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Keywords:

  • Down syndrome;
  • first trimester combined screening;
  • prenatal screening;
  • test characteristics;
  • trisomy 18

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Objective  The objective of this study was to follow up and evaluate the statewide first-trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia.

Design  Retrospective population cohort.

Setting  Maternal Serum Screening Laboratory records.

Sample  All women screened between February 2000 and June 2002 (16 153 pregnancies).

Methods  Screening results were matched to Victorian perinatal and birth defect data via record linkage, with an ascertainment of 96.8% of pregnancy outcomes. Manual follow up with health professionals increased ascertainment to more than 99%.

Main outcome measures  Fetal Down syndrome or trisomy 18, and combined screen results, to calculate test characteristics.

Results  Using a risk threshold of 1 in 300 at time of ultrasound, the sensitivities for standard first-trimester combined screening and augmented 13-week combined screening for Down syndrome were 87.3 and 90.5% and the false-positive rates (FPR) were 4.1 and 3.9%, respectively. The sensitivity for trisomy 18 was 66.7% (10/15, 95% CI 42.8–90.5%) with a 0.4% FPR and 15.2% positive predictive value (1 in 250 risk threshold).

Conclusions  The combined use of record linkage and manual follow-up techniques was effective in ascertaining more than 99% of pregnancy outcomes for calculations of accurate test characteristics of the combined screen. The sensitivity for Down syndrome at Genetic Health is comparable to similar populations. However, the sensitivity for trisomy 18 is lower than that elsewhere, which may reflect the overall low birth prevalence of trisomy 18 and associated small numbers in this particular cohort.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Prenatal screening for Down syndrome and other chromosomal abnormalities has become increasingly available in Victoria, Australia, where approximately 63 000 women give birth each year.1 The Maternal Serum Screening Laboratory at Genetic Health Services Victoria introduced a combined first-trimester screening pilot programme in February 2000, and this became a full service in July 2002. This test combines the nuchal translucency (NT) ultrasound measurement with first-trimester maternal serum, together with maternal age, weight and gestation to produce a risk estimate of the fetus having Down syndrome or trisomy 18. There are various reported sensitivities of the combined screen for Down syndrome (73–93%)2–13 and trisomy 18 (91–100%).9,14,15 Variations between test characteristics can be a reflection of different maternal age distributions, methods of calculating the risk estimates and risk thresholds.

Having a newly established service in Victoria, the aim of this study was to follow up and evaluate data from the pilot programme to determine the test characteristics for the combined screen for the detection of Down syndrome and trisomy 18. This would allow for comparisons with well-established services elsewhere and provide local information to those receiving testing and to those planning future services.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Combined first-trimester screening

The central Genetic Health Screening Laboratory is the sole provider of maternal serum screening in Victoria. All blood samples for combined screening are taken offsite and couriered to Genetic Health, where they are processed within 24 hours of receipt without issuing a risk report. NT and crown-rump length (CRL) measurements are also measured offsite at 14 different private obstetric ultrasound practices at 13 metropolitan and 1 regional location, and these measurements are faxed to the laboratory for combination with the serum analytes. NT is measured from 11 weeks and 3 days to 13 weeks and 6 days (CRL 45–84 mm).16 All ultrasonologists involved in the pilot programme were accredited through the Fetal Medical Foundation (FMF). Additionally, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists now provide an accreditation programme, for which the CRL and NT are measured in accordance with the technique described by the FMF.17

The combined screen measures two analytes in the maternal serum—free beta human chorionic gonadotrophin and pregnancy-associated plasma protein A (PAPP-A). The gestational range for processing blood samples is usually between 8 and 12 weeks. We recommend that blood is taken at 10 weeks due to the decreasing separation between affected and unaffected PAPP-A medians in Down syndrome pregnancies from 10 to 13 weeks.18 In practice, most bloods are taken from 10 to 12 weeks, to be assayed in the laboratory approximately 1 week before the ultrasound is performed.

