A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

A general calculus of fitness landscapes finds genes under selection in cancers.

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype-phenotype relationship and discover genes associated with complex traits and diseases.

Prenatal mental health and emotional experiences during the pandemic: associations with infant neurodevelopment screening results.

BACKGROUND: This study determined whether parental mental health and emotional experiences during the prenatal period were linked to infant developmental outcomes through the Ages and Stages Questionnaire (ASQ-3) at 8-10 months. METHODS: Participants included 133 individuals who were living in the US and were pregnant or had given birth within 6 months prior to enrollment. Respondents were majority White with high education and income levels. Online surveys were administered from May 2020 to September 2021; follow-up surveys were administered from November 2020 to August 2022. RESULTS: Parent generalized anxiety symptoms were positively associated with infant communication (ß = 0.34, 95% CI [0.15, 1.76], p < 0.05), while parent-fetal bonding was positively associated with infant communication (ß = 0.20, 95% CI [0.05, 0.76], p < 0.05) and personal-social performance (ß = 0.20, 95% CI [0.04, 0.74], p < 0.05). COVID-19-related worry was negatively associated with infant communication (ß = -0.30, 95% CI [-0.75, -0.12], p < 0.05) and fine motor performance (ß = -0.25, 95% CI [-0.66, -0.03], p < 0.05). CONCLUSION: Parent mental health and emotional experiences may contribute to infant developmental outcomes in high risk conditions such as a pandemic. IMPACT STATEMENT: Maternal SARS-CoV-2 infection has been evaluated in relation to child outcomes, however, parent psychosocial experiences should not be overlooked when considering pandemic risks to child development. Specific prenatal mental health and pandemic-related emotional experiences are associated with infant developmental performance, as assessed by the Ages and Stages. Questionnaire (ASQ-3) at 8 to 10 months old. Findings indicate that parental prenatal anxiety and emotional experiences from the pandemic should be assessed when evaluating child developmental delays.

Patterns of peripartum depression screening and detection in a large, multi-site, integrated healthcare system.

The purpose of this study was to examine peripartum depression (PD) screening patterns within and across the prenatal and postpartum periods and assess the incidence of new positive screens during standard screening protocol timepoints to inform practice, particularly when limited screenings can be conducted.This is a retrospective observational study of women screened for PD through a large, integrated health system using the Edinburgh Postnatal Depression Scale (EPDS) within their obstetrics and pediatric practices. Pregnancies with an EPDS score for at least one obstetric and one pediatric appointment between November 2016 and October 2019 were included (n = 3240). The data were analyzed using chi-squared test, Student's t-test, and binary logistic regression analyses. An EPDS score of 10 or higher was considered a positive screen.The positive screening rate for this cohort was 18.5%, with a prenatal positive rate of 9.9% and a postpartum positive rate of 8.6%. Single relationship status showed a higher rate of PD overall. Two thirds of women were not screened until their third trimester, resulting in delayed detection for an estimated 28% of women who ultimately screened positive. Few new positive screens (1.3%) were detected after 9 weeks postpartum in women who had completed all recommended prior screens.Obstetric providers should screen for PD as early in pregnancy as possible and continue to screen as often as feasible regardless of previous negative EPDS scores. Prioritizing screening more often in pregnancy and before 9 weeks postpartum is optimal to avoid delays in detection and intervention.

Unexpected changes in birth experiences during the COVID-19 pandemic: Implications for maternal mental health.

