STEPHEN ROBSON

MFM & Perinatal Society of Turkey XI National Congress

Preeclampsia

(Early onset severe disease)

S. Robson

Professor of Fetal Medicine, Newcastle University

Early onset preeclampsia

Principles of diagnosis

Pregnancy induced (or exacerbated) hypertension

- SBP ≥ 140 mmHg or DBP ≥ 90 mm Hg after 20 wk (x 2 - 4 h apart) - Validated automatic sphymomanometer

PLUS

Proteinuria

Platelet count < 100,000 L * OR

Liver transaminases twice normal* OR

SCr > 97 mol/L or doubling in absence of CRD* OR Pulmonary oedema* OR

Cerebral or visual disturbances*

Severe PE – SBP ≥ 160 mm Hg or DBP ≥ 110 mm Hg (x2 – 4 h apart)

or any of above features* (+ persistent RUQ or epigastric pain unresponsive to Rx) NB 20% of HELLP & eclampsia unheralded

Preeclampsia

Gestational age at presentation

25% 60%

All PE 15%

2.5% population

Severe PE

1% population

50% 50%

%

Delivery < 34 34-37 >37

0.4% (1/250) primips deliver < 34 wk as a result of PE

8-10% all preterm births result from hypertensive disorders

22

34 37

Term Late preterm

Early preterm

26

Interventionist vs expectant care for severe PE between 23-34 weeks’ gestation

Risk ratios (95% CI)

Churchill et al. CDSR 2013

Maternal

Fetal/neonatal

4 studies [n=425]

*Length of stay (dy) – MD 11.14 [1.57, 20.72]

Eclampsia 0.30 [0.01, 6.97]

HELLP 0.53 [0.05, 5.68]

Pulmonary oedema 0.0 [0.0, 0.0]

Renal failure 0.30 [0.01, 6.97]

Placental abruption 0.80 [0.26, 2.40]

CS 1.09 [1.01, 1.18]

Death 1.08 [0.69, 1.71]

IVH or HIE 1.82 [1.06, 2.50]

Apgar < 7 at 5 min 1.48 [0.87, 2.50]

Hyaline membrane disease 2.30 [1.39, 3.81]

Baby ventilated 1.50 [1.11, 2.02]

Necrotising enterocolitis 2.10 [0.93, 4.79]

SGA 0.30 [0.14, 0.65]

NICU admission 1.35 [1.16, 1.58]*

Long term growth & development 6.01 [0.75, 48.14]

Preterm preeclampsia

Maternal complications with expectant management

* 1 Odendaal, 2 Sibai, 3 Olah, 4 Visser & Wallenburg, 5 Hall; 6 Vigil-DeGracia, 7 Chammas, 8 Haddad, 9 Oettle, 10 Shear

*

Expectant management of severe PE

Perinatal outcome according to gestation at onset of expectant management

0 20 40 60 80 100

24 25 26 27 28 29 30 31 >31

RDS BPD IVH NEC PMR

Haddad et al. 2004

%

wk

Early onset preeclampsia

Principles of antenatal management

• Admit, manage conservatively and ‘consultant plan’

• Corticosteroids

• Maternal monitoring

- Measure BP at least 4 times a day - Labetolol if BP ≥ 150/100 mm Hg - SPCR but If proteinuric do not repeat quantification

- SCr, electolytes, FBC, liver transaminases, bilirubin – 3 x weekly - [History & Examination (fundoscopy, DTRs)]*

- [sFlt-1/PlGF or PlGF]

• Fetal Monitoring

- Fetal size, AFV, UA Doppler (every 2 weeks)

- CTG (repeat if (a) RFM, (b) APH, (c) abdo pain, (d) maternal deterioration)

• ‘

Offer’ birth

- ‘Maternal or fetal indication develops [as defined in plan]

*Presenting symptoms in HELLP – Epigastric pain (65%), N & V (36%)

(Sibai et al 1993) Headache (31%), visual disturbance (10%)

Angiogenic factors: sFlt-1/PlGF ratio SR & meta-analysis: SaPPPhirE Study

15 studies (534 cases PE, 19587 controls) All studies

Se 0.80 (0.68-0.88) Sp 0.92 (0.87-0.96) LR+ 10.5 (6.2-18.0) LR- 0.22 (0.13-0.35)

