SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

Objective To evaluate the performance of a one-stop multidisciplinary clinic of screening for fetal chromosomal anomalies in the first trimester of pregnancy by a combination of maternal serum biochemistry and ultrasonography.

Design Retrospective review of screening performance.

Setting District General Hospital maternity unit.

Population All women booked for routine antenatal care at Harold Wood Hospital between 1 June 1998 and 31 May 2001. The population included 12,339 women with singleton pregnancies presenting at 10–14 weeks of gestation.

Methods Women were offered screening using a combination of maternal serum free β-hCG and pregnancy associated plasma protein-A (PAPP-A) and fetal nuchal translucency thickness. Those with an estimated risk of ≥1 in 300 of carrying a fetus with trisomy 21 or trisomy 18 or trisomy 13 were offered the option of an invasive diagnostic test. Follow up of the outcome of all pregnancies was carried out.

Main outcome measures Uptake of screening and invasive testing, detection rate for fetal chromosomal abnormalities and false positive rate.

Results The uptake of first trimester screening was 97.5% and the uptake of invasive testing in the increased risk group was 77%. The rate of detection of trisomy 21 was 92% (23 of 25), of trisomy 13 or 18 was 100% (all 15) and of all aneuploidies was 96% (49 of 51). The false positive rate was 5.2%.

Conclusion First trimester screening for trisomy 21 and other aneuploidies can be delivered in an efficient manner in a one-stop multidisciplinary clinic. The detection rates are far better than can be achieved by second trimester serum screening.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

Screening for trisomy 21, often in conjunction with screening for neural tube defects, by the measurement of second trimester maternal serum biochemical markers, has become an established part of obstetric practice in many countries. Although trisomy 21 screening protocols vary from centre to centre, the average detection rate in prospective studies has been 64% (range 48–75%) for a false positive rate of about 5%1,2. For the other major chromosomal anomalies, only algorithms for trisomy 18 have been successfully implemented in routine practice1,3,4.

During the last decade, extensive research has demonstrated that effective screening for chromosomal abnormalities can be achieved by maternal serum free β-hCG5 and pregnancy associated plasma protein-A (PAPP-A)6 and the ultrasonographic measurement of fetal nuchal translucency thickness7. In a multicentre study involving about 100,000 pregnancies screening by fetal nuchal translucency thickness, with measurements performed in a standardised way (defined by the Fetal Medicine Foundation; www.fetalmedicine.com) by suitably trained sonographers, the detection rate for trisomy 21 was 73% for a 5% screen positive rate8. Subsequently, it was estimated that a combination of fetal nuchal translucency with maternal serum free β-hCG and PAPP-A would increase the detection rate for trisomy 21 to about 90%9 and also allow the detection of 90% of other chromosomal anomalies, including trisomy 13, trisomy 18, Turners syndrome and triploidy10–14.

The advent of rapid immunoassays, suitable for point-of-care testing, has enabled the development of a multidisciplinary one-stop clinic for assessment of risk for fetal anomalies (OSCAR)15–17. Within a 1-hour visit, the patient can receive pre-test counselling, blood collection and biochemical testing, ultrasound examination and post-test counselling of a combined risk estimate16. The first year of prospective intervention screening using this approach has been reported17. In this paper we report results from three years of screening for chromosomal anomalies in our routine NHS OSCAR clinic.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

The maternity unit under study is located in the borough of Havering at the eastern boundary of Greater London. The screening population is predominantly white Caucasian from the London Borough of Havering (84.2% with an RM postcode) and the Local Authority of Brentwood (13.2% with a CM postcode), with a small proportion of women from the London Borough of Barking and Dagenham (2.3% with an IG postcode) and 0.3% from other adjacent areas. The two major areas comprise a relatively affluent population with approximately half the population in social class I or II. The 2000 Index of Multiple Deprivation provided by the Department of Environment, Transport and the Regions (www.urban.odpm.gov.uk/research/summaries/03100/index.htm) showed Havering with a rank of 233/354 districts in England and Wales, while that of Brentwood was 311/354. Barking and Dagenham on the other hand has a higher proportion of manual skilled, partly skilled and unskilled workforce. The Index of Multiple Deprivation in this Borough was ranked 24/354, showing considerably higher deprivation.

