PRENATAL DIAGNOSIS

Prenat 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 index and maternal serum PP13 as markers of pre-eclampsia Kevin Spencer1*, Nicholas J. Cowans1 , Ilana Chefetz2 , Joseph Tal3 , Ido Kuhnreich3 and Hamutal Meiri2 1

Department of Clinical Biochemistry, Harold Wood Hospital, Romford, UK Diagnostic Technologies Ltd., Yoqneam, Israel 3 Technostat, Kfar Saba, Israel 2

Objective To evaluate whether measurement of maternal serum PP13 at 22 to 24 weeks of gestation, alone or in combination with second-trimester biochemical markers or uterine artery pulsatility measured by Doppler velocimetry, 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 age and storage time for the maternal serum. PP13 was tested by an ELISA, with the samples blinded to pregnancy outcome. All patients also underwent uterine artery Doppler flow velocimetry at 22–24 weeks to measure the mean pulsatility index (PI). Results for Inhibin, Activin, PAPP-A and Free β-hCG were available from previous studies. Results There were 73 controls and five cases with early pre-eclampsia in which delivery was induced prior to 35 weeks. In addition, there were a further seven cases with pre-eclampsia in which delivery was not induced before term. Median PP13 levels for controls and all cases were 295.9 and 212.6 pg/ml, and 171.2 pg/ml amongst the early pre-eclampsia cases, with the MoMs 1.00, 0.94 and 0.63, respectively (p < 0.001). Receiver operator characteristic (ROC) curve analysis for either all cases or early cases versus controls yielded areas under 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. At a 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 in the 22–24 week period did not improve the detection of early, late or all cases of pre-eclampsia compared with either marker alone. Conclusion Late second-trimester PP13 alone is unlikely to be useful in predicting pre-eclampsia and early pre-eclampsia, and its prediction does not increase when coupled with second-trimester Doppler PI or other potential biochemical markers. Measuring between-trimester temporal changes may be worthy of further investigation. Copyright  2007 John Wiley & Sons, Ltd. KEY WORDS:

screening; hypertension; pregnancy; pre-eclampsia; PP13

INTRODUCTION Hypertensive disorders of pregnancy, particularly preeclampsia, are associated with significant morbidity and mortality, especially when it occurs before 34 weeks (Walker, 2000; Confidential Enquiries, 2001). The incidence of pre-eclampsia in the routine pregnant population is of the order of 5% (Walker, 2000; Roberts and Cooper, 2001). The symptoms of the disorder are well characterised and generally present in the late second to third trimester; however, the underlying pathology is present at early stages of pregnancy and there is evidence that it is associated with a failure of trophoblastic invasion of the maternal spiral arteries (Khong et al., 1986; Shanklin and Sibai, 1989; Pinenborg et al., 1991). A variety of proteins and hormones have been studied as potential early markers for pre-eclampsia. These include the second-trimester maternal serum markers *Correspondence to: Kevin Spencer, Department of Clinical Biochemistry, Harold Wood Hospital, Gubbins Lane, Romford, RM3 0BE, UK. E-mail: [email protected]

Copyright  2007 John Wiley & Sons, Ltd.

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; LambertMesserlian et al., 2000) and Inhibin–A (Cuckle et al., 1998; Aquilina et al., 1999, 2000; Lambert-Messerlian et al., 2000), some of which have been shown to be altered 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). Other markers that have been proposed include first- or secondtrimester 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), placental growth factor (Polliotti et al., 2003; Taylor et al., 2003; Levin et al., 2004) and sex hormone binding globulin (Wolf et al., 2002; Yu et al., 2004b; Spencer et al., 2005b). However, none of these solely have sufficiently good enough clinical discrimination to be used in a clinical context, although combinations of secondtrimester biochemical markers (Wald and Morris, 2001; Wald et al., 2006) and biochemical and ultrasound markers have been proposed (Aquilina et al., 2001; Spencer et al., 2005a, 2006). Received: 4 September 2006 Revised: 27 November 2006 Accepted: 5 December 2006 Published online: 5 February 2007

