The purpose is to determine cancer incidence and mortality from all causes among parents of children with solid tumors and to formulate hypotheses about heritable risks and associations with parental environmental exposures. A total of 2604 children ages < 15 years included in the Manchester Children’s Tumor Registry, 1954–1996, was eligible. Parents of index children were traced and followed up to December 31, 2000, through the United Kingdom National Health Service Central Register. Data on cancer diagnosis and all causes of deaths were obtained. Standardized incidence (SIR) and standardized mortality (SMR) ratios, Ps, and 95% confidence intervals were calculated from serial age and sex-specific cancer incidence and mortality data for England and Wales. There was a significant excess of cancers in parents overall (observed number = 481, expected number = 428.9, SIR = 1.1; P < 0.05) because of central nervous system tumors (SIR = 1.7; P < 0.05), carcinoma breast (SIR = 1.3; P < 0.05), bone and soft tissue sarcoma (SIR = 2.9; P < 0.01), and retinoblastoma (SIR = 62.1; P < 0.001). Diagnoses in the index children associated with excess risk of cancer in their parents were retinoblastoma (SIR = 1.8; P < 0.01) and gonadal germ cell tumors (SIR = 2.3; P < 0.01). There was no excess risk of death from all causes considered together (observed number = 791, expected number = 814.2) nor from any specific cause. These results indicate that there is a small excess of incident cancers among parents of children with solid tumors, probably mainly because of known genes, but mortality is similar to the general population. The study is very reassuring for families of children with cancer.

Genetic epidemiological studies show that certain cancers can manifest a tendency to aggregate in families, and it is known that mutations in certain cancer-associated genes predispose to the development of both specific childhood and adult onset cancers (1). Such an inherited susceptibility to tumors has been well documented for bilateral retinoblastoma and for Li-Fraumeni syndrome, which are linked to germ-line mutations in the tumor suppressor genes Rb1 and TP53, respectively (2, 3). The possibility that other unknown genes may also be involved exists. One way to assess this is to study cancer incidence in parents of children with cancer. A study covering the period 1943–1985 linked birth registry data to the Danish Cancer Registry (4). This study found no overall excess of cancers in parents. To date, this is the only comprehensive study of cancer in parents of children with cancer, but although population based with ∼4000 children included, there were some weaknesses. Notably, the cancer incidence data on the parents were coded in ICD3 7 (5), and a broad, nonspecific classification into 14 site-based cancer groups was used. The childhood cancer data were based on original registration documents dating back to 1943, and many diagnoses would therefore have been inconsistent with current classifications. Given these limitations, specific associations between childhood and adult cancers may not have been recognized.

We have carried out a study of cancer incidence and mortality in the parents of children with solid tumors by linking the parents of children with cancer included in a specialized, comprehensive pediatric tumor registry with the United Kingdom national central registration system, which provides continuous notification of cancer registrations and causes of death, including noncancer causes.

We formulated three prior hypotheses. First, there may be excesses of specific cancers in parents of children with certain tumors because of mutations in the TP53, NF1, NF2, patched, and Rb1 genes. Second, there may be excesses of carcinoma of the lung, leukemia, and non-Hodgkin’s lymphoma in the parents as a result of exposure to cigarette smoking, hydrocarbons, and agrochemicals. Third, the pattern of mortality from noncancer causes among the parents of children with cancer may provide indications of lifestyle factors that could increase or decrease the risk of childhood cancer. To test these hypotheses, we have used comprehensive population-based cancer incidence and mortality data to examine patterns of cancer, mortality from all causes, and specific causes of death in parents of children with solid tumors and compared these with the expected patterns in the general population.

Study Subjects.

Solid tumors, including lymphomas, were selected for study because previous analyses suggest there may be a higher degree of familial clustering among these diagnostic groups than among leukemias (1, 4). The parents of 2604 children with histologically confirmed solid tumors diagnosed younger than 15 years of age, who were included in the MCTR between January 1, 1954, and December 31, 1996, were eligible.

The MCTR is described in detail elsewhere (6). A summary is provided below. The MCTR is population based and includes all cases of malignant disease in children resident in a geographically defined area of Northwest England at the time of diagnosis of their cancer. The MCTR has near complete ascertainment of cases, and reporting practice has not changed over time. A computerized record-keeping system maintains detailed clinical and pathological records on each case. In addition, histopathological slides (stained and unstained) were available on virtually all cases. These were periodically re-reviewed by a panel of pathologists and diagnoses updated to take account of developments in histopathological classification. Frozen blood and tumor samples are also stored where possible to facilitate detailed studies in line with advances in medical technology, in particular, genetic techniques.

Tumors in all case children were individually coded according to the ICD-O (7) on the basis of diagnostic slides and clinical records. This procedure avoids possible misclassification of cases that might arise as a result of applying conversion codes from earlier coding systems to ICD-O. All cases were categorized on the basis of morphology and topography codes into broad groupings as follows: HD; NHL; astrocytoma; ependymoma; PNETs; other CNS tumors; Rb; neuroblastoma; peripheral PNETs; WT; HB; osteosarcoma and chondrosarcoma; RMS; other bone and soft tissue sarcoma; gonadal GCTs; nongonadal GCTs; ACC; malignant neoplasms of skin; carcinoma (excluding of skin); other rare specified tumors; and unspecified neoplasms. The morphology and topography code allocations defining these groups and algorithms for selecting the groups are available online.4

After approval from the appropriate research ethics committees, parents of the index children were traced and followed-up to December 31, 2000, through the United Kingdom NHSCR. Each traced individual was then flagged at NHSCR to provide continuous notification of details of cancer registrations and death notifications. Information required for successful flagging includes full names (including former names), dates of birth, current and previous residential addresses, and National Health Service number. It is sometimes possible to trace and flag with less than the optimum information. Information on parents was extracted from the MCTR records, other medical records, interview data, and birth records. A database was set up for sending data to NHSCR and for recording the quarterly flagging returns, including dates of diagnosis, morphology and topography codes for cancer registrations, and dates and causes of death. Cancer diagnoses and underlying causes of deaths in parents were coded according to the contemporaneous revision of ICD-O and the ICD, respectively. The United Kingdom national cancer registration scheme is described by Quinn et al.(8).

Statistical Methods.

