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
Corresponence: Dr K. Spencer, Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Gubbins Lane, Romford, Essex RM3 OBE, UK.
Objective To evaluate the introduction of a one stop multidisciplinary clinic for screening for fetal chromosomal abnormalities in the first trimester by a combination of maternal serum biochemistry and ultrasonography providing a risk of chromosomal abnormalities within a one hour clinic visit.
Design One year retrospective review of screening performance.
Population All women attending for routine antenatal care. The population included 4190 singleton pregnancies in women of all ages screened between 10 weeks and 3 days and 13 weeks and 6 days of gestation between the periods 1 June 1998 and 31 May 1999 in a district general hospital antenatal clinic.
Methods All women booked into the clinic were offered screening by a combination of maternal serum free β human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein A (PAPP-A) and fetal nuchal translucency thickness. Women at increased risk of carrying a fetus with trisomy 21 or trisomy 18/13 (≥ 1 in 300 at sampling) were offered counselling and an invasive diagnostic procedure. Follow up of the outcome of all pregnancies was carried out.
Main outcome measures The detection rate for trisomy 21, trisomy 18/13 and all aneuploides, false positive rate, uptake of screening, uptake of chorionic villus sampling in women identified at increased risk and fetal loss after chorionic villus sampling.
Results Overall 97.6% of the women (4088/4190) accepted first trimester screening. The rate of detection of trisomy 21 was 86% (6/7), for trisomy 18/13 100% (9/9) and for all aneuploides 95% (18/19). Fetal death at presentation was found in 1.6% of pregnancies (69/4088). Of women who accepted screening, 6.1% (257/4088) presented too late for fetal nuchal translucency measurement and 6.5% of the women (271/4088) presented too early. The false positive rate was 6.7% (253/3762). Uptake of invasive testing was 83% (207/253).
Conclusion First trimester prenatal screening for chromosomal abnormalities using a combination of maternal serum biochemistry and fetal nuchal translucency thickness can achieve detection rates in excess of 90%. These services can be provided in a one stop multidisciplinary clinic.
Screening for trisomy 21 in the second trimester of pregnancy by measurement of maternal serum biochemical markers has become an established part of obstetric practice in many countries. Our experience with the marker combination of maternal age, maternal serum free β human chorionic gonadotrophin (hCG) and alpha-fetoprotein over a seven-year period has shown a detection rate of 75% for a 5.1% false positive rate1.Similarly, prospective detection rates of 48 to 75% (average 64%, corrected for fetal loss) have been reported for a combination of maternal age, maternal serum levels of total hCG, alpha-fetoprotein and uncon-jugated oestriol2. Prospective detection rates for trisomy 18 using a standard protocol3 have been shown1 to match those in retrospective series, showing a 57% detection rate at a 0.7% false positive rate
Recently, interest in prenatal screening for chromosomal anomalies has been focused on the first trimester4. Of the biochemical markers investigated during this period, only maternal serum free β hCG and pregnancy associated plasma protein A (PAPP-A) have been shown to be of any potential clinical value. In a large retrospective series of 210 cases of trisomy 21 we have shown a detection rate in combination with maternal age of 67% at a 5% false positive rate when biochemical markers are used5. However, the single most predictive marker of chromosomal anomalies during the 10–14 week period is the sonographic measurement of fetal nuchal translu-cency thickness5,6. A recent multicentre study6 involving 100,000 screened pregnancies has demonstrated that screening by a combination of maternal age with fetal nuchal translucency thickness identified 82% of trisomy 21 cases and 78% of other chromosomal abnormalities.
In a retrospective study5 of 210 cases of trisomy 21, 50 cases of trisomy 187, 42 cases of trisomy 138, 59 cases of sex chromosomal abnormalities9 and 25 cases of triploidy10, we examined the potential impact of combining fetal nuchal translucency thickness with maternal serum free β hCG and PAPP-A in screening between 10 and 14 weeks of pregnancy using a novel rapid immunoassay technology5. These studies showed that combining fetal nuchal translucency thickness and maternal serum biochemistry would identify about 90% of cases of trisomy 21 and 90% of other chromosomal anomalies.
The rapid diagnostic immunoassay technology Kryp-tor can provide automated reproducible biochemical measurements within 30 minutes of obtaining a blood sample. This allowed us to propose the development of a multidisciplinary one stop clinic for assessment of risk (OSCAR) in which, within a one hour visit, the patient has pre-test counselling, blood collection and biochemical assessment, ultrasound assessment including measurement of crown-rump length and fetal nuchal translucency thickness, prior to receiving post test counselling and a combined risk report11. Here we report the results from the first year of screening for chromosomal anomalies in our one stop clinic.