All women booked for maternity care at Harold Wood Hospital, Essex are given an appointment to attend the antenatal clinic for the first time at around 12 weeks of gestation. Screening using the first trimester one-stop approach began in June 199817. In the first year of screening the qualifying gestational age was between 10 weeks 3 days and 13 weeks 6 days by ultrasound dating. During the second and third year the minimum gestation was increased to 11 to allow for better identification of fetal structural anomalies.

Women are initially seen in the community by a member of the community midwifery team (65% of cases) and they receive an information leaflet about the one-stop clinic service with their booking appointment letter. When they attend the hospital for their booking appointment, they are seen in the antenatal clinic with an adjacent laboratory and ultrasound suite. The women have a pre-test counselling session with a midwife and those opting into the screening programme go to the phlebotomy room where blood samples are taken for serum biochemical screening, in addition to samples for other routine antenatal investigations. The blood samples for biochemical screening are passed through to the adjacent laboratory and the women go to the ultrasound suite for the 11–14 weeks scan. The sonographers carrying out the scans have the Fetal Medicine Foundation Certificate of competence and in addition to taking measurements of fetal nuchal translucency thickness and crown–rump length they examine the fetal anatomy for any major fetal defects8 (www.fetalmedicine.com). The ultrasound examination is carried out transabdominally and is completed within 20 minutes in about 99% of cases. In less than 1% of cases, a transvaginal ultrasound examination is performed. All relevant clinical information is recorded on a networked fetal database (ViewPoint, Wessling, Germany). If the fetal crown–rump length is less than 45 mm (11 weeks), a new appointment for the OSCAR clinic is made. If the crown–rump length is more than 85 mm (13 weeks and 6 days), the laboratory is informed and α-fetoprotein, rather than PAPP-A, is measured in addition to free β-hCG.

During the time the mother is visiting the ultrasound suite, in the clinic laboratory the serum from the blood sample is separated and analysed for free β-hCG and PAPP-A using the Kryptor analyser (Brahms Diagnostica, Berlin, formerly CIS). The quality performance of this system has previously been described9,18. When the results are available (within 20 minutes) these are logged onto the fetal database and a composite risk report is produced by the time the woman has returned from the ultrasound suite. This risk report is then available for the midwife/counsellor to discuss with the woman and, if appropriate, further follow up and management is arranged. Patient-specific risks are calculated by a multivariate approach using population parameters established in our retrospective study9 and the age-related risk of the trisomy at the time of sampling19,20. Screening for neural tube defects and abdominal wall defects was by ultrasonography either as part of the 11–14 weeks scan or as part of the 20–23 weeks anomaly scan.

Women with a risk of ≥1 in 300 for trisomy 21 or trisomies 13/18 are referred to the Harris Birthright Centre for Fetal Medicine for chorionic villus sampling and fetal karyotyping. Provisional results from quantitative PCR were available within 48 hours and a confirmed diagnosis by conventional karyotyping within seven days.

Outcome of pregnancies was ascertained from delivery room records, hospital PAS system and Child Health records and was cross-checked with the fetal database. Cytogenetics records were obtained from the laboratory, Child Health computer records and the National Down's Syndrome register. Outcome follow up was achieved in all but 98 cases lost to follow up. None of these cases were identified as trisomy 21 on the National Down's Syndrome register.

Screening for women presenting beyond 14 weeks of gestation was provided with second trimester risk assessment using free β-hCG and α-fetoprotein as previously described1.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

During a three-year period (1 June 1998 to 31 May 2001), a total of 12,339 women with singleton pregnancies were offered first trimester screening in the OSCAR clinic. The uptake of first trimester screening was 97.5% (12,030/12,339). The population consisted of 93.9% Caucasian, 2.1% Afro-Caribbean, 2.1% Asian and 1.9% of either unknown or other ethnic origin. The median gestation was 12 weeks 2 days (range 10 weeks 4 days to 13 weeks 6 days) and the median crown–rump length was 60 mm (range 38 to 84). The median maternal age was 30 years (range 14.4 to 46.0) with a distribution as shown in Fig. 1. Based on the maternal age distribution of pregnancies and the risk of trisomy 21 at 12 weeks, we would expect to see 26 cases of trisomy 21 in the study population. The median maternal weight of the population was 65.8 kg (range 29.6 to 143.0). Cigarette smoking was self-reported in 18.1%, with 80.8% reporting themselves as non-smokers and the status unknown in 1.1% of cases.

image

Figure 1. Age distribution of the population screened in the first trimester.

