Are paternal or grandmaternal age associated with higher probability of trisomy 21 in offspring? A population-based, matched case-control study, 1995-2015.

BACKGROUND: Fetal aneuploidy risk increases with maternal age, but the majority of pregnancies complicated by trisomy 21 occur in younger women. It has been suggested that grandmaternal and/or paternal age may also play a role. OBJECTIVES: To assess the association between grandmaternal and paternal age and trisomy 21. METHODS: For the grandmaternal assessments, we included all offspring with trisomy 21 in a statewide birth defects surveillance system (1995-2015) that could be linked to 3-generation matrilineal pedigrees in the Utah Population Database. Ten sex/birth year-matched controls were selected for each case (770 cases and 7700 controls). For the paternal assessments, our cohort included all trisomy 21 cases (1995-2015) where both the mother and father resided in Utah at the time of birth (1409 cases and 14 090 controls). Ages were categorised by 5-year intervals (reference: 25-29 years). Conditional logistic regression, adjusting for potential confounding factors, was used to model the association between grandmaternal and paternal age and trisomy 21. RESULTS: No association between grandmaternal age and trisomy 21 was detected, whether age was assessed continuously (adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.98, 1.03) or categorically after adjusting for grandmaternal and grandpaternal race/ethnicity and grandpaternal age. Compared to fathers aged 20-29 years, fathers <20 years (OR 3.15, 95% CI 1.99, 4.98) and 20-24 years (OR 1.39, 95% CI 1.11, 1.73) had increased odds of trisomy 21 offspring, after adjusting for maternal and paternal race/ethnicity and maternal age. Results were consistent after excluding stillbirths, multiples, and trisomy 21 due to translocation or mosaicism. CONCLUSIONS: Maternal age is an important risk factor for trisomy 21 offspring; however, this population-based study shows that that young paternal age is also associated with trisomy 21, after taking into account maternal age and race/ethnicity.

Dying with dementia in nursing homes: A population-based study of decedents and their families.

BACKGROUND: Families play a critical role in end-of-life (EOL) care for nursing home (NH) residents with dementia. Despite the important role of family, little is known about the availability and characteristics of families of persons with dementia who die in NHs. METHODS: This is a retrospective cohort study of 18,339 individuals 65 years and older with dementia who died in a Utah NH between 1998 and 2016, linked to their first-degree family (FDF) members (n = 52,566; spouses = 11.3%; children = 58.3%; siblings = 30.3%). Descriptive statistics, chi-square tests, and t-tests were used to describe the study cohort and their FDF members and to compare sociodemographic and death characteristics of NH decedents with (n = 14,398; 78.5%) and without FDF (n = 3941; 21.5%). RESULTS: Compared with NH decedents with FDF, NH decedents with dementia without FDF members were more likely to be older (mean age 86.5 vs 85.5), female (70.5% vs 59.3%), non-White/Hispanic (9.9% vs 3.2%), divorced/separated/widowed (84.4% vs 61.1%), less educated (<12th grade; 42.2% vs 33.7%), have Medicare and Medicaid (20.8% vs 12.5%), and die in a rural/frontier NH (25.0% vs 23.4%). NH decedents who did not have FDF were also more likely to die from cancer (4.2% vs 3.9%), chronic obstructive pulmonary disease (COPD; 3.9% vs 2.5%), and dementia (40.5% vs 38.4%) and were less likely to have 2+ inpatient hospitalizations at EOL (13.9% vs 16.2%), compared with NH decedents with FDF. CONCLUSIONS: Findings highlight differences in social determinants of health (e.g., sex, race, marital status, education, insurance, rurality) between NH decedents with dementia who do and do not have FDF-factors that may influence equity in EOL care. Understanding the role of family availability and familial characteristics on EOL care outcomes for NH residents with dementia is an important next step to informing NH dementia care interventions and health policies.

BRCA1 and BRCA2 mutations and female fertility.

PURPOSE OF REVIEW: To review recent publications examining BRCA1 and BRCA2 mutations and their relationship with female fertility. RECENT FINDINGS: Eight relevant studies of female fertility, five of which were published since January 2010 and the remainder in the preceding decade. Several mechanisms suggest that reproduction will be adversely affected among BRCA1/2 mutation carriers, with one study finding lower oocyte production, another reporting fewer births, and a third showing lower rates of pregnancies. Four articles reported no significant difference in the number of children ever born between carriers and noncarriers whereas a 2012 study showed elevated natural fertility among mutation carriers. SUMMARY: This review shows that for most articles there are adverse or no fertility effects of being a BRCA1/2 mutation carrier. When no differences were detected for children-ever-born, those studies relied on current populations in which women had access to contraception. The sole analysis reporting elevated fertility was based on an historic population in which family planning methods were unavailable. Predictions that BRCA1/2 mutations adversely affect embryogenesis and genome integrity were not supported. The idea that BRCA1/2 mutations have antagonistic pleiotropic effects (enhancing fertility while reducing survival) was supported in the natural fertility study.

Tykes, Toddlers, Teens, and Twins of Robust Mothers: Do the Offspring of Twinning Mothers Share in Their Mother's Robust Phenotype?