SECOND-TRIMESTER MARKERS OF PRE-ECLAMPSIA

The use of Doppler ultrasound to assess increased impedance to blood flow in the maternal uterine arteries is probably the single most effective method of screening women in the second trimester. Studies at 20–24 weeks of gestation have reported detection rates of 50–70% for a 5% false-positive rate in women developing early pre-eclampsia (Papageorghiou et al., 2001, 2002). When this had been investigated in the early first trimester at 11–14 weeks (Martin et al., 2001; Gomez et al., 2005) the performance was much poorer, with only 27% of cases detected at a 5% false-positive rate, rising to 50% amongst those severe cases requiring delivery before 34 weeks of gestation. Placental protein 13 (PP13) is a 32-kD dimer and a member of a group of proteins that are highly expressed in the placenta. PP13 is a galectin (Burger et al., 2004; Than et al., 2004) that binds to proteins on the extracellular matrix between the placenta and the endometrium, and through its action as a lysophospholipase-A assists in placental implantation and maternal artery remodelling (Burger et al., 2004; Than et al., 2004; Visegrady et al., 2004). Early studies suggest that the gene for PP13 is down-regulated in women with pre-eclampsia requiring early delivery and that in early pre-eclampsia there is impaired placental functional responsiveness to PP13 during the first trimester (Burger et al., 2004; Tarsa et al., 2004). A recent study (Nicolaides et al., 2006) comparing a series of pregnancies (n = 10) resulting in delivery before 34 weeks due to early pre-eclampsia with normal controls (n = 434) has shown some possible benefits of using early first-trimester maternal serum measurement of PP13 in conjunction with early first-trimester uterine artery Doppler as a potential screening tool. Subsequently, several studies (Chefetz et al., 2006; Gonen et al., 2006) were carried out with a larger series of firsttrimester cases, in which the efficacy of using PP13 was similar. 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 conjunction with second-trimester uterine artery Doppler and showed a significant reduction in PP13 compared to normal outcome or to late pre-eclampsia, but only a marginal improvement was found in detection when Doppler was combined with PP13 compared with uterine pulsatility index (PI) alone. In the present study, we wish to further examine the potential value of second-trimester maternal serum PP13 measurement alone or in conjunction with secondtrimester uterine artery Doppler or other biochemical markers in predicting pre-eclampsia in women developing the disease.

MATERIALS AND METHODS During 2002, women attending for routine transvaginal colour Doppler flow measurement of the uterine artery PI at 22–24 weeks of gestation (Papageorghiou et al., 2001) were enrolled in the study. Women with a singleton pregnancy were asked to provide blood samples Copyright  2007 John Wiley & Sons, Ltd.

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for the investigation of a variety of biochemical markers. All blood samples were left to clot for 5 to 10 min and were then centrifuged at 10 000 g for 5 min prior to serum samples being aliquoted into 500 ul amounts for storage at −20 ◦ C in polypropylene micro tubes. A search of the database was made to identify all singleton pregnancies that had maternal serum collected and also had 22–24 week Doppler investigations. The hospital notes and delivery suite records of each of these patients were then searched to identify any pregnancy complications and obtain delivery details. Specifically, pregnancies with pre-eclampsia were identified, in which pregnancy induced hypertension was defined by a diastolic blood pressure of 90 mmHg or more on any one occasion or a systolic blood pressure of 140 mmHg or more on two consecutive occasions at least 4 h apart in previously normotensive women with no pre-existing renal disease, and the presence of either more than 300 mg of total protein in a 24-h urine collection or greater than a 1+ albumin on reagent strip (Davey and MacGillivray, 1988). A total of 24 cases with pre-eclampsia were identified, and 144 singleton normal pregnancies were selected to form the control group (six controls per case). Data on free β-hCG, PAPP-A, activin A and inhibin A concentrations were available from a previous study (Spencer et al., 2006), with each marker being tested on a fresh aliquot of serum. Of the samples from this previous study, 12 cases with pre-eclampsia (five severe enough to have warranted delivery before 35 weeks) and 73 controls had sufficient aliquots to allow the measurement of PP13. Fresh (previously unfrozen) aliquots of these samples were removed from −20 ◦ C storage. All samples were shipped to Israel on dry ice for analysis of PP13 using a solid phase sandwich ELISA, as described previously (Burger et al., 2004; Nicolaides et al., 2006). All samples were analysed blinded to the clinical outcome. The between-day precision at PP13 concentrations in the range 10–500 pg/ml was less than 10% and the limit of detection was 5 pg/ml.