PURPOSE: This study examined the rates of unexpected birth experiences due to the COVID-19 pandemic and its association with women's postpartum mental health symptoms (depression, generalized anxiety, and PTSD). METHODS: Our cross-sectional analysis included postpartum women (N = 506) who reported on birth plan changes attributed to the COVID-19 pandemic through the PEACE (Perinatal Experiences and COVID-19 Effects) Study, an online survey that took place between May 2020 and May 2021. Covariates included sociodemographic variables, number of days since the pandemic, pre-pregnancy mental health history, and protective factors such as social support, distress tolerance, and resilience. RESULTS: Prevalent COVID-19 pandemic changes in the birth experience included not having support people (e.g., partners and friends) permitted to participate in the baby's delivery (33.5%), reduced access to preferred medications before or after delivery (9.7%), unavailable health care providers for the baby's birth as planned (9.6%), and other changes (13.8%). The reduced access to medications was associated with those reporting higher levels of depressive (ß = .10, p < .01) and PTSD symptoms (ß = .07, p < .05). Separation from their baby for a long period after delivery (ß = .10, p < .05) and other changes (ß = .10, p < .01) were associated with higher levels of PTSD symptoms. CONCLUSION: Unexpected changes to the birth experience due to the COVID-19 pandemic may have small but persistent effects on depressive and PTSD symptoms. Given increased vigilance and its association with subsequent PTSD, acknowledging any fear of viral contagion within the hospital setting but informing women the plans for ensuring safety may be preventive for later mental health symptomatology.

Incidental Findings from Deep Phenotyping Research in Psychiatry: Legal and Ethical Considerations.

Substantial advancement in the diagnosis and treatment of psychiatric disorders may come from assembling diverse data streams from clinical notes, neuroimaging, genetics, and real-time digital footprints from smartphones and wearable devices. This is called "deep phenotyping" and often involves machine learning. We argue that incidental findings arising in deep phenotyping research have certain special, morally and legally salient features: They are specific, actionable, numerous, and probabilistic. We consider ethical and legal implications of these features and propose a practical ethics strategy for managing them.

Maternal-fetal bonding during the COVID-19 pandemic.

BACKGROUND: The pregnant population experienced unique COVID-19 physical and psychosocial stressors such as direct health concerns related to the virus and loss of access to resources since the COVID-19 emerged as a global pandemic in early 2020. Despite these COVID-19-related stress and concerns, the maternal experience of bonding with their unborn children has not been well studied. This work aimed to study the association between mental health history, current mental health symptoms, psychological factors, COVID-19-related worries, and self-reported maternal-fetal bonding of pregnant women. METHODS: This online, survey-based cross-sectional study focused on women pregnant during the pandemic and assessed 686 women using data collected from May 19, 2020 to October 3, 2020. Enrolled respondents completed assessments in which they self-reported maternal-fetal bonding, mental health symptomatology, psychological factors, and COVID-19-related worries regarding health, pregnancy, and resources. RESULTS: Depressive symptoms in pregnant women were associated with lower quality maternal-fetal bonding, while a higher level of anxiety was positively associated with bonding; however, past history of depression or generalized anxiety diagnosis did not appear to be as relevant as active symptomatology. Maternal resilience, but not distress tolerance, appeared to be a protective factor resulting in improved bonding. Higher levels of worry regarding impact of COVID-19 on health were significantly associated with improved bonding, while worries regarding the impact of COVID-19 on the pregnancy or resources were not significantly associated with bonding. The study also found associations between different sociodemographic variables and bonding, including a strong positive association between first time motherhood and bonding and a negative association between higher education and income and bonding. CONCLUSIONS: This study was the first to report potential protective and risk factors to the maternal-fetal bonding process in women pregnant during the COVID-19 pandemic. Unique COVID-19 concerns exist; however, anxiety and COVID-19 concerns do not appear to undermine maternal-fetal bonding while active depressive symptomatology may negatively influence bonding; interventions increasing maternal resilience may be particularly valuable.

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease.

The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or ß42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.

Predicting phenotype from genotype: Improving accuracy through more robust experimental and computational modeling.

