Does Prolonged Education Causally Affect Dementia Risk When Adult Socioeconomic Status Is Not Altered? A Swedish Natural Experiment in 1.3 Million Individuals.

Intervening on modifiable risk factors to prevent dementia is of key importance, since progress-modifying treatments are not currently available. Education is inversely associated with dementia risk, but causality and mechanistic pathways remain unclear. We aimed to examine the causality of this relationship in Sweden using, as a natural experiment, data on a compulsory schooling reform that extended primary education by 1 year for 70% of the population between 1936 and 1949. The reform introduced substantial exogenous variation in education that was unrelated to pupils' characteristics. We followed 18 birth cohorts (n = 1,341,842) from 1985 to 2016 (up to ages 79-96 years) for a dementia diagnosis in the National Inpatient and Cause of Death registers and fitted Cox survival models with stratified baseline hazards at the school-district level, chronological age as the time scale, and cohort indicators. Analyses indicated very small or negligible causal effects of education on dementia risk (main hazard ratio = 1.01, 95% confidence interval: 0.98, 1.04). Multiple sensitivity checks considering only compliers, the pre-/post- design, differences in health-care-seeking behavior, and the impact of exposure misclassification left the results essentially unaltered. The reform had limited effects on further adult socioeconomic outcomes, such as income. Our findings suggest that without mediation through adult socioeconomic position, education cannot be uncritically considered a modifiable risk factor for dementia.

The role of social capital in explaining mental health inequalities between immigrants and Swedish-born: a population-based cross-sectional study.

BACKGROUND: Social capital may theoretically explain health inequalities between social groups, but empirical evidence is lacking. Some studies indicate that social capital may be particularly important for immigrant health. Nearly 16% of Sweden's population are foreign-born immigrants and research has shown them to be susceptible to psychological distress, though significant variation has been found between groups. In this study, we investigate the following hypotheses: 1) if non-refugees have better mental health than Swedish-born, and refugees experience worse mental health than Swedish-born; 2) if mental health status converges with that of Swedish-born with longer duration of residence; and 3) if social capital mediates the effect of immigrant status on psychological distress for different immigrant groups as compared to Swedish-born. METHODS: This cross-sectional study uses baseline data from the Stockholm Public Health Cohort and includes 50,498 randomly-selected individuals from Stockholm County in 2002, 2006, and 2010. Mental health was measured as psychological distress, using the 12-item General Health Questionnaire. Social capital was measured using indicators of bonding, bridging, and linking social capital. Both cognitive and structural aspects were measured for the latter two indicators. Mediation was tested using logistic regression and the Sobel test. RESULTS: The results show that refugees generally had greater odds of psychological distress than non-refugees compared to their respective Swedish-born counterparts. Among immigrant men, both refugees and non-refugees had significantly greater odds of psychological distress than Swedish-born men. Only refugee women in Sweden 10 years or more had significantly greater odds of psychological distress compared to Swedish-born women. The mediation analysis demonstrated that indicators of social capital mediated the association for all immigrant men (except non-refugees in Sweden 3-9 years) and for refugee women in Sweden 10 years or more. While bonding social capital showed the greatest mediatory role among the three social capital types, adding them together had the strongest explanatory effect. CONCLUSIONS: Social capital explains differences in mental health for some immigrant groups, highlighting its role as a potentially important post-migration factor. Increased investment from policy-makers regarding how social capital can be promoted among new arrivals may be important for preventing psychological distress.

Residential area and physical activity: A multi-level study of 68,000 adults in Stockholm County.

AIM: To determine whether there are systematic differences in physical activity between residential areas after extensive control for sociodemographic factors at the individual level. METHODS: Multi-level regressions of walking/bicycling, sedentary activities, household work and exercise were carried out in a representative sample of 68,303 adults in 39 residential areas in Stockholm County, first adjusting at the individual level for country of birth, sex, age, education, occupational class and income. The type of housing was then considered at the individual level or, for walking/bicycling and exercise, at both the individual and area levels (as a measure of area density). RESULTS: After adjustment for sociodemographic factors, differences between residential areas remained in walking/bicycling, corresponding to 0.27 SD, or 50 min/week between the most and least active areas. Forty per cent of this difference could be explained by the type of housing at the area level. For sedentary activities and household work, respectively, much of the variation that remained after adjustment for sociodemographic factors was, in turn, explained by the type of housing at the individual level, leaving a difference of 0.16 SD (80 min/week) and 0.13 SD (60 min/week), respectively. For exercise, the corresponding difference was 0.11 SD (11 min/week, not sensitive to housing). CONCLUSIONS: Area level factors may influence walking/bicycling. High area density was associated with more activity. However, high density also comes with a type of housing (apartments) that is associated with less household work and, surprisingly, more sedentary activities, introducing a challenging trade-off. The differences in exercise were smaller than for all other types of activities.