Risk estimations for Down syndrome and trisomy 18 are calculated at the date of scan using multivariate probability distributions based on published methodology19,20 and using published unaffected and affected marker means and SDs used for estimating risk of Down syndrome21 and trisomy 18.22 The risks are calculated for the gestation at the time of NT measurement, and thresholds are set at 1 in 300 for Down syndrome and 1 in 250 for trisomy 18. In most cases (72%), the blood has been collected and assayed prior to the NT ultrasound, so a combined risk can be calculated immediately on receipt of ultrasound measurements. This enables to give women the option of waiting approximately 30 minutes at the clinic for their results or receiving their results later, from the ultrasound practice or their referring practitioner. In practice, about 50% of women wait at the clinic for their result, with 22% followed up within 24 hours. The remaining 28% of women have their blood taken on the day (12%), within 3 days (14%) or within 3 weeks (2%) of their NT. These results are issued within 2–3 days of receiving the blood sample. As the blood sample is usually taken prior to the ultrasound, our combined screen is different from many other programmes, such as the one stop clinic for assessment of risk.10

There is a small proportion of women (<5%) who have blood collected from 13 weeks 0 days to 13 weeks 6 days, and we were concerned that there is decreased separation using the first-trimester markers between Down syndrome and normal pregnancies at 13 weeks that have been previously reported.23–26 The first and second trimester evaluation of risk (FASTER) study also found that the sensitivity of NT or PAPP-A alone was lowest at 13 weeks, as was overall combined test performance.26 To counteract this effect of measuring PAPP-A and NT at 13 weeks, we took into account a recommendation from a modelling report suggesting that inhibin-A, unconjugated estriol and alpha fetoprotein could also be included into the standard combined screen when blood was collected at 13 weeks.27 The report suggested that this would maximise the sensitivity for Down syndrome in this group by increasing the sensitivity by 2.4%.27 In light of this, we are trialing an approach measuring these second-trimester analytes for all pregnancies where blood was collected at 13 weeks and refer to this as the augmented screen. These pilot data do not include enough pregnancies screened by this method to validate this approach; however, we are currently monitoring all 13-week combined tests to obtain a larger sample size, which will be reported on separately.

Study population

A population-based retrospective cohort study was used to follow up pregnancy outcomes of each woman screened during the pilot programme, where the result was issued between 1 February 2000 and 29 June 2002 (with an estimated date of delivery (EDD) no later than 31 December 2002). Due to the large number of hospitals and of individual doctors involved, an automated probabilistic technique was used to link health records from population-based databases.

The three databases used for record linkage were as follows:

  • 1
    Genetic Health prenatal screening database: records of all women who had combined first-trimester screening during the pilot programme, 16 153 screened pregnancies.
  • 2
    Victorian births held at the Perinatal Data Collection Unit (PDCU), Department of Human Services (Perinatal database): the mandatory registration system for all births of 20 weeks of gestation and more. Approximately 180 000 births occurred in the study period (1 February 2000 to 31 December 2002). Miscarriages (less than 20 weeks of gestation) are not registered births in Victoria. More than 99.6% of all births in Victorian hospitals were reported to the PDCU in 1996.28
  • 3
    The Birth Defects Register (BDR): it is also held at the PDCU but with additional notifications from multiple sources and includes data on terminations of pregnancy for birth defects at any gestation. There are approximately 2500 birth defects reported per year in Victoria. The overall notification of birth defects has been shown to be 88%, but notifications of chromosomal abnormalities apparent at birth was 100%.29 Approximately 85% of early terminations for birth defects were notified to the Victorian BDR between 1995 and 1999.30

Record linkage

Probabilistic record linkage is used to link exposure and outcome in retrospective follow-up studies. The purpose of record linkage is to collect data from two or more records that are believed to relate to the same person or family.31 It allows for matches on common identifying variables, such as maternal name, maternal date of birth and postcode, to link records. Record linkage calculates agreement or disagreement weights for each variable used when matching a pair of records, and the sum of these weights provides an overall score for the pair.32 Linked health data are invaluable resources for monitoring and evaluation of healthcare services.33 Record linkage techniques have been used in Victoria to investigate a number of public health outcomes including fetal outcome and maternal morbidity following early amniocentesis34 and evaluating the second-trimester maternal serum screening programme at Genetic Health Victoria.35 Record linkage has also been used in the UK to examine the uptake and outcome of prenatal screening and diagnosis.36

Eight passes of record linkage were performed. The first pass attempted to link the entire screening database on the three main common identifying variables (16 153 records) to the Perinatal database (>180 000 records). Subsequent passes were performed on the records that had not been matched using different matching criteria. Potential matches with a low agreement score were manually checked to identify true matches, and the accuracy of high-scoring matches was examined by means of a random selection. Variables such as baby’s date of birth, EDD and gestation were used to confirm whether the correct pregnancy had been matched, as some women had several pregnancies during the study period.