Statistical analysis Baseline and delivery characteristics were compared between cases and controls using the Fischer exact test for categorical variables and independent t-tests for continuous variables. All statistical analyses were performed 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 therefore we compared PP13 levels across the two outcome groups using the Wilcoxon Rank Sum test. It was seen that PP13 levels increased with gestational age. To take account of this effect, PP13 levels were converted to multiples of the normal median (MoM) for the controls at the same gestational age, based on a weighted (by number of cases) regression of the observed median at each completed week. We also examined maternal Prenat Diagn 2007; 27: 258–263. DOI: 10.1002/pd

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weight, height, body mass index, age, parity and ethnicity as potential confounders in the adjusted MoM analysis. Statistical modelling was used to assess the value of PP13 in predicting pre-eclampsia. Examination of the MoM values showed that they did not fit a Gaussian distribution either untransformed or after logarithmic transformation. Logistic regression was therefore used to estimate from the MoM the odds of being a case versus a control. Including an individual subject, whose risk of the pregnancy disorder we are trying to predict, in the data set that is used to ‘fit’ the regression model could lead to a biased result because of over-fitting the models. To avoid such a bias, each subject’s risk was computed on the basis of a model that excluded the subject, i.e. the model did not ‘learn’ from that subject but only from the others. Data for other markers were available as MoM calculated in our previous study (Spencer et al., 2006). Logistic regression was used to evaluate the accuracy of different combinations of biochemical markers and uterine artery mean Doppler PI in predicting preeclampasia. In order to avoid over-fitting of the model (due to the small number of cases in our sample), we estimated the probability to be a case using the leaveone-out rule, i.e. for each subject, the probability to be a case was estimated on the basis of all available data excluding her own. All markers were adjusted for gestational age, i.e. the analysis was based on MoM values. In order to establish the clinical utility of each marker, receiver operating characteristic (ROC) curves for each marker alone were constructed from the logistic regression to establish the area under the curve (AUC), and to assess for statistical significance the detection and false-positive rates for various were calculated. To assess the utility for pre-eclampsia prediction using the combination of a variety of markers, we used multiple regression analysis and ROC curves. A probability (P ) of <0.05 was considered statistically significant.

RESULTS PP13 levels were dependant on the gestational age (p < 0.001), and the median PP13 levels for controls adjusted for gestational week were 295.9 compared to 212.6 pg/ml in cases of pre-eclampsia and 171.2 pg/ml amongst the early pre-eclampsia cases, with the MoMs being 1.00, 0.94 and 0.63, respectively (p < 0.001). These differences were relatively small compared to the differences between cases and controls for the other markers (Table 1). Receiver operator characteristic (ROC) curve analysis yielded areas under the curve for PP13 of 0.588 (95% confidence interval (CI) 0.42–0.76; p = 0.156) for all pre-eclampsia cases and 0.693 (CI: 0.47–0.92; p = 0.0441) for early pre-eclampsia cases. At a specificity of 0.80, the sensitivities for PP13 in the early cases were 40 and 25% for all cases. It would appear that Copyright  2007 John Wiley & Sons, Ltd.

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

Group

Inhibin A

All PET Early PET Controls All PET Early PET Controls All PET Early PET Controls All PET Early PET Controls All PET Early PET Controls All PET Early PET Controls

Free β-hCG Activin PP13 PAPP-A PI

Median MoM

IQR

2.030 3.200 1.054 1.980 2.067 1.008 2.144 2.093 0.988 0.939 0.627 1.000 1.499 1.920 1.000 1.703 1.985 0.919

3.738 4.322 0.482 1.237 0.331 0.848 2.249 0.850 0.757 0.778 0.545 0.913 1.221 1.260 0.838 0.678 0.210 0.459

