douglas woelkers, md associate professor maternal fetal...

Douglas Woelkers, MD Associate Professor Maternal Fetal Medicine University of California, San Diego

Differences in preeclampsia between

Early preterm

Late preterm

Term preeclampsia

Fetal risks Maternal risks Constructing rational delivery plan Risk stratification by biomarkers

Stage II - Maternal Endothelial dysfunction Vasospasm

Hypertension Capillary leak

Edema Proteinuria

Stage I - Placental Poor implantation Defective remodeling Perfusion mismatch Hypoxia, inflammation

“Toxins”

•Nulliparity • In Vitro IVF •Preeclampsia •Multiples

•Chronic Hypertension •Renal disease • Lupus

•Age •Dyslipidemia •Diabetes •Obesity

Risk Factors

*Lain, et al. JAMA 2002

0%

5%

10%

15%

20%

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

Gestational Age

% Births

% PET

2009 Natality Statistics, CDC

% of all births

% preeclampsia births per week

65% 10% 25%

Early Preterm Late Preterm

Term

Higher prevalence of placental pathology

0

10

20

30

40

50

60

70

80

90

< 28 28-32 33-37 > 37

% P

reva

len

ce

Gestational Age

Placental Pathology in Preeclampsia

arteriopathy

infarction

hypermaturity

Moldenhauer, et al. AJOG 2003

Higher proportion of severe disease

0%

20%

40%

60%

80%

100%

24-28 28-34 34-37 >37

% o

f ca

ses

Gestational age (weeks)

265 Cases of Preeclampsia by Gestational Age

Mild

Severe

Lai, et al. SMFM 2007

Higher maternal mortality

0

5

10

15

20

25

>3733-3629-32< 28

Ris

k R

ati

o

Gestational Age (weeks)

Maternal Mortality Risk

MacKay, et al. Obstet Gynecol, 2001

Impact of preeclampsia and gestational hypertension on birth weight (n = 87,798), Alberta, Canada, 1991–1996.

Xiong X et al. Am. J. Epidemiol. 2002;155:203-209

Smaller Same Larger

Greater fetal growth delay

Gestational Age Morbidity in 8523 Neonates, 1997–1998

Lung maturity is not advanced in preeclampsia

Schiff, et al. AJOG 1993

0%

20%

40%

60%

80%

100%

PET CON PET CON PET CON PET CON

29-31 31-33 33-35 35-37

Mature Amnio Rate

ns

ns

ns

ns

RDS is not reduced in preeclampsia

Chang, et al. Obstet Gynecol 2004

Preeclampsia

Normotensive

RDS Incidence by Gestational Age

Per

cen

t R

DS

Deliver

For maternal benefit

For fetal benefit

Expectant management

For fetal benefit

Maternal risk

Depends on gestational age and outcomes

1st Trial (Sibai, 1984)

Unselected cohort, N=60

Severe preeclampsia

17 to 28 weeks

No steroids

Offered expectant management

Minimal monitoring

Complication N Percent

Abruption 13 22%

Eclampsia 10 17%

Coagulopathy 5 8%

Renal Failure 3 5%

Hypertensive Encephalopathy 2 3%

Hepatic Rupture 1 2%

Fetal Demise 21 35%

Neonatal Demise 31 52%

Neonatal Survival 8 12%

2nd Trial (Sibai, 1990)

Selected cohort

Maternal & fetal monitoring

Steroids, magnesium, anti-hypertensives

N=109

19-27 weeks

GA < 24 (n=25) Offered termination

Expectant (15) 1 survivor

Termination (10)

GA 24-27 (84) Steroids given

Delivery (30)

Expectant (54)

Outcomes Deliver (n=30)

Expectant (n=54)

Eclampsians 3.3% 5.6%

Abruptionns 6.7% 5.6%

HELLPns 13% 13%

Latency* 2 d 13.2 d

Gest age 26.3 wk 28.0 wk

Birth weight 709 gm 800 gm

Perinatal mortality*

64% 24%

Summary Outcomes of Previable Preeclampsia, <24 weeks

Author N Perinatal Death (%)

Maternal Complications (%)

Sibai, 1990 15 93 27

Moodley, 1993 10 100 50

Visser, 1995 25 84 NR

Gaugler-Seden, 2006 26 82 65

Hall, 2001 8 88 36

Budden, 2006 31 71 71

Fetal outcomes are poor Maternal risks are high Delivery should be considered with severe

preeclampsia before viability

Sibai, 1994

Severe preeclampsia

28-32 weeks ▪ Delivery 48 hrs after

steroids vs.

