Time Of Chorionic Villus Sampling Research Articles

Sexually dimorphic DNA methylation and gene expression patterns in human first trimester placenta

BackgroundFetal sex and placental development impact pregnancy outcomes and fetal–maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies.MethodsPregnant subjects were recruited in late first trimester (weeks 10–14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas.ResultsMethylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood.ConclusionsOverall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.

Sex differences in the late first trimester human placenta transcriptome

BackgroundDevelopment of the placenta during the late first trimester is critical to ensure normal growth and development of the fetus. Developmental differences in this window such as sex-specific variation are implicated in later placental disease states, yet gene expression at this time is poorly understood.MethodsRNA-sequencing was performed to characterize the transcriptome of 39 first trimester human placentas using chorionic villi following genetic testing (17 females, 22 males). Gene enrichment analysis was performed to find enriched canonical pathways and gene ontologies in the first trimester. DESeq2 was used to find sexually dimorphic gene expression. Patient demographics were analyzed for sex differences in fetal weight at time of chorionic villus sampling and birth.ResultsRNA-sequencing analyses detected 14,250 expressed genes, with chromosome 19 contributing the greatest proportion (973/2852, 34.1% of chromosome 19 genes) and Y chromosome contributing the least (16/568, 2.8%). Several placenta-enriched genes as well as histone-coding genes were identified to be unique to the first trimester and common to both sexes. Further, we identified 58 genes with significantly different expression between males and females: 25 X-linked, 15 Y-linked, and 18 autosomal genes. Genes that escape X inactivation were highly represented (59.1%) among X-linked genes upregulated in females. Many genes differentially expressed by sex consisted of X/Y gene pairs, suggesting that dosage compensation plays a role in sex differences. These X/Y pairs had roles in parallel, ancient canonical pathways important for eukaryotic cell growth and survival: chromatin modification, transcription, splicing, and translation.ConclusionsThis study is the first characterization of the late first trimester placenta transcriptome, highlighting similarities and differences among the sexes in ongoing human pregnancies resulting in live births. Sexual dimorphism may contribute to pregnancy outcomes, including fetal growth and birth weight, which was seen in our cohort, with males significantly heavier than females at birth. This transcriptome provides a basis for development of early diagnostic tests of placental function that can indicate overall pregnancy heath, fetal-maternal health, and long-term adult health.

The effect of infertility and assisted reproduction on first-trimester placental and fetal development

Our investigation of differences in first-trimester placentation and/or fetal biometry in pregnancies conceived spontaneously compared with those conceived through fertility treatment, and comparing less invasive fertility treatment with in vitro fertilization found no statistically significant difference in first-trimester abnormal placentation or fetal growth between pregnancies conceived spontaneously and those conceived through fertility treatment, or between the in vivo and in vitro subgroups.

Placental Weight in Pregnancies With Trisomy Confined to the Placenta

ObjectiveMosaicism with trisomy confined to the placenta is present in ~1% of ongoing pregnancies at the time of chorionic villus sampling. Some studies have found reduced fetal growth in confined placental trisomy. The objective of this study was to assess placental weight and feto-placental weight ratio in pregnancies with trisomy confined to the placenta, and to correlate them with the level of trisomy in the three major placental lineages. MethodsWe conducted a retrospective study of 69 pregnancies with prenatally diagnosed mosaic trisomy in which the trisomic cells were confined to the placenta. Placental weight and feto-placental weight ratio were compared to those of matched controls, and placental weight was also analyzed for associations with the type and level of trisomy. Placental pathology was also reviewed. ResultsThe pregnancies with mosaic trisomy were found to have lower placental weights than matched controls, but normal feto-placental weight ratios. Placental weight was not associated with the type or level of trisomic cells in the three placental lineages at term (chorionic plate, chorionic villus mesenchyme, and trophoblast). There were no pathognomonic findings on routine placental pathology of the trisomic placentas. ConclusionAlthough placental weight was reduced (with normal feto-placental weight ratio) in pregnancies with trisomy confined to the placenta, the level of placental trisomy was not correlated with placental weight. Thus, trisomy may alter placental function rather than have a direct hypoplastic effect on placental growth. More in-depth studies beyond routine pathology are required to identify how trisomy affects placental function.

