The Influence of Cabergoline and Coasting in Prevention of the Ovarian Hyperstimulation Syndrome in Patients Undergoing IVF/ICSI-ET Treatment: A Systematic Review and Meta-Analysis

Objective: To compare the effectiveness of two methods in preventing ovarian hyperstimulation syndrome (OHSS) with cabergoline and coasting. Design: Systematic review and meta-analysis of randomized clinical trials (RCTs). Patients: Women were considered as have risk of OHSS undergoing fertility treatment. Interventions: Cabergoline, coasting. Result: There were included five RCT studies. The clinical pregnancy rate was no significantly difference between two groups (RR 1.22, 95% CI [0.86, 1.71]), implantation rate (RR 1.00, 95% CI [0.75, 1.32]), severe OHSS (RR 0.93, 95% CI [0.38, 2.31]), fertilization rate (SMD 0.70, 95% CI [-0.10, 1.50]), number of oocytes retrieved (SMD 0.80, 95% CI [0.30, 1.30]), number of embryo transfer (SMD-0.04, 95% CI [-0.24, 0.17]), E2 value on the day of HCG injection (SMD 0.21, 95% CI [-0.25, 0.68]), number of MII oocytes (SMD 0.71, 95% CI [0.32, 1.11]), abortion rate (RR 0.61, 95% CI [0.21, 1.83]), number of follicles > 17 mm on day of HCG (SMD -0.01, 95% CI [-0.26, 0.24]), number of follicles 15 - 17 mm on day of HCG (SMD -0.08, 95% CI [-0.33, 0.17]), number of follicles 10 - 14 mm on day of HCG (SMD -0.06, 95% CI [-0.31, 0.19]). Conclusion: Both cabergoline and coasting prevent the occurrence of OHSS, but no statistically significant difference between them. Compared with coasting group, a daily dose of 0.5 mg cabergoline significantly increased the number of oocytes retrieved, MII oocytes, and fertilization rate, but decreased the abortion rate.


Introduction
In the light of the latest figures, the number of infertility predicted is up to 186 million [1]. With the popularization and widespread application of modern assisted reproductive technology, the incidence of ovarian hyperstimulation syndrome (OHSS) as an iatrogenic injury affected 1% -14% of in vitro fertilization cycles [2]. It usually has a self-limited course with unfavorable outcome when under the treatment of controlled ovarian stimulation, therefore received widespread attention by reproduction specialist in reproductive centers all around the world.
At present the pathological mechanism of the OHSS is not yet clear, consequently the treatment of OHSS is symptomatic treatment or expectant management, and prevention and timely detection is the key to treatment. Nowadays, the treatment of OHSS is mainly depended on each individual fertility doctors' experience. There is no substantive or strict guideline for doctors. Cabergoline [3], coasting [4], albumin [5], calcium supplements [6], aspirin [7] are the commonly used interventions. The most popular therapeutic method on prevention of OHSS is coasting [8], and cabergoline is a relatively definitive drug for preventing OHSS in recent years.
The results of recent years have shown that cabergoline is more effective than placebo group to prevent the occurrence of OHSS [9] [10] [11] [12]. However, it was greater in the cabergoline group than in the hydroxyethyl starch (HES) group.
Until now, there is no meta-analysis comparing the effects of cabergoline and coasting in the prevention of the occurrence of OHSS.
Our study is to compare the risk and effectiveness of using cabergoline or coasting in women who under the treatment of IVF/ICSI-ET in order to provide better guidance for clinical work.

Retrieval Strategies
Methods: This study did not directly treat patient, therefore ethical committee approval is not necessary. We searched in Pubmed, Medicine, Cochrane library, Embase, and Springer-Link with the terms of (Ovarian Hyperstimulation Syndrome) or (OHSS) and (cabergoline) and (coasting) and (dopamine agonists) and (IVF) in title and abstract as of March 2020. No restrictions on language were imposed when searching for documents. Meanwhile, we extracted the corresponding data from the articles, including rate of clinical pregnancy, the occurrence of OHSS, Advances in Reproductive Sciences number of retrieved oocytes, number of MII oocytes, implantation rate. The comparison was shown by the risk ratios (RRs) or Std Mean Differences (SMD) with their 95% confidence intervals (CIs). We also searched and screened the corresponding references at the end of the selected articles.

