Preeclampsia (PE) is an adverse outcome of pregnancy characterized by elevated blood pressure and proteinuria occurring from gestational week 20 . The prevalence of PE is 3%–5% in the developed world and even higher in the third world . PE is responsible for up to 25% of children born with iatrogenic very low birth weight (<1500 g) and is believed to cause 100,000 maternal deaths annually [1, 3, 4]. PE is thus a major contributor to both maternal and fetal morbidity and mortality. Furthermore, PE has been associated with later cardiovascular morbidity in affected women .
The etiology of PE remains elusive, but differentiation defects in early placenta  have been suggested based on the release of placental proteins in first trimester . PE is considered a two stage disorder: stage 1 is marked by reduced placental perfusion and abnormal implantation and vascular remodeling; stage 2 is marked by the maternal syndrome with systemic inflammation, endothelial dysfunction, thromboembolic complications, hypertension and multiple organ failure . However, immunological factors , oxidative stress [10, 11] and inflammation  have also been suggested to cause PE.
Several forms of PE have been identified, i.e. severe or mild PE, early or late PE, as well as PE associated with intrauterine growth retardation (IUGR) and PE not associated with IUGR . Hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome is considered a particularly serious form of maternal syndrome, but may not present as classical PE . There is no known treatment of PE except removal of placenta, which results in quick resolution , but early (first trimester) prophylaxis with aspirin has been suggested to have a protective effect [16, 17].
Early identification of pregnancies at risk for developing PE would be beneficial as it would enable a better clinical management and a sub classification that might facilitate identification of efficient treatment regimens. A number of demographic risk factors have been identified, e.g. obesity, age extremes and previous PE [1, 18], but none of these are per se efficient markers. Recently, a number of maternal serum markers and biometric markers for PE have been identified [3, 19, 20, 21]. One of the most promising markers is the maternal serum concentration of placental protein-13 (PP13).
PP13 was first isolated and characterized from human placental tissue as a 32 kDa homodimer in 1983 . The protein has been classified as a galectin containing a highly conserved carbohydrate recognition domain and showing significant homology with other members of the galectin family, particularly with the human Charcot-Leyden crystal protein (galectin-10) . PP13 is thought to have similar functions to other galectins and may be involved in modulating cell-cell, cell-matrix, cell signaling and cell adhesion interactions  as well as adaptive and innate immune responses . PP13 is predominantly expressed in the placenta at the maternal-fetal interface and specifically located in the cytoplasm and at the brush border membrane of the syncytiotrophoblast [26, 27].
Following the construction of an ELISA kit for PP13 , it was found that the PP13 concentration in maternal serum increased during pregnancy. Furthermore, a decreased level of PP13 in the first trimester of pregnancies developing PE was noted in several studies [20, 29, 30] and mean reductions in the order of 88%–93% were found in two small studies [21, 31]. PP13 values were particularly low early in first trimester  and increased compared to controls in second and third trimester, [31, 32]. In pregnancies at high-risk of developing PE, PP13 was found to be an efficient marker with a detection rate (DR) for early-onset PE of 71% for a false-positive rate of 10% . PP13 was also shown to be reduced in first trimester aneuploid pregnancies [34, 35], but conflicting reports have appeared concerning any association between PP13 and fetal growth disturbances or preterm birth [30, 36]. However, a recent study in weeks 11–14, employing a more robust DELFIA assay, did not confirm the very low first trimester PP13 values in PE pregnancies cited above .
Here we study the distribution of PP13 maternal serum concentration – determined with the DELFIA assay – in a large cohort of PE pregnancies as a function of clinical characteristics; we assess the diagnostic utility of PP13 in combination with pregnancy associated plasma protein A (PAPP-A) in population-based screening for PE and we examine the relation between PP13 and a new PE marker, free leptin index (fLI) .
