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Pre-eclampsia

Pre-eclampsia. “A common human-specific disease of pregnancy characterised by novel and progressive hypertension and proteinuria after 20 weeks gestation.”. Clinical features. Hypertension Proteinuria Fetal growth restriction Abdominal pain Headaches Visual scotoma Deranged LFTs

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Pre-eclampsia

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  1. Pre-eclampsia “A common human-specific disease of pregnancy characterised by novel and progressive hypertension and proteinuria after 20 weeks gestation.”

  2. Clinical features • Hypertension • Proteinuria • Fetal growth restriction • Abdominal pain • Headaches • Visual scotoma • Deranged LFTs • Thrombocytopenia • Haemolysis • DIC • Hyperreflexia • Seizures • Renal failure • Death εκ-λαμψια

  3. Older mothers (>40 years, RR=2) Primigravidae (RR=3) Previous pre-eclampsia (RR=7) Family history of pre-eclampsia (RR=3) Obesity (BMI>35, RR=4) New sexual partner Diabetes mellitus (RR=4) Chronic hypertension (40x higher prevalence in cases) Chronic kidney disease Thrombophilia Connective tissue diseases (RR=6) Multiple pregnancies (RR=3) Demographic and clinical risk factors

  4. No gold standard diagnostic test No (reliable) animal models Variable diagnostic criteria used Diagnosis

  5. Diagnosis • International Society for the Study of Hypertension in Pregnancy (ISSHP, 2001) • Research definition • De novo hypertension (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg) after 20 weeks’ gestation plus proteinuria (greater than 300mg/d or protein:creatinine ratio >30mg/mmol). • Clinical definition • As above but “in the absence of proteinuria the disease is highly suspect when increased blood pressure is accompanied by: • Headache • Blurred vision • Abdominal pain • Low platelets • Abnormal liver enzymes.”

  6. Incidence 2-8% of pregnancies 32,000 affected pregnancies/year in UK 6,500,000 affected pregnancies/year worldwide Epidemiology

  7. Directly led to the death of 18 mothers in the UK from 2002-2005 Implicated in 135 stillbirths in the UK in 2006 Epidemiology Lewis.G editor. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: Reviewing maternal deaths to make motherhood safer - 2003-2005. London: CEMACH; 2007 Acolet D editor. Confidential Enquiry into Maternal and Child Health (CEMACH) Perinatal Mortality 2006: England,Wales and Northern Ireland. London: CEMACH; 2008

  8. Directly implicated in 68,000 maternal deaths per year worldwide. Epidemiology

  9. Treatment of pre-eclampsia Deliver the fetus and placenta Serial monitoring of fetal growth Blood pressure control Clinical surveillance of impending eclampsia or HELLP Magnesium sulphate + betamethasone

  10. Prevention of pre-eclampsia What is the pathological process?

  11. Prevention of pre-eclampsia Abnormal placentation Endothelial dysfunction Coagulation abnormalities Cardiovascular maladaptation Immunological dysfunction Genetic predisposition Disordered endothelin metabolism Cytokines and growth factors Imbalanced prostaglandin metabolism Anti-AT2 IgG Anti-spermatazoa antibodies Anti-cardiolipin IgG and IgM Abnormal trophoblast invasion Decreased uteroplacental perfusion Cardiovascular or renal disease ADMA / nitric oxide imbalance Relaxin/ metalloprotease-2 deficiency Endoglin IL-6 NOS polymorphisms STOX-1 mutation s-Flt-1 IL-1α COMT deficiency ACE polymorphisms Fas ligand TNF-α VEGF PlGF

  12. Prevention of pre-eclampsia Diuretics Vitamin B6 Vitamin C and E Calcium supplements L-arginine Progesterone GTN Garlic Aspirin

  13. Prevention of pre-eclampsia Calcium supplements Systematic review 14949 women All women High risk women 52% relative risk reduction 78% relative risk reduction Dietary calcium is adequate in most patients. Supplementation only recommended with dietary insufficiency Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst.Rev. 2006 Jul 19;3:CD001059. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG 2007 Aug;114(8):933-943.

  14. Prevention of pre-eclampsia Aspirin Systematic review 37560 women All women High risk women 17% relative risk reduction 25% relative risk reduction NNT = 72 NNT = 19 Perinatal death RRR 14% Preterm delivery RRR 8% SGA RRR 10% Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst.Rev. 2007 Apr 18;(2)(2):CD004659.

  15. Prevention of pre-eclampsia

  16. The kidney in pre-eclampsia Hypertension Increased risk of ESRD Proteinuria AKI

  17. Pre-eclampsia and the kidney Glomerular endotheliosis Capillary endothelial oedema Vasospasm Microthrombi Light microscopy normal by 40 days post-partum GBM thickening can persist on EM

  18. Pre-eclampsia and AKI Intraglomerular thrombosis Endothelial dysfunction Systemic vasoconstriction Antihypertensive medication Intravascular fluid depletion Loss of autoregulation AKI Affects 1-2% Haemorrhage DIC Placental abruption Emergency Caesarean

  19. Pre-eclampsia – renal treatment Encourage baby extraction Keep them dry Dialyse when needed Wait for it all to go away

  20. Anaesthetists Being unlucky Patients die from fluid overload Patients don’t die from kidney failure

  21. What’s new in pre-eclampsia? Predicting pre-eclampsia Angiogenic factors Podocyturia Laboratory Imaging Biomarkers

  22. Angiogenic factors and pre-eclampsia s-Flt-1 increased in serum in PE2 Gene expression profiling of placental tissue from women with and without pre-eclampsia (PE)1 Up-regulation of soluble fms-like tyrosine kinase-1 (s-Flt-1)1 s-Flt-1 increased in urine in PE3 Binds to VEGF and Placental Growth Factor (PlGF) antagonising their function Serum PlGF decreased in PE2 Urine PlGF decreased in PE3 1 Maynard S, Min J-Y et al. J. Clin. Invest 2003;111:649 2 Levine RJ, Maynard SE et al. NEJM 2004;350:672 3 Buhimsci CS, Magloire L et al. Obstet Gynecol 2006;107:1103