All women booking for maternity care at Harold Wood Hospital, Essex are given an appointment to attend the antenatal clinic for the first time when they are between 10 weeks 3 days and 13 weeks 6 days. Women are first seen in the community by a member of the community midwifery team and they receive an information leaflet about the one stop clinic service. When they attend the clinic, they have a consultation with a senior midwife concerning the available tests and, if they elect to have prenatal screening for chromosomal abnormalities, all relevant clinical information is recorded on requests forms. We considered that introduction of this new service as routine was justified, based on the latest Royal College of Obstetricians and Gynaecologists first trimester screening guidelines4, our previous large scale retrospective studies5–10, and the fact that pre-test counselling is offered before opting into the screening program. After the pre-test counselling, women opting for screening go to the phlebotomy room where blood samples are taken for serum biochemistry, in addition to the samples for routine investigations. The prenatal screening blood samples are passed through to the clinic laboratory and the woman then moves on to the ultrasound suite where fetal nuchal translucency thickness and crown-rump length are measured using standard procedures6 by sonographers certified by the Fetal Medicine Foundation. All relevant clinical information is recorded on a networked fetal database. If the patient has a gestational age prior to 10 weeks 3 days (crown-rump length = 38 mm), then they are sent back to the reception area to be rebooked at a time when they are within the 10 week 3 day to 13 week 6 day period (crown-rump length = 84 mm). If the gestation is ≥ 14 weeks the laboratory is informed and alpha-fetoprotein measured instead of PAPP-A. In the laboratory each blood sample is separated and placed on the Kryptor analyser (CIS United Kingdom Ltd, High Wycombe, UK) for free β hCG and PAPP-A analysis. The performance of this system has been previously described5. When the results are available (20 minutes later) these are logged onto the 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 arranged. The patient-specific risks were calculated by the multivariate likelihood approach12 using the population parameters established in our retrospective study5 and the age related risk of the trisomy at the time of sampling13.
Patients with increased risk (≥ 1 in 300) of trisomy 21 or trisomy 13 or 18 are referred to the Harris Birthright Research Centre for Fetal Medicine for fetal karyotyping. Provisional results from karyotyping of chorionic villus sampling material were usually available within three days (direct preparation using polymerase chain reaction)14 and a confirmed diagnosis within seven days. Outcome of all pregnancies was ascertained from delivery room and child health records and cross checked with the fetal database and cytogenetic records obtained from the laboratory, child health computer records and from the National Down's Syndrome register.
In previous years maternal serum alpha-fetoprotein in the second trimester had been used for screening for neural tube defects, but since 1991 we had used ultrasound rather than amniotic fluid alpha-fetoprotein and acetyl cholinesterase as the diagnostic tests. When a decision was made to move to first trimester screening, it was done knowing that neural tube defect screening at this earlier time would not be possible15,16. However, our experience of ultrasound diagnosis at 18–22 weeks had not resulted in a case being missed. We were confident, therefore, to rely entirely on ultrasound to diagnose cases of neural tube defect.
During a one-year period (1 June 1998 to 31 May 1999), a total of 4190 women with a singleton pregnancy were offered late first trimester screening using the one stop clinic. The uptake of screening was 97.6% (4088/4190). Fetal death was noted on ultrasound examination in 1.6% (69/4088). According to the measurement of fetal crown-rump length the gestation was < 10 weeks in 6.5% of cases (271/4088), and these women were re-booked at the appropriate time for repeat blood and ultrasound examination. A further 6.1% of women (257/4088) presented too late for fetal nuchal translucency thickness measurement and these women had a conventional second trimester screen1 of alpha-fetoprotein and free β hCG. Additionally, 91 women were either second trimester transfers from other hospitals or booked with the hospital after the 14th week. In total 348 of all deliveries (8%) had a second trimester screen compared with 3762 (88%) having a first trimester screen.
The median age of all women screened in the first trimester was 29, including 12.7% who were aged ≥ 35 years and 6.1% who were aged ≥ 37 years or older. The median maternal weight of the population was 65.4 kg. The median fetal crown-rump length was 56.5 mm giving a median gestation of 84 days. Smoking status was by self assignment and 19.2% of women indicated themselves as smokers.
