Recurrence & Long-term Complications after Preeclampsia-eclampsia

Recurrence & Long-term
Complications after
Preeclampsia-eclampsia
Baha M. Sibai, M.D.
Professor
Department of Obstetrics and Gynecology
University of Cincinnati College of Medicine
Cincinnati, Ohio

Learning Objectives:
To review recurrence risk after
preeclampsia
To discuss subsequent cardiovascular
complications in women with
preeclampsia
To review long-term neurologic findings
after severe preeclampsia-eclampsia
To suggest future research in this area
B. Sibai

Preexisting Conditions Associated with
very high-risk of Preeclampsia
Previous preeclampsia/eclampsia
Chronic hypertension ± left ventricular
dysfunction
Pre-gestational DM
Increased insulin resistance (GDM/BMI)
Autoimmune disease
Features of metabolic syndrome
• Mother born FGR
• Placental vascular syndromes
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Risk of Recurrent Preeclampsia
Author # of Patients Preeclampsia %
Makkonen et al (2000) 144 14.5
Hnat et al (2002) 598 17.9
Trogstad et al (2004) 19,960 14.1
Poston et al (2006) 546 22.7
Hjartardottir et al (2006) 151 13.2
Brown et al (2007) 383 14
Spinnato et al (2007) 338 11.5
Villar et al (2007) 422 27
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%
60
50
40
30
20
10
0
Preeclampsia in 2 nd Pregnancy
n=1328
n=781
n=340
Preeclampsia in 1 st pregnancy (wks)
n=218
> 37 31-36 27-30 < 27
Sibai et al, AJOG 1986,1991 B. Sibai

Subsequent Pregnancy Outcome for Women with
Preeclampsia in 2 nd Trimester
%
40
30
20
10
0
(n = 169)
35
21 21

Preeclampsia According to Outcome as Nullipara
(BMJ 2009;338)
Preeclampsia %
35
30
25
20
15
10
5
0
Preeclampsia
Normotensive
4.1
0
14.7
1.1
31.9
1.0
1 2 3 4
33.3
1.0
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Early Onset Preeclampsia (< 34 wk) BMJ 2009;338:
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Outcome in Subsequent Pregnancy in those with
Preeclampsia in 1 st Pregnancy by Outcome in 2 nd
& 3 rd Pregnancies*
Preeclampsia in 1 st
Pregnancy
#
Preeclamps
ia #(%)
Normal 2 nd (n=4234) 3 369 (8.7)
Preeclampsia in 2 nd preg
normal in 3 rd (n=695)
*Hernandez-Diaz et al (BMJ 2009;338:b2255)
4 50 (7.2)
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Recurrent Preeclampsia-Eclampsia in Women
with Eclampsia
Chesley
Lopez-
Llera Adelusi Sibai
Women (#) 171 110 64 182
Pregnancies (#) 398 110 64 366
Eclampsia (%) 1.0 - 15.6 1.9
Preeclampsia (%) 23 35 27 22
Sibai et al, Am J Obstet Gynecol 1992
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%
35
30
25
20
15
10
Rate of Superimposed Preeclampsia in CHTN
5
0
Ray
n=337
McCowan
n=155
Sibai
n=763
Giannubilo
n=223
Chappell
n=822
Sibai
n=369
Magee
n=133
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Rate of Preeclampsia in Pregestational Diabetes
20
15
%
10
5
0
17
Poston
n=199
11
Xu
n=158
17
McCance
n=749
20
Sibai
n=462
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Rate of Preeclampsia in Pregestational Diabetes
40
35
30
25
20
15
10
5
0
Class B
(n=157)
Class C
(n=191)
Class D
(n=56)
Class R/F
(n=58)
Sibai BM et al. Am J Obstet Gynecol 2000
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Normal
Mild
Severe
Epigastric
pain
CNS
Bleeding
Nausea/vomiting
Blood
Pressure
Symptoms
Excessive
weight gain
Capillary
Leak
Low platelets
↑ Liver enzymes
Fibrinolysis
Hemolysis
Proteinuria
Facial edema
Pulmonary
edema
DIC
Ascites
Pleural
effusions
HELLP
Renal
failure
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Sibai, 2010
Placenta Associated Syndromes
Abruption
Vascular Stillbirth
PTD
FGR
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Susceptibility/
vulnerability
• Genetics
• Metabolic
syndrome
• Life style factors
• Socioeconomic
status
Pregnancy as the Stress Test of Life
Pregnancy
complications
• Hypertensive disorders
• FGR
• Preterm delivery
• Placental abruption
• Stillbirth
• Gestational diabetes
Mortality/
morbidity
• Cardiovascular
disease
• Type 2 diabetes
• Autoimmune
diseases?
• Stroke
• ESRD
• Early death
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Long-term Complications after Preeclampsia-eclampsia
Chronic hypertension
Coronary artery disease
Metabolic syndrome
Type-2 diabetes mellitus
Chronic renal failure
Stroke
Neurologic deficits
• MRI
• Memory loss
• Attention deficit
Premature death B. Sibai