AUROC 0.94 (0.91-0.96)

High risk (7 studies): Se 0.85 (0.66-0.94), Sp 0.87 (076-0.93)

Low risk (11 studies): Se 0.77 (0.61-0.88), Sp 0.94 (088-0.97)

Agrawal et al. 2018

Angiogenic factors: sFlt-1/PlGF ratio

Prediction of diagnosis & prognosis in suspected PE

PROGNOSIS study (Zeisler et al. 2016)

Singleton pregnancies in whom PE suspected (PIH [30%], PIP [37%], CHT [14%]

n=1050 (validation cohort 550) sampled at first visit at 24⁺⁰ – 36⁺⁶ wk.

sFlt-1/PlGF cut off 38

Rule out PE within 1 wk (≤ 38) & Rule in PE within 4 weeks (>38)

Angiogenic factors: sFlt-1/PlGF ratio Economic evaluation

NICE (2016)

Women presenting <35 wk with suspected PE

Triage PlGF and Elecys sFlt-1/PlGF

cost saving compared to standard clinical assessment

Data relate to use as a rule-out test

Schlembach et al. 2018 (German DRG Payer system)

Introduction sFlt-PlGF (with cut-off 38) would reduce % women hospitalised f rom 44.6 to 24.0%

Cost saving € 361 per patient

Klein et al. 2016

Hospitalisation decision changed

in 16.9%

women (65% changed to no hospitalization)

Me

Early onset PE

Fetal growth restriction

0 10 20 30 40 50 60 70 80

1 2 3 4 5 6 7 8 9 10 Mean

Non-reassuring fetal testing

50.4%

%%

Yu et al. 2008 N=30639

• FW/BW < 10

centile ~ 55% but

 gestational age at delivery

• SGA associated with higher rates intervention for ‘NRFT’

SGA - 57% vs AGA – 18%

(Shear et al. 2005)

• Umbilical artery Doppler

- 45% abnormal at presentation (more than half with AREDF) - 68% abnormal by delivery

(Robson et al. 2012)

- Interval between AEDF & NRFT

< 10 days (Arduini et al. 1993)

0 10 20 30 40 50 60 70 80 90 100

0 5 10 15 20 25 30

Hypertension Normotensive

Days from AEDV

Interval b

Expectant management of severe PE at < 26 wk

Withagen et al. (2001)

Gauler-Senden et al (2006, Netherlands)

Bunden et al. ^{(2006, NZ)}

Belhiti et al. (2011, US)*

Oosterwaard et al. (2017, Netherlands)*

Newcastle (1998-2014)*

N PMR

(%)

Maternal Complications

(%)

25 26 31 53 133

48

84 81 71 58 81

76²

65 71 43 54 64¹ 58

* Neonatal survival (to discharge): 0-6.6% at < 24 w to 50-57% at 24-25 w after active support.

1 If include HELLP O/A; ² No survivors with AEDF in UA Doppler < 25 wk

Expectant management severe PE 24-33 wk

Indications for delivery

Maternal Abruption

DIC

Pulmonary oedema

- CXR + hypoxaemia

Acute renal failure

- Oligo/anuria + SCr >120 mol/L Hepatic capsular rupture

(Recurrent)Eclampsia (Progressive) HELLP

Fetal

A/R ‘A’ wave on DV Doppler

Reduced STV on cCTG

REDF on UA Doppler

Early onset preeclampsia

Principles of delivery management

• Maintain MAP < 125 mm Hg

- Prevention cerebral ‘injury’

 PRE / eclampsia

 (Haemorrhagic) Stroke

- SBP ≥ 160 mm Hg - 96% vs DBP ≥ 110 ^{mm Hg –}13%

- Death 54%, complete recovery 11% (Martin et al. 2005)

- IV labetolol +/- hydralazine (or nicardipine)

• Magnesium sulphate (4g + 1g/h)

- Reduce risk of eclampsia (RR 0.42 [0.29, 0.60]) ^{CDSR 2015} NNT – ‘Imminent eclampsia - 36, mild PE - 400

