Skip to main content

Tamoxifen and pregnancy: an absolute contraindication?

Abstract

Purpose

Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy.

Methods

A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy.

Results

A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen.

Conclusion

There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. The Netherlands Cancer Registry, the Netherlands Comprehensive Cancer Organisation (IKNL). https://www.cijfersoverkanker.nl/home-36.html. Accessed 15 Oct 2018

  2. Breast Cancer, Dutch National Guideline, IKNL, version 1.0 (2018) https://richtlijnendatabase.nl/en/richtlijn/breast_cancer/breast_cancer.html. Accessed 15 Oct 2018

  3. EBCTCG, Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S et al (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials. Lancet 378(9793):771–784

    Article  CAS  Google Scholar 

  4. Barthelmes L, Gateley CA (2004) Tamoxifen and pregnancy. Breast 13(6):446–451

    Article  CAS  PubMed  Google Scholar 

  5. Faddy MJ (2000) Follicle dynamics during ovarian ageing. Mol Cell Endocrinol 163(1–2):43–48

    Article  CAS  PubMed  Google Scholar 

  6. Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N (1999) Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17(8):2365–2370

    Article  CAS  PubMed  Google Scholar 

  7. Berger JC, Clericuzio CL (2008) Pierre Robin sequence associated with first trimester fetal tamoxifen exposure. Am J Med Genet A 146(16):2141–2144

    Article  Google Scholar 

  8. Cullins SL, Pridjian G, Sutherland CM (1994) Goldenhar’s syndrome associated with tamoxifen given to the mother during gestation. JAMA 271(24):1905–1906

    Article  Google Scholar 

  9. Tewari K, Bonebrake RG, Asrat T, Shanberg AM (1997) Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 350(9072):183

    Article  CAS  PubMed  Google Scholar 

  10. Osborne CK (1998) Drug therapy: tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618

    Article  CAS  PubMed  Google Scholar 

  11. Scripture CD, Sparreboom A, Figg WD (2005) Modulation of cytochrome P450 activity: implications for cancer therapy. Lancet Oncol 6:780–789

    Article  CAS  PubMed  Google Scholar 

  12. Ruiz-Velasco V, Rosas-Arceo J, Matute MM (1979) Chemical inducers of ovulation: comparative results. Int J Fertil 24:61–64

    CAS  PubMed  Google Scholar 

  13. Tsuiki A, Uehara S, Kyono K, Saito A, Hoshi K, Hoshiai H et al (1984) Induction of ovulation with an estrogen antagonist, tamoxifen. Tohoku J Exp Med 144:21–31

    Article  CAS  PubMed  Google Scholar 

  14. Suginami H, Yano K, Kitagawa H, Matsubara K, Nakahashi N (1993) A clomiphene citrate and tamoxifen citrate combination therapy: a novel therapy for ovulation induction. Fertil Steril 59:976–979

    Article  CAS  PubMed  Google Scholar 

  15. Regon L, Braude PR, Trembath P (1989) Influence of past reproductive performance on risk of spontaneous abortion. Br Med J 299:541–545

    Article  Google Scholar 

  16. Jain JK, Meckstroth KR, Park M, Mishell DR Jr (1999) A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination. Contraception 60(6):353–356

    Article  CAS  PubMed  Google Scholar 

  17. Schiff R, Massarweh SA, Shou J, Bharwani L, Arpino G, Rimawi M et al (2005) Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: Implicated role of growth factor signaling and estrogen receptor coregulators. Cancer Chemother Pharmacol 56(suppl 1):10–20

    Article  CAS  PubMed  Google Scholar 

  18. Jyoti B, Bharat C, Ankita N, Munita B, Sudeep G (2016) Pregnancy on tamoxifen: case-report and review of literature. South Asian J Cancer 5(4):209–210

    Article  PubMed  PubMed Central  Google Scholar 

  19. Colleoni M, Munzone E (2015) Navigating the challenges of endocrine treatments in premenopausal women with ER-positive early breast cancer. Drugs 75(12):1311–1321