Women who bear twins may possess a robust phenotype compared to non-twinning mothers. We examine mortality patterns for the singleton offspring of mothers of twins compared to the offspring of non-twinning mothers to determine whether they share the hypothesized robust phenotype of their mothers. Using data from the Utah Population Database, we show that both male and female singleton offspring of twinning mothers experience a survival disadvantage prior to age 5, no survival benefit or penalty between ages 5 and 49, and - for males only - a statistically significant survival advantage after age 50. We further examine the survival effects on singletons born before and after a twinset. We observe a survival disadvantage in early life for singleton offspring of twinning mothers born after the twinset for both sexes. In addition, we find a significant survival advantage at older ages in certain categories of male singleton offspring - a likely reflection of mortality selection. The findings suggest that while bearing twins may reflect a robust maternal phenotype, the toll of bearing twins may disadvantage subsequent offspring, especially during infancy.

Differential Vulnerability to Early-Life Parental Death: The Moderating Effects of Family Suicide History on Risks for Major Depression and Substance Abuse in Later Life.

Only a portion of those individuals exposed to parental death in early life (PDE) develop behavioral health disorders. We utilized demographic pedigree data from the Utah Population Database to test for differential vulnerability to PDE by creating a risk score of familial susceptibility to suicide (FS) at the population level. Using logistic panel regression models, we tested for multiplicative interactions between PDE and FS on the risks of major depressive disorder (MDD) and substance abuse (SA), measured using Medicare claims, after age 65. The final sample included 155,983 individuals (born 1886-1944), yielding 1,431,060 person-years at risk (1992-2009). Net of several potential confounders, including probability of survival to age 65, we found an FS × PDE interaction for females, in which PDE and FS as main effects had no impact but jointly increased MDD risk. No statistically significant main or interactive effects were found for SA among females or for either phenotype among males. Our findings are consistent with a differential vulnerability model for MDD in females, in which early-life stress increases the risk for poor behavioral health only among the vulnerable. Furthermore, we demonstrate how demographic and pedigree data might serve as tools for investigating differential vulnerability hypotheses.

All-Cause and Cause-Specific Mortality After Hypertensive Disease of Pregnancy.

OBJECTIVE: To assess whether women with a history of hypertensive disease of pregnancy have increased risk for early adult mortality. METHODS: In this retrospective cohort study, women with one or more singleton pregnancies (1939-2012) with birth certificate information in the Utah Population Database were included. Diagnoses were categorized into gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; and eclampsia. Women with more than one pregnancy with hypertensive disease (exposed) were included only once, assigned to the most severe category. Exposed women were matched one to two to unexposed women by age, year of childbirth, and parity at the time of the index pregnancy. The causes of death were ascertained using Utah death certificates and the fact of death was supplemented with the Social Security Death Index. Hazard ratios for cause-specific mortality among exposed women compared with unexposed women were estimated using Cox regressions adjusting for neonatal sex, parental education, preterm delivery, race-ethnicity, and maternal marital status. RESULTS: A total of 60,580 exposed women were matched to 123,140 unexposed women; 4,520 (7.46%) exposed and 6,776 (5.50%) unexposed women had died by 2012. All-cause mortality was significantly higher among women with hypertensive disease of pregnancy (adjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.57-1.73). Exposed women's greatest excess mortality risks were from Alzheimer disease (adjusted HR 3.44, 95% CI 1.00-11.82), diabetes (adjusted HR 2.80, 95% CI 2.20-3.55), ischemic heart disease (adjusted HR 2.23, 95% CI 1.90-2.63), and stroke (adjusted HR 1.88, 95% CI 1.53-2.32). CONCLUSION: Women with hypertensive disease of pregnancy have increased mortality risk, particularly for Alzheimer disease, diabetes, ischemic heart disease, and stroke.

Life and death in the family: early parental death, parental remarriage, and offspring suicide risk in adulthood.

Early-life parental death (PD) may increase suicide and other mortality risk in adulthood. The potential implications of subsequent remarriage of the widowed parent (RWP) for suicide have not been well examined. Data came from the Utah Population Database for birth cohorts between 1886 and 1960, yielding a sample of N = 663,729 individuals, including 4533 suicides. Cox models showed PD was associated with increased adult suicide risk before age 50, and with increased risk of cardiovascular disease deaths (CVD) for adults of all ages. For females, RWP attenuated the suicide relationship before age 50 (though not statistically significant), but significantly exacerbated it after age 50. RWP had no significant impact for males. Further, for females, PD's positive association with suicide was stronger than with CVD before age 50. These findings reinforce the importance of biological and social mechanisms in linking early-life stressors to adult mental and physical health.

Survival of offspring who experience early parental death: early life conditions and later-life mortality.

We examine the influences of a set of early life conditions (ELCs) on all-cause and cause-specific mortality among elderly individuals, with special attention to one of the most dramatic early events in a child's, adolescent's, or even young adult's life, the death of a parent. The foremost question is, once controlling for prevailing (and potentially confounding) conditions early in life (family history of longevity, paternal characteristics (SES, age at time of birth, sibship size, and religious affiliation)), is a parental death associated with enduring mortality risks after age 65? The years following parental death may initiate new circumstances through which the adverse effects of paternal death operate. Here we consider the offspring's marital status (whether married; whether and when widowed), adult socioeconomic status, fertility, and later life health status. Adult health status is based on the Charlson Co-Morbidity Index, a construct that summarizes nearly all serious illnesses afflicting older individuals that relies on Medicare data. The data are based on linkages between the Utah Population Database and Medicare claims that hold medical diagnoses data. We show that offspring whose parents died when they were children, but especially when they were adolescents/young adults, have modest but significant mortality risks after age 65. What are striking are the weak mediating influences of later-life comorbidities, marital status, fertility and adult socioeconomic status since controls for these do little to alter the overall association. No beneficial effects of the surviving parent's remarriage were detected. Overall, we show the persistence of the effects of early life loss on later-life mortality and indicate the difficulties in addressing challenges at young ages.