second-trimester uterine artery doppler pulsatility index and maternal serum pp13 as markers of...

PRENATAL DIAGNOSISPrenat Diagn 2007; 27: 258–263.Published online 5 February 2007 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.1664

Second-trimester uterine artery Doppler pulsatility indexand maternal serum PP13 as markers of pre-eclampsia

Kevin Spencer1*, Nicholas J. Cowans1, Ilana Chefetz2, Joseph Tal3, Ido Kuhnreich3 and Hamutal Meiri2

1Department of Clinical Biochemistry, Harold Wood Hospital, Romford, UK2Diagnostic Technologies Ltd., Yoqneam, Israel3Technostat, Kfar Saba, Israel

Objective To evaluate whether measurement of maternal serum PP13 at 22 to 24 weeks of gestation, aloneor in combination with second-trimester biochemical markers or uterine artery pulsatility measured by Dopplervelocimetry, is useful in predicting those women at risk of developing pre-eclampsia.

Study Design A nested case-control study of pre-eclampsia cases with controls matched for gestational ageand storage time for the maternal serum. PP13 was tested by an ELISA, with the samples blinded to pregnancyoutcome. All patients also underwent uterine artery Doppler flow velocimetry at 22–24 weeks to measure themean pulsatility index (PI). Results for Inhibin, Activin, PAPP-A and Free β-hCG were available from previousstudies.

Results There were 73 controls and five cases with early pre-eclampsia in which delivery was induced prior to35 weeks. In addition, there were a further seven cases with pre-eclampsia in which delivery was not inducedbefore term. Median PP13 levels for controls and all cases were 295.9 and 212.6 pg/ml, and 171.2 pg/mlamongst the early pre-eclampsia cases, with the MoMs 1.00, 0.94 and 0.63, respectively (p < 0.001). Receiveroperator characteristic (ROC) curve analysis for either all cases or early cases versus controls yielded areasunder the curve of 0.588 (95% CI: 0.42–0.76; p = 0.1526) and 0.693 (0.47–0.92; p = 0.0441) for PP13. Ata specificity set to 0.80, the sensitivity for PP13 in the early cases was 0.40 and that in all cases was 0.25.Combining PP13 bivariately with any of the markers (PI, PAPP-A, Activin, Inhibin or Free β-hCG) tested inthe 22–24 week period did not improve the detection of early, late or all cases of pre-eclampsia comparedwith either marker alone.

Conclusion Late second-trimester PP13 alone is unlikely to be useful in predicting pre-eclampsia and earlypre-eclampsia, and its prediction does not increase when coupled with second-trimester Doppler PI or otherpotential biochemical markers. Measuring between-trimester temporal changes may be worthy of furtherinvestigation. Copyright 2007 John Wiley & Sons, Ltd.

KEY WORDS: screening; hypertension; pregnancy; pre-eclampsia; PP13

INTRODUCTION

Hypertensive disorders of pregnancy, particularly pre-eclampsia, are associated with significant morbidity andmortality, especially when it occurs before 34 weeks(Walker, 2000; Confidential Enquiries, 2001). The inci-dence of pre-eclampsia in the routine pregnant popula-tion is of the order of 5% (Walker, 2000; Roberts andCooper, 2001). The symptoms of the disorder are wellcharacterised and generally present in the late secondto third trimester; however, the underlying pathologyis present at early stages of pregnancy and there isevidence that it is associated with a failure of trophoblas-tic invasion of the maternal spiral arteries (Khonget al., 1986; Shanklin and Sibai, 1989; Pinenborg et al.,1991).

A variety of proteins and hormones have been stud-ied as potential early markers for pre-eclampsia. Theseinclude the second-trimester maternal serum markers

*Correspondence to: Kevin Spencer, Department of ClinicalBiochemistry, Harold Wood Hospital, Gubbins Lane, Romford,RM3 0BE, UK. E-mail: [email protected]