Materials and methods
Patients and controls
Serum samples from 120 patients who later developed PE and 267 controls were retrieved from patients recruited from a sub-study  of the Copenhagen First Trimester Screening Study . Patients that developed PE were identified from the Danish National Diagnosis Registry, and their files were retrieved and examined carefully for compliance with diagnostic criteria. Out of 6441 pregnant women that had serum taken, 160 verified PE pregnancies (2.5%) were identified. To participate in the current study, all patients furthermore had to have had registered all the examined clinical parameters and serum had to be available for the biochemical analysis. This last criterion left us with 120 PE pregnancies. Controls were selected at random but matched for maternal age, number of previous pregnancies and gestational age at biochemical examination. Gestational age was determined by crown-rump length., and gestational age at birth was from this and the date of birth . All samples were collected in dry containers and kept at 4°C for a maximum of 48 h until delivery to Statens Serum Institut. Samples were subsequently stored at –20°C until analysis. Clinical and demographic information of patients and controls are given in Tables 1 and 2.
The International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria was used to define PE . The diagnosis of PE required hypertension, systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg in a previously normotensive woman after 20 weeks of gestation in combination with proteinuria (>0.3 g per 24 h or urinstix>1+). Severe PE was defined by a diastolic blood pressure >110 mmHg in combination with subjective symptoms and/or abnormal laboratory findings. Subjective symptoms were headache, blurred vision, convulsions, dyspnea, pulmonary edema, epigastric pain and oliguria (<400 mL per 24 h). Abnormal laboratory findings included elevated liver enzymes (aspartate aminotransferase; ASAT>100 U/L) and raised s-bilirubin; severe proteinuria (>3 g per 24 h), s-urate >45 mmol/L, s-creatinine >110 mmol/L, thrombocytopenia (platelets<100×109/L), disseminated intravascular coagulation, hemolysis (s-lactate degydrogenase; LDH >1000 U/L and/or s-haptoglobin <1 μmol/L), activated partial thromboplastin time (>1.5 times starting value), antithrombin III<70; D-dimer >2 mg/L. The presence of hemolysis, elevated liver enzymes and low platelets defined the HELLP syndrome. Early PE was defined as PE pregnancies resulting in birth prior to week 34.
PP13 was quantified using the DELFIA AutoDELFIA® PP13 Research kit (No. 4062-0010, PerkinElmer Life and Analytical Sciences, Wallac OY, Turku, Finland). The assay was run on the AutoDELFIA® analytical platform (PerkinElmer Life and Analytical Sciences) as detailed by the manufacturer. The assay is a solid-phase time-resolved fluoroimmunoassay using two monoclonal antibodies reacting with different epitopes on PP13. The dynamic range of the assay was 10–540 pg/mL. The functional sensitivity is 0.15 pg/mL. The inter- and intra-assay coefficients of variation were <10%. The assay was calibrated using a standard provided by the manufacturer. The serum content of PP13 was constant for 72 h at 23°C and for 10 freeze-thaw cycles.
fLI was the concentration of leptin divided by the concentration of soluble leptin receptor. Both analytes were measured as single determinations using the commercially available ELISA kits Human Leptin ELISA development kit (DY398, R&D Systems, Minneapolis, USA) and the Human leptin sR immunoassay kit (DOBR00, R&D Systems), respectively. The assays were performed as described by the manufacturer.
The relation between the maternal serum concentration of PP13 and other parameters was examined by Loess non-parametric regression, non-parametric correlation ad modum (a.m.) Spearman or parametric regression a.m. Pearson as appropriate. Log-transformation was used to achieve compatibility with the normal distribution, which was in turn assessed by normal probability plot and Shapiro-Wilk’s test. Means were compared using either ANOVA or the Mann-Whitney U-test. Multiple log-linear regression analysis was used to construct maternal weight and/or gestational age independent multiples of the median (MoM). ANOVA was tested by F-test. The level of significance was chosen at p=0.05.
The population performance of screening for severe PE and HELLP syndrome using PP13 and combinations of PP13 and PAPP-A and fLI was estimated by Monte-Carlo simulation as described . Briefly, the log10MoM distributions of markers and their correlations were used to create a large number (in this case, 20,000) of representative combinations of markers. This enables the establishment of likelihood ratio distributions for affected and un-affected; these are then used in combination with the background risk to obtain risk distributions from which receiver operator characteristics (ROC) curves can be established within the truncation limits of 0.8 log10MoM (upper) and −0.8 log10MoM (lower). The background risk of severe PE and HELLP syndrome was estimated to be 1.4%. The calculations were performed using S-Plus version 6.0 (Statistical Solutions, Clearwater, FL, USA).