▪ Expectant management

Intensive maternal and fetal monitoring

Outcome Deliver (n=46)

Expectant (n=49)

Eclampsia ns 0 0

Abruption ns 2 2

HELLP ns 1 2

Latency * 2.3 d 15.4 d

GA delivery * 30.8 wks 32.9 wks

IUFD, NND ns 0 0

RDS * 50% 22.4%

NEC * 10.9% 0

ICH ns 6.5% 2%

Author GA (wks) N Latency (d)

Sibai 28-32 46 15 (3-32)

Odendaal 26-34 18 7.1

Sibai 24-27 54 13 (2-26)

Olah 24-32 28 9.5 (2-26)

Visser 26-31 229 14 (0-16)

Hall 26-34 340 10.3 (1-47)

Chammas 24-33 47 6 (1.5-28)

Vigil-DeGracia 24-34 129 8.5 (3-30)

Haddad 24-34 239 5 (2-35)

Oettle 23-34 131 11.6 (1-89)

Shear 24-34 155 5.3 (1-27)

Ganzevoort 24-34 216 11 (2-44)

No worsening of outcomes at earlier age

Maternal Outcomes of Expectant Management with Preeclampsia

by Gestational Age, N (%)

24-28

n=110

28-32

n=97

32-34

n=32

HELLP Syndrome 17 (16) 13 (13) 4 (13)

Abruption 7 (6.4) 5 (5) 2 (6)

D I C 3 (3) 0 0

Renal Insufficiency 6 (5) 5 (5) 2 (6)

Haddad, et al. AJOG 2004

Perinatal Outcomes of Expectant Management with Preeclampsia

by Gestational Age

24-28

(n=110)

28-32

(n=97)

32-34

(n=32)

Latency (d) * 6 (2-35) 4 (2-32) 4 (2-12)

IUGR * 28 (25) 27 (27) 3 (9)

Neonatal Mortality * 7 (7) 0 0

Ventilation (d) * 3 (0-60) 0 (0-17) 0 (0-4)

RDS * 69 (66) 36 (37) 1 (3)

BPD * 34 (33) 6 (6) 0

IVH * 6 (6) 0 0

NEC * 6 (6) 1 (1) 0

NICU (d)* 22.5 (0-100) 8 (0-57) 5 (0-18) Haddad, et al. AJOG 2004

RDS (%) 43 57 42

IVH (%) 14 10 7

NEC (%) 4.5 3.4 0

BPD (%) 16 22 7

Perinatal death (%) 14 0 0

Expectant Management with IUGR

Complication <5th % (n=44)

5-10th % (n=52)

> 10th % (n=59)

Liver injury 18 (41) 22(42) 19 (32)

Thrombocytopenia 13 (30) 10 (19) 19 (33)

Eclampsia 2 (4.5) 1 (2.1) 0 (0)

Abruption 6 (13.6) 3 (5.8) 0 (0)

Pulmonary edema 4 (9) 2 (3.8) 0 (0)

Shear, et al. AJOG 2005

Higher rates of

Abruption

Pulmonary edema

Perinatal death

Consider expectant management only if < 28 weeks

Shear, et al. AJOG 2005

Very high risk endeavor

3 series of expectant management true HELLP ▪ Latency 3 to 7 days

▪ 3 liver rupture, 1 maternal death

▪ No improvement neonatal outcome vs delivery

Recommend active or intermediate delivery option

Chamas, et al. 2000 Van Pampus, et al. 1998 Van Runnard, et al. 2006

Variable Indication

Maternal Persistent severe headache or visual changes; eclampsia

Shortness of breath or chest tightness with rales and/or pulse oximetry of < 94% on room air; or pulmonary edema

