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Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Background: Growing evidence suggests that liver disease originates in early life. Antihistamines cross the placenta and are frequently prescribed to pregnant women to treat nausea and vomiting, as well as allergy and asthma symptoms. Exposure to antihistamines in utero may impact the developing liver by reprogramming or inducing epigenetic changes in fetal hepatocytes., Methods: We examined in utero exposure to antihistamines and the risk of HCC in the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in the East Bay, CA, between 1959 and 1966 (n=14,507 mothers and 18,751 liveborn offspring). We reviewed mothers' medical records to identify those prescribed antihistamines during pregnancy, and diagnoses of HCC in adult (age ≥18 y) offspring were identified by linkage with a population-based cancer registry. Cox proportional hazard models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact., Results: About 15% of offspring (n=2759 of 18,751) were exposed in utero to antihistamines. Chlorpheniramine (51.8%) and diphenhydramine (15.4%) were the 2 most commonly prescribed antihistamines. Any in utero exposure was not associated with HCC (adjusted hazard ratio: 2.76, 95% CI: 0.70, 10.89), but the association differed by timing of exposure. Offspring exposed to antihistamines in the first or second trimester had a higher risk of HCC compared to offspring not exposed (adjusted hazard ratio: 4.64, 95% CI: 1.21, 17.78). Similarly, incidence rates were 4.3 per 100,000 (95% CI: 0.9, 12.6) for offspring exposed in the first or second trimester compared to 1.0 per 100,000 (95% CI: 0.3, 2.1) for offspring not exposed., Conclusions: In utero exposure to antihistamines in early pregnancy may increase the risk of HCC in adulthood., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental conditions currently diagnosed by behavioral assessment in childhood, with reported underdiagnosis in females. Though diagnosis in early life is linked to improved outcomes, we currently lack objective screening tools for newborns. To address this gap, we sought to identify a sex-specific DNA methylation signature for ASD using perinatal tissues that reflect dysregulation in the brain. DNA methylation was assayed from ASD and typically developing (TD) newborn blood, umbilical cord blood, placenta, and post-mortem cortex samples using whole genome bisulfite sequencing (WGBS) in a total of 511 samples. We found that methylation levels of differentially methylated regions (DMRs) differentiated samples by ASD diagnosis in females more than males across the perinatal tissues. We tested three theories for ASD sex differences in newborn blood, finding epigenetic support for an X chromosome-related female protective effect, as well as a high replication rate of DMRs (48.1%) in females across two independent cohorts. In our pan-tissue analysis, three genes (X-linked BCOR , GALNT9 , OPCML ) mapped to ASD DMRs replicated in all four female tissues. ASD DMRs from all tissues were enriched for neuro-related processes (females) and SFARI ASD-risk genes (females and males). Overall, we found a highly replicated methylation signature of ASD in females across perinatal tissues that reflected dysregulation in the brain and involvement of X chromosome epigenetics. This comparative study of perinatal tissues shows the promise of newborn blood DNA methylation biomarkers for early detection of females at risk for ASD and emphasizes the importance of sex-stratification in ASD studies., Competing Interests: Conflict of Interest The authors declare that they have no conflicting interests.

Background: Accumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring., Methods: Participants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9-11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15-17) depressive symptoms were assessed via self-report., Results: There were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002-0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8., Conclusions: Lower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

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., (© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