Download figure to PowerPoint

Fetal death was noted on the ultrasound examination in 1.8% (223 of 12,339) of cases. According to the measurement of fetal crown–rump length, the gestation was prior to the minimum acceptable period in 8.3% (1030 of 12,339) of cases and these women were rebooked for repeat examination at the appropriate gestation. Additionally, in 5.7% (702 of 12,339) of women the gestation was beyond 14 weeks and they had conventional second trimester screening1 with α-fetoprotein and free β-hCG. A further 594 women had second trimester screening because they were either transferred from other hospitals or they booked with our hospital after 14 weeks. In total, after exclusion of those women with fetal demise at presentation, those declining screening and those with crown–rump length beyond 84 mm, some 11,105 women with singleton pregnancies had first trimester screening performed. In total a further 1296 women had second trimester biochemical screening. No woman had both first trimester and second trimester screening for chromosomal anomalies, in line with the Trusts screening policy.

Failure to obtain a satisfactory nuchal translucency thickness measurement by either transabdominal or transvaginal ultrasound on the first clinic visit, necessitating a further clinic visit, occurred in less than 0.1% (5 of 11,105) of cases.

Of the women screened in the OSCAR clinic, 5.2% (577 of 11,105) had risks greater than the 1 in 300 cutoff. After counselling, 23% (135 of 577) declined the offer of an invasive diagnostic test, while 77% (442 of 577) accepted invasive testing. The rate of acceptance of offers of invasive testing was related to the level of the risk for trisomy 21 as shown in Table 1. Women with a risk of 1 in 300 to 1 in 200 were three times more likely to decline invasive testing than those with risk of 1 in 100 or greater. In the group of women declining invasive testing, one case of trisomy 21 was live born. Chorionic villus sampling was the procedure chosen by 97.1% (429 of 442) of women requesting invasive testing, while 2.9% (13 of 442) decided to wait until 16 weeks for amniocentesis. Fetal death within 28 days of the chorionic villus sampling procedure was observed in four cases and fetal death prior to termination of pregnancy for a fetal abnormality was observed in a further four cases. In total this represented a fetal loss rate of 1.9% (8 of 429) at the extreme and 0.9% (4 of 429) for normal pregnancies. No fetal loss occurred among the 13 women having amniocentesis.

Table 1.  Rate of declining invasive testing.
Risk (1 in)No. of casesNo. declining% declining
1 to 50157159.5
51 to 100992121.2
101 to 150991818.2
151 to 200551120.0
201 to 250943638.3
251 to 300733446.6

Among the singleton study population, 51 aneuploidies were ascertained (Table 2). A combination of maternal age, fetal nuchal translucency thickness, maternal serum free β-hCG and PAPP-A identified 92% (23 of 25) of cases with trisomy 21, 100% (all 15) with trisomies 13 or 18, and in total, 96% (49 of 51) of all cases of aneuploidy. There was one case of aneuploidy detected per nine chorionic villus sampling procedures and one case of trisomy 21 detected per 19 chorionic villus sampling procedures. All women with an identified chromosomal anomaly elected to terminate the pregnancy.

Table 2.  Women identified as being at high risk (equal or more than 1 in 300) by first trimester screening by a combination of fetal nuchal translucency thickness and maternal serum free β-hCG and PAPP-A. Values in parentheses are in (%).
FetusTotal casesRisk ≥1 in 300
Normal11,105577 (5.2)
Trisomy 212523 (92)
Trisomy 181111
Trisomy 1344
45x44
47xxy/xxx22
Triploidy55

The total screened population was examined based on the nuchal translucency thickness/maternal age risk and the biochemistry/maternal age risk, at a risk cutoff which gave a 5% false positive rate (1 in 300 for nuchal translucency thickness and 1 in 100 for biochemistry). For nuchal translucency thickness and age alone, 19 of 25 cases of trisomy 21 (76%) would have been identified while biochemistry and age alone identified 17 of 25 cases (68%). The addition of biochemistry to nuchal translucency thickness and age increased the detection rate by a further 16%; these results are consistent with our retrospective and modelled predictions9.

In the group of 309 women declining first trimester screening, two cases resulted in the birth of a baby affected by trisomy 21. Additionally, there was one live birth with trisomy 21 in a pregnancy identified by screening as being at increased risk but the mother declined invasive testing.

