Cumulative Stress Across the Life Course and Biological Aging in Adulthood.

OBJECTIVE: Psychosocial stressors have been linked with accelerated biological aging in adults; however, few studies have examined stressors across the life course in relation to biological aging. METHODS: In 359 individuals (57% White, 34% Black) from the Child Health and Development Studies Disparities study, economic (income, education, financial strain), social (parent-child relations, caretaker responsibilities) and traumatic (death of a sibling or child, violence exposure) stressors were assessed at multiple time points (birth and ages 9, 15, and 50 years). Experiences of major discrimination were assessed at age 50. Life period stress scores were then assessed as childhood (birth-age 15 years) and adulthood (age 50 years). At age 50 years, participants provided blood samples, and DNA methylation was assessed with the EPIC BeadChip. Epigenetic age was estimated using six epigenetic clocks (Horvath, Hannum, Skin and Blood age, PhenoAge, GrimAge, Dunedin Pace of Aging). Age acceleration was determined using residuals from regressing chronologic age on each of the epigenetic age metrics. Telomere length was assessed using the quantitative polymerase chain reaction-based methods. RESULTS: In linear regression models adjusted for race and gender, total life stress, and childhood and adult stress independently predicted accelerated aging based on GrimAge and faster pace of aging based on the DunedinPace. Associations were attenuated after adjusting for smoking status. In sex-stratified analyses, greater childhood stress was associated with accelerated epigenetic aging among women but not men. No associations were noted with telomere length. CONCLUSIONS: We found that cumulative stressors across the life course were associated with accelerated epigenetic age, with differences by sex (e.g., accelerated among women). Further research of this association in large and diverse samples is needed.

Sex-Specific Pathways From Prenatal Maternal Inflammation to Adolescent Depressive Symptoms.

Importance: Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the association between prenatal inflammation and offspring depression in adolescence has yet to be examined. Objective: To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations. Design, Setting, and Participants: This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023. Exposures: Levels of inflammatory biomarkers (interleukin 6 [IL-6], IL-8, IL-1 receptor antagonist [IL-1RA], and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy. Main Outcomes and Measures: Self-reported depressive symptoms at adolescent follow-up. Results: A total of 674 mothers (mean [SD] age, 28.1 [5.9] years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75). Conclusions and Relevance: In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.

Third Trimester Serum Amino Acid Metabolism is Associated with Maternal Breast Cancer Diagnosed within 15 years of Pregnancy.

A prospective metabolome-wide association study revealed widespread amino acid limitation in late pregnancy is associated with early onset breast cancer. Archival third trimester pregnancy serum samples from 172 women who subsequently were diagnosed with breast cancer within 38 years after pregnancy were compared to 351 women without breast cancer. No individual metabolite differed after false discovery rate adjustment, indicating that individual metabolites are unlikely to be useful for classification or prediction. Despite this, pathway enrichment analysis showed that amino acid pathways, including lysine, arginine, proline, aspartate, asparagine, alanine, tyrosine, tryptophan, histidine, branched-chain amino acid and urea cycle, were enriched among metabolites that differed at raw p < 0.05. Several of these pathways previously were linked to breast carcinogen exposures, including dichlorodiphenyltrichloroethane and perfluorinated alkyl substances. Network analyses showed that amino acids correlated with parity and the ratio of estriol to estrone and estradiol known risk factors for breast cancer in this cohort. Overall, amino acid associations were stronger for early onset breast cancer, defined here as occurring within the first 15 years following pregnancy. Although results must be interpreted cautiously, lower amino acid concentrations for histidine, threonine and proline, and stronger associations for tryptophan, histidine, and lysine pathways with breast cancer within 15 years, suggests that amino acid limitations during late pregnancy contribute to metabolic reprogramming that is causally related to early onset breast cancer. Environmental chemical effects on nutrient sensing could account for these effects through known oncogenic mechanisms linked to nutrient stress.

