Long-term cause-specific mortality among five-year survivors of childhood cancer

BACKGROUND: The purpose of our study was to assess long-term cause-specific mortality of 5-year childhood cancer survivors. PROCEDURE: The study population consisted of 1,378 patients who had been treated for childhood cancer in The Netherlands between 1966 and 1996 and survived at least 5 years; follow-up was complete for 99% of survivors. Cause-specific mortality was compared with general population rates to assess relative and absolute excess risks of death (standardized mortality ratio (SMR) and AER). RESULTS: After a median follow-up of 16.1 years, 120 patients had died. The overall SMR was 17-fold (95% CI: 14.3-20.6) increased compared to the general population. Our cohort experienced an excess of 7 deaths per 1,000 person-years. Patients who received combined modality treatment and were treated for at least one recurrence experienced the highest risk of death (SMR = 92.3; AER = 37.0 per 1,000 person-years). The SMR appeared to stabilize at an about 4 to 5-fold increased risk of death after 20 years of follow-up. Only after more than 20 years of follow-up excess mortality due to other causes than the primary cancer exceeded mortality from the primary childhood cancer (2.3 vs. 0.3/1,000 patients/year). The SMR for all causes other than primary cancer was 5.4 in 25-year survivors. The overall risks of death strongly decreased with increasing attained age, with an SMR of 1.6 (n.s.) and an AER of 0.3 per 1,000 person-years for survivors of 30 years or older. CONCLUSIONS: The first primary cancer contributes most to the absolute excess risk of death in 5-year survivors of childhood cancer, but after 25 years childhood cancer mortality is negligible. Relative risk of death due to other causes is still significantly increased after 25 years of follow-up.     

Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada

BACKGROUND: We examined second malignancies, a recognized late effect of therapy among survivors of childhood and adolescent cancer, among a recent, population-based cohort of 2,322 5-year survivors diagnosed before 20 years of age in British Columbia (BC), Canada between 1970 and 1995. PROCEDURE: Survivors and second malignancies were identified from the BC Cancer Registry. Risk of second malignancy was evaluated using standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative risk. The effect of demographic, temporal, and disease-related characteristics on risk was assessed. RESULTS: Fifty-five second malignancies were observed after 26,071 person-years of follow-up. Relative rate of developing a second malignancy among survivors was 5 times higher than expected (SIR = 5.0, 95% CI, 3.8-6.5), and absolute excess risk was 1.7 deaths per 1,000 person-years. Cumulative incidence of a second malignancy was 5.1% at 25 years after diagnosis of the first cancer. SIRs and absolute excess risk of subsequent cancer was higher among females (SIR = 5.9, 95% CI, 4.5-8.3 and AER = 2.66). While relative risk of second cancer was higher for those diagnosed before 10 years of age (SIR = 10.6, 95% CI, 7.1-16.0), absolute excess risk was slightly higher for those diagnosed after 10 years of age. SIRs were significantly elevated for all follow-up periods, but absolute excess risk of a second cancer was highest among patients surviving more than 15 years. CONCLUSIONS: Increased risk of a subsequent neoplasm is evident among childhood cancer survivors diagnosed in more recent periods than has been previously reported, continues years after diagnosis, and varies according to several risk factors. Continued surveillance is essential to quantify and characterize long-term and changing risks for appropriate follow-up.     

Cause of mortality in 5-year survivors of childhood cancer

Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,690 5-year survivors. Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources, then and coded and categorized as recurrent disease, sequel of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data. The cohort demonstrated an 8.2-fold excess in overall mortality (95% confidence interval, 7.9 to 8.5). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 57% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 15.0), along with cardiac (SMR = 6.9), and pulmonary (SMR = 8.7). There was no increase seen for automotive accidents (SMR = 1.0), other accidents (SMR = 1.3), or suicide (SMR = 1.0). While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.     