Expected numbers of cancers and deaths were calculated from serial age and sex-specific cancer incidence and mortality data for England and Wales applied to the similarly defined arrays of person-years at risk generated by the data. All population data were supplied by the Office for National Statistics, London, United Kingdom (9). For cancer incidence, parents entered the person-years at risk at their date of birth and left the person-years at risk on the date of cancer diagnosis, date last known to be alive, date of embarkation from the United Kingdom, or the closing date of the study, whichever was the earlier. Cancer risk was calculated from the parents’ dates of birth and not birth of the index child because a proportion of children survived malignancy even in the prechemotherapy era after treatment by surgery alone, and we wanted to allow for the possibility that some parents may have survived cancer in childhood (10). For mortality (morbidity), parents entered the person-years at risk at birth of the index child and left the person-years at risk on the date of death (diagnosis), date last known alive, date of embarkation, or the closing date of the study, whichever was the earlier. All subjects were censored on reaching their 85th birthday, i.e., they made no additional contributions to expected or observed numbers of cancers or deaths past this age. This is because the general population count is supplied by combining all those ages ≥ 85 years. If the age structure of this open-ended age group is different from that of parents, the expected and observed numbers would not be comparable. It is also thought that diagnoses and deaths were recorded with less accuracy for those over age 85 years (11), and this would make comparisons of the observed with expected numbers for a specific cancer unreliable. Parental cancers were classified into diagnostic groups using a morphology-based scheme developed for analyzing familial cancer patterns associated with childhood cancers (12). Two-sided Ps and 95% CIs of SMRs/ SIRs were computed on the assumption the observed numbers followed a Poisson distribution. All analyses have been carried out using Stata (13). Separate analyses were performed for each diagnostic group of childhood cancer, each diagnostic group in parents, or both.

A proportion of certain childhood cancers is known to be associated with germ-line mutations in specific genes, which can also predispose to adult-onset cancers. These genes include TP53, NF1, NF2, patched, and Rb1. The main childhood-onset cancers associated with mutations in these genes include CNS tumors, soft tissue sarcoma, osteosarcoma, chondrosarcoma, ACC, and retinoblastoma. The most frequent adult-onset cancers associated with such mutations are carcinoma of the breast, bone and soft tissue sarcoma, and CNS tumors (1, 2, 12). To test the extent to which these known genes might be responsible for the observed parental cancers, the parents of children with CNS tumors, bone and soft tissue sarcoma, ACC, and retinoblastoma were removed from the cohort, and the analyses repeated for parents of the remaining diagnostic groups.

Table 1 shows numbers of children eligible for the study, and the numbers of their parents traced. A total of 2604 children with solid tumors were eligible; 2288 mothers and 2204 fathers were successfully traced and flagged at NHSCR. Success rates of follow-up were 88 and 85% for mothers and fathers, respectively. Reasons for nontracing were adoption, emigration, in the armed services, or insufficient information.

Table 2 shows SIRs in parents of children with solid tumors by diagnostic group of cancer in the parents. In fathers and mothers combined, there were statistically significant excesses of: CNS tumors; SIR = 1.7 (95% CI, 1.1–2.4) P < 0.05; bone and soft tissue sarcomas SIR = 2.9 (95% CI, 1.5–4.9) P < 0.01; and retinoblastoma SIR = 62.1 (95% CI, 20.2–144.9). There was an excess of carcinoma of the stomach, SIR = 1.43 (95% CI, 0.95–2.07), which was borderline significance, P < 0.1. In mothers, there was a significant excess of carcinoma of the breast SIR = 1.3 (95% CI, 1.0–1.6) P < 0.05. Overall the SIR in mothers was 1.2 (95% CI, 1.0–1.3) P < 0.05. In fathers, the SIR was 1.1 (95% CI, 0.9–1.2), and in mothers and fathers combined the SIR was 1.1 (95% CI, 1.0–1.2) P < 0.05.

Table 3 shows SIRs in parents by diagnostic groups in children. Significant excesses of cancers in both parents were associated with retinoblastoma (SIR = 1.8; 95% CI, 1.2–2.6) and gonadal GCT (SIR = 2.3; 95% CI, 1.4–3.6) in their children. There were also excesses of cancers in mothers of children with primitive neuroectodermal tumors, osteosarcoma and chondrosarcoma, gonadal GCT, and skin cancers.

These results were consistent with our prior hypotheses about possible familial clustering associated with mutations in specific genes. We therefore divided the cohort of parents into two groups: (a) parents of children with cancers known to be associated with mutations in TP53, NF1, NF2, patched, and Rb1 (i.e., CNS tumors, soft tissue sarcoma, osteosarcoma, chondrosarcoma, ACC, and retinoblastoma); and (b) parents of children with other diagnoses. The analysis was then repeated with respect to incidence of carcinoma of the breast, bone and soft tissue sarcoma, and CNS tumors in the parents. Results are shown in Table 4. For carcinoma of the breast, there was a significant excess among mothers in group (i) but a smaller nonsignificant excess in group (ii) mothers. In mothers and fathers combined there was a significant excess of bone and soft tissue sarcoma for group (i), the ‘gene-associated’ group and a nonsignificant excess for group (ii). However, the SIR for sarcoma in mothers of children with diagnoses not known to be associated with the above genes (group ii) was significantly elevated (SIR = 3.7; 95% CI, 1.0–9.4). For CNS tumors among both parents, the highest SIR was seen for group ii (SIR = 1.9; 95% CI. 1.0–3.1), and there was also a significantly raised SIR (2.2) for fathers in this group.

The observed excess of cancers in parents of children with gonadal GCTs was not predicted, and this is examined in more detail (data not shown). Significant excesses were shown for GCTs (based on 1 case), SIR = 90.3 (95% CI, 2.3–503.3) and melanoma (based on 2 cases), SIR = 14.3 (95% CI, 1.7–51.8) P < 0.05 in mothers and carcinoma of the prostate in fathers (based on 3 cases), SIR = 9.6 (95% CI, 2.0–27.9) P < 0.01. In fathers and mothers combined, there was a significant excess of carcinoma of the kidney (based on 2 cases), SIR = 10.9 (95% CI, 1.3–39.3) P < 0.01.

