Hypertension in Pregnancy

Louise Kenny Director

The Irish Centre for Fetal and Neonatal Translation Research

•  287 000 maternal deaths occurred in 20101

•  Hypertensive disorders of pregnancy account for nearly 18% of all maternal deaths world-wide, with an estimated 62 000–77 000 deaths per year2

•  Eclampsia complicates 0.28% of pregnancies in low resource settings3 cf 2.7 cases per 10,000 maternities in the UK4 (Incidence in 1992 4.9 per 10,000 95% CI 4.5-5.4)5

1.  World Health Organization, UNICEF, UNFPA and the World Bank. Trends in Maternal Mortality: 1990 to 2010. Geneva: World Health Organization, 2012

2.  Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066–74.

3.  WHO Multicountry Survey on Maternal and Newborn Health Research Network. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG 2014; 121(Suppl. 1): 14–24.

4.  Knight, M. (2007), Eclampsia in the United Kingdom 2005. BJOG: An International Journal of Obstetrics & Gynaecology, 114: 1072–1078

5.  Douglas and Redman 1994 BMJ 309:1395-1400

Incidence

0

20

40

60

80

100

120

52-54

55-57

58-60

61-63

64-66

67-69

70-72

73-75

76-78

79-81

82-84

85-87

88-90

91-93

94-96

97-99

00-02

Eclampsia Preeclampsia

Maternal Mortality

•  Remains 2nd most common cause of Direct Death – rate unchanged over last 2 reports

•  22 deaths (including 3 from AFLP) •  9 due to intracranial haemorrhage directly related to

uncontrolled blood pressure •  5 after eclamptic fit •  3 from cardiac arrest post fit and 2 unknown cause

Standards of care: CMACE 2011

•  20 of the 22 cases demonstrated substandard care

•  In 14 cases this was classed as ‘major’

•  “There were, undoubtedly, avoidable deaths”

Standards of care: CMACE 2011

•  National Institute for Health and Clinical Excellence (NICE, UK), “Hypertension in Pregnancy”

•  Revised January 2011

Clinical practice guidelines

•  HSE & Institute of Obstetricians and Gynaecologist’s Guideline on “The Diagnosis and Management of Pre-eclampsia and Eclampsia”

•  Published September 2011

Clinical practice guidelines CLINICAL PRACTICE GUIDELINE THE DIAGNOSIS AND MANAGEMENT OF PRE-ECLAMPSIA AND ECLAMPSIA

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THE DIAGNOSIS AND MANAGEMENT OF PRE-ECLAMPSIA AND ECLAMPSIA CLINICAL PRACTICE GUIDELINE

Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland

and

Clinical Strategy and Programmes Directorate, Health Service Executive

Version 1.0

Guideline No. 3

Date of publication – September 2011

Revision date – September 2013

What happens to Blood Pressure in Pregnancy

•  Generalised vasodilatation causes a fall in peripheral vascular

resistance •  There is also an increase in heart-rate and plasma volume

expansion (leading to increase in stroke volume) •  However, the fall in peripheral vascular resistance exceeds the

increase in stroke volume and blood pressure falls •  This reaches a nadir by the end of the first trimester and blood

pressure slowly returns to pre-pregnancy values by term

Definition of Hypertension in Pregnancy

•  The booking blood pressure (or pre-pregnancy blood pressure) are important...

•  BUT hypertension is still defined as two measurement of 140/90 taken on two separate occasions and at least 4 hours apart

•  Significant proteinuria is defined as >1+ or >300mg in 24 hour collection of urine

How to Measure Blood Pressure

•  Position –  Sitting or Supine (left lateral with 30 degree tilt)

•  Sphygmomanometer –  At the level of the heart (the patient’s, not yours)

•  Manual or automatic? –  Most automated systems under-estimate BP in pregnancy. Use a manual system

initially and to validate your automated recordings •  Which Karotkoff sound?

–  Sound 5 is the most reproducible in pregnancy

•  There are three types of hypertension in pregnancy –  Hypertension that exists before pregnancy (chronic hypertension) –  Hypertension that develops during pregnancy without proteinuria

(gestational hypertension) –  Hypertension that develops during pregnancy with proteinuria (pre-

eclampsia

•  It is VITAL that you make a diagnosis and correctly classify which type of hypertension the patient has.

