27/2/24, 22:00 Overview of infertility and pregnancy outcome in cancer survivors - UpToDate
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Overview of infertility and pregnancy outcome in
cancer survivors
AUTHOR: Elyce H Cardonick, MD
SECTION EDITORS: Charles J Lockwood, MD, MHCM, Robert L Barbieri, MD, Patricia A Ganz, MD
DEPUTY EDITORS: Kristen Eckler, MD, FACOG, Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.
This topic last updated: Jul 24, 2019.
INTRODUCTION
One of the strongest predictors of emotional well-being in cancer survivors, besides sexual
function, appearance, and employability, is feeling healthy enough to be a good parent.
Parenthood can represent normalcy, happiness, and life fulfillment. Cancer survivors are
often fearful that their history of cancer or its treatment will have an adverse impact on
offspring conceived after their cancer treatment, such as placing them at risk for malignancy,
congenital anomalies, or impaired growth and development. They are also concerned about
the risks of cancer recurrence, infertility, miscarriage, and achieving a successful pregnancy
outcome.
This topic will discuss issues of infertility and pregnancy outcome in cancer patients. Related
topics on fertility preservation are found separately:
● (See "Fertility and reproductive hormone preservation: Overview of care prior to
gonadotoxic therapy or surgery".)
● (See "Fertility preservation in patients with endometrial carcinoma".)
FREQUENCY AND IMPACT OF COUNSELING
Ideally, patients facing cancer treatment receive fertility preservation counseling and
therapy, if desired and appropriate, prior to initiating gonadotoxic treatment
( algorithm 1). Despite concerns about future fertility and health of offspring, surveys of
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female cancer survivors in California and Sweden reported that only approximately 50
percent recalled receiving reproductive health counseling [1,2]; the proportion is higher in
male cancer survivors [2,3]. A subsequent study reported that receiving counseling about
reproductive loss and the option to try to preserve fertility before treatment was important
to survivors, even if they were unable to have children after chemotherapy [3].
Patient education regarding future reproductive function is an important component of the
care of individuals with cancer [3]. Others have noted that the rate of elective pregnancy
termination among female cancer survivors was higher compared with sibling controls
because of the fear that their prior cancer therapy would affect their children [4]. A
qualitative study of 34 female cancer patients age 23 to 39 years reported that fertility
preservation was important to all and the main patient feelings about fertility preservation
were safety (44 percent) and hope (23.5 percent) [5]. Time and/or financial issues were the
main obstacles to fertility preservation (82.4 percent). Ninety-one percent (31 of 34) of
patients noted that their quality of life and quality of relationships would have been
negatively impacted had they not undergone fertility preservation counseling and treatment.
FERTILITY ISSUES
Infertility in cancer survivors can be caused by injury to the hypothalamic-pituitary-gonadal
axis, as well as damage to the organs of the reproductive tract. Cytotoxic drugs, radiation
therapy, surgery, and the disease process itself can all cause infertility, which may be
temporary or permanent. The magnitude of risk depends on multiple factors, including:
● Type and stage of cancer
● Drug class and cumulative dose
● Radiation field, number of treatments, and cumulative dose
● Extent of surgical therapy
● Age (eg, prepubertal, postpubertal, near menopause)
● Gender
● Genetic factors
● Development of posttreatment hypothyroidism
The largest database on the risk of infertility in cancer survivors is the Childhood Cancer
Survivor Study (CCSS), a cohort study of several thousand five-year cancer survivors from 26
Canadian and United States institutions who were younger than 21 years at the time of
diagnosis (between January 1, 1970, and December 31, 1986) and who had an eligible
malignancy: leukemia, central nervous system (CNS) cancer, Hodgkin lymphoma, non-
Hodgkin lymphoma, Wilms' tumor, neuroblastoma, soft-tissue sarcoma, or bone tumors. In a
series of publications, fertility rates in female cancer survivors and female partners of male
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cancer survivors were compared with the rate in a sibling cohort [6-10]. Major findings of
studies from this cohort include:
● The relative risk (RR) of a pregnancy among female survivors was lower than in female
siblings (RR 0.81, 95% CI 0.73-0.90) [7]. Poor prognostic factors included:
• Hypothalamic/pituitary radiation dose ≥22 to 30 Gy [7,9].
