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Contains fulltext : 292727.pdf (Publisher’s version ) (Open Access) Pregnant women's perspectives should be included in the dialogue surrounding the expanding offers of non-invasive prenatal testing (NIPT), especially now that technological possibilities are rapidly increasing. This study evaluated women's experiences with the offer of genome-wide (GW) first-tier NIPT in a national screening program. A nationwide pre-and post-test questionnaire was completed by 473 pregnant women choosing between targeted NIPT (trisomies 21, 18 and 13 only) and GW-NIPT (also other findings) within the Dutch TRIDENT-2 study. Measures included satisfaction, reasons for or against choosing GW-NIPT, anxiety, and opinion on the future scope of NIPT. Most respondents (90.4%) were glad to have been offered the choice between GW-NIPT and targeted NIPT; 76.5% chose GW-NIPT. Main reasons to choose GW-NIPT were 'wanting as much information as possible regarding the child's health' (38.6%) and 'to be prepared for everything' (23.8%). Main reasons to choose targeted NIPT were 'avoiding uncertain results/outcomes' (33.7%) and 'not wanting to unnecessarily worry' (32.6%). Nearly all respondents received a low-risk NIPT result (98.7%). No differences were found in anxiety between women choosing GW-NIPT and targeted NIPT. Most respondents were favorable toward future prenatal screening for a range of conditions, including life-threatening disorders, mental disabilities, disorders treatable in pregnancy and severe physical disabilities, regardless of their choice for GW-NIPT or targeted NIPT. In conclusion, women who chose first-tier NIPT were satisfied with the choice between GW-NIPT and targeted NIPT, and most women were favorable toward a broader future screening offer. Our results contribute to the debate concerning the expansion of NIPT.

This study describes functional and health-related quality of life (HRQoL) outcomes in patients with Hirschsprung’s disease (HSCR) with associated learning disability or neurodevelopmental delay (LD), completing a core outcome set for HSCR. This was a cross-sectional study from a tertiary pediatric surgery center. Patients treated between 1977 and 2013 were prospectively contacted to complete an outcomes survey. Children under 12 and older patients with LD were assisted to complete these by a proxy. Bowel and urologic function were assessed (Rintala’s BFS and modified DanPSS) along with HRQoL (PedsQL/GIQLI/SF-36). Thirty-two patients with LD were compared to 186 patients with normal cognition. Patients with LD had 76% survival over the follow-up period, compared to 99% in the remainder of the cohort. Poor functional outcomes were common in the patients with LD, considerably higher than cognitively normal patients: with weekly issues withholding stool, soiling and fecal accidents in over half of patients surveyed (44–60%), and urinary incontinence in 46%. Use of permanent stoma was significantly higher (22% vs. 4%; p = 0.001). HRQoL was worse in domains of physical functioning in adults and children but not for social or emotional domains in adults. Subgroup analysis of patients with Down syndrome suggested similar functional results but better QoL. Multivariate analysis demonstrated a dramatically higher incidence of poor continence outcomes in patients with LD (adjusted OR 9.6 [4.0–23]).Conclusions: We provide LD-specific outcomes showing inferior function but similar HRQoL to other patients with HSCR, this is much needed in the counselling of families of these children. What is Known:• Hirschsprung’s disease is commonly associated with syndromes or other anomalies with resultant cognitive impairments.• The outcomes for these patients specifically have been poorly described in the literature. What is New:• Objective functional and quality of life surveys demonstrate significant differences from patients without cognitive impairment.• Patients with learning disability Patients with associated LD were almost ten times more likely to have an associated poor functional outcome, with very little impact on proxy-reported quality of life.

Background Psychiatric disorders, such as depression and anxiety, are commonly associated with epilepsy in the general population, but the relationship between psychiatric disorders and epilepsy among adults with intellectual disabilities is unclear. Aims To conduct a systematic review and meta-analysis to assess whether epilepsy is associated with an increased rate of psychiatric disorders in adults with intellectual disabilities. Method We included literature published between 1985 and 2020 from four databases, and hand-searched six relevant journals. We assessed risk of bias by using SIGN 50 and the Cochrane risk of bias tool. Several meta-analyses were carried out. Results We included 29 papers involving data on 9594 adults with intellectual disabilities, 3180 of whom had epilepsy and 6414 did not. Of the 11 controlled studies that compared the overall rate of psychiatric disorders between the epilepsy and non-epilepsy groups, seven did not show any significant inter-group difference. Meta-analysis was possible on pooled data from seven controlled studies, which did not show any significant inter-group difference in the overall rate of psychiatric disorders. The rates of psychotic disorders, depressive disorders and anxiety disorders were significantly higher in the non-epilepsy control groups compared with the epilepsy group, with effect sizes of 0.29, 0.47 and 0.58, respectively. Epilepsy-related factors did not show any definite association with psychiatric disorders. Conclusions It is difficult to pool data from such heterogeneous studies and draw any definitive conclusion because most studies lacked an appropriately matched control group, which will be required for future studies.

The "difference or delay paradigm" focuses on the question of whether children with developmental disabilities (DD) develop in a way that is only delayed, compared to typically developing children, or also qualitatively different. The current study aimed to examine whether qualitative differences exist in cognitive development of young children with and without DD on the basis of item scores on the Dutch Bayley-III Cognition scale. Differential item functioning was identified for 15 of the 91 items. The presence of DD was related to a higher number of Guttman errors, hinting at more deviation in the order of skill development. An interaction between group (i.e., with or without DD) and developmental quotient appeared to predict the number of Guttman errors. DD was related to a higher number of Guttman errors for the whole range of developmental quotients; children with DD with a small developmental quotient had the highest number. Combined, the results mean that qualitative differences in development are not to be excluded, especially in cases of severe developmental disabilities. When using the Bayley-III in daily practice, the possibility needs to be taken into account that the instruments' assumption of a fixed order in skill development does not hold. (DIPF/Orig.)

