According to the latest statistics, the relative 5-year survival rate for all childhood cancer s combined is approximately 84 and 87% among adolescent and young adult patients [1, 2]. It has been well documented in the literature that cancer and cancer therapies including surgeries, radiotherapy, and chemotherapy can compromise the fertility status of these survivors through various mechanisms ranging from alteration of body image and other psychosocial issues and sexual dysfunction to their negative impact on the quantity and quality of gametes [3–7]. In reality, many cancer survivors could maintain their fertility potential, depending on their baseline, pre-cancer fertility status, types and staging of cancers, nature and levels (e.g., dosage or intensity and duration of chemo- and radiotherapy) of treatment received, and their general mental and physical health statuses . Indeed, fertility is long recognized as one of the most important cancer survivorship issues, with over 75% of childless young cancer survivors stating their desire to have children and 80% viewing themselves very positively as potential parents [8]. It is also reported that fertility was consistently listed as one of the top three life goals among young cancer survivors [9]. Evidently young cancer survivors are concerned about their offspring’s health [10, 11]. In the following section we discuss the reproductive outcomes of cancer survivors’ offspring in three aspects, namely, the need of and access to assisted reproductive technologies, perinatal outcomes, and congenital anomalies.

Assisted reproductive technologies (ART’s ), including intrauterine insemination (IUI ), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI), have helped many couples who failed to achieve natural pregnancy to become biological parents. In the past two decades, there has been a significant increase in the number of reproductive centers worldwide. Simultaneously, with the increase in the efficacy and our understanding on the safety of these technologies [12, 13], their acceptance by societies and access by infertile couples have increased tremendously in recent years.

When experiencing infertility, both female and male cancer survivors with gonadal dysfunction post-cancer therapies may benefit from ARTs to use their fresh gametes for reproduction. In addition, fertility preservation, which involves cryopreservation of oocytes and sperm whenever feasible, is now part of the standard cancer management for postpubertal cancer patients [14]. ICSI is generally required when using cryopreserved gametes for reproduction. Thus, it is not surprising to see that some cancer survivors, particularly male survivors for whom sperm banking as a means of fertility preservation is much more widely available in most centers than oocyte harvesting for cryopreservation, have a significantly increased usage of IVF/ICSI compared to age-matched subjects in the population, as reported recently (adjusted OR 1.83, 95% CI 1.35–2.49) [15, 16].

With regard to the outcomes of IVF/ICSI using cryopreserved sperm , we recently reported that the usage rate of cryopreserved sperm is significantly lower among cancer survivors compared to noncancer patients (e.g., for infertility treatment) (11% vs. 31%), and that in the cancer survivor group a slightly higher number of IVF cycles were needed before achieving a pregnancy. Nonetheless, the live-birth rate of offspring with ICSI among male cancer survivors was comparable to that of noncancer patients [17]. Specifically, the average success rate of achieving parenthood using cryopreserved sperm was 62.1%, which was at least comparable to the infertile patient population : oligospermic and testicular sperm extraction (TESE) patients (40% and 48.6%, respectively). This provides evidence that cancer patients can bank sperm as effectively as men banking for infertility reasons. However, the cost of ARTs remains a significant barrier both to fertility preservation and to subsequent use of the technologies for procreation. As we recently demonstrated, in the absence of fees for sperm banking and subsequent storage, young cancer patients are willing to come for significantly more sperm banking sessions to preserve their fertility prior to cancer treatment, despite the fact that they are under significant level of stress and time constraint to begin treatment [18]. The result is that a great quantity of sperm would be available for their future use, potentially leading to a higher chance of procreation success.

There exist data among noncancer infertile couples indicating an increased risk o f adverse progeny outcomes among those who were conceived by ARTs. These risks include neonatal death, low birth weight, preterm birth, genetic and epigenetic conditions, congenital malformation , developmental anomalies, and cancer risk [19–24]. It should however be pointed out that the increased risks of adverse progeny outcomes with ARTs were not confirmed in other studies [25]. Further, it is possible that some of these adverse outcomes may be related to abnormal gametes health (e.g., impaired sperm chromatin integrity ) of the infertile parents undergoing ARTs rather than from the manipulation techniques of ARTs.

Various mechanisms have been proposed on how ARTs may increase the risks of adverse progeny outcomes. Interrupted gene and epigenetic regulation, tumor suppression, overcoming the natural selection, and survival mechanism present in spontaneous conception may leave gametes and embryos with higher risk for insults and higher risk to contain defects that could lead to developmental abnormalities leading to adverse outcomes [26–30]. It is also speculated that the exogenous hormone administration may affect the fetus during the critical period of growth and cell differentiation, thereby increasing the risk of endocrine-sensitive cancer later in life [31].

