Childhood cancer is a leading cause of child deaths in affluent countries, but little is known about its aetiology. Psychological stress has been suggested to be associated with cancer in adults; whether this is also seen in childhood cancer is largely unknown. We investigated the association between bereavement as an indicator of severe childhood stress exposure and childhood cancer, using data from Danish and Swedish national registers.
Population-based cohort study.
Denmark and Sweden.
All live-born children born in Denmark between 1968 and 2007 (n=2 729 308) and in Sweden between 1973 and 2006 (n=3 395 166) were included in this study. Exposure was bereavement by the death of a close relative before 15 years of age. Follow-up started from birth and ended at the first of the following: date of a cancer diagnosis, death, emigration, day before their 15th birthday or end of follow-up (2007 in Denmark, 2006 in Sweden).
Rates and HRs for all childhood cancers and specific childhood cancers.
A total of 1 505 938 (24.5%) children experienced bereavement at some point during their childhood and 9823 were diagnosed with cancer before the age of 15 years. The exposed children had a small (10%) increased risk of childhood cancer (HR 1.10; 95% CI 1.04 to 1.17). For specific cancers, a significant association was seen only for central nervous system tumours (HR 1.14; 95% CI 1.02 to 1.28).
Our data suggest that psychological stress in early life is associated with a small increased risk of childhood cancer.
Childhood cancer; bereavement; psychological stress; risk factor; follow up
Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization.
All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication.
A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95).
Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.
A depressed Apgar score at 5 minutes is a marker for perinatal insults, including neurologic damage. We examined the association between 5-minute Apgar score and the risk of epilepsy hospitalization in childhood.
Using records linked from population registries, we conducted a cohort study among singleton children born alive in the period 1978–2001 in North Jutland County, Denmark. The first hospital discharge diagnosis of epilepsy during the follow-up time was the main outcome. We followed each child for up to 12 years, calculated absolute risks and risk differences, and used a Poisson regression model to estimate risk ratios for epilepsy hospitalization. We adjusted risk ratio estimates for birth weight, gestational age, mode of delivery, birth presentation, mother's age at delivery, and birth defects.
One percent of the 131,853 eligible newborns had a 5-minute Apgar score <7. These children were more likely to be hospitalized with epilepsy during the follow-up than were children with an Apgar score of 7 or greater. The crude risk difference for epilepsy hospitalization was 2.5 cases per 100 (95% confidence interval [CI] 1.3 to 3.8). The risk difference estimates were greater in the presence of other perinatal risk factors. The adjusted risk ratio was 2.4 (95% CI 1.5 to 3.8). Half of the 12-year risk for epilepsy hospitalization in those with a depressed Apgar score occurred during the first year of life. The risk ratio during the first year of life was 4.9 (95% CI 2.0 to 12.3).
An Apgar score <7 at five minutes predicts an increase in the subsequent risk of epilepsy hospitalization. This association is amplified by other perinatal risk factors.
The aim of this study was to investigate the association between maternal socioeconomic position and a persistent low Apgar score (a score of < 7 at 1 and 5 min following birth).
The research is based on a population cohort study of 183 637 males born in Sweden between 1973 and 1976. Data from the Medical Birth Register were linked to Population and Housing Censuses.
There was evidence that mothers working in non-manual (Odds ratio (OR) 0.83 (0.72–0.97)) and self-employed (OR 0.64 (0.44–0.93)) occupations were less likely to have an infant with a low Apgar score, compared to manual workers. There was evidence that the risk of a low Apgar score decreased as the mother's level of education increased, if the infant was born by instrumental (OR 0.86 (0.74–0.99)) or caesarean section (OR 0.80 (0.68–0.93)) delivery, but not by unassisted vaginal delivery (OR 1.01 (0.92–1.10)).
There was a lower risk of poor birth condition in male infants born to more educated and non-manual/self-employed mothers. These differences may contribute to our understanding of socioeconomic differences in infant health and development although the results may not be applicable due to changes over the last 30 years.