The Effect of Individual or Study-Wide Report-Back on Knowledge, Concern, and Exposure-Reducing Behaviors Related to Endocrine-Disrupting Chemicals.

BACKGROUND: To make informed decisions about endocrine-disrupting chemicals (EDCs), people need functional understanding of exposures and health and an ability to act on their knowledge. The return of biomonitoring results is an opportunity to educate people about EDCs and motivate exposure reduction. OBJECTIVES: This study investigates environmental health knowledge about EDCs, concerns about health effects, and exposure-reducing behaviors before and after the return of individual-level exposure results or only study-wide results. METHODS: Women in the Child Health and Development Studies who were biomonitored for 42 EDCs were randomly assigned to receive a report with personal chemical results or only study-wide findings. We interviewed participants before and after report-back about their knowledge and concerns about EDCs and how frequently they performed exposure-related behaviors. We investigated baseline differences by education and race and examined changes after report-back by race and report type. RESULTS: Participants (n=135) demonstrated general understanding of exposure pathways and health impacts of EDCs. For 9 out of 20 knowledge questions, more than 90% of participants (n≥124) gave correct responses at baseline, including for questions about chemicals' persistence in the body and effects of early-life exposure. Most participants held two misconceptions-about chemical safety testing in the United States and what doctors can infer from EDC results-although errors decreased after report-back. Initially, concern was higher for legacy pollutants, but report-back increased concern for consumer product chemicals. After report-back, participants took some actions to reduce exposures, particularly to per- and polyfluoroalkyl substances, and total behavior was associated with knowledge and concern but not race, education, or report type. DISCUSSION: This study demonstrated that participants had foundational knowledge about EDCs and that report-back further built their environmental health literacy. We conclude that future communications should target misconceptions about chemicals regulation in the United States, because information about regulations is crucial for people to evaluate risks posed by consumer product chemicals and decide whether to engage with public policy. https://doi.org/10.1289/EHP12565.

Birth Defects in Offspring of Adolescent and Young Adults with a History of Cancer: A Population-Based Study of 27,000 Women.

BACKGROUND: We examined birth defects in offspring of adolescent and young adult (AYA) women with a history of cancer (age 15-39 years at diagnosis). METHODS: We identified AYA women diagnosed with cancer between January 1, 1999, and December 31, 2015 using population-based data from the Texas Cancer Registry; data were linked with live birth and fetal death certificates through December 31, 2016 to identify singleton births to AYA women after diagnosis. Birth defects in offspring through age 12 months were ascertained from the Texas Birth Defects Registry. We estimated risk of birth defects in offspring of AYA women and women without cancer (matched 3:1 by maternal race/ethnicity, maternal age, and offspring year of birth) and compared risk using log binomial regression models. RESULTS: There were 6,882 singleton births to AYA women after diagnosis. Common cancer types were thyroid (28.9%), lymphoma (12.5%), and breast (10.7%). Risk of any birth defect was higher in offspring of AYA women (6.0%) compared with offspring of women without cancer [n = 20,646; 4.8%; risk ratio (RR) 1.24; 95% confidence interval (CI), 1.11-1.38]. Risk of eye or ear (RR, 1.39; 95% CI, 1.03-1.90), heart and circulatory (RR, 1.32; 95% CI, 1.09-1.60), genitourinary (RR, 1.38; 95% CI, 1.12-1.69), and musculoskeletal (RR, 1.37; 95% CI, 1.13-1.66) defects was also higher. CONCLUSIONS: Risk of birth defects was elevated in liveborn and stillborn offspring of AYA women. IMPACT: Although birth defects are rare, AYA women making decisions about pregnancy and prenatal care should receive appropriate counseling and surveillance.

Exposome Epidemiology for Suspect Environmental Chemical Exposures during Pregnancy Linked to Subsequent Breast Cancer Diagnosis.

