Pharmacogenomics of preterm birth prevention and treatment

Pharmacogenomics and personalized medicine incorporate genetic factors, historical data, and environmental exposures to predict individual variation in response to medications. The study of pharmacology and pharmacogenomics is challenging in obstetrics, and knowledge lags behind other disciplines of medicine. However, some preliminary data suggest that some of the inter-individual variation seen in response to medications given for the prevention (progesterone) and treatment (nifedipine, terbutaline, others) of preterm labor may be due to pharmacogenomic effects. A comprehensive approach, integrating clinical data, environmental factors including concomitant medications, and genotype to optimize prevention and treatment strategies for preterm birth, is urgently needed

The genomics of prematurity in an era of more precise clinical phenotyping: A review

Spontaneous preterm birth is a major public health problem, with a clear genetic component. Genetic association studies have evolved substantially in recent years, moving away from the traditional candidate gene analyses to newer approaches utilizing sophisticated analysis platforms to examine sequencing data, and shifting towards functional studies including methylation analysis. It is becoming increasingly evident that careful clinical phenotyping is crucial to high quality genetic association studies regardless of the assay or platform being used. Nonetheless, genetic studies of prematurity are hampered by numerous challenges including small sample sizes, incomplete phenotying, population stratification, and multiple comparisons. As the costs of sequencing and functional analyses continue to decrease, unbiased genome-wide assays will be more widely available. Researchers have met improved success recently when critically applying clinical phenotyping knowledge to group women prior to analyzing genotyping results. Eventually, as the analytic approaches evolve, it is likely that this methodology (combining precisely clinically phenotyped subjects with genome-wide data) will provide key information regarding the pathophysiology of prematurity, and provide potential new avenues for exploring innovative therapeutic strategies

Epigenetic Aging and Cognitive Health: A Pilot Study

Chronological age is the strongest risk factor for disease, disability, and death. However, same-aged individuals may be differentially at risk because chronological time is an imperfect proxy of a person’s biological age. One promising approach to quantify biological aging is epigenetic biomarkers that use DNA methylation data to derive a person’s “epigenetic age”. Older epigenetic age, above and beyond chronological age, has been associated with increased risk of premature mortality and morbidity, however, links between epigenetic and cognitive aging are less well characterized, despite the burden of cognitive decline and dementia. The proposed pilot study aims to gather preliminary data in support of an external grant application that examines the longitudinal associations between epigenetic and cognitive aging across midlife, while addressing previous limitations in measuring epigenetic and cognitive aging. This project will leverage an existing longitudinal cohort of midlife adults with two waves of data collected 10-16 years apart to test whether accelerated epigenetic aging is predictive of future cognitive decline. In order to be competitive for this larger grant, preliminary data are needed to establish whether and to what degree (1) cognitive function and (2) epigenetic age change over the length of the 10-16 year follow-up provided by this cohort, and (3) to provisionally test in a subset of participants whether changes in epigenetic age are associated with changes in cognitive function over the follow-up interval. This pilot study, designed to provide the needed preliminary data, will examine cognitive and epigenetic aging using an extreme groups approach to identify two subgroups of individuals with different cognition trajectories over 10-16 years, and will use stored blood samples to quantify DNA methylation to estimate epigenetic age. A final aim of this project is to provide a rich training experience for undergraduates by immersing them in cutting-edge, hypothesis-driven health and aging research

Racial and ethnic differences in preterm birth: A complex, multifactorial problem

Preterm birth remains the leading cause of morbidity and mortality among nonanomalous neonates, and is a major public health problem. Non-Hispanic black women have a 2-fold greater risk for preterm birth compared with non-Hispanic white race. The reasons for this disparity are poorly understood and cannot be explained solely by sociodemographic factors. Underlying factors including a complex interaction between maternal, paternal, and fetal genetics, epigenetics, the microbiome, and these sociodemographic risk factors likely underlies the differences between racial groups, but these relationships are currently poorly understood. This article reviews the epidemiology of disparities in preterm birth rates and adverse pregnancy outcomes and discuss possible explanations for the racial and ethnic differences, while examining potential solutions to this major public health problem