Of the cases screened, 6.7% (253/3762) had risks which were greater than the 1 in 300 cut off for trisomy 21 (5.5%) or trisomy 18/13 (1.2%). When counselled about this risk, 82% (207/253) decided to undergo invasive testing, with 200 deciding on chorionic villus sampling and a further seven opting to wait until 14 weeks for amniocentesis. In the 200 women having chorionic villus sampling, fetal demise within 28 days of the procedure was observed in two cases (1%), of which one was a case of trisomy 21. The rate of acceptance of chorionic villus sampling was related to the trisomy 21 risk reported. Women with risks of ≥ 1 in 100 were three times more likely to accept chorionic villus sampling than those in the risk group 1 in 200 to 1 in 300.
In the study population some 19 aneuploidies were ascertained (Table 1). The combination of maternal age, fetal nuchal translucency thickness and maternal serum free β hCG and PAPP-A identified 86% (6/7) of the cases of trisomy 21, 100% (9/9) of the cases of trisomy 18 or 13 and 95% (18/19) of all cases of aneuploidy. There was one case of aneuploidy detected per 11 chorionic villus sampling procedures. In the population of women who declined further invasive testing no chromosomal abnormalities were observed. In the population of women who declined screening there was one case of trisomy 8 born to a 30 year old woman.
Table 1. Cases of aneuploidies identified in the screened population during the one year period June 1st 1998 to May 31st 1999. CRL = crown.rump length; PAPP.A = pregnancy associated plasma protein A; NT = fetal nuchal translucency thickness; MoM = multiple of the median; T18/T13 = trisomy 18/13; TOP = termination of pregnancy.
|1||34||51.5||79||1.39||0.23||3.19||1 in 6||1 in2||No||T21||Miscarried|
|2||37||41.3||75||2.73||0.17||3.01||1 in 4||1 in2||No||T21||TOP|
|3||38||60||86||3.32||0.37||0.90||1 in 584||1 in6||No||T21||TOP|
|4||30||38.3||73||3.02||0.46||0.91||1 in 3713||1 in 174||No||T21||TOP|
|5||33||53.5||82||1.83||0.14||2.88||1 in 8||1 in2||No||T21||TOP|
|6||34||71.4||92||1.39||0.79||0.90||1 in 2250||1 in 3315||No||T21||Live born|
|7||40||51.0||81||2.45||0.23||2.99||1 in 4||1 in 2||No||T21||TOP|
|8||39||39.7||78||0.40||0.79||3.19||1 in 2||1 in l6||Yes||T18||TOP|
|9||27||63.7||88||0.48||0.18||5.07||1 in lO||1 in 2||Yes||T18||TOP|
|10||28||55||83||0.14||0.20||6.87||1 in l3||1 in 8||Yes||T18||TOP|
|11||33||59.9||86||0.37||0.17||2.25||1 in 26||1 in 3||Yes||T18||TOP|
|12||33||56.5||84||0.55||0.19||7.39||1 in 7||1 in 2||Yes||T18||TOP|
|13||40||42.4||76||0.42||0.25||4.21||1 in 3||1 in 2||Yes||T18||TOP|
|14||38||43.1||76||0.77||0.28||5.49||1 in 3||1 in 2||Yes||T18||TOP|
|15||40||59.8||86||0.26||0.12||0.96||1 in 378||1 in 24||Yes||T13||TOP|
|16||28||52.1||82||1.08||0.36||3.01||1 in 13||1 in 4||No||T13||TOP|
|17||27||55.8||84||5.69||0.38||3.46||1 in 14||1 in 2||No||Triploidy||TOP|
|18||23||54.6||83||0.06||0.05||0.90||1 in 6851||1 in 29||Yes||Triploidy||TOP|
|19||33||50.3||81||0.19||0.26||1.25||1 in 791||1 in 996||Yes||47xxx||TOP|
In the group of 253 cases identified as ‘at increased risk’ (in addition to the anomalies in Table 1) there were three cases with fetal death at 18–22 weeks of gestation, five cases of fetal renal abnormalities, one case of mytonic dystrophy (the patient had a previously affected pregnancy and in this pregnancy diagnosis was made by DNA analysis of the chorionic villus sampling sample) and five cases with major cardiac defects. In total, outcome analysis identified 10 cases with major cardiac defects of which 5 of the 10 (50%) showed an increased risk of chromosomal anomalies. Although increased fetal nuchal translucency thickness is associated with an increased risk of cardiac abnormalities17, in two of the five cases identified the fetal nuchal translucency thickness was normal but the free β hCG was greatly elevated.
In total seven cases of neural tube defect were observed along with two cases with ventral wall defects. Both cases with ventral wall defects were observed on the first trimester scan, as were two of the seven cases with neural tube defect. The remaining five cases of neural tube defect were identified at the 18–22 week anomaly scan. No case of neural tube defect was missed by ultrasound scanning.
