Pregnancy After Breast Cancer: From Psychosocial Issues Through Conception

The number of women considering pregnancy after breast cancer is currently on the rise for several reasons. First, the incidence of breast cancer is increasing in women of all ages, and 25% of all breast cancer cases occur in premenopausal women.[1] Second, many women are delaying childbirth for personal, professional, or educational reasons.[1] Consequently, many premenopausal women are facing breast cancer treatment before they have started or completed childbearing.

Recent reviews of breast cancer associated with pregnancy have focused on the traditional definition—that the cancer was diagnosed during or within 1 year following pregnancy.[1] Our review looks at the problem from a different viewpoint. It explores the various issues women face if they have ever had breast cancer and are now either pregnant or considering pregnancy. These issues fall into seven major categories: (1) sexual functioning, (2) infertility, (3) congenital anomalies, (4) breast-feeding, (5) methods for monitoring breast cancer recurrence, (6) risk of recurrent breast cancer, and (7) antiestrogen therapy. A search of the English literature in OVID from 1966 to 1997 forms the basis of this report.

Sexual Functioning

Ever since psychological issues became a focus of attention in oncology, breast cancer treatment has been seen as producing significant sexual disruption.

Effects of Surgery
It was hoped that breast-conserving surgery or breast reconstruction would have a clear, significant advantage over mastectomy in helping women stay sexually active and functional, as well as psychologically stable. This has not proved to be the case, however.[2]

A woman’s overall psychological health, satisfaction with her relationships, and premorbid sexual life appear to be stronger predictors of sexual satisfaction after breast cancer treatment than the extent of damage to her breast. In 12 studies that compared quality of life after mastectomy with that after breast-conserving surgery and radiotherapy, patients treated with breast conservation consistently had more positive feelings about their bodies.[2] General psychological distress, psychiatric disorders, marital happiness, frequency of sex, and sexual dissatisfaction, however, were the same in the two groups. Bias may have been introduced if women who cared most about their appearance declined to undergo mastectomy, and yet studies that randomly assigned patients to mastectomy or breast conservation showed similar results as the nonrandomized series.[3-5]

As with breast conservation, breast reconstruction has its strongest impact on improving body image.[6-9] The most common motivations for breast reconstruction are to feel whole again, eliminate the need for a breast prosthesis, and wear a wider variety of clothing.[7-9]

Effects of Systemic Therapy
Systemic treatment may also adversely affect sexual desire.[10] Lasting consequences of chemotherapy, such as weight gain, fatigue, and change in the appearance of the hair, may decrease sexual desire or performance. In a cross- sectional study of two large metropolitan areas, tamoxifen(Drug information on tamoxifen) (Nolvadex) had no impact on the sexual functioning among women age 50 years and older.[10a] We need more information on how chemotherapy and hormonal therapy affect women’s sex lives.

Infertility

Infertility is a prominent concern of many women considering treatment for breast cancer. Breast cancer itself poses no known threat to fertility.[11] In addition, although surgery and radiation treatment may impair a woman’s ability to breast-feed in the future (see “Breast-Feeding” below), these modalities do not decrease the likelihood of pregnancy.

Effects of Chemotherapy
Chemotherapy, on the other hand, has been shown to cause amenorrhea in premenopausal females. Endocrine hormone profiles obtained in premenopausal patients who developed drug-induced amenorrhea are consistent with primary ovarian failure.[12-15] Estradiol(Drug information on estradiol) and progesterone(Drug information on progesterone) levels remain consistently low and cease to show normal cyclic changes, whereas the pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are elevated to postmenopausal levels. Serum dehydroepiandrosterone and prolactin levels are not affected, which is consistent with intact pituitary and adrenal function, respectively. Since adjuvant chemotherapy is indicated in most women with early-stage breast cancer,[16] many premenopausal women face the possibility of infertility before they have completed childbearing.

Several general conclusions can be drawn from recent reviews focusing on the impact of chemotherapy on fertility[11,17,18]:

1) The chance of infertility is proportional to the age of the patient (Table 1).[18-21] The average age of menopause in US women is between 50 and 52 years. For women treated with chemotherapy, the median age is 38 to 46 years.[18]

Sutton et al studied FAC (fluoro-uracil, Adriamycin, and cyclophosphamide(Drug information on cyclophosphamide)) chemotherapy in women £ 35 years old. Of the 128 patients whose menstrual histories were known, 59% continued to menstruate after chemotherapy, whereas 32% and 9% experienced temporary and permanent amenor- rhea, respectively.[21] In a study by Dnistrian et al, two patients under age 30 years showed no evidence of ovarian suppression after 24 cycles (2 years) of CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil)) therapy.[13]