ObjectiveTo examine prevalence, time of diagnosis and outcome of fetuses with an exomphalos or gastroschisis, diagnosed since the introduction of a national prenatal screening program in 2007.MethodsA prospective cohort study was undertaken in two fetal medicine units in the Netherlands. Cases were included if the estimated due date was between 2009 and 2013. Outcome measures were gestational age at diagnosis, presence of additional anomalies and pregnancy outcome.ResultsA total of 141 exomphalos and 44 gastroschisis cases were included in the study, of which, respectively, 96 and 95% were diagnosed prenatally. The majority of the cases are visualized prior to the 20-week scan. In the exomphalos group, 83% had additional anomalies of which 57% had a chromosomal anomaly. Additional anomalies were present in 11% of the gastroschisis cases of which 40% had a chromosomal anomaly. The pregnancy termination rate was 61% (exomphalos) and 14% (gastroschisis).ConclusionAlmost all exomphalos and gastroschisis cases are diagnosed prenatally, the majority in the first trimester. Associated anomalies are far more common in exomphalos with a fourfold lower survival rate than gastroschisis. In the exomphalos group, the pregnancy termination rate doubled, while in the gastroschisis group the rate remained low. (c) 2017 John Wiley & Sons, Ltd.

ObjectiveTo examine prevalence, time of diagnosis and outcome of fetuses with an exomphalos or gastroschisis, diagnosed since the introduction of a national prenatal screening program in 2007. MethodsA prospective cohort study was undertaken in two fetal medicine units in the Netherlands. Cases were included if the estimated due date was between 2009 and 2013. Outcome measures were gestational age at diagnosis, presence of additional anomalies and pregnancy outcome. ResultsA total of 141 exomphalos and 44 gastroschisis cases were included in the study, of which, respectively, 96 and 95% were diagnosed prenatally. The majority of the cases are visualized prior to the 20-week scan. In the exomphalos group, 83% had additional anomalies of which 57% had a chromosomal anomaly. Additional anomalies were present in 11% of the gastroschisis cases of which 40% had a chromosomal anomaly. The pregnancy termination rate was 61% (exomphalos) and 14% (gastroschisis). ConclusionAlmost all exomphalos and gastroschisis cases are diagnosed prenatally, the majority in the first trimester. Associated anomalies are far more common in exomphalos with a fourfold lower survival rate than gastroschisis. In the exomphalos group, the pregnancy termination rate doubled, while in the gastroschisis group the rate remained low. (c) 2017 John Wiley & Sons, Ltd.

Background Population-based prenatal screening has become a common and widely available obstetrical practice in majority of developed countries. Under the patient autonomy principle, women should understand the screening options, be able to take their personal preferences and situations into account, and be encouraged to make autonomous and intentional decisions. The majority of the current research focuses on the prenatal screening uptake rate, women’s choice on screening tests, and the influential factors. However, little attention has been paid to women’s choice-making processes and experiences in prenatal screening and their influences on choice satisfaction. Understanding women’s choice-making processes and experiences in pregnancy and childbirth is the prerequisite for designing women-centered choice aids and delivering women-centered maternity care. This paper presents a pilot study that aims to investigate women’s experiences when they make choices for screening tests, quantify the choice-making experience, and identify the experiential factors that affect women’s satisfaction on choices they made. Method We conducted a mixed-method research at Helsinki and Uusimaa Hospital District (HUS) in Finland. First, the women’s choice-making experiences were explored by semi-structured interviews. We interviewed 28 women who participated in prenatal screening. The interview data was processed by thematic analysis. Then, a cross-sectional self-completion survey was designed and implemented, assessing women’s experiences in choice-making and identifying the experiential factors that influence choice satisfaction. Of 940 distributed questionnaires, 185 responses were received. Multivariable linear regression analysis was used to detect the effects of the variables. Results We developed a set of measurements for women’s choice-making experiences in prenatal screening with seven variables: activeness, informedness, confidence, social pressure, difficulty, positive emotion and negative emotion. Regression revealed that activeness in choice-making (β = 0.176; p = 0.023), confidence in choice-making (β = 0.388; p

Background Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups. Methods Using the British Present Psychiatric State–learning Disabilities assessment (PPS‐LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. The median age of those with FXS (59 years) was higher than of those with DS (50 years) and WS (53 years). Results Most study participants with DS (80%) and FXS (89%) were or had been moderately or severely intellectually disabled while most participants with WS (73%) were or had been mildly or moderately disabled at adolescent age. The adolescent (premorbid) level of ID did not correlate with the dementia score. The median scores were 11/27, 1/27, and 0/27 in DS, WS, and FXS subgroups, respectively. Dementia that was confirmed by brain imaging, manifested as Alzheimer disease and as moya‐moya disease associated vascular dementia in DS and as vascular dementia in WS. Conclusions This survey suggests that the risk of dementia varies depending on the cause of ID and that the severity of ID in adolescence does not predict the development of dementia at a later age. Consequently, the ID and dementia should be understood as separate clinical entities that need to be taken into account in the health management of intellectually disabled people. This is important for the arrangement of appropriate and timely interventions, which can be expected to delay the need for institutionalization.

ObjectiveTo examine prevalence, time of diagnosis and outcome of fetuses with an exomphalos or gastroschisis, diagnosed since the introduction of a national prenatal screening program in 2007. MethodsA prospective cohort study was undertaken in two fetal medicine units in the Netherlands. Cases were included if the estimated due date was between 2009 and 2013. Outcome measures were gestational age at diagnosis, presence of additional anomalies and pregnancy outcome. ResultsA total of 141 exomphalos and 44 gastroschisis cases were included in the study, of which, respectively, 96 and 95% were diagnosed prenatally. The majority of the cases are visualized prior to the 20-week scan. In the exomphalos group, 83% had additional anomalies of which 57% had a chromosomal anomaly. Additional anomalies were present in 11% of the gastroschisis cases of which 40% had a chromosomal anomaly. The pregnancy termination rate was 61% (exomphalos) and 14% (gastroschisis). ConclusionAlmost all exomphalos and gastroschisis cases are diagnosed prenatally, the majority in the first trimester. Associated anomalies are far more common in exomphalos with a fourfold lower survival rate than gastroschisis. In the exomphalos group, the pregnancy termination rate doubled, while in the gastroschisis group the rate remained low. (c) 2017 John Wiley & Sons, Ltd.

