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"O'Connor, Thomas"
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The persisting effect of maternal mood in pregnancy on childhood psychopathology
Developmental or fetal programming has emerged as a major model for understanding the early and persisting effects of prenatal exposures on the health and development of the child and adult. We leverage the power of a 14-year prospective study to examine the persisting effects of prenatal anxiety, a key candidate in the developmental programming model, on symptoms of behavioral and emotional problems across five occasions of measurement from age 4 to 13 years. The study is based on the Avon Longitudinal Study of Parents and Children cohort, a prospective, longitudinal study of a large community sample in the west of England (n = 7,944). Potential confounders included psychosocial and obstetric risk, postnatal maternal mood, paternal pre- and postnatal mood, and parenting. Results indicated that maternal prenatal anxiety predicted persistently higher behavioral and emotional symptoms across childhood with no diminishment of effect into adolescence. Elevated prenatal anxiety (top 15%) was associated with a twofold increase in risk of a probable child mental disorder, 12.31% compared with 6.83%, after allowing for confounders. Results were similar with prenatal depression. These analyses provide some of the strongest evidence to date that prenatal maternal mood has a direct and persisting effect on her child's psychiatric symptoms and support an in utero programming hypothesis.
Journal Article
Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology—A global perspective
There is clear evidence that the mother's stress, anxiety, or depression during pregnancy can alter the development of her fetus and her child, with an increased risk for later psychopathology. We are starting to understand some of the underlying mechanisms including the role of the placenta, gene–environment interactions, epigenetics, and specific systems including the hypothalamic–pituitary–adrenal axis and cytokines. In this review we also consider how these effects may be different, and potentially exacerbated, in different parts of the world. There can be many reasons for elevated prenatal stress, as in communities at war. There may be raised pregnancy-specific anxiety with high levels of maternal and infant death. There can be raised interpersonal violence (in Afghanistan 90.2% of women thought that “wife beating” was justified compared with 2.0% in Argentina). There may be interactions with nutritional deficiencies or with extremes of temperature. Prenatal stress alters the microbiome, and this can differ in different countries. Genetic differences in different ethnic groups may make some more vulnerable or more resilient to the effects of prenatal stress on child neurodevelopment. Most research on these questions has been in predominantly Caucasian samples from high-income countries. It is now time to understand more about prenatal stress and psychopathology, and the role of both social and biological differences, in the rest of the world.
Journal Article
Harm Reduction in Male Patients Actively Using Anabolic Androgenic Steroids (AAS) and Performance-Enhancing Drugs (PEDs): a Review
Anabolic androgenic steroid (AAS) and performance-enhancing drug (PED) use is a prevalent medical issue, especially among men, with an estimated 2.9–4 million Americans using AAS in their lifetime. Prior studies of AAS use reveal an association with polycythemia, dyslipidemia, infertility, hypertension, left ventricular hypertrophy, and multiple behavioral disorders. AAS withdrawal syndrome, a state of depression, anhedonia, and sexual dysfunction after discontinuing AAS use, is a common barrier to successful cessation. Clinical resources for these patients and training of physicians on management of the patient using AAS are limited. Many men are hesitant to seek traditional medical care due to fear of judgment and lack of confidence in physician knowledge base regarding AAS. While proposed approaches to weaning patients off AAS are published, guidance on harm reduction for actively using patients remains sparse. Medical education regarding the management of AAS use disorder is paramount to improving care of this currently underserved patient population. Management of these patients must be non-judgmental and focus on patient education, harm reduction, and support for cessation. The approach to harm reduction should be guided by the specific AAS/PEDs used.
Journal Article
Characteristics and Attitudes of Men Using Anabolic Androgenic Steroids (AAS): A Survey of 2385 Men
Additional characterization of patients using anabolic androgenic steroids (AAS) is needed to improve harm reduction and cessation resources for patients. Our group sought to expand upon the currently limited data regarding AAS use by performing a web-based survey assessing experiences of males using AAS. Participants included men over the age of 18 with history of AAS use within the past 5 years. Data were collected between August 2019 and April 2020. Primary outcome measures included age when starting AAS, dose of AAS, motivations for use, experiences with health-care professionals, and rate of successful cessation. The survey was accessed 3640 times, resulting in 2385 completed surveys meeting the inclusion criteria (68.93% participation rate).
Average participant age was 31.69 ± 10.09 years. Over half of respondents were from the United States (n = 1271, 53.3%). Motives to use AAS included improving appearance (n = 1959, 82.2%), strength gain (n = 1192, 50%), and self-esteem/body image issues (n = 712, 29.87%). Participants rated physicians poorly, regarding knowledge of AAS (4.08 ± 2.23). Most participants did not reveal AAS use to their health-care providers (n = 1338, 56.1%); of those that did, 55.30% (n = 579) reported feeling discriminated against for their use. Of 46.16% (n = 1101) attempting AAS cessation, 60.22% (n = 663) were unsuccessful. Challenges in the management of AAS use include early onset of use, supraphysiologic doses used, and frequently present body image disorders stress. Distrust of health-care providers, poor cessation rates, and lack of physician training further exacerbate this. These findings should serve to reinforce previous calls to action for further research on the treatment of AAS use disorder.
Journal Article
Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program
Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress.
We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships.
We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS.
