This meta-analysis aimed to assess the correlation between serum Ca-125 level and clinical pregnancy in in vitro fertilization. Before ET, our meta-analysis showed that there was no significant correlation between serum Ca-125 level and clinical pregnancy in IVF, and the same conclusion was also reached in patients without endometriosis; After ET, the result revealed that there was a significant correlation between serum Ca-125 level and clinical pregnancy in IVF.
Although we included women who underwent IVF treatment with or without ICSI, five studies excluded patients with endometriosis [12–15, 17]. It is likely that Ca-125 concentrations are known to be elevated in endometriosis ; therefore, evidence related to the correlation between serum Ca-125 level in endometriosis and pregnant outcome is still lacking, which may reduce the overall applicability of the evidence.
We found that there was significant heterogeneity among studies on the outcome of correlation between serum Ca-125 level before ET and clinical pregnancy in IVF (I2 = 88%). The sources of heterogeneity might be explained by the differences in the methods of ca-125 detected, the time of sample collected, the inclusion and exclusion of patiens (eg. Some studies excluded patients with endometriosis), and the ovarian stimulation protocols. However, we found no reduction in heterogeneity when we excluded studies that might include patiens with endimeriosis, and the same as we only included studies which used Immunoradiometric methods. This suggests that patient inclusion criteria or testing methods are not at least the only sources of heterogeneity. The sensitivity analysis found that the conclusion where there was no significant difference in the serum Ca-125 level before ET between clinical pregnant group and nonpregnant group had changed after excluding the study by Baalbergen et al. or Vujisic et al [15,17], which may be attributed to Ca-125 assay used, both of them used enzyme immunoassay. Unfortunately, enzyme immunoassay is a less susceptive detection methods of Ca-125 comparad with Immunoradiometric and Chemiluminescence methods . In addition, subgroup analyses showed that there was a significant correlation between serum Ca-125 level before ET and clinical pregnancy in IVF by Immunoradiometric or Chemiluminescence methods; which indicated that detecting Ca-125 using more sensitive assays can better predict pregnant outcome in IVF. We should be cautious to assess the impact of conclusion on Ca-125 level before ET, because we used randomized effect model that dealt with the heterogeneity of data by increasing the weight of small sample data and reducing the weight of large sample data , and the direction of effect altered when we used fixed effect model; Therefore, further studies should increase sample sizes to reduce accidental errors.
First of all, the concentration of serum Ca-125 fluctuated throughout the menstrual cycle. The different observations reveal that Ca-125 levels were significantly elevated during menstruation [21, 22]. The reason may be that the endometrium was destroyed during menstruation, which caused Ca-125 to be released into the blood; So Ca-125 was somehow associated with the integrity of the endometrium. Secondly, immunohistochemistry of Ca-125 showed that the concentration of Ca-125 in endometrium was 20-fold higher than that in ovary and 2-fold higher than those in fallopian tubes; In addition, only in the endometrium Ca-125 content has a significant circulatory change . This suggests that endometrium might be the main source of serum Ca-125, and therefore, an endocrine or a paracrine function would be possible. However, our meta-analysis showed no correlation between serum Ca-125 level before ET and clinical pregnancy in IVF, the same as patients without endometriosis. The reasons for this phenomenon may be as follows: (1) Although there is some evidence that endometrium is one of the sources of serum Ca-125, other factors (eg. Endometrial thickness, endometrial volume, endometrial pattern, pulsatility index and resistance index of the subendometrial blood flow) play a greater role in the endometrial receptivity ; (2) The achievement of a clinical pregnancy in IVF results from too many factors, such as maternal age and embryo quality, so serum CA-125 level can not directly predict the success of pregnancy in an IVF cycle; (3) Despite the controversy, studies have shown changes of Ca-125 concentration during ovarian stimulation [16, 25], hence, changes of the serum Ca-125 level due to ovarian stimulation may mask the changes caused by endometrium.
After ET, the meta analysis showed that the serum Ca-125 level had a small but significantly increase in the clinical pregnant group than in the nonpregnant group. In the first trimester of pregnancy, serum Ca-125 level rised in patients with vaginal bleeding and miscarriage [26, 27]. Therefore, the increase of Ca-125 concentration might indicate the destruction of decidua. However, these observations were all made over 5 weeks gestation. In our meta analysis, there were 2 studies which reported the correlation between serum Ca-125 level after ET and clinical pregnancy in IVF, one study detected Ca-125 on or closer to post-ET day 11, the another one was on 14 days after ET. Hence, higher Ca-125 levels might reflect a successful interaction between the embryo and the endometrium in that time period.
This study has several limitations. Firstly, we conducted a comprehensive search of the corrlation between serum Ca-125 level and clinical pregnancy in IVF. However, It is possible that our findings on serum Ca-125 level before ET cannot be interpreted as truly negative because of the small sample sizes and significant heterogeneity between studies; Secondly, the evidence on Ca-125 level after ET between clinical pregnancy and nonpregnancy is limited, as only two trials were included for our investigation, and needs to be further investigated; Third, publication bias could not be assessed besause of the limited number of studies; Fourth, four studies didn’t directly report mean and its SD, and we employed the method recommended by Wan et al to handle the dates , and it may result certain deviation.