although second-trimester PP13 alone is significantly lower than controls, differences in its level at this period of pregnancy could not be used to separate all cases of pre-eclampsia from controls and has relatively low sensitivity for early onset pre-eclampsia. Of the other second-trimester markers, mean PI or Activin seemed to provide a much higher sensitivity. Assessment of the value of combining PP13 and PI (or other biochemical markers) in the clinical discrimination of any or early pre-eclampsia is shown in Table 2. It appears that combination with other biochemical or ultrasound markers did not improve the detection rate, and the best markers were mean PI, activin or their combination (Spencer et al., 2006). We have previously published the results of firsttrimester PP13 in predicting pre-eclampsia on its own or when combined with second-trimester Doppler PI (Spencer et al., 2006b). In this previous study, we tested women in the same hospital during 2001 with samples collected at 11–13 weeks and stored under similar conditions to our current series. The two study populations were otherwise the same in terms of maternal age, parity, ethnicity or frequency of pre-eclampsia. When we compared the results of PAPP-A and PP13 in this study with our previous study in the first trimester (Spencer et al., 2007), we found a significant temporal shift in the marker patterns between trimesters. We have thus attempted to compare the two studies. For PP13 in the first trimester the levels were lower in both the early PET and the all PET group; however, in the second trimester the marker was similarly reduced only in the early PET group (Figure 1), but the level was similar to controls for the all PET cases. In comparison, PAPP-A levels were reduced in the first trimester in the early cases and all PET cases but in the second trimester the levels were increased. This observation may lead to more clinical discrimination being achieved by looking at the rate of change of marker levels between trimesters, Prenat Diagn 2007; 27: 258–263. DOI: 10.1002/pd

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Table 2—Area under the curve (AUC) and sensitivity for each marker and combination of PP13 and PI for the prediction of various classification of pre-eclamptic cases using logistic regression with a specificity set to 0.80. (Pre-eclampsia of any severity (ALL), early pre-eclampsia (early PET), late onset PET (PET)) Markers ACTIVIN FBETA INHIBIN PAPP-A PI PP13 PA PI PP13 PI PP13 ACTIVIN PI PP13 FBETA PI PP13 INHIBIN PI PP13 PA PI

Disorder

AUC (95% CI)

All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET All PET PET Early PET

0.82 (0.69–0.95) 0.84 (0.66–1.01) 0.73 (0.49–0.97) 0.57 (0.36–0.78) 0.23 (0.02–0.44) 0.67 (0.36–0.98) 0.77 (0.6–0.93) 0.69 (0.42–0.96) 0.72 (0.38–1.05) 0.53 (0.31–0.75) 0.39 (0.11–0.67) 0.51 (0.13–0.9) 0.85 (0.74–0.96) 0.7 (0.54–0.86) 0.97 (0.93–1.01) 0.44 (0.29–0.6) 0.18 (0.07–0.28) 0.53 (0.29–0.78) 0.79 (0.66–0.93) 0.52 (0.23–0.81) 0.8 (0.54–1.05) 0.8 (0.65–0.94) 0.62 (0.4–0.84) 0.93 (0.88–0.99) 0.89 (0.8–0.97) 0.84 (0.69–0.99) 0.92 (0.85–1) 0.78 (0.63–0.92) 0.58 (0.36–0.79) 0.93 (0.86–0.99) 0.79 (0.64–0.94) 0.55 (0.27–0.83) 0.91 (0.84–0.99) 0.79 (0.64–0.94) 0.61 (0.41–0.82) 0.88 (0.79–0.98)

P 0.0004 0.0033 0.0870 0.4621 0.0178 0.2119 0.0033 0.0995 0.1029 0.7524 0.3360 0.9269 0.0001 0.0805 0.0005 0.5363 0.0048 0.7987 0.0011 0.8715 0.0269 0.0010 0.2950 0.0012 <0.0001 0.0030 0.0016 0.0024 0.5012 0.0014 0.0014 0.6642 0.0021 0.0014 0.3254 0.0043

Sensitivity 0.75 0.71 0.60 0.50 0.00 0.40 0.58 0.57 0.60 0.42 0.00 0.60 0.75 0.43 1.00 0.00a 0.00a 0.00a 0.58 0.43 0.60 0.75 0.29 1.00 0.83 0.71 1.00 0.67 0.14 1.00 0.67 0.29 1.00 0.67 0.43 0.80

a For PP13, only five cases of early pre-eclampsia and seven cases of pre-eclampsia at term had enough blood. Thus, owing to the small number of cases in our sample, we estimated the probability to 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 trimester as potential markers for the prediction of pre-eclampsia. As was previously reported (Papageorghiou et al., 2001), second-trimester mean PI is higher in pregnancies developing pre-eclampsia and the mean PI is further increased with more severe or early pre-eclampsia. While the overall second-trimester mean PI was a more significant predictor of pre-eclampsia than any of the serum markers, it is a late predictor on its own. There is therefore a requirement to identify a serum marker that will identify a significant proportion of cases 10–12 weeks earlier, Copyright  2007 John Wiley & Sons, Ltd.

