PREECLAMPSIA Answers to Questions and Questions to Answer 2018 Priscilla Kincaid-Smith Lecture

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1 PREECLAMPSIA Answers to Questions and Questions to Answer 2018 Priscilla Kincaid-Smith Lecture Professor Shaun Brennecke Department of Maternal-Fetal Medicine University of Melbourne Department of Obstetrics Gynaecology Royal Women s Hospital Parkville, Victoria, Australia

2 Professor Priscilla Kincaid-Smith

3 PRISCILLA KINCAID-SMITH MAJOR AWARDS AND HONOURS

4

5

6 KEY THEMES

7 The health, nutrition and lifestyle of women and the quality of care during pregnancy and delivery establish a foundation of physical health and intellectual and social development for the next generation Report of the Director General World Health Organisation March 1992

8 FETAL ORIGINS OF ADULT DISEASES CellDivisions

9 PLACENTAL ORIGINS OF PREGNANCY DISEASES Genome ~ Transcriptome ~ Proteome ~ Metabolome ~ Exosome Preeclampsia ~ Fetal Growth Restriction ~ Preterm Labour ~ Gestational Diabetes Mellitus

10 PRECISION MEDICINE

11 PERSONALISED MEDICINE

12 BENCH to BEDSIDE and BACK

13 HOW DOES KNOWLEDGE PROGRESS?

14 If we are to go forward, we must first look back Martin Luther King Jr American Civil Rights Leader 1954

15 The gods did not reveal, from the beginning, All things to us, but in the course of time Through seeking we may learn and know things better. But as for certain truth, no man has known it Nor shall he know it, neither of the gods Nor yet of all the things of which I speak. For even if by chance he were to utter The final truth, he would himself not know it: For all is but a woven web of guesses.

16 SIR KARL POPPER Falsification The refutation of a hypothesis or theory by empirical evidence Universal hypotheses are falsifiable, but not verifiable. All swans are white can be accepted as a tentative hypothesis, until the first non-white swan is sighted. The longer a (falsifiable) hypothesis resists falsification, the more reliable it is. The interplay between tentative theories (conjectures) and error elimination (refutation) advances scientific knowledge.

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18 THE EPPI TRIAL Am J Obstet Gynecol. (2017) Mar;216(3):296e e.14.

19 ENTHUSIASM PROGRESS OF KNOWLEDGE HYPOTHESIS ACCEPTANCE FURTHER TESTING REJECTION TIME

20 WHAT IS PREECLAMPSIA?

21 Preeclampsia is a disease of theories Paul Zweifel German Obstetrician 1916

22 Brown M. Pregnancy Hypertension (2018)

23 SYNDROME Greek derivation meaning concurrence A set of clinical signs and symptoms that are correlated with each other A syndrome can be very closely correlated with an aetiology or pathogenesis e.g. Down syndrome, or it may be not specific to only one disease

24 WHAT IS THE GOLD STANDARD FOR DIAGNOSING PREECLAMPSIA?

25 PREECLAMPSIA ABNORMAL PLACENTATION

26 SPIRAL ARTERIOLES IN NORMAL AND PREECLAMPTIC PREGNANCIES Extent of Trophoblast Invasion

27 PREECLAMPSIA IS A MULTISYSTEM DISORDER PREECLAMPSIA IS A SYNDROME

28 MATERNAL CIRCULATING PLGF IS ABNORMALLY LOW IN PREECLAMPSIA Levine RJ et al (2004) NEJM 350(7):

29 MATERNAL CIRCULATING sflt-1 IS ABNORMALLY HIGH IN PREECLAMPSIA Maynard SE et al. J Clin Invest (2003)

30 sflt-1/plgf RATIO AND PREGNANCY OUTCOME Schoofs K et al. J Perinat Med (2014)

31 sflt-1/plgf RATIO A Test of Placental Dysfunction

32 QUESTION TO ANSWER Can preeclampsia be diagnosed pathognomonically using the sflt-1/plgf ratio test?

33 CAN PREECLAMPSIA BE PREDICTED?

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36 The PROGNOSIS Study

37 The PROGNOSIS Study Key Points Sample size n=1050 A single sflt/plgf ratio cut-off value of 38 is appropriate for gestational ages weeks A low sflt-1/plgf ratio ( 38) rules out preeclampsia within one week (NPV of 99.3%) and within four weeks (NPV of 94.3%) A high sflt-1/plgf ratio (> 38) predicts preeclampsia within four weeks (PPV of 36.7%)

38 sflt-1/plgf Prediction Diagnosis Progression sflt-1/plgf is a test not a treatment Hasten slowly

39 Whether or not patients are better off from undergoing a diagnostic test will depend on how test information is used to guide subsequent decisions on starting, stopping or modifying treatment Ben Mol et al Semin Reprod Med (2003) 21(1):17-25

40 QUESTIONS TO ANSWER Can further studies evaluating the use of biomarkers improve the ability to predict and manage preeclampsia? Can the further use of biomarkers minimise observer bias and user error, and increase clinician confidence in their use? Can using biomarkers as inclusion criteria for clinical trials assessing preeclampsia interventions help identify those at highest risk and thereby better target those most likely to benefit?

