Obstetrics & Gynecology:
Comparison of Serum Markers in First-Trimester Down Syndrome Screening
Canick, Jacob A. PhD1; Lambert-Messerlian, Geralyn M. PhD1; Palomaki, Glenn E. BS1; Neveux, Louis M. BA1; Malone, Fergal D. MD2,3; Ball, Robert H. MD4,5; Nyberg, David A. MD6; Comstock, Christine H. MD7; Bukowski, Radek MD8; Saade, George R. MD8; Berkowitz, Richard L. MD2,9; Dar, Pe'er MD10; Dugoff, Lorraine MD11; Craigo, Sabrina D. MD1,2; Timor-Tritsch, Ilan E. MD1,3; Carr, Stephen R. MD1; Wolfe, Honor M. MD14; D'Alton, Mary E. MD2; for the First and Second Trimester Evaluation of Risk (FASTER) Trial Research Consortium
From the 1Women and Infants Hospital and Brown Medical School, Providence, Rhode Island; 2Columbia University College of Physicians and Surgeons, New York, New York; 3Royal College of Surgeons in Ireland, Dublin, Ireland; 4University of Utah and Intermountain Healthcare, Salt Lake City, Utah; 5University of California at San Francisco, San Francisco, California; 6Swedish Medical Center, Seattle, Washington; 7William Beaumont Hospital, Royal Oak, Michigan; 8University of Texas Medical Branch, Galveston, Texas; 9Mount Sinai School of Medicine, New York, New York; 10Montefiore Medical School/Albert Einstein College of Medicine, Bronx, New York; 11University of Colorado Health Sciences Center, Denver, Colorado; 12Tufts University School of Medicine, Boston, Massachusetts; 13New York University School of Medicine, New York, New York; 14University of North Carolina Medical Center, Chapel Hill, North Carolina.
* For members of the First and Second Trimester Evaluation of Risk Consortium, see the Appendix.
Funded by the National Institute of Child Health and Human Development (R01 HD 38652).
Corresponding author: Prof. Fergal D. Malone, Department of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland, the Rotunda Hospital, Parnell Square, Dublin 1, Ireland; e-mail: firstname.lastname@example.org.
OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free β-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency.
METHODS: Seventy-nine matched case–control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free β-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated.
RESULTS: Median multiples of the median levels of free β-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free β-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other.
CONCLUSION: Although levels of free β-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11–13 weeks of pregnancy.
LEVEL OF EVIDENCE: II-2
The measurement of maternal serum analytes of placental origin is an integral part of prenatal screening for Down syndrome.1 In the early second trimester, the most informative maternal serum markers are total hCG or its free β-hCG subunit and inhibin A. In the late first trimester, the most informative maternal serum markers have been shown to be the placental products, pregnancy-associated plasma protein-A (PAPP-A) and free β-hCG, although the single best marker in the late first trimester is fetal nuchal translucency thickness, measured by ultrasound. When taken together, nuchal translucency, PAPP-A, and free β-hCG achieve screening performance of about 85% detection rate for a 5% false-positive rate.2–5
The timing of screening within the late first trimester seems to be critical to marker performance. Nuchal translucency and PAPP-A performance declines, whereas free β-hCG performance improves during the 11–13 week period.3,5,6 Data on first-trimester performance of the other markers of placental origin, total hCG, and inhibin A are at this point less clearly defined, but there are indications that their quality as screening markers does not suddenly turn on at 15 weeks. Rather, their performance, as does that of free β-hCG, seems to improve between 11 and 13 weeks.5,7–10
The First and Second Trimester Evaluation of Risk (FASTER) Trial was an intervention study involving more than 38,000 pregnancies which compared first- and second-trimester markers in the same women.3 We were able to use the FASTER sample bank to develop a large case–control set with which to further our understanding of the relative performance of free β-hCG, total hCG, and inhibin A, alone and in combination with nuchal translucency and PAPP-A, during the late first trimester.
MATERIALS AND METHODS
Patients were enrolled at 15 prenatal centers across the United States from October 1999 to December 2002 in a study to compare first- and second-trimester screening, as previously described.3 All enrollment centers and the laboratory center at Women and Infants' Hospital obtained approval for this study from their institutional review boards, and all patients provided informed consent.
