Angiogenic Markers in Transition

Editorial Commentary Angiogenic Markers in Transition Thinking Positive Henning Hagmann, Ravi I. Thadhani See related article, pp 731–738

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reeclampsia is a potentially devastating multisystem disorder affecting 3% to 8% of all pregnancies worldwide. A major contributor to maternal morbidity and mortality, as well as to premature delivery and its resulting neonatal consequences, preeclampsia imposes a substantial economic burden on society and an intense emotional strain on families. Newly diagnosed hypertension and proteinuria >300 mg/d or other signs of end-organ dysfunction after the 20th week of gestation have historically defined the condition. Although preeclampsia has been recognized since the ancient times,1 research performed in the last 2 decades has advanced our understanding of the potential mechanisms underlying its pathogenesis. Along with the contribution by Sovio et al2 in this issue, this new knowledge has allowed new diagnostic criteria to be established and opened doors for novel treatment strategies. In preeclamptic pregnancies, antiangiogenic soluble VEGF receptor 1 (vascular endothelial growth factor, also known as sFlt-1 [soluble fms-like tyrosine kinase-1]) is pathologically overexpressed by the placenta and excessively secreted into the bloodstream.3 The excess circulating sFlt-1 scavenges VEGF and other proangiogenic factors, such as PlGF (placental growth factor), thereby opposing the otherwise natural trophic signal of VEGF on endothelial cells and consequently producing endothelial damage and dysfunction. The utility of using sFlt-1 and PlGF plasma levels as diagnostic tools in patients with suspected preeclampsia was suggested over a decade ago, when the rise in sFlt-1 and decline in PlGF plasma levels was shown to antedate clinical symptoms by ≈4 weeks.4,5 Several case-controlled studies have suggested that measurement of angiogenic factors in combination with either ultrasound studies or clinical characteristics in patients with suspected preeclampsia may be used to predict, diagnose, and prognosticate preeclampsia.6–8 More recently, the large multicenter prospective study by Zeisler et al9 established a cutoff of ≤38 for the sFlt-1:PlGF ratio to exclude the risk of preeclampsia in the ensuing week.

The tremendous negative predictive value (>99%) achieved in their study provides firm guidance for managing women who present to the obstetrics ward with suspected but otherwise unconfirmed preeclampsia. Achieving such a high negative predictive value was likely aided by the low incidence/prevalence of this disease. The same ratio of 38 evaluated in their post hoc analysis achieved a more modest positive predictive value of ≈37%. Although a higher positive predictive value would have been ideal, the authors appropriately argue that this new cutoff represents an improvement over the currently accepted predictive measures of hypertension and proteinuria, even though their study was not designed to achieve such a milestone. In this context, the single-center prospective cohort study (n=4099) by Sovio et al2 reaffirmed the robust (>99%) negative predictive value of an sFlt-1:PlGF ratio of ≤38 near term (≈36 weeks) to exclude the possibility of preeclampsia with severe features in the ensuing weeks. Similar to the study by Zeisler et al, the positive predictive values of this same threshold were ≈30%. When maternal risk factors were combined with an sFlt:PlGF ratio of >38, the authors were able to stratify three quarters of nulliparous women, identifying 5% as high risk and 70% as low risk. Importantly, the majority of patients with severe disease were identified using this model. Additionally, during mid-trimester (ie, at 28 weeks of gestation), the study boasted a positive predictive value of ≈60% for delivery with preterm preeclampsia when the sFlt-1:PlGF ratio exceeds 85. An alternative strategy to develop a test with a high positive predictive value would be to somehow increase the prevalence of the condition being tested, that is, by restricting the test to women at high risk for the condition. Instead, Sovio et al2 examined the utility of the test in an otherwise unselected population of nulliparous women presenting to an obstetric ward for routine ultrasound dating and evaluated whether its positive predictive value could be increased by modifying the cut point of the positive test. The cut point of 85 had previously been examined in other cohorts10; however, the study by Sovio et al2 was unique in that they examined the utility of this threshold in an otherwise unselected population of nulliparous women. Once confirmed, a diagnosis of preeclampsia requires different strategies of clinical management depending on the gestational age of the patient. When a diagnosis is confirmed after 34 weeks of gestation, the accepted clinical focus is timely delivery of the placenta (and fetus) to shut down preeclampsia. For pregnancies at or >36 weeks of gestation, Sovio et al2 proposed a ratio of >110 or >38 plus maternal risk factors. Among women meeting these thresholds, 43% delivered with the diagnosis of preeclampsia, and many had severe features. Identifying patients at risk for preeclampsia near term may

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department II of Internal Medicine and Nephrology and Center for Molecular Medicine Cologne, University of Cologne, Germany (H.H.); and Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston (R.I.T.). Correspondence to Ravi I. Thadhani, Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. E-mail [email protected] (Hypertension. 2017;69:578-579. DOI: 10.1161/HYPERTENSIONAHA.116.08739.) © 2017 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.116.08739