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry (HRMS) of pregnancy cohort biospecimens in the Child Health and Development Studies (CHDS) to test for associations with breast cancer identified via the California Cancer Registry. Second (T2) and third (T3) trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database (T3DB) for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both T2 and T3 to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol (DNP), linked to variations in amino acid and nucleotide pathways in T2 and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in T3. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.

Exposome epidemiology for suspect environmental chemical exposures during pregnancy linked to subsequent breast cancer diagnosis.

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.

Racial socialization and discrimination-related psychological distress in middle-aged Black men and women.

Our objectives were to evaluate gender-specific associations of racial discrimination with psychological sequelae among middle-aged Blacks and to evaluate the capacity of racial socialization to moderate the association between discrimination and psychological distress, accounting for relevant prospectively assessed childhood factors. We used data from the Child Health and Development Disparities Study that followed a Northern California-based group of Blacks from the prenatal period through midlife (N = 244, 49.6% female). Multiple regression analyses were performed separately by gender to assess (a) the main effects of racial socialization and racial discrimination on adult psychological distress, (b) racial socialization as a moderator of the association between racial discrimination and adult psychological distress, and (c) whether controls for prospectively assessed childhood factors changed conclusions regarding the role of racial socialization. Seventy percent of the middle-aged Blacks in our sample reported having at least one type of major experience of racial discrimination. Increased reports of racial discrimination were positively associated with psychological distress in men, but not in women. Similarly, racial socialization was associated with decreased overall distress for men, but not for women. Discrimination-related distress was attenuated for men who reported higher levels of racial socialization. These findings remained after adjustment for childhood socioeconomic status (SES), childhood internalizing symptoms, parental marital separation, and number of siblings. Findings suggest that racial socialization conferred a protective psychological effect through midlife to Black men who experienced racial discrimination, a commonplace experience in this cohort. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adverse birth outcomes of adolescent and young adult women diagnosed with cancer during pregnancy.

BACKGROUND: We examined adverse birth outcomes among adolescent and young adult women diagnosed with cancer (AYA women, ages 15-39 years) during pregnancy. METHODS: We linked data from the Texas Cancer Registry, vital records, and Texas Birth Defects Registry to identify all singleton births to AYA women diagnosed during pregnancy from January 1999 to December 2016. We compared prevalence of adverse live birth outcomes between AYA women and women without cancer (matched 1:4 on age, race and ethnicity, and year). Among AYA women, we used log-binomial regression to identify factors associated with these outcomes. Statistical tests were 2-sided. RESULTS: AYA women had 1271 singleton live births and 20 stillbirths. AYA women (n = 1291) were 33.3% Hispanic and 9.8% non-Hispanic Black and most commonly had breast (22.5%), thyroid (19.8%), and gynecologic (13.3%) cancers. Among live births, AYA women had a higher prevalence of low birth weight offspring (30.1% vs 9.0%), very preterm (5.7% vs 1.2%), and preterm birth (25.1% vs 7.2%); cesarean delivery (44.3% vs 35.2%); and low Apgar score (2.7% vs 1.5%), compared with women without cancer (n = 5084) (all P < .05). Prevalence of any birth defect by age 12 months did not statistically differ (5.2% vs 4.7%; P = .48), but live births to AYA women more often had heart and circulatory system defects (2.2% vs 1.3%; P = .01). In adjusted models, cancer type and chemotherapy were associated with adverse live birth outcomes. CONCLUSIONS: AYA women diagnosed during pregnancy have higher prevalence of adverse birth outcomes and face difficult decisions in balancing treatment risks and benefits.

In utero exposure to antiemetic and risk of adult-onset colorectal cancer.

