Hypertensive disorders of pregnancy
Updated 2012 Apr 12 11:31:00 AM: subclinical hypothyroidism may increase risk of
hypertensive disorders in pregnancy (Obstet Gynecol 2012 Feb) view updateShow more
updates
Related Summaries:
Hypertension (list of topics)
Pregnancy
Complicated pregnancy
Screening and monitoring during pregnancy
Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) syndrome
General Information
Description:
hypertension during pregnancy(1-5)
o systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg
during pregnancy
o may be pre-existing hypertension in woman with chronic hypertension
o may be gestational hypertension (new onset after 20 weeks gestation)
preeclampsia(1-5)
o typically defined as hypertension with proteinuria (protein > 300 mg in 24-hour
urine specimen) after 20 weeks gestation
o severe preeclampsia if any of
blood pressure ≥ 160/110 mm Hg on 2 occasions at least 6 hours apart
during bed rest
proteinuria ≥ 5 g/24 hours or ≥ 3+ on 2 random urine specimens at least 4
hours apart
cerebral or visual disturbances, including headache
epigastric or right upper quadrant pain
fetal growth restriction
impaired liver function
oliguria < 500 mL/24 hours
pulmonary edema
thrombocytopenia
cyanosis
Also called:
preeclampsia
gestational hypertension
pregnancy-induced hypertension
PIH
toxemia of pregnancy
gestosis
preeclamptic toxemia
gestational hypertension has replaced term pregnancy-induced hypertension(1)
Types:
definitions used in American guidelines(1,2,4-6)
o chronic hypertension defined as systolic blood pressure ≥ 140 mm Hg or diastolic
blood pressure ≥ 90 mm Hg on > 2 occasions before 20 weeks gestation or
beyond 12 weeks postpartum
mild - 140-150 mm Hg systolic or 90-109 mm Hg diastolic
severe - ≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic
o gestational hypertension
replaces term of pregnancy-induced hypertension
hypertension without proteinuria developing after 20 weeks gestation
temporary diagnosis - either progresses to preeclampsia or chronic
hypertension, or resolves and becomes transient hypertension
o transient hypertension - gestational hypertension with normal blood pressure by
12 weeks postpartum
o preeclampsia
hypertension (blood pressure ≥ 140/90 mm Hg) and proteinuria (> 300
mg/24 hours) after 20 weeks gestation
severe preeclampsia is preeclampsia with any of
blood pressure ≥ 160/110 mm Hg on 2 occasions at least 6 hours
apart during bed rest
proteinuria ≥ 5 g/24 hours or ≥ 3+ on 2 random urine specimens at
least 4 hours apart
cerebral or visual disturbances
epigastric or right upper quadrant pain
fetal growth restriction
impaired liver function
oliguria < 500 mL/24 hours
pulmonary edema
thrombocytopenia
cyanosis
o preeclampsia superimposed on chronic hypertension
in woman with hypertension before 20 weeks gestation - new onset
proteinuria
in woman with hypertension and proteinuria before 20 weeks gestation -
any of
sudden 2- to 3-fold increase in proteinuria
sudden increase in blood pressure
thrombocytopenia
elevated aspartate aminotransferase (AST) or alanine
aminotransferase (ALT)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for classification of hypertensive disorders of pregnancy(3)
o hypertension in pregnancy defined as diastolic blood pressure ≥ 90 mm Hg, based
on average of at least 2 measurements using same arm (SOGC Grade II-2B)
o severe hypertension defined as systolic blood pressure ≥ 160 mm Hg or diastolic
blood pressure ≥ 110 mm Hg (SOGC Grade II-2B)
o for diagnosis of clinically significant proteinuria
strongly suspect proteinuria when urinary dipstick proteinuria ≥ 2+
(SOGC Grade II-2A)
proteinuria defined as ≥ 0.3 g/day in 24-hour urine collection or ≥ 30
mg/mmol urinary creatinine in spot (random) urine sample (SOGC Grade
II-2B)
insufficient evidence for recommendations on accuracy of urinary
albumin:creatinine ratio (SOGC Grade II-2I)
o definitions of preeclampsia
in women with pre-existing hypertension - resistant hypertension, new or
worsening proteinuria, or ≥ 1 of other adverse conditions (SOGC Grade II-
2B)
in women with gestational hypertension - new-onset proteinuria or ≥ 1 of
other adverse conditions (SOGC Grade II-2B)
o severe preeclampsia defined as preeclampsia with onset before 34 weeks gestation,
with heavy proteinuria or with ≥ 1 adverse conditions (SOGC Grade II-2B)
o adverse conditions include
maternal symptoms of hypertension such as headache, visual changes,
abdominal pain
maternal signs of end-organ dysfunction
abnormal maternal laboratory testing
elevated aspartate aminotransferase (AST), alanine aminotransferase
(ALT), lactate dehydrogenase (LDH) with symptoms
platelet count < 100 × 109/L
albumin < 20 g/L
fetal morbidity
Organs involved:
placenta(1-3)
multiorgan involvement associated with preeclampsia includes(1,2)
o kidneys
o brain
o liver
o cardiovascular system
Who is most affected:
for preeclampsia(2,4)
o women with pre-existing chronic hypertension (especially if ≥ 4 years)
o nulliparas
o multiple gestations
o women at > 20 weeks gestation
o more frequent in women near term
Incidence/Prevalence:
hypertensive disorders(1-3,5)
o most common medical complication of pregnancy
o complicate about 5%-8% of pregnancies in United States
o about 1% of pregnancies complicated by pre-existing hypertension
o increasing number of hypertension-associated delivery hospitalizations in
United States based on retrospective cohort of 36,537,061 delivery discharges from
1998-2006 Nationwide Inpatient Sample of the Healthcare Cost and
Utilization Project
prevalence of hypertensive disorders among delivery hospitalizations
67.2 per 1,000 deliveries in 1998
81.4 per 1,000 deliveries in 2006
Reference - Obstet Gynecol 2009 Jun;113(6):1299
o 9.8% women have hypertensive disorder in pregnancy in Australia based on study of 250,173 women and 255,931 infants discharged from
hospital following birth in New South Wales between 2000 and 2002
24,517 women (9.8%) had hypertensive disorder including gestational
hypertension (4.3%), preeclampsia (4.2%), chronic hypertension (0.6%)
and chronic hypertension with superimposed preeclampsia (0.3%)
Reference - Med J Aust 2005 Apr 4;182(7):332 full-text
o 7% rate of gestational hypertension in 39,615 pregnancies in World Health
Organization (WHO) Antenatal Care Trial (Am J Obstet Gynecol 2006
Apr;194(4):921)
preeclampsia
o median incidence of preeclampsia 3.9% based on systematic review of 36 studies with 1,699,073 pregnant women
Reference - BJOG 2007 Dec;114(12):1477
o 2.2% rate of preeclampsia in 39,615 pregnancies in WHO Antenatal Care Trial
(Am J Obstet Gynecol 2006 Apr;194(4):921)
o 4.2% rate of preeclampsia among 804,448 pregnancies with first child, singleton
birth after 24 weeks gestation in Norway between 1967 and 2003 (JAMA 2006
Sep 20;296(11):1357 full-text), correction can be found in JAMA 2006 Dec
27;296(24):2926
o 3.8% rate of preeclampsia among 3,494 women giving birth in Norwegian
population-based study (BMJ 2007 Nov 10;335(7627):978 full-text), editorial can
be found in BMJ 2007 Nov 10;335(7627):945, commentary can be found in BMJ
2007 Nov 24;335(7629):1059
o higher prevalence among women with hypertension(3,4)
occurs in about 25% of women with chronic hypertension
develops in about 35% of women with gestational hypertension with onset
< 34 weeks gestation
severe preeclampsia (including hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome and eclampsia) expected to occur in 0.39% deliveries
o based on case-control study from population of 48,865 women delivering in
United Kingdom
o compared with 4 randomly selected controls for each case, risk factors for severe
preeclampsia were age > 34 years, nonwhite ethnic group, past or current
hypertension, previous preeclampsia, diabetes, antenatal admission to hospital,
multiple pregnancy, and social exclusion
o Reference - BMJ 2001 May 5;322(7294):1089 full-text
Causes and Risk Factors
Causes:
cause unknown in most cases of hypertension during pregnancy, especially for
preeclampsia(1)
Pathogenesis:
reduced organ perfusion due to vasospasm and activation of coagulation cascade (Am J
Obstet Gynecol 2000 Jul;183(1):S1), commentary can be found in Am J Obstet Gynecol
2001 Aug;185(2):522
preeclampsia
o abnormal and shallow placentation (due to failure of normal trophoblastic
invasion of spiral arteries) is hallmark of preeclampsia(2)
o hypotheses on pathogenesis
abnormal placental implantation(1)
defects in trophoblasts
defects in spiral arterioles
angiogenic factors(1)
increased soluble fms-like tyrosine kinase 1 (sFlt-1), placental
receptor that binds angiogenic growth factors (J Clin Invest 2003
Mar;111(5):600 full-text)
decreased placental growth factor levels
increased placental neurokinin B production (Nature 2000 Jun
15;405(6788):797)
review of circulating angiogenic factors in pathogenesis and
prediction of preeclampsia can be found in Hypertension 2005
Nov;46(5):1077 full-text
cardiovascular maladaptation and vasoconstriction(1)
genetic predisposition (for example, maternal or paternal thrombophilias)(1)
immunologic intolerance between fetoplacental and maternal tissue(1)
platelet activation(1)
vascular endothelial damage or dysfunction(1-3)
possible 2-stage process causing mismatch between uteroplacental
supply and fetal demands, leading to maternal endothelial cell
dysfunction and maternal and fetal manifestations
in first stage, placenta produces specific proteins or
trophoblastic debris that enter maternal circulation
in second stage, clinical disease dependent on circulating
factors and health of mother
endothelial dysfunction implicated in case-control study (JAMA
2001 Mar 28;285(12):1607)
mRNA expression of pregnancy-specific beta1 glycoprotein and
trophoblast glycoprotein increased in study of 5 women with preeclampsia
and 5 controls (Obstet Gynecol 2007 Nov;110(5):1130)
prostacyclin (PGI2) deficiency implicated (JAMA 1999 Jul
28;282(4):356), commentary can be found in JAMA 2000 Mar 22-
29;283(12):1568
increased sympathetic vasoconstrictor activity (N Engl J Med 1996 Nov
14;335(20):1480 full-text), commentary can be found in N Engl J Med
1997 May 1;336(18):1326
o review of pathogenesis and genetics of preeclampsia can be found in Lancet 2001
Jan 6;357(9249):53
o review of uric acid as pathogenic factor in preeclampsia can be found in Placenta
2008 Mar;29 Suppl A:S67
Likely risk factors:
more important risk factors for preeclampsia (consider specialty referral if ≥ 1 factor
present)(1,3)
o maternal age ≥ 40 years
o medical, family and social history
previous preeclampsia, especially if severe or before 32 weeks gestation
family history of preeclampsia (mother or sister)
antiphospholipid antibody syndrome
pre-existing hypertension or diastolic blood pressure ≥ 90 mm Hg at first
antenatal visit
pre-existing renal disease or proteinuria at first antenatal visit
pre-existing diabetes mellitus
obesity (body mass index ≥ 35 kg/m2)
o risk factors in current pregnancy
multiple pregnancy
first ongoing pregnancy
interpregnancy interval ≥ 10 years
blood pressure ≥ 130 mm Hg systolic or ≥ 80 mm Hg diastolic at first
antenatal visit
less important risk factors for preeclampsia (consider special referral risk if ≥ 2 risk
factors present)(1,3)
o demographic risk factors
lower socioeconomic status
Nordic, Black, South Asian, or Pacific Island ethnicity
o medical, family and social history
heritable thrombophilias
nonsmoking (based on observational studies)
increased prepregnancy triglyceride levels
family history of early-onset cardiovascular disease
cocaine and methamphetamine use
o risk factors in current pregnancy
interpregnancy interval < 2 years
use of reproductive technologies
new partner
gestational trophoblastic disease
excessive weight gain in pregnancy
infection during pregnancy (for example, urinary tract infection,
periodontal disease)
o possible risk factors occurring in second or third trimester of current pregnancy
elevated blood pressure
abnormal maternal serum screening
abnormal uterine artery Doppler velocimetry
cardiac output > 7.4 L/minute
elevated uric acid
evidence regarding specific risk factors
o estimated relative risks for multiple risk factors for preeclampsia based on systematic review of 48 controlled cohort studies
previous history of preeclampsia (relative risk [RR] 7.19, 95% CI
5.85-8.83)
antiphospholipid antibodies (RR 9.72, 95% CI 4.34-21.75)
pre-existing diabetes (RR 3.56, 95% CI 2.54-4.99)
multiple gestations (RR 2.93, 95% CI 2.04-4.21)
nulliparity (RR 2.91, 95% CI 1.28-6.61)
family history (RR 2.9, 95% CI 1.7-4.93)
diastolic blood pressure ≥ 80 mm Hg (RR 1.38, 95% CI 1.01-1.87)
increased body mass index before pregnancy (RR 2.47, 95% CI
1.66-3.67) or at presentation (RR 1.55, 95% CI 1.28-1.88)
maternal age > 40 years (RR 1.96, 95% CI 1.34-2.87) for
multiparous women
additional possible risk factors based on individual studies
interval ≥ 10 years since previous pregnancy
autoimmune disease
renal disease
chronic hypertension
Reference - BMJ 2005 Mar 12;330(7491):565 full-text, editorial can be
found in BMJ 2005 Mar 12;330(7491):549
o adjusted odds ratios for multiple risk factors for preeclampsia based on prospective cohort study of 3,572 healthy, nulliparous women
with singleton pregnancy
preeclampsia in 5.3%
clinical risk factors at 15 weeks gestation for preeclampsia
family history of preeclampsia (adjusted odds ratio [OR] 2, 95%
CI 1.3-3)
vaginal bleeding ≥ 5 days (adjusted OR 2, 95% CI 1.1-3.8)
family history of coronary artery disease (adjusted OR 1.9, 95% CI
1.2-2.8)
increase of 5 mm Hg in mean arterial pressure (calculated at 14-16
weeks gestation) (adjusted OR 1.4, 95% CI 1.3-1.5)
Reference - BMJ 2011 Apr 7;342:d1875 full-text
o additional risk factors and subsequent studies include
obesity as risk factor supported by multiple subsequent studies prepregnancy BMI > 35 kg/m
2 associated with preeclampsia in
systematic review of 36 studies with 1,699,073 pregnant women
(BJOG 2007 Dec;114(12):1477)
being or becoming obese or overweight between pregnancies
associated with increased risk of preeclampsia in retrospective
cohort study with 136,884 women without preeclampsia in first
pregnancy (Obstet Gynecol 2007 Dec;110(6):1319) and
retrospective cohort study of 17,773 pregnant women with history
of preeclampsia in first pregnancy (Obstet Gynecol 2010
Sep;116(3):667)
prepregnancy overweight and obesity associated with increased
risk of hypertensive disorders of pregnancy in retrospective cohort
of 13,722 women (Am J Obstet Gynecol 2007 Nov;197(5):490.e1),
commentary can be found in Am J Obstet Gynecol 2008
Jul;199(1):e20
multiple gestation associated with increased risk of pregnancy-related
hypertensive disease based on cohort of 34,374 pregnancies with 1-4 fetuses with no
hypertension at prenatal booking and delivery after 28 weeks
gestation
incidence of pregnancy-related hypertensive conditions 6.5% for
singleton pregnancies vs. 12.7%-19.6% for multifetal pregnancies
(p < 0.001)
incidence of severe pregnancy-related hypertensive conditions
(hemolysis, elevated liver enzymes, low platelets [HELLP]
syndrome, disseminated intravascular coagulation, eclampsia, low
platelets, renal failure, abruption) was 0.5% for singleton
pregnancies vs. 1.6% for twin and 3.1% for triplet pregnancies (p <
0.001)
independent risk factors for pregnancy-related hypertensive
conditions were increasing fetal number, nulliparity, and advanced
maternal age
Reference - Obstet Gynecol 2005 Nov;106(5):927
preterm delivery in setting of preeclampsia and low fetal growth
associated with increased risk of preeclampsia in subsequent
pregnancy based on retrospective cohort of 536,419 women with first and
second singleton deliveries in Denmark from 1978 to 2007
Reference - Obstet Gynecol 2009 Jun;113(6):1217
rheumatologic disease associated with higher risk of preeclampsia based on cohort of 114 mothers with rheumatologic disease
(systemic lupus erythematosus, rheumatoid arthritis,
antiphospholipid antibody syndrome, or other rheumatologic
disease) vs. 18,534 mothers without rheumatologic disease
Reference - Obstet Gynecol 2004 Jun;103(6):1190
migraine headaches associated with increased risk of hypertensive
disorders in pregnancy based on prospective cohort of 702 normotensive women with
singleton pregnancy at 11-16 weeks gestation
migraine diagnosis in 38.5%
hypertensive disorder developed in 9.1% women with migraines vs.