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., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Obesity is a well-established risk factor for CRC, and fetal or developmental origins of obesity may underlie its effect on cancer in adulthood. We examined associations of maternal obesity, pregnancy weight gain, and birth weight and CRC in adult offspring., Design: The Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California (N=18 751 live births among 14 507 mothers). Clinical information was abstracted from mothers' medical records 6 months prior to pregnancy through delivery. Diagnoses of CRC in adult (age ≥18 years) offspring were ascertained through 2019 by linkage with the California Cancer Registry. We used Cox proportional hazards models to estimate adjusted HR (aHR); we examined effect measure modification using single-referent models to estimate the relative excess risk due to interaction (RERI)., Results: 68 offspring were diagnosed with CRC over 738 048 person-years of follow-up, and half (48.5%) were diagnosed younger than age 50 years. Maternal obesity (≥30 kg/m 2 ) increased the risk of CRC in offspring (aHR 2.51, 95% CI 1.05 to 6.02). Total weight gain modified the association of rate of early weight gain (RERI -4.37, 95% CI -9.49 to 0.76), suggesting discordant growth from early to late pregnancy increases risk. There was an elevated association with birth weight (≥4000 g: aHR 1.95, 95% CI 0.8 to 4.38)., Conclusion: Our results suggest that in utero events are important risk factors for CRC and may contribute to increasing incidence rates in younger adults., Competing Interests: Competing interests: CM reports consulting for Freenome; AGS reports consulting/advisory boards for Bayer, Eisai, Genentech, BMS, Exelixis, Exact Sciences, and GRAIL; PMC, NYK, ML, TZ, EB and BAC have no financial disclosures or conflicts of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Study participants want to receive their biomonitoring results for environmental chemicals, and ethics guidelines encourage reporting back. However, few studies have quantitively assessed participants' responses to individual exposure reports, and digital methods have not been evaluated., Objectives: We isolated effects of receiving personal results vs. only study-wide findings and investigated whether effects differed for Black participants., Methods: We randomly assigned a subset of 295 women from the Child Health and Development Studies, half of whom were Black, to receive a report with personal environmental chemical results or only study-wide (aggregate) findings. Reports included results for 42 chemicals and lipids and were prepared using the Digital Exposure Report-Back Interface (DERBI). Women were interviewed before and after viewing their report. We analyzed differences in website activity, emotional responses, and intentions to participate in future research by report type and race using Wilcoxon rank sum tests, Wilcoxon-Pratt signed ranks tests, and multiple regression., Results: The personal report group spent approximately twice as much time on their reports as the aggregate group before the post-report-back interview. Among personal-report participants ( n = 93 ), 84% (78) viewed chemical group information for at least one personal result highlighted on their home page; among aggregate-report participants ( n = 94 ), 66% (62) viewed any chemical group page. Both groups reported strong positive feelings (curious, informed, interested, respected) about receiving results before and after report-back and mild negative feelings (helpless, scared, worried). Although most participants remained unworried after report-back, worry increased by a small amount in both groups. Among Black participants, higher post report-back worry was associated with having high levels of chemicals., Conclusions: Participants were motivated by their personal results to access online information about chemical sources and potential health effects. Report-back was associated with a small increase in worry, which could motivate appropriate action. Personal report-back increased engagement with exposure reports among Black participants. https://doi.org/10.1289/EHP9072.

Background: Serum DDTs during or just after pregnancy were associated with breast cancer in mothers (F0), and with breast cancer, mammographic density, and obesity in adult daughters (F1) in the Child Health and Development Studies multi-generational cohort in prior publications. Here, we investigate F0 perinatal serum DDT associations with granddaughters'(F2) measured obesity at a median age of 26 and self-reported age at menarche., Methods: F2 weight, height and waist circumference were measured by trained examiners. o,p' -DDT, p,p' -DDT and p,p'- DDE were measured in archived F0 perinatal serum. F0 DDT associations with F2 outcomes, accounting for F1 characteristics, were estimated in log-linear models adjusted for F0 and F1 body mass index (BMI), race, and menarche timing ( N = 258 triads for obesity; N = 235 triads for early menarche). Interactions between F0 BMI and DDTs were estimated., Results: F0 o,p' -DDT was associated with F2 obesity [Odds ratio (OR), 2.6; 95% confidence interval (CI), 1.3-6.7; tertile 3 vs. 1), among normal weight F0 (70%), but not among overweight and obese F0 ( P interaction = 0.03), independent of other DDTs. F0 o,p' -DDT was also associated with F2 early menarche (OR, 2.1; 95% CI, 1.1-3.9, tertile 3 vs. 1) and this association was not modified by F0 BMI., Conclusions: Ancestral exposure to environmental chemicals, banned decades ago, may influence the development of earlier menarche and obesity, which are established risk factors for breast cancer and cardiometabolic diseases., Impact: Discovery of actionable biomarkers of response to ancestral environmental exposures in young women may provide opportunities for breast cancer prevention. See related commentary by Fenton and Boyles, p. 1459 ., (©2021 American Association for Cancer Research.)