The effect of infertility and assisted reproduction on first trimester fetal growth

OBJECTIVE: Studies have demonstrated that infants of assisted reproductive technologies (ART) are at increased risk for adverse outcomes, such as low birth weight, compared with naturally conceived pregnancies. It is unclear, at what gestational age these changes are initiated, and whether these risks are a result of infertility or the fertility treatment. Thus, the objectives of our study were: 1) to compare first trimester fetal biometry, as an early marker of fetal growth, in patients conceiving either spontaneously or through infertility treatment; and 2) to compare early fetal biometry in pregnancies resulting from in-vitro fertilization (IVF) to those from other fertility treatments (in-vivo fertilization).DESIGN: Retrospective case-control study.MATERIALS AND METHODS: Analysis was conducted on all singleton pregnancies who presented to our institution for chorionic villus sampling (CVS) from 7/2000 to 4/2004. Ultrasounds were performed at the time of CVS between 9 and 12 weeks. Women were classified as either receiving infertility treatments or conceiving spontaneously. Infertility patients were further divided into those achieving pregnancy through IVF or through other fertility treatments. The mean gestational age (by LMP, date of IUI, or date of oocyte aspiration) and mean crown rump length (CRL) was calculated for each group. Data was analyzed using the T-test to compare means, or Fisher's exact test.RESULTS: 1,535 patients who spontaneously conceived, and 135 patients who conceived through ART, were included in the analysis. In the fertile and infertile patients, mean CRL was 51.6 and 50.8 mm, respectively. When we compared the patients who conceived through IVF (n = 64) to those who conceived through in-vivo treatments (n = 63), mean CRL for each group was 51.6 and 50.8 mm, respectively. These results were not significantly different. In the fertile and infertile groups, mean maternal age was 39.0 and 39.7. This difference was small, though statistically significant. No significant differences were found in other parameters when comparing groups.CONCLUSIONS: Pregnancies conceived by infertile couples are not smaller in the late first trimester when compared to spontaneously conceived pregnancies. In addition, there is no difference in the size of pregnancies conceived through ART compared to those from in-vivo treatments. Although ART pregnancies have been associated with low birth weight, this does not appear to be a phenomenon that occurs early in gestation. OBJECTIVE: Studies have demonstrated that infants of assisted reproductive technologies (ART) are at increased risk for adverse outcomes, such as low birth weight, compared with naturally conceived pregnancies. It is unclear, at what gestational age these changes are initiated, and whether these risks are a result of infertility or the fertility treatment. Thus, the objectives of our study were: 1) to compare first trimester fetal biometry, as an early marker of fetal growth, in patients conceiving either spontaneously or through infertility treatment; and 2) to compare early fetal biometry in pregnancies resulting from in-vitro fertilization (IVF) to those from other fertility treatments (in-vivo fertilization). DESIGN: Retrospective case-control study. MATERIALS AND METHODS: Analysis was conducted on all singleton pregnancies who presented to our institution for chorionic villus sampling (CVS) from 7/2000 to 4/2004. Ultrasounds were performed at the time of CVS between 9 and 12 weeks. Women were classified as either receiving infertility treatments or conceiving spontaneously. Infertility patients were further divided into those achieving pregnancy through IVF or through other fertility treatments. The mean gestational age (by LMP, date of IUI, or date of oocyte aspiration) and mean crown rump length (CRL) was calculated for each group. Data was analyzed using the T-test to compare means, or Fisher's exact test. RESULTS: 1,535 patients who spontaneously conceived, and 135 patients who conceived through ART, were included in the analysis. In the fertile and infertile patients, mean CRL was 51.6 and 50.8 mm, respectively. When we compared the patients who conceived through IVF (n = 64) to those who conceived through in-vivo treatments (n = 63), mean CRL for each group was 51.6 and 50.8 mm, respectively. These results were not significantly different. In the fertile and infertile groups, mean maternal age was 39.0 and 39.7. This difference was small, though statistically significant. No significant differences were found in other parameters when comparing groups. CONCLUSIONS: Pregnancies conceived by infertile couples are not smaller in the late first trimester when compared to spontaneously conceived pregnancies. In addition, there is no difference in the size of pregnancies conceived through ART compared to those from in-vivo treatments. Although ART pregnancies have been associated with low birth weight, this does not appear to be a phenomenon that occurs early in gestation.