Maternal smoking during pregnancy and offspring's tobacco dependence. A study of exposure-discordant sibling pairs.

BACKGROUND: Prenatal exposure to maternal smoking has previously been linked to tobacco dependence, but confounding from genetic and early-environmental factors is of concern. The aim of this study was to clarify if maternal smoking during pregnancy may affect the onset and manifestations of tobacco dependence after taking such factors into account. METHODS: The study is based on a matched cohort of 1538 siblings discordant for prenatal exposure to maternal smoking, who participated in a survey conducted in 2010 in Sweden. Analyses were based on pairs where both siblings had been daily smokers (193 pairs) or snus users (173 pairs) at some time in their life. Participants were 19-27 years old at the time of participation. Outcomes were tobacco dependence measured with the Cigarette Dependence Scale (CDS-12) in smokers and with the adapted Smokeless Tobacco Dependence Scale (STDS-12) in snus users, and previous quit attempts. Exposure to maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. RESULTS: There was no difference in dependence scores in exposure-discordant siblings (mean difference 0.36 on CDS-12 [95% confidence interval: -1.23 to 1.95] and 0.61 on STDS-12 [95% confidence interval: -1.20 to 2.43]). Neither did the siblings differ with regard to previous quit attempts. CONCLUSIONS: Maternal smoking during pregnancy does not appear to influence tobacco dependence in adult offspring. A potential effect of heavy maternal smoking during pregnancy cannot be excluded, but genetic and environmental influences seem to be more influential for the onset of tobacco dependence.

The effect of the work environment on future sleep disturbances: a systematic review.

Workers often attribute poor sleep to factors at work. Despite the large number of workers with sleep disturbances, there is a lack of consensus on the relationship between the work environment and sleep. The purpose of this systematic review therefore was to conduct a comprehensive evaluation. To this end, we employed standardized methods to systematically locate, review, and tabulate the results of prospective or randomized studies of the impact of work factors on sleep disturbances. From the 7981 articles located in five databases, 24 fulfilled our inclusion criteria and formed the base of the review including meta-analyses of the effect sizes. Results showed that the psychosocial work variables of social support at work, control, and organizational justice were related to fewer sleep disturbances, while high work demands, job strain, bullying, and effort-reward imbalance were related to more future sleep disturbances. Moreover, working a steady shift was associated with disturbances while exiting shift work was associated with less disturbed sleep. We conclude that psychosocial work factors and the scheduling of work have an impact on sleep disturbances and this might be utilized in the clinic as well as for planning work environments. Future research needs to employ better methodology and focus on underlying mechanisms.

Advancing paternal age and schizophrenia: the impact of delayed fatherhood.

OBJECTIVE: It is well known that advancing paternal age is associated with an increased risk of schizophrenia in offspring, but the mechanism behind this association remains unknown. This study investigates if delayed fatherhood rather than advancing paternal age per se might explain the increased risk of schizophrenia in offspring associated with advancing paternal age. METHODS: This is a register-based study of the Swedish population looking at people born 1955-1985 who have 1 or 2 siblings (n = 2 589 502). The main analysis investigated whether the association between advancing paternal age and schizophrenia was explained by delayed fatherhood. Possible confounding factors were taken into account. Cox regression was used throughout. RESULTS: In the main analysis the association between advancing paternal age and increased risk of schizophrenia in offspring disappeared after controlling for delayed fatherhood (hazard ratio [HR] = 0.93, 95% CI = 0.72-1.21 comparing 45+ years old fathers to those 25-29), whereas delayed fatherhood showed an association with increased risk of schizophrenia in offspring comparing 35-39 and 40-44 years old fathers to 25-29 year olds (HR = 1.37, 95% CI = 1.18-1.58; HR = 1.81, 95% CI = 1.44-2.28, respectively). The results remained when controlling for possible confounders. CONCLUSIONS: This study suggests that the association between paternal age and schizophrenia is not due to paternal age per se, but rather to an unknown factor associated with both delayed fatherhood and schizophrenia.

