Tailoring fertility treatments to your genetic profile: Why your DNA matters

Many people face challenges getting pregnant or staying pregnant, because of underlying health conditions or the natural effects of aging. As women get older, fewer eggs remain in the ovaries, and the success rates of fertility treatment tend to go down. When ovarian reserve is low, every decision in an IVF cycle matters, especially the choice of medication, both for the success of treatment and, most importantly, for your own health and safety. Genetic testing can add useful information to these decisions: it can show how your body handles some fertility medications and whether you carry inherited variants that raise the risk of blood clots. Here is what is known, and where the evidence is still limited.

Which health conditions should be treated before fertility treatment?

Before starting fertility treatment, a baseline assessment helps identify the causes of infertility. Blood tests for hormones such as anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH) and estradiol, together with an ultrasound, help assess ovarian reserve and the health of the uterus. Depending on the cause, other treatments may come first. Endometriosis, for example, may need medication or surgery.

For women with polycystic ovary syndrome (PCOS) and excess weight, losing even a modest amount of weight can restore ovulation in some cases. GLP-1 weight-loss medications such as Ozempic, Wegovy and Mounjaro may help, but they are not fertility treatments, and they need to be planned carefully. Semaglutide (Ozempic, Wegovy) should be stopped at least two months before trying to conceive, and tirzepatide (Mounjaro) can make birth control pills less effective. Talk to your doctor about timing before you start or stop these medications.

What types of genetic tests are used in fertility care?

• Carrier screening tests both parents for inherited conditions they could pass on to a child.
• Pharmacogenetic testing looks at how the mother’s body is likely to handle certain medications, and can include inherited variants that affect blood clotting.
• Preimplantation genetic testing (PGT) screens embryos for genetic abnormalities to help choose which embryo to transfer.

What are the options for ovarian stimulation?

Ovarian stimulation is the part of IVF in which hormone medications encourage the ovaries to mature more than one egg in a cycle. Many people take daily injections for about 10 to 12 days, plus another medication to prevent ovulation too early. The goal is to collect several mature eggs, which can increase the chance of creating embryos. Your fertility specialist will choose an approach based on your age, ovarian reserve, response to previous cycles, PCOS and personal preferences.

Hormonal stimulation has risks. The most important is ovarian hyperstimulation syndrome (OHSS), in which the ovaries over-respond, causing fluid build-up, abdominal swelling and, in severe cases, blood clots. Modern protocols have made severe OHSS less common. Hormonal treatments and pregnancy also raise the risk of blood clots in the veins and, rarely, in the brain. Learn more about hormones and blood clots.

• Standard stimulation uses injections of FSH, with or without luteinizing hormone (LH), and adds a GnRH antagonist mid-cycle to prevent early ovulation. This protocol is relatively short and carries a lower risk of OHSS than older protocols. Variants in genes for these hormones and their receptors (FSHB, LHB, FSHR, LHCGR) may affect the response to stimulation, but this is still a research area and is not part of routine testing.
• Minimal stimulation (mini-IVF) uses clomiphene or letrozole tablets with low doses of injected hormones. It produces fewer eggs but is gentler, less expensive and carries a lower risk of OHSS.
• Natural cycle IVF collects the single egg produced in a normal monthly cycle, without stimulating hormones. It involves the lowest medication exposure and may be considered in some situations.

How does CYP2D6 affect clomiphene?

Clomiphene is used to trigger ovulation and in some minimal stimulation protocols. It is a “prodrug”: the liver enzyme CYP2D6 converts it into its most active forms. In a study of healthy women, those with no working CYP2D6 had 8 to 12 times lower peak levels of the active forms than women with normal CYP2D6. This may help explain why some women respond poorly to clomiphene.

However, the clinical evidence is still limited. Two small studies in women treated with clomiphene did not find that CYP2D6 genotype alone predicted ovulation, and there is no international pharmacogenetic guideline for clomiphene yet. A CYP2D6 result is therefore one piece of information your fertility specialist can consider, especially if you have had a poor response to clomiphene, rather than a yes-or-no answer. CYP2D6 results are also useful for many other medications, including some antidepressants and pain medications such as codeine and tramadol.

Letrozole is now often preferred to clomiphene for ovulation induction in women with PCOS, because it led to more live births in a large clinical trial. Letrozole is broken down mainly by the enzymes CYP2A6 and CYP3A4, and there is no pharmacogenetic guidance for it.

