For clinicians
Cyclophosphamide
CYC, Cytoxan
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Bottom lineBottom line: avoid in the first trimester (teratogen). Reserve for severe or organ/life-threatening maternal disease in the second/third trimester. Gonadotoxic, so address fertility preservation before use. Not compatible with breastfeeding; paternal exposure warrants a pre-conception gap.
By reproductive phase
| Phase | Position | Detail | Evidence |
|---|---|---|---|
| Pre-conception | Stop pre-conception | Avoid peri-conception; gonadotoxic. Discuss fertility preservation (GnRH agonist co-treatment, oocyte/sperm cryopreservation).[1] | ●●●○moderate evidencestrong |
| 1st trimester | Avoid | Avoid; recognised teratogen in the first trimester.[1, 2] | ●●●○moderate evidencestrong |
| 2nd/3rd trimester | Individualise | May be used for severe/life-threatening maternal disease in the second/third trimester after multidisciplinary discussion.[1, 2] | ●●○○low evidenceconditional |
| Breastfeeding | Avoid | Contraindicated in lactation.[3] | ●●●○moderate evidencestrong |
| Paternal | Individualise | EULAR 2024: dose-related risk of irreversible infertility; counsel on fertility preservation (sperm cryopreservation) before treatment. No evidence of clinically relevant offspring harm from paternal exposure per se.[1, 2] | ●●●○moderate evidenceconditional |
Guideline comparison
| Guideline | Position | Strength |
|---|---|---|
| ACR 2020 | Strongly recommend against before pregnancy (stop 3 months prior to conception; address fertility preservation). During pregnancy: strongly against in the first trimester (teratogen), but conditionally recommended for life- or organ-threatening maternal disease in the second and third trimesters. Breastfeeding: strongly recommend against. Paternal: strongly recommend discontinuing 12 weeks (about 3 months) before attempting conception (impaired spermatogenesis and possible mutagenicity).[1] | Strong against (maternal; conditional for life/organ-threatening disease in 2nd/3rd trimester); strong discontinue (paternal) |
| EULAR 2024 | Teratogenic; discontinue before pregnancy (2a/B); may be considered only for severe maternal disease in the 2nd/3rd trimester (4/C). Avoid in lactation (4/D). In men: dose-related risk of irreversible infertility (2b/B), counsel on fertility preservation before starting.[2] | Oxford LoE/GoR as shown |
| BSR 2022/23 | Exceptional circumstances only (life- or organ-threatening maternal disease) at peri-conception and in both trimesters; NOT compatible with breastfeeding, and NOT compatible with paternal exposure.[3] | Verified against BSR Table 1 |
=Guideline divergence. VERIFIED DIVERGENCE (paternal). BSR 2023 Table 1 marks paternal cyclophosphamide exposure as NOT compatible. EULAR 2024 does not place cyclophosphamide on its continuable-in-men list either, but frames the male issue as a dose-related risk of irreversible infertility (2b/B) requiring fertility-preservation counselling before starting, rather than a prohibition on conceiving. Both agree it is teratogenic and reserved for life- or organ-threatening maternal disease.
Key points
| Point | Evidence |
|---|---|
| Cumulative-dose and age-dependent gonadotoxicity; plan fertility preservation before treatment.[1] | ●●●○moderate evidencestrong |
Special populations
- Offer GnRH-agonist co-treatment for ovarian protection during IV cyclophosphamide and consider gamete cryopreservation. ●●●○moderate evidenceconditional[1]
Monitoring
- Fertility preservation counselling before treatment.
- Effective contraception during and after treatment.
References
- Sammaritano LR, et al. 2020 ACR Guideline for the Management of Reproductive Health in RMD. Arthritis Rheumatol. 2020;72(3):529-556. https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.41191
- Ruegg L, et al. EULAR recommendations for antirheumatic drugs in reproduction, pregnancy, and lactation: 2024 update. Ann Rheum Dis. 2025;84(6):910-926. https://ard.eular.org/article/S0003-4967(25)00818-0/fulltext
- Russell MD, et al. BSR guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory drugs and corticosteroids. Rheumatology (Oxford). 2023;62(4):e48-e88. https://academic.oup.com/rheumatology/article/62/4/e48/6783012