3.1% without migraines (adjusted odds ratio 2.85, p < 0.05)
Reference - Cephalalgia 2009 Mar;29(3):286
prepregnancy lipid and blood pressure levels associated with risk for
preeclampsia based on cohort study of 3,494 women in Norway
Reference - BMJ 2007 Nov 10;335(7627):978 full-text, editorial
can be found in BMJ 2007 Nov 10;335(7627):945, commentary
can be found in BMJ 2007 Nov 24;335(7629):1059
higher maternal triglyceride levels may be associated with higher risk
for preeclampsia based on systematic review of 19 case-control and 3 prospective
cohort studies
Reference - BJOG 2006 Apr;113(4):379
microalbuminuria or nephropathy associated with increased risk of
preterm labor and preeclampsia in women with diabetes mellitus type
1 based on cohort of 240 pregnant women with diabetes mellitus
type 1
Reference - Diabetes Care 2001 Oct;24(10):1739
women born small for gestational age are at higher risk for
preeclampsia
based on population-based cohort study of 118,634 women
registered as newborns and as mothers in Sweden
Reference - BJOG 2007 Mar;114(3):319
genetic predisposition
o mother, aunt or paternal grandmother with preeclampsia associated with
increased risk of preeclampsia based on population-based study of linked generational data from Norway
with 438,597 mother-offspring pairs and 286,945 father-offspring pairs
Reference - BMJ 2005 Oct 15;331(7521):877 full-text
o genetic predisposition comes from both mother and father (fetus from father who
fathered a preeclamptic pregnancy increases risk) (BMJ 1998 May
2;316(7141):1343 full-text)
interpregnancy interval
o interpregnancy interval > 59 months associated with increased risk for
preeclampsia and eclampsia based on 456,889 women delivering singleton infants between 1985 and
1997
pregnancy interval > 59 months in 19.5%
Reference - BMJ 2000 Nov 18;321(7271):1255
o increasing interpregnancy interval associated with increasing risk for
preeclampsia based on study of 551,478 women with 2 singleton deliveries and 209,423
women with 3 singleton deliveries
preeclampsia in 3.9% with first pregnancy, 1.7% with second pregnancy
and 1.8% with third pregnancy
if > 10 years, odds ratio for preeclampsia 1.12 for each 1-year increase in
interbirth interval
Reference - N Engl J Med 2002 Jan 3;346(1):33, commentary can be
found in N Engl J Med 2002 Jun 6;346(23):1831
periodontal disease may be associated with increased risk of preeclampsia, but
evidence inconsistent
o periodontitis during pregnancy not associated with preeclampsia in 1 cohort
study based on retrospective cohort study
786 pregnant women with periodontal exam < 20 weeks' gestation
evaluated retrospectively following delivery
311 women with periodontal disease
475 women without periodontal disease
preeclampsia defined as hypertension (blood pressure ≥ 140/90 mm Hg)
with proteinuria after 20 weeks' gestation
periodontal disease not associated with preeclampsia (adjusted odds ratio
0.71, 95% CI 0.37-1.36, p = 0.3)
preeclampsia associated with chronic hypertension (adjusted odds ratio
3.54, 95% CI 1.48-8.48, p < 0.005)
Reference - Am J Obstet Gynecol 2009 May;200(5):497e1
o active periodontal disease during pregnancy associated with increased risk of
preeclampsia in 1 cohort study 1,115 healthy pregnant women enrolled before 26 weeks' gestation,
periodontal exams done at enrollment and within 48 hours of delivery
preeclampsia defined as blood pressure > 140/90 mm Hg on 2 occasions
and proteinuria on catheterized urine at least once
analysis based on 763 women who delivered live infants and had data
available
39 (5.1%) had preeclampsia
severe periodontal disease associated with 2.1-2.4 times risk of
preeclampsia
based on exam before 26 weeks' gestation, risk of preeclampsia at time of
delivery was
2% if healthy gums
5% if mild periodontal disease
6% if severe periodontal disease
based on exam at time of delivery, risk of preeclampsia was
3% if healthy gums
5% if mild periodontal disease
10% if severe periodontal disease
Reference - Obstet Gynecol 2003 Feb;101(2):227
o periodontal disease and urinary tract infection during pregnancy may be
associated with increased risk of preeclampsia based on systematic review with heterogeneity
systematic review of 49 cohort, cross-sectional and case-control studies
periodontal disease associated with preeclampsia (odds ratio 1.76, 95% CI
1.43-2.18) in 6 studies with high degree of heterogeneity (I2 = 79%)
urinary tract infection associated with preeclampsia (odds ratio 1.57, 95%
CI 1.45-1.70) in 17 studies with high degree of heterogeneity (I2 = 80%)
no association found with HIV infection, malaria, or presence of
antibodies to Chlamydia pneumoniae, Helicobacter pylori, and
cytomegalovirus
Reference - Am J Obstet Gynecol 2008 Jan;198(1):7, commentary can be
found in Evid Based Dent 2008;9(2):46
Possible risk factors:
in utero diethylstilbestrol (DES) exposure associated with preeclampsia o based on 2 cohort studies
o cohort study of 7,313 live births, including 4,759 with in utero DES exposure
incidence of preeclampsia was 4.4% in DES exposed and 2.9% DES
unexposed pregnancies
Reference - Obstet Gynecol 2007 Jul;110(1):113
o retrospective cohort study of 4,653 women exposed to DES in utero and 1,927
women without DES exposure
DES exposure associated with increased risk of preeclampsia compared to
no exposure (26.4% vs. 13.7%, p < 0.05)
Reference - N Engl J Med 2011 Oct 6;365(14):1304
polycystic ovary syndrome associated with increased risk of preeclampsia,
gestational diabetes, and very preterm birth o based on prospective cohort study
o 3,787 births among women with polycystic ovary syndrome and 1,191,336 births
among women without polycystic ovary syndrome were evaluated for adverse
pregnancy outcomes
o polycystic ovary syndrome associated with increased risk of
preeclampsia (adjusted OR 1.45, 95% CI 1.24-1.69)
very preterm birth (adjusted OR 2.21, 95% CI 1.69-2.9)
gestational diabetes (adjusted OR 2.32, 95% CI 1.88-2.88)
o infants born to mothers with polycystic ovary syndrome had increased risk of
being large for gestational age (adjusted OR 1.39, 95% CI 1.19-1.62)
meconium aspiration (adjusted OR 2.02, 95% CI 1.13-3.61)
low Apgar score (< 7) at 5 minutes (adjusted OR 1.41, 95% CI 1.09-1.83)
o Reference - BMJ 2011 Oct 13;343:d6309 full-text, editorial can be found in BMJ
2011 Oct 13;343:d6407
subclinical hypothyroidism may increase risk of hypertensive disorders in
pregnancy o based on prospective cohort study
o 24,883 women who delivered a singleton infant were assessed for hypertension in
pregnancy
o 2.1% had subclinical hypothyroidism
o overall incidence of hypertensive disorders in pregnancy
10.9% in patients with subclinical hypothyroidism (p = 0.016 vs. other
groups)
6.2% in patients with subclinical hyperthyroidism
8.5% in euthyroid patients
o subclinical hypothyroidism associated with increased risk of severe preeclampsia
(adjusted odds ratio 1.6, 95% CI 1.1-2.4)
o Reference - Obstet Gynecol 2012 Feb;119(2 Pt 1):315
higher HbA1c associated with increased risk of preeclampsia in women with type 1
diabetes o based on prospective cohort analysis of DAPIT trial
o 127 (17% of original trial) women with type 1 diabetes had preeclampsia and 83
(11%) had gestational hypertension
o preeclampsia associated with higher HbA1c before and during pregnancy (p <
0.05 vs. no preeclampsia development)
o HbA1c ≥ 8% in early pregnancy increased risk of preeclampsia (odds ratio [OR]
3.68, 95% CI 1.17-11.6) (vs. HbA1c 6.1% as optimal control)
o increased risk of preeclampsia at 26 weeks gestation with (vs. HbA1c < 6.1%)
HbA1c 6.1%-6.9% (OR 2.09, 95% CI 1.03-4.21)
HbA1c 7%-7.9% (OR 3.2, 95% CI 1.47-7)
HbA1c ≥ 8% (OR 3.81, 95% CI 1.3-11.1)
o increased risk of preeclampsia at 34 weeks gestation (vs. HbA1c < 6.1%)
HbA1c 7%-7.9% (OR 3.27, 1.31-8.2)
HbA1c ≥ 8% (OR 8.01, 2.04-31.5)
o no significant association of glycemic control with gestational hypertension risk
o Reference - Diabetes Care 2011 Aug;34(8):1683
angiogenesis-related biomarkers associated with risk of preeclampsia
o elevated levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and reduced
levels of placental growth factor (PlGF) third trimester increases in sFlt-1 receptor and decreases in placental
growth factor levels associated with preeclampsia, specifically severe
disease, based on systematic review of 24 studies (Obstet Gynecol 2007
Jan;109(1):168)
elevated levels of sFlt-1 and reduced levels of PlGF associated with
increased risk of preeclampsia in case-control study (N Engl J Med 2004
Feb 12;350(7):672), commentary can be found in N Engl J Med 2004 May
6;350(19):2003
o other maternal serum angiogenesis-related biomarkers associated with
preeclampsia in case-control study comparing 40 women with preeclampsia and
100 controls
increased soluble endoglin (sEng)
increased ratio sFlt-1/placental growth factor (PlGF)
increased ratio soluble endoglin/transforming growth factor-beta1 (TGF-
beta1)
increased combined ratio of (sFlt-1 + soluble endoglin)/(PlGF + TGF-
beta1)
decreased TGF-beta1
Reference - Obstet Gynecol 2008 Jun;111(6):1403, correction can be
found in Obstet Gynecol 2008 Sep;112(3):710
moderate-to-high levels of anticardiolipin antibodies may increase risk of
preeclampsia o based on systematic review limited by heterogeneity
o systematic review of 12 studies evaluating association of anticardiolipin
antibodies and preeclampsia
o moderate-to-high levels of anticardiolipin antibodies associated with increased
risk of
preeclampsia (odds ratio [OR] 2.86, 95% CI 1.37-5.98) in analysis of 12
studies, results limited by heterogeneity
severe preeclampsia (OR 11.15, 95% CI 2.66-46.75) in analysis of 5
studies, results limited by heterogeneity
o Reference - Obstet Gynecol 2010 Dec;116(6):1433
HLA-DR genotypes (particularly DR4) may be associated with preeclampsia risk
o based on systematic review of 22 studies of HLA allele frequencies in association
with preeclampsia or intrauterine growth retardation
o 9 of 10 studies suggested DR allelic differences associated with preeclampsia
o 2 of 3 studies suggested no association between HLA alleles and intrauterine
growth retardation
o 6 studies of HLA homozygosity as risk factor for preeclampsia had mixed results
o Reference - Obstet Gynecol 2005 Jul;106(1):162
cytokine genotype associated with preeclampsia in case-control study of 150
primiparous preeclamptic women and 661 primiparous normotensive women (Am J
Obstet Gynecol 2005 Jul;193(1):209)
plasma adiponectin levels < 6.4 mcg/mL associated with hypertensive disorders in
pregnancy, especially preeclampsia, in case-control study (Obstet Gynecol 2005
Aug;106(2):340)
history of fertility treatment and recurrent miscarriage may be associated with
increased risk of preeclampsia in pregnant nulliparous women o based on cohort study in Norway
o 20,846 nulliparous women with singleton pregnancies completed questionnaires
on miscarriage and infertility
o preeclampsia diagnosis retrieved from national registry
o preeclampsia associated with
recurrent miscarriage and fertility treatment (p < 0.05)
fertility treatment (p < 0.05)
recurrent miscarriage (not significant)
o Reference - BJOG 2009 Jan;116(1):108
in vitro fertilization with donor egg associated with increased risk of gestational
hypertension and preeclampsia compared with autologous in vitro fertilization o based on retrospective cohort study
o 158 pregnancies resulting from donor egg or autologous in vitro fertilization were
evaluated
o comparing donor ovum vs. autologous in vitro fertilization
gestational hypertension in 24.7% vs. 7.4% (p < 0.01)
preeclampsia in 16.9% vs. 4.9% (p = 0.02)
premature delivery in 34.2% vs. 19% (p = 0.03)
o Reference - Obstet Gynecol 2010 Dec;116(6):1387
advanced maternal age with in vitro fertilization in case report (Reprod Health 2008 Dec
30;5(1):12 full-text)
molar pregnancy and severe preeclampsia at 19 weeks gestation in case report (J Obstet
Gynaecol 2006 Nov;26(8):817)
Factors not associated with increased risk:
smoking
o smoking in pregnancy associated with decreased risk of preeclampsia in
younger women without pregestational hypertension
based on cohort study of 674,250 singleton pregnancies in New York City
from 1995-2003
smoking associated with overall reduced risk of preeclampsia (adjusted
odds ratio 0.88, p < 0.05) with greatest effect observed in women ≤ 30
years
smoking not associated with reduced risk of preeclampsia in women with
chronic hypertension (adjusted odds ratio 1.04, p > 0.05)
Reference - Am J Epidemiol 2009 Jan 1;169(1):33
o moderate smoking during pregnancy (1-9 cigarettes/day) associated with
DECREASED risk of preeclampsia in retrospective analysis of 127,721
singleton pregnancies, reasons unknown (Acta Obstet Gynecol Scand 1999
Sep;78(8):693)
o smoking during pregnancy in overweight and obese women may not protect
against preeclampsia based on retrospective cohort of 7,757 healthy primigravid women with
singleton pregnancies between 1959 and 1965
smoking decreased risk of preeclampsia in underweight and normal
weight women
Reference - Am J Epidemiol 2008 Aug 15;168(4):427 full-text
history of abortion or preterm birth does not increase risk of preeclampsia
compared to nulliparous women o based on retrospective study of 140,773 pregnancies
o history of term pregnancy decreases risk
o Reference - Am J Obstet Gynecol 2002 Oct;187(4):1013 in JAMA 2003 Jan
15;289(3):280
psychosocial stress before 24 weeks gestation does not appear associated with
increased incidence of preeclampsia or gestational hypertension during first
pregnancy o based on cohort study with low completion rates
o 3,679 nulliparous women pregnant with singleton pregnancy completed
questionnaires on sociodemographic and psychosocial factors before 24 weeks
gestation
preeclampsia in 3.5%
gestational hypertension in 4.4%
o no association observed between preeclampsia or gestational hypertension and
work stress, anxiety, pregnancy-related anxiety or depression
o Reference - BJOG 2008 Apr;115(5):607
inhaled corticosteroids not associated with increased risk of pregnancy-induced
hypertension o based on case control study
o 302 cases of pregnancy-induced hypertension (including 165 cases of
preeclampsia) compared with 3,013 matched controls (including 1,643 matched
controls for preeclampsia comparison)
o no significant differences in either outcome with adjusted odds ratios about 1
o oral corticosteroids were associated with
increased risk for pregnancy-induced hypertension (adjusted odds ratio
1.57, 95% CI 1.02-2.41)
trend for preeclampsia (adjusted odds ratio 1.72, 95% CI 0.98-3.02)
o Reference - BMJ 2005 Jan 29;330(7485):230 full-text
angiotensin-1 converting enzyme gene (ACD-I/D) variant not likely to affect risk of
preeclampsia o no significant association in large case-control study with 665 cases and 1,046
healthy pregnant controls
o significant association in meta-analysis of 22 studies with 2,596 cases and 3,828
controls, but significant differences mostly attributed to smaller studies
o Reference - PLoS Med 2006 Dec;3(12):e520 full-text
Complications and Associated Conditions
Complications:
Eclampsia:
eclampsia (generalized seizures) - convulsive stage of preeclampsia(1-3)
o may be life-threatening
o eclamptic seizures may follow increasingly severe preeclampsia or occur
unexpectedly in patients with no apparent or minimally elevated blood pressure
and no proteinuria
o often preceded by premonitory signs, such as headache, visual disturbances,
epigastric pain, constricting sensation in thorax, apprehension, excitability and
hyperreflexia
o most convulsions occur prepartum, intrapartum or ≤ 48 hours postpartum
o seizures usually isolated
o neuroimaging may show ischemia with edema
rate of eclampsia 0.38 per 1,000 deliveries in Canada from 1991 to 2001 based on 973
cases, 4 deaths (0.4% case fatality rate) (CMAJ 2005 Sep 27;173(7):759 full-text)
incidence of eclampsia 6.2 per 10,000 deliveries with case fatality 1 in 74 in the
Netherlands from 2004 to 2006 based on cohort study of 371,021 pregnancies (Obstet
Gynecol 2008 Oct;112(4):820)
postpartum eclampsia complicated by brain edema and ischemic and hemorrhagic strokes
in case presentation (N Engl J Med 2009 Mar 12;360(11):1126)
late postpartum eclampsia can occur from 48 hours to several weeks after delivery
o 90% of postpartum eclampsia cases occur within 7 days of delivery discharge based on retrospective cohort study of 152 women meeting criteria for
diagnosis of delayed postpartum preeclampsia at > 2 days to ≤ 6 weeks
following delivery
no preceding diagnosis of hypertensive disorder in 63.2%
headache was most common presenting symptom (69.1%)
postpartum eclampsia
developed in 22 patients (14.5%)
90% of cases presented within 7 days of discharge after delivery
mean age 23 years in patients who developed eclampsia vs. 28 years in
patients without eclampsia (p = 0.03)
Reference - Obstet Gynecol 2011 Nov;118(5):1102
o late postpartum eclampsia 16 days after cesarean delivery in case report (J Am
Board Fam Pract 2000 Jan-Feb;13(1):39)
o late postpartum eclampsia 11 days after cesarean delivery in case report (Am Fam
Physician 2002 Aug 1;66(3):378)
o late-onset eclampsia presenting 8 days postpartum with bilateral cortical blindness
in case report (Am Fam Physician 2005 Mar 1;71(5):856)
o late-onset eclampsia presenting 9 days postpartum with bilateral cortical blindness
in case report (BMJ 2005 Nov 5;331(7524):1070), commentary can be found in
BMJ 2005 Nov 19;331(7526):1204, correction can be found in BMJ 2005 Dec
10;331(7529):1390
Maternal complications:
possible maternal complications include(1-3)
o stroke (may occur at systolic blood pressure of 160 mm Hg)
o pulmonary edema
o oliguria
o acute respiratory distress syndrome (ARDS)
o placental abruption
o renal manifestations
glomerular endotheliosis (glomerular lesion)
acute tubular necrosis
acute renal failure
o liver manifestations
elevated transaminase levels
subcapsular hemorrhage
capsular rupture
intraabdominal bleeding
o coagulation abnormalities
microangiopathic hemolysis
thrombocytopenia
disseminated intravascular coagulation (DIC)
hypertensive-associated delivery hospitalizations associated with increased risk for
severe obstetric complications o based on retrospective cohort of 36,537,061 delivery discharges from 1998 to
2006 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project
o compared with delivery hospitalizations without hypertensive disorders, risk of
severe obstetric complications for delivery hospitalizations with any hypertensive
disorder (pregnancy-induced hypertension, preeclampsia, eclampsia) (p < 0.05 for
all)
acute renal failure (adjusted odds ratio [OR] 10.7)
pulmonary edema (adjusted OR 4.7)
adult respiratory distress syndrome (adjusted OR 4.1)
puerperal cerebrovascular disorder (adjusted OR 5.1)
disseminated intravascular coagulation syndrome (adjusted OR 4.5)
ventilation (adjusted OR 4)
mortality (adjusted OR 2.7)
o Reference - Obstet Gynecol 2009 Jun;113(6):1299
hypertensive disorders in pregnancy (HDP) may increase risk of subsequent stroke
with greatest risk in women < 18 years, > 35 years or with preterm delivery o based on retrospective cohort study
o 1,092 women aged 15-40 years in Taiwan with newly diagnosed hypertensive
disorder of pregnancy in 2000-2004 compared to 4,715 control women without
HDP who were followed through 2008
o incidence of stroke 30.1/10,000 person-years with HDP vs. 12.8/10,000 person-
years without HDP (hazard ratio [HR] 2.04, 95% CI 1.18-3.51)
o increased risk of stroke with HDP and
preterm delivery (HR 3.22, 95% CI 1.48-6.99)
age 15-18 years (HR 13.4, 95% CI 1.54-116.7)
age ≥ 35 years (HR 5.56, 95% CI 1.47-21)
o Reference - Stroke 2011 Mar;42(3):716
Fetal/childhood complications:
possible fetal complications(1-3)
o intrauterine growth restriction (IUGR) may complicate up to 30% of preeclampsia
pregnancies
o oligohydramnios
o preterm birth
o fetal death
hypertension in pregnancy associated with increased risk of preterm birth and small
for gestational age birth o based on study of all 250,173 women and 255,931 infants discharged from
hospital following birth in New South Wales from 2000 to 2002
o Reference - Med J Aust 2005 Apr 4;182(7):332 full-text
exposure to pregnancy-induced hypertension in children born after 37 weeks
gestation may be associated with increased risk of epilepsy in childhood o based on population-based cohort study
o 1,537,860 children born in Denmark were assessed for epilepsy and maternal
preeclampsia/eclampsia
45,288 (2.9%) exposed to preeclampsia and 654 (0.04%) to eclampsia
20,260 (1.3%) had epilepsy during follow-up period of up to 27 years
o incidence rate ratios (IRR) of epilepsy for children born at term (37-41 weeks
gestational age)
1.16 IRR for mild preeclampsia (p < 0.05)
1.41 IRR for severe preeclampsia (p < 0.05)
1.29 IRR for eclampsia (p < 0.05)
o incidence rate ratios of epilepsy for children born postterm (≥ 42 weeks
gestational age)
1.68 IRR for mild preeclampsia (p < 0.05)
2.57 IRR for severe preeclampsia (p < 0.05)
5.03 IRR for eclampsia (p < 0.05)
o no significant association with preeclampsia or eclampsia for children born
preterm (< 37 weeks gestational age)
o Reference - Pediatrics 2008 Nov;122(5):1072
Associated conditions:
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome may occur in up to
20% of pregnancies complicated by severe preeclampsia(1)
cardiovascular disease
o women with preeclampsia and preterm delivery have increased long-term
risk for cardiovascular mortality based on study of 626,272 first deliveries with up to 25 years of follow-up
Reference - BMJ 2001 Nov 24;323(7323):1213 full-text
o preeclampsia associated with increased risk of future development of
hypertension and diabetes based on cohort of 15,065 women with first singleton birth between 1967
and 1995
9.5% had hypertensive disorder in ≥ 1 pregnancy
preeclampsia associated with increased risk of
diabetes (adjusted odds ratio 3.8, 95% CI 2.1–6.6)
future use of antihypertensive medication (adjusted odds ratio 3.1,
95% CI 2.2 to 4.3)
Reference - Obstet Gynecol 2009 Nov;114(5):961, editorial can be found
in Obstet Gynecol 2009 Nov;114(5):958
o maternal placental syndrome associated with increased incidence of
cardiovascular disease in women retrospective cohort study of 1,026,265 pregnant women in Ontario,
Canada free from cardiovascular disease before first documented delivery
at ages 14-50 years, median follow-up 8.7 years
75,380 (7%) had maternal placental syndromes defined as preeclampsia,
gestational hypertension, placental abruption and placental infarction
composite outcome of cardiovascular disease included coronary artery
disease (occurring in 75% of those reaching composite outcome),
cerebrovascular disease (occurring in 21%) and peripheral arterial disease
(occurring in 5.5%)
incidence of cardiovascular disease per 100,000 person-years
20 for women without maternal placental syndrome
50 for women with maternal placental syndrome (adjusted hazard
ratio 2, 95% CI 1.7-2.2)
adjusted hazard ratios for cardiovascular disease were
2.1 (95% CI 1.8-2.4) for 36,982 women with preeclampsia
1.8 (95% CI 1.4-2.2) for 20,942 women with gestational
hypertension
1.7 (95% CI 1.3-2.2) for placental abruption (11,156 women) or
infarction (9,303 women)
3.1 (95% CI 2.2-4.5) for 4,390 women with maternal placental
syndrome and poor fetal growth
4.4 (95% CI 2.4-7.9) for 1,171 women with maternal placental
syndrome and intrauterine fetal death
Reference - Lancet 2005 Nov 19;366(9499):1797
preeclampsia associated with increased risk of microalbuminuria o based on systematic review of 7 observational studies evaluating kidney outcomes
in 273 women with history of preeclampsia compared with 333 women with
uncomplicated pregnancies
o weighted mean follow-up 7.1 years postpartum
o history of preeclampsia associated with increased risk of microalbuminuria (31%
vs. 7%, relative risk [RR] 4.31, 95% CI 2.7-6.89)
o history of severe preeclampsia associated with increased risk of microalbuminuria
compared with
uncomplicated pregnancies (RR 8.17, 95% CI 1.19-44.93]
pregnancy-induced hypertension without proteinuria (RR 2.2, 95% CI
1.17-4.13)
mild preeclampsia (RR 4.64, 95% CI 2.47-8.7)
o Reference - Am J Kidney Dis 2010 Jun;55(6):1026
small increased risk of end-stage renal disease in women with preeclampsia o based on medical chart review of 570,433 women having a singleton birth in
Norway from 1967 to 1991
o end-stage renal disease developed in 477 (0.08%) women after mean 17 years
from first pregnancy (overall rate 3.7 per 100,000 women/year)
o risk of end-stage renal disease
significantly increased if preeclampsia during first pregnancy
increased with preeclampsia in each additional pregnancy
associated with having low-birth-weight or preterm infant
o Reference - N Engl J Med 2008 Aug 21;359(8):800, editorial can be found in N
Engl J Med 2008 Aug 21;359(8):858
increased serum concentration of soluble fms-like tyrosine kinase 1 during
preeclampsia associated with subclinical hypothyroidism during pregnancy o based on nested case-control and population based study
o Reference - BMJ 2009 Nov 17;339:b4336 full-text, editorial can be found in BMJ
2009 Dec 8;339:b5183
History and Physical
History:
Chief concern (CC):
may be asymptomatic
hypertensive disorders in pregnancy may present with(1-3)
o rapid weight gain
o generalized edema (affecting face and hands)
o visual disturbances (for example, blurred vision, scotomata, and cortical blindness
[rarely])
o severe headache
o nausea and/or vomiting
o epigastric or right upper quadrant pain
o oliguria
o hyperreflexia
o chest pain
o dyspnea
History of present illness (HPI):
preeclampsia(2)
o blood pressure highest at night (reversal of normal circadian rhythm)