Item does not contain fulltext A low number of antral follicles may result in the selection of suboptimal oocytes that are prone to meiotic errors. The aim of this case-control study was to evaluate women receiving IVF treatment with low oocyte yield (defined as three or fewer oocytes retrieved after ovarian stimulation) who are at an increased risk of a trisomic pregnancy. Data were obtained from Danish and Dutch medical registries between 1983 and 2011. Analyses were carried out in 105 cases and 442 controls matched by age and year of IVF treatment. Cases were women with a trisomic pregnancy (trisomies 13, 18 or 21) resulting from fresh IVF treatment and confirmed by karyotyping. Cases were included regardless of pregnancy outcome. Controls were women with a live born child without a trisomy, resulting from fresh IVF treatment. Low oocyte yield was observed in 6.6% (29/440) of the women, of which 8.4% (7/83) were cases and 6.2% (22/357) controls. Low oocyte yield in IVF treatment was not associated with a higher risk of trisomic pregnancy (OR 1.43, 95% CI 0.64 to 3.19). Stratification for female age, adjustment for history of ovarian surgery, and gonadotrophin-releasing hormone protocol used did not change the results.

Objective To evaluate preferences and decision‐making among high‐risk pregnant women offered a choice between Non‐Invasive Prenatal Testing (NIPT), invasive testing or no further testing. Methods Nationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first‐trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice. Results A total of 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. Overall, 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (odds ratio (OR) = 3.51[1.70–7.22], p, What's already known about this topic? NIPT is offered as alternative to invasive testing to screen pregnant women at high risk for fetal aneuploidy.Although NIPT has many advantages, concerns have been raised about the consequences for informed decision‐making. What does this study adds? Implementation of NIPT in a national healthcare‐funded prenatal screening program, accompanied by pre‐test counseling, results in most women having sufficient knowledge and making an informed choiceCompared to women choosing invasive testing, women undergoing NIPT have less intention to terminate the pregnancy for Down syndrome.

The pig is an emerging animal model, complementary to rodents for basic research and for biomedical and agronomical purposes. However despite the progress made on mouse and rat models to produce genuine pluripotent cells, it remains impossible to produce porcine pluripotent cell lines with germline transmission. Reprogramming of pig somatic cells using conventional integrative strategies remains also unsatisfactory. In the present study, we compared the outcome of both integrative and non-integrative reprogramming strategies on pluripotency and chromosome stability during pig somatic cell reprogramming. The porcine cell lines produced with integrative strategies express several pluripotency genes but they do not silence the integrated exogenes and present a high genomic instability upon passaging. In contrast, pig induced pluripotent-like stem cells produced with non-integrative reprogramming system (NI-iPSLCs) exhibit a normal karyotype after more than 12 months in culture and reactivate endogenous pluripotency markers. Despite the persistent expression of exogenous OCT4 and MYC, these cells can differentiate into derivatives expressing markers of the three embryonic germ layers and we propose that these NI-iPSLCs can be used as a model to bring new insights into the molecular factors controlling and maintaining pluripotency in the pig and other non-rodent mammalians.

Objective To analyze trends in the number and type of invasive procedure, reasons for referral, maternal age and chromosomal abnormalities over a 10-year period and correlate the trends to changes in the national prenatal screening policy.Methods Data from 10 706 invasive prenatal procedures yielding a full karyotype, performed between 2000 and 2009 were extracted from the cytogenetic database in the central region of The Netherlands. Trends were analyzed.Results Over a 10-year period, the number of invasive procedures halved and the percentage of chromosomal abnormalities detected, increased from 5.5 to 9.4%. After 2007, however, 5.7% of karyotypes in women over 36 years were found to be abnormal, versus 18.1% in women below 36 years. In 2009, 71.5% of women over 36 are still referred for invasive prenatal diagnosis on the indication advanced maternal age.Conclusions Changes in prenatal screening policy significantly increased referral after screening and improved the efficacy of invasive prenatal diagnosis. We show the continuing effect of the different policies applied in the past to women below and above the age of 36. To further improve efficacy of invasive prenatal diagnosis, first trimester combination screening should be actively offered to women of all ages. Copyright (C) 2011 John Wiley & Sons, Ltd.

Objective To analyze trends in the number and type of invasive procedure, reasons for referral, maternal age and chromosomal abnormalities over a 10-year period and correlate the trends to changes in the national prenatal screening policy. Methods Data from 10 706 invasive prenatal procedures yielding a full karyotype, performed between 2000 and 2009 were extracted from the cytogenetic database in the central region of The Netherlands. Trends were analyzed. Results Over a 10-year period, the number of invasive procedures halved and the percentage of chromosomal abnormalities detected, increased from 5.5 to 9.4%. After 2007, however, 5.7% of karyotypes in women over 36 years were found to be abnormal, versus 18.1% in women below 36 years. In 2009, 71.5% of women over 36 are still referred for invasive prenatal diagnosis on the indication advanced maternal age. Conclusions Changes in prenatal screening policy significantly increased referral after screening and improved the efficacy of invasive prenatal diagnosis. We show the continuing effect of the different policies applied in the past to women below and above the age of 36. To further improve efficacy of invasive prenatal diagnosis, first trimester combination screening should be actively offered to women of all ages. Copyright (C) 2011 John Wiley & Sons, Ltd.

Although sibling interactions play an important role in children’s early development, they are rarely studied in very young children with an older brother or sister with autism spectrum disorder (ASD). This study used a naturalistic, observational method to compare interactions between 18-month-old infants and their older sibling with ASD (n = 22) with a control group of 18-month-old infants and their typically developing (TD) older sibling (n = 29). In addition, role (a)symmetry and the influence of gender were evaluated. Sibling interactions in ASD-dyads were characterized by higher levels of negativity. Although somewhat less pronounced in ASD-dyads, role asymmetry was present in both groups, with the older child taking the dominant position. Finally, siblings pairs with an older sister were characterized by more positive behaviours. Since differences in sibling interactions may alter the developmental trajectories of both siblings, these early relationships should be taken into account in future ASD research and interventions.