• Ovarian/uterine radiation dose >5 Gy.
• A summed alkylating agent dose score of three or four (the alkylating agent dose
score was calculated by adding the tertile score [1, 2, or 3] for each of the alkylating
agents given to a particular patient. Nonexposed patients had a score of 0).
• Treatment with lomustine or cyclophosphamide.
● When compared with unaffected siblings, female cancer survivors had a more than 10-
fold increased risk of nonsurgical premature menopause (NSPM, defined as cessation
of menses ≥6 months in duration occurring 5 years after diagnosis and before age 40
that was not due other conditions, such as pregnancy; odds ratio [OR] 10.5, 95% CI 4.2-
26.3) [11]. The prevalence of NSPM was 9.1 percent by age 40. Independent risk factors
included exposure to a procarbazine dose ≥4000 mg/m2, any dose of ovarian radiation,
and receipt of a stem cell transplantation. A different cross-sectional study of 924
cancer survivors similarly reported a 10.9 percent prevalence of NSPM [12].
● Males who were not surgically sterile were less likely to father a pregnancy than
siblings (hazard ratio [HR] 0.56, 95% CI -0.49 to 0.63) [6]. Poor prognostic factors
included:
• Radiation dose >7.5 Gy to the testes
• Higher cumulative alkylating agent dose score
• Treatment with cyclophosphamide or procarbazine
● Female survivors had an increased risk of clinical infertility compared with their siblings
(RR 1.48, 95% CI 1.23-1.78; >1 year of attempts at conception without success), which
was most pronounced at early reproductive ages [8]. Despite being equally likely to
seek treatment for infertility, female survivors were less likely than their siblings to be
prescribed infertility medications (RR 0.57, 95% CI 0.46-0.70). Risk factors for infertility
included increasing doses of uterine radiation and alkylating agent chemotherapy.
Although survivors had an increased time to pregnancy compared with their siblings,
64 percent of 455 participants with self-reported clinical infertility eventually achieved a
pregnancy.
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● Female survivors were at higher risk of nonsurgical premature menopause than
siblings (8 versus 0.8 percent; RR 13.21, 95% CI 3.26-53.51) [10]. Risk factors for
nonsurgical premature menopause included:
• Attained age.
• Exposure to increasing doses of radiation to the ovaries. Although the risk of
nonsurgical premature menopause was most elevated among survivors exposed to
the highest doses of ovarian irradiation (≥1000 cGy), exposure to doses as low as 1
to 99 cGy were associated with an increased risk of nonsurgical premature
menopause compared with that in survivors who received no radiation.
• Increasing alkylating agent score (based on number of alkylating agents and
cumulative dose). The risk for nonsurgical premature menopause was increased at
all levels of exposure to alkylating agents and the risk increased with exposure to
increasing quantities of alkylating agents. For survivors treated with both alkylating
agents and abdominopelvic radiation, the cumulative risk of nonsurgical premature
menopause approached 30 percent.
• A diagnosis of Hodgkin lymphoma.
For survivors who were treated with alkylating agents plus abdominopelvic radiation,
the cumulative incidence of nonsurgical premature menopause approached 30 percent.
● Postcancer hypothyroidism appears to be a prognostic factor for worse reproductive
outcomes. In adjusted analysis, women reporting hypothyroidism after cancer
treatment were twice as likely to fail to achieve their desired family size (adjusted OR
[aOR] 1.91; 95% CI 1.09-3.33) and be childless (aOR 2.13, 95% CI 1.25-3.65). They were
also more likely to report having unprotected intercourse for at least 6 months without
conceiving (aOR 1.37, 95% CI 0.66-2.83) [13].
The risk of infertility in specific clinical settings is described in more detail separately,
including but not limited to the following topics:
● (See "Effects of cytotoxic agents on gonadal function in adult men".)
● (See "Oophorectomy and ovarian cystectomy", section on 'Fertility following unilateral
oophorectomy'.)
● (See "Approach to the care of long-term testicular cancer survivors", section on
'Infertility'.)
● (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies
during childhood".)
● (See "Overview of side effects of chemotherapy for early-stage breast cancer", section
on 'Chemotherapy-induced amenorrhea'.)
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Pretreatment approaches to preservation of fertility — In both sexes, gonadal shielding
from radiation therapy and limiting the extent of surgery, when possible, can help preserve
fertility.
