Hum. Reprod. Advance Access originally published online on June 10, 2008
Human Reproduction 2008 23(9):1968-1975; doi:10.1093/humrep/den224
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Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free β-hCG and pregnancy-associated plasma protein-A
1 Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, Denmark Hill, London SE5 8RX, UK 2 Department of Obstetrics and Gynaecology, University of Tuebingen, Germany 3 Department of Mathematics and Statistics, University of Plymouth, UK
4 Correspondence address. E-mail: kypros{at}fetalmedicine.com.
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Abstract |
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BACKGROUND: A beneficial consequence of screening for trisomy 21 is the early diagnosis of trisomies 18 and 13. Our objective was to examine the performance of first-trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and maternal serum-free β-hCG and pregnancy-associated plasma protein-A (PAPP-A).
METHODS: Prospective screening for trisomy 21 by maternal age, fetal NT, free β-hCG and PAPP-A at 11+0–13+6 weeks in singleton pregnancies, including 56 376 normal cases, 395 with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculation of patient-specific risks for each of the three trisomies based on maternal age, NT, FHR, free β-hCG and PAPP-A. Detection (DR) and false positive rates (FPR) were calculated and adjusted according to the maternal age distribution of pregnancies in England and Wales in 2000–2002.
RESULTS: The DR and FPR were 90% and 3%, respectively, for trisomy 21, 91% and 0.2% for trisomy 18 and 87% and 0.2% for trisomy 13. When screen positivity was defined by an FPR of 3% on the risk for trisomy 21 in conjunction with an FPR of 0.2% on the maximum of the risks for trisomies 13 and 18, the overall FPR was 3.1% and the DRs of trisomies 21, 18 and 13 were 91%, 97% and 94%, respectively.
CONCLUSIONS: As a side effect of first-trimester screening for trisomy 21, 
95% of trisomy 13 and 18 fetuses can be detected with an 0.1% increase in the FPR.
Key words: nuchal translucency/pregnancy-associated plasma protein-A/serum-free β-hCG/first trimester/trisomy
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Introduction |
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Effective screening for trisomy 21 is provided by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum-free β-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 11+0–13+6 weeks of gestation with a detection rate of
90% for a false positive rate (FPR) of 5% (Snijders et al., 1998
; Nicolaides et al., 2005). A beneficial consequence of screening for trisomy 21 is the early diagnosis of trisomies 18 and 13, which are the second and third most common chromosomal abnormalities. At 11+0–13+6 weeks, the relative prevalence of trisomies 18 and 13 to trisomy 21 are one to three and one to seven, respectively (Snijders et al., 1994, 1995, 1999). All three trisomies are associated with increased maternal age, increased fetal NT and decreased maternal serum PAPP-A, but in trisomy 21 serum-free β-hCG is increased whereas in trisomies 18 and 13 this is decreased (Snijders et al., 1994, 1995, 1998, 1999; Tul et al., 1999; Spencer et al., 2000; Nicolaides et al., 2005; Wright et al., 2008). In addition, trisomy 13, unlike trisomies 21 and 18, is associated with fetal tachycardia (Hyett et al., 1996; Liao et al., 2000; Papageorghiou et al., 2006).
We have recently reported the development of a specific algorithm for trisomy 18 (Kagan et al., 2008a). When the algorithm for trisomy 21 (Kagan et al., 2008b) was used and screen positivity was fixed at an FPR of 3%, and in addition the algorithm for trisomy 18 was used and screen positivity was fixed at an FPR of 0.2%, the overall FPR was 3.1% and the detection rates of trisomies 21 and 18 were 90% and 97%, respectively (Kagan et al., 2008a).
The aims of this study are: first, to derive a specific algorithm for trisomy 13 based on maternal age, fetal NT thickness, fetal heart rate (FHR) and maternal serum-free β-hCG and PAPP-A; secondly, to incorporate FHR in our previously reported specific algorithms for trisomies 21 and 18 based on maternal age, fetal NT thickness and maternal serum biochemistry (Kagan et al., 2008a, b) and thirdly, to examine the performance of each of the three algorithms and in combination in the early detection of the three trisomies.