which could be beneficial for the further development of strategies for combining prediction with prevention and patient follow-up. The question thus remains, if women miss firsttrimester screening, does a possible combination of PAPP-A or PP13 and uterine artery Doppler offer an alternative screening strategy in the last second trimester? The findings of this study demonstrate that in pregnancies with pre-eclampsia, late second-trimester maternal serum levels of the protein PP13 are of little value in discriminating all cases with pre-eclampsia. However, in the severe cases requiring early delivery, PP13 has some benefits and the significantly reduced second-trimester levels produce a 50% sensitivity for an 80% specificity and a likelihood ratio approaching 2.5. Also, we have shown that second-trimester levels of PAPP-A are elevated in cases with any pre-eclampsia with a sensitivity of 60% and a likelihood ratio of 3. Prenat Diagn 2007; 27: 258–263. DOI: 10.1002/pd

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ACKNOWLEDGEMENT

2nd

1.4

This study was supported in part by a grant from NHS R&D (RF4: Risk Assessment in Pregnancy) to Professor Kevin Spencer and in part by the Office of the Chief Scientist, Israel Government Grants #41913 to Dr Hamutal Meiri.

PP13 MoM

1.2 1 0.8 0.6 0.4 0.2 0 Control

All PET 1st

Early PET

2nd

3

PAPP-A MoM

2.5 2 1.5 1 0.5 0 Control

All PET

Early PET

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

Contrary to our observations in the first trimester, combining second-trimester Doppler with second-trimester PP13 or PAPP-A or all three together did not improve detection compared with using Doppler PI alone. Thus, it is not worthwhile to include either PP13 or PAPPA if screening is limited to the second trimester, and other markers such as Activin are more advantageous. The changing temporal pattern of PAPP-A and the apparent temporal change of PP13 in less severe cases of pre-eclampsia may be potentially useful if considered in a repeat measures concept as has been proposed for Down syndrome screening (Wright and Bradbury, 2005). In fact, the initial indication for this was found in a longitudinal study in Israel (Gonen et al., 2006), with a second test taken earlier (GA 16–20) and a third test taken later (GA 24–28), and additionally in a longitudinal study in Germany (Huppertz et al., 2006), but none had Doppler or PAPP-A to be compared with. Recent work has shown the value of longitudinal changes in marker levels not only as a tool for predicting disorders but also for the follow up of the biochemical make-up of the continuum of the disorder. This is of particular value to provide reassurance of the predicted risk or to monitor the potential usefulness of putative preventive medications. Further studies are required in larger populations to establish the real potential of PP13, PAPP-A and Doppler as individual markers and the ideal combination for combined, sequential and multiple testing. Copyright  2007 John Wiley & Sons, Ltd.

