Valor predictivo del ratio SFlt-1/PlGF en mujeres con sospecha de preeclampsia

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1 Valor predictivo del ratio SFlt-1/PlGF en mujeres con sospecha de preeclampsia Por fin tenemos forma de modificar la evolución de nuestras pacientes? Dr. Alberto Rodríguez Melcón Departamento de Obstetricia, Ginecología y Reproducción del Hospital Universitario Dexeus (Barcelona)

2 Por fin tenemos forma de modificar la evolución de nuestras pacientes? o Por fin tenemos forma de modificar la evolución de nuestras pacientes!

3 INTRODUCCIÓN La DISFUNCIÓN PLACENTARIA: CIR + DPPNI + PE-E produce una importante MORBILIDAD y MORTALIDAD tanto para la madre como para el feto en todo el mundo. CONOCIMIENTO FISIOPATOLÓGICO: Disbalance factores anti-angiogénicos (sflt-1) y factores pro-angiogénicos (PlGF) NO HAY CAMBIOS: PREDICCIÓN-DIAGNÓSTICO-MANEJO

4 FISIOPATOLOGÍA Perfusión placentaria: arterias espirales Placentación: invasión por 2 oleadas de células trofoblásticas extravellosas intersticiales y endovasculares. 1ª Oleada entre la w 2ª Oleada entre la w Remodelación en vasos de baja resistencia y elevada capacitancia

5 FISIOPATOLOGÍA

6 FISIOPATOLOGÍA

7 FISIOPATOLOGÍA FALLO INMUNO TOLERANCIA DESTRUCCIÓN CITOTROFOBLASTO ISQUEMIA PLACENTARIA INFLAMACIÓN VASCULAR ESTRÉS OXIDATIVO LIBERACIÓN ANTI- ANGIOGÉNICOS DESEQUILIBRIO ANGIOGÉNICO

8 FISIOPATOLOGÍA ENDOTELIO PREVIO DAÑADO ENDOTELIO PREVIO NORMAL PLACENTACIÓN NORMAL PLACENTACIÓN ANORMAL PLACENTACIÓN ANORMAL NO ESTRÉS OXIDATIVO PLACENTARIO ESTRÉS OXIDATIVO PLACENTARIO ESTRÉS OXIDATIVO PLACENTARIO DISFUNCIÓN ENDOTELIAL INFLAMATORIA MATERNA EQUILIBRIO ANGIOGÉNICO NORMAL HIPERTENSIÓN Y PROTEINURIA DISFUNCIÓN ENDOTELIAL INFLAMATORIA MATERNA DESEQUILIBRIO ANGIOGÉNICO NORMOTENSIÓN FUNCIÓN ENDOTELIAL MATERNA NORMAL PE MATERNA/TARDIA SIN CIR PE PLACENTARIA O MIXTA PRECOZ CON CIR CIR SIN PREECLAMPSIA

9 RATIO sflt-1/plgf durante la gestación Herraiz I, Simon E, Gómez-Arriaga P, et al. Angiogenesis-Related Biomarkers (sflt-1/plgf) in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration. Int J Mol Sci. 2015;16(8):

10 RATIO sflt-1/plgf: APLICACIONES CLÍNICAS Int. J. Mol. Sci. 2015, Table 1. Potential clinical applications of the angiogenesis-related biomarkers (sflt-1/plgf ratio) in placental dysfunction-related disorders. Proposed Application Comments Prediction of PD and stratification of care Early diagnosis of PD Differential diagnosis Management of PE Cost-efficiency Treatment First trimester (11 14 weeks): for the selection of women potentially benefit from the use of preventive measures such as low dose aspirin (only PlGF); Second and third trimester: for the precise stratification of patients that should receive intensive following-up in a specialized center. sflt-1/plgf ratio increases significantly 5 to 8 weeks before the appearance of clinical manifestations. Uncertain cases; Atypical cases. Categorize those cases susceptible to receive an expectant management. Avoidance of other diagnostic tests or reducing admissions for false PD suspicion. Development of new treatments based on the angiogenic balance regulation and monitorization of its efficacy (especially sflt-1). PD, placental dysfunction; PE, preeclampsia; sflt-1, soluble fms-like tyrosine kinase1; PlGF, placental growth factor First-Trimester Prediction and Prevention of Placental Dysfunction-Related Disorders Herraiz I, Simon E, Gómez-Arriaga P, et al. Angiogenesis-Related Biomarkers (sflt-1/plgf) in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration. Int J Mol Sci. 2015;16(8): Low-dose aspirin prophylaxis of PD has been advocated under the hypothesis that its antiaggregatory and vasodilatory properties may promote a greater depth of placental invasion. In the

