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Keywords:

  • A desintegrin and metalloproteinase 12;
  • first-trimester;
  • placental growth factor;
  • placental protein 13;
  • pre-eclampsia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Please cite this paper as: Wortelboer E, Koster M, Cuckle H, Stoutenbeek P, Schielen P, Visser G. First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. BJOG 2010;117:1384–1389.

Objective  To investigate the predictive value of maternal serum pregnancy-associated plasma protein A (PAPP-A), free β subunit of human chorionic gonadotrophin (fβ-hCG), placental protein 13 (PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first-trimester identification of early-onset pre-eclampsia.

Design  Nested case–control study.

Setting  Routine first-trimester screening for trisomy 21 in the Netherlands.

Population  Eighty-eight women who developed pre-eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls.

Methods  PP13, PlGF and ADAM12 were measured in stored first-trimester serum, previously tested for PAPP-A and fβ-hCG. All marker levels were expressed in multiples of the gestation-specific normal median (MoMs). Model predicted detection rates for fixed false-positive rates were obtained for statistically significant markers alone and in combination.

Main outcome measures  Development of pre-eclampsia or HELLP syndrome.

Results  PP13 and PlGF were reduced in women with pre-eclampsia, with medians 0.68 MoM and 0.73 MoM respectively (< 0.0001 for both). PAPP-A was reduced (median 0.82 MoM, < 0.02) whereas ADAM12 and fβ-hCG did not differ between control women and those with pre-eclampsia. In pre-eclampsia complicated by a small-for-gestational-age fetus, all markers except fβ-hCG had lower values, compared with pregnancies involving fetuses of normal weight. The model-predicted pre-eclampsia detection rate for a combination of PP13 and PlGF was 44% and 54%, respectively, for a fixed 5% and 10% false-positive rate.

Conclusion  This study demonstrates that PP13 and PlGF in the first-trimester might be promising markers in risk assessment for early pre-eclampsia/HELLP syndrome but for an adequate screening test additional characteristics are necessary.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Identifying pregnant women at risk for pre-eclampsia is one of the most important challenges in prenatal care because pre-eclampsia is a serious complication of pregnancy that affects approximately 1–2% of all pregnant women worldwide. It is a leading cause of maternal and perinatal morbidity and mortality, especially when it occurs before 34 weeks of gestation. It occurs mainly in nulliparous women, who are a priori at low risk and without an obstetric history. Therefore screening in an unselected population is important. Maternal serum markers have been investigated and found to be potentially useful as predictors of pre-eclampsia. Previous studies have reported that in the first-trimester concentrations are reduced for placental protein 13 (PP13), anti-angiogenic factors such as placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12) in pregnancies with early-onset pre-eclampsia (delivery before 34 weeks of gestation) and pre-eclampsia later in pregnancy, with a higher predictive value in the former group.1–6 However, the number of cases studied for early-onset pre-eclampsia was generally low, ranging from 6 to 34. Recently, a detection rate of 86% of early-onset pre-eclampsia has been predicted at a false-positive rate of 10%, by combining maternal characteristics, obstetrics history, serum PlGF and uterine artery pulsatility index at 11–14 weeks of gestation.6

The aim of this study was to investigate the predictive value of the markers PP13, PlGF, ADAM12 and the current routine markers for trisomy 21, pregnancy-associated plasma protein A (PAPP-A) and free β subunit of human chorionic gonadotrophin (fβ-hCG), for the first-trimester identification of severe and early-onset pre-eclampsia. This study was performed on stored first-trimester serum samples from 88 women who underwent delivery with severe pre-eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, before 34 weeks of gestation together with controls.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Study population

First-trimester prenatal screening for trisomy 21 is part of routine obstetric care in the Netherlands. Serum samples were collected between 2004 and 2006 as part of the routine first-trimester screening programme. Samples taken at a gestational age of 8 weeks 0 days to 13 weeks 6 days were stored at −30°C for research purposes. This was a case–control study. Serum samples (cases and controls) where retrieved from storage and thawed once or twice. For all samples maternal age, sample date, gestational age at sampling, maternal weight and smoking status were recorded. Pregnancy outcome (chromosomal disorders, date of birth, birthweight, pre-eclampsia, HELLP syndrome and hypertension) was evaluated by questionnaires and collected through self-reporting by the participating women. Six months after the expected delivery date, a reminder letter was sent to these women to collect missing data.