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Methods |
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This was a prospective screening study for trisomy 21 in singleton pregnancies by a combination of maternal age, fetal NT thickness and maternal serum-free β-hCG and PAPP-A in a one-stop-clinic for first-trimester assessment of risk (OSCAR) at 11–13+6 weeks of gestation (Nicolaides et al., 2005
). Transabdominal ultrasound examination was performed to diagnose any major fetal defects and for measurement of crown-rump length (CRL) and fetal NT thickness (Snijders et al., 1998; Nicolaides et al., 2005). The pregnancy was dated according to the last menstrual period, but if the dates were uncertain or the estimated gestation by CRL was discordant by more than 7 days from the estimated gestation from dates, the CRL was used to date the pregnancy. During the examination, pulsed-wave Doppler was routinely used to obtain 6–10 cardiac cycles during fetal quiescence and the FHR was calculated by the ultrasound machine software. Automated machines that provide reproducible results within 30 min were used to measure PAPP-A and free β-hCG (Bindra et al., 2002; Spencer et al., 2003; Kryptor system, Brahms AG, Berlin, Germany or Delfia Express System, Perkin Elmer, Waltham, USA). Maternal demographic characteristics, ultrasononographic measurements and biochemical results were recorded in a computer database. Karyotype results and details on pregnancy outcomes were added into the database as soon as they became available. A search of the database was done to identify all singleton pregnancies in which first-trimester combined screening was carried out from July 1999 to April 2007.
Statistical analysis
The following steps were taken to develop a specific algorithm for the calculation of patient-specific risk of trisomy 21, trisomy 18 and trisomy 13. First, the maternal age-related risk for each trisomy at term was calculated and adjusted according to the gestational age at the time of screening (Snijders et al., 1994, 1995, 1999). Secondly, the measured NT was transformed into likelihood ratio for each trisomy using the mixture model of NT distributions (Wright et al., 2008). In both, trisomic and unaffected pregnancies fetal NT follows two distributions, one in which NT increases with CRL (CRL-dependent) and another which is CRL-independent (Fig. 1) (Wright et al., 2008). Thirdly, the measured free β-hCG and PAPP-A were converted into a multiples of the median (MoM) for gestational age adjusted for maternal weight, ethnicity, smoking status, method of conception, parity and machine for the assays (Kagan et al., 2008c). Fourthly, regression analysis was used to model mean levels of FHR in terms of gestational age, maternal age, weight, ethnicity, smoking status and method of conception. This analysis showed that deviations from the expected normal mean (delta values) were well approximated by a Gaussian distribution. Fifthly, trivariate Gaussian distributions were fitted to the joint distribution of delta FHR, log MoM free β hCG and log MoM PAPP-A in normal, trisomy 21, trisomy 18 and trisomy 13 pregnancies. Parameters associated with the distribution of log MoM free β hCG and log MoM PAPP-A were obtained from our previous studies (Kagan et al., 2008a, b, c). Sixthly, the likelihood ratios for NT, FHR and for the biochemical markers were multiplied with the age-related odds at the time of screening in each case. Seventhly, detection rates and FPR were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000–2002 (Office for National Statistics, 2000–2002).
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Results |
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Study population
The search of the database identified 60 172 singleton pregnancies. In 3053 (5.1%) cases, the outcome or one of the covariates was not available and in 165 (0.3%) cases there was a chromosomal abnormality other than trisomies 21, 18 or 13. Thus, our study population consisted of 56 376 pregnancies with a normal karyotype or delivery of a phenotypically normal baby (unaffected group), 395 cases of trisomy 21, 122 cases of trisomy 18 and 61 cases of trisomy 13. The characteristics of the study population are summarized in Table I.
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Fetal NT thickness
The distribution of NT in fetuses with trisomies 21, 18 and 13 is shown in Fig. 1. The estimated proportions of trisomies 21, 18 and 13 and unaffected fetuses that followed the CRL-independent distribution were 95%, 70%, 85% and 5%, respectively. The median CRL-independent NT was 2.0 mm for the euploid group, 3.4 mm in trisomy 21, 5.5 mm in trisomy 18 and 4.0 mm in trisomy 13 (Wright et al., 2008
, Table II).
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Maternal serum biochemistry
Contour plots for free β-hCG and PAPP-A MoM in trisomies 21, 18 and 13 and unaffected pregnancies are shown in Fig. 2.
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In unaffected pregnancies, the median free β-hCG was 1.0 MoM (range 0.03–30.4) and the median PAPP-A was 1.0 MoM (range 0.02–7.9), in the trisomy 21 pregnancies the median free β-hCG was 2.0 MoM (range 0.1–11.3) and the median PAPP-A was 0.5 MoM (range 0.05–2.2), in the trisomy 18 pregnancies the median free β-hCG was 0.2 MoM (range 0.02–4.7) and the median PAPP-A was 0.2 MoM (range 0.03–4.1) and in the trisomy 13 pregnancies the median free β-hCG was 0.5 MoM (range 0.19–3.3) and the median PAPP-A was 0.3 MoM (range 0.09–1.2).
