Wayne J. Huttly

Antenatal screening for Down's syndrome with the quadruple test

Second trimester screening for Downs syndrome is widely practised throughout the world. We assessed the performance of antenatal serum screening for Downs syndrome with the quadruple test in 46193 pregnancies from 14 hospitals over 5 years. Women who screened positive (risk > or =1 in 300) were offered diagnostic amniocentesis or chorionic villus sampling. Of 88 observed Downs syndrome pregnancies, 71 (81%) had a positive screening result (81% detection rate, 95% CI 72-89), and of 46105 unaffected pregnancies, 3200 tested positive (7% false-positive rate). These results show that the quadruple test is a better method of screening for Downs syndrome than use of maternal age alone (51% detection rate, 14% false-positive rate) and is more effective than other second trimester screening tests. Therefore, we conclude that the quadruple test should be the test of choice in second trimester screening for Downs syndrome.

Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening

To examine the Downs syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non–IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE3), free β–human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free α‐hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE3 levels were 6% lower (P= 0.003), median free β–hCG 9% higher (P= 0.024), and median total hCG 14% higher (P= 0.026) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE3 levels remain unexplained. In Downs syndrome screening in IVF pregnancies hCG and uE3 values should be adjusted to avoid the high screen positive rate.

Prevention of Neural Tube Defects: A Cross-Sectional Study of the Uptake of Folic Acid Supplementation in Nearly Half a Million Women

Background Taking folic acid supplements before pregnancy to reduce the risk of a neural tube defect (NTD) is especially important in countries without universal folic acid fortification. The extent of folic acid supplementation among women who had antenatal screening for Down’s syndrome and NTDs at the Wolfson Institute of Preventive Medicine, London between 1999 and 2012 was assessed. Methods and Findings 466,860 women screened provided details on folic acid supplementation. The proportion of women who took folic acid supplements before pregnancy was determined according to year and characteristics of the women. The proportion of women taking folic acid supplements before pregnancy declined from 35% (95% CI 34%–35%) in 1999–2001 to 31% (30%–31%) in 2011–2012. 6% (5%–6%) of women aged under 20 took folic acid supplements before pregnancy compared with 40% of women aged between 35 and 39. Non-Caucasian women were less likely to take folic acid supplements before pregnancy than Caucasian women; Afro-Caribbean 17% (16%–17%), Oriental 25% (24%–25%) and South Asian 20% (20%–21%) compared with 35% (35%–35%) for Caucasian women. 51% (48%–55%) of women who previously had an NTD pregnancy took folic acid supplements before the current pregnancy. Conclusions The policy of folic acid supplementation is failing and has led to health inequalities. This study demonstrates the need to fortify flour and other cereal grain with folic acid in all countries of the world.

Down's syndrome screening in the UK in 1998

The extent of antenatal screening for Downs syndrome with serum or ultrasound markers has increased over the past decade. We here present a survey of screening in the UK in 1998 and compare the results with similar surveys from 1991 and 1994.

Empirical validation of risk screening for Down's syndrome.

Objective— To validate individual risk estimates in antenatal serum screening for Downs syndrome. Methods— Women screened for Downs syndrome using maternal serum a fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophs (hCG) with maternal age (the triple test) or AFP, uE3, free β subunit and free a subunit of hCG with maternal age (the quadruple test) were grouped according to their predicted risk of having an affected pregnancy. The mean predicted risk in each category was then compared with the observed prevalence based on the number of affected and unaffected pregnancies in each category. Subjects— About 100 000 pregnant women screened for Downs syndrome from 1989 to 1995. Results— There was close agreement between the predicted term risk and the prevalence at birth for both the triple test and the quadruple test. For example, with the quadruple test the predicted risk in the highest risk group was 1 in 3.3 and the prevalence was 1 in 2.6; in the lowest risk group these were 1 in 3000 and 1 in 2300 respectively. Conclusion— Risk estimates based on multiple marker screening for Downs syndrome are accurate. The technique used to demonstrate this is simple and offers a useful empirical check on screening performance.

Ultrasound findings after screening for Down syndrome using the integrated test.

OBJECTIVE: To evaluate the incidence and significance of fetal anomalies and “soft markers” after screening for Down syndrome using the integrated test. METHODS: This study is a retrospective study of 2,332 women at University College London Hospitals, United Kingdom. All women were screened for Down syndrome by the integrated test. Subsequently, a detailed anomaly scan was performed. All scan reports and screening results were analyzed statistically using SPSS 11.0 software. RESULTS: Sixty-eight (2.9%) patients were categorized as high risk. There were 12 cases affected by Down syndrome, 10 (10 of 68) in the high-risk group and two (two of 2,264) in the low-risk group. Soft markers or structural anomalies were found in 13.0% of the low-risk group, in 29.4% of the high-risk group, and in 50% of the fetuses affected by Down syndrome. Multiplying the likelihood ratio of each marker with the risk of Down syndrome from the integrated test reduced the false-positive rate of the integrated test from 2.5% to 1.8%, but was accompanied by a reduction in the detection rate from 83% to 75%. CONCLUSION: Absence of structural anomalies or markers should not prevent offering karyotyping to women in the high-risk group, because this would result in a significant reduction in the detection rate of Down syndrome. Women screened as low risk by the integrated test who have isolated soft markers should not be offered an amniocentesis. LEVEL OF EVIDENCE: II

Practical issues drawn from the implementation of the integrated test for Down syndrome screening into routine clinical practice.

