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Objective: To understand the influence of cancer-related infertility on women's long-term distress and quality of life. Women diagnosed at age 40 or less with invasive cervical cancer, breast cancer, Hodgkin disease, or non-Hodgkin lymphoma were interviewed an average of 10 years later. We predicted that women whose desire for a child at diagnosis remained unfulfilled would be significantly more distressed.
Methods: Participants completed a semi-structured phone interview, including the SF-12®, Brief Symptom Inventory-18, Impact of Events Scale (IES), Reproductive Concerns Scale (RCS), brief measures of marital satisfaction or comfort with dating, sexual satisfaction, and menopause symptoms.
Results: Of 455 women contacted by phone, 240 (53%) participated. Seventy-seven women had wanted a child at diagnosis but did not conceive subsequently (38 remaining childless and 39 with secondary infertility). Even controlling for other psychosocial and health factors, this group had higher distress about infertility (RCS) (p<0.001), had more intrusive thoughts about infertility, and used more avoidance strategies when reminded of infertility (IES) (p<0.001). Childless women were the most distressed. Women with adopted or stepchildren were intermediate, and those with at least one biological child were least distressed. Infertility-related distress did not differ significantly by cancer site.
Conclusions: Even at long-term follow-up, distress about interrupted childbearing persists, particularly in childless women. Social parenthood buffers distress somewhat, but not completely. Not only is it important to offer fertility preservation before cancer treatment, but interventions should be developed for survivors to alleviate unresolved grief about cancer-related infertility. Copyright © 2010 John Wiley & Sons, Ltd.
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Infertility related to cancer treatment has received increasing attention in the past ten years. More women are delaying pregnancy until their thirties, only to have cancer interrupt their life plans 1. By age 39, one in 51 women will be diagnosed with an invasive cancer 2.
Treatment for the cancers most common in premenopausal women often decreases fertility or leads to permanent ovarian failure. For example, after adjuvant chemotherapy for breast cancer with current regimens, only 10–20% of women under age 35 experience permanent amenorrhea. However, the risk of ovarian failure increases tenfold for women treated in their late thirties, and up to 90% of women aged 40 and older are left with permanent ovarian failure 3, 4.
Even in young women who continue or resume menstruation after chemotherapy, diagnostic tests reveal that ovarian reserve is diminished. Ultrasound imaging of the ovaries to measure volume and antral follicle counts as well as testing levels of anti-Müllerian hormone are more sensitive measures of potential fertility than amenorrhea 5, 6. These tests indicate reduced numbers of primordial follicles not only in breast cancer survivors but also in women treated for Hodgkin disease (HD) 7 or pediatric malignancies 8–10. Although many of these women can become pregnant after cancer treatment, they will probably experience permanent ovarian failure at an age far younger than normal.
Most women treated for cervical cancer can no longer carry a pregnancy because they have had radical hysterectomy or a large dose of pelvic radiotherapy. Only those with very early stage disease are eligible for the fertility-sparing surgical options of conization or trachelectomy 11. Irradiation of the uterus 12 can also cause pregnancy complications including miscarriage, prematurity, and low birth weights 13. Occult damage to heart or lung function after cancer treatment can manifest as acute illness during the physiological stress of pregnancy 14. Furthermore, some women forego pregnancy because of fears about triggering a cancer recurrence or having a child with birth defects 15, even though pregnancy is not associated with recurrence even after breast cancer 16 and children born to cancer survivors have no excess rate of malformations 17.
With the increasing success of assisted reproductive technology 18, fertility preservation before cancer treatment has become an option. Several professional organizations have published ethical and practice guidelines 13, 19, 20. Most women can delay cancer treatment for several days to surgically harvest ovarian tissue 21, or up to two to three weeks in order to undergo a cycle of ovarian stimulation to collect oocytes that can be cryopreserved in the unfertilized state 22 or used to create embryos for freezing 23, 24. Unfortunately, only a few live births have occurred from auto-transplanted ovarian tissue 21. The chance of a conception and live birth from stored oocytes or embryos is far more reasonable, at least for women under age 35. However, insurance coverage for fertility preservation is not mandated nationally or in any state 25, 26, making it unaffordable for the majority of eligible women. Even if women wish to consider fertility preservation, many do not receive timely information. Two recent surveys of oncologists concur that less than half routinely refer young female patients for fertility preservation 27, 28. These barriers undoubtedly contribute to a 20% reduction in achieving a first pregnancy in women who survive childhood cancer 29 and a 50% decrease in women diagnosed as young adults 30, 31, even though marriage rates in female survivors are only slightly less than in peers 32.