o may rapidly progress
o fulminant preeclampsia may progress from mild to severe, or to eclampsia, in
hours
eclampsia(1,2)
o eclamptic seizures may follow increasingly severe preeclampsia or occur
unexpectedly in patients with mildly elevated blood pressure and no proteinuria
o seizure lasts 60-90 seconds
o postictal phase may follow
o most eclamptic convulsions occur antepartum (about 53%), intrapartum (about
19%) or within 48 hours postpartum (about 28%)
o late postpartum eclampsia may occur from 48 hours to several weeks after
delivery
eclampsia may be preceded by premonitory symptoms, such as(2)
o headache
o visual disturbances
o epigastric pain
o constricting sensation in thorax
o apprehension
o excitability
symptoms preceding eclamptic seizure
o based on series of 46 women with eclamptic seizure
o prodromal headache reported in 80%
o prodromal visual disturbance reported in 45%
o prodromal epigastric pain reported in 20%
o absence of any prodromal symptoms preceding eclamptic seizure in 17%
o Reference - Obstet Gynecol 2011 Nov;118(5):995, editorial can be found in
Obstet Gynecol 2011 Nov;118(5):976
Past medical history (PMH):
ask about(1,3)
o previous preeclampsia, especially if severe or before 32 weeks gestation
o antiphospholipid antibody syndrome
o pre-existing hypertension
o pre-existing renal disease
o pre-existing diabetes mellitus
o obesity (body mass index ≥ 35 kg/m2)
o heritable thrombophilias
o increased prepregnancy triglyceride levels
o interpregnancy interval (increased risk if ≥ 10 years or < 2 years)
Family history (FH):
ask about family history of(3)
o preeclampsia
o early-onset cardiovascular disease
mother, aunt or paternal grandmother with preeclampsia associated with increased risk of
preeclampsia in population-based study of linked generational data from Norway with
438,597 mother-offspring pairs and 286,945 father-offspring pairs (BMJ 2005 Oct
15;331(7521):877 full-text)
Social history (SH):
ask about cocaine and methamphetamine use(3)
work outside the home associated with increases in blood pressure among hypertensive
pregnant patients (Obstet Gynecol 2001 Mar;97(3):361), commentary can be found in
Am Fam Physician 2001 Oct 15;64(8):1444
Physical:
General physical:
blood pressure highest at night (reversal of normal circadian rhythm)(2)
generalized edema (including face and hands) often present with preeclampsia(1)
Skin:
jaundice may be a late finding, indicating disseminated intravascular coagulation (DIC)
or another diagnosis(3)
HEENT:
choroidal ischemia seen on ophthalmoscopy in patient with pregnancy-induced
hypertension (picture in N Engl J Med 2001 Mar 8;344(10):739)
Neuro:
hyperreflexia may be present(1)
occurrence of neurologic exam findings (in descending order) among 40 women with
eclampsia in prospective cohort study
o memory deficits
o increased deep tendon reflexes (some asymmetric)
o visual perception deficits
o visual information processing deficits
o altered mental status
o cranial nerve deficits
o Reference - J Neurol Sci 2008 Aug 15;271(1-2):158
Diagnosis
Making the diagnosis:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for classification of hypertensive disorders of pregnancy(3)
o hypertension in pregnancy defined as diastolic blood pressure ≥ 90 mm Hg, based
on average of at least 2 measurements using same arm (SOGC Grade II-2B)
o severe hypertension defined as systolic blood pressure ≥ 160 mm Hg or diastolic
blood pressure ≥ 110 mm Hg (SOGC Grade II-2B)
o for diagnosis of clinically significant proteinuria
strongly suspect proteinuria when urinary dipstick proteinuria ≥ 2+
(SOGC Grade II-2A)
proteinuria defined as ≥ 0.3 g/day in 24-hour urine collection or ≥ 30
mg/mmol urinary creatinine in spot (random) urine sample (SOGC Grade
II-2B)
insufficient evidence for recommendations on accuracy of urinary
albumin:creatinine ratio (SOGC Grade II-2I)
o definitions of preeclampsia
in women with pre-existing hypertension - resistant hypertension, new or
worsening proteinuria, or ≥ 1 of other adverse conditions (SOGC Grade II-
2B)
in women with gestational hypertension - new-onset proteinuria or ≥ 1 of
other adverse conditions (SOGC Grade II-2B)
o severe preeclampsia defined as preeclampsia with onset before 34 weeks gestation,
with heavy proteinuria or with ≥ 1 adverse conditions (Grade II-2B)
o adverse conditions include
maternal symptoms of hypertension such as headache, visual changes,
abdominal pain
maternal signs of end-organ dysfunction
abnormal maternal laboratory testing
elevated aspartate aminotransferase (AST), alanine aminotransferase
(ALT), lactate dehydrogenase (LDH) with symptoms
platelet count < 100 × 109/L
albumin < 20 g/L
fetal morbidity
definitions used in American guidelines(1,2,4-6)
o chronic hypertension defined as systolic blood pressure ≥ 140 mm Hg or diastolic
blood pressure ≥ 90 mm Hg on > 2 occasions before 20 weeks gestation or
beyond 12 weeks postpartum
mild - 140-150 mm Hg systolic or 90-109 mm Hg diastolic
severe - ≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic
o gestational hypertension
replaces term of pregnancy-induced hypertension
hypertension without proteinuria developing after 20 weeks gestation
temporary diagnosis - either progresses to preeclampsia or chronic
hypertension, or resolves and becomes transient hypertension
o transient hypertension - gestational hypertension with normal blood pressure by
12 weeks postpartum
o preeclampsia
hypertension (blood pressure ≥ 140/90 mm Hg) and proteinuria (> 300
mg/24 hours) after 20 weeks gestation
severe preeclampsia is preeclampsia with any of
blood pressure ≥ 160 mm Hg (systolic) or 110 mm Hg (diastolic)
on 2 occasions at least 6 hours apart during bed rest
proteinuria ≥ 5 g/24 hours or ≥ 3+ on 2 random urine specimens at
least 4 hours apart
cerebral or visual disturbances
epigastric or right upper quadrant pain
fetal growth restriction
impaired liver function
oliguria < 500 mL/24 hours
pulmonary edema
thrombocytopenia
cyanosis
o preeclampsia superimposed on chronic hypertension
in woman with hypertension before 20 weeks gestation - new onset
proteinuria
in woman with hypertension and proteinuria before 20 weeks gestation -
any of
sudden 2- to 3-fold increase in proteinuria
sudden increase in blood pressure
thrombocytopenia
elevated aspartate aminotransferase (AST) or alanine
aminotransferase (ALT)
Rule out:
for preeclampsia
o acute fatty liver of pregnancy
o thrombotic thrombocytopenic purpura (TTP)/hemolytic-uremic syndrome (HUS)
o systemic lupus erythematosus (SLE) exacerbation
o gestational thrombocytopenia and autoimmune thrombocytopenia
o intracerebral hemorrhage
o migraine
o hepatitis
o cholestasis
o pancreatitis
o cocaine intoxication
case series with 11 women in third trimester presenting with preeclampsia-
like symptoms (Obstet Gynecol 1993 Apr;81(4):545)
case report of cocaine intoxication mimicking preeclampsia postpartum
(Int J Gynaecol Obstet 2006 Jan;92(1):73)
for eclampsia, rule out other causes of seizure
o stroke
o hypertensive encephalopathy
o pheochromocytoma
o other lesions of central nervous system (for example, brain tumor, brain abscess)
o metabolic disorders (for example, hypoglycemia, uremia, syndrome of
inappropriate antidiuretic hormone secretion (SIADH) resulting in water
intoxication)
o infection (for example, meningitis, encephalitis)
o thrombotic thrombocytopenic purpura (TTP)
o thrombophilia
o idiopathic epilepsy
o illicit drug use
o cerebral vasculitis
o reversible posterior leukoencephalopathy syndrome (RPLS)
mimics of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
o acute fatty liver of pregnancy
o thrombotic thrombocytopenic purpura (TTP)
o hemolytic-uremic syndrome (HUS)
o acute exacerbation of systemic lupus erythematosus (SLE)
o Reference - Obstet Gynecol 2007 Apr;109(4):956
Testing overview:
Maternal testing:
measure blood pressure
American College of Obstetricians and Gynecologists (ACOG) recommendations o in women with chronic hypertension
(6)
pre-conception or early pregnancy evaluation of possible end-organ
involvement (ACOG Level C)
specific testing may include renal function evaluation,
electrocardiography, echocardiography, and ophthalmologic
evaluation
choice of tests depends on severity of chronic hypertension
evaluation for secondary cause in young women with chronic
hypertension diagnosis early in pregnancy, especially if hypertension
severe, including
pheochromocytoma
primary aldosteronism
Cushing disease
sleep apnea
methamphetamine or cocaine use
renal artery stenosis
o initial testing in preeclampsia (perform weekly in mild preeclampsia, more often
if disease progression suspected)(5)
renal function
liver enzymes
platelet count
12-24 hour urine collection for protein
o consider invasive hemodynamic monitoring in preeclamptic women with severe
cardiac disease, renal disease, refractory hypertension, pulmonary edema or
unexplained oliguria (ACOG Level B)(5)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o for blood pressure monitoring
blood pressure should be measured with woman in sitting position with
arm at level of heart (SOGC Grade II-2A)
appropriately sized cuff (length 1.5 times circumference of arm) should be
used (SOGC Grade II-2A)
Korotkoff phase V should be used to designate diastolic blood pressure
(SOGC Grade III-B)
arm with higher blood pressure (if consistent difference) should be used
(SOGC Grade III-B)
women with systolic blood pressure ≥ 140 mm Hg should be followed
closely for development of diastolic hypertension (SOGC Grade II-2B)
o for measurement of proteinuria
urinary dipstick testing may be used for screening if low suspicion of
preeclampsia (SOGC Grade II-2B)
use more definitive proteinuria testing if suspicion of preeclampsia
(SOGC Grade II-2A)
urinary protein:creatinine ratio
24-hour urine collection
o for women with pre-existing hypertension
measure serum creatinine, serum potassium, and urinalysis in early
pregnancy if not previously documented (SOGC Grade II-2B)
consider additional baseline laboratory testing based on other
considerations deemed important by healthcare providers (SOGC Grade
III-C)
o for women with suspected preeclampsia (SOGC Grade II-2B)
hemoglobin (higher in women with preeclampsia unless microangiopathic
hemolytic anemia)
white blood cell (WBC) count and differential (higher in preeclampsia)
platelet count (lower in preeclampsia)
blood film (shows microangiopathy with red blood cell fragments in
preeclampsia)
serum creatinine (higher in preeclampsia)
serum uric acid (higher in preeclampsia)
glucose
aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
(higher in preeclampsia)
lactate dehydrogenase (LDH) (higher in preeclampsia)
albumin (lower in preeclampsia)
bilirubin (higher in preeclampsia)
urinalysis (routine and microscopy)
proteinuria (assessed by urinary dipstick, spot or 24-hour) (higher in
preeclampsia)
coagulation tests if presence of thrombocytopenia or placental abruption
INR and activated partial thromboplastin time (aPTT)
fibrinogen (lower in preeclampsia)
o repeat initial testing if ongoing concern about preeclampsia (for example, change
in maternal or fetal condition) (SOGC Grade III-C)
o in hypertensive pregnant women, uterine artery Doppler velocimetry may support
placental origin for hypertension, proteinuria or adverse conditions (SOGC Grade
II-2B)
Fetal monitoring:
American College of Obstetricians and Gynecologists (ACOG) recommendations for
fetal testing in women with chronic hypertension(6)
o ultrasound to evaluate fetal growth (ACOG Level C)
o if suspected growth restriction, monitor fetal status by
nonstress testing or biophysical profile testing twice weekly
umbilical vessel Doppler velocimetry
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for fetal testing in women with suspected preeclampsia (SOGC Grade II-IB)(3)
o fetal movement count (lower in preeclampsia)
o nonstress test (nonreassuring fetal heart rate in preeclampsia)
o biophysical profile (lower score in preeclampsia)
o deepest amniotic fluid pocket (lower in preeclampsia)
o ultrasound for fetal growth (usually asymmetrical intrauterine growth in
preeclampsia)
o umbilical artery Doppler (increased resistance, absent or reversed end-diastolic
flow in preeclampsia)
o umbilical artery Doppler velocimetry may support placental origin for intrauterine
fetal growth restriction (SOGC Grade II-2B)
fetal monitoring during expectant management of mild preeclampsia(1)
o nonstress test twice weekly
o amniotic fluid index once or twice weekly
o biophysical profile may be done weekly as substitute for 1 twice weekly nonstress
test and amniotic fluid index
o ultrasound for fetal growth every 3-4 weeks
fetal monitoring in severe preeclampsia(1)
o continuous fetal heart rate monitoring
o nonstress test on admission
o ultrasound for estimated fetal weight
o amniotic fluid volume
o umbilical artery Doppler measurements
Blood tests:
hematocrit may be very low or very high in severe preeclampsia(5)
o may be very low due to hemolysis
o may be very high secondary to hemoconcentration in absence of hemolysis
uric acid not useful in predicting complications of preeclampsia o based on systematic review of 18 studies with 3,913 women with preeclampsia
o Reference - BJOG 2006 Apr;113(4):369
transient hypothyroxinemia with spontaneous normalization of thyroid hormone levels
reported in 26 of 80 (33%) women with preeclampsia, gestational hypertension, or
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (Obstet Gynecol
2005 Nov;106(5):973)
ratio of serum soluble fms-like tyrosine kinase to placental growth factor (sFlt-
1/PIGF) appears specific for preeclampsia (level 2 [mid-level] evidence) o based on case-control study
o 71 patients with preeclampsia and 280 gestational age-matched controls had 595
serum samples measured for soluble fms-like tyrosine kinase (sFlt-1) and
placental growth factor (PIGF) using automated immunoassay platform
o preeclampsia detection for sFlt-1/PIGF cutoff ≥ 85
sensitivity 82%
specificity 95%
o Reference - Am J Obstet Gynecol 2010 Feb;202(2):161e1
Urine studies:
spot urine protein/creatinine ratio
o spot protein/creatinine ratio may be effective for ruling out proteinuria in
hypertensive pregnant women but optimal cut-off point unclear based on systematic review of observational studies
systematic review of 15 observational studies comparing spot urinalysis
(13 evaluated urine protein/creatinine ratio and 2 evaluated
albumin/creatinine ratio) vs. 24 hour urinalysis in women with suspected
or confirmed hypertensive pregnancy
laboratory assays not well described
prevalence of significant proteinuria (≥ 0.3 g/day) ranged from 21% to 83%
in 11 studies
in analysis of spot protein/creatinine ratio
8 different cut-off points reported in 9 studies with ranging from
17 mg/mmol (0.15 mg/mg) to 57 mg/mmol (0.5 mg/mg)
pooled values of spot protein/creatinine ratio 30 mg/mmol in 9
studies with 1,003 women
sensitivity 83.6% (95% CI 77.5%-89.7%)
specificity 76.3% (95% CI 72.6%-80%)
positive likelihood ratio 3.53 (95% CI 2.83-4.49)
negative likelihood ratio 0.21 (95% CI 0.13-0.31)
insufficient data for pooled analysis in 2 studies evaluating
albumin/creatinine ratio in 225 women
optimal cut-off point for proteinuria of ≥ 0.3 g/day was 2 mg/mmol
optimal cut-off point for albuminuria was 27 mg/mmol
Reference - BMJ 2008 May 3;336(7651):1003 full-text, editorial can be
found in BMJ 2008 May 3;336(7651):968, commentary can be found in
ACP J Club 2008 Oct;149(4):14
o random urine protein/creatinine ratio < 130-150 mg/g or > 600 mg/g in
pregnant patients with suspected preeclampsia may eliminate need for 24-
hour urine collection based on systematic review with heterogeneity
systematic review of 7 studies evaluating different cut-off points of urine
protein/creatinine ratio (from 130 mg/g to 700 mg/g) for predicting protein
≥ 300 mg in 24-hour urine collection in 1,717 women (primarily inpatients)
with suspected preeclampsia
mean gestational age 32-36 weeks
mean prevalence of preeclampsia by 24-hour urine 38%
for protein/creatinine ratio < 130-150 mg/g (meta-analysis not possible
due to heterogeneity)
sensitivity 90%-99%
specificity 32.7%-65%
positive predictive value 40.7%-81.7%
negative predictive value 58.8%-98.1%
for protein/creatinine ratio 600-700 mg/g in 1 study with 105 patients
sensitivity 85%-87%
specificity 96%-97%
positive predictive value 95%-96.1%
negative predictive value 88.1%-89.4%
Reference - Obstet Gynecol 2008 Jul;112(1):135
o urinary protein/creatinine ratio significantly correlated with 24-hour
proteinuria in hospitalized pregnant women with hypertensive disorders of
pregnancy based on study with inception and validation cohorts
927 hospitalized pregnant women at ≥ 20 weeks gestational age with
hypertensive disorders had protein/creatinine ratios in random urine
samples and protein contents of 24-hour urine samples measured
protein excretion ≥ 300 mg/24 hours in 282 (30.4%) patients
urine protein/creatinine ratio and 24-hour protein excretion significantly
correlated (p < 0.001)
protein/creatinine ratio ≥ 0.3 was indicator of protein excretion ≥ 300
mg/24 hours
sensitivity 98.2%
specificity 98.8%
similar results in validation cohort of 161 pregnant women
Reference - Clin Chem 2007 Sep;53(9):1623 PDF, commentary can be
found in Evid Based Med 2008 Jun;13(3):84
o review of clinical significance of proteinuria in pregnancy can be found in Obstet
Gynecol Surv 2007 Feb;62(2):117
degree of proteinuria not associated with accurate prediction of maternal or fetal
complications in preeclampsia o based on systematic review of 16 articles evaluating maternal and fetal
complications in women with preeclampsia in 6,749 women
o proteinuria a poor predictor of maternal complications of eclampsia, placental
abruption and hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome in women with preeclampsia in analysis of 10 studies
o Reference - BMC Med 2009 Mar 24;7(1):10 full-text, commentary can be found
in BMC Med 2009 Mar 24;7:11 full-text
hypocalciuria may occur in preeclampsia
o hypocalciuria (mean 1.5 mmol/24 hours) significantly associated with
preeclampsia in case-control study of 47 women with preeclampsia and 50
controls (Eur J Obstet Gynecol Reprod Biol 2006 Apr 1;125(2):193)
o total (and fractional) urinary calcium excretion significantly lower in women with
preeclampsia (mean 82 mg/24 hours) compared to controls (mean 171 mg/24
hours) in cross-sectional study of 26 women with preeclampsia and 26
normotensive controls (J Steroid Biochem Mol Biol 2007 Mar;103(3-5):803)
Other diagnostic testing:
Blood pressure measurement:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o if blood pressure consistently higher in 1 arm, use that arm for all blood pressure
measurements (SOGC Grade III-B)
o ambulatory blood pressure monitoring may detect isolated (white coat)
hypertension (SOGC Grade II-2B)
o recommendations for diagnosis of hypertension
make diagnosis based on office or in-hospital blood pressure
measurements (SOGC Grade II-2B)
hypertension in pregnancy defined as diastolic blood pressure ≥ 90 mm
Hg, based on mean of ≥ 2 measurements taken on same arm (SOGC Grade
II-2B)
for severe hypertension, take repeat measurement for confirmation in 15
minutes (SOGC Grade III-B)
isolated (white coat) hypertension defined as office diastolic blood
pressure of ≥ 90 mm Hg, but home blood pressure < 135/85 mm Hg
(SOGC Grade III-B)
mean arterial pressure may be better predictor of preeclampsia than systolic and
diastolic blood pressures o based on systematic review
o systematic review and meta-analysis of 34 trials with variable methodology of
blood pressure measurement during first and second trimester of pregnancy used
to predict preeclampsia in 60,599 women
o 3,341 (5.5%) cases of preeclampsia occurred
o second trimester mean arterial pressure ≥ 90 mm Hg had positive likelihood ratio
3.5 (95% CI 2-5) and negative likelihood ratio 0.46 (95% CI 0.16-0.75)
o diastolic blood pressure ≥ 75 mm Hg at 13-20 weeks gestation best predicted
preeclampsia in women at high-risk with positive likelihood ratio 2.8 (95% CI
1.8-3.6) and negative likelihood ratio 0.39 (95% CI 0.18-0.71)
o Reference - BMJ 2008 May 17;336(7653):1117 full-text
no randomized trials identified to evaluate use of ambulatory blood pressure
monitoring in pregnancy o based on Cochrane review
o Reference - systematic review last updated 2001 Aug 17 (Cochrane Library 2002
Issue 2:CD001231)
24-hour blood pressure monitoring may be better than office monitoring for
predicting preeclampsia o based on 2 cohort studies
o cohort of 254 women in third trimester having 24-hour noninvasive blood
pressure monitoring
preeclampsia in
5.8% with normal blood pressure
7.1% with white-coat hypertension
61.7% with hypertension
Reference - JAMA 1999 Oct 20;282(15):1447
o cohort of 241 women with early pregnancy diagnosis of essential hypertension
who had 24-hour ambulatory blood pressure monitoring
prepregnancy diagnosis in 35.6%
white coat hypertension diagnosed in 32% (40% developed benign
gestational hypertension)
proteinuric preeclampsia developed in
8% with white coat hypertension
22% with essential hypertension
Reference - BJOG 2005 May;112(5):601
Treatment
Treatment overview:
hospitalize if severe hypertension or severe preeclampsia (SOGC Grade II-2B),
preeclampsia remote from term, signs of disease progression or compliance difficulties
(including logistic barriers)
delivery
o indicated if
preeclampsia and mature fetus (gestational age ≥ 37 weeks) (SOGC Grade
III-B)
gestational age ≥ 34 weeks and maternal or fetal distress
o consider vaginal delivery unless cesarean section required for usual obstetric
indications (SOGC Grade II-2B)
o cervical ripening should be used if vaginal delivery planned with unfavorable
cervix (SOGC Grade I-A)
o regional analgesia and/or anesthesia for delivery may be appropriate if no
coagulopathy
o labor induction at term may reduce severe hypertension but not other maternal
outcomes in women with gestational hypertension or mild preeclampsia (level 2
[mid-level] evidence)
if mild preeclampsia expectant management includes monitoring of mother and fetus,
such as
o blood pressure twice weekly
o weekly blood tests - complete blood count (CBC), platelet count, liver enzymes,
lactate dehydrogenase (LDH), uric acid, creatinine
o fetal monitoring - nonstress test twice weekly, amniotic fluid index once or twice
weekly
insufficient evidence to evaluate bed rest or restriction of activity for women with
hypertension during pregnancy
o some bed rest in hospital (vs. unrestricted activity at home) may be useful for
women with gestational hypertension without preeclampsia (SOGC Grade I-B)
o strict bed rest NOT recommended for hospitalized women with preeclampsia
(SOGC Grade I-D)
antihypertensive medications
o American College of Obstetricians and Gynecologists (ACOG) recommends
antihypertensive therapy for diastolic blood pressure ≥ 105-110 mm Hg (ACOG
Level C)
o Canadian guidelines recommend target blood pressure 130-155/80-105 mm Hg,
or 130-139/80-89 mm Hg if comorbid conditions (SOGC Grade III-C)
o unclear whether antihypertensive therapy is useful in mild to moderate
hypertension during pregnancy
o medications for chronic or mild to moderate hypertension
methyldopa 0.5-3 g/day in 2 divided doses
labetalol 200-1,200 mg/day in 2-3 divided doses
other beta blockers (except atenolol)
nifedipine 30-120 mg/day of slow-release preparation
hydralazine 50-300 mg/day in 2-4 divided doses
hydrochlorothiazide 25 mg/day
o medications for acute severe hypertension (doses in different guidelines vary)
hydralazine 5-10 mg IV every 20 minutes as needed
labetalol 20 mg IV bolus, then 40 mg in 10 minutes if needed, then 80 mg
every 10 minutes (maximum 220 mg)
nifedipine 10-30 mg orally, repeat in 45 minutes if needed
last resort - sodium nitroprusside 0.5-10 mcg/kg/minute (risk of fetal
cyanide toxicity if used > 4 hours)
magnesium sulfate
o most studied dose is loading dose 14 g (4 g IV plus 5 g intramuscularly in each
buttock) then either 1 g/hour IV infusion or 4 g intramuscularly every 4 hours for
24 hours
o first-line treatment for eclampsia (SOGC Grade I-A, ACOG Level A);
magnesium sulfate reduces recurrence of seizures compared to diazepam or
phenytoin in women with eclampsia (level 1 [likely reliable] evidence)
o recommended if severe preeclampsia (SOGC Grade I-A, ACOG Level A);
magnesium sulfate in women with preeclampsia reduces risk of eclampsia (level 1
[likely reliable] evidence) and appears more effective than phenytoin or
nimodipine (level 2 [mid-level] evidence)
o may be considered if nonsevere preeclampsia (SOGC Grade I-C)
follow-up after delivery to evaluate for and treat hypertension and related conditions
insufficient evidence to recommend
o dietary salt restriction
o plasma volume expansion (minimizing fluid intake recommended)
o low-dose aspirin
Treatment setting:
indications for hospitalization(2,5)
o suspicion of preeclampsia
o severe preeclampsia
o preeclampsia remote from term
o signs of disease progression
o compliance difficulties (including logistic barriers)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for place of care(3)
o provide inpatient care for women with severe hypertension or severe preeclampsia
(SOGC Grade II-2B)
o for women with nonsevere preeclampsia or non-severe (pre-existing or gestational)
hypertension, consider care through hospital day units (SOGC Grade I-B) or
home care (SOGC Grade II-2B)
antenatal day care as alternative to hospitalization
o antenatal day care may reduce risk of inpatient hospital admission but
increase number of outpatient visits (level 2 [mid-level] evidence) based on Cochrane review with limited evidence
systematic review of 3 randomized trials comparing referral to day care vs.
