2005 © Oxford University Press
Pregnancy Outcomes in Survivors of Childhood Cancer
Author affiliations: Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Correspondence to: Rajaram Nagarajan, MD, MS, Pediatric Epidemiology and Clinical Research, University of Minnesota, MMC 484, 420 Delaware St. SE, Minneapolis, MN 55455 (e-mail: nagar003{at}umn.edu).
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ABSTRACT |
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 TopNotes Abstract INTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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During the past several decades, survival rates of many childhood cancers have risen at a remarkable pace. The ever-growing population of cancer survivors is at potential risk for developing a broad spectrum of adverse outcomes relating to cancer diagnosis and treatment, including infertility, adverse pregnancy-related outcomes, and health problems of offspring. Unfortunately, these topics have not been extensively studied, particularly among pediatric cancer survivors receiving more recent therapies. Based on the current literature, therapy for childhood cancer, in general, does not appear to have a significant impact on pregnancy outcomes and on the health of offspring of childhood cancer survivors. Additional investigations, incorporating more rigorous designs, need to be conducted to further address potential long-term risks relating to birth outcomes, including birth weight. Studies currently underway to evaluate the incidence of and risk factors for birth defects, occurrence of cancer, and other serious health-related outcomes will provide valuable information to guide researchers, clinicians, and survivors and their families.
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INTRODUCTION |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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Contemporary cancer therapies have improved the overall survival from pediatric cancers to over 75% (Fig. 1). The increasing number of survivors has resulted in the call for more in-depth evaluation of the long-term effects of cancer therapy (1). There are numerous articles published examining late effects among survivors of childhood cancer (2). However, only a limited number of studies directly address the outcomes of the offspring of childhood cancer survivors. While limited in number and depth, the information available on offspring of pediatric cancer survivors exceeds that available for offspring of adult survivors of malignancies.
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Cancer and cancer therapies, including radiotherapy and certain chemotherapeutic agents, can effect pregnancy outcomes and impact the offspring by direct effects on the female reproductive tract or neuroendocrine pathways and by mutation of germ cells (3). To what extent they effect pregnancy outcomes and introduce germ-line mutations leading to adverse pregnancy outcomes, congenital abnormalities among offspring, or cancer predisposition in offspring are important questions. Answers to these questions, obtained from well-conducted studies, will inform cancer survivors of potential late effects of therapy and guide recommendations regarding appropriate follow-up.
Specific issues that have been addressed when looking at the offspring of childhood cancer survivors include the following: 1) increased adverse pregnancy outcomes in the survivors including low birth weight; 2) increased incidence of congenital abnormalities; 3) altered sex ratio; and, 4) development of cancer in the offspring. Provided below is a review of selected studies from the literature and discussion of the implications for future research.
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PREGNANCY OUTCOMES/BIRTH WEIGHT |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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There are several studies of pregnancy-related outcomes including normal live births, abortions (therapeutic and spontaneous), and abnormal births (low birth weights, prematurity and birth defects) (4–18). As would be expected, the results have varied substantially from study to study, based largely on the primary tumor and the therapy received. However, more importantly, most studies are based on small study populations and often do not reflect contemporary treatment strategies, and therefore, make it difficult to draw conclusions. Two of the larger studies addressed pregnancy outcomes among Wilms tumor survivors (4,5). Both studies reported increased frequency of low birth weight/premature birth outcomes in female survivors, while only Li et al. reported increased perinatal mortality. Both concluded that uterine radiation is a likely risk factor for adverse outcomes. These findings were subsequently corroborated in other studies (19–21). In contrast to the findings in Wilms tumor survivors, Hodgkin disease survivors were found to have fewer complications occurring in offspring (6–8,22). However, the majority of studies among Hodgkin survivors included survivors diagnosed in adulthood. They have shown that among those able to become pregnant there are minimal detrimental effects on outcomes of the pregnancies. Although some studies (6,22) have shown minimal increased frequency of stillbirths, spontaneous abortions, and congenital abnormalities, all studies were retrospective and had small numbers (average number of pregnancies is 55).