Pregnancy and pediatric outcomes were assessed as previously described and were obtained in 97% of cases.3 In the population screened (median age 30.1±5.8 years), 112 cases of Down syndrome would be expected, and 117 cases were actually identified, suggesting complete ascertainment. To estimate the expected number of cases in the cohort, the proportion of women at each maternal age times the published prior risk at that age were summed across all ages. Of the 117 cases of Down syndrome pregnancy, 25 were identified by first-trimester ultrasonography (septated cystic hygroma) and did not have serum collected. At the time that stored serum samples were assessed for this study, 79 of a final total of 92 cases of Down syndrome with stored first-trimester serum had been identified. Sixteen of the 79 Down syndrome cases had their first-trimester samples collected at 11 weeks of gestation, 38 at 12 weeks, and 25 at 13 weeks of gestation.
Each of the 79 cases of Down syndrome was matched to five control samples from unaffected pregnancies for gestational age at first and second trimester serum, date of sample collection (±6 months), African-American compared with non–African-American race, and enrollment site. Demographics and other matching criteria are shown in Table 1. A 5:1 match was chosen to increase the reliability of population estimates by having more samples available for computing medians and providing more confident estimates among unaffected pregnancies. However, matching was not used in data analysis (see below).
Down syndrome and matched control samples from the first trimester were removed from −80°C freezer storage as a set. Once thawed, samples were assayed for levels of total hCG (Immulite, Diagnostic Products Corporation, Los Angeles, CA; the total hCG assay will measure intact hCG plus any free β-hCG that is present), free β-hCG, and inhibin A (Diagnostic Systems Laboratories, Webster, TX). Pregnancy-associated plasma protein A, free β-hCG, and nuchal translucency data were available from the main FASTER trial, but free β-hCG levels were reassayed alongside total hCG to account for any effect that freezer storage might have had on hormone levels. The assay sensitivities for total hCG, free β-hCG, and inhibin A were 2 milliInternational Units/mL, 1 milliInternational Unit/mL, and 10 pg/mL, respectively, and all interassay and intra-assay coefficients of variation were less than 15%.
Median levels of total hCG, free β-hCG, and inhibin A in unaffected pregnancies were calculated from regression of observed median mass values of each analyte compared with gestational age (in days) using the control samples only. Polynomial regression (after appropriate logarithmic transformation) was employed, using a best-fit analysis. The curve was of the form Median=a0+a1×days+a2×days2. Regressed medians were then used to generate multiples of the median for each case and control sample. Probability plots (not shown) of the log multiples of the median values for samples from Down syndrome and unaffected pregnancies for free β-hCG, total hCG, and inhibin A were used to assess the range of values that distributed in a log-normal Gaussian fashion and to determine both the spread and the separation of the cases and controls. The standard deviations of the log multiples of the median values in cases and controls were calculated from the slopes of those plots after appropriate trimming.11 Briefly, a straight line was fit to the linear portion of the probability plots, usually between the fifth and 95th centiles. Standard deviations for each of the three markers were also calculated for each gestational week, with no statistically significant difference observed for any of the serum markers between weeks (one-way analysis of variance). Therefore, given the small number of cases and controls at each gestational week, separate standard deviations for each serum marker at each gestational week were not used.
To create reliable smoothed median levels for the markers in Down syndrome pregnancies by gestational age, we reviewed relevant meta-analyses6,12 (Palomaki GE, Lambert-Messerlian G, Canick JA. A summary analysis of Down syndrome markers in the late first trimester. In: Makowski G, editor. Advances in Clinical Chemistry. Elsevier; 2006 [in press]) that summarized up to 1,020, 742, and 380 observations in Down syndrome pregnancies between 9 and 14 weeks of gestation for free β-hCG, total hCG, and inhibin A, respectively. All three meta-analyses fitted curves rather than straight lines to the changes in free β-hCG and total hCG median multiples of the median levels in the first trimester, and the one meta-analysis that addressed inhibin A (Palomaki et al) also demonstrated that a curve was a better fit to the data. All used log-transformed data. The current data set contained estimates for only 3 weeks (11, 12, and 13 weeks), and because of this limited range, it was necessary to constrain the curve fitting using estimates from the literature. This was done for inhibin A and total hCG by adding a single artificial data point to the regression analysis placed at 15.0 weeks with a value of 2.0 multiples of the median. For free β-hCG, it was necessary to add both 15.0 and 10.5 week boundary values (of 2.4 and 1.7 multiples of the median, respectively). Sensitivity analysis showed that the choice of values for these data points was not critical (eg, setting the total hCG boundary to 1.7 or 2.3 had virtually no effect on the regression equation). All final regression lines fell within the 95% confidence intervals of the observed multiples of the median levels for each of the 3 weeks studied.
