J. Hyett

Current controversies in prenatal diagnosis 4: Should fetal surgery be done in all cases of severe diaphragmatic hernia?

J. A. Deprest1, J. A. Hyett2*, A. W. Flake3, K. Nicolaides1 and E. Gratacos1 1Fetal Medicine Unit, University Hospital, Leuven, Belgium, on behalf of the FETO—Task Force (Fetal Medicine Units of University Hospitals Leuven, Belgium, Hospital Clinic, Barcelona, Spain, and King’s College Hospital, London, UK) 2Department of High Risk Obstetrics, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia 3Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, USA

Anti‐D in pregnant women with the RHD(IVS3+1G>A)‐associated DEL phenotype

BACKGROUND: Pregnant women with the DEL phenotype appear to be D– by routine serology. Women with DEL phenotypes that show a partial D‐like epitope loss may develop anti‐D. It has been proposed that this alloantibody could have a deleterious effect with respect to hemolytic disease in the fetus and newborn.

Strategy for managing maternal variant RHD alleles in Rhesus D negative obstetric populations during fetal RHD genotyping

Fetal RHD screening programs that aim to reduce unnecessary antenatal anti‐D prophylaxis are being introduced into clinical practice. Strategies to manage women serologically typed as Rhesus D negative who have maternal RHD variants are needed. This study describes maternal RHD allelic variants detected in nonselected and alloimmunised Rhesus D negative obstetric populations and explores a mathematical approach to identify these variants.

Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis

Chromosomal aneuploidy is responsible for a significant proportion of pregnancy failures, whether conceived naturally or through in vitro fertilization (IVF). In an effort to improve the success rate of IVF, screening embryos for aneuploidy - or pre-implantation genetic screening (PGS) - has been proposed as a means of ensuring only euploid embryos are selected for transfer. Early PGS approaches were based on fluorescence in situ hybridization testing, and have been shown not to improve live birth rates. Recent developments in genetic testing technologies - such as next-generation sequencing and quantitative polymerase chain reaction, coupled with embryo biopsy at the blastocyst stage - have shown promise in improving IVF outcomes, but they remain to be validated in adequately powered, prospective randomized trials. The extent to which IVF with PGS lowers the a priori risk of aneuploidy in ongoing pregnancies so conceived has been poorly described, rendering it difficult to incorporate the potential benefit of PGS into existing prenatal aneuploidy screening regimens such as cell-free DNA testing or conventional combined nuchal translucency and maternal biochemistry assessment. Further data on the sensitivity and specificity of various forms of molecular PGS testing would improve our understanding of the effectiveness and accuracy of these technologies. This, in addition to further research into methods of risk combination and assessment, would allow us to help our patients make better- informed decisions about whether or not to proceed with invasive diagnostic tests.

TNF-R1 as a first trimester marker for prediction of pre-eclampsia

Abstract Objective: To examine whether the maternal serum concentration of the soluble receptor-1 of tumor necrosis factor-α (TNF-R1) at 11–13 + 6 weeks of gestation is a predictor of development of pre-eclampsia (PE). Methods: This is a nested case–control study in which the concentration of TNF-R1 at 11 + 0 to 13 + 6 weeks was measured in 426 pregnant women in the first trimester. TNF-R1 values were expressed as multiples of the median (MoM) adjusted for maternal factors. The distributions of log TNF-R1 MoM in the control group and hypertensive disorders (early-PE [ePE], late-PE [lPE] and gestational hypertension [GH]) groups were compared. Logistic regression analysis was used to determine whether maternal factors, TNF-R1 or their combination make a significant contribution to the prediction of PE. Screening performance was determined by analysis of receiver–operating characteristics curves. Results: Median concentration of TNF-R1 (ng/ml) was higher in ePE (2.62 ± 0.67), lPE (2.12 ± 0.56) and GH (2.19 ± 0.45) compared to controls (2.04 ± 0.42), p = 0.001. Logistic regression analysis demonstrated that the addition of TNFR-1 to maternal factors did not make a significant contribution to the prediction of PE. Conclusions: The maternal serum TNF-R1 concentration at 11–13 + 6 weeks of gestation was increased in pregnancies which developed hypertensive disorders, however, the addition of TNFR-1 did not improve the detection rate of these conditions compared with maternal factors alone.

Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases.

BACKGROUND Preeclampsia is a pregnancy specific disorder affecting 3-5% of pregnancies worldwide. It is clinically divided into early-onset and late-onset subtypes. Placental factors are involved in the pathogenesis of preeclampsia. Growth differentiation factor 15 (GDF15), a protein of the transforming growth factor beta superfamily, is highly expressed in the placenta. However, it is unclear whether the circulating levels of GDF15 are altered in preeclampsia at the time of or prior to disease presentation. METHODS Serum samples across three trimesters from 29 healthy pregnancies, third trimester sera from 34 women presenting with preeclampsia (early-onset n=16, late-onset n=18) and 66 gestation-age-matched controls, and sera at 11-13weeks of pregnancy from women who later did (n=36) or did not (n=33) develop late-onset preeclampsia, were examined for GDF15 by ELISA. RESULTS Serum GDF15 levels increased significantly with gestation in normal pregnancy. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia compared to their gestation-age-matched controls. This reduction was apparent in both early-onset and late-onset subtypes, but it was more profound in late-onset cases. At 11-13weeks of gestation, however, serum levels of GDF15 were similar between women who subsequently did and did not develop late-onset preeclampsia. CONCLUSION Serum GDF15 increased with gestation age, reaching the highest level in the third trimester. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia, especially in late-onset cases. However, serum GDF15 was not altered in the first trimester in women destined to develop late-onset preeclampsia.

Early screening and prevention of preterm pre‐eclampsia with aspirin: time for clinical implementation

Despite all the research published in the last three decades on screening and prevention of preeclampsia (PE), this condition remains one of the main causes of maternal and perinatal morbidity and mortality, both in low and high-income countries. It affects 2-8% of all pregnancies, being responsible for one out of five maternal deaths and 15% of all premature deliveries1. An ideal screening test requires identification of women at high-risk of developing severe and early-onset forms of the disease, a high detection rate (DR) with an acceptable false-positive rate (FPR), and the availability of an effective preventive measure2.

Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood

High temperature requirement factor A3 (HtrA3), a member of the HtrA protease family, is highly expressed in the developing placenta, including the maternal decidual cells in both mice and humans. In this study we deleted the HtrA3 gene in the mouse and crossed females carrying zero, one, or two HtrA3-expressing alleles with HtrA3+/− males to investigate the role of maternal vs fetal HtrA3 in placentation. Although HtrA3−/− mice were phenotypically normal and fertile, HtrA3 deletion in the mother resulted in intra-uterine growth restriction (IUGR). Disorganization of labyrinthine fetal capillaries was the major placental defect when HtrA3 was absent. The IUGR caused by maternal HtrA3 deletion, albeit being mild, significantly altered offspring growth trajectory long after birth. By 8 months of age, mice born to HtrA3-deficient mothers, independent of their own genotype, were significantly heavier and contained a larger mass of white fat. We further demonstrated that in women serum levels of HtrA3 during early pregnancy were significantly lower in IUGR pregnancies, establishing an association between lower HtrA3 levels and placental insufficiency in the human. This study thus revealed the importance of maternal HtrA3 in optimizing placental development and its long-term impact on the offspring well beyond in utero growth.

Noninvasive fetal RHD genotyping of RhD negative pregnant women for targeted anti‐D therapy in Australia: A cost‐effectiveness analysis

To undertake a cost‐effectiveness analysis of noninvasive fetal RHD genotyping to target pregnant women for antenatal anti‐D prophylaxis therapy.

Effects of sample processing and storage on the integrity of cell‐free miRNAs in maternal plasma

Cell‐free fetal miRNAs have been identified as potential biomarkers for fetal abnormalities and/or placental function. Factors affecting the stability of cell‐free fetal miRNA samples (type of collection tube and time interval between sampling and analysis) have not previously been reported.