Recently, two very large studies from the Childhood Cancer Survivor Study (CCSS) examined the pregnancy outcomes of male and female childhood cancer survivors compared with a cohort of siblings of cancer survivors (23,24). Of the 4029 pregnancies among 1915 female survivors, Green et al. reported that 63% resulted in a live birth, 1% in stillbirth, 15% in miscarriage, 17% in abortions, and 3% were unknown or in gestation, whereas there were 1903 pregnancies in the sibling cohort in which 71% resulted in a live birth, 1% in a stillbirth, 15% in a miscarriage, 12% in an abortion, and 2% with an unknown outcome (Fig. 2). Within this large cohort, small but significant findings (P<0.05) included the following: 1) survivors were less likely to have a live birth than the controls, regardless of treatment history (RR ranging from 0.55 to 0.87); 2) more medical abortions were reported by survivors than in sibling across all diagnoses, except for survivors of non-Hodgkin lymphoma (RR ranging from 1.32 to 2.40); 3) pelvic and craniospinal radiation therapy appeared to carry some increased risk of miscarriage with a relative risk (RR) of 1.65 (1.05 to 2.59) and 3.63 (1.70 to 7.78), respectively; and, 4) survivors were more likely to have an infant weighing less than 2500 grams (RR = 2.05 [1.42 to 2.95]). Although differences were seen, their magnitude was small and the overall decrease in live births compared to siblings may be attributable to the increase in the number of abortions, which is suggested by the authors to be caused by "postponement of marriage (and) concern regarding risk of disease in the offspring, or other issues" (23). As seen in other studies radiation therapy also increases the likelihood of miscarriages and low-birth-weight infants. The authors attributed the influence of pelvic radiation and spinal radiation (scatter to the uterus) to radiation-induced alterations in uterine structure and function, and cranial radiation (damage to the hypothalamic–pituitary axis) as possible factors in causing miscarriages.
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In a separate publication from the CCSS, the same authors reported pregnancy outcomes of partners of male childhood cancer survivors (24). There were 1227 males who reported 2323 pregnancies, in which 69% resulted in a live birth, 1% stillbirth, 13% in miscarriage, 13% abortion, and 5% unknown, compared with 75%, 0.4%, 12%, 10%, and 2%, respectively, as seen in the sibling cohort (Fig. 2). Overall, the proportion of pregnancies that resulted in a live birth was less than that of the sibling control group (RR = 0.79 [0.65 to 0.96]). Those with testicular radiation had very few live births, while those with cranial or spinal radiation did not have an increased frequency of miscarriage. The only chemotherapeutic agent that resulted in a decrease in live births was dactinomycin, while the rate of miscarriage was only increased with procarbazine. No other alkylating agent was implicated. In terms of birth weight of offspring of partners of male childhood cancer survivors, only those treated with a non-alkylating agent were more likely to weigh less than 2500 grams. Overall, male survivors of childhood cancer did not appear to have a significantly increased frequency of adverse pregnancy outcomes; however, those treated with dactinomycin and procarbazine may warrant further study. Again, there appeared to fewer live births than the siblings and may be the result of the increased number of abortions.
Results of these two analyses from the CCSS have provided important information regarding the distribution of pregnancy outcomes occurring in pediatric cancer survivors compared to their siblings. It still remains unclear if all the observed differences are attributable to treatment-related effects versus non-treatment factors (e.g., psychosocial). There are concerns for low birth weight for certain female survivors necessitating close follow-up of these patients during their pregnancy. Cardiovascular decompensation is an additional concern for females during and after pregnancy especially following higher levels of exposure to anthracyclines and chest radiation. Additional research, however, is needed to determine a precise estimate of incidence and associated risk factors (25,26). Further follow-up of these patient cohorts will provided further verification of these findings, but additional studies, of more recently treated childhood cancer survivors, will be needed to evaluate how more contemporary therapy influences pregnancies.