inpatient or routine care in 504 women with complicated pregnancy
largest trial described below
day care associated with
lower risk of hospital admission (risk ratio 0.46, 95% CI 0.34-0.62)
in analysis of 2 trials with 109 women
reduced length of stay for those admitted in 2 trials
lower risk of labor induction (risk ratio 0.43, 95% CI 0.22-0.83) in
1 trial with 54 women
more outpatient hospital visits (mean difference 1.5 visits, 95% CI
0.54-2.46 visits) in 1 trial with 54 women
most women satisfied with care received, but preferred day care
no significant differences between groups in other outcomes
Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD001803
o hospitalization and antenatal day care associated with similar cost and
perinatal outcomes (level 2 [mid-level] evidence) based on randomized trial with inadequate power to detect clinically
relevant differences
395 women with nonproteinuric hypertension, proteinuric hypertension,
and preterm premature rupture of membranes were randomized to
hospitalization vs. antenatal day care
no significant differences in cost, maternal or perinatal outcomes
greater patient satisfaction reported in day care group
Reference - Lancet 2004 Apr 3;363(9415):1104, editorial can be found in
Lancet 2004 Apr 3;363(9415):1089
Delivery:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o for timing of delivery in women with preeclampsia consider immediate delivery for women at ≥ 37 weeks gestation with
preeclampsia (severe or nonsevere) (SOGC Grade III-B)
for women at 34-36 weeks gestation with nonsevere preeclampsia,
insufficient evidence to recommend for or against expectant management
(SOGC Grade III-I)
for women at < 34 weeks gestation, expectant management of
preeclampsia (severe or nonsevere) may be considered in perinatal centers
able to care for very preterm infants (SOGC Grade I-C)
o for mode of delivery in women with hypertensive disorders of pregnancy for women with any hypertensive disorder of pregnancy, consider vaginal
delivery unless cesarean section required for usual obstetric indications
(SOGC Grade II-2B)
cervical ripening should be used if vaginal delivery planned and
unfavorable cervix (SOGC Grade I-A)
o for anesthesia administration during delivery inform anesthesiologist when woman with preeclampsia admitted to
delivery suite (SOGC Grade II-3B)
perform platelet count in all women with hypertensive disorder of
pregnancy admitted to delivery suite (but tests of platelet function NOT
recommended) (SOGC Grade III-C)
regional analgesia and/or anesthesia appropriate for women with platelet
count > 75 × 109/L unless (SOGC Grade III-B)
coagulopathy
falling platelet concentration
co-administration of antiplatelet agent or anticoagulant
regional anesthesia appropriate for
women taking low-dose aspirin in absence of coagulopathy and in
presence of adequate platelet count (SOGC Grade I-A)
women on low-molecular-weight heparin 12 hours after
prophylactic dose or 24 hours after therapeutic dose (SOGC Grade
III-B)
early insertion of epidural catheter recommended for pain control (if no
contraindications) (SOGC Grade I-A)
fixed IV fluid bolus should NOT be given prior to regional analgesia
and/or anesthesia (SOGC Grade I-D)
small doses of phenylephrine or ephedrine may be used to prevent or treat
hypotension during regional anesthesia (SOGC Grade I-A)
in absence of contraindications, acceptable methods of anesthesia for
women having cesarean include (SOGC Grade I-A)
epidural
spinal
combined spinal-epidural
general
indications for delivery(1)
o gestational age ≥ 40 weeks
o gestational age ≥ 37 weeks with
labor
favorable cervix (Bishop score ≥ 6)
worsening maternal or fetal condition
o gestational age ≥ 34 weeks with
labor or rupture of membranes
severe preeclampsia and nonreassuring fetal status
maternal distress in severe preeclampsia
treatment-resistant severe hypertension
thrombocytopenia
imminent eclampsia
pulmonary edema
hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome
o gestational age 24-34 weeks with severe preeclampsia and
persistent severe symptoms
multiorgan dysfunction
severe intrauterine growth restriction (IUGR) (estimated fetal weight <
fifth percentile)
suspected placental abruption
nonreassuring fetal testing
indications for cesarean delivery
o emergent - immediate threat to life of woman or fetus
o other indications
maternal or fetal compromise that is not immediately life-threatening
failure to progress in labor
placenta previa
morbidly adherent placenta
in women with previous cesarean delivery, Doppler ultrasound
may be used for initial diagnosis, magnetic resonance imaging may
help confirm diagnosis
intervention options for women with morbidly adherent placenta
include cross-matching blood and planned cesarean delivery with
consultant obstetrician, anesthesiologist, and pediatrician present,
and senior hematologist on call
breech presentation
multiple pregnancy
cephalopelvic disproportion in labor
mother to child transmission of maternal infections
HIV if mother not receiving antiretroviral therapy or has viral load
≥ 400 copies per mL with any antiretroviral therapy
hepatitis C if mother has co-infection with HIV
primary genital herpes simplex in third trimester
maternal request after discussion about risks and benefits and offer of
support (including perinatal mental health support for women with anxiety
about vaginal delivery)
o Reference - National Institute for Health and Clinical Excellence (NICE)
guideline on cesarean section (NICE 2011 Nov:CG132), summary can be found
in BMJ 2011 Nov 23;343:d7108
labor induction may reduce severe hypertension but not other maternal outcomes in
women with gestational hypertension or mild preeclampsia (level 2 [mid-level]
evidence) o based on randomized trial without blinding and with limited data for clinical
outcomes
o 756 patients with singleton pregnancy at 36-41 weeks gestation with gestational
hypertension or mild preeclampsia randomized to induction of labor vs. expectant
monitoring
o comparing induction of labor vs. expectant monitoring in randomized women
severe hypertension (systolic blood pressure) in 15% vs. 23% (p = 0.003,
NNT 13)
severe hypertension (diastolic blood pressure) in 16% vs. 27% (p < 0.0001,
NNT 10)
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in 1%
vs. 3% (p = 0.07)
intensive maternal hospital care in 2% vs. 4% (p = 0.059)
o no significant difference or insufficient cases to make comparison in
maternal death (0 vs. 0 cases)
severe proteinuria
eclampsia (0 vs. 0 cases)
lung edema
postpartum hemorrhage
thromboembolic disease
placental abruption (0 vs. 0 cases)
neonatal death (0 vs. 0 cases)
composite neonatal morbidity
o Reference - HYPITAT trial (Lancet 2009 Sep 19;374(9694):979), editorial can be
found in Lancet 2009 Sep 19;374(9694):951, commentary can be found in Lancet
2010 Jan 9;375(9709):119
o induction of labor reported to be more cost-effective than expectant management
based on HYPITAT trial (BJOG 2010 Dec;117(13):1577), editorial can be found
in BJOG 2010 Dec;117(13):1575
Medications during delivery:
continue antihypertensive treatment throughout labor and delivery to maintain systolic
blood pressure < 160 mm Hg and diastolic blood pressure < 110 mm Hg (SOGC Grade
II-2B)(3)
use oxytocin 5 units IV or 10 units intramuscularly for active management of third stage
of labor, especially if thrombocytopenia or coagulopathy (SOGC Grade I-A)(3)
ergometrine should not be given in any form (SOGC Grade II-3D)(3)
perioperative prophylactic platelet transfusion for cesarean delivery(3)
o not necessary if platelets > 50 × 109/L
o consider if platelets < 10-20 × 109/L
Fluid and electrolytes:
Plasma volume expansion:
plasma volume expansion NOT recommended for women with preeclampsia (SOGC
Grade I-E)(3)
insufficient evidence for any reliable estimates of effects of plasma volume
expansion o based on Cochrane review
o systematic review of 3 randomized trials evaluating plasma volume expansion in
61 women with hypertension during pregnancy (with or without proteinuria)
o all trials compared colloid solution vs. no plasma volume expansion but wide
confidence intervals result in no significant differences
o 14 citations awaiting classification may alter conclusions of Cochrane review
once assessed
o Reference - systematic review last updated 1999 Jul 12 (Cochrane Library 1999
Issue 4:CD001805)
Additional considerations:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o minimize IV and oral fluid intake in women with preeclampsia (SOGC Grade II-
1B)
o fluid administration should NOT be routinely administered for oliguria (< 15
mL/hour) (SOGC Grade III-D)
o dopamine or furosemide NOT recommended for persistent oliguria (SOGC Grade
I-D)
o central venous access NOT routinely recommended (if inserted, should be used to
monitor trends, not absolute values) (SOGC Grade II-2D)
o pulmonary artery catheterization NOT recommended unless specific associated
indication (SOGC Grade III-D), and only in high-dependency unit setting (SOGC
Grade III-B)
Diet:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for diet changes in hypertensive disorders of pregnancy(3)
o new dietary salt restriction NOT recommended (SOGC Grade II-2D)
o insufficient evidence for recommendations on usefulness of
ongoing salt restriction in women with pre-existing hypertension (SOGC
Grade III-I)
heart-healthy diet (SOGC Grade III-I)
calorie restriction for obese women (SOGC Grade III-I)
insufficient evidence to recommend increasing or decreasing salt intake during
pregnancy o based on Cochrane review
o systematic review of 2 randomized trials of reduced dietary salt intake during
pregnancy with 603 women, no significant differences but confidence intervals
were wide
o no trials of increased dietary salt intake found
o Reference - systematic review last updated 2005 Jun 23 (Cochrane Library 2005
Issue 4:CD005548)
Activity:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for lifestyle changes in hypertensive disorders of pregnancy(3)
o insufficient evidence for recommendations about exercise, workload reduction or
stress reduction (SOGC Grade III-I)
o bed rest
some bed rest in hospital (vs. unrestricted activity at home) may be useful
for women with gestational hypertension without preeclampsia (SOGC
Grade I-B)
strict bed rest NOT recommended for hospitalized women with
preeclampsia (SOGC Grade I-D)
insufficient evidence for bed rest for all other women with hypertensive
disorders of pregnancy (SOGC Grade III-C)
consider thromboprophylaxis for women prescribed bed rest (SOGC
Grade II-2C)
insufficient evidence to evaluate bed rest or restriction of activity for women with
hypertension during pregnancy o based on Cochrane review
o systematic review of 4 randomized trials evaluating bed rest for 449 women with
hypertension in pregnancy
o 2 trials (145 women) compared strict bed rest with some rest in hospital for
women with proteinuric hypertension; insufficient evidence to demonstrate any
differences between groups for reported outcomes
o 2 trials (304 women) compared some bed rest in hospital with routine activity at
home for nonproteinuric hypertension
1 trial with 218 women reported reduced risk of severe hypertension
(relative risk [RR] 0.58, 95% CI 0.38-0.89) and borderline reduction in
risk of preterm birth (RR 0.53, CI 0.29-0.99) with some rest
1 trial with 86 women reported more women in bed rest group opted not to
have similar management in future pregnancies if choice were given (RR
3, 95% CI 1.43-6.31)
no significant differences for any other outcomes
o Reference - Cochrane Database Syst Rev 2010 Feb 17;(2):CD003514
Medications:
Antihypertensive therapy:
Target blood pressure:
American College of Obstetricians and Gynecologists (ACOG) recommends
antihypertensive therapy for diastolic blood pressure ≥ 105-110 mm Hg (ACOG Level
C)(5)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o if nonsevere hypertension (blood pressure 140-159/90-109 mm Hg)
for women without comorbid conditions - antihypertensive drugs
recommended to maintain blood pressure 130-155 mm Hg systolic and 80-
105 mm Hg diastolic (SOGC Grade III-C)
for women with comorbid conditions - antihypertensive drugs
recommended to maintain blood pressure 130-139 mm Hg systolic and 80-
89 mm Hg diastolic (SOGC Grade III-C)
o if severe hypertension (blood pressure > 160 mm Hg systolic or ≥ 110 mm Hg
diastolic) - blood pressure should be lowered to < 160 mm Hg systolic and < 110
mm Hg diastolic (SOGC Grade II-2B)
insufficient evidence to determine target blood pressure in pregnant women with
mild-to-moderate hypertension o based on Cochrane review
o systematic review of randomized trials comparing tight to very tight control of
mild-to-moderate pre-existing or nonproteinuric gestational hypertension
2 pilot trials with 256 pregnant women met inclusion criteria
mild-to-moderate hypertension defined as systolic blood pressure 140-169
mm Hg or diastolic pressure 90-109 mm Hg
tight control defined as blood pressure < 140/90 mm Hg and very tight
control defined as blood pressure < 130/80 mm Hg
o only 3 perinatal deaths occurred and no cases of eclampsia, stroke, or maternal
deaths reported
o comparing tight vs. very tight control
no significant differences in
incidence of severe preeclampsia in analysis of both trials
cesarean delivery in analysis of both trials
labor induction in 1 trial with 125 patients
intrauterine growth retardation in analysis of both trials
admission to neonatal intensive care unit in analysis of both trials
wide confidence intervals cannot rule out possibility of clinically relevant
differences between groups
hospitalization during pregnancy in 29% of tight group vs. 11% of very
tight group (p < 0.05, NNT 6 favoring very tight control) in 1 trial with
125 patients
o Reference - Cochrane Database Syst Rev 2011 Jul 6;(7):CD006907
Efficacy of antihypertensive therapy in mild to moderate hypertension:
unclear whether antihypertensive therapy is useful in mild to moderate
hypertension during pregnancy o based on Cochrane review
o systematic review of 46 randomized trials of any antihypertensive drugs in 4,282
patients with mild to moderate hypertension during pregnancy
o where possible women with severe hypertension (systolic blood pressure ≥ 170
mm Hg or diastolic blood pressure ≥ 110 mm Hg) were excluded
o comparing any antihypertensive drug vs. none
9.3% vs. 19.5% severe hypertension (p < 0.00001, NNT = 10) in 19 trials
with 2,409 women
14.7% vs. 8.4% maternal side effects (p = 0.01, NNH 15) in 11 trials with
934 women, but meta-analysis limited by heterogeneity (p = 0.01)
64.8% vs. 71.6% elective delivery (induction of labor and elective
cesarean delivery) (p = 0.05, NNT 15) in 5 trials with 710 women
1.5% vs. 5.8% respiratory distress syndrome (p = 0.002, NNT 24) in 5
trials with 825 women
o no significant differences (but wide confidence intervals do not exclude clinically
relevant differences) in
proteinuria/preeclampsia
severe preeclampsia
eclampsia
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
neonatal mortality
maternal mortality
preterm birth
small for gestational age infants
o Reference - systematic review last updated 2006 Nov 14 (Cochrane Library 2007
Issue 1:CD002252), commentary can be found in ACP J Club 2007 Jul-
Aug;147(1):9
oral beta blockers effective at reducing blood pressure for women with mild to
moderate hypertension (blood pressure < 170/110 mm Hg) during pregnancy but no
clear evidence of effect on clinical outcomes o based on Cochrane review
o systematic review of 29 controlled trials evaluating beta blockers in about 2,500
women with mild to moderate hypertension during pregnancy
o 13 trials with 1,480 women comparing beta blockers to placebo or no treatment
found reduced risk of severe hypertension and need for additional
antihypertensive agents, but insufficient data regarding perinatal mortality or
preterm delivery, possible decreases in maternal hospital admission and
respiratory distress syndrome, and possible increase in small for gestational age
babies and neonatal bradycardia
o 13 trials with 854 women comparing beta blockers to methyldopa found no
significant differences in outcomes
o authors note that there is insufficient evidence regarding the effect of
antihypertensive therapy in general on clinical outcomes in this patient population
o Reference - systematic review last updated 2003 Mar 6 (Cochrane Library 2003
Issue 3:CD002863)
Antihypertensive drug selection:
American College of Obstetricians and Gynecologist (ACOG) recommendations o for treatment of chronic hypertension in pregnancy
(6)
women with severe hypertension require antihypertensive medications for
acute blood pressure elevation (ACOG Level B)
labetalol is good first-line option (ACOG Level B)
oral dose 200-2,400 mg/day in 2-3 divided doses
IV dose for urgent control of severe acute hypertension with either
of
20 mg IV bolus, then 20-80 mg every 5-15 minutes up to
maximum 300 mg
constant infusion 1-2 mg/minute
thiazide diuretics do not need to be discontinued if started before
pregnancy (ACOG Level B)
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers contraindicated in pregnancy (ACOG Level A)
atenolol not recommended for treatment of chronic hypertension in
pregnancy due to association with growth restriction (ACOG Level B)
o for treatment of preeclampsia and eclampsia (ACOG Level C)(5)
hydralazine or labetalol for diastolic blood pressure ≥ 105-110 mm Hg
hydralazine 5-10 mg IV every 15-20 minutes until desired response
labetalol 20 mg IV bolus, followed by
40 mg if not effective within 10 minutes, then 80 mg every 10
minutes
maximum total dose 220 mg
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o for nonsevere hypertension (blood pressure 140-159/90-109 mm Hg)
initial treatment options include
methyldopa (SOGC Grade I-A)
labetalol (SOGC Grade I-A)
other beta blockers (for example, acebutolol, metoprolol, pindolol,
propranolol) (SOGC Grade I-B)
calcium channel blockers (for example, nifedipine) (SOGC Grade
I-A)
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers should NOT be used (SOGC Grade II-2E)
atenolol and prazosin NOT recommended (SOGC Grade I-D)
o for severe hypertension (blood pressure > 160 mm Hg systolic or ≥ 110 mm Hg
diastolic)
initial treatment options include
labetalol (SOGC Grade I-A)
nifedipine capsules (SOGC Grade I-A)
nifedipine extended-release (PA) tablets (SOGC Grade I-B)
hydralazine (SOGC Grade I-A)
continuous fetal heart rate monitoring recommended until blood pressure
stable (SOGC Grade III-I)
magnesium sulfate NOT recommended as antihypertensive agent (SOGC
Grade II-2D)
nifedipine and magnesium sulfate can be used simultaneously (SOGC
Grade II-2B)
American Society of Hypertension (ASH) recommendations(2)
o for chronic hypertension in pregnancy
methyldopa 0.5-3 g/day in 2 divided doses (Pregnancy Category B)
labetalol 200-1,200 mg/day in 2-3 divided doses (Pregnancy Category C)
nifedipine 30-120 mg/day of slow-release preparation (Pregnancy
Category C)
hydralazine 50-300 mg/day in 2-4 divided doses (Pregnancy Category C)
hydrochlorothiazide 25 mg/day (Pregnancy Category C)
beta blockers - dose depends on specific agent (Pregnancy Category C)
contraindicated medications include ACE inhibitors and angiotensin
receptor antagonists (ARBs) (Pregnancy Category D)
o for urgent control of severe hypertension in pregnancy
hydralazine (1 of 2 options)
initial dose 5 mg IV or intramuscularly, followed by 5-10 mg every
20-40 minutes
continuous infusion 0.5-10 mg/hour
labetalol (1 of 2 options)
initial dose 20 mg IV, followed by 20-80 mg every 20-30 minutes
(maximum 300 mg)
continuous infusion 1-2 mg/minute
nifedipine
10-30 mg orally, repeat in 45 minutes if needed
tablets recommended only
might interfere with labor
relatively contraindicated - sodium nitroprusside
agent of last resort
continuous infusion 0.5-10 mcg/kg/minute
associated with risk of cyanide toxicity
Seventh Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure (JNC 7) recommendations(4)
o for chronic hypertension in pregnancy
methyldopa preferred based on long-term studies supporting safety
labetalol increasingly preferred to methyldopa due to reduced side effects
beta blockers generally safe, but reports of intrauterine growth retardation
with atenolol
diuretics probably safe, but not first-line agents
clonidine has limited data
calcium channel blockers have limited data, but no increase in major
teratogenicity
contraindicated medications include ACE inhibitors and ARBs
o for treatment of acute severe hypertension in preeclampsia
hydralazine 5 mg IV bolus, then 10 mg every 20-30 minutes to maximum
25 mg, repeat in several hours as needed
labetalol (second-line) 20 mg IV bolus, then 40 mg 10 minutes later, then
80 mg every 10 minutes for 2 additional doses to maximum 220 mg
nifedipine (controversial)
10 mg orally, repeat every 20 minutes to maximum 30 mg
caution if used with magnesium sulfate due to risk for precipitous
blood pressure decreases
short-acting nifedipine not FDA approved for hypertension
for rare use when other treatments fail - sodium nitroprusside
0.25-5 mcg/kg/minute
fetal cyanide toxicity may occur if used > 4 hours
insufficient evidence to favor any specific drug for severe hypertension during
pregnancy o based on Cochrane review
o systematic review of 24 randomized trials comparing antihypertensive drugs (12
comparisons) in 2,949 women with severe hypertension during pregnancy
o compared to hydralazine
calcium channel blockers associated with lower risk of persistent high
blood pressure (6% vs. 18%, NNT 8.3) in 5 trials with 263 women
ketanserin associated with higher risk of persistent high blood pressure (27%
vs. 6%, NNH 4.7) in 4 trials with 200 women but
ketanserin associated with fewer side effects (3 trials with 120 women,
relative risk [RR] 0.32, 95% CI 0.19-0.53)
ketanserin associated with lower risk of hemolysis, elevated liver enzymes,
low platelets (HELLP) syndrome (1 trial with 44 women, RR 0.43, 95%
CI 0.18-1.02)
o labetalol, compared with diazoxide, associated with higher risk of hypotension (1
trial with 90 women, RR 0.06, 95% CI 0-0.99) and cesarean section (RR 0.43, 95%
CI 0.18-1.02)
o nimodipine compared with magnesium sulfate
higher risk of persistent high blood pressure (65% vs. 47%, NNH 5.5) in 2
trials with 1,683 women
higher risk of eclampsia (RR 2.24, 95% CI 1.06-4.73) and respiratory
difficulties (RR 0.28, 95% CI 0.08-0.99)
lower rate of side effects (RR 0.68, 95% CI 0.54-0.86) and postpartum
hemorrhage (RR 0.41, 95% CI 0.18-0.92)