The screened pregnancies not matched to the Perinatal database were subsequently matched with the BDR for terminations at less than 20 weeks of gestation. For pregnancies that did not match with either the Perinatal database or the BDR, a written request for pregnancy outcome information was sent to the referring health professional. Pathology and cytogenetics reports were collected for confirmation of birth defects and/or karyotypes.

Research approval

Permission for access to the Perinatal database and BDR was obtained from the Consultative Council on Obstetric and Paediatric Mortality and Morbidity. Ethics approval was sought and granted from the Victorian Department of Human Services and the University of Melbourne Human Research Ethics Committees, as required by the Health Records Act 2001 (Victoria).

Data analysis

Data were coded and analysed using SPSS (version 12; SPSS Inc., Chicago, IL, USA). Sensitivity (detection rate), false-positive rate (FPR) and positive predictive value (PPV) were calculated for Down syndrome and trisomy 18. The statistical significance of differences in proportions was assessed using chi-square tests (including Fisher’s exact test where expected cell frequencies were less than five). Comparisons between groups are presented as relative risks (RR) with 95% confidence intervals. We present the data as standard combined screening (all risks calculated using first-trimester markers only, regardless of the gestation of testing) and as augmented combined screening (risks calculated by the standard test where blood was collected at 8–12 weeks and risks calculated by the augmented 13-week test where blood was collected during the 13th week). Maternal age categories used are <37 and ≥37 years of age because in Victoria, 37 years is the cutoff age for free prenatal diagnostic testing.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Of the 16 153 screening records, pregnancy outcome was determined for 16 002 (99.1%). Record linkage found the pregnancy outcome for 15 630 of the screened pregnancies (96.8%) and a further 372 (2.3%) were ascertained through manual follow up with health professionals, leaving 151 lost to follow up. Live births from manual follow up included 198 interstate, 33 Victorian (including homebirths), 14 overseas and 14 in unknown locations. Manual follow up also ascertained 17 cases of Down syndrome (all terminations), 3 cases of trisomy 18 (two terminations and one unknown pregnancy outcome), 68 miscarriages (<20 weeks of gestation), 41 terminations of pregnancy (36 for birth defects), 2 neonatal deaths and 1 stillbirth (≥20 weeks of gestation). The trisomy 18 case with an unknown pregnancy outcome is reported in the ‘lost to follow up’ group but included in the calculations of test characteristics, as the karyotype was known. Eighty-one of the women lost to follow up had moved overseas (47) or interstate (34). In some cases, doctors did not respond to the contact letter (30), the woman was unknown to them (23) or the doctor was unable to be contacted (11). Participation was declined for five cases.

Women lost to follow up were not more likely to be at increased risk for Down syndrome (RR = 1.5, 95% CI 0.8–2.8, P= 0.2) or to be aged 37 years or older (RR = 1.2, 95% CI 0.9–1.6, P= 0.3) when compared with women who were able to be followed up. Women living in rural Victoria were more likely to be lost to follow up compared with those living in metropolitan areas (RR = 2.1, 95% CI 1.6–2.7, P < 0.01).

Maternal age ranged from 16 to 51 years, with a mean and median age of 33 years, which is higher than the mean age of 30 years in the general Victorian population of women who had babies in 2001–02.1 As shown in Figure 1, the maternal age distribution of screened women was statistically different (χ2[6df] = 4696, P < 0.001) than that of the general population.1

image

Figure 1. Age distribution of screened women and the general victorian population of women who had a baby in 2001–02.

Download figure to PowerPoint

Screening for down syndrome

Six hundred and ninety-two (4.3%) women had an increased risk for Down syndrome. Thirteen percent (376/2985) of women aged 37 years and older had an increased risk result compared with 2% (316/13 168) of younger women (RR = 5.3, 95% CI 4.5–6.1, P < 0.001). There were 63 cases of Down syndrome ascertained in this population, which was comparable to the 66 expected cases calculated from our maternal age distribution.16

The sensitivity of the standard combined screen for the detection of Down syndrome (i.e. all pregnancies screened using standard first-trimester markers, between 10 and 13 weeks of gestation) was 87.3% (95% CI 79.1–95.5%), with a FPR of 4.1%. For the screening test augmented with second-trimester markers for those screened at 13 weeks (and standard markers for those screened <13 weeks), the sensitivity was 90.5% (95% CI 83.2–97.7%), with a 3.9% FPR (Table 1). There were three cases of Down syndrome that were screened at 13 weeks, all of which were at increased risk using the 13-week screening method, with only one being at increased risk from the standard combined screen.

