Ovarian stimulation protocols pose risk of ectopic pregnancy

Ovarian stimulation protocols, especially the use of clomiphene citrate (CC), may put women at high risk of ectopic pregnancy (EP), study has found.

The analysis was based on 68,851 clinical pregnancies after fresh single embryo transfer, of which 1,049 (1.46 percent) cases were EPs. The mean maternal age was 35 years. EP occurred with greater frequency among women with vs without a tubal factor (2.07 percent vs 1.41 percent; p<0.001), while unexplained infertility was more common in the EP vs non-EP group (98.6 percent vs 1.4 percent; p=0.007).

In terms of ovarian stimulation protocols, the highest number of EP cases was noted among women who received CC plus gonadotropin (2.2 percent; 221/10,158), followed by CC alone (1.81 percent; 160/8,837), GnRH antagonist (1.57 percent; 216/13,781), and GnRH agonist (1.47 percent; 415/28,237). The lowest was seen among women with natural cycle (0.47 percent; 37/7,838).

The mean number of retrieved oocytes was larger in the EP than the non-EP group (mean, 6.3 vs 5.8; p=0.001). It was lowest among women with natural cycle (mean, 1.3), followed by those who received CC alone (mean, 2.1), CC plus gonadotropin (mean, 3.9), GnRH antagonist (mean, 7.2, SD ¼ 4.6), and GnRH agonist (mean, 8.2).

In multivariable logistic regression models, all ovarian stimulation protocols conferred a significantly elevated risk of EP compared with natural cycle. The highest risk increase was observed with protocols using CC alone (odds ratio [OR], 3.9, 95 percent confidence interval [CI], 2.3–6.7) and in combination with gonadotropin (OR, 4.5, 95 percent CI, 2.6–7.7).

Of note, the association between ovarian stimulation protocols and EP was stronger when the number of retrieved oocytes was low (1–3) to moderate (4–7), but not when the number of retrieved oocytes was high (≥8).