Letrozole vs Clomid for PCOS: Which Works Better for Getting Pregnant?
In the largest head-to-head trial, letrozole led to more live births than clomiphene in women with PCOS (27.5% vs 19.1%), and a 2022 Cochrane review of 41 trials agreed. That is why the 2023 guideline makes letrozole the first-line ovulation drug, even though its FDA label covers only breast cancer.
By Kymata Health Editorial Published Last checked
This guide
PCOS & Cycle- Question
- Is letrozole or clomiphene (Clomid) better for getting pregnant with PCOS?
- Sources
- 6 cited
- Quick answers
- 3 questions
- Clinician review
- None; sources cited inline
Key takeaways
4 points- In a 750-woman double-blind trial, cumulative live births were 27.5% with letrozole vs 19.1% with clomiphene over up to five treatment cycles1.
- A 2022 Cochrane review of 41 trials (6,522 women) rated letrozole's live-birth advantage as high-certainty: odds ratio 1.72, or about one extra birth for every 10 women treated2.
- Miscarriage, multiple pregnancy and ovarian hyperstimulation rates were similar with the two drugs in the Cochrane review2.
- The 2023 international guideline makes letrozole the first-line drug to induce ovulation in PCOS, noting its use is off-label in many countries3. In the US, letrozole (Femara) is FDA-approved only for breast cancer, and its label says it is contraindicated in pregnancy4.
The head-to-head trial
The Pregnancy in Polycystic Ovary Syndrome II trial randomly assigned 750 women aged 18 to 40 with PCOS to letrozole or clomiphene for up to five treatment cycles. Every woman had at least one open fallopian tube and a partner with a sperm concentration of at least 14 million per milliliter, and neither the women nor their doctors knew which drug they were taking1.
Cumulative live births were 103 of 374 (27.5%) with letrozole vs 72 of 376 (19.1%) with clomiphene, a rate ratio of 1.44. Ovulation was also more frequent: 61.7% of letrozole cycles vs 48.3% of clomiphene cycles1. The trial was funded by the NIH's child-health institute (NICHD) and others1.
What the Cochrane review found
A 2022 Cochrane review pooled 41 randomized trials with 6,522 women. With timed intercourse, live births were higher with letrozole than with clomiphene-type drugs (odds ratio 1.72; 11 trials, 2,060 women; high-certainty evidence). In practical terms, where clomiphene gives a 20% chance of a live birth, letrozole would give about 27% to 35%2.
Miscarriage (24% of pregnancies with letrozole vs 25% with clomiphene-type drugs) and multiple pregnancy (1.6% vs 2.2%) did not differ meaningfully, and ovarian hyperstimulation syndrome occurred in 0.5% of women in both groups2. The reviewers removed several previously included trials over concerns about the validity of their data, and a funnel plot hinted that some trials favouring clomiphene might be missing2.
Side effects and twins
In the head-to-head trial, clomiphene caused more hot flushes, while letrozole caused more fatigue and dizziness. Twin pregnancies were 3.4% with letrozole and 7.4% with clomiphene, a difference that was not statistically significant1.
Clomid's FDA label warns that blurred vision, spots or flashes can occur, become more common with higher total doses or longer use, and should prompt stopping the drug and getting a full eye exam5. The label reports multiple pregnancies in 7.98% of pregnancies in its clinical trials and says long-term use is not recommended beyond about six cycles in total5.
Is letrozole safe for the baby?
Letrozole's label is written for its approved use in breast cancer: it says the drug can cause fetal harm, is contraindicated in pregnancy, and cites post-marketing reports of miscarriages and birth defects when it was taken during pregnancy4. For fertility, it is used to trigger ovulation before conception, and the 2023 guideline says it should not be given if there is any chance of an existing pregnancy, while noting no evidence of more birth defects than with other ovulation drugs3.
In the head-to-head trial there were 4 major congenital anomalies in the letrozole group vs 1 with clomiphene, a difference that was not statistically significant1. A Canadian review of 911 babies conceived after either drug found malformations in 2.4% after letrozole and 4.8% after clomiphene, and concluded there was no difference in overall rates6. That study was retrospective, so it cannot rule out a small risk.
Who should not take them
Both are prescription drugs that need a clinician to confirm you are not ovulating and to rule out other causes of infertility first. Clomid's label lists pregnancy, liver disease, abnormal uterine bleeding of unknown cause, ovarian cysts not due to PCOS, uncontrolled thyroid or adrenal disease, and pituitary tumors as reasons not to use it5.
Neither drug fixes the metabolic side of PCOS; see our guide to birth control vs metformin for PCOS. If you are weighing supplements alongside treatment, our review of inositol for PCOS covers what the fertility trials show.
- Do not start either drug if you could already be pregnant35.
- Stop clomiphene and see an eye doctor if you notice blurring, spots or flashes5.
- Expect monitoring: Clomid's label calls for a pelvic exam before the first and each later course5.
- Tell your clinician promptly about abdominal or pelvic pain, bloating or weight gain during treatment; Clomid's label lists these as early warning signs of ovarian enlargement or hyperstimulation5.
Quick answers
Questions
3 answersIs letrozole FDA-approved for fertility?
No. In the US, Femara (letrozole) is approved for breast cancer in postmenopausal women4. Using it to induce ovulation is off-label, which the 2023 PCOS guideline acknowledges while still recommending it first-line3.
How many cycles of Clomid can I take?
Clomid's label says most women who will ovulate do so after the first course, that treatment should stop if three ovulatory cycles do not lead to pregnancy, and that use beyond about six cycles in total is not recommended5.
More in PCOS & Cycle
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- Birth Control Pill vs Metformin for PCOS: What the 2023 Guideline Recommends
- Inositol for PCOS: What the Trials Show for Cycles, Weight and Fertility
- Berberine vs Metformin for PCOS: What the Trials Show, and Why the Evidence Is Shaky
- Is Metformin Safe in Pregnancy? What the PCOS Trials Found for Mother and Child
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- Next in this topicHow PCOS (PMOS) Is Diagnosed: Cycle Length, Androgens and the AMH TestPCOS, now called PMOS, is diagnosed with 2 of 3 features: irregular cycles, high androgens and polycystic ovaries.
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References
Every study and document cited in this guide, numbered as in the text.
Sources
6 sources- 1Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med, 2014. PMID 25006718
- 2Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev, 2022. PMID 36165742
- 3Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab, 2023. PMID 37580314
- 4Femara (letrozole) tablets: prescribing information. U.S. Food and Drug Administration, 2018.
- 5Clomid (clomiphene citrate tablets USP): prescribing information. U.S. Food and Drug Administration, 2017.
- 6Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril, 2006. PMID 16650422
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