Christian Litton

Positive cell-free fetal DNA testing for trisomy 13 reveals confined placental mosaicism

Purpose:We report on a case in which cell-free fetal DNA was positive for trisomy 13 most likely due to confined placental mosaicism. Cell-free fetal DNA testing analyzes DNA derived from placental trophoblast cells and can lead to incorrect results that are not representative of the fetus.Methods:We sought to confirm commercial cell-free fetal DNA testing results by chorionic villus sampling and amniocentesis. These results were followed up by postnatal chromosome analysis of cord blood and placental tissue.Results:First-trimester cell-free fetal DNA test results were positive for trisomy 13. Cytogenetic analysis of chorionic villus sampling yielded a mosaic karyotype of 47,XY,+13[10]/46,XY[12]. G-banded analysis of amniotic fluid was normal, 46,XY. Postnatal cytogenetic analysis of cord blood was normal. Karyotyping of tissues from four quadrants of the placenta demonstrated mosaicism for trisomy 13 in two of the quadrants and a normal karyotype in the other two.Conclusion:Our case illustrates several important aspects of this new testing methodology: that cell-free fetal DNA may not be representative of the fetal karyotype; that follow-up with diagnostic testing of chorionic villus sampling and/or amniotic fluid for abnormal test results should be performed; and that pretest counseling regarding the full benefits, limitations, and possible testing outcomes of cell-free fetal DNA screening is important.Genet Med 15 9, 729–732.Genetics in Medicine (2013); 15 9, 729–732. doi:10.1038/gim.2013.26

Genomic loss of imprinting in first-trimester human placenta.

OBJECTIVE The purpose of this study was to investigate imprinting patterns in first-trimester human placentas. STUDY DESIGN Using samples of 17 first-trimester and 14 term placentas from uncomplicated pregnancies, we assessed loss of imprinting (LOI) at the RNA level in a panel of 14 genes that are known to be imprinted in the placenta with the use of a quantitative allele-specific reverse transcriptase polymerase chain reaction analysis of those genes that contained readout single nucleotide polymorphisms in their transcripts. RESULTS There is significant LOI (ie, biallelic expression) in all 14 genes in first-trimester placentas. LOI was more variable and generally at lower levels at term. Although there is little difference in gene expression, the level of LOI is higher in the first-trimester placentas, compared with term placentas. CONCLUSION Genomic imprinting appears to be a dynamic maturational process across gestation in human placenta. In contrast with prevailing theories, epigenetic imprints may continue to evolve past 12 weeks of gestation.

Noninvasive prenatal diagnosis: past, present, and future.

The presence of fetal cells in the maternal circulation was first noted by Georg Schmorl when he documented the presence of multinucleated syncytial giant cells of placental origin in the lung tissue of women who had died from complications of eclampsia. In the intervening century, advances in cellular and molecular biology further elucidated both the physiology and pathophysiology of communication within the fetomaternal unit. This concept is at the foundation of the rapidly expanding field of noninvasive prenatal diagnosis. However, the clinical utility of this phenomenon had been limited until the presence of cell-free fetal DNA circulating in the maternal plasma was reported in 1997 and fetal messenger RNA was demonstrated to circulate in the maternal plasma in 2000. These circulating nucleic acids are found free-floating in the maternal plasma, unencumbered by a surrounding fetal cell. The analysis of these 3 fetal markers (fetal cells, cell-free fetal DNA, and fetal messenger RNA) for diagnostic and screening purposes is now being developed. The scope of noninvasive prenatal diagnosis is not limited to only the diagnosis of fetal genetic traits and aneuploidies. Recently, researchers have focused their investigations on the role of cell-free fetal DNA and fetal messenger RNA in preeclampsia, intrauterine growth restriction, and preterm labor. These biomarkers, the result of inherent placental dysfunction or the byproducts of placental trophoblastic apoptosis, may allow for improvements in the diagnosis and management of high-risk pregnancies.

Successful Management of a Consecutive Cervical Pregnancy by Sonographically Guided Transvaginal Local Injection Case Report and Review of the Literature

The purpose of this study was to describe the successful management of a recurrent cervical pregnancy with local injection and to review similarly treated cases to determine adverse outcomes.

First-trimester chorionic bump--Association with fetal aneuploidy in a high-risk population

To determine the relationship between the first‐trimester chorionic bump and fetal aneuploidy.

Ultrasound Measurement of the Fetal Adrenal Gland as a Predictor of Spontaneous Preterm Birth

OBJECTIVE: To estimate whether ultrasound measurement of the fetal adrenal gland remote from delivery in asymptomatic women can accurately predict spontaneous preterm birth. METHODS: We conducted a prospective multicenter observational nested cohort study of asymptomatic nulliparous women with a singleton pregnancy to study adverse pregnancy outcomes. Between 22 0/7 and 30 6/7 weeks of gestation, credentialed ultrasonographers measured the width (width), length (length), and, when able, depth (depth) of the “fetal zone” of the fetal adrenal gland as well as the width (Width), length (Length), and depth (Depth) of the total gland. We used the ratios of each measurement (width/Width, length/Length, and depth/Depth) to control for variation in adrenal size by gestational age. The accuracy of each ratio measurement in predicting spontaneous preterm birth at less than 37 0/7 weeks of gestation and spontaneous preterm birth at less than 34 0/7 weeks of gestation was assessed by receiver operating characteristic curves using area under the curve. RESULTS: Pregnancy outcomes were available for 1,697 women with one or more fetal adrenal gland measurements. Spontaneous preterm birth at less than 37 0/7 weeks of gestation and spontaneous preterm birth at less than 34 0/7 weeks of gestation occurred in 82 (4.8%) and six women (0.4%), respectively. None of the fetal adrenal gland measurements distinguished spontaneous preterm birth from term birth. The areas under the curve (95% confidence intervals) for spontaneous preterm birth at less than 37 0/7 weeks of gestation were 0.51 (0.45–0.58), 0.50 (0.44–0.56), and 0.52 (0.41–0.63) for width/Width, length/Length, and depth/Depth ratios, respectively. The areas under the curve for spontaneous preterm birth at less than 34 0/7 weeks of gestation were 0.52 (0.25–0.79) and 0.55 (0.31–0.79) for width/Width and length/Length ratios, respectively. Additionally, none of the means of the gland measurements were statistically different between those delivering at term and spontaneous at preterm (P>.05). CONCLUSION: Fetal adrenal size, as measured by ultrasonography between 22 0/7 and 30 6/7 weeks of gestation, is not predictive of spontaneous preterm birth in asymptomatic nulliparous women.

Prenatal aneuploidy screening using cell-free DNA

REFERENCES 1. Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015;212:505.e1-13. 2. Ment LR, Ådén U, Lin A, et al. Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates. Pediatr Res 2014;75: 241-50. 3. Klinger G, Sokolover N, Boyko V, et al. Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-low-birthweight infants. Am J Obstet Gynecol 2013;208:115.e1-9. 4. Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala O, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor. J Pediatr 1994;124:782-8.

Clinical pitfalls in misoprostol-based medical management of first-trimester induced and presumed spontaneous abortion.

When administered inappropriately, first‐trimester misoprostol management of induced or spontaneous abortion can result in loss or damage of a continuing pregnancy. Despite these serious consequences, such misoprostol exposures continue to occur. Unfortunately, contributing factors and preventive measures receive little attention. We describe the cases of 4 women in whom misoprostol was inappropriately administered during management of induced and presumed spontaneous abortion. In each case, careful adherence to published clinical guidance could have avoided the exposures.