2) Infertility is related to the type of chemotherapy. Alkylating agents, specifically, cyclophosphamide (Cytoxan, Neosar), are more likely to cause infertility than are nonalkylating agents. Alkylators are believed to act on undeveloped oocytes and, possibly, on the pregranulosa cells of primordial follicles.[22]

The antibiotic doxorubicin(Drug information on doxorubicin), the antimetabolite cytarabine(Drug information on cytarabine), and the Vinca extract vinblastine(Drug information on vinblastine) also appear to be toxic to the germinal epithelium. Most other antimetabolites, however, including fluorouracil, methotrexate, and mercaptopurine(Drug information on mercaptopurine) (Purinethol), do not appear to damage the germinal epithelium.[23] There is little clinical information on doxorubicin. In a study that compared MOPP (mechlorethamine, Oncovin, procarbazine(Drug information on procarbazine), and prednisone(Drug information on prednisone)) and ABVD (Adriamycin, bleomycin(Drug information on bleomycin), vinblastine, and dacarbazine(Drug information on dacarbazine)) in the treatment of Hodgkin’s disease, ovarian failure occurred less often in the ABVD group.[24] In animal studies, doxorubicin has been shown to cause testicular damage.[18]

3) The risk of infertility increases as the total dose of chemotherapy escalates. In younger women, higher cumulative doses are needed to induce gonadal failure: The average dose of single-agent cyclophosphamide before the onset of amenorrhea was 5,200 mg in 49-year-olds, 9,300 mg in 30-year-olds, and 20,400 mg in 20-year-olds.[15] The higher rate of gonadal failure noted in older women may be explained by the lower number of remaining follicles. From 2,000,000 follicles at birth, 200,000 remain at puberty and approximately 400 at menopause.[25]

4) The effect of shorter durations of some currently used dose regimens has not been adequately studied.[11,17,18] There is no conclusive evidence that duration of treatment, dose intensity, schedule, or route of administration are independent variables.[18]

5) It may be difficult to discern whether authors are referring to permanent or temporary amenorrhea.[18] Little information is available regarding reversibility. Bianco et al described women in whom menstrual periods resumed from 4 to 29 months after breast cancer treatment.[26]

Congenital Anomalies

In the event that a woman becomes pregnant after breast cancer is diagnosed and treated, her risk of bearing a child with congenital anomalies appears to be no greater than that of the general population. Most physicians recommend that a women wait 2 to 5 years after breast cancer treatment before becoming pregnant. The primary reason for this recommendation is that most recurrences of breast cancer occur within the first 2 years of diagnosis. Also, chemotherapy drugs demonstrate teratogenic effects if they are administered during the first trimester of pregnancy.[27,28]

Limited data suggest that the administration of chemotherapy to patients in the second or third trimester is not detrimental to the fetus.[27,29] The multidrug-resistant P-glycoprotein has been found in the gravid endometrium and may offer some protection to the fetus from a drug such as doxorubicin.[30]

The results of pregnancy following breast cancer diagnosis are shown in Table 2.[21,31-33] The number of elective abortions was much more common in early reports[31] compared to later studies,[33] as pregnancy became more accepted after breast cancer.

A case-control study compared parents of children with a congenital anomaly born between April 1979 and December 1986 with a matched sample of parents of children without anomalies. This study found no association between congenital anomalies in the offspring and any type of cancer treatment in either the mother or father.[34]

Little is known about the late effects of chemotherapy on offspring, such as impaired physical growth, intellectual and neurologic function, or gonadal function and reproductive capacity; transplacental carcinogenesis, transplacental mutagenesis of germ-line tissue; and secondary carcinogenesis.[11,35]

Mulvihill et al reported the results of a retrospective review of pregnancy outcome among female patients treated for a variety of advanced malignancies in Cancer and Leukemia Group B trials.[36] A total of 58 pregnancies occurred at a mean of 27 months after chemotherapy (range, 2 to 104 months). In the first year after chemotherapy, there were unexpected increases in low birthweight, stillbirth, and premature termination of pregnancy, with no excess of congenital anomalies. These effects reflect dysfunction in the milieu required to maintain pregnancy, rather than damage of oocytes.[36]

In a pregnant patient with metastatic cancer, the question arises of possible hematogenous dissemination involving the products of conception. Experimental studies of nonbreast tumors in animals hint that this occurrence is quite unusual, and suggest that the low frequency may be due to an ill-defined resistance of placental tissue to metastatic tumor growth.[37,38]

Clinical reports confirm the rarity of this event. From 1866 to 1989, there were only 52 cases in the western literature.[39] Only melanoma, leukemia, lymphoma, and one case of hepatocellular carcinoma have caused fetal metastases.[1] Of the 24 cases Potter and Schoeneman collected from the world literature, there were 4 documented cases of metastasis from breast cancer to the placenta, and only 1 case exhibited invasion of the chorionic villi; no fetal involvement occurred, and all 4 children were reported to be disease-free.[40]