Asphyxia neonatorum; Infant; Newborn; Obstetrical care; Socioeconomic status
Prenatal stress may increase the susceptibility to childhood cancer by affecting immune responses and hormonal balance. We examined whether antenatal stress following maternal bereavement increased the risk of childhood cancer.
All children born in Denmark from 1968 to 2007 (N=2 743 560) and in Sweden from 1973 to 2006 (N=3 400 212) were included in this study. We compared cancer risks in children born to women who lost a first-degree relative (a child, spouse, a parent, or a sibling) the year before pregnancy or during pregnancy with cancer risks in children of women who did not experience such bereavement.
A total of 9795 childhood cancer cases were observed during follow-up of 68 360 707 person years. Children born to women who lost a child or a spouse, but not those who lost other relatives, had an average 30% increased risk of any cancer (hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.96–1.77). The HRs were the highest for non-Hodgkin disease (512 cases in total, HR 3.40, 95% CI 1.51–7.65), hepatic cancer (125 cases in total, HR 5.51, 95% CI 1.34–22.64), and testicular cancer (86 cases in total, HR 8.52, 95% CI 2.03–37.73).
Our data suggest that severe antenatal stress following maternal bereavement, especially due to loss of a child or a spouse, is associated with an increased risk of certain childhood cancers in the offspring, such as hepatic cancer and non-Hodgkin disease, but not with childhood cancer in general.
childhood cancer; bereavement; prenatal stress; mother; association
OBJECTIVE: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. DESIGN: Population based case-control study. SETTING: Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. SUBJECTS: Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. MAIN OUTCOME MEASURES: Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). RESULTS: There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). CONCLUSIONS: Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.
Objective. To study mode of birth, perinatal health and death in children born to mothers with intellectual disability (ID) in Sweden. Design. Population-based register study. Setting. National registers; the National Patient Register linked to the Medical Birth Register. Sample. Children of first-time mothers with ID (n = 326; classified in the International Classification of Diseases 8–10) were identified and compared with 340 624 children of first-time mothers without ID or any other psychiatric diagnosis between 1999 and 2007. Methods. Population-based data were extracted from the National Patient Register and the Medical Birth Register. Main outcome measures. Mode of birth, preterm birth, small for gestational age, Apgar score, stillbirth and perinatal death. Results. Children born to mothers with ID were more often stillborn (1.2 vs. 0.3%) or died perinatally (1.8 vs. 0.4%) than children born to mothers without ID. They had a higher proportion of cesarean section birth (24.5 vs. 17.7%) and preterm birth (12.2 vs. 6.1%), were small for gestational age (8.4 vs. 3.1%) and had lower Apgar scores (<7 points at five minutes; 3.7 vs 1.5%) compared with children born to mothers without ID. Logistic regression adjusted for maternal characteristics confirmed an increased risk of small for gestational age (odds ratio 2.25), stillbirth (odds ratio 4.53) and perinatal death (odds ratio 4.25) in children born to mothers with ID. Conclusions. Unborn and newborn children of mothers with ID should be considered a risk group, and their mothers may need better individual-based care and support.
Intellectual disability; national registers; newborn outcomes; stillbirth; perinatal death
In a large population-based cohort in Denmark to examine if maternal use of antibiotics during pregnancy, as a marker of infection, increases the risk of febrile seizures in childhood in a large population-based cohort in Denmark.
All live-born singletons born in Denmark between January 1, 1996 and September 25, 2004 and who were alive on the 90th day of life were identified from the Danish National Birth Registry. Diagnoses of febrile seizures were obtained from the Danish National Hospital Register and maternal use of antibiotics was obtained from the National Register of Medicinal Product Statistics. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazard regression models.
We followed 551,518 singletons for up to 5 years and identified a total of 21,779 children with a diagnosis of febrile seizures. Slightly increased hazard ratios were observed among most exposure groups when compared to the unexposed group, ex. HR 1.08 95% CI: 1.05–1.11 for use of any systemic antibiotic during pregnancy.
