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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