John M.G. van Vugt

Are pregnant women making informed choices about prenatal screening

Purpose: Prenatal screening should enable pregnant women to make informed choices. An informed decision is defined as being based on sufficient, relevant information and consistent with the decision makers values. This study aims to assess to what extent pregnant women make informed choices about prenatal screening, and to assess the psychological effects of informed decision-making.Methods: The study sample consisted of 1159 pregnant women who were offered the nuchal translucency measurement or the maternal serum screening test. Level of knowledge, value consistency, informed choice, decisional conflict, satisfaction with decision, and anxiety were measured using questionnaires.Results: Of the participants, 83% were classified as having sufficient knowledge about prenatal screening, 82% made a value-consistent decision to accept or decline prenatal screening, and 68% made an informed decision. Informed choice was associated with more satisfaction with the decision, less decisional conflict (this applied only to test acceptors), but was not associated with less anxiety.Conclusion: Although the rate of informed choice is relatively high, substantial percentages of women making uninformed choices due to insufficient knowledge, value inconsistency, or both, were found. Informed choice appeared to be psychologically beneficial. The present study underlines the importance of achieving informed choice in the context of prenatal screening.

Detection of Chromosome 21-encoded mRNA of Placental Origin in Maternal Plasma

BACKGROUND mRNA of placental origin (i.e., human placental lactogen and beta-human chorionic gonadotropin) has been demonstrated to be easily detectable in maternal plasma. We tested whether detection of chromosome 21-encoded mRNA of placental origin is possible in maternal plasma obtained during the first trimester. METHODS Plasma samples were obtained from pregnant women between weeks 9-13 of pregnancy. RNA was isolated from 800 or 1600 microL of plasma by silica-based affinity isolation and, after on-column DNase treatment, was subjected to two-step, one-tube reverse transcription-PCR with gene specific primers. RESULTS Three chromosome 21-encoded genes located within the Down syndrome critical region with overexpression in trisomy 21 placentas were screened for expression in early placental tissue to select their potential use for RNA based plasma screening. One of the chromosome 21-encoded genes (LOC90625) showed strong expression in first trimester placenta similar to CSH1 (human placental lactogen) and was selected for plasma analysis. The RNA isolation assay was validated with CSH1 mRNA, which could be detected in the plasma of all women tested in weeks 9-13 of pregnancy. RNA from the chromosome 21-encoded, placentally expressed gene, LOC90625, was present in maternal first-trimester plasma and could be detected in 60% of maternal plasma samples when 800 microL of plasma was used and in 100% of samples when 1600 microL of plasma was used. CONCLUSION The detection of chromosome 21-encoded mRNA of placental origin in maternal plasma during the first trimester may allow development of plasma-RNA-based strategies for prenatal prediction of Down syndrome. LOC90625 is a candidate gene for this purpose.

First-trimester diagnosis of cystic hygroma—Course and outcome

Objective: We studied the outcomes of fetuses in whom cystic hygroma was diagnosed in the first trimester of pregnancy through the application of transvaginal ultrasonography. Study Design: In the period 1990 to 1991 22 fetuses with cystic hygroma were found. All fetuses had karyotyping and a complete ultrasonographic search for associated anomalies. Results: Aneuploidy was found in seven of 22 fetuses: four trisomy 21, two trisomy 18, and one translocation. Monosomy X was absent in this series. In 15 of 22 cases there was a normal karyotype. In 10 of 15 euploid fetuses the small nonseptated hygroma resolved spontaneously. In four of 15 euploid fetuses other malformations were detected with ultrasonography (i.e., polycystic kidneys, coarctation of the aorta, bladder outlet obstruction, and fetal hydrops). Conclusion: Whenever a cystic hygroma is suspected in the antenatal period, even if of small size, a structured and detailed ultrasonographic examination and fetal karyotyping are recommended.

Enrichment of fetal trophoblast cells from the maternal peripheral blood followed by detection of fetal deoxyribonucleic acid with a nested X/Y polymerase chain reaction☆☆☆★★★

OBJECTIVE Fetal cells circulate in the maternal blood during early pregnancy. Because these cells are rare, noninvasive prenatal diagnosis from fetal cells can be achieved only after efficient enrichment procedures. Our aim was to develop a two-step enrichment procedure to isolate trophoblast cells from 20 ml of peripheral blood. STUDY DESIGN Blood was obtained from pregnant women between 6 and 15 weeks of gestation, before invasive procedures were performed. After enrichment, the success of isolating fetal cells was determined by amplification of Y chromosome sequences. RESULTS A highly specific X/Y polymerase chain reaction was established, sensitive enough to detect X and Y chromosome-specific sequences in one single cell and in one male among 100,000 female cells. Sex determination by polymerase chain reaction was compared with results from conventional karyotyping. The success rate was 91.7%. CONCLUSION Enrichment of trophoblast cells from maternal blood as described here might be useful for early noninvasive prenatal diagnosis.

Abnormal lymphatic development in trisomy 16 mouse embryos precedes nuchal edema

Ultrasound measurement of increased nuchal translucency is a method of risk assessment for heart malformations and trisomy 21 in human pregnancy. The developmental background of this nuchal edema is still not sufficiently understood. We have studied the process in trisomy 16 mice that show nuchal edema and heart malformations. We used trisomy 16 and wild‐type (WT) embryos from embryonic day (E) 12.5 to E18.5. In WT embryos at E13, bilateral jugular lymphatic sacs are visible that share a lymphatic–venous membrane with the jugular vein. We could not in any case discern a valve between these vessels. At E14 in the TS16 embryos, the lymphatic sacs become enlarged showing abnormally thickened endothelium, specifically at the site of the membrane. In these embryos, severe edema develops in the nuchal region. There is a very close colocalisation of the nerves with the vascular structures. The start of reorganization of the jugular lymphatic sac to a lymph node is observed in both wild‐type and TS16 but is diminished in the latter. In conclusion, abnormal size and structure of the jugular lymphatic sacs coincides with the development of nuchal edema. A disturbance of lymphangiogenesis might be the basis for increased nuchal translucency that is often observed in diseased human fetuses. Developmental Dynamics 230:378–384, 2004.

