Carter M. Owen

Assisted reproductive technology (ART) is responsible for 1.7% of births in the United States annually. Despite a large number of studies promoting the efficacy and safety of these practices, there have been reports of imprinting disorders occurring at higher frequencies in children born through ART. Driven by findings in animal studies, it has been postulated that various ART procedures employed at critical points in embryonic development may predispose the genomic imprinting process to errors. Alterations in DNA methylation patterns at imprinting control centers have been reported by some studies to occur more frequently in children with imprinting disorders conceived by ART compared with spontaneous conception, though these findings are not consistently demonstrated and controversy has surrounded the strength of these associations. The rarity of imprinting disorders with a reliance of studies on disease registry cohorts, wide variations in ART protocols, and a lack of proper control groups limit the ability to substantiate associations between imprinting disorders and ART. Large, prospective cohort studies with a focus on molecular etiologies of these conditions are needed to discern whether a true association exists. Based on current evidence, the absolute risk of imprinting disorders after ART is low and screening for imprinting disorders in children conceived by ART is not warranted.

Racial and ethnic health disparities in reproductive medicine exist across the life span and are costly and burdensome to our healthcare system. Reduction and ultimate elimination of health disparities is a priority of the National Institutes of Health who requires reporting of race and ethnicity for all clinical research it supports. Given the increasing rates of admixture in our population, the definition and subsequent genetic significance of self-reported race and ethnicity used in health disparity research is not straightforward. Some groups have advocated using self-reported ancestry or carefully selected single-nucleotide polymorphisms, also known as ancestry informative markers, to sort individuals into populations. Despite the limitations in our current definitions of race and ethnicity in research, there are several clear examples of health inequalities in reproductive medicine extending from puberty and infertility to obstetric outcomes. We acknowledge that socioeconomic status, education, insurance status, and overall access to care likely contribute to the differences, but these factors do not fully explain the disparities. Epigenetics may provide the biologic link between these environmental factors and the transgenerational disparities that are observed. We propose an integrated view of health disparities across the life span and generations focusing on the metabolic aspects of fetal programming and the effects of environmental exposures. Interventions aimed at improving nutrition and minimizing adverse environmental exposures may act synergistically to reverse the effects of these epigenetic marks and improve the outcome of our future generations.

To investigate whether biomarkers from different pathways of spontaneous preterm birth (cervical membrane degradation [fetal fibronectin], cervical remodeling [soluble E-cadherin], and inflammation (elafin, surfactant protein-D, interleukin-6 [IL-6]) were superior to one biomarker alone in predicting preterm birth. Our secondary objective was to examine the association of these biomarkers with cervical length in predicting preterm birth. We performed a single-center, prospective cohort study from August 2011 to November 2012 of asymptomatic women at risk for spontaneous preterm birth as a result of obstetric and gynecologic history. Cervicovaginal fluid and cervical length measurements were collected at two time points (20–23 6/7 weeks and 24–27 6/7 weeks of gestation). Among the 104 women with complete data, the preterm birth rate was 24.5%. Prior preterm birth (P=.006) and cervical length at visit 1 (P=.003) were significantly associated with preterm birth, whereas fetal fibronectin and median biomarker levels (elafin, soluble E-cadherin, IL-6) were not. Median surfactant protein-D levels at visit 1 by preterm birth status were statistically but not clinically different (0.44 ng/mL compared with 0.40 ng/mL, P<.001). Analyses of biomarkers from more than one pathway were not superior to single biomarker analyses in predicting prematurity. Neither inclusion of biomarkers nor fetal fibronectin improved the predictive ability of cervical length alone. Cervical length assessment and obstetric history but not fetal fibronectin or biomarkers were useful in the risk stratification of women identified to be at greatest risk for spontaneous preterm birth. II

Worldwide use of assisted reproductive technology (ART) accounts for an estimated 1 to 3% of births. Since 2002, a series of reports have suggested an increased risk of imprinting disorders (Beckwith-Wiedemann syndrome and Angelman syndrome) in children conceived by ART. Definitive conclusions are difficult to substantiate due to the rarity of imprinting disorders and the variability in ART protocols. Despite these limitations, there is biological plausibility for alteration in nongenomic inheritance caused by ART. Animal studies have shown that ART procedures can alter normal imprinting, specifically DNA methylation patterns. Collectively, studies suggest an association between ART and loss of maternal methylation. More recent reports examined a possible association between ART and global hypomethylation of DNA. Three other imprinting disorders (Silver-Russell syndrome, maternal hypomethylation syndrome, and retinoblastoma) have also been implicated, but there is insufficient evidence to establish an association of these syndromes with ART. Based on current evidence, the absolute risk of imprinting disorders after ART remains small and does not warrant routine screening. Large prospective studies are needed to better understand the risks associated with imprinting disorders, imprinting defects, and ART.