The role of body mass index at diagnosis of colorectal cancer on Black-White disparities in survival: a density regression mediation approach.

The study of racial/ethnic inequalities in health is important to reduce the uneven burden of disease. In the case of colorectal cancer (CRC), disparities in survival among non-Hispanic Whites and Blacks are well documented, and mechanisms leading to these disparities need to be studied formally. It has also been established that body mass index (BMI) is a risk factor for developing CRC, and recent literature shows BMI at diagnosis of CRC is associated with survival. Since BMI varies by racial/ethnic group, a question that arises is whether differences in BMI are partially responsible for observed racial/ethnic disparities in survival for CRC patients. This article presents new methodology to quantify the impact of the hypothetical intervention that matches the BMI distribution in the Black population to a potentially complex distributional form observed in the White population on racial/ethnic disparities in survival. Our density mediation approach can be utilized to estimate natural direct and indirect effects in the general causal mediation setting under stronger assumptions. We perform a simulation study that shows our proposed Bayesian density regression approach performs as well as or better than current methodology allowing for a shift in the mean of the distribution only, and that standard practice of categorizing BMI leads to large biases when BMI is a mediator variable. When applied to motivating data from the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium, our approach suggests the proposed intervention is potentially beneficial for elderly and low-income Black patients, yet harmful for young or high-income Black populations.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

Bayesian kernel machine regression-causal mediation analysis.

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75th percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.

Doppler-Guided Acoustically Active Injection Catheter: Transendocardial Delivery Assessed by an Efficacy Testing Animal Model.

Percutaneous transendocardial injections of therapeutic agents into the myocardium may not always be effective. We used an animal model for assessing the efficacy of the injections using linoleic acid as a testing agent. Efficacious delivery into the myocardium of a beating heart was indicated by rapidly developed local myocardial necrosis and wall motion abnormalities using echocardiography. We employed this experimental model to test our innovative technology, an acoustically active injection catheter. The Doppler ultrasound-guided acoustically active injection catheter effectively delivers the substance to the myocardium but needs further technical improvements to minimize an unwanted systemic distribution of the agent.

Safety of magnetic resonance imaging in patients with cardiac implantable electronic devices with generator and lead(s) brand mismatch.

Magnetic resonance imaging (MRI) is a valuable imaging modality for the assessment of both cardiac and non-cardiac structures. With a growing population of patients with cardiovascular implantable electronic devices (CIEDs), 50%-75% of these patients will need an MRI. MRI-conditional CIEDs have demonstrated safety of MRI scanning with such devices, yet non-conditional devices such as hybrid CIEDs which have generator and lead brand mismatch may pose a safety risk. In this retrospective study, we examined the outcomes of patients with hybrid CIEDs undergoing MRI compared to those patients with non-hybrid CIEDs. A total of 349 patients were included, of which 24 patients (7%) had hybrid CIEDs. The primary endpoint was the safety of MRI for patients with hybrid CIEDs as compared to those with non-hybrid devices, measured by the rate of adverse events, including death, lead or generator failure needing immediate replacement, loss of capture, new onset arrhythmia, or power-on reset. Secondary endpoints consisted of pre- and post-MRI changes of decreased P-wave or R-wave sensing by ≥50%, changes in pacing lead impedance by ≥50 ohms, increase in pacing thresholds by ≥ 0.5 V at 0.4 ms, and decreasing battery voltage of ≥ 0.04 V. The primary endpoint of any adverse reaction was present in 1 (4.2%) patient with a hybrid device, and consistent of atrial tachyarrhythmia, and in 10 (3.1%) patients with a non-hybrid device, and consisted of self-limited atrial and non-sustained ventricular arrhythmias; this was not statistically significant. No significant differences were found in the secondary endpoints. This study demonstrates that MRI in patients with hybrid CIEDs does not result in increased patient risk or significant device changes when compared to those patients who underwent MRI with non-hybrid CIEDs.

P-Values and Power in Orthopedic Research: Myths and Reality.

