The number of embryos transferred was based on the criteria of the Ministry of Health, and was a maximum of 2 for women aged under 35 years undergoing embryo transfer for the first time, and 2—3 in women aged 35 years or older undergoing retransplantation. The treatment regimen i. Clinical pregnancy was determined by the presence of gestational sacs in B ultrasound images 5 weeks post-transfer.
Details of the delivery and infant health status were obtained during follow-up through letters or telephone calls. The occurrences of any adverse events such as bleeding, itching, or inflammation at the injection sites were recorded.
Patients were able to withdraw from the study if severe adverse events occurred. A P-value less than 0. A diagram showing participant flow through the study, including details of patient eligibility, reasons for exclusion, treatment group allocation, loss to follow-up and number included in the final analysis, is shown in Fig 1.
There were no statistically significant differences between the Gel Group and Inj Group in patient age, endometrial thickness, endometrial preparation time, number of embryos transferred, number of high-quality embryos transferred and embryo recovery rate Table 1.
After the exclusion of cycles withdrawn from the study, the primary analysis included cycles in the Gel Group and cycles in the Inj Group. As shown in Table 2 , there were no statistically significant differences between the Gel Group and Inj Group in the rates of live births Both univariate and multivariate logistic regression analysis revealed that the odds ratios Gel Group vs.
Twenty-nine cycles were withdrawn from the Gel Group, 24 due to embryo recovery failure and 5 due to vaginal bleeding or itching that necessitated a change to intramuscular progesterone injection.
Twenty-four cycles were withdrawn from the Inj Group, 16 due to embryo recovery failure and eight due to inflammation at the injection sites that necessitated a change to a vaginal gel these symptoms were alleviated after therapy with hot compresses. No other adverse events occurred in the women involved in this study. This prospective randomized study was designed to compare the clinical effects of using Crinone vaginal progesterone gel in FET cycles with those of progesterone supplementation by intramuscular injection.
Analysis of the primary outcomes indicated that there were no statistically significant differences in the rates of live births, clinical pregnancy, implantation, abortion and ectopic pregnancy between the Gel Group and the Inj Group. There has been debate as to whether the live birth rate achieved following use of Crinone vaginal gel during FET cycles is comparable to that obtained following intramuscular administration of progesterone.
Several studies of in vitro FET cycles [ 8 — 11 ] have reported that similar results are achieved when progesterone is administered via vaginal gel and intramuscular injection. In contrast, another report [ 12 ] showed that luteal phase support with a vaginal gel produced significantly higher live birth rates than intramuscular progesterone administration.
A prospective study by Gibbons et al. Jobanputra et al. However, the statistical powers of these two early prospective studies, as well as that conducted by Toner [ 15 ], were poor due to the limited sample sizes. A retrospective study by Berger et al. Kaser et al. However, a recent study by Shapiro et al.
These clinical trials are all evidence-based retrospective studies with many confounding factors between the two groups, emphasizing the need for higher-quality prospective studies in order to reach a more reliable conclusion. In the present study, no significant differences were observed between groups in pregnancy outcomes, including the rates of clinical pregnancy and live birth.
It is notable that in our study, Crinone gel and intramuscular progesterone were both initiated on day 0, and all patients had equivalent exposure to dydrogesterone and estradiol valerate before the transfer was carried out.
Thus, our findings would not appear to be consistent with the proposal of Kaser et al. It has been reported that multiple factors affect the synchronization between the embryonic stage and endometrial receptivity, including the application of estrogen, endometrial thickness, luteal support before embryo transfer, embryo quality, embryo number and FET technology [ 19 ]. In the randomized prospective trial reported here, no differences were observed between women in the Gel Group and those in the Inj Group with regard to age, endometrial thickness, endometrial preparation, and the number and quality of embryos transferred.
Thus, confounding factors with the potential to influence the clinical outcome of FET did not differ between the participants in the two groups. Furthermore, the lack of significant difference between groups in clinical outcomes was supported by multivariate logistic regression analysis in which adjustments were made for these covariates. Additionally, since dydrogesterone is highly selective for progesterone receptors and has an immunomodulatory effect that may induce protection of the pregnancy, all patients enrolled in this study were medicated with an equal dose of this compound [ 20 ].