- Reduce risk of CP (RR 0.69 [0.55, 0.88] Constantine et al. 2009

NNT - ≤ 28 wk – 29, > 28 wk – 265

• Fluid replacement

• Mode of delivery

- Successful IOL: 24-28 w – 6%, 28-32 w – 47% (Alanis et al. 2008) 0

55

40 80 120 160

Mean arterial pressure (mm Hg)

Normotensive patient

Hypertensive patient CBF

(ml/100g/min)

T2 DWI

Duration of Mg postpartum in severe PE

Ludmir et al 1113 Stop at delivery vs. 1/555 (0.18%) RR 0.7 ^(0.1-3.3)

2018 continue 24 PP 2/558 (0.35%)

Garcia et al. 284 24 h PP vs. 0/143 (0%)

2017 6 h PP 0/141 (0%)

No differences in adverse maternal outcomes, reduced time to ambulation & start of lactation

Performance of risk prediction models for PE

LR+ PPV

Method

DR

PE < 32 w < 37 w < 37 w < 37 w

NPV

< 37 w

FPR

NICE 41 (18-67) 39 (27-53) 3.8 (2.7-5.3) 2.6 (1.8-3.5) 99.5 (99.4-99.6) 10.2 ACOG 94 (71-100) 90 (78,96) 1.4(1.3-1.5) 0.9(0.8-1.0) 99.8 (99.5-99.9) 64.2 ACOG ASA 6 (1,27) 5 (2,14) 4.2 (1.8-9.9) 2.8 (1.2-6.4) 99.3 (99.3-99.4) 0.2

ACOG

Any risk factor Nulliparity, age > 40 y

BMI >30 IVF conception

PH – PE FH – PE, CHT

CRD, DM

SLE or thrombophilia

NICE

One high risk factor

PH – HDP CRD

Autoimmune Disease DM

CHT

NICE

2 moderate risk factors

Nulliparity

Inter-preg interval > 10 y BMI > 35

FH - PE

ACOG

ASA

PH – PE < 34 w PH – PE x 2

Performance of risk prediction models for PE

LR+ PPV

Method

DR

PE < 32 w < 37 w < 37 w < 37 w

NPV

< 37 w

FPR

NICE 41 (18-67) 39 (27-53) 3.8 (2.7-5.3) 2.6 (1.8-3.5) 99.5 (99.4-99.6) 10.2 ACOG 94 (71-100) 90 (78,96) 1.4(1.3-1.5) 0.9(0.8-1.0) 99.8 (99.5-99.9) 64.2 ACOG ASA 6 (1,27) 5 (2,14) 4.2 (1.8-9.9) 2.8 (1.2-6.4) 99.3 (99.3-99.4) 0.2 FMF (1;100)* 100 (80,100) 76 (69-82) 8.1 (7.4-8.8) 5.5 (5.0-5.9) 99.8 (99.7-99.9) 9.2

* Bayes’ theorem based method

Maternal factors (Race, CHT, parity, conception method) MAP

Uterine artery Doppler PI PlGF and PAPP-A

Poon et al. 2014

Prediction of PE

Review of reviews (2444 citations, 126 reviews (2-254 studies), 90 predictors & 52 models High risk of bias (population representativeness & study attrition) Townsend et al. 2018

Best performance Se Sp

BMI > 35 21 (12-31) 92 (89-95)

First trimester uterine artery Doppler* 26 (23-31) 93 (90-96)

PLGF 65 (63-67) 89 (89-89)

PP13 37 (33-41) 88 (87-89)

‘No single marker had test performance suitable for routine clinical practice.

Models combining markers show promise but none undergone external validation.’

ISUOG Guidelines 2018: Role of US in screening for PE

• Combination of maternal factors, maternal MAP, uterine artery Doppler and PlGF at 11-13 wk appears to be most effective model for identification of women at risk of PE (Grade B)

DR (for 10% FPR): < 37 wk: 75% (O’Gorman et al. 2016), 77% (Rolnik et al. 2017)

 37 wk: 47% (O’Gorman et al. 2016), 43% (Rolnik et al. 2017)

• Given superiority of combined screening, the use of Doppler as stand alone screening modality should be avoided if combined screening (Grade B)

Aspirin

Impact of starting aspirin in early pregnancy

Bujold et al. 2010 Outcome Number of

studies

Prevalence (%) in:

Treated Control

RR (95% CI)