Several additional methods have been developed or are under investigation for fertility
preservation in women. Cryopreservation of embryos or oocytes is a proven approach, while
cryopreservation of ovarian tissue is considered investigational. In some cases, ovarian
function can be preserved by transposition of gonads; auto-transplantation of gonadal tissue
is an investigational procedure. The safety and efficacy of gonadotropin-releasing hormone
(GnRH) agonists for prevention of ovarian toxicity is controversial and an active area of
investigation.
The primary approach to fertility preservation in men is cryopreservation of sperm.
Suppression of testicular function during chemotherapy by administration of GnRH agonists
has not been successful.
These methods for preserving fertility in women and men are reviewed in detail separately.
(See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic
therapy or surgery".)
Resources are available to offset the financial costs of these interventions (eg,
LIVESTRONG Fertility).
Assessment of fertility potential after cancer therapy — The assessment of fertility
potential after cancer therapy is challenging because fertility may be transiently impaired.
Whether infertility is transient or permanent, and the duration of transient infertility, cannot
be predicted reliably. Furthermore, the presence of functioning gonads does not reliably
predict that pregnancy will occur.
Premenopausal women who have amenorrhea or irregular menstrual cycles should be
evaluated for premature ovarian failure. The clinical manifestations are similar to those in
women with spontaneous ovarian failure. However, in young women with amenorrhea after
chemotherapy, diagnosis of premature ovarian failure can be problematic since ovarian
dysfunction may not be permanent. (See "Clinical manifestations and diagnosis of primary
ovarian insufficiency (premature ovarian failure)", section on 'Diagnosis'.)
Premenopausal women with regular menstrual cycles should undergo assessment of
ovarian reserve. A low anti-müllerian hormone (AMH) level may be the best test for
prediction of diminished ovarian reserve in this population [14-17]. Data from a variety of
infertility patients (including breast cancer survivors) planning in vitro fertilization (IVF)
suggest that a low AMH level before the procedure is a useful marker for predicting women
at risk for a poor response or no response to ovarian stimulation. (See "Female infertility:
Evaluation", section on 'Assessment of ovarian reserve'.)
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In men, fertility potential is evaluated by semen analysis. If repeated semen analyses
demonstrate severe oligozoospermia (less than 5 million spermatozoa/mL) or azoospermia,
basal serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone
should be measured. (See "Approach to the male with infertility".)
Risk of cancer recurrence — With the possible exception of gestational trophoblastic
disease, pregnancy does not affect the risk of recurrence of any type of cancer. In particular,
the risk of recurrent melanoma [18,19] or breast cancer, including estrogen-sensitive breast
cancer [20-23], does not appear to be affected by a subsequent pregnancy. A multicenter
retrospective cohort study comparing breast cancer patients who did (333 women) and did
not (874 women) become pregnant reported no impact of pregnancy status on disease-free
survival for women with either estrogen receptor (ER) positive or negative breast cancer [23].
Pregnant women had somewhat better overall survival (HR 0.72, 95% CI 0.54-0.97), with no
impact of emergency department status. Pregnancy outcome and breast cancer-to-
pregnancy interval did not appear to impact the risk of relapse.
The optimal timing of pregnancy after conclusion of cancer treatment is uncertain and
depends, in part, on patient-specific factors (eg, type of treatment, tumor type, prognosis). In
general, as the highest risk for cancer recurrence is in the first two years after completing
treatment, most authors suggest waiting this time period before attempting conception,
after a thorough evaluation confirming cancer remission or cure. However, a pregnancy that
occurs spontaneously within the first two years after completing cancer treatment does not
suggest that cancer is more likely to recur. (See "Gestational breast cancer: Epidemiology and
diagnosis" and "Tumor, node, metastasis (TNM) staging system and other prognostic factors
in cutaneous melanoma".)
Treatment of infertility — The treatment of infertility after cancer therapy depends on the
cause(s). Several factors may be contributing to infertility and some or all of these factors
may have been present prior to therapy. Treatment is generally the same as that for patients
without a history of cancer. Exceptions may include estrogen receptor positive breast cancer
survivors and women treated with high-dose radiation involving the uterus. Women with
estrogen-receptor positive breast cancer may benefit from ovulation induction with
tamoxifen or aromatase inhibitors. Women with a history of uterine radiation are counseled
that limited evidence suggests lower fecundity and an increased incidence of pregnancy
complications after uterine radiation [24]. (See "Female infertility: Treatments" and
"Treatments for male infertility" and "Fertility and reproductive hormone preservation:
Overview of care prior to gonadotoxic therapy or surgery".)