Table 5 shows the SMRs by cause of death. Overall, the O of deaths from all causes is close to the expected (O = 791, E = 814.2, SMR = 0.97; 95% CI, 0.91–1.04). There was no significant excess mortality from any specific cancer or all cancers (O = 269, E = 268.9, SMR = 1.0; 95% CI, 0.9–1.1). Similarly, there was no excess mortality from noncancer causes of death (O = 522, E = 545.3, SMR = 0.96; 95% CI, 0.88–1.04). However, there were significant deficits of deaths from diseases of the nervous system, SMR = 0.4 (95% CI, 0.2–0.9) and suicide SMR = 0.3 (95 CI, 0.1–0.8).

We set out to explore three prior hypotheses. Our first hypothesis concerned the role of mutations in certain specified genes. The results indicate that overall there is a small excess cancer risk among parents of children with solid tumors mainly because of CNS tumors, carcinoma breast, bone and soft tissue sarcoma, and retinoblastoma. Mutations in known genes such as Rb1, TP53, patched, NF1, and NF2 may account for most of this excess. However, novel associations were also found for parents of children with gonadal GCT in that they have excess cancer risk in general and specifically in prostate, kidney, and melanoma.

This is unlikely to be explained by chance because of selection in the ascertainment procedure (14) because in this population-based study, a near complete ascertainment of children with solid tumors in a well-defined geographical area was achieved. In addition, the observed excesses were associated with specific diagnostic groups. Neither can these excesses be explained by the healthy parent effect, by analogy with the healthy worker effect (15, 16), whereby the cohort of parents may experience a lower morbidity than the general population because these individuals must be reproductively fit (17). If anything, this would bias the SMR/SIR in the opposite direction. Furthermore, there is no reporting bias because all data were obtained from population registries. This may represent a new multiple cancer syndrome, and the most biologically feasible interpretation would be inherited mutations in an unknown gene transmitted from a carrier parent. However, numbers of cases in this group are small, and a chance association cannot be ruled out. Confirmation of this finding in an independent dataset is required.

Li (18) pointed out that inherited cancer genes are the most potent oncogenic influence in humans, exceeding the effects of such environmental agents as ionizing radiation, tobacco, and occupational carcinogens. Although mutations in known genes, including TP53, NF1, NF2, patched, and Rb1, may account for a substantial part of the excess cancer risk, other unknown genes may also be contributing to the development of cancers in parents of children with certain diagnoses other than GCTs. It has been demonstrated recently that germ-line mutations to TP53 predispose to a specific spectrum of mainly rare cancers (12). Such mutations are unlikely to account for the excess of CNS tumors in parents of children with types of cancers not known to be associated with germ-line TP53 mutations. Other genes associated with increased risk of specific childhood cancers, e.g., WT1 are not known to predispose to adult-onset cancers. It is possible, therefore, that rare predisposing mutations in an unknown gene or genes may be present in a few families.

Certain parental environmental exposures may increase the risk of cancer in offspring. Our second hypothesis proposed that parental exposures to such environmental agents might result in increased cancer risks in the parents as well as their offspring. Three such exposures that have been most consistently linked with childhood cancer risk are parental smoking behavior and occupational exposures to hydrocarbons (especially vehicle related) and agrochemicals (especially pesticides; Refs. 19, 20, 21, 22, 23). Such exposures may also lead to increased risk of lung cancer, leukemia, and lymphoma in the parents themselves (24, 25, 26). We therefore hypothesized that there may be an excess of specific cancers in the parents of children with cancer because of the relevant exposures. Such excesses of cancers in parents would support an etiological role for the corresponding environmental agents in childhood cancer.

However, this study does not provide evidence that parental tobacco use and parental occupational exposures to hydrocarbons and agrochemicals are risk factors for childhood solid tumors because we did not find excess carcinoma of the lung in parents and similarly, we failed to detect excesses of leukemia and lymphoma. We cannot reject the possibility of links between such parental exposures and risk of childhood cancer, but the present results do not support our prior hypothesis.

Our third hypothesis was that the pattern of mortality from noncancer causes among parents of children with cancer might indicate lifestyle factors that could influence childhood cancer risk. However, with respect to mortality, this study does not suggest that families of children with cancer experience greater mortality than the rest of the population. The observed number of deaths overall is close to that expected in the general population, and there were deficits of deaths from nervous system diseases and suicide. Although having a child with cancer or the death of a child because of cancer is a severe adverse life event that could increase the likelihood of suicide (27), the deficit of deaths from suicide suggests that this is not the case. However, in the general population, reasons for suicide include other life events such as divorce, separation, and unemployment. We do not have information about such life events in our cohort.

This study has a number of advantages over previous studies. Data on childhood cases were population based with near complete ascertainment in a geographically defined area. Although the study covers nearly half a century, histopathological material was available for review, and cases were classified according to current criteria. Adult onset cancers in parents were also derived from population-based data, and a good follow-up rate was achieved. Furthermore, in the United Kingdom national cancer registration system, cancers are classified by morphology as well as site. Information for both the observed and expected cancers in the parents was derived from the same source. Thus, ascertainment bias and information bias were unlikely. In addition, uniquely, the study has examined deaths from all causes, including noncancer causes and, therefore, provided an opportunity to explore shared environmental and lifestyle hypotheses and to assess the general health of the parental cohort in terms of general mortality rate.

In conclusion, we found a small excess cancer risk in parents of children with solid tumors, including novel associations in certain subgroups. Additional pedigree studies and in molecular studies among selected members of the families may clarify this aspect. This study lends additional credence to the hypothesis that familial factors play a role in the etiology of childhood tumors, but high penetrance mutations in cancer-associated genes probably account for a small percentage of cases only. Overall, the parents of children with cancer do not experience poorer health than the general population in terms of mortality from any specific cause. These results are very reassuring for families of children with cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

The project is supported by Cancer Research UK.

3

The abbreviations used are: ICD, International Classification of Diseases; MCTR, Manchester Children’s Tumor Registry; NHSCR, National Health Service Central Register; HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma; PNET, primitive neuroectodermal tumor; CNS, central nervous system; Rb, retinoblastoma; ACC, adrenocortical carcinoma; WT, Wilms’ tumor; HB, hepatoblastoma; RMS, rhabdomyosarcoma; CI, confidence interval; SMR, standardized mortality ratio; SIR, standardized incidence ratio; O, observed number; E, expected number.

4

Internet address: http://www.biomed2.man.ac.uk/crcpfcrg/CRUKPFCRG/PFCRG.htm.