Understanding pregnant women's decision making concerning prenatal screening

OBJECTIVE This study is aimed at enhancing understanding prenatal screening decision making through testing a hypothesized decision model based on decision theory and health behavior theory. DESIGN We obtained questionnaires from 1,666 pregnant women who were offered prenatal screening for Downs syndrome. Path analysis (using LISREL) resulted in a final model with reasonable model fit, which was verified by split-sample cross-validation. MAIN OUTCOME MEASURES These included perceived probability, perceived severity, attitude toward termination, response efficacy, attitude toward prenatal screening, subjective norm, child-related anxiety, and intention to undergo prenatal screening. RESULTS Attitude toward termination of pregnancy, perceived test efficacy, and subjective norm regarding the desirability of having prenatal screening determined a womans attitude toward having a prenatal test. Anxiety was influenced by perceived risk and perceived severity of having a child with Downs syndrome, and by subjective norm, but this appeared to be a weak predictor of intention to test. Pregnant women with a positive attitude toward prenatal screening, and who perceived a subjective norm in favor of undergoing prenatal screening, showed a greater intention to have prenatal screening done. CONCLUSION These findings suggest that more attention should be paid toward the values and social context of pregnant women during the counseling process.

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.

Predicting pulmonary hypoplasia with 2- or 3-dimensional ultrasonography in complicated pregnancies

OBJECTIVE The aim of this study was to compare 3-dimensional (3D) lung volume measurements with 2-dimensional (2D) biometric parameters in predicting pulmonary hypoplasia in complicated pregnancies. STUDY DESIGN In this prospective study, 1-4 scans of the fetal lungs were obtained in 33 pregnancies complicated by various disorders or complications with regard to pulmonary hypoplasia. The 3D lung volumes vs gestational age or estimated fetal weight, the thoracic circumference vs gestational age or femur length, the thoracic/abdominal circumference ratio, and the thoracic/heart area ratio were measured. RESULTS Of the 33 infants, 16 (48.5%) were diagnosed with pulmonary hypoplasia on postmortem examination or the clinical and radiological presentation. Three dimensional lung volume measurements had a better diagnostic accuracy for predicting pulmonary hypoplasia (sensitivity, 94%; specificity, 82%; positive predictive value [PPV], 83%; negative predictive value [NPV], 93%), compared with the best 2D biometric measurement thoracic/heart area ratio (sensitivity, 94%; specificity, 47%; PPV, 63%; NPV, 89%). CONCLUSION 3D lung volume measurements seem to be useful in predicting pulmonary hypoplasia prenatally.

44 Single-Nucleotide Polymorphisms Expressed by Placental RNA: Assessment for Use in Noninvasive Prenatal Diagnosis of Trisomy 21

For noninvasive prenatal diagnosis, markers that directly reflect changes in chromosome dosage are preferred over indirect markers that are associated with epiphenomena(1)(2). The RNA:single-nucleotide polymorphism (SNP) allelic ratio strategy was described recently as a means to directly assess fetal chromosome dosage in maternal plasma(2). Quantitive comparison of the allelic expression ratios of a placentally expressed, chromosome 21–encoded gene, placenta-specific 4 ( PLAC4 ), enabled detection in maternal plasma of the differences between 2 (normal) or 3 copies of chromosome 21(2). The RNA:SNP ratio strategy is currently limited to a subset of the population with heterozygosity of the SNP used. Theoretically, an increase in population coverage can be obtained by inclusion of additional SNPs within PLAC4 or other chromosome 21–encoded transcripts with placental expression and detectability in maternal plasma(2). We therefore tested 44 SNPs expressed by 7 chromosome 21–encoded, placentally expressed genes(2), PLAC4 , collagen, type VI, alpha 2 ( COL6A2 ), collagen, type VI, alpha 1 ( COL6A1 ), BTG family, member 3 ( BTG3 ), ADAM metallopeptidase with thrombospondin type 1 motif, 1 ( ADAMTS1 ), chromosome 21 open reading frame 105 ( C21orf105 ), and amyloid …

Jugular lymphatic maldevelopment in Turner syndrome and trisomy 21: different anomalies leading to nuchal edema.

Increased nuchal translucency (NT), morphologically known as nuchal edema, is an ultrasound marker for aneuploidy. Turner syndrome presents with massive NT, called cystic hygroma. Conflicting data exist as to whether cystic hygroma and increased NT are different entities. Both are associated with jugular lymphatic distension. The authors investigated jugular lymphatics of trisomy 21, Turner syndrome, and normal karyotype fetuses. Fetuses were investigated using immunohistochemistry for blood vascular, lymphatic, and smooth muscle cell markers. Trisomy 21 fetuses showed nuchal cavities within the mesenchymal edema negative for endothelial markers. These were extremely large in Turner fetuses, showing similar characteristics. The skin showed numerous dilated lymphatics in the case of trisomy 21 and scanty small lymphatics in Turner fetuses. A jugular lymphatic sac was present in control and trisomy 21 fetuses and was enlarged in trisomy 21 cases. In Turner fetuses, no jugular lymphatic sac was observed. Nuchal edema in trisomy 21 and Turner syndrome appears to be a similar entity caused by different lymphatic abnormalities.