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Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000207562.09858.16
Original Research: Lead Article

First-Trimester Combined Screening for Down Syndrome and Other Fetal Anomalies

O’Leary, Peter PhD, BSc1; Breheny, Nikki GDipSocRes1; Dickinson, Jan E. MD2; Bower, Carol MBBS, PhD3; Goldblatt, Jack MB, ChB4; Hewitt, Beverley MBBS5; Murch, Ashleigh PhD6; Stock, Rosanne RN7

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Author Information

From the 1Genomics Directorate, Department of Health Western Australia; 2School of Women’s and Infants’ Health, the University of Western Australia; 3Birth Defects Registry, Women’s and Children’s Health Service, Centre for Child Health Research, Telethon Institute for Child Health Research, the University of Western Australia; 4Genetic Services of Western Australia, Women’s and Children’s Health Service, School of Paediatrics, the University of Western Australia; 5Park Ultrasound, West Perth, Western Australia; and 6PathWest, Women’s and Children’s Health Service.

Corresponding author: Dr. Peter O’Leary, PhD, BSc, Director, Genomics Directorate, Department of Health Western Australia, PO Box 8172 Stirling Street, Perth WA 6849 Australia; e-mail: peter.oleary@health.wa.gov.au.

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Abstract

OBJECTIVE: This study assessed fetal outcomes for pregnancies identified at increased risk for Down syndrome by first-trimester combined ultrasound examination and maternal serum biochemistry screening.

METHODS: First-trimester combined screening data were obtained from ultrasound clinics across Western Australia between August 2001 and October 2003. Prenatal screening data were linked with pregnancy outcome information held in state health database registers using probabilistic record-linkage techniques.

RESULTS: In 50 of the 60 pregnancies affected by Down syndrome, the adjusted risk was greater than 1 in 300, providing a detection rate of 83% (95% confidence interval [CI] 74–93%). Among all women screened (n = 22,280), 827 had increased risk results but did not have a Down syndrome pregnancy, representing a false-positive rate of 3.7% (95% CI 3.5–3.9%). Ten cases of Down syndrome were detected among women considered not at increased risk, consistent with a false-negative rate of 1 in 2,227. First-trimester combined screening reduced the number of Down syndrome births by 50 in 22,280 (2.24 cases per 1,000 births), which represents the detection of one case of fetal Down syndrome for every 446 women screened. Furthermore, 25% of pregnancies with other birth defects occurred among those identified at increased risk of Down syndrome, and 1 in 8 pregnancies at increased risk were found to have a significant chromosomal or structural defect.

CONCLUSION: First-trimester combined screening in Western Australia detected 83% (95% CI 74–93%) of Down syndrome pregnancies at a 3.7% (95% CI 3.5–3.9%) false-positive rate.

LEVEL OF EVIDENCE: II-2

The risk to any pregnant couple of having a liveborn infant with a chromosomal abnormality or structural defect is between 3% and 5%.1 However, the relationship between advancing maternal age and the chance of having a fetus with a chromosomal disorder, particularly Down syndrome (trisomy 21), has been recognized for over 40 years and formed the basis for age-related screening tests.2,3 More recently, other predictive markers have refined the risk estimation for Down syndrome and expanded the range of fetal defects that can be detected through prenatal screening. Second-trimester maternal serum hormone markers4 and first-trimester ultrasound measurement of fetal nuchal translucency,5,6 in combination with maternal serum biochemistry markers,7,8 are now the established standard of care in Australia.9 In initial studies, first-trimester screening detection rates for Down syndrome exceeded 90%.8,10,11 However, others have more recently reported less optimistic results, ranging from 79% in the BUN multicenter study,12 to 83% in the Serum, Urine and Ultrasound Screening Study (SURUSS) trials,13 and up to 87% in the First and Second Trimester Evaluation of Risk trial (FASTER),14 and each at a 5% false-positive rate.