We found weak associations between the use of pharmacologically different antibiotics during pregnancy and febrile seizures in early childhood which may indicate that some infections, or causes or effects of infections, during pregnancy could affect the fetal brain and induce susceptibility to febrile seizures.
Many different aetiologies for childhood cancer have been suggested, but few are well established. One is that parental autoimmune disease is linked with susceptibility for haematopoietic malignancies in their offspring during childhood. The present study is the first to investigate this hypothesis using a follow-up design. A cohort of 53 811 children of more than 36 000 patients diagnosed with a systemic, organ-specific or suspected autoimmune disease were followed up for cancer incidence in the Danish Cancer Registry during 1968–1993. The parents were identified through the National Registry of Patients, while their children were traced in the Central Population Register. Cancer incidence among the offspring was compared with that in the corresponding childhood population of Denmark. In total, 115 cancers were observed among children aged 0–19 years, yielding a non-significant standardized incidence ratio of 1.07. Lymphomas contributed 21 cases to the overall number of tumours, 60% more than expected (95% confidence interval (CI) 1.0–2.4); leukaemia contributed 37 cases representing an excess of 30% (95% CI 0.9–1.8). Our results give some support to the hypothesis that parental autoimmune disease is associated with childhood lymphoma and leukaemia. © 2000 Cancer Research Campaign
childhood lymphoma; childhood leukaemia; parental autoimmune disease
Advancing paternal age has been linked to autism.
To further expand knowledge about the relation between paternal age and autism by studying the effect of grandfathers’ age on childhood autism.
Population-based multigenerational case-control study.
Nationwide Multi-Generation and Patient registers in Sweden.
We conducted a study of individuals born in Sweden since 1932. Parental age at birth was obtained for over 90% of the cohort. Grandparental age at the time of birth of the parent was obtained for a smaller subset (5,936 cases and 30,923 controls).
Main Outcome Measures
International Classification of Diseases (ICD) diagnosis of childhood autism in the Patient Registry.
There was a statistically significant monotonic association between advancing grandpaternal age at the time of birth of the parent and risk of autism in grandchildren. Men who had a daughter when they were 50 or older were 1.79 times (95% confidence interval: 1.35-2.37, p<0.001) more likely to have a grandchild with autism, and men who had a son when they were 50 or older were 1.67 times (95% confidence interval: 1.35-2.37, p<0.001) more likely to have a grandchild with autism, compared to men who had children when they were 20-24, after controlling for birth year, sex, age of the spouse, family history of psychiatric disorders, highest family education and residential county. There was also a statistically significant monotonic association between advancing paternal age and risk of autism in the offspring. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on grandparental age.
Advanced grandparental age was associated with increased risk of autism, suggesting that risk for autism could develop over generations. The results are consistent with mutations and/or epigenetic alterations associated with advancing paternal age.
Objective: To examine whether the combination of a low five minute Apgar score and symptoms of neonatal encephalopathy is associated with minor impairments at school age.
Design: Population based cohort study.
Participants: All 727 children of the cohort were born between 1983 and 1987, had normal birth weights, no congenital malformations, and no major neurological abnormalities. The cohort comprised three groups with five minute Apgar scores of 0–3, 4–6, and 7–10, and were followed from birth to 8–13 years of age by combining data from The Medical Birth Registry, questionnaires, hospital discharge summaries, and the National Insurance Scheme.
Main outcome measure: Neurodevelopmental impairments such as learning, behavioural, and minor motor difficulties.