Computational prediction yields efficient and scalable initial assessments of how variants of unknown significance may affect human health. However, when discrepancies between these predictions and direct experimental measurements of functional impact arise, inaccurate computational predictions are frequently assumed as the source. Here, we present a methodological analysis indicating that shortcomings in both computational and biological data can contribute to these disagreements. We demonstrate that incomplete assaying of multifunctional proteins can affect the strength of correlations between prediction and experiments; a variant's full impact on function is better quantified by considering multiple assays that probe an ensemble of protein functions. Additionally, many variants predictions are sensitive to protein alignment construction and can be customized to maximize relevance of predictions to a specific experimental question. We conclude that inconsistencies between computation and experiment can often be attributed to the fact that they do not test identical hypotheses. Aligning the design of the computational input with the design of the experimental output will require cooperation between computational and biological scientists, but will also lead to improved estimations of computational prediction accuracy and a better understanding of the genotype-phenotype relationship.

Infant neurodevelopment during the COVID-19 pandemic: Associations with maternal pandemic-related experiences, parenting stress, and self-efficacy.

BACKGROUND: Although pandemic-related experiences have been linked to the psychological well-being of mothers, the effects of the COVID-19 pandemic on infant neurodevelopmental outcomes have not been sufficiently studied. AIMS: To assess whether maternal COVID-19-related experiences (i.e., COVID-19-related health, risk, resource worries, and feelings of grief), parenting stress, and maternal self-efficacy are associated with infant neurodevelopment as measured by the Ages and Stages Questionnaire, Third Edition (ASQ-3) maternal report when infants were between 8 to 10 months of age. Furthermore, this study examined the moderating effect of maternal self-efficacy between maternal COVID-19-related experiences and infant neurodevelopment. METHODS: This cross-sectional study included 122 women who were drawn from the Perinatal Experiences and COVID-19 Effects (PEACE) Study, with online surveys administered between November 2020 and August 2022. RESULTS: After controlling for maternal anxiety and depression symptoms and demographic factors, hierarchical regression analysis indicated that parenting stress showed no effect on ASQ-3 scores. However, more adverse COVID-19-related experiences and higher levels of maternal self-efficacy were associated with better infant neurodevelopment. Moreover, there was a significant interaction effect between maternal self-efficacy and COVID-19-related experiences on infant neurodevelopment. For mothers with moderate to high levels of self-efficacy, more adverse COVID-19-related experiences were associated with better infant neurodevelopment. For mothers with low levels of self-efficacy, more adverse COVID-19-related experiences were associated with poorer developmental outcomes in infants. CONCLUSIONS: Under adverse conditions, confidence in caregiving may afford more optimal infant neurodevelopment. Interventions aimed at fostering maternal self-efficacy and addressing specific stressors can be valuable in promoting positive developmental trajectories for infants born during the pandemic.

Postpartum experiences among individuals with suspected and confirmed prenatal generalized anxiety disorder during the COVID-19 pandemic: Implications for help-seeking.

Prenatal generalized anxiety disorder (GAD) is a common and underdiagnosed condition with negative health consequences to both the pregnant individual and child. Here we studied the relationship between diagnosis and treatment status of GAD during pregnancy (no GAD diagnosis, suspected but not diagnosed, diagnosed but not treated, diagnosed and treated) during the COVID-19 pandemic and postpartum mental health outcomes, while considering the potential influence of individual psychological factors such as distress tolerance and resilience and the role of COVID-19-related health worries. In this sample of predominantly highly educated and white birthing individuals, one in five respondents experienced GAD during pregnancy and another one in six suspected GAD but was not diagnosed. Amongst those with a GAD diagnosis, 30% did not receive treatment. We found that those with a GAD diagnosis during pregnancy who did not receive treatment showed the highest levels of postpartum anxiety and depressive symptoms in the postpartum, even after controlling for covariates, and experienced the most COVID-19-related health worries. In comparison, individuals with a GAD diagnosis during pregnancy who received treatment experienced significantly lower anxiety symptom burden and depressive symptom burden, with a symptom burden similar to those without a confirmed or suspected diagnosis after controlling for individual psychological factors. We conclude that clinicians should strongly consider screening for and treating prenatal anxiety to prevent suboptimal postpartum mental health outcomes.

Subjective social status, COVID-19 health worries, and mental health symptoms in perinatal women.