The degree of uncertainty15 about the actual performance of prenatal screening programs prompted a retrospective evaluation of the first-trimester screening outcomes in our region. Population screening across public and private health sectors is difficult to monitor at a statewide level, particularly because Western Australia makes up a third of Australia’s total land area,16 with almost 2,000 general practitioners and obstetricians providing antenatal services. However, unique statewide health data collections, including registries for midwives notifications, birth defects, and hospital separations, combined with the individual providers’ ultrasound prenatal screening data, enabled us to review the performance of first-trimester prenatal screening in Western Australia. This study estimated the detection and false-positive rates of the first-trimester combined screening program in Western Australia, which incorporates maternal age data, fetal nuchal translucency measurements, maternal serum biochemistry markers, free β-hCG, and pregnancy-associated plasma protein-A (PAPP-A). The study also enabled evaluation of the secondary outcomes of first-trimester screening, including the ascertainment of nonchromosomal fetal anomalies in Western Australia.

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MATERIALS AND METHODS

In Western Australia, first-trimester combined screening between 11 weeks and 13 weeks plus 6 days of gestation incorporates fetal nuchal translucency and maternal serum free β-hCG and PAPP-A measurements, conducted through independent and government-supported facilities that are accredited by the Fetal Medicine Foundation in the United Kingdom.17 We were able to access data on women who had a first-trimester combined screening test between August 2001 and October 2003 (n = 26,641). The biochemistry markers, free β-hCG and PAPP-A, were converted to multiples of the median (MoM, laboratory specific) and adjusted for maternal weight. Data from multiple pregnancies or incomplete screens were excluded (n = 3,946), and those without pregnancy outcome data were removed before final analysis (n = 415). The number of pregnancies analyzed in the final screening data set was 22,280. Pregnancies were identified at increased risk if the chance of having a Down syndrome pregnancy was greater than 1 in 300.

Defects reported to the Birth Defects Registry include structural or functional abnormalities present at conception or those that occurred before the end of the pregnancy and are diagnosed by 6 years of age. Minor malformations are excluded unless they are disfiguring or require treatment.1 We reviewed the Midwives Notification System and the Birth Defects Registry for records of children born to women who had first-trimester screens performed between August 2001 and October 2003. At that time, children in the data set were aged between 3 and 30 months. It is possible some more children may yet have birth defects diagnosed because the Registry accepts congenital diagnoses up to age 6 years.

The King Edward Memorial Hospital Ethics Committee endorsed the evaluation using patient-identified health information for surveillance of population health screening programs. The Confidentiality of Health Information Committee at the Department of Health approved access to pregnancy outcome information, including data from the West Australian Midwives Notification System, Birth Defects Registry, Mortality Register, and the Morbidity Database. The Birth Defects Registry uses multiple sources of notification (both statutory and voluntary) and has been validated on several occasions.18,19 Validation studies have found a high level of case ascertainment, including terminations of pregnancy for fetal abnormality.

During the study period, all 13 ultrasound practices undertaking first-trimester combined screening in Western Australia, including 70 sonographers, provided nuchal translucency measurements. To become accredited by the Fetal Medicine Foundation under the auspices of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), each sonographer was required to attend a theoretical training course, submit 25 images demonstrating the practitioner’s ability to comprehensively measure nuchal translucency and complete a practical examination. The sonographer then becomes certified to use the fetal medicine software PIA–Fetal Database (Viewpoint, Munich, Germany). Ongoing accreditation requires sonographers to submit ultrasound images for review on a regular basis for an external quality assurance program run by RANZCOG. An encrypted copy of the patient database was obtained from each of the 13 accredited ultrasound clinics to link with outcome data.

Using structured query language software, identified information was extracted and collated into a single composite data set. The first-trimester screening data set was then linked with pregnancy outcome information using probabilistic record-linkage techniques.20–22

All data linkage was completed under established security protocols and no intervention occurred in the management of women because of this study. Identifying information was removed from the final data set before analysis.

Of all first-trimester pregnancies reviewed in the composite data set (n = 22,695), 415 cases with no outcome were excluded (1.8%). These patients may have miscarried, terminated the pregnancy, or relocated overseas, or interstate. Follow-up for these patients was impractical. Data were analyzed with SPSS 12 (SPSS Inc, Chicago, IL).

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RESULTS

The group-specific maternal demographic characteristics are shown in Table 1. The median maternal age in the screened population was 31 years (range 14–47 years), compared with 29 years for all West Australian mothers giving birth during the same period.23 One in 5 women screened was aged 35 years or older, and 51% of babies identified with Down syndrome through screening were within this age group. The median gestation at the time of the ultrasound scan was 12 weeks 4 days (range 70–101 days) and 12 weeks 3 days (range 62–100 days) for blood collection. Body weights were available for 90% of women, with a median of 65 kg (range 33–160 kg), and 10% of women weighed 100 kg or more. Two laboratories generated the biochemistry data, using either Kryptor-Brahms (Berlin, Germany) (92%) or Wallac (Perkin Elmer, Wellesley, MA) (8%) assays, and medians for free β-hCG and PAPP-A were 0.94 and 1.01 MoMs, respectively. The median nuchal translucency was 1.5 mm (range 0.1–12 mm).