Classification of Hypertension in Pregnancy

•  Hypertension that exists before pregnancy –  Is chronic hypertension –  Remember ‘essential hypertension’ is a diagnosis of exclusion –  Chronic hypertension may co-exist with renal impairment –  Chronic hypertension (with or without renal involvement) = a high risk

pregnancy

Chronic Hypertension in Pregnancy

•  Benign hypertension occurring after 20 weeks gestation but most commonly in the 3rd trimester

•  Not accompanied by proteinuria •  ‘Complicates’ 10% of pregnancies •  Does not need treating and is associated with good outcomes for

mother and baby •  BUT….at least 30% of women with gestational hypertension will

develop pre-eclampsia.

Gestational Hypertension

•  Multi-system disease unique to pregnancy

•  Defined as hypertension and proteinuria arising after the 20th week of gestation in a previously normotensive woman

What is pre-eclampsia?

Who is at risk of pre-eclampsia?

•  First pregnancies: RR 2.91 (95% CI 1.28-6.61) •  Family history: RR 2.90 (95% CI, 1.70-4.93) •  Mothers over 40: primips RR 1.68, (95% CI 1.23-2.29) and multips

RR 1.96 (98% CI 1.34-2.87) women •  Obese women: RR 2.12 (95% CI, 1.56-2.88) •  Multiples: RR of 2.93 (95% CI 2.04-4.21) •  Previous pre-eclampsia: RR7.19 (95%CI 5.85-8.83) •  Women with pre-existing medical conditions

Who is at risk of pre-eclampsia?

MAP  >84  

BMI  >30    FH  PET   PET  N  

No  PET  N  

%    MAP/BMI/FH    with  PET    

%  PET  

N   N   N   102   3506   3%   37%  

Y   N   N   65   852   8%   23%  

Y   Y   N   33   376   9%   12%  

N   Y   N   30   373   8%   11%  

N   N   Y   16   323   5%   6%  

Y   N   Y   17   98   17%   6%  

Y   Y   Y   12   47   26%   4%  

N   Y   Y   3   48   6%   1%  

BP, BMI and FH to predict pre-eclampsia

MAP  >84  

BMI  >30    FH  PET   PET  N  

No  PET  N  

%    MAP/BMI/FH    with  PET    

%  PET  

N   N   N   102   3506   3%   37%  

Y   N   N   65   852   8%   23%  

Y   Y   N   33   376   9%   12%  

N   Y   N   30   373   8%   11%  

N   N   Y   16   323   5%   6%  

Y   N   Y   17   98   17%   6%  

Y   Y   Y   12   47   26%   4%  

N   Y   Y   3   48   6%   1%  

BP, BMI and FH to predict pre-eclampsia

•  Known essential hypertension on treatment –  If  contempla:ng  pregnancy-­‐  refer  to  CUMH  for  pre-­‐conceptual  advice  –  Op:mise  modifiable  risk  factors,  alter  drugs  –  In  par:cular  d/c  ACE  and  ARBs  –  Labetalol  1st  line,  nifedipine  (long  ac:ng)  2nd  line,  methyldopa  3rd  line  –  Aspirin:  meta-­‐analysis  showed  that  low-­‐dose  aspirin  prophylaxis  at  or  before  16  weeks’  

gesta:on  resulted  in  a  89%  reduc:on  of  preeclampsia  delivered  before  37  weeks’  gesta:on,  but  had  no  effect  on  the  risk  of  term  preeclampsia.    