During this study period 88 pregnancies were complicated by severe pre-eclampsia or HELLP syndrome resulting in a delivery before 34 weeks of gestation. In 67 of these cases pregnancy-related data such as blood pressure, amount of proteinuria, HELLP syndrome, fetal weight and outcome could be confirmed at the participating hospitals rather than by the study questionnaire alone. This was approved by the Scientific Ethics Committee of the University Medical Centre, Utrecht, the Netherlands.

Definitions

Pre-eclampsia was defined as an increased systolic blood pressure ≥140 mmHg and/or diastolic blood pressure (≥90 mmHg) on at least two occasions 4 hours apart developing after 20 weeks of gestation in previously normotensive women with proteinuria (≥300 mg/24 hours) or at least one dipstick with ≥2+ on urinalysis according to the definition of the International Society for the Study of Hypertension in Pregnancy.7 The diagnosis of HELLP syndrome was made when the following laboratory abnormalities were present: aspartate aminotransferase >70 U/l, alanine aminotransferase >70 U/l, lactate dehydrogenase >600 U/l, platelet count <100 × 109/l and evidence of haemolysis. Pre-eclampsia combined with HELLP was defined as hypertension, proteinuria and HELLP. The participating hospitals classified the women with HELLP syndrome or pre-eclampsia. The cases were classified according to centile of birthweight using the Kloosterman growth chart and regarded as small for gestational age (SGA) if birthweight was under the 5th centile.8

Sample selection and analysis

Women with pre-eclampsia were individually matched to control women (n = 480) who delivered after 36 weeks of gestation, for the same gestational age at the sample date (exact) and for the duration of specimen storage (±4 months). Control women were women who reported ‘no complications during pregnancy’ on the questionnaire after delivery. The concentration of PP13, PlGF and ADAM12, was measured in the thawed specimens (controls and pre-eclampsia samples frozen an equal number of times, not exceeding two), whereas PAPP-A and fβ-hCG had been measured during screening, all using a time-resolved fluorescence assay (autoDELFIA; PerkinElmer, Turku, Finland). Before analysis extensive validation was performed for the PP13, PlGF and ADAM12 assays. Mean intra-assay and inter-assay coefficients of variation for the assays were below 5% at all levels.

Statistical analysis

To predict the performance of the screening (in terms of detection rates and false-positive rates), a statistical concept was applied that is widely used in prenatal screening for trisomy 21 and which is extensively described elsewhere.9,10 In short, the first-trimester concentration of each marker was converted into a multiple of the median (MoM). Values of MoM were adjusted for variables such as gestation, weight, smoking and ethnicity where MoM values differed significantly between groups (within controls), following the standard methods described by Cuckle and Wald.11 For each marker the standard deviation and correlation coefficients between log MoMs in cases and controls were calculated.

Model-predicted detection rates (sensitivity) for fixed 5% and 10% false-positive rates (1-specificity) were obtained for each statistically significant marker and different combinations of markers by numerical integration.9 This assumed multivariate log Gaussian distributions fitted both pre-eclamptic and unaffected pregnancies. The theoretical range of MoMs was divided into a number of equal sections, which formed a ‘grid’ in multidimensional space. The Gaussian distributions were then used to calculate for each section (square for two markers, cube for three, etc.) the proportion of pre-eclamptic and unaffected pregnancies in the section and the average likelihood ratio in the section. This yielded histograms of likelihood ratios in affected and unaffected pregnancies. The 95th and 90th centiles (corresponding to 5% and 10% false-positive rates, respectively) of likelihood ratio in the histogram for unaffected pregnancies was determined and the proportion of the histogram for pre-eclamptic pregnancies with these values or higher was the predicted detection rate. For every detection rate the 95% CI was calculated. The model parameters were the observed medians, standard deviations and correlation coefficients. Data were analysed using sas (SAS Institute, Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Baseline characteristics of the study populations are shown in Table 1. A larger proportion of cases were in nulliparous women and the median age was lower than for controls. The maternal age was not significantly correlated with the level of serum markers. The proportion of smokers was greater in the cases and the median weight was higher, although these differences did not reach statistical significance.

Table 1.   Maternal baseline characteristics in control women and those with pre-eclampsia
Maternal characteristicsControls (n = 480)Pre-eclampsia (n = 88)P value
  1. GA, gestational age.