Correlation between each pair of serum marker multiples of the median in cases and in controls was determined using Pearson's correlation after log transformation of the multiples of the median values for pairs of variables. Screening performance was calculated as previously described,2,3 using the maternal age distribution in the United States in 2000,13 with truncation limits for the range of values used for each marker, as follows: nuchal translucency, 0.5–2.5 multiples of the median; PAPP-A, 0.2–3.0 multiples of the median; free β-hCG, 0.3–5.0 multiples of the median; total hCG, 0.4–4.0 multiples of the median; inhibin A, 0.3–4.0 multiples of the median.
Confidence intervals for the Down syndrome detection rates (and paired differences between detection rates) were computed, using 40 separate Monte Carlo simulations. For each simulation, the logarithmic means, standard deviations, and correlation coefficients for cases and controls were randomly selected from a Gaussian distribution centered on the reported values at 12 weeks of gestation. The variation around that value was derived using standard statistical techniques.14 The same sample size (79 for cases and 395 for controls) was used to estimate variability for all three measures because 1) a single set of standard deviations and correlation coefficients was used for all weeks and 2) the data were regressed to estimate the 12-week mean values for Down syndrome pregnancies. This increases the power to identify real differences in detection rates between various marker combinations. If only the number of cases or controls per week were to be used, the power of the study to find differences would be greatly reduced. The estimated detection rates (at a 5% false-positive rate) and the paired differences between detection rates were computed for each run, with the highest and lowest of the 40 estimates being excluded to define the 95% confidence interval (CI). If the interval for a paired difference did not include 0, it was considered statistically significant.
All Down syndrome cases were in women enrolled at 11 weeks 1 day through 13 weeks 6 days. Therefore, all results are necessarily limited to that narrow window of gestation. A description of the demographics and other criteria used for matching cases and controls is provided in Table 1.
In unaffected pregnancies, the levels of free β-hCG, total hCG, and inhibin A declined as gestation increased from 11 through 13 weeks. Using daily medians calculated from the weighted second-order regression analyses of the analyte levels in the 395 unaffected pregnancies, all case and unaffected values were converted to multiples of the medians (Fig. 1).
The week-specific median values and standard deviations (SDs) from the case–control data for free β-hCG, total hCG, and inhibin A, and the comparable medians and SDs for PAPP-A and nuchal translucency from the principal findings of the FASTER Trial,3 are shown in Table 2. The data for PAPP-A and nuchal translucency are included in the table because they were used in multivariate performance calculations. Nuchal translucency was the only marker noted to have changing SDs with increasing gestation; therefore week-specific SDs for nuchal translucency, shown in Table 2, were used.
Free β-hCG levels were increasingly elevated in Down syndrome pregnancies between 11 and 13 weeks. Levels of total hCG and inhibin A in Down syndrome pregnancies were increased at 11 weeks, although not to the extent of free β-hCG, and continued to increase through the next 2 weeks. The SDs for total hCG and inhibin A in cases and controls were narrower than the comparable SDs for free β-hCG.
Correlation coefficients between each pair of serum markers, including PAPP-A (using log multiples of the median values), were calculated in cases and controls for the overall data, rather than for each gestational week. Correlations were moderate between total hCG and free β-hCG (r=0.704 and 0.637, for controls and cases, respectively), inhibin A and total hCG (r=0.635 and 0.702 for controls and cases, respectively), and inhibin A and free β-hCG (r=0.416 and 0.585 for controls and cases, respectively). Correlations between PAPP-A and each of the other serum analytes were low (PAPP-A and free β-hCG, r=0.177 and 0.032; PAPP-A and total hCG, r=0.235 and 0.180; PAPP-A and inhibin A, r=0.277 and 0.050, for controls and cases, respectively). Correlations between nuchal translucency and each of the serum markers (PAPP-A, free β-hCG, total hCG, inhibin A) were very low (r<0.1); therefore, r values of zero were used in assessing nuchal translucency in combination with each of the other markers (data not shown).