Table 1

Numbers of eligible children and traced parentsa

Diagnostic group in the index childChildrenMothersFathers
HD 163 152 144 
NHL 190 159 156 
Astrocytoma 406 327 303 
Ependymoma 103 81 77 
PNETs 188 183 183 
Other CNS tumors 162 105 100 
Rb 124 100 95 
Neuroblastoma 274 246 232 
Peripheral neuroectodermal tumors 87 86 86 
WT 223 219 214 
HB 31 31 31 
Osteosarcoma and chondrosarcoma 113 107 104 
RMS 148 146 143 
Other bone and soft tissue sarcoma 80 74 74 
Gonadal GCT 53 50 50 
Nongonadal GCT 74 74 70 
ACC 12 11 11 
Malignant neoplasms of skin 33 26 26 
Other carcinoma excluding skin 65 45 43 
Other rare specified tumors 28 27 26 
Unspecified neoplasms 47 39 36 
Total 2604 2288 2204 
Diagnostic group in the index childChildrenMothersFathers
HD 163 152 144 
NHL 190 159 156 
Astrocytoma 406 327 303 
Ependymoma 103 81 77 
PNETs 188 183 183 
Other CNS tumors 162 105 100 
Rb 124 100 95 
Neuroblastoma 274 246 232 
Peripheral neuroectodermal tumors 87 86 86 
WT 223 219 214 
HB 31 31 31 
Osteosarcoma and chondrosarcoma 113 107 104 
RMS 148 146 143 
Other bone and soft tissue sarcoma 80 74 74 
Gonadal GCT 53 50 50 
Nongonadal GCT 74 74 70 
ACC 12 11 11 
Malignant neoplasms of skin 33 26 26 
Other carcinoma excluding skin 65 45 43 
Other rare specified tumors 28 27 26 
Unspecified neoplasms 47 39 36 
Total 2604 2288 2204 
a

A total of 716 parents is untraced because of (a) insufficient information such as no name, no date of birth, and so on, and (b) “out” category from ONS, including adoption, emigration, in prison, and in the armed forces.

Table 2

Standardized incidence ratios in parents of children with solid tumors by diagnostic groups in parents

Diagnostic groups in parentsMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
Leukemia 4.4 0.7 0.1 2.0 6.7 0.4 0.1 1.3 11.0 0.5 0.2 1.2 
Lymphoma 7.6 0.8 0.3 1.7 10 11.0 0.9 0.4 1.7 16 18.6 0.9 0.5 1.4 
CNS tumors 11 6.9 1.6 0.8 2.8 14 8.2 1.7 0.9 2.9 25 15.1 1.7a 1.1 2.4 
Carcinoma breast 95 73.5 1.3a 1.0 1.6 0.0 0.0   95 73.5 1.3a 1.0 1.6 
Carcinoma lung 24 20.9 1.1 0.7 1.7 51 58.0 0.9 0.7 1.2 75 78.9 1.0 0.7 1.2 
Carcinoma colorectal 16 21.5 0.7 0.4 1.2 28 29.2 1.0 0.6 1.4 44 50.7 0.9 0.6 1.2 
Carcinoma stomach 5.4 1.5 0.6 2.9 20 14.1 1.4 0.9 2.2 28 19.5 1.4 1.0 2.1 
Carcinoma bladder 4.7 0.6 0.1 1.9 13 16.4 0.8 0.4 1.4 16 21.1 0.8 0.4 1.2 
Carcinoma cervix 13.3 0.7 0.3 1.3 0.0 0.0   13.3 0.7 0.3 1.3 
Carcinoma ovary 10 12.9 0.8 0.4 1.4 0.0 0.0   10 12.9 0.8 0.4 1.4 
Carcinoma prostate 0.0 0.0   26 18.9 1.4 0.9 2.0 26 18.9 1.4 0.9 2.0 
Carcinoma pancreas 4.4 0.2 0.0 1.3 6.6 0.8 0.2 1.8 11.0 0.5 0.2 1.2 
Carcinoma uterus 10 9.0 1.1 0.5 2.0 0.0 0.0   10 9.0 1.1 0.5 2.0 
Carcinoma esophagus 3.0 1.4 0.4 3.5 10 6.4 1.6 0.7 2.9 14 9.4 1.5 0.8 2.5 
Carcinoma kidney 2.9 1.0 0.2 3.1 6.0 0.7 0.2 1.7 8.9 0.8 0.3 1.6 
Carcinoma head and neck 3.7 1.9 0.8 3.9 14 10.4 1.3 0.7 2.3 21 14.1 1.5 0.9 2.3 
Carcinoma other sites 11 8.3 1.3 0.7 2.4 8.6 0.8 0.3 1.7 18 16.9 1.1 0.6 1.7 
GCTs 0.5 1.9 0.0 10.8 4.0 0.5 0.1 1.8 4.5 0.7 0.1 1.9 
Bone and soft tissue sarcoma 2.2 3.2a 1.3 6.5 2.3 2.6 0.9 5.6 13 4.5 2.9b 1.5 4.9 
Melanoma 6.6 1.4 0.6 2.6 4.4 0.7 0.1 2.0 12 11.0 1.1 0.6 1.9 
Myeloma 2.0 1.0 0.1 3.6 3.1 1.0 0.2 2.8 5.1 1.0 0.3 2.3 
Rb 0.0 45.5b 5.5 164.4 0.0 82.0c 16.9 239.6 0.1 62.1c 20.2 144.9 
Other specified cancers 3.0 1.0 0.2 2.9 3.7 0.5 0.1 1.9 6.7 0.7 0.2 1.7 
Unspecified cancers 3.8 1.3 0.4 3.1 4.9 1.4 0.6 3.0 12 8.7 1.4 0.7 2.4 
All 250 212.4 1.2a 1.0 1.3 231 216.5 1.1 0.9 1.2 481 428.9 1.1a 1.0 1.2 
Diagnostic groups in parentsMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
Leukemia 4.4 0.7 0.1 2.0 6.7 0.4 0.1 1.3 11.0 0.5 0.2 1.2 
Lymphoma 7.6 0.8 0.3 1.7 10 11.0 0.9 0.4 1.7 16 18.6 0.9 0.5 1.4 
CNS tumors 11 6.9 1.6 0.8 2.8 14 8.2 1.7 0.9 2.9 25 15.1 1.7a 1.1 2.4 
Carcinoma breast 95 73.5 1.3a 1.0 1.6 0.0 0.0   95 73.5 1.3a 1.0 1.6 
Carcinoma lung 24 20.9 1.1 0.7 1.7 51 58.0 0.9 0.7 1.2 75 78.9 1.0 0.7 1.2 
Carcinoma colorectal 16 21.5 0.7 0.4 1.2 28 29.2 1.0 0.6 1.4 44 50.7 0.9 0.6 1.2 
Carcinoma stomach 5.4 1.5 0.6 2.9 20 14.1 1.4 0.9 2.2 28 19.5 1.4 1.0 2.1 
Carcinoma bladder 4.7 0.6 0.1 1.9 13 16.4 0.8 0.4 1.4 16 21.1 0.8 0.4 1.2 
Carcinoma cervix 13.3 0.7 0.3 1.3 0.0 0.0   13.3 0.7 0.3 1.3 
Carcinoma ovary 10 12.9 0.8 0.4 1.4 0.0 0.0   10 12.9 0.8 0.4 1.4 
Carcinoma prostate 0.0 0.0   26 18.9 1.4 0.9 2.0 26 18.9 1.4 0.9 2.0 
Carcinoma pancreas 4.4 0.2 0.0 1.3 6.6 0.8 0.2 1.8 11.0 0.5 0.2 1.2 
Carcinoma uterus 10 9.0 1.1 0.5 2.0 0.0 0.0   10 9.0 1.1 0.5 2.0 
Carcinoma esophagus 3.0 1.4 0.4 3.5 10 6.4 1.6 0.7 2.9 14 9.4 1.5 0.8 2.5 
Carcinoma kidney 2.9 1.0 0.2 3.1 6.0 0.7 0.2 1.7 8.9 0.8 0.3 1.6 
Carcinoma head and neck 3.7 1.9 0.8 3.9 14 10.4 1.3 0.7 2.3 21 14.1 1.5 0.9 2.3 
Carcinoma other sites 11 8.3 1.3 0.7 2.4 8.6 0.8 0.3 1.7 18 16.9 1.1 0.6 1.7 
GCTs 0.5 1.9 0.0 10.8 4.0 0.5 0.1 1.8 4.5 0.7 0.1 1.9 
Bone and soft tissue sarcoma 2.2 3.2a 1.3 6.5 2.3 2.6 0.9 5.6 13 4.5 2.9b 1.5 4.9 
Melanoma 6.6 1.4 0.6 2.6 4.4 0.7 0.1 2.0 12 11.0 1.1 0.6 1.9 
Myeloma 2.0 1.0 0.1 3.6 3.1 1.0 0.2 2.8 5.1 1.0 0.3 2.3 
Rb 0.0 45.5b 5.5 164.4 0.0 82.0c 16.9 239.6 0.1 62.1c 20.2 144.9 
Other specified cancers 3.0 1.0 0.2 2.9 3.7 0.5 0.1 1.9 6.7 0.7 0.2 1.7 
Unspecified cancers 3.8 1.3 0.4 3.1 4.9 1.4 0.6 3.0 12 8.7 1.4 0.7 2.4 
All 250 212.4 1.2a 1.0 1.3 231 216.5 1.1 0.9 1.2 481 428.9 1.1a 1.0 1.2 
a