Table 1.  Results of prenatal screening for Down syndrome and trisomy 18 with combined first-trimester screening, including the sensitivity (DR), FPR and PPV
Screened conditionNumber of screened pregnanciesNumber of increased risksTest characteristics (%)
Total*ConditionTotalConditionDRFPRPPV
PresentAbsentPresentAbsent
  • DR, detection rate.

  • *

    Includes one abnormal karyotype (trisomy 18) with unknown pregnancy outcome.

  • **

    Augmented first-trimester combined screen.

  • ***

    Standard first-trimester combined screen.

Down syndrome
Risk ≥1 in 300**16 0036315 9406835762690.53.98.4
Risk ≥1 in 300***16 0036315 9407145565987.34.17.7
Bloods <13 weeks of gestation***15 2436015 1836055555091.73.69.1
Fixed 5% FPR, risk ≥1 in 351**16 0036315 9407995874192.15.07.3
Women aged <37 years**13 0503513 0153143028485.72.29.6
Women aged ≥37 years**29532829253692734296.411.77.3
Trisomy 18
Risk ≥1 in 250**16 0031515 98866105666.70.415.2
Risk ≥1 in 25**16 0031515 98829101966.70.134.5
Women aged <37 years**13 050613 0444043666.70.310.0
Women aged ≥37 years**2953929442662066.70.723.1
Bloods <13 weeks of gestation***15 2431515 22866105666.70.415.2

Women younger than 37 years who had augmented screening had lower sensitivity and FPR (85.7% [95% CI 74.1–97.3%] and 2.2%, respectively) than women aged 37 years and older (96.4% [95% CI 89.6–100%] and 11.7%, respectively).

If a 5% fixed FPR had been used in the augmented screen (risk threshold = 1 in 351), 117 extra pregnancies, including one with Down syndrome, would have been at increased risk, changing the sensitivity to 92.1% (95% CI 85.4–98.7%). When women screened at 13 weeks (n= 760) were excluded from the 5% fixed FPR analysis, the sensitivity and FPR remained similar to the overall sensitivity of 91.7% (95% CI 84.7–98.7%) and 3.6%, respectively.

Screening for trisomy 18

Sixty-six women (0.4%) were screen positive for trisomy 18, with a higher proportion of women aged ≥37 years at increased risk (0.9%) than younger women (0.3%) (RR = 2.2, 95% CI 1.6–2.9, P < 0.001). Of those at increased risk, 42 (64%) were also at increased risk for Down syndrome. The overall sensitivity for trisomy 18 was 66.7% (95% CI 42.8–90.5), and this did not vary between the two age groups (Table 1). There were no cases of trisomy 18 screened during the 13th week. Detailed information on the screening results and analyte measurements for the five low-risk cases of trisomy 18 are shown in Table 2.

Table 2.  Detailed information of fetuses with T18 that had low-risk combined screening results for T18 and DS and MoMs for NT, PAPP-A and beta hCG
Maternal age (years)Gestation at time of test (weeks + days)Pregnancy outcomeGestation of pregnancy outcome (weeks)Combined screen T18 risk (1 in X)Combined screen DS risk (1 in X)NT (MoMs)PAPP-A (MoMs)Beta-hCG (MoMs)
  1. hCG, human chorionic gonadotrophin; MoM, multiples of the normal median; T18, trisomy 18; DS, Down syndrome.

3610 + 6Stillbirth2034929800.710.330.19
3711 + 1UnknownUnknown103036401.070.590.23
379 + 2Live birth3910 60018400.970.490.45
3811 + 2Neonatal death3313 00055000.871.050.31
3410 + 1Stillbirth2345 30016 2000.840.910.71

The FPR for trisomy 18 was lower in younger (0.3%) than older women (0.7%), as was the PPV (10 and 23%, respectively). Nine of the 15 (60%) fetuses with trisomy 18 were categorised as at increased risk for both Down syndrome and trisomy 18. Only 40% (6/15) of the fetuses with trisomy 18 were at increased risk from NT alone (in combination with CRL and maternal age). The lowest true positive risk was 1 in 24, and therefore, setting the risk threshold at ≥1 in 25 would have produced the same sensitivity but with a lower FPR (0.1%) and higher PPV (35.5% or 1 in 3). However, of the 37 women who would have changed from an increased to a low risk for trisomy 18 (i.e. those with a risk between 1 in 26 and 1 in 250 for trisomy 18), 15 (41%) were also at increased risk for Down syndrome.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Screening for Down syndrome