Contains fulltext : 80912.pdf (Publisher’s version ) (Closed access) BACKGROUND: Favorable results of treatment with bosentan in patients with Eisenmenger syndrome are available. However, data in Down patients are lacking. In this study, we evaluate the therapeutic role of bosentan treatment in Down patients with Eisenmenger syndrome. METHODS: In this open-label study, 24 Down patients (>18 years) with Eisenmenger syndrome (17 males) were treated with bosentan. Their mean age was 38 years (range 19-55 years). All Down patients were evaluated at baseline and during follow-up with laboratory tests, six-minute walk test (6-MWT), Doppler echocardiography, and quality of life questionnaires. RESULTS: The median follow-up of Down patients treated with bosentan was 11.5 months (range 3-23 months). Induction of oral bosentan therapy was well tolerated among all 24 Down patients. Bosentan treatment was generally well tolerated. No serious adverse drug reactions were noted. Median 6-MWT increased from 296 m (range 40-424 m) to 325 m (range 84-459 m, p

In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs). TGCT is the most common type of malignant disorder in men aged 15-40 years. Its incidence has increased sharply in recent years. Fortunately, survival of patients with TGCT has improved enormously, which can chiefly be attributed to the cisplatin-based polychemotherapy that was introduced in the nineteen eighties to treat patients with metastasized TGCT. In addition, new strategies have been developed in the surgical approach to metastasized/non-metastasized TGCT and alterations have been made to the radiotherapy technique and radiation dose for seminoma. Family history of TGCT is among the strongest risk factors for this tumour type. Although this fact and others suggest the existence of genetic predisposition to develop TGCT, no germline mutations conferring high risk of developing TGCT have been identified so far. A small deletion, referred to as gr/gr, identified on the Y chromosome is probably associated with only a modest increase in TGCT risk, and linkage of familial TGCT to the Xq27 region has not been confirmed yet. Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men. Various studies have suggested the existence of an inherited predisposition to development of these tumours. Genome-wide screens subsequently provided evidence of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that might also predispose to cryptorchism. However, this putative gene has yet to be identified, and other TGCT susceptibility genes probably exist. Completion of the human gene map and advances in genetic research will facilitate further investigation of genetic predisposition to TGCT. Insight into inheritance of TGCT might lead to the identification of individuals at increased risk of developing the disorder, increase our understanding of the mutation pathways that lead to sporadic cases, and contribute to improvement in diagnosis and treatment. Clinicians should record the family history of cancer and urogenital differentiation defects in patients with TGCT.

BACKGROUND. In patients with hereditary or constitutional chromosomal anomalies, testicular carcinoma can develop sporadically or on the basis of an underlying hereditary genetic defect. Greater knowledge of these genetic defects would provide more insight into the molecular pathways that lead to testicular carcinoma. To the authors' knowledge, little attention has been paid to date to the comorbid occurrence of testicular carcinoma in patients with hereditary disorders or constitutional chromosomal anomalies.METHODS. The authors performed a review of the literature.RESULTS. Twenty-five different hereditary disorders or constitutional chromosomal anomalies have been reported in patients who developed seminomatous or nonseminomatous testicular carcinoma.CONCLUSIONS. Although most of these malignancies were too rare to enable the detection of statistically significant correlations between the chromosomal/hereditary disorder and the testicular tumor, it was striking that many of the patients had also other urogenital abnormalities. Susceptibility to urogenital abnormalities seems to disrupt normal urogenital differentiation and suggests a correlation with testicular dysgenesis and, thus, also with testicular carcinoma. Other evidence of causal involvement has been found in the field of tumor cytogenetics. Some of the genes responsible for hereditary disorders have been mapped to regions that are of interest in the development of sporadic testicular carcinoma. Molecular studies on candidate genes will be required to provide definite answers. Completion of the human gene map and the availability of advanced gene arrays and bioinformatics are expected to greatly facilitate further exploration of the role of hereditary genetic defects in testicular carcinoma.

We evaluated urinary beta-core human chorionic gonadotropin (beta-core hCG) in the detection of fetal Down's syndrome (DS) in the first trimester of pregnancy. Urine was collected prior to performing chorionic villous sampling (CVS) between 10 and 12 completed weeks from the last menstrual period. In the 9 months of the study, there were 15 chromosomal abnormalities detected by CVS: five trisomy 21, four monosomy X, two trisomy 18, and four cases of confined placental mosaicism (CPM). In these 15 aneuploid pregnancies, the levels of urinary beta-core hCG were expressed as multiples of the median (MOM) of the ratio of beta-core hCG/creatinine for gestational age. The MOMs of this ratio in each of the five DS pregnancies were 0.2, 0.5, 1.3, 1.4, and 1.7. No difference was found between fetuses with DS or any of the other chromosomal abnormalities tested and normal fetuses. Contrary to optimistic reports of urinary beta-core hCG in the second-trimester detection of fetal DS, our data suggest that this is not a useful screening test for DS in the first trimester of pregnancy. (C) 1997 by John Wiley & Sons, Ltd.

We evaluated urinary beta-core human chorionic gonadotropin (beta-core hCG) in the detection of fetal Down's syndrome (DS) in the first trimester of pregnancy. Urine was collected prior to performing chorionic villous sampling (CVS) between 10 and 12 completed weeks from the last menstrual period. In the 9 months of the study, there were 15 chromosomal abnormalities detected by CVS: five trisomy 21, four monosomy X, two trisomy 18, and four cases of confined placental mosaicism (CPM). In these 15 aneuploid pregnancies, the levels of urinary beta-core hCG were expressed as multiples of the median (MOM) of the ratio of beta-core hCG/creatinine for gestational age. The MOMs of this ratio in each of the five DS pregnancies were 0.2, 0.5, 1.3, 1.4, and 1.7. No difference was found between fetuses with DS or any of the other chromosomal abnormalities tested and normal fetuses. Contrary to optimistic reports of urinary beta-core hCG in the second-trimester detection of fetal DS, our data suggest that this is not a useful screening test for DS in the first trimester of pregnancy. (C) 1997 by John Wiley & Sons, Ltd.

We evaluated first-trimester maternal serum alpha-fetoprotein (MS-AFP) as a marker for fetal chromosomal disorders. The multicentre study was performed under the auspices of the Dutch Working Party on Prenatal Diagnosis. MS-AFP was measured in 2404 normal pregnancies and 72 chromosomally abnormal pregnancies. The median multiple of the normal median (MOM) in 32 Down's syndrome pregnancies was 0.83 with a 95 per cent confidence interval ranging from 0.60 to 1.04. The difference between the distributions of first-trimester MS-AFP in normal and Down's syndrome pregnancies was statistically significant (t-test: t = 2.34, P

We evaluated first-trimester maternal serum alpha-fetoprotein (MS-AFP) as a marker for fetal chromosomal disorders. The multicentre study was performed under the auspices of the Dutch Working Party on Prenatal Diagnosis. MS-AFP was measured in 2404 normal pregnancies and 72 chromosomally abnormal pregnancies. The median multiple of the normal median (MOM) in 32 Down's syndrome pregnancies was 0.83 with a 95 per cent confidence interval ranging from 0.60 to 1.04. The difference between the distributions of first-trimester MS-AFP in normal and Down's syndrome pregnancies was statistically significant (t-test: t = 2.34, P

