Oral Clefts and Academic Performance in Adolescence: The Impact of Anesthesia-Related Neurotoxicity, Timing of Surgery, and Type of Oral Clefts.

OBJECTIVE: Early life exposure to anesthesia and surgery is suspected to associate with cognitive impairment later in life. We compared academic achievement among adolescents with cleft lip only (CL), cleft palate only (CP), and cleft lip and cleft palate (CLP) with a noncleft control group to investigate whether outcome depends on timing and number of operations during childhood and/or type of oral cleft. DESIGN: Nationwide register-based follow-up study. SETTING: Danish birth cohort 1986 to 1990. PARTICIPANTS: Five hundred fifty-eight children with isolated CL (n = 171), CLP (n = 222), or CP (n = 195), of which 509 children had been exposed to anesthesia and one or more cleft operation(s), and a 5% sample of the birth cohort (n = 14,677). MAIN OUTCOME MEASURE(S): Test score in the Danish standardized ninth-grade exam and proportion of nonattainment, defined as "results for ninth-grade exam unavailable." Data adjusted for sex, birth weight, parental age, and parental level of education. RESULTS: Compared to controls, children with CL achieved higher scores (mean difference 0.12, 95% CI -0.05; 0.29) and children with CLP presented with lower scores (mean difference -0.06, 95% CI -0.21; 0.09), albeit both statistically insignificant. Children with CP achieved significantly lower scores, mean difference -0.20 (95% CI -0.38; -0.03). Odds ratios for nonattainment at final exam were: CL 0.79 (95% CI 0.46; 1.35), CLP 1.07 (95% CI 0.71; 1.61), CP 2.59 (95% CI 1.78; 3.76). CONCLUSIONS: Oral cleft type rather than number and timing of anesthesia and operations associate to poorer academic performance. Although a potential neurotoxic effect due to anesthetic agents is not reflected in the data, it cannot be completely excluded.

Cancer and aging: Epidemiology and methodological challenges.

Epidemiological cancer data shed light on key questions within basic science, clinical medicine and public health. For decades, Denmark has had linkable health registers that contain individual level data on the entire population with virtually complete follow-up. This has enabled high quality studies of cancer epidemiology and minimized the challenges often faced in many countries, such as uncertain identification of the study base, age misreporting, and low validity of the cancer diagnoses. However, methodological challenges still remain to be addressed, especially in cancer epidemiology studies among the elderly and the oldest-old. For example, a characteristic pattern for many cancer types is that the incidence increases up to a maximum at about ages 75-90 years and is then followed by a decline or a leveling off at the oldest ages. It has been suggested that the oldest individuals may be asymptomatic, or even insusceptible to cancer. An alternative interpretation is that this pattern is an artifact due to lower diagnostic intensity among the elderly and oldest-old caused by higher levels of co-morbidities in this age group. Currently, the available cancer epidemiology data are not able to provide clear evidence for any of these hypotheses.

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study.

BACKGROUND: Few human cohort studies on anesthesia-related neurotoxicity and the developing brain have focused on and compared specific surgeries and conditions. These studies cannot disentangle the effects of anesthesia from those of the surgery and underlying conditions. This study aimed at assessing the impact of specific neurosurgical conditions and procedures in infancy on mortality and academic achievements in adolescence. METHODS: A nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared academic performances of all children having undergone neurosurgeries as infants with a randomly selected, age-matched 5% sample of the same cohorts. The two groups were compared regarding mortality prior to June 1st, 2006, average test scores at ninth grade, and finally the proportion of children not attaining test scores. RESULTS: The exposure group comprised 228 and the control group 14 698 individuals. Hydrocephalus (n = 130), craniotomy (n = 43), and myelomeningocele/encephalocele children (n = 55) had a higher mortality (18.5.0%, 18.6%, and 7.3%, respectively) vs controls (1.3%; P < 0.00001, P < 0.00001, and P = 0.0052, respectively). Average test scores were significantly lower than controls in hydrocephalus and craniotomy (P = 0.0043 and P = 0.0077) but not myelomeningocele/encephalocele children (P = 0.2785); the proportion of available test scores were significantly lower in all three groups (40.8%, 60.0%, and 67.3%, respectively) vs 86.8% in controls (P < 0.00001, P = 0.000077, and P = 0.000064). CONCLUSION: Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Pooling of major/minor conditions and major/minor surgeries should be avoided.

Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study.

BACKGROUND: Immature animals exposed to anesthetics display apoptotic neurodegeneration with subsequent long-term cognitive dysfunctions. Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study investigated the association between exposure to surgery and anesthesia for pyloric stenosis (PS) before 3 months of age and subsequent educational outcome in adolescence. METHODS: This nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared the educational outcome of all children having undergone surgery for PS before 3 months of age with a randomly selected, age-matched 5% sample of the same cohort. Primary analysis compared the average test scores at ninth grade adjusting for gender, birth weight, and parental age and education. Secondary analysis compared the proportions not attaining the test scores between the two groups. RESULTS: The exposure group comprised 779 and the control group consisted of 14 665 individuals. Although the exposure group performed lower than the control group (average score 0.17 lower, 95% CI: 0.08-0.25), after adjusting for known confounders, no statistically significant difference (-0.04, 95% CI: -0.09 to 0.08) between the 2 groups could be demonstrated. However, we found an odds ratio (OR) for test score nonattainment-associated PS repair of 1.37 (95% CI: 1.11-1.68). CONCLUSION: Children operated for PS before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged.

Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study.

BACKGROUND: Although animal studies have indicated that general anesthetics may result in widespread apoptotic neurodegeneration and neurocognitive impairment in the developing brain, results from human studies are scarce. We investigated the association between exposure to surgery and anesthesia for inguinal hernia repair in infancy and subsequent academic performance. METHODS: Using Danish birth cohorts from 1986-1990, we compared the academic performance of all children who had undergone inguinal hernia repair in infancy to a randomly selected, age-matched 5% population sample. Primary analysis compared average test scores at ninth grade adjusting for sex, birth weight, and paternal and maternal age and education. Secondary analysis compared the proportions of children not attaining test scores between the two groups. RESULTS: From 1986-1990 in Denmark, 2,689 children underwent inguinal hernia repair in infancy. A randomly selected, age-matched 5% population sample consists of 14,575 individuals. Although the exposure group performed worse than the control group (average score 0.26 lower; 95% CI, 0.21-0.31), after adjusting for known confounders, no statistically significant difference (-0.04; 95% CI, -0.09 to 0.01) between the exposure and control groups could be demonstrated. However, the odds ratio for test score nonattainment associated with inguinal hernia repair was 1.18 (95% CI, 1.04-1.35). Excluding from analyses children with other congenital malformations, the difference in mean test scores remained nearly unchanged (0.05; 95% CI, 0.00-0.11). In addition, the increased proportion of test score nonattainment within the exposure group was attenuated (odds ratio = 1.13; 95% CI, 0.98-1.31). CONCLUSION: In the ethnically and socioeconomically homogeneous Danish population, we found no evidence that a single, relatively brief anesthetic exposure in connection with hernia repair in infancy reduced academic performance at age 15 or 16 yr after adjusting for known confounding factors. However, the higher test score nonattainment rate among the hernia group could suggest that a subgroup of these children are developmentally disadvantaged compared with the background population.

Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study.

The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival.

Declining cancer incidence at the oldest ages: Hallmark of aging or lower diagnostic activity?

BACKGROUND: The incidence of most cancers increases with age from early adulthood into old age but tends to level off or decrease at the highest ages. This decline may be caused by age-related mechanisms or due to lower diagnostic activity, leaving some cancers undiagnosed at the oldest ages. METHODS: For breast, colon, lung, and all sites except non-melanoma skin cancer, age-specific incidence rates of verified as well as suspected cancer were estimated up to ages 95+ years for a random sample of the Danish population, 1994-2011, based on nationwide health registers (40,008 verified and 9110 suspected cancers). Moreover, for cancers diagnosed in Denmark, 1978-2012 (613,384 cancers), age-specific percentages of tumors with microscopic verification (histological/cytological/hematological examination) were calculated. RESULTS: The age-specific cancer incidence rates reached a peak between ages 65-89 years after which rates declined. The corresponding incidence pattern of suspected but not verified cancer was similar, with a trend of a slight absolute and relative decrease with age compared to verified cancer incidence. The proportion of cancers with microscopic verification decreased linearly from approximately 95% at ages 0-69 years all years to 70% (1978-1982) and to 80% (2010-2012) at ages 90+ years. CONCLUSIONS: The lower diagnostic verification of cancer at the highest ages suggests a lower diagnostic activity among the oldest-old. However, the proportion of suspected but not verified cancers did not increase with age, possibly partially due to lack of registration. The declining cancer incidence at oldest ages is probably partly due to lower diagnostic activity.

