Hypertensive Disorders of Pregnancy

Overview and Recommendations / Background
[+]Updated 2019 Nov 07 01:12 PM (ET)

Hypertension is the most common medical condition complicating

pregnancy.
Topic Editor Elliot M. Levine, MD, FACOG
Recommendations Editor Amir Qaseem, MD, PhD, MHA, FACP
Deputy Editor Alan Ehrlich, MD
Overview and Recommendations

Background
Hypertension is the most common medical condition complicating pregnancy.
There are multiple possible risk factors, the strongest of which are: prior preeclampsia, preexisting
hypertension or diabetes, chronic kidney disease, antiphospholipid antibody syndrome, and multifetal
pregnancy. Other important risk factors include advanced maternal age and elevated prepregnancy body
mass index (BMI).
Hypertension is defined as a persistent systolic blood pressure ≥ 140 mm Hg and/or diastolic blood
pressure ≥ 90 mm Hg.
Severe hypertension is defined as systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110
mm Hg, measured twice, at least 15 minutes apart.
Non-severe hypertension is defined as systolic blood pressure 140-159 mm Hg or diastolic blood
pressure 90-109 mm Hg.
Hypertensive disorders of pregnancy include both chronic hypertension diagnosed before pregnancy or prior
to 20 weeks gestation, and new-onset hypertension developing after 20 weeks gestation in a current
pregnancy.
Gestational hypertension is new-onset hypertension that develops at ≥ 20 weeks gestation, without
evidence of preeclampsia.
Preeclampsia is hypertension with new onset proteinuria (> 300 mg/24 hours) after 20 weeks gestation,
or, if no proteinuria, diagnosis requires ≥ 1 of severe features, which include:
thrombocytopenia (< 100,000 platelets/mcL)
impaired liver function (elevated serum liver transaminases to twice normal concentration)
new renal insufficiency (elevated serum creatinine > 1.1 mg/dL or doubling of serum creatinine in
patient without other renal disease)
pulmonary edema
new-onset cerebral or visual disturbances
Preeclampsia with severe features is characterized by severe hypertension or non-severe hypertension in

the presence of other severe complications, including, but not limited to those listed above.
Other types of hypertension in pregnancy include:
preeclampsia superimposed on chronic hypertension
eclampsia, defined as new-onset generalized seizures in woman with preeclampsia
Evaluation
In women with known or suspected chronic hypertension:
Perform preconception or early pregnancy evaluation to rule out secondary (potentially curable)
hypertension and identify possible end-organ involvement (Strong recommendation).
Obtain baseline testing for comparison if preeclampsia is suspected later in pregnancy (Strong
recommendation), including:
blood tests to assess serum creatinine, electrolytes, liver enzymes, and platelet count
urinalysis (dipstick test or quantification of urine protein)
In women with gestational hypertension or preeclampsia:

Initial evaluation includes
blood tests for assessment of (Strong recommendation):
complete blood count with platelet estimate
serum creatinine
liver enzymes
urinalysis for measurement of proteinuria (Strong recommendation)

Urinary dipstick testing is recommended for screening if suspicion of preeclampsia is low.
Definitive testing with urinary protein:creatinine ratio or 24-hour urine collection is recommended if
urinary dipstick proteinuria is ≥ 1+ in women with either of the following (Strong recommendation):
hypertension and rising blood pressure
normal blood pressure, but symptoms or signs suggestive of preeclampsia
Perform frequent monitoring in women < 37 weeks gestation and without severe features, including:
blood pressure (twice weekly including in-office assessment of blood pressure ≥ 1 time/week)
(Strong recommendation)
platelet counts, serum creatinine, and liver enzymes (weekly)
urine collection (once weekly) to assess for proteinuria (in women with gestational hypertension)
Fetal monitoring is recommended during expectant management in women with gestational hypertension or
preeclampsia without severe features.
Measurement of angiogenic factors has been investigated as tool to predict clinical outcomes in women
who initially present with early features of preeclampsia; however, no single test has been shown to reliably
predict preeclampsia and further study is needed to determine clinical utility.
Management
Hospitalization is recommended if there is any of the following:
systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg (Strong recommendation)
development of gestational hypertension or preeclampsia with severe features
concerns about adherence to frequent monitoring in women without severe features
Active management of third stage of labor is recommended, especially in women with thrombocytopenia or
a coagulopathy (Strong recommendation).
Early insertion of an epidural catheter is recommended for control of labor pain in women without
contraindications / Background
to an epidural (Strong recommendation).
Blood pressure thresholds for initiation of antihypertensive medications and treatment goal thresholds for
hypertensive disorders of pregnancy exist and vary by professional organization.
Specific management by type of hypertensive disorder
In women at moderate-to-high risk of preeclampsia or with chronic hypertension, use low-dose aspirin
(75-162 mg daily) starting at 12 weeks gestation and continuing until delivery (Strong recommendation)
For management of women with gestational hypertension or preeclampsia without severe features:
Indications for expectant management include
gestational hypertension or preeclampsia without severe features and stable maternal and fetal
conditions up until 37 weeks gestation
preeclampsia without severe features at 24-33 6/7 weeks gestation but only by a perinatal center
capable of caring for very preterm infant (Weak recommendation)
chronic hypertension with no additional maternal or fetal complications until 38 weeks gestation if
not prescribed antihypertensive medications or until 37 weeks gestation if prescribed
maintenance antihypertensive medications
chronic hypertension with superimposed preeclampsia and severe features < 34 weeks gestation
Delivery is recommended rather than continued observation at ≥ 37 weeks gestation (Strong
recommendation).
Consider vaginal delivery unless cesarean section is indicated for other obstetric indications (Weak
recommendation).
For management of women with gestational hypertension or preeclampsia with severe features:
Antihypertensive medications (Strong recommendation) and hospitalization are recommended.
Delivery is recommended soon after maternal stabilization for women who are ≥ 34 weeks gestation
or have unstable maternal or fetal conditions, regardless of gestational age (Strong
recommendation).
Consider vaginal delivery unless cesarean section is indicated for other obstetric indications (Weak
recommendation).
Use magnesium sulfate to reduce the risk of eclampsia (Strong recommendation).
Standard dosing options for magnesium sulfate:
4- to 6-g IV loading dose followed by maintenance dose of 1-2 g/hour for ≥ 24 hours
postpartum
4-g IV bolus followed by 1-g/hour infusion
10 g intramuscular loading dose followed by 5 g intramuscular every 4 hours or 1 g/hour
infusion until delivery and for ≥ 24 hours postpartum
Give corticosteroids to women receiving expectant management at ≤ 34 weeks gestation to benefit

fetal lung maturity (Strong recommendation).
For preeclampsia superimposed on chronic hypertension without severe features, consider expectant
management until 37 weeks gestation under stable maternal and fetal conditions (Weak
recommendation).
Antihypertensive medications are recommended for urgent control of acute severe hypertension (doses in
different guidelines vary) (Strong recommendation):
labetalol (in 1 of 2 dosing options):
10- to 20 mg IV bolus, then 20-80 mg every 10-30 minutes up to a maximum cumulative dose of 300
mg
constant infusion of 1-2 mg/minute IV
nifedipine immediate release 10-20 mg orally, repeated in 30 minutes as needed, then 10-20 mg every 2-6
hours (maximum daily dose 180 mg)
hydralazine in 1 of 2 dosing options:
5 mg IV or intramuscularly (IM), then 5-10 mg IV every 20-40 minutes up to a maximum cumulative
dose of 20 mg
constant infusion of 0.5-10 mg/hour
Related Summaries
Cardiovascular Disease in Pregnancy
Routine Prenatal Care
Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) Syndrome
General Information
Description
preexisting or new hypertensive disorder complicating pregnancy(1, 2, 4, 5)
hypertensive disorders that may occur during pregnancy include
chronic hypertension
essential
secondary
masked hypertension
white coat hypertension
gestational hypertension
transient gestational hypertension
preeclampsia (with and without severe features)
chronic hypertension with superimposed hypertension
hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome
eclampsia
Also called
pregnancy-induced hypertension
PIH
preeclampsia
toxemia of pregnancy
gestosis
preeclamptic toxemia
gestational hypertension has replaced the term pregnancy-induced hypertension(1)
Types
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommendations for classification
of hypertensive disorders of pregnancy(6)
new-onset hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic ≥ 90 mm Hg) that is
diagnosed ≥ 20 weeks gestation, including
preeclampsia, defined as hypertension > 20 weeks gestation accompanied by proteinuria and/or
either of
evidence of any of the following
maternal acute kidney injury (creatinine ≥ 1 mg/dL)
liver dysfunction (elevated transaminases [ALT or AST > 40 units/L] with or without right upper
quadrant or epigastric abdominal pain)
neurological features, such as eclampsia, altered mental status, blindness, stroke, clonus,
severe headaches, persistent visual scotomata
hematological complications, including thrombocytopenia (platelet count < 150,000/mcL,
disseminated intravascular coagulation [DIC], hemolysis)
uteroplacental dysfunction, possibly indicated by any of the following

fetal growth restriction
abnormal umbilical artery Doppler wave form analysis
stillbirth
transient gestational hypertension, defined as hypertension that arises at any gestation that resolves
without treatment during the pregnancy
gestational hypertension, defined as hypertension > 20 weeks gestation in the absence of proteinuria
and without biochemical or hematological abnormalities
preeclampsia superimposed upon chronic hypertension, defined as development of maternal organ
dysfunction consistent with preeclampsia in women with chronic essential hypertension
increases in blood pressure not sufficient to diagnose superimposed preeclampsia due to
increase in blood pressure typically seen after 20 weeks gestation
in absence of preexisting proteinuria, new-onset proteinuria in the setting of increased blood
pressure is sufficient to diagnose superimposed preeclampsia
hypertension known before pregnancy or present < 20 weeks gestation, including

chronic hypertension, defined as hypertension predating the pregnancy or diagnosed < 20 weeks
gestation; may be due to essential hypertension or secondary causes (uncommon)
white-coat hypertension, defined as elevated office/clinic blood pressure (≥ 140/90 mm Hg) but
normal blood pressure measured at home or work (< 135/85 mm Hg)
masked hypertension, characterized by normal blood pressure in office or clinic setting but elevated
at other times, most typically diagnosed by 24-hour ambulatory blood pressure monitoring (ABPM) or
automated home blood pressure monitoring (HBPM).
American College of Obstetricians and Gynecologists (ACOG) recommendations for classification of

hypertensive disorders of pregnancy(4, 5)
gestational hypertension
defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg on 2
occasions ≥ 4 hours apart in woman with previously normal blood pressure
considered severe if systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 110 mm
Hg
should be diagnosed as preeclampsia if any severe features present, even in the absence of
proteinuria (ACOG Level C)
preeclampsia, defined as blood pressure ≥ 140/90 mm Hg on 2 occasions ≥ 4 hours apart and proteinuria
at > 20 weeks gestation
proteinuria defined as either of
≥ 300 mg per 24 hour urine collection
protein/creatinine ratio ≥ 0.3 mg/dL or dipstick reading of 2+ (should be used only if other
quantitative methods are not available)
if no proteinuria, diagnosis requires new-onset hypertension with new onset of ≥ 1 severe feature
severe features of preeclampsia include
Overview andsystolic blood pressure /≥ Background
Recommendations 160 mm Hg and/or diastolic blood pressure 110 mm Hg on 2 occasions
≥ 4 hours apart (unless hypertensive therapy is initiated before this time)
impaired liver function (elevated serum liver transaminases to twice normal concentration) plus
severe persistent right upper quadrant or epigastric pain unresponsive to medication and not
accounted for by other diagnoses
new renal insufficiency (elevated serum creatinine > 1.1 mg/dL or doubling of serum creatinine in
patient without other renal disease)
pulmonary edema
new-onset headache unresponsive to medication and not accounted for by other diagnoses
visual disturbances
hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome
more severe form of preeclampsia
may not present with either hypertension or proteinuria (reported in up to 15% of women)
typical criteria used to make diagnosis include
lactate dehydrogenase (LDH) ≥ 600 units/L
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > twice the upper limit of
normal
platelet count < 100,000 x 109/L
see Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) Syndrome topic for additional
information
eclampsia, defined as new-onset tonic-clonic, focal, or multifocal seizures in absence of other causative
conditions, such as epilepsy, cerebral arterial ischemia and infarction, intracranial hemorrhage, or drug
use
chronic hypertension is hypertension that predates pregnancy or detected before 20 weeks gestation
reported in 0.9%-1.5% of pregnant women
may not be diagnosed until well into postpartum period
preeclampsia superimposed on chronic hypertension, defined as preeclampsia with history of

hypertension before pregnancy or < 20 weeks gestation
difficult to diagnose and often a diagnosis of exclusion
consider diagnosis in women with
sudden exacerbation of hypertension or proteinuria
new-onset thrombocytopenia (< 100,000 platelets/mcL)
sudden increase in liver enzymes to abnormal levels
sudden development of symptoms suggestive of preeclampsia
elevated uric acid levels
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for classification of

hypertensive disorders of pregnancy (endorsed by Hypertension Canada)(2)
hypertension in pregnancy defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood
pressure ≥ 90 mm Hg based on average of ≥ 2 measurements taken at least 15 minutes apart using
same arm (SOGC Grade B, Level II-2)
severe hypertension defined as systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110
mm Hg based on average of ≥ 2 measurements taken at least 15 minutes apart using same arm (SOGC
Grade B, Level II-2)
for diagnosis of clinically significant proteinuria
Overview strongly suspect significant/ proteinuria
and Recommendations Background when urinary dipstick proteinuria is ≥ 1+ (SOGC Grade A, Level
II-2)
significant 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 B, Level II-2)
insufficient evidence for recommendations on accuracy of urinary albumin:creatinine ratio (SOGC
Grade L, Level II-2)
definitions of preeclampsia
in women with preexisting hypertension, preeclampsia defined as resistant hypertension, new or
worsening proteinuria ≥ 1 adverse condition, or ≥ 1 severe complication (SOGC Grade B, Level II-2)
in women with gestational hypertension, preeclampsia defined as new-onset proteinuria, ≥ 1 adverse
condition, or ≥ 1 severe complication (SOGC Grade B, Level II-2)
preeclampsia with severe features defined as preeclampsia with ≥ 1 severe complication (SOGC Grade B,
Level II-2)
adverse conditions include
maternal central nervous system involvement, such as headache and/or visual changes
maternal cardiorespiratory involvement, such as chest pain, dyspnea, and/or oxygen saturation < 97%
maternal hematological abnormalities, such as
elevated white blood cell (WBC) count
elevated international normalized ration (INR) or activated partial thromboplastin time (aPTT)
low platelet count
maternal renal abnormalities, such as elevated serum creatinine or serum uric acid
maternal hepatic involvement, such as
nausea or vomiting
right upper quadrant or epigastric pain
elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate
dehydrogenase (LDH), or bilirubin
low plasma albumin
fetoplacental indications, such as

abnormal fetal heart rate (FHR)
intrauterine growth restriction (IUGR)
oligohydramnios
absent or reversed end-diastolic flow by Doppler velocimetry
severe complications of preeclampsia that warrant delivery include

maternal central nervous system involvement, such as
eclampsia
posterior reversible leukoencephalopathy syndrome (PRES)
cortical blindness or retinal detachment
Glasgow coma scale < 13
stroke, transient ischemic attack, or reversible ischemic neurological deficit (< 48 hours)
maternal cardiorespiratory involvement, such as

uncontrolled severe hypertension over 12 hours refractory to use of 3 antihypertensive agents
oxygen saturation < 90%, need for ≥ 50% oxygen for > 1 hour intubation (other than for cesarean
section), or pulmonary edema
positive inotropic support
myocardial ischemia or infarction
9
Overview platelet count < 50 x 10 L and/or
and Recommendations transfusion of any blood product
/ Background
maternal renal complications, such as
acute kidney injury (creatinine > 150 mcmol without history of renal disease)
new indications for dialysis
maternal hepatic complications, such as

hepatic dysfunction (INR > 2 in absence of disseminated intravascular coagulation or warfarin)
hepatic hematoma or rupture
fetoplacental complications, such as

placental abruption with signs of maternal or fetal compromise
reverse ductus venosus A wave
stillbirth
Epidemiology
Incidence/Prevalence
hypertensive disorders
reported to complicate up to 10% of pregnancies in United States(1)
increasing number of hypertension-associated delivery hospitalizations in United States
based on cross-sectional study
36,537,061 delivery discharges from 1998 to 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

hypertensive disorder of pregnancy in about 9.8% of women in Australia
250,173 women and 255,931 infants discharged from hospital following birth in New South Wales
between 2000 and 2002 evaluated
24,517 women (9.8%) had hypertensive disorder, including
gestational hypertension in 4.3%
preeclampsia in 4.2%
chronic hypertension in 0.6%
chronic hypertension with superimposed preeclampsia in 0.3%
Reference - Med J Aust 2005 Apr 4;182(7):332 full-text

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)
chronic hypertension reported in 0.9%-1.5% of pregnant women(5)

preeclampsia
higher prevalence among women with hypertension(2)
prevalence of preeclampsia 3.8% in United States in 2010
120,000,000 women hospitalized for delivery from 1980 to 2010 in United States were analyzed
in 2010, prevalence of
any preeclampsia 3.8%
severe preeclampsia 1.4%
mild preeclampsia 2.5%
Reference - BMJ 2013 Nov 7;347:f6564
mean incidence of preeclampsia about 3.6%

based on systematic review of observational studies
systematic review of 36 studies with 1,699,073 pregnant women
60,584 women (3.6%) had preeclampsia
Reference - BJOG 2007 Dec;114(12):1477
incidence of early-onset preeclampsia 0.3% and late-onset preeclampsia 2.7% in Washington state
between 2000 and 2008
based on cohort study of all (670,120) deliveries in Washington state between 2000 and 2008
preeclampsia rate among singleton births 3%
early-onset (< 34 weeks gestation) preeclampsia in 0.3%
late-onset preeclampsia in 2.7%
Reference - Obstet Gynecol 2014 Oct;124(4):771
severe preeclampsia expected to occur in about 0.39% of deliveries in United Kingdom

based on case-control study
48,865 women delivering in United Kingdom matched to 4 randomly selected controls each
severe preeclampsia ((including hemolysis, elevated liver enzymes, low platelets [HELLP] syndrome
and eclampsia) developed in 0.39% of deliveries
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
Reference - BMJ 2001 May 5;322(7294):1089 full-text
superimposed preeclampsia may develop in about 26% of women with chronic hypertension
systematic review of 55 observational studies evaluating association between chronic hypertension
and complications of pregnancy in 795,221 women and 812,772 neonates
definition of chronic hypertension before or during pregnancy was variable across studies
estimated incidence of adverse maternal outcomes
superimposed preeclampsia 25.9% (95% CI 21%-31.5%) in analysis of 38 studies
cesarean section 41.4% (95% CI 35.5%-47.7%) in analysis of 27 studies
analyses limited by significant heterogeneity
Reference - BMJ 2014 Apr 15;348:g2301 full-text
2.2% rate of preeclampsia in 39,615 pregnancies in WHO Antenatal Care Trial ( Am J Obstet Gynecol
2006 Apr;194(4):921)
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), correction can be
found in JAMA 2006 Dec 27;296(24):2926
3.8% rate of preeclampsia among 3,494 women giving birth in Norwegian population-based study ( BMJ
Overview and
2007 Recommendations
Nov / Background
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
prevalence of postpartum hypertension appears to increase when using new ACC/AHA criteria for
diagnosis of hypertension among women with hypertensive disorders of pregnancy
based on secondary analysis of 2 cohort studies
secondary analysis of the Pre-Eclampsia New Emerging Team (PE-NET) cohort and the Maternal Health
Clinic (MHC) cohort to evaluate impact of American College of Cardiology(ACC)/American Heart
Association (AHA) blood pressure criteria for diagnosis of hypertension on diagnosis of hypertension in
pregnancy
hypertension screening at 12 months in PE-NET cohort and at 6 months in MHC cohort
women were reclassified according to new blood pressure criteria as follows
normal (systolic < 120 mm Hg and diastolic < 80 mm Hg)
elevated (systolic 120-129 mm Hg and diastolic < 80 mm Hg)
stage I hypertension (systolic 130-139 mm Hg or diastolic 80-89 mm Hg)
stage II hypertension (systolic ≥ 140 mm Hg or diastolic ≥ 90 mm Hg)
comparing postpartum hypertension diagnosis rates using new ACC-AHA criteria (stage I and stage II
hypertension or taking antihypertensives with normal blood pressure) vs. old ACC-AHA criteria (≥140/90
mm Hg)
22% vs. < 1% in women with uncomplicated pregnancy (PE-NET control)
56.4% vs. 20.9% in women with pregnancy complicated by preeclampsia (women with preeclampsia
in PE-NET cohort)
67.2% vs. 31.3% in women referred to MHC due to pregnancy complicated by any hypertensive
disorder of pregnancy
Reference - Am J Perinatol 2019 Mar;36(4):440
Risk factors
Overview of risk factors
for preeclampsia(1, 3, 4)
women at high-risk include those with any
autoimmune disease (such as systemic lupus erythematosus or antiphospholipid antibodies)
preeclampsia or hypertensive disease in previous pregnancy
chronic kidney disease
preexisting diabetes mellitus
chronic hypertension or renal disease
women at moderate risk include those with > 1 moderate-risk factor, including
family history of preeclampsia
maternal age > 35 years
first pregnancy
pregnancy interval > 10 years
multiple gestation pregnancy
women with BMI ≥ 30 kg/m2 at first visit
estimated relative risks of multiple risk factors for preeclampsia in systematic review
systematic review of 48 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)
preexisting 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
Reference - BMJ 2005 Mar 12;330(7491):565 full-text, editorial can be found in BMJ 2005 Mar
12;330(7491):549
risk factors present at 15 weeks gestation might predict onset of preeclampsia
based on a prospective multicenter cohort
3,572 healthy, nulliparous women with singleton pregnancy evaluated
clinical risk factors present at 15 weeks gestation in women who developed 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
nonspecific risk factors for severe complications of preeclampsia include(2)

immigrant status
young maternal age
nulliparity
lower maternal weight
early-onset preeclampsia in current pregnancy
many medical factors in early pregnancy associated with increased risk of preeclampsia
systematic review of 92 cohort studies (37 prospective and 55 retrospective studies) evaluating clinical
factors in early pregnancy (≤ 16 weeks gestation) and risk of preeclampsia in 25,356,688 pregnancies
most analyses limited by significant statistical heterogeneity
obstetrical factors at ≤ 16 weeks gestation associated with increased risk of preeclampsia included
prior preeclampsia (relative risk [RR] 8.4, 95% CI 7.1-9.9) in analysis of 20 studies with 3,720,885
women
multifetal pregnancy (RR 2.9, 95% CI 2.6-3.1) in analysis of 8 studies with 7,309,227 women
prior stillbirth (RR 2.4, 95% CI 1.7-3.4) in analysis of 2 studies with 63,814 women
nulliparity (RR 2.1, 95% CI 1.9-2.4) in analysis of 25 studies with 2,975,158 women
prior placental abruption (RR 2, 95% CI 1.4-2.7) in analysis of 3 studies with 291,134 women
older maternal age
Overview and> Recommendations
40 years (RR 1.5, 95% /CIBackground
1.2-2) in analysis of 16 studies with 4,260,202 women
> 35 years (RR 1.2, 95% CI 1.1-1.3) in analysis of 22 studies with 5,244,543 women
no significant difference in risk of preeclampsia associated with prior intrauterine growth restriction in
1 study with 55,542 women
medical factors at ≤ 16 weeks gestation associated with increased risk of preeclampsia included
chronic hypertension (RR 5.1, 95% CI 4-6.5) in analysis of 20 studies with 6,589,661 women
pregestational diabetes (RR 3.7, 95% CI 3.1-4.3) in analysis of 19 studies with 2,553,117 women
antiphospholipid antibody syndrome (RR 2.8, 95% CI 1.8-4.3) in analysis of 3 studies with 220,156
women
systemic lupus erythematosus (RR 2.5, 95% CI 1-6.3) in analysis of 2 studies with 2,413,908 women
increased prepregnancy body mass index (BMI)
BMI > 30 kg/m2 (RR 2.8, 95% CI 2.6-3.1) in analysis of 40 studies with 5,921,559 women
BMI > 25 kg/m2 (RR 2.1, 95% CI 2-2.2) in analysis of 38 studies with 3,644,747 women
chronic kidney disease (RR 1.8, 95% CI 1.5-2.1) in analysis of 5 studies with 966,505 women
Reference - BMJ 2016 Apr 19;353:i1753 full-text
Medical risk factors

chronic medical conditions
including(2, 4, 6)
antiphospholipid antibody syndrome
preexisting hypertension or diastolic blood pressure ≥ 90 mm Hg at first antenatal visit (typically in
early pregnancy)
preexisting renal disease or proteinuria at first antenatal visit (typically in early pregnancy)
inherited thrombophilias
increased prepregnancy triglycerides
higher HbA1c associated with increased risk of preeclampsia in women with type 1 diabetes
based on prospective cohort analysis of DAPIT trial
210 women with type 1 diabetes and hypertensive disorders in pregnancy evaluated
127 with preeclampsia
83 with gestational hypertension
preeclampsia associated with higher HbA1c before and during pregnancy (p < 0.05 vs. no
preeclampsia development)
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)
compared to HbA1c < 6.1%, increased risk of preeclampsia
at 26 weeks gestation with
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)
at 34 weeks gestation with