In the group of women who were too late for first trimester screening (702 cases presenting through OSCAR and 594 late bookers), second trimester maternal serum biochemical screening using a term risk cutoff of 1 in 250 identified 6.1% (79 of 1296) at increased risk. An invasive diagnostic procedure was carried out in 70 cases and trisomy 21 was identified in two of these cases, resulting in termination of both pregnancies. There were no fetal losses in the 70 women who had amniocentesis.

One of the criticisms raised of moving screening into the first trimester is the loss of ability to screen for neural tube defects or abdominal wall defects. Maternal serum α-fetoprotein has been shown21–23 to be ineffective at screening for these conditions prior to 14 weeks. In our programme we have relied upon ultrasonography at the 11–14 weeks scan or the 20–23 weeks anomaly scan to identify such abnormalities24–26. In total we observed 19 cases with neural tube defects and 12 further cases with abdominal wall defects. Of the neural tube defects cases, 10 were classified as acrania/exencephaly/anencephaly, with 8 cases being diagnosed at the 11–14 weeks scan and only 2 cases identified on the 20–23 weeks scan. Spina bifida was identified in seven cases only at the 20–23 weeks scan and in a further two cases at 17 weeks as a result of a raised α-fetoprotein in a second trimester screen for trisomy 21. No case of neural tube defects was missed by ultrasound scanning. All cases with abdominal wall defects were seen on the 11–14 weeks scan.

Periodic audit of the clinic response time to deliver a risk report to women showed that on average, the time between the clinic appointment and the time when a report was discussed with the mother was 56 minutes.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

This study has demonstrated the feasibility and efficacy of introducing an OSCAR for chromosomal abnormalities in a District General Hospital. The uptake of first trimester screening was 97.5% and the uptake of invasive testing in the screen positive group was 77%. For a false positive rate of about 5%, the rate of detection of trisomy 21 was 92% and of all aneuploidies was 96%. In the first trimester, the prevalence of trisomy 21 and other aneuploidies is considerably greater than at term or indeed at the second trimester. Our prevalence of 25 cases per 11,105 women is consistent with that expected from the maternal age profile of our population and the risk of trisomy 21 at 12 weeks of gestation.

The importance of accurate risk estimates is shown by the reduction in the number of unnecessary invasive tests as one fetal aneuploidy was detected per nine chorionic villus sampling procedures and by the influence that risk has on women's acceptance of invasive testing. An important additional finding of our study is that all cases of fetal neural tube and abdominal wall defects were identified by ultrasound examination either in the first or in the second trimesters of pregnancy.

The findings of the study confirm our prediction that a combination of maternal serum free β-hCG and PAPP-A with fetal nuchal translucency thickness at 11–14 weeks of gestation would identify about 90% of trisomy 21 pregnancies for a 5% false positive rate9, which is far superior to the average sensitivity of 65% achievable by second trimester biochemical screening2. Even when fetal loss rates are taken into account27, the detection rate is more then 20% higher than in the second trimester. Additionally, our findings provide further justification for the recommendations of the 32nd Study Group of the Royal College of Obstetricians and Gynaecologists in 1997. The Study Group concluded that the evidence on first trimester screening for trisomy 21 by nuchal translucency and/or biochemical methods was sufficiently well developed to move out of the research phase into routine practice and that the detection rates by the combined use of biochemistry and ultrasound in early pregnancy would be superior to those obtained with biochemical screening in the second trimester28.

Combining fetal nuchal translucency thickness measurement with maternal serum biochemical markers was first suggested by Brizot et al.29, when PAPP-A was combined with fetal nuchal translucency thickness. Subsequently, others have shown very consistent detection rates in studies using the Fetal Medicine Foundation NT data and maternal serum biochemistry in large scale retrospective studies (Table 3) and in prospective practice17,33. In view of the evidence in favour of first trimester screening, this method is being widely adopted in many European countries. In Britain, however, the UK National Screening Committee and its subsidiary Antenatal Screening Sub Committee are proposing a National Down's Syndrome Screening Programme based on a second trimester service (www.nelh.nhs.uk/screening/antenatal_pps/down.html).