11 PREDICCIÓN DE PREECLAMPSIA Detección del 34.6% de PE Tasa de falsos positivos 10.6% Wright, D.; Nicolaides, K.H. Competing risks model in screening for preeclampsia by maternal characteristics and medical history. Am. J. Obstet. Gynecol Hypertension in pregnancy the management of hypertensive disorders during pregnancy. NICE Guideline. RCOG. 2011

12 Copyright ã 2011 John Wiley & Sons, Ltd. Prenat Diagn 2011; 31: DOI: /pd Valor predictivo del ratio sflt-1/plgf PREDICCIÓN DE PREECLAMPSIA Table 4 Performance of screening for early, intermediate and late pre-eclampsia (PE) by maternal factors only and maternal factors with pregnancy-associated plasma protein-a (PAPP-A), uterine artery pulsatility index (PI), mean arterial pressure (MAP), placental growth factor (PLGF), placental protein 13 (PP13), soluble endoglin (seng), inhibin-a, activin-a, pentraxin 3 (PTX3), P-selectin and their combinations Detection rate (95% confidence interval) for fixed FPR Early PE Intermediate PE Late PE Screening test 5% 10% 5% 10% 5% 10% Maternal factors 33.0 ( ) 46.4 ( ) 27.8 ( ) 37.4 ( ) 24.5 ( ) 34.7 ( ) Maternal factors plus PAPP-A 47.0 ( ) 58.3 ( ) 31.4 ( ) 43.2 ( ) 25.8 ( ) 37.2 ( ) Uterine artery PI 54.1 ( ) 66.1 ( ) 36.9 ( ) 48.9 ( ) 27.1 ( ) 38.6 ( ) MAP 49.7 ( ) 62.6 ( ) 41.1 ( ) 53.7 ( ) 33.1 ( ) 44.6 ( ) PLGF 53.5 ( ) 65.0 ( ) 40.3 ( ) 52.7 ( ) 27.0 ( ) 38.7 ( ) PP ( ) 51.9 ( ) 30.2 ( ) 41.4 ( ) 26.2 ( ) 37.8 ( ) sendoglin 46.2 ( ) 58.8 ( ) 31.0 ( ) 42.2 ( ) 25.7 ( ) 37.1 ( ) Inhibin-A 44.4 ( ) 56.7 ( ) 32.6 ( ) 44.2 ( ) 30.8 ( ) 42.5 ( ) Activin-A 40.4 ( ) 53.1 ( ) 33.7 ( ) 46.0 ( ) 34.1 ( ) 47.0 ( ) PTX ( ) 50.1 ( ) 31.2 ( ) 43.2 ( ) 25.6 ( ) 36.8 ( ) P-Selectin 38.5 ( ) 50.5 ( ) 31.1 ( ) 42.6 ( ) 28.5 ( ) 40.5 ( ) Maternal factors plus biophysical markers 66.5 ( ) 77.8 ( ) 48.7 ( ) 61.2 ( ) 34.3 ( ) 46.6 ( ) plus PAPP-A and PLGF 77.8 ( ) 86.7 ( ) 56.6 ( ) 68.9 ( ) 35.2 ( ) 48.5 ( ) plus PAPP-A, PLGF, Inhibin-A and Activin-A 83.4 ( ) 90.0 ( ) 63.6 ( ) 74.8 ( ) 47.9 ( ) 61.4 ( ) plus PAPP-A, PLGF, Inhibin-A, Activin-A and sendoglin 86.7 ( ) 92.1 ( ) 68.6 ( ) 79.5 ( ) 50.5 ( ) 64.2 ( ) Maternal factors plus all markers 91.0 ( ) 95.2 ( ) 79.4 ( ) 88.3 ( ) 60.9 ( ) 71.1 ( ) Akolekar, R.. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at weeks. Prenat. Diagn. 2011, 31, R. AKOLEKAR et al.

13 PREDICCIÓN DE PREECLAMPSIA

14 PREDICCIÓN DE PREECLAMPSIA

15 ESTRATIFICACÍON DEL MANEJO Momento óptimo: semanas Razones Fisiopatológicas Razones Fetales Resultados > 80% S

16 ESTRATIFICACÍON DEL MANEJO Crispi,F et al. Predictivevalue of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet. Gynecol. 2008, 31,

17 ESTRATIFICACÍON DEL MANEJO Crispi,F et al. Predictivevalue of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet. Gynecol. 2008, 31,

18 ESTRATIFICACÍON DEL MANEJO Stubert, J.; Ullmann, S.; Bolz, M.; Ku lz, T.; Dieterich, M.; Richter, D.-U.; Reimer, T. Prediction of preeclampsia and induced delivery at <34 weeks gestation by sflt-1 and PlGF in patients with abnormal midtrimester uterine Doppler velocimetry: A prospective cohort analysis. BMC Pregnancy Childbirth 2014, 14, 292.