Exposure to maternal smoking during pregnancy as a risk factor for tobacco use in adult offspring.

Nicotine from maternal smoking during pregnancy can cross the placental barrier, possibly resulting in fetal brain sensitization, as indicated by studies in which prenatal exposure to maternal smoking was associated with an increased risk of tobacco use among adolescent offspring. We investigated whether this association persists beyond adolescence by studying cigarette smoking and the use of snus (Swedish oral moist snuff) among 983 young adults from a prospective cohort study conducted in Stockholm, Sweden, between 2006 and 2010. Self-reported questionnaire data were linked with data from national population-based registers from 1983 onward. Maternal smoking during pregnancy was consistently associated with snus use in offspring (e.g., for lifetime daily snus use, adjusted odds ratio = 2.04, 95% confidence interval: 1.32, 3.16; for use of >3 cans of snus per week vs. less, odds ratio = 3.85, 95% confidence interval: 1.57, 10.15). No association was apparent with offspring's smoking, age at onset of tobacco use, or changes in use between 2006 and 2010. These findings indicate that prenatal exposure to maternal smoking is associated with regular and heavy nicotine intake from smokeless tobacco rather than from smoking. This should be further explored in epidemiologic studies that simultaneously address the roles of genetics and social environments.

Parental age and the risk of autism spectrum disorders: findings from a Swedish population-based cohort.

BACKGROUND: The objectives of this study were to examine the independent and dependent associations of maternal and paternal age and risk of offspring autism spectrum disorders (ASD), with and without intellectual disability (ID). METHODS: The sample consisted of 417 303 Swedish children born 1984-2003. ASD case status (N = 4746) was ascertained using national and regional registers. Smoothing splines in generalized additive models were used to estimate associations of parental age with ASD. RESULTS: Whereas advancing parental age increased the risk of child ASD, maternal age effects were non-linear and paternal age effects were linear. Compared with mothers at the median age 29 years, those <29 had similar risk, whereas risk increased after age 30, with an odds ratio (OR) of 1.75 [95% (CI): 1.63-1.89] at ages 40-45. For fathers, compared with the median age of 32 years, the OR for ages 55-59 was 1.39 (1.29-1.50). The risk of ASD was greater for older mothers as compared with older fathers. For example, mothers aged 40-45 (≥97.2th percentile) had an estimated 18.63 (95% CI: 17.25-20.01) ASD cases per 1000 births, whereas fathers aged 55-59 (≥99.7th percentile) had 16.35 (95% CI: 15.11-17.58) ASD cases per 1000 births. In analyses stratified by co-parental age, increased risk due to advancing paternal age was evident only with mothers ≤35 years. In contrast, advancing maternal age increased risk regardless of paternal age. Advancing parental age was more strongly associated with ASD with ID, compared with ASD without ID. CONCLUSIONS: We confirm prior findings that advancing parental age increases risk of ASD, particularly for ASD with ID, in a manner dependent on co-parental age. Although recent attention has emphasized the effects of older fathers on ASD risk, an increase of n years in maternal age has greater implications for ASD risk than a similar increase in paternal age.

Deviance in fetal growth and risk of autism spectrum disorder.

OBJECTIVE: Understanding the relationship between fetal growth and autism spectrum disorder (ASD) is likely to advance the search for genetic and nongenetic causes of ASD. The authors explored the associations between fetal growth, gestational age, and ASD with and without comorbid intellectual disability in a Scandinavian study population. METHOD: The authors conducted a matched nested case-control study within the Stockholm Youth Cohort that included all children ages 0-17 who resided in Stockholm County from 2001 to 2007 (N=589,114). The authors identified 4,283 children with ASD: 1,755 with intellectual disability and 2,528 without, and they selected 36,588 age- and sex-matched comparison subjects. ASD case subjects were ascertained from unique identifiers assigned to all Swedish residents and linkage with official registers covering all pathways of assessment or care of ASD in Stockholm County. The authors calculated z scores of deviance in fetal growth from a reference curve using records from the national Swedish Medical Birth Registry, which included ultrasound dating of gestational age as well as birth weight. Crude and adjusted odds ratios for ASD, ASD with intellectual disability, and ASD without intellectual disability were the main outcome measures. RESULTS: ASD risk increased with fetal growth 1.50 standard deviations below and >2.00 standard deviations above the mean for gestational age; the greatest risk was for fetal growth that was less than 2.00 standard deviations below the mean (adjusted odds ratio=1.70; 95% CI=1.44-2.01) or greater than 2.00 standard deviations above the mean (adjusted odds ratio=1.50; 95% CI=1.27-1.77). The same overall pattern was observed for ASD with and without intellectual disabilities. However, poor fetal growth (i.e., growth below the mean) was more strongly associated with ASD with intellectual disabilities than without. Regardless of fetal growth, preterm birth increased ASD risk. CONCLUSIONS: Deviance in fetal growth at either distributional extreme may be a significant antecedent to the development of ASD through genetic and/or nongenetic mechanisms.

