Can tofacitinib (Janus kinase inhibitor) cause infertility?

Tofacitinib and Infertility

Based on current evidence, tofacitinib does not cause infertility in humans, but contraception is strongly advised for both male and female patients due to insufficient safety data on pregnancy outcomes and theoretical concerns from animal studies. 1

Key Evidence on Fertility Effects

Male Fertility

• Tofacitinib has no demonstrated effect on male fertility in humans. Animal studies at extremely high doses (133 times the recommended human dose) showed no impact on male fertility, sperm motility, or sperm concentration 2
• The Leydig cell tumors observed in rat carcinogenicity studies were due to off-target inhibition of prolactin signaling through JAK2, a mechanism not relevant to humans since human Leydig cells lack prolactin dependence for normal function 3
• Limited human data exists on birth outcomes after paternal tofacitinib exposure, but available case reports show no concerning patterns 1

Female Fertility

• In animal studies, tofacitinib reduced female fertility only at very high doses (17 times the recommended human dose) due to increased post-implantation loss, with no impairment at doses equivalent to human therapeutic levels 2
• No evidence of direct infertility effects in human females has been reported in clinical practice

Pregnancy and Contraception Guidance

Why Contraception is Required

The recommendation for contraception is based on:

• Teratogenicity in animal studies: Tofacitinib caused birth defects in rats and rabbits and affected parturition and peri/postnatal development 1
• Insufficient human safety data: While small case series show outcomes similar to background population rates, the data remains too limited for definitive conclusions 4, 5
• Small molecule properties: As a small molecule, tofacitinib can cross the placental barrier 5

Specific Recommendations

• Both male and female patients should use contraception while taking tofacitinib 1
• Wait 4 weeks after the last tofacitinib dose before attempting conception due to the drug's short plasma half-life 1
• Tofacitinib should be avoided in women of childbearing age actively contemplating pregnancy, with alternative therapeutic options preferred 1
• Switch to alternative medications with more safety data when planning conception 1

Available Human Pregnancy Data

Maternal Exposure Outcomes

From clinical trials and postmarketing surveillance:

• UC studies: 11 maternal exposures resulted in 15 healthy newborns, no fetal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations 5
• RA/psoriasis studies: 47 pregnancies showed outcomes appearing similar to the general population, with 1 congenital pulmonary valve stenosis, 7 spontaneous abortions, and 25 healthy newborns 4
• Overall assessment: Rates of adverse outcomes appear consistent with background population rates, but sample sizes remain too small for definitive safety conclusions 4, 5

Paternal Exposure Outcomes

• 44 cases of paternal exposure in RA/psoriasis studies showed 5 spontaneous abortions and 23 healthy newborns 4
• 14 cases in UC studies showed no concerning patterns 5

Critical Clinical Pitfalls

• Do not confuse the absence of infertility with pregnancy safety: Tofacitinib does not impair fertility, but this does not mean it is safe during pregnancy 1, 2
• Do not rely on animal Leydig cell tumor data to counsel patients about human fertility risk: This mechanism is not relevant to humans 3
• Do not assume oral contraceptives are ineffective with tofacitinib: Tofacitinib has no clinically relevant effect on ethinylestradiol or levonorgestrel pharmacokinetics 6
• Do not continue tofacitinib in patients who become pregnant: The drug should be discontinued immediately given insufficient safety data 1

Comparison with Other JAK Inhibitors

• Filgotinib reduces spermatogenesis in a dose-dependent manner in animal studies, though this has not been observed in humans to date, with definitive human studies still underway 1
• All JAK inhibitors (baricitinib, upadacitinib, filgotinib, tofacitinib) should be avoided during pregnancy and breastfeeding due to insufficient data 1