Lyn S. Chitty

First and Second Trimester Antenatal Screening for Down's Syndrome: The Results of the Serum, Urine and Ultrasound Screening Study (SURUSS):

Objectives To identify the most effective, safe and cost-effective method of antenatal screening for Downs syndrome using nuchal translucency (NT), maternal serum and urine markers in the first and second trimesters of pregnancy, and maternal age in various combinations.Design A prospective study of women who booked for their antenatal care at about 8-14 weeks of gestation, with follow-up to identify pregnancies with Downs syndrome ascertained through second trimester screening or at birth.Setting Twenty-five maternity units (24 in the UK and one in Austria) offering second trimester Downs syndrome serum screening that agreed to collect observational data in the first trimester.Participants The results were based on 47,053 singleton pregnancies, including 101 pregnancies with Downs syndrome.Measurements and tests NT measurements were included if obtained between 9 and 13 weeks of pregnancy; serum and urine samples were also taken and stored. Another pair of serum and urine samples was collected in the second trimester and included if obtained between 14 and 20 weeks. Urine and serum samples from each affected pregnancy and five matched controls were tested for:Serum:alphafetoprotein (AFP)total human chorionic gonadotrophin (hCG)unconjugated oestriol (uE(3))pregnancy associated plasma protein A (PAPP-A)free beta-hCG.dimeric inhibin-A.Urine:invasive trophoblast antigen (ITA)beta-core fragmenttotal hCGfree beta-hCG.The matching criteria were gestation (using an ultrasound crown-rump length or biparietal diameter measurement), duration of storage, and centre. Screening performance of the individual markers and combinations of markers together with maternal age was assessed using standard methods. In addition pairs of first and second trimester serum samples from 600 controls were tested to secure a larger set in which screening performance could be determined using distribution parameters based on dates (time since first day of the last menstrual period).Main outcome measures The following were determined for different combinations of markers:efficacy (by assessing screening performance, focusing on the false-positive rate (FPR) for an 85% detection rate (DR))safety (focusing on the number of fetal losses due to amniocentesis (or chorionic villus sampling) in 100,000 women screened)cost-effectiveness (focusing on the cost of screening 100,000 women and the cost per Downs syndrome pregnancy diagnosed).Results Efficacy (screening performance) The false-positive rates for an 85% detection rate for the main screening tests are shown in the above table, in decreasing order of screening performance:With the serum integrated test, 10 weeks is the preferred time in pregnancy for the PAPP-A measurement. For the integrated test and the combined test, the timing of the measurement of the first trimester markers is less critical.Safety The lower false-positive rate with the integrated test compared with other tests means that at an 85% detection rate there would be nine diagnostic procedure-related unaffected fetal losses per 100,000 women screened compared with 44 using the combined test or 45 with the quadruple test.Cost-effectiveness Screening using the integrated test is less costly than might be expected because the extra screening costs tend to be offset by savings in the cost of diagnosis arising from the low false-positive rate. It was estimated that to achieve an 85% detection rate the cost to the UK NHS would be pound15,300 per Downs syndrome pregnancy detected. The corresponding cost using the second trimester quadruple test would be pound16,800 and using the first trimester combined test it would be pound19,000.Conclusions Implications for healthcare The results showed that screening performance in the first trimester of pregnancy was virtually the same as that in the second trimester, and in either it was much less effective than integrating screening measurements from both trimesters into a single test. In applying these results to screening practice several conclusions can be drawn. The following tests offer the most effective and safe method of screening:overall: the integrated testif an NT measurement is not available: the serum integrated testfor women who do not attend for antenatal care until the second trimester of pregnancy: the quadruple testfor women who choose to have a screening test in the first trimester: the combined test.At a constant detection rate, the cost-effectiveness of these four tests is broadly similar, any extra screening costs tending to be offset by fewer diagnostic costs. The evidence presented in this report does not support retaining the double test, the triple test, or NT measurements on their own (with or without maternal age) because each would lead to many more women having invasive diagnostic tests, without increasing the proportion of Downs syndrome pregnancies detected.

Charts of fetal size: 1. Methodology

Objectives To discuss the features of study design and analysis which are necessary to derive valid reference centiles for fetal size. To describe a study which meets the stated criteria.

Effectiveness of routine ultrasonography in detecting fetal structural abnormalities in a low risk population.

OBJECTIVE--To review the efficacy of routine prenatal ultrasonography for detecting fetal structural abnormalities. DESIGN--Retrospective study of the ultrasonographic findings and outcome of all pregnancies in women scanned in 1988-9. SETTING--Maternity ultrasonography department of a district general hospital. SUBJECTS--8785 fetuses. MAIN OUTCOME MEASURES--Correlation of prenatal ultrasonographic findings with outcome in the neonate. RESULTS--8733 babies were born during 1988-9, and 52 pregnancies were terminated after a fetal malformation was identified. 8432 (95%) of the fetuses were examined by ultrasonography in the second trimester. 130 fetuses (1.5%) were found to have an abnormality at birth or after termination of pregnancy, 125 of which had been examined in the second trimester. In 93 cases the abnormality was detected before 24 weeks (sensitivity 74.4%, 95% confidence interval to 66.7% to 82.1%. Two false positive diagnoses occurred, in both cases the pregnancies were not terminated and apparently normal infants were born. This gives a specificity of 99.98% (99.9% to 99.99%). The positive predictive value of ultrasonography in the second trimester was 97.9% (92.6% to 99.7%). Of the 125 abnormalities, 87 were lethal or severely disabling; 72 of the 87 were detected by the routine screening programme (sensitivity 82.8%, 73.2% to 90.0%). CONCLUSION--Routine fetal examination by ultrasonography in a low risk population detects many fetal structural abnormalities but can present several dilemmas in counselling.