Table 3.  Modelled trisomy 21 detection rates using fetal nuchal translucency thickness and maternal serum biochemistry at a 5% false positive rate.
StudyCases (biochemistry)Controls (biochemistry)Gestation (weeks)Source of nuchal translucency thicknessDetection rate (%)
Wald and Hackshaw30773878–14Estimated from literature80
Orlandi et al.31774410–14Own, Fetal Medicine Foundation trained87
Spencer et al.921094610–14Fetal Medicine Foundation89
Cuckle and van Lith32Meta-analysis of published data 8–14Fetal Medicine Foundation87

One-stop clinics have developed in several clinical areas over the past decade, ranging from breast cancer screening to cardiovascular risk clinics and one-stop surgical clinics. These services, which integrate diagnostic and therapeutic services, aim to improve efficiency and provide a higher quality of clinical care. They also aim to improve patient satisfaction by reducing the number of visits and minimising travel cost, patient anxiety and stress. In the context of prenatal screening for chromosomal anomalies, integration of counselling, ultrasound, biochemistry, midwifery and obstetrics in a one-stop clinic does seem to be acceptable to women and, while offering maximum utilisation of hospital outpatient resources, provides a high diagnostic efficiency and the potential for a more informed choice.

The setting up of our one-stop clinic required little change to our normal obstetric practice. Since 1997, our obstetric ultrasound department has been part of the Fetal Medicine Foundation project8 and the introduction of fetal nuchal translucency thickness scanning was carried out by reorganising scanning times and did not require additional resources. Our early booking clinic was already in place for dating pregnancies and the only change that was required was to relocate the biochemistry analyser from the main laboratory to the clinic laboratory. The appointment of a midwife counsellor in the clinic was already planned as part of our improvement to second trimester screening. The reagent/instrument costs of biochemical screening using this new technology were estimated to be comparable to that of screening in the second trimester, with costs per screen of the order of £6.00.

We believe it is time for national policymakers to examine the real evidence of what can be achieved in routine District General Hospitals and we agree that it is time for a total shift to first trimester screening for Down's Syndrome34.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

The OSCAR clinic is a multidisciplinary clinic which functions because of the dedication of all contributors to the team. The authors would like to thank all the staff in midwifery, obstetrics, sonography, pathology and administration for their support and contributions.

Contributors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

KS designed and implemented the OSCAR clinic. KS, CES, MP, CD collected data. KHN provided training for sonographers and supervised diagnostic testing. KS wrote the paper with all authors commenting on the drafts. KS is the guarantor.

