Mild Ovarian Stimulation has similar Live Birth Rates as Compared with Hyper Stimulation for Treatment of Poor Responding IVF Patients of Advanced Maternal

The number of patients with poor ovarian response (POR) for in vitro fertilization (IVF) varies from 9 to 25%, especially high in patients of advanced maternal age. Although various stimulation protocols have been developed to improve clinical outcomes in patients with POR, a typical and effective protocol remains improvement. Some physicians prefer a mild stimulation protocol, while others like hyper stimulation protocol to obtain more eggs. This study was designed to compare the efficiency of a mild stimulation protocol with hyper stimulation protocol in patients with POR, particularly focused on live birth rate after IVF. Data were collected from 30 poor responders (over 39 years old). Patients were assigned to 2 protocols at the start of ovarian stimulation: Patients in group A were treated with a hyper stimulation (GnRH-antagonist) protocol and patients in group B were treated with a mild stimulation protocol. The ovarian stimulation characteristics, gonadotropin doses, number of eggs collected, number of high quality embryos, clinical pregnancy rates and live birth rates were compared between two groups. Although number of eggs, number of high quality embryos, clinical pregnancy rates were significantly higher in group A than in group B, miscarriage rate was also higher in group A than group B, which eventually resulted in a similar live birth rate (6.7%) in both groups. However, dosages of gonadotropins were smaller and stimulation days were shorter in group B than in group A. When poorly responding patients were treated for IVF, similar live birth rates were observed with mild stimulation protocol and hyper-stimulation protocol. After considering the higher dosages of gonadotropins and longer stimulation days in patients with hyper-stimulation protocol, it is suggested that poor responders may benefit with the mild stimulation protocol for IVF. DOI : 10.14302/issn.2576-2818.jfb-17-1812 Corresponding author: Wei-Hua Wang, Houston Fertility Laboratory, 2500 Fondren Rd., Suite 350, Houston TX 77063. Phone: 713-490-2528, E-mail: wangweihua11@yahoo.com Running head: Ovarian stimulation for infertility treatment


Introduction
The number of women over 40 years old requiring assisted reproductive technology to get pregnancy has increased significantly in the past decades [1,2]. It has been reported that clinical pregnancy rates are 10~15% in these patients after in vitro fertilization (IVF) [3]. Poor response to ovarian stimulation is one of the main reasons for the low pregnancy rate. In addition to patient's age, poor ovarian response (POR) can also be related to other causes, such as endometriosis, genetic factors, ovarian surgery, and iatrogenic factors. Although there is a lack of uniform definition of POR [4], the most common criterion used for diagnosis of POR is small number of oocytes collected after ovarian stimulation [5].

Recently, The European Society for Human
Reproduction and Embryology consensus conference [6] published the "Bologna criteria" to define POR as the presence of two of the following three features: (i) advanced maternal age (≥40 years) or any other risk factor for POR; (ii) a previously characterized POR cycle (≤3 oocytes with a conventional stimulation protocol); (iii) an abnormal ovarian reserve test (<5-7 antral follicle count or <0. 5 [13,14], but some physicians tried it in older patients [15][16][17]. It has been found that mild stimulation works for both good and poor responding patients [13][14][15][16][17]. However, a direct comparison on live birth rate between a mild stimulation protocol and regular hyper stimulation protocol has not been reported in patients with POR. Therefore, the present study was designed to compare two different protocols in poor responders in terms of ovarian stimulation characteristics, gonadotropin doses, number of eggs collected, number of high quality embryos, clinical pregnancy rates and live birth rates.

Mild Stimulation Group (Group B)
The patients for mild stimulation protocol received 100 mg/day clomiphene citrate (Serophene, Merck-Serono, Switzerland) for 5 days from the 2nd to Values were expressed as mean ± standard deviation (SD) unless otherwise stated.

Results
As shown in Table 1, there were no statistical differences between the two groups in terms of base A previous study with 2386 IVF cycles in women aged ≥40 years showed that overall clinical pregnancy rate was 13.4% and live birth rate was 6.7% per cycle [18]. They also found that the cancellation rate was 16% per cycle, and the cancellation rate increased significantly in patients at 45 years old and above. In our study, we also obtained a similar live birth rate (6.7%) in patients with two different stimulation protocols.
However, we found that cancelation rate was 10% in group A, which was significantly lower than that (48.6%) in group B. This may be due to high dose of gonadotropins that initialized more follicles to grow in patients of group A.
It is still a challenge for clinicians to choose the suitable stimulation protocols for older patients (more than 40 years old) with a diminished ovarian reserve.
Several studies have compared the efficiency of different kinds of protocols in the past few years. In one retrospective study, it was found that there was no significant difference in fertilization rates, or embryo development rates among standard long protocol, short protocol and GnRH-antagonist protocol [19]. Several meta-analysis and Cochrane reviews also tried to examine different treatment protocols in PORs, but so far none of these attempts has drawn any conclusion [20][21][22]. Compared to a GnRH-antagonist protocol with high dose of gonadotropins, mild stimulation with a low dose of gonadotropins is an interesting alternative for patients with poor ovarian reserve, which may produce more high quality embryos, and result in better implantation and pregnancy rates when these embryos were transferred [23].
In the present study, patients in group A produced more high quality (based on morphology assessment) embryos, more patients were pregnant and more embryos implanted; however, most women got miscarriage during the first trimester. It has been reported that more embryos from poor responders (especial old patients) are aneuploidy, which leads to early miscarriage and loss of pregnancy during the first trimester [24]. Some laboratory procedures may be beneficial to the poor responders, such as preimplantation genetic screening. However, due to the limited number of eggs and embryos, cancellation rates are very high in patients with advanced maternal ages with or without poor response after preimplantation genetic screening procedure [25]. It is still unclear whether high doses of gonadotropins could cause more chromosomal anomalies in old women, but it has been found that mild stimulation and natural cycles provide better clinical outcomes in patients with POR [26]. However, a direct comparison with more patients between mild and hyper stimulations may be necessary to draw a solid conclusion of whether mild stimulation is similar to or better than hyper stimulation for POR.
Our present study indicates that mild stimulation has a similar livebirth rate as hyper stimulation in PORs.
There data were similar with previous studies with more patient population [26,27] in which ongoing pregnancy rates were reported between two groups. Our current study further provided the evidence that mild stimulation and hyper stimulation have the similar live birth rate.