The results of statistical tests in orthopedic studies are typically reported using P-values. If a P-value is smaller than the pre-determined level of significance (eg, < .05), the null hypothesis is rejected in support of the alternative. This automaticity in interpreting statistical results without consideration of the power of the study has been denounced over the years by statisticians, since it can potentially lead to misinterpretation of the study conclusions. In this paper, we review fundamental misconceptions and misinterpretations of P-values and power, along with their connection with confidence intervals, and we provide guidelines to orthopedic researchers for evaluating and reporting study results. We provide real-world orthopedic examples to illustrate the main concepts. Please visit the followinghttps://youtu.be/bdPU4luYmF0for videos that explain the highlights of the paper in practical terms.

Study Types in Orthopaedics Research: Is My Study Design Appropriate for the Research Question?

When performing orthopaedic clinical research, alternative study designs can be more appropriate depending on the research question, availability of data, and feasibility. The most common observational study designs in total joint arthroplasty research are cohort and cross-sectional studies. This article describes methodological considerations for different study designs with examples from the total joint arthroplasty literature. We highlight the advantages and feasibility of experimental and observational study designs using real-world examples. We illustrate how to avoid common mistakes, such as incorrect labeling of matched cohort studies as case-control studies. We further guide investigators through a step-by-step design of a case-control study. We conclude with considerations when choosing between alternative study designs. Please visit the followinghttps://youtu.be/Zvce61cMYi8for videos that explain the highlights of the article in practical terms.

Avoiding Systematic Bias in Orthopedics Research Through Informed Variable Selection: A Discussion of Confounders, Mediators, and Colliders.

There are 3 common variable types in orthopedic research-confounders, colliders, and mediators. All 3 types of variables are associated with both the exposure (eg, surgery type, implant type, body mass index) and outcome (eg, complications, revision surgery) but differ in their temporal ordering. To reduce systematic bias, the decision to include or exclude a variable in an analysis should be based on the variable's relationship with the exposure and outcome for each research question. In this article, we define 3 types of variables with case examples from orthopedic research. Please visit the followinghttps://youtu.be/V-grpgB1ShQfor videos that explain the highlights of the article in practical terms.

Measurement Error and Misclassification in Orthopedics: When Study Subjects are Categorized in the Wrong Exposure or Outcome Groups.

Datasets available for orthopedic research often contain measurement and misclassification errors due to errors in data collection or missing data. These errors can have different effects on the study results. Measurement error refers to inaccurate measurement of continuous variables (eg, body mass index), whereas misclassification refers to assigning subjects in the wrong exposure and/or outcome groups (eg, obesity categories). Misclassification of any type can result in underestimation or overestimation of the association between exposures and outcomes. In this article, we offer practical guidelines to avoid, identify, and account for measurement and misclassification errors. We also provide an illustrative example on how to perform a validation study to address misclassification based on real-world orthopedic data. Please visit the followinghttps://youtu.be/9-ekW2NnWrsor videos that explain the highlights of the article in practical terms.

The impact of patient and partner personality traits on learning success for a cognitive rehabilitation intervention for patients with MCI.

The Memory Support System (MSS) is the memory compensation tool used in the HABIT Healthy Action to Benefit Independence and Thinking® Program. People diagnosed with mild cognitive impairment (pwMCI; n = 153) participated in this cognitive rehabilitative programme with a partner. We first aimed to determine if prior research on the positive impact of higher baseline cognitive status on successful MSS learning would be replicated in a new sample. We further evaluated the impact of the pwMCI's and partner's personality traits, as measured by the Ten Item Personality Inventory, on successful learning. Better global cognitive status was again shown to increase the odds for MSS learning success. In terms of personality, the highest odds of learning success occurred when the pwMCI was high in Openness to Experience (OR = 5.43), followed by high partner Openness (OR = 2.53) or high Openness in both the pwMCI and partner (OR = 2.31). In sum, when the pwMCI possessed both better cognitive status and openness to new experience they were better able to master a cognitive rehabilitation tool for MCI.

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders.