Details on the biochemical parameters estimates for each chromosomal abnormality are given in Tables II and III. In trisomy 21 pregnancies, there was a significant increase with gestation in both log MoM PAPP-A (P < 0.0001) and log MoM free β-hCG (P = 0.039). In trisomy 18 pregnancies, there was no significant association with gestation for either log MoM free β-hCG (P = 0.879) or log MoM PAPP-A (P = 0.900). In trisomy 13 pregnancies, there was no significant association between log MoM MoM PAPP-A and gestation (P = 0.38). The association between log MoM free β-hCG and gestation was approaching significance (P = 0.07).
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Fetal heart rate
In the multiple regression analysis of the FHR, there were significant effects of gestational age (quadratic), maternal age, ethnicity, smoking status (P < 0.0001) and IVF conception (P = 0.004) but not maternal weight (P = 0.57). However, for the purpose of screening, we took into account only the effect of gestation because the effects of maternal age (over a 25 year range), ethnicity, smoking status and IVF conception were <1 bpm:
Mean FHR = 265.98 – 1.7631 x gestation in days + 0.0064445 x gestation in days2.
Parameters for the fitted Gaussian distributions are given in Table IV. There was no significant association between NT and delta FHR (P = 0.61). Although there were significant associations between log MoM values for the biochemical markers and delta FHR (P < 0.0001), the magnitude of the correlations was very small (Table IV).
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In trisomy 21 fetuses, the mean FHR was above the appropriate mean for gestation in unaffected pregnancies by
1 bpm and there was no evidence of change with gestation (Tables II and IV). In trisomy 21 fetuses, the FHR was above the 95th and 99th centiles of unaffected pregnancies in 13.7% and 6.3% of cases, respectively.
In trisomy 18 fetuses, the mean FHR was below the appropriate mean for gestation in unaffected pregnancies by 3 bpm and there was no evidence of change with gestation (Tables II and IV). In trisomy 18 fetuses, the FHR was below the 5th and 1st centiles of unaffected pregnancies in 17.2% and 9.0% of cases, respectively (Fig. 3).
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In trisomy 13 pregnancies, there was a significant association between delta FHR and gestational age (P = 0.02):
Mean delta FHR in trisomy 13 = 52.43 – 0.40476 x gestation in days.
In 85.2% of trisomy 13 fetuses, the FHR was above the 95th centile of unaffected pregnancies and in 62.3% cases it was above the 99th centile. The mean FHR in trisomy 13 fetuses was above the appropriate mean for gestation in unaffected pregnancies by 20 bpm at 11 weeks, 17 bpm at 12 weeks and 14 bpm at 13 weeks (Tables II and IV).
Performance of screening
Table V shows the detection rates for given FPR in screening for trisomies 21, 18 and 13 by each individual risk algorithm.
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In screening for trisomy 21 by the risk algorithm for trisomy 21 based on maternal age and fetal NT, the detection rate was 75% for a 3% FPR. Screening by maternal age, fetal NT and serum biochemistry increased the detection rate to 89% and 90% with the addition of FHR.
In screening for trisomy 18 by the risk algorithm for trisomy 18 based on maternal age and fetal NT, the detection rate was 61% for a 0.2% FPR. Screening by maternal age, fetal NT and serum biochemistry increased the detection rate to 93% and this was not improved by the addition of FHR (detection rate 91%).
In screening for trisomy 13 by the risk algorithm for trisomy 13 based on maternal age and fetal NT, the detection rate was 45% for a 0.2% FPR. Screening by maternal age, fetal NT and serum biochemistry increased the detection rate to 77% and this was further improved to 87% by the addition of FHR.
Table VI shows the performance of screening for trisomies 21, 18 and 13 using each of the algorithms for trisomy 21, trisomy 18 and trisomy 13, based on maternal age, fetal NT, FHR and maternal serum free β-hCG and PAPP-A. At a 3% FPR, the estimated detection rates of trisomies 21, 18 and 13 using the algorithm for trisomy 21 were 90%, 74% and 77%, respectively. The use of the algorithm for trisomy 18 identified 23%, 91% and 84% of fetuses with trisomies 21, 18 and 13, respectively, at an FPR of 0.2%. Similarly, the use of the algorithm for trisomy 13 identified 16%, 63% and 87% of fetuses with trisomies 21, 18 and 13, respectively, at an FPR of 0.2%.
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Table VII shows the total FPR and detection rates of trisomies 21, 18 and 13 by the combined use of specific algorithms for trisomy 21, trisomy 18 and trisomy 13. Screen positivity was defined by a 3% FPR using the algorithm for trisomy 21 and a 0.2% FPR applied to the maximum of the risks for trisomies 18 and 13. For an overall total FPR of 3.1%, this gave detection rates for trisomies 21, 18 and 13 of 91%, 97% and 94%, respectively.