19 DIAGNÓSTICO PRECOZ EN PACIENTES SINTOMÁTICAS PROGNOSIS STUDY Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sflt-1:plgf Ratio in Women with Suspected Preeclampsia. New England Journal of Medicine. 2016;374(1):13-22.

20 DIAGNÓSTICO PRECOZ EN PACIENTES SINTOMÁTICAS PROGNOSIS STUDY Preeclampsia 1 week Estimate VPN 99.1% (98.2 to 99.6) VPP 16.7% (12.3 to 21.9) Sensibilidad 85.7% (72.8 to 94.1) Especificidad 79.1% (76.5 to 81.6) Preeclampsia 4 week Estimate VPN 94.9% (93.1 to 96.3) VPP 38.6% (32.6 to 45.0) Sensibilidad 70.3% (61.9 to 77.8) Especificidad 83.4% (80.5 to 85.5) Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sflt-1:plgf Ratio in Women with Suspected Preeclampsia. New England Journal of Medicine. 2016;374(1):13-22.

21 OPTIMIZACIÓN DEL MANEJO Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125,

22 OPTIMIZACIÓN DEL MANEJO Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125,

23 OPTIMIZACIÓN DEL MANEJO Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125,

24 OPTIMIZACIÓN DEL MANEJO Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125,

25 OPTIMIZACIÓN DEL MANEJO Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125, Verlohren, S.; Herraiz, I.; Lapaire, O.; Schlembach, D.; Moertl, M.; Zeisler, H.; Calda, P.; Holzgreve, W.; Galindo, A.; Engels, T.; et al. 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

26 RESÚMEN 1. CLASIFICAR A LA POBLACIÓN Y OPTIMIZAR RECURSOS EN LAS GESTACIONES DE ALTO RIESGO Y MEJORAR EL SEGUIMIENTO. EXCELENTE VPN 2. DIAGNÓSTICO PRECOZ EN PACIENTES AÚN ASINTOMÁTICAS 3. DIAGNÓSTICO DIFERENCIAL 4. RIESGO DE COMPLICACIONES 5. TIEMPO HASTA FINALIZACIÓN

27 PROTOCOLO CRITERIA DEFINING THE A PRIORI RISK FOR PLACENTAL DISFUNCTION-RELATED DISEASES MAYOR CRITERIA MINOR CRITERIA Previous PE Chronic HT Chronic Kidney disease Pregestatiional Diabetes Mellitus Trombofhilias, SLE Maternal Age > 40 years Nulliparous or 10 years since last delivery BMI 35 at the beginning of pregnancy Family history of PE(mother/sister) 1 mayor criteria or 2 minor criteria No mayor criteria o 1 minor criteria Uterine artery Doppler at 18-22w A priori High Risk A priori LowRisk < p75 p75 p95 < p95 UtA Doopler At 26w < p95 p95 Herraiz I, Simon E, Gómez-Arriaga P, et al. Angiogenesis-Related Biomarkers (sflt-1/plgf) in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration. Int J Mol Sci. 2015;16(8): INTENSIVE FOLLOW-UP First check up at 24-28w All suspected PD under 34w CONVENTIONAL FOLLOW-UP

28 PROTOCOLO No PD S/P <38 4-6w later No PD S/P <38 REGULAR FOLLOW-UP (consider S/P reevaluation at w) 24-28w chech-up or suspected PD at Emergency Department No PD S/P w CHECK-UP No PD S/P w CHECK-UP PD or S/P >85 S/P >85 or symptomatic PD Every 48-96h until delivery CHECK-UP Check-up 1.Fetal growth scan:biometry + amniotic fluid index + Umbilical artery Doppler (+Ut A Doppler at 24-28w) 2.Blood pressure 3.Proteinuria 4.sFlt-1/PlGF ratio If Preeclampsia or IUGR is diagnosed current guidelines should be followed Herraiz I, Simon E, Gómez-Arriaga P, et al. Angiogenesis-Related Biomarkers (sflt-1/plgf) in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration. Int J Mol Sci. 2015;16(8):

29 Muchas gracias por su atención