P < 0.05.

b

P < 0.01.

c

P < 0.001.

Table 3

Standardized incidence ratios in parents of children with solid tumors by diagnostic groups in children

Diagnostic groups in childrenMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
HD 18 16.6 1.1 0.6 1.7 10 18.9 0.5a 0.3 1.0 28 35.4 0.8 0.5 1.1 
NHL 15 15.0 1.0 0.6 1.6 18 16.3 1.1 0.7 1.7 33 31.4 1.1 0.7 1.5 
Astrocytoma 23 34.0 0.7 0.4 1.0 39 30.0 1.3 0.9 1.8 62 64.0 1.0 0.7 1.2 
Ependymoma 7.9 0.9 0.4 1.8 10 6.9 1.4 0.7 2.7 17 14.9 1.1 0.7 1.8 
PNETs 26 16.4 1.6a 1.0 2.3 17 18.3 0.9 0.5 1.5 43 34.7 1.2 0.9 1.7 
Other CNS tumors 11 9.1 1.2 0.6 2.2 10.3 0.9 0.4 1.7 20 19.4 1.0 0.6 1.6 
Rb 13 7.9 1.6 0.9 2.8 14 7.1 2.0a 1.1 3.3 27 15.0 1.8b 1.2 2.6 
Neuroblastoma 19 18.8 1.0 0.6 1.6 17 17.4 1.0 0.6 1.6 36 36.2 1.0 0.7 1.4 
Peripheral neuroectodermal tumors 10.7 0.7 0.3 1.5 17 11.4 1.5 0.9 2.4 25 22.2 1.1 0.7 1.7 
WT 19 17.2 1.1 0.7 1.7 15 18.6 0.8 0.5 1.3 34 35.8 1.0 0.7 1.3 
HB 1.4 2.9 0.8 7.4 1.6 0.6 0.0 3.5 3.0 1.7 0.5 3.9 
Osteosarcoma and chondrosarcoma 23 13.2 1.7a 1.1 2.6 14 14.8 0.9 0.5 1.6 37 28.1 1.3 0.9 1.8 
RMS 17 13.0 1.3 0.8 2.1 17 12.8 1.3 0.8 2.1 34 25.8 1.3 0.9 1.8 
Other bone and soft tissue sarcoma 7.5 1.1 0.5 2.1 7.7 1.2 0.5 2.2 17 15.1 1.1 0.7 1.8 
Gonadal GCT 12 3.8 3.1b 1.6 5.4 4.3 1.6 0.6 3.3 19 8.2 2.3b 1.4 3.6 
Nongonadal GCT 5.7 0.5 0.1 1.5 5.4 1.1 0.4 2.4 11.1 0.8 0.4 1.5 
ACC 0.8 3.6 0.8 10.6 0.9 2.1 0.3 7.6 1.8 2.8 0.9 6.6 
Malignant neoplasms of skin 2.0 3.5b 1.4 7.1 2.3 0.9 0.1 3.2 4.3 2.1 1.0 4.0 
Other carcinoma excluding skin 4.4 1.8 0.8 3.6 4.3 0.9 0.3 2.4 12 8.7 1.4 0.7 2.4 
Other rare specified tumors 1.9 1.6 0.3 4.6 1.8 0.0   3.7 0.8 0.2 2.4 
Unspecified neoplasms 5.2 1.1 0.4 2.5 5.4 0.9 0.3 2.1 11 10.7 1.0 0.5 1.8 
Total 250 212.4 1.2a 1.0 1.3 231 216.5 1.1 0.9 1.2 481 428.9 1.1a 1.0 1.2 
Diagnostic groups in childrenMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
HD 18 16.6 1.1 0.6 1.7 10 18.9 0.5a 0.3 1.0 28 35.4 0.8 0.5 1.1 
NHL 15 15.0 1.0 0.6 1.6 18 16.3 1.1 0.7 1.7 33 31.4 1.1 0.7 1.5 
Astrocytoma 23 34.0 0.7 0.4 1.0 39 30.0 1.3 0.9 1.8 62 64.0 1.0 0.7 1.2 
Ependymoma 7.9 0.9 0.4 1.8 10 6.9 1.4 0.7 2.7 17 14.9 1.1 0.7 1.8 
PNETs 26 16.4 1.6a 1.0 2.3 17 18.3 0.9 0.5 1.5 43 34.7 1.2 0.9 1.7 
Other CNS tumors 11 9.1 1.2 0.6 2.2 10.3 0.9 0.4 1.7 20 19.4 1.0 0.6 1.6 
Rb 13 7.9 1.6 0.9 2.8 14 7.1 2.0a 1.1 3.3 27 15.0 1.8b 1.2 2.6 
Neuroblastoma 19 18.8 1.0 0.6 1.6 17 17.4 1.0 0.6 1.6 36 36.2 1.0 0.7 1.4 
Peripheral neuroectodermal tumors 10.7 0.7 0.3 1.5 17 11.4 1.5 0.9 2.4 25 22.2 1.1 0.7 1.7 
WT 19 17.2 1.1 0.7 1.7 15 18.6 0.8 0.5 1.3 34 35.8 1.0 0.7 1.3 
HB 1.4 2.9 0.8 7.4 1.6 0.6 0.0 3.5 3.0 1.7 0.5 3.9 
Osteosarcoma and chondrosarcoma 23 13.2 1.7a 1.1 2.6 14 14.8 0.9 0.5 1.6 37 28.1 1.3 0.9 1.8 
RMS 17 13.0 1.3 0.8 2.1 17 12.8 1.3 0.8 2.1 34 25.8 1.3 0.9 1.8 