Background: Obesity is a malnourishment epidemic worldwide. A meta-analysis of prospective human studies across the world demonstrated a consistent positive association between maternal exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) and children with obesity. The present study evaluates the association of maternal exposure to DDT and DDE with the risk of obesity in daughters during their mid-life in a prospective birth cohort with up to 53 years of follow-up., Methods: Gravidas' blood was collected during their 1959-1967 enrollment into the prospective Child Health and Development Studies birth cohort in California. Their daughters aged 44-53 years had their height, weight, and waist circumference measured during a home visit to evaluate associations of daughters' adiposity and relative risk of overweight and obesity with their mothers' prenatal serum levels of DDT and DDE quantified by gas chromatograph-tandem mass spectrometer (n = 511)., Results: Maternal o,p'-DDT was positively associated with body mass index (β = 0.59 kg/m 2 per ln ng/ml (95th percentile confidence interval, 95% CI: 0.17, 1.00)) and waist circumference (β = 1.19 cm per ln ng/ml (95% CI: 0.26, 2.13)) in multivariable models. Maternal o,p'-DDT was positively associated with a 26% (95% CI: 6-49) to 31% (95% CI: 6-62) higher risk of overweight and the same magnitude of additional risk for obesity, based on waist circumference and BMI definitions respectively, in multivariable models., Conclusions: These data indicate maternal DDT exposure is significantly associated with increased obesity risk among middle-aged women independent of the obesity definition, confounding, and obesity risk factors. Our findings suggest that policies supporting the use of DDT for malaria vector abatement need to consider the obesity risk as a health cost when weighing the benefits of using DDT in malaria vector control.

Background: Obesity is present in 17% of US youth, age 2-19 years, but the extent to which obesity in childhood is associated with higher BMI and fat mass in middle age is unclear. In this study, links between childhood body size and BMI and body composition at age ∼50 were assessed. Methods: Child Health and Development Studies participants, born between 1960 and 1963 in Alameda County, and still living in California, from whom anthropometric data were collected at age 5, 9-11, and/or 15-17 years were followed-up at age ∼50 for anthropometric outcomes (251 women; 249 men). Linear regression analyses assessed whether overweight (85th to <95th BMI percentile) or obesity (≥95th BMI percentile) at age 5 were associated with BMI, fat mass index (FMI), and lean mass index (LMI) at age ∼50. Results: At age 50, participants with obesity at age 5 had BMI scores that were 6.51 units higher [95% confidence interval (CI) = 3.67-9.35] than participants who were normal weight at age 5; FMI and LMI scores were 4.15 (95% CI = 1.98-6.32) and 2.36 (95% CI = 1.45-3.26) units higher, respectively. However, obesity experienced at age 5 had only a modest positive predictive value for predicting the presence of obesity at age 50 (67%), whereas obesity present at age 15-17 had a higher positive predictive value (86%). Conclusions: The experience of obesity at age 5 for members of this birth cohort was associated with significantly higher BMI, FMI, and LMI at age ∼50.

Intrauterine and early-life exposures, including intrauterine smoke exposures and infant growth are associated with mammographic breast density (MBD), a strong breast cancer risk factor. We investigated whether placental morphometry, which is affected by intrauterine smoke exposure and also influences infant growth, predicts %MBD at ages 37-47. In 247 daughters in the Child Health and Development Studies, we found that larger placental surface area and placental thickness were associated with lower %MBD (-0.32 per cm 2 , 95% CI -0.6, -0.05; -37.8 per 0.5 cm, 95% CI= -73.3, -2.3 respectively) independent of mothers' smoking, age, weight, parity and daughters' birthweight and age at mammogram. We also observed a positive interaction between placental surface area and thickness (p < 0.05) such that the highest breast dense area was observed for offspring with the thickest and largest placentas. Factors that impact placental morphometry, in addition to in utero smoke exposure, may influence adult breast architecture and breast cancer risk., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2019. Published by Elsevier Inc.)