The overall sensitivities of the combined screen for Down syndrome by the standard combined screen (88%) and the augmented combined screen (91%) are comparable to other studies which have demonstrated sensitivities between 83 and 93%.6–8,10,12,14 The difference between the combined screen group and the augmented screen group (3.2%) was small, which is consistent with the modelling data (2.4% increased detection).27 The FPR was marginally greater in the standard combined screen group than in the augmented group (4.1 versus 3.9%), but there were only 760 pregnancies screened at 13 weeks, and a larger number is required to fully evaluate the augmented combined screen as a stand-alone test.

Using a different risk threshold of ≥1 in 250, slightly lower FPRs (2.18 and 3.3%6) have been demonstrated elsewhere with similar sensitivities to our cohort (91 and 88%, respectively). The sample sizes were smaller than our study at 64118 and 2860,6 and the follow-up rate was slightly lower (96 and 97%, respectively). Other programmes, using a threshold of ≥1 in 250, have demonstrated a higher FPR between 5 and 6% with varying sensitivities of 73,2 82,4 865 and 93%.7 Screening programmes using a risk threshold of ≥1 in 300 have also shown a slightly higher range of FPR, between 5.2 and 7.2% with sensitivities ranging between 83 and 92%.9–13 Overall, the 3.9% FPR in the Victorian population is extremely satisfactory and acceptable.

The method of carrying out the combined screen by Genetic Health uses a single central laboratory with multiple ultrasound practices, and the sensitivity of the augmented combined screen was similar to those of the one-stop method (92–93%).10,12,37 However, FPRs demonstrated by the one-stop method have been higher (6.8–7.5%) than those in our study. The median age of the women screened through the one-stop clinic was slightly higher at 34 years10,37 than the median age of our cohort (33 years), and this may have influenced the difference in FPR. At a 5% fixed FPR, the one-stop method has demonstrated a similar sensitivity for Down syndrome at 90%10,37 to the population screened by Genetic Health (92%). As previously proposed,38 these data suggest that setting a fixed FPR will produce similar sensitivities in different populations.

Screening for trisomy 18

The lower FPR for trisomy 18 (0.4%) than reported elsewhere (0.8–2%)9 may be a result of the lower sensitivity in our cohort (67 versus 91–100%).9,14,15 It is well known that the fetal loss rate of trisomy 18 is high,16 and in our cohort, there was only one missed case of trisomy 18 delivered at term. If ascertainment of pregnancy outcomes for this cohort had been from a single hospital or laboratory, rather than the statewide birth registry (including those <20 weeks of gestation), these earlier stillbirths would have been more difficult to find. Although our follow-up rate of 99.1% appears very similar to the 97% follow up reported in other studies,9,14,15 by following up the last 2.3% through contact with health professionals, we were able to ascertain an extra 3 cases of trisomy 18 and 17 cases of trisomy 21 (as well as 68 miscarriages and 41 terminations of pregnancy). These pregnancies would have otherwise been lost to follow up, and this highlights the importance of following up the last 2–3% of unmatched records. If three of the five missed trisomy 18 cases had not been ascertained by our follow-up methods, the calculated sensitivity would have been higher (83% or 10/12 compared with 67% or 10/15) and more in line with the sensitivities found in other follow-up studies. Furthermore, the missed trisomy 18 cases in our cohort appeared to be physically more normal than detected cases as judged by the NT measurement, and these cases may have been less likely to be detected during pregnancy by routine morphology ultrasound scans. Nonetheless, the lower sensitivity for trisomy 18 could be due to the small numbers of trisomy 18 in our cohort, with the confidence interval around the sensitivity ranging from 43 to 91%.