To assess the clinic response time in the delivery of risk reports a time audit was carried out of the clinic process. A survey of 210 women showed that the average time between their clinic appointment and the time when a report was being discussed with the patients was 57 minutes.
In 1997 the 32nd Study Group4 of the Royal College of Obstetricians and Gynaecologists concluded that there was evidence that first trimester screening for Down's Syndrome by nuchal translucency and/or biochemical methods was sufficiently well developed to move out of the research phase into routine practice and that the combined use of biochemical markers and nuchal translucency would give detection rates superior to that obtained with biochemical screening in the second trimester.
The availability of new immunodiagnostic technology in the form of Kryptor (a random access, continuous access immunoassay analyser using the Nobel Prize winning TRACE technology) has allowed the development of rapid homogenous immunoassays. This technology has made it possible for us to propose a revolutionary scheme in the management of prenatal screening for Down's Syndrome in the first trimester. We have set up a first trimester combined biochemistry and nuchal translucency single risk assessment clinic where the biochemical testing and ultrasound scanning are all carried out within the confines of one clinic. This has enabled the woman, within a one hour visit, to be booked, receive pre-test counselling, to have ultrasound and biochemical measurements performed and a single risk assessment calculated, before receiving post test counselling with an obstetrician or midwife counsellor.
Our previous retrospective studies5,7–10 have shown that detection rates of 90% could be achieved for the major chromosomal abnormalities using a combination of fetal nuchal translucency thickness and maternal serum biochemistry. Our current analysis of the first year of prospective intervention screening in our one stop clinic has confirmed the predictions from our retrospective studies with detection rates of 86% for trisomy 21 and 95% for all aneuploidies. Dunstan and Nix18 have shown that in order for a first trimester test to be considered superior to that in the second trimester, the detection rate should be at least 8.3% higher in order to account for the fetal loss rate between first and second trimesters. Our findings demonstrate that first trimester screening by fetal nuchal translucency thickness and maternal serum biochemistry is superior to second trimester biochemistry alone, since with the latter method the detection rate is on average 65%2.
The one stop clinic approach was viewed very favourably by pregnant women in our clinic as shown by the very high uptake of screening. The 98% uptake of the offer of screening is higher than any study report in the second trimester with average uptakes of 73% for a triple marker approach and 88% for a double marker approach2. Our uptake of 98% is also considerably higher than the 87% achieved over seven years of second trimester screening1. Whether this increased uptake is due solely to screening being carried out at the earlier period or whether this is due to the mode of service delivery in a one stop clinic, is the subject of further psychological studies. The possibility that patient anxiety around the screening process is reduced by being delivered in a one stop clinic is also being addressed in ongoing studies.
The setting up of our one stop clinic clinic required little change to our normal obstetric practice. Since 1997 our obstetric ultrasound department has been part of the Fetal Medicine Foundation project6 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 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 a requirement for second trimester screening. The reagent/instrument costs of biochemical screening using this new technology was estimated to be comparable to that of screening in the second trimester, with costs per screen being of the order of £6.00.
The exclusion of second trimester maternal serum screening for neural tube defect and the reliance on ultrasound identification of ventral wall defects and neural tube defect's, either at the first trimester or the second trimester scan, was successful, with no case of either anomaly being missed.
This study has demonstrated the feasibility of introducing an one stop clinic service as part of routine antenatal care in a district general hospital. An integration of ultrasonographic, biochemical and counselling services into a single clinic, which has been achieved with a minimum of expense, has proven to be popular with women and medical staff and has identified more than 90% of all aneuploides in the first trimester of pregnancy. Preliminary data suggest that such a service can also help to identify women at risk of other fetal abnormalities and may provide the basis for screening for pregnancy complications, such as pre-eclampsia and intrauterine growth restriction19,20. The role of audit and quality assurance will become increasingly important in the future for both biochemistry and ultrasound in this screening context. We endorse the views expressed in the Royal College of Obstetricians and Gynaecologists guidelines4 that ultrasound audit should be carried out by an independent agency (as is already provided by the Fetal Medicine Foundation), that centres using maternal serum biochemistry must take part in the UKNEQAS scheme for first trimester screening21 and that the organisational management of devolved screening should be monitored as part of a larger regional audit program.
The authors would like to thank all the obstetricians for their support in introducing our one stop assessment of risk clinic and all of the members of the interdisciplinary team, including sonographers, biochemistry staff, Ms L. Jenkins and the midwifery staff, for their efforts. The biochemical functions of the one stop clinic were kindly funded by CIS (UK) Ltd.