o choice of antihypertensive agent should depend on the clinician’s experience and
familiarity with a particular drug and its adverse effects
o drugs NOT recommended include diazoxide, ketanserin, nimodipine and
magnesium sulfate
o Reference - systematic review last updated 2006 Mar 31 (Cochrane Library 2006
Issue 3:CD001449), commentary to earlier version can be found in ACP J Club
2003 Jul-Aug;139(1):4
hydralazine does not appear superior to nifedipine or labetalol for treatment of
severe hypertension in pregnancy (grade B recommendation [inconsistent or limited
evidence]) o based on systematic review
o systematic review and meta-analysis of 21 randomized trials of short-acting
antihypertensives for 893 women with severe hypertension in pregnancy, 8
compared hydralazine vs. nifedipine, 5 compared hydralazine vs. labetalol
o hydralazine was associated with
trend towards less persistent severe hypertension compared to labetalol (2
trials)
more severe hypertension than nifedipine or isradipine (4 trials), results
limited by heterogeneity and differences in methodologic quality
o hydralazine associated with increased rates of maternal hypotension (13 trials),
cesarean sections (14 trials), placental abruption (5 trials), maternal oliguria (3
trials), adverse effects on fetal heart rate (12 trials), and low 1-minute Apgar
scores (3 trials)
o hydralazine associated with more maternal side effects (12 trials) but less neonatal
bradycardia (3 trials) than labetalol
o Reference - BMJ 2003 Oct 25;327(7421):955 full-text
Magnesium sulfate:
recommendations
o Society of Obstetricians and Gynaecologists of Canada (SOGC)
recommendations(3)
magnesium sulfate recommended for first-line treatment of eclampsia
(SOGC Grade I-A)
magnesium sulfate recommended for preventing eclampsia in women with
severe preeclampsia (SOGC Grade I-A)
magnesium sulfate may be considered for women with nonsevere
preeclampsia (SOGC Grade I-C)
dosing
magnesium sulfate 4 g IV bolus, followed by 1 g/hour infusion
treat recurrent seizure with additional 2-4 g IV bolus
phenytoin and benzodiazepines should NOT be used for eclampsia
prophylaxis or treatment unless magnesium sulfate contraindicated or
ineffective (SOGC Grade I-E)
o American College of Obstetricians and Gynecologists (ACOG)
recommendations(5)
use magnesium sulfate for prevention and treatment of seizures in women
with severe preeclampsia or eclampsia (ACOG Level A)
sample protocol is 4-6 g loading dose in 100 mL fluid IV given over 15-20
minutes, then 2 g/hour continuous infusion
magnesium sulfate dosing
o loading dose 14 g given as
4 g IV
10 g intramuscularly (5 g in each buttock)
o followed by 24 hours of either
1 g/hour IV infusion
4 g intramuscularly every 4 hours
o DynaMed commentary -- avoid use of MgSO4 abbreviation which may be
confused with morphine sulfate (MSO4)
dosing variations
o insufficient evidence to evaluate different magnesium sulfate treatment
regimens for prevention and treatment of eclampsia based on Cochrane review
systematic review of 6 randomized trials comparing different regimens for
administration of magnesium sulfate in 866 women with preeclampsia or
eclampsia
most trials too small to draw reliable conclusions
1 treatment trial comparing loading dose alone vs. loading dose plus
maintenance therapy for 24 hours in 401 women with preeclampsia
reported no significant difference in risk of recurrence of convulsions or
stillbirth, but confidence intervals were wide
Reference - Cochrane Database Syst Rev 2010 Aug 4;(8):CD007388
o limiting magnesium sulfate to 12 hours postpartum may be safe in women
with mild preeclampsia (level 2 [mid-level] evidence) based on randomized trial with inadequate power to detect small
differences
200 women with mild preeclampsia randomized to magnesium sulfate for
12 vs. 24 hours of postpartum therapy
extension of magnesium sulfate for severe preeclampsia occurred in 6.9%
12 hour vs. 1.1% 24 hour group (p = 0.07)
no cases of seizures, magnesium sulfate toxicity or intolerance
Reference - Obstet Gynecol 2006 Oct;108(4):833, editorial can be found
in Obstet Gynecol 2006 Oct;108(4):824
o magnesium sulfate 14 g reported to prevent recurrent seizure in patients
with eclampsia (level 3 [lacking direct] evidence) based on uncontrolled cohort study
121 patients aged 14-38 years with eclampsia in Nigeria were treated with
magnesium sulfate 14 g given as
4 g IV over 14 minutes
10 g intramuscularly (5 g in each buttock)
recurrent seizure in 7.4% within 4 hours of loading dose
maternal mortality 9.9%
stillbirths in 55.4% (most fetal deaths occurred prior to hospital admission)
Reference - BMC Res Notes 2009 Aug 19;2:165 full-text
efficacy
o magnesium sulfate in women with preeclampsia reduces risk of eclampsia
(level 1 [likely reliable] evidence) and appears more effective than phenytoin
or nimodipine (level 2 [mid-level] evidence) based on Cochrane review
magnesium sulfate in women with preeclampsia reduces risk of
eclampsia (level 1 [likely reliable] evidence) based on Cochrane review
systematic review of 15 randomized trials evaluating
anticonvulsants for preeclampsia
6 trials with 11,444 women with preeclampsia compared
magnesium sulfate vs. placebo or no anticonvulsant
magnesium sulfate associated with
reduced risk of eclampsia (relative risk [RR] 0.41,
95% CI 0.29-0.58; NNT 100, 95% CI 50-100)
reduced risk of placental abruption (RR 0.64, 95%
CI 0.5 - 0.83; NNT 100, 95% CI 50-1,000)
increased risk of cesarean section (RR 1.05 95% CI
1-10)
nonsignificant reduction in mortality (RR 0.54, 95%
CI 0.26-1.1)
no significant difference in stillbirth or neonatal death (RR
1.04, 95% CI 0.93-1.15)
magnesium sulfate reduced risk of eclampsia (RR 0.08, 95% CI
0.01-0.6) compared to phenytoin in analysis of 3 trials with 2,291
women; largest trial summarized below
magnesium sulfate reduced risk of eclampsia compared to
nimodipine in 1 trial with 1,650 women (RR 0.33, 95% CI 0.14-
0.77) summarized below
Reference - Cochrane Database Syst Rev 2010 Nov
10;(11):CD000025
magnesium sulfate reduces risk of eclampsia (level 1 [likely reliable]
evidence) based on randomized trial (largest trial in Cochrane review)
10,141 women (in 33 countries) who were pregnant or within 24
hours postpartum and had blood pressure at least 140/90 mm Hg
and proteinuria 1+ (30 mg/dL) or more were randomized to
magnesium sulfate vs. placebo (normal saline under double-blind
conditions with allocation concealment)
magnesium sulfate was given as 4 g IV loading dose over 10-15
minutes then maintenance of either 1 g/hour IV or 5 g
intramuscularly into each buttock (10 g total) every 4 hours for 24
hours
women who received magnesium sulfate loading before trial entry
or needed to continue treatment after 24 hours were included, and
this may introduce bias against efficacy of magnesium sulfate by
introducing magnesium sulfate to placebo group
follow-up data available for 10,110 (99.7%) women and 9,024
(98.6%) babies (babies of women with treatment initiated
postpartum were not evaluated)
comparing magnesium sulfate vs. placebo
eclamptic convulsions in 0.8% vs. 1.9% (NNT 91, 95% CI
62.5-143)
NNT 63 for women with severe preeclampsia (95%
CI 38-181)
NNT 109 for women without severe preeclampsia
(95% CI 72-225)
eclampsia in 2% vs. 6% with multiple pregnancy
(NNT 25)
maternal death in 0.2% vs. 0.4% (study underpowered to
detect statistical significance)
placental abruption in 2% vs. 3.2% (NNT 84)
potential harms comparing magnesium sulfate vs. placebo
no clear differences in maternal morbidity
no clear differences in neonatal mortality (12.7% vs. 12.4%)
or morbidity
16% vs. 12% stopped treatment early (NNH 25)
side effects in 24% vs. 5% (NNH 5), most frequently
flushing which was more common with IV regimen (24%
vs. 2%, NNH 4.5) than intramuscular regimen (16% vs. 2%,
NNH 7)
Reference - Magpie trial (Lancet 2002 Jun 1;359(9321):1877),
editorial can be found in Lancet 2002 Jun 1;359(9321):1872,
commentary can be found in BMJ 2002 Sep 21;325(7365):609,
Lancet 2002 Oct 26;360(9342):1329, BMJ 2003 Jan
4;326(7379):50, Evidence-Based Medicine 2003 Jan-Feb;8(1):9
magnesium more cost-effective in lower-income countries based on subgroup analyses of 9,996 women in Magpie
trial
NNT 324 to prevent 1 case of eclampsia in countries with
high gross national income, incremental cost $21,202
NNT 184 in middle-income countries, incremental cost
$2,473
NNT 43 in low-income countries, incremental cost $456
Reference - BJOG 2006 Feb;113(2):144
magnesium sulfate associated with less eclampsia compared to
phenytoin in women with hypertension (level 2 [mid-level] evidence) based on randomized trial with inadequate allocation concealment
2,138 women with hypertension admitted for labor and delivery
randomized to magnesium sulfate vs. phenytoin continued for 24
hours postpartum
magnesium given as 10 g intramuscular loading dose, then
5 g maintenance dose intramuscularly every four hours;
additional 4 g loading dose IV for women with severe
preeclampsia
phenytoin given as 1,000 mg loading dose infused over 1
hour plus 500 mg orally 10 hours later
eclampsia occurred in 0 with magnesium and 0.92% with
phenytoin (p = 0.004)
cesarean section in 27% vs. 22% (p = 0.047, NNH 20)
no significant differences in other maternal or neonatal outcomes
Reference - N Engl J Med 1995 Jul 27;333(4):201 full-text
magnesium sulfate appears more effective than nimodipine for
preventing seizures in severe preeclampsia (level 2 [mid-level]
evidence) based on randomized trial with unclear allocation concealment
1,650 women with severe preeclampsia were randomized to
magnesium sulfate IV based on institutional protocol vs.
nimodipine 60 mg orally every 4 hours until 24 hours postpartum
hydralazine IV used as needed to control blood pressure
0.8% magnesium sulfate patients vs. 2.6% nimodipine patients had
witnessed tonic-clonic seizure (p = 0.01, NNT 56) with difference
primarily related to increased postpartum seizure rate with
nimodipine (0 vs. 1.1%)
more magnesium sulfate patients required hydralazine for blood
pressure control (54% vs. 46%)
no significant differences in neonatal outcomes
Reference - N Engl J Med 2003 Jan 23;348(4):304, editorial can be
found in N Engl J Med 2003 Jan 23;348(4):275, correction can be
found in N Engl J Med 2003 Apr 24;348(17):1730, commentary
can be found in N Engl J Med 2003 May 22;348(21):2154
o magnesium sulfate reduces recurrence of seizures compared to diazepam or
phenytoin in women with eclampsia (level 1 [likely reliable] evidence) based on Cochrane reviews and large randomized trial
magnesium sulfate reduces maternal mortality and recurrent seizures
more than diazepam for treatment of eclampsia (level 1 [likely reliable]
evidence) based on Cochrane review
systematic review of 7 randomized trials comparing magnesium
sulfate (IV or intramuscular) vs. diazepam in 1,441 women with
clinically diagnosed eclampsia
magnesium sulfate associated with reduced risk of maternal death,
recurrent seizures (NNT 7, 95% CI 6-10), 5-minute Apgar scores <
7, and special baby unit care > 7 days compared to diazepam
Reference - systematic review last updated 2003 Mar 4 (Cochrane
Library 2003 Issue 4:CD000127)
magnesium sulfate reduces recurrent seizures, pneumonia and
intensive care more than phenytoin for treatment of eclampsia (level 1
[likely reliable] evidence) based on Cochrane review
systematic review of 7 randomized trials comparing magnesium
sulfate (IV or intramuscular) vs. phenytoin in 974 women with
clinically diagnosed eclampsia
magnesium sulfate associated with
reduced recurrence of seizures in analysis of 6 trials with
972 women
risk ratio (RR) 0.34 (95% CI 0.24-0. 49)
NNT 7-10 assuming recurrent seizures in 20% of
phenytoin group
trend toward reduced maternal mortality (RR 0.5, 95% CI
0.24-1.05) in analysis of 3 trials with 847 women
reduced pneumonia and admission to intensive care unit in
individual trials
trend toward increased renal failure (RR 1.52, 95% CI
0.98-2.36) in analysis of 3 trials with 902 women
fewer admissions to a special care baby unit in 1 trial with
518 babies
Reference - Cochrane Database Syst Rev 2010 Oct
6;(10):CD000128
magnesium sulfate reduces recurrence of seizures compared to
diazepam or phenytoin in women with eclampsia (level 1 [likely
reliable] evidence) based on randomized trial (largest trial in Cochrane reviews above)
910 women with eclampsia (at 23 centers in 8 countries)
randomized to magnesium sulfate vs. diazepam
777 women with eclampsia (at 4 centers in South Africa and India)
randomized to magnesium sulfate vs. phenytoin
magnesium sulfate dosing
intramuscular regimen - 4 g IV loading dose over 5 minutes
plus 5 g intramuscularly into each buttock, then 5 g
intramuscularly every 4 hours (if respiratory rate > 16
breaths/minute, urine output > 25 mL/hour and knee jerks
present) for 24 hours
IV regimen - 4-5 g IV loading dose, then 1 g/hour infusion
for 24 hours
recurrent seizures occurred in
13.2% with magnesium sulfate vs. 27.9% with diazepam (p
< 0.0001)
5.7% with magnesium sulfate vs. 17.1% with phenytoin (p
< 0.0001)
maternal mortality nonsignificantly lower in magnesium sulfate
groups
Reference - Collaborative Eclampsia Trial (Lancet 1995 Jun
10;345(8963):1455)
o magnesium sulfate may reduce maternal death, serious morbidity and
recurrence of seizures compared to lytic cocktail in women with eclampsia
(level 2 [mid-level] evidence) based on Cochrane review of low-to-moderate quality trials
systematic review of 3 randomized trials comparing magnesium sulfate
(IV or intramuscularly) vs. lytic cocktail in 397 women with clinical
diagnosis of eclampsia
lytic cocktail (usually chlorpromazine, promethazine and pethidine
[meperidine]) was once standard treatment in India but no longer widely
used
magnesium sulfate associated with reduced
maternal mortality in analysis of all trials
risk ratio (RR) 0.14 (95% CI 0.03-0.59)
NNT 15-35 assuming 7% mortality in lytic cocktail group
seizure recurrence in analysis of all trials
RR 0.06 (95% CI 0.03-0.12)
NNT 1-2 assuming 55% seizure recurrence in lytic cocktail
group
respiratory depression (2 trials), coma (1 trial), pneumonia (2 trials)
no significant differences between groups in perinatal mortality in analysis
of 2 trials with 177 infants
Reference - Cochrane Database Syst Rev 2010 Sep 8;(9):CD002960
reviews
o review of magnesium sulfate for treatment of eclampsia can be found in Stroke
2009 Apr;40(4):1169
o review of obstetric magnesium sulfate use can be found in Obstet Gynecol 2009
Sep;114(3):669, editorial can be found in Obstet Gynecol 2009 Sep;114(3):500,
commentary can be found in Obstet Gynecol 2010 Jan;115(1):186
o review of therapeutic uses of magnesium can be found in Am Fam Physician
2009 Jul 15;80(2):157
Corticosteroids:
give antenatal corticosteroid therapy for all women with preeclampsia before 34 weeks
gestation (SOGC Grade I-A)(3)
antenatal corticosteroid therapy may be considered before 34 weeks gestation for women
with gestational hypertension (despite absence of proteinuria or adverse conditions) if
delivery planned within 7 days (SOGC Grade III-I)(3)
Medications with limited role or insufficient evidence:
low-dose aspirin NOT recommended for preeclampsia (SOGC Grade I-E)(3)
phenytoin and benzodiazepines should NOT be used for eclampsia prophylaxis or
treatment unless magnesium sulfate contraindicated or ineffective (SOGC Grade I-E)(3)
insufficient evidence to evaluate low-dose dopamine in women with severe
preeclampsia and oliguria o based on Cochrane review
o systematic review of randomized trials comparing low-dose dopamine (5
mcg/kg/minute or lower) to placebo or no dopamine in women with severe
preeclampsia and acute renal failure
o only 1 trial found, comparing low-dose dopamine vs. placebo in 40 postpartum
women with oliguria
o dopamine increased urinary output over 6 hours but clinical benefit not
established
o Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD003515
postnatal furosemide may decrease need for postnatal antihypertensive therapy in
hospital in women with preeclampsia (level 3 [lacking direct] evidence) o based on Cochrane review of poor quality trials with inadequate power
o systematic review of 8 randomized trials evaluating interventions to prevent or
treat postpartum hypertension
o 3 prevention trials compared furosemide or nifedipine capsules vs. placebo or no
therapy in 313 women with antenatal hypertension
postnatal furosemide associated with trend toward reduced use of
antihypertensive therapy in hospital (risk ratio 0.74, 95% CI 0.55-1) in 1
trial with 264 women
no significant difference in antihypertensive use at hospital discharge in
analysis of 2 furosemide trials with 282 women
o in treatment trials, no significant differences in use of additional antihypertensive
therapy
3 trials compared oral timolol, oral hydralazine, or oral nifedipine vs. oral
methyldopa in 189 women with mild to moderate postpartum hypertension
2 compared IV hydralazine vs. either sublingual nifedipine or IV labetalol
in 120 women with severe postpartum hypertension
o no maternal deaths or severe hypotension reported
o Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD004351
insufficient evidence for recommendations on usefulness of treatment with
o activated protein C (SOGC Grade III-I)
o antithrombin (SOGC Grade I-I)
o heparin (SOGC Grade III-I)
o L-arginine (SOGC Grade I-I)
o long-term epidural anesthesia (SOGC Grade I-I)
o N-acetylcysteine (SOGC Grade I-I)
o probenecid (SOGC Grade I-I)
o sildenafil (SOGC Grade III-I)
no randomized trials identified to evaluate Chinese herbal medicines for women
with preeclampsia o based on Cochrane review
o Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD005126
Consultation and referral:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o at scheduling of antenatal care, offer obstetric consultation to women with
markers of increased risk for preeclampsia (SOGC Grade II-2B)
o consider risk stratification involving multivariable clinical and laboratory
approach for women at increased risk of preeclampsia (SOGC Grade II-2B)
o obstetric consultation mandatory for women with severe preeclampsia (SOGC
Grade III-B)
Other management:
Expectant management:
American College of Obstetricians and Gynecologists (ACOG) recommends
considering expectant management for women remote from term with mild preeclampsia
(ACOG Level C)(5)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for maternal and fetal wellbeing surveillance in preeclampsia(3)
o antenatal and postpartum serial surveillance of maternal wellbeing recommended
(SOGC Grade II-3B)
o frequency of maternal surveillance should be at least once weekly antenatally and
at least once in first 3 days postpartum (SOGC Grade III-C)
o serial surveillance of fetal wellbeing recommended (SOGC Grade II-2B)
o antenatal fetal surveillance should include umbilical artery Doppler velocimetry
(SOGC Grade I-A)
o women who develop gestational hypertension without proteinuria or adverse
conditions prior to 34 weeks gestation should be followed closely for maternal
and perinatal complications (SOGC Grade II-2B)
expectant management of mild preeclampsia(1)
o measure blood pressure twice weekly
o obtain lab tests weekly
complete blood count (CBC)
platelet count
alanine transaminase (ALT)
aspartate transaminase (AST)
lactate dehydrogenase (LDH)
uric acid
creatinine
o assess for proteinuria
screen with dipstick or spot protein:creatinine ratio
obtain periodic 24-hour urine collections
o fetal monitoring
obtain nonstress test twice weekly
measure amniotic fluid index once or twice weekly
biophysical profile may be done weekly to replace 1 of the twice-weekly
nonstress tests and amniotic fluid index
perform ultrasound for fetal growth every 3-4 weeks
Abdominal decompression:
abdominal decompression may improve perinatal outcomes in women with
preeclampsia or impaired fetal growth (level 2 [mid-level] evidence) o based on Cochrane review of trials with inadequate allocation concealment
o systematic review of 3 randomized or quasi-randomized trials evaluating
abdominal decompression (negative pressure to space around abdomen) in 356
women with preeclampsia or impaired fetal growth
o all trials had inadequate allocation concealment
o 1 trial included women with preeclampsia, essential hypertension, or chronic
nephritis; 2 trials included women with small for gestational age fetus
o comparing abdominal decompression vs. no decompression
unchanged or worsening preeclampsia in 19% vs. 52.6% in 1 trial with 80
patients (p = 0.004, NNT 3)
fetal distress in labor in 14.3% vs. 38.6% in 1 trial with 140 patients (p =
0.0026, NNT 4)
low birth weight in 37.7% vs. 75.3% in analysis of 2 trials with 304
patients (p = 0.00001, NNT 3), results may be limited by significant
heterogeneity (p = 0.001)
Apgar score < 6 at 1 minute in 10% vs. 38.6% in 1 trial with 140 patients
(p = 0.00052, NNT 4)
perinatal mortality 7.1% vs. 18.4% in analysis of 3 trials with 367 patients
(p = 0.0021, NNT 9)
o Reference - Cochrane Database Syst Rev 2009 Jan 21;(1):CD000004
Postdelivery care:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o for care during first 6 weeks postpartum measure blood pressure during time of peak postpartum blood pressure at
3-6 days after delivery (SOGC Grade III-B)
antihypertensive therapy
antihypertensive medication can be restarted postpartum,
especially in women with severe preeclampsia and women who
delivered preterm (SOGC Grade II-2I)
treat severe postpartum hypertension with antihypertensive
medication to keep systolic blood pressure < 160 mm Hg and
diastolic blood pressure < 110 mm Hg (SOGC Grade II-2B)
antihypertensive medication can be used to treat nonsevere
postpartum hypertension, especially in women with comorbidities
(SOGC Grade III-I)
antihypertensive medications acceptable for use in breastfeeding
include (SOGC Grade III-B)
nifedipine extended-release
labetalol
methyldopa
captopril
enalapril
confirm resolution of end-organ dysfunction (SOGC Grade III-I)
nonsteroidal anti-inflammatory drugs (NSAIDs) should NOT be given
postpartum if any of following criteria present (SOGC Grade III-I)
hypertension difficult to control
oliguria
elevated creatinine
platelets < 50 × 109/L
consider postpartum thromboprophylaxis in women with preeclampsia,
especially after antenatal bed rest for > 4 days or after cesarean section
(SOGC Grade III-I)
low-molecular-weight heparin should NOT be given postpartum until ≥ 2
hours after epidural catheter removal (SOGC Grade III-B)
o for care beyond 6 weeks postpartum
for women with history of severe preeclampsia, especially those who