Pregnant women and those who have recently given birth are considered an at-risk population during the COVID-19 pandemic with regards to the impact of both general stress and pandemic-related stressors. The extent to which subjective social status (SSS), one's perception of relative standing compared to others in a social hierarchy, might mitigate the effects of COVID-19-related health worries on mental health has not yet been reported, despite SSS often outperforming socioeconomic status as a predictor of various health outcomes including depression. This cross-sectional survey study tested the moderating effect of SSS on association between COVID-19- related health worries and mental health symptoms (depressive and generalized anxiety) among a sample of 1,637 perinatal women from the United States who took part in the Perinatal Experiences and COVID-19 Effects (PEACE) Study between May 2020 and June 2021. We found that high subjective social status was protective against depressive symptoms when self-reported COVID-19-related worry was low. When COVID-19-related worry was high, subjective social status was no longer influential. Higher levels of COVID-19-related health worries were associated with more anxiety symptoms, and higher subjective social status did not moderate anxiety symptomatology at either level of COVID-19-related worry. Although higher SSS has historically been protective against mental health decline, in the context of the COVID-19 pandemic it may not be sufficiently protective against anxiety, or against depression for those who experience high levels of worry regarding the effects of COVID-19 on health.

Menopausal Hormone Therapy and the Mind: The Role of Hormone Replacement in the Prevention and Treatment of Cognitive Decline, Dementia, and Cognitive Dysfunction of Depression.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Outline the clinical recommendations for menopausal hormone treatment related to cognitive concerns• Debate and discuss the various research pieces on the use of menopausal hormone therapy cognitive decline, dysfunction, and dementia. ABSTRACT: Menopause has been associated with subjective cognitive dysfunction and elevated rates of depression. While menopausal hormone therapy (MHT) is Food and Drug Administration-approved for the treatment of vasomotor symptoms related to menopause, a potential role for MHT in treating and preventing cognitive decline, dysfunction, and dementia has remained unclear and a topic of continued interest and debate across decades of research. Increasing numbers of patients are seeking help for subjective cognitive decline, and those with poorer mental health are substantially more likely to perceive themselves to be at high risk of developing dementia; thus, mental health professionals are likely to encounter such patients and may be asked to provide advice concerning MHT, cognition, and indications for MHT use. Here, we synthesize the neurobiological effects of MHT, make recommendations for its use in current clinical practice in the contexts of cognitive dysfunction associated with major depressive disorder, cognitive decline, and Alzheimer's disease, and discuss the frontiers being explored by ongoing research on this topic. We conclude that MHT to improve cognitive functioning has only a few scenarios where it would be recommended and that particular caution may be warranted for carriers of the APOE ε4 allele.

COVID-19-related health worries and generalized anxiety symptoms: Higher risks in perinatal women without a pre-existing generalized anxiety diagnosis.

The perinatal period has been well-established as a time of vulnerability to anxiety, as has the COVID-19 pandemic. Perinatal women with a prior diagnosis of Generalized Anxiety Disorder (GAD) may be anticipated to be at particular risk for elevated symptom burden when facing the overlay of these stressors. This study examined whether pre-existing anxiety exacerbates COVID-19-related health worries on anxiety symptom severity among a sample of women who entered perinatal status during the COVID-19 pandemic. We assessed COVID-19-related health worries, past diagnosis of GAD, and current generalized anxiety symptoms cross-sectionally in 1,587 perinatal U.S. women during the COVID-19 pandemic (May 21, 2020 to June 24, 2021). Among perinatal women who reported high levels of COVID-19-related health worries, those with a pre-existing GAD diagnosis were 3.56 times more likely to score at clinically significant levels of generalized anxiety, while those without a pre-existing GAD diagnosis were 6.51 times more likely. COVID-19-related health worries posed a larger risk for elevated anxiety symptoms among those without a pre-existing diagnosis of GAD. Greater access to treatment and psychoeducation for such individuals may be warranted for individuals without a pre-existing mental health diagnosis.