  2. The median (interquartile range) or number (percentage) is shown. P values were calculated using either a Mann–Whitney U test or a Pearson’s chi-square test.

  3. *Complete data for parity was not always available.

Age (years)36.0 (33.3–38.2)34.6 (31.0–37.3)0.002
White466 (96.3%)85 (96.6%)1
Weight (kg)66 (62–74)69 (63–77)0.085
Smoking21 (4.3%)7 (8.0%)0.175
GA enrolment (days)84 (78–88)84 (77–88)0.787
GA delivery (weeks)40.1 (39.0–41.0)32.1 (30.0–33.1)<0.001
Birth weight (gr)3500 (3210–3840)1338 (1038–1733)<0.001
Nulliparity*93 (36.2%)57 (81.4%)<0.001

In both control and pre-eclampsia/HELLP groups, there was a statistically significant correlation between PlGF and PAPP-A, with correlation coefficients of 0.18 (< 0.0001) and 0.36 (= 0.001), respectively. PP13 was correlated with PAPP-A, fβ-hCG and ADAM12 in both groups: 0.20, 0.36 and 0.34 (all P< 0.0001), respectively, in the control group and 0.29 (< 0.01), 0.30 (< 0.005) and 0.31 (< 0.005), respectively, in the women with pre-eclampsia. In the control group there was a negative correlation between PlGF and PP13 (−0.14, < 0.005) but not in pre-eclampsia (0.10, = 0.36).

Among the control women the smokers had statistically significantly lower PP13 levels with a median of 0.61 MoM (95% CI 0.50–0.72; < 0.0001) and higher PlGF levels (1.40 MoM; 95% CI 1.26–1.58; < 0.0001). Levels of PAPP-A only tended to be reduced with a median of 0.82 MoM (95% CI 0.65–1.07; = 0.38). A similar pattern of PP13 and PlGF levels was also seen in the women with pre-eclampsia/HELLP.

Smaller effects were seen between ethnic groups. Among the controls there were statistically significant reductions in PP13 levels (median 0.84 MoM; < 0.05) and increase in PlGF (1.28 MoM; = 0.02). PP13 and PlGF were adjusted for gestation, weight, smoking and ethnicity to obtain the model parameters.

Table 2 shows the median MoM values for each marker. There was a highly statistically significant reduction in PP13 and PlGF levels among women with pre-eclampsia/HELLP (0.68 and 0.73 MoM respectively, P < 0.0001 for both). PAPP-A levels were also reduced, though to a lesser extent with a median of 0.82 MoM (< 0.02). ADAM12 and fβ-hCG MoM values did not differ between control women and those with pre-eclampsia/HELLP.

Table 2.   Median MoM and standard deviation (SD) of log10MoM of marker levels of PP13, PlGF, ADAM12, PAPP-A and fβ-hCG for control women and those with pre-eclampsia
MarkerControlsPre-eclampsiaP value
  1. MoM estimated by the 10–90th centile range on a log-scale divided by 2.563. In its simplest form, the data of this table can be crafted into a likelihood ratio (LR) for every single marker with the equation: LR = (SDcontrols/SDcases) × exp(−0.5(Zcases×Zcases−Zcontrols×Zcontrols)) where Z = (log10(observed MoM) − log10(Median MoM)/SD. To make an algorithm for a combination of markers dedicated software is needed.

PP130.99 (0.19)0.68 (0.20)<0.0001
PlGF1.00 (0.14)0.73 (0.19)<0.0001
ADAM121.00 (0.13)1.02 (0.17)0.76
PAPP-A0.99 (0.25)0.82 (0.31)<0.02
fβ-hCG0.98 (0.24)0.98 (0.28)0.93

In pregnancies complicated by a SGA fetus (birthweight under the 5th centile), there was a tendency for all markers except fβ-hCG to be lower, than in cases with fetuses with normal weight (Table 3). This effect was statistically significant.

Table 3.   Median MoMs of PP13, PlGF, ADAM12, PAPP-A and fβ-hCG in women with pre-eclampsia according to centile of birthweight using the Kloosterman growth chart and regarding infants as small-for-gestational age (SGA) if birthweight was under the 5th centile (n = 85, birthweight was unknown in three cases)
MarkerBirthweight centileP value
≥10th (n = 53)5–10th (n = 11)≤5th (SGA) (n = 21)Any centileSGA
PP130.750.710.48<0.02<0.005
PlGF0.750.660.600.06<0.05
ADAM121.100.920.78<0.05<0.02
PAPP-A1.050.590.49<0.001<0.001
fβ-hCG1.050.780.850.290.15

There were no clear differences in MoM values of the markers between women with pre-eclampsia, pre-eclampsia and HELLP syndrome, or just HELLP syndrome (Table 4).