Epigastric/right upper quadrant pain with AST or ALT > 2x the ULN

Oliguria (<500 mL/24 hr) or creatinine of >1.5 mg/dL

Persistent platelet count < 100,000

Suspected abruptio, labor, rupture of membranes

Fetal Severe growth restriction (<5%)

Persistent severe oligo (AFI < 5 or absent 2 x 2 pocket)

Repetitive variable or late decelerations

Biophysical profile (BPP) ≤ 2; or = 4 on two occasions

Reversed umbilical artery diastolic fow

Fetal death

Expectant management of severe preeclampsia remote from term

Requires expert management in tertiary center

Appropriate in selected cases

Yields comparable maternal outcomes to delivery

▪ Except eclampsia, abruption, HELLP, renal failure

Is associated with improved neonatal outcomes

▪ RDS, IVH, NEC

▪ Survival, IUGR

34 to 37 weeks

15-25% of preeclampsia

#1 indication for late preterm delivery

Optimal management is not defined

Neonatal morbidities decreasing…

But not absent

%

Outcomes (%) Gestational Age

340-6 350-6 360-6

Hyperbilirubinemia 22 15 12

NEC 1.2 0.4 0.1

O2 support 21 13 6.5

RDS 6.7 3.2 0.5

TTN 7.2 5.5 3.6

ICH 0.7 0.2 0.5

Convulsions 0.0 0.5 0.6

• Persistent neonatal risks 34 to 37 weeks

• Review of 1,864 cases of LP Preeclampsia

Langeveld, et al. 2011

Hypertensive vs normotensive infants Lower birth weights at 35-36 weeks

Greater need oxygen support (O2S) at 37 weeks

Greater NICU admit and length of stay at all ages

0%

10%

20%

30%

40%

50%

60%

SGA O2S NICU SGA O2S NICU SGA O2S NICU

35 36 37

Normotensive

Hypertensive*

* *

*

*

*

Habli, et al. AOG 2007

Severe preeclampsia, HELLP Syndrome Expedited delivery

Preeclampsia with co-morbidity (ie diabetes, CHTN) Delivery in 36-37th week

Non-severe preeclampsia Expectant management until 37 weeks

Risks of Expectant Management Incidence

Severe hypertension 10-15%

Eclampsia 0.2-0.5%

HELLP 1-2%

Abruption 0.5-2%

Growth restriction 10-20%

Fetal death 0.2-0.5% Sibai, et al. Semin Perinat 2011

Is amniocentesis useful?

34 to 37 weeks

51 patients with mature amnio ▪ Stable mild preeclampsia

Compared to 51 with no amnio ▪ Indicated delivery or labor

Same rate of RDS

Amnio has 10% false negative rate

9.8% 9.8%

0%

2%

4%

6%

8%

10%

12%

Mature amnio,elective delivery

No amnio,indicateddelivery

Ra

te o

f R

DS

Lewis, et al. 2009

No trials comparing options

HYPITAT Trial supports delivery over expectant management at 36 to 41 weeks ▪ For gestational hypertension (DBP >95) or preeclampsia

HYPITAT II (34+0 to 36+6) in progress

Expert opinion says…

Indications for delivery in LP Preeclampsia

Severe hypertension Preterm labor or ROM

Vaginal bleeding Growth restriction (<5%)

Oligohydramnios Recurrent FHR decelerations

Absent or reverse umbilical artery flow BPP ≤ 6

Sibai, et al. 2011

---- cut-off levels (5th centile)

100% sensitivity 96% specificity

Early Onset Preeclampsia Fetal Growth Restriction

100% sensitivity 86% specificity

---- cut-off levels (5th centile)

Placental IUGR Preeclampsia

Case-Control Cohort

Benton J, et al. Am J Obstet Gynecol 206(2); 2011

PELICAN Study (2012 UK)

