Mireille N. Bekker

Ultrafast Scan Magnetic Resonance in Prenatal Diagnosis

Objective: To determine whether magnetic resonance (MR) can give additional information in prenatal diagnosis of congenital anomalies, when the ultrasound (US) analysis is not conclusive. Methods: Ultrafast MR scanning examined 39 pregnant women with 41 fetuses in whom US was suspicious of fetal congenital abnormalities. Two techniques were used namely (1) HASTE inversion recovery sequence and (2) FISP 2D. Results: Thirty-nine patients with 41 fetuses were referred for MR because of an equivocal US with regard to brain, spine, skeletal and miscellaneous anomalies. In 1 twin pregnancy, 1 co-twin has not been examined with MRI because of its demise. In 22 of them, additional information was obtained by MR. In 9 the MR was confirmative with the US examination. Four were false negative, comparing with the postnatal diagnosis. Three failed because of maternal claustrophobia and in 2 a diagnosis could not be made. From the 40 fetuses in this study, 38 were examined postnatally by MR, US, plain X-ray or autopsy was performed to confirm the prenatal diagnosis. Conclusion: The use of MRI in obstetrics has been limited, until recently. With fast MRI sequences it is not necessary to sedate the fetus. It is advisable in cases where US is equivocal concerning congenital anomalies of the fetus to use MR with fast or ultrafast scan technique, especially when the central nervous system is concerned.

Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing. Part I - Clinical Impact

To evaluate the clinical impact of nationwide implementation of genome‐wide non‐invasive prenatal testing (NIPT) in pregnancies at increased risk for fetal trisomies 21, 18 and 13 (TRIDENT study).

Increased nuchal translucency and distended jugular lymphatic sacs on first-trimester ultrasound

To investigate the presence and volume of jugular lymphatic sacs (JLS) in first‐trimester fetuses with normal nuchal translucency thickness (NT) and in those with increased NT.

Nuchal edema and venous-lymphatic phenotype disturbance in human fetuses and mouse embryos with aneuploidy

Objective: Nuchal edema (NE) is a clinical indicator for aneuploidy, cardiovascular anomalies, and several genetic syndromes. Its etiology, however, is unknown. In the nuchal area, the endothelium of the jugular lymphatic sacs (JLS) develops by budding from the blood vascular endothelium of the cardinal veins. Abnormal distension of the jugular sacs is associated with NE. We hypothesize that a disturbed lymphatic endothelial differentiation and sac formation causes NE. We investigated endothelial differentiation of the jugular lymphatic system in human and mouse species with NE. Methods: Aneuploid human fetuses (trisomy 21; trisomy 18) were compared with euploid controls (gestational age 12 to 18 weeks). Trisomy 16 mouse embryos were compared with wild type controls (embryonic day 10 to 18). Trisomy 16 mice are considered an animal model for human trisomy 21. Endothelial differentiation was investigated by immunohistochemistry using lymphatic markers (prox-1, podoplanin, lymphatic vessel endothelial hyaluronan receptor [LYVE]-1) and en blood vessel markers (neuropilin [NP]-1 and ligand vascular endothelial growth factor [VEGF]-A). Smooth muscle actin (SMA) was included as a smooth muscle cell marker. Results: We report a disturbed venous-lymphatic phenotype in aneuploid human fetuses and mouse embryos with enlarged jugular sacs and NE. Our results show absent or diminished expression of the lymphatic markers Prox-1 and podoplanin in the enlarged jugular sac, while LYVE-1 expression was normal. Additionally, the enlarged JLS showed blood vessel characteristics, including increased NP-1 and VEGF-A expression. The lumen contained blood cells and smooth muscle cells lined the wall. Conclusion: A loss of lymphatic identity seems to be the underlying cause for clinical NE. Also, abnormal endothelial differentiation provides a link to the cardiovascular anomalies associated with NE.