presented or delivered before 34 weeks gestation, screen for
pre-existing hypertension (SOGC Grade II-2B)
underlying renal disease (SOGC Grade II-2B)
thrombophilia (SOGC Grade II-2C)
advise women that intervals between pregnancies < 2 or ≥ 10 years
associated with recurrent preeclampsia (SOGC Grade II-2D)
encourage overweight women to attain healthy body mass index (BMI) for
decreasing risk in future pregnancies (SOGC Grade II-2A) and for long-
term health (SOGC Grade I-A)
women with pre-existing hypertension should have (if not done previously)
(SOGC Grade III-I)
urinalysis
serum sodium, potassium and creatinine
fasting glucose
fasting total cholesterol, high-density lipoprotein cholesterol, low-
density lipoprotein cholesterol and triglycerides
standard 12-lead electrocardiography
consider assessing traditional cardiovascular risk markers in normotensive
women with hypertensive disorders of pregnancy (SOGC Grade II-2B)
advise all women with history of hypertensive disorder of pregnancy to
pursue healthy diet and lifestyle (SOGC Grade I-B)
Follow-up:
Neonatal follow-up:
early hematologic screening may identify neutropenia or thrombocytopenia in
infants born to hypertensive mothers o based on retrospective cohort study
o 249 newborns of hypertensive mothers had complete blood counts
o 19 (7.6%) had neutropenia, 35 (14.1%) had thrombocytopenia (11 [4.4%] had
both)
o 52 of 54 infants with hematologic abnormalities had abnormalities within 5 days
of life
o 2 neutropenic infants developed nosocomial infection
o 7 thrombocytopenic infants had bleeding
o Reference - J Paediatr Child Health 1996 Feb;32(1):31
Prognosis
preeclampsia rarely remits spontaneously and usually worsens with time but resolves
after delivery(4)
stroke and pulmonary edema most common causes of maternal death in preeclampsia(3)
severity and duration of preeclampsia associated with increasing time to resolution
of hypertension o based on prospective cohort study
o 205 women hospitalized with preeclampsia from 1990 to 1992 in the Netherlands
followed for 2 years after delivery
o persistent hypertension (defined as blood pressure ≥ 140/90 mm Hg or use of
antihypertensive drugs) in
39% at 3 months postpartum
18% at 2 years postpartum
o persistent proteinuria (defined as ≥ 0.3 g/day) in
14% at 3 months postpartum
2% at 2 years postpartum
o time to resolution of hypertension increased by
60% for every 10 mm Hg increase in maximal systolic blood pressure (p <
0.001)
40% for every 10 mm Hg increase in maximal diastolic blood pressure (p
= 0.044)
3.6% for every 1 day increase in time from preeclampsia diagnosis to
delivery (p = 0.001)
o time to resolution of proteinuria increased by 16% for every 1 g/day increase in
maximal proteinuria (p = 0.001)
o Reference - Obstet Gynecol 2009 Dec;114(6):1307
Maternal outcomes:
physiologic changes of pregnancy may reveal risk of chronic diseases, preeclampsia and
gestational diabetes may predict cardiovascular and metabolic diseases (JAMA 2005 Dec
7;294(21):2751)
preeclampsia may be associated with future maternal risk of cardiovascular disease
o preeclampsia associated with increased risk of vascular disease and overall
mortality but not cancer based on systematic review of cohort studies
systematic review of 25 cohort studies with 3,488,160 women
198,252 women (5.7%) developed preeclampsia
29,495 (0.85%) had episodes of cardiovascular disease and cancer
preeclampsia associated with increased subsequent overall mortality
(7,537 of 49,049 women [15.3%] with preeclampsia), relative risk 1.49 in
4 studies with 794,462 women followed for mean 14.5 years
preeclampsia significantly associated with subsequent increased risk for
chronic hypertension developed in 1,885 of 3,658 women (51.5%)
with preeclampsia, relative risk (RR) 3.7 in 13 studies with 21,030
women followed for mean 14.1 years
ischemic heart disease developed in 5,097 of 121,487 women
(4.2%) with preeclampsia, RR 2.16 in 8 studies with 2,346,997
women followed for mean 11.7 years
stroke developed in 907 of 64,551 women (1.4%) with
preeclampsia, RR 1.81 in 4 studies with 1,671,578 women
followed for mean 10.4 years
venous thromboembolism developed in 470 of 35,772 women
(1.3%) with preeclampsia, RR 1.79 in 3 studies with 427,693
women followed for mean 4.7 years
cancer was not significantly associated with preeclampsia in meta-analysis
of 3 studies with 729,025 women followed for mean 13.9 years
Reference - BMJ 2007 Nov 10;335(7627):974 full-text, editorial can be
found in BMJ 2007 Nov 10;335(7627):945, commentary can be found in
BMJ 2007 Nov 24;335(7629):1059
o preeclampsia/eclampsia associated with future cardiovascular disease and
severity of preeclampsia may be associated with increased risk based on systematic review of cohort and case-control studies
meta-analysis of 5 case-control and 10 cohort studies with 116,175 women
evaluated for cardiovascular disease > 6 weeks postpartum
compared to women without preeclampsia/eclampsia, women with
preeclampsia/eclampsia had increased risk for
subsequent cardiac disease (relative risk [RR] 2.33, 95% CI 1.95-
2.78)
cerebrovascular disease (RR 2.03, 95% CI 1.54-2.67)
cardiovascular mortality (RR 2.29, 95% CI 1.73-3.04)
relative risk of subsequent cardiac disease by severity of
preeclampsia/eclampsia
mild RR 2 (95% CI 1.83-2.19)
moderate RR 2.99 (95% CI 2.51-3.58)
severe RR 5.36 (95% CI 3.96-7.27)
Reference - Am Heart J 2008 Nov;156(5):918
o increasing severity of hypertensive disease in pregnancy associated with
increasing risk of ischemic heart disease based on 15-year follow-up of 403,550 women giving birth to first child
Reference - BJOG 2005 Nov;112(11):1486
o hypertension in pregnancy associated with increased risk of maternal death
and major morbidity based on study of all 250,173 women and 255,931 infants discharged from
hospital following birth in New South Wales from 2000 to 2002
Reference - Med J Aust 2005 Apr 4;182(7):332 full-text
o preeclampsia/eclampsia associated with increased risk of stroke during first
year postpartum based on retrospective cohort study of 1,132,019 parturients in Taiwan
from 1999 to 2003
women followed for 1 year postpartum
stroke incidence 21.47 cases per 100,000 deliveries
Reference - Stroke 2009 Apr;40(4):1162
o preeclampsia associated with 3.6 times risk of fatal stroke in later life based on cohort study with 3,593 women
Reference - BMJ 2003 Apr 19;326(7394):845 full-text, commentary can
be found in Am Fam Physician 2003 Dec 1;68(11):2270
preeclampsia associated with > 2 times risk of venous thromboembolism o based on study of 12,849 women with preeclampsia and 284,188 control women
followed for mean 3 years after delivery
o rates of venous thromboembolism were 0.12% (41.7 per 100,000 person-years) in
preeclampsia group and 0.01%-0.08% (3-33.8 per 100,000 person-years) among
10 different control groups
o Reference - BMJ 2003 Apr 12;326(7393):791 full-text, correction can be found in
BMJ 2003 Jun 21;326(7403):1362
fullPIERS model may predict risk of life-threatening complications within 48 hours
of hospital admission in women with preeclampsia (level 2 [mid-level] evidence)
o based on prospective cohort study without external validation
o 2,023 women with preeclampsia were analyzed
o 5% had life-threatening complications within 48 hours of hospital admission
o risk model based on
gestational age
chest pain or dyspnea
oxygen saturation
platelet count
creatinine concentration
aspartate transaminase concentration
o predictive performance of fullPIERS for complications within 48 hours of
hospital admission in internal validation
sensitivity 75.5%
specificity 86.9%
positive predictive value 23.6%
negative predictive value 98.5%
o Reference - Lancet 2011 Jan 15;377(9761):219, editorial can be found in Lancet
2011 Jan 15;377(9761):185
eclampsia associated with increased risk of maternal mortality o based on cohort study of 1,910,729 women and their newborns delivered in
Canada from 2003-2009
o incidence of eclampsia fell from 12.4 per 10,000 deliveries in 2003 to 5.9 per
10,000 deliveries in 2009
o eclampsia associated with increased risk of
maternal mortality (adjusted odds ratio [OR] 26.8, 95% CI 9.7-73.8)
assisted ventilation (adjusted OR 102.3, 95% CI 78.2-133.8)
respiratory distress syndrome (adjusted OR 36.2, 95% CI 15.3-85.3)
acute renal failure (adjusted OR 20.9, 95% CI 11.4-38.3)
obstetric embolism (adjusted OR 9.1, 95% CI 4.1-19.9)
o Reference - Obstet Gynecol 2011 Nov;118(5):987, editorial can be found in
Obstet Gynecol 2011 Nov;118(5):976
Child outcomes:
perinatal mortality
o perinatal mortality with preeclampsia has declined based on study of 33,835 pregnancies with first child, singleton birth after
24 weeks gestation and preeclampsia in Norway
rate of perinatal death was 5.64% in 1967 to 1978, 1.76% in 1979 to 1990,
and 0.86% in 1991 to 2003
rate of stillbirth was 4.41% in 1967 to 1978, 1.19% in 1979 to 1990, and
0.58% in 1991 to 2003
Reference - JAMA 2006 Sep 20;296(11):1357, correction can be found in
JAMA 2006 Dec 27;296(24):2926
o highest antepartum diastolic blood pressure 70-90 mm Hg associated with
highest birth weight and lowest risk of perinatal mortality based on prospective study of 210,814 first singleton births among women
without hypertension prior to 20 weeks gestation
Reference - BMJ 2004 Dec 4;329(7478):1312 full-text
DynaMed commentary -- study does not establish that interventions to
modify blood pressure would alter birth weight or perinatal mortality
severe preeclampsia before 24 weeks gestation associated with very low perinatal
survival (level 2 [mid-level] evidence) o based on retrospective cohort study
o 46 women (with 51 fetuses) with severe preeclampsia at < 27 weeks gestation
evaluated
o corticosteroids given beyond 23 weeks
o median 6 days of pregnancy prolongation (range 2-46 days)
o overall perinatal survivor 57% (29 of 51)
o perinatal survival by gestational age
0 of 7 with gestational age < 23 weeks
20% (2 of 10) for 23 weeks to 23 6/7 weeks
71% (5 of 7) for 24 weeks to 24 6/7 weeks
76% (13 of 17) for 25 weeks to 25 6/7 weeks
90% (9 of 10) for 26 weeks to 26 6/7 weeks
o 46% overall rate of composite maternal morbidity (hemolysis, elevated liver
enzymes, low platelets [HELLP] syndrome, pulmonary edema, eclampsia, renal
insufficiency)
o Reference - Am J Obstet Gynecol 2008 Sep;199(3):247 e1, editorial can be found
in Am J Obstet Gynecol 2008 Sep;199(3):209
severe early-onset maternal hypertensive disorder may be associated with moderate
delays in mental and psychomotor development at age 1 year o based on prospective cohort study
o 172 children (median gestational age 31.6 weeks) born to mothers with severe
early-onset maternal hypertensive disorder
o infant outcomes at 1 year
moderately delayed mental development in 37%
moderately delayed psychomotor development in 51%
severe delays in mental and/or psychomotor development in 18%
o Reference - BJOG 2008 Jan;115(2):290
eclampsia associated with increased risk of neonatal mortality, respiratory distress
syndrome (RDS) and small-for-gestational age (SGA) birth o based on cohort study of 1,910,729 women and their newborns delivered in
Canada from 2003-2009
o incidence of eclampsia fell from 12.4 per 10,000 deliveries in 2003 to 5.9 per
10,000 deliveries in 2009
o eclampsia associated with increased risk of
neonatal mortality (adjusted [OR] odds ratio 2.9, 95% CI 1.6-5.5)
RDS (adjusted OR 5.1, 95% CI 4.1-6.3)
SGA birth (adjusted OR 2.6, 95% CI 2.3-3)
o Reference - Obstet Gynecol 2011 Nov;118(5):987, editorial can be found in
Obstet Gynecol 2011 Nov;118(5):976
Recurrence of preeclampsia:
preeclampsia associated with increased risk for recurrence of preeclampsia o based on prospective cohort study of 763,795 mothers having first births in
Sweden from 1987 to 2004
o risk of preeclampsia
4.1% in first pregnancy overall
1.7% in later pregnancies overall
1% in multiparous women without history of preeclampsia
14.7% in second pregnancy of women with preeclampsia in first
pregnancy
31.9% in women with preeclampsia in previous 2 pregnancies
o incidence of preeclampsia associated with delivery < 34 weeks gestation
0.42% in primiparous women without history of preeclampsia
0.11% in multiparous women without history of preeclampsia
6.8% in women with preeclampsia in 1 previous pregnancy
12.5% in women with preeclampsia in 2 previous pregnancies
o Reference - BMJ 2009 Jun 18;338:b2255 full-text
Prevention and Screening
Prevention:
Recommendations for prevention of preeclampsia:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations
for preventing preeclampsia and complications(3)
o preconceptual counseling recommended for women with pre-existing
hypertension (SOGC Grade III-I)
o at first antenatal care visit women with increase risk for preeclampsia should be
offered obstetric consultation (SOGC Grade II-2B)
o for women at increased risk
low-dose aspirin (SOGC Grade I-A)
75-100 mg/day (SOGC Grade III-B)
given at bedtime (SOGC Grade I-B)
start prepregnancy or from diagnosis of pregnancy, but before 16
weeks gestation (SOGC Grade III-B)
continue until delivery (SOGC Grade I-A)
calcium supplementation ≥ 1 g/day for women with low calcium intake (<
600 mg/day) (SOGC Grade I-A)
strategies recommended for other beneficial effects in pregnancy
abstain from alcohol (SOGC Grade II-2E)
periconceptual use of folate-containing multivitamin (SOGC Grade
I-A)
smoking cessation (SOGC Grade I-E)
strategies that may be useful include
avoiding interpregnancy weight gain (SOGC Grade II-2E)
increased rest at home in third trimester (SOGC Grade I-C)
reducing workload or stress (SOGC Grade III-C)
interventions NOT recommended for preeclampsia prevention
prostaglandin precursors (SOGC Grade I-C), but may be useful for
preventing other pregnancy complications
magnesium supplementation (SOGC Grade I-C), but may be useful
for preventing other pregnancy complications
calorie restriction in overweight women during pregnancy (SOGC
Grade I-D)
weight maintenance in obese women during pregnancy (SOGC
Grade III-D)
antihypertensive therapy specifically to prevent preeclampsia
(SOGC Grade I-D)
vitamin C and vitamin E (SOGC Grade I-E)
insufficient evidence for recommendations about usefulness of
dietary salt restriction during pregnancy (SOGC Grade III-I)
heart healthy diet (SOGC Grade III-I)
exercise (SOGC Grade I-I)
heparin (even among women with thrombophilia and/or prior
preeclampsia) (SOGC Grade II-2I)
selenium (SOGC Grade I-I)
garlic (SOGC Grade I-I)
zinc (SOGC Grade III-I)
pyridoxine supplementation (SOGC Grade III-I)
iron supplementation with or without folate (SOGC Grade III-I)
multivitamins (with or without micronutrients) (SOGC Grade III-I)
o for women at low risk
calcium supplementation ≥ 1 g/day orally recommended for women with
low dietary calcium intake (< 600 mg/day) (SOGC Grade I-A)
strategies recommended for other beneficial effects in pregnancy
abstain from alcohol (SOGC Grade II-2E)
exercise for maintenance of fitness (SOGC Grade I-A), but may
also be useful for prevention of preeclampsia (SOGC Grade II-2B)
periconceptual use of folate-containing multivitamin for prevention
of neural tube defects (SOGC Grade I-A), may also be useful for
prevention of preeclampsia (SOGC Grade I-B)
smoking cessation (SOGC Grade I-E)
interventions NOT recommended for preeclampsia prevention
prostaglandin precursors (SOGC Grade I-C), but may be useful for
preventing other pregnancy complications
magnesium supplementation (SOGC Grade I-C), but may be useful
for preventing other pregnancy complications
zinc supplementation (SOGC Grade I-C), but may be useful for
preventing other pregnancy complications
dietary salt restriction during pregnancy (SOGC Grade I-D)
calorie restriction in overweight women during pregnancy (SOGC
Grade I-D)
low-dose aspirin (SOGC Grade I-E)
vitamin C and vitamin E (SOGC Grade I-E)
thiazide diuretics (SOGC Grade I-E)
insufficient evidence for recommendations about usefulness of
heart healthy diet (SOGC Grade II-2I)
workload or stress reduction (SOGC Grade II-2I)
iron supplementation with or without folate (SOGC Grade I-I)
pyridoxine supplementation (SOGC Grade I-I)
Seventh Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure (JNC 7) recommendations for prevention of
preeclampsia(4)
o identify high-risk women
o perform close clinical and laboratory monitoring for early recognition
o institute intensive monitoring or delivery when indicated
American College of Obstetricians and Gynecologists (ACOG)(5)
o does NOT recommend low-dose aspirin to prevent preeclampsia in women at low
risk (ACOG Level A)
o does NOT recommend daily calcium supplementation to prevent preeclampsia
(ACOG Level A)
for women considered at risk for preeclampsia, low-dose aspirin throughout pregnancy,
starting from second trimester, recommended over no treatment (ACCP Grade 1B)
o Reference - American College of Chest Physicians (ACCP) guidelines on venous
thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy (Chest
2012 Feb;141(2 Suppl):e691S)
systematic review of methods of prediction and prevention of preeclampsia can be found
in Health Technol Assess 2008 Mar;12(6):iii full-text
Rest and exercise:
daily rest may reduce risk of preeclampsia for women with normal blood pressure
(level 3 [lacking direct] evidence) o based on Cochrane review without clinical outcomes
o systematic review of 2 randomized trials evaluating rest or advice to reduce
physical activity for preventing preeclampsia and its complications in 106 women
with normal blood pressure
o trials did not report allocation concealment or blinding of outcome assessor
o both trials included nulliparous women with singleton pregnancy at moderate risk
of preeclampsia from 28-32 weeks gestation
o 1 trial with 32 women found rest for 4-6 hours/day associated with statistically
significant reduction in risk of preeclampsia, but reduced risk of gestational
hypertension was not statistically significant
o 1 trial with 74 women found rest for 30 minutes/day plus nutritional
supplementation associated with reduction in risk of preeclampsia and gestational
hypertension
o Reference - Cochrane Database Syst Rev 2010 Feb 17;(2):CD005939
insufficient evidence to determine if exercise is helpful in prevention of preeclampsia o based on Cochrane review
o systematic review of 2 small, good quality randomized trials in 45 women both
comparing moderate intensity regular aerobic exercise with maintenance of
normal physical activity during pregnancy
o confidence intervals were wide and not statistically significant for all reported
outcomes including preeclampsia (relative risk 0.31, 95% CI 0.01-7.09)
o Reference - systematic review last updated 2006 Jan 17 (Cochrane Library 2006
Issue 2:CD005942)
Calcium:
calcium supplementation during pregnancy may reduce risk of preeclampsia (level 3
[lacking direct] evidence)and composite outcome of maternal death or serious
morbidity (level 1 [likely reliable] evidence) o based on Cochrane review
o systematic review of 13 randomized placebo-controlled trials evaluating calcium
supplementation with at least 1 g/day in 15,730 pregnant women
o calcium supplementation associated with reduced
preeclampsia in analysis of 13 trials with 15,730 women
risk ratio (RR) 0.45 (95% CI 0.31-0.65)
NNT 25-48 assuming preeclampsia in 6% of placebo group
results limited by heterogeneity
composite outcome of maternal death or serious morbidity in analysis of 4
trials with 9,732 women
RR 0.8 (95% CI 0.65-0.97)
NNT 72-834 assuming outcome in 4% of placebo group
almost all women were low-risk and had a low-calcium diet
results almost entirely based on WHO trial
systolic blood pressure > 95th percentile in childhood in 1 trial with 514
children
high blood pressure (RR 0.65, 95% CI 0.53-0.81) in analysis of 12 trials
with 15,470 women, results limited by heterogeneity
o for outcomes of preeclampsia and preterm birth, greater risk reductions observed
in high-risk women, those with low baseline calcium intake and in trials with <
400 women (smaller trials tended to enroll high-risk women)
o calcium supplementation increased risk of hemolysis, elevated liver enzymes, low
platelets (HELLP) syndrome (RR 2.67, 95% CI 1.05-6.82) in analysis of 2 trials
with 12,901 women
o no significant differences in risk of stillbirth or death before hospital discharge in
analysis of 11 trials with 15,665 infants
o Reference - Cochrane Database Syst Rev 2010 Aug 4;(8):CD001059
inconsistent evidence for calcium supplementation on risk of preterm birth (level 2
[mid-level] evidence) o based on 2 Cochrane reviews with differences potentially attributed to differences
in inclusion criteria
o systematic review of 13 randomized placebo-controlled trials evaluating calcium
supplementation with at least 1 g/day in 15,730 pregnant women
calcium supplementation associated with reduced preterm birth < 37
weeks gestation in analysis of 11 trials with 15,275 women
RR 0.76 (95% CI 0.6-0.97)
NNT 25-334 assuming preterm birth in 10% of placebo group
results limited by heterogeneity
for outcomes of preeclampsia and preterm birth, greater risk reductions
observed in high-risk women, those with low baseline calcium intake, and
in trials with < 400 women (smaller trials tended to enroll high-risk
women)
no significant differences in risk of stillbirth or death before hospital
discharge in analysis of 11 trials with 15,665 infants
Reference - Cochrane Database Syst Rev 2010 Aug 4;(8):CD001059 full-
text
o systematic review of 21 randomized trials comparing any dose of calcium
supplementation to placebo or no treatment in 16,602 pregnant women
use of calcium for treatment or prevention of hypertension not evaluated
no significant difference between groups in
preterm birth < 37 weeks gestation in analysis of 12 trials with
15,615 women
low birth weight (< 2,500 g) in analysis of 5 trials with 13,638
infants
admission to neonatal intensive care unit (ICU) in analysis of 4
trials with 14,062 infants
stillbirth or fetal death in analysis of 4 trials with 14,083 infants
borderline reduction in maternal death with calcium supplementation in
WHO trial with 8,325 women (p = 0.098)
Reference - Cochrane Database Syst Rev 2011 Oct 5;(10):CD007079 full-
text
calcium supplementation reduces risk of eclampsia and neonatal death in pregnant
women in communities with low dietary calcium intake (level 1 [likely reliable]
evidence)
o based on randomized trial (WHO trial was largest trial in both Cochrane reviews)
o 8,325 healthy nulliparous women in communities with low dietary calcium intake
(< 600 mg/day) were randomized to calcium carbonate (500 mg of calcium) vs.