649 subjects with suspected preeclampsia

▪ 278 subjects < 35 weeks (mean 31.0)

▪ PlGF determined at presentation

▪ Managed according to provider

▪ Final diagnosis determined after delivery

1Knudsen, et al. Pregnancy Hyperten 2;2012 In Press Circulation

Preeclampsia requiring delivery within 14 days

Sensitivity 67/71 0.94 0.86 – 0.98

Specificity 116/207 0.56 0.49 – 0.63

NPV 116/120 0.97 0.92 – 0.99

PPV 67/158 0.42 0.35 – 0.51

Preeclampsia requiring preterm delivery

Sensitivity 102/114 0.90 0.82 – 0.94

Specificity 108/164 0.66 0.58 – 0.73

NPV 108/120 0.90 0.83 – 0.95

PPV 102/158 0.65 0.57 – 0.72

GA < 35+0 using 5 %tile cutoffs

Preeclampsia requiring delivery within 14 days

Positive likelihood ratio 2.15

Negative likelihood ratio 0.10

Application of test into practice

Prior odds: 71 cases, 207 non-cases 0.33

Pre-test probability: 26%

If test positive: posterior odds: 0.74

Post-test probability: 43%

If test negative: posterior odds: 0.034

Post-test probability 3.3%

20 25 30 35 40 450

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Gestational Age

Pro

po

rtio

n o

f W

om

en

Un

de

live

red

Length of Pregnancy, Sample GA < 35+0 (N=278)

PlGF High (n=120)

PlGF Med (n=93)PlGF Low (n=65)

Hazard Ratio for Time-To-Delivery* PlGF Med 2.31 (1.68-3.18) PlGF Low (<12 pg/ml) 10.61 (7.09- 15.89)

*adjusted for gestational age at sampling and final diagnosis.

All patients tested before 35 weeks (N=278)

High

Low

Med

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Receiver Operator Curve (ROC) analysis

Endpoint is preterm pre-eclampsia delivering within 14 days

PlGF outperforms all other tests (AUC 0.88)

PlGF sensitivity for the endpoint is 96% (73/76)*

PlGF NPV for the endpoint is 98% (118/121)*

Standard tests individually or in combination (AUC 0.69) have poor discrimination

*cutoff 100pg/mL

SBP = Systolic BP, DBP = Diastolic BP, ALT =Alanine transaminase

0.00

0.25

0.50

0.75

1.00

Sensitiv

ity

0.00 0.25 0.50 0.75 1.00

1-Specificity

Test: ROC area (SE)

PlGF: 0.88 (0.03)

SBP: 0.65 (0.04)

DBP: 0.65 (0.05)

Urate: 0.68 (0.05)

ALT: 0.58 (0.05)

PlGF is superior to other tests for diagnosis of preterm pre-eclampsia delivering in 14 days

39 not for print or distribution

SBP = Systolic BP, DBP = Diastolic BP, ALT =Alanine transaminase, Uric Acid uses a GA-dependent cutoff. Cutoffs are based on PRECOGII Guideline. BMJ 2009;339:b3129

<35w GA % Sens % Spec % PPV % NPV OR

PlGF <100 pg/mL 96.1 55.9 44.0 97.5 30.87

Dipstick ≥2+ 66.7 81.0 52.6 88.4 8.50

Uric acid* 43.6 88.0 60.0 79.1 5.66

SBP ≥170 mmHG 26.7 86.3 40.8 76.8 2.28

DBP ≥110 mmHg 17.3 85.8 30.2 74.5 1.27

ALT ≥32 IU/L 11.3 88.7 28.6 71.4 1.00

PlGF is superior to other tests for diagnosis of preterm pre-eclampsia delivering in 14 days

PlGF n Time to Delivery, d

Median (IQR)

Undetectable < 12 pg/ml 12 9 (6.2 – 10.5)

Low < 5th %tile 22 18 (8.5 – 22.0)

Normal > 5th %tile 14 56 (39.2 – 76.7)

48 cases with 1) hypertension, or 2) proteinuria, but not both

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