We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of
[95% confidence interval (CI):
,
],
(95% CI:
,
),
(95% CI:
,
),
(95% CI:
, 0.06), and
(95% CI:
,
), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age:
(95% CI: 0.38, 0.83),
(95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [
; 95% highest posterior density (HPD):
,
] and decreased odds of large-for-gestational-age (
; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress.
Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.
Journal Article
Real-World Experience among Elderly Metastatic Breast Cancer Patients Treated with CDK4/6 Inhibitor-Based Therapy
The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration.
Journal Article
Antioxidative and anticancer effects of Tacca chantrieri extract enhancing cisplatin sensitivity in cholangiocarcinoma cells
Cholangiocarcinoma (CCA) poses a significant healthcare challenge due to the limited effects of chemotherapeutic drugs. Natural products have gained widespread attention in cancer research according to their promising anti-cancer effects with minimal adverse side effects. This study explored the potential of Tacca chantrieri (TC), a plant rich in bioactive compounds, as a therapeutic agent for CCA. TC, a traditional remedy in Southeast Asia, exhibits anti-inflammatory and cytotoxic properties against cancer cells. Ethanol extraction of TC’s rhizome was conducted, and antioxidant activities were assessed through various assays, including total phenolic and flavonoid contents, DPPH radical scavenging, and FRAP assays. The cytotoxic effects of TC extracts on CCA cell lines (KKU-213A and KKU-213C) were evaluated using MTT assays and flow cytometry. Protein levels of Bax and Bcl-2 were determined through western blot analysis. Additionally, the study investigated whether the combined impact of TC extract and cisplatin on CCA cells enhanced cisplatin’s efficacy as an anti-cancer treatment. Results indicated that ethanolic extracts from TC contained phenolic and flavonoid compounds with robust antioxidant activity. TC treatments reduce CCA cell viability, inhibiting growth and inducing apoptosis in a dose-dependent manner. The Bax/Bcl-2 ratio increases, signifying a pro-apoptotic shift. Importantly, TC extract not only decreases cell viability but also augments the inhibitory effect of cisplatin in CCA cells. These results provide valuable insights into TC’s therapeutic mechanisms and its potential to synergize with conventional chemotherapeutic agents, offering a promising avenue for the development of alternative and more effective strategies for CCA treatment.
Journal Article
Maternal prenatal anxiety and child COMT genotype predict working memory and symptoms of ADHD
Maternal prenatal anxiety is an important risk factor for altered child neurodevelopment but there is uncertainty concerning the biological mechanisms involved and sources of individual differences in children's responses. We sought to determine the role of functional genetic variation in COMT, which encodes catechol-O-methyltransferase, in the association between maternal prenatal anxiety and child symptoms of ADHD and working memory. We used the prospectively-designed ALSPAC cohort (n = 6,969) for our primary data analyses followed by replication analyses in the PREDO cohort (n = 425). Maternal prenatal anxiety was based on self-report measures; child symptoms of ADHD were collected from 4-15 years of age; working memory was assessed from in-person testing at age 8 years; and genetic variation in COMT at rs4680 was determined in both mothers and children. The association between maternal prenatal anxiety and child attention/hyperactivity symptoms and working memory was moderated by the child's rs4680 genotype, with stronger effects obtained for the val/val (G:G) genotype relative to val/met (A:G) (all p<0.01) and met/met (A:A) groups (all p<0.05). Similar findings were observed in the PREDO cohort where maternal prenatal anxiety interacted with child rs4680 to predict symptoms of ADHD at 3.5 years of age. The findings, from two cohorts, show a robust gene-environment interaction, which may contribute to inter-individual differences in the effects of maternal prenatal anxiety on developmental outcomes from childhood to mid-adolescence.
Journal Article
Organophosphate ester exposure in pregnancy, gestational weight gain, and postpartum body composition in a U.S.-based longitudinal pregnancy cohort
Background
Organophosphate esters (OPEs) are replacement flame retardants that have been implicated as metabolic disruptors and linked to birth size across a number of epidemiologic studies. Little is known about how OPEs impact maternal weight and body composition from pregnancy through the postpartum period.
Methods
We measured OPE metabolites in mid-pregnancy urine samples from participants in a pregnancy cohort study based in Rochester, NY, USA. We calculated total gestational weight gain (GWG) based on clinical records (
n
= 278) and additionally measured weight retention and body fat percentage through bioelectric impedance at 6 (
n
= 205) and 12 months postpartum (
n
= 167). We fitted adjusted linear and logistic regression models examining OPE concentrations in relation to the outcome measures and secondarily, fitted models stratified by earliest pregnancy BMI (< 25 kg/m
2
versus ≥ 25 kg/m
2
).
Results
In main models, most associations were null. Several highly prevalent OPEs such as bis(1,3-dichloro-2-propyl) phosphate (BDCPP; β: -1.02 lbs 95%CI: -2.00, -0.03) were associated with lower GWG, while detection of other, less prevalent OPEs like BMPP (bis(methylphenyl) phosphate; β: 2.86 lbs, 95%CI: -0.21, 5.94) was associated with greater GWG. In stratified analyses, associations tended to be stronger in women who started pregnancy overweight or obese, including findings that several OPEs were associated with higher fat percentage at 6 and 12 months postpartum. Few associations with postpartum weight retention were observed.
Discussion
Evidence linking gestational OPE exposure with GWG and body composition in the postpartum was limited and mixed, with the strongest associations observed for BDCPP. In light of the growing literature on OPEs’ impacts on birth size and child outcomes, greater research into maternal metabolic disruption is warranted.
Journal Article