  23. PlGF PlGF PlGF sVEGF-R1 sFlt-1 sVEGF-R1 sFlt-1 VEGF VEGF VEGF VEGF VEGF VEGF-R1 Angiogenesis Anti-angiogenesis Displacement of VEGF from inactive receptors sVEGF-R1 sFlt-1 Placenta Activation of VEGF-R2 by transphosphorylation VEGF-R1 Flt-1 VEGF-R2 VEGF-R2 Flk-1 Endothelial cell Tyrosine kinase Destabilise inactive VEGF-R heterodimers No signal Survival, migration and differentiation of endothelial cells Pre-eclampsia Normal pregnancy

  24. Other supportive evidence s-Flt-1 Proteinuria Hypertension

  25. Other supportive evidence Proteinuria Hypertension

  26. Other supportive evidence …in humans?

  27. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J.Matern.Fetal.Neonatal Med. 2008 Jan;21(1):9-23.

  28. Diagnosis of pre-eclampsia will change Elevated serum sFlt1:PlGF ratio • International Society for the Study of Hypertension in Pregnancy (ISSHP, 2001) • Research definition • De novo hypertension (systolic blood pressure >140mmHg, diastolic blood pressure >90mmHg) after 20 weeks’ gestation plus proteinuria (greater than 300mg/d or protein:creatinine ratio >30mg/mmol). • Clinical definition • As above but “in the absence of proteinuria the disease is highly suspect when increased blood pressure is accompanied by: • Headache • Blurred vision • Abdominal pain • Low platelets • Abnormal liver enzymes.” Elevated urine sFlt1:PlGF ratio Elevated serum endoglin Presence of podocyturia or podocyte-specific mRNA

  29. Predicting pre-eclampsia Pre-eclampsia affects 5% of pregnancies 50% of patients with pre-eclampsia have no risk factors 90% of patients with risk factors do not develop pre-eclampsia

  30. Current clinical practice Aspirin Demographic and clinical risk factors Frequent monitoring Uterine artery doppler (20-24 weeks) High risk – 14.4% No uterine artery notch – 9.2% Uterine artery notch – 30% Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization Systematic Review of Screening Tests for Preeclampsia. Obs. Gynecol. 2004;104(6),1367-1391

  31. Predicting pre-eclampsia Antiphospholipid antibodies N-acetyl-β-glucosaminidase Human chorionic gonadotrophin Uterine artery doppler “As of 2004, there is no clinically useful screening test to predict the development of pre-eclampsia.” Inhibin A Alpha-fetoprotein Pregnancy-associated plasma protein A Oestriol Homocysteine Corticotrophin releasing hormone Urinary calcium excretion Activin A Fibronectin Microtransferrinuria Urine kallikrein Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization Systematic Review of Screening Tests for Preeclampsia. Obs. Gynecol. 2004;104(6),1367-1391

  32. Combining biomarkers AFP > 2.5MoM + hCG > 2.5MoM + PI > 95% centile + bilateral uterine artery notches @ 20-24 weeks Sensitivity 64% Specificity 97% PlGF + PAPP-A + PI + mean arterial pressure + “multiple maternal demographic factors” @ 11-13 weeks Sensitivity 93% Specificity 95% Giguère Y, Charland M, Bujold E et al. Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review. Clin Chem 2010;56(3):361-374

  33. Combining biomarkers “Numerous papers have been published on potential biomarkers for identifying women predisposed to development of PE before the onset of clinical symptoms… …new tests that will contribute to better predictive performance characteristics of a PE-risk model need to be developed.” Giguère Y, Charland M, Bujold E et al. Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review. Clin Chem 2010;56(3):361-374

  34. A two stage pathological process 0 5 10 15 20 25 30 35 40 weeks Generalised maternal endothelial dysfunction Impaired trophoblast invasion of myometrium Clinical manifestations of pre-eclampsia Placental ischaemia Systemic release of pro-inflammatory and antiangiogenic mediators Poor spiral artery adaptation Abnormal implantation Hypertension Proteinuria

  35. Participants

  36. Outcomes

  37. Participants No differences in demographic and clinical details at recruitment between normal and pre-eclamptic pregnancies

  38. SELDI spectra Participant 1 Participant 2

  39. ANN results 793 peaks differentially expressed between normal pregnancy and pre-eclampsia ANN modelling selected a panel of 5 protein peaks 9080 Da 8020 Da 4648 Da 4813 Da 11320 Da • Cross validation model results: • Normal pregnancy correctly classified: 100% • Pre-eclampsia correctly classified: 92%

  40. 9080 Da 8020 Da 4648 Da 4813 Da 11320 Da ANN results

  41. Model performance Sensitivity: 87% Specificity: 82%

  42. Pre-eclampsia is common AKI from pre-eclampsia is rare and managed by timely delivery and supportive care Pregnant patients with CKD should receive aspirin from 12 weeks to delivery Improved knowledge re: pathophysiology may lead to new treatments to delay or prevent pre-eclampsia Predictive tests for pre-eclampsia are on the horizon. Summary

  43. Case studies

  44. 23 year old G2 P0+1 Chronic pyelonephritis/reflux No recent infections 10 weeks pregnant Case 1

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