Background
Preeclampsia, fetal growth restriction (FGR) and preterm delivery are major contributors to perinatal mortality and morbidity. They not only alter the immediate outcomes of pregnancy at the time of delivery but also the long-term cardiovascular health of the affected women and children. For example, a history of preeclampsia increases a female’s risk of myocardial infarction, stroke or diabetes mellitus by two to eight fold over the next two decades [
1]. Moreover, newborns diagnosed with FGR at birth have a two to eight fold increased risk for hypertension, cardiovascular disease, diabetes mellitus or renal disease as adults [
2,
3].
Recent evidence suggests that the underlying pathology of preeclampsia, FGR and preterm delivery takes place in the first trimester. Earlier assessment before the establishment of placental dysfunction may have the potential to improve treatment and prognosis for clinical practice. Numerous stutdies have shown that abnormal concentration of first trimester serum markers is related to the onset of preeclampsia, small for gestational age and preterm delivery. With the increased use of first-trimester screening for Down syndrome, there is the opportunity to ‘piggy back’ screening tests for preeclampsia, FGR and preterm delivery onto existing tests.
The purpose of our review was to investigate the accuracy of serum biochemical markers (Pregnancy- Associated Plasma Protein-A (PAPP-A), human Chorionic Gonadotropin (hCG), Placental Growth Factor (PlGF), Placental Protein 13 (PP13) used in first trimester serum screening in predicting preelampsia, small for gestational age (SGA) and preterm delivery. We systematically reviewed the available literature and meta-analysed the data.
Methods
Identification of studies
We searched MEDLINE, EMBASE and Cochrane Library from inception to April 2014 for relevant citations. The reference lists of all known primary and review articles were examined to identify cited articles not captured by electronic searches. The search strategy consisted of MeSH (medical subject heading) terms, Emtree terms, and keywords related to the disease (preeclampsia, small for gestational age, preterm birth, preterm delivery, etc.) combined with serum markers(PAPP-A, hCG, PP13, PlGF, etc.). Details of the search strategy are available from the authors. Language restrictions were not applied. A comprehensive database of relevant articles was constructed.
Study selection
The first stage of study selection was the scrutinizing of the database by two reviewers to identify articles from title and/or abstract. In a second stage, a search based on keywords for each of the analytes under review was performed within the Reference Manager database. The results of this search were scrutinized by a second reviewer. In the final stage of study selection the full papers of identified articles were obtained with final inclusion or exclusion decisions made after independent and duplicate examination of the papers. We included studies that reported on singleton pregnancies at low risk in any healthcare setting before the 14th week of gestation. Test accuracy studies allowing generation of 2 × 2 tables were included.
Data extraction and study quality assessment
Acceptable reference standards for preeclampsia were: persistent systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg with proteinuria ≥ 0.3 g/24 h or ≥ 1+ dipstick (= 30 mg/dl in a single urine sample), new after 20 weeks of gestation. Early preeclampsia was defined as preeclampsia resulting in a delivery before 34 weeks of gestation. Late preeclampsia was defined as preeclampsia resulting in a delivery after 34 weeks of gestation. Acceptable reference standards for SGA included birth weight < 10th centile adjusted for gestational age and based on local population values. We also included severe SGA defined as birth weight < 5th centile. Preterm delivery was defined as delivery < 37 weeks. We also included preterm delivery < 34 weeks.
All included manuscripts were assessed by at least one reviewer for study and reporting quality using validated tools. Items considered important for a good quality paper were prospective design with consecutive recruitment, prospective design, adequate description of selection criteria, patient spectrum,test and use of appropriate reference standard.
Data synthesis and analysis
From the 2 ×2 tables the following were calculated with their 95 % confidence intervals for individual studies; sensitivity (true positive rate), specificity (true negative rate) and the likelihood ratios (LR). Results were pooled among groups of studies with similar characteristics, the same threshold and same adverse outcomes. Where 2 × 2 tables contained zero cells, 0.5 was added to each cell to enable calculations. All statistical analyses were performed using Stata 11.0 statistical package.
Discussion
We evaluated the accuracy of five serum screening markers commonly used in first trimester screening for preeclampsia, SGA and preterm delivery. The results showed low predictive accuracy overall. For preeclampsia, the best predictor was PlGF. However, it is important to point out that this threshold was determined from a receiver operating characteristic curve and based only 2 studies. For early and late preeclampsia, the best predictor was also PlGF. Generally, the predictive value of serum markers for early preeclampsia is better than that of late preeclampsia. For SGA the best predictor overall was PP13 while PAPPA < 1st centile was the best predictor of SGA < 5th centile. These results were both based on single studies. For preterm delivery, the best predictor was PP13 while PAPPA < 0.3 MoM was the best predictor of preterm delivery < 34 weeks.
