First trimester Down syndrome screening: public health implications

Down syndrome (DS) screening has been an integral part of routine prenatal screening for the last three decades. Recent efforts have been directed at developing additional non-invasive prenatal screening techniques that could not only improve sensitivity of prenatal screening, but also be employed in the first trimester to offer earlier diagnostic and interventional opportunities. Nuchal translucency has proven to be an effective and cost-effective screening test that, when combined with serum markers (hCG and pregnancy-associated plasma protein [PAPP-A]) in the first and/or second trimester, broadens the diagnostic possibilities and improves the diagnostic capabilities of current prenatal DS screening methods. Despite the potential benefits, significant operational issues regarding access to and availability of such testing may limit its widespread application and necessitates the maintenance of both non-sonographic and second trimester screening methods. The implementation of first trimester DS testing requires the development and maintenance of nationally standardized quality control systems to ensure the reliability of serum and ultrasound measurements and the accurate assessment of risk. Future efforts to improve prenatal screening should continue to emphasize the need for improved access to all aspects of prenatal care, stress the importance of provider education and the necessity for extensive patient counseling, and reinforce the role of patient education and choice.     

First trimester screening for Down syndrome in multiple pregnancy

The incidence of twins, triplets, and high-order multiples has increased substantially in the last two decades secondary to fertility treatments and to delayed childbearing. Prenatal diagnosis in these patients is challenging. Options for screening tests are limited. First trimester screening for Down syndrome in patients with multiples appears promising. This paper will review the advantages of first trimester screening in this high-risk patient population.     

First trimester screening for Down syndrome in rhesus negative women

OBJECTIVES: To explore the effect of maternal rhesus status on first-trimester screening markers for Down syndrome. METHODS: We accessed a database of singleton pregnancies undergoing first-trimester genetic screen with maternal Rh status documented and pregnancy outcome information available. Excluded were cases of fetal chromosomal or structural abnormalities, or maternal systemic disease. Results of maternal serum pregnancy-associated plasma protein A (PAPP-A) and beta-human chorionic gonadotrophin (beta-hCG) adjusted for gestational age were compared between Rh-negative and Rh-positive women with p < 0.05 considered significant. RESULTS: Two thousand two hundred and two pregnancies fulfilled the study criteria, and 160 of them (7%) were Rh negative. Only free beta-hCG corrected multiples of the median (MoM) values were statistically increased in Rh-negative women (p < 0.009). Using a cut-off of 1:300, screen-positive rates of maternal serum biochemistry were not significantly different between Rh-negative and Rh-positive women (12.5 vs 10.4%, p = 0.41). CONCLUSION: The present study focused on measurements of beta-hCG and PAPP-A in the sera of women with Rh-negative blood group. Women with Rh-negative blood type have similar first-trimester serum PAPP-A MoM values as Rh-positive women, but significantly higher beta-hCG MoM values. However, there was no significant difference in the screen-positive rate for Down syndrome between the two groups.     

Medically assisted reproduction and second-trimester maternal serum marker screening for Down syndrome

OBJECTIVES: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on total hCG, free ss-hCG, AFP and unconjugated estriol (uE3) used as markers for second-trimester Down syndrome maternal serum screening. METHODS: Second-trimester maternal sera from 1515 singleton pregnancies (970 by IVF, 545 by ICSI) were compared with control sera (21 014 cases). Free ss-hCG, total hCG, AFP and uE3 were compared between the control group and the medically assisted reproduction groups. The percentages of at-risk patients (>/=1/250) were also compared. RESULTS: No differences in values of the maternal serum markers were observed between the medically assisted and control groups. When maternal age was taken into account, the screen-positive rate for Down syndrome screening did not differ between the two groups. CONCLUSION: Patients undergoing assisted reproduction techniques can be counseled for maternal serum Down syndrome screening with the same efficacy as patients with naturally conceived pregnancies.     