Other bone and soft tissue sarcoma 7.5 1.1 0.5 2.1 7.7 1.2 0.5 2.2 17 15.1 1.1 0.7 1.8 
Gonadal GCT 12 3.8 3.1b 1.6 5.4 4.3 1.6 0.6 3.3 19 8.2 2.3b 1.4 3.6 
Nongonadal GCT 5.7 0.5 0.1 1.5 5.4 1.1 0.4 2.4 11.1 0.8 0.4 1.5 
ACC 0.8 3.6 0.8 10.6 0.9 2.1 0.3 7.6 1.8 2.8 0.9 6.6 
Malignant neoplasms of skin 2.0 3.5b 1.4 7.1 2.3 0.9 0.1 3.2 4.3 2.1 1.0 4.0 
Other carcinoma excluding skin 4.4 1.8 0.8 3.6 4.3 0.9 0.3 2.4 12 8.7 1.4 0.7 2.4 
Other rare specified tumors 1.9 1.6 0.3 4.6 1.8 0.0   3.7 0.8 0.2 2.4 
Unspecified neoplasms 5.2 1.1 0.4 2.5 5.4 0.9 0.3 2.1 11 10.7 1.0 0.5 1.8 
Total 250 212.4 1.2a 1.0 1.3 231 216.5 1.1 0.9 1.2 481 428.9 1.1a 1.0 1.2 
a

P < 0.05.

b

P < 0.01.

Table 4

Risks of carcinoma breast, sarcoma and CNS tumors in parents of children with tumors known or not known to be associated with specified genes

Cancer in parentsGenes associated childhood tumorsMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
Breast                
 (i) knownc 53 35.2 1.5b 1.1 2.0 0.0 0.0   53 35.2 1.5b 1.1 2.0 
 (ii) not knownd 44 38.5 1.1 0.8 1.5 0.0 0.0   44 38.5 1.1 0.8 1.5 
Sarcoma                
 (i) knowne 1.1 2.6 0.5 7.7 1.2 4.3a 1.4 10.1 2.3 3.5b 1.5 6.9 
 (ii) not knownd 1.1 3.7 1.0 9.4 1.2 0.9 0.0 4.7 2.3 2.2 0.7 5.1 
CNS                
 (i) knowne 3.5 1.7 0.6 3.7 4.1 1.5 0.5 3.2 12 7.6 1.6 0.8 2.8 
 (ii) not knownd 3.4 1.5 0.5 3.4 4.1 2.2a 1.0 4.2 14 7.5 1.9a 1.0 3.1 
All cancer                
 (i) knowne 131 109.8 1.2 1.0 1.4 131 108.8 1.2a 1.0 1.4 262 218.8 1.2b 1.1 1.4 
 (ii) not knownd 122 102.7 1.2 1.0 1.4 102 107.7 0.9 0.8 1.1 224 210.7 1.1 0.9 1.2 
Cancer in parentsGenes associated childhood tumorsMotherFatherFather and mother
OESIR95% CIOESIR95% CIOESIR95% CI
Breast                
 (i) knownc 53 35.2 1.5b 1.1 2.0 0.0 0.0   53 35.2 1.5b 1.1 2.0 
 (ii) not knownd 44 38.5 1.1 0.8 1.5 0.0 0.0   44 38.5 1.1 0.8 1.5 
Sarcoma                
 (i) knowne 1.1 2.6 0.5 7.7 1.2 4.3a 1.4 10.1 2.3 3.5b 1.5 6.9 
 (ii) not knownd 1.1 3.7 1.0 9.4 1.2 0.9 0.0 4.7 2.3 2.2 0.7 5.1 
CNS                
 (i) knowne 3.5 1.7 0.6 3.7 4.1 1.5 0.5 3.2 12 7.6 1.6 0.8 2.8 
 (ii) not knownd 3.4 1.5 0.5 3.4 4.1 2.2a 1.0 4.2 14 7.5 1.9a 1.0 3.1 
All cancer                
 (i) knowne 131 109.8 1.2 1.0 1.4 131 108.8 1.2a 1.0 1.4 262 218.8 1.2b 1.1 1.4 
 (ii) not knownd 122 102.7 1.2 1.0 1.4 102 107.7 0.9 0.8 1.1 224 210.7 1.1 0.9 1.2 
a

P < 0.05.

b

P < 0.01.

c

Known tumors refer to LFS- and Rb-associated childhood tumors, including CNS, RMS, osteosarcoma + chondrosarcoma, ACC, and Rb.

d

Not known tumors refers to the rest of tumors after removing (a) or (d), respectively.

e

Known tumors refer to LFS, Rb1, NF1 and NF2 associated childhood tumors, including CNS, bone and soft tissue sarcoma, osteosarcoma + chondrosarcoma, ACC, and Rb.