Mortality experiences among 15+ year survivors of childhood and adolescent cancers

BACKGROUND: Studies of childhood and adolescent cancer survivorship have tended to focus on limited survival intervals (e.g., 5 and 10 years). Our report evaluates gender-specific overall mortality, as well as mortality by age group, and by cause, among 15+ year survivors of cancer diagnosed during childhood or adolescence. PROCEDURE: This was a retrospective cohort study of 565 15+ year childhood cancer survivors from Roswell Park Cancer Institute's Long-Term Follow-Up Project. Sex- and age-specific person-years at risk were accumulated and applied to age-specific mortality rates for New York State, excluding New York City. Standardized mortality ratios (SMRs), and 95% confidence intervals, were calculated and compared to mortality risks of the general population. RESULTS: Second malignancy was the leading cause of death among male and female survivors (15/38 deaths, 39%). Excess overall mortality was noted among both males (SMR = 284) and females (SMR = 371). Significant mortality excesses were seen in both genders for deaths due to primary malignant neoplasms and secondary malignancies, as well as cardiac deaths among males. Excess mortality was noted across most age strata. In the scenario of no cancer relapse, overall mortality in both genders did not differ significantly from the general population. CONCLUSIONS: Long-term survivors of childhood and adolescent cancers continue to demonstrate significant excess mortality. However, overall mortality among 15+ year survivors without a relapse appears to be comparable to the general population. The leading cause of death among 15+ year survivors is second malignancy in this study, which represents a novel and important finding in terms of long-term follow-up.     

Mortality in childhood-onset epilepsy

OBJECTIVES: To evaluate mortality in children with newly diagnosed epilepsy, to determine the risk of death, and to identify predictors of death from the point of diagnosis. DESIGN: Prospective community-based cohort of 613 children with newly diagnosed epilepsy. The outcome measure was death. Chi2 Tests were used for bivariate analyses and the Cox proportional hazards model for multivariable analyses. Standardized mortality ratios were used to quantify the excess mortality in the cohort relative to the population. RESULTS: Thirteen deaths occurred during 4733 person-years of follow-up, for a crude death rate of 2.7 per 1000 person-years (0.52 per 1000 person-years in those with nonsymptomatic epilepsy and 12.6 per 1000 person-years in those with symptomatic epilepsy). Ten deaths were associated with the underlying cause of the seizures, 2 were associated with the occurrence or probable occurrence of seizures, and 1 was unrelated to seizures or the underlying disorder. On multivariable analysis, symptomatic etiology (rate ratio, 10.2; 95% confidence interval [CI], 2.1-49.6) and epileptic encephalopathy (rate ratio, 13.3; 95% CI, 3.4-51.7) were independently associated with mortality. The overall standardized mortality ratio for the cohort was 7.54 (95% CI, 4.38-12.99). In children with symptomatic epilepsy, the standardized mortality ratio was 33.46 (95% CI, 18.53-60.43), and in those with nonsymptomatic epilepsy, it was 1.43 (95% CI, 0.36-5.73). CONCLUSIONS: Children with epilepsy have an increased risk of death. Most deaths occur in children with severe underlying conditions and are not directly related to the occurrence of seizures.     

Mortality and diabetes from a population based register in Yorkshire 1978-93

OBJECTIVE: To investigate mortality of children diagnosed with insulin dependent diabetes mellitus (IDDM) and to identify common factors before death. DESIGN: Follow up of a population based cohort of children diagnosed with IDDM to ascertain deaths. SETTING: Children were diagnosed in Yorkshire but followed up throughout the United Kingdom. SUBJECTS: From the Yorkshire Children's Diabetes Register details of 1854 children aged 0-16 years (1978-93) were submitted to the NHS Central Register. MAIN OUTCOME MEASURE: Notification and causes of death. RESULTS: 98.3% of cases were traced and 26 deaths identified. Follow up ranged from 1-18 years (median 9.3 years), providing 17,350 person-years of IDDM. Fifteen deaths (58%) were attributed to diabetes or its complications; 11 (42%) were unrelated and included one suicide. For mortality from all causes, the standardised mortality ratio (SMR) of 247 (95% confidence interval (CI) 163 to 362) was significantly increased for those under 34 years. The largest number of deaths (n = 10) occurred in the 15-19 year age range, with an SMR of 442 (95% CI 209 to 802). Case note examination showed a clear tendency towards poor diabetic control, and worries over control were expressed before death by health care professionals. CONCLUSIONS: Despite advances in treatment, IDDM still carries an increased mortality for young people, particularly in the "transition" age range.     

