Version November 2024
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 parent. Parenthood can represent normalcy, happiness, and life fulfillment. Cancer survivors are often concerned about the risks of cancer recurrence, infertility, miscarriage, and achieving a successful pregnancy outcome. They are also 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.
This topic will discuss issues of fertility and pregnancy outcome in cancer patients. Related topics on fertility preservation are found separately:
●(See "Fertility preservation: Cryopreservation options".)
PRETREATMENT CONSIDERATIONS
Fertility preservation counseling — Ideally, patients facing cancer treatment receive fertility preservation counseling and therapy, if desired, prior to initiating gonadotoxic treatment. Despite concerns about future fertility and health of offspring, surveys of female cancer survivors reported approximately 50 percent recalled receiving reproductive health counseling [1,2]; male cancer survivors were more likely to report having received counseling [2,3]. Despite varied rates of counseling, cancer survivors also reported that receiving counseling about options for fertility preservation before treatment was important to them, even if they were unable to have children after treatment [3]. In one study of 34 female cancer patients age 23 to 39 years, the main feelings about fertility preservation were safety and hope while the main obstacles were time and financial constraints [4]. 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. (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).
Fertility preservation techniques — In both sexes, options for fertility preservation include cryopreservation techniques and fertility-preserving approaches to radiation and surgical treatment. Cryopreservation can be applied to embryos, sperm, eggs, and, in study protocol settings, ovarian or testicular tissue. In females, the safety and efficacy of gonadotropin-releasing hormone (GnRH) agonists for prevention of ovarian toxicity is controversial and an active area of investigation. Suppression of testicular function during chemotherapy by administration of GnRH agonists has not been successful.
Established methods for preserving fertility in females and males are reviewed in detail separately.
●(See "Fertility preservation: Cryopreservation options".)
Discussions specific to surgical treatment for specific cancers include:
●(See "Fertility-sparing surgery for cervical cancer".)
●(See "Fertility preservation in patients with endometrial carcinoma".)
Risk modifiers for infertility — Infertility in cancer survivors can be caused by injury to the hypothalamic-pituitary-gonadal axis and/or 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)
●Genetic factors, including genetic sex
●Development of posttreatment hypothyroidism
GENERAL SUMMARY — Several longitudinal registry studies of childhood cancer survivors suggest that pregnancy and offspring outcomes among cancer survivors are generally reassuring [5-11]. Increased risks of preterm birth, low birth weight, and preeclampsia have been reported. Despite generally reassuring outcomes for fertility and pregnancy, one cohort study reported that patients’ perceived infertility risk had low agreement with their objective risk, as assessed by estimated gonadotoxicity of treatment, menstrual patterns, and ovarian reserve testing [12].
Common limitations of the available data 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.
Representative studies include:
●US Childhood Cancer Survivor Study (CCSS)– The largest database on the risk of infertility in cancer survivors is the Childhood Cancer Survivor Study , 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 cancer survivors were compared with the rate in a sibling cohort [5-9].
●St Jude Lifetime Cohort (SJLIFE) – SJLIFE was established in 2007 to medically assess the health status of survivors of childhood cancer treated at St Jude Children’s Research Hospital (Memphis, TN, USA) [10]. Goals included modifying the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and adding grading rubrics from other sources for chronic conditions that were not, or were inadequately, included in the CTCAE. Eligibility criteria were expanded in 2015 to include five-year survivors of any age.
●British Childhood Cancer Survivor Study (BCCSS) – The BCCSS is a large-scale population-based cohort of nearly 18,000 five-year survivors of childhood cancer [11]. Using data from the British National Registry of Childhood Tumours, identified individuals were diagnosed with cancer between ages 0 to 14 years during the time period 1940 to 1991.
COMMON FERTILITY CONCERNS
Females
Ability to conceive — Female and male cancer survivors appear to have reduced odds of conceiving/fathering a pregnancy compared with untreated siblings or expected pregnancy rates [5-7,13,14].
●Sibling comparison – In one study, 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 [7]. 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.
●Population comparison – A meta-analysis including over 8 million women from the general population and 113,000 breast cancer patients reported similar findings [15]. Breast cancer survivors were less likely to have subsequent pregnancy compared with the general population (RR 0.40). Among breast cancer survivors, pregnancy was associated with fewer recurrences. (See 'Impact of pregnancy on cancer recurrence' below.)
Poor prognostic factors for female fertility include [6]:
●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.
●Hypothalamic/pituitary radiation dose ≥22 to 30 Gy [6,8].
Adverse pregnancy outcomes — Cancer therapy, particularly abdominal radiation, appears to increase the risks of pregnancy loss (miscarriage), preterm birth, and low birth weight [14]. Increased risk of preterm birth may be related to elevated risk of preeclampsia.
●Impact of treatment type – 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 – Chemotherapy does not appear to damage the uterus, which may account for the generally favorable pregnancy outcome in exposed patients [16],
•Abdominal/pelvic radiation – 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 [17-20]. In a questionnaire study that compared 7300 pregnancy outcomes of cancer survivors with general population data (England and Wales), abdominal radiation was associated with increased risk of preterm birth (odds ratio [OR] 3.2, 95% CI 2.1-4.7) and low birth weight (OR 1.9, 95% CI 1.1-3.2) as well as a small increase in risk of pregnancy loss (OR 1.4, 95% CI 1.0-1.9) [14].
●Trend toward increased obstetric risks – While early studies suggested no increased risk of adverse pregnancy outcomes among female childhood cancer survivors or female partners of male survivors [14,21-24], subsequent studies have reported increased risk of preterm birth, low birth weight, and preeclampsia.