Results: Children with a five minute Apgar score of 3 or less and signs consistent with neonatal encephalopathy had a significantly increased risk of developing minor motor impairments (odds ratio (OR) 12.8, 95% confidence interval (CI) 2.6 to 63.2), epilepsy (OR 7.0, 95% CI 1.3 to 39.2), need of extra resources in kindergarten (OR 7.0, 95% CI 1.3 to 39.2) or at school (OR 3.4, 95% CI 1.8 to 6.3), and had reduced performance in reading (OR 4.6, 95% CI 2.3 to 9.5) and mathematics (OR 3.3, 95% CI 1.5 to 7.3), compared with children with normal Apgar scores and no neonatal symptoms. They also more often had problems related to tractability, aggressivity, passivity, anxiety, academic performance, and fine motor development.
Conclusion: Children with low Apgar scores and subsequent signs of cerebral depression who do not develop cerebral palsy may still have an increased risk of developing a variety of neurodevelopmental impairments and learning difficulties.
Objectives To assess the association of Apgar score 5 minutes after birth with cerebral palsy in both normal weight and low birthweight children, and also the association with the cerebral palsy subdiagnoses of quadriplegia, diplegia, and hemiplegia.
Design Population based cohort study.
Setting The Medical Birth Registry of Norway was used to identify all babies born between 1986 and 1995. These data were linked to the Norwegian Registry of Cerebral Palsy in Children born 1986-95, which was established on the basis of discharge diagnoses at all paediatric departments in Norway.
Population All singletons without malformations born in Norway during 1986-95 and who survived the first year of life (n=543 064).
Main outcome measure Cerebral palsy diagnosed before the age of 5 years.
Results 988 children (1.8 in 1000) were diagnosed with cerebral palsy before the age of 5 years. In total, 11% (39/369) of the children with Apgar score of less than 3 at birth were diagnosed with cerebral palsy, compared with only 0.1% (162/179 515) of the children with Apgar score of 10 (odds ratio (OR) 53, 95% CI 35 to 80 after adjustment for birth weight). In children with a birth weight of 2500 g or more, those with an Apgar score of less than 4 were much more likely to have cerebral palsy than those who had an Apgar score of more than 8 (OR 125, 95% confidence interval 91 to 170). The corresponding OR in children weighing less than 1500 g was 5 (95% CI 2 to 9). Among children with Apgar score of less than 4, 10-17% in all birthweight groups developed cerebral palsy. Low Apgar score was strongly associated with each of the three subgroups of spastic cerebral palsy, although the association was strongest for quadriplegia (adjusted OR 137 for Apgar score <4 v Apgar score >8, 95% CI 77 to 244).
Conclusions Low Apgar score was strongly associated with cerebral palsy. This association was high in children with normal birth weight and modest in children with low birth weight. The strength of the association differed between subgroups of spastic cerebral palsy. Given that Apgar score is a measure of vitality shortly after birth, our findings suggest that the causes of cerebral palsy are closely linked to factors that reduce infant vitality.
The authors evaluated the association between gestational age, birth weight, intrauterine growth and epilepsy in a population-based cohort of 1.4 million singletons born in Denmark (1979-2002). A total of 14,334 individuals were registered with epilepsy in the Danish National Hospital Register as inpatients (1979-2002) and outpatients (1995-2002). Information on gestational age and birth weight was obtained from Danish Medical Birth Registry. Children small at birth were identified through two methods: 1) sex-, birth order-, and gestational-age-specific z-score, and 2) deviation from the expected birth weight estimated based on the birth weight of an older sibling. The incidence rates of epilepsy increased consistently with decreasing gestational age and birth weight. The incidence rate ratios (IRR) for epilepsy in the first year of life were more than five-fold in children born at 22-32 weeks compared with children born at 39-41 weeks, and in children with a birth weight <2,000 grams compared with children of 3,000-3,999 grams. The IRRs decreased with age, but remained elevated into early adulthood. Children identified as growth-restricted according to either of the two methods had increased IRRs for epilepsy, even among children with a ‘normal’ birth weight of 3,500-3,999 grams. Low gestational age at birth and low birth weight are associated with an increased risk of epilepsy throughout childhood and persisting into puberty. Intrauterine growth restriction is associated with an increased risk of epilepsy, even among children with a birth weight in a normal range.