HbA1c 7%-7.9% (OR 3.27, 1.31-8.2)
HbA1c ≥ 8% (OR 8.01, 2.04-31.5)
no significant association of glycemic control with gestational hypertension risk
Reference - Diabetes Care 2011 Aug;34(8):1683
polycystic ovary syndrome associated with increased risk for maternal and neonatal complications
polycystic ovary syndrome associated with increased risk for preterm delivery, preeclampsia, and
gestational diabetes
based on systematic review of cohort studies and additional large cohort study
systematic review of 23 cohort studies (8 prospective, 15 retrospective) reporting association
between polycystic ovary syndrome (PCOS) and pregnancy outcomes in 2,544 women with PCOS
and 89,848 women without PCOS
PCOS associated with increased risk of
preterm delivery (odds ratio [OR] 2.2, 95% CI 1.6-3)
preeclampsia (OR 4.2, 95% CI 2.8-6.5)
pregnancy-induced hypertension (OR 4, 95% CI 2.8-6)
gestational diabetes (OR 2.8, 95% CI 1.9-4)
infants born to mothers with PCOS had increased risk of small-for-gestational-age (OR 2.62,
95% CI 1.35-5.1)
no significant association between PCOS and cesarean delivery, operative vaginal delivery, and
birth of large-for-gestational-age infants
Reference - Am J Obstet Gynecol 2011 Jun;204(6):558.e1
prospective cohort study comparing 3,787 births among women with PCOS and 1,191,336 births
among women without PCOS
preeclampsia (adjusted odds ratio [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)
infants born to mothers with PCOS 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)
Reference - BMJ 2011 Oct 13;343:d6309 full-text, editorial can be found in BMJ 2011 Oct
13;343:d6407, commentary can be found in J Midwifery Womens Health 2012 Mar-
Apr;57(2):202
polycystic ovary syndrome associated with increased risk of neonatal intensive care unit admission,
hypertensive disorders in pregnancy, and gestational diabetes
systematic review of 27 observational studies evaluating pregnancy and neonatal complications in
4,994 pregnancies complicated by PCOS and 1,196,775 pregnancies without PCOS
neonatal intensive care unit admission (odds ratio [OR] 2.32, 95% CI 1.4-3.85) in analysis of 5
studies
preeclampsia (OR 3.28, 95% CI 2.06-5.22) in analysis of 15 studies, results limited by
significant heterogeneity
pregnancy-induced hypertension (OR 3.07, 95% CI 1.82-5.18) in analysis of 14 studies, results
limited by significant heterogeneity
gestational diabetes (OR 2.81, 95% CI 1.99-3.98) in analysis of 21 studies, results limited by
Overview andnoRecommendations
significant difference/ in
Background
preterm delivery in analysis of 14 studies, results limited by significant heterogeneity
birth weight in analysis of 19 studies, results limited by significant heterogeneity
cesarean section in analysis of 10 studies, results limited by significant heterogeneity
Reference - Reprod Biol Endocrinol 2013 Jun 26;11:56 full-text
higher maternal triglyceride levels may be associated with increased risk for preeclampsia
systematic review of 5 cohort studies and 24 case-control studies evaluating association between
hypertriglyceridemia and preeclampsia in 5,867 pregnant women
preexisting maternal hypertriglyceridemia associated with increased risk for preeclampsia
(weighted mean difference [WMD] 0.78 mmol/L, 95% CI 0.6-0.96) in analysis of 24 case-control
studies with 2,720 women
(WMD 0.24, 95% CI 0.13-0.34) in analysis of 5 cohort studies with 3,147 women
Reference - BJOG 2013 Oct;120(11):1321
medical conditions in pregnancy

periodontal disease during pregnancy may increase risk for preeclampsia
periodontal disease associated with increased risk for preeclampsia
based on systematic review of observational studies limited by clinical heterogeneity
systematic review of 15 studies (3 cohorts, 12 case-controls) evaluating association between
periodontal disease (PD) and preeclampsia in 5,023 pregnant women
study limited by clinical heterogeneity in definitions and diagnosis of PD and preeclampsia across
studies
periodontal disease associated with increased risk for preeclampsia (odds ratio [OR] 2.17, 95% CI
1.38-3.41) in analysis of all studies
in subgroup analysis analyzed according to definition of periodontal disease
increased risk of preeclampsia with PD defined as probing pocket depth (PPD) and clinical
attachment level (CAL) (OR 2.5, 95% CI 1.54-4.04) in analysis of 10 studies with 3,902 women
no significant differences in risk for preeclampsia with PD defined as
CAL alone (OR 1.45, 95% CI 0.36-5.78) in analysis of 3 studies with 1,001 women
PPD alone (OR 2,85, 95% CI 0.99-8.19) in analysis of 2 studies with 111 women
Reference - PLoS One 2013;8(8):e71387 full-text

periodontal disease and urinary tract infection during pregnancy may each be associated with
increased risk of preeclampsia
based on systematic review of observational studies limited by clinical heterogeneity
systematic review of 49 studies (19 cohorts, 3 cross-sectional, and 27 case-controls)
periodontal disease associated with preeclampsia (odds ratio 1.76, 95% CI 1.43-2.18) in 6 studies,
results limited by heterogeneity (I2 = 79%)
urinary tract infection associated with preeclampsia (odds ratio 1.57, 95% CI 1.45-1.70) in 17
studies, results limited by 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
sleep-disordered breathing in pregnant women associated with increased risk of preeclampsia and
gestational diabetes
systematic review of 31 observational studies evaluating association between sleep-disordered
breathing and adverse pregnancy outcomes in pregnant women
sleep-disordered breathing associated with increased risk of
gestational hypertension or preeclampsia (adjusted odds ratio 2.34, 95% CI 1.6-3.09) in analysis of
5 studies
gestational diabetes (adjusted odds ratio 1.86, 95% CI 1.3-2.42) in analysis of 5 studies
Reference - Am J Obstet Gynecol 2014 Jan;210(1):52.e1, editorial can be found in Am J Obstet
Gynecol 2014 Jan;210(1):3
migraine headaches associated with increased risk of hypertensive disorders in pregnancy

based on prospective cohort study
702 normotensive women with singleton pregnancy at 11-16 weeks gestation evaluated
38.5% had migraine headaches
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
rheumatologic disorders associated with increased risk of preeclampsia

based on retrospective cohort study
18,648 women who delivered during 33-month period at single institution evaluated
0.6% had rheumatologic disorders (systemic lupus erythematosus, rheumatoid arthritis,
antiphospholipid antibody syndrome, or other rheumatologic disease)
preeclampsia developed in 8.8% with rheumatologic disorders vs. 2.3% without rheumatologic
disorders (p < 0.001)
vitamin D insufficiency during pregnancy associated with increased risk of preeclampsia

systematic review of 31 observational studies evaluating association between maternal serum 25-
hydroxyvitamin D level during pregnancy, and pregnancy and neonatal outcomes
9 studies evaluated risk for preeclampsia
insufficient maternal serum 25-hydroxyvitamin D level associated with increased risk of preeclampsia
(odds ratio 1.79, 95% CI 1.25-2.58) in analysis of 7 studies
Reference - BMJ 2013 Mar 26;346:f1169 full-text
similar results found in systematic review of 15 observational studies evaluating association between
serum 25-hydroxyvitamin D level during pregnancy and risk of preeclampsia ( J Clin Endocrinol Metab
2013 Aug;98(8):3165-73)
some antidepressants used during pregnancy associated with increased risk of preeclampsia but not
selective serotonin reuptake inhibitors
69,448 pregnant women with depression had no treatment or monotherapy with selective serotonin
reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRIs), or tricyclic
antidepressants (TCAs)
risk of preeclampsia increased with use of SNRIs and TCAs
use during gestational weeks 10-20 (vs. no antidepressant use)
SNRIs (adjusted relative
Overview and Recommendations risk [RR] 1.95, 95% CI 1.25-3.03)
/ Background
TCAs (adjusted RR 3.23, 95% CI 1.87-5.59)
use during gestational weeks 10-24 among women with prepregnancy antidepressant use (vs.
discontinued use during gestational weeks 10-24)
SNRIs (adjusted RR 3.43, 95% CI 1.77-6.65)
TCAs (adjusted RR 3.26, 95% CI 1.04-10.24)
no significant differences with use of SSRIs

Reference - Am J Epidemiol 2012 May 15;175(10):988
Obstetric risk factors

preconceptual risk factors
maternal age ≥ 35 years(2, 4)
increasing maternal age associated with increased risk of hypertensive disorders of pregnancy
203,517 women (15% ≥ 35 years old) with singleton gestation stratified by maternal age
compared with women aged 25-29.9 years, increased risk of hypertensive disorders of pregnancy
in women aged
35-39.9 years (adjusted odds ratio [OR] 1.22, 95% CI 1.12-1.33)
40-44.9 years (adjusted OR 1.63, 95% CI 1.42-1.88)
≥ 45 years (adjusted OR 1.89, 95% CI 1.21-2.96)
Reference - Obstet Gynecol 2013 Dec;122(6):1184
short duration of sexual relationship with current partner(2)

interpregnancy interval ≥ 10 years(2)
use of reproductive technologies(2, 6)
use of assisted reproductive technology associated with increased risk of preeclampsia
systematic review of 92 cohort studies (37 prospective and 55 retrospective studies) evaluating
clinical factors in early pregnancy (≤ 16 weeks gestation) and risk of preeclampsia in 25,356,688
pregnancies
use of assisted reproductive technology associated with increased risk of preeclampsia (relative
risk 1.8, 95% CI 1.6-2.1) in analysis of 20 studies with 1,463,529 women, analysis limited by
Reference - BMJ 2016 Apr 19;353:i1753 full-text
history of fertility treatment and recurrent miscarriage may be associated with increased risk of
preeclampsia in pregnant nulliparous women
based on cohort study
20,846 nulliparous women with singleton pregnancies in Norway completed questionnaires on
miscarriage and infertility
preeclampsia diagnosis retrieved from national registry
preeclampsia associated with
recurrent miscarriage and fertility treatment (p < 0.05)
fertility treatment (p < 0.05)
recurrent miscarriage (not significant)
Reference - BJOG 2009 Jan;116(1):108
past obstetric history risk factors
history of preeclampsia(2)
history of miscarriage at ≤ 10 weeks gestation with same partner(2)
preterm delivery in setting of preeclampsia and low fetal growth associated with increased risk of
preeclampsia in subsequent pregnancy
536,419 women with first and second singleton deliveries in Denmark from 1978 to 2007
increased risk of preeclampsia in subsequent pregnancy in women with preterm delivery and
preeclampsia (odds ratio [OR] 2.08, 95% CI 1.87-2.31)
low fetal growth (OR 1.62, 95% CI 1.34-1.96)
antepartum risk factors

maternal body mass index (BMI) > 30 kg/m2(2, 4, 6)
overweight/obesity
overweight and obesity associated with increased risk of preeclampsia
based on cohort study of 2,637 pregnant women
9% developed preeclampsia
overweight/obesity (compared with BMI ≤ 25) associated with increased risk of preeclampsia
overweight (BMI > 25-30 kg/m2) (adjusted odds ratio [OR] 1.65, 95% CI 1.13-2.41)
class 1 obesity (BMI > 30-35 kg/m2) (adjusted OR 2.34, 95% CI 1.51-3.61)
class 2 obesity (BMI > 35-40 kg/m2) (adjusted OR 3.59, 95% CI 2.13-6.03)
class 3 obesity (BMI > 40 kg/m2) (adjusted OR 6.04, 95% CI 3.56-10.24)
excessive maternal weight gain in pregnancy

increase of ≥ 3 BMI units between first and second pregnancies associated with increased risk of
pregnancy-induced hypertension in normal and underweight women
7,897 women with first 2 consecutive deliveries between 2009 and 2011 evaluated for
interpregnancy weight change (difference between prepregnancy body mass indices [BMI] of
first and second pregnancies)
for normal and underweight women only, increase in interpregnancy interval by ≥ 3 BMI units
associated with increased risk of pregnancy-induced hypertension (adjusted odds ratio 3.76,
95% CI 2.16-6.57)
Reference - Obstet Gynecol 2013 Nov;122(5):999
vaginal bleeding in early pregnancy(2)

gestational trophoblastic neoplasia(2)
multiple gestation(2, 4, 6)
intrauterine growth restriction (IUGR)(2)
abnormal uterine artery Doppler(2)
systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg at first antenatal visit
(typically in early pregnancy)(2)
higher blood pressure associated with increased risk of preeclampsia compared with blood pressure
Overview <and Recommendations / Background
140/90 mm Hg in women with chronic hypertension before 20 weeks gestation
based on secondary analysis of Maternal-Fetal Medicine Units Network’s High-risk Aspirin
preeclampsia prevention trial
759 women with singleton pregnancy and chronic hypertension diagnosed before 20 weeks
gestation were stratified by blood pressure (< 140/90, 140-150/90-99, or 151-159/100-109 mm
Hg)
chronic hypertension defined as blood pressure ≥ 140/90 mm Hg on 2 occasions ≥ 4 hours apart,
or previously diagnosed and on antihypertensive therapy
compared with blood pressure < 140/90 mm Hg, increased risk of preeclampsia with blood
pressure
140-150/90-99 mm Hg (adjusted odds ratio [OR] 1.7, 95% CI 1.2-2.5)
151-159/100-109 mm Hg (adjusted OR 2.4, 95% CI 1.3-4.3)
Reference - Obstet Gynecol 2014 May;123(5):966
chronic hypertension associated with increased risk of preeclampsia

chronic hypertension associated with increased risk of preeclampsia (adjusted odds ratio 2.72,
95% CI 1.78-4.13)
Family history risk factors

family history of preeclampsia (mother or sister)(2, 4)
family history of early-onset cardiovascular disease(2)
genotypes
HLA-DR genotypes (particularly DR4) may be associated with preeclampsia risk
systematic review of 22 studies of HLA allele frequencies in association with preeclampsia or
intrauterine growth retardation
9 of 10 studies suggested DR allelic differences associated with preeclampsia
2 of 3 studies suggested no association between HLA alleles and intrauterine growth retardation
6 studies of HLA homozygosity as risk factor for preeclampsia had mixed results
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)
Biomarkers
abnormal pregnancy-associated plasma protein-A (PAPP-A), free human chorionic gonadotrophin (bhCG),
inhibin A, or estradiol(2)
angiogenesis-related biomarkers associated with risk of preeclampsia
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
Overview case-control
and Recommendations
study ( N Engl/JBackground
Med 2004 Feb 12;350(7):672), commentary can be found in N Engl J
Med 2004 May 6;350(19):2003
greater median soluble fms-like tyrosine kinase-1 to placental growth factor ratios observed in
pregnancies with preeclampsia or hemolysis, elevated liver enzymes and low platelets syndrome,
fetal growth restriction, or both
171 singleton pregnancies complicated by fetal growth restriction, preeclampsia or hemolysis,
elevated liver enzymes and low platelets syndrome (HELLP), or preeclampsia or HELLP plus fetal
growth restriction matched with 171 healthy control pregnancies and maternal serum
measurements of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PIGF)
taken at both < 34 and ≥ 34 weeks gestation
median values of sFlt-1/PIGF ratio at < 34 weeks gestation (p < 0.001 for all vs. controls)
3 in controls
231 with preeclampsia or HELLP
90 with fetal growth restriction
514 with preeclampsia or HELLP plus fetal growth restriction
median values of sFlt-1/PIGF ratio at ≥ 34 weeks gestation (p < 0.001 for all vs. controls)
11 in controls
67 with preeclampsia or HELLP
117 with fetal growth restriction
165 with preeclampsia or HELLP plus fetal growth restriction
Reference - Obstet Gynecol 2014 Aug;124(2 Pt 1):265
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
elevated plasma kynurenic acid may be associated with increased risk of preeclampsia
2,936 women with singleton pregnancies evaluated for 6 kynurenine pathway metabolites at
approximately 18 weeks gestation
4% subsequently developed preeclampsia
kynurenic acid concentration > 95th percentile associated with increased risk of preeclampsia compared
to kynurenic acid concentration in 25th-75th percentile (adjusted odds ratio 3.6, 95% CI 1.9-6.8)
plasma adiponectin levels < 6.4 mcg/mL associated with increased risk of hypertensive disorders in
pregnancy
based on nested case-control study
82 women with preeclampsia (34) or gestational hypertension (48) from cohort study matched to 82
normotensive controls with uneventful pregnancies
plasma adiponectin concentrations < 6.4 mcg/mL in 34% with hypertensive pregnancies vs. 7% of
controls (p < 0.001)
Reference - Obstet Gynecol 2005 Aug;106(2):340
Additional risk factors
smoking
cocaine and methamphetamine use
higher maternal blood lead concentrations may be associated with increased risk of preeclampsia
systematic review of 12 studies (6 cohort studies and 5 case-control studies) evaluating association
between preeclampsia and lead poisoning in 6,069 women
studies varied widely in time of blood collection (11-41 weeks gestation), mean lead levels in patients
with preeclampsia (1.32 micrograms/dL-37.68 micrograms/dL), and mean lead levels in controls (1.32
micrograms/dL-27.95 micrograms/dL)
each increase of 1 mcg/dL of lead levels associated with 1.6% increase in likelihood of preeclampsia
Reference - Environ Res 2018 Jan;160:12
in utero diethylstilbestrol exposure may be associated with increased risk for preeclampsia
retrospective cohort of 6,580 women evaluating adverse health outcomes associated with DES
cohort included
4,653 women exposed to DES in utero
1,927 women without DES exposure
DES exposure associated with increased risk of preeclampsia (26.4% vs. 13.7%, p < 0.05)
Reference - N Engl J Med 2011 Oct 6;365(14):1304
New-onset postpartum preeclampsia

risk factors for new-onset late postpartum preeclampsia in case-control study
34 women with new-onset late postpartum preeclampsia (LPP) after normal delivery and 68 women
without new-onset LPP matched by delivery date were evaluated
increased risk of new-onset LPP associated with
age ≥ 40 years (adjusted odds ratio [OR] 24.83, p = 0.03)
black race (adjusted OR 78.35, p < 0.001)
Latino ethnicity (adjusted OR 19.08, p = 0.01)
gestational diabetes (adjusted OR 72.91, p < 0.001)
Reference - Am J Obstet Gynecol 2014 Apr;210(4):338.e1
Possible risk factors

anticardiolipin antibodies, MTHFR homozygosity, and hyperhomocysteinemia may increase risk for
preeclampsia but evidence conflicting for women with mutations in factor V Leiden or prothrombin G20210A
moderate-to-high levels of anticardiolipin antibodies may be associated with preeclampsia
based on systematic review of observational studies limited by heterogeneity
systematic review of 12 studies (cohorts, case-controls, or cross-sectional studies) evaluating
association of anticardiolipin antibodies and preeclampsia
moderate-to-high levels of anticardiolipin antibodies associated with
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)
Overview Reference - Obstet Gynecol/2010
and Recommendations Dec;116(6):1433
Background
factor V Leiden heterozygosity, prothrombin heterozygosity, MTHFR homozygosity, anticardiolipin
antibodies, and hyperhomocysteinemia each associated with preeclampsia
based on systematic review of trials with significant heterogeneity and observational studies
systematic review of 79 randomized trials or observational studies (prospective or retrospective)
evaluating pregnant women or women up to 6 weeks postpartum with thrombophilia
compared to women without thrombophilia, risk for preeclampsia increased with
factor V Leiden heterozygosity (odds ratio [OR] 2.19, 95% CI 1.46-3.27) in analysis of 14 studies
with 3,922 women (results limited by significant heterogeneity)
prothrombin heterozygosity (OR 2.54, 95% CI 1.52-4.23) in analysis of 8 studies with 2,099 women
MTHFR homozygosity (OR 1.37, 95% CI 1.07-1.76) in analysis of 12 studies with 3,686 women
anticardiolipin antibodies (OR 2.73, 95% CI 1.65-4.51) in analysis of 8 studies with 2,645 women
hyperhomocysteinemia (OR 3.49, 95% CI 1.21-10.11) in analysis of 2 studies with 405 women
Reference - Br J Haematol 2006 Jan;132(2):171
mutations in factor V Leiden and prothrombin G20210A may not be associated with preeclampsia
systematic review of 10 prospective cohort studies comparing pregnancy complications in pregnant
women with prothrombin gene mutation or factor V Leiden with women without these conditions
review limited by heterogeneity due to baseline differences in study populations
compared to women without thrombophilia, no significant difference in risk for preeclampsia in
women with
factor V Leiden (homozygous or heterozygous) in analysis of 9 studies with 21,833 women
prothrombin G20210A mutation (homozygous or heterozygous) in analysis of 6 studies with
14,254 women
Reference - PLoS Med 2010 Jun 15;7(6):e1000292 full-text
see Thrombophilia in Pregnancy for details
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)
57,346 women from Danish National Birth Cohort completed food frequency questionnaire for previous 4
weeks at 25 weeks gestation
diagnosis of preeclampsia, eclampsia, and HELLP obtained through Danish National Patient Registry
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)
Reference - BJOG 2009 Jun;116(7):964 full-text
kidney donation may increase risk of gestational hypertension and preeclampsia during pregnancy in
donors
85 women (median age 29 years) who donated kidney and had ≥ 1 pregnancy with gestation ≥ 20 weeks
after donation (131 total pregnancies) were matched to 510 healthy women who did not donate kidney
(788 pregnancies) from general population
median follow-up 10.9 years
gestational hypertension or preeclampsia in 11% of donors vs. 5% of nondonors (p = 0.01)
Reference - N Engl J Med 2015 Jan 8;372(2):124
Factors not associated with increased risk

smoking appears to decrease risk for preeclampsia except in overweight or obese women
smoking in pregnancy associated with decreased risk of preeclampsia in women without pregestational
hypertension, especially women aged ≤ 30 years
674,250 singleton pregnancies in New York City from 1995 to 2003 evaluated
smoking associated with overall reduced risk of preeclampsia (adjusted odds ratio 0.88, 95% CI 0.82-
0.94) with greatest effect observed in women ≤ 30 years
smoking not associated with reduced risk of preeclampsia in women with chronic hypertension
Reference - Am J Epidemiol 2009 Jan 1;169(1):33 full-text
moderate smoking during pregnancy (1-9 cigarettes/day) associated with decreased risk of
preeclampsia
127,721 singleton pregnancies evaluated
moderate smoking during pregnancy (1-9 cigarettes/day) associated with reduced risk for
preeclampsia (odds ratio 0.4, 95% CI 0.22-0.6)
Reference - Acta Obstet Gynecol Scand 1999 Sep;78(8):693
smoking during pregnancy may not protect against preeclampsia in overweight and obese women
7,757 healthy primigravid women with singleton pregnancies between 1959 and 1965 evaluated
smoking associated with decreased risk for preeclampsia in underweight (p = 0.002) and normal
weight (p = 0.009) women, but effects not significant in overweight or obese women (p = 0.4)
Reference - Am J Epidemiol 2008 Aug 15;168(4):427 full-text
family history of preeclampsia and advanced maternal age ≥ 40 years not associated with increased risk of
preeclampsia
in adjusted analyses, family history of preeclampsia and advanced maternal age ≥ 40 years not
associated with increased risk of preeclampsia
history of abortion or preterm birth does not appear to increase risk of preeclampsia
140,773 women who delivered between 1993 and 1999 in 49 hospitals in Canada evaluated
history of abortion or preterm birth not associated with increased risk for preeclampsia
Reference - Am J Obstet Gynecol 2002 Oct;187(4):1013
psychosocial stress before 24 weeks gestation does not appear to be associated with increased incidence
of preeclampsia or gestational hypertension during first pregnancy
based on cohort study with low completion rates
3,679 nulliparous women pregnant with singleton pregnancy completed questionnaires on
sociodemographic and psychosocial factors before 24 weeks gestation
gestational hypertension in 4.4%
no association observed between preeclampsia or gestational hypertension and work stress, anxiety,
pregnancy-related / Background
anxiety, or depression
Reference - BJOG 2008 Apr;115(5):607
inhaled corticosteroids do not appear to be associated with increased risk of pregnancy-induced

hypertension
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)
no significant differences in either outcome with adjusted odds ratios about 1
oral corticosteroids were associated with
increased risk for pregnancy-induced hypertension (adjusted odds ratio 1.57, 95% CI 1.02-2.41)
nonsignificant increased risk for preeclampsia (adjusted odds ratio 1.72, 95% CI 0.98-3.02)
Reference - BMJ 2005 Jan 29;330(7485):230 full-text
serum folate levels in early pregnancy appear similar in normotensive and hypertensive pregnant women
exposed to folic acid supplementation
based on nested case-control study
214 pregnant women who developed a hypertensive disorder of pregnancy compared with 428 similar
normotensive pregnant women
> 98% took folic acid supplement 0.4-2 mg/day before the end of the first trimester
no patients considered folate deficient (< 10 nmol/L)
mean serum folate level 60.1 nmol/L in women with hypertensive disorder vs. 57.9 nmol/L in controls
(not significant)
Associated conditions
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome may occur in up to 20% of pregnancies
complicated by severe preeclampsia(1)
secondary hyperparathyroidism plus low vitamin D level associated with preeclampsia
1,141 pregnant women of low-income and minority status were analyzed
secondary hyperparathyroidism plus 25-hydroxyvitamin D < 20 ng/mL associated with preeclampsia
(adjusted odds ratio 2.86, 95% CI 1.28-6.41)
Reference - Am J Clin Nutr 2013 Sep;98(3):787
thyroid disorders
subclinical hypothyroidism associated with hypertensive disorders in pregnancy
24,883 women who delivered a singleton infant were assessed for hypertension in pregnancy
2.1% had subclinical hypothyroidism
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
subclinical hypothyroidism associated with increased risk of severe preeclampsia (adjusted odds
ratio 1.6, 95% CI 1.1-2.4)
Reference - Obstet Gynecol 2012 Feb;119(2 Pt 1):315
increased
Overview serum concentration
and Recommendations of soluble fms-like tyrosine kinase 1 during preeclampsia associated
/ Background
with subclinical hypothyroidism during pregnancy
based on nested case-control and population based study
141 women with preeclampsia and serum measurements at < 21 weeks gestation (baseline) and
after onset of preeclampsia (predelivery) matched to 141 normotensive controls with serum
measurements at similar gestational ages
population based cohort included 7,121 women who first gave birth ≥ 1967 with subsequent
measurements of serum levels of thyroid-stimulating hormone (TSH)
increase in TSH concentrations (subclinical hypothyroidism) associated with increased serum
concentration of soluble fms-like tyrosine kinase 1 during preeclampsia
at baseline (p for trend 0.002)
predelivery (p < 0.001)
Reference - BMJ 2009 Nov 17;339:b4336 full-text, editorial can be found in BMJ 2009 Dec
8;339:b5183
Etiology and Pathogenesis

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
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(1)
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 phenomena(1)
vascular endothelial damage and oxidative stress(1, 2)
mismatch between uteroplacental supply and fetal demands, leading to maternal endothelial cell
dysfunction and maternal and fetal manifestations
placenta produces specific proteins or trophoblastic debris that enter maternal circulation
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
Overview study
and Recommendations / Background
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
significant structural capillary rarefaction (Obstet Gynecol 2012 May;119(5):967)
History and Physical

History
Chief concern (CC)
may be asymptomatic(4, 6)
severe hypertensive disorders in pregnancy may present with(1, 2)
rapid weight gain
generalized edema affecting face and hands
new onset headache (severe) or visual disturbances
nausea and/or vomiting
epigastric or right upper quadrant pain
oliguria
hyperreflexia
dyspnea
History of present illness (HPI)

preeclampsia(2)
may have a diminished or no decrease in blood pressure at night
may rapidly progress
eclampsia(1)
eclamptic seizures are a life-threatening emergency that may be preceded by central nervous system
symptoms such as headache (80%) and visual changes (45%)
seizure lasts 60-90 seconds
postictal phase may follow
most eclamptic convulsions occur antepartum (about 53%), intrapartum (about 19%), or postpartum
(about 28%)
eclampsia may be preceded by premonitory symptoms, such as(1, 4)

persistent occipital or frontal headache
blurred vision
photophobia
altered mental status
symptoms preceding eclamptic seizure
based on series of 46 women with eclamptic seizure
prodromal headache reported in 80%
prodromal visual disturbance reported in 45%
prodromal epigastric pain reported in 20%
absence of any prodromal symptoms preceding eclamptic seizure in 17%
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, 2)
previous preeclampsia, especially if severe or before 32 weeks gestation
preexisting hypertension
preexisting renal disease
obesity (body mass index ≥ 35 kg/m2)
inherited thrombophilias
increased prepregnancy triglyceride levels
interpregnancy interval (increased risk if ≥ 10 years or < 2 years)
Family history (FH)

ask about family history of(2)
preeclampsia
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(2)
work outside the home associated with increases in blood pressure among hypertensive pregnant patients (
Obstet Gynecol 2001 Mar;97(3):361)
Physical
General physical
women with gestational hypertension require frequent monitoring, with in-office assessment of blood
pressure ≥ 1 time/ week in addition to weekly measurement of blood pressure at home or in office(4)
blood pressure monitoring
women with preeclampsia may have a diminished or no decrease in blood pressure at night(2)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for blood pressure
monitoring(2)
if blood pressure consistently higher in 1 arm, use that arm for all blood pressure measurements
(SOGC Grade B, Level III)
procedure
measure blood pressure with woman in sitting position with arm at level of heart (SOGC Grade A,
Level II-2)
use appropriately sized cuff (length 1.5 times circumference of arm) (SOGC Grade A, Level II-2)
designate diastolic blood pressure with Korotkoff phase V (SOGC Grade B, Level III)
blood pressure can be measured using mercury sphygmomanometer, calibrated aneroid device, or
automated blood pressure machine validated for use in preeclampsia (SOGC Grade A, Level II-2)
women with systolic blood pressure ≥ 140 mm Hg should be followed closely for development of
diastolic hypertension (SOGC Grade B, Level II-2)
Overview ambulatory blood pressure/monitoring
and Recommendations Backgroundor home blood pressure monitoring may help confirm
persistently elevated blood pressure if in-office blood pressure is not severe and preeclampsia is not
suspected (SOGC Grade C, Level II-2)
recommendations for diagnosis of hypertension
make diagnosis based on office or in-hospital blood pressure measurements (SOGC Grade B,
Level II)
hypertension defined as in-office (or in-hospital) systolic blood pressure ≥ 140 mm Hg and/or
diastolic blood pressure ≥ 90 mm Hg, based on mean of ≥ 2 measurements taken on same arm
≥ 15 minutes apart (SOGC Grade B, Level II-2)
severe hypertension in any setting defined as systolic blood pressure ≥ 160 mm Hg and/or
diastolic blood pressure ≥ 110 mm Hg, based on mean of ≥ 2 measurements taken on same
arm ≥ 15 minutes apart (SOGC Grade B, Level II-2)
isolated (white-coat) hypertension defined as in-office systolic blood pressure ≥ 140 mm Hg or
diastolic blood pressure of ≥ 90 mm Hg, but home blood pressure < 135/85 mm Hg (SOGC Grade
B, Level III)
masked hypertensive effect defined as in-office systolic blood pressure < 140 mm Hg or diastolic
blood pressure of < 90 mm Hg, but home blood pressure ≥ 135/85 mm Hg (SOGC Grade B, Level
III)
24-hour blood pressure monitoring may help predict preeclampsia