BACKGROUND: Incidence rates of colorectal cancer (CRC) are increasing among adults born in and after the 1960s, implicating pregnancy-related exposures introduced at that time as risk factors. Dicyclomine, an antispasmodic used to treat irritable bowel syndrome, was initially included in Bendectin (comprising doxylamine, pyridoxine, and dicyclomine), an antiemetic prescribed during pregnancy in the 1960s. METHODS: We estimated the association between in utero exposure to Bendectin and risk of CRC in offspring of the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in Oakland, CA, between 1959 and 1966 (n = 14 507 mothers and 18 751 liveborn offspring). We reviewed prescribed medications from mothers' medical records to identify those who received Bendectin during pregnancy. Diagnoses of CRC in adult (aged ≥18 years) offspring were ascertained by linkage with the California Cancer Registry. Cox proportional hazards models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact. RESULTS: Approximately 5% of offspring (n = 1014) were exposed in utero to Bendectin. Risk of CRC was higher in offspring exposed in utero (adjusted hazard ratio = 3.38, 95% confidence interval [CI] = 1.69 to 6.77) compared with unexposed offspring. Incidence rates of CRC were 30.8 (95% CI = 15.9 to 53.7) and 10.1 (95% CI = 7.9 to 12.8) per 100 000 in offspring exposed to Bendectin and unexposed, respectively. CONCLUSIONS: Higher risk of CRC in offspring exposed in utero may be driven by dicyclomine contained in the 3-part formulation of Bendectin used during the 1960s. Experimental studies are needed to clarify these findings and identify mechanisms of risk.

In-utero exposure to antibiotics and risk of colorectal cancer in a prospective cohort of 18 000 adult offspring.

BACKGROUND: Incidence rates of colorectal cancer (CRC) are increasing among younger adults and in mid-life, implicating exposures in early life as risk factors. We examined the association between in-utero exposure to antibiotics and risk of CRC in adult offspring. METHODS: The Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California, with deliveries through June 1967. Diagnosed conditions and all prescribed medications were abstracted from mothers' medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received antibiotics in pregnancy, including penicillins, tetracyclines, short-acting sulfonamides and long-acting sulfonamides. Diagnoses of CRC in adult (age ≥18 years) offspring were ascertained through 2021 by linkage with the California Cancer Registry. Cox proportional models were used to estimate adjusted hazard ratios (aHR), with follow-up accrued from birth through cancer diagnosis, death or last contact. RESULTS: Of 18 751 liveborn offspring, about 15% (n = 2635) were exposed in utero to antibiotics: 5.4% (n = 1016) to tetracyclines, 4.9% (n = 918) to penicillins, 4.2% (n = 785) to short-acting sulfonamides and 1.5% (n = 273) to long-acting sulfonamides. Compared with offspring not exposed, associations between in-utero exposure and CRC in adult offspring were: aHR 1.03 (95% CI 0.32, 3.31) for tetracyclines; aHR 1.12 (95% CI 0.35, 3.58) for penicillins; aHR 0.83 (95% CI 0.20, 3.42) for short-acting sulfonamides; and aHR 4.40 (95% CI 1.63, 11.88) for long-acting sulfonamides. CONCLUSION: Our findings support an association between in-utero exposure to long-acting sulfonamides and CRC in adulthood.

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.

BACKGROUND: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. METHODS: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. RESULTS: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. CONCLUSIONS: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Stillbirth After Adolescent and Young Adult Cancer: A Population-Based Study.