Apgar score is used for rapid assessment of newborns. Low five-minute Apgar score has been associated with increased risk of severe neurologic outcome, but data on milder outcomes, particularly in the long term, are limited. We aimed to examine the association of five-minute Apgar score with prevalence of neurologic disability and with cognitive function in early adulthood.
We conducted a prevalence study among draft-liable men born in Denmark in 1978–1983 and presenting for the mandatory army evaluation in a northern Danish conscription district. We linked records of this evaluation, which includes medical exam and intelligence testing, with the conscripts' records in the Medical Birth Registry, containing perinatal data. We examined prevalence of neurologic disability and of low cognitive function according to five-minute Apgar score.
Less than 1% (136/19,559) of the conscripts had 5-minute Apgar scores <7. Prevalence of neurologic disability was 2.2% (435/19,559) overall; among conscripts with Apgar scores <7, 7–9, and 10 (reference), it was 8.8%, 2.5%, and 2.2% respectively. The corresponding prevalences of low cognitive function (intelligence test score in the bottom quartile) were 34.9%, 27.2%, and 25.0%. The outcomes were more prevalent if Apgar score <7 was accompanied by certain fetal or obstetric adversities. After accounting for perinatal characteristics, 5-mintue Apgar score <7 was associated with prevalence ratios of 4.02 (95% confidence interval: 2.24; 7.24) for neurologic disability and 1.33 (0.94; 1.88) for low cognitive function.
A five-minute Apgar score <7 has a consistent association with prevalence of neurologic disability and with low cognitive function in early adulthood.
Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are fluorinated organic compounds present in the general population at low concentrations. Animal studies have shown that they may affect neuromuscular development at high concentrations.
We investigated the association between plasma levels of PFOS and PFOA in pregnant women and motor and mental developmental milestones of their children.
We randomly selected 1,400 pairs of pregnant women and their children from the Danish National Birth Cohort. PFOS and PFOA were measured in maternal blood samples taken in early pregnancy. Apgar score was abstracted from the National Hospital Discharge Register in Denmark. Developmental milestones were reported by mothers using highly structured questionnaires when the children were around 6 months and 18 months of age.
Mothers who had higher levels of PFOA and PFOS gave birth to children who had similar Apgar scores and reached virtually all of the development milestones at the same time as children born to mothers with lower exposure levels. Children who were born to mothers with higher PFOS levels were slightly more likely to start sitting without support at a later age.
We found no convincing associations between developmental milestones in early childhood and levels of PFOA or PFOS as measured in maternal plasma early in pregnancy.
maternal blood; mental developmental milestones; motor developmental milestones; PFOA; PFOS
To examine the relationship between birth characteristics and childhood cancer mortality, a retrospective cohort study of Korean children was conducted using data collected by the national birth register between 1995 and 2006, which were then individually linked to death data. A cohort of 6,479,406 children was followed from birth until their death or until December 31, 2006. Poisson regression analyses were used to calculate rate ratios of childhood cancer deaths according to birth characteristics. A total of 1,469 cancer deaths were noted and the childhood cancer mortality rate was found to be 3.43 per 100,000 person-years in Korea during the period of 1995-2006. The birth characteristics examined in this study (i.e. , birth weight, gestational age, multiple births, parental ages, and number of siblings) were generally found to be not significantly associated with childhood cancer mortality, and the associations did not vary meaningfully with gender nor with cancer sites. However, among children aged 5-11 yr, higher birth weight was associated with elevated childhood cancer mortality (rate ratio = 1.28, 95% confidence interval 1.04-1.58). Our results offer no overall associations between childhood cancer mortality and birth characteristics, but suggest that the association may be specific to age group.
Birth Weight; Child; Cohort Studies; Mortality; Neoplasms
Improved survival after childhood cancer raises concerns over the possible long-term reproductive health effects of cancer therapies. We investigated whether children of female childhood cancer survivors are at elevated risk of being born preterm or exhibiting restricted fetal growth and evaluated the associations of different cancer treatments on these outcomes.