based on 2 cohort studies
cohort of 254 women in third trimester having 24-hour noninvasive blood pressure monitoring
preeclampsia developed in
5.8% with normal blood pressure
7.1% with white-coat hypertension (blood pressure elevated in office and low on ambulatory or
home monitoring)
61.7% with hypertension
Reference - JAMA 1999 Oct 20;282(15):1447
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
mean arterial pressure may be better predictor of preeclampsia than systolic and diastolic blood
pressures (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 34 studies with evaluation of blood pressure measurement during first and
second trimester of pregnancy to predict preeclampsia in 60,599 women
studies had variable methodology of blood pressure measurements
3,341 (5.5%) cases of preeclampsia occurred
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)
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)
Reference - BMJ 2008 May 17;336(7653):1117 full-text
no randomized trials identified to evaluate use of ambulatory blood pressure monitoring in pregnancy
based on Cochrane review
Reference - Cochrane Database Syst Rev 2002;(2):CD001231 (review updated 2012 Mar 9)
HEENT
choroidal ischemia seen on ophthalmoscopy in patient with pregnancy-induced hypertension (picture in N
Engl J Med 2001 Mar 8;344(10):739 full-text)
Cardiovascular
no randomized trials found evaluating pulmonary artery flow catheters for monitoring fluid status in
women with severe preeclampsia
Reference - Cochrane Database Syst Rev 2012 Jun 13;(6):CD008882
Pulmonary
in women with suspected preeclampsia, consider pulse oximetry to assess oxygen saturation (SpO2 < 97%
associated with increased risk of severe complications)(2)
Extremities
generalized edema (including face and hands) common with preeclampsia(2)
Neuro
hyperreflexia may be present(1)
neurologic exam findings (in descending order of occurrence) among 40 women with eclampsia in
prospective cohort study
memory deficits
increased deep tendon reflexes (some asymmetric)
visual perception deficits
visual information processing deficits
altered mental status
cranial nerve deficits
Reference - J Neurol Sci 2008 Aug 15;271(1-2):158
Diagnosis
Making the diagnosis
chronic hypertension defined as systolic ≥ 140 mm Hg or ≥ 90 mm Hg on 2 occasions ≥ 4 hours apart at ≤ 20
weeks gestation(1, 5)
gestational hypertension is hypertension without proteinuria developing after 20 weeks gestation(1, 2, 4)
American College of Obstetricians and Gynecologists (ACOG) criteria for diagnosis of preeclampsia(4)
hypertension (blood pressure ≥ 140/90 mm Hg) and proteinuria (> 300 mg/24 hours) after 20 weeks
gestation
if no proteinuria, diagnosis requires ≥ 1 severe feature
severe features of preeclampsia include
Overview blood pressure ≥ 160 mm Hg
and Recommendations or diastolic blood pressure ≥ 110 mm Hg on 2 occasions ≥ 4 hours apart
/ Background
(unless hypertensive therapy is initiated before this time)
impaired liver function indicated by ≥ 1 of the following
elevated serum liver transaminases to twice normal concentration
severe, persistent right upper quadrant or epigastric pain refractory to medication and not
accounted for by alternative diagnosis
progressive renal insufficiency (elevated serum creatinine > 1.1 mg/dL or doubling of serum
creatinine in patient without other renal disease)
pulmonary edema
new onset cerebral or visual disturbances, including headache
chronic hypertension with superimposed preeclampsia defined as preeclampsia with history of
hypertension before pregnancy or < 20 weeks gestation
not easy to diagnose and is often a diagnosis of exclusion
consider diagnosis in women with
sudden exacerbation of hypertension or proteinuria
new-onset thrombocytopenia (< 100,000 platelets/mcL)
sudden increase in liver enzymes to abnormal levels
sudden development of symptoms suggestive of preeclampsia
elevated uric acid levels
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for classification of

hypertensive disorders of pregnancy(2)
hypertension in pregnancy defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood
pressure ≥ 90 mm Hg based on average of ≥ 2 measurements taken ≤ 15 minutes apart using same arm
(SOGC Grade B, Level II)
severe hypertension defined as systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110
mm Hg based on average of ≥ 2 measurements taken ≤ 15 minutes apart using same arm (SOGC Grade
B, Level II-2)
for diagnosis of clinically significant proteinuria
strongly suspect significant proteinuria when urinary dipstick proteinuria is ≥ 1+ (SOGC Grade A, Level
II-2)
significant 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 B, Level II-2)
insufficient evidence for recommendations on accuracy of urinary albumin:creatinine ratio (SOGC
Grade L, Level II-2)
definitions of preeclampsia
in women with preexisting hypertension, preeclampsia defined as resistant hypertension, new or
worsening proteinuria ≥ 1 adverse conditions, or ≥ 1 severe complications (SOGC Grade B, Level II-2)
in women with gestational hypertension, preeclampsia defined as new-onset proteinuria, ≥ 1 adverse
conditions, or ≥ 1 severe complications (SOGC Grade B, Level II-2)
severe preeclampsia defined as preeclampsia with ≥ 1 severe complications (SOGC Grade B, Level II-2)
Differential diagnosis
for secondary hypertension(5)
chronic kidney disease
pheochromocytoma
primary aldosteronism
renovascular hypertension
hyperthyroidism
obstructive sleep apnea
Cushing disease
for preeclampsia(2, 4)
acute fatty liver of pregnancy
thrombotic thrombocytopenic purpura (TTP)/hemolytic-uremic syndrome (HUS)
systemic lupus erythematosus (SLE) exacerbation
hepatitis
cholestasis
malignant hypertension, regardless of cause
disseminated intravascular coagulation (DIC) from any cause
vasculitis or other systemic rheumatic condition
sepsis
medications
cavernous hemangiomas
malignancy
cocaine intoxication
cocaine intoxication with preeclampsia-like symptoms in third trimester in 11 women in case series (
Obstet Gynecol 1993 Apr;81(4):545)
cocaine intoxication mimicking preeclampsia postpartum in case report ( Int J Gynaecol Obstet 2006
Jan;92(1):73)
for eclampsia, rule out other causes of seizure(4)

stroke
cerebral arterial ischemia and infarction
intracranial hemorrhage
idiopathic epilepsy
illicit drug use
conditions that mimic hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
acute fatty liver of pregnancy
thrombotic thrombocytopenic purpura (TTP)
hemolytic-uremic syndrome (HUS)
acute exacerbation of systemic lupus erythematosus (SLE)
Reference - Obstet Gynecol 2007 Apr;109(4):956
Testing overview
maternal testing
monitor blood pressure
American College of Obstetricians and Gynecologists (ACOG) recommendations for testing
in women with known or suspected chronic hypertension
perform preconception or early pregnancy evaluation to rule out secondary (potentially curable)
hypertension and identify possible end-organ involvement(5)
testing may include
baseline evaluation for comparison if preeclampsia suspected later in pregnancy, including
blood tests to assess
Overview and Recommendations serum creatinine, electrolytes, liver enzymes, and complete blood
/ Background
count with platelets
urinalysis (dipstick test or quantification of urine protein)
echocardiography or electrocardiography for assessment of left ventricular function in women

with severe hypertension with duration > 4 years
screen for other causes of secondary hypertension (most commonly chronic kidney disease) in
young women diagnosed with chronic hypertension early in pregnancy, especially if hypertension
severe; testing may include
routine blood tests and urinalysis
renal ultrasound if evidence of chronic kidney disease or strong family history of kidney
disease
in women with gestational hypertension or preeclampsia

initial evaluation should include
blood tests to assess serum creatinine, electrolytes, liver enzymes, and complete blood count
with platelets
urinalysis for measurement of proteinuria
continued observation recommended for women without severe features < 37 weeks gestation,
including
urinalysis in women with gestational hypertension to assess for proteinuria (once weekly)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for testing

in women with chronic hypertension
perform blood tests and urinalysis in early pregnancy if not previously documented (SOGC Grade
B, Level II-2)
consider additional baseline laboratory testing based on other considerations deemed important
by healthcare providers (SOGC Grade C, Level III)(2)
in women with suspected preeclampsia (SOGC Grade B, Level II-2)

perform urinalysis (routine and microscopy) for measurement of proteinuria
additional testing may include
pulse oximetry to assess oxygen saturation (SpO2 < 97% associated with increased risk of
severe complications)
complete blood count and blood film
serum chemistry
coagulation tests if presence of thrombocytopenia or placental abruption
repeat initial testing if ongoing concern about preeclampsia (for example, change in maternal or fetal
condition) (SOGC Grade C, Level III)(2)
in hypertensive pregnant women, uterine artery Doppler velocimetry may support placental origin for
hypertension, proteinuria, or adverse conditions (SOGC Grade B, Level II-2)(2)
perform regular fetal monitoring, including fetal ultrasound, nonstress testing, biophysical profile testing, and
umbilical vessel Doppler velocimetry during expectant management in women with gestational hypertension
and suspected or confirmed preeclampsia
measurement of angiogenic factors has been investigated as tool to predict clinical outcomes in women
who initially present with early features of preeclampsia; however, no single test has been shown to reliably
predict preeclampsia and further study is needed to determine clinical utility
Blood tests
blood tests in women with chronic hypertension
perform blood tests in early pregnancy to establish baseline for comparison if preeclampsia suspected
later in pregnancy, including(2, 5)
serum creatinine and serum potassium
electrolytes
liver enzymes
complete blood count with platelets
routine blood chemistry to screen for other causes of secondary hypertension (most commonly chronic
kidney disease) in young women diagnosed with chronic hypertension early in pregnancy, especially if
hypertension severe(5)
blood tests in women with gestational hypertension or preeclampsia (confirmed or suspected)(2, 4)

initial testing should include
complete blood count (CBC) and blood film, including assessment of
hemoglobin (higher in women with preeclampsia unless microangiopathic hemolytic anemia)
white blood cells and differential (higher in preeclampsia)
platelet count (lower in preeclampsia)
blood film (shows microangiopathy with red blood cell fragments in preeclampsia)
serum chemistry, including assessment of
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)
coagulation tests if presence of thrombocytopenia or placental abruption
international normalized ratio (INR) and activated partial thromboplastin time (aPTT)
fibrinogen (lower in preeclampsia)
continued observation recommended for women without severe features < 37 weeks gestation, including
uric acid test may be considered if possible preeclampsia superimposed on chronic hypertension
uric acid
uric acid associated with low positive and negative predictive values for complications of preeclampsia
(level 2 [mid-level] evidence)
systematic review of 18 studies evaluating accuracy of serum uric acid for predicting maternal and
fetal complications in 3,913 women with preeclampsia
definition of preeclampsia and uric acid test thresholds varied widely between studies
likelihood ratios of serum uric acid with cutoff ≥ 350 mcmol/L for predicting likelihood of maternal
Overview complications
for eclampsia in analysis of 3 studies
positive likelihood ratio (PLR) 2.1 (95% CI 1.4-3.5)
negative likelihood ratio (NLR) 0.38 (95% CI 0.18-0.81)
for severe hypertension in analysis of 6 studies

PLR 1.7 (95% CI 1.3-2.2)
NLR 0.49 (95% CI 0.38-0.64)
for cesarean section in analysis of 2 studies

PLR 2.4 (95% CI 1.3-4.7)
NLR 0.39 (95% CI 0.2-0.76)
Reference - BJOG 2006 Apr;113(4):369
angiogenic markers
International Society for the Study of Hypertension in Pregnancy (ISSHP) states that measurement of
angiogenic factors may predict clinical outcomes for women when they initially present with early
features of preeclampsia but clinical utility is unclear(6)
American College of Obstetricians and Gynecologists (ACOG) states that although measurement of
some angiogenic markers, such as soluble fms-like tyrosine kinase (sFlt-1), placental growth factor
(PIGF), and soluble endoglin, in second trimester may serve as tools for prediction of early-onset
preeclampsia, no single test reliably predicts preeclampsia and further study is needed to demonstrate
clinical utility(4)
higher placental growth factor level helps rule out preeclampsia in pregnant women < 35 weeks
gestational age (level 1 [likely reliable] evidence)
based on diagnostic cohort study
625 pregnant women with suspected preeclampsia had measurement of placental growth factor
(PlGF) in plasma
287 pregnant women gestational age 20 to < 35 weeks
137 pregnant women gestational age 35 weeks to < 37 weeks
201 pregnant women gestational age ≥ 37 weeks
outcome was confirmed preeclampsia requiring delivery within 14 days by consensus diagnosis of 2-
3 senior physicians (reference standard)
preeclampsia prevalence by reference standard
26.4% at gestational age 20 to < 35 weeks
49% at gestational age 35 weeks to < 37 weeks
43% at gestational age ≥ 37 weeks
diagnostic thresholds for preeclampsia were PlGF levels < 5th percentile for gestational age
(Pregnancy Hypertens 2013 Apr;3(2):124)
< 76.4 pg/mL at 20-24 weeks
< 141.1 pg/mL at 24-29 weeks
< 139.3 pg/mL at 29-32 weeks
< 31.7 pg/mL at 35 -37 weeks
diagnostic performance of PlGF < 5th percentile for detection of preeclampsia
Overview andatRecommendations
gestational age 20 to/<Background
35 weeks
sensitivity 96%
specificity 55%
positive predictive value 43%
negative predictive value 98%
at gestational age 35 weeks to < 37 weeks, sensitivity 70% and specificity 64%
at gestational age ≥ 37 weeks, sensitivity 57% and specificity 77%
Reference - Circulation 2013 Nov 5;128(19):2121
addition of PlGF criteria to guideline-based management reduces time to preeclampsia diagnosis and
risk of maternal adverse events in women with singleton pregnancy and suspected preeclampsia at <
37 weeks gestational age (level 1 [likely reliable] evidence)
based on stepped-wedge cluster randomized trial
11 maternity units in United Kingdom using National Institute for Health and Care Excellence (NICE)
guidelines for management of hypertension in pregnancy were randomized to time of addition of PlGF
criteria to guideline-based management at 6-week intervals
1,023 women with singleton pregnancy and suspected preeclampsia at gestational age 20 to < 37
weeks were enrolled
suspected preeclampsia defined as new onset or worsening of existing hypertension, dipstick
proteinuria, epigastric or right upper quadrant pain, headache with visual disturbances, fetal
growth restriction, or abnormal maternal blood tests suggestive of disease (including
thrombocytopenia and hepatic or renal dysfunction)
all women had PlGF test, 56% (576 women) with guideline-based management plus PlGF criteria
and 44% (447 women) guideline-based management alone
PlGF criteria
if PlGF > 100 pg/mL (normal), continue with usual management
if PlGF ≥ 12 pg/mL and ≤ 100 pg/mL (low), consider increased surveillance
if PlGF < 12 pg/mL (very low), assess as preeclampsia
primary outcome was time to documented preeclampsia diagnosis in women who received diagnosis
99% included in analysis
360 women overall received confirmed preeclampsia defined by ISSHP recommendations (36% in
guideline plus PlGF group and 35% in guideline alone group)
comparing guideline management plus PlGF criteria vs. guideline management alone
in women with preeclampsia
median time to preeclampsia diagnosis 1.9 days vs. 4.1 days (p = 0.027)
preeclampsia diagnosed within 24 hours in 20% vs. 16% (p = 0.027, NNT 25)
in overall analysis
severe maternal adverse events in 3.8% vs. 5.4% (p = 0.043, NNT 63)
median gestational age at delivery 36.6 weeks vs. 36.8 weeks (not significant)
perinatal adverse outcomes in 15% vs. 14% (not significant)
no significant differences in severe preeclampsia, perinatal deaths, preterm delivery before 37 weeks
gestational age, birthweight, or neonatal unit admissions
Reference - PARROT trial (Lancet 2019 May 4;393(10183):1807 full-text), editorial can be found in
Lancet 2019 May 4;393(10183):1775
serum sFlt-1:PlGF ratio with cutoff < 38 rules out development of preeclampsia within 1 week (level 1
[likely reliable] evidence)
based
Overview andonRecommendations
diagnostic study with/ independent
Backgroundderivation and validation cohorts
derivation cohort included 500 women with singleton pregnancy between 24 and 37 weeks gestation and
suspected preeclampsia who were assessed for serum levels of soluble fms-like tyrosine kinase-1 (sFlt-
1) and placental growth factor (PlGF)
reference standard was laboratory criteria for preeclampsia and/or hemolysis, elevated liver enzymes,
low platelets (HELLP) syndrome
optimal cutoff for both ruling out preeclampsia within 1 week and predicting preeclampsia within 4
weeks in derivation cohort was sFlt-1:PlGF ratio > 38
validation cohort included 550 similar women
17.8% developed preeclampsia by reference standard in validation cohort
performance of sFlt-1:PlGF ratio with cutoff > 38 for development of preeclampsia in validation cohort
within 1 week
sensitivity 80%
specificity 78.3%
negative predictive value 99.3%
within 4 weeks
sensitivity 66.2%
specificity 83.1%
positive predictive value 36.7%
Reference - N Engl J Med 2016 Jan 7;374(1):13, editorial can be found in N Engl J Med 2016 Jan
7;374(1):83
addition of serum sFlt-1:PlGF ratio to standard clinical management for women with suspected
preeclampsia improves prediction of preeclampsia (level 1 [likely reliable] evidence) and may not increase
hospital admission rates (level 2 [mid-level] evidence)
based on randomized trial with wide confidence intervals for hospitalization outcomes
374 pregnant women at 24-37 weeks gestation with suspected preeclampsia were assessed for sFlt-1
and PlGF and were randomized to 1 of 2 management strategies
standard clinical management plus results of sFlt-1:PlGF ratio
standard clinical management alone (sFlt-1:PlGF ratio was not revealed to clinician)
mean body mass index was 28.3 in reveal group vs. 26.7 in nonreveal group (p = 0.045)
in sFlt-1:PlGF ratio group cutoff for elevated risk of developing preeclampsia within 7 days was sFlt-
1:PlGF ratio > 38 (low threshold for admission or increased surveillance indicated)
99% completed follow-up and were included in analysis
preeclampsia diagnosed in 23%
comparing of sFlt-1:PIGF plus standard clinical management vs. standard clinical management alone
diagnostic performance for prediction of preeclampsia-related admission within 7 days
sensitivity 100% vs. 83.3% (p = 0.038)
specificity 77.8% vs. 80.1%
positive predictive value 40% vs. 31.3%
negative predictive value 100% vs. 97.8%
rates of preeclampsia-related admission (no significant differences, but CIs include possibility of
benefit or harm)
within 24 hours 32.3% vs. 26.1% (risk ratio [RR] 1.24, 0.89-1.70)
within 7 days 37.6% vs. 35% (RR 1.06, 0.1-1.39)
Reference - INSPIRE trial (Hypertension 2019 Aug 12 early online), editorial can be found in
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)
Urine studies
perform urinalysis for measurement of proteinuria(2, 4, 5, 6)
in early pregnancy to establish a baseline for comparison in women with chronic hypertension
as part of initial testing in women with suspected preeclampsia
urinary dipstick testing may be used for screening if low suspicion of preeclampsia (SOGC Grade B,
Level II-2)
suspect significant proteinuria if urinary dipstick proteinuria is ≥ 1+ (SOGC Grade A, Level II-2)
use more definitive proteinuria testing if suspicion of preeclampsia; consider either of (SOGC Grade A,
Level II-2)
urinary protein:creatinine ratio
24-hour urine collection
proteinuria without red blood cells or casts may indicate preeclampsia
proteinuria testing does not need to be repeated once significant proteinuria of preeclampsia has
been established (SOGC Grade A, Level II-2)
insufficient evidence to make a recommendation regarding the accuracy of urinary albumin:creatinine
ratio (SOGC Grade L, Level II-2)
12-hour urine collection may help diagnose proteinuria in women with suspected preeclampsia
12-hour urine collection appears to diagnose proteinuria with similar efficacy to 24-hour urine
collection in women with suspected preeclampsia (level 2 [mid-level] evidence)
based on systematic review with study-specific quality measures not reported
systematic review of 7 prospective cohort studies evaluating 12-hour urine collection for proteinuria
in pregnant women at > 20 weeks gestation with suspected preeclampsia
proteinuria defined as 24-hour urine protein > 300 mg (reference standard)
incidence of proteinuria ranged from 14% to 86%
cutpoint for positive 12-hour urine collection ranged from 100 to 165 mg
for detection of proteinuria with 12-hour urine collection
sensitivity 92% (95% CI 86%-96%) in analysis of all studies, results limited by significant
heterogeneity
specificity 99% (95% CI 75%-100%) in analysis of all studies, results limited by significant
heterogeneity
area under receiver operating characteristic curve 97% (95% CI 95%-98%) in analysis of all studies
optimal cutpoint for 12-hour urine collection based on receiver operating characteristic curve was 150
mg
12-hour urine protein > 165 mg appears to predict 24-hour proteinuria and may help rule out proteinuria
in women with suspected preeclampsia (level 2 [mid-level] evidence)
based on diagnostic cohort study without validation
90 pregnant women at > 20 weeks gestational age (median age 30 years) with suspected
preeclampsia were assessed for 12-hour and 24-hour urine protein and for spot urine protein to
creatinine ratio
28 women had proteinuria defined as 24-hour urine protein ≥ 300 mg (reference standard)
for detection of significant proteinuria
Overview and12-hour urine protein with
Recommendations cutoff > 165 mg had
/ Background
sensitivity 96%
specificity 100%
spot urine protein to creatinine ratio with cutoff > 0.15 had
sensitivity 89%
specificity 49%
Reference - Am J Obstet Gynecol 2012 Sep;207(3):233.e1
spot urine protein:creatinine ratio may help diagnose proteinuria in women with suspected preeclampsia
spot protein-to-creatinine ratio appears to have moderate accuracy for detecting proteinuria in women
with suspected preeclampsia (level 2 [mid-level] evidence)
systematic review of 20 diagnostic studies (15 cohort, 4 cross-sectional, 1 case-control) evaluating
urinary spot protein-to-creatinine ratio or albumin-to-creatinine ratio for detection of significant
proteinuria or adverse pregnancy outcome in 2,978 pregnant women with suspected preeclampsia
significant proteinuria defined as ≥ 0.3 g/24 hours
reference standards were 24-hour total urine collection for protein or adverse pregnancy outcome
clinical heterogeneity due to variations across studies in patient populations, reference test, and
cutoff values for spot protein-to-creatinine ratio
in 13 studies evaluating spot protein/creatinine ratio
diagnostic cutoff values ranged from 0.13 to 0.5 mg/mg
no diagnostic cutoff gave > 80% estimate for both sensitivity and specificity
pooled predictive performance of spot protein/creatinine ratio using cutoff of 0.3 mg/mg for
detecting significant proteinuria in analysis of 5 studies
sensitivity 81%
specificity 76%
positive likelihood ratio 3.33
negative likelihood ratio 0.25
insufficient evidence to support specific cutoff for detection of significant proteinuria in 5 studies
evaluating albumin-to-creatinine ratio
Reference - BMJ 2012 Jul 9;345:e4342 full-text, commentary can be found in Nat Rev Nephrol 2012
Oct;8(10):563
spot protein-to-creatinine ratio may help rule out proteinuria in pregnant women with hypertension but
optimal cutoff point unclear (level 2 [mid-level] evidence)
based on systematic review of diagnostic studies
systematic review of 15 diagnostic 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
Overview and8 Recommendations
different cutoff points/reported in 9 studies with ranging from 0.15 mg/mg (17 mg/mmol) to 0.5
Background
mg/mg (57 mg/mmol)
pooled values of spot protein-to-creatinine ratio 30 mg/mmol in 9 studies with 1,003 women
sensitivity 83.6%
specificity 76.3%
positive likelihood ratio 3.53
negative likelihood ratio 0.21
insufficient data for pooled analysis in 2 studies evaluating albumin/creatinine ratio in 225 women
optimal cutoff point for proteinuria of ≥ 0.3 g/day was 2 mg/mmol
optimal cutoff 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
random urine protein-to-creatinine ratio < 130-150 mg/g or > 600 mg/g in pregnant women with
suspected preeclampsia may eliminate need for 24-hour urine collection (level 2 [mid-level] evidence)
systematic review of 7 studies evaluating different cutoff 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-to-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-to-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
urinary protein-to-creatinine ratio significantly correlated with 24-hour proteinuria in hospitalized

pregnant women with hypertensive disorders of pregnancy
based on diagnostic cohort 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-to-creatinine ratio and 24-hour protein excretion significantly correlated (p < 0.001)
protein-to-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 full-text, commentary can be found in Evid Based Med
2008 Jun;13(3):84
review of clinical significance of proteinuria in pregnancy can be found in Obstet Gynecol Surv 2007
Feb;62(2):117
degree of proteinuria may not be associated with maternal or fetal complications in preeclampsia
based on systematic review
systematic review of 16 studies evaluating accuracy of proteinuria for predicting maternal and fetal
complications in 6,749 women with preeclampsia
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
Reference - BMC Med 2009 Mar 24;7(1):10 full-text, commentary can be found in BMC Med 2009 Mar
24;7:11
mean 24-hour protein excretion and prevalence of proteinuria appear greater in twin compared with
singleton pregnancies not complicated by hypertension (level 2 [mid-level] evidence)
50 twin and 49 singleton pregnancies between 24 and 36 weeks gestation (mean gestational age 30
weeks) not complicated by hypertension were evaluated for mean 24-hour urinary protein excretion
comparing twin vs. singleton pregnancies
mean 24-hour urinary protein excretion 269 mg vs. 204 mg (p = 0.004)
proteinuria (≥ 300 mg/day) in 38% vs. 8.2% (p < 0.001)
among women with proteinuria, development of hypertensive disorder in 21% vs. 25% (not significant)
hypocalciuria may occur in preeclampsia

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)
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 case-control study of 26 women with
preeclampsia and 26 normotensive controls ( J Steroid Biochem Mol Biol 2007 Mar;103(3-5):803)
Fetal monitoring
recommendations for fetal monitoring in women with gestational hypertension or preeclampsia without
severe features
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommendations(6)
perform the following at first diagnosis of preeclampsia
fetal biometry (bi-parietal diameter together with head circumference, abdominal circumference,
and femur length to produce estimate of fetal weight)
amniotic fluid volume assessment
fetal Doppler waveform analysis
for confirmed preeclampsia with fetal growth restriction, serial evaluation of fetal growth, amniotic
fluid volume, and umbilical artery Doppler is recommended from 24 weeks gestation until delivery,
with evaluation of fetal growth at no more than 2 week intervals
consider more frequent ultrasound measurement if high umbilical artery resistance or absent or
reversed end-diastolic flow
American College of Obstetricians and Gynecologists (ACOG) recommendations for initial evaluation(4)
ultrasound to evaluate (ACOG Level C)
Overview andfetal growth every 3-4 weeks
Recommendations / Background
amniotic fluid volume at least once weekly
nonstress testing or biophysical profile testing 1-2 times per week (ACOG Level C)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations (SOGC Grade B, Level
II-1)(2)
initial testing may include
nonstress test (abnormal or atypical fetal heart rate in preeclampsia)
deepest amniotic fluid pocket (lower in preeclampsia)
ultrasound for fetal growth (usually asymmetrical intrauterine growth in preeclampsia)
umbilical artery Doppler (increased resistance, absent or reversed end-diastolic flow in
preeclampsia)
ductus venosus Doppler (increased resistance, especially absent or reverse A wave)
middle cerebral artery Doppler
cerebral distribution (decreased resistance or brain-sparing effect)
may be lost in extreme cases preceding fetal death
umbilical artery Doppler velocimetry may support placental origin for intrauterine fetal growth
restriction (SOGC Grade B, Level II-2)
insufficient evidence to recommend biophysical profile for fetal testing in women with a hypertensive
disorder of pregnancy (SOGC Grade L, Level II-2)
repeat initial testing if ongoing concern about preeclampsia (for example, change in maternal or fetal
condition) (SOGC Grade C, Level III)
Management
Management overview
indications for hospitalization include
severe hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg)
gestational hypertension or preeclampsia with severe features
chronic hypertension with superimposed preeclampsia and severe features < 34 weeks gestation
concerns about adherence to frequent monitoring in women with gestational hypertension or
preeclampsia without severe features
delivery
indications for delivery include
preeclampsia with severe features and gestational age < 34 weeks with deterioration of maternal or
fetal condition (ACOG Level B)
gestational hypertension or preeclampsia with severe features and gestational age ≥ 34 weeks after
maternal stabilization or with labor or prelabor rupture of membranes (ACOG Level B)
gestational hypertension or preeclampsia and gestational age ≥ 37 weeks (ACOG Level A; SOGC
Grade B, Level III; ESC Class I, Level B)
preeclampsia with severe features or hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome, regardless of gestational age (SOGC Grade C, Level III)
preeclampsia with adverse conditions (such as visual disturbances or hemostatic disorders) (ESC
Class I, Level C)
chronic hypertension who develop superimposed preeclampsia with severe features ≥ 34 weeks
gestation (ACOG Level B)
consider vaginal delivery unless cesarean section required for usual obstetric indications (SOGC Grade B,
Overview and
Level Recommendations / Background
II-2)
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)
indications for expectant management

gestational hypertension, preeclampsia, or chronic hypertension and superimposed preeclampsia
without severe features and stable maternal and fetal conditions up until 37 weeks gestation (ACOG
Level C)
preeclampsia without severe features at 24-33 6/7 weeks gestation (if in perinatal center capable of
caring for very preterm infant) (SOGC Grade B, Level I)
chronic hypertension with no additional maternal or fetal complications < 38 weeks gestation if not
prescribed antihypertensive medications or < 37 weeks gestation if prescribed maintenance
antihypertensive medications (ACOG Level B)
antihypertensive therapy for chronic hypertension or urgent control of acute severe hypertension
(hypertensive emergency)
blood pressure criteria for initiation of antihypertensive therapy for hypertensive disorders of pregnancy
World Health Organization (WHO) recommends treatment with antihypertensive drugs for all women
with severe hypertension during pregnancy (WHO Strong recommendation, Very low certainty
evidence) (WHO 2018)
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends
antihypertensive therapy for any hypertensive disorder of pregnancy meeting the following blood
pressure criteria(6)
> 160/110 mm Hg in a monitored setting
consistently ≥ 140/90 mm Hg in clinic or office or ≥ 135/85 mm Hg at home
American College of Obstetricians and Gynecologists (ACOG) recommends antihypertensive therapy