Unfortunately, with regard to the offspring of cancer survivors, there is a lack of data evaluating their long-term health risks specifically in the context of ARTs in the literature. In fact, most registry studies (see below) on the outcomes of cancer survivors’ offspring failed to make a distinction on the mode of conception (i.e., whether through natural intercourse or with various forms of ARTs with or without the use of donor gametes). This limits our ability to properly counsel cancer survivors on the health risks of their offspring with the use of ARTs. Given that cancer survivors are at risk to have impaired gamete quality both from cancer and cancer therapies [3], there is an urgent need to have further data to better define the long-term health risks of offspring of cancer survivors conceived with ARTs .

Several groups have reported perinatal outcomes of offspring of cancer survivors. Female childhood cancer survivors who received abdominal, pelvic, or total body irradiation appeared to be at risk to have stillbirth and neonatal death [32] in addition to offspring with preterm birth (<37 weeks of gestation), hypertension, gestational diabetes mellitus, anemia, and low birth weight (<2500 g) [33–39]. The exact biological mechanisms remain to be fully established, particularly with regard to the risks of hypertension, gestational diabetes, and anemia. Chronic radiation-induced renal injury and uterine damage leading to myometrial fibrosis and impaired vascular development of the uterus are among the proposed mechanisms. Such risks are less consistent among female cancer survivors with cancer occurred in adulthood, with some investigators reporting increased risks of preterm birth, low birth weight, and perinatal death [15, 36, 40–42] while others not observing an increase in such risks [15, 43–48]. The outcomes for offspring of male cancer survivors, on the other hand, are reassuring, with most studies reporting no significant increase in perinatal adverse events [15, 32, 49, 50]. Taken together, extra vigilance may be required during pregnancy of women who survived childhood cancer treated with radiotherapy.

Whereas the nature, mechanisms, and extents of gamete damage from cytotoxic anticancer therapies are important research questions, for cancer survivors one of the most important clinical questions is the health risks to their offspring after cancer. There exists an extensive volume of evidence in the current literature in animal models, as we reviewed recently [3], supporting the negative impacts of chemo- and radiotherapy affecting the health of offspring [51, 52]. In human, on the contrary, earlier studies exploring the risk for congenital anomalies in offspring of cancer survivors did not find an increased risk for these outcomes [43, 44, 53–55]. However, studies from other investigators [40] including a recent large register-based study, combining Danish and Swedish data [56], reported an elevated risk for both all congenital anomalies and major congenital anomalies in almost 9000 offspring of male cancer survivors compared with a healthy population control. Other investigators have weighed in to further explore this controversy on the potential risk of congenital anomalies among offspring of young cancer survivors. The following is a description of the findings of a selected group of recent large-scale registry studies from various countries.

Data from Childhood Cancer Survivor Study, a multicenter cohort study which evaluated 4699 children from 1128 male and 1627 female childhood cancer survivors who received chemo- and radiotherapy, reported no significant increase in the risk of congenital anomalies (including, in addition to congenital malformation , cytogenetic abnormalities such as Down syndrome and single-gene defects such as achondroplasia) in their offspring [57]. The investigators found no association between congenital anomalies and radiation doses specifically to the ovaries or testes. Even a higher dose of an alkylating agent was not associated with an increased risk of congenital anomalies. In contrast, a Norwegian study using their cancer and medical birth registries reported an increased risk of major congenital anomalies only among offspring of ovarian cancer survivors (adjusted OR 3.23, CI 1.15–9.09) but not among other types of cancer combined [15].