Maternal age‐specific fetal loss rates in Down syndrome pregnancies

Pregnancies affected by Down syndrome (DS) have a greater risk of spontaneous fetal loss than those that are unaffected. In this article, we investigate the relationship between maternal age and the risk of spontaneous fetal loss in DS pregnancies. Fetal loss at different maternal ages were estimated by survival analysis using follow-up of 5177 prenatally diagnosed cases. The maternal age effect on loss rate was subsequently confirmed by a re-analysis of published comparisons of the maternal age-specific prevalence of DS at different gestational ages. The average fetal loss rate between the time of chorionic villus sampling (CVS) and term was 32% (95% CI: 26-38), increasing from 23% (95% CI: 16-31) for women aged 25 to 44% (33-56) for women aged 45. The average fetal loss rate between the time of amniocentesis and term was 25% (21-31), increasing from 19% (14-27) to 33% (26-45) across the same age range. The fetal loss rate in DS pregnancies increases with maternal age, and this has consequences when estimating the live birth prevalence of DS in the presence of prenatal diagnosis and termination, and when assessing the performance of prenatal screening techniques.

Fetal gender and sonographic assessment of crown-rump length: implications for multifetal pregnancy reduction.

Fetal size is a common criterion for the selection of an individual fetus to be reduced during multifetal pregnancy reduction. We investigated whether a difference in crown-rump length (CRL) exists between male and female fetuses at 9-13 weeks' gestation. A total of 883 singleton pregnancies was evaluated at the time of chorionic villus sampling. The mean gestational age at the time of intervention was 10.9 weeks. Pregnancies were dated by certain last menstrual period (LMP). Pregnancies with uncertain dating by LMP or with a sonographic difference of gestational age > 1 week compared with LMP were excluded, as were all cases with chromosomal abnormalities. CRL differences between male and female fetuses were compared using Student's t-test. A total of 417 female and 466 male fetuses fulfilled our study criteria. Their gestational ages ranged between 9.3 and 13.9 weeks. We found no significant difference in size between the male and female fetuses. Using the CRL to guide multifetal pregnancy reduction should not result in a clinically significant selection of either gender.

Screening for aneuploidy in twin pregnancies: maternal age- and race-specific risk assessment between 9-14 weeks.

The aim of this study was to calculate the risk for aneuploidy in twin pregnancies between 9-14 weeks utilizing maternal age, race and dizygotic twinning rates. Using previously published risks for aneuploidy in singletons and twins at the time of amniocentesis and at term, we calculated new risk estimates for twins at 9-14 weeks gestation or at the time of chorionic villus sampling. Using these tables, the risk for trisomy 21 in at least one fetus of a twin gestation in a 32-year-old at 9-14 weeks is 1/285 for Whites and for African-Americans. This is equivalent to the risk for trisomy 21 (1/265) in a 35-year-old woman with a singleton at the same gestational age. The risks for trisomies 18 and 13 also follow similar trends. In counseling women with twin pregnancies at the time of first trimester nuchal translucency screening or chorionic villus sampling, it should be noted that the maternal age-related risk for aneuploidy for a 32-year-old is equivalent to that of a 35-year-old woman with a singleton gestation.

Screening for Aneuploidy in Twin Pregnancies: Maternal Age- and Race-specific Risk Assessment Between 9–14 Weeks

The aim of this study was to calculate the risk for aneuploidy in twin pregnancies between 9–14 weeks utilizing maternal age, race and dizygotic twinning rates. Using previously published risks for aneuploidy in singletons and twins at the time of amniocentesis and at term, we calculated new risk estimates for twins at 9–14 weeks gestation or at the time of chorionic villus sampling. Using these tables, the risk for trisomy 21 in at least one fetus of a twin gestation in a 32-year-old at 9–14 weeks is 1/285 for Whites and for African- Americans. This is equivalent to the risk for trisomy 21 (1/265) in a 35-year-old woman with a singleton at the same gestational age. The risks for trisomies 18 and 13 also follow similar trends. In counseling women with twin pregnancies at the time of first trimester nuchal translucency screening or chorionic villus sampling, it should be noted that the maternal age-related risk for aneuploidy for a 32-year-old is equivalent to that of a 35-year-old woman with a singleton gestation.

Does chorionic villus sampling (CVS) influence fetal growth?