Table 5

SMR in parents of children with solid tumors

CausesICD-9MotherFatherFather and mother
OESMR95% CIOESMR95% CIOESMR95% CI
All neoplasms: 140–239 123 117.3 1.0 0.9 1.3 146 151.6 1.0 0.8 1.1 269 268.9 1.0 0.9 1.1 
 Leukemia 204–208 2.8 1.1 0.2 3.2 4.0 0.3 0.0 1.4 6.7 0.6 0.2 1.5 
 Lymphoma 200–202 3.3 0.6 0.1 2.2 5.2 1.3 0.5 2.8 8.5 1.1 0.5 2.0 
 CNS a 3.7 1.1 0.3 2.8 10 5.4 1.9 0.9 3.4 14 9.1 1.5 0.8 2.6 
 Breast 174 35 28.7 1.2 0.8 1.7 0.0 0.0   35 28.7 1.2 0.8 1.7 
 Lung 162 18 18.8 1.0 0.6 1.5 41 50.6 0.8 0.6 1.1 59 69.4 0.9 0.6 1.1 
 Colorectal 153–154 11.6 0.5 0.2 1.1 14 16.5 0.8 0.5 1.4 20 28.1 0.7 0.4 1.1 
 Stomach 151 4.3 1.6 0.7 3.4 14 11.2 1.3 0.7 2.1 21 15.5 1.4 0.8 2.1 
 Bladder 188 1.6 1.8 0.4 5.3 5.2 0.8 0.2 2.0 6.8 1.0 0.4 2.1 
 Cervix 180 5.0 0.8 0.2 2.1 0.0 0.0   5.0 0.8 0.2 2.1 
 Ovary/testis 183, 186 9.3 1.0 0.4 1.8 0.6 0.0   9.9 0.9 0.4 1.7 
 Prostate 185 0.0 0.0   12 9.6 1.3 0.6 2.2 12 9.6 1.3 0.6 2.2 
 Pancreas 157 4.4 0.2 0.0 1.3 6.5 0.8 0.3 1.8 10.8 0.6 0.2 1.2 
 Uterus 179, 182 2.3 1.7 0.5 4.4 0.0 0.0   2.3 1.7 0.5 4.4 
 Esophagus 150 2.7 1.5 0.4 3.8 6.7 1.2 0.5 2.4 12 9.4 1.3 0.7 2.2 
 Kidney 1890 1.6 0.0   3.4 0.3 0.0 1.6 5.0 0.2 0.0 1.1 
 Head and neck b 2.0 1.5 0.3 4.5 4.6 1.3 0.5 2.8 6.6 1.4 0.6 2.6 
 Bone and soft tissue 158, 170–171 1.0 1.0 0.0 5.8 1.3 3.1 0.8 7.9 2.3 2.2 0.7 5.2 
 Melanoma 172 1.5 0.7 0.0 3.8 1.5 0.7 0.0 3.6 3.0 0.7 0.1 2.4 
 Myeloma 203 1.5 0.7 0.0 3.8 2.1 1.0 0.1 3.5 3.5 0.8 0.2 2.5 
 Others c 18 11.8 1.5 0.9 2.4 13 17.2 0.8 0.4 1.3 31 29.0 1.1 0.7 1.5 
Noncancers:                 
 Infective 1–139 2.6 1.1 0.2 3.4 4.1 0.7 0.2 2.1 6.7 0.9 0.3 1.9 
 Endocrine 240–279 5.1 1.4 0.6 2.8 6.5 1.1 0.4 2.2 14 11.5 1.2 0.7 2.0 
 Blood 280–289 1.0 1.0 0.0 5.5 1.2 0.0   2.2 0.4 0.0 2.5 
 Mental 290–319 2.6 1.2 0.2 3.4 3.0 0.7 0.1 2.4 5.6 0.9 0.3 2.1 
 Nervous system 320–389 6.5 0.8 0.2 1.8 8.0 0.1d 0.0 0.7 14.5 0.4e 0.2 0.9 
 Circulatory system 390–459 103 106.7 1.0 0.8 1.2 221 230.6 1.0 0.8 1.1 324 337.4 1.0 0.9 1.1 
 Respiratory system 460–519 24 28.7 0.8 0.5 1.2 60 49.1 1.2 0.9 1.6 84 77.8 1.1 0.9 1.3 
 Digestive system 520–579 14 11.7 1.2 0.7 2.0 19 16.0 1.2 0.7 1.9 33 27.7 1.2 0.8 1.7 
 Genitourinary system 580–629 3.7 1.9 0.8 3.9 4.7 1.1 0.3 2.5 12 8.4 1.4 0.7 2.5 
 Skin 680–709 0.4 2.5 0.1 14.0 0.3 0.0   0.7 1.4 0.0 8.0 
 Musculoskeletal 710–739 2.5 0.0   1.4 2.1 0.4 6.2 3.9 0.8 0.2 2.3 
 Signs and symptoms 780–799 0.8 1.2 0.0 6.8 1.0 3.0 0.6 8.9 1.8 2.2 0.6 5.7 
 Accidents 800–949 6.6 0.5 0.1 1.3 14 16.4 0.9 0.5 1.4 17 23.0 0.7 0.4 1.2 
 Suicide 950–959 4.1 0.2 0.0 1.3 8.6 0.3 0.1 1.0 12.8 0.3d 0.1 0.8 
 Others  5.0 0.2 0.0 1.1 6.1 0.8 0.3 1.9 11.1 0.5 0.2 1.2 
All causes  299 305.0 1.0 0.9 1.1 492 509.1 1.0 0.9 1.1 791 814.2 0.97 0.91 1.04 
CausesICD-9MotherFatherFather and mother
OESMR95% CIOESMR95% CIOESMR95% CI
All neoplasms: 140–239 123 117.3 1.0 0.9 1.3 146 151.6 1.0 0.8 1.1 269 268.9 1.0 0.9 1.1 
 Leukemia 204–208 2.8 1.1 0.2 3.2 4.0 0.3 0.0 1.4 6.7 0.6 0.2 1.5 
 Lymphoma 200–202 3.3 0.6 0.1 2.2 5.2 1.3 0.5 2.8 8.5 1.1 0.5 2.0 