recommended for women with(4, 5)
persistent chronic hypertension with systolic blood pressure ≥ 160 mm Hg or diastolic blood
pressure ≥ 105 mm Hg (ACOG Level B)
gestational hypertension or preeclampsia with severe hypertension (sustained systolic blood
pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg ≥ 15 minutes) (ACOG Level B)
Hypertension Canada (in partnership with the Society of Obstetricians and Gynaecologists of Canada)
recommends antihypertensive therapy for average systolic blood pressure 140 mm Hg or diastolic
blood pressure 90 mm Hg in pregnant women with chronic hypertension, gestational hypertension, or
preeclampsia (Hypertension Canada Grade C) (Can J Cardiol 2018 May;34(5):526)
European Society of Cardiology (ESC) recommendations(3)
antihypertensive therapy recommended for women with
systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 95 mm Hg (ESC Class I,
Level C)
systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg if (ESC Class I,
Level C)
gestational hypertension or pre-existing hypertension superimposed by gestational
hypertension
subclinical organ damage or symptoms
target blood pressure after initiation of antihypertensive therapy for hypertensive disorders of pregnancy
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends(6)
target office diastolic blood pressure 85 mm Hg (and systolic blood pressure 110-140 mm Hg)
reduce or discontinue antihypertensive drugs if diastolic blood pressure < 80 mm Hg
Overview American College of Obstetricians
and Recommendations and Gynecologists (ACOG) recommends maintaining blood
/ Background
pressure between 120 and 160 mm Hg systolic and 80 and 110 mm Hg diastolic for women with
chronic hypertension taking antihypertensive therapy(4, 5)
recommends antihypertensive drugs to maintain diastolic blood pressure < 85 mm Hg in pregnant
women with
chronic hypertension or gestational hypertension (Hypertension Canada Grade B)
preeclampsia (Hypertension Canada Grade D)
Reference - Can J Cardiol 2018 May;34(5):526
antihypertensive medications for chronic or nonsevere hypertension (ACOG Level B for labetalol and
nifedipine; ESC Class I, Level B for methyldopa; ESC Class I, Level C for nifedipine and labetalol;
Hypertension Canada Grade C for all)
first-line oral agents include
labetalol 200-2,400 mg/day orally in 2-3 divided doses
nifedipine 30-120 mg/day orally (slow-release preparation)
methyldopa 0.5-3 g/day orally in 2-4 divided doses
oxprenolol (recommended by ISSHP without dosing suggestions)
other oral beta-blockers (acebutolol, metoprolol, pindolol, and propranolol) (recommended by
Hypertension Canada in partnership with Society of Obstetricians and Gynaecologists of Canada)
second-line agents include

clonidine (Hypertension Canada Grade D)
hydralazine (Hypertension Canada Grade D)
thiazide diuretics (dose varies by agent) (Hypertension Canada Grade D)
prazosin (recommended by ISSHP)
antihypertensive medications for urgent control of acute severe hypertension (doses in different
guidelines vary)
World Health Organization (WHO) recommends that choice and route of administration of
antihypertensive drugs for treatment of severe hypertension during pregnancy should be based
primarily on the prescribing clinician's experience with any particular drug, its cost, and local
availability (WHO Conditional recommendation, Very low certainty evidence) (WHO 2018)
labetalol in 1 of 2 dosing options ( SOGC Grade A, Level I; ESC Class I, Level C)
10-20 mg IV bolus, then 20-80 mg every 10-30 minutes up to maximum cumulative dose of 300
mg
constant infusion 1-2 mg/minute IV
nifedipine immediate release 10-20 mg orally repeated in 30 minutes as needed, then 10-20 mg every
2-6 hours (maximum daily dose 180 mg)(SOGC Grade A, Level I; ESC Class I, Level C)
hydralazine in 1 of 2 dosing options ( SOGC Grade A, Level I); no longer considered drug of choice by
ESC
5 mg IV or intramuscular, then 5-10 mg IV every 20-40 minutes up to maximum cumulative dose of
20 mg
constant infusion 0.5-10 mg/hour
methyldopa 0.5-3 g/day orally in 2-3 divided doses ( SOGC Grade B, Level I; ESC Class I, Level C); no
longer considered drug of choice by ACOG
nitroglycerin IV 5 mcg/minute gradually increased every 3-5 minutes to maximum of 100 mcg/minute
if preeclampsia associated with pulmonary edema (ESC Class I, Level C)
refractory hypertension can be treated with sodium nitroprusside (SOGC Grade B, Level III), but should be
last choice due to risk of fetal cyanide poisoning upon prolonged use
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, renin inhibitors, and
mineralocorticoid / Background
receptor antagonists generally not recommended (ACOG Level B; ESC Class III, Level C
)
magnesium sulfate for women with gestational hypertension or preeclampsia with severe features, or
eclampsia
magnesium sulfate recommended to prevent and treat seizures in women with gestational hypertension
and preeclampsia with severe features or eclampsia (ACOG Level A; SOGC Grade A, Level I)
ideal dosing for magnesium sulfate unclear
4-6 g IV loading dose followed by maintenance dose of 1-2 g/hour for ≥ 24 hours postpartum
(suggested by ACOG)
4 g IV bolus followed by 1 g/hour infusion (SOGC Grade A, Level I)
10 g intramuscular loading dose followed by 5 g intramuscular every 4 hours or 1 g/hour infusion
until delivery and for ≥ 24 hours postpartum(6)
magnesium sulfate reduces recurrence of seizures compared to diazepam or phenytoin in women

with eclampsia (level 1 [likely reliable] evidence)
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)
magnesium sulfate may be considered in women with nonsevere preeclampsia (SOGC Grade C, Level
I)
some bed rest in hospital (vs. unrestricted activity at home) may be useful for women with gestational
hypertension without preeclampsia (SOGC Grade B, Level I), but not recommended for hospitalized women
with preeclampsia (SOGC Grade D, Level I)
follow-up after delivery to evaluate for and treat hypertension and related conditions
Treatment setting
hospitalize women with severe hypertension, defined as ≥ 160/110 mm Hg (or ≥ 170/110 mm Hg per ESC)
(ESC Class I, Level C)(2, 3, 4, 6)
American College of Obstetricians and Gynecologists (ACOG) recommends hospitalization for the
following(4, 5)
gestational hypertension or preeclampsia with severe features
concerns about adherence to frequent monitoring in women with gestational hypertension or
preeclampsia without severe features
chronic hypertension who develop superimposed preeclampsia with severe features < 34 weeks
gestation (ACOG Level B)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for place of care(2)
provide inpatient care for women with severe hypertension or preeclampsia with severe features (SOGC
Grade B, Level II-2)
for women with hypertension (chronic or gestational) or preeclampsia without severe features, consider
care through hospital day units (SOGC Grade B, Level I) or home care (SOGC Grade B, Level II-2)
antenatal day care may reduce risk of inpatient hospital admission but increase number of outpatient visits
compared to inpatient or routine care in women with complicated pregnancy (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
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
Fluid and electrolytes

Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for fluid administration in
women with anesthesia(2)
minimize IV and oral fluid intake in women with preeclampsia to avoid pulmonary edema (SOGC Grade B,
Level II-2)
routine fixed IV fluid bolus not recommended prior to regional analgesia and/or anesthesia (SOGC Grade
E, Level I)
fluid should not be routinely administered for oliguria (< 15 mL/hour for 6 consecutive hours) (SOGC
Grade D, Level III)
plasma volume expansion not recommended for women with preeclampsia (SOGC Grade E, Level I)(2, 6)
insufficient evidence for any reliable estimates of effects of plasma volume expansion
systematic review of 3 randomized trials evaluating plasma volume expansion in 61 women with
hypertension during pregnancy (with or without proteinuria)
all trials compared colloid solution vs. no plasma volume expansion but wide confidence intervals result
in no significant differences
14 citations awaiting classification may alter conclusions of Cochrane review once assessed
Reference - Cochrane Database Syst Rev 2000;(2):CD001805 (review updated 2009 Oct 1)
Diet
consider limiting weight gain to < 6.8 kg (15 lbs) in obese women (≥ 30 kg/m2) (ESC Class IIa, Level C)(3)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for diet changes in
for prevention of preeclampsia
new dietary salt restriction not recommended (SOGC Grade D, Level I)
calorie restriction not recommended for obese women during pregnancy (SOGC Grade D, Level I)
for treatment of hypertensive disorders, insufficient evidence for recommendations on usefulness of

new or ongoing salt restriction in women with preexisting hypertension (SOGC Grade L, Level III)
heart-healthy diet (SOGC Grade L, Level III)
calorie restriction for obese women (SOGC Grade L, Level III)
insufficient evidence to recommend increasing or decreasing salt intake during pregnancy
systematic review of 2 randomized trials of reduced dietary salt intake during pregnancy with 603
women, no significant differences but confidence intervals were wide
no trials of increased dietary salt intake found
Reference - Cochrane Database Syst Rev 2005 Oct 19;(4):CD005548 (review updated 2012 Jan 18)
Activity
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends exercise during
pregnancy to maintain health, appropriate body weight, and reduce the likelihood of hypertension(6)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for lifestyle changes in
women with hypertensive disorders of pregnancy(2)
insufficient evidence to recommend exercise, workload reduction or stress reduction (SOGC Grade L,
Level III)
bed rest
some bed rest in hospital (vs. unrestricted activity at home) may be useful for women with gestational
hypertension without preeclampsia (SOGC Grade B, Level I)
strict bed rest not recommended for hospitalized women with preeclampsia (SOGC Grade D, Level I)
insufficient evidence for bed rest for all other women with hypertensive disorders of pregnancy (SOGC
Grade C, Level III)
insufficient evidence to evaluate bed rest or restriction of activity for women with hypertension during
pregnancy
systematic review of 4 randomized trials evaluating bed rest for 449 women with hypertension in
pregnancy
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
2 trials (304 women) compared some bed rest in hospital with routine activity at home for nonproteinuric
hypertension
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 in 1 trial with 218 women
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) in 1 trial with 86 women
no significant differences for any other outcomes
Reference - Cochrane Database Syst Rev 2010 Feb 17;(2):CD003514
Medications
Antihypertensive therapy
Indications and target blood pressure
blood pressure criteria for initiation of antihypertensive therapy for hypertensive disorders of pregnancy
World Health Organization (WHO) recommends treatment with antihypertensive drugs for all women with
severe hypertension during pregnancy (WHO Strong recommendation, Very low certainty evidence) (WHO
2018)
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends antihypertensive
Overview and for
therapy Recommendations / Background
any hypertensive disorder of pregnancy meeting the following blood pressure criteria(6)
> 160/110 mm Hg in a monitored setting
consistently ≥ 140/90 mm Hg in clinic or office or ≥ 135/85 mm Hg at home
American College of Obstetricians and Gynecologists (ACOG) recommends antihypertensive therapy
recommended for women with(4, 5)
persistent chronic hypertension with systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure
≥ 105 mm Hg (ACOG Level B)
gestational hypertension or preeclampsia with severe hypertension (sustained systolic blood
pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 110 mm Hg ≥ 15 minutes) (ACOG Level B)
recommends antihypertensive therapy for average systolic blood pressure 140 mm Hg or diastolic blood
pressure 90 mm Hg in pregnant women with chronic hypertension, gestational hypertension, or
preeclampsia (Hypertension Canada Grade C) (Can J Cardiol 2018 May;34(5):526)
antihypertensive therapy recommended for women with
systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 95 mm Hg (ESC Class I, Level
C)
systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg if (ESC Class I, Level
C)
gestational hypertension or pre-existing hypertension superimposed by gestational
hypertension
subclinical organ damage or symptoms
target blood pressure after initiation of antihypertensive therapy for hypertensive disorders of pregnancy
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends(6)
target office diastolic blood pressure 85 mm Hg (and systolic blood pressure 110-140 mm Hg)
reduce or discontinue antihypertensive drugs if diastolic blood pressure < 80 mm Hg
recommends antihypertensive drugs to maintain diastolic blood pressure < 85 mm Hg in pregnant
women with
chronic hypertension or gestational hypertension (Hypertension Canada Grade B)
preeclampsia (Hypertension Canada Grade D)
American College of Obstetricians and Gynecologists (ACOG) recommends maintaining blood pressure
between 120 and 160 mm Hg systolic and 80 and 110 mm Hg diastolic for women with chronic
hypertension taking antihypertensive therapy(4, 5)
diastolic blood pressure target 85 mm Hg does not appear to reduce pregnancy loss or need for high-
level neonatal care, but may reduce risk of severe hypertension compared to target 100 mm Hg in
pregnant women with preexisting or gestational hypertension (level 2 [mid-level] evidence)
based on randomized trial with low adherence
1,030 pregnant women at 14 to < 34 gestational weeks with nonproteinuric preexisting hypertension
(75%) or gestational hypertension were randomized to target diastolic blood pressure 85 mm Hg vs.
100 mm Hg and followed until corrected postgestational age 36 weeks in infants
at baseline all women had diastolic blood pressure 90-105 mm Hg or 85-105 mm Hg if taking
antihypertensive medications (56%)
"clinically reasonable" adherence (defined as actions taken to achieve diastolic pressure within 5 mm
Hg of target) in 82% with target 85 mm Hg vs. 76.6% with target 100 mm Hg (p = 0.04)
981 women (95%) and 981 neonates were included in analyses
comparing diastolic target blood pressure 85 mm Hg vs. 100 mm Hg
pregnancy loss in 2.7% vs. 3% (not significant)
need for high-level neonatal care for > 48 hours in first 28 postnatal days in 29% vs. 29.4% (not
significant)
severe hypertension (≥ 160/110 mm Hg) in 27.5% vs. 40.6% (p < 0.001, NNT 8)
serious maternal complications at 6 weeks postpartum or hospital discharge in 2% vs. 3.7% (not
significant)
mean diastolic blood pressure until delivery 85.3 mm Hg vs. 89.9 mm Hg (p < 0.001)
no significant differences in
maternal outcomes of placental abruption or preeclampsia
neonatal outcomes of small for gestational age, respiratory complications, or serious
complications
consistent outcomes in subgroup analyses of women with preexisting hypertension and gestational
hypertension
Reference - CHIPS trial (N Engl J Med 2015 Jan 29;372(5):407), editorial can be found in N Engl J Med
2015 Jan 29;372(5):475
insufficient evidence to determine target blood pressure in pregnant women with mild-to-moderate
hypertension
systematic review of randomized trials comparing tight to very tight control of mild-to-moderate
preexisting 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
only 3 perinatal deaths occurred and no cases of eclampsia, stroke, or maternal deaths reported
comparing tight vs. very tight control
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
Reference - Cochrane Database Syst Rev 2011 Jul 6;(7):CD006907
Antihypertensive drug selection for treatment of nonsevere or chronic

hypertension
International Society for the Study of Hypertension in Pregnancy recommendations for treatment of chronic
hypertension in pregnancy(6)
acceptable initial antihypertensives include labetalol, oxprenolol, methyldopa, nifedipine, and diltiazem
second- or third-line agents include prazosin and hydralazine
American College of Obstetricians and Gynecologist (ACOG) recommendations for treatment of chronic
hypertension in pregnancy(5)
initial treatment options include
labetalol; dosing options include (ACOG Level B)
200-2,400 mg/day orally in 2-3 divided doses; commonly initiated at 100-200 mg twice daily
for urgent control of severe acute hypertension either of
10-20 mg IV bolus, then 20-80 mg every 10-30 minutes up to maximum cumulative dose of 300
mg
nifedipine; dosing options include (ACOG Level B)

30-120 mg/day orally (slow-release preparation), commonly initiated at 30-60 mg once daily
for urgent control of severe acute hypertension, recommended dose is 10-20 mg orally repeated in
20 minutes as needed, then 10-20 mg every 2-6 hours for a maximum daily dose of 180 mg
methyldopa 0.5-3 g/day orally in 2-4 divided doses, commonly initiated at 250 mg twice or three times
daily
hydrochlorothiazide 12.5-50 mg daily can be considered as second- or third-line agent
not recommended for women with uncomplicated chronic hypertension are angiotensin-converting
enzyme (ACE) inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor
antagonists
recommendations for antihypertensive therapy for nonsevere hypertension (blood pressure 140-159/90-109
mm Hg)
initial antihypertensive therapy should be monotherapy; first-line drugs include (Hypertension Canada
Grade C)
oral labetalol
oral methyldopa
long-acting oral nifedipine
other oral beta-blockers (acebutolol, metoprolol, pindolol, and propranolol)
second-line antihypertensive drugs include (Hypertension Canada Grade D)
clonidine
hydralazine
thiazide diuretics
angiotensin-converting enzyme inhibitors (Hypertension Canada Grade C) and angiotensin receptor
blockers (Hypertension Canada Grade D) should not be used in pregnant women
if target blood pressure (diastolic blood pressure 85 mm Hg) is not achieved with standard dose
monotherapy
consider use of additional antihypertensive drugs (Hypertension Canada Grade C)
add-on drugs should be from a different drug class chosen from first- or second-line options
(Hypertension Canada Grade D)

treatment options include
methyldopa (ESC Class I, Level B)
labetalol (ESC Class I, Level C)
calcium channel blockers (such as nifedipine) (ESC Class I, Level C)
not recommended for use during pregnancy are ACE inhibitors, angiotensin receptor blockers, and direct
renin inhibitors (ESC Class III, Level C)
low-dose furosemide may be considered in case of oliguria, but diuretics are best avoided
labetalol and nifedipine modified release may be associated with similar blood pressure control in
pregnant women with chronic hypertension (level 3 [lacking direct] evidence)
based on nonclinical outcomes from randomized trial
114 pregnant women with chronic hypertension at 12 weeks to 27 6/7 weeks gestation were randomized
to labetalol 200-1,800 mg orally daily vs. nifedipine-modified release 20-80 mg orally daily until delivery
chronic hypertension defined as prenatal diagnosis of chronic hypertension or blood pressure ≥ 140 mm
Hg systolic or ≥ 90 mm Hg diastolic before 20 weeks gestation requiring antihypertensive treatment
before 27 6/7 weeks gestation
both treatments were adjusted to reach target diastolic blood pressure 85 mm Hg
98% completed trial and were included in analysis
blood pressure control outcomes comparing labetalol vs. nifedipine
mean blood pressure 134/84 mm Hg vs. 134/85 mm Hg (not significant)
maximum blood pressure 161/101 mm Hg vs. 163/105 mm Hg (not significant)
1 additional oral antihypertensive agent in 27% vs. 35% (no p value reported)
> 2 additional oral antihypertensive agents in 4% vs. 2% (no p value reported)
additional IV antihypertensive agents in 4% vs. 14% (no p value reported)
maternal and neonatal outcomes comparing labetalol vs. nifedipine

superimposed preeclampsia in 15% vs. 26% (not significant)
cesarean section in 56.4% vs. 56.1% (no p value reported)
preterm birth at < 37 weeks gestation in 22% vs. 35% (no p value reported)
preterm birth at < 34 weeks gestation in 18% vs. 19% (no p value reported)
live birth in 93% vs. 91% (no p value reported)
admission to neonatal intensive care unit in 22% vs. 29% (not significant)
Reference - PANDA trial (Hypertension 2017 Nov;70(5):915)
Efficacy of antihypertensive therapy in nonsevere hypertension

antihypertensive therapy in pregnant women with nonsevere hypertension may reduce risk of severe
hypertension but effects on maternal and neonatal outcomes are uncertain
antihypertensive drugs may reduce risk of severe hypertension without increasing maternal side
effects in pregnant women with mild-to-moderate hypertension (level 2 [mid-level] evidence)
based on Cochrane review with inconsistent results in high-quality trials
systematic review of 63 randomized trials evaluating antihypertensive drugs in pregnant women with
mild-to-moderate hypertension (systolic blood pressure 140-169 mm Hg and/or diastolic blood
pressure 90-109 mm Hg)
antihypertensive drugs included beta-blockers, methyldopa, calcium channel blockers, and
vasodilators
31 trials compared any antihypertensive drug vs. placebo or no antihypertensive drug (control)
antihypertensive drugs associated with
reduced risk of severe hypertension in analysis of 20 trials with 2,558 women
risk ratio 0.49 (95% CI 0.4-0.6)
NNT 9-13 with severe hypertension in 20% of control group
no significant difference in 1 of 2 high-quality trials included in analysis
drugs associated with risk reduction included beta-blockers alone, or in combination with other
drugs, and methyldopa
reduced risk of neonatal respiratory distress syndrome in analysis of 6 trials with 925 neonates,
but CI includes differences that may not be clinically important
risk ratio 0.53 (95% CI 0.29-0.99)
NNT 14-1,000 with respiratory distress syndrome (RDS) in 10% of control group
risk reduction was seen only with beta-blockers
no significant differences
maternal side effects in analysis of 11 trials with 934 women
risk of proteinuria or preeclampsia in analysis of 23 trials with 2,851 women
maternal mortality in analysis of 5 trials with 525 women
fetal or neonatal mortality including miscarriage in analysis of 29 trials with 3,365 women
risk of preterm birth at < 37 weeks in analysis of 15 trials with 2,141 women
risk of cesarean delivery in analysis of 21 trials with 2,724 women
small for gestational age infants in analysis of 21 trials with 2,686 neonates
risk of severe preeclampsia in analysis of 3 trials with 416 women
risk of placental abruption in analysis of 13 trials with 1,568 women
oral beta blockers may help reduce blood pressure in women with mild-to-moderate hypertension
during pregnancy but insufficient evidence to determine effect on clinical outcomes
systematic review of 29 randomized trials evaluating beta blockers in about 2,500 women with mild-
to-moderate hypertension during pregnancy
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
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 infants and neonatal bradycardia
13 trials with 854 women comparing beta blockers to methyldopa found no significant differences in
outcomes
authors note that there is insufficient evidence regarding the effect of antihypertensive therapy in
general on clinical outcomes in this patient population
Reference - Cochrane Database Syst Rev 2003;(3):CD002863 (review updated 2012 Jul 4)
maternal use of beta-blockers for hypertension during first trimester may not be associated with
increased risk of congenital malformations (level 2 [mid-level] evidence)
based on population-based cohort study
18,477 pregnant women with hypertension and their offspring were evaluated
19% were from Nordic countries who gave birth to live singleton infants between 1996 and 2010
81% were identified in Medicaid database in United States between 2000 and 2010 (women were
12-55 years old who had live births)
13% used beta-blockers in first trimester
women using beta-blockers were older and were more likely to have given birth previously and use
antidiabetic medication compared to women who did not use beta-blockers
overall prevalence of congenital malformations was 4.4%
comparing maternal use of beta-blockers vs. no use of beta-blockers in first trimester, no significant
differences in risk of
Overview andmajor congenital malformation
Recommendations (adjusted relative risk [RR] 1.07, 95% CI 0.89-1.3)
/ Background
any cardiac malformation (adjusted RR 1.12, 95% CI 0.83-1.51)
cleft lip or palate (adjusted RR 1.97, 95% CI 0.74-5.25)
central nervous system malformations (adjusted RR 1.37, 95% CI 0.58-3.25)
Reference - Ann Intern Med 2018 Oct 16 early online, editorial can be found in Ann Intern Med 2018
Oct 16 early online
Antihypertensive drug selection for treatment of acute severe hypertension

World Health Organization (WHO) recommends that choice and route of administration of antihypertensive
drugs for treatment of severe hypertension during pregnancy should be based primarily on the prescribing
clinician's experience with any particular drug, its cost, and local availability (WHO Conditional
recommendation, Very low certainty evidence) (WHO 2018)
American College of Obstetricians and Gynecologist (ACOG) recommendations for treatment of severe
acute hypertension (hypertensive emergency) in pregnancy(4)
labetalol, either of
10-20 mg IV bolus, then 20-80 mg every 10-30 minutes to maximum cumulative dose of 300 mg
nifedipine (immediate release) - recommended dose is 10-20 mg orally repeated in 20 minutes as

needed, then 10-20 mg every 2-6 hours for a maximum daily dose of 180 mg
hydralazine in 1 of 2 dosing options
5 mg IV or intramuscular, then 5-10 mg IV every 20-40 minutes to maximum cumulative dose of 20
mg
constant infusion 0.5-10 mg/hour
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations(2)

for severe hypertension (blood pressure > 160 mm Hg systolic or ≥ 110 mm Hg diastolic)
initial treatment options for use in hospital setting include
nifedipine short-acting capsules (SOGC Grade A, Level I)
parenteral hydralazine (SOGC Grade A, Level I)
parenteral labetalol (SOGC Grade A, Level I)
alternative antihypertensive medications include
nitroglycerin infusion (SOGC Grade B, Level I)
oral methyldopa (SOGC Grade B, Level I)
oral labetalol (SOGC Grade B, Level I)
oral clonidine (SOGC Grade B, Level III)
oral captopril (postpartum only) (SOGC Grade B, Level III)
refractory hypertension can be treated with sodium nitroprusside (SOGC Grade B, Level III)
nifedipine and magnesium sulfate can be used simultaneously (SOGC Grade B, Level II-2)
magnesium sulfate not recommended as sole antihypertensive agent (SOGC Grade E, Level I)
continuous fetal heart rate monitoring recommended until blood pressure stable (SOGC Grade L,
Level III)

for severe hypertension, use
labetalol IV (ESC Class I, Level C)
oral methyldopa (ESC Class I, Level C)
oral nifedipine (ESC Class I, Level C)
nitroglycerin IV if preeclampsia associated with pulmonary edema (ESC Class I, Level C)
suggested initial dosing 5 mcg/minute
gradually increase dosing every 3-5 minutes to maximum of 100 mcg/minute
hydralazine IV no longer drug of choice due to perinatal adverse effects but commonly used if other
medications fail to adequately control blood pressure
urapidil may be considered
sodium nitroprusside should be last choice due to risk of fetal cyanide poisoning upon prolonged use
Efficacy of antihypertensive therapy in severe hypertension

oral nifedipine may decrease risk of persistent maternal hypertension and neonatal death compared to IV
labetalol in pregnant women with severe hypertension (level 2 [mid-level] evidence)
based on systematic review with wide confidence intervals
systematic review of 7 randomized trials comparing oral nifedipine vs. IV labetalol in 363 pregnant
women with severe hypertension
nifedipine and labetalol doses varied across trials, most common doses were 50-90 mg for nifedipine
and 220-300 mg for labetalol (5 trials each)
all women were enrolled in second or third trimester
oral nifedipine associated with decreased risk of

persistent maternal hypertension in analysis of all trials
risk ratio (RR) 0.42 (95% CI 0.18-0.96), confidence interval includes possibility of no clinically
important effect
NNT 16-313, with persistent maternal hypertension in 8% of IV labetalol group
neonatal death in analysis of 4 trials with 221 patients
RR 0.27 (95% CI 0.09-0.87)
NNT 11-77, with neonatal death in 10% of IV labetalol group
maternal side effects (RR 0.57, 95% CI 0.35-0.94) in analysis of 3 trials with 207 patients
no significant differences in risk of other maternal or fetal and perinatal outcomes including
maternal death (5 trials), serious maternal morbidity (5 trials), hypotension (6 trials), or cesarean
section (4 trials)
intrauterine death (5 trials), fetal heart rate abnormalities (5 trials), low Apgar score (2 trials), or
neonatal intensive care unit admission (5 trials)
oral nifedipine may be as effective as IV hydralazine in achieving target blood pressure in women with
severe hypertension during pregnancy (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 16 randomized trials evaluating oral antihypertensive agents in 915 women with
severe hypertension during pregnancy or postpartum period
most trials had ≥ 1 limitation including
unclear allocation concealment
unclear or no blinding
most women had severe hypertension during pregnancy

severe hypertension defined as systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥
Overview
110and
mmRecommendations
Hg / Background
comparing oral nifedipine to IV hydralazine
achievement of target blood pressure in analysis of 5 trials with 273 women
maternal hypotension in analysis of 4 trials with 246 women, but 2 events overall
perinatal outcomes (cesarean delivery, adverse fetal heart rate effects, Apgar score < 7 at 5
minutes, perinatal death, neonatal death, and stillbirth)
no maternal mortality in 3 trials with 96 women