COVID-19 Pandemic Experiences and Maternal Stress in Neonatal Intensive Care Units.

COVID-19 compounds the already high levels of psychological distress experienced by NICU mothers. We aimed to describe the rates of NICU-related maternal stress during the COVID-19 pandemic and to determine how COVID-19 experiences correlate with high levels of stress experienced by NICU mothers. We conducted a cross-sectional analysis based on responses to a nationwide online survey to understand the relationship between COVID-19-related experiences and the stress experienced by mothers of infants admitted to U.S. NICUs (n = 108) during the pandemic. Results indicate that 61.9% of surveyed mothers reported experiencing high levels of stress on the Parental Stressor Scale: NICU. COVID-19-related grief was significantly associated with higher levels of maternal stress, as it related to seeing the baby's appearance and behavior in the NICU and exposure to sights and sounds within the NICU environment. No significant associations were noted between parental stress and COVID-19-related health worries or worries about resources. Of note, our recruitment relied on convenience sampling, limiting the generalizability of study results. In conclusion, mothers who experience COVID-19-related grief appear to be more vulnerable to NICU-related stress. Prioritizing parent involvement and enhancing psychosocial support are essential strategies to mitigate the long-term consequences of heightened stress for NICU families.

Maternal Self-Efficacy Buffers the Effects of COVID-19-Related Experiences on Postpartum Parenting Stress.

OBJECTIVE: To examine the associations of maternal self-efficacy (MSE) and perceived social support with parenting stress during the postpartum period during the COVID-19 pandemic and whether these two psychosocial factors account for variance in parenting stress in addition to the effects of COVID-19-related experiences and sociodemographic factors. DESIGN: Cross-sectional survey. SETTING: Online survey, the Perinatal Experiences and COVID-19 Effects (PEACE) study, launched in May 2020. PARTICIPANTS: Participants included 310 women who gave birth in the past 24 weeks. METHODS: The survey included self-report quantitative measures of MSE, social support, COVID-19-related experiences, parenting stress, symptoms of depression and anxiety, and a range of sociodemographic factors. RESULTS: Hierarchical multiple regression analysis indicated that MSE and social support were negatively associated with postpartum parenting stress in addition to the effects of COVID-19-related experiences, maternal symptoms of depression and anxiety, and a range of demographic factors. Furthermore, MSE interacted with COVID-19-related experiences such that higher levels of MSE mitigated the effects of COVID-19-related experiences on parenting stress. CONCLUSION: Our findings underscore the importance of protective factors at the individual and interpersonal levels and provide insights for prevention and intervention programs aimed at mitigating postpartum parenting stress during a wide-scale disaster such as the COVID-19 pandemic.

Longer wait time after identification of peripartum depression symptoms is associated with increased symptom burden at psychiatric assessment.

Untreated peripartum depression (PD) affects one in seven women and is associated with negative maternal outcomes. This retrospective observational study used health record data from an integrated health system in Texas to assess the extent to which time to access reproductive psychiatry influences the mental health of peripartum women. Women with at least one screening for depression symptoms conducted in obstetric or pediatric settings between May 2014 and October 2019 and subsequently seen by the reproductive psychiatry clinic (n=490) were included. Descriptive and inferential statistics were used to assess timing and factors related to psychiatry follow-up. Findings from this study demonstrated that the average time between a positive screen and a psychiatry assessment was 5 weeks. At psychiatry referral appointments, 85% of women continued to screen positive for PD symptoms. Depression symptom scores at the psychiatry appointment were significantly higher than scores precipitating the referral (p = 0.002). Wait time between initial positive screen and referral appointment was positively correlated with clinically meaningful increases in depression symptom scores (p < 0.001). Each week spent waiting for an appointment produced a 13% increase in odds of clinically meaningful worsening of PD scores and 9% increase in odds of developing new self-harm ideation. Given the findings that a longer period between primary care referral and subspecialty appointment has a negative impact on the mental health of women, this study supports the need for earlier psychiatric assessment to minimize decompensation. Expansion of reproductive psychiatry services are needed to support peripartum women and improve maternal outcomes.