Purpose: To examine the relationship between CVS and birth weight.Methods: A cohort of singleton pregnancies with CVS carried out in Denmark (n = 19737) was compared to the total population of singleton pregnancies without AC (amniocentesis) or CVS (n = 873254) for infants born in the years between 1980 and 1996. Exclusion criteria were multiple pregnancies, infants with malformations, chromosomal abnormalities, stillbirths, and death within the first living year. The pregnancies with CVS were grouped according to gestational age (8–12th week of gestation) at the time of CVS, and mean birth weight was calculated for each group. Maternal age, parity and previous abortions were taken into account when comparing mean birth weights. To exclude social status as a confounder, the overall mean birth weight (pregnancies without CVS or AC) was also compared to the mean birth weight of a subgroup of infants (also without CVS or AC) born to women who undergo CVS in some other pregnancy.Results: The mean birth weight of the CVS cohort was found to be significantly higher than that of the total population and inversely related to the gestational age at CVS.Conclusion: The invasive procedure seems to stimulate growth. No known potential cofounders can explain the higher birth weight after pregnancies with CVS.

Significance of chromosome 22q11 analysis after detection of an increased first-trimester nuchal translucency.

To determine the value of performing routine fluorescent in situ hybridization (FISH) for microdeletions of chromosome 22q11 when karyotyping fetuses with increased nuchal translucency. This was a prospective observational study carried out over an 18-month period. Fetal karyotyping by chorionic villus sampling was offered to 5429 women attending for a routine booking scan in the first trimester when their nuchal translucency adjusted risk for Down syndrome was > or = 1 in 300. Cytogenetic samples were routinely tested for the 22q11 microdeletion when the nuchal translucency was > or = 3 mm. The prevalence of increased nuchal translucency > or = 2.5 mm was 180 (3.3%) and > or = 3.5 mm was 42 (0.8%). None of 75 fetuses with an increased nuchal translucency and normal karyotype demonstrated a 22q11 microdeletion on FISH analysis. In the same cohort, 3 of 20 (15%) cases of major congenital heart defects in which nuchal translucency was measured, had a nuchal translucency measurement > or = 2.5 mm. Routine FISH analysis for chromosome 22q11 microdeletions at the time of chorionic villus sampling for increased first-trimester nuchal translucency is of limited value. As a significant proportion of fetuses with increased nuchal translucency will be found to have congenital heart defects later in the pregnancy, FISH analysis for chromosome 22q11 microdeletions can be targeted to fetuses with specific congenital heart defects. Tissue from the chorionic villus sampling should therefore be stored for subsequent analysis, until after detailed echocardiography is performed.

A meta-analysis of case-control and cohort studies with interval-censored exposure data: application to chorionic villus sampling.

Chorionic villus sampling (CVS) is a valued method of prenatal diagnosis that is often preferred over amniocentesis because it can be performed earlier, but which has also raised concern over a possible association with increased risk of terminal transverse limb deficiency (TTLD). We present and apply a meta-analytic method for estimating a combined dose-response effect from a series of case-control and cohort studies in which the exposure variable is interval-censored. Assuming coarsening at random for the interval-censoring, and calling upon the familiar result of Cornfield to pool case-control and cohort information on the association between a rare binary outcome and a multilevel exposure variable, we form a likelihood-based model to assess the effect of gestational age at the time of CVS on the presence or absence of a rare birth defect. Effect estimates are computed with a variant of the EM algorithm termed the method of weights, which enables the use of standard weighted regression software. Our findings suggest that CVS exposure at early gestational age leads to an increased risk of TTLD.

Improved Specificity of NRBC Detection in Chorionic Villus Sample Supernatant Fluids Using Anti-Zeta and Anti-Epsilon Monoclonal Antibodies