Female cancer survivors who elect in vitro fertilization (IVF) are counseled regarding the
options of using autologous or donor oocytes. For female cancer survivors diagnosed within
the five years prior to undergoing assisted reproductive techniques (ART), use of donor
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oocytes appears to result in higher live birth rates compared with autologous oocytes. In a
population-based cohort study of women undergoing IVF with autologous oocytes within
five years of entry into a cancer registry, women with prior cancer treatments (all types) had
reductions of greater than 60 percent in pregnancy and live birth rates compared with
women without cancer [25]. Of the cancer survivors, the live birth rate varied from 54
percent for women with melanoma to 14 percent for women with breast cancer (the average
live birth rate after IVF for women without cancer was 47 percent). In contrast, when women
underwent IVF with donor oocytes, there were no differences in the pregnancy rates
regardless of cancer treatment or cancer type. Once women with cancer became pregnant,
their likelihood of having a live birth did not differ significantly from women without cancer
whether donor or autologous oocytes were used. Of note, women who were diagnosed with
breast cancer more than six months prior to ART had a live birth rate similar to the overall
live birth rate for women with cancer (23.3 versus 24.7 percent). While more data are needed,
this study suggests a negative effect of recent malignancy itself on ART success separate
from the negative impact of chemotherapy on ovarian follicles.
Men with severe oligospermia may require IVF with intracytoplasmic sperm injection (ICSI).
Men with azoospermia who did not bank sperm prior to chemotherapy/radiation may have
some residual spermatogenesis, so evaluation and possible extraction of testicular sperm
(TESE) may be appropriate. (See "Treatments for male infertility".)
PREGNANCY ISSUES
Available data on pregnancy and offspring outcomes among cancer survivors are generally
reassuring. Limitations of most studies of this issue include retrospective study designs,
inadequate adjustment for confounders, recall bias, small numbers of adverse events, loss to
follow-up, misclassification and underreporting of some outcomes, and uncertain validity of
data obtained from surveys and linked birth-cancer registries.
Preconception — Women with a history of cancer benefit from a consultation with a
maternal-fetal medicine specialist to review their prior history, discuss the possible impact of
treatment on pregnancy outcomes, assess the need for preconception testing (eg,
echocardiogram for women treated with anthracycline chemotherapy, Herceptin, or left-
sided chest radiation), and plan for any additional antenatal monitoring that may be
warranted.
Conception — In a retrospective cohort study from the Childhood Cancer Survivor Study
(CCSS) that compared survivors of childhood cancer treated with chemotherapy only with
their unaffected siblings, the survivors were somewhat less likely to conceive/father a
pregnancy (38 versus 62 percent) or have at least one live birth (83 versus 90 percent)
compared with their siblings [26]. In multivariate analysis that compared male with female
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survivors, male survivors had a lower likelihood of pregnancy or live birth than female
survivors (for pregnancy: hazard ratio [HR] 0.63 versus 0.87; for live birth: HR 0.36 versus
0.82). In male survivors, reduced likelihood of pregnancy was associated with upper tertile
doses of cyclophosphamide, ifosfamide, procarbazine, and cisplatin. For female survivors,
busulfan and lomustine (doses ≥411 mg/m2) were associated with decreased rates of
pregnancy (HR 0.22 and 0.41, respectively).
Risk of congenital and chromosomal abnormalities — In studies including several
thousand offspring, female cancer survivors and male cancer survivors who were treated for
childhood cancer with chemotherapy, radiation therapy, or both had no increased risk of
congenital anomalies, single gene disorders, or chromosomal syndromes in their offspring
[27-37]. These studies primarily evaluated pregnancies that were conceived years after
treatment. Some representative examples are illustrated below:
● The CCSS performed a retrospective cohort analysis of validated cases of congenital
anomalies among 4699 children of 1128 male and 1627 female childhood cancer
survivors [35]. Chemotherapy with alkylating agents and radiotherapy doses to the
testes and ovaries were quantified and related to risk of congenital anomalies using
logistic regression. Major findings were:
• The overall prevalence of anomalies was 2.7 percent.