Using data from the Childhood Cancer Survivor Study, a large multicenter cohort of childhood cancer survivors, we studied the singleton live births of female cohort members from 1968 to 2002. Included were 2201 children of 1264 survivors and 1175 children of a comparison group of 601 female siblings. Data from medical records were used to determine cumulative prepregnancy exposures to chemotherapy and radiotherapy. Logistic regression was used to estimate odds ratios (ORs) for the association between quantitative therapy exposures and preterm (<37 weeks) birth, low birth weight (<2.5 kg), and small-for-gestational-age (SGA) (lowest 10th percentile) births. All statistical tests were two-sided.
Survivors’ children were more likely to be born preterm than the siblings’ children (21.1% versus 12.6%; OR = 1.9, 95% confidence interval [CI] = 1.4 to 2.4; P<.001). Compared with the children of survivors who did not receive any radiotherapy, the children of survivors treated with high-dose radiotherapy to the uterus (>500 cGy) had increased risks of being born preterm (50.0% versus 19.6%; OR = 3.5, 95% CI = 1.5 to 8.0; P = .003), low birth weight (36.2% versus 7.6%; OR = 6.8, 95% CI = 2.1 to 22.2; P = .001), and SGA (18.2% versus 7.8%; OR = 4.0, 95% CI = 1.6 to 9.8; P = .003). Increased risks were also apparent at lower uterine radiotherapy doses (starting at 50 cGy for preterm birth and at 250 cGy for low birth weight).
Late effects of treatment for female childhood cancer patients may include restricted fetal growth and early births among their offspring, with risks concentrated among women who receive pelvic irradiation.
Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research.
All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years.
Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49% false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using –3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased.
Choosing –3 standard deviations for identifying children born SGA is a viable, though not optimal solution for identifying children born SGA. Overall the data in the registry is of sufficient quality to be used in further medical research.
Childhood cancer is rare and symptoms tend to be unspecific and vague. Using the utilization of health care services as a proxy for symptoms, the present study seeks to determine when early symptoms of childhood cancer are seen in general practice.
A population-based matched comparative study was conducted using nationwide registry data. As cases, all children in Denmark below 16 years of age (N = 1,278) diagnosed with cancer (Jan 2002-Dec 2008) were included. As controls, 10 children per case matched on gender and date of birth (N = 12,780) were randomly selected. The utilization of primary health care services (daytime contacts, out-of-hours contacts and diagnostic procedures) during the year preceding diagnosis/index date was measured for cases and controls.
During the six months before diagnosis, children with cancer used primary care more than the control cohort. This excess use grew consistently and steadily towards the time of diagnosis with an IRR = 3.19 (95%CI: 2.99–3.39) (p<0.0001) during the last three months before diagnosis. Children with Central Nervous System (CNS) tumours had more contacts than other children during the entire study period. The use of practice-based diagnostic tests and the number of out-of-hours contacts began to increase four to five months before cancer diagnosis.
The study shows that excess health care use, a proxy for symptoms of childhood cancer, occurs months before the diagnosis is established. Children with lymphoma, bone tumour or other solid tumours had higher consultation rates than the controls in the last five months before diagnosis, whereas children with CNS tumour had higher consultation rates in all twelve months before diagnosis. More knowledge about early symptoms and the diagnostic pathway for childhood cancer would be clinically relevant.
Among 4380 children born in 1987–1997 of women with a diagnosis of diabetes and alive at the age of one, 10 were registered in the Swedish Cancer Registry before the end of 1998. The odds ratio for having a childhood cancer after maternal diabetes, stratified for year of birth, maternal age, parity, multiple birth, and 500 g birth weight class was 2.25 (95%CI 1.22–4.15). Among 5842 children born during the period 1973–1997 whose mothers had other auto-immune diseases (SLE, rheumatoid arthritis, Crohn, ulcerous colitis, multiple sclerosis or thyroiditis), the number of observed childhood cancers (9) was close to that expected (8.5). Maternal diabetes but not other auto-immune diseases may be a risk factor for childhood cancer.