Objective: Fetal erythrocytes leak from fetal capillaries at the time of chorionic villus sampling (CVS). It has been reported that in approximately 60% of CVS cases fetal nucleated red blood cells (NRBC) can be isolated from the supernatant fluid by immunophenotyping with monoclonal antibody (Ab) against the γ-chain of fetal hemoglobin and used as an additional source for confirmation of the fetal karyotype. However, the increased prevalence of β-thalassemia mutations in countries such as Greece results in many pregnant women who produce γ-positive cells. This makes it difficult to distinguish between the fetal and maternal origin of the NRBC. Use of Abs against embryonic hemoglobin chains ζ and ε may increase specificity for fetal NRBC detection. Methods: Mouse monoclonal Abs against Hb-ζ and Hb-ε were used in order to examine if specificity for fetal NRBC detection in CVS supernatant fluids could be improved. 41 samples were studied using anti-ζ and 20 using anti-ε monoclonal Abs. Results: Anti-ζ or anti-ε positive erythrocytes were, respectively, identified in 52 of 61 CVS samples and anti-ζ or anti-ε positive NRBC were present in all cases. The mean number of Hb-positive erythrocytes identified with the anti-ζ Ab was 58 and the mean number of NRBC 29. The mean number of anti-ε positive erythrocytes was 30 and of NRBC 23. FISH with X and Y chromosome specific probes was performed in 26 cases and the results were concordant with the CVS karyotype. Statistical analysis using the correlation test showed that anti-ζ and anti-ε were more specific for the detection of embryonic NRBCs. Conclusions: Since embryonic monoclonal Abs show increased specificity, they should be preferentially used for NRBC detection in CVS supernatant fluids. Furthermore, the increased specificity of anti-ζ and anti-ε Abs may considerably improve prenatal diagnosis from fetal cells isolated from maternal circulation.

Maternal serum S100 protein in normal and Down syndrome pregnancies

Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of which is coded for at the 22.2-22.3 region of the long arm of chromosome 21. This region has also been shown to be responsible for the phenotypic expression of Down syndrome. Previous studies demonstrated increased immunoreactivity to protein S100 in brain tissue from adults with Down syndrome. We have previously observed a higher concentration of S100 protein in the fetal blood of trisomy 21 fetuses compared with normal subjects. The aim of this study was therefore to investigate the use of measuring S100 protein concentration in maternal blood for Down syndrome screening. Maternal blood was taken at the time of chorionic villus sampling or cordocentesis (11-38 weeks' gestation) for fetal karyotyping. Protein S100 was measured by a two-site immunoradiometric assay (S-100 IRMA, Sangtec). There was no significant difference in the concentration of maternal S100 protein between normal and trisomy 21 pregnancies (p<0.10). Moreover, there was no significant association between maternal serum S100 protein concentration and gestational age (r(s)=0.27, p=0.07), maternal age (r(s)=-0.17, p=0.7) or maternal weight (r(s)=-0.013, p=0.9). This study shows that measurement of maternal serum S100 protein concentration does not appear to have a value in Down syndrome screening.

Fetal loss in Down syndrome pregnancies

It is recognized that pregnancies with Down syndrome are liable to end in spontaneous fetal loss. It is important to determine the magnitude of this effect so that it can be taken into account when assessing the results of antenatal screening programmes for Down syndrome. Failure to do so will tend to overestimate the detection rate in intervention studies in which the screening results are used to identify women for a diagnostic test and the offer of a termination of pregnancy if indicated. We present new data on the spontaneous fetal loss in Down syndrome pregnancies from the National Down Syndrome Cytogenetic Register (1989-1996). We compare our results with published results of other studies on the subject to obtain a summary estimate. We exclude one study from the meta analysis due to incorrect methodology resulting in an overestimate of fetal loss. Based on the combined data (i) between the time of chorionic villus sampling and term an estimated 43 per cent (95 per cent CI: 31-54 per cent) of pregnancies ended in a miscarriage or still birth, (ii) between the time of amniocentesis and term an estimated 23 per cent (95 per cent CI: 19 28 per cent) of pregnancies ended in a miscarriage or still birth, and (iii) 12 per cent (95 per cent CI: 2-23 per cent) of births were stillborn or resulted in a neonatal death.

Estimating the spontaneous loss of Down syndrome fetuses between the times of chorionic villus sampling, amniocentesis and livebirth

Recent publications concerning the prevalence of Down syndrome at times of chorionic villus sampling (CVS), amniocentesis and livebirth were reviewed with particular interest in estimates of spontaneous loss of Down syndrome fetuses during pregnancy. Data from several studies were combined to provide information on 258 206 pregnancies. A logistic regression was applied to provide new estimates and confidence intervals (CIs) for spontaneous loss rates between the time of CVS and livebirth (estimate=39 per cent; 90 per cent CI 32 to 45 per cent), and the time of amniocentesis and livebirth (estimate=12 per cent; 90 per cent CI 5 to 18 per cent). Copyright © 1998 John Wiley & Sons, Ltd.

