Reviewing treatments for unexplained infertility

This review established recommendations for the treatment of unexplained infertility. 

There is no clear cause for up to 30% of infertility cases. There are several treatment options for these couples. Expectant management uses intercourse to achieve conception. Ovarian stimulation (OS) treatment causes the ovaries to produce multiple eggs. However, OS carries a risk of multiple pregnancies (twins or triplets), which is dangerous to both the mother and babies. Gonadotropin hormone injections and the oral medications clomiphene citrate (CC; Clomid) and letrozole (Femara) are used for OS. Gonadotropins have a higher risk of multiple pregnancies than oral OS drugs.

IUI is a process where sperm is injected directly into the uterus. IUI can be used with a natural menstrual cycle or with OS. IVF is a process where eggs are collected and fertilized and the embryos are implanted in the uterus. IVF is usually used with OS. IVF is the most effective fertility treatment, but it is also the most complicated and expensive.

This review article summarizes treatment for couples with unexplained infertility.

Oral OS are recommended to be used with IUI. There is strong evidence of a higher live birth rate with OS and IUI than expectant management or IUI alone (during a natural cycle). A trial with 201 couples found that CC-IUI led to significantly higher birth rates than expectant management (31% vs. 9% over three cycles). Two studies found that CC-IUI led to a better pregnancy rate than IUI alone. Four studies found that CC-IUI and letrozole-IUI were equally effective.

CC with intercourse, letrozole with intercourse, or natural cycle IUI are not recommended. There is good evidence that these treatments are not more effective than expectant management. Gonadotropin with intercourse is also not recommended. There is strong evidence that although gonadotropins have a higher pregnancy rate than oral OS drugs, they also have a higher risk of multiple pregnancies.

CC-IUI and letrozole-IUI are recommended for couples with unexplained infertility. Letrozole is not FDA-approved for the treatment of unexplained infertility. However, it is considered an effective and well tolerated alternative. Gonadotropins-IUI is not recommended for unexplained infertility. One trial of 900 women found gonadotropin-IUI had a higher birth rate than CC-IUI (32.2% vs. 23.3%). However, the risk of multiple births was much higher with gonadotropins (32% vs. 5.7%). 

For women under 38 years old, 3 cycles of OS-IUI prior to IVF leads to lower costs and similar outcomes compared to immediate IVF. Women over 38 may have higher pregnancy rates with immediate IVF. A trial of 503 women found that CC-IUI followed directly by IVF led to pregnancy faster and had lower costs than CC-IUI followed by gonadotropin-IUI followed by IVF.

This review provided evidence-based recommendations for couples with unexplained infertility.