British Journal of Cancer (2002) 86, 1078–1080. DOI: 10.1038/sj/bjc/6600192 www.bjcancer.com
© 2002 Cancer Research UK
diabetes; childhood cancer; auto-immune disease
Background & Aims
Studies on pregnancy characteristics and mode of delivery and risk of later celiac disease in offspring are inconsistent. In recent decades rates of cesarean delivery and preterm birth survival have increased while at the same time the prevalence of celiac disease has doubled.
In this population-based case-control study we examine the risk of celiac disease in individuals exposed to cesarean delivery and adverse fetal events (i.e. low Apgar score, small for gestational age, low birth weight, preterm birth, and neonatal infections). Prospectively recorded pregnancy data were obtained from the Swedish Medical Birth Register between 1973 and 2008. Study participants consisted of 11,749 offspring with biopsy-verified celiac disease identified through histopathology reports from Sweden’s 28 pathology departments and 53,887 age- and sex-matched controls from the general population.
We found a positive association between elective cesarean delivery and later celiac disease (adjusted odds ratio (AOR) = 1.15; 1.04-1.26; p = 0.005), but no increased risk of celiac disease following emergency (AOR = 1.02; 0.92-1.13; p = 0.749) or any cesarean delivery (AOR = 1.06; 0.99-1.13; p = 0.074). Infants born small for gestational age were at a 21% increased risk of celiac disease (95% CI = 1.09-1.35; p = 0.001), whereas other pregnancy exposures did not increase the risk of future celiac disease.
The positive association with elective, but not emergency, cesarean delivery is consistent with the hypothesis that the bacterial flora of the newborn plays a role in the development of celiac disease.
cesarean section; prematurity; register
Previous studies have shown a decreased risk of prostate cancer for childless men; however, the cause of the association remains to be elucidated. The aim of our study was to assess the risk of prostate cancer by fatherhood status, also considering potential confounding factors. In a case–control study in Prostate Cancer data Base Sweden 2.0, a nationwide, population-based cohort, data on number of children, marital status, education, comorbidity and tumor characteristics obtained through nationwide healthcare registers and demographic databases for 117,328 prostate cancer cases and 562,644 controls, matched on birth year and county of residence, were analyzed. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for prostate cancer overall and by risk category, adjusting for marital status and education. Childless men had a decreased risk of prostate cancer compared to fathers, OR = 0.83 (95% CI = 0.82–0.84), and risk was lower for low-risk prostate cancer, OR = 0.74 (95% CI = 0.72–0.77), than for metastatic prostate cancer, OR = 0.93 (95% CI = 0.90–0.97). Adjustment for marital status and education attenuated the association in the low-risk category, adjusted OR = 0.87 (95% CI = 0.84–0.91), whereas OR for metastatic cancer remained virtually unchanged, adjusted OR = 0.92 (95% CI = 0.88–0.96). Our data indicate that the association between fatherhood status and prostate cancer to a large part is due to socioeconomic factors influencing healthcare-seeking behavior including testing of prostate-specific antigen levels.
prostate cancer; epidemiology; case–control studies; hypogonadism; androgens
OBJECTIVE—Low birth weight is consistently associated with an increased risk of type 2 diabetes in adulthood, but the individual contributions from poor fetal growth and preterm birth are not known. We therefore investigated the significance of these two factors separately.
RESEARCH DESIGN AND METHODS—We identified a cohort of subjects born preterm or with low birth weight at term at four major delivery units in Sweden from 1925 through 1949. A comparison cohort of subjects was identified from the same source population. Of 6,425 subjects in all, 2,931 were born at <37 weeks of gestation and 2,176 had a birth weight <2,500 g. Disease occurrence among participants was assessed through nationwide hospital registers from 1987 through 2006.
