Dena Towner

Genome-wide hypermethylation coupled with promoter hypomethylation in the chorioamniotic membranes of early onset pre-eclampsia

Pre-eclampsia is the leading cause of fetal and maternal morbidity and mortality. Early onset pre-eclampsia (EOPE) is a disorder that has severe maternal and fetal outcomes, whilst its etiology is poorly understood. We hypothesize that epigenetics plays an important role to mediate the development of EOPE and conducted a case-control study to compare the genome-wide methylome difference between chorioamniotic membranes from 30 EOPE and 17 full-term pregnancies using the Infinium Human Methylation 450 BeadChip arrays. Bioinformatics analysis tested differential methylation (DM) at CpG site level, gene level, and pathway and network level. A striking genome-wide hypermethylation pattern coupled with hypomethylation in promoters was observed. Out of 385 184 CpG sites, 9995 showed DM (2.6%). Of those DM sites, 91.9% showed hypermethylation (9186 of 9995). Over 900 genes had DM associated with promoters. Promoter-based DM analysis revealed that genes in canonical cancer-related pathways such as Rac, Ras, PI3K/Akt, NFκB and ErBB4 were enriched, and represented biological functional alterations that involve cell cycle, apoptosis, cancer signaling and inflammation. A group of genes previously found to be up-regulated in pre-eclampsia, including GRB2, ATF3, NFKB2, as well as genes in proteasome subunits (PSMA1, PMSE1, PSMD1 and PMSD8), harbored hypomethylated promoters. Contrarily, a cluster of microRNAs, including mir-519a1, mir-301a, mir-487a, mir-185, mir-329, mir-194, mir-376a1, mir-486 and mir-744 were all hypermethylated in their promoters in the EOPE samples. These findings collectively reveal new avenues of research regarding the vast epigenetic modifications in EOPE.

Nighttime delivery and risk of neonatal encephalopathy.

OBJECTIVE The objective of the study was to determine the relationship between nighttime delivery and neonatal encephalopathy (NE). STUDY DESIGN The design of the study was a retrospective population-based cohort of 1,864,766 newborns at a gestation of 36 weeks or longer in California, 1999-2002. We determined the risk of NE associated with nighttime delivery (7:00 (PM) to 6:59 (AM)). RESULTS Two thousand one hundred thirty-one patients had NE (incidence 1.1 per 1000 births). Nighttime delivery was associated with increased NE (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.03-1.20), birth asphyxia (OR, 1.18; 95% CI, 1.08-1.29), and neonatal seizures (OR, 1.17; 95% CI, 1.07-1.28). In adjusted analyses, nighttime delivery was an independent risk factor for NE (OR, 1.10; 95% CI, 1.01-1.21), as were severe intrauterine growth retardation (OR, 3.8; 95% CI, 3.1-4.8); no prenatal care (OR, 2.0; 95% CI, 1.4-2.9); primiparity (OR, 1.5; 95% CI, 1.4-1.7); advanced maternal age (OR, 1.3; 95% CI, 1.16-1.45); and infant male sex (OR, 1.3; 95% CI, 1.2-1.4). CONCLUSION Future studies of time of delivery may generate new strategies to reduce the burden of NE.

Operative vaginal delivery : A cause of birth injury or is it?

Operative vaginal delivery has been maligned since the days of W.J. Little with the word “forceps” becoming nearly synonymous with “Birth Injury” and “Cerebral Palsy.” However in his presentation to the Obstetrical Society of London in 1861, Littles emphasis was on difficult labors being the culprit in subsequent disabilities in the offspring. Instrumented deliveries in that era were the end result of a long, obstructed labor performed for maternal benefit and to avoid a destructive procedure to the fetus thus allowing a chance at life. If there had been a normal progress in labor, operative assistance for delivery would not have been needed. Thus, was it the instrument or the obstructed labor that led to fetal injury? In this article, we will review what injuries to the fetus and the mother can be directly attributable to the instrument. We will explore the processes of labor, conduct of labor management, and concurrent fetal factors that can modulate the occurrence of birth trauma. Evidence regarding inexperience and improper use as contributing to injury will also be explored.

Obstetric, perinatal, and fetal outcomes in pregnancies with false-positive integrated screening results.

OBJECTIVE: To assess the risk of adverse obstetric, perinatal, and fetal outcomes for pregnant women participating in prenatal sequential integrated screening through the California Prenatal Screening Program who had a false-positive screening result. METHODS: Women who underwent first- and second-trimester prenatal integrated screening plus nuchal translucency measurement with outcome information available were included. Fetuses and neonates with chromosomal or neural tube defects were excluded. We compared the risk of adverse outcomes for all women with a positive screening result compared with a 10% random sample of women with a negative screening result. Logistic binomial regression was used to compare adverse outcomes in screen-positive compared with screen-negative women. RESULTS: We identified 9,051 screen-positive and 30,928 screen-negative pregnancies with outcome information available. Compared with screen-negative pregnancies, screen-positive women were more likely to be diagnosed with preeclampsia, placenta previa, or abruption (7.6% screen-positive, 3.8% screen-negative; relative risk 1.7, 95% confidence interval [CI] 1.6–1.8) or experience fetal loss before 20 weeks of gestation (1.9% screen-positive, 0.2% screen-negative; relative risk 3.5, 95% CI 3.2–3.8). Women with positive results for more than one screened condition were at substantially greater risk of fetal and neonatal mortality (relative risks 33.6–156.7, 95% CIs 21.8–194.4). CONCLUSION: Among pregnancies without chromosomal or neural tube defects, prenatal sequential integrated screening provides information regarding risk across a variety of adverse pregnancy outcomes. LEVEL OF EVIDENCE: II