Background and aims: Among cardiovascular risk factor, people with Down syndrome have a lower plasma homocysteine level. In a previous study, we have shown that DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase la), a serine/threonine kinase found on human chromosome 21, is implicated on homocysteine metabolism regulation. Indeed, mice that overexpress in liver this kinase have a lower plasma homocysteine level concomitant with an increased hepatic S-adenosyhomocysteine hydrolase (SAHH) activity, which depends on the activation of NAD(P)H:quinone oxidoreductase-1 (NQO1). Since NQO1 gene transcription is under the control of NRF2 and AhR, the aim of the present study was to analyze the effect of DYRK1A overexpression in mice onto NRF2 and AhR signaling pathways. Methods: Effects of DYRK1A overexpression were examined in mice overexpressing Dyrk1 a treated with an inhibitor, harmine, by real-time quantitative reverse-transcription polymerase reaction and western blotting. Results: We found that overexpression of DYRK1A increases the nuclear NRF2 quantity, concomitant with the activation of ERK1/2. We also show that the overexpression of Dyrk1 a has no effect on PI3K/AKT activation, and AhR signaling pathway in liver of mice. Conclusions: Our results reveal a link between DYRK1A and NRF2 signaling pathway. (C) 2011 Elsevier Inc. All rights reserved.

Objective To analyze trends in the number and type of invasive procedure, reasons for referral, maternal age and chromosomal abnormalities over a 10-year period and correlate the trends to changes in the national prenatal screening policy. Methods Data from 10 706 invasive prenatal procedures yielding a full karyotype, performed between 2000 and 2009 were extracted from the cytogenetic database in the central region of The Netherlands. Trends were analyzed. Results Over a 10-year period, the number of invasive procedures halved and the percentage of chromosomal abnormalities detected, increased from 5.5 to 9.4%. After 2007, however, 5.7% of karyotypes in women over 36 years were found to be abnormal, versus 18.1% in women below 36 years. In 2009, 71.5% of women over 36 are still referred for invasive prenatal diagnosis on the indication advanced maternal age. Conclusions Changes in prenatal screening policy significantly increased referral after screening and improved the efficacy of invasive prenatal diagnosis. We show the continuing effect of the different policies applied in the past to women below and above the age of 36. To further improve efficacy of invasive prenatal diagnosis, first trimester combination screening should be actively offered to women of all ages. Copyright (C) 2011 John Wiley & Sons, Ltd.

This within-family study investigated whether mothers differentiate between children in their interactive behavior. Mothers were observed during a play and a task interaction separately with their child with autism spectrum disorder (ASD) (between 46 and 84 months old, M = 68) and with a younger sibling (between 29 and 67 months old, M = 48). Additionally, the social behavior of the children with ASD and their non-ASD siblings was compared. Results show that mothers differentiated in their responsiveness but not in their initiatives toward the children. Children with ASD and their non-ASD siblings were equally responsive but children with ASD were more imperative toward their caregiver. Several interpretations of these findings are discussed. Finally, it is concluded that family-based interventions will benefit from a better understanding of the effect of ASD on mother-child interactions within families with a child with ASD. Therefore, between-family studies should be complemented with within-family studies. Autism Res 2011,4:358-367. © 2011 International Society for Autism Research, Wiley Periodicals, Inc.

We measured the maternal serum cancer antigen 125 (MS-CA 125) levels in 98 nonpregnant women, 765 first- and second-trimester pregnancies with chromosomally-normal fetuses, and 54 chromosomally-abnormal pregnancies. To determine the MS-CA 125 concentration, we used a new automated microparticle enzyme immunoassay with low inter-assay variability. The median MS-CA 125 level decreased from the first to the second trimester of pregnancy and was higher than that in non-pregnant women. We found no difference between normal and Down's syndrome (n=29) pregnancies (t-test: t=0.57, p>0.5). The MS-CA 125 levels in pregnancies with other chromosomal abnormalities showed no difference either, compared with the normals. We conclude that MS-CA 125 is not a useful marker for fetal Down's syndrome, nor for other chromosomal disorders in pregnancy.

We measured the maternal serum cancer antigen 125 (MS-CA 125) levels in 98 nonpregnant women, 765 first- and second-trimester pregnancies with chromosomally-normal fetuses, and 54 chromosomally-abnormal pregnancies. To determine the MS-CA 125 concentration, we used a new automated microparticle enzyme immunoassay with low inter-assay variability. The median MS-CA 125 level decreased from the first to the second trimester of pregnancy and was higher than that in non-pregnant women. We found no difference between normal and Down's syndrome (n=29) pregnancies (t-test: t=0.57, p>0.5). The MS-CA 125 levels in pregnancies with other chromosomal abnormalities showed no difference either, compared with the normals. We conclude that MS-CA 125 is not a useful marker for fetal Down's syndrome, nor for other chromosomal disorders in pregnancy.

In northwest European countries maternal age is increasing. This will lead to an increase of the prevalence of Down syndrome conceptuses. Meanwhile, the increased use of prenatal cytogenetic diagnosis (PCD) will lead to a decrease in the prevalence of Down syndrome among livebirths. We were interested to know what the result of these two opposite developments would be in the near future, and we describe here a model to quantify these processes and the resulting livebirth prevalence of Down syndrome. The model is demonstrated for The Netherlands from 1992 to 2001. The predicted livebirth prevalence for The Netherlands in 1992 is 1.36 per 1000. Demographic factors will cause an increase to 1.76 per 1000 in 2001 with present indications for PCD and a utilization ratio of 50%. An increase of the utilization ratio to 90% in 2001 will lead to a prevalence of 1.22 per 1000, a little less than the present prevalence. Alternative screening programs, including maternal serum screening, could lead to a further decrease of the livebirth prevalence. The model described here can be used for evaluation of the consequences of alternative forms of Down syndrome screening.

We studied the opinions and experiences concerning maternal serum screening of two groups of women: (A) women who were not eligible for prenatal diagnosis; and (B) women for whom prenatal diagnosis was available because of advanced maternal age, and who either underwent chorionic villus sampling or amniocentesis. Many of the women were in favour of the availability of serum screening and would apply for this test in a future pregnancy. This applied also to many respondents who had previously undergone prenatal diagnosis. Most of these women, however, did not intend to decline diagnostic amniocentesis if the screening results did not indicate an increased risk. The majority of the group of respondents of 36 years and over did not consider it acceptable if age indication was dropped altogether. A system based on serum screening will have other implications than a policy based on age indication, since specific individual risk assessment is perceived as being of more significance than a risk statistically derived from age alone. Serum screening is often seen as a means of reassurance and many women are not aware of the possible drawbacks. As technology becomes increasingly complicated, counselling has to be adjusted correspondingly. Further research is needed to establish whether and how distress can be minimized and well-considered individual choice can be achieved.