INTRODUCTION: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. METHODS: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. RESULTS: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. DISCUSSION: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Prenatal exposure to a mixture of elements and neurobehavioral outcomes in mid-childhood: Results from Project Viva.

BACKGROUND: Lead (Pb), manganese (Mn), selenium (Se) and methylmercury (MeHg) can be neurotoxic individually, despite Mn and Se also being essential elements. Little is known about the joint effects of essential and non-essential elements on neurobehavior, particularly for prenatal exposures. OBJECTIVES: To evaluate associations of prenatal exposure to multiple elements with executive function and neurobehavior in children. METHODS: Participants included 1009 mother-child pairs from the Project Viva pre-birth cohort. We estimated maternal erythrocyte Pb, Mn, Se, and Hg concentrations prenatally. In 6-11-year old children (median 7.6 years), parents and teachers rated children's executive function-related behaviors using the Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score and behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) total difficulties score. We evaluated associations of element mixtures with neurobehavior using Bayesian kernel machine regression (BKMR), multivariable linear regression, and quantile g-computation. RESULTS: Median erythrocyte Pb, Mn, Se, and Hg concentrations were 1.1 µg/dL, 33.1 µg/L, 204.5 ng/mL, and 3.1 ng/g, respectively. Findings from BKMR and quantile g-computation models both showed worse (higher) parent-rated BRIEF and SDQ z-scores with higher concentrations of the mixture, although estimates were imprecise. When remaining elements were set at their median within BKMR models, increases in Pb and Se from the 25th to 75th percentile of exposure distributions were associated with 0.08 (95% CI: 0.02, 0.19) and 0.07 (95% CI: 0.03, 0.16) standard deviation increases in parent-rated BRIEF scores, and 0.08 (95% CI: 0.02, 0.17) and 0.05 (95% CI: 0.03, 0.13) standard deviation increases in SDQ scores, respectively. There was no evidence of element interactions. DISCUSSION: Although associations were small in magnitude, we found a trend of worsening neurobehavioral ratings with increasing prenatal exposure to an element mixture. However, we may be observing a limited range of dose-dependent impacts given the levels of exposure within our population.

Immortal Time Bias in the Analysis of Time-to-Event Data in Orthopedics.

Many outcomes in arthroplasty research are analyzed as time-to-event outcomes using survival analysis methods. When comparison groups are defined after a time-delayed exposure or intervention, a period of immortal time arises and can lead to biased results. In orthopedics research, immortal time bias often arises when a minimum amount of follow-up is required for study inclusion or when comparing outcomes in staged bilateral vs unilateral arthroplasty patients. We present an explanation of immortal time and the associated bias, describe how to correctly account for it using proper data preparation and statistical techniques, and provide an illustrative example using real-world arthroplasty data. We offer practical guidelines for identifying and properly handling immortal time to avoid bias. Please visit the followinghttps://youtu.be/58p8w5o-ci4for a video that explains the highlights of the paper in practical terms.

Competing Risk Analysis: What Does It Mean and When Do We Need It in Orthopedics Research?

Most orthopedic studies involve survival analysis examining the time to an event of interest, such as a specific complication or revision surgery. Competing risks commonly arise in such studies when patients are at risk of more than one mutually exclusive event, such as death, or when the rate of an event depends on the rates of other competing events. In this article, we briefly describe the survival analysis censoring methodology, common fatal and nonfatal competing events, and define circumstances where standard survival analysis can fail in the setting of competing risks with real-world examples from orthopedics. Please visit the followinghttps://youtu.be/ifj_Mm3eGu8for a video that explains the highlights of the paper in practical terms.

Adjusted Survival Curves Improve Understanding of Multivariable Cox Model Results.

Kaplan-Meier survival curves are the most common methods for unadjusted group comparison of outcomes in orthopedic research. However, they may be misleading due to an imbalance of confounders between patient groups. The Cox model is frequently used to adjust for confounders, but graphical display of adjusted survival curves is not commonly utilized. We describe the circumstances when adjusted survival curves are useful in orthopedic research, describe and use 2 different methods to obtain adjusted curves, and illustrate how they can improve understanding of the multivariable Cox model results. We further provide practical strategies for identifying the need for and performing adjusted survival curves. Please visit the followinghttps://youtu.be/ys0hy2CiMCAfor a video that explains the highlights of the paper in practical terms.