Mortality among patients with a history of Kawasaki disease: The third look

Abstract Background: Long-term prognosis of Kawasaki disease is still unclear.
Methods: In a cohort study, 6576 patients with Kawasaki disease were observed from their first medical encounter because of the disease through the end of 1994, or until death. Standardized mortality ratios (SMR) with 95% confidence intervals (CI) were calculated with vital statistics data of Japan used for the control. Results: Of 6576 patients who met the eligibility criteria, 6550 (99.6%) were followed through either the end of the study or the date of death. Twenty patients (14 male, 6 female subjects) died during the study period; an overall SMR of 1.35 (95% CI 0.82–2.08) was calculated. The SMR was 1.45 (95% CI 0.79–2.44) for male subjects and 1.15 (95% CI 0.42–2.52) for female subjects. During the acute phase of the disease (the first 2 months after the first visit to hospital), the SMR was higher, particularly in male subjects (SMR 10.13, 95% CI 3.72–22.08). After the acute phase, however, both boys and girls had low SMR. Nine of the 20 deaths were caused by Kawasaki disease; there were three deaths as a result of congenital heart diseases and two subjects died of malignant neoplasms of lymphatic or hematopoietic tissues.
Conclusions: Although the mortality rate among those with a history of Kawasaki disease was elevated in Japan, many of the deaths that caused the elevation occurred during the acute phase of the disease. The mortality rate was not increased after the acute phase of the disease.     

Mortality in childhood progressive encephalopathy from 1985 to 2004 in Oslo, Norway: a population-based study

AIMS: The aims were to estimate case fatality and survival rates, standardized mortality ratio (SMR), and independent prognostic factors for survival, in a population-based cohort of progressive encephalopathy (PE) patients. METHODS: We divided onset of disease into neonatal and postneonatal groups and aetiology into metabolic (n=55), neurodegenerative (n=27) and HIV encephalopathy (n=2) groups. Case fatality was the number of deaths divided by the number of patients. Cumulative survival probability at 10 years of follow-up and independent risk factors for mortality were analyzed using the Kaplan-Meier survival curve and the Cox model. RESULTS: Case fatality was 36.9% and the mean and median follow-up times were 3109 and 2887 days. At 1 and 10 years, the cumulative probability of survival was 81% and 66%. Neonatal onset showed increased risk of death compared to postneonatal onset (RR 3.0; 95% CI 1.4-6.2). Metabolic aetiology showed increased risk of death compared to other aetiology (RR 1.25; 95% CI 1.10-1.46). The SMR of 37.7 for boys and 23.8 for girls was significantly increased (p<0.001) compared to the total Norwegian population stratified by gender and age. CONCLUSIONS: Children with PE showed a vast excess in mortality compared to the general population stratified by gender and age. Neonatal presentation and metabolic aetiology were the most significant factors for increased risk of death.     

Pancreatic exocrine and endocrine function after pancreatectomy for persistent hyperinsulinaemic hypoglycaemia of infancy

