Preeclampsia is a common hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality.1 It remains a challenging diagnosis owing to variable clinical presentation, unpredictable progression, and limited management options. Despite decades of research, an incomplete understanding of disease pathophysiology and attachment to established practice norms has hindered progress.2–4 The inability to reliably identify pregnancies at highest risk for adverse outcomes has led to a conservative approach, which results in unnecessary interventions and health care costs, including prolonged inpatient care and iatrogenic preterm delivery.5 In addition, the emotional and financial burden borne by women and their families can be substantial. Meaningful advances in the management of preeclampsia and other hypertensive disorders of pregnancy are needed, and will require objective tools to aid in timely, accurate diagnosis and risk stratification.
Angiogenic factors, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), have been the dominant focus of placental biomarkers studies in preeclampsia over the past 15 years (reviewed in references 6 and 7). PlGF, a proangiogenic member of the vascular endothelial growth factor family, normally increases during pregnancy as a function of gestational age, peaking at approximately 30 weeks of gestation.8–11 A dramatic reduction in PlGF is observed in preeclampsia, which precedes the onset of disease and reflects underlying placental dysfunction.11–15 Therefore, numerous studies have examined the utility of PlGF-based tests for predicting preeclampsia.16–19
Prospective observational studies evaluating the performance of point-of-care PlGF tests have shown that a low PlGF (less than the 5th percentile or less than 100 pg/mL) before 35 weeks of gestation has a high sensitivity and negative predictive value for the prediction of preeclampsia requiring delivery within 14 days.20,21 Although PlGF varies by gestational age, absolute cutoffs have been adopted in many studies instead of percentile-for-gestational-age cutoffs because similar test performance has been reported.20 Few studies have evaluated the association between abnormal PlGF and the broad range of outcomes associated with preeclampsia and placental insufficiency. Therefore, we performed a secondary analysis of the Preeclampsia Triage by Rapid Assay Trial (PETRA) to evaluate whether PlGF is associated with adverse neonatal and maternal outcomes.
ROLE OF THE FUNDING SOURCE
The original PETRA study was an investigator-led study supported by funding from Alere.21 No funding was received for the present study. Alere had no role in the study design, analysis or interpretation of the data, or writing of the manuscript. No author has been paid by Alere to write or submit this manuscript for publication. Baha M. Sibai was previously a paid consultant for Alere. The authors had access to relevant aggregated study data and other information required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The authors' personal interests, financial or nonfinancial, relating to this research and its publication have been disclosed.
This was a secondary analysis of PETRA, a prospective, multicenter, observational study that recruited women from 2010 to 2012 at 24 North American centers (Appendix 1, available online at http://links.lww.com/AOG/B721).21 The inclusion criteria and protocol for the original trial, as well as details about the Triage PlGF Assay have been described.21 Briefly, women enrolled in PETRA were 18–45 years of age, with a singleton or multiple pregnancy between 20 and 41 weeks of gestation, and presenting with signs or symptoms of preeclampsia, including hypertension, proteinuria, abnormal laboratory results, excessive weight gain, fetal growth restriction, or symptoms (headache, epigastric or right upper quadrant pain, or nausea and vomiting). The final diagnosis of preeclampsia or other hypertensive disorder was adjudicated by an independent panel of three experts using definitions established in 2013 by the American College of Obstetricians and Gynecologists (ACOG) Hypertension in Pregnancy Task Force.22 Plasma obtained and stored at enrollment was used for PlGF measurements using the Triage PlGF Test. PlGF measurements were performed retrospectively after final pregnancy outcomes were recorded. Participating centers received institutional review board approval before initiation of the study. A list of the PETRA investigators and clinical sites is provided in Appendix 1 (http://links.lww.com/AOG/B721).
For the present secondary analysis, women who participated in PETRA were eligible for inclusion if they had a singleton pregnancy and documented PlGF. We excluded women with missing demographic or clinical data. Institutional review board approval for the study was obtained from the University of Texas Health Science Center at Houston under a waiver of informed consent.