Using data collected from 1953 to 2004 from registries (e.g., national cancer, population birth, and hospital discharge registries) on close to 7000 offspring of cancer survivors with congenital anomalies and over 35,000 offspring of these survivors’ siblings, another recent population-based cohort study from Finland reported insignificant increase in the prevalence of congenital anomalies in offspring of cancer survivors of 3.2% compared to 2.7% in offspring of the survivors’ siblings [58]. The prevalence of anomaly observed was consistent with that reported in other similar epidemiological studies [43, 53, 56, 57]. Further, a similar observation was noted regardless whether the cancer was diagnosed and treated during childhood, adolescence, or young adulthood (20–34 years). The only anomalies that reached a statistically significant increase in adjusted prevalence ratio (2.1, 95% CI 1.1–3.99) among offspring of cancer survivors was non-extremity-related skeletal system anomalies (e.g., abdominal wall defects, craniosynostosis, diaphragmatic hernia). However, it should be noted that this group of diagnoses contains a large variety of anomalies and frequency of cases was low (0.2% in survivors’ offspring vs. 0.1% in siblings’ offspring). Interestingly, offspring of survivors diagnosed and treated with cancer in the earlier decades between 1955 and 1964 were at a significantly elevated risk (prevalence ration 2.77, 95% CI 1.26–6.11) for congenital anomalies in comparison with offspring of their siblings. On the other hands, no significant difference in the risk for congenital anomalies was detected in offspring of survivors diagnosed and treated for cancer in the more recent decades. While the exact reasons of this finding remained unclear, presumably it is in part related to reduced toxicity of more recent cancer treatment modalities and improved prenatal screening.

The inconsistency of the risk of congenital anomalies in human compared to animal studies can be explained by several differences in the synthesis of evidence. For instance, unlike studies in animal models, epidemiological data from human studies are mostly observational as it is rarely feasible to conduct such studies with a prospective interventional design. The differences among various human studies in samples sizes and power, study designs, definitions of cases or study outcomes, and inherent selection biases may lead to the different conclusions generated. To reduce the risk of bias, with regard to the choice of comparison group, many investigators consider siblings as a better choice than general healthy subjects in the population, as the former group allowed controlling for shared unmeasured familial confounders such as genetic background, early lifestyle, and social/economical (e.g., healthcare access) factors. Thus, the use of siblings as a comparison group allows for a proper evaluation of additional risk attributable to cancer and cancer therapies rather than risk originating from various confounders.

Determining the extent of genetic risks on offspring of cancer survivors is challenging, given the rarity of individual genetic disorders and insufficiency of detailed information on cancer treatment exposures on each subject. Indeed, often these data sets included a large variety of cancer diagnoses at various stages, comorbidities, treatment regimens, and duration. Since both early-onset cancer and congenital anomalies are rare outcomes, large epidemiological studies are needed to explore the risk for congenital anomalies in offspring of cancer survivors. But even with large data sets, analyses of events occurring at low frequency could be prone to bias [59]. Thus, the detected risks, particularly those derived from sub-analyses with small numbers, may be due to chance and their clinical significance must be interpreted with caution.

There are additional biases readers should keep in mind when using epidemiological data to evaluate the health of offspring of cancer survivors. For instance, many of these survivors are under heightened health surveillance. Thus their children may be diagnosed with more congenital anomalies. The types of anomalies registered and reported should also be examined in depth. What one may consider minor, non-dysfunctional , and non-life-threatening anomalies in offspring from comparison group may be registered in offspring from the study group that can result in biased conclusions.

A few caveats must be noted before concluding that the results from most of these new registry studies are reassuring with regard to the risks of congenital anomalies in offspring of cancer survivors. First, most registry studies did not make a distinction whether the offspring was conceived naturally or with fertility treatments. Stahl et al. reported a significantly higher risk of birth abnormalities in offspring of men with a history of cancer (relative risk 1.17, 95% CI = 1.02–1.31) not only with natural conception but also with assisted reproduction [56]. Presumably, a higher proportion of offspring from some cancer survivor groups may have been conceived with fertility treatment and assisted reproduction, as we discussed earlier [15, 16]. The observed increased risks among offspring of cancer survivors using ARTs may thus also be attributed to both the use of damaged gametes and gamete and embryo manipulations in ARTs.

Perhaps more importantly, these data do not address adequately other important reproductive outcomes such as time required to achieve pregnancy, risks of lower number of offspring, or rate of miscarriage, particularly early (<20 weeks) miscarriage. Based on animal studies, these are some of the important reproductive outcome measures that one might predict to be affected. Several studies have reported that cancer survivors have a significantly reduced probability of having children [16, 40, 54, 60, 61]. The reasons for this may be secondary to psychosocial factors such as reduced marriage rate [16], but it may also be secondary to their impaired reproductive health. While infertility presenting as failure to achieve pregnancy is devastating, those infertile couples who have achieved pregnancy but experienced miscarriage and perinatal loss may also have significant emotional distress that put them at risk to have posttraumatic stress [62]. Thus, in addition to focusing just on the health of live offspring born to parents who are cancer survivors, information on their risks to experience prolonged time to achieve pregnancy, having lower number of children, miscarriage, perinatal death, and still birth are important when counseling cancer survivors on their reproductive prospects.