REFERENCES Aquilina J, Barnett A, Thompson O, Harrington K. 1999. Second trimester maternal serum inhibin concentrations as an early marker for pre-eclampsia. Am J Obstet Gynecol 181: 131–136. Aquilina J, Maplethorpe R, Ellis P, Harrington K. 2000. Correlation between second trimester maternal serum inhibin-A and human chorionic gonadotrophin for the prediction of pre-eclampsia. Placenta 21: 487–492. Aquilina J, Thompson O, Thiliganathan B, Harrington K. 2001. Improved early prediction of pre-eclampsia by combining secondtrimester maternal serum inhibin A and uterine artery Doppler. Ultrasound Obstet Gynecol 17: 477–484. Burger O, Pick E, Zwickel J, et al. 2004. Placental Protein 13 (PP-13): Effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies. Placenta 25: 608–622. Chefetz I, Kuhnreich I, Sammar M, et al. 2007. First trimester placental protein 13 screening for pre-eclampsia, intrauterine protein 13 screening for pre-eclampsia, intrauterine growth restriction and preterm delivery. Am J Obstet Gynecol In Press. Confidential Enquiries. 2001. The National Institute for Clinical Excellence, Scottish Executive Health Department; department of Heath, Social Services and Public Safety, Northern Ireland: The fifth report of the confidential enquires into maternal deaths in the United Kingdom 1997–1999. RCOG Press: London; 76–91. Cuckle H, Sehmi I, Jones R. 1998. Maternal serum inhibin A can predict pre-eclampsia. Br J Obstet Gynaecol 105: 1101–1103. Davey DA, MacGillivray I. 1988. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 158: 892–898. Gomez O, Martinez JM, Figueras F, et al. 2005. Uterine artery Doppler at 11–14 weeks of gestation to screen for hypertensive disorders and associated complications in an unselected population. Ultrasound Obstet Gynecol 26: 490–494. Gonen R, Shahar R, Grimpel YI, et al. 2007. Longitudinal assessment of maternal serum placental protein 13 for predicting pre-eclampsia. Am J Obstet Gynecol In Press. Huppertz B, Chefetz I, Neumaier-Wagner P, Hebisch G, Sammar M, Meiri H. 2006. Longitudinal detection of PP13 levels in maternal serum distinguish pre-eclampsia and preterm delivery from cervix insufficiency prior to onset of clinical symptoms. Am J Obstet Gynecol 193: S75. Khong TY, De Wolf F, Robertson WB, Brosens I. 1986. Inadequate maternal adequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small for gestational age infants. Br J Obstet Gynaecol 93: 1049–1059. Lambert-Messerlian GM, Silver HM, Petraglia F, et al. 2000. Second trimester levels in maternal serum human chorionic gonadotrophin and inhibin A as predictors of pre-eclampsia in the third trimester of pregnancy. J Soc Gynecol Investig 7: 170–174. Levin RJ, Maynard SE, Qian C, et al. 2004. Circulating angiogenic factors and the Risk of Pre-eclampsia. N Engl J Med 350: 672–683. Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. 2001. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation. Ultrasound Obstet Gynecol 18: 583–586. Maynard SE, Min JY, Merchan J, et al. 2003. Excess placental soluble fms-like tyrosine kinases 1 (sFlt1) may contribute to endothelial dysfunction, hypertension and proteinuria in preeclampsia. J Clin Invest 405: 649–658. Muttukrishna S, North RA, Morris J, et al. 2000. Serum inhibin A and activin A are elevated prior to the onset of pre-eclampsia. Hum Reprod 15: 1640–1645, Erratum in Hum Reprod 2001; 16: 2477. Prenat Diagn 2007; 27: 258–263. DOI: 10.1002/pd

SECOND-TRIMESTER MARKERS OF PRE-ECLAMPSIA Nicolaides KH, Bindra R, Turzan OM, et al. 2006. A novel approach to first trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound. Ultrasound Obstet Gynecol 27: 12–17. Ong CYT, Liao AW, Spencer K, Munim S, Nicolaides KH. 2000. First trimester maternal serum free beta human chorionic gonadotropin and pregnancy associated plasma protein-A as predictors of pregnancy complications. BJOG 107: 1265–1270. Ong CYT, Liao AW, Munim S, Spencer K, Nicolaides KH. 2004. First trimester maternal serum activin A in pre-eclampsia and fetal growth restriction. J Matern Fetal Neonatal Med 15: 176–180. Papageorghiou AT, Yu CKH, Bindra R, Pandis G, Nicolaides KH. 2001. Mutlicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 18: 441–449. Papageorghiou AT, Yu CK, Cicero S, Bower S, Nicolaides KH. 2002. Second trimester uterine artery Doppler screening in unselected populations: a review. J Matern Fetal Neonatal Med 12: 78–88. Pinenborg R, Anthony J, Davey DA, et al. 1991. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol 98: 648–655. Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. 2003. Second trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early onset pre-eclampsia. Obstet Gynecol 101: 1266–1274. Pouta AM, Hartikained AL, Vuolteenaho OJ, Ruokonen AO, Laatikainen TJ. 1998. Mid trimester N-terminal proatrial natriuretic peptide, free beta hCG and alpha fetoprotein in predicting preeclampsia. Obstet Gynecol 91: 940–944. Raty R, Koskinen P, Alanen A, Irjala K, Matinlauri I, Ekblad U. 1999. Prediction of pre-eclampsia with maternal mid-trimester total rennin, inhibin A, AFP and free β-hCG levels. Prenat Diagn 19: 122–127. Roberts JM, Cooper DW. 2001. Pathogenesis and genetics of preeclampsia. Lancet 357: 53–56. Sebire NJ, Roberts L, Noble P, Wallace E, Nicolaides KH. 2000. Raised maternal serum inhibin A concentration at 10 to 14 weeks of gestation is associated with pre-eclampsia. BJOG 107: 795–797. Shanklin DR, Sibai BM. 1989. Ultrastructural aspects of preeclampsia. I: Placental bed and boundary vessels. Am J Obstet Gynecol 161: 735–741. Sorensen TK, Malinow MR, Williams MA, et al. 1999. Elevated second trimester serum homocysteine levels and subsequent risk of pre-eclampsia. Gynecol Obstet Invest 48: 98–103. Spencer K, Yu CKH, Cowans NJ, Otigbah C, Nicolaides KH. 2005a. Prediction of pregnancy complications by first trimester maternal serum PAPP-A and free β-hCG and with second trimester uterine artery Doppler. Prenat Diagn 25: 949–953. Spencer K, Yu CKH, Rembouskos G, Bindra R, Nicolaides KH. 2005b. First trimester sex hormone binding globulin and subsequent

