The Effectiveness and Safety of the Early Follicular Phase Prolonged Down-regulation Protocol for Controlled Ovarian Hyperstimulation: a Randomized, Paralleled, Controlled, Multicenter Trial

Background:

Since the first "tube baby", Louise Brown, was born in the United Kingdom in 1978, many infertile couples have been benefitted from in vitro fertilization and embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI). It is reported that there are over 5 million babies born with the help of assisted reproductive technology (ART). According to the 2015 national data published by Human Fertility and Embryology Authority (HFEA, 48,147 women received 61,726 IVF/ICSI cycles and gave birth to 17,041 newborns. In the United States, 169,602 IVF/ICSI cycles were performed in 2014 and 68,791 tubal babies were born. China has a huge population base, and therefore has a substantial number of infertile couples. Although a late starter, China is developing rapidly in ART and playing a more and more important role in the area of reproductive medicine.

In spite of the continuous development in ART, so far, the overall success rate of IVF/ICSI is still hovering around 25-40%. The live birth rate per stimulated cycle is 25.6% in the UK in 2015, fluctuating from 1.9% in women aged 45 and elder to 32.2% in women younger than 35 years old. The IVF/ICSI success rate in 2014 in the US is similar. In China, according to the data submitted by 115 reproductive medicine centers on the ART data reporting system developed by Chinese Society of Reproductive Medicine, the delivery rate is about 40%. Hence, there is much room for improvement regarding the live birth rate of IVF/ICSI, which is of great significance to infertile couples.

There are many factors influencing the success rate of IVF/ICSI, e.g. the infertile couples' age, the controlled ovarian hyperstimulation (COH) protocol, the quality and number of embryos for transferring, the endometrium and luteal phase support protocol, etc.. Among them, an appropriate COH protocol is directly associated with the number of oocyte retrieved, as well as the number and quality of embryos, which exert an important influence on the success rate of IVF/ICSI. The luteal phase pituitary down-regulation protocol is one of the most widely used COH protocols in clinical practice, particularly in China. In this protocol, gonadotropin releasing hormone agonist (GnRHa) administered in the previous luteal phase induces a state of down regulation of the pituitary gland via competitive occupying and further exhausting the GnRH receptors in the pituitary, which inhibits the endogenous luteinizing hormone (LH) peak and avoid spontaneous ovulation, decreasing the cycle cancellation rate. But the classic down-regulation protocol may lead to an increased incidence of ovarian hyperstimulation syndrome (OHSS), as well as a negative impact on endometrial receptivity due to the progesterone elevation after multiple oocytes development. The coping strategy is to freeze all the embryos and transfer in the next cycle. Though avoiding the above mentioned adverse effects, such strategy increases the time to pregnancy (TTP) and therefore results in certain psychological and economic burdens for infertile couples.

In recent years, some Chinese researches applied the early follicular down-regulation protocol that is always performed to women with endometriosis to a more general IVF/ICSI population and found a clinical pregnancy rate of 64% in the fresh embryo transfer cycle, much higher than that of the luteal phase down-regulation protocol. The possible mechanism is that it may improve the down regulation of LH and the endometrial receptivity, therefore having a better control of LH during COH, increasing the endometrial thickness on hCG day, as well as the embryo implantation rate and clinical pregnancy rate. Furthermore, since this protocol decrease the risk of progesterone elevation on hCG day, it increases the fresh embryo transfer rate and shortens TTP.