Univariate screening performance of free β-hCG, total hCG, and inhibin A (without maternal age) was estimated for each gestational week (Table 3). For nuchal translucency and PAPP-A, univariate performance, at a 5% false-positive rate, was almost identical in the primary FASTER study3 and the present case–control study (nuchal translucency at 11, 12, and 13 weeks was 63% compared with 69%, 60% compared with 62%, and 55% compared with 52%, respectively; PAPP-A at 11, 12, and 13 weeks was 51% compared with 50%, 44% compared with 44%, and 37% compared with 39%, respectively). Although the free β-hCG values of the samples measured in the present case–control study and those measured originally as part of the main FASTER Trial were highly correlated (r=0.956 and 0.957 for controls and cases, respectively), the performance of free β-hCG was somewhat better in the present study than in the main FASTER study, especially at 13 weeks; therefore, the measures from the present study were used in the subsequent multivariate analyses, so as not to limit the contribution of free β-hCG.
Nuchal translucency was the most informative single screening marker, followed by PAPP-A, free β-hCG, inhibin A, and total hCG, in that order. Nuchal translucency and PAPP-A decreased in performance, while free β-hCG, total hCG, and inhibin A increased in performance between 11 and 13 weeks. At 11 weeks, the detection rates for total hCG and inhibin A, univariately (13% and 15% for a 5% false-positive rate, respectively), were lower than the detection rate for free β-hCG (28%). By 13 weeks, all three markers had higher performance (free β-hCG and total hCG, 37%; inhibin A, 47%). Overall, free β-hCG had better univariate performance (31% detection rate for a 5% false-positive rate) than either total hCG (23%) or inhibin A (29%).
In practice, first-trimester screening is recommended only when serum markers are combined with nuchal translucency measurement. Therefore, the performance of various combinations of serum markers, with nuchal translucency and maternal age always included, was calculated at a false-positive rate of 5% (Table 4). Screening performance decreased between 11 and 13 weeks when nuchal translucency plus PAPP-A plus maternal age were used (82% to 73%). Overall, any one of the three analytes, free β-hCG, total hCG, and inhibin A, combined with PAPP-A plus maternal age, provided almost the same increase in detection rate when nuchal translucency was part of the performance calculation. At 11 weeks, free β-hCG, total hCG, and inhibin A added 2–4 percentage points to the detection rate provided by nuchal translucency plus PAPP-A plus maternal age. For example, the detection rate for nuchal translucency plus PAPP-A plus maternal age was 82%. The addition of free β-hCG, total hCG, or inhibin A increased the detection rate to 86%, 84%, or 85%, respectively. At 12 and 13 weeks, all three analytes were able to more substantially increase the detection rate beyond that achieved with nuchal translucency plus PAPP-A plus maternal age.
Addition of two serum markers (either free β-hCG and inhibin A or total hCG and inhibin A) to PAPP-A plus nuchal translucency marginally improved screening performance compared with adding one marker to PAPP-A (Table 4). At any given gestational week, the increase in detection rate for a 5% false-positive rate ranged from 1 to 6 percentage points.
To determine whether the calculated detection rates for various combinations of markers were significantly different from each other, we computed 95% confidence intervals for the differences between selected detection rates at 12 weeks (Table 5). Targeting the 12-week performance was done because that performance is close to the average performance seen over the 11- to 13-week range. The aim was to answer two questions: 1) is it worthwhile to add a second biochemical marker (ie, free β-hCG, total hCG, or inhibin A) to a baseline protocol including maternal age in combination with nuchal translucency and PAPP-A measurements and 2) are any of the candidate “second serum markers” associated with a significantly higher detection rate than other combinations? All comparisons were performed at a fixed 5% false-positive rate. Table 5 shows that for all three serum markers, there is significant improvement in Down syndrome detection over the 78% found for the baseline combination at 12 weeks of gestation. For example, adding free β-hCG improved performance by 5.8% (95% CI 3.0–10.5%). Although the addition of free β-hCG is associated with a large improvement in detection, the difference between its performance as a second biochemical marker is not statistically significantly better than adding another second marker. For example, when free β-hCG is compared with total hCG as the second marker, the difference in performance is +0.9%, but the 95% CI (−3.3 to 6.3%) includes zero, indicating that the difference is not statistically significant. Computing the confidence with 40 simulations seemed to be reliable, as the observed 2.5th and 97.5th centiles were always close to that predicted using the mean and standard deviations of the 40 observed results. We did not model performance at other gestational weeks, but the differences will likely favor free β-hCG at 11 weeks, as opposed to total hCG and inhibin A at 13 weeks.