Reference - BJOG 2014 Sep;121(10):1210 full-text
oral nifedipine may improve blood pressure control without adverse outcomes at 6 hours but may increase
neonatal admission to intensive care unit compared to oral labetalol or methyldopa in women with severe
hypertension during pregnancy (level 2 [mid-level] evidence)
based on randomized trial without blinding
894 pregnant women gestational age ≥ 28 weeks with severe hypertension requiring pharmacological
blood pressure control were randomized to 1 of 3 treatments
nifedipine 10 mg orally with ≤ 2 additional doses provided each hour (total treatment dose 30 mg) if
systolic blood pressure > 155 mm Hg or diastolic blood pressure > 105 mm Hg
labetalol 200 mg orally with ≤ 2 additional doses provided each hour (total treatment dose 600 mg) if
systolic blood pressure > 155 mm Hg or diastolic blood pressure > 105 mm Hg
methyldopa 1,000 mg orally as single dose
primary outcome was blood pressure control (systolic blood pressure 120-150 mm Hg and diastolic
pressure 70-100 mm Hg) within 6 hours without adverse outcomes, including hypotension, fetal
compromise, severe headache, or eclampsia during study period, or cesarean section for fetal distress ≤
2 hours after end of study period
97.2% of women completed treatment, all included in analysis
blood pressure control within 6 hours without adverse outcome in
84% with nifedipine (p = 0.03 vs. methyldopa, NNT 13; p = 0.05 vs. labetalol)
77% with labetalol (not significant vs. methyldopa)
76% with methyldopa
neonatal admission to intensive care unit in
18% with nifedipine (p = 0.009 vs. labetalol, NNH 12; p = 0.004 vs. methyldopa, NNH 12)
10% with labetalol (not significant vs. methyldopa)
10% with methyldopa
no significant differences among groups in mode of delivery, neonatal death, or neonatal morbidity
serious adverse events included intrapartum seizure in 1 woman in labetalol group and 6 stillbirths (1 in
nifedipine group, 2 in labetalol group, and 3 in methyldopa group)
Reference - Lancet 2019 Aug 1 early online, editorial can be found in Lancet 2019 Aug 1 early online
hydralazine does not appear superior to nifedipine or labetalol for treatment of severe hypertension in
pregnancy and may increase maternal side effects (level 2 [mid-level] evidence)
based on systematic review with incomplete assessment of trial quality
systematic review of 21 randomized trials of short-acting antihypertensive therapy in 893 women with
severe hypertension in pregnancy
8 trials compared hydralazine vs. nifedipine
5 trials compared hydralazine vs. labetalol
hydralazine associated with
Overview nonsignificant reduction in /persistent
and Recommendations Backgroundsevere hypertension compared to labetalol (relative risk [RR]
0.29, 95% CI 0.08-1.04) in analysis of 2 trials
nonsignificant increase in severe hypertension compared to nifedipine or isradipine (RR 1.41, 95% CI
0.95-2.09) in analysis of 4 trials, results limited by heterogeneity and differences in methodologic
quality
compared to other antihypertensive agents, hydralazine associated with increased rates of
maternal hypotension (RR 3.29, 95% CI 1.5-7.23) in analysis of 13 trials
cesarean sections (RR 1.3, 95% CI 1.08-1.59) in analysis of 14 trials
placental abruption (RR 4.17, 95% CI 1.19-14.28) in analysis of 5 trials
maternal oliguria (RR 4, 95% CI 1.22-12.5) in analysis of 3 trials
adverse effects on fetal heart rate (RR 2.04, 95% CI 1.32-3.16) in analysis of 12 trials
low 1-minute Apgar scores (RR 2.7, 95% CI 1.27-5.88) in analysis of 3 trials
compared to labetalol, hydralazine associated with
increased maternal side effects (RR 1.5, 95% CI 1.16-1.94) in analysis of 12 trials
less neonatal bradycardia (RR -0.24, 95% CI -0.42 to -0.06) in analysis of 3 trials
Reference - BMJ 2003 Oct 25;327(7421):955 full-text
Magnesium sulfate
Recommendations
indications for magnesium sulfate(2, 4, 6)
magnesium sulfate should be used for prevention and treatment of seizures in women with gestational
hypertension and preeclampsia with severe features or eclampsia (ACOG Level A; SOGC Grade A, Level I)
for women with severe hypertension
nifedipine and magnesium sulfate can be used simultaneously (SOGC Grade B, Level II-2)
magnesium sulfate not recommended as sole antihypertensive agent (SOGC Grade E, Level I)
for women with preexisting or gestational hypertension at < 32 weeks gestation, consider magnesium
sulfate for fetal neuroprotection in setting of imminent preterm birth (within 24 hours) (SOGC Grade A,
Level I)
magnesium sulfate may be considered in women with nonsevere preeclampsia (SOGC Grade C, Level I)
American College of Obstetricians and Gynecologists (ACOG) recommends continuation of intraoperative

administration of parenteral magnesium sulfate in women with preeclampsia having cesarean delivery to
prevent eclampsia(4)
delivery should not be delayed in order to administer antenatal magnesium sulfate in setting of maternal
and/or fetal indications for emergency delivery (SOGC Grade E, Level III)
routine monitoring of serum magnesium levels not recommended (SOGC Grade E, Level I)
phenytoin and benzodiazepines should not be used for eclampsia prophylaxis or treatment unless
magnesium sulfate contraindicated or ineffective (SOGC Grade E, Level I)
Dosing
ideal dosing for magnesium sulfate unclear; dosing options may include
4-6 g IV loading dose followed by maintenance dose of 1-2 g/hour for ≥ 24 hours postpartum(4)
4 g IV bolus followed by 1 g/hour infusion (SOGC Grade A, Level I)(2)
10 g intramuscular loading dose followed by 5 g intramuscular every 4 hours or 1 g/hour infusion until
delivery and for ≥ 24 hours postpartum(6)
dosing variations
insufficient evidence to evaluate different magnesium sulfate treatment regimens for prevention and
treatment of eclampsia
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
limiting magnesium sulfate to 12 hours postpartum may be safe in women with mild preeclampsia
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% for 12-hour group vs. 1.1%
for 24-hour group (p = 0.07)
no cases of seizures, magnesium sulfate toxicity, or intolerance reported
Reference - Obstet Gynecol 2006 Oct;108(4):833, editorial can be found in Obstet Gynecol 2006
Oct;108(4):824
magnesium sulfate 14 g reported to prevent recurrent seizure in patients with eclampsia (level 3
[lacking direct] evidence)
based on case series
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
magnesium sulfate reduces risk of eclampsia in women with preeclampsia and appears more effective than
nimodipine
magnesium sulfate reduces risk of eclampsia in women with preeclampsia (level 1 [likely reliable]
evidence)
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)
Overview andnoRecommendations
significant difference in stillbirth or neonatal death (RR 1.04, 95% CI 0.93-1.15)
/ Background
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
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%) infants (infants 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
magnesium sulfate appears more effective than nimodipine for preventing seizures in women with
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
eclampsia (defined as a witnessed tonic-clonic seizure) in 0.8% with magnesium sulfate vs. 2.6% with
nimodipine (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 full-text, 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
in women with eclampsia, magnesium sulfate reduces maternal mortality, morbidity, and seizure recurrence
more than diazepam or phenytoin
magnesium sulfate reduces maternal mortality and recurrent seizures more than diazepam for
treatment of eclampsia (level 1 [likely reliable] evidence)
systematic review of 7 randomized trials comparing magnesium sulfate (IV or intramuscular) vs.
diazepam in 1,396 women with clinically diagnosed eclampsia
magnesium sulfate associated with reduced risk of
maternal death (risk ratio [RR] 0.59, 95% CI 0.38-0.92) in analysis of 7 trials with 1,396 women
recurrent seizures (RR 0.43, 95% CI 0.33-0.55, NNT 7, 95% CI for NNT 5-9) in analysis of 7 trials
with 1,390 women
Apgar scores < 7 at 5 minutes (RR 0.7, 95% CI 0.54-0.9) in analysis of 3 trials with 643 neonates
special care unit stay > 7 days (RR 0.66, 95% CI 0.46-0.96) in analysis of 3 trials with 631 neonates
maternal risk of stroke or other serious morbidity including renal failure, cardiac arrest, liver failure,
respiratory depression, or pneumonia
perinatal mortality, neonatal mortality, or admission to special care unit
Reference - Cochrane Database Syst Rev 2010 Dec 8;(12):CD000127
magnesium sulfate reduces recurrent seizures, pneumonia, and intensive care more than phenytoin for
treatment of eclampsia (level 1 [likely reliable] evidence)
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 with recurrent seizures in 20% of phenytoin group
nonsignificant reduction in 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
nonsignificant increase in 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
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
Overview recurrent seizures in
13.2% with magnesium sulfate vs. 27.9% with diazepam (p < 0.0001, NNT 7)
5.7% with magnesium sulfate vs. 17.1% with phenytoin (p < 0.0001, NNT 9)
maternal mortality nonsignificantly lower in magnesium sulfate groups
Reference - Collaborative Eclampsia Trial (Lancet 1995 Jun 10;345(8963):1455)
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 with mortality in 7% of lytic cocktail group
seizure recurrence in analysis of all trials

RR 0.06 (95% CI 0.03-0.12)
NNT 1-2 with seizure recurrence in 55% of 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
Adverse effects on fetus

magnesium sulfate does not appear to increase neonatal adverse events (level 2 [mid-level] evidence)
based on cohort analysis of data from randomized trial
1,047 pregnant women who were at imminent risk for preterm delivery at 24-31 weeks gestation who
were previously randomized to magnesium sulfate (6 g loading dose over 20 minutes followed by 2
g/hour until delivery) vs. placebo were analyzed
44% of neonates had exposure to magnesium sulfate
composite adverse neonatal outcome included any of the following: 5-minute Apgar score < 7, oxygen
administration, intubation, chest compressions, hypotonicity, or hypotension treated with vasopressors
comparing magnesium sulfate vs. placebo
composite outcome in 70.3% vs. 74.6% (not significant)
small for gestational age 3.2% vs. 1.5% (p = 0.07)
no significant differences in individual outcomes within composite endpoint

Reference - Am J Obstet Gynecol 2015 Sep;213(3):424.e1
reviews
review of magnesium sulfate for treatment of eclampsia can be found in Stroke 2009 Apr;40(4):1169
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
review of therapeutic uses of magnesium can be found in Am Fam Physician 2009 Jul 15;80(2):157
systematic review evaluating antenatal magnesium sulfate to improve maternal and infant outcomes can
be found / Background
in BMC Pregnancy Childbirth 2013 Oct 21;13:195 full-text
Corticosteroids
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommendations for prenatal
corticosteroid for fetal lung maturation(6)
recommended for women between 24 and 34 weeks gestation with hypertensive disorders of pregnancy
may be considered up to 38 weeks gestation in cases of elective delivery by cesarean section
American College of Obstetricians and Gynecologists (ACOG) recommends corticosteroids to benefit fetal
lung maturity if delivery is indicated < 34 weeks gestation in woman with gestational hypertension or
preeclampsia with severe features(4)
consider antenatal corticosteroid therapy for
all women who present with preeclampsia at ≤ 34 6/7 weeks gestation (SOGC Grade A, Level I)
women who present with gestational hypertension at ≤ 34 6/7 weeks (despite absence of proteinuria
or adverse conditions) if delivery planned within 7 days (SOGC Grade L, Level III)
consider rescue dose of corticosteroids for women at ≤ 34 6/7 weeks gestation who remain at high risk
for preterm delivery ≥ 7 days after initial course of corticosteroids (SOGC Grade C, Level I)
consider antenatal corticosteroids in women who deliver by cesarean section at ≤ 38 6/7 weeks
gestation to reduce respiratory morbidity (SOGC Grade B, Level I)
corticosteroids not recommended for women with hemolysis, elevated liver enzymes, low platelets
(HELLP) syndrome as not proven to decrease maternal morbidity (SOGC Grade L, Level II-3)
Other medications
phenytoin and benzodiazepines should not be used for eclampsia prophylaxis or treatment unless
magnesium sulfate contraindicated or ineffective (SOGC Grade E, Level I)(2)
insufficient evidence for recommendations on usefulness of treatment with(2)
selenium (SOGC Grade L, Level I)
zinc (SOGC Grade L, Level III)
pyridoxine (SOGC Grade L, Level III)
iron (with or without folate) (SOGC Grade L, Level III)
vitamin D (SOGC Grade L, Level III)
multivitamins with or without micronutrients (SOGC Grade L, Level III)
insufficient evidence to evaluate low-dose dopamine in women with severe preeclampsia and oliguria
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
only 1 trial found, comparing low-dose dopamine vs. placebo in 40 postpartum women with oliguria
dopamine increased urinary output over 6 hours but clinical benefit not established
no randomized trials identified to evaluate Chinese herbal medicines for women with preeclampsia
Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD005126
Consultation
Overview and referral / Background
and Recommendations
at scheduling of antenatal care, offer obstetric consultation to women with markers of increased risk for
preeclampsia (SOGC Grade B, Level II-2)
obstetric consultation mandatory for women with severe preeclampsia (SOGC Grade B, Level III)
Other management
abdominal decompression may improve perinatal outcomes in women with preeclampsia or impaired fetal
growth (level 2 [mid-level] evidence)
based on Cochrane review of trials with inadequate allocation concealment
systematic review of 3 randomized or quasi-randomized trials comparing abdominal decompression
(negative pressure to space around abdomen) to no decompression in 356 women with preeclampsia or
impaired fetal growth
abdominal decompression achieved using rigid dome encircling abdomen covered with airtight suit that
allows decompression of space around abdomen to -50 to -100 mm Hg for 15-30 seconds of each
minute for a half hour, either 3 times daily or continuously during labor
1 trial included women with preeclampsia, essential hypertension, or chronic nephritis; 2 trials included
women with small-for-gestational-age fetus
comparing abdominal decompression to no decompression
abdominal decompression associated with decreased risk of
perinatal mortality in analysis of 3 trials with 367 infants
risk ratio (RR) 0.39 (95% CI 0.22-0.71)
NNT 7-19 with perinatal mortality in 19% in no decompression group
low birth weight in analysis of 2 trials with 304 infants, results limited by significant heterogeneity
RR 0.5 (95% CI 0.4-0.63)
NNT 3-4 with low birth weight in 75% of no decompression group
fetal distress in labor in 14.3% vs. 38.6% (p = 0.0026, NNT 5) in 1 trial with 140 infants
Apgar score < 6 at 1 minute in 10% vs. 38.6% (p = 0.00052, NNT 4) in 1 trial with 140 infants
unchanged or worsening preeclampsia in 19% vs. 52.6% (p = 0.004, NNT 3) in 1 trial with 80 women

insufficient evidence to determine if guided imagery reduces severe hypertension or preeclampsia in
women with hypertension during pregnancy
systematic review of randomized trials comparing guided imagery vs. other nonpharmacologic methods
for managing hypertension in 99 pregnant women
neither trial reported primary maternal outcomes (severe hypertension, severe preeclampsia) or primary
neonatal outcome (perinatal death)
antihypertensive drug use in 47% with guided imagery vs. 37% with quiet rest (not significant) in 1 trial
with 69 women
Reference - Cochrane Database Syst Rev 2019 Apr 27;(4):CD011337
Delivery and expectant management

Expectant management
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommendations for expectant
management in women with preeclampsia(6)
expectant management recommended for women with onset of preeclampsia between 34 and 37 weeks
gestation
expectant management at a center with maternal-fetal medicine expertise recommended for women with
onset of preeclampsia < 34 weeks gestation
women with preeclampsia with a fetus < 24 weeks gestation should be counseled that termination of
pregnancy may be needed
American College of Obstetricians and Gynecologists (ACOG) recommendations(4, 5)

in women with gestational hypertension, preeclampsia, or chronic hypertension and superimposed
preeclampsia without severe features and stable maternal and fetal conditions, consider expectant
management until 37 weeks gestation (ACOG Level C)
in women with gestational hypertension or preeclampsia with severe features diagnosed ≥ 34 weeks
gestation, expectant management not recommended
in women with chronic hypertension and no additional maternal or fetal complications, expectant
management recommended (ACOG Level B)
until 38 weeks gestation if not prescribed antihypertensive medications
until 37 weeks gestation if prescribed maintenance antihypertensive medications
in women who develop superimposed preeclampsia with severe features < 34 weeks gestation (ACOG
Level B)
≥ 34 weeks gestation (ACOG Level B)

< 34 weeks gestation (ACOG Level B)
if evidence of deteriorating maternal or fetal status
if neonatal survival is not anticipated

for women with nonsevere preeclampsia at 24-33 6/7 weeks gestation, consider expectant management
if in perinatal center capable of caring for very preterm infant (SOGC Grade B, Level I)
insufficient evidence to make a recommendation for or against expectant management in women with
nonsevere preeclampsia at 34-36 6/7 weeks gestation (SOGC Grade L, Level III)
gestational hypertension without preeclampsia at < 37 weeks gestation (SOGC Grade L, Level III)
maternal and fetal surveillance for women with expectant management of nonsevere preeclampsia(1, 6)
measure blood pressure twice weekly
obtain lab tests weekly, including complete blood count (CBC), platelet count, hemoglobin, alanine
transaminase (ALT), aspartate transaminase (AST), and creatinine
assess for proteinuria (if not already present)
screen with dipstick or spot protein:creatinine ratio
obtain periodic 24-hour urine collections
fetal monitoring
obtain nonstress test twice weekly
measure amniotic fluid index weekly
perform ultrasound for fetal growth every 3 weeks
early elective delivery may increase neonatal morbidity compared to expectant care in women with severe
preeclampsia between 24 and 34 weeks gestation (level 2 [mid-level] evidence)
systematic review of 6 randomized trials comparing intervention vs. expectant care in 748 women with
severe preeclampsia between 24 and 34 weeks gestation
interventionist care defined as policy of early elective delivery by induction of labor or cesarean section
neonatal outcomes
interventionist care associated with
increased intraventricular hemorrhage in analysis of 2 trials with 537 women
risk ratio (RR) 1.94 (95% CI 1.15-3.29)
NNH 6-95 with intraventricular hemorrhage in 7% of expectant care group
increased respiratory distress due to hyaline membrane disease in analysis of 2 trials with 133
women
RR 2.3 (95% CI 1.39-3.81)
NNH 1-11 with respiratory distress due to hyaline membrane disease in 22% of expectant care
group
increased need for neonatal ventilation in analysis of 2 trials with 300 women
RR 1.5 (95% CI 1.11-2.02)
NNH 3-30 with neonatal ventilation in 30% of expectant care group
reduced risk of small for gestational age in analysis of 3 trials with 400 women
RR 0.38 (95% CI 0.24-0.61)
NNT 5-10 with small for gestational age in 27% of expectant care group
death of baby (stillbirth, neonatal, or infant) (RR 1.08, 95% CI 0.74-1.6) in analysis of 6 trials with
760 women
admission to neonatal intensive care unit or necrotizing enterocolitis in analysis of 3-4 trials
maternal outcomes
maternal death in 2 trials with 320 women (0 deaths reported)
eclampsia in 1 trial with 264 women
pulmonary edema, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, or
delivery by cesarean section in analyses of 2-6 trials
elective delivery may not increase perinatal mortality (level 2 [mid-level] evidence)
based on randomized trial with wide confidence interval
267 women at 28-33 weeks gestation with severe hypertensive disorder and living in Latin America
were randomized to 1 of 2 groups
steroids plus expectant management (delivery only for specific maternal/fetal indications or
reaching 34 weeks gestation)
steroids followed by prompt delivery within 24-72 hours
exclusion criteria included small-for-gestational-age at time of admission

antihypertensive medications used to maintain systolic blood pressure < 160 mm Hg and diastolic
blood pressure < 110 mm Hg were different between groups
in prompt delivery group bolus doses of hydralazine, labetalol, or oral nifedipine were used;
frequency of use not reported
in expectant management group oral antihypertensive medications used only in some hospitals,
Overview anduse
Recommendations
reported in 46.5% of/ women
Background
in expectant management group
neonatal morbidity was composite outcome including respiratory distress syndrome, necrotizing
enterocolitis, intraventricular hemorrhage, and neonatal sepsis
maternal morbidity was composite outcome including placental abruption, eclampsia, pulmonary
edema, renal insufficiency, oliguria, disseminated intravascular coagulation, and hemolysis, elevated
liver enzymes, low platelet count (HELLP) syndrome
comparing expectant management vs. prompt delivery
perinatal mortality 8.7% vs. 9.4% (relative risk 0.91, 95% CI 0.34-1.93)
neonatal morbidity in 55.6% vs. 56.4% (not significant)
maternal morbidity in 25.2% vs. 20.3% (not significant)
small gestational age in 21.7% vs. 9.4% (p = 0.005, NNH 8)
placental abruption in 7.6% vs. 1.5% (p = 0.01, NNH 16)
mean pregnancy prolongation was 10.3 days vs. 2.2 days (p = 0.0001)
Reference - MEXPRE Latin trial (Am J Obstet Gynecol 2013 Nov;209(5):425.e1), commentary can be
found in Am J Obstet Gynecol 2013 Nov;209(5):e1
Decision to deliver and timing of delivery

International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends delivery for women
with onset of preeclampsia ≥ 37 weeks gestation(6)
delivery < 37 weeks is recommended for any of the following indications
repeated episodes of severe hypertension despite treatment with 3 classes of antihypertensive
agents
maternal pulse oximetry < 90%
progressive thrombocytopenia
progressive deterioration in liver function, creatinine, hemolysis, or platelet count
abnormal neurological features such as severe intractable headache, repeated visual scotomata, or
convulsions
placental abruption
non reassuring fetal status
stillbirth
American College of Obstetricians and Gynecologists (ACOG) recommendations for delivery in women with
gestational hypertension, preeclampsia, or chronic hypertension with superimposed preeclampsia(4, 5)
consider delivery rather than continued observation for women ≥ 37 weeks gestation with gestational
hypertension or preeclampsia without severe features (ACOG Level A)
for women with gestational hypertension or preeclampsia with severe features
at < 34 weeks gestation with stable maternal and fetal conditions, continued pregnancy should be
undertaken only at facilities with adequate maternal and neonatal intensive care resources (ACOG
Level B)
at ≥ 34 weeks gestation, delivery recommended soon after maternal stabilization or with labor or
prelabor rupture of membranes (ACOG Level B)
during expectant management, delivery recommended if unstable maternal or fetal conditions
regardless of gestational age (ACOG Level B)
maternal conditions
uncontrolled severe-range blood pressures (persistent systolic blood pressure ≥ 160 mm Hg or
diastolic blood pressure ≥ 110 mm Hg not responsive to antihypertensive medication
persistent headaches, refractory to treatment
epigastric pain or right upper pain unresponsive to repeat analgesics
visual disturbances, motor deficit, or altered sensorium
stroke
myocardial infarction
hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome
new or worsening renal dysfunction (serum creatinine > 1.1 mg/dL or twice baseline)
pulmonary edema
eclampsia
suspected acute placental abruption or vaginal bleeding in absence of placenta previa
fetal conditions
abnormal fetal testing
death
no expectation for survival at time of maternal diagnosis
persistent reversed end-diastolic flow in umbilical artery
for women with chronic hypertension who develop superimposed preeclampsia with severe features ≥ 34
weeks gestation (ACOG Level B)

for timing of delivery in women with preeclampsia
for women with severe preeclampsia, immediate delivery recommended regardless of gestational age
SOGC Grade C, Level III)
for women with nonsevere preeclampsia
at ≥ 37 weeks gestation, immediate delivery recommended (SOGC Grade A, Level I)
at 34 to < 37 weeks gestation, insufficient evidence to make a recommendation about the benefits
and risks of expectant management (SOGC Grade L, Level III)
at 24 to < 34 weeks gestation, consider expectant management in perinatal centers able to care
for very preterm infants (SOGC Grade B, Level I)
for women with nonsevere preeclampsia complicated by HELLP syndrome at 24 to < 35 weeks
gestation, consider delaying delivery long enough to administer antenatal corticosteroids if temporary
improvement in maternal test results (SOGC Grade B, Level II-2)
for women with preeclampsia complicated by HELLP syndrome at ≥ 35 weeks gestation, consider
immediate delivery (SOGC Grade B, Level II-2)
for timing of delivery in women with gestational hypertension without preeclampsia

if ≥ 37 weeks gestation, discuss inducing delivery within days (SOGC Grade B, Level I)
if < 37 weeks gestation, insufficient evidence to make a recommendation about the benefits and risks
of expectant management (SOGC Grade L, Level III)
for women with uncomplicated preexisting hypertension who are well at ≥ 37 weeks gestation, consider
delivery at 38 to < 40 weeks gestation (SOGC Grade B, Level II-1)
continue antihypertensive treatment throughout labor and delivery to maintain systolic blood pressure <
160 mm Hg and diastolic blood pressure < 110 mm Hg (SOGC Grade B, Level II-2)

for women with gestational hypertension or mild preeclampsia delivery at 37 weeks gestation
recommended (ESC Class I, Level B)
expedited delivery recommended if preeclampsia with adverse conditions (such as visual disturbances or
hemostatic disorders) (ESC Class I, Level C)
planned delivery may reduce maternal morbidity and severe hypertension, but may increase neonatal unit
admissions / Background
compared to expectant management in women with late preterm preeclampsia (level 2 [mid-
level] evidence)
901 adult women (mean age 30 years) with late preterm preeclampsia who were at 34 to < 37 weeks
gestation with singleton or dichorionic diamniotic twin pregnancy were randomized to planned delivery
vs. expectant management
co-primary maternal and perinatal outcomes were
composite of maternal morbidity based on fullPIERS outcomes and systolic blood pressure ≥ 160 mm
Hg
composite of neonatal death within 7 days of delivery and perinatal death or neonatal unit admission
outcomes in fullPIERS model were maternal death; adverse central nervous system, cardiorespiratory,
hematological, or hepatic events; acute renal failure; or placental abruption
trial designed to test noninferiority of planned delivery compared to expectant management for perinatal
outcome, but superiority statistics also reported
99.7% of women were included in analysis
comparing planned delivery vs. expectant management
maternal composite outcome in 65% vs. 75% (adjusted relative risk 0.86, 95% CI 0.79-0.94)
composite maternal morbidity in 15% vs. 20% (p < 0.05, NNT 20)
systolic blood pressure ≥ 160 mm Hg in 60% vs. 69% (p < 0.05, NNT 12)
admission to neonatal unit in 42% vs. 34% (p < 0.05, NNH 12)
progression to severe preeclampsia in 64% vs. 74% (p < 0.05, NNT 10)
antihypertensive medication before delivery in 85% vs. 90% (p < 0.05, NNT 20)
no perinatal deaths or neonatal deaths within 7 days of delivery occurred

no significant differences in placental abruption, confirmed sepsis, birthweight, need for respiratory
support or supplemental oxygen in neonates, or total time in neonatal unit
Reference - PHOENIX trial (Lancet 2019 Aug 28 early online full-text), editorial can be found in Lancet
2019 Aug 28 early online full-text
labor induction may reduce severe hypertension in women with gestational hypertension or mild
preeclampsia, and might reduce intensive maternal hospital care (level 2 [mid-level] evidence)
based on randomized trial without blinding of outcome assessors
756 women (mean age 29 years) with gestational hypertension or mild preeclampsia and singleton
pregnancy at 36-41 weeks gestation were randomized to induction of labor vs. expectant monitoring
maternal adverse outcome was composite of maternal death, thromboembolic complications, pulmonary
edema, HELLP syndrome, eclampsia, placental abruption, progression to severe hypertension or
proteinuria, and major postpartum hemorrhage
median time from randomization to onset of labor was 0.79 days in immediate delivery group vs. 6.3
days in expectant monitoring group (p < 0.0001)
46% of women randomized to expectant monitoring were induced due to maternal or fetal indications,
gestational age > 41 weeks, or choice
comparing induction of labor vs. expectant monitoring
maternal adverse outcome in 31% vs. 44% (p < 0.0001, NNT 8)
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)
HELLP syndrome in 1% vs. 3% (p = 0.07)
intensive maternal hospital care in 2% vs. 4% (p = 0.059)
cesarean delivery in 14% vs. 19% (p = 0.085)
median duration of neonatal hospital stay was 3 days vs. 4 days (p = 0.077)
no significant
Overview differences in severe
and Recommendations proteinuria, lung edema, postpartum hemorrhage, thromboembolic
/ Background
disease, duration of maternal hospital stay, composite neonatal morbidity, intensive neonatal hospital
care
no cases of maternal death, eclampsia, placental abruption, or neonatal death
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
labor induction associated with decrease in high-risk maternal complications compared to expectant
monitoring in women with longer cervix
based on post hoc analysis of HYPITAT trial with all women evaluated for cervix length (median
length 30 mm, range 0-64 mm)
compared to expectant monitoring, labor induction associated with decrease in high-risk maternal
complications with increasing cervix length (p = 0.03)
for expectant monitoring, each 1-cm increase in cervical length associated with 32% increase in high-
risk maternal complications
for labor induction, each 1-cm increase in cervical length associated with 3% decrease in high-risk
maternal complications
no significant differences in cesarean delivery or neonatal outcomes with increasing cervix length
Reference - BJOG 2012 Aug;119(9):1123 full-text
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
labor induction associated with decrease in high-risk maternal complications compared to expectant
monitoring in women with longer cervix
based on post hoc analysis of HYPITAT trial with all women evaluated for cervix length (median length 30
mm, range 0-64 mm)
compared to expectant monitoring, labor induction associated with decrease in high-risk maternal
complications with increasing cervix length (p = 0.03)
for expectant monitoring, each 1 cm increase in cervical length associated with 32% increase in high-risk
for labor induction, each 1 cm increase in cervical length associated with 3% decrease in high-risk
no significant differences in cesarean delivery or neonatal outcomes with increasing cervix length
Reference - BJOG 2012 Aug;119(9):1123 full-text
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
Mode of delivery
American College of Obstetricians and Gynecologists (ACOG) recommendations for mode of delivery in
women with gestational hypertension or preeclampsia (with or without severe features)(4)
mode of delivery should be determined by routine obstetric considerations
decision to perform cesarean delivery should be individualized, based on anticipated probability of
vaginal delivery and on the nature and progression of preeclampsia disease state
neuraxial anesthesia (either spinal or epidural anesthesia) can be considered in women with platelet
counts > 70 x 109/L provided platelet count is stable and there is no other acquired or congenital
coagulopathy, platelet function is normal, and patient is not taking antiplatelet or anticoagulation therapy
(ACOG Level C)