The main exposure variable was abnormal PlGF. Two established cutoffs for abnormal PlGF were used: low (100 pg/mL or less) and very low (less than 12 pg/mL; detection limit of the assay).20,21 The primary outcomes were composite adverse neonatal and maternal outcomes. Composite adverse neonatal outcome was defined as any of the following: fetal death, neonatal death, Apgar score less than 4 at 5 minutes, seizure, grade III or IV intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, or necrotizing enterocolitis. Composite adverse maternal outcome included complications attributable to preeclampsia, and was defined as any of the following: death; eclampsia; hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; pulmonary edema; placental abruption; receipt of a third antihypertensive agent; or occurrence of other rare maternal complication: acute renal failure, myocardial infarction, hypertensive encephalopathy, cortical blindness, retinal detachment, stroke, disseminated intravascular coagulation, microangiopathy (such as thrombotic thrombocytopenia purpura), acute fatty liver of pregnancy, or liver hematoma or rupture. The secondary neonatal and maternal outcomes included respiratory distress syndrome, small-for-gestational-age (SGA) birth weight (less than the 10th percentile for gestational age), preterm delivery before 37 and 34 weeks of gestation, postpartum hemorrhage, and cesarean delivery.
In PETRA, maternal hypertensive disorder diagnoses were adjudicated using 2013 ACOG criteria.22 For the present analysis, these diagnoses were reclassified using 2019 ACOG recommendations and stratified according to PlGF.23 In accordance with the most recent guidelines, women were grouped into one of four categories: 1) preeclampsia with severe features, 2) preeclampsia without severe features or gestational hypertension, 3) chronic hypertension (without evidence of preeclampsia), or 4) no hypertensive disorder. Preeclampsia with severe features included cases of gestational hypertension with severe range blood pressure and superimposed preeclampsia. Women with isolated gestational proteinuria were included in the no hypertensive disorder group.
Differences in baseline characteristics, hypertensive disorder categories, and neonatal and maternal outcomes stratified by PlGF (low PlGF: 100 pg/mL or less vs greater than 100 pg/mL; very low PlGF: less than 12 pg/mL vs 12 pg/mL or greater) were examined using t-test for continuous variables and χ2 or Fisher exact tests for categorical variables, as appropriate. We used multivariable Poisson regression models with robust error variance to examine the association between PlGF (low or very low) and the risks of neonatal and maternal outcomes while adjusting for maternal age (younger than 20, 20–34, 35 years or older), nulliparity, history of preeclampsia in a prior pregnancy, chronic hypertension, gestational diabetes, and gestational age at enrollment. These potential confounders were identified based on analysis of baseline maternal demographic or clinical characteristics. In addition, we assessed the frequency of the composite adverse neonatal outcome stratified by hypertensive disorder and SGA, and performed a subgroup analysis to assess the composite adverse neonatal and maternal outcomes among women without a hypertensive disorder. The results were presented as adjusted relative risk (aRR) with 95% confidence interval (CI). We also reported the sensitivity, specificity, positive predictive value, and negative predictive value of the PlGF test. P<0.05 was considered significant. All statistical analyses were conducted using SAS 9.4 and STATA 15.
Of 1,258 women enrolled in PETRA, 1,112 (88.4%) met inclusion criteria for this analysis (Fig. 1). Plasma PlGF was low in 742 (66.7%) women and very low in 353 (31.7%). The mean gestational age at enrollment was 33 weeks. Women with low PlGF were more likely to be younger than 20 or 35 years or older, nulliparous, and to have gestational diabetes, and less likely to have a personal history of preeclampsia or chronic hypertension. Women with a very low PlGF were more likely to be younger than 20 and nulliparous. Women with low PlGF tended to be enrolled at a slightly later gestational age than women with normal PlGF (greater than 100 pg/mL), whereas those with very low PlGF were enrolled approximately 2 weeks earlier on average than those with PlGFs of 12 pg/mL or greater (Table 1).
Adverse neonatal outcomes were significantly more likely to occur among women with abnormal PlGFs (Table 2). The rate of the composite adverse neonatal outcome was 6.4% overall. Women with low or very low PlGF had higher rates of the composite adverse neonatal outcome (9.2% vs 0.8% for low; 16.5% vs 1.7% for very low). After adjusting for potential confounders, neonates were significantly more likely to experience the composite adverse outcome if the PlGF was low (aRR 17.2, 95% CI 5.2–56.3) or very low (aRR 6.7, 95% CI 3.7–12.2). Similarly, respiratory distress syndrome, SGA, and preterm delivery were more likely to occur in the context of an abnormal PlGF value. The mean gestational age of delivery for neonates with the composite adverse outcome was 27.9±3.6 weeks vs 36.0±3.4 weeks for those without the composite outcome (P<.001). The frequency of perinatal death was 2.2% (n=25) overall. All perinatal deaths occurred in women with low PlGF.
