PRENATAL DIAGNOSISPrenat Diagn 2002; 22: 877–879.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.420

A first trimester trisomy 13/trisomy 18 risk algorithmcombining fetal nuchal translucency thickness, maternalserum free β-hCG and PAPP-A

Kevin Spencer1* and Kypros H. Nicolaides2

1Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Gubbins Lane, Romford RM3 0BE, UK2Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, Denmark Hill, London SE5 8RX, UK

This study examines 45 cases of trisomy 13 and 59 cases of trisomy 18 and reports an algorithm to identifypregnancies with a fetus affected by trisomy 13 or 18 by a combination of maternal age fetal nuchal translucency(NT) thickness, and maternal serum free β-hCG and PAPP-A at 11–14 weeks of gestation. In this mixedtrisomy group the median MoM NT was increased at 2.819, whilst the median MoMs for free β-hCG andPAPP-A were reduced at 0.375 and 0.201 respectively. We predict that with the use of the combined trisomy13 and 18 algorithm and a risk cut-off of 1 in 150 will for a 0.3% false positive rate allow 95% of thesechromosomal defects to be identified at 11–14 weeks. Such algorithms will enhance existing first trimesterscreening algorithms for trisomy 21. Copyright 2002 John Wiley & Sons, Ltd.

KEY WORDS: prenatal screening; aneuploidy; trisomy 13; trisomy 18; nuchal translucency; free β-hCG; PAPP-A

INTRODUCTION

Trisomies 18 and 13 are the second and third most com-mon autosomal trisomies after trisomy 21. In the firsttrimester of pregnancy trisomy 21 occurs at a frequencyeight times that of trisomy 13 and three times that of tri-somy 18. Ultrasonographic features of trisomies 13 and18 in the first trimester include increased fetal nuchaltranslucency thickness (NT) (Sherod et al., 1997; Sni-jders et al., 1999), as is also the case with trisomy 21.However, unlike cases with trisomy 21, levels of mater-nal serum free β-hCG and pregnancy associated plasmaprotein-A (PAPP-A) are both reduced (Tul et al., 1999;Spencer et al., 2000a), and it is not possible to devise aspecific algorithm which will differentiate between casesof trisomy 13 and trisomy 18. In order to enhance ourfirst trimester screening programme we have sought toderive an algorithm which will provide a combined riskof trisomy 13 or trisomy 18 and to assess the likelydetection rate using such an approach.

METHODS

Individual fetal NT and maternal serum free β-hCGand PAPP-A results for 42 cases with trisomy 13 and50 cases with trisomy 18 were available from previousstudies (Spencer et al., 2000a; Tul et al., 1999). Thesecases were supplemented with data from an additionalthree cases of trisomy 13 and nine cases of trisomy 18which were identified during prospective first trimesterscreening in the OSCAR clinic at Harold Wood Hos-pital (Spencer et al., 2000b). In all cases fetal NT was

*Correspondence to: Kevin Spencer, Endocrine Unit, ClinicalBiochemistry Dept., Harold Wood Hospital, Gubbins Lane, Rom-ford RM3 0BE, UK. E-mail: KevinSpencer1@aol.com

measured under standardised conditions (Snijders et al.,1998) by sonographers certified by the Fetal MedicineFoundation. All biochemical measurements were per-formed using the Kryptor analyser (Brahms DiagnosticaGmbH, Berlin) and the performance of this system hasbeen previously described (Spencer et al., 1999a). Pop-ulation parameters for the unaffected population wereobtained from previous studies (Nicolaides et al., 1998;Spencer et al., 1999a).

Statistical analysis

All marker measurements were converted to MoMsusing medians derived from normal pregnancies at thesame gestation (Spencer et al., 1999a). Correction offree β-hCG and PAPP-A MoM for maternal weight wasalso performed using the reciprocal-linear regressionweight correction procedure of Neveux et al. (1996)with locally derived parameters (Spencer et al., 2000c).

Assessment of the combined risk algorithm as a poten-tial screening procedure was examined using standardstatistical modelling techniques (Royston and Thomp-son, 1992). We used previously identified parametersfor PAPP-A and free β-hCG for unaffected pregnan-cies (Spencer et al., 1999a) and similarly data for nuchaltranslucency from 95 476 unaffected pregnancies (Nico-laides et al., 1998; Snijders et al., 1998). For trisomy 13and trisomy 18 affected pregnancies we used the com-bined population parameters from this analysis. Usingthese population parameters, a series of 15 000 randomMoM values were selected for each marker from withinthe Gaussian distributions of the affected and unaffectedpregnancies. These values were then used to calculatea likelihood ratio (Reynolds and Penney, 1990) for thecombination of the three markers. These likelihood ratioswere then used, together with the derived combined agerelated risk for trisomy 13 or trisomy 18 in the first

Copyright 2002 John Wiley & Sons, Ltd. Received: 13 February 2002Revised: 9 May 2002

Accepted: 14 May 2002

878 K. SPENCER AND K. H. NICOLAIDES

trimester from the data of Snijders et al. (1995), to cal-culate the expected detection rate of affected pregnanciesat a fixed false positive rate in a population with thematernal age distribution of pregnancies in England andWales (Office of National Statistics, 2000)

RESULTS

Table 1 identifies the risk of trisomies 13 and 18 at12 weeks of gestation for different maternal ages andalso shows the combined risk of either trisomy occurringin an individual pregnancy.

