First trimester aneuploidy screening combining biochemical and ultrasound markers

The different strategies applied for Down syndrome (DS) screening in a single center are presented and the results are analyzed taking into account the number of invasive procedures needed for the diagnosis of one affected pregnancy. The use of advanced maternal age as a single criterion, from 1980 to 1992 proved to be poorly effective since 102 amniocentesis are needed to diagnose one DS affected pregnancy (1:102) or 52 to diagnose any aneuploidy (1:52) With the use of second trimester screening with serum markers (AFP and hCG) at 14-18 weeks in 8711 women less than 38 years, from 1993 to 1999 the ratios were improved to 1:82 and 1:47 respectively. With the introduction of the combined test in 1999 using free hCG, PAPP-A (sampling at 9-10 weeks) and NT (measured at 12 weeks) in 3644 women under 38 years, and gestational weeks adjusted by US in 3644 singleton pregnancies with complete follow-up, the ratios were substantially improved to 1:16 procedures for DS or 1:8 for any aneuploidy. The detection rate achieved was 90% for a false positive rate of 3.4%. Comparing the different strategies applied in our Unit it is clear that the combined test applied in the first trimester provides a substantial improvement in detection rates and reduction of unnecessary invasive testing.     

First trimester screening for aneuploidy: Serum biochemical markers

The article reviews screening for Down syndrome in the first trimester (8-13 gestational weeks) with maternal serum analytes. In the first trimester, 2 serum markers stand out: pregnancy-associated plasma protein-A, a large glycoprotein tetramer, and free beta-human chorionic gonadotropin (beta-hCG), 1 of the 2 subunits of the glycoprotein hormone hCG. Some data indicate that hCG itself may be as effective as free beta-hCG in the first trimester. Maternal serum levels of pregnancy-associated plasma protein-A are low and free beta-hCG are high (consensus multiple of the medians, 0.4 and 1.8, respectively) in Down syndrome pregnancy. The consensus estimate of screening performance by using pregnancy-associated plasma protein-A and free beta-hCG in combination with maternal age is 60% detection rate at a 5% false positive rate. This is similar to the screening performance of second trimester double markers, but not as good as the screening performance of second trimester triple or quad markers. For this reason, first trimester screening with serum markers alone cannot be recommended except in cases in which second trimester screening cannot be done.     

First trimester screening for aneuploidy: Nuchal translucency sonography

Prenatal diagnosis of fetal aneuploidy is a continuously and rapidly evolving area of research. Currently in the United States, the standard of care for screening pregnancies for aneuploidy involves assessment of maternal age together with the use of multiple second trimester maternal serum markers. This screening approach identifies approximately 60% of pregnancies with fetuses affected with Down syndrome and provides results in the second trimester of pregnancy. First trimester screening for aneuploidy by using nuchal translucency sonography is one of the most promising areas of research in the detection of Down syndrome. This screening method involves measuring the normal space located between the cervical spine and overlying fetal skin at 10 to 14 weeks' gestation. Studies from both high risk and unselected patient populations suggest significant advantages to this approach for Down syndrome detection compared with currently available second trimester screening methods. The combination of first trimester biochemical screening and nuchal translucency measurements may further improve the efficacy of prenatal screening for aneuploidy. The article reviews studies suggesting a role for nuchal-translucency-based aneuploidy screening and describes areas of ongoing research in this field.     

First trimester PAPP-A MoM values predictive for breech presentation at term of pregnancy

Abstract

Introduction: Our aim was to state the role of first trimester pregnancy-associated plasma protein A (PAPP-A)-multiple of the median (MoM) value as a predictor for breech presentation at term of pregnancy.

Materials and methods: In this retrospective study, we present data for 1100 singleton full-term deliveries that took place in a third-level hospital setting in northeast Italy between January 2004 and July 2007. For each case, PAPP-A, free beta-human chorionic gonadotropin and nuchal translucency were measured during prenatal trisomies screening (between 11 weeks and 13 weeks and 6?d). A wide range of predictive factors for breech presentation at term of pregnancy and other confounding elements were considered.

Results: Of the 1100 singleton deliveries at term considered in our study, 40 babies were in breech presentation. Using bivariate analysis and multivariate logistic regression, a lower PAPP-A MoM than 0.63 (first quartile of our distribution) in the first trimester (OR 2.41, CI.95 1.25–4.67), and placental index at term higher than the median value (OR 2.04, CI.95 1.00–4.17) were proven to be associated with breech presentation at term.

Conclusions: A low PAPP-A during the first trimester was a predictive factor for breech presentation at term of pregnancy. Acknowledging and acting on this predictor could enable improved management of breech foetuses in the future.     

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 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.     

Second trimester markers of aneuploidy.

The risks of aneuploidy associated with identification of a sonographic marker in the low risk population is controversial. Prior risk estimates have been derived usually from high risk populations. Screening programmes in the first trimester, second trimester and combined first and second trimester will undoubtedly alter the second trimester scan as a screening tool for aneuploidy. This chapter reviews the current sonographic markers and the difficulties in their application to the general population.     

