douglas woelkers, md associate professor maternal fetal...
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Douglas Woelkers, MD Associate Professor Maternal Fetal Medicine University of California, San Diego
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Differences in preeclampsia between
Early preterm
Late preterm
Term preeclampsia
Fetal risks Maternal risks Constructing rational delivery plan Risk stratification by biomarkers
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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
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*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
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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
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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
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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
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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
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Gestational Age Morbidity in 8523 Neonates, 1997–1998
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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
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RDS is not reduced in preeclampsia
Chang, et al. Obstet Gynecol 2004
Preeclampsia
Normotensive
RDS Incidence by Gestational Age
Per
cen
t R
DS
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Deliver
For maternal benefit
For fetal benefit
Expectant management
For fetal benefit
Maternal risk
Depends on gestational age and outcomes
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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%
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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%
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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
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Fetal outcomes are poor Maternal risks are high Delivery should be considered with severe
preeclampsia before viability
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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%
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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)
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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
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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
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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
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Higher rates of
Abruption
Pulmonary edema
Perinatal death
Consider expectant management only if < 28 weeks
Shear, et al. AJOG 2005
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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
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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
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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
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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
%
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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
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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
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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
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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
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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
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---- 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
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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
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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
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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%
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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
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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
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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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Thank You