Maternal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births.

This study examines the familial clustering and relative influence of genetic and environmental effects on postterm birth in the Swedish population by considering all full- and half-siblings born in Sweden between 1992 and 2004. Of the eligible 475,429 births, 21% occurred after 41 completed weeks and 5.5% occurred after 42 completed weeks of gestation. Odds of postterm birth increased if mothers were older, heavier, more educated, primiparous, or carrying a male fetus. The highest odds increase was seen in women with a previous postterm birth, both with the same partner (odds ratio = 4.4, 95% confidence interval: 4.0, 4.6) and after a partner change (odds ratio = 3.4, 95% confidence interval: 2.9, 3.9). Sisters of women with a postterm birth were also at increased odds of postterm birth (odds ratio = 1.8, 95% confidence interval: 1.6, 2.0) while brothers' partners were not. Half of the variation in postterm birth could not be explained by factors shared in families, and the remaining half was explained by genetic factors, namely fetal (26%) and maternal (21%) genetic factors. Familial clustering of postterm birth is attributed to genetic effects, and fetal genetic effects have a considerable influence on the liability of postterm birth.

Cohort profile: The Stockholm Public Health Cohort.

The Stockholm Public Health Cohort was set up within the Stockholm County Council public health surveys to inform on determinants and consequences of significant contributors to the current burden of disease. Participants are 89 268 randomly selected individuals from the adult population of Stockholm County. Baseline surveys took place in 2002, 2006 and 2010 via self-administered questionnaires. So far, participants recruited in 2002 were re-surveyed twice, in 2007 and 2010, and those enrolled in 2006 were re-surveyed once, in 2010. Self-reported data are regularly supplemented by information from national and regional health data and administrative registers, for study participants and their relatives (including their offspring). Available data are extensive and include a wide array of health, lifestyle, perinatal, demographic, socio-economic and familial factors. The cohort is an international resource for epidemiological research, and the data available to the research community for specific studies obtained approval from the Stockholm Public Health Cohort Steering Committee and the Stockholm Regional Ethical Review Board.

Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings.

CONTEXT: It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. OBJECTIVES: To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. DESIGN: We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. SETTING: Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. PARTICIPANTS: In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. MAIN OUTCOME MEASURES: Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. RESULTS: Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P < 10-10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; P < .01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). In the case of depression, this more than compensated for the lower fecundity of affected individuals. CONCLUSIONS: Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.

Family history of schizophrenia and bipolar disorder as risk factors for autism.

CONTEXT: The clinical and etiologic relation between autism spectrum disorders (ASDs) and schizophrenia is unclear. The degree to which these disorders share a basis in etiology has important implications for clinicians, researchers, and those affected by the disorders. OBJECTIVE: To determine whether a family history of schizophrenia and/or bipolar disorder is a risk factor for ASD. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control evaluation of histories of schizophrenia or bipolar disorder in first-degree relatives of probands in 3 samples­population registers in Sweden, Stockholm County (in Sweden), and Israel. Probands met criteria for ASD, and affection status of parents and siblings for schizophrenia and bipolar disorder were established. RESULTS: The presence of schizophrenia in parents was associated with an increased risk for ASD in a Swedish national cohort (odds ratio [OR], 2.9; 95% CI, 2.5-3.4) and a Stockholm County cohort (OR, 2.9; 95% CI, 2.0-4.1). Similarly, schizophrenia in a sibling was associated with an increased risk for ASD in a Swedish national cohort (OR, 2.6; 95% CI, 2.0-3.2) and an Israeli conscription cohort (OR, 12.1; 95% CI, 4.5-32.0). Bipolar disorder showed a similar pattern of associations but of lesser magnitude. CONCLUSIONS: Findings from these 3 registers along with consistent findings from a similar study in Denmark suggest that ASD, schizophrenia, and bipolar disorder share common etiologic factors.

