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Pregnancy After Breast Cancer: From Psychosocial Issues Through Conception

Pregnancy After Breast Cancer: From Psychosocial Issues Through Conception

ABSTRACT: Women face numerous issues if they either contemplate childbearing or become pregnant after the diagnosis of breast cancer. Based on a search of the English medical literature from 1966 to 1997, we make the following conclusions regarding pregnancy after breast cancer: (1) Sexual function is not affected by the decision to treat breast cancer by breast conservation vs mastectomy. (2) Infertility after breast cancer treatment is directly proportional to patient age and the use and dose of alkylating agents. There is no conclusive information on the effects of duration, dose intensity, schedule, or route of administration of chemotherapy on subsequent fertility. (3) There appears to be no increase in birth defects in children whose parents were exposed to chemotherapy earlier in life. (4) Milk production of the irradiated breast is likely to be limited. Also, breast-feeding appears to decrease the risk of breast cancer. (5) With respect to monitoring pregnant women for breast cancer recurrence, in general the recommendations made by the American Society of Clinical Oncology (ASCO) regarding monitoring in nonpregnant women should be followed. (6) Pregnancy does not increase the risk of recurrent breast cancer. (7) Adjuvant tamoxifen (Nolvadex) therapy has adverse effects on pregnancy in vivo and in laboratory animals. No reports exist on the effects of tamoxifen on human pregnancy.[ONCOLOGY 12(5):759-773, 1998]

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 (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 and
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) 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, and 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, the antimetabolite cytarabine, and the
Vinca extract vinblastine also appear to be toxic to the germinal
epithelium. Most other antimetabolites, however, including
fluorouracil, methotrexate, and 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, and prednisone) and ABVD
(Adriamycin, bleomycin, vinblastine, and 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]

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