for mode of delivery in women with hypertensive disorders of pregnancy
Overview for
andwomen with any hypertensive
Recommendations disorder of pregnancy, consider vaginal delivery unless cesarean
/ Background
section required for usual obstetric indications (SOGC Grade B, Level II-2)
utilize cervical ripening if vaginal delivery planned and unfavorable cervix (SOGC Grade A, Level I)
cesarean section may be beneficial if gestational age remote from term and evidence of fetal
compromise (SOGC Grade B, Level II-2)
active management recommended for third stage of labor, especially if thrombocytopenia or
coagulopathy (SOGC Grade A, Level I)
ergometrine maleate not recommended in women with any hypertensive disorders of pregnancy,
especially preeclampsia or gestational hypertension; consider alternate oxytocic agent (SOGC Grade
D, Level III-3)
for anesthesia administration during delivery
inform anesthesiologist when woman with preeclampsia admitted to delivery suite (SOGC Grade B,
Level II-3)
perform platelet count upon admission to delivery suite in women with preeclampsia (SOGC Grade A,
Level II-1)
regional analgesia and/or anesthesia appropriate in women
with platelet count ≥ 75 million/L (SOGC Grade B, Level II-2)
with preeclampsia if no associated coagulation concerns (SOGC Grade E, Level II-2)
with adequate platelet count taking low-dose acetylsalicylic acid (SOGC Grade A, Level I)
taking unfractionated heparin ≤ 10,000 units/day subcutaneously at 4 hours after last dose and
possibly immediately after last dose without any delay (SOGC Grade B, Level III)
taking unfractionated heparin > 10,000 units/day if normal activated partial thromboplastin time 4
hours after last dose (SOGC Grade B, Level III)
taking heparin IV in therapeutic dose if normal activated partial thromboplastin time 4 hours after
last dose (SOGC Grade B, Level III)
taking low-molecular-weight heparin 10-12 hours after prophylactic dose, or 24 hours after
therapeutic dose (SOGC Grade B, Level III)
early insertion of epidural catheter recommended for control of labor pain in women without
contraindications to epidural (SOGC Grade A, Level I)
in absence of contraindications, acceptable methods of anesthesia for women having cesarean
include (SOGC Grade A, Level I)
epidural
spinal
combined spinal-epidural
general anesthesia
small doses of phenylephrine or ephedrine may be used to prevent or treat hypotension during
regional anesthesia (SOGC Grade A, Level I)
routine fixed IV fluid bolus not recommended prior to regional analgesia and/or anesthesia (SOGC
Grade E, Level I)
planned cesarean delivery may not reduce maternal and perinatal mortality and complications compared to
planned vaginal delivery in women with eclampsia (level 2 [mid-level] evidence)
based on randomized trial with inadequate statistical power
200 women with singleton pregnancy gestational age ≥ 34 weeks and antepartum or intrapartum
eclampsia randomized to cesarean delivery vs. vaginal delivery
27% of vaginal delivery group required cesarean delivery
maternal complications included respiratory depression, ventilation, pulmonary edema, pneumonia, renal
failure, hepatic failure, coagulopathy, admission to intensive care unit
power calculation estimated sample size at least 294 women per arm necessary to show 10% difference
in composite of complications and death
comparing cesarean delivery vs. vaginal delivery
maternal death in 2% vs. 2% (not significant)
maternal complications or death in 10.9% vs. 7.1% (not significant)
stillbirth or death in first week in 4% vs. 5% (not significant)
Apgar score < 7 at 5 minutes in 10.9% vs. 17.2% (not significant)
delivery room intubation in 6.9% vs. 13.1% (not significant)
admission to special baby care unit in 4.9% vs. 8.1% (not significant)
Follow-up
Postdelivery care
women with preeclampsia should be monitored for ≥ 3 days postpartum at least every 4 hours while
awake
continue antenatally-administered antihypertensive medications immediately postpartum;
antihypertensive therapy may be withdrawn gradually over a period of days
nonsteroidal anti-inflammatory drugs (NSAIDs) for postpartum analgesia should be avoided in women
with preeclampsia unless other analgesics are ineffective
follow-up at 3 months postpartum should ensure that blood pressure, urinalysis, and laboratory
abnormalities have normalized
American College of Obstetricians and Gynecologists (ACOG) recommends nonsteroidal anti-inflammatory

drugs (NSAIDs) over opioid analgesics for postpartum pain relief (ACOG Level A)
for care during first 6 weeks postpartum
measure blood pressure during time of peak postpartum blood pressure, 3-6 days after delivery
(SOGC Grade B, Level III)
assess for new or worsening preeclampsia in women with postpartum hypertension (SOGC Grade B,
Level II-2)
antihypertensive therapy
consider continuing antihypertensive therapy postpartum, especially in women with antenatal
preeclampsia and women who delivered preterm (SOGC Grade L, Level II-2)
treat severe postpartum hypertension with antihypertensive therapy to keep systolic blood
pressure < 160 mm Hg and diastolic blood pressure < 110 mm Hg (SOGC Grade A, Level I)
in women with nonsevere postpartum hypertension
with comorbidities (other than pregestational diabetes), treat with antihypertensive therapy to
keep blood pressure < 140 mm Hg systolic and < 90 mm Hg diastolic (SOGC Grade C, Level III)
without comorbidities, consider antihypertensive therapy to keep blood pressure < 140 mm Hg
systolic and < 90 mm Hg diastolic (SOGC Grade L, Level III)
in women with pregestational diabetes, treat with antihypertensive therapy to keep blood pressure
< 130 mm Hg systolic and < 80 mm Hg diastolic (SOGC Grade C, Level III)
antihypertensive medications acceptable for use in breastfeeding include (SOGC Grade B, Level III)
nifedipine extended-release
labetalol
methyldopa
captopril
enalapril
quinapril
Overview confirm
resolution of end-organ dysfunction (SOGC Grade C, Level III)
nonsteroidal anti-inflammatory drugs (NSAIDs) should not be given postpartum if any of following
criteria present (SOGC Grade C, Level III)
hypertension difficult to control
evidence of kidney injury (oliguria and/or creatinine ≥ 90 micrometer)
platelets < 50 × 109/L
consider postpartum thromboprophylaxis in women with preeclampsia, especially if other risk factors
are present (SOGC Grade B, Level II-2)
for care beyond 6 weeks postpartum
for women with history of severe preeclampsia, especially those who presented or delivered at < 34
weeks gestation, screen for
preexisting hypertension (SOGC Grade B, Level II-2)
underlying renal disease (SOGC Grade B, Level II-2)
consider referral for internal medicine or nephrology for women with

postpartum hypertension that is difficult to control
preeclampsia in pregnancy and ongoing proteinuria, decreased estimated glomerular filtration
rate, and/or other indication of renal disease (such as abnormal urinary sediment) (SOGC Grade A,
Level III)
encourage overweight women to attain healthy body mass index (BMI) for decreasing risk in future
pregnancies (SOGC Grade A, Level II-2) and for long-term health (SOGC Grade A, Level I)
perform the following investigations in women with preexisting hypertension (if not done previously)
(SOGC Grade L, Level III)
urinalysis
serum sodium, potassium, and creatinine
fasting glucose
fasting lipid profile
standard 12-lead electrocardiography
consider assessing traditional cardiovascular risk markers in normotensive women with history of
hypertensive disorders of pregnancy (SOGC Grade B, Level II-2)
advise all women with history of hypertensive disorder of pregnancy to pursue healthy diet and
lifestyle (SOGC Grade B, Level I)
empiric postnatal furosemide may decrease need for postnatal antihypertensive therapy in women with
preeclampsia; no significant differences between various antihypertensives for treating postnatal
hypertension (level 3 [lacking direct] evidence)
based on nonclinical outcome in Cochrane review
systematic review of 9 randomized trials evaluating interventions for postpartum hypertension in 667
women with antenatal hypertensive disorder of pregnancy or de novo postpartum hypertension
postpartum hypertension defined as elevated blood pressure (≥ 140/90 mm Hg) measured twice ≥ 4
hours apart between delivery and 6 weeks postpartum
3 trials compared empiric interventions to placebo
comparing furosemide 20-40 mg orally once daily for 5-7 days to placebo or no therapy
furosemide plus potassium significantly decreased use of additional antihypertensive therapy in
hospital (34.8% with furosemide vs. 47% with placebo, p = 0.048, NNT 9) in 1 trial with 264 women
(summarized below)
no significant difference in postnatal antihypertensive medication use at hospital discharge in
analysis of 2 trials with 282 women
no significant difference in severe hypertension comparing
nifedipine 10 mg orally every 4 hours for 48 hours vs. placebo in 1 trial with 31 women
L-arginine given before delivery and for 3 days postpartum vs. placebo in 1 trial with 45 women
no maternal deaths reported
5 trials evaluated comparative efficacy of antihypertensive interventions for treating postpartum

hypertension
no trials compared antihypertensive therapy vs. placebo
no significant differences in use of additional antihypertensive therapy comparing
oral methyldopa to oral timolol, oral hydralazine, or oral nifedipine in analysis of 3 trials with 189
women with mild-to-moderate postpartum hypertension
IV hydralazine to sublingual nifedipine or IV labetalol in analysis of 2 trials with 120 women with
severe postpartum hypertension
no maternal deaths or severe hypotension reported
Reference - Cochrane Database Syst Rev 2013 Apr 30;(4):CD004351

furosemide is Pregnancy Category C and may inhibit lactation (FDA MedWatch March 2012)
empiric postnatal furosemide may decrease need for postnatal antihypertensive therapy in hospital in
women with severe preeclampsia (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes
264 women with preeclampsia or chronic hypertension randomized after delivery to empiric
furosemide (20 mg/day) and potassium (K-Dur, 20 mEq/day) for 5 days or no treatment
patients excluded if already taking diuretics or potassium, < 20 weeks gestation, or had peripartum
hemodynamic instability
treatment started after IV magnesium discontinued and spontaneous diuresis initiated
comparing empiric furosemide to placebo, furosemide associated with
for all patients
reduction in patients requiring additional hypertensive medication in hospital (34.8% vs. 47%,
no p value reported)
reduction in patients requiring additional hypertensive medication at discharge (28.8% vs.
37.1%, no p value reported)
in 70 patients with severe preeclampsia

significant reduction in number of patients with severe preeclampsia requiring additional
hypertensive medication at discharge (26% vs. 6%, p < 0.045)
51% hypertensive immediately postpartum and 43% upon transfer to postpartum ward
lower systolic blood pressure on second postpartum day (142 mm Hg vs. 153 mm Hg, p <
0.004)
no significant difference in diastolic blood pressure
no significant differences in mild preeclampsia and chronic hypertension groups

Reference - Obstet Gynecol 2005 Jan;105(1):29
prevalence of hypertension at 1 year after delivery may be higher with 24-hour ambulatory blood pressure
monitoring than with in-office blood pressure measurements in women with prior severe preeclampsia
200 women with history of severe preeclampsia had 24-hour ambulatory blood pressure monitoring
(ABPM) and 1 office blood pressure measurement 9-15 months after delivery
hypertension as measured by ABPM in 41.5% of women
masked hypertension in 17.5%
sustained hypertension in 14.5%
white-coat hypertension in 9.5%
hypertension as measured by single office blood pressure measurement in 24%

Reference - Hypertension 2018 Mar;71(3):491
Neonatal follow-up
early hematologic screening may identify neutropenia or thrombocytopenia in infants born to hypertensive
mothers
249 newborns of hypertensive mothers had complete blood counts
19 (7.6%) had neutropenia, 35 (14.1%) had thrombocytopenia (11 [4.4%] had both)
52 of 54 infants with hematologic abnormalities had abnormalities within 5 days of life
2 neutropenic infants developed nosocomial infection
7 thrombocytopenic infants had bleeding
Reference - J Paediatr Child Health 1996 Feb;32(1):31
Complications and Prognosis

Complications
Eclampsia
eclampsia (generalized seizures) - convulsive stage of preeclampsia(1, 4)
may be life-threatening
eclamptic seizures are often preceded by signs of cerebral irritation, such as severe and persistent
occipital or frontal headaches, blurred vision, photophobia, and altered mental status but may also occur
in absence of warning signs or symptoms
reported 20%-38% of women do not show classic signs of preeclampsia (hypertension or proteinuria)
before seizures
eclampsia may occur before, during, or after labor
usually generalized 60-90 second seizures
permanent white matter loss on magnetic resonance imaging has been reported in up to 25% of women;
however, these alterations may not result in significant neurologic deficits
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)
late postpartum eclampsia can occur from 48 hours to several weeks after delivery
90% of postpartum eclampsia cases occur within 7 days of delivery discharge
152 women meeting criteria for diagnosis of delayed postpartum preeclampsia at > 2 days to ≤ 6
weeks following delivery evaluated
63.2% had no history of hypertensive disorder
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
Overview =and Recommendations / Background
0.03)
Reference - Obstet Gynecol 2011 Nov;118(5):1102
late postpartum eclampsia 16 days after cesarean delivery in case report ( J Am Board Fam Pract 2000
Jan-Feb;13(1):39)
late postpartum eclampsia 11 days after cesarean delivery in case report ( Am Fam Physician 2002 Aug
1;66(3):378 full-text)
late-onset eclampsia presenting 9 days postpartum with bilateral cortical blindness in case report ( BMJ
2005 Nov 5;331(7524):1070), correction can be found in BMJ 2005 Dec 10;331(7529):1390, commentary
can be found in BMJ 2005 Nov 19;331(7526):1204
late-onset eclampsia presenting 8 days postpartum with bilateral cortical blindness in case report ( Am
Fam Physician 2005 Mar 1;71(5):856 full-text)
postpartum eclampsia complicated by brain edema and ischemic and hemorrhagic strokes in case report (
N Engl J Med 2009 Mar 12;360(11):1126)
preeclampsia
lower-range stage 1 hypertension (systolic blood pressure [BP] 130-135 mm Hg or diastolic BP 80-85
mm Hg) associated with increased risk of preeclampsia, indicated preterm delivery, and gestational
diabetes
based on post hoc secondary cohort analysis of randomized trial
3,134 nulliparous women with low-risk singleton pregnancies between 13 and 25 weeks gestation
were randomized to aspirin 60 mg/day vs. placebo until delivery
2,947 (94%) women (mean age 21 years) with singleton pregnancies and no missing data were
evaluated
5.6% had newly identified lower-range stage 1 hypertension (systolic BP 130-135 mm Hg or diastolic
BP 80-85 mm Hg) by 25 weeks gestation
preeclampsia defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg after 20 weeks
gestation plus proteinuria (≥ 300 mg/24 hours or ≥ 2+ by dipstick on ≥ 2 measurements)
analysis of 1,482 women receiving placebo comparing women with stage 1 hypertension vs. normal
blood pressure
any preeclampsia in 15.3% vs. 5.4% (relative risk [RR] 2.66, 95% CI 1.56-4.54)
severe preeclampsia in 6.1% vs. 2.5% (RR 2.04, 95% CI 0.82-5.09)
indicated preterm delivery in 4.2% vs. 1.1% (RR 3.83, 95% CI 1.3-11.31)
gestational diabetes in 6.1% vs. 2.5% (RR 2.51, 95% CI 1.08-5.84)
Renal disease
renal manifestations
proteinuria
glomerular endotheliosis (glomerular lesion)
acute tubular necrosis
preeclampsia associated with increased risk of end-stage kidney disease (level 2 [mid-level] evidence)
systematic review of 21 observational studies evaluating preeclampsia and risk of kidney-related
morbidity with follow-up ≥ 4 years in almost 2.8 million women
4% had preeclampsia
follow-up ranged from 4.4 years to > 30 years
Overview 11
andstudies included in meta-analysis
all results limited by significant heterogeneity
preeclampsia associated with
increased risk of end-stage renal disease (risk ratio [RR] 6.35, 95% CI 2.73-14.79) in analysis of 3
studies with 1,088,280 patients
no significant difference in risk of chronic kidney disease (estimated glomerular filtration rate < 60
mL/minute per 1.73 m2) (RR 2.03, 95% CI 0.58-7.32) in analysis of 5 studies with 262,318 patients
Reference - Kidney Int 2019 Sep;96(3):711
preeclampsia associated with increased risk of microalbuminuria
systematic review of 7 observational studies evaluating kidney outcomes in 273 women with
history of preeclampsia and 333 women with uncomplicated pregnancies
weighted mean follow-up 7.1 years postpartum
history of preeclampsia associated with increased risk of microalbuminuria (31% vs. 7%, relative
risk [RR] 4.31, 95% CI 2.7-6.89)
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)
Reference - Am J Kidney Dis 2010 Jun;55(6):1026
hypertensive disorders of pregnancy associated with increased risk of obstetric acute kidney failure (level
2 [mid-level] evidence)
2,193,425 in-hospital livebirths and stillbirths in Canada from 2003 to 2010 were analyzed
incidence of obstetric acute kidney failure 1.66 per 10,000 deliveries from 2003 to 2004 and 2.68 per
10,000 deliveries from 2009 to 2010
risk factors for obstetric acute kidney failure include (in adjusted analyses)
preexisting hypertension (odds ratio [OR] 3.14, 95% CI 1.67-5.89)
preexisting hypertension with proteinuria (OR 29.3, 95% CI 19.7-43.7)
gestational hypertension no proteinuria (OR 4.68, 95% CI 3.56-6.17)
gestational hypertension with proteinuria (OR 31.6, 95% CI 25.6-38.9)
eclampsia (OR 8.29, 95% CI 4.7-14.6)
unspecified hypertension (OR 9.54, 95% CI 5.04-18.1)
Reference - BMJ 2014 Jul 30;349:g4731 full-text , commentary can be found in Am J Kidney Dis 2015
May;65(5):650
preeclampsia associated with increased risk of chronic kidney disorders, especially within 5 years of latest
pregnancy
1,072,330 women in Denmark with pregnancy lasting ≥ 20 weeks in 1978-2015 were followed for
19,994,470 person-years
3.8% had preeclampsia during pregnancy
diagnoses of acute or chronic renal disease assessed at > 3 months after delivery
acute kidney disorders included acute kidney failure and acute tubulointerstitial nephritis
chronic kidney disorders included chronic kidney disease, hypertensive kidney disease, chronic
tubulointerstitial nephritis, and glomerular and proteinuric diseases
rate of renal disorders during follow-up (per 100,000 person-years)
3.6 acute renal disorders
1.9 chronic renal disorders
0.7 other specified renal disorders
1.1 unspecified renal disorders
compared to no history of preeclampsia, history of preeclampsia associated with

increased risk of any chronic kidney disorder in women with
early preterm delivery (adjusted hazard ratio [HR] 3.93, 95% CI 2.9-5.33)
late preterm delivery (adjusted HR 2.81, 95% CI 2.13-3.71)
term delivery (adjusted HR 2.27, 95% CI 2.02-2.55)
increased risk of acute kidney failure in women with term delivery (adjusted HR 1.57, 95% CI 1.21-
2.05)
increased risk of acute tubulointerstitial nephritis in women with late preterm delivery (adjusted HR
1.46, 95% CI 1.08-1.96)
in subgroup analyses stratified by chronic kidney disorder and timing of delivery, preeclampsia
associated with
increased risk of chronic kidney disease, hypertensive kidney disease, and glomerular and proteinuric
diseases in women with early preterm, late preterm, or term delivery
increased risk of chronic tubulointerstitial nephritis only in women with early preterm delivery
in subgroup analysis stratified by time since latest pregnancy, preeclampsia within 5 years associated
with
increased risk of chronic kidney disease (adjusted HR 6.11, 95% CI 3.84 to 9.72)
no significant risk of acute kidney disease
Reference - BMJ 2019 Apr 29;365:l1516 full-text
Other maternal complications

possible maternal complications include(1, 2)
cardiovascular disease, including
heart failure
myocardial ischemia
hypertensive disorders of pregnancy associated with increased risk of cardiomyopathy beyond

peripartum period, but overall risk low
1,075,763 women with ≥ 1 pregnancy (2,067,633 pregnancies) in Denmark were monitored for
development of cardiomyopathy after peripartum period (> 5 months after delivery)
hypertensive disorders of pregnancy occurred during 76,108 pregnancies (17% severe
preeclampsia, 59% moderate preeclampsia, and 24% gestational hypertension)
mean duration of follow-up 17.9 years
1,577 women (0.15%) developed cardiomyopathy
compared to no hypertensive disorders of pregnancy, increased risk of any cardiomyopathy at > 5
months after first delivery associated with
severe preeclampsia (adjusted hazard ratio [HR] 2.2, 95% CI 1.5-3.23)
moderate preeclampsia (adjusted HR 1.89, 95% CI 1.55-2.32)
gestational hypertension (adjusted HR 2.06, 95% CI 1.5-2.82)
consistent results for risk of any cardiomyopathy > 5 years after latest delivery and dilated
cardiomyopathy > 5 months after first delivery
Reference - JAMA 2016 Mar 8;315(10):1026
severe preeclampsia associated with elevated right ventricular systolic pressure and reduced global
right ventricular systolic strain compared to normotensive pregnancy
63 women with severe preeclampsia and 36 gestational age-matched normotensive pregnant
women were assessed by transthoracic echocardiography
all women had singleton pregnancies > 23 weeks gestation
severe preeclampsia defined as combination of
systolic blood pressure (BP) ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg measured on 2
occasions at least 4 hours apart
protein > 300 mg in 24-hour urine collection, or protein to creatinine ratio ≥ 0.3
women without proteinuria (who met BP criteria) were included if they had thrombocytopenia,
impaired liver function, progressive renal dysfunction, pulmonary edema, or new visual
disturbances
63.5% of women with preeclampsia were black vs. 19.4% of normotensive controls (p < 0.001)
echocardiographic parameters comparing women with preeclampsia vs. normotensive controls
mean right ventricular (RV) systolic pressure 31 mm Hg vs. 22.5 mm Hg (p < 0.001)
mean global RV longitudinal systolic strain -19.6% vs. -23.8% (p < 0.0001)
mean left atrial area 20.1 cm vs. 17.3 cm (p < 0.001)
median posterior wall thickness 1 cm vs. 0.8 cm (p < 0.001)
no significant differences between groups in right atrial area or right ventricular function
parameters
none of normotensive controls had abnormal echocardiographic parameters
12.7% of women with preeclampsia (8 women) had grade II diastolic dysfunction and 9.5% (6
women) had peripartum pulmonary edema
insufficient sample size to determine if echocardiographic outcomes varied by race
Reference - J Am Coll Cardiol 2018 Jul 3;72(1):1
stroke (may occur at systolic blood pressure of 160 mm Hg)

pulmonary edema
cortical blindness or retinal detachment
acute respiratory distress syndrome (ARDS)
placental abruption
liver manifestations
elevated transaminase levels
subcapsular hemorrhage
capsular rupture
intraabdominal bleeding
coagulation abnormalities
microangiopathic hemolysis
thrombocytopenia
disseminated intravascular coagulation (DIC)
hypertensive-associated delivery hospitalizations associated with increased risk for severe obstetric
complications
36,537,061 delivery discharges from 1998 to 2006 Nationwide Inpatient Sample of the Healthcare Cost
Overview
andand Recommendations
Utilization / Background
Project evaluated
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)
fatal necrotizing pancreatitis in patient with severe preeclampsia in case report ( Obstet Gynecol 2012
Aug;120(2 Pt 2):453)
Fetal/childhood complications
possible fetal complications(1, 2)
intrauterine growth restriction (IUGR) (reported in up to 30% of preeclampsia pregnancies)
placental abruption
oligohydramnios
reverse ductus venosus A wave
stillbirth
fetal death
higher maternal blood pressure associated with increased risk of perinatal death, preterm birth, and small
for gestational age compared with blood pressure < 140/90 mm Hg in women with mild chronic
hypertension before 20 weeks gestation
based on secondary analysis of Maternal-Fetal Medicine Units Network’s High-risk Aspirin preeclampsia
prevention trial
759 women with singleton pregnancy and chronic hypertension diagnosed before 20 weeks gestation
(blood pressure ≥ 140/90 mm Hg on two occasions ≥ 4 hours apart or previously diagnosed and on
antihypertensive therapy) stratified by blood pressure (< 140/90, 140-150/90-99, or 151-159/100-109 mm
Hg)
compared with blood pressure < 140/90 mm Hg
blood pressure 140-150/90-99 mm Hg associated with increased risk of
perinatal death (adjusted odds ratio [OR] 2.6, 95% CI 1.2-5.7)
any preterm birth (adjusted OR 1.8, 95% CI 1.3-2.6)
blood pressure 151-159/100-109 mm Hg associated with increased risk of

any preterm birth (adjusted OR 3, 95% CI 1.7-5.4)
small for gestational age (adjusted OR 3.8, 95% CI 1.8-7.9)
superimposed preeclampsia may be associated with higher rates of adverse neonatal outcomes than
exacerbation of chronic hypertension
862 women with singleton pregnancies with chronic hypertension between 2000 and 2014 were included
Overview stable chronic hypertension/ in
and Recommendations 270 women (31.3%)
Background
exacerbated chronic hypertension in 429 women (49.8%)
superimposed preeclampsia on chronic hypertension in 163 women (18.9%)
compared to exacerbation of chronic hypertension, superimposed preeclampsia associated with
increased risk of
neonatal composite of death, respiratory support, umbilical arterial pH < 7, 5-minute Apgar ≤ 3, and
seizures (adjusted odds ratio [OR] 2.2, 95% CI 1.37-3.64)
preterm birth < 35 weeks gestation (adjusted OR 3.1, 95% CI 2.1-4.6)
severe hypertension requiring use of IV antihypertensives in labor (adjusted OR 2.6, 95% CI 1.75-3.91)
primary cesarean section (adjusted OR 2, 95% CI 1.24-3.1)
no significant differences comparing stable chronic hypertension and exacerbated chronic hypertension
for any outcomes measured
Reference - Am J Perinatol 2018 Nov 5 early online
low cardiac output and high total vascular resistance may be associated with increased small-for-
gestational age infant in women with hypertensive disorders of pregnancy
216 women with singleton pregnancies were included
183 women had hypertensive disorders of pregnancy (HDP)
142 women (65.7%) delivered appropriate-for-gestational age (AGA) infants
41 women (19%) delivered small-for-gestational age (SGA) infants
33 women (15.3%) with normotensive pregnancies delivered AGA infants

comparing HDP/SGA vs. HDP/AGA vs. control
mean arterial pressure 110 vs. 112 vs. 95.8 (mm Hg) (p < 0.001 for both HDP groups compared to
control)
mean cardiac output 6.5 vs. 7.6 vs. 7.6 (L/min) (p < 0.03 comparing HDP/SGA vs. HDP with AGA and
control)
mean cardiac index 3.6 vs. 3.9 vs. 4 (p < 0.03 comparing HDP/SGA vs. HDP/AGA and control)
mean total vascular resistance (dynes/s/cm-5) 1,399 vs. 1,214 vs. 1,082
p ≤ 0.002 comparing both HDP groups with control
p = 0.008 comparing HDP/SGA with HDP/AGA
no significant difference in cardiovascular parameters comparing HDP onset < 34 weeks gestation with
HDP onset > 34 weeks gestation for both SGA and AGA groups
Reference - Am J Obstet Gynecol 2018 Jan;218(1):124.e1
hypertensive disorders of pregnancy associated with increased risks of autism spectrum disorder (ASD)
and attention deficit hyperactivity disorder (ADHD) in children
systematic review of 61 cohort or case-control studies evaluating association between hypertensive
disorders of pregnancy and risk of neurodevelopmental disorders in children
hypertensive disorders of pregnancy included preeclampsia and gestational, masked, transient, and
20 studies evaluated risk of ASD, 10 studies evaluated risk of ADHD, and 31 studies evaluated risk of
other neurodevelopmental disorders
prevalence of hypertensive disorders of pregnancy 1.3%-9.1% in cohort studies of ASD and 0.1%-20.8% in
cohort studies of ADHD
compared to no hypertensive disorders of pregnancy, hypertensive disorders of pregnancy associated
with
Overview increased risk of ASD (adjusted
and Recommendations odds ratio 1.35, 95% CI 1.11-1.64) in analysis of 11 studies, results
/ Background
limited by significant heterogeneity
increased risk of ADHD (adjusted odds ratio 1.29, 95% CI 1.22-1.36) in analysis of 6 studies
Reference -JAMA Psychiatry 2018 Aug 1;75(8):809
exposure to pregnancy-induced hypertension in children born after 37 weeks gestation may be associated
with increased risk of epilepsy in childhood
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
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)
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)
no significant association with preeclampsia or eclampsia for children born preterm (< 37 weeks
gestational age)
Reference - Pediatrics 2008 Nov;122(5):1072
Prognosis
Maternal outcomes
General prognosis
hypertensive disorders of pregnancy associated with increased risk of post pregnancy hypertension
starting at 1 year postpartum
based on 2 population-based cohort studies
15,080,900 women in Danish registry with pregnancy lasting ≥ 20 weeks were assessed for post
pregnancy hypertension starting after pregnancy
cohort 1 included 482,972 primiparous women with live or stillbirth between 1995 and 2012
cohort 2 included 1,025,118 women with ≥ 1 pregnancy ending in live or stillbirth between 1978 and
2012
exclusion criteria included any cardiac or circulatory system disorder before delivery and pregestational
hypertension
in cohort 1
4.8% had hypertensive disorder during pregnancy and 3.4% developed post pregnancy hypertension
with follow-up beginning 3 months after delivery
10-year incidence of hypertension comparing hypertensive disorder of pregnancy vs. normotensive
pregnancy
13.7% vs. 4% in women aged 20-29 years
20.3% vs. 5.7% in women aged 30-39 years
32.4% vs. 11.3% in women aged 40-49 years
in cohort 2
5.8% had hypertensive disorder during ≥ 1 pregnancies and 17.9% developed post pregnancy
hypertension
gestational hypertension or severe or moderate preeclampsia associated with significantly increased
risk of post pregnancy hypertension at 1 year, 10-14 years, and ≥ 20 years postpartum compared to
normotensive pregnancy
Reference - BMJ 2017 Jul 12;358:j3078 full-text, editorial can be found in BMJ 2017 Jul 13;358:j3245
risk of chronic hypertension increases with increasing body mass index in women with history of
hypertensive disorder of pregnancy
54,588 parous women aged 32-59 years enrolled in Nurses' Health Study II who had reproductive history
available were assessed for incidence of chronic hypertension based on history of hypertensive disorders
of pregnancy
exclusion criteria included nulliparity or previous chronic hypertension (outside of pregnancy), myocardial
infarction, or stroke
10% had self-reported history of hypertensive disorder of pregnancy
incidence of chronic hypertension 2 per 100 person-years
increasing BMI associated with increasing risk of chronic hypertension in women aged 32-39 years, 40-
49 years, and 50-59 years (p for trend < 0.001 for each age group) in women with and women without
history of hypertensive disorders of pregnancy
for all age groups, increasing BMI associated with excess increase in risk of chronic hypertension in
women with history compared to women without history of hypertensive disorders of pregnancy
Reference - BMJ 2017 Jul 12;358:j3024 full-text, editorial can be found in BMJ 2017 Jul 13;358:j3245
untreated chronic hypertension associated with increased risk of preeclampsia