We studied the opinions and experiences concerning maternal serum screening of two groups of women: (A) women who were not eligible for prenatal diagnosis; and (B) women for whom prenatal diagnosis was available because of advanced maternal age, and who either underwent chorionic villus sampling or amniocentesis. Many of the women were in favour of the availability of serum screening and would apply for this test in a future pregnancy. This applied also to many respondents who had previously undergone prenatal diagnosis. Most of these women, however, did not intend to decline diagnostic amniocentesis if the screening results did not indicate an increased risk. The majority of the group of respondents of 36 years and over did not consider it acceptable if age indication was dropped altogether.A system based on serum screening will have other implications than a policy based on age indication, since specific individual risk assessment is perceived as being of more significance than a risk statistically derived from age alone. Serum screening is often seen as a means of reassurance and many women are not aware of the possible drawbacks. As technology becomes increasingly complicated, counselling has to be adjusted correspondingly. Further research is needed to establish whether and how distress can be minimized and well-considered individual choice can be achieved.

Objectives To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome.Design Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months.Setting Data from 22 EUROCAT congenital anomaly registers in 12 European countries.Participants Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age >= 20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome.Main outcome measures Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression.Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). Results The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26).Conclusions There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

Various genes may influence intestinal barrier function, including MAGI2, MY09B, and PARD3, which are associated with celiac disease. Because direct measurement of intestinal permeability is difficult, antibodies against gliadin (AGA) and Baker's yeast (anti-Saccharomyces cerevisiae antibodies [ASCA]) can be used as an indirect test. The objective of this study was to investigate whether intestinal permeability, represented by AGA, was correlated with MAGI2, MY09B, and PARD3. Analyses were performed in patients with Down syndrome, a population with suspected increased intestinal permeability. Correlations between AGA and ASCA were investigated. Patients with Down syndrome (n = 126) were genotyped for six single-nucleotide polymorphisms in MAGI2 (rs1496770, rs6962966, rs9640699), MY09B (rs1457092, rs2305764), and PARD3 (rs10763976). An allele dosage association of these risk genes and AGA levels was performed. The correlation between AGA and ASCA was studied. A strong correlation was found between AGA and ASCA (p

Objective To investigate normal fetal heart rate in early pregnancy and assess the hypothesis that abnormal fetal heart rate is associated with fetal chromosomal abnormalities.Design Prospective descriptive cross-sectional study.Setting Antenatal clinic associated to the University Clinic of Obstetrics, University Hospital Groningen, The Netherlands.Subjects 424 pregnant women who attended for prenatal counselling.Interventions Measurements of fetal heart rate from 6-16 weeks gestation, cross-sectional study.Main outcome measures Fetal heart rate expressed as beats/min.Results Karyotyping showed a normal chromosomal pattern in 414 fetuses. The median fetal heart rate increased from 138 beats/min at 6 weeks to 177 beats/min at 9 weeks, thereafter, fetal heart rate gradually decreased to 150 beats/min at 16 weeks. Karyotyping showed 10 abnormalities: five trisomies 21, three trisomies 18, and two mosaic pattern in chorionic villi. Fetal heart rate of the trisomic fetuses was distributed around the median with that of all Down's syndrome fetuses within the normal range. In one fetus with trisomy 18, the heart rate exceeded the 90th centile, in another it fell under the 10th centile. The two fetuses with a mosaic pattern in chorionic villi had heart rates outside the normal range.Conclusion Fetal heart rate in chromosomally abnormal fetuses in early pregnancy do not appear to be consistently different from that in normal fetuses. The use of a single measurement of fetal heart rate is not valuable for screening purposes. Chromosomal mosaicism in chorionic villi may be associated with abnormal fetal heart rate.

Objective To investigate normal fetal heart rate in early pregnancy and assess the hypothesis that abnormal fetal heart rate is associated with fetal chromosomal abnormalities. Design Prospective descriptive cross-sectional study. Setting Antenatal clinic associated to the University Clinic of Obstetrics, University Hospital Groningen, The Netherlands. Subjects 424 pregnant women who attended for prenatal counselling. Interventions Measurements of fetal heart rate from 6-16 weeks gestation, cross-sectional study. Main outcome measures Fetal heart rate expressed as beats/min. Results Karyotyping showed a normal chromosomal pattern in 414 fetuses. The median fetal heart rate increased from 138 beats/min at 6 weeks to 177 beats/min at 9 weeks, thereafter, fetal heart rate gradually decreased to 150 beats/min at 16 weeks. Karyotyping showed 10 abnormalities: five trisomies 21, three trisomies 18, and two mosaic pattern in chorionic villi. Fetal heart rate of the trisomic fetuses was distributed around the median with that of all Down's syndrome fetuses within the normal range. In one fetus with trisomy 18, the heart rate exceeded the 90th centile, in another it fell under the 10th centile. The two fetuses with a mosaic pattern in chorionic villi had heart rates outside the normal range. Conclusion Fetal heart rate in chromosomally abnormal fetuses in early pregnancy do not appear to be consistently different from that in normal fetuses. The use of a single measurement of fetal heart rate is not valuable for screening purposes. Chromosomal mosaicism in chorionic villi may be associated with abnormal fetal heart rate.

The Dutch Working Party on Prenatal Diagnosis has initiated a study on the possibilities of first-trimester screening for fetal chromosomal disorders. We report on maternal serum human chorionic gonadotrophin (MS-hCG) measurements in 1348 pregnancies with a chromosomally normal fetus and 53 pregnancies with a chromosomally abnormal fetus. The median MS-hCG concentration in 24 pregnancies with Down's syndrome was 1.19 multiples of the normal median (MoM). The MS-hCG distributions in normal and Down's syndrome pregnancies did not differ significantly (t-test: t = 1.945,p > 0.05). We also found no difference between normal pregnancies and pregnancies with other chromosomal disorders (six cases of trisomy 18, MoM = 0.80; four cases of sex chromosome abnormality, MoM = 1.01; 17 cases of chromosomal mosaicism in chorionic villi, MoM = 1.11). Selecting an upper limit at the 90th centile could detect 25 per cent of pregnancies with Down's syndrome. We conclude that, in the first trimester, MS-hCG as a screening factor for Down's syndrome is of minor value. However, MS-hCG could be a useful factor in a first-trimester screening programme based on a combination of markers.