BACKGROUND: Gonadotoxic effects of cancer treatment may increase risk of adverse birth outcomes in adolescent and young adult (AYA, aged 15-39 years) women diagnosed with cancer. We estimated risk of stillbirth (fetal death of gestational age ≥20 weeks or weighing ≥350 grams) in a population-based sample of AYA women. METHODS: AYA women diagnosed with cancer between January 1, 1995, and December 31, 2015, were identified using the Texas Cancer Registry and linked to live birth and fetal death certificates through December 31, 2016. Among AYA women, cumulative incidence of stillbirth was estimated by gestational age, and Poisson regression models identified factors associated with stillbirth. Standardized fetal mortality ratios (SMR) compared the observed fetal mortality rate in AYA women with the expected fetal mortality rate in the general population. RESULTS: A total of 11 628 live births and 68 stillbirths occurred to 8402 AYA women after diagnosis. Cumulative incidence of stillbirth in AYA women was 0.70% (95% confidence interval [CI] = 0.51% to 0.96%) at 40 weeks of gestation. Risk of stillbirth was higher among Hispanic (risk ratio [RR] = 2.64, 95% CI = 1.29 to 5.41) and non-Hispanic Black (RR = 4.13, 95% CI = 1.68 to 10.16) women compared with non-Hispanic White women; there was no association with receipt of chemotherapy or time since diagnosis. Age- and race and ethnicity-adjusted fetal mortality rate in AYA women was similar to the general population (SMR = 0.99, 95% CI = 0.77 to 1.26). CONCLUSIONS: AYA women may be counseled that overall risk of stillbirth is low, and for most, cancer does not appear to confer additional risk.

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Infection and higher cortisol during pregnancy and risk for depressive symptoms in adolescent offspring.

Prenatal infection, particularly at mid-gestation, has been associated with various psychopathological outcomes in offspring; however, findings linking prenatal infection to offspring depression outcomes have been mixed. Previous research indicates that it may be the co-occurrence of prenatal adversities (e.g., infection and stress) that are associated with depression outcomes in offspring. Nevertheless, no study to date has investigated whether higher levels of biomarkers linked to prenatal stress (e.g., cortisol) in the presence of infection may account for these outcomes. Participants were drawn from the Child Health and Development Studies (CHDS), a prospective, longitudinal study of pregnant women and their offspring. The present study included mother-offspring dyads from the Adolescent Study, a subsample of the CHDS cohort, whose offspring were assessed in adolescence and whose mothers also provided sera to be assayed for cortisol (n = 695). Hierarchical multivariable regressions were conducted to examine whether maternal cortisol during the first and second trimesters of pregnancy interacted with maternal infection to predict increased risk for symptoms of depression in adolescent offspring. There was a significant interaction of second trimester infection and higher cortisol on offspring depression scores during adolescence, controlling for maternal education (p = 0.04). Findings suggest that higher maternal cortisol may sensitize mothers and their offspring to the disruptive influences of infection during mid-pregnancy, conferring greater risk of depressive symptomatology in offspring.

Comparing different operationalizations of allostatic load measured in mid-life and their patterning by race and cumulative life course socioeconomic status.

Since its conceptualization, there has been a lack of consensus on the best way to operationalize allostatic load (AL). As a marker of the cumulative, physiological wear and tear on the body resulting from chronic exposure to stressors, it follows that AL should be higher among people who have faced more stressful life experiences. Thus, the purpose of this study was to construct AL scores using different operationalizations and, as a measure of construct validity, compare whether each construction produced expected disparities in AL by race and a composite socioeconomic status (SES) variable which accounts for measures over the life course; we also explored differences by sex. We conducted the study in a sample of 45-52-year-old offspring from the Child Health and Development Studies, a longitudinal birth cohort established in the early 1960s. AL scores were constructed in 6 different ways and included 10 biomarkers from inflammatory, neuroendocrine, cardiovascular, and metabolic systems. Our main approach to constructing AL was to sum across high-risk biomarker quartiles, correct for medication use, and use sex-specific high-risk quartiles for specific biomarkers. Alternative constructions did not use sex-specific quartiles and/or weighted biomarkers within subsystems and/or did not correct for medication use. We estimated differences in AL scores by race, SES, sex and their pairwise interactions. All constructions of AL, including the main approach, produced expected disparities by race (higher scores for Black vs. non-Black participants) and life course SES (higher scores for low vs. high SES participants). However, disparities by sex only emerged when the AL score was constructed via approaches that did not use sex-specific high-risk quartiles; for these alternative constructions, overall, female participants had higher AL scores than male participants and Black female participants had the highest AL scores in the sample. For most constructions, the pairwise interaction between sex and SES, showed a stronger disparity in AL scores between low and high-SES female compared with low- and high-SES male participants; this suggests that, in terms of lowering AL, high life course SES may be more important for female than male participants. In conclusion, our results suggest that the basic AL concept is consistently expressed in different operationalizations, making it an especially useful and robust tool for understanding disparities by race and SES.