CHARTS OF FETAL SIZE .3. ABDOMINAL MEASUREMENTS

Objective To construct new size charts for fetal abdominal circumference and area.

Charts of Fetal Size

For those arriving on the Tuesday evening we are being entertained by the Lady Mayor at a Civic reception in the Town Hall. On Wednesday night we have booked a favourite local band, Hamps Tramps. They play some great R & B and soul and were the unanimous choice of our departmental staff. They will be playing in the Royal Hotel where there will also be a substantial buffet meal with a glass of wine on arrival.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

Non‐invasive prenatal determination of fetal sex: translating research into clinical practice

Hill M, Finning K, Martin P, Hogg J, Meaney C, Norbury G, Daniels G, Chitty LS. Non‐invasive prenatal determination of fetal sex: translating research into clinical practice.

Digital PCR Analysis of Maternal Plasma for Noninvasive Detection of Sickle Cell Anemia

BACKGROUND Cell-free fetal DNA (cffDNA) constitutes approximately 10% of the cell-free DNA in maternal plasma and is a suitable source of fetal genetic material for noninvasive prenatal diagnosis (NIPD). The objective of this study was to determine the feasibility of using digital PCR for NIPD in pregnancies at risk of sickle cell anemia. METHODS Minor-groove binder (MGB) TaqMan probes were designed to discriminate between wild-type hemoglobin A and mutant (hemoglobin S) alleles encoded by the HBB (hemoglobin, beta) gene in cffDNA isolated from maternal plasma samples obtained from pregnancies at risk of sickle cell anemia. The fractional fetal DNA concentration was assessed in male-bearing pregnancies with a digital PCR assay for the Y chromosome-specific marker DYS14. In pregnancies with a female fetus, a panel of biallelic insertion/deletion polymorphism (indel) markers was developed for the quantification of the fetal DNA fraction. We used digital real-time PCR to analyze the dosage of the variant encoding hemoglobin S relative to that encoding wild-type hemoglobin A. RESULTS The sickle cell genotype was correctly determined in 82% (37 of 45) of male fetuses and 75% (15 of 20) of female fetuses. Mutation status was determined correctly in 100% of the cases (25 samples) with fractional fetal DNA concentrations >7%. The panel of indels was informative in 65% of the female-bearing pregnancies. CONCLUSIONS Digital PCR can be used to determine the genotype of fetuses at risk for sickle cell anemia. Optimization of the fractional fetal DNA concentration is essential. More-informative indel markers are needed for this assays comprehensive use in cases of a female fetus.

Will the introduction of non-invasive prenatal diagnostic testing erode informed choices? An experimental study of health care professionals

OBJECTIVE Informed choice is a fundamental concept within prenatal care. The present study assessed the extent to which the introduction of non-invasive prenatal diagnosis (NIPD) of Downs syndrome may undermine the process of making informed choices to undergo prenatal testing or screening for Downs syndrome by altering the quality and quantity of pre-test counselling. METHODS 231 obstetricians and midwives were randomly allocated one of three vignettes, each describing a different type of test: (a) invasive prenatal diagnosis (IPD), (b) non-invasive prenatal diagnosis (NIPD) or (c) Downs syndrome screening (DSS). Participants were then asked to complete a questionnaire assessing (1) the information considered important to communicate to women, (2) whether test offer and uptake should take place on different days, and (3) whether signed consent forms should be obtained prior to testing. RESULTS Across the three test types, five out of the seven presented topics were considered equally important to communicate, including the information that testing is the womans choice. Compared with participants receiving the IPD vignette, those receiving the NIPD and DSS vignettes were less likely to report that counselling and testing should occur on different days (IPD 94.7% versus 74.1% and 73.9% for NIPD and DSS respectively, p=.001) and that written consent was a necessity (IPD 96.1% versus 68.3% and 75.4% for NIPD and DSS respectively, p<.001). CONCLUSION This study provides the first empirical evidence to demonstrate that practitioners may view the consent process for NIPD differently to IPD. There is potential for the introduction of NIPD to undermine women making informed choices in the context of prenatal diagnostic testing for conditions like DS. PRACTICE IMPLICATIONS Given the importance of informed choice in reproductive decision-making, implementation of any programme based on NIPD should be designed to facilitate this.

Women’s and health professionals’ preferences for prenatal tests for Down syndrome: a discrete choice experiment to contrast noninvasive prenatal diagnosis with current invasive tests

Purpose:To compare the preferences of women and health professionals for key attributes of noninvasive prenatal diagnosis for Down syndrome relative to current invasive tests.Methods:A questionnaire incorporating a discrete choice experiment was used to obtain participants’ stated preference for diagnostic tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and provision of information about Down syndrome only or Down syndrome and other conditions. Women and health professionals were recruited from five maternity services in England and a patient support group.Results:Questionnaires from 335 women and 181 health professionals were analyzed. Safe tests, conducted early in pregnancy, with high accuracy and information about Down syndrome and other conditions were preferred. The key attribute affecting women’s preferences for testing was no risk of miscarriage, whereas for health professionals it was accuracy.Conclusions:Policies for implementing noninvasive prenatal diagnosis must consider the differences between women’s and health professionals’ preferences to ensure the needs of all stakeholders are met. Women’s strong preference for tests with no risk of miscarriage demonstrates that consideration for safety of the fetus is paramount in decision making. Effective pretest counseling is therefore essential to ensure women understand the possible implications of results.Genet Med 2012:14(11):905–913