Prior studies in the Child Health and Development Studies (CHDS) found in utero exposure to the pesticide, dichlorodiphenyltrichloroethane (DDT), increased breast cancer risk by age 52. Mammographic density is considered a primary risk factor for breast cancer. We conducted a study of 309 daughters from the CHDS to examine in utero DDT exposure and mammographic density in midlife. Among daughters with high (>75th percentile) exposure to p,p'-Dichlorodiphenyldichloroethylene (DDE), p,p'-DDT was significantly correlated with increased dense area and percent density regardless of her body mass in midlife. In the subset of women with lower (<75th percentile) p,p-DDE, p,p'-DDT was associated with increased non-dense breast area. This was explained by adjustment for midlife BMI suggesting that p,p'-DDT may be obesogenic. In aggregate our findings indicate that early life p,p'-DDT exposure impacts breast density in a complex way that depends on the hosts biological ability to sequester and process DDT and levels of exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020. Published by Elsevier Inc.)

Studies measuring dichlorodiphenyltrichloroethane (DDT) exposure during key windows of susceptibility including the intrauterine period suggest that DDT exposure is associated with breast cancer risk. We hypothesized that prenatal DDT exposure is associated with DNA methylation. Using prospective data from 316 daughters in the Child Health and Development Study, we examined the association between prenatal exposure to DDTs and DNA methylation in blood collected in midlife (mean age: 49 years). To identify differentially methylated regions (DMRs) associated with markers of DDTs (p,p'-DDT and the primary metabolite of p,p'-DDT, p,p'-DDE, and o,p'-DDT, the primary constituents of technical DDT), we measured methylation in 30 genes important to breast cancer. We observed DDT DMRs in three genes, CCDC85A, CYP1A1 and ZFPM2, each of which has been previously implicated in pubertal development and breast cancer susceptibility. These findings suggest prenatal DDT exposure may have life-long consequence through alteration in genes relevant to breast cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We tested the hypothesis that maternal perinatal serum levels of poly and perfluoroalkyl substances (PFASs) predict risk for breast cancer in daughters in a 54-year follow-up of 9300 daughters born 1959-1967 in the Child Health and Development Studies pregnancy cohort. Total cholesterol and PFASs were measured in archived maternal perinatal serum for 102 daughter breast cancer cases diagnosed by age 52, and 310 controls matched on birth year and blood draw trimester. High maternal N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), a precursor of perfluorooctane sulfonic acid (PFOS), in combination with high maternal total cholesterol predicted a 3.6-fold increased risk of breast cancer (p interaction <0.05). Conversely, maternal PFOS was associated with decreased daughters' breast cancer risk. Predictions were robust to alternative modeling and independent of other maternal factors. Future generations continue to be exposed to ubiquitous, persistent PFASs. These findings are relevant to breast cancer prevention if confirmed experimentally and where possible, in additional epidemiology studies of internal doses of PFASs and other chemical mixtures especially during vulnerable windows in early life., (Copyright © 2019. Published by Elsevier Inc.)

We examined the relationship between intrauterine dichlorodiphenyltrichloroethane (DDT) exposure (o,p'-DDT, p,p'-DDT, and p,p'-DDE) and mammographic breast density (MBD) in midlife, one of the strongest risk factors for breast cancer. We focused our analyses on o,p'-DDT exposure given our previous report of a positive association between intrauterine o,p'-DDT exposure and daughter's breast cancer (BC) risk. Here we estimated associations of intrauterine serum DDTs with MBD in 224 daughters of women in the Child Health and Development Studies pregnancy cohort whose mothers did not develop BC (MBCa-) and 156 daughters whose mothers did develop BC (MBCa+). In MBCa+ daughters, highest relative to lowest quartile of o,p'-DDT exposure was associated with a 17-unit higher dense area (95% CI = 2.6-31.2; P trend  = 0.01). We did not observe an association between o,p'-DDT and density measures in MBCa- daughters. MBD, an intermediate marker of BC risk, may be affected by intrauterine DDT exposures; MBCa status may modify the association., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We examined the link between gestational biomarkers and breast cancer in 9169 daughters born into the Child Health and Development Studies from 1959 to 1967. We identified 137 breast cancer cases diagnosed by age 52 as of 2012. Markers of increased risk included higher placental volume and rapid 2nd trimester gestational weight gain. Protective markers were placental hemorrhage and fibrin deposition, indicators of resistance to placental trophoblast invasion. Paradoxically, higher ponderal index at birth was protective suggesting that fetal and placental pathways to breast cancer are multiple and distinct. Results link placental and fetal phenotypes to breast cancer, characterizing some as restrictive and others as permissive markers of tumor development. We found new biomarkers of breast cancer risk that can be mined to discover 'omic correlates in the pregnancy exposome using archived and contemporary pregnancy samples. This line of investigation may discover new pathways to risk and new opportunities for prevention., (Copyright © 2019. Published by Elsevier Inc.)

