Stephen E. Gilman

Prenatal immune programming of the sex-dependent risk for major depression

Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case–control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age=39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-α was associated with reduced odds of depression among both male and female offspring (odds ratio (OR)=0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-α to IL-10 ratio, a measure of the ratio of pro- to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (χ2=13.9, degrees of freedom=4, P=0.008). Among females, higher maternal TNF-α:IL-10 was associated with reduced odds of depression (OR=0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-α:IL-10 was associated with elevated odds of depression (OR=1.86; CI=1.02, 3.39). Thus, the balance between TNF-α and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-α in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis.

Early childhood social disadvantage is associated with poor health behaviours in adulthood

Abstract Background: Individual health behaviours are considered important risk factors for cardiometabolic diseases. These behaviours may be socially patterned by early exposure to social disadvantage, but few studies have prospectively tested this hypothesis empirically. Aim: This study investigated whether childhood social disadvantage was associated with likelihood of engaging in less healthy behaviours 40 years later. Subjects and methods: Prospective data were analysed from the New England Family Study, a 2005–2007 adult follow-up of a cohort initiated in 1959–1966 (nu2009=u2009565). Childhood social environment (age 7 years) was assessed using a cumulative index of socioeconomic and family stability factors. Logistic regression models evaluated associations between social disadvantage and each health-related behaviour and obesity in adulthood. Results: Relative to low disadvantage, higher disadvantage was associated with 3.6-fold greater odds of smoking (95% CIu2009=u20091.9–7.0), 4.8-fold greater odds (in women only) of excess alcohol consumption (95% CIu2009=u20091.6–14.2) and 2.7-fold greater odds of obesity (95% CIu2009=u20091.3–5.5), but was not associated with unhealthy diet or physical inactivity. Conclusion: These findings suggest childhood social disadvantage may contribute to adult cardiometabolic disease by predisposing children to adopt certain unhealthy behaviours. If replicated, such findings may support intervention strategies that target social environmental factors and behavioural pathways that are established early in life.

Association of the World War II Finnish Evacuation of Children With Psychiatric Hospitalization in the Next Generation

Importance Although there is evidence that adverse childhood experiences are associated with worse mental health in adulthood, scarce evidence is available regarding an emerging concern that the next generation might also be affected. Objective To compare the risk of psychiatric hospitalization in cousins whose parents were vs were not exposed to the Finnish evacuation policy that involved a mean 2-year stay with a Swedish foster family. Design, Setting, and Participants This multigenerational, population-based cohort study of Finnish individuals and their siblings born between January 1, 1933, and December 31, 1944, analyzed the association of evacuee status as a child during World War II in the first generation with the risk of psychiatric hospitalization among offspring in the second generation. Evacuee status during World War II was determined using the Finnish National Archive’s registry of participants in the Finnish evacuation. Data on evacuee status were linked to the psychiatric diagnoses in the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012, for offspring (nu2009=u200993 391) born between January 1, 1950, and December 31, 2010. Sex-specific Cox proportional hazards regression models were used to estimate hazard ratios for risk of psychiatric hospitalization during the follow-up period. Because offspring of evacuees and their nonevacuated siblings are cousins, the Cox proportional hazards regression models included fixed effects to adjust for confounding factors in families. Data analysis was performed from June 15, 2016, to August 26, 2017. Exposures Parental participation in the evacuation during World War II (coded 1 for parents who were evacuated and placed in foster care and 0 for those not evacuated). Main Outcomes and Measures Offspring’s initial admission to the hospital for a psychiatric disorder, obtained from the Finnish Hospital Discharge Register from January 1, 1971, through December 31, 2012. Results Of the 93 391 study persons, 45 955 (49.2%) were women and 47 436 (50.8) were men; mean (SD) age in 2012 among survivors was 45.4 (6.58) years. Female offspring of mothers evacuated to Sweden during childhood had an elevated risk of psychiatric hospitalization (hazard ratio for any type of psychiatric disorder: 2.04 [95% CI, 1.04-4.01]; hazard ratio for mood disorder: 4.68 [95% CI, 1.92-11.42]). There was no excess risk of being hospitalized for a psychiatric disorder among women whose fathers were exposed to the Finnish evacuation policy during World War II or among men whose mothers or fathers were exposed. Conclusions and Relevance In a prior follow-up study of the Finnish evacuees, girls evacuated to Swedish foster families during World War II were more likely to be hospitalized for a psychiatric disorder—in particular, a mood disorder—in adulthood than their nonevacuated sisters. The present study found that the offspring of these individuals were also at risk for mental health problems that required hospitalization and suggests that early-life adversities, including war-related exposures, may be associated with mental health disorders that persist across generations.

Gestational cytokine concentrations and neurocognitive development at 7 years

Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959–1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (Bu2009=u2009−2.51, 99% CI: −4.84,−0.18), higher problem scores in visual-motor maturity (Bu2009=u20090.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (Bu2009=u2009−1.28, 99% CI: −2.49,−0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children.

Depressive and anxious symptoms and 20-year mortality: Evidence from the Stirling County study

Depression and anxiety disorders are highly comorbid, and share significant symptom overlap. Whereas depression has been consistently associated with excess mortality, the association between anxiety and mortality is less clear. Our aim was to identify constellations of anxious and depressive symptoms and examine their associations with mortality.