Table 2 summarises the distribution parameters forthe unaffected population and for the combined trisomy13 and trisomy 18 populations. As reported in ourprevious studies (Spencer et al., 1999a) in the unaffectedpopulation there was no significant correlation betweenlog10 MoMs for NT and free β-hCG (r = −0.057) andbetween the log10 MoMs for NT and PAPP-A (r =0.000). There was a small significant correlation between

Table 1—Risk of trisomy 13 and trisomy 18 at 12 weeks’gestation at various maternal ages and the combined risk foreither trisomy in any one individual pregnancy

Maternalage

Risk ofT13

Risk ofT18

Risk of eitherT13 or T18

15 7890 2545 192416 7860 2535 191717 7825 2524 190918 7780 2510 189819 7720 2490 188320 7640 2465 186321 7535 2431 183822 7405 2389 180623 7235 2334 176524 7020 2265 171225 6755 2179 164826 6430 2074 156827 6040 1948 147328 5595 1805 136529 5090 1642 124130 4545 1466 110931 3980 1284 97132 3415 1102 83333 2870 926 70034 2370 765 57835 1920 619 46836 1535 495 37437 1210 390 29538 945 305 23039 730 235 17840 560 181 13741 425 137 10442 325 105 7943 245 79 6044 185 60 4545 140 45 3446 105 34 2647 75 24 1848 55 18 1349 40 13 1050 30 10 7

Table 2—Distribution parameters for the combined trisomy13/18 and unaffected populations

Free β-hCG PAPP-A NT

Log10 meanMoMunaffected

0.0040 −0.0040 0.0000

Log10 SDunaffected

0.2558 0.2431 0.1200

Log10 meanMoM affected

−0.4262 −0.6976 0.4500

Log10 SDaffected

0.3165 0.3000 0.2521

Table 3—Trisomy 13/18 detection rates andfalse positive rate for the combined NT andmaternal serum biochemistry marker combina-tions modelled against the age distribution ofpregnancies in England and Wales

Risk cutoff

False positiverate %

Detectionrate %

1 in 50 0.10 93.151 in 100 0.20 94.611 in 150 0.30 95.351 in 200 0.39 95.831 in 250 0.47 96.191 in 300 0.54 96.47

log10 MoMs for free β-hCG and PAPP-A (r = 0.160). Inthe combined trisomy 13 and 18 group there was a smallsignificant correlation between log10 MoMs for NT andfree β-hCG (r = 0.152) but not between log10 MoMs forNT and PAPP-A (r = 0.068), or between log10 MoMsfor free β-hCG and PAPP-A (r = 0.105). The medianMoM free β-hCG, PAPP-A and NT in the combinedtrisomy group was 0.375, 0.201 and 2.819 respectively.

When the observed statistical parameters were usedin the mathematical model of a population with thematernal age distribution of pregnancies in England andWales the detection rate and false positive rates thatwould be achieved at different risk cut-offs are shownin Table 3.

DISCUSSION

Although the birth prevalence of trisomies 13 and 18are considerably lower than that for trisomy 21 (1 in5000 versus 1 in 650), the relative incidences at the11 to 14 week ultrasound examination are considerablyhigher (1 in 800 versus 1 in 400) (Snijders et al., 1995).Thus at the time of first trimester screening it would beadvantageous to be able to identify such cases at riskfrom those that have increased nuchal translucency as aresult of trisomy 21 or other causes. It is well establishedthat the biochemical pattern in pregnancies affected bytrisomies 13 or 18 are different from that of trisomy21 in that free β-hCG levels are reduced and that thelow levels of PAPP-A are carried through into the sec-ond trimester (Spencer et al., 1999b). It is therefore not

Copyright 2002 John Wiley & Sons, Ltd. Prenat Diagn 2002; 22: 877–879.

SCREENING FOR TRISOMIES 13 AND 18 879

possible to create an algorithm which will distinguishbetween trisomies 13 and 18. However, the constructionof a combined algorithm would allow clear identificationof at-risk pregnancies. Using our combined algorithm wepredict that at a 1 in 150 risk cut-off 95% of cases couldbe identified for an invasive testing rate of 0.3%. Thiscompares well with the 90% detection for a 5% falsepositive rate achieved retrospectively (Spencer et al.,1999a) and prospectively (Spencer et al., 2000b) for tri-somy 21. We believe this simple algorithm would benefitand enhance screening procedures in the first trimester.

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Copyright 2002 John Wiley & Sons, Ltd. Prenat Diagn 2002; 22: 877–879.