Can a genetic test show my risk of blood clots during IVF and pregnancy?

IVF and pregnancy naturally increase blood-clotting factors. For most people, the absolute risk of a serious blood clot remains low, but it is higher in people who carry certain inherited variants, especially Factor V Leiden (in the F5 gene) and the prothrombin G20210A variant (in the F2 gene). These variants are found in a large share of women who develop a blood clot in a vein during pregnancy.

A meta-analysis of prospective studies found that women with Factor V Leiden had a 52% higher odds of pregnancy loss, mainly later in pregnancy, although the absolute difference was small (4.2% compared with 3.2%). Whether a woman with one of these variants needs preventive blood thinners during stimulation or pregnancy depends on the specific variant, whether she has one or two copies, her personal and family history of blood clots, and her specialist’s assessment. Current guidelines do not recommend testing all women with recurrent pregnancy loss for these inherited variants, so the decision to test should be made with your health care provider.

How can a Pillcheck test help?

A Pillcheck test reports CYP2D6, which activates clomiphene and many other medications, along with Factor V Leiden (F5) and prothrombin (F2) variants. A pharmacist reviews your results together with all your medications, and your report can be shared with your fertility specialist and family doctor. Your results also stay useful during pregnancy and after birth, for example when choosing pain medications or antidepressants.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• A baseline health assessment and treatment of conditions such as PCOS and endometriosis come before fertility treatment. GLP-1 weight-loss medications need careful timing around conception.
• Ovarian stimulation options range from standard stimulation to minimal stimulation and natural cycle IVF. OHSS and blood clots are the main risks of hormonal stimulation.
• CYP2D6 converts clomiphene into its active forms. Poor metabolizers form much less active drug, but clinical studies have not yet shown that genotype alone predicts response.
• Factor V Leiden and prothrombin variants raise the risk of blood clots during IVF and pregnancy. Testing and preventive treatment should be discussed with your specialist.
• Genetic results may be especially worth discussing if you have a personal or family history of blood clots, a poor response to clomiphene, or previous severe pregnancy complications.

Frequently asked questions

Can a genetic test tell me whether IVF will work?

No. Genetic results can help your specialist choose medications and assess blood clot risk, but many other factors, such as age, ovarian reserve and embryo quality, affect whether IVF succeeds.

I am a CYP2D6 poor metabolizer. Should I avoid clomiphene?

Not necessarily. Poor metabolizers form less of clomiphene’s active forms, but clinical studies have not shown that genotype alone predicts whether ovulation will occur. Discuss your result with your fertility specialist, who may consider it together with your past response and other options such as letrozole.

If I carry Factor V Leiden, will I need blood thinners during IVF?

Not always. The decision depends on the variant, whether you have one or two copies, and your personal and family history of blood clots. Your specialist, sometimes together with a hematologist, will advise you.

Should my partner be tested too?

Pharmacogenetic results are personal and guide the medications each person takes. Carrier screening, which looks for inherited conditions that could be passed on to a child, is a different test that is usually offered to both partners.

References

Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS. CYP2D6 is primarily responsible for the metabolism of clomiphene. Drug Metab Pharmacokinet. 2008;23(2):101-105.

Mürdter TE, Kerb R, Turpeinen M, et al. Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites. Hum Mol Genet. 2012;21(5):1145-1154.

Ji M, Kim KR, Lee W, et al. Genetic polymorphism of CYP2D6 and clomiphene concentrations in infertile patients with ovulatory dysfunction treated with clomiphene citrate. J Korean Med Sci. 2016;31(2):310-314.

Robin C, Hennart B, Broly F, et al. Could cytochrome P450 2D6, 3A4 and 3A5 polymorphisms explain the variability in clinical response to clomiphene citrate of anovulatory PCOS women? Front Endocrinol (Lausanne). 2021;12:718917.

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119-129.

Conforti A, et al. Impact of gonadotropin genetic profile and ovarian reserve on controlled ovarian stimulation: data from prospective cohort of the GENOCS trial. Front Endocrinol (Lausanne). 2025;16:1601803.

Farooqui AB, et al. Cerebral venous thrombosis and hypercoagulability associated with in vitro fertilization. Stroke. 2021;52(9):e554-e557.

Rodger MA, Betancourt MT, Clark P, et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010;7(6):e1000292.

ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;2023(1):hoad002.