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CONGENITAL ABNORMALITIES |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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In the normal population, the reported range of major and minor congenital abnormalities is 1–4% and 8–10%, respectively (27–31). Within the context of establishing accurate incidence and conducting research, issues leading to the over- and under-reporting of abnormalities can include the method by which the data were collected (passive and active reporting, physician report, parent report) and how abnormalities are defined and classified (major or minor). Given these difficulties, there are a number of studies that have attempted to look at the incidence of congenital abnormalities in the offspring of childhood cancer survivors (4–6,10–18,22,27,32–34) (Fig. 3). Most studies have shown no significant increase in the number of congenital abnormalities. Notably large studies include Byrne et al.'s study of childhood cancer survivors from the Five Center Study, which included those diagnosed and treated before 1976 (32). There were 2198 offspring of cancer survivors, with 3.4% reporting an abnormality compared to 3.1% in the control group; however, it must be noted that only 22% of the survivors received potentially mutagenic therapy. A nested case-control study was also performed to compare those who received mutagenic therapy and those who did not and showed no association. Hawkins et al. reported their findings of childhood cancer survivors born before 1963 with 80% treated before 1970 (16). They found 46 malformations in 1033 live and still births, which was similar to that expected in the general population. One additional study examined childhood cancer survivors who were diagnosed between 1960 and 1984 (17). The authors specifically investigated exposure to mutagenic chemotherapy and its relation to abnormalities. They concluded that among the 100 offspring studied, there was no substantial increase compared to previous studies. Although the reported studies have shown promising results that the mutational effects of the cancer therapy appear to have minimal, if any, effects on the next generation , the therapies reflected in the studies, in general, do not include therapies using today's chemotherapy schedules or dosing. Additionally, the diagnoses of survivors reported in these studies are not reflective of the diagnoses of survivors today, e.g., acute leukemias account for very few of the survivors treated in the previous reports. Continued research in to this area research is needed to better assess today's treatments.
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SEX RATIO |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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Alterations in sex ratio of the offspring of childhood cancer survivors are thought also to be an indicator of germ cell mutagenicity. It was thought that the mutagenic exposure, be it radiation or chemotherapy, would increase the male-to-female ratio in male cancer survivors and decrease the male-to-female ratio in female survivors due to sex-linked lethal mutations. Schull and Neel initially described an altered sex ratio in their study of the survivors of the atomic bombings of Hiroshima and Nagasaki (35). This was eventually refuted by further studies of the atomic bomb exposure in Japan (36). Additionally, several other studies of childhood cancer survivors (32,37,38) demonstrated no significant alterations in the sex ratio, including a study be Winter et al. of 1100 survivors producing 2130 children. Other large studies have produced conflicting results: One study from the CCSS reporting on the pregnancy outcomes of female survivors (23) reported no alterations of the sex ratio, while another study reporting on the outcomes of pregnancies produced by male survivors (24) reported a male-to-female ratio of 1.0 : 1.03 (versus 1.24 : 1.0 in the sibling controls). This deviates from U.S. population statistics and is significantly different from the controls. Additionally, this is in the opposite direction of the above-proposed hypothesis.
It appears that childhood cancer treatment has none to minimal influence on the sex ratio of subsequent offspring; however, the majority of cited studies of childhood cancer survivors were treated prior to the use of multiagent chemotherapy [before 1977 (37), between 1945 and 1975 (32), between 1945 and 1996 (38)] and may not reflect today's therapy and impact on the sex ratio. Interestingly, in a follow-up analysis of Byrne's and Hawkin's studies, Meistrich et al. combined their sex ratio data sets while narrowing their analyses to those who received "potentially mutagenic" therapy and found a male-to-female ratio of 0.85 (39). This was in line with the original hypothesis, but was only marginally significant and requires further investigation. This emphasizes the need for continued follow-up of children treated with more contemporary therapy to help determine how today's treatment will affect the sex ratio of the offspring.
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DEVELOPMENT OF CANCER |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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Multiple studies have investigated the incidence of cancer in offspring of childhood cancer survivors and, in the absence of known cancer predisposition syndromes (e.g., hereditary retinoblastoma, hereditary Wilms', Li–Fraumeni, Neurofibromatosis, etc.) (9–11,13,15,16,33,38,40–44), virtually all studies have found no increased risk in the development of cancer (Table 1). There are two large studies that warrant further discussion.