First trimester genetic sonogram for screening fetal Down syndrome: A population-based study

ObjectiveTo evaluate the performance of first trimester sonomarkers in the detection of fetal Down syndrome among Thai pregnant women.Materials and methodsPregnant women at 11–13⁺⁶ weeks’ gestation underwent ultrasound examination for assessment of nuchal translucency (NT), nasal bone (NB), tricuspid regurgitation (TR), and abnormal ductus venosus (aDV) Doppler waveforms. The women were followed up for final outcomes. Fetal abnormalities other than trisomy 21 were excluded. The performances of each sonomarker and their combinations in predicting fetal Down syndrome were calculated.ResultsA total of 7820 pregnant women meeting the inclusion criteria were available for analysis, including 20 cases with fetal Down syndrome and 7800 unaffected cases. Of the four sonomarkers, NT, as a single sonomarker, had the highest detection rate (55.0% at a false positive rate of about 5%), whereas the remaining single sonomarkers had low detection rate (15–20%). The combination of all sonomarkers had the highest detection rate of 70% but the false positive rate was as high as 10.8%. The combination of NT and NB had a detection rate of 60% with an acceptable false positive rate of 6.9%, whereas the other combinations yielded relatively high false positive rates.ConclusionThe first trimester genetic sonogram in screening for Down syndrome among Asian women is acceptably effective and may be offered to some selected groups of the population. NT is the best sonomarker with a detection rate of 55% at 5% false positive rate and its combination with NB can improve performance with minimal increase in false positive rate.     

First trimester biochemical screening for Down syndrome: free beta hCG versus intact hCG

To compare free beta hCG versus intact hCG in first trimester Down syndrome screening we analysed 63 cases of Down syndrome and 400 unaffected control pregnancies between 10 and 13 weeks' gestation. The Down syndrome median multiple of the median (MoM) was significantly higher (p=0.001) for free beta hCG (1.89 MoM) than for intact hCG (1.37 MoM). Although distributions for free beta hCG (unaffected, 0.2157; DS, 0.2322) are wider than for intact hCG (unaffected, 0.1697; DS, 0.2158), overall 27% of Down syndrome cases were above the 95th percentile for free beta hCG compared to 19% for intact hCG. Combined with maternal age, free beta hCG detected 45% of Down syndrome pregnancies at a 5% false positive rate. Intact hCG combined with maternal age demonstrated a detection efficiency comparable to maternal age alone (35% versus 32%). In contrast, a recent study (Haddow et al., 1998-NEJM 338: 955-961) indicated that intact hCG yielded a higher first trimester Down syndrome detection efficiency than free beta hCG (29% versus 25% respectively). Re-analysis of distribution parameters in the Haddow et al. study, however, show that free beta hCG was actually the better marker (23% detection for intact hCG versus 29% for free beta hCG).     

Current concepts of Down syndrome screening tests in assisted reproduction twin pregnancies: another double trouble

Assisted reproductive technologies (ART) have increased both the number of pregnancies in women beyond the age of 35 and the incidence of multiple pregnancies. Various methods of screening for Down syndrome (DS) were introduced in clinical practice during the last two decades, and specific problems were encountered when they were applied for twin pregnancies. The current review aims to explore the problematic issue of prenatal DS screening in ART twins. Overall, more women with twin pregnancies (mainly those who conceived via assisted reproduction) are found to be false positive for DS. This is because mid-trimester maternal serum screening is associated with a higher false-positive rate secondary to changes in the feto-placental endocrinologic metabolism, reflected mainly in high human chorionic gonadotrophin (hCG) levels in the ART pregnancies. First-trimester nuchal translucency (NT) measurement in twin pregnancies is not affected by the problems encountered in serum screening. This sonographic screening approach enables a fetus-specific identification of those fetuses at high risk of DS and is associated with a lower false-positive rate than mid-trimester serum screening. DS screening in ART twins presents several challenges in determining the most appropriate screening test modality. Whether there is any significant benefit of adding first-trimester biochemistry or nasal bone scanning in screening ART-conceived twins awaits further investigation.     

First trimester screening with free beta-hCG,PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction

OBJECTIVE: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT). METHODS: First trimester maternal dried whole blood specimens from 74 singleton pregnancies (32 by IVF and 42 by ICSI) and 30 twin pregnancies (16 by IVF and 14 by ICSI) in which conception was achieved with assisted reproduction techniques were matched with five controls resulting in 370 singleton controls and 150 twin controls. NT was measured using the Fetal Medicine Foundation protocol. Free beta-hCG, PAPP-A and NT levels were compared between the IVF and control groups and between the ICSI and control groups using the Mann-Whitney U test. RESULTS: In singleton pregnancies, the only significant difference was a 21% (95% CI: -35%--7%) reduction in PAPP-A in IVF cases. In twin pregnancies, the only significant difference was a 12% (95% CI: -34%--3%) reduction in NT in IVF cases. In singleton pregnancies, the false-positive rate for Down syndrome screening was 1.4% and 1.9% greater for the IVF and ICSI groups, respectively, compared to controls for a general screening population. CONCLUSIONS: Patients undergoing assisted reproduction techniques should be counseled about the possibility of increased false-positive rates. Larger studies are needed to confirm this observation and to develop appropriate adjustment factors to reduce false-positive rates.     