Fetal adrenal-derived OH-DHEAS is the primary precursor for maternal estriol, an abundant, human, placental estrogen. We measured maternal pregnancy estriol as a marker of fetal adrenal function + placenta capacity to synthesize estriol. We hypothesized that maternal estriol is directly correlated with the adrenal hormone, DHEAS, in young adult women. We tested this hypothesis in a subset of women in the Child Health and Development Studies (351 of 470 eligible). 176 of these had serum samples collected at ages 27-30 for DHEAS assays, archived maternal pregnancy serum for estriol assays, and childhood growth data. In regression analyses, both maternal estriol and accelerated growth in middle childhood were independently, directly associated with DHEAS (+19% for quartile 4 versus quartile 1 of estriol, 95%CI=+ 2%, +36% and +12% for quartile 4 versus quartile 1 for middle childhood growth, 95%CI= +3%, +21%). Adrenal function may be programmed in utero and middle childhood with long-term consequences., (Copyright © 2019. Published by Elsevier Inc.)

Background: Studies of body mass index and semen quality have reported mixed results, but almost all were cross-sectional and many were conducted in selected populations. Longitudinal studies in population-based cohorts are necessary to identify how timing and duration of excess adiposity may affect semen quality., Methods: In 193 members of the Child Health and Development Studies birth cohort, we examined associations of birth weight and adiposity at six time points spanning early childhood and adulthood with sperm concentration, motility, and morphology at mean age 44 years, as well as with corresponding 2010 World Health Organization (WHO) subfertility reference levels., Results: Birth weight for gestational age percentile was positively associated with square-root sperm concentration (regression coefficient B [95% confidence interval] = 0.02 × 103 sperm/ml [0.004, 0.04]). Overweight/obesity in men's 20s was associated with lower percent progressive motility (B =-5.2 [-9.9, -0.63]), higher odds of low motility (odds ratio (OR) = 2.4 [1.3, 4.4]), and higher odds of poor morphology (OR = 1.9 [0.94, 3.8]). Those who were overweight/obese in their 20s were also more likely to meet two or three WHO subfertility criteria (OR = 3.9 [1.6, 9.4]) compared with normal-weight men. Each additional adult decade in which a participant was overweight/obese was associated with higher odds of low motility (OR = 1.3 [0.96, 1.6]) and higher odds of meeting two or three WHO subfertility criteria (OR = 1.5 [1.0, 2.2])., Conclusions: In our data, associations among adiposity and sperm concentration, motility, and morphology varied according to timing and duration of exposure, potentially reflecting different biological mechanisms that influence these semen parameters.

Background: In a previous Child Health and Development Studies report, p, p'-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50-54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure., Methods: We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50-54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31-49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1-3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p'-DDT, o, p'-DDT, and p, p'-DDE. Odds ratios (ORs) below are given for doubling of serum p, p'-DDT. All statistical tests were two-sided., Results: For early postmenopausal breast cancer, p, p'-DDT was associated with risk for all women (ORDDT 50-54 = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (ORDDT 50-54 for first exposure after infancy = 2.83, 95% CI = 1.96 to 4.10 vs ORDDT 50-54 for first exposure during infancy = 0.56, 95% CI = 0.26 to 1.19; Pinteraction DDT x age at first exposure = .01). In contrast, for premenopausal breast cancer, p, p'-DDT was associated with risk among women first exposed during infancy through puberty, but not after (ORDDT<50 for first exposure during infancy = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03)., Conclusions: p, p'-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause., (© The Author(s) 2019. Published by Oxford University Press.)