Young cancer survivors are often encouraged to consider adoption, yet they face discrimination from international and domestic agencies, as well as from birth mothers choosing a family for independent adoptions 33. Only a minority of cancer survivors consider using oocyte donors or gestational carriers to become parents 15. High out-of-pocket costs and legal restrictions may also limit third-party reproduction.
Cancer-related infertility is likely to be distressing, since most women in the United States want to have children. In 2002, the National Survey of Family Growth interviewed over 7500 women aged 15–44 34. Forty-two percent said they would be bothered a great deal and 29% somewhat, if they never had a child. In a survey of young cancer survivors, 75% of those without children wanted to have one in the future 15.
Although considerable research has documented women's high distress during infertility treatment 35, few studies have assessed the long-term impact of unresolved infertility. Research in women whose infertility was unrelated to cancer suggests lingering distress when women remain childless. In a qualitative study of 14 women 20 years after unsuccessful infertility treatment, marital relationships, sexuality, and self-esteem remained problematic. Emotional distress was exacerbated when peers began to have grandchildren 36. Three to 15 years after in vitro fertilization (IVF), women who remained childless had lower well-being and life satisfaction scores than those who had a child 37–40. Women who adopted a child had intermediate scores 40.
A recent analysis of responses of 2894 women from the population-based National Survey of Fertility Barriers confirms that women who are involuntarily childless have higher rates of depression and lower life satisfaction than women who have not experienced infertility 41. Women who had lost a pregnancy and were still childless had particularly poor mental health, even at an average follow-up of 7 years, suggesting that involuntary childlessness is a traumatic event. It is possible that women who suffer the dual traumas of a cancer diagnosis and infertility would also have more severe symptoms.
Aims and hypotheses
Since having cancer at a young age is emotionally distressing in itself 42, it is unclear how much cancer-related infertility influences quality of life in long-term cancer survivors. To answer this question, we conducted a cross-sectional survey of younger women diagnosed with cancer, unselected for their desire for children at diagnosis, and now 5–10 years post-treatment. Our hypotheses were as follows:
Even with other medical and demographic factors taken into account, women who wanted a child at cancer diagnosis and were unable to have one would have significantly higher general and infertility-specific distress, and poorer health-related quality of life, than women who did not want a child at diagnosis or women who had a child after cancer.
Within the group of women whose childbearing was interrupted, those childless at follow-up would be the most distressed.
Within the group of women who wanted a child at diagnosis, those who had a biological child after cancer would be less distressed than women who became social parents through adoption or step-parenting.
Because of their unique concerns about the impact of pregnancy or hormonal treatments for infertility on cancer recurrence, survivors of breast cancer would be more distressed about childbearing issues than women with other types of cancer.
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Our primary hypothesis was partially supported. At an average of ten years after their illness, women who reported that cancer interrupted desired childbearing had significantly more distress about cancer-related infertility, intrusive thoughts, and use of avoidance in dealing with this painful issue, even when other medical and demographic factors were taken into account, including age, cancer recurrence, second primary tumors, income, education, type of cancer treatment, and menopause symptoms.
An unfulfilled desire for a child was not associated with a higher level of general emotional distress, however, as measured by the BSI-18. Women whose childbearing had been interrupted by cancer did have lower Mental Health Component scores on the SF-12 than their peers, but this relationship was no longer significant after controlling for medical and demographic factors. In general, women in our sample had good overall psychological adjustment. The mean SF-12 scores were very close to norms for community dwelling women on both mental and physical health. Only 20% of women had clinically significant levels of distress on the BSI-18, similar to rates of 18–22% in larger samples of survivors of pediatric and adult cancers 56. Thus, the distress appears to be limited to the fertility issue.