First trimester screening for Down syndrome using free beta hCG, total hCG and PAPP-A: an exploratory study

OBJECTIVE: To investigate the potential utility of first trimester screening for Down syndrome using Free beta-hCG, total hCG and PAPP-A. MATERIALS AND METHODS: Using estimates from the literature, a simulation study was undertaken to estimate the performance of tests incorporating, Free beta-hCG, total hCG and PAPP-A at gestations of 8-12 weeks. We used sensitivity analysis to assess the effect of departures from the assumed model. RESULTS: We estimate that detection rates in excess of 75% for a false positive rate (FPR) of 3% can be achieved with first trimester measures of PAPP-A, total hCG and Free beta-hCG at 8 weeks-the addition of total hCG adding 11%. Detection rates of around 90% for a FPR of 3% can be achieved through the inclusion of nuchal translucency (NT) at 12 weeks to these early first trimester biochemical markers. Our analysis indicates that the marginal benefit of adding total hCG diminishes rapidly with gestational age and that there is little benefit from adding total hCG later than 10 weeks of gestation. CONCLUSION: The performance of first trimester screening using early combinations of total hCG, Free beta-hCG and PAPP-A should be assessed in further studies.     

First trimester screening for preeclampsia

PURPOSE OF REVIEW: Aspirin therapy from the first trimester of pregnancy may benefit women at high risk for preeclampsia. We review publications from the past year that examine first-trimester screening studies for preeclampsia. RECENT FINDINGS: For a false positive rate of 5%, first-trimester uterine artery Doppler studies will detect 50-65% of women who will develop severe preeclampsia (i.e. needing delivery before 35 weeks). Measurement of placental volume with three-dimensional ultrasound at 11-14 weeks detected 20% for a false positive rate of 10% in one study and further evaluation of this technique is needed. Maternal serum placental growth factor, vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 have shown initial promise, but recent studies have shown no improvement in screening compared with using uterine artery Doppler alone. Placental protein 13 is the most promising serum marker and in combination with uterine Doppler may predict up to 90% of cases of severe preeclampsia for a false positive rate of 9%. SUMMARY: First-trimester uterine artery Doppler can identify over half of women who will develop preeclampsia. Detection rates may be increased by a combination of uterine artery Doppler with first-trimester maternal serum markers, especially placental protein 13. Such high-risk women may be the most likely to benefit from pharmacological intervention in future trials.     

First trimester screening

Screening for aneuploidy has traditionally been reserved for women of advanced maternal age. More recent advances in serum screening and ultrasound technology have allowed women of all ages to be offered screening in the second and even first trimester. These methods and their effectiveness are discussed.     

Gender impact on first trimester markers in Down syndrome screening

The influence of fetal gender on the level in the first trimester of the serological markers alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (betahCG) and on nuchal translucency is described for 2637 singleton pregnancies with normal outcome. Mean log MoM values for pregnancies with female and male fetuses were calculated using regression of log marker values on gestational age expressed as crown rump length and on maternal weight. A pronounced gender impact was found for free betahCG, being 16% higher for female than for male fetuses.     

First trimester screening: economic implications

The implementation of new strategies for the detection of Down syndrome will have economic implications. These economic considerations must be considered before implementation, since resources are limited and health care costs in the Unites States are soaring. Economic analyses of prenatal diagnosis have unique challenges that must be considered. Most analyses include only direct medical costs, ignoring indirect and intangible costs.     

First trimester screening for fetal abnormalities

The debate over the application of nuchal translucency measurement in Down's syndrome screening is still unresolved in some clinicians' minds. Although different authors report a range of sensitivities for Down's syndrome, none question the validity of the association between increased nuchal translucency and fetal aneuploidy. The published literature reveals a lack of congruence over a standard, reproducible method for measuring nuchal translucency. Only with the adoption of uniform methodology, and the establishment of international standards for nuchal translucency measurement, is the true potential of this test likely to be realized. The increasing use of first trimester ultrasound has focused attention on the value of this investigation in confirming fetal viability, estimation of gestational age, and screening for congenital abnormality. This review summarizes the role of ultrasound and maternal serum biochemistry in first trimester screening.