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Long-term Maternal Morbidities in Women with
HELLP Syndrome
Morbidities (n=123) n(%)
Depression 39 (32)
Essential hypertension 40 (33)
Anxiety 32 (26)
Diabetes Mellitus 5 (4)
Thyroid disorders – hypothyroidism 5 (4)
Retinal disease – blindness 2 (1.6)
Renal disease requiring hemodialysis 3 (2.4)
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Prevalence of Metabolic Syndrome at 7.8 yrs after HDP
in Nulliparous Women*
HDP Control
n=168 n = 168 OR (95% C.I.)
CHTN # (%) 22 (13 2 (1) 12.5 (2.9-54)
Waist Circum (≥ 80 cm) 87 (52) 52 (31) 2.4 (1.5-3.7)
Diabetes 5 (3) 0 (0) P = 0.06
Metabolic Syndrome 33 (20 8 (5) 4.9 (2.0-10.9)
*Forest et al, Obstet Gynecol 2005;105:1373-80.
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Pre-pregnancy BMI, GH, & Long-term Mortality
The Jerusalem Perinatal Study*
Mortality after GH in Survivors ≥15 yrs.
BMI OR 95% C.I.
Underweight (< 18.5) 1.31 0.18-9.76
Normal (18.5-24.9) 1.26 0.74-2.14
Overweight (25-29.9) 1.86 1.07-3.20
Obese (≥ 30) 2.90 1.28-6.58
*Samuels-Kalow et al (Am J Obstet Gynecol 2007;197:490)
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Preeclampsia & Risk of CVD in Later Life:
Systematic Review (Bellamy, BMJ 2008)
Average Follow-Up
(year) RR
CHTN 14.10 3.70
Ischemic heart disease 11.70 2.16
Ischemic stroke 10.4 1.81
Venous thromboembolism 4.7 1.19
Overall death 14.5 1.49
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Cardiovascular Disease Among Patients &
Their Mothers at 7 yrs After Preeclampsia*
Patient Mother
Preecl Control Preecl Control
n=50 n=106 n=35 n=68
Age at F-up (yr) 36.2 ± 5.8 39.2 ± 5.6 60.6 ± 8.9 61.3 ± 7.3
Duration of F-up (yr) 7 ± 5.6 13.1 ± 5.7 35.2 ± 5.1 36.9 ± 5.8
CHTN (%) 46.7 8.9 59.4 42.6
Diabetes (%) 4.3 0 14.3 8.8
Metab syndrome (%) 38.3 12.3 69.7 44.1
*Berends et al, Hypertension 2008;51:1034-41.
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Hypertensive Pregnancy & Subsequent
Cardiovascular Morbidity & Type 2 DM
Lykke et al, Hypertension 2009
National Patient Registry in Norway
Singleton deliveries Jan. 1978 – Oct. 2007
First delivery at 15-50 yrs (n=782,287)
• Second delivery >15-50 yrs (n=536-419)
Primary exposure was GH or preeclampsia
End points studied were:
• CHTN
• Cardiovascular disease
• Type 2 diabetes
• Thromboembolism
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Recurring Complications in Second Pregnancy
GA
PE
1 st
preg
%
PE
2 nd
preg
% OR
SGA
2 nd
preg
% OR
ABR
2 nd
preg
% OR
SB
2 nd
preg
% OR
>37 84 14.1 1 3.1 1 1.0 1 0.5 1
32-36 10.3 25.2 2.08 9.6 3.47 2.2 2.38 1.1 2.31
28-32 2.0 32.4 3.00 17.3 7.21 3.1 3.72 1.8 3.75
20-27 0.4 37.9 3.89 17.2 8.39 3.4 4.77 2.3 5.57
1 st preg HTN disorders 5% Preeclampsia 4.1% GHTN 0.9%
Lykke J, Paidas MJ, Langhoff-Roos J. Recurring Complications in
Second Pregnancy. Obstet Gynecol. 2009 Jun;113(6):1217-24.
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Subsequent Hypertension
Complication Rate HR CI p
No hypertensive disorder 13.5 1 (reference)
Gestational hypertension 82.7 5.72 (5.28-6.20)