placebo chewable tablets 3 times daily (at meal time but > 3 hours from iron
supplements) until delivery
o exclusion criteria at enrollment were gestational week > 20, systolic blood
pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, history of chronic
hypertension or renal disease, history or symptoms of nephrolithiasis, parathyroid
disorder or need for digoxin, phenytoin or tetracycline
o assigned treatment discontinued if nephrolithiasis occurred or magnesium sulfate
used to treat preeclampsia
o 9 women determined not to be pregnant and 4 women lost to follow-up before
starting treatment were excluded, so 8,312 women analyzed
o calcium status of patients not reported
o comparing calcium vs. placebo
85% vs. 86% tablets ingested
11.2% vs. 10.2% dropout rate (not statistically significant)
2 vs. 3 cases of nephrolithiasis
o preeclampsia outcomes comparing calcium vs. placebo
4.1% vs. 4.5% had preeclampsia defined as new hypertension (blood
pressure 140/90 mm Hg or higher twice at least 4 hours apart) and new
proteinuria (at least +2 on dipstick or at least 300 mg/24 hours) (not
statistically significant)
0.8% vs. 1.1% had severe preeclampsia defined as systolic blood pressure
at least 160 mm Hg or diastolic blood pressure at least 110 mm Hg twice
at least 4 hours apart or eclampsia (not statistically significant)
0.5% vs. 0.5% had preeclampsia before 32 weeks gestation (not
statistically significant)
1% vs. 1.4% had severe gestational hypertension (blood pressure at least
160/110 mm Hg) without proteinuria (NNT 250)
o preeclampsia complications comparing calcium vs. placebo
0.4% vs. 0.6% had eclampsia (NNT 500)
2.7% vs. 3.5% had severe preeclamptic complication defined as severe
preeclampsia, preeclampsia before 32 weeks gestation, eclampsia,
placental abruption, hemolysis, elevated liver enzymes, low platelets
(HELLP) syndrome or severe gestational hypertension (NNT 125)
o other complications comparing calcium vs. placebo
9.9% vs. 10.8% had preterm delivery before 37 weeks gestation (not
significant)
2.6% vs. 3.2% had preterm delivery before 32 weeks gestation (NNT 167)
with significant effect limited to subgroup with age 20 years or younger
(2.4% vs. 3.8%, NNT 71)
2.8% vs. 3.3% had any maternal admission to intensive or special care unit
(NNT 200)
o mortality comparing calcium vs. placebo
0.024% vs. 0.144% had maternal death (NNT 833)
0.94% vs. 1.34% had neonatal death (NNT 250)
o Reference - Am J Obstet Gynecol 2006 Mar;194(3):639
calcium and linoleic acid during third trimester may reduce incidence of
preeclampsia in high-risk patients (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes
o 1,676 healthy primigravid patients at 28-32 weeks gestation screened for high-risk
of preeclampsia (defined as biopsychosocial profile score of 3 or more, positive
roll-over test and mean arterial pressure at least 85 mm Hg)
o 89 women (5.3%) met high-risk criteria and were randomized to linoleic acid 450
mg plus calcium 600 mg vs. placebo orally once daily
o 9.3% treatment vs. 37.2% placebo had preeclampsia (defined as blood pressure >
140/90 repeatedly and proteinuria > 0.3 g/L) (NNT 4)
o 4.7% vs. 14% severe preeclamptic toxemia (not statistically significant)
o no side effects reported
o Reference - Obstet Gynecol 1998 Apr;91(4):585 in Am Fam Physician 1998
Jul;58(1);252
o DynaMed commentary
use of < 6% screened patients and atypical inclusion criteria limits
generalizability of results
this trial excluded from Cochrane review because of co-treatment with
linoleic acid
see also Calcium intake and supplementation
Antiplatelet agents:
antiplatelet agents, mostly low-dose aspirin, may reduce incidence of preeclampsia,
preterm birth, and fetal or neonatal death (level 2 [mid-level] evidence) o based on Cochrane review with significant differences dependent on lower-
quality trials
o systematic review of 59 randomized trials with 37,560 women at risk of
developing preeclampsia
o 18 trials had adequate allocation concealment, of which 14 were placebo-
controlled; higher-quality trials tended toward fewer significant differences
o comparing antiplatelet agents vs. placebo or no treatment overall
6.6% vs. 8% rate of preeclampsia (p < 0.0001, NNT 72), based on 46 trials
with 32,590 women, results limited by heterogeneity (p = 0.0006)
16.7% vs. 18% rate of preterm birth < 37 weeks (p = 0.001, NNT 77),
based on 29 trials with 31,151 women
2.5% vs. 2.9% rate of fetal or neonatal deaths (p = 0.02, NNT 250), based
on 40 trials with 33,098 women
8.3% vs. 9.1% rate of small for gestational age infants (p = 0.02, NNT
125), based on 36 trials with 23,638 women
0.3% vs. 0.3% rate of eclampsia in 9 trials with 22,584 women
0.047% vs. 0.016% maternal mortality (not significant) in 3 trials with
12,709 women
o comparing antiplatelet agents vs. placebo or no treatment in high-risk women
15.6% vs. 20.7% rate of preeclampsia (p = 0.0001, NNT 20), based on 18
trials with 4,121 women, results limited by heterogeneity (p = 0.03)
33.7% vs. 38.1% rate of preterm birth < 37 weeks (p = 0.01, NNT 23),
based on 10 trials with 3,252 women
4% vs. 5.8% rate of fetal or neonatal deaths (p = 0.006, NNT 56), based on
17 trials with 4,443 women
8.7% vs. 9.7% rate of small for gestational age infants (not significant),
based on 13 trials with 4,239 women
o further information needed to guide patient selection, timing and dose
o Reference - systematic review last updated 2007 Feb 7 (Cochrane Library 2007
Issue 2:CD004659)
low-dose aspirin initiated prior to 16 weeks gestation associated with decrease in
preeclampsia and intrauterine growth restriction (IUGR) (level 2 [mid-level]
evidence) o based on systematic review of mostly moderate-quality trials
o systematic review of 34 trials evaluating incidence of preeclampsia and IUGR
with use of low-dose aspirin (50-150 mg acetylsalicylic acid daily alone or with <
300 mg dipyridamole) vs. placebo (or no treatment) in 11,348 pregnant women at
risk for preeclampsia
o risk of preeclampsia included nulliparity, history of preeclampsia or other
hypertensive disorders, abnormal uterine artery Doppler ultrasound
o low-dose aspirin initiated prior to 16 weeks gestation associated with decreased
incidence of
preeclampsia in analysis of 9 trials with 764 women
relative risk (RR) 0.47 (95% CI 0.34-0.65)
NNT 9 (95% CI 6-25)
IUGR in analysis of 9 trials with 853 women
RR 0.44 (95% CI 0.3-0.65)
NNT 11 (95% CI 8-20)
o no significant difference between low-dose aspirin initiated after 16 weeks
gestation vs. placebo (or no treatment) in incidence of
preeclampsia in analysis of 18 trials
IUGR in analysis of 15 trials
o Reference - Obstet Gynecol 2010 Aug;116(2 Part 1):402
antiplatelet agents during pregnancy associated with reduced risk of preeclampsia,
birth < 34 weeks gestation, and pregnancy with serious adverse outcomes o based on meta-analysis of individual patient data from 31 randomized trials with
32,217 women and 32,819 babies
o Reference - Lancet 2007 May 26;369(9575):1791, editorial can be found in
Lancet 2007 May 26;369(9575):1765, commentary can be found in Lancet 2007
Nov 17;370(9600):1685
low-dose aspirin (50-150 mg/day) may reduce risk of perinatal death and
preeclampsia in high-risk women
o based on systematic review of 14 randomized trials of aspirin in 12,416 women
with risk factors for preeclampsia
o aspirin reduced rates of perinatal death, preeclampsia and spontaneous preterm
birth
o Reference - Obstet Gynecol 2003 Jun;101(6):1319
review of low-dose aspirin and preeclampsia reduction can be found in J Fam Pract 2008
Jan;57(1):54
Heparin:
antenatal heparin associated with decrease in intrauterine growth restriction
(IUGR), preeclampsia, and eclampsia in women at risk of placental dysfunction
(level 2 [mid-level] evidence) o based on Cochrane review of fair- to good-quality trials
o systematic review of 5 randomized trials evaluating antenatal antithrombotic
therapy in women at risk of placental dysfunction
o risk based on prior history of preeclampsia, eclampsia, renal disease, fetal growth
restriction, or fetal death
o 4 trials compared heparin (alone or in combination with dipyridamole) with no
treatment in 324 women
heparin associated with lower risk of
preeclampsia in analysis of 2 trials with 100 women
risk ratio (RR) 0.23 (95% CI 0.08-0.68)
NNT 4-10 assuming preeclampsia in 32% of controls
eclampsia in 1 trial with 110 women (1.8% vs. 14.5% in no
treatment group, NNT 8)
birth weight < 10th percentile in analysis of all trials
RR 0.35 (95% CI 0.2-0.64)
NNT 5-12 assuming IUGR in 25% of controls
no significant difference in perinatal mortality, birth < 34 weeks gestation,
or major neurodevelopmental delay at child follow-up
o 1 trial compared trapidil with placebo in 160 women; no significant difference in
preeclampsia
o Reference - Cochrane Database Syst Rev 2010 Jun 16;(6):CD006780
prophylactic enoxaparin may reduce preeclampsia in women with previous
placental abruption (level 2 [mid-level] evidence) o based on randomized trial without blinding
o 160 women with previous placental abruption without fetal loss during first
pregnancy and negative for antiphospholipid antibodies randomized to enoxaparin
4,000 units once daily subcutaneously started at positive pregnancy test vs. no
enoxaparin
o comparing enoxaparin vs. no enoxaparin
composite placental complications in 12.5% vs. 31.3% (p = 0.04, NNT 6)
abruptio placenta in 1.3% vs. 3.8% (not significant)
preeclampsia in 7.5% vs. 22.5% (p = 0.009, NNT 2)
birth weight < 5th percentile in 2.5% vs. 7.5% (not significant)
fetal loss after 20 weeks in 2.5% vs. 6.3% (not significant)
o Reference - NOH-AP trial (Thromb Haemost 2010 Oct;104(4):771)
Antioxidants:
Concomitant vitamin C and E:
vitamin C and E supplementation does not reduce risk of preeclampsia and
increases risk of gestational hypertension and premature rupture of membranes
(level 1 [likely reliable] evidence) o based on systematic review
o systematic review of 9 randomized trials evaluating vitamin C 1,000 mg and
vitamin E 400 units supplement daily for prevention of preeclampsia in 19,810
women at ≤ 22 weeks gestation
o no significant difference in risk of preeclampsia comparing vitamin C and E vs.
placebo in
all women in analysis of 9 trials with 19,810 women
women with low/moderate risk in analysis of 3 trials with 13,525 women
women with high risk in analysis of 7 trials with 6,285 women
o vitamin C and E supplement associated with
increased risk of gestational hypertension in analysis of 7 trials with
19,003 women
relative risk (RR) 1.11 (95% CI 1.05-1.17)
NNH 47 assuming gestational hypertension in 19% of placebo
group
decreased risk of abruptio placentae in analysis of 5 trials with 13,075
women
RR 0.63 (95% CI 0.43-0.94)
NNT 280 assuming abruptio placentae in 1% of placebo group
increased risk of premature rupture of membranes in analysis of 2 trials
with 3,070 women
RR 1.73 (95% CI 1.34-2.23)
NNH 25 assuming premature rupture of membranes in 6% of
placebo group
o no significant differences in adverse fetal or perinatal outcomes
o Reference - Am J Obstet Gynecol 2011 Jun;204(6):503.e1
concomitant vitamin C and vitamin E supplementation does not reduce risk of
preeclampsia or its complications (level 1 [likely reliable] evidence) o based on randomized trial
o 10,154 nulliparous women at low risk for preeclampsia randomized to begin
vitamin C 1,000 mg plus vitamin E 400 units vs. placebo daily supplementation
between weeks 9-16 of pregnancy and continue through delivery
randomized women had completed 2-week placebo run-in with > 50%
adherence
77% taking prenatal vitamin or multivitamin at baseline
o 9,969 (98%) women who completed trial included in analysis
o comparing vitamin supplementation vs. placebo
preeclampsia in 7.2% and 6.7% (not significant)
pregnancy-associated hypertension in 29.2% vs. 26.6% (p = 0.004, NNH
38)
medically indicated delivery due to hypertension in 10.3% vs. 9.6% (not
significant)
antepartum bleeding in 1.1% vs. 0.9% (not significant)
premature rupture of membranes in 2.5% vs. 2.6% (not significant)
postpartum pulmonary edema in 0.1% vs. 0.2% (not significant)
median hospital stay was 2 days vs. 2 days (not significant)
preterm birth in 10.3% vs. 10.6% (not significant)
o no significant differences for women with mild or severe hypertension in
elevated liver enzyme levels
thrombocytopenia
elevated creatinine levels
eclamptic seizure in
medically indicated preterm birth
fetal growth restriction
perinatal death
o Reference - N Engl J Med 2010 Apr 8;362(14):1282
concomitant vitamin C and vitamin E supplementation does not appear to reduce
risk of preeclampsia or complications in women with type 1 diabetes (level 2 [mid-
level] evidence) o based on randomized trial with wide confidence intervals
o 762 women ≥ 16 years old with type 1 diabetes presenting with singleton
pregnancy at 8-22 weeks gestation were randomized to vitamin C 1,000 mg plus
vitamin E 400 units daily vs. placebo until delivery
o modified intention-to-treat analysis included 749 (98%) pregnancies > 20 weeks
gestation
o preeclampsia defined as gestational hypertension with proteinuria
o no significant differences comparing antioxidant vitamins vs. placebo in
preeclampsia in 15% vs. 19% (risk ratio 0.81, 95% CI 0.59-1.12)
gestational hypertension in 11% vs. 11%
birth weight < 10th percentile for gestational age in 6% vs. 10% (p = 0.08,
risk ratio 0.64, 95% CI 0.39-1.05)
birth at < 34 weeks gestation in 3% vs. 3%
birth at < 37 weeks gestation in 11% vs. 13% (risk ratio 0.89, 95% CI
0.61-1.31)
admission to neonatal intensive care unit in 54% vs. 56%
o no significant differences in any clinical neonatal outcome (including fetal
malformation, fetal loss, infant death, or miscarriage, or various complications);
most of these outcomes occurred in ≤ 1% patients so wide confidence intervals
o Reference - DAPIT trial (Lancet 2010 Jul 24;376(9737):259 full-text),
commentary can be found in Lancet 2010 Jul 24;376(9737):214
Other antioxidants:
antioxidant supplementation may not affect risk of preeclampsia or clinical
outcomes (level 2 [mid-level] evidence) o based on Cochrane review with heterogeneity and wide confidence intervals
o systematic review and meta-analysis of 10 randomized trials of antioxidants for
prevention of preeclampsia in 6,533 women
o 5 trials met all quality criteria (allocation concealment, full blinding, < 3%
excluded)
o comparing antioxidants vs. placebo or no antioxidants
10.1% vs. 11.4% preeclampsia (not significant, p = 0.1) in meta-analysis
of 9 trials with 5,446 patients, analysis limited by heterogeneity (p = 0.02)
5.7% vs. 4.6% severe preeclampsia (not significant) in meta-analysis of 2
trials with 2,495 patients
3% vs. 2.7% any baby death (not significant) in meta-analysis of 4 trials
with 5,144 patients
0.05% vs. 0.05% maternal death (not significant) in meta-analysis of 2
trials with 4,272 patients
36.3% vs. 32.7% labor induction or elective cesarean delivery (not
significant, p = 0.08) in meta-analysis of 2 trials with 2,077 patients
o Reference - systematic review last updated 2007 Oct 26 (Cochrane Library 2008
Issue 1:CD004227)
low dietary intake of vitamin C may be associated with increased incidence of severe
preeclampsia, eclampsia, or HELLP (hemolysis, elevated liver enzymes, low
platelets) syndrome (level 2 [mid-level] evidence) o based on prospective cohort study
o 57,346 women from Danish National Birth Cohort completed food frequency
questionnaire for previous 4 weeks at 25 weeks gestation
o diagnosis of preeclampsia, eclampsia and HELLP diagnosis obtained through
Danish National Patient Registry
o decreasing trend in severe preeclampsia, eclampsia and HELLP syndrome with
increasing intake of vitamin C (reference 130-170 mg/day) (p = 0.04 in test for
overall significance)
o Reference - BJOG 2009 Jun;116(7):964 full-text
insufficient evidence to support vitamin E supplementation in pregnancy o based on systematic review of 4 randomized or quasi-randomized trials of vitamin
E in 566 pregnant women with or at high risk for preeclampsia
o no significant differences in stillbirth, neonatal death, perinatal death, preterm
birth, intrauterine growth restriction, or birth weight
o Reference - systematic review last updated 2004 Dec 17 (Cochrane Library 2005
Issue 2:CD004069)
L-arginine:
L-arginine plus antioxidant supplementation during pregnancy reduces risk of
preeclampsia and preterm delivery in high-risk women (level 1 [likely reliable]
evidence) o based on randomized trial
o 672 pregnant women at high risk of preeclampsia randomized to supplementation
with medical food bar containing L-arginine plus antioxidant vitamins vs.