Informed consent was obtained. Blood sampling was performed as part of the Copenhagen First Trimester Screening Study  and approved by the Scientific Ethics Committee for Copenhagen and Frederiksberg Counties [No. (KF) 01-288/97].
Distribution of PP13 values in normal and PE pregnancies
The distribution of PP13 concentration values in controls and PE pregnancies is shown in Figure 1. The values in PE pregnancies are reduced throughout the gestational age window examined. Thus, PP13 concentrations in PE pregnancies were significantly (p=0.037, Mann-Whitney U-test) lower than in controls, median PP13: 51.8 pg/mL (range: 13.1–534.0 pg/mL) and 54.8 pg/mL (range: 15.4–142.6 pg/mL), respectively Table 1. The distribution of PP13 concentrations in PE pregnancies broken down with respect to clinical severity is given in Figure 2 and Table 2. The concentration levels did not differ significantly between groups (p=0.1, Kruskal-Wallis test). However when severe PE and HELLP pregnancies were pooled (n=26), with a median PP13: 35.8 pg/mL (range: 17.8–85.5 pg/mL), and compared to mild PE pregnancies (n=94), median PP13: 53.1 pg/mL (range: 13.1–534 pg/mL), the levels were significantly different (p=0.03, Mann-Whitney U-test).
The PP13 concentrations in controls and mild PE cases did not differ (p=0.24, Mann-Whitney U-test). A subgroup of PE pregnancies (n=10; two mild PE, five severe PE, and three HELLP cases) which delivered prematurely (<238 days=≤33+6 weeks) had significantly lower median PP13 than in the remaining (controls+PE pregnancies) 30.6 pg/mL (range: 13.1–50.1 pg/mL) and 54.2 pg/mL (range: 15.4–534 pg/mL), respectively (p<0.001). In the 18 severe and HELLP pregnancies delivering in or later than 34th week, the median PP13 concentration was 52.6 pg/mL (range: 18.7–85.5 pg/mL), only marginally lower than in controls and mild PE pregnancies. Thus, the PP13 concentrations were reduced in severe PE and HELLP cases and, in particular, in PE cases resulting in a birth<week 34.
Correlation between PP13 and clinical parameters
PP13 concentrations correlated significantly with maternal body mass index (BMI) in controls (Spearman’s ρ=−0.23, p<0.001), but not in PE pregnancies (p=0.4) (Figure 3). There were no correlations between PP13 and gestational age, pregnancy length, maternal age or birth weight in either controls or PE pregnancies.
Establishment of normalized PP13 values
A regression analysis was performed in controls using log10 PP13 concentration as the dependent variable and BMI as the independent variable: log10 PP13=−0.014×BMI (kg/m2)+2.049, R2=0.068, p<0.001. All PP13 concentrations were transformed to MoMs for the BMI. Following the transformation, the difference between controls and PE pregnancies, was not longer significant (p=0.6); however, the combined severe PE and HELLP group (n=26), mean log10MoM PP13: −0.10 (SD: 0.21), was significantly lower (p=0.015, ANOVA) than in controls combined with mild PE cases (n=361), with a mean log10MoM PP13 of −0.005 (SD: 0.19); Figure 4 shows the distributions. This corresponds to an 18% reduction in log10MoM PP13 values in severe PE and HELLP cases compared to controls. In both groups, the log10MoM PP13 values were normally distributed as judged from Shapiro-Wilk’s test, p=0.1 in the first group and 0.05 in the latter. Following elimination of a single high outlier, the p-value increased to 0.09.
The log10MoM PP13 values in controls correlated significantly in PE pregnancies with BMI (Figure 5A; Spearman’s ρ=0.19, p=0.04), and borderline significantly with birth weight (Figure 5B; Spearman’s ρ=0.12, p=0.05), but not with gestational age, pregnancy length or maternal age in either group.