OBJECTIVE—To investigate mortality of children diagnosed with insulin dependent diabetes mellitus (IDDM) and to identify common factors before death.
DESIGN—Follow up of a population based cohort of children diagnosed with IDDM to ascertain deaths.
SETTING—Children were diagnosed in Yorkshire but followed up throughout the United Kingdom.
SUBJECTS—From the Yorkshire Children''s Diabetes Register details of 1854 children aged 0-16 years (1978-93) were submitted to the NHS Central Register.
MAIN OUTCOME MEASURE—Notification and causes of death.
RESULTS—98.3% of cases were traced and 26 deaths identified. Follow up ranged from 1-18 years (median 9.3 years), providing 17 350 person-years of IDDM. Fifteen deaths (58%) were attributed to diabetes or its complications; 11 (42%) were unrelated and included one suicide. For mortality from all causes, the standardised mortality ratio (SMR) of 247 (95% confidence interval (CI) 163 to 362) was significantly increased for those under 34 years. The largest number of deaths (n = 10) occurred in the 15-19 year age range, with an SMR of 442 (95% CI 209 to 802). Case note examination showed a clear tendency towards poor diabetic control, and worries over control were expressed before death by health care professionals.
CONCLUSIONS—Despite advances in treatment, IDDM still carries an increased mortality for young people, particularly in the "transition" age range.

     

Family history of cancer in children and young adults with colorectal cancer.

BACKGROUND: Family history of colorectal cancer among adult patients has been reported in the literature. Although extremely rare in children, colorectal cancer in this population may represent a unique group in whom genetic factors play a significant etiologic role. The aim of the present study was to assess genetic contribution, as measured by family history, to the development of colorectal cancer in probands under 21 years of age at diagnosis. PROCEDURE: Detailed family histories were obtained from surviving patients or their parents. The risk [standardized incidence ratio (SIR)] of cancer in the relatives was calculated by comparing the observed and the expected incidence based on rates in the general population and person-years at risk. RESULTS: Twenty-five patients (median age at diagnosis 15 years) diagnosed with colorectal cancer at St. Jude Children's Research Center since 1964 or their surviving next of kin were available for interview. The 461 relatives contributed 18,908 person-years of follow-up. Statistically significant increased risk of colorectal cancer was present among all relatives (SIR = 6.0, 95% CI, 2.7-10.6), and the increased risk of colorectal cancer was confined to relatives of probands who were under 15 years of age at diagnosis (SIR = 10.0, 95% CI, 4.5-17.6). In addition, there was an excess of uterine/cervical cancer among all female relatives (SIR = 6.5, 95% CI, 3.2-10.9). CONCLUSIONS: The observed excess of colorectal cancer, in relatives of younger probands, suggests the need to examine these kindreds for genetic instability resulting from defects in mismatch repair genes to characterize further the patterns of risk observed.     

Marriage and divorce among childhood cancer survivors

Many childhood cancer survivors have psychosocial late effects. We studied the risks for cohabitation and subsequent separation. Through the Danish Cancer Register, we identified a nationwide, population-based cohort of all 1877 childhood cancer survivors born from 1965 to 1980, and in whom cancer was diagnosed between 1965 and 1996 before they were 20 years of age. A sex-matched and age-matched population-based control cohort was used for comparison (n=45,449). Demographic and socioeconomic data were obtained from national registers and explored by discrete-time Cox regression analyses. Childhood cancer survivors had a reduced rate of cohabitation [rate ratio (RR) 0.78; 95% confidence interval (CI): 0.73-0.83], owing to lower rates among survivors of both noncentral nervous system (CNS) tumors (RR 0.88; 95% CI: 0.83-0.95) and CNS tumors (RR 0.52; 95% CI: 0.45-0.59). Male CNS tumor survivors had a nonsignificantly lower rate (RR 0.47; 95% CI: 0.38-0.58) than females (RR 0.56; 95% CI: 0.47-0.68). The rates of separation were almost identical to those of controls. In conclusion, the rate of cohabitation was lower for all childhood cancer survivors than for the population-based controls, with the most pronounced reduction among survivors of CNS tumors. Mental deficits after cranial irradiation are likely to be the major risk factor.     