• The prevalence of anomalies was not increased among children whose mothers
were exposed to radiation or alkylating agents (3.0 versus 3.5 percent in those with
no exposure) nor among children of male survivors (1.9 versus 1.7 percent in those
with no exposure).
• Neither ovarian radiation dose nor testicular radiation dose was related to risk of
congenital anomalies.
● A case-control study using computerized record linkage determined the incidence of
cancer in parents of children born with an anomaly versus a matched sample of parents
of children without congenital anomalies [29]. Over 170,000 mothers and fathers were
included. The incidence of cancer was similar in the parents of anomalous and
nonanomalous children. In addition, there was no association between congenital
anomalies in offspring and any type of cancer treatment (eg, radiation therapy or
chemotherapeutic treatment with an alkylating agent).
● An international study of over 25,000 survivors of childhood cancer in the United States
and Denmark who gave birth to or fathered over 6000 children reported no significant
difference in the incidence of genetic disease in children born to survivors and those
born to sibling controls (3.7 and 4.1 percent, respectively, in the United States and 6.1
and 5.0 percent, respectively in Denmark) [36].
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● The offspring of 1915 female survivors of childhood or adolescent cancer had a gender
ratio (male:female) of 1.09:1.00 among their 4029 pregnancies [4]. This figure is
consistent with that in the general population and not significantly different from that
for offspring of female siblings of the female survivors. This finding argues against
transmission of lethal X-linked mutations as a result of cancer treatment. Similar
findings have been reported by others [38].
In contrast to these generally reassuring studies, at least two studies have observed an
increased risk of congenital anomalies in offspring of cancer survivors. One was a relatively
small study of survivors of Wilms' tumor treated with radiation therapy that included only 20
malformed infants, suggesting chance may have accounted for the findings [39]. The other
was a population-based study from Sweden and Denmark restricted to offspring of male
cancer survivors [40]. In this study, offspring of male cancer survivors had a slightly but
statistically higher rate of major congenital anomalies than offspring of fathers with no
history of cancer (relative risk [RR] 1.17, 95% CI 1.05-1.31; absolute rate 3.7 versus 3.2
percent). One explanation for these findings, which are discordant with almost all previous
studies, is that offspring of cancer survivors were examined more closely because of their
paternal history, resulting in ascertainment bias.
Risk of miscarriage, preterm birth, growth restriction, stillbirth — The risk of adverse
pregnancy outcomes (eg, miscarriage, preterm delivery, fetal growth restriction, stillbirth) in
female cancer survivors depends, in part, on the type of therapy they received
(chemotherapy, radiation therapy, surgery) and to non-treatment factors (eg, age at start of
pregnancy, type and site of neoplasm). Chemotherapy does not appear to damage the
uterus, which may account for the generally favorable pregnancy outcome in exposed
patients [41], while exposing the uterus to high doses of radiation can restrict uterine growth
and cause vascular changes that impair uterine blood flow, which may lead to preterm birth,
fetal growth restriction, and stillbirth [33,42-44]. However, while early studies suggested no
increased risk of adverse pregnancy outcomes among female childhood cancer survivors or
female partners of male survivors [4,31,39,45,46], subsequent studies have reported
increased risk of preterm birth, low birth weight, and preeclampsia.
A 2017 registry study comparing pregnancy outcomes of nearly 2600 adolescent and young
adult cancer survivors with nearly 13,000 control women reported an approximately 50
percent increased prevalence of preterm birth and low birth weight in the cancer survivors
[47]. In a 2018 prospective cohort study comparing donor-egg pregnancy outcomes in 31
women with a history of cancer with 212 women without, risk of preterm birth and
preeclampsia was significantly higher in women with prior cancers [48]. In an attempt to
understand the factors underlying the seemingly elevated risk of preterm birth, a different
study compared registry data of first deliveries from over 1700 cancer survivors with more
than 5100 first deliveries of matched controls [49]. When compared with control women with
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the same conditions, cancer survivors only had an increased risk of preterm delivery if they
also experienced vaginal bleeding or preeclampsia. It is unknown if physician decision
making is influenced by the patient's cancer history and results in lowering the threshold for
inducing a preterm birth for perinatal complications such as bleeding or preeclampsia.
