Pre eclampsia
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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

Pre-eclampsia

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


Clinical features

Clinical features

  • Hypertension

  • Proteinuria

  • Fetal growth restriction

  • Abdominal pain

  • Headaches

  • Visual scotoma

  • Deranged LFTs

  • Thrombocytopenia

  • Haemolysis

  • DIC

  • Hyperreflexia

  • Seizures

  • Renal failure

  • Death

εκ-λαμψια


Demographic and clinical risk factors

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


Diagnosis

No gold standard diagnostic test

No (reliable) animal models

Variable diagnostic criteria used

Diagnosis


Diagnosis1

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.”


Epidemiology

Incidence

2-8% of pregnancies

32,000 affected pregnancies/year in UK

6,500,000 affected pregnancies/year worldwide

Epidemiology


Epidemiology1

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


Epidemiology2

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

Epidemiology


Treatment of pre eclampsia

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


Prevention of pre eclampsia

Prevention of pre-eclampsia

What is the

pathological process?


Prevention of pre eclampsia1

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


Prevention of pre eclampsia2

Prevention of pre-eclampsia

Diuretics

Vitamin B6

Vitamin C and E

Calcium supplements

L-arginine

Progesterone

GTN

Garlic

Aspirin


Prevention of pre eclampsia3

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.


Prevention of pre eclampsia4

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.


Prevention of pre eclampsia5

Prevention of pre-eclampsia


The kidney in pre eclampsia

The kidney in pre-eclampsia

Hypertension

Increased risk of

ESRD

Proteinuria

AKI


Pre eclampsia and the kidney

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


Pre eclampsia and aki

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


Pre eclampsia renal treatment

Pre-eclampsia – renal treatment

Encourage baby extraction

Keep them dry

Dialyse when needed

Wait for it all to go away


Pre eclampsia

Anaesthetists

Being unlucky

Patients die from fluid overload

Patients don’t die from kidney failure


What s new in pre eclampsia

What’s new in pre-eclampsia?

Predicting pre-eclampsia

Angiogenic factors

Podocyturia

Laboratory

Imaging

Biomarkers


Angiogenic factors and pre eclampsia

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


Pre eclampsia

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


Other supportive evidence

Other supportive evidence

s-Flt-1

Proteinuria

Hypertension


Other supportive evidence1

Other supportive evidence

Proteinuria

Hypertension


Other supportive evidence2

Other supportive evidence

…in humans?


Pre eclampsia

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.


Diagnosis of pre eclampsia will change

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


Predicting pre eclampsia

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


Current clinical practice

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


Predicting pre eclampsia1

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


Combining biomarkers

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


Combining biomarkers1

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


Pre eclampsia

A two stage pathological process

0510152025303540 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


Pre eclampsia

Participants


Pre eclampsia

Outcomes


Pre eclampsia

Participants

No differences in

demographic and clinical details at recruitment

between normal and pre-eclamptic pregnancies


Pre eclampsia

SELDI spectra

Participant 1

Participant 2


Pre eclampsia

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%


Pre eclampsia

9080 Da

8020 Da

4648 Da

4813 Da

11320 Da

ANN results


Pre eclampsia

Model performance

Sensitivity: 87%

Specificity: 82%


Summary

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


Case studies

Case studies


Case 1

23 year old

G2 P0+1

Chronic pyelonephritis/reflux

No recent infections

10 weeks pregnant

Case 1


Case 11

No medication

BP 125/78

Urine dip: Prot +, Leu -, Nit –

Urine P:CR 43 mg/mmol

Serum creatinine: 138 µmol/l

Case 1


Case 12

Case 1

Will pregnancy affect

kidney disease?

Will she have a

successful pregnancy?


Baseline renal function

Baseline renal function


Pre eclampsia

Blood pressure


Case 13

Case 1

What to do?