The ability of PP13 to discriminate between severe PE and HELLP pregnancies and the rest (controls+mild PE) was assessed in empirical ROC-curves (Figure 6A). PP13, AUC of 0.65 (95% confidence interval: 0.53–0.78), seemed to discriminate slightly, albeit not significantly, better than the log10MoM values with an AUC of 0.62 (95% confidence interval: 0.49–0.74). Likewise, the ability to discriminate between PE pregnancies resulting in birth<34 weeks of gestation, and the remaining pregnancies was assessed by ROC-curve analysis. Also here, the PP13 concentrations discriminated slightly better, with an AUC of 0.78 (95% confidence interval: 0.63–0.93), p=0.002 versus an AUC of 0.74 (95% confidence interval: 0.57–0.91), p=0.007 for log10MoM PP13 (Figure 6B).
PP13 and PAPP-A
PAPP-A concentration values were available from the result of first trimester screening. The concentration values of PAPP-A (in mIU/L) were log-regressed on BMI and gestational age in controls: log10 PAPP-A=−0.019×BMI+ 0.022×gestational age (days)+1.985, R2=0.185, p<0.001. All PAPP-A concentration values were transformed into log10MoM PAPP-A values and all distributions were compatible with the normal distribution. The level in controls, mean log10MoM PAPP-A=0.04 (SD: 0.25) was not significantly different from the values in PE pregnancies, mean log10MoM PAPP-A=0.003 (SD: 0.27), p=0.17 (Mann-Whitney U-test). The finding that the mean log10MoM PAPP-A in controls is not 0.00 is due to the controls being a sample from an ideal large population with a mean log10MoM PAPP-A of 0.00. PAPP-A concentrations were 32% lower in severe PE and HELLP syndrome compared with controls and mild PE cases, mean log10MoM PAPP-A: −0.11 (SD: 0.23) and 0.04 (SD: 0.26), respectively, p=0.003. Log10MoM values of PAPP-A and PP13 correlated significantly in controls (Spearman’s ρ=0.23, p<0.001), but not in PE pregnancies (Spearman’s ρ=0.13, p=0.2). They correlated in the combined severe PE and HELLP cases (Spearman’s ρ=0.23, p<0.001), whereas they did not correlate in controls and mild PE cases (Spearman’s ρ=0.08, p=0.44), PAPP-A and PP13 correlated clearly, albeit insignificantly – due to the low number of cases (n=10) – in cases giving birth prior to week 34.
PP13 and fLI
fLI values were converted to log10MoM values. In severe PE and HELLP pregnancies, the mean log10MoM fLI was significantly higher (p<0.001, Mann-Whitney) than the mean log10MoM fLI in controls and mild PE cases; 0.16 (SD: 0.22) and 0.04 (SD: 0.27), respectively. In both controls and mild PE as well as severe PE and HELLP pregnancies, PP13 did not correlate significantly with fLI (Spearman’s ρ=0.004, p=0.96, and Spearman’s ρ=−0.30, p=0.14, respectively). FLI correlated significantly with PAPPA in controls and mild PE cases, (Spearman’s ρ=0.19, p<0.001) but not in severe PE and HELLP syndrome (Spearman’s ρ=−0.06, p=0.9).
PP13 in population screening for PE
To assess the potential of PP13 and PAPP-A in population-based screening for severe PE and HELLP syndrome in association with the first trimester serum screening for Downs syndrome we used the log10MoM distributions of PP13 and PAPP-A as well as the correlations given above in Monte-Carlo simulation of performance. A population prevalence of 5% for PE as well as 1% of severe PE and 0.4% of HELLP syndrome (both severe PE and HELLP prevalence estimates are based on the relative prevalence in the present study) was used in the calculations. The results of the simulation are given in Table 3. The screening performance of PP13 is not greatly improved by adding PAPP-A, whereas fLI is more efficient.