Timing of conception — In a birth registry study of over 2.3 million births, women with a
history of breast cancer had an increased risk of preterm birth, low birth weight, and small
for gestational age (SGA), especially if they received chemotherapy or gave birth within two
years of their breast cancer diagnosis date [50]. A different retrospective cohort study
similarly reported an increased risk of preterm birth for any cancer survivor whose
pregnancies were conceived <1 year after starting chemotherapy. Women who conceived ≥1
year after starting chemotherapy without radiation or ≥2 years after chemotherapy with
radiation did not have an increased risk of preterm birth [51].
Cervical surgery for treatment of cervical cancer can also affect future risks of miscarriage
and preterm delivery [51,52]. The risk of preterm birth in cervical cancer survivors largely
persisted but was somewhat lower in pregnancies conceived after the first year (for
pregnancies conceived ≤1 year after diagnosis: RR 3.5, 95% CI 2.2-5.4; for pregnancies
conceived >1 year after diagnosis: RR 2.4, 95% CI 1.6-3.5) [51].
● Chemotherapy – In the CCSS, women who received chemotherapy alone or with other
therapies (surgery, radiation therapy, or both) had lower rates of live birth than their
female siblings (range RR 0.52 [chemotherapy alone] to 0.71 [chemotherapy, surgery,
radiation therapy]) [4]. This appeared to be due primarily to a higher rate of pregnancy
termination, as the rates of miscarriage and stillbirth were generally statistically similar
for the survivors and their siblings. In addition, the male:female sex ratio of 1.09:1.0 in
offspring of female survivors was similar to that in the general population and in
offspring of female siblings of the female survivors, suggesting exposure to mutagenic
agents (chemotherapy, radiation therapy) did not increase transmission of lethal X-
linked mutations. Lastly, the rate of live birth was not lower for patients treated with
any particular drug compared with those not treated with that drug. The most
frequently used chemotherapeutic drugs in this study were cyclophosphamide,
doxorubicin, vincristine, dactinomycin, and daunorubicin.
The same investigators also compared pregnancy outcomes in the partners of male
survivors of childhood cancer with the outcomes in the partners of their male siblings
[45]. Although the proportion of pregnancies that resulted in a live birth was
significantly lower for the partners of the male survivors than for the partners of the
survivors’ siblings (RR 0.79, 95% CI 0.65-0.96), this was due, in part, to a higher rate of
pregnancy termination among the partners of male survivors compared with partners
of their siblings. The rate of miscarriage was generally similar in both groups, with a
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possibly higher risk for some individual chemotherapeutic agents, which may have
been due to chance. The stillbirth rate and the birth weight distribution were similar in
both groups. Interestingly, this study reported a male:female sex ratio of 1.00:1.03,
which is lower than that in female cancer survivors and the general population.
Possible explanations for this finding are chance and lower testosterone levels from
exposure to chemotherapeutic agents [53,54]. It is hypothesized that sex proportions of
mammalian offspring are partially controlled by hormone levels of both parents at the
time of conception and low levels of testosterone are associated with a high proportion
of daughters [55].
● Radiation therapy – The partners of men who receive testicular radiation do not
appear to be at increased risk of adverse pregnancy outcome [33,56]. In contrast, girls
and young women who undergo pelvic radiation are at risk of developing abnormalities
of the pelvic vasculature, which may decrease uteroplacental perfusion; radiation-
induced myometrial changes, such as fibrosis, which may decrease uterine elasticity,
distensibility, and volume; and injury to the endometrium, which may prevent normal
decidualization [57-63]. These changes may account for some adverse pregnancy
outcomes (fetal growth restriction, preterm delivery, placenta accreta, stillbirth) that
have been reported in pregnancies occurring after pelvic radiation
[4,31,33,39,42,43,47,57-59,64-69]. The risk of these outcomes depends on the total
radiation dose, site irradiated, and the woman's age at the time of irradiation (the
prepubertal uterus is particularly vulnerable) [33,63,70,71]. Sex steroid replacement
significantly increases uterine volume, endometrial thickness, and uterine blood flow
[72,73].