Table 4.   Median MoMs for each marker in women with pre-eclampsia, with HELLP syndrome or with pre-eclampsia according to the presence of HELLP syndrome
MarkerPre-eclampsia (n = 45)HELLP (n = 21)Pre-eclampsia/HELLP (n = 22)
PP130.620.660.87
PlGF0.750.680.72
ADAM120.991.041.03
PAPP-A0.760.830.90
fβ-hCG0.951.080.94

Because we had too few complete data to include baseline characteristics (such as medical history, parity, blood pressure, etc.), none of these variables were included in the final model. Model-predicted detection rates for early pre-eclampsia/HELLP, for fixed false-positive rates, are shown in Table 5. When taken together, PP13 and PlGF predicted 44% and 54% of cases at false-positive rates of 5% and 10%, respectively. Addition of PAPP-A did not improve this detection rate. Receiver operating characteristic curves for PP13 and PlGF were generated for all cases of pre-eclampsia (Figure 1).

Table 5.   Model predicted early pre-eclampsia detection rate (95% CI) for fixed false-positive rates of 5% and 10% for seven marker combinations
Marker combinationFalse-positive rate
5%10%
PlGF alone31 (22–41)41 (32–53)
PP13 alone24 (16–34)36 (27–47)
PAPP-A alone14 (8–22)22 (14–31)
PlGF and PP1344 (34–55)54 (43–63)
PlGF, PP13 and PAPP-A45 (35–56)55 (44–66)
PlGF and PAPP-A32 (23–42)43 (33–54)
PP13 and PAPP-A26 (18–36)37 (27–47)
image

Figure 1.  Receiver operating characterstic curves depicting the sensitivity (detection rates) and 1-specificity (false-positive rate) of the first-trimester maternal serum PP13 and PlGF, PP13 alone or PlGF alone for the identification of pre-eclampsia.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

This retrospective study showed the predictive value of maternal serum first-trimester PP13 and PlGF for first-trimester identification of early-onset pre-eclampsia. The predictive value is probably better when pre-eclampsia is complicated by a SGA fetus but more cases are needed to establish this. Risk assessment using these markers together with other variables such as blood pressure, Doppler flow velocity waveform patterns of the uterine artery and maternal history may result in a detection rate suitable for a cost-effective screening programme.

The risk assessment we used is a standard method in antenatal screening.9,10 It was first used for neural tube defect screening and for at least 20 years in the assessment of markers for trisomy 21.10,12 It has the advantage over regression analysis of being ‘parsimonious’ and avoids over-fitting of the model, which makes it more robust when applied to other study populations. This method has been used in previous reports on risk assessment for pre-eclampsia.3,9,11

Eighty-eight pregnancies were complicated by severe pre-eclampsia or HELLP syndrome, resulting in delivery before 34 weeks of gestation. In 67 of these 88 cases and in more than half of the controls, pregnancy-related data such as blood pressure, amount of proteinuria, HELLP syndrome, birthweight and outcome could be confirmed with the patient records of the participating hospitals rather than the study questionnaire alone. However, there are several limitations to our study. We have no indication that the missing outcomes may have led to significant ascertainment bias but there might have been some recall bias. In all 67 cases in which we could study patient notes, the initial diagnosis was confirmed. Moreover, this study is based on data collected previously as part of the Dutch national screening programme for trisomy 21.

Levels of PP13 and PlGF were significantly reduced in pregnancies complicated by pre-eclampsia or HELLP syndrome for the whole gestational age range of 8–13 weeks of gestation. Among the controls the smokers had, on average, lower PP13 and PAPP-A and increased PlGF levels. So, to accomplish a better risk assessment for early-onset pre-eclampsia the measured concentration should be adjusted for smoking. Furthermore, there were too few non-white women in the study population to establish an effect of ethnicity on PP13 and PlGF MoMs.