The Survival of Spouses Marrying Into Longevity-Enriched Families.

BACKGROUND: Studies of longevity-enriched families are an important tool to gain insight into the mechanisms of exceptionally long and healthy lives. In the Long Life Family Study, the spouses of the members of the longevity-enriched families are often used as a control group. These spouses could be expected to have better health than the background population due to shared family environment with the longevity-enriched family members and due to assortative mating. METHODS: A Danish cohort study of 5,363 offspring of long-lived siblings, born 1917-1982, and 4,498 "first spouses" of these offspring. For each offspring and spouse, 10 controls were drawn from a 5% random sample of the Danish population matched on birth year and sex. Mortality was assessed for ages 20-69 years during 1968-2013 based on prospectively collected registry data. RESULTS: During the 45-year follow-up period, 437 offspring deaths and 502 offspring spouse deaths were observed. Compared with the background population, the hazard ratio for male offspring was 0.44 (95% confidence interval [CI]: 0.38-0.50) and for female offspring it was 0.57 (95% CI: 0.49-0.66). For male spouses, the hazard ratio was 0.66 (95% CI: 0.59-0.74), whereas for female spouses it was 0.64 (95% CI: 0.54-0.76). Sensitivity analyses in restricted samples gave similar results. CONCLUSION: The mortality for ages 20-69 years of spouses marrying into longevity-enriched families is substantially lower than the mortality in the background population, although long-lived siblings participation bias may have contributed to the difference. This finding has implications for the use of spouses as controls in healthy aging and longevity studies, as environmental and/or genetic overmatching may occur.

Low tobacco-related cancer incidence in offspring of long-lived siblings: a comparison with Danish national cancer registry data.

PURPOSE: Familial clustering of longevity is well documented and includes both genetic and other familial factors, but the specific underlying mechanisms are largely unknown. We examined whether low incidence of specific cancers is a mechanism for familial clustering of longevity. METHODS: The study population of individuals from longevity-enriched families consisted of 3267 offspring from 610 Danish long-lived families defined by two siblings attaining an age of 90 years or more. The offspring of the long-lived siblings were followed from 1968 to 2009. Using high-quality registry data, observed numbers of cancers were compared with expected numbers based on gender-, calendar period-, and age-specific incidence rates in the general population. RESULTS: During the 41-year-follow-up period, a total of 423 cancers occurred in 397 individuals. The standardized incidence ratios (95% confidence interval) for offspring of long-lived individuals were 0.78 (0.70-0.86) for overall cancer; 0.66 (0.56-0.77) for tobacco-related cancer; 0.34 (0.22-0.51) for lung cancer; 0.88 (0.71-1.10) for breast cancer; 0.91 (0.62-1.34) for colon cancer. CONCLUSIONS: The low incidence of tobacco-related cancers in long-lived families compared with non-tobacco-related cancers suggests that health behavior plays a central role in lower early cancer incidence in offspring of long-lived siblings in Denmark.

Cancer and longevity--is there a trade-off? A study of cooccurrence in Danish twin pairs born 1900-1918.

BACKGROUND: Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin. METHODS: A total of 4,354 twin pairs born 1900-1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943-2008 through the Danish Cancer Registry. RESULTS: The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and, 2,524 cancers were diagnosed. A negative association between age at death of a twin and cancer incidence in the cotwin was found in the overall analyses as well as in the subanalysis stratified on sex, zygosity, and random selection of one twin from each twin pair. CONCLUSIONS: This study did not find evidence of a cancer-longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity.