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).
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).
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, V22.214.171.124) 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.
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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