Table 1
Table 1
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All cases of Down syndrome and major congenital anomalies were collected by the West Australian Midwives Notification System and the Birth Defects Registry. Prenatal diagnosis of 50 cases of Down syndrome were identified by screening and confirmed by fetal karyotyping after amniocentesis or chorionic villus sampling. Postnatal diagnosis of 10 cases of Down syndrome were based on phenotypic presentation and cytogenetic confirmatory tests. Other major birth defects were reported by pediatric medical specialists.

The risk of Down syndrome was greater than 1 in 300 in 50 of the 60 pregnancies later confirmed to be Down syndrome cases, providing a detection rate of 83% (95% confidence interval [CI] 74–92%). Among all women screened (n = 22,280), 877 (3.9%) received an increased risk result, and 50 of these were found to have a Down syndrome pregnancy. We were unable to determine how many women undertook invasive diagnostic procedures such as amniocentesis or chorionic villus sampling after screening. Although this is a limitation of the study, it is nevertheless consistent with routine obstetric practice, where women can choose to purchase private diagnostic tests, regardless of the screening results.

Among the women with risk results of 1 in 300 or less, 10 cases of Down syndrome were later detected, consistent with a false-negative rate of 1 in 2,227. The maternal age-specific and gestation-related risk, calculated for the screened population and adjusted for a fetal loss rate of 25%,23 predicted 58 cases of Down syndrome, and 60 cases were observed (95% CI 57–63). In women aged 35 years or older, 28 cases of Down syndrome were expected and 31 were observed (95% CI 27–35). The majority (65%) of all of the Down syndrome cases occurred in women over 35 years of age (Fig. 1). First-trimester combined screening reduced the number of Down syndrome births by 50 cases in 22,280 births (2.24 cases per 1,000 births), which represents the detection of one case of fetal Down syndrome for every 446 women screened. Screening performance based on nuchal translucency alone, biochemistry alone, and combined biochemistry with nuchal translucency is shown in Table 2.

Fig. 1
Fig. 1
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Table 2
Table 2
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There were no significant differences between the 110 preterm births (20–30 weeks of gestation) and those that progressed beyond 31 weeks (median 39.3 weeks) in terms of maternal weight, fetal nuchal translucency, or maternal serum PAPP-A measurements (P > .05, analysis of variance). Mean maternal serum free β-hCG was significantly higher (P < .007) in the preterm birth group (1.35 ± 0.05 MoM) than in those who delivered nearer term (1.19 ± 0.079 MoM). However, one or more birth defects were reported in 1 in 11 preterm births, compared with 1 in 45 in those delivered close to term (odds ratio [OR] 4.40, 95% CI 2.3–8.5, P < .001).

Although pregnancies identified at increased risk represented only 3.9% of all pregnancies screened, a quarter of all birth defects (n = 233) were diagnosed in the screened cohort. Overall, 25% of all defects occurring in the fetuses of screened women were detected prenatally, 64% were reported to the Birth Defects Registry after birth, and 11% were identified in a postmortem examination. Of all birth defects reported, 15% were chromosomal, 21% cardiovascular, 26% urogenital, and 24% musculoskeletal. The rates of hydrops fetalis and congenital anomalies of the ear, face, and neck were over 20 times more prevalent among increased-risk pregnancies. Table 3 shows the different adverse outcomes stratified according to risk status. Chromosomal anomalies were the most common abnormalities found within the increased-risk group, led by Down syndrome, trisomies 13 and 18, triploidy, and Turner’s syndrome. The next most common group of fetal anomalies in the increased-risk category was musculoskeletal defects such as talipes. This was followed by cardiovascular defects, including ventriculoseptal defects, congenital anomalies of the ear, face, and neck, urogenital defects such as hydronephrosis, and gastrointestinal defects such as cleft lip. Odds ratios for all of these categories of birth defect were significantly raised, except for the gastrointestinal defect category (Table 3). There were 12 cases in which nervous system defects were detected, all with spina bifida, and none occurred in the increased-risk group. Among chromosomally normal pregnancies (n = 22,144), 530 women had fetuses with one or more nonchromosomal defects. These were largely cardiovascular (n = 117), urogenital (n = 121), or musculoskeletal (n = 167).