Nine of the ten cases of trisomy 18 at increased risk were also at increased risk of Down syndrome, and these women would have been offered prenatal diagnosis based on the Down syndrome risk. There are some problems with specifically screening for chromosomal abnormalities other than Down syndrome which do not fit the screening programme criteria mainly because of the low prevalence and high mortality rate of the condition.39 Although, incidental detection of other chromosomal abnormalities following an increased risk for Down syndrome may be reasonable, as it does not increase the proportion of women who have invasive testing. However, there were only 24 women (0.1%) at increased risk for trisomy 18 alone (i.e. not also at increased risk for Down syndrome), and therefore, the overall increase in proportion of pregnancies referred for prenatal diagnosis is not markedly high in our population.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The record linkage and manual follow-up technique achieved excellent ascertainment of pregnancy outcomes and has been proven as a valuable methodology for future prenatal screening evaluations. The combined screen at Genetic Health is performing well for the detection of Down syndrome, with the test characteristics being akin to the performance of other similar prenatal screening services. Augmenting the analysis for bloods collected at 13 weeks increased the detection rate by 3.4%. However, further assessment with larger numbers is required. The sensitivity of the combined screen for trisomy 18 is somewhat lower than that seen elsewhere, but this could be a result of the low FPR, due to small numbers, or as a result of the high ascertainment of pregnancy outcome. On account of the performance of this test in the Victorian population, public health funding of this test should be considered.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