Pregnancy outcome in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurologic and psychiatric symptoms. Treatment is challenging in pregnancy, because little data exist to guide management. CASE: A 24-year-old woman with a known diagnosis of anti-NMDA receptor encephalitis using intravenous immunoglobulin therapy became pregnant. Her pregnancy was uncomplicated with no relapses. She delivered at 35 4/7 weeks of gestation after having preterm premature rupture of membranes. She had a relapse of symptoms after delivery. CONCLUSION: This patient with anti-NMDA receptor encephalitis had an uneventful pregnancy with overall good outcome; however, she experienced relapse soon after delivery. This disease may mimic other autoimmune diseases, with improvement during pregnancy and risk for relapse postpartum.

Sonographic Detection of In Utero Isolated Cerebellar Hemorrhage

Cerebellar hemorrhage is a relatively rare phenomenon in neonates, and most cases are associated with intraventricular hemorrhage (IVH). Prenatally diagnosed intracranial hemorrhage is rare, and diagnoses of cerebellar hemorrhage are even rarer. In our literature search, we discovered 3 cases of prenatal diagnosis of cerebellar hemorrhage, all accompanied by IVH. None of the neonates survived. We report a case initially observed in utero by sonography of cerebellar hemorrhage without evidence of IVH, causing ventriculomegaly in a 32-week twin fetus who was subsequently successfully treated.

Genome-scale hypomethylation in the cord blood DNAs associated with early onset preeclampsia

BackgroundPreeclampsia is one of the leading causes of fetal and maternal morbidity and mortality worldwide. Preterm babies of mothers with early onset preeclampsia (EOPE) are at higher risks for various diseases later on in life, including cardiovascular diseases. We hypothesized that genome-wide epigenetic alterations occur in cord blood DNAs in association with EOPE and conducted a case control study to compare the genome-scale methylome differences in cord blood DNAs between 12 EOPE-associated and 8 normal births.ResultsBioinformatics analysis of methylation data from the Infinium HumanMethylation450 BeadChip shows a genome-scale hypomethylation pattern in EOPE, with 51,486 hypomethylated CpG sites and 12,563 hypermethylated sites (adjusted P <0.05). A similar trend also exists in the proximal promoters (TSS200) associated with protein-coding genes. Using summary statistics on the CpG sites in TSS200 regions, promoters of 643 and 389 genes are hypomethylated and hypermethylated, respectively. Promoter-based differential methylation (DM) analysis reveals that genes in the farnesoid X receptor and liver X receptor (FXR/LXR) pathway are enriched, indicating dysfunction of lipid metabolism in cord blood cells. Additional biological functional alterations involve inflammation, cell growth, and hematological system development. A two-way ANOVA analysis among coupled cord blood and amniotic membrane samples shows that a group of genes involved in inflammation, lipid metabolism, and proliferation are persistently differentially methylated in both tissues, including IL12B, FAS, PIK31, and IGF1.ConclusionsThese findings provide, for the first time, evidence of prominent genome-scale DNA methylation modifications in cord blood DNAs associated with EOPE. They may suggest a connection between inflammation and lipid dysregulation in EOPE-associated newborns and a higher risk of cardiovascular diseases later in adulthood.

Potential Pitfalls and Methods of Improving In Utero Diagnosis of Transposition of the Great Arteries, Including the Baby Bird’s Beak Image

The goal of this study was to analyze our recent experience with fetuses with transposition of the great arteries (TGA) to identify potential pitfalls and possible methods to better detect conotruncal anomalies such as TGA.

Prenatal Diagnosis of Ebstein Anomaly A Potential Pitfall

Ebstein anomaly is a rare congenital cardiac malformation characterized by varying degrees of downward displacement of the tricuspid valve leaflets into the cavity of the right ventricle. 1-3 It is an uncommon congenital abnormality with a prevalence of 0.2% to 0.5% of all cardiac malformations. 4,5 It can appear at any age, from fetal life to adulthood, with a highly variable clinical course. In the fetus and neonate, a targeted echocardiogram has been proven to be reliable in differentiating the variants of Ebstein anomaly. 6,7 However, because targeted fetal echocardiography cannot be used routinely for all obstetric patients, the ability to recognize Ebstein anomaly from a routine prenatal obstetric sonographic examination is important. The 4-chamber view of the heart, a component of the American Institute of Ultrasound in Medicine guidelines for fetal structural evaluations, is most helpful for the detection of many congenital heart defects, including Ebstein anomaly. The 4-chamber view, however, does have limitations in the diagnosis of certain cardiac malformations. We present a case of prenatal sonography in a fetus with severe Ebstein anomaly that was diagnosed by fetal echocardiography after an initial routine obstetric sonogram showed a normal-appearing 4-chamber view of the heart. However, there were certain sonographic clues on the prenatal sonogram suggesting the diagnosis of Ebstein anomaly.

Medical Faculty Development: A Modern-Day Odyssey

Academic medical centers must make systematic changes to improve the quality of life—and thus productivity—of their faculty. Academic medical centers (AMCs) are pillars of the community; they provide health care, create jobs, educate biomedical professionals, and engage in research and innovation. To sustain their impact on human health, AMCs must improve the professional satisfaction of their faculty. Here, we describe ways to enhance recruitment, retention, creativity, and productivity of health science faculty.