Addition of intramuscular to vaginal progesterone for luteal phase support in fresh embryo transfer cycles: A cross-sectional study

Abstract Background Luteal phase deficiency is common in assisted reproductive technology and is characterized by inadequate progesterone production. Various studies have shown that administration of progesterone in fresh embryo transfer cycles increases the rate of clinical pregnancy and live birth rate. Progesterone administration has variable types: oral, vaginal, oil-based intramuscular, and subcutaneous. Objective This study aims to compare the effect of adding intramuscular progesterone to the vaginal progesterone for luteal phase support in the fresh embryo transfer cycle. Materials and Methods This study reviewed the information related to 355 women who had a fresh embryo transfer between March 2020 and February 2021 at the Yazd Reproductive Sciences Institute, Yazd, Iran. The participants population were divided into 2 groups based on the type of luteal phase support regime: group I (n = 173) received 400 mg vaginal progesterone alone twice a day from the day of ovum pick up; and group II (n = 182) received 50 mg IM of progesterone in addition to vaginal progesterone 400 mg twice a day from the day of ovum pick up. Chemical and clinical pregnancy rates were compared between groups. Results The basic characteristics of groups were statistically similar. The rates of chemical and clinical pregnancy were higher in the vaginal plus IM progesterone group than in the vaginal progesterone group. Moreover, chemical pregnancy showed a significant difference between the groups (p = 0.011). Conclusion Our findings demonstrated that the addition of IM progesterone to the vaginal progesterone improves the chemical pregnancy rate in fresh embryo transfer.


Introduction
The luteal phase starts after ovulation, supported by progesterone which increases implantation and the pregnancy rate in assisted reproductive technology (ART) cycles (1). Luteal phase deficiency is a common result of ART and is characterized by inadequate progesterone production, so luteal phase support (LPS) is needed for better implantation in the ART cycle (2). Progesterone supplementation is imperative to maintain implantation and early pregnancy until the luteo-placental shift, which occurs during the second trimester of pregnancy (3). Various studies have shown that supporting the luteal phase by administration of progesterone in fresh embryo transfer cycles increases the rate of clinical pregnancy and live birth rate (4)(5)(6).
Progestogen can begin on the day of oocyte retrieval. or one day later, or the day of embryo transfer, and should continue until positive pregnancy test or 10-12 wk after gestation or until a negative serum human chorionic gonadotropin (HCG) (7).
The progesterone administration has variable types: oral, vaginal, oil-based intramuscular (IM), and subcutaneous progesterone (8). Vaginal and IM progesterone are preferred while oral progesterone alone is usually avoided because it is associated with inadequate bioavailability (9).
Some studies have shown that the use of vaginal progesterone causes a lower rate of miscarriage than IM progesterone (5,10).
The same percentage of pregnancies and miscarriages has been reported in participants receiving vaginal or IM progesterone (11). Therefore, there is an ongoing requirement to assess the LPS in fresh in vitro fertilization cycles (12).
However, there is a general agreement on the use of progesterone in fresh cycles; the choice of preparation, and its duration remains a matter of debate. So far, this study aimed to evaluate the effect of adding IM progesterone to vaginal progesterone on increasing pregnancy rate, and whether it reduces miscarriage in fresh embryo transfer cycles. The study also compared the results with those obtained from vaginal progesterone administration alone. LPS was continued until 12 wk of gestation.

Data collection
Demographic characteristics, including age, duration and type of infertility, and body mass index, as well as laboratory information, including anti-mullerian hormone (AMH), endometrial thickness, embryo grading, and type of progesterone consumption were recorded for all women. Furthermore, the rates of positive or negative chemical and clinical pregnancy were recorded in this study.

Ethical considerations
The study protocol was reviewed and

Statistical analysis
Descriptive data were summarized as mean ± SD and/or percentage. The normality of the data was checked before the analysis by the

Discussion
The prescription of vaginal progesterone as an effective drug for luteal support has been well recognized in many studies (8,13,14). However, despite the common use of the progesterone for luteal support, the best route and dosing of progesterone is still unidentified In fresh embryo transfer cycles, multiple corpora luteums are accessible in both ovaries.
However, there is a relative mid-luteal phase hCG/LH deficiency after the aspiration of granulosa cells during oocyte retrieval (18).
Exogenous progesterone is usually administered for LPS in the ovarian stimulation cycle and fresh embryo transfer (19). LPS via progesterone in fresh and frozen embryo transfer cycles increases pregnancy (5

Limitations and suggestions
One limitation of this research is its retrospective nature. Moreover, according to our criteria, most of the gynecologic disorders that could affect endometrial receptivity were excluded. So, these results cannot cover the women with insufficient endometrial receptivity. Future studies are recommended to be conducted on the efficacy of vaginal progesterone and IM progesterone during the early implantation period.

Conclusion
This