This study shows that PP13 is markedly reduced in weeks 10–13 of pregnancies that develop severe PE and HELLP syndrome and result in birth prior to week 34. On the contrary, PP13 is not perturbed in pregnancies that develop mild PE. These findings are compatible with another study also employing a modern robust Delfia assay . Previous studies, employing the first PP13 ELISA assay , reported very low PP13 values in PE pregnancies in first trimester [21, 30, 31] and this may be due to a dubious technical performance of the first-generation PP13 assay . This underscores the need of careful technical assessment of assays to be employed in large-scale screening. The situation could be analogous to the problems with the first- and second-generation assays for ADAM12 . Another possibility is differences in assay performance due to varying ability to react with the different splice forms of PP13 reported to exist in PE pregnancies .
As seen in an earlier study , PAPP-A correlates with PP13, resulting in a very low additive effect of PAPP-A and PP13 in screening for severe and HELLP pregnancies. It is believed that PP13 contributes to placentation and plays a role in the maintenance of placental integrity [25, 26] PAPP-A is also a placenta-synthesized protein and the correlation between PP13 and PAPP-A may be due to this passive relationship. It may, however, be more complicated as both molecules have a plethora of suggested and proven functional roles in placenta and the feto-maternal interface [24, 25, 26, 45, 46].
The lack of correlation between PP13 and fLI may reflect that in addition to the leptin synthesized by the placenta, the largest contributor to maternal serum fLI is maternal adipose tissue . It may also reflect that leptin plays no role in the pathological processes leading to reduced PP13 synthesis. However, from a practical point of view, the lack of correlation makes the combination of fLI with PP13 an efficient marker combination for the detection of severe PE and HELLP syndrome.
The DRs obtained in this study (Table 3), are not so large that PP13 – even with the addition of both PAPP-A and fLI – constitutes a clinically satisfactory marker for severe PE and HELLP; however, they may, in association with first trimester Doppler ultrasound, bring us further towards the clinical implementation of a first trimester screening for development of PE . It is satisfactory that PP13 is only a marker of severe PE and HELLP and premature birth, as there is a greater clinical relevance in identifying the severe PE cases, who are at greater risk of serious fetal and/or maternal morbidity. An improvement in the use of PP13 is the use of PP13 both in first and second trimester, as the slope between the concentrations in the two parts of pregnancy is a very sensitive PE marker . The use of second trimester markers, be it Doppler ultrasound or PP13, however, precludes the use of PE screening to identify at risk pregnancies that may benefit from prophylactic aspirin treatment . However, this prophylactic treatment needs to be ascertained in large prospective studies, as the vitamin C and E prophylaxis did not survive this test . The use of PP13, PAPP-A, that is available from the Down syndrome screening and fLI, may help define a high-risk group of pregnancies that may particularly benefit from prophylaxis.
PP13 is only a marker of severe PE and HELLP associated with premature birth, this corroborates that the different clinical types of PE are different diseases [6, 14]. However, it is also interesting that PP13, considered an early marker of problems with placental organization, defines the occurrence of the maternal syndrome.
The level of PP13 in maternal serum is defined by placental synthesis, which is decreased in syncytiotrophoblast in PE pregnancies  as well as in cells isolated from the maternal circulation in pregnancy , and the extent of shedding of PP13 from a suffering placenta . This can explain why PP13 is decreased in early PE pregnancies and increased when hypoperfusion interferes with placental function – one step towards the debut of the maternal syndrome .
In conclusion, we have shown that PP13 is a moderately effective first trimester maternal serum marker for the development of severe PE and HELLP syndrome associated with premature birth and that the discriminatory effect of combining PP13 with PAPP-A is poor but considerably better when combining PP13 with fLI.
We gratefully acknowledge the expert technical assistance of Pia Lind. We acknowledge the financial support of the Danish Medical Research Council, The John and Birthe Meyer Foundation, The Ivan Nielsen Foundation, The Else and Mogens Wedell-Wedellsborg Foundation, The Dagmar Marshall Foundation, The Egmont Foundation, The Fetal Medicine Foundation, The Augustinus Foundation, The Gangsted Foundation, The A.P. Møller Foundation and The Mads Clausens Foundation. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation.
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About the article
Published Online: 2017-07-12
Published in Print: 2017-11-27
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.