NNT (95% CI) Preeclampsia

16 w or less More than 16 w

Severe preeclampsia 16 w or less

More than 16 w Gestational HT

16 w or less More than 16 w Preterm birth

16 w or less

More than 16 w SGA (BW < 10^th)

16 w or less

More than 16 w Abruption

16 w or less More than 16 w

9 18

3 2 7 14

4 16

5 10

4 6

9.3 7.3 0.7 0.6 16.7 11.6 3.5 18.6 10.7 13.4 1.1 2.3

21.3 8.1 15.0

2.4 29.7 15.0 16.9 20.8 23.0 16.0 3.3 1.4

0.47 (0.34-0.65)**

0.81 (0.63-1.03) 0.09 (0.02-0.37)**

0.26 (0.05-1.26) 0.62 (0.45-0.84)*

0.63 (0.47-0.85)*

0.22 (0.10-0.49)**

0.90 (0.83-0.97)*

0.47 (0.30-0.74)**

0.92 (0.78-1.10) 0.62 (0.08-5.03) 1.56 (0.96-2.55)

9 (6-25)

7 (5-13)

8 (5-17) 29 (17-50)

8 (6-15) 46 (25-100)

9 (5-17)

Aspirin

Impact of starting aspirin in early pregnancy

Recent SR & meta-analysis (Cui et al. 2018)

10 RCTs (3168 participants) aspirin commenced  16 weeks All PE 0.67 [0.57, 0.80]

Preterm PE 0.35 [0.13, 0.94]

Term PE 1.10 [0.60, 1.70]

PIH 0.80 [0.65, 0.99]

IUGR or SGA 0.71 [0.58, 0.89]

SB or death 0.34 [0.19, 0.59]

Individual participant data meta-analysis (Meher et al. 2017)

PE Death of baby SGA PTB (< 34w) Randomised < 16 w 0.90 [0.79,1.03] 0.89 [0.73,1.09] 0.76 [0.61,0.94] 0.90 [0.77, 1.04]

13-17 trials (n=6393-9241)

Randomised  16 w 0.90 [0.83,0.98] 0.92 [0.79, 1.07] 0.95 [0.84,1.08] 0.91 [0.82, 1.00]

19-22 trials (14996-21429)

Prevention of PE

Aspirin: Time of ingestion

24 h MESOR (as % baseline) SBP

DBP

Randomised double-blind chronotherapy trial (n=350 high risk women)

PE 15.5% 1.7%

Awakening +8 h or bedtime

p=0.04 Ayala et al. 2013

Prevention of PE

Aspirin: Effect of dose

≤ 16 wk - all preeclampsia

50 mg (1 trial, n=66) 0.33 (0.04,3.04) 60 mg (4 trials, n=3328) 0.93 (0.25-1.15) 75 mg (2 trials, n=373) 0.42 (0.25-0.70) 80 mg (4 trials, n=270) 0.52 (0.26-1.01) 100 mg (7 trials, n=987) 0.48 (0.31-0.74) 150 mg (1 trial, n=93) 0.07 (0.0-1.25)

All (19 trials, n=5113) 0.57 (0.43, 0.75)

> 16 wk (21 trials, n=15371) 0.81 (0.66,0.99)

≤ 16 wk - severe preeclampsia

60 mg (3 trials, n=3280) 0.96 (0.71-1.28) 75 mg (2 trials, n=373) 0.24 (0.09-0.65) 100 mg (3 trials, n=334) 0.23 (0.08-0.64) 150 mg (1 trial, n=93) 0.07 (0.0-1.25)

All (19 trials, n=4079) 0.47 (0.26, 0.83)

> 16 wk (10 trials, n=1136) 0.85 (0.64,1.14) Roberge et al. 2017

Aspirin vs. Placebo in pregnancies at high risk of preterm PE

26941 women screened

2971 (11.0%) high risk at 11⁰-13⁶ wk

Risk preterm PE

>1 in 100

2641 eligible for inclusion

332 excluded

2641 eligible for inclusion

865 declined

878

Aspirin 150 mg

898 Placebo

1Analysis 822 798

ASA Risk preterm PE

at 11-13 w (%) PE < 37 w

SGA < 37w*

PE < 34 w PE ≥ 37 w

Placebo 2.3

(1.4-4.8) 13 (1.6)