The Dutch Working Party on Prenatal Diagnosis has initiated a study on the possibilities of first-trimester screening for fetal chromosomal disorders. We report on maternal serum human chorionic gonadotrophin (MS-hCG) measurements in 1348 pregnancies with a chromosomally normal fetus and 53 pregnancies with a chromosomally abnormal fetus. The median MS-hCG concentration in 24 pregnancies with Down's syndrome was 1.19 multiples of the normal median (MoM). The MS-hCG distributions in normal and Down's syndrome pregnancies did not differ significantly (t-test: t = 1.945,p > 0.05). We also found no difference between normal pregnancies and pregnancies with other chromosomal disorders (six cases of trisomy 18, MoM = 0.80; four cases of sex chromosome abnormality, MoM = 1.01; 17 cases of chromosomal mosaicism in chorionic villi, MoM = 1.11). Selecting an upper limit at the 90th centile could detect 25 per cent of pregnancies with Down's syndrome. We conclude that, in the first trimester, MS-hCG as a screening factor for Down's syndrome is of minor value. However, MS-hCG could be a useful factor in a first-trimester screening programme based on a combination of markers.

In order to gain more insight into the association between alpha-fetoprotein (AFP) and fetal chromosomal disorders, especially Down's syndrome, we measured AFP in fetal serum, amniotic fluid, and maternal serum at cordocentesis. We compared the concentration and gradient of AFP in these three compartments. Our data confirm earlier findings on second-trimester fetal serum AFP concentration. The results indicate that low maternal serum AFP in pregnancies with fetal chromosomal disorders could result from an impaired fetal kidney function as well as from impaired membrane or placental passage of AFP, rather than from reduced fetal AFP production.

Background Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Mouse models for DS show behavioural and cognitive defects, synaptic plasticity defects, and reduced hippocampal and cerebellar neuron numbers. Early postnatal development of both human and mouse-model DS shows the reduced capability of neuronal precursor cells to generate neurons. The exact molecular cause of this reduction, and the role played by increased dosage of individual HSA21 genes, remain unknown. Results We have subcutaneously injected mouse pluripotent ES cells containing a single freely segregating supernumerary human chromosome 21 (HSA21) into syngeneic mice, to generate transchromosomic teratomas. Transchromosomic cells and parental control cells were injected into opposite flanks of thirty mice in three independent experiments. Tumours were grown for 30 days, a time-span equivalent to combined intra-uterine, and early post-natal mouse development. When paired teratomas from the same animals were compared, transchromosomic tumours showed a three-fold lower percentage of neuroectodermal tissue, as well as significantly reduced mRNA levels for neuron specific (Tubb3) and glia specific (Gfap) genes, relative to euploid controls. Two thirds of transchromosomic tumours also showed a lack of PCR amplification with multiple primers specific for HSA21, which were present in the ES cells at the point of injection, thus restricting a commonly retained trisomy to less than a third of HSA21 genes. Conclusion We demonstrate that a supernumerary chromosome 21 causes Inhibition of Neuroectodermal DIfferentiation (INDI) of pluripotent ES cells. The data suggest that trisomy of less than a third of HSA21 genes, in two chromosomal regions, might be sufficient to cause this effect.

Objective To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design Description of a novel phenotype associated with a presenilin 1 mutation. Setting The subject was an outpatient who was diagnosed at the local referral center. Patient A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1 ) S170F mutation was detected. Main Outcome Measures We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ 42 and Aβ 40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N–terminally truncated Aβ species ending at both residues 40 and 42. Conclusion These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.

We screened 115 children with Down syndrome for celiac disease, using antigliadin, antiendomysium, and antireticulin serum antibodies and an intestinal permeability test, Celiac disease was diagnosed in eight children, giving a frequency of 7.0%. We recommend screening for celiac disease in all persons with Down syndrome, with the use of at least the antiendomysium antibody determination.

We screened 115 children with Down syndrome for celiac disease, using antigliadin, antiendomysium, and antireticulin serum antibodies and an intestinal permeability test, Celiac disease was diagnosed in eight children, giving a frequency of 7.0%. We recommend screening for celiac disease in all persons with Down syndrome, with the use of at least the antiendomysium antibody determination.

BACKGROUND In patients with hereditary or constitutional chromosomal anomalies, testicular carcinoma can develop sporadically or on the basis of an underlying hereditary genetic defect. Greater knowledge of these genetic defects would provide more insight into the molecular pathways that lead to testicular carcinoma. To the authors' knowledge, little attention has been paid to date to the comorbid occurrence of testicular carcinoma in patients with hereditary disorders or constitutional chromosomal anomalies. METHODS The authors performed a review of the literature. RESULTS Twenty-five different hereditary disorders or constitutional chromosomal anomalies have been reported in patients who developed seminomatous or nonseminomatous testicular carcinoma. CONCLUSIONS Although most of these malignancies were too rare to enable the detection of statistically significant correlations between the chromosomal/hereditary disorder and the testicular tumor, it was striking that many of the patients had also other urogenital abnormalities. Susceptibility to urogenital abnormalities seems to disrupt normal urogenital differentiation and suggests a correlation with testicular dysgenesis and, thus, also with testicular carcinoma. Other evidence of causal involvement has been found in the field of tumor cytogenetics. Some of the genes responsible for hereditary disorders have been mapped to regions that are of interest in the development of sporadic testicular carcinoma. Molecular studies on candidate genes will be required to provide definite answers. Completion of the human gene map and the availability of advanced gene arrays and bioinformatics are expected to greatly facilitate further exploration of the role of hereditary genetic defects in testicular carcinoma. Cancer 2003;97:984–92. © 2003 American Cancer Society. DOI 10.1002/cncr.11155