• In the CCSS, compared with female survivors who did not receive any radiotherapy,
female survivors who received high-dose radiotherapy to the flank/uterus (>500 cGy)
were at significantly increased risk of preterm birth (50.0 versus 19.6 percent), low
birth weight (36.2 versus 7.6 percent), and having an SGA infant (18.2 versus 7.8
percent) [43]. These risks were also noted at lower uterine radiotherapy doses
(starting at 50 cGy for preterm birth and at 250 cGy for low birth weight). In addition,
uterine and ovarian irradiation significantly increased the risk of stillbirth and
neonatal death at doses greater than 10 Gy (RR 9.1, 95% CI 3.4-24.6; 5/18 [18
percent]) [33]. For girls treated before menarche, irradiation of the uterus and
ovaries at doses as low as 1.00 to 2.49 Gy significantly increased the risk of stillbirth
or neonatal death (RR 4.7, 95% CI 1.2-19.0; 3/69 [4 percent]).
• Large studies of survivors of Wilms' tumor have compared the pregnancy outcome
of those who did or did not receive abdominal radiotherapy [39,44,64]. Women who
received flank radiation therapy as part of the treatment for unilateral Wilms' tumor
were at increased risk of pregnancy-induced hypertension, fetal malposition and
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premature labor, and the increase in risk correlated with higher doses of radiation
[44].
• At least two studies indicates abdominal radiotherapy may be associated with
increased risk of obstetric complications, separate from miscarriage, preterm birth,
and growth restriction reviewed above [68,74]. In a cohort study comparing female
survivors of childhood cancer who received abdominal radiation with survivors who
did not, treatment with abdominal radiation therapy was associated with a threefold
increased risk of gestational diabetes and twofold increased risk of anemia
complicating pregnancy [74]. In addition, women who received radiation therapy for
Wilms tumor had a threefold increased risk of hypertension in pregnancy. Possible
mechanisms include interstitial renal disease and pancreatic islet cell injury as result
of the radiation fields.
Pregnancy after breast cancer — (See "Approach to the patient following treatment for
breast cancer", section on 'Fertility and pregnancy after breast cancer' and 'Risk of cancer
recurrence' above.)
Pregnancy management — There are no standards for antenatal monitoring of cancer
survivors for potential pregnancy complications. Women who received radiation therapy
appear to be at highest risk for adverse pregnancy outcome. Therefore, in addition to
standard prenatal care and screening, the author obtains a sonogram at approximately 18
weeks of gestation in patients who were treated with pelvic radiation in order to evaluate the
placenta, fetus, and uterus/cervix. Patients who received flank radiation may benefit from
cervical length screening at their 18-week ultrasound, but patients exposed to radiation in
other locations or to chemotherapy do not have an increased risk for spontaneous preterm
labor. In addition, an ultrasound is obtained at approximately 28 weeks for fetal growth
assessment in all patients with a history of radiation therapy at any location.
Female survivors of childhood cancer who received abdominal radiation may be at risk for
gestational diabetes. We perform an early second trimester glucose challenge test,
particularly if the patient has additional risk factors for gestational diabetes, followed by
routine testing if negative.
Breastfeeding after treatment for breast cancer need not be discouraged except from the
irradiated breast. Most women who have undergone irradiation for breast cancer are able to
produce milk on the affected side, but the amount of milk produced may be less than that in
a nonirradiated breast, particularly if the lumpectomy site was close to the areolar complex
or transected many ducts [75]. Even when breast milk is produced, breastfeeding from the
irradiated breast is not advised because mastitis will be difficult to treat if it occurs [76,77].
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CANCER RISK IN OFFSPRING
An excess risk of cancer in offspring of cancer survivors has not been demonstrated [78,79],
unless the parent’s tumor is a component of an inherited syndrome, such as retinoblastoma
and the various cancers associated with the Li-Fraumeni syndrome (see "Li-Fraumeni
syndrome" and "Retinoblastoma: Clinical presentation, evaluation, and diagnosis"). Survivors
of ovarian or breast cancer who are positive for BRCA1 or 2 mutation have a 50 percent
chance of passing the mutation to their offspring. (See "Overview of hereditary breast and
ovarian cancer syndromes".)
Other malignancies that are less well recognized as having a familial component (eg, brain
tumors and acute leukemia) may also aggregate in the relatives of some families. If an
underlying genetic predisposition for such tumors is suggested in these families, pedigree
analysis of the survivors' family should be elicited. (See "Risk factors for brain tumors" and
"Acute myeloid leukemia: Pathogenesis", section on 'Familial acute leukemia and
myelodysplasia syndromes'.)