17 (2.2) 3 (0.4) 53 (6.6)

2.6 (1.5-4.8)

35 (4.3)

18 (2.2) 15 (1.8) 59 (7.2)

OR

(95% CI)

0.38

(0.20-0.74)

1.01

(0.42-2.46)

0.18

(0.03-1.03)

0.95

(0.57-1.57

*Without PE

No differences in GH, SGA, fetal loss, PTB Any adverse outcome

Rolnik et al. 2017 NNT

38

(23-100)

NNT

70

(41-27)

LMW heparin (in addition to aspirin) for prevention of PE in high risk women

• Meta-analysis

suggests heparin more effective than aspirin alone (RR 0.54, 95% CI 0.31-0.92) but..

• All studies high risk of bias (quality of evidence low / very low) and none based on current screening methods

Need for further research

Early onset preeclampsia

Conclusions

• Significant cause of maternal and fetal adverse outcome (especially <26 wk)

• Fetal growth retardation / abnormal UA Doppler very common

• Units should have management guidelines and consider referral to regional centres with EO disease

• Adequate control of hypertension is critical

• Reliable first trimester prediction by combined screening possible – aspirin (150 mg at night) reduces risk

• sFlt-1/PlGF useful to rule out PE prior to 37 weeks

• May be possible to predict ‘non-responders’ – candidates for further therapy

(?heparin)

PE: Prediction

Angiogenic factors

Soluble fms-like tyrosine kinase 1 (sFlt-1)

• Short form VEGF receptor (Flt-1) – lacks transmembrane domian

• (Over)expressed by trophoblast

• Serum levels increase in PE (before presentation /  severity)

• Decoy receptor for VEGF and PlGF

Placental growth factor (PlGF)

• Member VEGF sub-family – pro-angiogenic

• (Under)expressed by trophoblast

• Serum levels decreased in PE (before presentation / severity)

Soluble endoglin (sEng)

• Derived from cell surface co-receptor for TGF-

• (Over)expressed by trophoblast

• Serum levels increased in PE (before presentation)

PE: Prediction

Angiogenic factors

Soluble fms-like tyrosine kinase 1 (sFlt-1)

Placental growth factor (PlGF)

Triage PlGF

< 12 pg/mL + (Very abn: suggest severe placental dysfunction / inc risk PTD) 12-100 pg/mL + (Abn: suggest placental dysfunction / inc risk PTD)

 100 pg/mL - (N: suggest normal placental function / unlikely deliver within 14 d) Elecsys sFlt/PlGF

Aid to diagnosis PE – R/O cut-off - 20 w to Delivery 33 R/I cut-off - 20 – 33⁺⁶ w 85

34 w to Delivery 110 R/I 110 Short term prediction PE 24 – 36⁺⁶ w – R/O cut off <38

R/I cut-off >38

NICE 2016: Both tests recommended as Rule Out for PE at 20 – 34⁺⁶ wk Neither test recommended as Rule In for PE at 20 – 34⁺⁶ wk

(further research recommended)

Early screening for preterm PE at 11-13 wk Maternal factors & biomarkers

3 prospective non-intervention studies (n=61174)

Incidence PE - 2.9%, preterm PE (<37 wk) 0.8%, early PE (<34 wk) 0.2%

Risk cut-off  1 in 100

PE: Prediction

Angiogenic factors

Prediction of PE (measurement ≤24 wk)

• 11-14 wk (combined with other biomarkers)

Poon et al. 2014, Rolnik et al 2017

• 20-24 wk (combined with other biomarkers)

• 16-24 wk (single or serial)

Widner et al. 2015

Prediction Prevention

+ + ++ -

+/- -

Impact on PE < 34 wk

Aid to diagnosis / prognosis (measurement 20-37 wk)

• Diagnosis of superimposed PE in CKD and CHT

• Diagnosis of PE in gestational hyperternsion or proteinuria

• Prediction of early delivery in women with PE

PE: Prediction

Angiogenic factors

Prediction of PE (measurement ≤24 wk)

Widner et al. 2015 (198/5121 [3.9%] developed PE, 0.9% < 34 wk)