Haemophilus influenzae type b (Hib) conjugate vaccines have proved extremely efficacious in healthy children. True Hib vaccine failures are rare. Hib conjugate vaccines were introduced for routine immunization in the United Kingdom and the Republic of Ireland in 1992. Coincident with this, active prospective and national surveillance via pediatricians, microbiologists, and public health physicians was commenced to assess the clinical and immunological factors associated with vaccine failure. During the 6 years of the study, 115 children with true vaccine failure were reported. Of the children who were vaccinated before 12 months of age, a clinical risk factor was detected in 20%, an immunological deficiency was detected in 30%, and one or both were detected in 44%. Children who were vaccinated after 12 months of age were more likely to have one or both factors (67%). Thirty percent (33 of 105) of children with true vaccine failure had a low Hib antibody response (concentration, !1.0 mg/mL) after disease, but the majority then responded to a further dose of Hib vaccine. Children who develop Hib disease despite vaccination deserve further clinical and immunological evaluation. The first vaccine to be developed against Haemophilus influenzae type b (Hib) was composed of polyribosylribitol phosphate (PRP), the organism’s capsular polysaccharide. An early trial of this vaccine demonstrated 190% efficacy in children who received vaccine when they were >18 months of age, but it provided no protection in younger children [1]. The conjugation of PRP to protein has lead to the development of Hib vaccines with enhanced immunogenicity in infants and the ability to induce immunological memory. The subsequent implementation of these vaccines has resulted in dramatic reductions in the rate of Hib disease [2].

A (semi-) randomized controlled study with long-term follow-up was conducted to compare the effects of transabdominal chorionic villus sampling and early amniocentesis on fetal mortality and child morbidity. Women requesting early prenatal diagnosis for advanced maternal age were allocated to early amniocentesis or transabdominal chorionic villus sampling either by randomization or, if they declined randomization, by their own choice. Of the 212 women who entered the study, 117 were randomized, 70 chose early amniocentesis and 25 chose transabdominal chorionic villus sampling. Overall, 130 women underwent early amniocentesis and 74 underwent transabdominal chorionic villus sampling at a median gestation of 12 weeks. Two women were excluded because of fetal death before the procedure. Mosaic karyotypes were found in 5.4 per cent of the early amniocenteses and in none of the chorionic villus samples. All unintended fetal losses occurred after early amniocentesis with a frequency of 6.2 per cent (95 per cent confidence interval: 2.7 per cent to 11.8 per cent). Talipes equinovarus was only observed after early amniocentesis with a frequency of 3.1 per cent (95 per cent confidence interval: 0.8 per cent to 7.7 per cent). We conclude that chorionic villus sampling remains the method of choice if prenatal diagnosis is needed in the first trimester of pregnancy. (C) 1998 John Wiley & Sons, Ltd.

We evaluated urinary beta-core human chorionic gonadotropin (beta-core hCG) in the detection of fetal Down's syndrome (DS) in the first trimester of pregnancy. Urine was collected prior to performing chorionic villous sampling (CVS) between 10 and 12 completed weeks from the last menstrual period. In the 9 months of the study, there were 15 chromosomal abnormalities detected by CVS: five trisomy 21, four monosomy X, two trisomy 18, and four cases of confined placental mosaicism (CPM). In these 15 aneuploid pregnancies, the levels of urinary beta-core hCG were expressed as multiples of the median (MOM) of the ratio of beta-core hCG/creatinine for gestational age. The MOMs of this ratio in each of the five DS pregnancies were 0.2, 0.5, 1.3, 1.4, and 1.7. No difference was found between fetuses with DS or any of the other chromosomal abnormalities tested and normal fetuses. Contrary to optimistic reports of urinary beta-core hCG in the second-trimester detection of fetal DS, our data suggest that this is not a useful screening test for DS in the first trimester of pregnancy. (C) 1997 by John Wiley & Sons, Ltd.

We evaluated first-trimester maternal serum alpha-fetoprotein (MS-AFP) as a marker for fetal chromosomal disorders. The multicentre study was performed under the auspices of the Dutch Working Party on Prenatal Diagnosis. MS-AFP was measured in 2404 normal pregnancies and 72 chromosomally abnormal pregnancies. The median multiple of the normal median (MOM) in 32 Down's syndrome pregnancies was 0.83 with a 95 per cent confidence interval ranging from 0.60 to 1.04. The difference between the distributions of first-trimester MS-AFP in normal and Down's syndrome pregnancies was statistically significant (t-test: t = 2.34, P < 0.05). Thirty-one per cent of the Down's syndrome pregnancies were found below the tenth percentile. We found no difference between normal pregnancies and pregnancies with other chromosomal disorders (eight cases with trisomy 18, MOM = 1.26; seven cases with sex chromosome abnormalities, MOM = 1.07; 22 cases with a chromosomal mosaic pattern in chorionic villi, MOM = 1.08). We conclude that first-trimester MS-AFP can discriminate between normal and Down's syndrome pregnancies, but is not an effective marker. First-trimester MS-AFP has no value as a marker for other fetal chromosomal disorders.

We investigated the effect of maternal serum screening on the amniocentesis (AC) rate in women of advanced maternal age. The AC rate after maternal serum screening was compared in two groups of women with a singleton pregnancy, 855 women of 30-35 years and 98 of 36 years and older. In our population, 34.1 per cent of the women of 36 years or older were 'screen-positive' for Down syndrome. Only 41.2 per cent of these women chose to undergo AC as opposed to 88.2 per cent in the younger age group. Within the older age group, the tendency to avoid AC increased with increasing age. Maternal serum screening led to a significant decrease in the AC rate in the older women. In this group, a comparison between the 'a priori' and the calculated risk n-tight have had more influence on the decision to undergo AC than being screen-positive or screen-negative as such. We conclude that maternal serum screening had a major effect on the AC rate in women of advanced maternal age. This is of importance in a society in which the average maternal age is steadily increasing.

We measured the maternal serum cancer antigen 125 (MS-CA 125) levels in 98 nonpregnant women, 765 first- and second-trimester pregnancies with chromosomally-normal fetuses, and 54 chromosomally-abnormal pregnancies. To determine the MS-CA 125 concentration, we used a new automated microparticle enzyme immunoassay with low inter-assay variability. The median MS-CA 125 level decreased from the first to the second trimester of pregnancy and was higher than that in non-pregnant women. We found no difference between normal and Down's syndrome (n=29) pregnancies (t-test: t=0.57, p>0.5). The MS-CA 125 levels in pregnancies with other chromosomal abnormalities showed no difference either, compared with the normals. We conclude that MS-CA 125 is not a useful marker for fetal Down's syndrome, nor for other chromosomal disorders in pregnancy.