Estimating the spontaneous loss of Down syndrome fetuses between the times of chorionic villus sampling, amniocentesis and livebirth

Recent publications concerning the prevalence of Down syndrome at times of chorionic villus sampling (CVS), amniocentesis and livebirth were reviewed with particular interest in estimates of spontaneous loss of Down syndrome fetuses during pregnancy. Data from several studies were combined to provide information on 258,206 pregnancies. A logistic regression was applied to provide new estimates and confidence intervals (CIs) for spontaneous loss rates between the time of CVS and livebirth (estimate = 39 per cent; 90 per cent CI 32 to 45 per cent), and the time of amniocentesis and livebirth (estimate = 12 per cent; 90 per cent CI 5 to 18 per cent).

Incidence and outcome of chromosomal mosaicism found at the time of chorionic villus sampling

OBJECTIVE: Chromosomal mosaicism has been reported in about 1% to 3% of chorionic villus sampling specimens. This report provides incidence and outcome information that should be useful in counseling patients found to have mosaicism on chorionic villus sampling. STUDY DESIGN: A retrospective analysis of 11,200 consecutive patients undergoing chorionic villus sampling at the University of California, San Francisco, during the period from Jan. 1, 1984, to June 1, 1996, was undertaken. RESULTS: A total of 140 cases of mosaicism were identified for an incidence of 1.3%. Follow-up information was available for 130 cases, 26 of which (20%) were confirmed in fetal tissue. Confirmation rates for specific types of mosaicism were as follows: autosomal trisomy 7.6%, sex chromosome 25%, structural abnormality 27.3%, and marker chromosome 77.8%. Neonatal outcome was normal in all cases for which pregnancy continued. CONCLUSION: The data indicate that in most cases of chromosomal mosaicism found by chorionic villus sampling the mosaicism is unlikely to be clinically significant in the fetus. (Am J Obstet Gynecol 1997;176:1349-53.)

Selective miscarriage of Down's syndrome fetuses in women aged 35 years and older.

To estimate the fetal loss of Down's syndrome fetuses between the time of chorionic villus sampling (10 weeks gestation) and the time of amniocentesis (16 weeks gestation) and term in women aged 35 years and older. The age specific prevalence rates in the first trimester of Down's syndrome were estimated using the Danish cytogenetic register in combination with results from four published studies. These were compared with the reported prevalence at the time of amniocentesis and at birth. 5927 singleton pregnancies undergoing chorionic villus sampling (71 cases of Down's syndrome and 5856 unaffected cases). This was combined with published data on a further 231 cases of Down's syndrome and 16,620 unaffected cases. Age specific prevalences at the time of chorionic villus sampling. Proportion of pregnancies lost between the time of chorionic villus sampling and the time of amniocentesis and term. Thirty-two percent of Down's syndrome pregnancies are lost between the time of chorionic villus sampling (10 weeks) and the time of amniocentesis (16 weeks) and 54% are lost by term. The high fetal loss rates of Down's syndrome between the time of chorionic villus sampling and term introduce problems when evaluating first trimester screening tests with respect to their effective detection rates at term. A recommendation for quoting term risks is made.

New estimates of Down syndrome risks at chorionic villus sampling, amniocentesis, and livebirth in women of advanced maternal age from a uniquely defined population.

Current measures of livebirth prevalence of Down syndrome are derived from data obtained up to 20 years ago, before the introduction of the prenatal diagnostic tests amniocentesis and chorionic villus sampling (CVS). For women aged 36-52 years, but who were not tested prenatally, we proposed to make a direct estimate of current livebirth prevalence of Down syndrome. We could also determine prevalence at the time of CVS and amniocentesis in women of the same age undergoing prenatal testing. Differences in these prevalences allow an estimation of the relative loss of Down syndrome during pregnancy. In Victoria, Australia, we identified 3041 women having CVS, 7504 having amniocentesis, and 13,139 having no test. Smoothed regression estimates of age-specific livebirth prevalence were found to be higher than in the early studies. The estimate of spontaneous loss was 17 per cent between the time of CVS and amniocentesis, and 18 per cent after the time of amniocentesis. The latter figure is lower than previous estimates and may be explained by a greater likelihood of a Down syndrome fetus surviving to be liveborn, given the modern approach to early obstetric intervention. These current risk estimates of livebirth may be useful updates for genetic counselling, but perhaps more importantly, may be used as precise maternal age-related risk figures, necessary in the design and implementation of prenatal screening programmes for Down syndrome.