In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring.

BACKGROUND: 17α-hydroxyprogesterone caproate is a synthetic progestogen initially approved in the 1950s to treat gynecologic and obstetrical conditions. Despite continued concerns about safety and short-term efficacy regarding the use of 17α-hydroxyprogesterone caproate for the prevention of preterm birth in pregnant women, little is known about the long-term effects of 17α-hydroxyprogesterone caproate on the health of the offsprings. OBJECTIVE: To examine the association between in utero exposure to 17α-hydroxyprogesterone caproate and the risk of cancer in the offspring. STUDY DESIGN: The Child Health and Development Studies was a population-based cohort of >18,000 mother-child dyads receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, CA) between 1959 and 1966. Clinical information was abstracted from the mothers' medical records beginning 6 months before pregnancy through delivery. We identified the number and timing of 17α-hydroxyprogesterone caproate injections during pregnancy. Incident cancers diagnosed in the offspring were ascertained through 2019 by linkage to the California Cancer Registry. We used the Cox proportional hazard models to estimate the adjusted hazard ratios and their 95% confidence intervals, with the follow-up time accrued from the date of birth through the date of cancer diagnosis, death, or last contact. RESULTS: A total of 1008 offspring were diagnosed with cancer over 730,817 person-years of follow-up. Approximately 1.0% of the offspring (n=234) were exposed in utero to 17α-hydroxyprogesterone caproate. Exposure in the first trimester was associated with an increased risk of any cancer (adjusted hazard ratio, 2.57; 95% confidence interval, 1.59-4.15), and the risk increased with the number of injections (1-2 injections: adjusted hazard ratio, 1.80; 95% confidence interval, 1.12-2.90; ≥3 injections: adjusted hazard ratio, 3.07; 95% confidence interval, 1.34-7.05). Exposure in the second or third trimester conferred an additional risk for the male (adjusted hazard ratio, 2.59; 95% confidence interval, 1.07-6.28) but not for the female (adjusted hazard ratio, 0.30; 95% confidence interval, 0.04-1.11) offspring. The risk of colorectal (adjusted hazard ratio, 5.51; 95% confidence interval, 1.73-17.59), prostate (adjusted hazard ratio, 5.10; 95% confidence interval, 1.24-21.00), and pediatric brain (adjusted hazard ratio, 34.72; 95% confidence interval, 7.29-164.33) cancer was higher in the offspring first exposed to 17α-hydroxyprogesterone caproate in the first trimester than the offspring not exposed. CONCLUSION: Caution using 17α-hydroxyprogesterone caproate in early pregnancy is warranted, given the possible link with cancer in the offspring.

SARS-CoV-2 vaccine protection and deaths among US veterans during 2021.

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine effectiveness against infection (VE-I) and death (VE-D) by vaccine type in 780,225 veterans in the Veterans Health Administration, covering 2.7% of the US population. From February to October 2021, VE-I declined for all vaccine types, and the decline was greatest for the Janssen vaccine, resulting in a VE-I of 13.1%. Although breakthrough infection increased risk of death, vaccination remained protective against death in persons who became infected during the Delta variant surge. From July to October 2021, VE-D for age <65 years was 73.0% for Janssen, 81.5% for Moderna, and 84.3% for Pfizer-BioNTech; VE-D for age ≥65 years was 52.2% for Janssen, 75.5% for Moderna, and 70.1% for Pfizer-BioNTech. Findings support continued efforts to increase vaccination, booster campaigns, and multiple additional layers of protection against infection.