Mortality from birth to adult life: a longitudinal study of twins

We have examined mortality from birth through adult life in a cohort of 2562 twins born in Birmingham, UK, between 1950 and 1954. Their birthweights and obstetric details had been recorded as part of a longitudinal study of births in Birmingham. There were a total of 151 perinatal deaths (perinatal mortality rate = 116 per 1000 births) and 227 infant deaths (infant mortality rate = 94 per 1000 live births). 70 deaths occurred after the age of one year. In comparison with national mortality rates in the UK, overall mortality in the twins was high (standard mortality rate, SMR = 259, 95% CI 221-300). Mortality was highest in the first year of life and, although it then declined progressively, it remained significantly higher that that of the general population until age 5 years. The excess mortality was largely due to conditions originating in the perinatal period but there were excess rates of congenital abnormalities, diseases of the respiratory system, digestive system and nervous and sensory organs. A Cox proportional Hazards analysis showed that the risk of death was related to low birthweight, prematurity and male sex. Death of the co-twin was highly predictive of mortality throughout the period of follow up. These studies not only underline the excess mortality associated with twin birth but show for the first time that this excess mortality extends into childhood.     

Cancer mortality following cardiac catheterization: a preliminary follow-up study on 4,891 irradiated children

A retrospective cohort study was conducted on the risk of radiation-induced cancer mortality following cardiac catheterization. The study included 4,891 children with congenital heart disease who were assessed by cardiac catheterization during 1946 to 1968 at The Hospital for Sick Children, Toronto. The cohort was matched against the Ontario cancer death file from 1950 to 1975. The average period of follow-up was 13 years and more than 66,000 person-years have been accrued from the cohort. No deaths from breast cancer or thyroid cancer were identified. Five cancer deaths were observed and compared with 4.8 expected deaths based on Ontario cancer death rates. The five cancer deaths resulted from three leukemias, one Wilms' tumor, and one unspecified nervous system tumor. The preliminary findings did not demonstrate a significant leukemia risk arising from diagnostic cardiac catheterizations. Continued follow-up of this cohort is required to evaluate the risk of breast and thyroid cancers which can occur more than 20 years following radiation exposure.     

Second primary tumors in children and young adults in the North of England (1968-99)

BACKGROUND: This study describes the risk of second malignancy in patients diagnosed with cancer under the age of 25 years, registered on the Northern Region Young Person's Malignant Disease Registry. PROCEDURE: Incidence rates were calculated to describe the occurrence of second malignancies, rate ratios were estimated to compare rates between subgroups. Standardized incidence ratios (SIRs) were calculated for comparison with a reference population. RESULTS: There were 4,072 children and young adults diagnosed with a first malignancy from 1968 to 1999, of whom 68 had a second malignancy (including basal cell carcinomas and meningiomas). The incidence rate of second malignancy is 1.7 per 1,000 survivor person-years (95% CI: 1.4, 2.2), reflecting a four-fold increased risk of malignancy compared with the general population. The rate of second malignancy was non-significantly higher for those diagnosed during young adulthood rather than childhood (RR = 1.2, 95% CI: 0.7, 2.0), significantly higher in females than males (RR = 1.8, 95% CI: 1.1, 3.0) and significantly lower for those diagnosed in more recent years (RR = 0.4, 95% CI: 0.2, 0.8). In contrast, the SIRs indicated that children were at substantial increased risk; whilst males and females, and those diagnosed in earlier and later time periods, were at equivalent risks. CONCLUSIONS: There is evidence of a sustained increased risk of second malignancy in those treated for primary cancer, especially those diagnosed in childhood; with no evidence that this risk is reducing.     