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In 1987, Mulvihill et al. (41) reported results from a retrospective cohort study of 2238 five-year survivors of childhood cancer diagnosed between 1945 and 1975 and over the age of 21 at the time of interview. The interview elicited information on pregnancies and the health of offspring. Also identified were cancer survivor siblings who would serve as controls. The overall observed number of cancers (n = 7) was not significantly elevated in the offspring of the cancer survivors when compared to the controls (n = 11). One of the deficiencies in this study as stated by the authors is that survivors in the study predated the use of multimodal therapy with the majority receiving surgery only.
A more recent study by Sankila et al. (44), examined the incidence of cancer in offspring of childhood cancer survivors in a large five-country cohort (Denmark, Finland, Iceland, Norway, and Sweden) that includes familial cancer syndromes and compared incidences to population data. There were 14 652 survivors who were diagnosed under the age of 20 between 1943 and 1991 and have lived to the age of 15 years. There were 44 cancers diagnosed in 5847 offspring of cancer survivors with 86 780 years of follow-up. This resulted in a standardized incidence ratio (SIR) of 2.6 (1.9–3.5), which includes familial cancers, but when offspring with familial retinoblastomas and other familial syndromes were removed there were a total of 22 malignancies with an SIR of only 1.3 (0.8–2.0). The age at diagnosis of the cancer survivor appeared predictive with those under the age of 10 years at diagnosis having an SIR of 3.9 (2.1–6.7), whereas those over the age of 10 had an SIR of 1.1 (0.6–1.8). The authors concluded that the risk of malignancy in the offspring was small and limited to survivors who were diagnosed with their cancer before the age of 10 years.
Though these studies give a consistent message that, within the absence of known genetic syndromes, there is minimal to no increased risk for cancer in offspring of childhood cancer survivors, many of the studies comment on not having long enough follow-up or sufficient number of cancer survivors to detect small increases in risk. Additionally, some of these studies reflect the cancer treatments that predate contemporary multimodal regimens and therefore do not contain many survivors with leukemia (41,42) and do not account for some of today's high-dose and more intensive regimens.
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CONCLUSIONS |
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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Overall, childhood cancer therapy does not appear to have a significant impact on pregnancy outcomes and on the health of offspring of the child cancer survivor. However, new cohorts of childhood cancer survivors representing more contemporary therapies are needed to determine if newer, more intensive therapies may appreciably alter risk. Additionally, accurate assessments of exposures, as well as prospective follow-up, will be important issues in future studies. The prospective follow-up will help ensure that information regarding pregnancies or offspring is gathered accurately (without recall bias) and may facilitate greater access to medical records. Aspects of pregnancy-related outcomes that are more difficult to assess and need more study are the "social" and "societal issues" relating to becoming pregnant (i.e., the use/incidence of assistive reproductive techniques) or maintaining a pregnancy (i.e., decision-making process for terminating pregnancies).
In order to assess the potential mutagenicity of therapy, work is currently being done to develop methods of determining biologic and genetic endpoints that are reflective of transgenerational cellular damage due to chemotherapy and radiation therapy. One measure under study is the assessment of expanded simple tandem repeats mutation rates, also called minisatellite regions (45,46). This area of research will be important, as it will allow for more rapid assessment of potentially mutagenic therapy, as opposed to waiting for follow-up assessments of survivors' offspring.
A large multinational study is currently underway to investigate, in detail, the occurrence of adverse pregnancy-related outcomes among adult survivors of childhood cancer. This investigation, directed by Dr. John Boice of the International Epidemiology Institute, uses two large cohorts of childhood cancer survivors including the Childhood Cancer Survivor Study and a Danish cohort that has been ascertained and followed through unique record-linkage capabilities and blood samples. The size of the study population, along with a study design that overcomes many of the deficiencies of earlier studies, holds great promise in providing not only more precise estimates of incidence and risk, but also new insights into biologic mechanisms.
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NOTES |
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1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
This work was supported by National Institutes of Health Grants U24-CA55727 and T32-CA09607, Bethesda, MD and the Children's Cancer Research Fund, Minneapolis, MN.
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TopNotesAbstractINTRODUCTIONPREGNANCY OUTCOMES/BIRTH WEIGHTCONGENITAL ABNORMALITIESSEX RATIODEVELOPMENT OF CANCERCONCLUSIONSReferences |
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