antioxidant vitamins alone vs. placebo during pregnancy starting at 14-32 weeks
gestation and followed until delivery
o 125 patients (18.6%) discontinued assigned treatment but were followed and
analyzed by intention-to-treat
Results:
Outcome Placebo Antioxidants
Alone L-arginine Plus Antioxidants
Preeclampsia or
eclampsia 30%
23% (p = 0.052
vs. placebo)
13% (p < 0.001 vs. placebo, NNT
6; p = 0.004 vs. antioxidants
alone, NNT 10)
Preterm delivery 20% 23%
11% (p = 0.003 vs. placebo, NNT
11; p < 0.001 vs. antioxidants
alone, NNT 9)
Spontaneous
preterm delivery 6% 7% 5%
Cesarean delivery 68.4% 66.6% 67.9%
o adverse effects more common with medical food bar with L-arginine compared to
placebo included
nausea (p = 0.019, NNH 20)
dyspepsia (p = 0.04, NNH 33)
dizziness (p = 0.039, NNH 33)
palpitations (p = 0.019, NNH 25)
headache (p = 0.01, NNH 16)
o Reference - BMJ 2011 May 19;342:d2901 full-text, editorial can be found in BMJ
2011 May 19;342:d2777
Other dietary and supplement considerations:
higher total dietary fiber intake in early pregnancy may reduce risk for
preeclampsia (level 3 [lacking direct] evidence) o based on prospective cohort study without clinical outcomes
o 1,538 pregnant women completed food frequency questionnaire to assess fiber
intake during 3 months prior to pregnancy and during early pregnancy
o total dietary fiber intake ≥ 21.2 g/day associated with reduced risk for
preeclampsia compared to total dietary intake < 11.9 g/day (adjusted relative risk
0.28, 95% CI 0.11-0.75)
o Reference - Am J Hypertens 2008 Aug;21(8):903
daily coenzyme Q10 supplementation may reduce risk of preeclampsia (level 3
[lacking direct] evidence) o based on randomized trial without intention to treat analysis and without clinical
outcomes
o 235 pregnant women (mean age 17.5 years) randomized at gestational week 20 to
coenzyme Q10 200 mg daily vs. placebo until delivery
o 83.8% completed follow-up (attended ≥ 2 visits)
o 65.5% analyzed (patients taking < 80% coenzyme Q10 softgels excluded)
o overall rate of preeclampsia 20%
o preeclampsia developed in 14.4% with coenzyme Q10 vs. 25.6% with placebo (p
= 0.035, NNT 9)
o Reference - Int J Gynaecol Obstet 2009 Apr;105(1):43
insufficient evidence to recommend garlic for preventing preeclampsia o based on Cochrane review
o systematic review of randomized trials of garlic for prevention of preeclampsia
and its complications
o only 1 placebo-controlled trial of uncertain quality with 100 women met inclusion
criteria; 1 other trial excluded due to 29% loss to follow-up
o comparing garlic vs. placebo
preeclampsia in 14% vs. 18% (not significant)
gestational hypertension in 18% vs. 36% (p = 0.051)
no significant differences in adverse effects except for more frequent
occurrence of odor in garlic group (p = 0.003)
o Reference - Cochrane Database Syst Rev 2010 Feb 17;(2):CD006065
Other medications:
insufficient evidence to recommend use of diuretics for preventing preeclampsia o based on Cochrane review of trials with poor reporting
o systematic review of 5 randomized trials comparing thiazide diuretics with
placebo or no intervention for preventing preeclampsia in 1,836 women
o allocation concealment not reported in 4 trials; 1 trial with allocation concealment
had differential loss to follow up
o no significant differences in
perinatal death in analysis of 5 trials with 1,836 women
preterm birth in analysis of 2 trials with 465 women
wide confidence intervals cannot exclude possible clinical benefit
o diuretics associated with
trend toward lower risk of preeclampsia in analysis of 4 trials with 1,391
women (risk ratio [RR] 0.68, 95% CI 0.45-1.03)
increased risk of nausea and vomiting in analysis of 2 trials with 1,217
women (RR 5.81, 95% CI 1.04-32.46)
o Reference - Cochrane Database Syst Rev 2010 Jul 7;(7):CD004451
atenolol may prevent preeclampsia based on preliminary trial o pregnant nulliparous women with no significant medical complications or
pregnant women with insulin-requiring diabetes and proteinuria < 1 g/24 hours
from university-based maternal infant care clinic underwent Doppler cardiac
output screening at 22-25 weeks gestation
o patients with cardiac output > 7.4 L/minute (increased risk for preeclampsia) were
randomized to atenolol 100 mg/day vs. placebo for remainder of pregnancy
o comparing atenolol vs. placebo
3.8% vs. 18% preeclampsia (NNT 7)
29% vs. 71% hypertension (NNT 3)
mean birth weight in nulliparous patients 440 g less with atenolol
no significant difference in mean birth weight in diabetic group
o Reference - Obstet Gynecol 1999 May;93(5 Part 1):725 in J Fam Pract 1999
Aug;48(8):580
progesterone does not prevent preeclampsia or perinatal mortality (level 1 [likely
reliable] evidence) o based on Cochrane review
o systematic review of 4 randomized trials evaluating progesterone in 1,445 women
for prevention of preeclampsia
o no significant differences in
preeclampsia in analysis of 3 trials with 1,277 women (nonsignificant
increase with risk ratio 1.25, 95% CI 0.95-1.63)
pregnancy-induced hypertension in 1 trial with 168 women
cesarean section in analysis of 2 trials with 1,146 women
stillbirths or neonatal deaths in analysis of 4 trials with 2,594 infants
(higher numbers because 2 trials were in twin pregnancies, risk ratio 1.34,
95% CI 0.78-2.31)
small for gestational age in 1 trial with 168 infants
preterm birth in 3 trials with 1,313 women
o Reference - Cochrane Database Syst Rev 2011 Jun 15;(4):CD006175
insufficient evidence for use of nitric oxide donors for preventing preeclampsia and
its complications o based on Cochrane review
o systematic review of 6 randomized trials of nitric oxide donor or precursors in
310 women at risk for preeclampsia
o 4 of 6 trials had good quality
o 4 trials compared nitric oxide donors (glyceryl trinitrate) or precursors (L-arginine)
to placebo or no intervention in 170 women
o 1 trial (36 women) compared nitric oxide donor to nifedipine
o 1 trial (76 women) comparing nitric oxide donor to antiplatelet agents
o no significant differences in any efficacy analysis but wide confidence intervals
make conclusions unreliable
o Reference - systematic review last updated 2007 Jan 15 (Cochrane Library 2007
Issue 2:CD006490)
Screening:
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(3)
o for blood pressure monitoring
blood pressure should be measured with woman in sitting position with
arm at level of heart (SOGC Grade II-2A)
appropriately sized cuff (length 1.5 times circumference of arm) should be
used (SOGC Grade II-2A)
Korotkoff phase V should be used to designate diastolic blood pressure
(SOGC Grade III-B)
arm with higher blood pressure (if consistent difference) should be used
(SOGC Grade III-B)
women with systolic blood pressure ≥ 140 mm Hg should be followed
closely for development of diastolic hypertension (SOGC Grade II-2B)
o for measurement of proteinuria
assess all pregnant women for proteinuria (SOGC Grade II-2B)
urinary dipstick testing may be used for screening if low suspicion of
preeclampsia (SOGC Grade II-2B)
use more definitive proteinuria testing if suspicion of preeclampsia
(SOGC Grade II-2A)
urinary protein:creatinine ratio
24-hour urine collection
o for diagnosis of clinically significant proteinuria
strongly suspect proteinuria when urinary dipstick proteinuria ≥ 2+
(SOGC Grade II-2A)
proteinuria defined as ≥ 0.3 g/day in 24-hour urine collection or ≥ 30
mg/mmol urinary creatinine in spot (random) urine sample (SOGC Grade
II-2B)
insufficient evidence for recommendations on accuracy of urinary
albumin:creatinine ratio (SOGC Grade II-2I)
no clinically useful screening test during pregnancy to predict development of
preeclampsia o based on systematic review of 87 studies with 211,369 women
o Reference - Obstet Gynecol 2004 Dec;104(6):1367, correction can be found in
Obstet Gynecol 2005 Oct;106(4):869, editorial can be found in Lancet 2005 Apr
16-22;365(9468):1367
insufficient evidence to support hyperuricemia as predictive of preeclampsia o based on systematic review
o systematic review of 5 studies evaluating serum uric acid measurement before 25
weeks gestation and risk of preeclampsia in 572 women
o 44 women developed preeclampsia
o pooling of data not appropriate due to heterogeneity and poor reporting of
methodology between studies
o incidence of preeclampsia ranged from 3.4% to 40.1%
o sensitivity of serum uric acid ranged from 0% to 55.6%, specificity ranged from
76.9%-94.9%
o Reference - Acta Obstet Gynecol Scand 2006;85(5):519
algorithm may detect women in first trimester at risk for pregnancy-associated
hypertension o based on prospective cohort study
o population-based cohort of 7,797 women with singleton pregnancies
o 34 developed early preeclampsia (preeclampsia requiring delivery before 34
weeks)
o 123 developed late preeclampsia (with delivery ≥ 34 weeks)
o algorithm based on maternal variables including mean arterial pressure, uterine
artery pulsatility index, pregnancy-associated plasma protein-A, and placental
growth factor
o early and late preeclampsia associated with
increased mean arterial pressure
increased uterine artery pulsatility index
decreased pregnancy-associated plasma protein-A
decreased placental growth factor
o Reference - Hypertension 2009 May;53(5):812, editorial can be found in
Hypertension 2009 May;53(5):747
urinalysis
o National Academy of Clinical Biochemistry laboratory medicine practice
guideline recommends against routinely screening for antenatal evaluation of
hypertension or preeclampsia with urine dipstick testing at point of care
(grade B recommendation [inconsistent or limited evidence]) fair evidence that protein dipstick testing in this environment largely
ineffective (level 2 [mid-level] evidence)
Reference - National Academy of Clinical Biochemistry laboratory
medicine practice guideline on renal function testing (National Guideline
Clearinghouse 2007 Oct 22:10822)
o repeated routine urinalysis throughout pregnancy (in absence of
hypertension) is NOT useful for predicting preeclampsia based on prospective study of 913 pregnant women
35 had dipstick proteinuria at first antenatal visit, of whom 2 (6%) were
diagnosed with preeclampsia at some time during pregnancy
among 867 women without dipstick proteinuria at first antenatal visit, 338
(39%) developed dipstick proteinuria but only 6 of these women (1.8%)
developed proteinuria before onset of hypertension
Reference - Med J Aust 2002 Nov 4;177(9):477 full-text
uterine artery Doppler ultrasound
o uterine artery Doppler ultrasound in second trimester may predict severe
preeclampsia (level 2 [mid-level] evidence)
o Doppler ultrasound screening of uterine artery in low risk women in second
trimester does not appear to improve pregnancy outcome (level 2 [mid-level]
evidence)
o see Prenatal ultrasound screening for details
Guidelines and Resources
Guidelines:
International guidelines:
international expert paper on critical pathways for management of preeclampsia and
severe preeclampsia in institutionalised healthcare settings can be found in BMC
Pregnancy Childbirth 2003 Oct 3;3(1):6 full-text
United States guidelines:
American Society of Hypertension (ASH) position paper on hypertension in pregnancy
can be found in J Am Soc Hypertens 2008 Nov;2(6):484, J Clin Hypertens (Greenwich)
2009 Apr;11(4):214-25
American College of Obstetricians and Gynecologists (ACOG)
o Practice Bulletin 33 on diagnosis and management preeclampsia and eclampsia
can be found in Obstet Gynecol 2002 Jan;99(1):159, summary can be found in
Am Fam Physician 2002 Jul 15;66(2):330, reaffirmed 2010 Jun
o Practice Bulletin 125 on chronic hypertension in pregnancy can be found in
Obstet Gynecol 2012 Feb;119(2 Pt 1):396
o Practice Bulletin 6 on thrombocytopenia in pregnancy can be found in Obstet
Gynecol 1999 May, Obstet Gynecol 2007 Dec;110(6):1469, reaffirmed 2009 Jun
o Practice Bulletin 100 on critical care in pregnancy can be found in Obstet
Gynecol 2009 Feb;113(2 Pt 1):443, reaffirmed 2012 Feb or at National Guideline
Clearinghouse 2009 Jul 13:14179
o Committee Opinion 514 on emergent therapy for acute-onset, severe hypertension
with preeclampsia or eclampsia can be found in Obstet Gynecol 2011
Dec;118(6):1465
Joint National Committee (JNC) seventh report on prevention, detection, evaluation, and
treatment of high blood pressure can be found at JNC Reference Card, Express Report, or
at JNC 2004 PDF
o summary can be found in Hypertension 2003 Dec;42(6):1206 full-text,
commentary can be found in Hypertension 2004 Jan;43(1):1 full-text,
Hypertension 2004 Apr;43(4):e27 full-text, or in Hypertension 2004
May;43(5):e31 full-text
o summary can be found in JAMA 2003 May 21;289(19):2560, correction can be
found in JAMA 2003 Jul 9;290(2):197, considerable commentary can be found in
JAMA 2003 Sep 10;290(10):1312
o summary can be found in Am Fam Physician 2003 Jul 15;68(2):376 full-text,
editorial can be found in Am Fam Physician 2003 Jul 15;68(2):228
National High Blood Pressure Education Program (NHBPEP) Working Group report on
high blood pressure in pregnancy can be found in Am J Obstet Gynecol 2000
Jul;183(1):S1 or at NHLBI 1990 PDF, commentary can be found in Am J Obstet Gynecol
2001 Aug;185(2):522
o summary can be found in Am Fam Physician 2001 Jul 15;64(2):263 full-text,
correction can be found in Am Fam Physician 2002 Feb 15;65(4):560, editorial
can be found in Am Fam Physician 2001 Jul 15;64(2):225 full-text
o DynaMed commentary -- document is archived for historical purposes only but is
referred to in multiple citations, including
Am Fam Physician 2008 Jul 1;78(1):93 full-text
American Society of Hypertension (ASH) position paper on hypertension
in pregnancy (J Am Soc Hypertens 2008 Nov;2(6):484)
American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice
Guidelines for Antithrombotic Therapy and Prevention of Thrombosis (Ninth Edition)
recommendation on venous thromboembolism, thrombophilia, antithrombotic therapy,
and pregnancy can be found in Chest 2012 Feb;141(2 Suppl):e691S or at National
Guideline Clearinghouse 2012 Jun 4:35275
United Kingdom guidelines:
National Institute for Health and Clinical Excellence (NICE) guideline on management of
hypertensive disorders during pregnancy can be found at NICE 2010 Aug:CG107 or at
National Guideline Clearinghouse 2011 May 9:24122, summary can be found in BMJ
2010 Aug 25;341:c2207
National Institute for Health and Clinical Excellence (NICE) guideline on cesarean
section can be found at NICE 2011 Nov:CG132, summary can be found in BMJ 2011
Nov 23;343:d7108
Royal College of Obstetricians and Gynaecologists (RCOG) guideline on management of
severe preeclampsia/eclampsia can be found at RCOG 2006 Mar PDF
Royal College of Obstetricians and Gynaecologists (RCOG) guideline on maternal
collapse in pregnancy and puerperium can be found at RCOG 2011 Jan PDF
Action on Pre-eclampsia (APEC) preeclampsia community guidelines (PRECOG)
o on screening of preeclampsia in community can be found in BMJ 2005 Mar
12;330(7491):576 full-text, editorial can be found in BMJ 2005 Mar
12;330(7491):549 full-text
o on assessing onset of preeclampsia in hospital day unit (PRECOG II) can be
found at APEC 2009 PDF, summary can be found in BMJ 2009 Sep 9;339:b3129
Canadian guidelines:
Society of Obstetricians and Gynaecologists of Canada (SOGC)
o guideline on diagnosis and classification of hypertensive disorders of pregnancy
can be found at National Guideline Clearinghouse 2009 Apr 27:13381
o guideline on treatment of hypertensive disorders of pregnancy can be found at
National Guideline Clearinghouse 2009 Apr 27:13401
o guideline on prediction, prevention, and prognosis of preeclampsia can be found
at National Guideline Clearinghouse 2009 Apr 27:13400
European guidelines:
Finnish Medical Society Duodecim evidence-based guideline on systemic diseases in
pregnancy can be found at National Guideline Clearinghouse 2008 Jan 21:11046
French Society of Anesthesia and Intensive Care/French National College of Gynecology
and Obstetrics/French Society of Perinatal Medicine/French Society of Neonatology
(SFAR/CNGOF/SFMP/SFNN) guideline on
o drugs during preeclampsia: fetal risks and pharmacology can be found in Ann Fr
Anesth Reanim 2010 Apr;29(4):e37 [French]
o management of preeclampsia in perinatal network can be found in Ann Fr Anesth
Reanim 2010 Apr;29(4):e47 [French]
o intrahospital management of women with preeclampsia can be found in Ann Fr
Anesth Reanim 2010 Apr;29(4):e51 [French]
o criteria of pregnancy termination in women with preeclampsia can be found in
Ann Fr Anesth Reanim 2010 Apr;29(4):e59 [French]
o prehospital management of severe preeclampsia can be found in Ann Fr Anesth
Reanim 2010 Apr;29(4):e69 [French]
o eclampsia can be found in Ann Fr Anesth Reanim 2010 Apr;29(4):e75 [French]
o kidney and preeclampsia can be found in Ann Fr Anesth Reanim 2010
Apr;29(4):e83 [French]
o circulatory and respiratory problems in preeclampsia can be found in Ann Fr
Anesth Reanim 2010 Apr;29(4):e91 [French]
o liver and preeclampsia can be found in Ann Fr Anesth Reanim 2010
Apr;29(4):e97 [French]
o multidisciplinary management of severe preeclampsia (PE) can be found in Ann
Fr Anesth Reanim 2009 Mar;28(3):275
Australian and New Zealand guidelines:
Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) 2008 guideline
on management of hypertensive disorders of pregnancy can be found in Aust N Z J
Obstet Gynaecol 2009 Jun;49(3):242
Central and South American guidelines:
Colegio Mexicano de Especialistas en Ginecología y Obstetricia (COMEGO) clinical
practice guideline on diagnosis and treatment of preeclampsia-eclampsia can be found in
Ginecol Obstet Mex 2010 Jun;78(6):S461 [Spanish]
Mexican expert clinical guideline on detection and diagnosis of hypertensive pregnancy
disease can be found in Rev Med Inst Mex Seguro Soc 2011 Mar-Apr;49(2):213 [Spanish]
Review articles:
review of preeclampsia, eclampsia, and hypertension can be found in Am Fam Physician
2009 May 15;79(10):895
review can be found in Mayo Clin Proc 2000 Oct;75(10):1071
review can be found in BMJ 1999 May 15;318(7194):1332 full-text
reviews of preeclampsia
o review of preeclampsia can be found in Lancet 2010 Aug 21;376(9741):631
o review of preeclampsia can be found in BMJ 2006 Feb 25;332(7539):463 full-text
o review of preeclampsia can be found in Lancet 2005 Feb 26;365(9461):785
o review of preeclampsia can be found in Am Fam Physician 2004 Dec
15;70(12):2317 full-text
o review of preeclampsia can be found in JAMA 2002 Jun 26;287(24):3183,
commentary can be found in JAMA 2002 Oct 16;288(15):1847
o review of preeclampsia can be found in Lancet 2000 Oct 7;356(9237):1260,
commentary can be found in Lancet 2001 Jan 27;357(9252):312
o review of preeclampsia with emphasis on prevention can be found in Lancet 2001
Jan 20;357(9251):209, commentary can be found in Lancet 2001 May
12;357(9267):1534, Lancet 2001 Jun 30;357(9274):2140
o review of prediction and prevention of recurrent preeclampsia can be found in
Obstet Gynecol 2008 Aug;112(2 Pt 1):359
o review of potential markers of preeclampsia can be found in Reprod Biol
Endocrinol 2009 Jul 14;7:70 full-text
review of eclampsia can be found in Obstet Gynecol 2005 Feb;105(2):402
review of chronic hypertension in pregnancy can be found in N Engl J Med 2011 Aug
4;365(5):439, correction can be found in N Engl J Med 2011 Oct 27;365(17):1650
review of diagnosis and management of atypical preeclampsia-eclampsia can be found in
Am J Obstet Gynecol 2009 May;200(5):481e1
review of diagnosis and management of gestational hypertension and preeclampsia can
be found in Obstet Gynecol 2003 Jul;102(1):181, summary can be found in Am Fam
Physician 2004 Feb 15;69(4):979
AHRQ Evidence Report on Management of Chronic Hypertension During Pregnancy
2000 Aug:14
review of treatment for mild to moderate hypertension in pregnancy can be found in J
Fam Pract 2004 Jun;53(6):492
review of treatment of hypertension in pregnancy can be found in N Engl J Med 1996 Jul
25;335(4):257
review of interpreting abnormal proteinuria in pregnancy can be found in Obstet Gynecol
2010 Feb;115(2 Pt 1):365
review of recent developments in obstetrics can be found in BMJ 2003 Sep
13;327(7415):604 full-text
review of liver disease in pregnancy can be found in Lancet 2010 Feb 13;375(9714):594
case report of false-positive amphetamine toxicology screen results in three pregnant
women using labetalol can be found in Obstet Gynecol 2011 Feb;117(2 Pt 2):503
case report of 28-year-old primigravida with atypical eclampsia can be found in J Pak
Med Assoc 2009 Jul;59(7):489
MEDLINE search:
to search MEDLINE for (Hypertensive disorders of pregnancy) with targeted search
(Clinical Queries), click therapy, diagnosis, or prognosis
Patient Information
handout on pregnancy-induced hypertension from American Academy of Family
Physicians or in Spanish
handout on high blood pressure in pregnancy from National Heart, Lung and Blood
Institute (NHLBI)
handout on high blood pressure during pregnancy from American College of
Obstetricians and Gynecologists
handout on high blood pressure during pregnancy from American Academy of Family
Physicians or in Spanish
ICD-9/ICD-10 CodesReferences
General references used:
1. Leeman L, Fontaine P. Hypertensive disorders of pregnancy. Am Fam Physician. 2008
Jul 1;78(1):93-100. full-text
2. Lindheimer MD, Taler SJ, Cunningham FG. ASH position paper: hypertension in
pregnancy. J Clin Hypertens (Greenwich). 2009 Apr;11(4):214-25.
3. Magee LA, Helewa M, Moutquin JM, von Dadelszen P, Hypertension Guideline
Committee, Society of Obstetricians and Gynaecologists of Canada. Diagnosis,
evaluation, and management of the hypertensive disorders of pregnancy. J Obstet
Gynaecol Can 2008 Mar;30(3 Suppl 1):S1-48. PDF.
4. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and
Blood Institute, National High Blood Pressure Education Program Coordinating
Committee. Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-
52. full-text, commentary can be found in Hypertension 2004 Jan;43(1):1 full-text,
Hypertension 2004 Apr;43(4):e27 full-text, Hypertension 2004 May;43(5):e31. full-text
o summary can be found at Seventh Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) Reference
Card, Express Report PDF
o summary can be found in JAMA 2003 May 21;289(19):2560, correction can be
found in JAMA 2003 Jul 9;290(2):197, considerable commentary can be found in
JAMA 2003 Sep 10;290(10):1312
o summary can be found in full-text, editorial can be found in Am Fam Physician
2003 Jul 15;68(2):228
5. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice
Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of
preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002
Jan;99(1):159-67.
6. ACOG Practice Bulletin No. 125: Chronic hypertension in pregnancy. Obstet Gynecol.
2012 Feb;119(2 Pt 1):396-407
Recommendation grading systems used:
American College of Obstetricians and Gynecologists (ACOG) levels of evidence
o Level A - based on good and consistent scientific evidence
o Level B - based on limited or inconsistent scientific evidence
o Level C - based primarily on consensus and expert opinion
o References
ACOG practice bulletin on diagnosis and management of preeclampsia
and eclampsia (Obstet Gynecol 2002 Jan;99(1):159)
ACOG Practice Bulletin 125 on chronic hypertension in pregnancy
(Obstet Gynecol 2012 Feb;119(2 Pt 1):396)
Society of Obstetricians and Gynaecologists of Canada grades of recommendation
o quality of evidence assessment
I - evidence obtained from ≥ 1 properly randomized controlled trial
II-1 - evidence from well-designed controlled trials without randomization
II-2 - evidence from well-designed cohort (prospective or retrospective) or
case-control studies, preferably from more than 1 center or research group
II-3 - evidence obtained from comparisons between times or places with
or without the intervention; dramatic results in uncontrolled experiments
(such as the results of treatment with penicillin in the 1940s) could also be
included in this category
III - opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert committees
o classification of recommendations
A - good evidence to recommend clinical preventive action
B - fair evidence to recommend clinical preventive action
C - existing evidence is conflicting and does not allow to make
recommendation for or against use of clinical preventive action; however,
other factors may influence decision-making
D - fair evidence to recommend against clinical preventive action
E - good evidence to recommend against clinical preventive action
I - insufficient evidence (in quantity or quality) to make recommendation;
however, other factors may influence decision-making
o Reference - Society of Obstetricians and Gynaecologists of Canada. Diagnosis,
evaluation, and management of the hypertensive disorders of pregnancy (J Obstet
Gynaecol Can 2008 Mar;30(3 Suppl 1):S1 PDF)
American College of Chest Physicians (ACCP) grades
o Grade 1 - strong recommendation based on clear risk/benefit balance
o Grade 2 - weak recommendation based on unclear or close risk/benefit balance
o Grade A - high-quality evidence based on consistent evidence from randomized
trials without important limitations or exceptionally strong evidence from
observational studies
o Grade B - moderate-quality evidence based on randomized trials with important
limitations (inconsistent results, methodologic flaws, indirect or imprecise results)
or very strong evidence from observational studies
o Grade C - low- or very low-quality evidence based on observational studies, case
series, or randomized trials with serious flaws or indirect evidence
o Reference - ACCP Evidence-Based Clinical Practice Guidelines (Ninth Edition)
Methodology for the Development of Antithrombotic Therapy and Prevention of
Thrombosis Guidelines (Chest 2012 Feb;141(2 Suppl):53S full-text)
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Special acknowledgements:
Antigoni K. Woodland, MD (Obstetrician and Gynecologist, Danvers, Massachusetts,
USA) provides peer review.
Dr. Woodland has declared no financial or other competing interests related to this topic.
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