as an easier, less painful, less time-consuming route of P administration, and is associated with less discomfort. In our opinion, this analysis adds to the wealth of accumulating efficacy 168 Zarutskie and Phillips Vaginal versus IM progesterone for ART LPS Vol. 92, No. 1, July 2009

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