Women who viewed themselves as infertile reported lower sexual and relationship satisfaction than women who believed they had normal fertility. Although cancer treatment and premature ovarian failure undoubtedly contributed to sexual problems in this sample, women treated for infertility also have excess rates of sexual dysfunction and relationship stress 57.
Since we interviewed our cohort, two cross-sectional surveys of the impact of infertility on younger adult female cancer survivors 58, 59 and one prospective survey of survivors of hematopoietic cell transplant 60 have been published. The samples in these studies were small (N's ranged from 70 to 131). One focused only on transplant survivors 60 and one on breast cancer survivors 59. However, their findings concur with ours. A woman's unfulfilled desire for a child at the time of cancer diagnosis, whether assessed prospectively or retrospectively, remains strong and influences her quality of life even 5–10 years after cancer treatment. Women who remain childless are the most distressed group 58–60. A strength of our study was having a large enough sample to compare women who had completed their families before cancer diagnosis to those who still wanted children.
Most surveys, including ours, have asked retrospectively about desire for a child at cancer diagnosis. It is possible that women currently distressed about fertility are over-reporting their past desire for a child. However, the agreement between the results of the prospective and retrospective studies of cancer survivors, and the very similar outcomes in a large, population-based study of women with unresolved infertility 41 do not suggest a large impact of recall bias. Of course prospective research would be desirable in the future.
None of the studies has recruited an appropriate comparison group to look at the emotional impact of infertility after cancer treatment compared to infertility from other causes. Hammond and colleagues had transplant survivors bring a sibling or friend as control 60. The groups showed equal rates of distress about infertility. Rates of infertility in the control group were much higher than would be expected, however, undoubtedly due to recruitment bias. Carter et al. compared their cancer survivors to 50 infertile women on a waiting list to receive oocyte donation 58. The groups had similar levels of depression and distress about infertility, which is not surprising. Women who pursue assisted reproductive technology include less than 2% of infertile women in the United States and are thus likely to be more distressed than women who do not seek help 61. The question of dual trauma remains unresolved.
Our study was also able to compare women who became social versus biological parents. As in the literature on women seeking assisted reproductive technology 37, 38, 40, social parenting does not resolve distress completely. However, we combined step-parents with adoptive parents. Mothers who create a family after infertility appear to value their children more than women who conceived without a problem 62, 63. This held true in a comprehensive, longitudinal study whether children were conceived with IVF, with donor sperm or oocytes, or adopted, although with adoption there was slightly less warmth between mother and child at adolescence 62. Similarly, longitudinal research is needed on parenting and family relationships for cancer survivors who adopt or conceive using third-party reproduction.
We had hypothesized that women with breast cancer would be more distressed about cancer-related infertility than women with HD/NHL or cervical cancer, because of lingering uncertainty about whether risk of recurrence could be increased by fertility treatment 64 or pregnancy 65. No differences in psychosocial adjustment were observed according to cancer site, however, nor did distress over interrupted childbearing interact with cancer site.
A major limitation of this survey is the difficulty we had in contacting the majority of women listed in our tumor registry. The women with cervical cancer were the most difficult to find, which is consistent with the lower socioeconomic status and greater geographic mobility of this group 66. Another major problem was women who did not answer their phone or return messages. Response rates for telephone surveys have dropped precipitously in the last ten years with the advent of call screening, women working outside of the home, and more households using cell phones rather than landlines 67. Our phone contact rate of 37% is not unusually low. On the other hand, 53% of women contacted did participate in the study, a much higher response rate than we have achieved in postal surveys 15, 43. Our participants were also similar to the original sample in age and race, though we seem to have missed some Hispanic women.
These data certainly highlight the importance of fertility preservation for young women facing cancer treatment. Perhaps the most important task for oncology professionals is to lobby for insurance coverage for these procedures so that women can afford them 25, 26. However, we already have many thousands of younger women in the United States who have unresolved grief about interrupted childbearing. We are developing an evidence-based cognitive-behavioral intervention to provide women with social support 40, help them find meaning in their experience of cancer and infertility 68, and make informed decisions about whether to live without children or to pursue infertility treatment, adoption, or third party reproduction. Given the difficulty of building groups of younger female survivors outside of large urban areas, we hope to compare an Internet 69 or phone-based format to a more traditional, in-person group.