Alex J. Eggink

Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia.

To assess the value of antenatally determined observed to expected fetal lung area to head circumference ratio (LHR) in the prediction of postnatal survival in isolated, congenital diaphragmatic hernia (CDH).

Prenatal prediction of survival in isolated left-sided diaphragmatic hernia

To investigate the potential value of antenatally determined intrathoracic herniation of the liver and the ratio of fetal lung area to head circumference (LHR) in the prediction of postnatal survival in isolated, left‐sided congenital diaphragmatic hernia (CDH).

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.

Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells

Blood plasma of pregnant women contains circulating cell-free fetal DNA (ccffDNA), originating from the placenta. The use of this DNA for non-invasive detection of fetal aneuploidies using massively parallel sequencing (MPS)-by-synthesis has been proven previously. Sequence performance may, however, depend on the MPS platform and therefore we have explored the possibility for multiplex MPS-by-ligation, using the Applied Biosystems SOLiD™ 4 system. DNA isolated from plasma samples from 52 pregnant women, carrying normal or aneuploid fetuses, was sequenced in multiplex runs of 4, 8 or 16 samples simultaneously. The sequence reads were mapped to the human reference genome and quantified according to their genomic location. In case of a fetal aneuploidy, the number of reads of the aberrant chromosome is expected to be higher or lower than in normal reference samples. To statistically determine this, Z-scores per chromosome were calculated as described previously, with thresholds for aneuploidies set at > +3.0 and < -3.0 for chromosomal over- or underrepresentation, respectively. All samples from fetal aneuploidies yielded Z-scores outside the thresholds for the aberrant chromosomes, with no false negative or positive results. Full-blown fetal aneuploidies can thus be reliably detected in maternal plasma using a multiplex MPS-by-ligation approach. Furthermore, the results obtained with a sample from a pregnancy with 45,X in the cytotrophoblastic cell layer and 46,XX in the mesenchymal core cells show that ccffDNA originates from the cytotrophoblastic cell layer. Discrepancies between the genetic constitution of this cell layer and the fetus itself are well known, and therefore, care should be taken when translating results to the fetus itself.

Phenotypic variability of atypical 22q11.2 deletions not including TBX1

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.

Placental Characteristics of Monoamniotic Twin Pregnancies in Relation to Perinatal Outcome

OBJECTIVE To study placental characteristics in relation to perinatal outcome in 55 pairs of monochorionic monoamniotic (MA) twins. METHODS Between January 1998 and May 2008 55 pairs of MA twins were delivered in 4 tertiary care centers and analysed for mortality, birth weight discordancy and twin-to-twin transfusion syndrome (TTTS) in relation to type of anastomoses, type and distance between cord insertions and placental sharing. Five acardiac twins, 2 conjoined twins, 4 higher order multiples and one early termination of pregnancy were excluded, leaving 43 MA placentas for analysis. Of these 43, one placenta could not be analysed for placental vascular anastomoses due to severe maceration after single intra-uterine demise leaving 42 placentas for analysis of anastomoses. RESULTS Arterio-arterial (AA), venovenous (VV) and arteriovenous (AV) anastomoses were detected in 98%, 43% and 91% of MA placentas, respectively. Velamentous cord insertion was found in 4% of cases. Small distance between both umbilical cord insertions (<5 cm) was present in 53% of MA placentas. Overall perinatal loss rate was 22% (19/86). We found no association between mortality and type of anastomoses, type and distance between cord insertions and placental sharing. The incidence of TTTS was low (2%) and occurred in the only pregnancy with absent AA-anastomoses. CONCLUSION Perinatal mortality in MA twins was not related to placental vascular anatomy. The almost ubiquitous presence of compensating AA-anastomoses in MA placentas appears to prevent occurrence of TTTS.

Non‐targeted whole genome 250K SNP array analysis as replacement for karyotyping in fetuses with structural ultrasound anomalies: evaluation of a one‐year experience

We evaluated both clinical and laboratory aspects of our new strategy offering quantitative fluorescence (QF)‐PCR followed by non‐targeted whole genome 250K single‐nucleotide polymorphism array analysis instead of routine karyotyping for prenatal diagnosis of fetuses with structural anomalies.

Cohort Profile: The Rotterdam Periconceptional Cohort (Predict Study)

Cohort Profile: The Rotterdam Periconceptional Cohort (Predict Study) Régine PM Steegers-Theunissen,* Jennifer JFM Verheijden-Paulissen, Evelyne M van Uitert, Mark F Wildhagen, Niek Exalto, Anton HJ Koning, Alex J Eggink, Johannes J Duvekot, Joop SE Laven, Dick Tibboel, Irwin Reiss and Eric AP Steegers Department of Obstetrics and Gynaecology, Research Office Sophia Sophia, Department of Bioinformatics, Intensive Care and Department of Pediatric Surgery and Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Denys–Drash syndrome and congenital diaphragmatic hernia: Another case with the 1097G > A(Arg366His) mutation†

Congenital diaphragmatic hernia (CDH) is a disorder of the development of the lung and diaphragm and is associated with pulmonary hypoplasia and pulmonary hypertension. Denys–Drash syndrome (DDS) is a well‐known syndrome caused by several different germline mutations in the WT1‐gene. CDH in DDS is rare. We present the third case of CDH with clinical features of DDS and the same, rare Arg366His mutation in the WT1‐gene, as reported in the other two known cases. This report provides additional evidence that WT1 mutations can result in diaphragmatic hernia.

Intra-uterine tissue engineering of full-thickness skin defects in a fetal sheep model

In spina bifida the neural tube fails to close during the embryonic period and it is thought that prolonged exposure of the unprotected spinal cord to the amniotic fluid during pregnancy causes additional neural damage. Intra-uterine repair might protect the neural tissue from exposure to amniotic fluid and might reduce additional neural damage. Biodegradable collagen scaffolds may be useful in case of fetal therapy for spina bifida, but biochemical properties need to be studied. The aim of this study was to investigate whether biodegradable collagen scaffolds can be used to treat full-thickness fetal skin defects. We hypothesized that the pro-angiogenic growth factors VEGF and FGF2 would enhance vascularization, epidermialization and lead to improved wound healing. To investigate the effect of these two growth factors, a fetal sheep model for skin defects was used. Compared to wounds treated with bare collagen scaffolds, wounds treated with growth factor-loaded scaffolds showed excessive formation of capillaries and less myofibroblasts were present in these wounds, leading to less contraction. This study has demonstrated that collagen scaffolds can be used to treat fetal skin defects and that the combination of collagen scaffolds with VEGF and FGF2 had a beneficial effect on wound healing.