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development of pre-eclampsia or other adverse pregnancy complications. Hypertens Pregnancy 24: 303–311. Spencer K, Yu CKH, Savvidou M, Papageorghiou AT, Nicolaides KH. 2006a. Prediction of pre-eclampsia by uterine artery Doppler ultrasonography and maternal serum pregnancy associated plasma protein-A, free β-human chorionic gonadotropin, activin A and inhibin A at 22+0 to 24+6 weeks’ gestation. Ultrasound Obstet Gynecol 27: 658–663. Spencer K, Cowans NJ, Chefetz I, Tal J, Meiri H. 2007. First trimester maternal serum PP13, PAPP-A and second trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia. Ultrasound Obstet Gynecol 28: In Press. Tarsa M, Hull AD, Moore TR, Bogic LV. Gene expression profiles suggest pre-inflammatory predominance at the maternal-fetal interface in severe preeclapmsia at preterm (sPPE). In Signalling and the Placental; Proceeding of the Placenta Association of the American Conference, Asilomar CA, Insley J, Myatt L (eds); Elsevier, Amsterdam; September 25–29, 2004. Taylor RN, Grimwood J, Taylor RS, McMasters MT, Fisher SJ, North RA. 2003. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathological pregnancies. Am J Obstet Gynecol 188: 177–182. Than NG, Pick E, Bellyei S, et al. 2004. Functional analysis of placenta protein 13/galectin 13. Eur J Biochem 271: 1065–1078. Visegrady B, Than NG, Kiler F, Sumegi B, Than GN, Bohn H. 2004. Homology modelling and molecular dynamic studies of human placental tissue protein human placental tissue protein 13 (galectin13). Protein Eng 14: 875–880. Wald NJ, Morris JK. 2001. Multiple marker second trimester screening for pre-eclampsia. J Med Screen 8: 65–68. Wald NJ, Morris JK, Ibison J, Wu T, George LM. 2006. Screening in early pregnancy for pre-eclampsia using Down syndrome quadruple test markers. Prenat Diagn 26: 559–564. Walker JJ. 2000. Pre-eclampsia. Lancet 356: 1260–1265. Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. 2002. First trimester insulin resistance and subsequent pre-eclampsia: a prospective study. J Clin Endocrinol Metab 87: 1563–1568. Wright DE, Bradbury I. 2005. Repeated measures screening for Down’s Syndrome. BJOG 112: 80–83. Yaron Y, Cherry M, Kramer RL. 1999. Second trimester maternal serum screening: maternal serum α-fetoprotein, β-chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome. Am J Obstet Gynecol 181: 968–974. Yu CKH, Lakasing L, Papageorghiou AT, Spencer K, Nicolaides KH. 2004a. Uterine artery Doppler and mid trimester maternal plasma homocysteine in subsequent pre-eclampsia. J Matern Fetal Neonatal Med 16: 134–139. Yu CKH, Papageorghiou AT, Bindra R, Spencer K, Nicolaides KH. 2004b. Second trimester sex hormone binding globulin and subsequent development of pre-eclampsia. J Matern Fetal Neonatal Med 16: 158–162.

Prenat Diagn 2007; 27: 258–263. DOI: 10.1002/pd