Angiogenic factors

Prediction of PE requiring delivery within 14 d in women with CKD and CHT

Bramham et al. 2016

(n=79)

121 CKD (19% developed PE) & 45 CHT (31% developed PE)

Predictive ability confirmed in validation cohort PlGF < 5^th centile AUC 0.84 (0.02) sFlt-1/PlGF >85 AUC 0.83 (0.06)

Angiogenic factors: sFlt-1/PlGF ratio

Prediction of diagnosis & prognosis in suspected PE

n=1273 (234 with P$, 468 matched controls) Early (24-33⁺⁶ wk) & late (34-36⁺⁶ wk)

sFlt-1/PlGF cut-offs

 33 (rule out)

 85 (rule in)

Verlorhren et al. 2014

Angiogenic factors: sFlt-1/PlGF ratio

Prediction of prognosis in suspected PE

Time to delivery

Ratio > 38

- 2.9 fold greater likelihood imminent delivery (day of test)

- Shorter remaining time to delivery

17 ^[10-26] vs 51 [30-75] d y Median [IQR) Zeisler et al. 2016

Adverse fetal outcomes

Ratio > 38 - PPV at 4 weeks - 47.5 [38.4-56.8]%, NPV within 1 wk – 99.3 [97.9-99]%

Zeisler et al. 2016 (Death, birth < 34 w, FGR, abruption, RDS, NEC, IVH)

Adverse maternal outcomes

Ratio < 38 - No death, pulmonary oedema, ARF, cerebral haemorrhage, DIC) within 4 wk Zeisler et al. 2016

Ratio < 85 - No elevated ELLP, abruption, pulmonary oedema, eclampsia) within 2 wk Rana et al. 2013

Women without PE Women with PE

Angiogenic factors: sFlt-1/PlGF ratio

Predictive ability in low risk nulliparous women

Prediction (AUROC)

20 wk – PE with delivery < 28 wk 0.70 (0.43-0.97) 28 wk – PE with delivery < 36 wk 0.80 (0.70-0.89) 36 wk – PE with severe features* 0.81 (0.77-0.86)

* Severe HT, hepatic, renal, haematologic, cerebral or pulmonary complications

4099 nulliparous women

PE: overall 6.5%, < 28 wk 0.10%, <37 wk 0.65%, severe PE after 36 wk 2.8%

sFlt-1/PlGF > 38

Sovio et al. 2017

Angiogenic factors: sFlt-1/PlGF ratio SR & meta-analysis: SaPPPhirE Study

15 studies (534 cases PE, 19587 controls) All studies

Se 0.80 (0.68-0.88) Sp 0.92 (0.87-0.96) LR+ 10.5 (6.2-18.0) LR- 0.22 (0.13-0.35)

AUROC 0.94 (0.91-0.96)

High risk (7 studies): Se 0.85 (0.66-0.94), Sp 0.87 (076-0.93)

Low risk (11 studies): Se 0.77 (0.61-0.88), Sp 0.94 (088-0.97)

Agrawal et al. 2018

Expectant management of severe PE

Maternal complications according to GA at onset

0 5 10 15 20 25 30 35 40

24 25 26 27 28 29 30 31 32-33

AP HELLP Abruption Pulmonary oedema

DIC Renal insufficiency

Haddad et al. 2004

%

Thrissur O & G Society 2018

Managing early onset (severe) preeclampsia

S. Robson

Professor of Fetal Medicine, Newcastle University

• Diagnosis

• Management

• Prevention

• Prediction

Me

PE: Small-for-gestational age Prediction & Prevention

Tan et al. 2018 (based on data from SPREE & ASPRE trials)

Screening at 11-13 w (based on maternal characteristics, MAP, UtA PI & PlGF)

DR SGA; < 37 w 46%

< 32 w 56%

(Risk cut-off >1;100, SPR 12.2%)

Aspirin reduced incidence SGA < 37 w by 20%

and < 32 w by 40%

Prediction and prevention

Prediction

PE / PIH  PE

History

Maternal haemodynamics

Uterine Artery Doppler

Biochemistry

DS markers

- (Anti-) angiogenic markers

Prevention

Aspirin

Calcium

Antihypertensives Heparin

Folic Acid

Vitamin D Exercise

Statins

Vitamins, Fish Oils, NO Donors