Detection of fused genes in eukaryotic genomes using gene deFuser: analysis of the Tetrahymena thermophila genome.

BACKGROUND: Fused genes are important sources of data for studies of evolution and protein function. To date no service has been made available online to aid in the large-scale identification of fused genes in sequenced genomes. We have developed a program, Gene deFuser, that analyzes uploaded protein sequence files for characteristics of gene fusion events and presents the results in a convenient web interface. RESULTS: To test the ability of this software to detect fusions on a genome-wide scale, we analyzed the 24,725 gene models predicted for the ciliated protozoan Tetrahymena thermophila. Gene deFuser detected members of eight of the nine families of gene fusions known or predicted in this species and identified nineteen new families of fused genes, each containing between one and twelve members. In addition to these genuine fusions, Gene deFuser also detected a particular type of gene misannotation, in which two independent genes were predicted as a single transcript by gene annotation tools. Twenty-nine of the artifacts detected by Gene deFuser in the initial annotation have been corrected in subsequent versions, with a total of 25 annotation artifacts (about 1/3 of the total fusions identified) remaining in the most recent annotation. CONCLUSIONS: The newly identified Tetrahymena fusions belong to classes of genes involved in processes such as phospholipid synthesis, nuclear export, and surface antigen generation. These results highlight the potential of Gene deFuser to reveal a large number of novel fused genes in evolutionarily isolated organisms. Gene deFuser may also prove useful as an ancillary tool for detecting fusion artifacts during gene model annotation.

Family history is a predictor of current preterm birth.

BACKGROUND: Reliable prediction of spontaneous preterm birth remains limited, particularly for nulliparous and multiparous women without a personal history of preterm birth. Although previous preterm birth is a risk factor for recurrent preterm birth, most spontaneous preterm births occur in women with no previous history of preterm birth. OBJECTIVE: This study aimed to determine whether patients' self-reported maternal family history of preterm births among siblings and across 3 generations was an independent risk factor for spontaneous preterm births after controlling for potential confounders. STUDY DESIGN: This was a retrospective analysis of a prospectively acquired cohort using a comprehensive single, academic center database of deliveries from August 2011 to July 2017. The objective of the current analysis was to evaluate the risk of preterm birth among women with and without a family history of preterm birth. All subjects in the database were directly queried regarding familial history across 3 generations, inclusive of obstetrical morbidities. Index subjects with probable indicated preterm birth (eg, concurrent diagnosis of preeclampsia; hemolysis, elevated liver enzymes, and low platelet count; or placenta previa or placenta accreta) were excluded, as were nonsingleton pregnancies. Univariate and multivariate analyses with logistic regression were used to determine significance and adjusted relative risk. RESULTS: In this study, 23,816 deliveries were included, with 2345 (9.9%) born prematurely (<37 weeks' gestation). Across all subjects, preterm birth was significantly associated with a maternal family history of preterm birth by any definition (adjusted relative risk, 1.44; P<.001), and the fraction of preterm birth occurring in women with a positive family history increased with decreasing gestational age at which the index subjects of preterm birth occurred. For nulliparous women, a history in the subject's sister posed the greatest risk (adjusted relative risk, 2.25; P=.003), whereas for multiparous women with no previous preterm birth, overall family history was most informative (P=.003). Interestingly, a personal history of the index subject herself being born preterm presented the greatest individual risk factor (adjusted relative risk, 1.94; P=.004). CONCLUSION: Spontaneous preterm birth in the current pregnancy was significantly associated with a maternal family history of preterm birth among female relatives within 3 generations and notably sisters. The risk persisted among gravidae without a previous preterm birth, demonstrating the capacity for familial history to independently predict risk of spontaneous preterm birth even in the context of a negative personal history. This study provides evidence that self-reported maternal family history is relevant in a US population cohort and across more distant generations than has previously been reported.