100,029 deliveries from 1998 to 2008 were examined
1,074 mothers with chronic hypertension untreated during pregnancy
97,820 mothers without hypertension
compared to no hypertension, chronic hypertension not treated during pregnancy associated with
increased risk of preeclampsia (adjusted odds ratio 7.02, 95% CI 5.54-8.89)
early- and late-onset preeclampsia associated with increased risk of severe maternal morbidity
rate of severe maternal morbidity (excluding obstetric trauma) per 100 deliveries (including but not
limited to respiratory morbidity, cardiovascular morbidity, thromboembolism, central nervous system
morbidity, blood transfusion, acute renal failure, acute liver failure, and hysterectomy)
12.2 for early-onset (< 34 weeks gestation) preeclampsia (p < 0.05 vs. no preeclampsia)
5.5 for late-onset preeclampsia (p < 0.05 vs. no preeclampsia)
about 3 for no preeclampsia
increased severity and duration of preeclampsia associated with increasing time to resolution of
hypertension
205 women hospitalized with preeclampsia from 1990 to 1992 in the Netherlands followed for 2 years
after delivery
persistent hypertension (defined as blood pressure ≥ 140/90 mm Hg or use of antihypertensive drugs) in
Overview 39%
and at 3 months postpartum
18% at 2 years postpartum
persistent proteinuria (defined as ≥ 0.3 g/day) in
14% at 3 months postpartum
2% at 2 years postpartum
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)
time to resolution of proteinuria increased by 16% for every 1 g/day increase in maximal proteinuria (p =
0.001)
Reference - Obstet Gynecol 2009 Dec;114(6):1307
placental growth factor may help predict preterm delivery in women with hypertensive disorders of
pregnancy (level 2 [mid-level] evidence)
systematic review of 17 cohort studies evaluating placental growth factor (PIGF) for predicting maternal
or fetal complications in 4,488 women with hypertensive disorders of pregnancy
9 studies evaluated PIGF alone and 8 studies evaluated PIGF plus other angiogenic factors
median maternal age was 31 years, and most women (56%) were nulliparous
studies varied in patient population, cutoff for PIGF or soluble fms-like tyrosine kinase-1(sFlt-1)/PIGF
ratio, and definitions of adverse maternal outcomes and preterm delivery
pooled performance of PIGF alone for predicting preterm delivery in analysis of 5 studies
median sensitivity 81.5% (range 28%-96%)
median specificity 84.4% (range 55%-92.9%)
for predicting adverse maternal outcomes (postpartum hemorrhage), PIGF alone had sensitivity 73.1%
and specificity 76.7% in 1 study
pooled performance of sFlt-1/PIGF ratio for predicting
preterm delivery in analysis of 4 studies
median sensitivity 74.5% (range 66.7%-92.6%)
median specificity 94% (range 78.1%-97.8%)
adverse maternal outcomes in analysis of 3 studies

median sensitivity 61.9% (range 52.1%-100%)
median specificity 69.4% (range 51.7%-77.9%)
Reference - Hypertension 2017 Dec;70(6):1228 full-text
Maternal mortality
stroke and pulmonary edema are most common causes of maternal death in preeclampsia(2)
chronic hypertension, preeclampsia, and eclampsia associated with increased maternal mortality at
delivery hospitalization
1,084,862 women with singleton pregnancies evaluated
1.8% had chronic hypertension, and 4.1% had preeclampsia or eclampsia
132 maternal deaths occurred (including 24 women with chronic hypertension and 42 women with
preeclampsia or eclampsia) / Background
factors associated with increased maternal mortality during delivery hospitalization
chronic hypertension (adjusted odds ratio [OR] 7.7, 95% CI 4.7-12.5)
preeclampsia or eclampsia (adjusted OR 8.1, 95% CI 5.5-12.1)
Reference - Obstet Gynecol 2013 Sep;122(3):627
eclampsia associated with increased maternal mortality

1,910,729 women and their newborns delivered in Canada from 2003 to 2009
incidence of eclampsia fell from 12.4 per 10,000 deliveries in 2003 to 5.9 per 10,000 deliveries in 2009
eclampsia associated with increased
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)
Nov;118(5):976
hypertensive disorders of pregnancy associated with increased maternal mortality at ≤ 50 years old
932,788 women with ≥ 1 singleton birth in Utah between 1939 and 2012 were assessed
57,384 women with hypertensive disorder of pregnancy were age-, year of childbirth-, and parity-matched
to 114,768 women without hypertensive disorder of pregnancy
as of 2016, mortality was 8.2% in women with hypertensive disorder of pregnancy and 6.3% in women
without hypertensive disorder of pregnancy
compared to women without hypertensive disorder of pregnancy, ≥ 2 pregnancies with hypertensive
disorder associated with increased mortality due to
all-cause (adjusted hazard ratio [HR] 2.04, 95% CI 1.76-2.36]
stroke (adjusted HR 5.1, 95% CI 2.62-9.92)
diabetes (adjusted HR 4.33, 95% CI 2.21-8.47)
ischemic heart disease (adjusted HR 3.3, 95% CI 2.02-5.4)
consistent results in women with 1 pregnancy with hypertensive disorder or for deaths occurring at ≤ 50
years of age
Reference - Am J Obstet Gynecol 2018 Jul;219(1):107.e1
early-onset preeclampsia associated with increased risk of maternal mortality

1 maternal death reported among 2,374 women with early-onset preeclampsia
2 maternal deaths reported among 17,890 women with late-onset preeclampsia
rate of maternal mortality per 100,000 deliveries
42.1 for early-onset (< 34 weeks gestation) preeclampsia (p < 0.05 vs. no preeclampsia)
11.2 for late-onset preeclampsia (not significant vs. no preeclampsia)
4.2 for no preeclampsia
fullPIERS model may predict risk of life-threatening complications within 48 hours of hospital admission in
women with preeclampsia (level 2 [mid-level] evidence)
based
prognostic cohort study with representative sample not at same point in course of disease
/ Background
2,023 women with preeclampsia were analyzed
definitions for diagnosis of preeclampsia varied widely within the study population, and included women
with and without proteinuria
5% had life-threatening complications within 48 hours of hospital admission
risk model based on
gestational age
chest pain or dyspnea
oxygen saturation
platelet count
creatinine concentration
aspartate transaminase concentration
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%
Reference - Lancet 2011 Jan 15;377(9761):219, editorial can be found in Lancet 2011 Jan
15;377(9761):185
Cardiovascular disease and stroke

preeclampsia associated with increased risk of subsequent maternal cardiovascular disease and
cardiovascular-related mortality
preeclampsia associated with increased risk of cardiovascular mortality, heart failure, coronary heart
disease, and stroke
systematic review of 22 observational studies evaluating association between preeclampsia and risk
of adverse cardiovascular outcomes in 6,456,379 women
all results limited by significant heterogeneity
compared to women without preeclampsia, women with preeclampsia had increased risk of
cardiovascular mortality (adjusted risk ratio [RR] 2.21, 95% CI 1.83-2.66) in analysis of 4 studies
with 2,614,180 women
heart failure (adjusted RR 4.19, 95% CI 2.09-8.38) in analysis of 4 studies with 1,986,285 women
coronary heart disease (adjusted RR 2.5, 95% CI 1.43-4.37) in 6 studies with 2,068,673 women
stroke (adjusted RR 1.81, 95% CI 1.29-2.55) in analysis of 6 studies with 4,131,344 women
Reference - Circ Cardiovasc Qual Outcomes 2017 Feb;10(2):e003497
preeclampsia associated with increased risk of overall mortality, hypertension, venous

thromboembolism, coronary heart disease, and stroke
systematic review of 25 cohort studies with 3,488,160 women
compared to women without preeclampsia, women with preeclampsia had increased risk of
overall mortality (relative risk [RR] 1.49, 95% CI 1.05-2.14) in analysis of 4 studies with 794,462
women
chronic hypertension (RR 3.7, 95% CI 2.7-5.05) in analysis of 13 studies with 21,030 women
venous thromboembolism (RR 1.19, 95% CI 1.37-2.33) in analysis of 3 studies with 427,693
Overview andwomen
coronary heart disease (RR 2.16, 95% CI 1.86-2.52) in analysis of 8 studies with 2,346,997 women
stroke (RR 1.81, 95% CI 1.45-2.27) in analysis of 4 studies with 1,671,578 women
women with preeclampsia did not have increased risk of cancer in analysis of 3 studies with 729,025
women
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
history of preeclampsia might be associated with increased risk of higher coronary artery calcification
score > 30 years after pregnancy
80 asymptomatic women (mean age at imaging 59.5 years) without prior cardiovascular events who
delivered between 1976 and 1982 (mean age at delivery 24 years) had computed tomography to
measure coronary artery calcification
40 women (50%) had history of preeclampsia
comparing no history of preeclampsia vs. history of preeclampsia
current clinical diagnosis of hypertension in 20% vs. 60% (p < 0.001)
body mass index 25.3 kg/m2 vs. 29.8 kg/m2 (p = 0.023)
mean frequency of a coronary artery calcification score > 50 Agatston units in 0% vs. 23% (p =
0.001)
history of preeclampsia associated with increased risk of higher coronary artery calcification score
compared to no history of preeclampsia (odds ratio 3.54, 95% CI 1.39-9.02) but not significant after
adjusting for BMI and current hypertension (adjusted OR 2.48, 95% CI 0.86-7.19)
Reference - Am J Obstet Gynecol 2016 Apr;214(4):519.e1 full-text
study evaluating cardiovascular disease risk in women with hypertensive disorders of pregnancy based
on 2016 Canadian Cardiovascular Society recommendation to use 10-year modified Framingham Risk
Score can be found in J Obstet Gynaecol Can 2019 Jan 14 early online
additional patient and disease characteristics appear to modify the effect of preeclampsia on future risk
severity of preeclampsia may be associated with increased risk of future cardiovascular disease
systematic review of 15 studies (5 case-control, 10 cohorts) evaluating incidence of cardiovascular
disease > 6 weeks post partum in 116,175 women
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

preeclampsia during first and only pregnancy associated with greater risk of cardiovascular death than
preeclampsia during first of ≥ 2 pregnancies
836,147 women with first singleton birth between 1967 and 2002 were followed for median 25 years
4.2% had preeclampsia during first pregnancy and 84% had ≥ 2 children
2.8% overall mortality during follow-up including 3,891 cardiovascular-related deaths
compared to no preeclampsia during first pregnancy, preeclampsia during first pregnancy associated
with increased risk of cardiovascular death in overall analysis (adjusted hazard ratio [HR] 1.9, 95% CI
1.6-2.2)
compared to no preeclampsia during first pregnancy and term birth, risk of cardiovascular death
increased with
term preeclampsia during first pregnancy (adjusted HR 1.6, 95% CI 1.4-2)
preterm preeclampsia during first pregnancy (adjusted HR 3.7, 95% CI 2.7-4.8)
compared to no preeclampsia during first pregnancy and term birth and ≥ 2 lifetime pregnancies, risk
of cardiovascular death increased with
term preeclampsia during first and only lifetime pregnancy (adjusted HR 3.4, 95% CI 2.6-4.6)
preterm preeclampsia during first and only lifetime pregnancy (adjusted HR 9.4, 95% CI 6.5-13.7)
term preeclampsia during first pregnancy in multiparous women (adjusted HR 1.5, 95% CI 1.2-2)
preterm preeclampsia during first pregnancy in multiparous women (adjusted HR 2.4, 95% CI 1.5-
3.9)
Reference - BMJ 2012 Nov 27;345:e7677 full-text
presence of ≥ 2 components of metabolic syndrome associated with future hypertension in women with
preeclampsia who are normotensive at initial postpartum screen
683 primiparous women with history of preeclampsia evaluated for obesity, hypertension, insulin
resistance, dyslipidemia, and microalbuminuria at postpartum screening
among women initially normotensive at postpartum screening, 4% developed hypertension during
median 6-year follow-up
compared with presence of < 2 components of metabolic syndrome, increased risk of hypertension
following normal postpartum screening if
2 components of metabolic syndrome (adjusted hazard ratio [HR] 2.9, 95% CI 1.2-7.5)
≥ 3 components of metabolic syndrome (adjusted HR 8.1, 95% CI 2.8-22.9)
maternal placental syndrome associated with increased risk of cardiovascular disease, heart failure, and
atrial dysrhythmia
maternal placental syndrome associated with increased incidence of cardiovascular disease in women
1,026,265 pregnant women in Ontario, Canada free from cardiovascular disease before first
documented delivery at ages 14-50 years with median follow-up 8.7 years included
75,380 women (7%) had maternal placental syndromes (defined as preeclampsia, gestational
hypertension, placental abruption, or placental infarction)
composite outcome of cardiovascular disease included coronary artery disease, cerebrovascular
disease, and peripheral arterial disease
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 compared to no maternal placental syndrome 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
history of maternal placental syndrome associated with increased risk of hospitalization for heart
failure and atrial dysrhythmia
1,130,764 pregnant women in Ontario, Canada free from cardiovascular or thyroid disease before first
documented delivery at ages 14-50 years were followed for median 7.8 years
6.7% had maternal placental syndrome (MPS) defined as gestational hypertension, preeclampsia, or
placental abruption and/or infarction at baseline
rate of hospitalization for heart failure or atrial or ventricular dysrhythmia starting 1 year after delivery
2.54 per 10,000 person-years in women with MPS
1.28 per 10,000 person-years in women without MPS
history of MPS associated with

increased risk of hospitalization for heart failure or atrial or ventricular dysrhythmia (adjusted
hazard ratio [HR] 1.61, 95% CI 1.35-1.91)
increased risk of hospitalization for heart failure (adjusted HR 1.8, 95% CI 1.42-2.29)
increased risk of hospitalization for atrial dysrhythmia (adjusted HR 1.48, 95% CI 1.1-1.98)
nonsignificantly increased risk of hospitalization for ventricular dysrhythmia (adjusted HR 1.41,
95% CI 0.96-2.07)
Reference - Heart 2012 Aug;98(15):1136, editorial can be found in Heart 2012 Aug;98(15):1109
preeclampsia during pregnancy associated with increased risk of stroke and stroke-related mortality
preeclampsia associated with increased risk of fatal stroke in later life
3,593 women with first singleton birth from 1951 to 1970 completed questionnaire regarding current
vital and cardiovascular health status in 1999
1,199 with preeclampsia/eclampsia in pregnancy
1,197 with gestational hypertension in pregnancy
1,197 controls
preeclampsia associated with increased risk for stroke-related mortality (adjusted rate ratio 3.59, 95%
CI 1.04-12.4)
Reference - BMJ 2003 Apr 19;326(7394):845 full-text
hypertensive disorders in pregnancy may increase risk of subsequent stroke with greatest risk in
women aged < 18 years, > 35 years, or with preterm delivery
1,092 women aged 15-40 years in Taiwan with newly diagnosed hypertensive disorder of pregnancy
(HDP) in 2000-2004 compared to 4,715 control women without HDP who were followed through 2008
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)
increased risk of stroke with HDP and
age 15-18 years (HR 13.4, 95% CI 1.54-116.7)
age ≥ 35 years (HR 5.56, 95% CI 1.47-21)
preterm delivery (HR 3.22, 95% CI 1.48-6.99)
Reference - Stroke 2011 Mar;42(3):716
preeclampsia/eclampsia associated with increased risk of hemorrhagic stroke during first year
postpartum
1,132,019 women who gave birth in Taiwan from 1999 to 2003 were evaluated
women followed for 1 year postpartum
stroke incidence 21.47 cases per 100,000 deliveries
women with preeclampsia had increased risk for
hemorrhagic stroke
from 6 weeks to 6 months postpartum (adjusted relative risk [RR] 11.76, 95% CI 4.05-34.11)
from 6 months to 1 year postpartum (adjusted RR 19.9, 95% CI 7.75-51.11)
ischemic stroke from 6 weeks to 6 months postpartum (adjusted RR 11.6, 95% CI 3.3-40.82)
Reference - Stroke 2009 Apr;40(4):1162
Other maternal complications

preeclampsia associated with increased risk of postpartum venous thromboembolism
based on 2 cohort studies
287,037 women followed for mean 3 years after delivery
2,849 with preeclampsia
284,188 controls
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
Reference - BMJ 2003 Apr 12;326(7393):791 full-text, correction can be found in BMJ 2003 Jun
21;326(7403):1362
4,169 women aged 15-44 years with venous thromboembolism from delivery to 12 weeks postpartum
stratified by insurance coverage
among privately insured patients, preeclampsia associated with increased risk of venous
thromboembolism (adjusted odds ratio 2.31, 95% CI 2.06-2.69)
similar results noted for Medicaid patients
hypertensive disorder of pregnancy associated with increased risk of postpartum diabetes

5,666 women aged 19-40 years evaluated
1,139 with first hypertensive disorder of pregnancy
4,527 women with normal pregnancy
no patients had prior gestational diabetes, diabetes, or hypertension

compared to normal pregnancy, hypertensive disorder of pregnancy associated with increased risk of
postpartum diabetes
overall (hazard ratio [HR] 3.42, 95% CI 2.07-5.64)
in women with hyperlipidemia and obesity (HR 39.5, 95% CI 13-120.6)
Reference - Am J Med 2012 Mar;125(3):251

eclampsia and eclampsia-associated white-matter lesions may increase risk of long-term visual function
deficits (level 2 [mid-level] evidence)
based
retrospective cohort /study
Background
94 women evaluated for long-term visual function 10-11.5 years following index pregnancy
47 formerly eclamptic women
47 matched parous controls with normotensive pregnancies
vision-specific health-related quality of life questionnaire consisted of base set of 25 questions and 14
additional questions generating vision-targeted subscales with each subscale question scored 0-100
(100 being best possible score)
white-matter lesions found on magnetic resonance imaging in 35.7% of formerly eclamptic women
subscale composite scores comparing formerly eclamptic women vs. controls
general vision score 80.5 vs. 83.3 (not significant)
vision-related driving difficulties score 75.6 vs. 85.9 (p = 0.001)
peripheral vision score 90.8 vs. 98.4 (p = 0.002)
subscale composite scores comparing formerly eclamptic women with vs. without white-matter lesions
general vision score 75 vs. 85 (p = 0.01)
vision-related role function score 90.6 vs. 100 (p = 0.028)
peripheral vision score 87.5 vs. 100 (p = 0.045)
Neonatal outcomes
perinatal mortality
perinatal mortality appears to be declining in women with preeclampsia
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
perinatal mortality about 4% in women with chronic hypertension in pregnancy

systematic review of 55 observational studies evaluating association between chronic hypertension
and complications of pregnancy in 795,221 women and 812,772 neonates
estimated incidence of perinatal mortality from 20 gestational weeks to 1 month post birth 4% (95%
CI 2.9%-5.4%) in analysis of 27 studies
severe preeclampsia before 24 weeks gestation associated with very low perinatal survival (level 2
46 women (with 51 fetuses) with severe preeclampsia at < 27 weeks gestation evaluated
corticosteroids given beyond 23 weeks
median 6 days of pregnancy prolongation (range 2-46 days)
overall perinatal survivor 57% (29 of 51)
perinatal survival by gestational age
Overview and0 Recommendations
of 7 with gestational age < 23 weeks
/ Background
20% (2 of 10) for 23 weeks to 23 6/7 weeks
46% overall rate of composite maternal morbidity (hemolysis, elevated liver enzymes, low platelets
[HELLP] syndrome, pulmonary edema, eclampsia, renal insufficiency)
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
eclampsia associated with increased neonatal mortality, respiratory distress syndrome, and small-for-
gestational age birth
1,910,729 women and their newborns delivered in Canada from 2003 to 2009
incidence of eclampsia fell from 12.4 per 10,000 deliveries in 2003 to 5.9 per 10,000 deliveries in 2009
eclampsia associated with increased
neonatal mortality (adjusted odds ratio [OR] 2.9, 95% CI 1.6-5.5)
respiratory distress syndrome (adjusted OR 5.1, 95% CI 4.1-6.3)
small-for-gestational age birth (adjusted OR 2.6, 95% CI 2.3-3)
Nov;118(5):976
chronic hypertension in pregnancy associated with about 28% preterm delivery rate, and low birth weight in
about 16.9% of neonates
systematic review of 55 observational studies evaluating association between chronic hypertension and
complications of pregnancy in 795,221 women and 812,772 neonates
estimated incidence of adverse neonatal outcomes
preterm delivery at < 37 gestational weeks 28.1% (95% CI 22.6%-34.4%) in analysis of 30 studies
low birth weight < 2,500 g 16.9% (95% CI 13.1%-21.5%) in analysis of 14 studies
neonatal unit admission 20.5% (95% CI 15.7%-26.4%) in analysis of 16 studies

untreated chronic hypertension associated with increased risk of preterm delivery, intrauterine growth
restriction, and small-for-gestational age infants (level 2 [mid-level] evidence)
100,029 women with delivery from 1998 to 2008 were evaluated, including
1,074 women with chronic hypertension untreated during pregnancy
97,820 women without hypertension
compared to no hypertension, chronic hypertension untreated during pregnancy associated with

increased risk of
preterm delivery (adjusted odds ratio [OR] 1.89, 95% CI 1.59-2.25)
intrauterine growth restriction (adjusted OR 2.09, 95% CI 1.51-2.89)
small-for-gestational age birth (adjusted OR 2.06, 95% CI 1.44-2.95)

severe early-onset maternal hypertensive disorder may be associated with moderate delays in mental and
psychomotor development at age/1Background
year
172 children (median gestational age 31.6 weeks) born to mothers with severe early-onset maternal
hypertensive disorder
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%

insufficient evidence to determine utility of placental growth factor for predicting adverse perinatal
outcomes in women with hypertensive disorders of pregnancy
systematic review of 17 cohort studies evaluating placental growth factor (PIGF) for predicting maternal
or fetal complications in 4,488 women with hypertensive disorders of pregnancy
9 studies evaluated PIGF alone and 8 studies evaluated PIGF plus other angiogenic factors
median maternal age was 31 years, and most women (56%) were nulliparous
3 studies evaluated PIGF alone or soluble fms-like tyrosine kinase-1(sFlt-1)/PIGF ratio for predicting risk
of adverse perinatal/neonatal outcomes
for predicting small for gestational age
PIGF alone (cutoff ≤ 12 pg/mL) had sensitivity 72.7% and specificity 62.7% in 1 study with 89 women
sFlt-1/PIGF ratio ≥ 871 had sensitivity 36.9% and specificity 84.6% in 1 study with 501 women
for predicting stillbirth or neonatal death, sFlt-1/PIGF ratio ≥ 871 had sensitivity 67.3% and specificity
84.3% in 1 study with 501 women
for predicting composite of adverse neonatal outcomes, sFlt-1/PlGF ratio > 655 had sensitivity 92.8% and
specificity 54.1% in 1 study with 55 women
Reference - Hypertension 2017 Dec;70(6):1228
DynaMed commentary -- There is insufficient evidence to conclude on the performance of placental
growth factor for predicting adverse neonatal outcomes due to variability in the tests under investigation
and in the outcome measures.
Recurrence of preeclampsia
preeclampsia associated with increased risk for recurrence of preeclampsia in subsequent pregnancies
763,795 mothers having first births in Sweden from 1987 to 2004 evaluated
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
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
Reference - BMJ 2009 Jun 18;338:b2255 full-text
Prevention and Screening