The Down syndrome screening markers most commonly combined in the first trimester are the ultrasonographic measurement of nuchal translucency, together with two serum analytes, PAPP-A, and free β-hCG. The screening performance of this combination of markers, based on a review of seven studies, is in the range of an 82–85% detection rate for a 5% false-positive rate.4 Three recently completed large-scale population studies, the Biochemistry, Ultrasound, Nuchal Translucency (BUN) study in the United States, Serum, Urine and Ultrasound Screening Study in the United Kingdom, and the FASTER Trial in the United States, had results consistent with this performance estimate (detection rates for a 5% false-positive rate of 79%, 85%, and 86%, for BUN, Serum, Urine and Ultrasound Screening Study, and FASTER, respectively).2–3,5,15
Free β-hCG increases in relative concentration and in quality as a Down syndrome screening marker beginning as early as 9 gestational weeks, reaching almost twice unaffected values by 13 weeks.2,8,16 Levels of total hCG and inhibin A also begin to increase in the late first trimester of Down syndrome pregnancy (Palomaki et al).2,7–9,16 The pattern of results reported here are consistent with published estimates, with a modest increase in total hCG at 11 weeks and larger increases at 12 and 13 weeks. Two large studies that examined first-trimester changes in total hCG levels also have shown that total hCG elevation begins at 11 weeks.2,16 In the present study, inhibin A levels were modestly increased at 11 weeks and continued to increase at 12 and 13 weeks, similar to the published estimates (Palomaki et al).2 An earlier study did not find elevations in inhibin A levels at 11–13 weeks.7
Overall, substituting either total hCG or inhibin A for free β-hCG provided a detection rate that was not significantly different from that provided by free β-hCG, because nuchal translucency and PAPP-A are more effective markers than any of the other three, with the nuchal translucency, PAPP-A combination most effective at 11 weeks,5,6,16 when free β-hCG, total hCG, and inhibin A are least effective.
In FASTER, for reasons of appropriate clinical management, patients whose fetuses were noted to have a cystic hygroma at the time of the first-trimester ultrasound visit, did not have first or second trimester serum samples obtained, although these patients were included in computing the nuchal translucency characteristics. The exclusion of these cases from the analysis of biochemical testing is likely to have little or no impact, because nuchal translucency measurements and biochemical markers are virtually independent of each other, as shown previously in large studies2 and by us in the FASTER trial.3
The findings in this study support already published data that free β-hCG is a better first-trimester marker, univariately, than either total hCG or inhibin A. However, in practice, first-trimester screening is most efficient when using multiple markers, with nuchal translucency and PAPP-A clearly being the most informative of all the markers currently available. Our data show that the choice of a third marker, whether it is free β-hCG, total hCG, or inhibin A, is not critical; any of the three are similarly effective in improving first-trimester screening performance between 11 and 13 weeks of gestation.
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The authors acknowledge the work of the First and Second Trimester Evaluation of Risk (FASTER) Trial Research Consortium members: K. Welch, MS, R. Denchy, MS (Columbia University), F. Porter, MD, M. Belfort, MD, B. Oshiro, MD, L. Cannon, BS, K. Nelson, BSN, C. Loucks, RNC, A. Yoshimura (University of Utah and IHC Perinatal Centers, Salt Lake City, Provo and Ogden, UT), D. Luthy, MD, S. Coe, MS (Swedish Medical Center), J. Esler, BS, D. Schmidt, MA (William Beaumont Hospital), G. Hankins, MD, J. Lee, MS (University of Texas Medical Branch, Galveston), K. Eddleman, MD, Y. Kharbutli MS (Mt. Sinai Medical Center), I. Merkatz, MD, S. Gross, MD, S. Carter, MS (Montefiore Medical Center), J. Hobbins, MD, L. Schultz, RN (University of Colorado Health Science Center), M. Paidas, MD, J. Borsuk, MS (New York University Medical Center), D. W. Bianchi, MD, B. Isquith, MS, B. Berlin, MS (Tufts University), C. Duquette, RDMS, (Women and Infants Hospital), R. Baughman, MS (University of North Carolina), J. Hanson, MD, F. de la Cruz (National Institute of Child Health and Human Development), K. Dukes, PhD, T. Tripp, MA, D Emig, MPH, L. Sullivan PhD (DM-STAT, Medford, MA), N. Wald, FRCP, J. Bestwick (Wolfson Institute of Preventive Medicine, London, UK). Cited Here...
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