Differences in the rates of adverse maternal outcomes were also observed among women with abnormal PlGF values (Table 3). Overall, 53 (4.8%) women experienced the composite adverse maternal outcome. Among those with a low PlGF, the rate of the composite maternal outcome was 6.2% vs 1.9% among those with normal PlGF (aRR 3.6, 95% CI 1.7–8.0); for very low PlGF, the rate was 9.6% vs 2.5% (aRR 3.1, 95% CI 1.8–5.3). Certain serious but rare events included in the composite outcome did not occur during the study (maternal death, acute myocardial infarction, hypertensive encephalopathy, cortical blindness, and liver hematoma or rupture). There was a small but significant increase in the risk of cesarean delivery among women with abnormal PlGF. The risk of postpartum hemorrhage was not associated with PlGF.
In this high-risk cohort, low PlGF had a sensitivity of 95.8% and a specificity of 35.3% for the composite neonatal outcome; sensitivity and specificity for the composite maternal outcome were 86.8% and 34.3%, respectively (Table 4). Using the very low cutoff decreased the sensitivity and increased the specificity of PlGF. The positive predictive value of low PlGF was poor for neonatal and maternal outcomes (9.2% and 6.2%, respectively). However, low PlGF had a high negative predictive value for both neonatal (99.2%) and maternal outcomes (98.1%).
Given the established and robust association between abnormal PlGF and preeclampsia, we examined the rate of hypertensive disorders stratified by PlGF (Appendix 2, available online at http://links.lww.com/AOG/B721). Preeclampsia with severe features was the most common diagnosis, occurring in 684 women (61.5%), reflective of the enrichment for high-risk women in PETRA. As expected, a final diagnosis of preeclampsia was more common among women with abnormal PlGF. Low PlGF was also associated with SGA (Table 2), consistent with prior studies.14,15,24–27 Therefore, we questioned the extent to which the relationship between abnormal PlGF and adverse neonatal outcomes was affected by SGA (Appendix 3, available online at http://links.lww.com/AOG/B721). The overall rate of SGA was 29.8%; SGA occurred in 36.4% pregnancies complicated by preeclampsia with severe features vs 20.2%, 23.5%, and 16.6% of women with preeclampsia without severe features or gestational hypertension, chronic hypertension, and no hypertensive disorder, respectively. As expected, SGA neonates were more likely to experience the composite adverse outcome compared with non-SGA neonates. Interestingly, low PlGF was associated with a 14.5% frequency of the composite neonatal outcome among SGA neonates, whereas the composite outcome did not occur in the context of normal PlGF (greater than 100).
To investigate the significance of abnormal PlGFs among normotensive women, we analyzed outcomes for the subgroup of 190 women (17.1%) with no hypertensive disease. The risk of the composite adverse neonatal outcome was not significantly increased among women with low PlGF in this small sample (7.6% vs 0.9%; crude RR 8.2, 95% CI 1.0–67.2). The risk of the composite adverse maternal outcome was also not significantly increased (4.9% vs 2.8%; crude RR 1.8, 95% CI 0.4–7.8). Multivariable adjusted regression analyses were not feasible owing to small case numbers.
In this secondary analysis of a large and diverse cohort of high-risk women, we examined the relationship between abnormal PlGF and adverse neonatal and maternal outcomes among women presenting with signs or symptoms of preeclampsia. Using either of two established cutoffs, we found that abnormal plasma PlGF at the time of clinical presentation was significantly associated with the composite adverse neonatal and maternal outcomes, as well as respiratory distress syndrome, SGA, preterm delivery, and cesarean delivery. Low PlGF had a high sensitivity and negative predictive value for both neonatal and maternal composite outcomes, but poor positive predictive value. Notably, among women with normal PlGF, there were no perinatal deaths and no SGA neonates with the composite adverse outcome. Collectively, our results suggest that normal PlGF is reassuring and may identify women and neonates at lower risk for adverse outcomes, although only 1 in 3 women undergoing evaluation for preeclampsia had a normal PlGF value in our study.
The primary PETRA analysis showed that PlGF is significantly correlated with time to delivery; the median time from enrollment to delivery was 45, 10, and 2 days for normal, low, and very low PlGF, respectively.21 Our analysis reveals the serious neonatal and maternal consequences of earlier delivery in the abnormal PlGF groups. Among women enrolled before 34 weeks of gestation (n=570), early preterm delivery (before 34 weeks of gestation) occurred in 12.8% with normal PlGF at enrollment compared with 81.3% with low and 90.8% with very low PlGF.