Living With Survival Analysis in Orthopedics.

Time to event data occur commonly in orthopedics research and require special methods that are often called "survival analysis." These data are complex because both a follow-up time and an event indicator are needed to correctly describe the occurrence of the outcome of interest. Common pitfalls in analyzing time to event data include using methods designed for binary outcomes, failing to check proportional hazards, ignoring competing risks, and introducing immortal time bias by using future information. This article describes the concepts involved in time to event analyses as well as how to avoid common statistical pitfalls. Please visit the followinghttps://youtu.be/QNETrx8B6IUandhttps://youtu.be/8SBoTr9Jy1Qfor videos that explain the highlights of the paper in practical terms.

Real-World Patient Experience With Erenumab for the Preventive Treatment of Migraine.

BACKGROUND: Erenumab, a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody, has been well tolerated with good efficacy for the preventive treatment of episodic and chronic migraine in phase 2 and phase 3 clinical trials. Limited post-market observations are available to validate these findings in a real-world tertiary headache clinic population with complex comorbidities and refractory migraine. OBJECTIVE: The goal of this study is to demonstrate the real-world performance of erenumab among patients in a tertiary care headache clinic by describing patient selection, experience, and clinical characteristics after 6 months of erenumab therapy. METHODS: A retrospective, exploratory, observational study was conducted on patients receiving at least 1 erenumab injection (70 or 140 mg). Baseline data obtained by chart review and telephone calls were compared to 6-month follow-up telephone calls. The primary outcome was the reduction in self-reported headache days per month at baseline compared to 6 months for those with complete 6-month data. The significance level was set at P < .05. Secondary analyses explored the distribution of headache severity, responder rates, Migraine Disability Assessment scores, adverse effects, ineffective preventives, comorbidities, wearing-off, and discontinuation. RESULTS: Of the 101 patients who consented to participate, 89.1% (90/101) were women, and the mean age of all patients was 49 years (range, 19-80 years). At baseline, 94.1% (95/101) of patients had chronic migraine, 5.0% (5/101) had episodic migraine, and 18.8% (19/101) had medication overuse headache. The mean (SD) number of baseline headache and migraine days per month for the entire cohort were 24.3 (8.2) and 18.2 (9.3) days, respectively. Participants had numerous comorbidities and had tried a mean of 11.2 unique oral medications and 4.8 unique medication categories before receiving erenumab, including 83.2% (84/101) who had also received onabotulinumtoxinA. Six-month post-erenumab follow-up data were available for 42.6% (43/101) of participants. For these 43 participants, the number of headache days per month decreased significantly by 6.5 days from a baseline mean (SD) of 24.8 (6.47) days to 18.3 (12) days at 6-month follow-up (P < .001); similarly, the monthly migraine days decreased significantly by 8.4 days from a baseline mean of 19.1 (9.3) days to 10.7 days at 6-month follow-up (P < .001). The 50% responder rate was 34.9% (15/43) for monthly headache days and 54.8% (23/43) for monthly migraine days. Of all 101 participants, 28 (27.7%) discontinued erenumab, primarily because it was ineffective (39.3%, 11/28) or because of adverse effects (42.9%, 12/28). CONCLUSION: This post-market observational study of patient experience describes response to erenumab in a real-world tertiary headache clinic with a complex patient population. Overall, these complex patients had a significant positive clinical response to erenumab, but with high rates of discontinuation. This study also noted a 1-week wearing-off response and high rates of constipation. Further post-market studies are needed to better characterize patient selection and real-world response to erenumab.

Prenatal cortisol modifies the association between maternal trauma history and child cognitive development in a sex-specific manner in an urban pregnancy cohort.