Case 14

Case 1

Aspirin 75mg od from 12 weeks

to delivery


Case 15

20 weeks

No symptoms

Aspirin 75mg od

BP 110/72

Creat 119 µmol/l

Urine pro +, leu +, nit +

P:CR 55 mg/mmol

Case 1


Case 16

MC+S

Coliforms

Sensitive to ciprofloxacin, trimethoprim, nitrofurantoin, cefalexin and co-amoxiclav

Resistant to amoxicillin

Case 1


Drugs ckd and pregnancy

Drugs, CKD and pregnancy

Antibiotics

  • Quinolones

  • Tetracyclines

  • Trimethoprim

  • (in 1st trimester)

  • 2. Nitrofurantoin

  • (in 3rd trimester)

  • Cephalosporins

  • Penicillins

  • Gentamicin

  • Erythromycin


Case 17

26 weeks gestation

Aspirin 75mg od

Dysuria x 2 days

BP 131/81

Urine: Pro +, Bld ++, Leu +, Nit +

MC+S: Coliforms again

Case 1


Case 18

Case 1

What to do?


Pre eclampsia

Management of CKD and hypertension in pregnancyUrinary tract infection

In pregnancy

Asymptomatic bacteruria

Non-pyelonephritic

UTI

Treat

Pyelonephritis

Second or more episode in pregnancy?

Asymptomatic bacteruria

Non-pyelonephritic

UTI

Treat

Prophylaxis

Pyelonephritis


Case 19

33 weeks

Well

Aspirin 75mg od, cefalexin 125mg nocte

BP 153/91

Creat 143 µmol/l

P:CR 80 mg/mmol

Case 1


Case 110

Repeat BP 154/92, 166/88, 149/90

Case 1


Case 111

Case 1

What to do?


Pre eclampsia

Management of CKD and hypertension in pregnancyBlood pressure control

Do not treat to

DBP<80mmHg

Target BP <150/100

Chronic hypertension

Target BP <140/90

Chronic hypertension

+ CKD

Target BP <140/90

Chronic hypertension

+ proteinuric CKD


Drugs ckd and pregnancy1

Drugs, CKD and pregnancy

Antihypertensives

  • ACE inhibitors

  • ARBs

  • Spironolactone

  • Aliskiren

  • Moxonidine

  • Minoxidil

  • Diltiazem

  • Labetalol

  • Methyldopa

  • Nifedipine

  • Hydralazine


Case 112

34 weeks

Abdominal pain – RUQ

Headache

Aspirin 75mg od, cefalexin 125mg od, labetalol 200mg tds

BP 173/105

PCR 205 mg/mmol

Serum creatinine 192 µmol/l

Case 1


Case 113

Case 1

What to do?


Case 114

Admit to maternity unit

Add nifedipine or methyldopa

CTG

FBC, LFTs, clotting

Consider magnesium sulphate

Plan for delivery

Case 1


Case 2

Case 2


Case 21

Preconception counselling

35 year old.

Nulliparous

FSGS

Case 2


Case 22

Ramipril 10mg od

Simvastatin 40mg od

BP 118/64

Serum creatinine 84 µmol/l, eGFR 73 ml/min

Urine PCR 342 mg/mmol

Serum albumin 38g/l

Case 2


Case 115

Case 1

Will pregnancy affect

kidney disease?

Will she have a

successful pregnancy?


Proteinuria

Proteinuria?

Imbasciati E et al. AJKD 2007;49:753


Proteinuria1

Proteinuria

p=0.60

p=0.03

p=0.86


Case 23

Case 2

What to do?


Case 24

Stop statin

Stop ACEi

Advise to commence aspirin from 12 weeks

Folic acid

Case 2

?


Case 25

6 months later

Oedema x 2 months

Cellulitis left leg

BP 163/91

Urine PCR 854 mg/mmol

Serum albumin 21 g/l

Serum creatinine 114 µmol/l, eGFR 54ml/min

Case 2


Case 26

2 weeks later

Acute dyspnoea, pleuritic chest pain, left flank pain, episode of haematuria.

Case 2


Case 27

BP 181/104

Serum creatinine 434 µmol/l

US: Renal vein thrombosis

V/Q: Extensive mismatch. High probability of PE.