The predict value of first trimester analytes is not worse compare to that of the second trimester markers. Previous studies show in the second trimester, the most accurate predictor of hCG for preeclampsia was hCG > 2.0 MoM, with LR+ 2.45 (1.57, 3.84), LR- 0.89 (0.83, 0.96); for SGA was hCG > 2.0 MoM, with LR+ 1.74 (1.48, 2.04), LR-0.95 (0.93, 0.96). The most accurate predictor of PAPPA for preeclampsia was PAPP-A < 5
th centile, with LR + 2.10 (1.57, 2.81), LR- 0.95 (0.93, 0.98); for SGA was PAPP-A < 1
st centile; LR+ 3.50 (2.53, 4.82), LR- 0.98 (0.97, 0.99). On the other hand, our meta-analysis shows the most accurate predictor of hCG for preeclampsia was hCG < 0.6 MoM; LR+ 1.41 (1.10, 1.82), LR- 0.90 (0.82, 0.99), for SGA was calculated from receiver operating curve analysis; LR+ 3.44 (3.26, 3.63), LR-0.73 (0.71, 0.74). The most accurate predictor of PAPPA for preeclampsia was PAPPA < 0.4 MoM; LR+ 2.17 (1.48, 3.17), LR- 0.91 (0.85, 0.97), for SGA was PAPPA < 1
st centile; LR+ 3.59 (2.77, 4.40), LR- 0.98 (0.97, 0.98). A possible explanation for the apparent difference of hCG change between first trimester and second trimester is that the low levels at first trimester are the consequence of impaired placentation and smaller placental mass, whereas the high levels in the second trimester may be the result of ‘leakage’ or hypoperfusion-related stimulation of production of this hormone [
47]. Although the symptoms of preeclampsia and FGR generally manifest in the second to third trimester of pregnancy, their underlying pathology takes place in the first trimester. One possible reason why preventive strategies have proven very disappointing at present is that the proposed interventions have commenced in the mid to late second trimester, when the underlying placental dysfunction may already be established. Earlier assessment before the establishment of placental dysfunction may have the potential to improve predictive value for clinical practice. With the increased use of first-trimester screening for Down syndrome, there is the opportunity to ‘piggy back’ screening tests for preeclampsia, FGR and preterm delivery onto existing tests.
As preeclampsia and SGA are diseases with relatively low prevalence, a clinically useful test would need to have a high positive LR (> 10) and low negative LR (< 0.10) [
48]. From the results of this review it is unlikely that any first trimester serum screening marker in isolation will provide this. Future research should thus concentrate in two areas. The first is to improve the knowledge of the biological mechanisms for the abnormal clinical tests by focusing on the exact placental pathology resulting in the changes seen in preeclampsia, FGR and preterm delivery. Preliminary findings suggest that genomic studies can improve our understanding of the early pathophysiology of preeclampsia/FGR/preterm delivery at the molecular level. It is hoped that proteomics, metabolomics, and other techniques will allow us to provide potential targets for the development of biomarkers with high enough predictive and prognostic information to be translated into clinical practice. Secondly, future research should attempt to improve the predictive value by combining Doppler sonography, different maternal serum analytes and clinical characteristics. The use of multiple parameters increases the specificity and sensitivity of the screening possibly because they reflect different pathways to the disease process, with abnormal Doppler reflecting the inadequate trophoblastic invasion of the maternal spiral arteries and abnormal biomarkers demonstrating the dysregulated secretory activity by the trophoblasts. However, some studies showed no additive effect of combining different markers, likely secondary to correlation between the markers (such as ADAM12 and PAPP-A, sFlt-1 and sEng) [
47]. Sequential measurements of markers might also improve the risk assessment as individual changes from the first to second trimesters have been shown to occur in preeclampsia and FGR.
Our result also showed the detection rate of first trimester serum markers for early preeclampsia is better than that for late preeclampsia. This disparity may result from different etiologies between early and late preeclampsia. Early preeclampsia is said to be associated with inadequate and incomplete trophoblast invasion of maternal spiral arteries, and is often complicated with a fetal growth restriction. In contrast, the late onset type of preeclampsia is often related to enlarged placental mass or surface (diabetes, multiple pregnancies, anemia, high altitude). It often shows normal or only slightly altered behavior of the uterine spiral arteries and thus no changes in the blood flow of the umbilical arteries. Fetus with late onset preeclampsia often shows no signs of any growth restriction [
49]. Since abnormal concentration of serum markers in the first trimester is caused by intrinsic alteration of the villous trophoblast, it is reasonable that predictive value would be poorer for late onset preeclampsia with normal or only slightly altered trophoblast invasion in the first trimester.
The strength of the study includes generally sufficient quality and a quality assessment of studies based on recognized criteria. However, there are still some limitations. First, there is large discordance in reports of cutoff points, thus, a formal meta-analysis with estimated overall relative risks was not feasible. Secondly, the number of studies for some cutoffpoints is so small that they lead to some contradictive results. For example, our analysis shows the best predictor for preterm delivery was hCG < 0.5 MoM while the best predictor for preterm delvery < 34 weeks is a hCG > 95th centile. This odd result is probably due to the small numbers of studies since there is only one study for each threshold. Clearly large scale studies are needed for more reliable evaluation. Thirdly, all of the studies we selected are population of low risk so we are unable to perform a sub analysis. We didn’t choose the population of high risk since there are few studies on it. More studies are needed to analyse predictive accuracy by the type of population.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
YD and FZ independently selected the articles, and independently extracted data on study characteristics, quality and results. YZ designed the study, performed the statistical analysis, and draft the manuscript. All authors read and approved the final manuscript.