Mortality of twin and singleton livebirths under 30 weeks' gestation: a population-based study

OBJECTIVE: To determine the mortality rates of liveborn twins compared with singletons of less than 30 weeks' gestation in relation to gestational age, mode of delivery and year of birth in a geographically defined population. STUDY DESIGN: Comparison of early neonatal, late neonatal and infant death rates in 479 twin babies and 1538 singletons, liveborn between 23 and 29 completed weeks of gestation in the north of England over two epochs, 1998-2001 and 2002-5. RESULTS: Twins and singletons had similar mortality rates except at the extreme of gestation (23-25 weeks) where twins had higher infant mortality (OR 2.04, 95% CI 1.37 to 3.02). This higher rate was attributable to early and late neonatal deaths (OR 1.86, 95% CI 1.28 to 2.72, and 2.11, 95% CI 1.13-3.94, respectively). When analysed in two epochs, the excess mortality was confined to babies born in 1998-2001. There was no effect of gender or chorionicity. CONCLUSIONS: The excess mortality among twins of less than 30 weeks' gestation was confined to neonatal deaths in babies of 25 weeks or less, and to the earlier epoch (1998-2001). In the modern era, there appears to be no excess mortality in neonates less than 30 weeks' gestation when compared with singletons.     

Mortality among persons with a history of Kawasaki disease in Japan: Can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

Aim: To clarify the question of whether patients with Kawasaki disease suffer a higher mortality rate after the incidence of the disease in comparison with age-matched healthy individuals. Methods: Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new, definite diagnosis of Kawasaki disease. Patients were followed up until 31 December 2001 or their death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Results: Of 6576 patients enrolled, 29 (20 males and 9 females) died. The standardized mortality ratio (SMR: the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.15 (95% CI: 0.77-1.66). In spite of the high SMRs during the acute phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the SMR after the acute phase was 0.75 for those without cardiac sequelae, six males (but none of the females) with cardiac sequelae died during this period; and the SMR for the male group with cardiac sequelae was 1.95 (95% CI: 0.71-4.25). The mortality from congenital anomalies of the circulatory system was elevated, but no increase in cancer deaths was observed.

Conclusion: Although it was not statistically significant, the mortality rate among males with cardiac sequelae due to Kawasaki disease appeared to be higher than in the general population. On the other hand, the mortality rates for females with the sequelae and both males and females without sequelae were not elevated.     

Long-term mortality in pediatric solid organ recipients—A nationwide study

Background

The present study aimed at investigating long-term mortality of patients who underwent solid organ transplantation during childhood and at identifying their causes of death.

Methods

A cohort of 233 pediatric solid organ transplant recipients who had a kidney, liver, or heart transplantation between 1982 and 2015 in Finland were studied. Year of birth-, sex-, and hometown-matched controls (n = 1157) were identified using the Population Register Center registry. The Causes of Death Registry was utilized to identify the causes of death.

Results

Among the transplant recipients, there were 60 (25.8%) deaths (median follow-up 18.0 years, interquartile range of 11.0–23.0 years). Transplant recipients' risk of death was nearly 130-fold higher than that of the controls (95% CI 51.9–1784.6). The 20-year survival rates for kidney, liver, and heart recipients were 86.1% (95% CI 79.9%–92.3%), 58.5% (95% CI 46.2%–74.1%), and 61.4% (95% CI 48.1%–78.4%), respectively. The most common causes of death were cardiovascular diseases (23%), infections (22%), and malignancies (17%). There were no significant differences in survival based on sex or transplantation era.

Conclusion

The late mortality is still significantly higher among pediatric solid organ recipients in comparison with controls. Cardiovascular complications, infections, and cancers are the main causes of late mortality for all studied transplant groups. These findings emphasize the cruciality of careful monitoring of pediatric transplant recipients in order to reduce long-term mortality.     