used for aneuploidy screening, such as alpha-fetoprotein(AFP) (Raty et al., 1999; Yaron et al., 1999), hCG(Pouta et al., 1998; Aquilina et al., 2000; Lambert-Messerlian et al., 2000) and Inhibin–A (Cuckle et al.,1998; Aquilina et al., 1999, 2000; Lambert-Messerlianet al., 2000), some of which have been shown to bealtered also in the first trimester (Ong et al., 2000;Sebire et al., 2000) along with the first-trimester marker,PAPP-A (Ong et al., 2000; Spencer et al., 2005a). Othermarkers that have been proposed include first- or second-trimester measurement of activin (Muttukrishna et al.,2000; Ong et al., 2004), homocysteine (Sorensen et al.,1999; Yu et al., 2004a), soluble fms-like tyrosine kinase(sflt-1) (Maynard et al., 2003; Levin et al., 2004), pla-cental growth factor (Polliotti et al., 2003; Taylor et al.,2003; Levin et al., 2004) and sex hormone bindingglobulin (Wolf et al., 2002; Yu et al., 2004b; Spenceret al., 2005b). However, none of these solely have suf-ficiently good enough clinical discrimination to be usedin a clinical context, although combinations of second-trimester biochemical markers (Wald and Morris, 2001;Wald et al., 2006) and biochemical and ultrasound mark-ers have been proposed (Aquilina et al., 2001; Spenceret al., 2005a, 2006).

Copyright 2007 John Wiley & Sons, Ltd. Received: 4 September 2006Revised: 27 November 2006Accepted: 5 December 2006

Published online: 5 February 2007

SECOND-TRIMESTER MARKERS OF PRE-ECLAMPSIA 259

The use of Doppler ultrasound to assess increasedimpedance to blood flow in the maternal uterine arteriesis probably the single most effective method of screeningwomen in the second trimester. Studies at 20–24 weeksof gestation have reported detection rates of 50–70%for a 5% false-positive rate in women developing earlypre-eclampsia (Papageorghiou et al., 2001, 2002). Whenthis had been investigated in the early first trimester at11–14 weeks (Martin et al., 2001; Gomez et al., 2005)the performance was much poorer, with only 27% ofcases detected at a 5% false-positive rate, rising to 50%amongst those severe cases requiring delivery before34 weeks of gestation.

Placental protein 13 (PP13) is a 32-kD dimer and amember of a group of proteins that are highly expressedin the placenta. PP13 is a galectin (Burger et al., 2004;Than et al., 2004) that binds to proteins on the extracel-lular matrix between the placenta and the endometrium,and through its action as a lysophospholipase-A assistsin placental implantation and maternal artery remod-elling (Burger et al., 2004; Than et al., 2004; Visegradyet al., 2004). Early studies suggest that the gene forPP13 is down-regulated in women with pre-eclampsiarequiring early delivery and that in early pre-eclampsiathere is impaired placental functional responsiveness toPP13 during the first trimester (Burger et al., 2004; Tarsaet al., 2004).

A recent study (Nicolaides et al., 2006) comparinga series of pregnancies (n = 10) resulting in deliverybefore 34 weeks due to early pre-eclampsia with normalcontrols (n = 434) has shown some possible benefitsof using early first-trimester maternal serum measure-ment of PP13 in conjunction with early first-trimesteruterine artery Doppler as a potential screening tool. Sub-sequently, several studies (Chefetz et al., 2006; Gonenet al., 2006) were carried out with a larger series of first-trimester cases, in which the efficacy of using PP13 wassimilar. In a study performed by us (Spencer et al., 2007)in, a large series of early (n = 44) and late (n = 44)cases of pre-eclampsia, PP13 was measured in con-junction with second-trimester uterine artery Dopplerand showed a significant reduction in PP13 comparedto normal outcome or to late pre-eclampsia, but onlya marginal improvement was found in detection whenDoppler was combined with PP13 compared with uter-ine pulsatility index (PI) alone.

In the present study, we wish to further examinethe potential value of second-trimester maternal serumPP13 measurement alone or in conjunction with second-trimester uterine artery Doppler or other biochemicalmarkers in predicting pre-eclampsia in women devel-oping the disease.

MATERIALS AND METHODS

During 2002, women attending for routine transvaginalcolour Doppler flow measurement of the uterine arteryPI at 22–24 weeks of gestation (Papageorghiou et al.,2001) were enrolled in the study. Women with a sin-gleton pregnancy were asked to provide blood samples

for the investigation of a variety of biochemical mark-ers. All blood samples were left to clot for 5 to 10 minand were then centrifuged at 10 000 g for 5 min priorto serum samples being aliquoted into 500 ul amountsfor storage at −20 ◦C in polypropylene micro tubes.

A search of the database was made to identify allsingleton pregnancies that had maternal serum collectedand also had 22–24 week Doppler investigations. Thehospital notes and delivery suite records of each of thesepatients were then searched to identify any pregnancycomplications and obtain delivery details. Specifically,pregnancies with pre-eclampsia were identified, in whichpregnancy induced hypertension was defined by a dias-tolic blood pressure of 90 mmHg or more on any oneoccasion or a systolic blood pressure of 140 mmHg ormore on two consecutive occasions at least 4 h apartin previously normotensive women with no pre-existingrenal disease, and the presence of either more than300 mg of total protein in a 24-h urine collection orgreater than a 1+ albumin on reagent strip (Davey andMacGillivray, 1988).