Thus, our results show no significant differences between the two groups in the live birth rate and other outcome measures clinical pregnancy rate, implantation rate, abortion rate and ectopic pregnancy rate.
Exogenous progesterone supplementation in FET cycles is often required until 12 weeks of gestation, a longer period than that required for fresh embryo transfer cycles.
Although the use of intramuscular progesterone lowers patient costs, it requires daily injections and is associated with a number of drawbacks; for example, hospital visits may be required for treatment, and inflammatory responses may occur at the injection site [ 6 ]. In this study, eight women in the Inj Group were switched to vaginal gel administration due to inflammation at the injection sites. Importantly, our study shows that Crinone vaginal gel and intramuscular progesterone are equivalent in terms of pregnancy outcomes, with the vaginal gel route offering the additional advantages of improved administration convenience, comfort and compliance [ 8 , 21 , 22 ].
Interestingly, Alsbjerg et al. Thus, it is possible that a higher rate of live births would have been observed in the present study if a twice-daily dosing regimen had been employed in the Gel Group. Therefore, additional prospective, randomized, controlled, blinded trials are merited to determine the optimal dosing regimen for Crinone vaginal gel. The present study has several limitations. First, the study was conducted in a single center; thus, further large-scale prospective cohort studies are required to validate our findings and increase the generalizability of our conclusions.
Second, it was not possible to conduct a blinded study; however, confounding factors were minimized where possible. Third, the study did not contain a control comparator group consisting of patients administered oral dydrogesterone and estradiol valerate only, precluding assessment of whether additional progesterone supplementation with either Crinone gel or intramuscular injections resulted in improved pregnancy outcomes in patients receiving dydrogesterone.
Fourth, the incidence of vaginal bleeding or spotting in each group before and after the pregnancy test was not assessed as an outcome measure. Fifth, the doses of Crinone vaginal gel and intramuscular progesterone used in the present study were lower than those used in previous studies conducted in the USA, limiting the comparison of our protocols to those commonly used in the USA.
Our results indicate that the live birth rates were similar when progesterone supplementation of FET cycles was achieved using vaginal gel and intramuscular progesterone, and that Crinone vaginal gel does not affect other pregnancy outcomes. Since the use of intramuscular progesterone injections for endometrial preparation in progesterone-supplemented FET cycles has disadvantages in terms of convenience and patient tolerance, the results of this study suggest that Crinone vaginal gel is an effective and tolerable alternative during the induction of secretory transformation of the endometrium.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U. PLoS One. Published online Jul Norbert Gleicher, Editor. Author information Article notes Copyright and License information Disclaimer. Competing Interests: The authors have declared that no competing interests exist. Received Jan 12; Accepted Jun This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
This article has been cited by other articles in PMC. S2 Text: Checklist. Abstract To compare Crinone vaginal progesterone gel with intramuscularly injected progesterone for luteal phase support in progesterone-supplemented frozen-thawed embryo transfer FET cycles, a randomized prospective study of patients qualified for FET was conducted between September and January at a hospital in Shanghai, China.
Introduction The use of frozen-thawed embryo transfer FET to achieve a successful pregnancy was first reported in , and since then, FET has been applied widely in assisted reproduction [ 1 ], achieving an increased cumulative pregnancy rate while reducing patient costs. Materials and Methods Study design This was a single-center, prospective, randomized, two-arm trial.
Randomization A computer-based random allocation table was generated by researchers who were blind to this study. Adverse events The occurrences of any adverse events such as bleeding, itching, or inflammation at the injection sites were recorded. Results Baseline characteristics of the patients A diagram showing participant flow through the study, including details of patient eligibility, reasons for exclusion, treatment group allocation, loss to follow-up and number included in the final analysis, is shown in Fig 1.