We have evaluated a cohort of women booked for antenatal care at University College London Hospitals. The uptake of screening was 64.4% and was significantly higher (73 versus 46%) in women who booked before 14 weeks. Of the women who booked before 14 weeks, 96.8% opted for the integrated test (IT). Overall, 5.3% failed to attend for the second blood test. The false‐positive rate in the women who had the IT was 2.9%. All 11 cases of Down syndrome were detected prenatally. Our study is the first to evaluate implementation of the IT into routine clinical practice.

First trimester Down's syndrome screening marker values and cigarette smoking: new data and a meta-analysis on free β human chorionic gonadotophin, pregnancy-associated plasma protein-A and nuchal translucency

Objectives To examine the effect of smoking on three first trimester screening markers for Downs syndrome that constitute the Combined test, namely nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free β human chorionic gonadotophin (free β-hCG) and to use the results to determine which of these markers need to be adjusted for smoking and by how much. Methods The difference in the median multiple of the median (MoM) values in smokers compared to non-smokers was determined for NT, PAPP-A and free β-hCG in 12,517 unaffected pregnancies that had routine first trimester Combined test screening. These results were then included in a meta-analysis of published studies and the effect of adjusting for smoking on screening performance of the Combined test was estimated. Results The results using the routine screening data were similar to the summary estimates from the meta-analysis of all studies. The results from the meta-analysis were; median MoM in smokers compared to non-smokers: 1.06 NT (95% confidence interval 1.03 to 1.10), 0.81 PAPP-A (0.80 to 0.83) and 0.94 free β-hCG (0.89 to 0.99). The effect of adjusting for smoking on the Combined test is small, with an estimated less than half percentage point increase in the detection rate (the proportion of affected pregnancies with a positive result) for a 3% false-positive rate (the proportion of unaffected pregnancies with a positive result) and less than 0.2 percentage point decrease in the false-positive rate for an 85% detection rate. Conclusion Adjusting first trimester screening markers for smoking has a minimal favourable effect on screening performance, but it is simple to implement and this paper provides the adjustment factors needed if a decision is made to make such an adjustment.

The pattern of maternal serum inhibin‐A concentrations in the second trimester of pregnancy

Maternal serum inhibin‐A concentration is a useful marker in prenatal screening for Down syndrome in the second trimester. We measured inhibin‐A concentrations in 4304 pregnancies without Down syndrome between 14 and 22 weeks of pregnancy to determine the median values according to gestational age. There was a U‐shaped pattern of inhibin‐A concentration against gestational age with a minimum concentration at 17 weeks and 1 day (120 days). We suggest that screening centres use a quadratic equation when estimating their normal median inhibin‐A level, constraining the shape of the curve and fixing the lower point of the curve to occur at 120 days, but allowing its position in relation to the vertical inhibin‐A axis to be set according to the local data. This approach will systematically allow for the changing inhibin‐A concentration without introducing the instability of deriving a fresh quadratic equation for each screening centre and each time a centres medians are revised.

Distribution of nuchal translucency in antenatal screening for Down's syndrome.

Objective To determine whether the standard deviation of nuchal translucency (NT) measurements has decreased over time and if so to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Downs syndrome. Setting Data from a routine antenatal screening programme for Downs syndrome comprising 106 affected and 22,640 unaffected pregnancies. Methods NT measurements were converted into multiple of the median (MoM) values and standard deviations of log10 MoM values were calculated in affected and unaffected pregnancies. The screening performance of the Combined and Integrated tests (that include NT measurement) were compared using previous and revised estimates of the standard deviation. Results The standard deviation of NT in unaffected pregnancies has reduced over time (from 1998 to 2008) (e.g. from 0.1329 to 0.1105 [log10 MoM] at 12–13 completed weeks of pregnancy, reducing the variance by about 30%). This was not observed in affected pregnancies. Compared with results from the serum, urine and ultrasound screening study (SURUSS), use of the revised NT standard deviations in unaffected pregnancies resulted in an approximate 20% decrease in the false-positive rate for a given detection rate; for example, from 2.1% to 1.7% (a 19% reduction) at a 90% detection rate using the Integrated test with first trimester markers measured at 1 1 completed weeks’ gestation and from 4.4% to 3.5% (a 20% reduction) at an 85% detection rate using the Combined test at 11 completed weeks. Conclusions The standard deviation of NT has declined over time and using the revised estimates improves the screening performance of tests that incorporate an NT measurement.