We thank all the referring doctors, ultrasonologists and their staff, who referred women with ultrasound results to Genetic Health for combined first-trimester screening. Victoria Dixon and the staff members of Maternal Serum Screening Laboratory from Genetic Health Services Victoria; Robert Williamson, former director of the Murdoch Childrens Research Institute; Merilyn Riley, Odette Taylor, Sonia Palma, Jenny O’Callaghan, Rosemary Warren and James King from the PDCU and the large number of health professionals for their contribution with pregnancy outcome data during the manual follow-up process.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
  • 1
    Riley M, King J. Births in Victoria 2001-2002. Melbourne: Perinatal Data Collection Unit, Public Health, Victorian Government Department of Human Services, 2003. [www.dhs.vic.gov.au/phd/perinatal/pubs.htm]. Accessed January 2006.
  • 2
    Muller F, Benattar C, Audibert F, Roussel N, Dreux S, Cuckle H. First-trimester screening for Down syndrome in France combining fetal nuchal translucency measurement and biochemical markers. Prenat Diagn 2003;23:8336.
  • 3
    Niemimaa M, Suonpaa M, Perheentupa A, Seppala M, Heinonen S, Laitinen P, et al. Evaluation of first trimester maternal serum and ultrasound screening for Down’s syndrome in Eastern and Northern Finland. Eur J Hum Genet 2001;9:4048.
  • 4
    Crossley JA, Aitken DA, Cameron AD, McBride E, Connor JM. Combined ultrasound and biochemical screening for Down’s syndrome in the first trimester: a Scottish multicentre study. BJOG 2002;109:66776.
  • 5
    Schuchter K, Hafner E, Stangl G, Metzenbauer M, Höfinger D, Philipp K. The first trimester ‘combined test’ for the detection of Down syndrome pregnancies in 4939 unselected pregnancies. Prenat Diagn 2002;22:21115.
  • 6
    Borrell A, Casals E, Fortuny A, Farre MT, Gonce A, Sanchez A, et al. First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study. Prenat Diagn 2004;24:5415.
  • 7
    Stenhouse EJ, Crossley JA, Aitken DA, Brogan K, Cameron AD, Connor JM. First trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice. Prenat Diagn 2004;24:77480.
  • 8
    Wøjdemann K, Shalmi A, Christiansen M, Larsen S, Sundberg K, Brocks V, et al. Improved first-trimester Down syndrome screening performance by lowering the false positive rate: a prospective study of 9941 low-risk women. Ultrasound Obstet Gynecol 2005;25:22733.
  • 9
    Spencer K, Spencer C, Power M, Moakes A, Nicolaides K. One stop clinic for assessment of risk for fetal anomalies: a report of the first year of prospective screening for chromosomal anomalies in the first trimester. BJOG 2000;107:12715.
  • 10
    Bindra R, Heath V, Liao A, Spencer K, Nicolaides K. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks: a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol 2002;20:21925.
  • 11
    Von Kaisenberg CS, Gasiorek-Wiens A, Bielicki M, Bahlmann F, Meyberg H, Kossakiewicz A, et al. Screening for trisomy 21 by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-14 weeks: a German multicenter study. J Matern Fetal Neonatal Med 2002;12:8994.
  • 12
    Spencer K, Spencer CE, Power M, Dawson C, Nicolaides KH. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years prospective experience. BJOG 2003;110:2816.
  • 13
    Nicolaides K, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:2216.
  • 14
    Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW Jr, Macri JN. First trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstet Gynecol 2000;96:20713.
  • 15
    Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:140513.
  • 16
    Nicolaides K. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:4567.
  • 17
    The Fetal Medicine Foundation. The 10-14 Week Scan Theoretical Course. London: The Fetal Medicine Foundation, 1999. [www.fetalmedicine.com/lab_cert.htm]. Accessed January 2006.
  • 18
    Cuckle HS, Van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn 1999;19:50512.
  • 19
    Reynolds TM, Penney MD. The mathematical basis of multivariate risk screening: with special reference to screening for Down’s syndrome associated pregnancy. Ann Clin Biochem 1990;27:4528.
  • 20
    Wald N, Cuckle H, Densem J, Kennard A, Smith D. Maternal serum screening for Down’s syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight. Br J Obstet Gynaecol 1992;99:1449.
  • 21
    Wald N, Hackshaw AK. Combining ultrasound and biochemistry in first-trimester screening for Down’s syndrome. Prenat Diagn 1997;17:8219.
  • 22
    Tul N, Spencer K, Noble P, Chan C, Nicolaides K. Screening for trisomy 18 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation. Prenat Diagn 1999;19:103542.
  • 23
    Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353:200111.
  • 24
    Spencer K, Crossley JA, Aitken DA, Nix AB, Dunstan FD, Williams K. Temporal changes in maternal serum biochemical markers of trisomy 21 across the first and second trimester of pregnancy. Ann Clin Biochem 2002;39:56776.
  • 25
    Wald N, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7:188.
  • 26
    Malone FD, Wald NJ, Canick JA, Ball RH, Nyberg DA, Comstock CH, et al. First- and second-trimester evaluation of risk (FASTER) trial: principal results of the NICHID multicenter Down syndrome screening study. Am J Obstet Gynecol 2003;189:S56.
  • 27
    Anonymous. AFP or PAPP-A. Down’s Screening News 2000, p. 41.
  • 28
    Riley M, Griffin O. Validating a statewide data collection: differences in information technology resources between hospitals. Health Inf Manag 1997;27:678.
  • 29
    Riley M, Phyland S, Halliday J. Validation study of the Victorian Birth Defects Register. J Paediatr Child Health 2004;40:5448.
  • 30
    Riley M, Howard J, Dale K, Palma S, Halliday J. Validating notifications of pregnancy terminations for birth defects before 20 weeks gestation. Health Inf Manag 2001;30:2.
  • 31
    Bruinsma F, Venn A, Skene L. Legal and ethical issues in record linkage studies. Australian Epidemiologist 1999;6:15–17.
  • 32
    Taylor R. Automated record linkage. In: KerrC, TaylorR, HeardG, editors. Handbook of Public Health Methods, 1st edn. Sydney: The McGraw-Hill Companies Inc, 1998:1847.
  • 33
    Kelman C, Bass A, Holman C. Research use of linked health data – a best practice protocol. Aust N Z J Public Health 2002;26:2514.
  • 34
    Collins V, Webley C, Sheffield L, Halliday J. Fetal outcome and maternal morbidity after early amniocentesis. Prenat Diagn 1998;18:76772.
  • 35
    Jaques AM, Collins VR, Haynes K, Sheffield LJ, Francis I, Forbes R, et al. Using record linkage and manual follow-up to evaluate the Victorian maternal serum screening quadruple test for Down’s syndrome, trisomy 18 and neural tube defects. J Med Screen 2006;13:813.
  • 36
    Alberman E, Huttly W, Hennessy E, McIntosh A. The use of record linkage for auditing the uptake and outcome of prenatal serum screening and prenatal diagnostic tests for Down syndrome. Prenat Diagn 2003;23:8016.
  • 37
    Avgidou K, Papageorghiou A, Bindra R, Spencer K, Nicolaides KH. Prospective first trimester screening for trisomy 21 in 30,564 pregnancies. Am J Obstet Gynecol 2005;192:17617.
  • 38
    Huang T, Watt HC, Wald NJ. The effect of differences in the distribution of maternal age in England and Wales on the performance of prenatal screening for Down’s syndrome. Prenat Diagn 97;17:61521.
  • 39
    Wald N, Canick JA. Seeking other disorders within antenatal serum screening programmes for Down’s syndrome. J Med Screen 2002;9:1456.