Gonadotropins versus oral ovarian stimulation agents for unexplained infertility: a systematic review and meta-analysis

Gonadotropins for ovarian stimulation and intrauterine insemination (IUI) in patients with unexplained infertility increases the risk of multiple birth without an overall increase in live birth. Because the goal is a singleton live birth, the use of gonadotropins with IUI should be avoided.

Volume 113, Issue 2, Pages 417–425.e1


Jessica R. Zolton, D.O., Peter G. Lindner, M.D., Nancy Terry, M.L.S., Alan H. DeCherney, M.D., Micah J. Hill, D.O.



To compare live birth and multiple gestation in patients diagnosed with unexplained infertility undergoing intrauterine insemination after ovarian stimulation (OS-IUI) with oral medications versus gonadotropins.


Systemic review and meta-analysis.


Not applicable.


Patients undergoing OS-IUI for treatment of unexplained infertility.


Clomiphene, letrozole, or gonadotropins for OS-IUI.

Main Outcome Measure(s)

Live birth and multiple gestation.


Eight total trials were identified that met the inclusion criteria and comprised 2,989 patients undergoing 6,590 cycles. One study reported a significant increase in both live births and multiple gestations with the use of gonadotropins, two studies found an increased likelihood of live birth with the use of gonadotropins, and two studies found an increased risk of twins with gonadotropins. The relative risk of live birth in subjects receiving gonadotropins was 1.09. The relative risk of multiple gestation in subjects receiving gonadotropins was 1.06. Clinical pregnancy was higher in protocols with lax cancellation policies or higher gonadotropin doses, with subsequent increased relative risks of multiple gestations of 1.20 and 1.15, respectively. Singleton births per subject were similar between the two groups. The results did not change in per-protocol, per cycle, or fixed-effect model sensitivity analyses.


For every birth gained with the use of gonadotropins, a similar increased risk of multiple gestation occurs. The randomized data do not support the use of gonadotropin for OS-IUI in women with unexplained infertility.

Clinical Trial Registration Number

Prospero CRD4201911998

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Go to the profile of M. Blake Evans
over 2 years ago

In a clinically important contribution to the existing literature, these data do not support gonadotropin use w/ IUI in unexplained infertility patients. Click here to see the Fertility and Sterility #Tweetorial

The content in this manuscript is an important discussion I will frequently have with my patients when faced with the decision of moving from failed clomid/IUI cycles to IVF. Although the cost of IVF is a significant burden, especially in non-mandated states, the risks of multiples must be considered. The high cost of gonadotropins and elevated multiples risk outweighs the high success rates of IVF and ability to transfer a single embryo.