Patients with heritable cancers should be counseled about risk of the disease in their
offspring. (See "Overview of cancer survivorship care for primary care and oncology
providers", section on 'Genetic implications'.)
A genetics counselor can discuss options for prenatal diagnosis or preimplantation genetic
diagnosis, if this is desired. (See "Preimplantation genetic testing".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Female infertility".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
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Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Preserving fertility after cancer treatment in
children (The Basics)" and "Patient education: Preserving fertility after cancer treatment
in men (The Basics)" and "Patient education: Preserving fertility after cancer treatment
in women (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Cytotoxic drugs, radiation therapy, surgery, and the disease process itself can all cause
infertility, which may be temporary or permanent. The magnitude of risk depends on
multiple factors, including:
• Type and stage of cancer
• Drug class and cumulative dose
• Radiation field, number of treatments, and cumulative dose
• Extent of surgical therapy
• Age (eg, prepubertal, postpubertal, near menopause)
• Gender
• Genetic factor
● In both sexes, gonadal shielding from radiation therapy and limiting the extent of
surgery, when possible, can help preserve fertility. Cryopreservation of embryos or
oocytes is a proven approach for fertility preservation, and ovarian function can
sometimes be preserved by transposition of gonads. The primary approach to fertility
preservation in men is cryopreservation of sperm. (See 'Pretreatment approaches to
preservation of fertility' above.)
● The assessment of fertility potential after cancer therapy is challenging because fertility
may be transiently impaired. Whether infertility is transient or permanent, and the
duration of transient infertility, cannot be predicted reliably, and the presence of
functioning gonads does not reliably predict that pregnancy will occur. Fertility
potential is assessed in women with tests such as anti-müllerian hormone (AMH) level
and by semen analysis in men. (See 'Assessment of fertility potential after cancer
therapy' above.)
● Infertility treatment is generally the same as that for patients without a history of
cancer. Estrogen receptor positive breast cancer survivors are an exception; such
patients may benefit from ovulation induction with tamoxifen or aromatase inhibitors
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(see 'Treatment of infertility' above). For female cancer survivors diagnosed within the
five years prior to undergoing assisted reproductive techniques, the use of donor
oocytes appears to result in higher live birth rates compared with autologous oocytes.
● Parents who have been treated for childhood cancer with chemotherapy, radiation
therapy, or both are not at increased risk of having children with congenital or
chromosomal anomalies. (See 'Risk of congenital and chromosomal abnormalities'
above.)
● The available data do not support an adverse effect of prior chemotherapy on the risk
of miscarriage, fetal demise, or birth weight. Pregnancy in women who have received
prior pelvic irradiation appears to be associated with complications such as
miscarriage, preterm labor and delivery, low birth weight, and placenta accreta (see
'Risk of miscarriage, preterm birth, growth restriction, stillbirth' above). The birth
weights of the offspring after radiation of any location, including outside of the female
pelvis, are statistically lower compared with the offspring of survivors treated only with
chemotherapy.
● The offspring of cancer survivors are not at increased risk for cancer, unless the
parent’s tumor was a component of an inherited syndrome. (See 'Cancer risk in
offspring' above.)
● With the possible exception of gestational trophoblastic disease, pregnancy does not
affect the risk of recurrence of any type of cancer. (See 'Risk of cancer recurrence'
above.)
Use of UpToDate is subject to the Terms of Use.
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Topic 4801 Version 38.0
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GRAPHICS
Approach to fertility preservation for patients undergoing gonadotoxic
therapy*
* For detailed discussions of fertility preservation techniques and their application, refer to UpToDate
content on ovulation induction, in vitro fertilization, and fertility preservation.
¶ Testicular cryopreservation is under investigation and not yet routinely available.
Δ In most patients, random-start protocols allow ovarian stimulation to be initiated at any time
without needing to wait for menses.
◊ Choice of agent for ovarian stimulation is impacted by the presence of an estrogen-sensitive tumor.
§ While ovarian stimulation for cryopreservation of embryos or oocytes is the most established
method of fertility preservation, some women may elect ovarian tissue cryopreservation instead.
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Graphic 119461 Version 1.0
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