41 CAN PREECLAMPSIA BE PREVENTED?

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43 Combined Multi-Marker Screening and Randomised Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention

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45

46 Am J Obstet Gynecol. (2017) Feb;216(2): e6.

47 Am J Obstet Gynecol. (2017) Feb;216(2): e.2.

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49

50 LDA DECREASES sflt1/plgf RATIO IN PE SERA TREATED BeWo CELLS

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52 QUESTIONS TO ANSWER Low dose Aspirin How much? When? Mechanism(s)? What time?

53 DOES ANTENATAL CARE IMPROVE MORBIDITY AND MORTALITY FROM PREECLAMPSIA?

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55 DECREASING PREECLAMPSIA MORTALITY Historical Perspective Dr John Ballantyne Edinburgh Perinatologist Apostle of Antenatal Care

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58 DECLINE IN PREECLAMPSIA MATERNAL MORTALITY ENGLAND AND WALES Cause as a percentage of 1935 Toxaemia Maternal mortality rates per 10,000 births. Source: A. Macfarlane and M. Mugford, Birth Counts: Statistics of Pregnancy and Childbirth (London, 1984), ii

59 A MODEL FOR A NEW PYRAMID OF PRENATAL CARE BASED ON THE 11 TO 13 WEEKS ASSESSMENT Pyramid of prenatal care: past (left) and future (right) Nicolaides KH, Prenat Diag (2011): 31: 3-6

60 QUESTIONS TO ANSWER Is there a better pregnancy care model? Can we reverse the over-medicalisation of pregnancy that has evolved since the start of antenatal care?

61 QUESTIONS TO ANSWER Do we now have the potential to provide the right care to the right woman at the right time by improving risk assignment so as to minimise false positives and false negatives, by reducing direct and indirect costs to the health system and society via the more efficient use of expensive resources by optimising patient access to management that is targeted and ultimately improves outcomes by preventing disease early in its development?

62 DOES PREECLAMPSIA IMPACT ON LATER LIFE MATERNAL HEALTH?

63 PREECLAMPSIA AND LONG TERM MATERNAL MORTALITY Irgens et al. BMJ (2001) 323, 7323:

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65 PREECLAMPSIA AND MATERNAL MORTALITY

66 "There are very few identified risk factors for later life heart disease in women; preeclampsia is one of the few warning signs we'll get and we should take advantage of it" Eleni Tsigas, Executive Director, Pre-eclampsia Foundation

67 Female Sex and Cardiovascular Disease Risk Factors

68 LIFE LONG SURVEILLANCE OF CARDIOVASCULAR HEALTH Weight Exercise Diet Blood Lipids Blood Pressure Smoking Diabetes Screening Alcohol Depression and Stress

69 LINKING PREECLAMPSIA AND SUBSEQUENT INCREASED RISK OF LATER LIFE CARDIOVASCULAR DISEASE

70 PREECLAMPSIA Genetic Predisposition Percentage of preeclamptic women among relatives of index women Daughters 23.8% Daughters-in-law 6.5% Mothers 15.9% Mothers-in-law 4.4% Cooper, Brennecke and Wilton (1993) J Hyperten Preg 12(1), 1-23

71 GENOME WIDE ASSOCIATION SCANS IDENTIFY NOVEL MATERNAL SUSCEPTIBILITY LOCI FOR PRE-ECLAMPSIA M Johnson, S Brennecke, AC Iversen, C East, G Olsen, J Kent, T Dwyer, J Said, L Roten, L Abraham, JA Zwart, B Winsvold, A Haberg, M Huentelman, H Krokan, M Gabrielsen, R Austgulen, J Blangero, E Moses Zuspan Award for most outstanding basic science work in relation to the study of hypertension in pregnancy

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73 Polygenic risk scores A weighted sum of the number of risk alleles carried by an individual, where the risk alleles and their weights are defined by the loci and their measured effects as detected by genome wide association studies. Nat Rev Genet. (2018) May 22 doi: /s x.

74 QUESTION TO ANSWER Can we use the known link between preeclampsia and long term maternal mortality risk to improve health outcomes for women?

75 IN CONCLUSION. Does the exciting potential of placentomics provide a revolutionary opportunity for a new paradigm of personalised medicine in pregnancy care which will lead to a life time benefit for mothers and their babies and an improvement in the health of the population as a whole?