High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: The purpose of this study was to assess when in the life-course race-by-sex disparities in body mass index (BMI) emerge., Methods: Child Health and Development Studies participants, from whom height and weight data were collected at ages 5, 9-11, and 15-17 years, were followed up at the age of 50 years for anthropometric outcomes. Follow-up was completed for 605 subjects, 460 of whom were assessed for height and weight at the age of 50 years, had at least one available childhood BMI measure, and self-identified as either non-Hispanic black or non-Hispanic white. Linear regression analyses were conducted to determine whether interactions existed between race (black vs. white) and sex for predicting BMI at ages 5, 9-11, 15-17, and 50 years., Results: At age 5 years, BMI was independent of sex for both blacks and whites, but by the age of 9-11 years, BMI was sex-dependent in blacks, with higher BMI observed among black females. This sex dependence for BMI among blacks persisted at ages 15-17 years and age 50 years. The race-by-sex interaction was significant at ages 9-11, 15-17, and 50 years (P for interaction = 0.001, 0.002, and 0.01, respectively)., Conclusions: Race-by-sex disparities in body size were observed by the age of 9-11 years and persisted until the age of 50 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship., Method: Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9-11, mothers completed a questionnaire assessing psychological symptoms., Results: Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only., Conclusion: These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Many suspected breast cancer risk factors, including the pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE), are stored in fat where they could influence carcinogenesis. We tested the hypothesis that the relationship of DDT and DDE (DDTs) with adiposity is modified by disposition to develop breast cancer. We predicted that concentrations of serum DDTs would be inversely correlated with body mass index (BMI) during active exposure when DDTs move into the larger fat pool. We described this correlation at an average of 17 years before breast cancer was diagnosed, in a prospective nested case-control study in the Child Health and Development Studies. Women entered the study during pregnancy from 1959 to 1966 when DDT was in active use. In total, 133 breast cancer cases were diagnosed under the age of 50 as of 1998. Mean time to diagnosis was 17 years. In total, 133 controls were matched to cases on birth year. We observed the expected inverse correlation of serum DDTs with BMI only in women who remained cancer-free and not in women who ultimately developed breast cancer (p for interaction < 0.05). Findings suggest that vulnerability to breast cancer before the age of 50 may be associated with an uncoupling of the inverse correlation between BMI and serum DDTs. Investigation into mechanisms may eventually reveal early biomarkers of breast cancer risk.

Purpose: Studies suggests that intrauterine exposure to maternal smoking both accelerates or delays age at menarche. We hypothesize that these opposing findings relate to different infant and childhood growth patterns across cohorts., Methods: Using data from an adult follow-up study of the Child Health and Development Studies and the National Collaborative Perinatal Project, we examined, using generalized estimating linear regression models, whether intrauterine exposure to maternal smoking was associated with age at menarche in 1090 daughters before and after accounting for growth in weight., Results: Compared to the nonexposed, intrauterine exposure to maternal smoking was associated with a 4-month acceleration in menarche in the National Collaborative Perinatal Project (β = -0.35 years; 95% confidence interval [CI]: -0.63, -0.08), but a 6-month delay in menarche in the Child Health and Development Studies (β = 0.48 years; 95% CI: 0.13, 0.83), despite having a similar reduction in birth weight in both cohorts (∼300 g). The results were more consistent across cohorts when we stratified by postnatal growth patterns. For example, in those with rapid weight gain (increasing two growth references from 0 to 4 years), intrauterine exposure to maternal smoking was related to a 7-month acceleration in menarche (β = -0.56 years; 95% CI: -0.95, -0.17)., Conclusions: These findings suggest that the association of intrauterine exposure to maternal smoking on age at menarche depends on postnatal growth patterns., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Full-term pregnancy is associated with a transient increase and life-time decrease in maternal breast cancer risk. Estrone (E1), estradiol (E2), and estriol (E3) are in high concentration during the third trimester. E1 and E2 metabolism produces carcinogenic intermediaries, and E3 metabolism does not., Objective: We tested the hypothesis that higher E3 in pregnancy is protective while higher E1 plus E2 increases risk., Design: Prospective case-cohort study (n = 620; 204 cases) nested in a 38-year follow-up of 15,528 pregnant women in the Child Health and Development Studies. We measured E1, E2, and E3 in archived third trimester serum and estimated associations with breast cancer., Setting: Northern California Kaiser members receiving obstetric care from 1959 to 1967., Main Outcome Measure: Breast cancer diagnosed through 1997., Results: Doubling of E1+E2 was associated with greater risk [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2 to 2.4]. In contrast, doubling of E3 or the E3/E1+E2 ratio was associated with protection (HR, 0.7; 95% CI, 0.5 to 1.0; HR, 0.6; 95% CI, 0.4 to 0.8, respectively). Associations were stronger for diagnoses within 15 years after delivery compared with 16 to 38 years (Pinteraction = 0.0002) for gravidas >27 years at delivery vs ≤27 (Pinteraction = 0.01) and for primiparas vs multiparas (Pinteraction = 0.02)., Conclusions: Relatively high third trimester E3 levels might protect parous women from breast cancer and E1 and E2 might enhance the risk. If findings are confirmed, third trimester pregnancy estrogens could help explain how parity affects breast cancer., (Copyright © 2017 Endocrine Society)

Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005-2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex-specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04-mm Hg decrement in adult systolic BP (95% confidence interval (CI): -2.14, 0.06) and a 0.63-mm Hg decrement in diastolic BP (95% CI: -1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to -0.90 mm Hg (95% CI: -1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., -1.22 mm Hg (95% CI: -5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Extensive evidence leads us to expect that health disparities by race and socioeconomic status found in one generation might be reproduced in the next. To the extent that this occurs it is important to assess life course processes responsible for the reproduction. Prospective evidence concerning such life course processes is hard to come by as it requires long-term follow-up of individuals from childhood through adult life. We present data from the Child Health and Development Disparities study that provides evidence relevant to this issue with respect to self-rated health. Mothers and offspring recruited in California's Bay Area between 1959 and 1967 were assessed during pregnancy with follow-up exams of offspring along with in-person interviews with mothers (at offspring ages 5, 9-11, 15-17) and offspring (at ages 15-17, ∼50). Available data allow us to assess the importance of three potential life course pathways in the reproduction of inequalities in self-rated health - socioeconomic pathways, cognitive pathways and pathways involving emerging health itself. As expected we found that race and SES disparities in SRH are reproduced across generations. They are evident in mothers, not strong or significant in offspring at 15-17, but present once again in offspring at age ∼50. Concerning potential pathways, we found that indicators of child health were related to adult SRH and played some role in accounting for race but not SES disparities in adult SRH. Cognitive abilities were unrelated to adult SRH with childhood SES controlled. Childhood SES was associated with adult SRH independent of other childhood factors and is reduced to non-significance only when offspring college attainment is controlled. Race and SES disparities in self-reported health in one generation are re-expressed in the next with strongest support for SES pathways in this transmission., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We tested the hypothesis that irregular menstruation predicts lower risk for ovarian cancer, possibly due to less frequent ovulation. We conducted a 50-year prospective study of 15,528 mothers in the Child Health and Development Studies cohort recruited from the Kaiser Foundation Health Plan from 1959 to 1966. Irregular menstruation was classified via medical record and self-report at age 26. We identified 116 cases and 84 deaths due to ovarian cancer through 2011 via linkage to the California Cancer Registry and Vital Statistics. Contrary to expectation, women with irregular menstrual cycles had a higher risk of ovarian cancer incidence and mortality over the 50-year follow-up. Associations increased with age (p <0.05). We observed a 2-fold increased incidence and mortality by age 70 (95% confidence interval [CI] = 1.1, 3.4) rising to a 3-fold increase by age 77 (95% CI = 1.5, 6.7 for incidence; 95% CI = 1.4, 5.9 for mortality). We also found a 3-fold higher risk of mortality for high-grade serous tumors (95% CI = 1.3, 7.6) that did not vary by age. This is the first prospective study to show an association between irregular menstruation and ovarian cancer-we unexpectedly found higher risk for women with irregular cycles. These women are easy to identify and many may have polycystic ovarian syndrome. Classifying high-risk phenotypes such as irregular menstruation creates opportunities to find novel early biomarkers, refine clinical screening protocols and potentially develop new risk reduction strategies. These efforts can lead to earlier detection and better survival for ovarian cancer., (© 2016 UICC.)