Inclusive Criteria
The inclusion criteria are as follows: 1) The population of study was high-risk OHSS patients who undergoing IVF or Intracytoplasmic Sperm Injection (ICSI) and received the GnRha long protocol; 2) The included articles were randomized controlled trials (Randomized Controlled Trials, RCT), the treatment including cabergoline and coasting; 3) The results included the rate of clinical pregnancy, implantation rate, severe OHSS, number of MII oocytes, abortion rate.

Literature Screening and Data Extraction
The abstracts of all keywords retrieved by the two researchers were jointly screened. (Lin Liu and Xin Wang). Cross-checked and qualified abstract were evaluated separately by two researchers (Jie Jyu and Tonghui Meng). The divergent on abstract of the two researchers were resolved through discussion or submitting to a third party for assistance. If the abstract of the article meets the criteria, then two researchers (Fang Lyu and Xiaomei Zhang) carefully read and evaluate the full text. The extracted content mainly includes: 1) basic information, including the first author, the time of publication, 2) the basic situation of the research object, 3) the specific details of the intervention, 4) the key elements of the risk assessment, 5) the end of concern indicator and result measurement data.

Statistical Analysis
We used Review Manager 5.3 for statistical analysis. Data are showed by mean ± standard deviation or percentage (%). The results are expressed by the risk ratios (RRs) or Std. Mean Differences (SMD) and their 95% confidence intervals (CIs).
The heterogeneity between the included studies was analyzed by the χ 2 test, and I 2 and P value were used to assess the heterogeneity between the articles. If the I 2 = 0 or P > 0.10, there is no statistical heterogeneity among the results of these studies, the Mantel-Haenszel fixed-effects model is used for meta-analysis. Otherwise, random-effects model was used for analysis after eliminated the effect of obvious clinical heterogeneity, and further analysis of heterogeneity sources is necessary. Significant clinical heterogeneity is treated by subgroup analysis or sensitivity analysis or only descriptive analysis. Since the number of included studies is less than 10, the funnel plot was not applicable.

Evaluation the Risk of Bias
The risk of bias summary is done by the two researchers in subject to the Cochrane handbook for systematic reviews of interventions version 5.1.0 [13]. The review authors judged the risk of biased item for every article included in the study.

Basic Characteristics of the Studies and Bias Risk Assessment
The basic characteristics of the study were shown in Table 1. The results of bias risk assessment were shown in Figure 2 and which were judged by two independent reviewers. When encountering non-conformity, they jointly seek solutions from the third reviewer, and discussion again to solve the solution.

Pregnancy Rate
Of the 5 articles included, only 4 [14] [15] [16] [18] reported rate of clinical pregnancy (Figure 3(a)). There were no statistical significance difference between the two groups (RR 1.22, 95% CI 0.86 -1.71; P > 0.05), I 2 = 23%, suggested that there was a low degree of heterogeneity between the studies. And subgroup analysis based on different countries was performed. When the participants were all from Iranian, the comparison of pregnancy rate between the two groups was statistically different. I 2 = 0, suggested that there was no heterogeneity between the articles, the results demonstrated that the pregnant rate of the cabergoline group was better than coasting group (RR 2.00, 95% CI 1.08 -3.72; P < 0.05). But in the other subgroup, there was no statistical significance (RR 1.04, 95% CI 0.79 -1.36; P = 0.78).

Implantation Rate
Three studies of included in this meta-analysis reported implantation rate ( Figure  3(b)). The results displayed there was no significant difference between the two groups in implantation rate (RR 1.00, 95% CI 0.75 -1.32; P = 0.97). No heterogeneity between studies (I 2 = 0).

The Incidence of OHSS
The incidence of OHSS was reported in 5 articles (Figure 3(c)). Pooling their results showed that there was no significant difference in the incidence of OHSS between the two groups (RR 0.93, 95% CI 0.38 -2.31; P = 0.88). There was no heterogeneity between articles (I 2 = 0). Advances in Reproductive Sciences

Fertilization Rate
Only 3 pieces provided fertilization rate (Figure 3(d)). There was no significant difference in fertilization rate (SMD 0.70, 95% CI −0.10, 1.50; P = 0.09). While, there were high heterogeneity among the articles (I 2 = 88%), so subgroup analysis was conducted by the dose of cabergoline. It turns out there was a significant difference between cabergoline with 0.5 mg/d and coasting groups regarding the fertilization rate (SMD 1.08, 95% CI 0.66, 1.50; P < 0.001), and the cabergoline-treated group showed a higher fertilization rate with no heterogeneity (I 2 = 0). However, the other group under the treatment of 0.25 mg/d with cabergoline is of little significance (SMD 0.03, 95% CI −0.25, 0.31; P = 0.82).