This is the first study in which the analysis of PP13 was performed using a time resolved fluorescence assay and combined with PlGF. Both markers individually had almost similar predictive values of 36% and 41% at a 10% false-positive rate, respectively. In pre-eclampsia complicated by a SGA fetus PP13 was even more reduced than PlGF (Table 3). Furthermore, as shown in Table 4, there was no difference between PlGF, PP13 and the severity of pre-eclampsia defined by pre-eclampsia, pre-eclampsia and HELLP or HELLP syndrome alone.

The effects of PP13 on implantation and maternal vascular remodelling are not fully understood. It is known that PP13 is produced in the trophoblast and that it binds to sugar residues of the extracellular matrix molecules, which are involved in placental implantation. From the first trimester onward, levels of PP13 slowly increase in healthy pregnancies. Furthermore, PP13 increases the release of prostaglandins, which are important for vascular remodelling in early placental development.13,14 Therefore, it is plausible that a reduced level of PP13 may impair several functions that are necessary for normal placental development and vascular remodelling. In two earlier studies in which PP13 was measured using a solid-phase sandwich enzyme-linked immunosorbent assay, significantly lower values were found in cases developing early pre-eclampsia.3,15

Placental growth factor is a pro-angiogenic protein, and is also involved in the regulation of placental vascular development and maternal endothelial function during pregnancy. Previous studies have shown that PlGF concentrations are reduced during the clinical phase of pre-eclampsia.4,5,16 Our study and other recent studies have shown that PlGF levels are reduced in the first and second trimesters, i.e. before the clinical phase of the disease.6,17,18 Our findings regarding ADAM12 support a previous study indicating that ADAM12 does not provide useful prediction of SGA, pre-eclampsia or preterm delivery19 and contradict two previous reports showing that in pregnancies developing pre-eclampsia the serum ADAM12 concentration is reduced.1,2 We only found a small, although significant, reduction of ADAM12 levels in pregnancies complicated by pre-eclampsia who subsequently delivered a SGA neonate. This may be explained by the fact that ADAM12 is a placental product involved in the control of fetal growth.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

This study demonstrates that lower maternal serum first-trimester PP13 and PlGF levels are associated with pre-eclampsia/HELLP syndrome. It is possible that if combined with other variables such as blood pressure, uterine artery Doppler flow velocity waveforms and maternal history they may have some value in the prediction of early pre-eclampsia in a low-risk population. Larger prospective and longitudinal studies are necessary to support these findings. In clinical practice, early detection of pre-eclampsia may result in closer and intensive maternal and fetal surveillance and possibly in better outcomes.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

EJW is the main and corresponding author; MPHK, PhS and PCJIS contributed to the study design, conduct of the study and interpretation of the results, HC is responsible for the statistics and GHAV is the main supervisor. All the authors participated and contributed to the writing of the manuscript.

Details of ethics approval

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

The study was approved by University Medical Centre Utrecht Ethics Committee (January 29, 2008).

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

We thank Mr. I. Belmouden, Mr M. Jonker and Ms E.M. van Logchem for their excellent technical assistance at the RIVM. Moreover we thank all the participating Dutch hospitals for their willingness to complete the data in this study; Academic Medical Centre, Amsterdam; Amphia Hospital, Breda; Catharina Hospital, Eindhoven; Deventer Hospital, Deventer; Erasmus Medical Centre, Rotterdam; Flevo Hospital, Almere; Gemini Hospital, Den Helder; Groene Hart Hospital, Gouda; Haga Hospital, The Hague; Jeroen Bosch Hospital, Den Bosch; Academic Medical Centre, Leiden; Medical Spectrum Twente, Enschede; Onze Lieve Vrouwe Gasthuis, Amsterdam; Reinier de Graaf Group, Delft; Rijnland Hospital, Leiderdorp; Rivierenland Hospital, Tiel; Rode Kruis Hospital, Beverwijk; Sint Antonius Hospital, Nieuwegein; Sint Elisabeth Hospital, Tilburg; Slingeland Hospital, Doetichem; ‘T Lange Land Hospital, Zoetermeer; TweeSteden Hospital, Tilburg; University Medical Centre, Maastricht; University Medical Centre St Radboud, Nijmegen; VieCurie Medisch Centre, Venlo; Vlietland Hospital, Vlaardingen; Waterland Hospital, Purmerend; Westfries Gasthuis, Hoorn; Zaans Medical Centre, Zaandam.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
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