Open in a separate window. Fig 1. Table 1 Comparison of the baseline characteristics of the patients included in the analysis. Clinical outcomes After the exclusion of cycles withdrawn from the study, the primary analysis included cycles in the Gel Group and cycles in the Inj Group.
Table 2 Clinical outcomes in the two groups and odds ratios Gel Group vs. Inj Group for clinical outcomes. Adverse effects Twenty-nine cycles were withdrawn from the Gel Group, 24 due to embryo recovery failure and 5 due to vaginal bleeding or itching that necessitated a change to intramuscular progesterone injection.
Discussion This prospective randomized study was designed to compare the clinical effects of using Crinone vaginal progesterone gel in FET cycles with those of progesterone supplementation by intramuscular injection. Supporting Information S1 Text Study protocol. DOCX Click here for additional data file. S2 Text Checklist. DOC Click here for additional data file. Data Availability All relevant data are within the paper and its Supporting Information files.
References 1. Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature ; : — If pregnancy occurs, treatment may be continued for up to 12 weeks. To insert progesterone vaginal gel, hold the applicator by the thick end and shake down to ensure the contents are at the thin end.
Twist off the tab and gently insert the thin end of the applicator into the vagina while you are in a sitting position or when lying on your back with your knees bent. Press the thick end of the applicator firmly to deposit the gel.
Remove and discard the applicator. Applicators are intended for a single use only. Vaginal tablets: The recommended dose of progesterone vaginal tablets is mg inserted into the vagina 2 or 3 times daily starting the day after egg retrieval.
If pregnancy occurs, treatment may be continued for up to 10 weeks. To insert progesterone vaginal tablets, place one tablet in the space provided at the end of the applicator.
The tablet should fit snugly and not fall out. While sitting, standing, or lying on your back with your knees bent, gently insert the thin end of the applicator the one containing the tablet well into the vagina. Push the plunger to release the tablet. Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are using the medication without consulting your doctor.
It is important to use this medication exactly as prescribed by your doctor. If you miss a dose, use it the following day and continue with your regular schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice. Store this medication at room temperature, protect it from extreme heat or cold, and keep it out of the reach of children. Do not dispose of medications in wastewater e.
Ask your pharmacist how to dispose of medications that are no longer needed or have expired. Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent. The side effects listed below are not experienced by everyone who uses this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.
Many of these side effects can be managed, and some may go away on their own over time. Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects. Although most of the side effects listed below don't happen very often, they could lead to serious problems if you do not seek medical attention.
Stop using the medication and seek immediate medical attention if any of the following occur:. Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are using this medication. Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health.
These factors may affect how you should use this medication. Blood clots: This medication may cause blood clots. If you experience pain, swelling, or redness in your calf or leg; chest pain; shortness of breath; difficulty breathing; eye pain or vision changes; get immediate medical attention.
Depression: Hormones, such as progesterone, have been known to cause mood swings and symptoms of depression. If you have depression or a history of depression, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. If you experience symptoms of depression such as poor concentration, changes in weight, changes in sleep, decreased interest in activities, or notice them in a family member who is taking this medication contact your doctor as soon as possible.
Diabetes: Progesterone may cause an increase in blood sugar levels may cause a loss of blood glucose control and glucose tolerance may change.
People with diabetes may find it necessary to monitor their blood sugar more frequently while using this medication. Do not drive or operate machinery until you know how this medication affects you. Fluid retention: Progesterone can cause fluid retention. If you have epilepsy, migraines, asthma, or heart or kidney problems, discuss with your doctor how this medication may affect your medical condition and whether any special monitoring is needed.
Heart attack: The risk of heart attack is increased with the use of progesterone, due to the increased risk of blood clots. If you experience symptoms of heart attack, such as sudden chest pain or pressure on the chest, a sense of dread, difficulty breathing, nausea or pain radiating from the shoulder to the jaw or arm, seek immediate medical help. Liver: This medication may cause liver problems. If you experience yellowing of the skin or eyes, nausea, vomiting, abdominal pain, light-coloured stools, or dark urine, contact your doctor.
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