    Article  CAS  PubMed  Google Scholar 

  20. Braems G, Denys H, De Wever O, Cocquyt V, Van de Broecke R (2011) Use of tamoxifen before and during pregnancy. Oncologist 16(11):1547–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou MH, Han GZ, Chu YH (1991) Effects of antiestrogenic drug tamoxifen on human placental secretion of progesterone and human chorionic gonadotropin during early gestation. Yao Xue Xue Bao 26(11):801–804

    CAS  PubMed  Google Scholar 

  22. Furukawa S, Hayashi S, Usuda K, Abe M, Ogawa I (2012) The impairment of metrial gland development in tamoxifen exposed rats. Exp Toxicol Path 64:121–126

    Article  CAS  Google Scholar 

  23. Isaacs RJ, Hunter W, Clark K (2001) Tamoxifen as systemic treatment of advanced breast cancer during pregnancy-case report and literature review. Gynecol Oncol 80(3):405–408

    Article  CAS  PubMed  Google Scholar 

  24. Weiss G (2000) Endocrinology of parturition. J Clin Endocrinol Metab 85(12):4421–4425

    CAS  PubMed  Google Scholar 

  25. Product information. Nolvadex. Zeneca Pharmaceuticals (1997)

  26. Furr BJ, Valcaccia B, Challis JR (1976) The effects of Nolvadex (tamoxifen citrate: ICI 46,474) on pregnancy in rabbits. J Reprod Fertil 48:367–369

    Article  CAS  PubMed  Google Scholar 

  27. Clark JH, McCormack SA (1980) The effect of clomid and other triphenylethylene derivatives during pregnancy and the neonatal period. J Steroid Biochem 12:47–53

    Article  CAS  PubMed  Google Scholar 

  28. Pasqualini JR, Gulino A, Sumida C, Screpanti I (1984) Anti-estrogens in fetal and newborn target tissues. J Steroid Biochem 20:121–128

    Article  CAS  PubMed  Google Scholar 

  29. Gulino A, Screpanti I, Pasqualini JR (1984) Differential estrogen and antiestrogen responsiveness of the uterus during development in the fetal, neonatal and immature guinea pig. Biol Reprod 31:371–381

    Article  CAS  PubMed  Google Scholar 

  30. Nguyen BL, Giambiagi N, Mayrand C, Lecerf F, Pasqualini JR (1986) Estrogen and progesterone receptors in the fetal and newborn vagina of guinea pig: biological, morphological, and ultrastructural responses to tamoxifen and estradiol. Endocrinology 119:978–988

    Article  CAS  PubMed  Google Scholar 

  31. Pasqualini JR, Giambiagi N, Sumida C, Nguyen BL, Gelly C, Mayrand C et al (1986) Biological responses of tamoxifen in the fetal and newborn vagina and uterus of the guinea-pig and in the R-27 mammary cancer cell line. J Steroid Biochem 24:99–108

    Article  CAS  PubMed  Google Scholar 

  32. Hines M, Alsum P, Roy M, Gorski RA, Goy RW (1987) Estrogenic contributions to sexual differentiation in the female guinea pig: influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development. Horm Behav 21:402–417

    Article  CAS  PubMed  Google Scholar 

  33. Cunha GR, Taguchi O, Namikawa R, Nishizuka Y, Robboy SJ (1987) Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract. Hum Pathol 18:1132–1143

    Article  CAS  PubMed  Google Scholar 

  34. Chamness GC, Bannayan GA, Landry LA Jr, Sheridan PJ, McGuire WL (1979) Abnormal reproductive development in rats after neonatally administered antiestrogen (tamoxifen). Biol Reprod 21:1087–1090