A total of 24 cases with pre-eclampsia were identified,and 144 singleton normal pregnancies were selected toform the control group (six controls per case). Data onfree β-hCG, PAPP-A, activin A and inhibin A concen-trations were available from a previous study (Spenceret al., 2006), with each marker being tested on a freshaliquot of serum. Of the samples from this previousstudy, 12 cases with pre-eclampsia (five severe enoughto have warranted delivery before 35 weeks) and 73 con-trols had sufficient aliquots to allow the measurement ofPP13. Fresh (previously unfrozen) aliquots of these sam-ples were removed from −20 ◦C storage. All sampleswere shipped to Israel on dry ice for analysis of PP13using a solid phase sandwich ELISA, as described previ-ously (Burger et al., 2004; Nicolaides et al., 2006). Allsamples were analysed blinded to the clinical outcome.The between-day precision at PP13 concentrations in therange 10–500 pg/ml was less than 10% and the limit ofdetection was 5 pg/ml.

Statistical analysis

Baseline and delivery characteristics were comparedbetween cases and controls using the Fischer exacttest for categorical variables and independent t-testsfor continuous variables. All statistical analyses wereperformed using Analyse-It (Analyse-It Software Ltd,Leeds) and Microsoft Excel or with SPSS 12 (SPSS,Woking) or SAS version 9.1 (SAS Institute, Cary, NC,USA).

PP13 levels were not normally distributed and there-fore we compared PP13 levels across the two outcomegroups using the Wilcoxon Rank Sum test. It was seenthat PP13 levels increased with gestational age. To takeaccount of this effect, PP13 levels were converted tomultiples of the normal median (MoM) for the con-trols at the same gestational age, based on a weighted(by number of cases) regression of the observed medianat each completed week. We also examined maternal

Copyright 2007 John Wiley & Sons, Ltd. Prenat Diagn 2007; 27: 258–263.DOI: 10.1002/pd

260 K. SPENCER ET AL.

weight, height, body mass index, age, parity and eth-nicity as potential confounders in the adjusted MoManalysis.

Statistical modelling was used to assess the value ofPP13 in predicting pre-eclampsia. Examination of theMoM values showed that they did not fit a Gaussiandistribution either untransformed or after logarithmictransformation. Logistic regression was therefore used toestimate from the MoM the odds of being a case versusa control. Including an individual subject, whose risk ofthe pregnancy disorder we are trying to predict, in thedata set that is used to ‘fit’ the regression model couldlead to a biased result because of over-fitting the models.To avoid such a bias, each subject’s risk was computedon the basis of a model that excluded the subject, i.e.the model did not ‘learn’ from that subject but only fromthe others.

Data for other markers were available as MoMcalculated in our previous study (Spencer et al., 2006).

Logistic regression was used to evaluate the accu-racy of different combinations of biochemical markersand uterine artery mean Doppler PI in predicting pre-eclampasia. In order to avoid over-fitting of the model(due to the small number of cases in our sample), weestimated the probability to be a case using the leave-one-out rule, i.e. for each subject, the probability to bea case was estimated on the basis of all available dataexcluding her own. All markers were adjusted for ges-tational age, i.e. the analysis was based on MoM values.

In order to establish the clinical utility of eachmarker, receiver operating characteristic (ROC) curvesfor each marker alone were constructed from the logis-tic regression to establish the area under the curve(AUC), and to assess for statistical significance thedetection and false-positive rates for various were cal-culated.

To assess the utility for pre-eclampsia predictionusing the combination of a variety of markers, weused multiple regression analysis and ROC curves. Aprobability (P ) of <0.05 was considered statisticallysignificant.

RESULTS

PP13 levels were dependant on the gestational age(p < 0.001), and the median PP13 levels for controlsadjusted for gestational week were 295.9 compared to212.6 pg/ml in cases of pre-eclampsia and 171.2 pg/mlamongst the early pre-eclampsia cases, with the MoMsbeing 1.00, 0.94 and 0.63, respectively (p < 0.001).These differences were relatively small compared to thedifferences between cases and controls for the othermarkers (Table 1).

