Grand Rounds

How Does Letrozole Compare to Clomiphene Citrate for Women with Unexplained Infertility?

BACKGROUND AND PURPOSE:

There is previous evidence for the use of letrozole for ovulation induction in women with PCOS (see ‘Related ObG Topic’ below)
Letrozole, an aromatase inhibitor, has other potential benefits as well, including lack of antiestrogenic effects on endometrium, shorter half-life and fewer side effects
Eskew et al. (Obstetrics & Gynecology, 2019) compared effectiveness of letrozole vs. clomiphene for ovarian stimulation in women with unexplained infertility

Systematic review and meta-analysis
- RCTs comparing clomiphene citrate with letrozole
- Participants
  - Unexplained infertility >1 year
  - Normal ovulation
  - At least 1 patent tube
  - ≥5 million sperm/mL after wash and before IUI
Primary outcome: Positive pregnancy test per patient
Secondary outcomes included
- Positive pregnancy test per cycle | Clinical pregnancy | Live birth | Spontaneous miscarriage | Twins | Mean serum estradiol (E2) | Endometrial thickness | Number of dominant follicles

8 RCTs | 2,647 women
Primary outcome: Positive pregnancy test per patient
- No significant differences were found comparing letrozole (24%) to clomiphene citrate (23%)
- Pooled Relative risk (RR) 1.08 (95% CI, 0.85–1.36)
Significant heterogeneity was noted between studies (I2=60.8%, with >30% considered significant)
There were also no significant differences in secondary outcomes
- Clinical pregnancy: Pooled RR 1.15 (95% CI 0.71–1.85)
- Live birth: Pooled RR 0.94 (95% CI, 0.83–1.08)
- Spontaneous miscarriage: Pooled RR 0.92 (95% CI, 0.61–1.38)
Twin gestation: Pooled RR 0.81 (95% CI, 0.39–1.68)
Mean serum E2 was significantly lower in the letrozole group

Letrozole does not appear to confer any benefit when compared to clomiphene citrate for ovarian stimulation in women with unexplained infertility
The authors acknowledge an important limitation in this study was the high heterogeneity between studies

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