Researchers concerned over early egg retrieval after cancer treatment - doctors advised to monitor pregnancies as mice study reveals problems

An international team of fertility experts is asking doctors to monitor carefully the pregnancies and babies of all women who undergo egg retrieval and IVF after cancer chemotherapy.

Research on mice has shown that cylophosphamide - a commonly used drug belonging to a group of anti-cancer agents known as alkylating agents - causes fetal malformations and pregnancy failure. More importantly, the new study reveals that the effect on the embryo is influenced by the stage of egg follicle development at the time of exposure to the drug.

Although the researchers stress that there is no evidence as yet to suggest equivalent treatment-induced problems in human eggs, they believe that their findings indicate that eggs collected from women within six to 12 months of treatment could be particularly vulnerable to damage.

The study has been carried out by Dr Dror Meirow at the Rabin Medical Centre and Schneider Children Medical Centre in Israel, Drs Michal Epstein and Hadassa Lewis at the Hadassah Medical Centre in Jerusalem, Dr David Nugent at the University of Leeds in the UK, and Professor Roger Gosden at the Royal Victoria Hospital, Montreal, Canada.

The results are reported today* (Thursday 29 March) in Europe's leading fertility journal, Human Reproduction.

Although research has already shown that cyclophosphamide can induce genetic damage and has raised concerns about pregnancies in cancer survivors and the health of the children, all the studies on pregnancy outcome to date have been reassuring, suggesting that these concerns are unfounded. However, the research was on women who became pregnant a long time after treatment stopped.

New reproductive techniques mean that many centres offer egg retrieval and embryo freezing before starting cancer treatment that is likely to result in infertility. But delaying life-saving treatment while patients undergo egg-retrieval cycles may be inadvisable. So some centres now offer IVF and embryo cryopreservation during a break in treatment or when patients go into remission following initial non-sterilising chemotherapy prior to more intensive treatment - for example, before bone marrow transplant.

Dr Meirow said: "Eggs retrieved at these points have suffered very recent exposure to chemotherapy and may therefore have been at growth stages rather than the dormant primordial stage. So we are in a new situation and it has become essential to determine if there are greater risks associated with eggs exposed to chemotherapy during or immediately before growth stages. Our study was designed to see whether, in mice, the stage of egg development at the time of exposure to cylophosphamide altered the risk to resultant conceptions."

Groups of mice were mated at various points between one and 12 weeks after treatment when they were at different stages of follicular growth . (Humans take from 6 to 12 months to go from the dormant primordial stage to the immediately pre-ovulatory stage. This corresponds to about three weeks in mice.)

The researchers found fewer pregnancies in mice whose follicles were at a mature stage when they received chemotherapy. There was also a highly significant abortion rate and and10 times the rate of malformation across the treated groups compared with the control group, with a peak of one third of embryos malformed in the group of mice treated at a early stages of follicular growth.

As the interval between exposure and mating lengthened the malformation rate gradually fell, reaching normal levels in the group mated 12 weeks after treatment.

Said Dr Meirow: "This suggests that the effect of cyclophosphamide on eggs and, subsequently on future reproduction, is influenced by the stage of maturity the egg has reached at the time of treatment. It is clear that early fertilisation post-chemotherapy can result in a high rate of pregnancy failure and malformation."

More research was needed to know whether the same applied in humans. "If it does, it will become vital to define a 'safety period' between treatment stopping and egg retrieval. Until we know more, it would seem advisable to monitor the pregnancy outcome of all cancer patients who undergo IVF and embryo cryopreservation after chemotherapy, and possibly to screen fetuses and babies for chromosomal aberrations and birth defects."

He suggested that women would be wise to avoid becoming pregnant too soon after chemotherapy. This applied not only to cancer patients but also to women suffering from autoimmune diseases such as lupus. These were also sometimes treated with low, non-sterilising doses of cyclophosphamide - for example to prevent kidney failure in lupus nephritis.

*Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Human Reproduction. Vol. 16. No 4. pp 632-637.

The research was supported by grants from the Israel Cancer Association, Barclay Family Cancer Research Foundation (UK) and WellBeing (UK).

Notes:
1 PDF version of this press release and full embargoed text of the paper with complete results and participating research teams, can be found from 09.00 hrs BST Tuesday 27 March on website: http://www3.oup.co.uk/eshre/press-release/apr01.pdf.
2 Human Reproduction is a monthly journal of the European Society of Human Reproduction and Embryology (ESHRE). Please acknowledge Human Reproduction as a source. ESHRE�s website is: http://www.eshre.com.
3 Printed texts available on request from Dr Helen Beard, Managing Editor.Tel: +44 (0) 1954 212404 or email: beardh@humanreproduction.co.uk.