Heparin and warfarin commenced

Amlodipine 5mg od

Case 2


Case 28

2 months later

BP 144/85

Serum creatinine 312 µmol/l

Urine PCR 443mg/mmol

Serum albumin 24 g/l

Transplant work-up and dialysis planning

Case 2


Case 29

Case 2

A little pessimistic…

…but a risk worth considering


Pre eclampsia

Quiz


Pre eclampsia

Quiz

No conferring

No Google

My word is final


Question 1

Which of the following statements about pregnancy and haemodialysis is incorrect?

Target weight increases by about 300g/week from the second trimester

At least 20 hours/week dialysis is recommended

ESA requirement increases by about 85%

Preterm labour is commonly caused by oligohydramnios

Antihypertensive treatment should be titrated to maintain blood pressure <140/90 mmHg

Question 1


Question 2

Approximately, how many pregnancies are there per year in the UK?

400000

500000

600000

700000

800000

Question 2


Question 3

The risk of pre-eclampsia is increased with:

Aspirin

Calcium supplements

Cigarettes

Singleton pregnancies

First time pregnancies

Question 3


Question 4

Which of the following is safe to use in pregnancy?

Ciprofloxacin

Cyclophosphamide

Cyclosporine

Chlorambucil

Candesartan

Question 4


Question 5

A renal biopsy during pregnancy should be considered for which of the following:

De novo nephrotic syndrome at 37 weeks

Persistent invisible haematuria, urine PCR 55 mg/mmol and serum creatinine 99 µmol/l from booking

Severe de novo hypertension and proteinuria at 26 weeks

ANCA positive, oliguric AKI with blood and protein and a creatinine of 446 µmol/l at 33 weeks

BP 141/89, urine blood ++, protein ++, creat 131 µmol/l, ANA +ve, dsDNA +ve at 23 weeks

Question 5


Question 6

What is the chance of a woman with serum creatinine 200 µmol/l at conception needing dialysis within a year of pregnancy?

1 in 6

1 in 5

1 in 4

1 in 3

1 in 2

Question 6


Question 7

A woman on PD thinks she might be pregnant. Serum βHCG is equivalent to an 8 week old fetus. Ultrasound scanning does not show a fetal heart rate as expected. What advice should be given?

Molar pregnancy likely – requires hysteroscopy and curettage

Measure serum alfa-fetoprotein

Repeat serum βHCG and ultrasound in 1 – 2 weeks

Diagnosis of missed abortion – consolation

Explain βHCG is elevated in ESRD

Question 7


Question 8

A 32 year old with asthma, previous depression and diabetic nephropathy develops gestational hypertension. Which treatment is most appropriate?

Methyldopa

Valsartan

Bendroflumethiazide

Labetalol

Nifedipine

Question 8


Question 9

You are asked to see a 26 year old following her first pregnancy which ended in severe pre-eclampsia yesterday at 35 weeks. She is oliguric and creatinine has climbed from 121 to 158 µmol/l in 24 hours. CVP is 4 mmHg and BP 185/83 mmHg on labetalol 200mg bd. Renal ultrasound shows mild left hydronephrosis.

Question 9


Question 91

You are asked to see a 26 year old following her first pregnancy which ended in severe pre-eclampsia yesterday at 35 weeks. She is oliguric and creatinine has climbed from 121 to 158 µmol/l in 24 hours. CVP is 4 mmHg and BP 185/83 mmHg on labetalol 200mg bd. Renal ultrasound shows mild left hydronephrosis.

Question 9

  • What is the most appropriate management plan?

  • Ask how the baby is and repeat bloods in 6 hours

  • Oral magnesium glycerophosphate 2 tabs bd

  • Aspirin 75mg od

  • Nephrostomy left kidney

  • IV colloid 500ml stat followed by 0.9% sodium chloride – 1000ml/4 hours


Question 10

How are babies made?

Nobody knows

When a mummy and a daddy love each other very much they give each other a special kiss

By a woman sitting on a seat warmed by a man’s bottom

Stork

By doing “the filthy thing”

Question 10


Congratulations

Congratulations

You have survived.


Pre eclampsia

Slides available at

http://emrt.org.uk


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