–  If  already  pregnant  refer  to  Perinatal  Medicine  Clinic  

How to manage the hypertensive pregnant patient

•  Newly hypertensive in pregnancy –  Check  for  proteinuria  –  If  posi:ve,  refer  urgently  –  If  nega:ve,  refer  to  clinic  –  In  hypertensive  crisis:  give  200mg  oral  labetalol  immediately  –  Do  NOT  give  sub  lingual  nifedipine  

How to manage the hypertensive pregnant patient

•  Pregnancy is a stress test

•  Women who develop pre-eclampsia or have a growth restricted fetus:

–  Have  4-­‐7  :mes  increased  risk  of  long  term  hypertension  –  Have  2-­‐3  :mes  increased  risk  of  coronary  artery  disease  –  Have  4-­‐7  :mes  increased  risk  of  chronic  renal  failure  

•  Opportunity for intervention: well woman clinic

The hypertensive pregnant patient: long term follow up

Consequences of poor placentation STAGE 1

8–18 weeks

STAGE 2 > 20 weeks

Pre-eclampsia with FGR

Poor Placentation

Placental Oxidative

Stress

FGR Pre-eclampsia without FGR

Complications

Consequence of management: •  Prematurity

Maternal consequences of placental dysfunction •  HELLP Syndrome •  Eclampsia

Fetal consequence of placental dysfunction •  Severe FGR •  Stillbirth

Maternal endothelial / inflammatory dysfunction

Predisposition to maternal disease

Typically preterm Typically term ?

What’s new in pre-eclampsia?

l  PlGF as a diagnostic test l  Various screening tests l  Viagra for fetal growth restriction

Placental Growth Factor

l  Angiogenic, pro-inflammatory factor produced by trophoblast cells l  Four isoforms (PlGF-1, -2, -3, -4) l  Receptor: Cell surface Flt-1 and soluble Flt-1 (VEGFR-1) l  PlGF circulates free or in complexes (with sFlt-1) l  Modern assays measure only free PlGF l  Abnormally low PlGF likely to be a good marker of oxidatively

damaged placenta

*** ***

*†† †

Control * p<0.05 ** p<0.01 *** p<0.001 Case † p<0.05 †† p<0.01

Rises then falls in normal pregnancy

Significantly decreased when preeclampsia

diagnosed

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**

*

*

*

Lower in women destined to develop preeclampsia

0100200300400500600700800900

10001100

8-12 13-16 17-20 21-24 25-28 29-32 33-36 37-41

Gestational Age (wks)

PlGF

(pg/m

l)Control Case Endpoint

Adapted from Levine et al 2004, Levine et al. NEJM 2004;350:672-83

Placental Growth Factor (PlGF)

... Potential as a diagnostic & prognostic marker?

•  Features •  Quantitative assay •  Specific to “free” PlGF-1 •  Dynamic range 12-3,000 pg/mL •  Plasma EDTA sample •  Whole blood capable soon •  Rapid results in only 15 minutes •  Built-in QC, QA functions

Alere Triage® PLGF Test

1. UNIVERSITY COLLEGE CORK2. ACCELOPMENT AG3. ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM 4. KAROLINSKA INSTITUTET 5. UNIVERSITY OF KEELE 6. MEDSCINET AB 7. METABOLOMIC DIAGNOSTICS LIMITED 8. PRONOTA NV 9. REGION HOVEDSTADEN

10. RIJKSUNIVERSITEIT GRONINGEN 11. KLINIKUM DER UNIVERSITAET ZU KOELN 12. THE UNIVERSITY OF LIVERPOOL

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Irish innovation in perinatal healthcare research leading the world: scientific excellence with societal and economic impact

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A pregnant woman dies every minute

CONNECTED HEALTH

Prof. Louise Kenny Professor  of  Obstetrics,  UCC  Prof. Geraldine Boylan Professor  of  Neonatal  Physiology,  UCC  Dr. Gene Dempsey Neonatologist  and  Senior  Lecturer,  CUMH  Dr. Deirdre Murray Paediatrician  and  HRB  Clinician  Scien:st,  UCC Dr. Liam Marnane Senior  Lecturer,  Electrical  and  Electronic  Engineering,  UCC Dr. Gordon Lightbody Senior  Lecturer,  Electrical  and  Electronic  Engineering,  UCC Dr. David Henshall Professor,  Physiology  &  Medical  Physics,  RCSI  Prof. Fred Adams Professor,  Health  Informa:on  Systems  Research  Centre,  UCC  Dr  Mariead  Kiely  Senior  Lecturer,  Food  Science    

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