Number of Oocytes Retrieved
Among the 5 articles included, 4 of them reported the number of oocytes retrieved (Figure 3(e)). The results showed that oocytes number increased significantly in the cabergoline group (SMD 0.80, 95% CI 0.30, 1.30, P = 0.002) with a high heterogeneity among the various articles (I 2 = 76%).

Number of Embryo Transfer
4 studies reported the number of embryo transfer, which were included in this meta-analysis (Figure 3(f)). The results demonstrated that no significant difference between the two groups in the number of embryo transfer (SMD −0.04, 95% CI −0.24, 0.17; P = 0.71) with no heterogeneity among these articles (I 2 = 0).

E2 on HCG day
The E 2 level on the day of HCG injection was all reported in the 5 selected articles (Figure 3(g)). It showed that there was no significant difference in E 2 level between the two groups (SMD 0.21, 95% CI −0.25, 0.68; P = 0.37) with a high heterogeneity among the articles (I 2 = 78%).

Number of Metaphase II Oocytes
All 5 articles reported number of MII oocytes (Figure 3(h)). The results showed that oocytes number (SMD 0.71, 95% CI 0.32, 1.11, P < 0.001) increased significantly in the cabergoline group with a high heterogeneity among the various articles (I 2 = 69%).

Abortion Rate
Three of five studies reported the abortion rate in this meta-analysis ( Figure  3(i)).

Discussion
This meta-analysis showed that in the process of assisted reproductive treatment who were at high-risk of OHSS patients received preventive treatment of "cabergoline" and "coasting". The conclusion is both two methods were all effective in preventing OHSS.
In this meta-analysis, we compared the effectiveness of two methods with cabergoline or coasting on the prevention of OHSS and the effectiveness on IVF-ET or ICSI-ET outcomes with high ovarian responders with FSH or HCG. It turns out no significant difference in the rate of implantation, E 2 level and number of follicles on the day of HCG injection, and number of embryo transfer between two groups. But in cabergoline group, there were more oocytes and MII oocytes, and higher rate of fertilization and clinical pregnancy. In the coasting group, a higher abortion rate was observed. Subgroup analysis result showed that 0.5 mg cabergoline daily was obviously increased fertilization rate and the abortion rate was significantly lower than coasting group. One study proved that the combined administration provided better protection without notable side effects [18]. However, Hwang [19] pointed out that the efficacy of cabergoline is not good in preventing severe OHSS through two cases.
A previous research showed that dopamine agonist is the first pathophysiological method for preventing or minimizing OHSS without affecting pregnancy outcome [20]. Furthermore, the dosing of cabergoline or coasting can effectively prevent mild to moderate OHSS [ [29]. The number of oocytes in coasting group was significantly lower than that in other treatment groups [30]. Mahvash [31] reported that the effect of cabergoline in 0.5 mg/d is superior to every two days in preventing OHSS compared with 0.25 mg/d ca- bergoline. Vascular heart disease should be taken into consideration when under the treatment of cabergoline, especially in a higher dosage [32]. Isaza [33] found that if treatment of coasting is prolonged for more than 4 days, there is a significantly decreased in the rate of implantation and the rate of pregnancy. Whilst there was still not high-quality evidence to identify that coasting was superior to other treatment, and there is too few data to determine whether there is any difference results between two groups [34].
Our research is the first meta-analysis to compare the safety and effectiveness of cabergoline and coasting in the prevention of OHSS. One of the advantages of this study is the integration of multi-country and multi-center data.

Conclusion
The effect of cabergoline and coasting in preventing severe OHSS is quite similar.
Simultaneously, it was demonstrated that the patients given cabergoline in a daily dose of 0.5 mg, the effect can also increase significantly in the number of oocytes retrieved, the number of MII oocytes, fertilization rate but decrease the abortion rate.