RESULTS—During follow-up, there were 508 cases of diabetes. Low birth weight was strongly negatively associated with risk of diabetes (P for trend <0.0001). Both short gestational duration and poor fetal growth were associated with later diabetes (P for trend <0.0001 and <0.0004, respectively). Very preterm birth (≤32 weeks of gestation at birth) was associated with a hazard ratio (HR) of 1.67 (95% CI 1.33–2.11) compared with term birth. Birth weights below 2 SDs of mean birth weight for gestational age were associated with an HR of 1.76 (1.30–2.38) compared with birth weights between the mean weight and the weight at 1 SD above the mean.
CONCLUSIONS—Our results suggest that the association between low birth weight and diabetes is due to factors associated with both poor fetal growth and short gestational age.
To increase our knowledge of the occurrence of substandard care during labour.
A population-based case–control study.
Infants born in the period 2004–2006 in Stockholm County.
Cases and controls were identified from the Swedish Medical Birth Register, had a gestational age of ≥33 complete weeks, had planned for a vaginal delivery, and had a normal cardiotocographic (CTG) recording on admission. We compared 313 infants with an Apgar score of <7 at 5 minutes of age with 313 randomly selected controls with a full Apgar score, matched for year of birth.
Main outcome measure
Substandard care during labour.
We found that 62% of cases and 36% of controls were subject to some form of substandard care during labour. In half of the cases and in 12% of the controls, CTG was abnormal for ≥45 minutes before birth. Fetal blood sampling was not performed in 79% of both cases and controls, when indicated. Oxytocin was provided without signs of uterine inertia in 20% of both cases and controls. Uterine contractions were hyperstimulated by oxytocin in 29% of cases and in 9% of controls, and the dose of oxytocin was increased despite abnormal CTG in 19% and 6% of cases and controls, respectively. Assuming that substandard care is a risk factor for low Apgar score, we estimate that up to 42% of the cases could be prevented by avoiding substandard care.
There was substandard care during labour of two-thirds of infants with a low Apgar score. The main reasons for substandard care were related to misinterpretation of CTG, not acting on an abnormal CTG in a timely fashion and incautious use of oxytocin.
Asphyxia; delivery; fetal surveillance; hyperstimulation; labour; oxytocin; substandard care; vacuum extraction.
Previous studies on the association between maternal age and risk of childhood leukemia found inconsistent results.
We aimed to assess whether there is an association between maternal age and risk of childhood leukemia and whether such an association is modified by maternal year of birth.
By linking nationwide Swedish registers, we analyzed leukemia incidence among all children between 1 and 5 years of age born between 1960 and 1999. We estimated incidence time trends by child year of birth (overall and stratified by maternal age) and incidence rate ratios (RRs) for maternal age groups stratified by maternal birth cohort. We tested the interaction between maternal age and child year of birth through the likelihood ratio test between nested Poisson regression models.
We observed 1,562 leukemia cases. The overall annual percent change (APC) was 1.00 [95% confidence interval (CI), 0.51 to 1.49]. Stratifying by maternal age classes, APCs decreased from 1.66 (0.68 to 2.65) for mothers ≤ 24 years to 0.23 (−0.93 to 1.40) for mothers ≥ 35 years at delivery. RRs for children born to the oldest with respect to the youngest mothers were 2.42 (1.31 to 4.67), 1.68 (1.00 to 2.72), 1.34 (0.87 to 2.01), and 0.87 (0.46–1.54) for mothers born in 1930–1934, 1940–1944, 1950–1954, and 1960–1964, respectively.
Childhood leukemia risk increased with maternal age for mothers born in the past, whereas maternal age had no effect on this risk for mothers born more recently. This finding may explain the inconsistency of previous studies and suggests that leukemia risk may be related to an environmental factor to which women’s exposure has changed over time.
childhood leukemia; epidemiology; maternal age; rate ratios; time trends