Increased NCAM Expression and Vascular Development in Trisomy 16 Mouse Embryos: Relationship with Nuchal Translucency

Increased nuchal translucency in the human fetus is associated with chromosomal abnormalities, enlarged jugular lymphatic sacs, cardiac defects and changed flow through the ductus venosus. The developmental background of this nuchal edema in relation to the associated anomalies remains elusive. We studied the morphologic correlation between neurogenesis and vasculogenesis in neck, heart, and ductus venosus region of wild type and trisomy 16 mice embryos (E10- E18), using an antibody against Neural Cell Adhesion Molecule (NCAM). Trisomy 16 mice are a model for the above described human phenotype. From E12 trisomy 16 mice showed an altered arrangement of cranial nerves IX, X and XI, which are positioned between the carotid artery, jugular vein and enlarged lymphatic sac. The vagal nerve was significantly smaller, compared with wild type embryos. NCAM was over expressed in both neuronal and cardiovascular structures in trisomy 16 mice, being particularly prominent in the 4th and 6th pharyngeal arch arteries, and the ductus venosus. In the 4th and 6th pharyngeal arch arteries, NCAM over expression was located to the part of the vessel wall that is closely related to the vagal and recurrent nerve. In case of 4th pharyngeal arch artery abnormalities NCAM expression, on the other hand, was reduced. In conclusion, the interaction between neurogenesis and vasculogenesis is disturbed in the trisomy 16 mouse model, and might be a common denominator in the spectrum of anomalies associated with increased nuchal translucency.

Aberrant lymphatic development in euploid fetuses with increased nuchal translucency including Noonan syndrome

Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60–70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation.

Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies

To evaluate the application of non‐invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing in pregnancies with abnormal ultrasound findings.

The effect of a decision aid on informed decision-making in the era of non-invasive prenatal testing: a randomised controlled trial

Early in pregnancy women and their partners face the complex decision on whether or not to participate in prenatal testing for fetal chromosomal abnormalities. Several studies show that the majority of pregnant women currently do not make informed decisions regarding prenatal testing. As the range of prenatal tests is expanding due to the development of new techniques such as non-invasive prenatal testing (NIPT), autonomous reproductive decision-making is increasingly challenging. In this study, a randomised controlled trial was conducted to evaluate the effect of a web-based multimedia decision aid on decision-making regarding prenatal testing. The decision aid provided both written and audiovisual information on prenatal tests currently available, that is, prenatal screening by first-trimester combined testing, NIPT and invasive diagnostic testing through chorionic villus sampling or amniocentesis. Furthermore, it contained values clarification exercises encouraging pregnant women to reflect on the potential harms and benefits of having prenatal tests performed. The use of the decision aid improved informed decision-making regarding prenatal testing. Of pregnant women allocated to the intervention group (n=130) 82.3% made an informed choice compared with 66.4% of women in the control group (n=131), P=0.004. As the vast majority of pregnant women made decisions consistent with their attitudes towards having prenatal testing performed, this improvement in informed decision-making could be attributed mainly to an increase in decision-relevant knowledge. This study shows that the implementation of a web-based multimedia decision aid directly facilitates the ultimate goal of prenatal testing for fetal chromosomal abnormalities, which is enabling informed autonomous reproductive choice.

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)‐A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF‐A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet‐derived growth factor (PDGF)‐B in the lymphatic endothelial cells of the JLS.

Persistence of Nuchal Edema and Distended Jugular Lymphatic Sacs in Noonan Syndrome

Objective: Noonan syndrome is one of the most common genetic syndromes manifesting at birth. Still, it is diagnosed late, often during infancy. Diagnosis is difficult because prenatal ultrasound findings are unspecific and the dysmorphias after birth can be subtle. Cases: Two women were referred to our university hospital because of an increased nuchal translucency in the first trimester of pregnancy. Further ultrasound examination showed the bilateral presence of distended jugular lymph sacs. Karyotyping revealed euploidy in both fetuses. The second trimester ultrasound scan showed a persistence of the jugular lymph sacs together with a nuchal fold, indicating a disturbed lymphatic development. There were no other anomalies. In 1 case the jugular lymph sacs containing newly formed lymph node tissue remained visible until 35 weeks’ gestation. Both newborns were diagnosed with Noonan syndrome after birth. Postnatal echocardiography revealed a mild pulmonary stenosis. Conclusion: Distension of the jugular lymph sacs is known to cause nuchal edema and normally resolves after the first trimester. In case of persistence of the jugular lymphatic sacs beyond the second trimester of pregnancy, the diagnosis of Noonan syndrome and subsequent DNA testing should be considered.