Sexual Orientation and Depressive Symptoms in Adolescents

In a recent national cohort, low family satisfaction, cyberbullying victimization, and unmet medical needs were unique contributors to sexual orientation disparities in adolescent depressive symptoms. OBJECTIVES: Sexual orientation disparities in adolescent depressive symptoms are well established, but reasons for these disparities are less well understood. We modeled sexual orientation disparities in depressive symptoms from late adolescence into young adulthood and evaluated family satisfaction, peer support, cyberbullying victimization, and unmet medical needs as potential mediators. METHODS: Data were from waves 2 to 6 of the NEXT Generation Health Study (n = 2396), a population-based cohort of US adolescents. We used latent growth models to examine sexual orientation disparities in depressive symptoms in participants aged 17 to 21 years, conduct mediation analyses, and examine sex differences. RESULTS: Relative to heterosexual adolescents, sexual minority adolescents (those who are attracted to the same or both sexes or are questioning; 6.3% of the weighted sample) consistently reported higher depressive symptoms from 11th grade to 3 years after high school. Mediation analyses indicated that sexual minority adolescents reported lower family satisfaction, greater cyberbullying victimization, and increased likelihood of unmet medical needs, all of which were associated with higher depressive symptoms. The mediating role of cyberbullying victimization was more pronounced among male than female participants. CONCLUSIONS: Sexual minority adolescents reported higher depressive symptoms than heterosexual adolescents from late adolescence into young adulthood. Collectively, low family satisfaction, cyberbullying victimization, and unmet medical needs accounted for >45% of differences by sexual orientation. Future clinical research is needed to determine if interventions targeting these psychosocial and health care–related factors would reduce sexual orientation disparities in depressive symptoms and the optimal timing of such interventions.

Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study

BACKGROUNDnEvidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear.nnnMETHODSnWe examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, nxa0=xa03038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36xa0months. At 30 and 36xa0months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations.nnnRESULTSnSixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings.nnnCONCLUSIONSnImmune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.

Timing of Maternal Depression and Sex-Specific Child Growth, the Upstate KIDS Study

Equivocal findings have been reported on the association between maternal depression and childrens growth, possibly because of the limited attention to its disproportionate impact by child sex. The relationship between the timing of maternal depression and childrens growth was assessed in a population‐based prospective birth cohort, with particular attention to sex differences.

Adolescent Sexual Orientation and Developmental Transition in Emerging Adulthood: Disparities in School, Work, Residence, and Transportation

PURPOSEnTo examine associations between adolescent sexual minority status and developmental transitions in school, work, residence, and transportation 5 years later.nnnMETHODnWe analyzed data from Waves 2 (Mean ageu202f=u202f17.2) and 7 (Mean ageu202f=u202f22.6) of the NEXT Generation Health Study (nu202f=u202f2,000). Relative risks were estimated using Poisson regressions.nnnRESULTSnRelative to heterosexual females, sexual minority females were more likely to report not attending school (relative risk [RR]u202f=u202f1.27, 95% confidence interval [CI]u202f=u202f1.02, 1.59), not anticipating college completion (RRu202f=u202f1.60, 95% CIu202f=u202f1.27, 2.01), and not having a drivers license (RRu202f=u202f2.64, 95% CI 1.38, 5.05) at Wave 7. Relative to heterosexual males, sexual minority males were more likely to report living in three or more places in the past year (RRu202f=u202f2.98, 95% CIu202f=u202f1.31, 6.76).nnnCONCLUSIONSnAdolescent sexual minority status predicted worse educational outcomes among females and more unstable living environment among males.

Early life disadvantage and adult adiposity: tests of sensitive periods during childhood and behavioural mediation in adulthood

BACKGROUNDnEarly exposure to socioeconomic disadvantage is associated with obesity. Here we investigated how early, and conducted mediation analyses to identify behavioural factors in adulthood that could explain why.nnnMETHODSnAmong 931 participants in the New England Family Study, we investigated the associations of family socioeconomic disadvantage measured before birth and at age 7 years with the following measures of adiposity in mid-adulthood (mean ageu2009=u200944.4u2009years): body mass index (BMI), waist circumference and, among 400 participants, body composition from dual-energy X-ray absorption scans.nnnRESULTSnIn linear regressions adjusting for age, sex, race and childhood BMI Z-score, participants in the highest tertile of socioeconomic disadvantage at birth had 2.6 additional BMI units in adulthood [95% confidence interval (CI)u2009=u20091.26, 3.96], 5.62 cm waist circumference (95% CIu2009=u20092.69, 8.55), 0.73 kg of android fat mass (95% CIu2009=u20090.25, 1.21), and 7.65 higher Fat Mass Index (95% CIu2009=u20092.22, 13.09). Conditional on disadvantage at birth, socioeconomic disadvantage at age 7 years was not associated with adult adiposity. In mediation analyses, 10-20% of these associations were explained by educational attainment and 5-10% were explained by depressive symptoms.nnnCONCLUSIONSnInfancy may be a sensitive period for exposure to socioeconomic disadvantage, as exposure in the earliest years of life confers a larger risk for overall and central adiposity in mid-adulthood than exposure during childhood. Intervention on these two adult risk factors for adiposity would, if all model assumptions were satisfied, only remediate up to one-fifth of the excess adult adiposity among individuals born into socioeconomically disadvantaged households.