Impact of treatment on ovarian function
●Acute ovarian insufficiency – Acute ovarian failure is loss of ovarian function within 5 years of the cancer diagnosis; presentations include lack of progression through puberty, lack of menarche by 18 years of age, or cessation of menses within 5 years from diagnosis [25,26]. In a cohort study of participants from the CCSS and St. Jude Lifetime Cohort (SJLIFE), approximately 6 percent of individuals in both studies experienced acute ovarian failure [26]. Risk factors included hematopoietic stem cell transplant, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and stem cell transplant.
●Ovarian insufficiency –
●Premature menopause – Premature menopause occurs when ovarian function is retained for at least 5 years following cancer diagnosis, but non-surgical menopause develops before the survivor reaches 40 years of age [27].
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 or more 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) [27]. 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 [28].
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) [9]. 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.
Hypothyroidism — 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) [29].
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".)
Impact of pregnancy on 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 [30,31] or breast cancer [15], including estrogen-sensitive breast cancer [32-35], does not appear to be affected by a subsequent pregnancy. In a systematic review including 113,000 breast cancer survivors of whom 7,505 became pregnant, pregnancy did not result in more recurrences, either in hormone receptor positive or hormone receptor negative disease [15]. Overall, breast cancer survivors with pregnancy had better disease-free survival (HR 0.66, 95% CI, 0.49 to 0.89) and overall survival (HR 0.56, HR, 0.56; 95% CI, 0.45 to 0.68) relative to those who did not become pregnant. Similar results were observed after correction for potential confounders.
CHILDHOOD OUTCOMES
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 [18,22,36-44]. 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 [42]. 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 [38]. 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) [43].
●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 [21]. 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 [45].
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 [23]. The other was a population-based study from Sweden and Denmark restricted to offspring of male cancer survivors [46]. 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 cancer in offspring — An excess risk of cancer in offspring of cancer survivors has not been demonstrated [47,48], 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 "Acute myeloid leukemia: Pathogenesis", section on 'Familial acute leukemia and myelodysplasia syndromes' and "Risk factors for brain tumors", section on 'Genetic predisposition 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".)
GENERAL APPROACH TO MANAGEMENT
Asses fertility potential — The assessment of fertility potential after cancer therapy is challenging because fertility may be transiently impaired. Whether infertility is permanent or transient, and the duration of transient infertility, cannot be predicted reliably. Furthermore, the presence of functioning gonads does not reliably predict that pregnancy will occur.
●Females – The approach to fertility evaluation in females depends in part of the presence of regular menstrual cycles.
•Amenorrhea or irregular menstrual cycles – Premenopausal females who have amenorrhea or irregular menstrual cycles should be evaluated for treatment-induced ovarian insufficiency . The clinical manifestations are similar to those in women with spontaneous ovarian insufficiency. However, even if diagnosed, ovarian dysfunction may not be permanent in young females. Evaluation should also include tests to exclude other disorders or sequelae of cancer treatment that may cause menstrual cycle dysfunction (eg, hypothyroidism).
-(See "Evaluation and management of secondary amenorrhea", section on 'Laboratory testing'.)
•Regular menstrual cycles – Premenopausal females 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 [49-52]. 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'.)
●Males – In males, 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".)
•(See "Effects of cytotoxic agents on gonadal function in adult men".)
Treat 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 [53]. (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 (see "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'). For female cancer survivors diagnosed within the five years prior to undergoing assisted reproductive techniques (ART), use of donor 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 [54]. 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".)
Provide preconception counseling
Identify multidisciplinary care team — 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. The need for speciality consultation is also identified.
Timing of conception — 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".)
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 [55]. 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 [56].
Cervical surgery for treatment of cervical cancer can also affect future risks of miscarriage and preterm birth [56,57]. 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) [56].
●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]) [21]. 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 [24]. 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 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 [58,59]. 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 [60].
●Radiation therapy – The partners of men who receive testicular radiation do not appear to be at increased risk of adverse pregnancy outcome [18,61]. 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 [62-68]. 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 [17-19,21-23,62-64,69-75]. 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) [18,68,76,77]. Sex steroid replacement significantly increases uterine volume, endometrial thickness, and uterine blood flow [78,79].
•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) [19]. 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]) [18]. 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 [20,23,69]. 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 premature labor, and the increase in risk correlated with higher doses of radiation [20].
•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 [74,80]. 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 [80]. 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
Tailor prenatal care — There are no standards for antenatal monitoring of cancer survivors for potential pregnancy complications. Information on pregnancy following specific cancers can be found in related content:
●Breast cancer – (See "Approach to the patient following treatment for breast cancer", section on 'Fertility and pregnancy after breast cancer' and 'Impact of pregnancy on cancer recurrence' above.)
●Cervical cancer – (See "Fertility-sparing surgery for cervical cancer".)
●Endometrial cancer – (See "Fertility preservation in patients with endometrial carcinoma".)
Antenatal fetal surveillance — 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.
Gestational diabetes — As patients treated with 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. In the BCCSS, all childhood cancer survivors who were treated with abdominal radiotherapy had a more than 3-fold increased risk of gestational diabetes compared with survivors who received other treatments (relative risk 3.35, 95% 1.41-7.93).
Concern for preterm delivery — 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 [73]. 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 [81]. 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 [82]. When compared with control women with the same conditions, cancer survivors only had an increased risk of preterm birth 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.
Lactation — 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 [83]. Even when breast milk is produced, breastfeeding from the irradiated breast is not advised because mastitis will be difficult to treat if it occurs [84,85].
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.
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 'Fertility preservation techniques' 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 'Asses fertility potential' 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 (see 'Treat 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 'Adverse pregnancy outcomes' 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 'Risk of cancer 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 'Impact of pregnancy on cancer recurrence' above.)
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