Receiver operator characteristic (ROC) curve analysisyielded areas under the curve for PP13 of 0.588 (95%confidence interval (CI) 0.42–0.76; p = 0.156) for allpre-eclampsia cases and 0.693 (CI: 0.47–0.92; p =0.0441) for early pre-eclampsia cases. At a specificityof 0.80, the sensitivities for PP13 in the early caseswere 40 and 25% for all cases. It would appear that

Table 1—Values of putative markers in second-trimester casesof all pre-eclampsia, early pre-eclampsia and normal cases.(IQR = Interquartile range)

Marker Group Median MoM IQR

Inhibin A All PET 2.030 3.738Early PET 3.200 4.322Controls 1.054 0.482

Free β-hCG All PET 1.980 1.237Early PET 2.067 0.331Controls 1.008 0.848

Activin All PET 2.144 2.249Early PET 2.093 0.850Controls 0.988 0.757

PP13 All PET 0.939 0.778Early PET 0.627 0.545Controls 1.000 0.913

PAPP-A All PET 1.499 1.221Early PET 1.920 1.260Controls 1.000 0.838

PI All PET 1.703 0.678Early PET 1.985 0.210Controls 0.919 0.459

although second-trimester PP13 alone is significantlylower than controls, differences in its level at this periodof pregnancy could not be used to separate all casesof pre-eclampsia from controls and has relatively lowsensitivity for early onset pre-eclampsia. Of the othersecond-trimester markers, mean PI or Activin seemed toprovide a much higher sensitivity.

Assessment of the value of combining PP13 and PI (orother biochemical markers) in the clinical discriminationof any or early pre-eclampsia is shown in Table 2.It appears that combination with other biochemical orultrasound markers did not improve the detection rate,and the best markers were mean PI, activin or theircombination (Spencer et al., 2006).

We have previously published the results of first-trimester PP13 in predicting pre-eclampsia on its ownor when combined with second-trimester Doppler PI(Spencer et al., 2006b). In this previous study, we testedwomen in the same hospital during 2001 with samplescollected at 11–13 weeks and stored under similar con-ditions to our current series. The two study populationswere otherwise the same in terms of maternal age, parity,ethnicity or frequency of pre-eclampsia.

When we compared the results of PAPP-A and PP13in this study with our previous study in the first trimester(Spencer et al., 2007), we found a significant temporalshift in the marker patterns between trimesters. We havethus attempted to compare the two studies. For PP13in the first trimester the levels were lower in both theearly PET and the all PET group; however, in the secondtrimester the marker was similarly reduced only in theearly PET group (Figure 1), but the level was similar tocontrols for the all PET cases. In comparison, PAPP-Alevels were reduced in the first trimester in the earlycases and all PET cases but in the second trimesterthe levels were increased. This observation may lead tomore clinical discrimination being achieved by lookingat the rate of change of marker levels between trimesters,



Table 2—Area under the curve (AUC) and sensitivity for each marker and combinationof PP13 and PI for the prediction of various classification of pre-eclamptic cases usinglogistic regression with a specificity set to 0.80. (Pre-eclampsia of any severity (ALL),early pre-eclampsia (early PET), late onset PET (PET))

Markers Disorder AUC (95% CI) P Sensitivity

ACTIVIN All PET 0.82 (0.69–0.95) 0.0004 0.75PET 0.84 (0.66–1.01) 0.0033 0.71Early PET 0.73 (0.49–0.97) 0.0870 0.60

FBETA All PET 0.57 (0.36–0.78) 0.4621 0.50PET 0.23 (0.02–0.44) 0.0178 0.00Early PET 0.67 (0.36–0.98) 0.2119 0.40

INHIBIN All PET 0.77 (0.6–0.93) 0.0033 0.58PET 0.69 (0.42–0.96) 0.0995 0.57Early PET 0.72 (0.38–1.05) 0.1029 0.60

PAPP-A All PET 0.53 (0.31–0.75) 0.7524 0.42PET 0.39 (0.11–0.67) 0.3360 0.00Early PET 0.51 (0.13–0.9) 0.9269 0.60

PI All PET 0.85 (0.74–0.96) 0.0001 0.75PET 0.7 (0.54–0.86) 0.0805 0.43Early PET 0.97 (0.93–1.01) 0.0005 1.00

PP13 All PET 0.44 (0.29–0.6) 0.5363 0.00a

PET 0.18 (0.07–0.28) 0.0048 0.00a

Early PET 0.53 (0.29–0.78) 0.7987 0.00a

PA PI All PET 0.79 (0.66–0.93) 0.0011 0.58PET 0.52 (0.23–0.81) 0.8715 0.43Early PET 0.8 (0.54–1.05) 0.0269 0.60

PP13 PI All PET 0.8 (0.65–0.94) 0.0010 0.75PET 0.62 (0.4–0.84) 0.2950 0.29Early PET 0.93 (0.88–0.99) 0.0012 1.00