Changing patterns of perinatal death, 1982-2000: a retrospective cohort study

OBJECTIVE: To describe trends in cause specific stillbirth and neonatal mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: 686,860 births in 1982-2000, to mothers resident in the Northern Region of England. MAIN OUTCOME MEASURES: Cause specific stillbirth and neonatal mortality; rate ratios (RR) and 95% confidence intervals (CI) in 1991-2000 compared with 1982-1990. RESULTS: In singletons, rates of stillbirth and neonatal mortality declined over time (RR stillbirths, 0.81 (95% CI 0.76 to 0.87); RR neonatal mortality, 0.76 (95% CI 0.70 to 0.82)). Death from congenital anomalies declined substantially for both stillbirths (RR 0.52; 95% CI 0.40 to 0.68) and neonatal mortality (RR 0.58; 95% CI 0.51 to 0.67). Mortality due to intrapartum hypoxia also fell, by nearly 50% for stillbirths and 30% for neonatal deaths. There was no reduction in stillbirths due to antepartum hypoxia in babies weighing > or = 2500 g, or in mortality attributed to infection. In multiples, the risk of death was higher (RR stillbirths, 4.13 (95% CI 3.68 to 4.64); RR neonatal death, 7.82 (95% CI 7.13 to 8.58)). Stillbirth rates declined significantly (RR 0.71; 95% CI 0.57 to 0.89) but neonatal mortality did not (RR 0.91; 95% CI 0.77 to 1.08). There was no reduction in neonatal mortality resulting from prematurity, or in mortality from congenital anomalies. CONCLUSIONS: There is considerable overlap in the causes of stillbirth and neonatal mortality. Future progress in reducing perinatal mortality requires better understanding of the aetiology of antepartum stillbirth, of the excess risks of prematurity facing multiple births, particularly in the light of their increasing incidence, and of strategies to prevent perinatal infection.     

Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients

OBJECTIVE: Patients who received pituitary-derived growth hormone (GH) are at excess risk of mortality from Creutzfeldt-Jakob disease. We investigated whether they were at increased risk of death from other conditions, particularly preventable conditions. STUDY DESIGN: A cohort (N=6107) from known US pituitary-derived GH recipients (treated 1963-1985) was studied. Deaths were identified by reports from physicians and parents and the National Death Index. Rates were compared with the expected rates for the US population standardized for race, age, and sex. RESULTS: There were 433 deaths versus 114 expected (relative risk [RR], 3.8; 95% confidence interval [CI], 3.4-4.2; P<.0001) from 1963 through 1996. Risk was increased in subjects with GH deficiency caused by any tumor (RR, 10.4; 95% CI, 9.1-12.0; P<.0001). Surprisingly, subjects with hypoglycemia treated within the first 6 months of life were at extremely high risk (RR, 18.3; 95% CI, 9.2-32.8; P<.0001), as were all subjects with adrenal insufficiency (RR, 7.1; 95% CI, 6.2-8.2; P<.0001). A quarter of all deaths were sudden and unexpected. Of the 26 cases of Creutzfeldt-Jakob disease, four cases have died since 2000. CONCLUSIONS: The death rate in pituitary-derived GH recipients was almost four times the expected rate. Replacing pituitary-derived GH with recombinant GH has eliminated only the risk of Creutzfeldt-Jakob disease. Hypoglycemia and adrenal insufficiency accounted for far more mortality than Creutzfeldt-Jakob disease. The large number of potentially preventable deaths in patients with adrenal insufficiency and hypoglycemia underscores the importance of early intervention when infection occurs in patients with adrenal insufficiency, and aggressive treatment of panhypopituitarism.     

Excess mortality and morbidity among small-for-gestational-age premature infants: a population-based study

OBJECTIVE: We examined the effect of intrauterine growth restriction on mortality and morbidity in the Israel cohort of very low birth weight premature infants. METHODS: The study population included 2764 singleton very low birth weight infants without congenital malformations born from 24 to 31 weeks of gestation during 1995 to 1999. Four hundred six (15%) were born small for gestational age (SGA). The effect of SGA on death, bronchopulmonary dysplasia, and retinopathy of prematurity was assessed using multiple logistic regression analysis. RESULTS: After adjustment for perinatal risk factors, SGA infants had a 4.52-fold risk for death (95% CI, 3.24-6.33), a 3.42-fold risk for bronchopulmonary dysplasia (95% CI, 2.29-5.13), and a 2.06-fold risk for grade 3 to 4 retinopathy of prematurity (95% CI, 1.15-3.66). CONCLUSIONS: SGA premature infants had an increased risk for death, and major morbidity among survivors was increased.