Women's experience of trauma may cause lifelong alterations in physiological stress regulation, which can be transmitted to offspring in utero. We investigated, in a prospective pregnancy cohort, associations among maternal lifetime interpersonal trauma (IPT) history, prenatal cortisol dysregulation, and children's memory domains. Sex-specific effects were also explored. Pregnant women were enrolled from Brigham & Women's Hospital and affiliated clinics near Boston, MA, in 2002-2007. IPT was assessed with the Revised Conflict Tactics Scale, short form. Salivary cortisol was measured at five time points on each of three days in one week at 29.0 ± 5.1 weeks gestation, and morning rise and diurnal slope were calculated. The Wide Range Assessment of Memory & Learning, 2nd Edition was administered at 6.5 ± 1.0 years and scores were generated for general memory and three sub-domains: verbal, visual, and attention/concentration. In total, 258 maternal-child dyads provided memory and IPT and/or cortisol data. IPT was positively associated with verbal memory in boys (ß ± SE: 4.6 ± 2.6) and inversely associated with visual memory score in girls (-6.5 ± 3.2). IPT did not predict prenatal cortisol, but prenatal cortisol modified the association between IPT history and child memory in varying coefficient models allowing for non-linear effect modification. The strongest evidence of interaction was for visual memory in boys: IPT history was associated with poorer visual memory only in those with flatter prenatal diurnal slope (interaction p = .005). Maternal lifetime IPT that leads to prenatal HPA dysregulation may have consequences for child memory, more so than either trauma or elevated cortisol alone. Boys may be more vulnerable to effects. Sex- and timing-specific effects require further investigation.

An overview of methods to address distinct research questions on environmental mixtures: an application to persistent organic pollutants and leukocyte telomere length.

BACKGROUND: Numerous methods exist to analyze complex environmental mixtures in health studies. As an illustration of the different uses of mixture methods, we employed methods geared toward distinct research questions concerning persistent organic chemicals (POPs) as a mixture and leukocyte telomere length (LTL) as an outcome. METHODS: With information on 18 POPs and LTL among 1,003 U.S. adults (NHANES, 2001-2002), we used unsupervised methods including clustering to identify profiles of similarly exposed participants, and Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) to identify common exposure patterns. We also employed supervised learning techniques, including penalized, weighted quantile sum (WQS), and Bayesian kernel machine (BKMR) regressions, to identify potentially toxic agents, and characterize nonlinear associations, interactions, and the overall mixture effect. RESULTS: Clustering separated participants into high, medium, and low POP exposure groups; longer log-LTL was found among those with high exposure. The first PCA component represented overall POP exposure and was positively associated with log-LTL. Two EFA factors, one representing furans and the other PCBs 126 and 118, were positively associated with log-LTL. Penalized regression methods selected three congeners in common (PCB 126, PCB 118, and furan 2,3,4,7,8-pncdf) as potentially toxic agents. WQS found a positive overall effect of the POP mixture and identified six POPs as potentially toxic agents (furans 1,2,3,4,6,7,8-hxcdf, 2,3,4,7,8-pncdf, and 1,2,3,6,7,8-hxcdf, and PCBs 99, 126, 169). BKMR found a positive linear association with furan 2,3,4,7,8-pncdf, suggestive evidence of linear associations with PCBs 126 and 169, and a positive overall effect of the mixture, but no interactions among congeners. CONCLUSIONS: Using different methods, we identified patterns of POP exposure, potentially toxic agents, the absence of interaction, and estimated the overall mixture effect. These applications and results may serve as a guide for mixture method selection based on specific research questions.

Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex.

OBJECTIVES: To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. STUDY DESIGN: Analyses included 314 mother-infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist-Revised. Fenton birthweight for gestational age z-scores (BWGA-z) were calculated. A 3-cm scalp-nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA-z and examine 2- and 3-way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA-z as a function of cortisol. RESULTS: Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1-unit increase in trauma score was associated with a 0.19-unit decrease in BWGA-z (95% CI, -0.34 to -0.04). Associations among females were nonsignificant, regardless of cortisol level. CONCLUSIONS: These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.