John Ilekis

Preeclampsia--a pressing problem: an executive summary of a National Institute of Child Health and Human Development workshop.

On September 21 and 22, 2006, the National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled “Preeclampsia—A Pressing Problem.” The purpose of the workshop was to bring together leaders in the field to present and discuss their diverse research areas, which ranged from basic science to clinical trials and management, and to identify scientific gaps. This article is a summary of the proceedings of that workshop. Although much progress is being made in understanding the underpinnings of preeclampsia, a number of research gaps are identified that, if filled, would hasten progress in the field. It is the overall consensus that preeclampsia is a multifactorial disease whose pathogenesis is not solely vascular, genetic, immunologic, or environmental but a complex combination of factors. In addition, a number of specific scientific gaps are identified including insufficient multidisciplinary and collaborative research, clinical trials and studies of patient management, and a lack of in-depth mechanistic research. The research community needs to focus on these gaps to better understand the disease, with the ultimate goal of preventing the disorder.

A genome-wide association study of early spontaneous preterm delivery.

Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple‐testing adjustments. We analyzed DNA samples from mother–infant pairs from early SPTB cases (200/7–336/7 weeks, 959 women and 979 neonates) and term delivery controls (390/7–416/7 weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P‐values between 10 × 10–5 and 10 × 10–6. The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P‐value of 1.0 × 10–6. Two neonatal SNPs reached the genome‐wide significance threshold, including rs17527054 on chromosome 6p22 with a P‐value of 2.7 × 10–12 and rs3777722 on chromosome 6q27 with a P‐value of 1.4 × 10–10. However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome‐wide case‐control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB.

Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface

Background Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. Methods Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene’s 5′ promoter or 3′-UTR regions of the set of genes which expression uniquely characterized the four phenotypes. Results The largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5′and 3′ UTR regions. Conclusions The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection.

Pharmacogenomics of 17‐alpha hydroxyprogesterone caproate for recurrent preterm birth: a case–control study

To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17‐alpha hydroxyprogesterone caproate (17‐P) administration for the prevention of recurrent preterm birth (PTB).

DASH, the data and specimen hub of the National Institute of Child Health and Human Development

The benefits of data sharing are well-established and an increasing number of policies require that data be shared upon publication of the main study findings. As data sharing becomes the new norm, there is a heightened need for additional resources to drive efficient data reuse. This article describes the development and implementation of the Data and Specimen Hub (DASH) by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to promote data sharing from NICHD-funded studies and enable researchers to comply with NIH data sharing policies. DASH’s flexible architecture is designed to archive diverse data types and formats from NICHD’s broad scientific portfolio in a manner that promotes FAIR data sharing principles. Performance of DASH over two years since launch is promising: the number of available studies and data requests are growing; three manuscripts have been published from data reanalysis, all within two years of access. Critical success factors included NICHD leadership commitment, stakeholder engagement and close coordination between the governance body and technical team.