    Article  CAS  PubMed  Google Scholar 

  35. Iguchi T, Hirokawa M, Takasugi N (1986) Occurrence of genital tract abnormalities and bladder hernia in female mice exposed neonatally to tamoxifen. Toxicology 42:1–11

    Article  CAS  PubMed  Google Scholar 

  36. Harper MJK (1992) Agents with antifertility effects during preimplantation stages of pregnancy. In: Moghissi KS, Hafez ESE (eds) Biology of mammalian fertilization and implantation. Charles C. Thomas, Springfield, pp 431–492

  37. Furr BJA, Jordan VC (1984) The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127–205

    Article  CAS  PubMed  Google Scholar 

  38. Grandvuillemin A, Rousseau T, Laurent N, Meyer F, Lebouvier M, Disson-Dautriche A (2009) A case of sexual ambiguity under tamoxifen during pregnancy. Fund Clin Pharmacol 23(Suppl 1):37

    Google Scholar 

  39. Koca T, Akgun Z, Yucel SB, Dag NZ, Teomete M (2011) Pregnancy a short time after multimodal therapy for bilateral breast cancer: a case report and review of literature. J Oncol Pharm Pract 17(4):440–443

    Article  CAS  PubMed  Google Scholar 

  40. Koca E, Kuzan TY, Babacan T, Turkbeyler IH, Furkan S, Altundag K (2013) Safety of tamoxifen during pregnancy: 3 case reports and review of the literature. Breast Care (Basel) 8(6):453–454

    Article  Google Scholar 

  41. Oksuzoglu B, Güler N (2002) An infertile patient with breast cancer who delivered a healthy child under adjuvant tamoxifen therapy. Eur J Obstet Gynecol Reprod Biol 104(1):79

    Article  PubMed  Google Scholar 

  42. Koizumi K, Aono T (1986) Pregnancy after combined treatment with bromocriptine and tamoxifen in two patients with pituitary prolactinomas. Fertil Steril 46(2):312–314

    Article  CAS  PubMed  Google Scholar 

  43. Ishizuka S, Satou S (2016) A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy. Breast Cancer 23(1):164–166

    Article  PubMed  Google Scholar 

  44. Andreadis C, Charalampidou M, Diamantopoulos N, Chouchos N, Mouratidou D (2004) Combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer. Gynecol Oncol 95(1):252–255

    Article  PubMed  Google Scholar 

  45. Clark S (1993) Prophylactic tamoxifen. Lancet 342:168

    Article  Google Scholar 

  46. Schönbeck U, Hindori-Mohangoo AD, Masurel N, Van der Pal-de Bruin KM (2015) TNO report: Congenital malformations in the Netherlands 2001–2013: Based on Netherlands Perinatal Registry. https://repository.tudelft.nl/view/tno/uuid%3A1879cf51-0f9e-4051-8829-296fdcad2847. Accessed 20 Dec 2018

  47. Nye L, Rademaker A, Gradishar WJ (2017) Breast cancer outcomes after diagnosis of hormone-positive breast cancer and subsequent pregnancy in the Tamoxifen Era. Clin Breat Cancer 17(4):e185–e189

    Article  CAS  Google Scholar 

  48. Hershman DL, Shao T, Kushi LH, Buono D, Yann Tsai W, Fehrenbacher L, Kwan M, Lin Gomez S, Neugut AI (2011) Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 126(2):529–537

    Article  CAS  PubMed  Google Scholar 

  49. Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (POSITVE). http://clinicaltrials.gov/ct2/show/NCT02308085. Accessed 15 Oct 2018

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. A. R. Lok.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Not applicable.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schuurman, T.N., Witteveen, P.O., van der Wall, E. et al. Tamoxifen and pregnancy: an absolute contraindication?. Breast Cancer Res Treat 175, 17–25 (2019). https://doi.org/10.1007/s10549-019-05154-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05154-7

Keywords

  • Tamoxifen
  • Breast cancer
  • Pregnancy
  • Teratogenicity
  • Fetal toxicity