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's syndrome using maternal serum PAPP-A and free β=hCG in combination with fetal nuchal translucency thickness

The aim of this study was to evaluate the potential effectiveness of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free β-hCG in combination with nuchal translucency thickness in first trimester screening for Down's syndrome. Maternal serum levels of PAPP-A and free β-hCG were assayed in stored sera from 32 Down's syndrome and 200 unaffected pregnancies. Fetal nuchal translucency was measured by ultrasound at the time of blood sampling. Screening of Down's syndrome using a combination of maternal age, PAPP-A, free β-hCG and nuchal translucency would achieve a detection rate of 75.8% for a false positive rate of 5%.     

First trimester ultrasound diagnosis of lethal multiple pterygium syndrome

OBJECTIVE: Diagnosis of lethal multiple pterygium syndrome in the first trimester of pregnancy. METHODS: A 38-year-old woman attended our ultrasound (US) clinic at 11.2 weeks gestation. She has had two previous stillbirths affected by lethal multiple pterygium syndrome. Transabdominal and transvaginal US were performed and identified a recurrence. Autopsy findings are compared to the fetal US findings. RESULTS: Fetal US showed a markedly increased nuchal translucency, fixed flexion deformities of the elbows and knees bilaterally, cutaneous webs across both elbow joints and absent fetal movements. The patient decided to terminate the pregnancy and a D&C was performed. Pathology of intact fetal parts showed flexion deformity of the right elbow with a cutaneous web, and ulnar deviation of the right wrist. CONCLUSION: Increased nuchal translucency, absent limb movements, multiple joint contractures and cutaneous webs on US allowed the diagnosis of lethal multiple pterygium syndromes in the first trimester of pregnancy.     

First and second trimester evaluation of risk for fetal aneuploidy: the secondary outcomes of the FASTER Trial

The FASTER Trial was a multicenter National Institute of Child Health and Human Development sponsored study of Down syndrome screening in a large unselected obstetric population using first and second trimester maternal serum markers and first trimester nuchal translucency sonography. The following paper will describe the FASTER Trial. It will review the outcomes of pregnancies complicated by cystic hygroma and the FASTER Trial's findings regarding first trimester nasal bone ultrasonography and screening for aneuploidy. Although the study's first and foremost goal was to compare various first and second trimester methods of screening for Down syndrome, the FASTER Trial has revealed a wealth of information not only on screening for aneuploidy but also on other obstetric issues.     

Pregnancy outcome in the setting of extremely low first trimester PAPP-A levels

Background: Serum pregnancy-associated plasma protein-A (PAPP-A) is part of first trimester Down syndrome screening. Low levels have been associated with adverse outcome as well as chromosomal abnormality.
Aims: To assess the incidence of adverse outcome when PAPP-A levels are at or below 0.2 multiples of the median (MoM).
Methods: Data on consecutive patients attending a first trimester screening program were collected. Those with PAPP-A levels ≤ 0.2 MoM were divided into three groups: ≤ 0.1 MoM; 0.11–0.15 MoM; and 0.16–0.2 MoM.
Results: Screening 44 535 patients resulted in 197 with PAPP-A levels ≤ 0.2 MoM. The incidence of karyotypic abnormality increased with decreasing PAPP-A levels. In the absence of chromosome abnormality, pregnancy outcomes were defined as 'normal' in at least 30% and 'good' in at least 60%, with both percentages increasing as the PAPP-A level rose. The PAPP-A levels were significantly lower in the group with a poor outcome. The incidence of prematurity was similar in the three groups, but higher than the statewide average, while the incidence of extreme prematurity appeared to be related to reducing PAPP-A levels. The incidence of growth restriction in the three groups was similar, but was still double the incidence in the normal population.
Conclusion: If the PAPP-A level is ≤ 0.2 MoM and the karyotype is normal, there is an increased risk of adverse outcome. Even with PAPP-A below 0.1 MoM, a good outcome can be expected in 60% of cases. Careful morphological assessment is suggested and later monitoring of fetal growth and well-being.     

Application of ductus venosus Doppler velocimetry for the detection of fetal aneuploidy in the first trimester of pregnancy

OBJECTIVE: To test the hypothesis the application of ductus venosus Doppler velocimetry may serve as a screening tool between 10 and 14 weeks' gestation for the detection of fetuses with chromosomal abnormalities. METHODS: 372 consecutive fetuses were studied. Based on prior study, a chromosomal abnormality was suspected when either the nuchal translucency was above the 95th centile, or there was reversed or absent flow in the ductus venosus during atrial contraction. Sensitivity, specificity, and the negative and positive predictive values were calculated. RESULTS: There were 29 chromosomally abnormal fetuses. Of these 29 fetuses, ductus venosus blood flow during atrial contraction was either absent (n = 2) or reversed (n = 25) in 93.1%. In the chromosomally normal fetuses (n = 343), only 6 (1.7%) had abnormal Doppler profiles in the ductus venosus (specificity = 98.3%, positive and negative predictive values = 81.8% and 99.4%, respectively). CONCLUSION: The Doppler waveform of the ductus venosus was at least equal to NT thickness measurement for the detection of chromosomal abnormalities.     

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.