Our report differs from prior studies of PlGF in that most have evaluated the utility of PlGF to predict preeclampsia or SGA, whereas we report composite adverse outcomes that encompass the range of complications associated with preeclampsia, placental insufficiency, and medically indicated preterm delivery.14–16,20,24–31 One of the largest studies to report on composite adverse perinatal outcomes was a secondary analysis of the PELICAN cohort from the United Kingdom,20 which showed that low PlGF performed better than ultrasound parameters and 46 other candidate biomarkers for the prediction of SGA less than the 3rd percentile.24 Despite differences in the evaluation and management of preeclampsia in the United Kingdom compared with the United States, our results agree with the primary finding that PlGF is a promising biomarker for adverse perinatal outcomes.32
In both PETRA21 and PELICAN,20 health care providers were blinded to PlGF results, leading to the outstanding question of how PlGF might be incorporated into clinical practice and whether its use will have any effect on outcomes. The largest study that attempted to answer this question was the recent PARROT trial, a multicenter, stepped-wedge, cluster-randomized controlled trial in the United Kingdom that included more than 1,000 women and compared time to preeclampsia diagnosis when PlGF results were revealed compared with concealed from health care providers.33 The primary finding was a decrease in the median time to preeclampsia diagnosis in the revealed compared with the concealed group (1.9 vs 4.1 days), which was associated with a statistically significant reduction in maternal adverse outcomes, but no difference in perinatal adverse outcome or gestational age at delivery. Despite being a randomized trial, the findings may not be applicable to women in the United States owing to differences in the manner by which preeclampsia is diagnosed and managed in the United Kingdom. Additionally, the study left some questions unanswered, including how PlGF affected time to diagnosis when it is not among the diagnostic criteria for preeclampsia, how often knowledge of PlGF led to a deviation from usual practice, and how the lack of universal ultrasound screening for fetal growth restriction may have resulted in selection bias.
The PETRA cohort differed from previously studied cohorts in important ways. PETRA was larger, included more women with preeclampsia, chronic hypertension, and obesity, and enrolled fewer smokers. Importantly, it was more racially and ethnically diverse, reflective of enrollment at predominantly U.S. sites. Despite demographic and management differences, analyses of the PETRA, PELICAN, and PARROT cohorts all concluded that PlGF may be a promising adjunct test for predicting indicated delivery, severe SGA, and adverse perinatal outcome.20,21,24,33 Indeed, in all of these large cohorts, perinatal death was restricted to women with low PlGF (less than 100 pg/mL), suggesting that risk stratification by PlGF could aid in the identification of pregnancies requiring higher surveillance, a higher level of care, or prompt delivery.
Perhaps the most compelling result of this study is the high negative predictive value of PlGF level. The strong association between normal PlGF level and a very low risk of serious adverse outcomes is consistent with prior research. Although PlGF has a low specificity and positive predictive value, it is worth noting that we currently rely on inferior clinical predictors of adverse outcome, such as blood pressure and maternal symptoms.20,34 We speculate that PlGF could be helpful in common cases of clinical uncertainty, such as differentiating superimposed preeclampsia from chronic hypertension exacerbation and distinguishing pathologic fetal growth restriction from constitutional smallness. Additionally, the availability of a blood test that is highly sensitive for stillbirth could potentially be used to inform fetal surveillance plans.
We acknowledge the limitations of the analysis. We included women enrolled at a broad range of gestational ages as these data were available and are relevant to clinical practice. Because approximately 25% of women with normal pregnancy outcomes will have low PlGF after 35 weeks of gestation,8 a proportion of normal term pregnancies were included in the abnormal PlGF group, which could have affected our results. However, this classification would tend to bias results toward the null hypothesis and underestimate the association between abnormal PlGF and adverse outcomes. Although we adjusted for potential confounders, the possibility of residual confounding exists, especially because our understanding of the biology of PlGF in pregnancy is incomplete.35 Given the overall low number of adverse outcomes in our study, the adjusted results should be interpreted with caution. Finally, because the data are observational, the clinical consequences of incorporating PlGF testing and the cost-benefit ratio of screening remain uncertain, although a recent cost-effectiveness analysis suggested overall cost savings.36
In summary, among women with suspected preeclampsia, abnormal PlGF was associated with a significant increase in the risk of adverse neonatal and maternal outcomes. The value of PlGF may be in discriminating lower risk pregnancies from higher risk, given its high sensitivity and negative predictive value. Such a test could, in theory, reduce the use of unnecessary maternal and fetal monitoring, hospitalization, iatrogenic preterm delivery, and activity restrictions for those at low risk for decompensation. As with all screening tests, the benefits would need to be weighed carefully against the harms of false positive and false negative results. While collectively the evidence to date suggests that PlGF may be the best single biomarker for poor outcomes related to preeclampsia and placental insufficiency, randomized trials including U.S. women will be required to determine the value of PlGF testing as an adjunct to current management, and would ideally include other objective measures of placental function, such as placental pathology, to further our understanding of the biology and significance of PlGF.
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