 CNS a 3.7 1.1 0.3 2.8 10 5.4 1.9 0.9 3.4 14 9.1 1.5 0.8 2.6 
 Breast 174 35 28.7 1.2 0.8 1.7 0.0 0.0   35 28.7 1.2 0.8 1.7 
 Lung 162 18 18.8 1.0 0.6 1.5 41 50.6 0.8 0.6 1.1 59 69.4 0.9 0.6 1.1 
 Colorectal 153–154 11.6 0.5 0.2 1.1 14 16.5 0.8 0.5 1.4 20 28.1 0.7 0.4 1.1 
 Stomach 151 4.3 1.6 0.7 3.4 14 11.2 1.3 0.7 2.1 21 15.5 1.4 0.8 2.1 
 Bladder 188 1.6 1.8 0.4 5.3 5.2 0.8 0.2 2.0 6.8 1.0 0.4 2.1 
 Cervix 180 5.0 0.8 0.2 2.1 0.0 0.0   5.0 0.8 0.2 2.1 
 Ovary/testis 183, 186 9.3 1.0 0.4 1.8 0.6 0.0   9.9 0.9 0.4 1.7 
 Prostate 185 0.0 0.0   12 9.6 1.3 0.6 2.2 12 9.6 1.3 0.6 2.2 
 Pancreas 157 4.4 0.2 0.0 1.3 6.5 0.8 0.3 1.8 10.8 0.6 0.2 1.2 
 Uterus 179, 182 2.3 1.7 0.5 4.4 0.0 0.0   2.3 1.7 0.5 4.4 
 Esophagus 150 2.7 1.5 0.4 3.8 6.7 1.2 0.5 2.4 12 9.4 1.3 0.7 2.2 
 Kidney 1890 1.6 0.0   3.4 0.3 0.0 1.6 5.0 0.2 0.0 1.1 
 Head and neck b 2.0 1.5 0.3 4.5 4.6 1.3 0.5 2.8 6.6 1.4 0.6 2.6 
 Bone and soft tissue 158, 170–171 1.0 1.0 0.0 5.8 1.3 3.1 0.8 7.9 2.3 2.2 0.7 5.2 
 Melanoma 172 1.5 0.7 0.0 3.8 1.5 0.7 0.0 3.6 3.0 0.7 0.1 2.4 
 Myeloma 203 1.5 0.7 0.0 3.8 2.1 1.0 0.1 3.5 3.5 0.8 0.2 2.5 
 Others c 18 11.8 1.5 0.9 2.4 13 17.2 0.8 0.4 1.3 31 29.0 1.1 0.7 1.5 
Noncancers:                 
 Infective 1–139 2.6 1.1 0.2 3.4 4.1 0.7 0.2 2.1 6.7 0.9 0.3 1.9 
 Endocrine 240–279 5.1 1.4 0.6 2.8 6.5 1.1 0.4 2.2 14 11.5 1.2 0.7 2.0 
 Blood 280–289 1.0 1.0 0.0 5.5 1.2 0.0   2.2 0.4 0.0 2.5 
 Mental 290–319 2.6 1.2 0.2 3.4 3.0 0.7 0.1 2.4 5.6 0.9 0.3 2.1 
 Nervous system 320–389 6.5 0.8 0.2 1.8 8.0 0.1d 0.0 0.7 14.5 0.4e 0.2 0.9 
 Circulatory system 390–459 103 106.7 1.0 0.8 1.2 221 230.6 1.0 0.8 1.1 324 337.4 1.0 0.9 1.1 
 Respiratory system 460–519 24 28.7 0.8 0.5 1.2 60 49.1 1.2 0.9 1.6 84 77.8 1.1 0.9 1.3 
 Digestive system 520–579 14 11.7 1.2 0.7 2.0 19 16.0 1.2 0.7 1.9 33 27.7 1.2 0.8 1.7 
 Genitourinary system 580–629 3.7 1.9 0.8 3.9 4.7 1.1 0.3 2.5 12 8.4 1.4 0.7 2.5 
 Skin 680–709 0.4 2.5 0.1 14.0 0.3 0.0   0.7 1.4 0.0 8.0 
 Musculoskeletal 710–739 2.5 0.0   1.4 2.1 0.4 6.2 3.9 0.8 0.2 2.3 
 Signs and symptoms 780–799 0.8 1.2 0.0 6.8 1.0 3.0 0.6 8.9 1.8 2.2 0.6 5.7 
 Accidents 800–949 6.6 0.5 0.1 1.3 14 16.4 0.9 0.5 1.4 17 23.0 0.7 0.4 1.2 
 Suicide 950–959 4.1 0.2 0.0 1.3 8.6 0.3 0.1 1.0 12.8 0.3d 0.1 0.8 
 Others  5.0 0.2 0.0 1.1 6.1 0.8 0.3 1.9 11.1 0.5 0.2 1.2 
All causes  299 305.0 1.0 0.9 1.1 492 509.1 1.0 0.9 1.1 791 814.2 0.97 0.91 1.04 
a

1910–1929, 1943, 1944, 225, 2273, 2274, 2370, 2371, 2375, 2376, 2379.

b

140, 160, 161, 1640, 193, 1941.

c

152, 155–156, 159, 163, 1641, 1642, 1643, 1648, 1649, 165, 175, 181, 184, 1870–1891, 1881–189, 190, 1940, 1945–1999, 2038.

d

P < 0.01.

e

P < 0.05.

We thank the staff of the National Health Service Central Registers for England and Wales and Scotland for flagging and tracing of parents by. We also thank Ewa Dale, Joy Hogg, and Terry Mather for their hard work on data preparation. We thank the families who took part in the study.

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