Risk of Type-2 DM after HDP in First Pregnancy*
Hypertensive Type 2 DM
Disorder % HR 95% C.I.
No Hypertension 0.8
GH 2.6 3.12 2.6-3.70
Mild Preeclampsia 2.8 3.53 3.23-3.85
Severe Preeclampsia 2.5 3.68 3.04-4.46
Preeclampsia + PTD 3.6 6.59 5.34-8.13
*Lykke et al, Hypertension 2009
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Risk of Type-2 DM after Preeclampsia
in First, Second or Both
Type-2 DM
% HR 95% C.I.
No PE in either Pregnancy 0.7 Reference Reference
PE in first Pregnancy 2.0 3.10 2.75-3.50
PE in second Pregnancy 2.7 3.55 2.96-4.26
PE in both 4.2 5.69 4.66-6.93
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Subsequent Thromboembolism
Rate HR CI p
No PE in neither pregnancies 3.2 1 (reference)
PE in first pregnancy 4.5 1.32 (1.09-1.60) 0.004
PE in second pregnancy 5.7 1.56 (1.18-2.06) 0.002
PE in both pregnancies 7.2 1.93 (1.37-2.71) Combination
Rate is number of events pr. 10,000 person-years; HR
denotes hazard ratio; PE denotes preeclampsia. Adjusted for
maternal age, year of delivery, time between pregnancies,
preterm delivery, small-for-gestational-age, placental
abruption, and stillbirth in both pregnancies.
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Preeclampsia & Risk of ESRD
Medical Birth Registry of Norway
N Engl J Med 2008;359:800-9
Unadjusted RR Adjusted RR (95% CI)
After 1 pregnancy 4.7 (3.6-6.1) 3.2 (2.2-4.5)
Woman ≥ 2 pregnancies
• Preecl in 1 st only 3.2 (2.2-4.9) 2.3 (1.3-4.1)
• Preecl in 2 nd only 6.7 (4.3-10.6) 4.7 (2.5-9.0)
• Preecl in both 6.4 (3.0-13.5) 2.6 (0.6-10.6)
Women ≥ 3 pregnancies
• Precl in 1 st only 6.0 (2.1-11.7) 2.6 (1.1-5.9)
• Preecl in 2 nd only 7.3 (3.0-18.1)
• Preecl in 3 rd only 14.3 (8.2-24.7) 3.0 (0.4-21.9)
• Preecl in ≥2 preg 15.5 (7.8-30.8)
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Rate of Preeclampsia & Adverse Effects on
Renal Function in Women with Renal Disease
Outcome
Serum cr levels prior or early in pregnancy
< 125 m mole/ℓ
< 1.4 mg/dl
125 – 180
1.4-2 mg/dl
> 180
> 2 mg/dl
Preeclampsia (%) 20 40 60
↓Renal function in preg(%) 20-25 30-35 70
Renal function 3-6 mo PP Usual level 40% ↓ 33% dialysis
Renal function long-term Minimal change 60% ESRD 100% ESRD
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Factors Affecting Long-term Renal Function
in Pregnancy with Renal Disease
Serum creatinine level at onset
Development of preeclampsia
Amount of proteinuria at onset
Level of hypertension at onset
Adequacy of BP control during pregnancy
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HDP (%)
70
60
50
40
30
20
10
0
43
Association of HDP with Peripartum
Cardiomyopathy
Elkayam
n=100
64
Witlin/Sibai
n=28
23 23
Habli/Sibai
n=70
Melniczuk
n=16,296
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Posterior Reversible
Encephalopathy Syndrome
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Brain Lesions Several Years after Eclampsia
Aukes et al (Am J Obstet Gynecol 2009;200:504)
73 patients (1988-2005)
• 69 invited to participate
• 46 agreed to participate
• 40 had MRI (5 excluded)
• 39 were good quality (age, 38 ± 6.2 yr)
Follow-up 6.4 ± 5.6 yrs
40 control
• 35 eligible (5 excluded)
• 31 had MRI
• 29 elevated (1 had tumor, 1 WML)
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Eclampsia Cases (n=39)
20 had HELLP syndrome
19 had 1 seizure
10 had 2 seizures
10 had ≥ 3 seizures
1 had lupus & 1 with IDDM
26 received MgSO 4
? # with migraine
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Neurologic Findings After Preeclampsia-eclampsia
Study Groups Findings
Brusse (2008) Preecl (n=10) Control (n=10) Impaired memory
Aukes (2007)** Eclampsia (n=30) Control (n-30) Or Cognition
Aukes (2009) Eclampsia (n=39) Control (n=29) 16/59*(41%) vs
5/29 (17%) WML
*2 had cortical infarction & 1 had lacunar infarcts
**Questionnaire
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Migraine & Cerebral Infarct-like Lesions on MRI
Authors Study Design OR (95% CI) WML
Swartz & Kern (2004) Meta-analysis 3.9 (2.3-6.7)
Kruit (2004) Case-control 13.7 (1.7-112)
Scher et al (2009) Population-based 31% vs 25%
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Risk Factors for Preeclampsia & Coronary
Artery Disease are Similar
Family History
Obesity
Hypertension
Insulin resistance
Dyslipidemia
Diabetes mellitus
Hyperhomocysteinemia
Exaggerated inflammation
Abnormal angiogenesis
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Intergenerational Factors & Pregnancy: A Missing Link
for Type 2 Diabetes, Metabolic Syndrome & CVD?
Risk Factors Prior to Conception
Genetic, Environmental
Preexisting conditions
Renal
Insufficiency
Physiologic changes in pregnancy
Hormonal, Hemodynamic
Placental vasculopathy
Pre/eclampsia GH only Heart
failure
Normal
Risk factors after pregnancy
One or more components of metabolic syndrome
Coronary artery disease
Stroke, neurologic deficit
ESRD, end stage heart disease B. Sibai