PP13 ACTIVIN PI All PET 0.89 (0.8–0.97) <0.0001 0.83PET 0.84 (0.69–0.99) 0.0030 0.71Early PET 0.92 (0.85–1) 0.0016 1.00

PP13 FBETA PI All PET 0.78 (0.63–0.92) 0.0024 0.67PET 0.58 (0.36–0.79) 0.5012 0.14Early PET 0.93 (0.86–0.99) 0.0014 1.00

PP13 INHIBIN PI All PET 0.79 (0.64–0.94) 0.0014 0.67PET 0.55 (0.27–0.83) 0.6642 0.29Early PET 0.91 (0.84–0.99) 0.0021 1.00

PP13 PA PI All PET 0.79 (0.64–0.94) 0.0014 0.67PET 0.61 (0.41–0.82) 0.3254 0.43Early PET 0.88 (0.79–0.98) 0.0043 0.80

a For PP13, only five cases of early pre-eclampsia and seven cases of pre-eclampsia at term hadenough blood. Thus, owing to the small number of cases in our sample, we estimated the probabilityto be a case using the leave-one-out rule in order to avoid over-fitting of the model.

as has been suggested for Downs syndrome screening(Wright and Bradbury, 2005).

DISCUSSION

This study is the first to measure, in parallel, PP13,PAPP-A and Doppler PI in the late second trimesteras potential markers for the prediction of pre-eclampsia.As was previously reported (Papageorghiou et al., 2001),second-trimester mean PI is higher in pregnancies devel-oping pre-eclampsia and the mean PI is further increasedwith more severe or early pre-eclampsia. While the over-all second-trimester mean PI was a more significantpredictor of pre-eclampsia than any of the serum mark-ers, it is a late predictor on its own. There is therefore arequirement to identify a serum marker that will identifya significant proportion of cases 10–12 weeks earlier,

which could be beneficial for the further developmentof strategies for combining prediction with preventionand patient follow-up.

The question thus remains, if women miss first-trimester screening, does a possible combination ofPAPP-A or PP13 and uterine artery Doppler offeran alternative screening strategy in the last secondtrimester? The findings of this study demonstrate thatin pregnancies with pre-eclampsia, late second-trimestermaternal serum levels of the protein PP13 are of lit-tle value in discriminating all cases with pre-eclampsia.However, in the severe cases requiring early delivery,PP13 has some benefits and the significantly reducedsecond-trimester levels produce a 50% sensitivity foran 80% specificity and a likelihood ratio approaching2.5. Also, we have shown that second-trimester levelsof PAPP-A are elevated in cases with any pre-eclampsiawith a sensitivity of 60% and a likelihood ratio of 3.


262 K. SPENCER ET AL.

Control All PET Early PET0

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Figure 1—First- and second-trimester PP13 and PAPP-A in theearly cases and All pre-eclampsia cases compared to normal. MedianMoM PP13 (+95% confidence) and PAPP-A are shown for first(11–14 weeks) and second (21–24 weeks) trimester for early and allpre-eclampsia

Contrary to our observations in the first trimester, com-bining second-trimester Doppler with second-trimesterPP13 or PAPP-A or all three together did not improvedetection compared with using Doppler PI alone. Thus,it is not worthwhile to include either PP13 or PAPP-A if screening is limited to the second trimester,and other markers such as Activin are more advanta-geous.

The changing temporal pattern of PAPP-A and theapparent temporal change of PP13 in less severe casesof pre-eclampsia may be potentially useful if consideredin a repeat measures concept as has been proposedfor Down syndrome screening (Wright and Bradbury,2005). In fact, the initial indication for this was foundin a longitudinal study in Israel (Gonen et al., 2006),with a second test taken earlier (GA 16–20) and athird test taken later (GA 24–28), and additionallyin a longitudinal study in Germany (Huppertz et al.,2006), but none had Doppler or PAPP-A to be comparedwith.

Recent work has shown the value of longitudinalchanges in marker levels not only as a tool for predictingdisorders but also for the follow up of the biochemicalmake-up of the continuum of the disorder. This is ofparticular value to provide reassurance of the predictedrisk or to monitor the potential usefulness of putativepreventive medications. Further studies are required inlarger populations to establish the real potential of PP13,PAPP-A and Doppler as individual markers and theideal combination for combined, sequential and multipletesting.

ACKNOWLEDGEMENT

This study was supported in part by a grant fromNHS R&D (RF4: Risk Assessment in Pregnancy) toProfessor Kevin Spencer and in part by the Office ofthe Chief Scientist, Israel Government Grants #41913 toDr Hamutal Meiri.

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