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Discussion |
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A beneficial side effect of first-trimester combined screening for trisomy 21 is the detection of a high proportion of fetuses with trisomies 18 and 13. At a 3% FPR, the estimated detection rates of trisomies 21, 18 and 13 using the algorithm for trisomy 21 were 90%, 74% and 77%, respectively. When FHR is taken into account in screening and specific algorithms for trisomies 18 and 13 in addition to the one for trisomy 21 are also used about 90% of fetuses with trisomy 21 and 95% of those with trisomies 13 and 18 can be detected for an overall FPR of 3.1%.
In normal pregnancy, the FHR increases from 110 bpm at 5 weeks of gestation to 170 bpm at 9 weeks and then gradually decreases to 150 bpm by 14 weeks (Liao et al., 2000; Wladimiroff and Seelen, 1972; Rempen et al., 1990; Robinson and Shaw-Dunn, 1973; Wisser and Dirschedl, 1994). The alterations in FHR observed in fetuses with trisomies 21, 18 and 13 are compatible with the results of previous studies (Hyett et al., 1996; Liao et al., 2000; Papageorghiou et al., 2006). Possible explanations for differences in heart rate between the various chromosomal abnormalities include differences in the types of associated cardiac defects or varying degrees of developmental delay (Hyett et al., 1997). The most common defects observed in trisomy 21 fetuses are atrioventricular or ventricular septal defects and relative narrowing of the aortic isthmus. In trisomy 13, there are atrioventricular or ventricular septal defects, valvular abnormalities and either narrowing of the isthmus and ascending aorta or truncus arteriosus. In trisomy 18, there are ventricular septal defects and/or polyvalvular abnormalities. Since trisomy 13 is associated with narrowing of the outflow tract from the left ventricle (Hyett et al., 1997), the tachycardia may be mediated by the action of baroreceptors in the aortic arch. In fetal life, the heart normally performs near the peak of the Frank–Starling curve of ventricular function (Teitel and Rudoph, 1985), and therefore tachycardia may represent a compensatory mechanism to increase cardiac output in the phase of left heart obstruction (Rudolph and Heyman, 1976).
Inclusion of FHR in first-trimester combined sonographic and biochemical screening for chromosomal abnormalities has a small impact on the detection of trisomies 21 and 18 but a major improvement in the detection of trisomy 13. Inclusion of FHR in the risk algorithm for trisomy 13 increased the detection rate of trisomy 13 from 77% to 87% at an FPR of 0.2%. In addition, inclusion of FHR is important in distinguishing between trisomy 18 and trisomy 13, which are otherwise similar in presenting with increased fetal NT and decreased maternal serum-free β-hCG and PAPP-A.
Trisomies 18 and 13, which are the second and third most common trisomies after trisomy 21, are lethal and the rate of spontaneous abortion or fetal death between 12 weeks of gestation and 40 weeks is 80%. The relative prevalence of trisomy 18 to trisomy 21 and trisomy 13 to trisomy 21 at 12 weeks is one to three and one to seven, respectively, whereas at birth the respective rates are 1–12 and 1–28 (Snijders et al., 1995). The median survival time for children born with these disorders is 7 days and only 5% of infants survive to the end of the first year (Embleton et al., 1996; Rasmussen et al., 2003). It could therefore be argued that it is unnecessary to subject women to the difficult decisions regarding invasive testing and ultimately pregnancy termination in an affected pregnancy. The alternative view is that since many trisomy 18 and 13 fetuses can be identified during the second trimester by the presence of multiple sonographic features, women could have the option of second-trimester termination of pregnancy and avoid the risk of invasive testing if the result of first-trimester screening proves to be false positive. However, most women prefer screening to be performed early in pregnancy and in addition termination of pregnancy is safer in the first than in the second trimester (de Graaf et al., 2002; Bartlett et al., 2004). As far as the FPR is concerned, this study has demonstrated that with the addition of only 0.1% to the overall rate, 95% of trisomy 18 and 13 fetuses can be identified by a first-trimester screening programme for trisomy 21 with the inclusion of specific algorithms for trisomies 18 and 13. In contrast, there is no algorithm for second-trimester sonographic screening and since many of the affected fetuses present only a few of 20 markers, the FPR is likely to be substantially higher than 0.1%.
The National Screening Committee in the UK recommends that a screening test for trisomy 21 should provide a detection rate of at least 75% for an FPR of 3% (National Screening Committee Policy, 2006). As demonstrated in our study, for an FPR of 3.1%, first-trimester sonographic and biochemical screening by the combined use of specific algorithms for trisomies 21, 18 and 13 can detect 90% of fetuses with trisomy 21 and 95% of those with trisomies 13 and 18. These findings require validation from prospective studies.
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This study was supported by a grant from the Fetal Medicine Foundation (Charity No: 1037116).
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Submitted on March 20, 2008; resubmitted on May 8, 2008; accepted on May 14, 2008.
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