Table 3
Table 3
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The number of pregnancies with one or more defects was almost 7-fold higher among women with increased risk than among low-risk women (Table 3). When pregnancies with Down syndrome were excluded, pregnancies with increased-risk status still had a greater number of defects, with 1 in 9 pregnancies at increased risk recording one or more defects, a 5-fold higher rate than for pregnancies with no increased risks (1 in 42).

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DISCUSSION

In this study, we demonstrated that 3.9% of pregnancies had an increased-risk first-trimester combined screening test result, which ascertained 83% of Down syndrome cases and a significantly higher incidence of fetal anomalies, including chromosomal, structural, musculoskeletal, cardiovascular, and urogenital defects reported to the Birth Defects Registry, compared with pregnancies with screening risks equal to or less than 1 in 300.

Because of the retrospective nature of this study, there are several limitations to the range of data and outcomes that are usual within a prospective clinical trial setting. We were unable to link our data with investigations of invasive testing, and so it was not possible to determine how many women proceeded to diagnostic karyotype testing, either by amniocenteses or chorionic villus sampling after first-trimester screening tests. Although it would have been interesting to evaluate the impact of second-trimester maternal serum screening on the detection of fetal anomalies, we were unable to incorporate a composite data set because of concerns about individual privacy.

A further limitation of this retrospective analysis of first-trimester screening data is related to fetal loss bias, leading to a probable overestimate of performance. The bias is due to screening that identifies Down syndrome pregnancies at an early stage of gestation and comparing them with those diagnosed later or liveborn. Partial adjustment for fetal loss bias is possible,12,23 but interventional studies such as the present one will still tend to overestimate performance in relation to the SURUSS13 and FASTER14 studies that are based on interventions at approximately 17 weeks of gestation. Nevertheless, the results of this study provide evidence that first-trimester combined screening performs comparably to that predicted by clinical trials. Although no adjustment was made for fetal losses between the time of screening and term, our study still provides essential information for service providers in monitoring the overall detection and false-positive rates, as well as enabling informed assessments for women about screening options.

In our unselected general obstetric population, a detection rate of 83% (50/60 cases identified) and false-positive rate of 3.7% are consistent with international practice.4,12–14 The majority (65%) of all the Down syndrome cases occurred in women aged 35 years or over, but restricting first-trimester combined screening to this age group would result in an overall detection rate of only 60%. Our detection rate is slightly lower than reported in an earlier study on first-trimester combined screening in Western Australia28 and reflects the current situation in the state, with an increased number of ultrasound providers accredited by the Fetal Medicine Foundation. Both participating laboratories are accredited with the national testing authorities and participate in external quality assurance programs including the National Endocrine Quality Assurance Scheme in the United Kingdom; one laboratory is also accredited with the Fetal Medicine Foundation.

Since this study was undertaken, the Fetal Medicine Foundation has issued new software (The 11–13 + 6 Weeks Scan, V2.0.1.123) and instituted individual accreditation for each operator, while the laboratories have moved to encourage an earlier collection of blood (10–12 weeks of gestation). As a result, current performance might differ slightly from that reported for 2001–2003. These modifications emphasize the importance of ongoing evaluation of the whole screening process, rather than the individual components.

The results of this retrospective study of first-trimester combined screening in clinical practice are remarkably consistent with similar recent studies29 and those reported from multicenter prospective clinical trials.11–14,23 The overall detection rate for Down syndrome is 84% (95% CI 80–89%), based on more that 100,000 pregnancies. Our results demonstrate that first-trimester combined screening is exceptionally robust in daily clinical practice, operating across 13 centers and involving 70 sonographers. Much of the success is due to the ongoing accreditation and quality assurance of sonography practitioners, which have maintained standardized Fetal Medicine Foundation protocols consistent with our local best-practice guidelines. Despite the fetal loss bias that is inherent in a study of this nature,26 this limitation is offset in clinical practice because most pregnant women undertake screening to ascertain the status of their own fetus at an early stage in the pregnancy. For this reason, we find that many women expect the risk assessment to be performed at the time of screening, rather than at the time of delivery. Our experience with first-trimester combined screening suggests that there are additional benefits afforded by the early detection of a number of potential birth defects other than Down syndrome. The increased risk associated with Down syndrome should also alert the practitioner to the possibility of other fetal anomalies and therefore should encourage vigilant management of the ongoing pregnancy.

First-trimester combined screening studies have largely focused on the adverse obstetric outcomes associated with single markers such as increased fetal nuchal translucency,30 low maternal serum PAPP-A,31 or abnormal free β-hCG levels,8 and a number of studies have reported more generally on the obstetric outcomes of pregnancies identified at increased risk.32,33 Among pregnancies screened at increased risk for Down syndrome, poor pregnancy outcomes, such as spontaneous abortion, placenta praevia,32 low birth weight, and preterm delivery34 have also been reported.

Previous reports10,35–38 note an association between increased risk of Down syndrome, identified through first-trimester prenatal screening, and other fetal anomalies. It has become evident that first-trimester measurements of nuchal translucency combined with maternal serum PAPP-A and free β-hCG provide information beyond the risk estimates of Down syndrome or trisomies 13 and 18. Low PAPP-A levels,39 abnormal free β-hCG,40 and nuchal translucency measurements41 are associated with fetal anomalies, including diaphragmatic hernia, exomphalos, body stalk anomaly, fetal akinesia, skeletal dysplasia, and fetal loss.12,42–44

If a pregnancy in this study was identified at increased risk (> 1:300) of Down syndrome by first-trimester combined screening tests, the positive predictive value was 1 in 17 for Down syndrome, but 1 in 4 for a significant birth defect, including chromosomal, structural, or functional conditions. Conversely, a pregnancy identified by first-trimester combined screening as not at increased risk had a 1 in 42 likelihood of having a major congenital defect, which was slightly lower than the population risk (1 in 36) in 2003.1 In Victoria, a fetal chromosome abnormality was detected in 12.8% of increased-risk pregnancies,27 equivalent to the rate found in the current study.

Increased fetal nuchal translucency measurements have been associated with structural abnormalities, including diaphragmatic hernia,45 exomphalos,46 and cardiac defects.42,47 Other first-trimester sonographic markers of chromosomal defects and fetal anomalies have been proposed,47 including absence of nasal bone,48 increased impedance to flow in the ductus venosus,49 and tricuspid regurgitation.50 However, inconsistencies in the available data make it unlikely that these markers will be incorporated into routine first-trimester screening scans in the near future.51

In women identified as being at increased risk, there are important associations with subsequent adverse pregnancy outcomes other than Down syndrome. Excluding Down syndrome, the rate of fetal defects among pregnancies identified at increased risk was 5-fold higher than among the group at no increased risk. Higher maternal age alone cannot account for this disparity because most pregnancies with one or more defects (72%), excluding Down syndrome, were in women less than 35 years old.

In conclusion, this study describes how the first-trimester screening test functions in a routine clinical setting in Western Australia, where it has now gained acceptance as part of antenatal practice by 45% of all pregnant women and is gradually replacing second-trimester maternal serum screening (10% uptake) as the preferred screening modality. The availability of early screening, acceptable detection, and low false-positive rates and close integration between screening, diagnostic, and obstetric services are some of the benefits favored by pregnant women. This study also indicates that first-trimester screening tests remain robust, even when applied outside the confines of a clinical research study. The State’s best practice guidelines for antenatal fetal anomaly screening recommend that medical practitioners offer screening to all pregnant women, followed by invasive diagnostic testing based on a risk of 1 in 300 or greater, and a 19-week fetal anatomy ultrasound scan of all fetuses. Antenatal fetal anomaly screening reveals a range of information about the status and expectations for each pregnancy that extends beyond screening for fetal Down syndrome to encompass risks of both obstetric and fetal complications. It is therefore important that pregnant women understand what information they might accrue and the decisions they might confront.

The results of this study provide important practical information about the increased chances of delivering an infant with Down syndrome or other significant anomalies if the pregnancy is identified as being at increased risk for Down syndrome through first-trimester combined screening. Furthermore, the study highlights the fact that first-trimester combined screening has utility, beyond screening for Down syndrome, in ascertaining a wider range of fetal anomalies.

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