Competing Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References

KS acts as an advisor to Brahms Diagnostica on matters of prenatal screening.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Contributors
  9. Funding
  10. Competing Interests
  11. References
  • 1
    Spencer K. Second trimester prenatal screening for Down's syndrome using α-fetoprotein and free β-hCG: a seven year review. Br J Obstet Gynaecol 1999;106: 12871293.
  • 2
    Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome. Health Technol Assess 1998;2: 1112.
  • 3
    Spencer K, Mallard AS, Coombes EJ, Macri JN. Prenatal screening for trisomy 21 with free beta hCG as a marker. BMJ 1993;307: 14551458.
  • 4
    Benn PA, Ying J, Beazoglou T, Egan JFX. Estimates for the sensitivity and false positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross identification and double positive results. Prenat Diagn 2001;21: 4651.
  • 5
    Spencer K, Macri JN, Aitken DA, Connor JM. Free β-hCG as a first trimester marker for fetal trisomy. Lancet 1992;339: 1480.
  • 6
    Brambati B, Lanzani A, Tului L. Ultrasound and biochemical assessment of first trimester pregnancy. In: ChapmanM, GrudzinskasJG, ChardT editors. The Embryo: Normal and Abnormal Development and Growth. New York : Springer-Verlag, 1991: 181194
  • 7
    Nicolaides KH, Azar G, Bryne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in the first trimester of pregnancy. BMJ 1992;304: 876879.
  • 8
    Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk for trisomy 21 by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Lancet 1999;18: 519521.
  • 9
    Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10–14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy associated plasma protein-A. Ultrasound Obstet Gynecol 1999;13: 231237.
  • 10
    Tul N, Spencer K, Noble P, Chan C, Nicolaides KH. 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 2000;19: 10351042.
  • 11
    Spencer K, Ong C, Skentou H, Liao AW, Nicolaides KH. Screening for trisomy 13 by fetal nuchal translucency and maternal serum free beta hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 2000a;20: 495499.
  • 12
    Spencer K, Tul N, Nicolaides KH. Maternal serum free beta hCG and PAPP-A in fetal sex chromosome defects in the first trimester. Prenat Diagn 2000;20: 390394.
  • 13
    Spencer K, Liao AWJ, Skentou H, Cicero S, Nicolaides KH. Screening for triploidy by fetal nuchal translucency and maternal serum free beta hCG and PAPP-A at 10–14 weeks of gestation. Prenat Diagn 2000;20: 495499.
  • 14
    Spencer K, Nicolaides KH. A first trimester Trisomy13/Trisomy 18 risk algorithm combining fetal nuchal translucency thickness, maternal serum free β-hCG and PAPP-A. Prenat Diagn 2002;22: 877879.
  • 15
    Spencer K. Point-of-care screening for chromosomal anomalies in the first trimester of pregnancy. Clin Chem 2002;48: 403404.
  • 16
    Spencer K. Near patient testing and Down's syndrome screening. Proc UK NEQAS 1998;3: 130.
  • 17
    Spencer K, Spencer CE, Power M, Moakes A, Nicolaides KH. 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. Br J Obstet Gynaecol 2000;107: 12711275.
  • 18
    Spencer K. Evaluation of effect of analytical imprecision in maternal serum screening for Down's syndrome. Ann Clin Biochem 2001;38: 413414.
  • 19
    Snijders RJM, Sebire NJ, Nicolaides KH. Maternal age and gestational age specific risks for chromosomal defects. Fetal Diagn Ther 1995;10: 356357.
  • 20
    Snijders RJM, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age and gestation specific risk for trisomy 21. Ultrasound Obstet Gynecol 1999;13: 167170.
  • 21
    Aitken DA, McCaw G, Crossley JA, et al. First trimester biochemical screening for fetal chromosomal abnormalities and neural tube defects. Prenat Diagn 1993;12: 681689.
  • 22
    Sebire NJ, Spencer K, Noble PL, Hughes K, Nicolaides KH. Maternal serum alpha-fetoprotein in fetal neural tube and abdominal wall defects at 10 to 14 weeks of gestation. Br J Obstet Gynaecol 1997;104: 849851.
  • 23
    Wald NJ, Cuckle H, Brock JH, et al. Report of the UK Collaborative study on alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Lancet 1997;1: 13231332.
  • 24
    Snijders RJM, Brizot ML, Faria M, Nicolaides KH. Fetal exomphalos at 11–14 weeks of gestation. J Ultrasound Med 1995;14: 569574.
  • 25
    Johnson SP, Sebire NJ, Snijders RJM, Tunkel S, Nicolaides KH. Ultrasound screening for anencephaly at 10–14 weeks of gestation. Ultrasound Obstet Gynecol 1996;9: 1416.
  • 26
    Nicolaides KH, Campbell S, Gabbe SG, Guidetti R. Ultrasound screening for spina bifida: cranial and cerebellar signs. Lancet 1986;2: 7274.
  • 27
    Spencer K. What is the true fetal loss rate in pregnancies affected by trisomy 21 and how does this influence whether first trimester detection rates are superior to those in the second trimester. Prenat Diagn 2001;21: 788789.
  • 28
    Grudzinskas JG, Ward RHT. Screening for Down Syndrome in the First Trimester. 1997 London : RCOG Press,
  • 29
    Brizot ML, Snijders RJM, Bersinger NA, Kohn P, Nicolaides KH. Maternal serum pregnancy associated plasma protein A and fetal nuchal translucency thickness for the prediction of fetal trisomies in early pregnancy. Obstet Gynecol 1994;84: 918922.
  • 30
    Wald NJ, Hackshaw AK. Combining ultrasound and biochemistry in first trimester screening for Down's syndrome. Prenat Diagn 1997;17: 821829.
  • 31
    Orlandi F, Damiani G, Hallahan TW, Krantz DA, Macri JN. First trimester screening for fetal aneuploidy: biochemistry and nuchal translucency. Ultrasound Obstet Gynecol 1997;6: 381386.
  • 32
    Cuckle HS, van Lith JMM. Appropriate biochemical parameters in first trimester screening for Down Syndrome. Prenat Diagn 1999;19: 505512.
  • 33
    Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW, Macri JN. First trimester Down syndrome screening using dried blood and nuchal translucency. Obstet Gynecol 2000;96: 207213.
  • 34
    Cuckle H. Time for a total shift to first trimester screening for Down's Syndrome. Lancet 2001;358: 16581659.