Refining pharmacologic research to prevent and treat spontaneous preterm birth

Preterm birth (PTB), delivery prior to 37 weeks’ gestation, is the leading cause of mortality among non-anomalous neonates. Survivors carry an increased risk for lifelong intellectual, physical, and social disabilities compared with their term counterparts (Russell et al., 2007; Bodeau-Livinec et al., 2008; Vohr, 2013; Manuck et al., 2014a, 2016b; Natarajan and Shankaran, 2016). In the US alone, more than 450,000 babies are born too soon and �25,000 die as a result (Hamilton et al., 2015). Approximately two-thirds of all PTBs are spontaneous PTB (SPTB), and occur following preterm premature rupture of membranes, cervical insufficiency, and/or uterine contractions leading to cervical dilation. To reduce the burden of SPTB, interventions must target both prematurity prevention prior to the onset of symptoms and acute treatment once the process of acute preterm labor has begun

17-alpha hydroxyprogesterone caproate for preterm birth prevention: Where have we been, how did we get here, and where are we going?

Prematurity is a major public health problem in the United States and worldwide. Women with a history of a previous preterm birth are at high risk for recurrence. Progesterone is a key hormone involved in pregnancy maintenance. In general, progesterone is thought to maintain pregnancy through several closely linked mechanisms: (1) promotion of uterine quiescence, (2) inhibition of pro-inflammatory cells, and (3) immunosuppressive action. 17-Alpha hydroxyprogesterone caproate is currently the only medication approved to prevent recurrent preterm birth. The purpose of this review is to discuss the history of 17-alpha hydroxyprogesterone caproate use for recurrent preterm birth prevention, the rationale behind 17-alpha hydroxyprogesterone caproate administration, and current evidence-based indications for 17-alpha hydroxyprogesterone caproate use

A sensitive and specific neural signature for picture-induced negative affect

Neuroimaging has identified many correlates of emotion but has not yet yielded brain representations predictive of the intensity of emotional experiences in individuals. We used machine learning to identify a sensitive and specific signature of emotional responses to aversive images. This signature predicted the intensity of negative emotion in individual participants in cross validation (n =121) and test (n = 61) samples (high–low emotion = 93.5% accuracy). It was unresponsive to physical pain (emotion–pain = 92% discriminative accuracy), demonstrating that it is not a representation of generalized arousal or salience. The signature was comprised of mesoscale patterns spanning multiple cortical and subcortical systems, with no single system necessary or sufficient for predicting experience. Furthermore, it was not reducible to activity in traditional “emotion-related” regions (e.g., amygdala, insula) or resting-state networks (e.g., “salience,” “default mode”). Overall, this work identifies differentiable neural components of negative emotion and pain, providing a basis for new, brain-based taxonomies of affective processes

Progesterone has no place in the prevention of preterm delivery: AGAINST: A call for a measured response to the OPPTIMUM trial

With the concluding words of her plenary talk at the 2016 Society for Maternal–Fetal Medi-cine Annual Meeting – ‘I wouldn’t advise my daughter take vaginal progesterone’ – had Jane Norman and the OPPTIMUM team placed a proverbial nail in the coffin of the only class of medication routinely used for the prevention of preterm birth (PTB)? For practitioners in a field with tragically few effective interventions, it is imperative that we cast a critical eye on even the most robust randomized controlled trial (RCT)

Screening for spontaneous preterm birth and resultant therapies to reduce neonatal morbidity and mortality: A review

Despite considerable effort aimed at decreasing the incidence of spontaneous preterm birth, it remains the leading cause of perinatal morbidity and mortality. Screening strategies are imperfect. Approaches used to identify women considered by historical factors to be low risk for preterm delivery (generally considered to be women with singleton pregnancies without a history of a previous preterm birth) as well as those at high risk for preterm birth (those with a previous preterm birth, short cervix, or multiple gestation) continue to evolve. Herein, we review the current evidence and approaches to screening women for preterm birth, and examine future directions for clinical practice. Further research is necessary to better identify at-risk women and provide evidence-based management

DRD4 polymorphism moderates the effect of alcohol consumption on social bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse. © 2012 Creswell et al