Familial aggregation of schizophrenia: the moderating effect of age at onset, parental immigration, paternal age and season of birth.

AIMS: An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia. METHODS: A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5,075,998 full siblings born between 1932 through to 1990, 16,346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected people. RESULTS: We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95% confidence interval (95% CI) 6.7-7.9) than of early onset cases (10.8; 95% CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95% CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95% CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95% CI 4.0-5.7, paternal immigrants 5.7; 95% CI 4.6-6.9) than among offspring to parents born in Sweden. CONCLUSIONS: The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.

Implications of advancing paternal age: does it affect offspring school performance?

Average paternal age is increasing in many high income countries, but the implications of this demographic shift for child health and welfare are poorly understood. There is equivocal evidence that children of older fathers are at increased risk of neurodevelopmental disorders and reduced IQ. We therefore report here on the relationship between paternal age and a composite indicator of scholastic achievement during adolescence, i.e. compulsory school leaving grades, among recent birth cohorts in Stockholm County where delayed paternity is notably common. We performed a record-linkage study comprising all individuals in Stockholm County who finished 9 years of compulsory school from 2000 through 2007 (n = 155,875). Data on school leaving grades and parental characteristics were retrieved from administrative and health service registers and analyzed using multiple linear regression. Advancing paternal age at birth was not associated with a decrease in school leaving grades in adolescent offspring. After adjustment for year of graduation, maternal age and parental education, country of birth and parental mental health service use, offspring of fathers aged 50 years or older had on average 0.3 (95% CI -3.8, 4.4) points higher grades than those of fathers aged 30-34 years. In conclusion, advancing paternal age is not associated with poorer school performance in adolescence. Adverse effects of delayed paternity on offspring cognitive function, if any, may be counterbalanced by other potential advantages for children born to older fathers.

The Janus face of statistical adjustment: confounders versus colliders.

It has long been established that controlling for confounders is essential to delineate the causal relationship between exposure and disease. For this purpose, statistical adjustment is widely used in observational studies. However, many researchers don't acknowledge the potential pitfalls of statistical adjustment. The aim of the present paper was to demonstrate that statistical adjustment is a double edged sword. By using numerically identical examples, we show that adjustment for a common consequence of the exposure and the outcome can lead to as much bias as absence of necessary adjustment for a confounder.

Maternal effects for preterm birth: a genetic epidemiologic study of 630,000 families.

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.

Fertility of first-degree relatives of patients with schizophrenia: a three generation perspective.

We explored the fertility in three generations; fertility of parents, siblings and offspring to patients with schizophrenia, to test the hypothesis that the decreased reproductive rate in the patients is compensated by an increased rate in their first-degree relatives. A population-based national database was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. To maximize follow-up time for schizophrenia and reproductive history, three birth cohorts were selected: parental generation, born 1918-1927 (n=274464); affected generation, born 1932-1941 (n=108502) and offspring to affected generation, born 1951-1960 (n=103105). Ratios of estimated mean number of offspring were measured (fertility ratios), comparing the study subjects to the general population. The fertility among males with schizophrenia was decreased by over 70% (fertility ratio(patients/population)=0.29, 95% CI 0.25-0.35), whereas female patients had less than half as many offspring as the general female population (fertility ratio(patients/population)=0.48, 95% CI 0.42-0.55). When accounting for selection bias of larger families, no statistically significant difference was found among parents of patients with and without a diagnosis of schizophrenia. Further, the fertility among siblings of schizophrenic patients did not differ from the general population. A reduction in fertility was found among offspring to patients with schizophrenia, male offspring had 12% fewer offspring (fertility ratio(offspring/population)=0.88, 95%CI 0.77-1.01), while female offspring had 6% fewer offspring (fertility ratio(offspring/population)=0.94, 95% CI 0.84-1.05). In conclusion, we found reduced fertility in patients with schizophrenia and among their offspring that was not compensated by higher parental or sibling fertility.