Preexisting Medical Conditions
Key Gaps
Limited to no data on long-term
outcome in women with superimposed
preeclampsia
Need for longitudinal studies to
evaluate long-term outcome following
preeclampsia-eclampsia
• Residual renal damage
• Cerebral injury
Need for impact of early intervention
studies
B. Sibai

Unanswered Questions for Future Research
Should all women be screened for risk factors
before conception?
• Results are positive
Attenuation or treatment of risk factors
↓ GDM and/or GH?
Should all women with GH or preeclampsia be
screened for cardiovascular risk factors at 3-6
months PP?
• Results are positive
Attenuation or treatment of risk factors
↓CHTN?
↓ Cardiovascular complications?
B. Sibai

Thank you for your attention.
Francois Boucher (French, 1703-1770), Allegory of Music, 1752, oil on canvas
Cover of JAMA 1998, Vol 23 B. Sibai

%
8
6
4
2
0
0.7
35
wk
Sibai BM, for CPEP Trial
1.5
2.2
3.4
5.6
7.4
6.0
36 37 38 39 40 41
GA at GH-preeclampsia in nulliparas reaching
35 wk (n=4094)
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Preeclampsia (%)
3
2.5
2
1.5
1
0.5
0
Prediction of Preeclampsia at 11-13 wk
Akolekar et al. Prenatal Diagnosis 2011;31:66
Parous (no PE)
n=16,196
Nulliparous
n=15,698
< 34 wk
34-37 wk
> 37 wk
Total