UPDATED August 11, 2016 // Chemotherapy is considered relatively safe for the fetus when administered in the second or third trimester of pregnancy, and recent studies have yielded reassuring data. However, new findings from a study in mice suggest that chemotherapy could affect the developing ovaries in a female fetus, with adverse effects not becoming apparent until years later.
The new findings come from a study published online August 11 in BMC Cancer.
"In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb," said study author Norah Spears, DPhil, professor of reproductive physiology at the University of Edinburgh, United Kingdom, in a release.
"This study suggests that chemotherapy treatment may have important longer-term effects on the babies of women who undergo chemotherapy while pregnant, which would only become apparent in adulthood," said Dr Spears. "This is an issue that has not been explored until now."
Previous Reassuring Data Are Short Term
Cancer during pregnancy is relatively uncommon ― it is diagnosed in about 1 of every 1000 pregnancies. Depending on the cancer type and stage, chemotherapy may be recommended.
Chemotherapy administration during the first trimester is now largely avoided, owing to the risk for congenital malformations and spontaneous abortion.
However, recent studies evaluating the use of chemotherapy have found no detrimental effect on the developing fetus when it is administered after the first trimester, as previously reported by Medscape Medical News.
These studies were headed by Frederic Amant, MD, gynecologic oncologist at the University Hospitals Leuven, Belgium, and the Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, and his group. Their findings showed that chemotherapy did not have any clear adverse effects on growth in the postnatal period, cognitive or cardiac function, or physical or mental development.
However, the follow-up from these studies is short, and long-term effects, which reach into adulthood, have not been evaluated in these patients.
The new study, although early and experimental, suggests that there may be detrimental, late effects many years after exposure.
The researchers used etoposide, which is commonly used in the treatment of ovarian and lung cancers, leukemias, and lymphomas and is considered safe for use during the second and third trimesters of pregnancy.
For their study, Dr Spears and colleagues collected fetal and neonatal ovaries from mice and cultured them in vitro with varying amounts of etoposide. However, the concentrations of etoposide used in their study were lower than those occurring in cancer patients, the researchers note.
The team reports that when the fetal ovaries were exposed to etoposide before follicle formation, damage occurred that was dependent on the dose of etoposide. The total number of follicles declined by 72% to 90% in response to medium and high doses of etoposide.
The fetal ovaries that were treated before follicular formation were damaged by 150 ng/ml etoposide, resulting in a nearly complete absence of healthy follicles.
However, for neonatal ovaries after follicle formation, exposure to etoposide was associated with only minor effects. Even at a dose of 200 ng/ml, there was no effect on the number of follicles, and the effect on follicle health was minor.
Therefore, note the authors, once the follicles have formed, the oocytes appear to be less susceptible to the deleterious effects of etoposide.
Dr Spears commented in a statement: "A woman's reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second trimester of pregnancy is particularly important, as this is when female germ cells form follicles, which will determine how many eggs a woman will be able to release in her lifetime. If the results we have seen in these mouse studies are found to be replicated in humans, some of that germ cell supply would be lost, which could later result in early menopause, thus reducing the woman's fertility window."
Commenting on the new findings in a statement, Adam Balen, MD, chairman of the British Fertility Society and spokesman for the Royal College of Obstetricians and Gynaecologists, said: "This is the first study to examine the long-term effects of chemotherapy during pregnancy, and the results suggest that etoposide, which has been proven safe during the second and third trimesters of pregnancy, may have an impact on the finite store of eggs being created within their daughter's ovaries whilst still in the womb.
"While this is important information for pregnant women who may need chemotherapy, it is too early to say the degree to which this study carried out in mice might relate to humans," Dr Balen commented. "We must also weigh any benefits of cancer treatment against these potential risks. These decisions should be made jointly between a woman and her specialist healthcare team."
The study was supported by grants from the Medical Research Council.
Dr Spears and most coauthors have disclosed no relevant financial relationships. Coauthor Nicola Powles-Glover is employed by AstraZeneca.
BMC Cancer. Published online August 11, 2016. Full text
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