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help clinicians improve outcomes by prompting the decision to induce delivery. Although expectant management and supportive care are still the best options before 34 weeks, novel treatment options are on the horizon.11,12 For the successful development of such options, they must be guided by tests that predict a high likelihood of disease. Although the study provides useful prediction of risk for the clinically important manifestations of preeclampsia at gestational ages between 28 and 36 weeks, it does not advise us on how to interpret a positive test. Conceivably, repeated measurements establishing a slope of the sFlt-1 increase may further enhance prediction. Moreover, testing for preeclampsia at earlier gestational ages between 20 and 28 weeks will become of greater clinical interest in the future. Additional cutoff values of the sFlt-1:PlGF ratio will be needed for any new time point because the biocharacteristics of sFlt-1 and PlGF in pregnancy do not allow for mere extrapolation. Finally, the study did not report on intrauterine fetal growth restriction, a condition that is linked to alterations in angiogenic factors.4,5 Although the American College of Obstetricians has removed growth restriction as one of the criteria for severe preeclampsia, knowledge of severe growth restriction may be critical for obstetricians to plan timing of delivery. Although we have gained confidence in the predictive value of the negative cut point from this and previous studies, Sovio et al2 additionally help us to transition our thinking to previously uncharted areas in preeclampsia, namely, from expectant management to treatment strategies that have real potential to improve outcomes. For example, data from the Sovio et al’s2 study lay the foundation for a HYPITAT-like trial (Hypertension and Preeclampsia Intervention Trial at Near Term),13 in which women at term with high sFlt-1:PlGF ratios could be randomized to immediate delivery or expectant management to confirm whether prediction of severe preeclampsia improves maternal and fetal outcomes. Of all the results presented, one of the most intriguing was the possibility to identify women preterm who would be amenable to interventions with potential to safely prolong pregnancy. At early gestational ages, when delivery is far from the preferred option, prediction of imminent preeclampsia and the time interval to symptom onset would not only be useful to direct specific follow-up care, but might also encourage high-risk women to enroll into clinical trials and, eventually, guide clinicians to treat patients with directed therapies. In this setting (ie, unselected population and low-incident disease), high positive predictive values are difficult to achieve. Nevertheless, and although numbers are small, this study suggests that ≈3 of 5 women testing positive (ratio >85) at 28 weeks will develop severe preeclampsia and require delivery within the ensuing 4 weeks. With a likelihood ratio of ≈70, the posttest probability of disease will be >70%. Armed with this information, we can use a positive test during mid-trimester (≈28 weeks) to identify women at the highest risk to enroll into clinical trials. Undoubtedly, such a population would be ideal to test novel targeted therapies.12 We conclude that this study marks a crucial transition toward defining precise cutoff values for angiogenic factors stratified by gestational age. Considering both the negative

predictive values to rule out disease, we are also prompted to think about “positive” predictive values to rule in the possibility of imminent severe preeclampsia. Improved interpretation of the balance in angiogenic biomarkers is indeed a positive step toward realizing precision medicine for preeclampsia and for testing promising targeted therapies.

Disclosures R.I. Thadhani has patents in diagnostics for preeclampsia that have been licensed to in vitro diagnostic companies. R.I. Thadhani is on the Scientific Advisory Committee for Aggamin LLC, is a consultant for Thermo Fisher and Roche Diagnostics, and has a grant from Kaneka Corporation. H. Hagmann has a grant from Kaneka Corporation.

References 1. Celsus AC, Rode J, Lee A, Targa L. Aur. Cor. Celsus on Medicine, in Eight Books, Latin and English. London: E. Cox; 1831. 2. Sovio U, Gaccioli F, Cook E, Hund M, Charnock-Jones DS, Smith GCS. Prediction of preeclampsia using the soluble fms-like tyrosine kinase 1 to placental growth factor ratio: a prospective cohort study of unselected nulliparous women. Hypertension. 2017;69:731–738. doi: 10.1161/ HYPERTENSIONAHA.116.08620. 3. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–658. doi: 10.1172/ JCI17189. 4. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–683. doi: 10.1056/ NEJMoa031884. 5. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP Study Group. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005. doi: 10.1056/ NEJMoa055352. 6. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. Firsttrimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53:812–818. doi: 10.1161/HYPERTENSIONAHA.108.127977. 7. Myatt L, Clifton RG, Roberts JM, Spong CY, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Sciscione A, Tolosa JE, Saade G, Sorokin Y, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development MaternalFetal Medicine Units Network. Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? BJOG. 2013;120:1183–1191. doi: 10.1111/1471-0528.12128. 8. Stepan H, Geide A, Faber R. Soluble fms-like tyrosine kinase 1. N Engl J Med. 2004;351:2241–2242. doi: 10.1056/NEJM200411183512123. 9. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374:13–22. doi: 10.1056/NEJMoa1414838. 10. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol. 2012;206:58.e1–58.e8. doi: 10.1016/j.ajog.2011.07.037. 11. Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124:940–950. doi: 10.1161/CIRCULATIONAHA.111.034793. 12. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of soluble fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol. 2016;27:903–913. doi: 10.1681/ASN.2015020157. 13. Koopmans CM, Bijlenga D, Groen H, et al; HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet. 2009;374:979–988. doi: 10.1016/S0140-6736(09)60736-4.

Angiogenic Markers in Transition: Thinking Positive Henning Hagmann and Ravi I. Thadhani


Hypertension. 2017;69:578-579; originally published online February 6, 2017; doi: 10.1161/HYPERTENSIONAHA.116.08739 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2017 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563

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