Prevention
Recommendations for prevention of preeclampsia
low dose aspirin (150 mg/day) should be started before 16 weeks of pregnancy for women at increased
risk for preeclampsia, particularly if any of the following conditions exist
previous preeclampsia
preexisting medical conditions, including chronic hypertension, underlying renal disease, or
pregestational diabetes mellitus
multiple gestations
obesity
assisted reproduction pregnancy
if low dietary calcium intake (< 600 mg/day), calcium supplementation 1.2-2.5 g/day recommended in
women at increased risk of preeclampsia
exercise ≥ 3 days per week for average 50 minutes using a combination of aerobic exercise, strength, and
flexibility training recommended in all pregnant women to maintain healthy weight and decrease risk of
hypertensive disorders of pregnancy
American College of Obstetricians and Gynecologists (ACOG) recommendations(4)

low-dose aspirin (81 mg) should be initiated between 12 and 28 weeks gestation and continuing until
delivery in women with any high-risk factors for preeclampsia or > 1 moderate risk factor for
preeclampsia
insufficient evidence to demonstrate effectiveness of vitamin C and E, fish oil, garlic, vitamin D, folic acid,
or sodium restriction
bed rest and physical activity restriction not recommended for primary prevention of preeclampsia and
associated complications
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for preventing
preeclampsia and complications(2)
preconceptual counseling recommended for women with preexisting hypertension (SOGC Grade C, Level
III)
offer obstetric consultation at first antenatal care visit to women with increased risk for preeclampsia
(SOGC Grade B, Level II-2)
for women at high risk for preeclampsia
if low dietary calcium intake (< 600 mg/day)
calcium supplementation ≥ 1 g/day orally recommended (SOGC Grade A, Level I)
low-dose acetylsalicylic acid (75-162 mg/day) recommended (SOGC Grade B, Level III)
administer at bedtime (SOGC Grade B, Level I)
initiate after diagnosis of pregnancy and before 16 weeks gestation (SOGC Grade B, Level I)
consider continuation of therapy after delivery (SOGC Grade C, Level I)
consider prophylactic doses of low-molecular-weight heparin in women with previous placental

complications (including preeclampsia) (SOGC Grade B, Level I)
L-arginine may be useful for preventing preeclampsia and its complications in high-risk women (SOGC
Overview Grade
and Recommendations
B, Level I) / Background
interventions not recommended for preeclampsia prevention
weight maintenance in obese women during pregnancy (SOGC Grade D, Level III)
antihypertensive therapy specifically to prevent preeclampsia (SOGC Grade D, Level I)
vitamin C and vitamin E (SOGC Grade E, Level I)
insufficient evidence for recommendations about usefulness of
heart healthy diet (SOGC Grade L, Level III)
exercise (SOGC Grade L, Level I)
selenium (SOGC Grade L, Level I)
garlic (SOGC Grade L, Level I)
zinc (SOGC Grade L, Level III)
pyridoxine supplementation (SOGC Grade L, Level III)
iron supplementation with or without folate (SOGC Grade L, Level III)
multivitamins with or without micronutrients (SOGC Grade L, Level III)

use low-dose aspirin (100-150 mg daily) from week 12 to week 36-37 in women at moderate to high risk
of preeclampsia (ESC Class I, Level A)
calcium orally 1.5-2 g/day suggested at first antenatal clinic in women with < 600 mg/day dietary intake
of calcium
vitamin C and vitamin E may not reduce risk of preeclampsia
Rest, exercise, and weight control

bed rest and physical activity restriction not recommended for primary prevention of preeclampsia and
associated complications(4)
exercise ≥ 3 days per week for average 50 minutes using a combination of aerobic exercise, strength, and
flexibility training recommended in all pregnant women to maintain healthy weight and decrease risk of
weight maintenance in obese women during pregnancy not recommended to prevent preeclampsia (SOGC
Grade D, Level III)
daily rest might reduce risk of preeclampsia in women with normal blood pressure (level 2 [mid-level]
evidence)
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
trials did not report allocation concealment or blinding of outcome assessor
both trials included nulliparous women with singleton pregnancy at moderate risk of preeclampsia from
28 to 32 weeks gestation
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
1 trial with 74 women found rest for 30 minutes/day plus nutritional supplementation associated with
reduction in risk of preeclampsia and gestational hypertension
physical activity may help prevent preeclampsia (level 2 [mid-level] evidence)
based on systematic review without assessment of trial quality
systematic review of 17 trials (10 prospective cohort, 6 case-control, 1 randomized) evaluating exercise
or physical activity to prevent preeclampsia
no significant benefit of physical activity in analysis of 10 prospective cohort studies
physical activity associated with reduced preeclampsia (odds ratio 0.77, 95% CI 0.64-0.91) in analysis of
6 case-control studies
low-intensity stretching (vs. moderate-intensity walking) beginning at 18 weeks gestation associated with
protective effect on development of preeclampsia (odds ratio 6.34, 95% CI 0.72-55.37) in analysis of 1
randomized trial
Reference - Acta Obstet Gynecol Scand 2012 Oct;91(10):1147
combined diet and exercise interventions may reduce gestational weight gain but may not reduce risk of
preeclampsia (level 2 [mid-level] evidence)
based on Cochrane review limited by significant heterogeneity for gestational weight gain and with wide
confidence interval for preeclampsia
systematic review of 23 randomized trials evaluating combined diet and exercise interventions in 8,918
pregnant women
review limited by heterogeneity in interventions, outcome definitions, and patient populations
comparing diet plus exercise to standard prenatal care
diet plus exercise associated with decreased gestational weight gain above Institute of Medicine
(IOM) recommendations in analysis of 11 trials with 4,556 women, results limited by significant
heterogeneity
risk ratio 0.87 (95% CI 0.79-0.96)
NNT 11-54 with gestational weight gain above IOM recommendations in 47% of standard prenatal
care group
preeclampsia (risk ratio 0.98, 95% CI 0.79-1.22) in analysis of 8 trials with 5,366 women, not
significant, but CI includes possibility of benefit or harm
pregnancy-induced hypertension and/or hypertension (risk ratio 0.78, 95% CI 0.47-1.27) in analysis
of 6 trials with 3,073 women, results limited by significant heterogeneity
Reference - Cochrane Database Syst Rev 2017 Nov 13;11:CD010443
metformin may reduce maternal weight gain and risk of preeclampsia, but may not improve neonatal
outcomes in obese pregnant women without diabetes (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
450 women (median age 32 years) with singleton pregnancy at 12-18 weeks gestation, without diabetes,
but with body mass index (BMI) > 35 kg/m2 were randomized to metformin 3 g/day vs. placebo until
delivery
all women received advice on healthy eating and were encouraged to exercise for 30 minutes/day
11.1% withdrew consent post randomization
maternal outcomes comparing metformin vs. placebo
median weight gain 4.6 kg (10 lbs) vs. 6.3 kg (14 lbs) (p < 0.001)
preeclampsia in 3% vs. 11.3% (p = 0.001, NNT 12)
gestational diabetes mellitus in 12.4% vs. 11.3% (not significant)
rate of pregnancy-induced hypertension, cesarean delivery, or postpartum hemorrhage
neonatal outcomes including median birth weight z-score, miscarriage, stillbirth, neonatal death,
delivery at < 37 weeks, and large-for-gestational-age
Reference - N Engl J Med 2016 Feb 4;374(5):434
10% reduction in prepregnancy body mass index associated with reduced risk of preeclampsia in
overweight and obese women / Background
226,958 women with singleton pregnancies evaluated for association between prepregnancy body mass
index (BMI) and adverse pregnancy outcomes
10% risk difference in adverse pregnancy outcomes defined as clinically meaningful
among overweight and obese women, 10% reduction in prepregnancy BMI associated with ≥ 10% lower
risk of preeclampsia
Reference - Obstet Gynecol 2015 Jan;125(1):133
Calcium
in women with < 600 mg/day dietary intake of calcium, supplemental calcium ≥ 1 g/day recommended
(SOGC Grade A, Level I)(2, 3, 6)
low-dose calcium supplementation starting before pregnancy up to 20 weeks gestation may not reduce
risk of preeclampsia in women with history of preeclampsia or eclampsia (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial with confidence interval that cannot exclude
differences that may be important
1,355 women intending to become pregnant who had preeclampsia or eclampsia during most recent
pregnancy in South Africa, Zimbabwe, and Argentina were randomized to calcium 500 mg/day orally vs.
placebo from prepregnancy enrollment until 20 weeks gestation
29% in calcium group and 28% in placebo group were lost to follow-up or withdrew before conception
all women who became pregnant received calcium 1.5 g/day after 20 weeks gestation
581 women (44% of calcium group and 42% of placebo group) who had pregnancy lasting ≥ 20 weeks
gestation were included in analysis
comparing calcium vs. placebo
preeclampsia (gestational hypertension and proteinuria after 20 weeks gestation) in 23% vs. 29% (risk
ratio [RR] 0.8, 95% CI 0.61-1.06), not significant, but CI cannot exclude differences that may be
clinically important
preeclampsia (all randomized women) in 10% vs. 12% (RR 0.84, 95% CI 0.62-1.14)
preeclampsia or pregnancy loss at any gestational age in 33% vs. 41% (RR 0.82, 95% CI 0.66-1)
severe preeclampsia (proteinuria plus diastolic blood pressure > 110 mm Hg or systolic blood
pressure > 160 mm Hg) in 18% vs. 21% (RR 0.83, 95% CI 0.59-1.16)
in prespecified subgroup analysis of 141 women with > 80% compliance from randomization up to 20
weeks gestation, preeclampsia in 20% with calcium vs. 32% with placebo (RR 0.64, 95% CI 0.36-1.13)
no serious adverse effects of calcium reported
Reference - Lancet 2019 Jan 26;393(10169):330 full-text, editorial can be found in Lancet 2019 Jan
26;393(10169):298, commentary can be found in Lancet 2019 Aug 17;394(10198):e6
no additional trials found evaluating calcium supplementation before pregnancy or during early
pregnancy (until 20 weeks gestation) for preventing preeclampsia and other hypertensive disorders of
pregnancy (Cochrane Database Syst Rev 2019 Sep 16;9:CD011192)
calcium supplementation ≥ 1 g/day during pregnancy reduces composite outcome of maternal death or
serious morbidity (level 1 [likely reliable] evidence) and may reduce preeclampsia and preterm birth (level
based on Cochrane review limited by heterogeneity for preeclampsia and preterm birth
systematic review of 27 randomized trials evaluating calcium supplementation in 18,064 pregnant
women
13 trials compared high-dose calcium supplementation (≥ 1 g/day) to placebo in 15,730 women
most women were low risk and had low-calcium diet
most trials used calcium 1.5-2 g/day
comparing / Background
calcium supplementation ≥ 1 g/day to placebo
calcium supplementation ≥ 1 g/day associated with
reduced maternal death or serious morbidity in analysis of 4 trials with 9,732 women
risk ratio (RR) 0.8 (95% CI 0.66-0.98)
NNT 69-1,163 with maternal death or serious morbidity in 4% of placebo group
results almost entirely based on WHO trial
reduced preeclampsia in analysis of 13 trials with 15,730 women, results limited by significant
heterogeneity
RR 0.45 (95% CI 0.31-0.65)
NNT 25-48 with preeclampsia in 6% of placebo group
reduced preterm birth in analysis of 11 trials with 15,275 women, results limited by significant
heterogeneity
RR 0.76 (95% CI 0.6-0.97)
NNT 25-334 with preterm birth in 10% of placebo group
increased risk of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) in
analysis of 2 trials with 12,901 women
RR 2.67 (95% CI 1.05-6.82)
NNH 171-20,000 with HELLP syndrome in 0.1% of placebo group
no significant difference in risk of

admission to neonatal intensive care unit (NICU) in analysis of 4 trials with 13,406 infants
stillbirth or death before discharge in analysis of 11 trials with 15,665 infants
high-dose calcium supplementation (2 g/day) associated with reduced risk of preeclampsia (RR 0.42,
95% CI 0.18-0.96) compared to low-dose calcium supplementation (500 mg/day) in 1 trial with 262
women
for preeclampsia with calcium supplementation ≥ 1 g/day compared to placebo, 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)
calcium 1,500 mg/day supplementation may not reduce risk of preeclampsia or maternal mortality, but
may reduce severity of preeclampsia, risk of eclampsia, and neonatal death in pregnant women with
low dietary calcium intake (level 2 [mid-level] evidence)
based on largest randomized trial in Cochrane review with inadequate statistical power
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
until delivery
mean gestation at randomization was 15.1 weeks for both groups
assigned treatment was discontinued if nephrolithiasis occurred or magnesium sulfate used to treat
preeclampsia
8,312 women (99.8%) were included in intention-to-treat analysis
study was underpowered to detect a 10% difference in incidence of preeclampsia
no difference comparing women with calcium supplementation vs. placebo for outcomes of
preeclampsia (4.1% vs. 4.5%)
severe preeclampsia (0.8% vs. 1.1%)
early-onset preeclampsia or eclampsia (< 32 weeks gestation) (0.46% vs. 0.53%)
calcium supplementation associated with reduced risk of
Overview andsevere gestational hypertension
Recommendations (adjusted risk ratio (RR) 0.71, 95% CI 0.61-0.82)
/ Background
eclampsia (adjusted RR 0.68, 95% CI 0.48-0.97)
composite of severe preeclamptic complications, defined as severe preeclampsia, preeclampsia
before 32 weeks gestation, eclampsia, placental abruption, hemolysis, elevated liver enzymes, low
platelets (HELLP) syndrome, or severe gestational hypertension (adjusted RR 0.76, 95% CI 0.66-
0.89)
any maternal admission to intensive or special care unit (adjusted RR 0.85, 95% CI 0.75-0.95)
comparing women with calcium supplementation vs. placebo
maternal death in 0.02% vs. 0.14% (RR 0.17, 95% CI 0.03-0.76)
neonatal death in 0.94% vs. 1.3% (RR 0.7, 95% CI 0.56-0.88)
Reference - WHO trial ( Am J Obstet Gynecol 2006 Mar;194(3):639)
calcium supplementation < 1 g/day during pregnancy may reduce risk of preeclampsia (level 3 [lacking
direct] evidence)
based on nonclinical outcome in Cochrane review limited by clinical heterogeneity
systematic review of 27 randomized trials evaluating calcium supplementation in 18,064 pregnant
women
12 trials evaluated low-dose calcium supplementation (< 1 g/day) in 2,334 women
4 trials evaluated calcium supplementation alone and 8 trials used cosupplements (including vitamin
D, linoleic acid, and antioxidants)
9 trials compared calcium supplementation to placebo or no treatment; 1 trial compared
supplementation to aspirin (control group not specified in 2 trials)
comparing calcium supplementation < 1 g/day to placebo

calcium supplementation < 1 g/day associated with
reduced preeclampsia in analysis of 9 trials with 2,234 women
risk ratio (RR) 0.38 (95% CI 0.28-0.52)
NNT 11-16 with preeclampsia in 13% of control group
most trials included women at high risk for preeclampsia
reduced risk of NICU admission (RR 0.44, 95% CI 0.2-0.99) in 1 trial with 442 infants
no significant difference in stillbirth or death before discharge in analysis of 5 trials with 1,025 infants
see also Calcium Intake and Supplementation
Antiplatelet agents (aspirin)

recommendations from professional organizations are generally consistent in recommending low-dose
aspirin for women at risk for preeclampsia; the timing of initiation differs slightly across society
recommendations, but typically suggest starting in second trimester and continuing until delivery
International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends low-dose aspirin
(75-162 mg/day, preferably 150 mg/day) for women with established strong clinical risk factors for
preeclampsia, including
previous preeclampsia
preexisting medical conditions, including chronic hypertension, underlying renal disease, or
pregestational diabetes mellitus
multiple gestations
obesity
assisted reproduction pregnancy
American College of Obstetricians and Gynecologists (ACOG) states that low-dose aspirin (81 mg)
should be initiated between 12 and 28 weeks gestation and continuing until delivery in women with any
high risk factor or > 1 moderate risk factor for preeclampsia(4)
American College of Chest Physicians (ACCP) recommends low-dose aspirin throughout pregnancy for
women considered at risk for preeclampsia, starting from second trimester, over no treatment (ACCP
Grade 1B) ( Chest 2012 Feb;141(2 Suppl):e691S full-text)
Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends low-dose acetylsalicylic
acid (75-162 mg/day) in women at high risk for preeclampsia (SOGC Grade B, Level III)
initiate after diagnosis of pregnancy and before 16 weeks gestation (SOGC Grade B, Level I)
take at bedtime (SOGC Grade B, Level I)
consider continuation of therapy after delivery (SOGC Grade C, Level I)
European Society of Cardiology (ESC) recommends low-dose aspirin (100-150 mg daily) from week 12 to
week 36-37 in women at moderate to high risk of preeclampsia (ESC Class I, Level A)(3)
antiplatelet agents may reduce incidence of preeclampsia, preterm birth, and fetal or neonatal death in
women at risk of developing preeclampsia
antiplatelet agents, mostly low-dose aspirin, may reduce incidence of preeclampsia, preterm birth, and
fetal or neonatal death in women at risk for preeclampsia (level 2 [mid-level] evidence)
based on Cochrane review with significant differences dependent on lower-quality trials
systematic review of 59 randomized trials with 37,560 women at risk of developing preeclampsia
18 trials had adequate allocation concealment, of which 14 were placebo-controlled; higher-quality
trials tended toward fewer significant differences
comparing antiplatelet agents (mostly low-dose aspirin) 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
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
further information needed to guide patient selection, timing, and dose
Reference - Cochrane Database Syst Rev 2007 Apr 18;(2):CD004659 (review updated 2008 Sep 1)
consistent findings for risk of preeclampsia in individual patient data meta-analysis with 32,217 high-
risk women from 31 randomized trials (by same authors as Cochrane review ( Lancet 2007 May
26;369(9575):1791)
consistent findings for risk of preterm birth in secondary analysis of individual patient data meta-
Overview analysis
including 28,797 women from 17 trials ( Obstet Gynecol 2017 Feb;129(2):327)
low-dose aspirin starting at 11-14 weeks gestation appears to reduce risk of preterm preeclampsia in
high-risk women with singleton pregnancies (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
1,776 women (median age 31 years) with singleton pregnancy at high risk for preterm preeclampsia
were randomized to aspirin 150 mg once daily at night vs. placebo from 11-14 weeks gestation until
36 weeks gestation or until onset of labor in case of early delivery
9% either withdrew or were lost to follow-up, 91% included in analysis
79.9% took ≥ 85% of required number of tablets
comparing aspirin vs. placebo
preterm preeclampsia (at < 37 weeks gestation) in 1.6% vs. 4.3% (p = 0.004, NNT 37)
any adverse outcomes at < 37 weeks gestation in 9.9% vs. 14.1% (not significant)
≥ 1 serious adverse event in 1.6% vs. 3.2% (no p value reported)
no significant differences in rates of adverse fetal or neonatal outcomes
Reference - ASPRE trial ( N Engl J Med 2017 Aug 17;377(7):613), editorial can be found in N Engl J
Med 2017 Aug 17;377(7):690, correspondence can be found in N Engl J Med 2017 Dec
14;377(24):2399
low-dose aspirin starting at 11-14 weeks gestation may reduce rate of neonates born < 32 weeks
gestation and length of stay in NICU (level 2 [mid-level] evidence)
based on post hoc analysis of ASPRE trial
1,571 live births (777 in aspirin group and 794 in placebo group) were included in analyses
neonates born < 32 weeks gestation 1.2% vs. 2.9% (odds ratio 0.42, 95% CI 0.19-0.93, NNT 59)
admission to neonatal intensive care unit (NICU) in 6.2% vs. 6.8% (not significant)
mean NICU stay in neonates admitted to NICU 11.1 days vs. 31.4 days (p = 0.008)
neonates admitted to NICU due to maternal preeclampsia 0.3% vs. 2.3% (odds ratio 0.11, 95%
CI 0.02-0.5, NNT 50)
low-dose aspirin associated with reduced risk of preeclampsia but not small-for-gestational age infant
in women with multiple gestations (level 2 [mid-level] evidence)
based on systematic review with trial-specific quality measures not reported
systematic review of 6 randomized trials with 898 multiple gestation pregnancies were included
low-dose aspirin associated with reduction in risk of
preeclampsia (relative risk [RR], 0.67, 95% CI 0.48-0.94)
mild preeclampsia (RR, 0.44, 95% CI 0.24-0.82)
no differences in effects in prespecified stratified comparison by timing (initiation at < 16 weeks vs. >
16 weeks)
low-dose aspirin not associated with decreased risk of
severe preeclampsia (RR 1.02, 95% CI 0.61-1.72)
small-for-gestational age infant (RR 1.09, 95% CI 0.8-1.47)
Reference - Am J Perinatol 2016 May;33(6):605
evidence is conflicting as to when in pregnancy to initiate antiplatelet agents

low-dose aspirin initiated at ≤ 16 weeks gestation associated with reduced preeclampsia and improved
neonatal outcomes in pregnant women at risk for preeclampsia
Overview aspirin initiated at ≤ 16 weeks
and Recommendations gestation appears to decrease risk of any preeclampsia, severe
/ Background
preeclampsia, and fetal growth restriction whereas initiation > 16 weeks appears to reduce risk of
preeclampsia but does not appear to reduce risk of severe preeclampsia or fetal growth restriction
based on systematic review with clinical heterogeneity and trial-specific quality measures not
reported
systematic review of 45 randomized trials with 20,909 pregnant women at risk of developing
preeclampsia
trials varied in aspirin dose (from 50 to 150 mg/day) and gestational age
initiation of aspirin
≤ 16 weeks gestation associated with reduced risk of
preeclampsia (relative risk [RR] 0.57, 95% CI 0.43-0.75)
severe preeclampsia (RR 0.47, 95% CI 0.26-0.83)
fetal growth restriction (RR 0.56, 95% CI 0.44-0.7)
> 16 weeks gestation associated with reduced risk of preeclampsia (RR 0.81, 95% CI 0.66-0.99,
results limited by significant heterogeneity)
significant dose response effect observed with higher dosages of aspirin (> 60 mg) whereas lower
doses (< 60 mg) had no effect on reducing risk of preeclampsia, severe preeclampsia, or fetal
growth restriction at ≤ 16 weeks or > 16 weeks gestation
Reference - Am J Obstet Gynecol 2017 Feb;216(2):110
initiating low-dose aspirin or other antiplatelet agents at < 16 weeks or ≥ 16 weeks gestation
associated with similar effects on preeclampsia, infant mortality, preterm birth, and small for
gestational age infant (level 2 [mid-level] evidence)
based on systematic review of subgroup analyses of randomized trials
meta-analysis of individual patient data from 31 randomized trials evaluating low-dose aspirin or
other antiplatelet agents in 32,217 pregnant women
no significant difference between antiplatelet treatment initiated at < 16 weeks vs. ≥ 16 weeks
gestation in
preeclampsia in analysis of 30,470 women in 23 trials
infant mortality in analysis of 30,962 women in 22 trials
preterm birth (< 34 weeks gestation) in analysis of 31,272 women in 26 trials
small for gestational age infant in analysis of 21,389 women in 19 trials
Reference - Am J Obstet Gynecol 2017 Feb;216(2):121
low-dose aspirin initiated at ≤ 16 weeks gestation associated with reduced risk of perinatal mortality
and other adverse perinatal outcomes in pregnant women with risk factors for preeclampsia (level 2
based on systematic review with inadequate assessment of trial quality
systematic review of 42 randomized trials comparing prophylactic low-dose aspirin (50-150
mg/day) with or without dipyridamole (≤ 300 mg/day) initiated at ≤ 16 weeks or > 16 weeks
gestation vs. placebo or no treatment (control) in 27,222 pregnant women with risk factors for
preeclampsia
risk factors for preeclampsia included nulliparity, multiple pregnancy, chronic hypertension,
cardiovascular or endocrine disease, prior gestational hypertension, fetal growth restriction,
and/or abnormal uterine artery Doppler
trial-specific quality measures not reported
perinatal mortality defined as fetal death at > 16 weeks gestation or neonatal death at < 28 days
old
comparing low-dose aspirin initiated at ≤ 16 weeks gestation vs. control, aspirin initiation at ≤ 16
weeks gestation associated with reduced
perinatal mortality (risk
Overview and Recommendations ratio [RR] 0.41, 95% CI 0.19-0.92) in analysis of 12 trials with 1,308
/ Background
women
preterm birth (RR 0.35, 95% CI 0.22-0.57) in analysis of 6 trials with 904 women
preeclampsia (RR 0.47, 95% CI 0.36-0.62) in analysis of 13 trials with 1,479 women
severe preeclampsia (RR 0.18, 95% CI 0.08-0.41) in analysis of 6 trials with 649 women
fetal growth restriction (RR 0.46, 95% CI 0.33-0.64) in analysis of 10 trials with 1,064 women
comparing low-dose aspirin initiated at > 16 weeks gestation vs. control
aspirin initiation at > 16 weeks gestation associated with reduced
preeclampsia (RR 0.78, 95% CI 0.61-0.99) in analysis of 20 trials with 10,673 women
preterm birth (RR 0.9, 95% CI 0.83-0.97) in analysis of 16 trials with 10,398 women
perinatal mortality in analysis of 20 trials with 9,557 women
severe preeclampsia in analysis of 5 trials with 1,494 women
fetal growth restriction in analysis of 17 trials with 7,196 women
in indirect comparisons of aspirin initiation at ≤ 16 weeks vs. > 16 weeks gestation, earlier
initiation associated with reduced risk of perinatal mortality (p = 0.02), preeclampsia and severe
preeclampsia (p < 0.01 for each), intrauterine growth restriction (p < 0.001), and preterm birth (p <
0.001)
Reference - Ultrasound Obstet Gynecol 2013 May;41(5):491 full-text, editorial can be found in
Ultrasound Obstet Gynecol 2013 May;41(5):479
low-dose aspirin initiated ≤ 16 weeks gestation associated with reduced preeclampsia in high-risk
women with abnormal uterine artery Doppler flow (level 2 [mid-level] evidence)
based on systematic review without assessment of trial quality
in single randomized trial (PREDO trial)
152 women at 12-14 weeks gestation at risk for preeclampsia and with abnormal uterine artery
Doppler velocimetry were randomized to aspirin 100 mg/day vs. placebo until 35 weeks
gestation or delivery
121 women were analyzed, unclear if 31 women were excluded before or after randomization
preeclampsia (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90
mm Hg in 2 consecutive measurements and proteinuria ≥ 0.3 g/24 hours) in 13.1% vs.
18.3% (not significant)
gestational hypertension in 16.4% vs. 10% (not significant)
severe preeclampsia (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure
≥ 110 mm Hg, and/or proteinuria ≥ 5 g/24 hours) in 4.9% vs. 13.3% (not significant)
systematic review identified 2 additional randomized trials comparing low-dose aspirin (50-150
mg/day) vs. placebo or no treatment started at or before 16 weeks gestation for preventing
preeclampsia in women with abnormal uterine artery Doppler flow
total number of women in these 3 trials was 346
aspirin associated with reduced risk of preeclampsia in analysis of 3 trials

risk ratio 0.55 (95% CI 0.37-0.83)
NNT 5-17 with preeclampsia in 36.3% of controls
aspirin associated with reduced risk of severe preeclampsia in analysis of 3 trials

risk ratio 0.27 (95% CI 0.11-0.69)
NNT 10-29 with preeclampsia in 11.3% of controls
Overview andReference
Recommendations
- BJOG 2013 /Jan;120(1):64
Background
low-dose aspirin starting at < 11 weeks gestation might not reduce risk of preeclampsia or gestational
hypertension in women with recurrent miscarriage or having in vitro fertilization (level 2 [mid-level]
evidence)
based on systematic review with confidence interval that includes differences that are not clinically
important
systematic review of 8 randomized trials comparing low-dose aspirin initiated at < 11 weeks gestation
vs. placebo or no treatment in 1,426 women
aspirin administration was until 36 weeks gestation in 7 trials and dose was 100 mg/day in 3
trials, 75-81 mg/day in 4 trials, and 50 mg/day in 1 trial
trial populations included women with history of miscarriage in 5 trials (1,140 women), women
having in vitro fertilization in 2 trials, and unselected nulliparous pregnant women in 1 trial
no significant difference in risk of

preeclampsia (risk ratio [RR] 0.52, 95% CI 0.23-1.17) in analysis of 6 trials with 819 women, CI
includes both clinically important and unimportant differences
gestational hypertension (RR 0.49, 95% CI 0.2-1.21) in analysis of 4 trials with 642 women, CI
includes both clinically important and unimportant differences
fetal growth restriction (RR 1.1, 95% CI 0.58-2.07) in analysis of 5 trials with 629 women
low-dose aspirin associated with

nonsignificant decreased risk of any hypertensive disorder (RR 0.59, 95% CI 0.33-1.04) in analysis
of all trials, CI includes both clinically important and unimportant differences
decreased risk of preterm birth at < 37 weeks gestation (RR 0.52, 95% CI 0.27-0.97) in analysis of 6
trials with 1,307 women
Reference - Am J Obstet Gynecol 2019 Sep 5 early online
risk of placental abruption or antepartum hemorrhage according to aspirin dose and gestational age at
onset of treatment
prophylactic aspirin < 100 mg/day initiated at ≤ 16 weeks or > 16 weeks gestation may not reduce risk
of placental abruption or antepartum hemorrhage, but prophylactic aspirin ≥ 100 mg/day might
decrease risk if initiated at ≤ 16 weeks gestation (level 2 [mid-level] evidence)
based on systematic review with wide confidence intervals
systematic review of 20 randomized trials comparing risk of placental abruption or antepartum
hemorrhage with prophylactic aspirin initiated at ≤ 16 weeks or > 16 weeks gestation vs. placebo or
no treatment (control) in 12,585 pregnant women
15 trials reported on placental abruption and 5 trials reported on antepartum hemorrhage
11 trials evaluated aspirin < 100 mg/day and 10 trials evaluated aspirin ≥ 100 mg/day
comparing prophylactic aspirin < 100 mg/day to control

no significant difference in risk of placental abruption or antepartum hemorrhage with initiation
at ≤ 16 weeks gestation (relative risk [RR] 1.11, 95% CI 0.52-2.36) in analysis of 4 trials with
1,673 women
at > 16 weeks gestation (RR 1.32, 95% CI 0.73-2.39) in analysis of 9 trials with 7,788 women
no significant difference in effect in indirect comparison by timing of initiation
comparing prophylactic aspirin ≥ 100 mg/day to control

no significant difference in risk of placental abruption or antepartum hemorrhage with initiation
at ≤ 16 weeks gestation (RR 0.62, 95% CI 0.31-1.26) in analysis of 6 trials with 2,318 women
at > 16 weeks gestation (RR 2.08, 95% CI 0.86-5.06) in analysis of 4 trials with 829 women
significant difference in effect favoring initiation at ≤ 16 weeks gestation in indirect comparison by
timing of initiation
all results limited by CIs including possibility of benefit or harm
Reference - Am J Obstet Gynecol 2018 May;218(5):483
in women at high risk for preeclampsia who are taking aspirin prophylaxis, the presence of diabetes,
obesity, prehypertension, or hypertension during the first trimester is associated with increased risk of
developing preeclampsia (level 2 [mid-level] evidence)
based on secondary analysis of cohort study
614 pregnant women at high risk for preeclampsia with initiation of aspirin 81 mg /day by 16 weeks
gestation evaluated
9.6% developed preeclampsia
comparing first trimester characteristics in women who developed preeclampsia vs. women who did not
develop preeclampsia
chronic hypertension in 30.5% vs. 13.9% (p < 0.001)
diabetes mellitus in 16.9% vs. 4.7% (p = 0.001)
obesity in 50.8% vs. 36.2% (p = 0.034)
blood pressure in prehypertension or hypertension range (by Joint National Committee on
Hypertension-7 criteria) in 74.6% vs. 40.9% (p < 0.001)
Reference - Obstet Gynecol 2014 Mar;123(3):611

cost-effective analysis of low-dose aspirin prophylaxis for prevention of preeclampsia can be found in Obstet
Gynecol 2015 Dec;126(6):1242
Anticoagulants
low-molecular weight heparin does not appear to help prevent preeclampsia or related adverse neonatal
outcomes in women at risk for preeclampsia, and the International Society for the Study of Hypertension in
Pregnancy (ISSHP) considers it to not be indicated even in women with a history of early-onset
preeclampsia(6); however, randomized trials of women with a history of severe preeclampsia or placental
abruption have shown benefit
low-molecular-weight heparin may not reduce risk of early-onset or severe preeclampsia, late pregnancy
loss, or placental abruption in women with history of placenta-mediated pregnancy complications (level 2
systematic review of individual patient data from 8 randomized trials comparing low-molecular-weight
heparin (LMWH) vs. control in 963 pregnant women with history of placenta-mediated pregnancy
complications
LMWH included dalteparin (3 trials), nadroparin (2 trials), and enoxaparin (3 trials)
control treatments included no LMWH (4 trials), aspirin alone (4 trials), or placebo (1 trial)
history of placenta-mediated complications included preeclampsia (62%), placental abruption (32%),
small-for-gestational-age neonate (< 10th percentile, 35%), or pregnancy loss (29% had ≥ 1 loss after
16 weeks gestation and 25% had ≥ 2 losses after 12 weeks gestation)
42% had thrombophilia and 20% had chronic hypertension
use of concomitant aspirin varied among trials, with aspirin used as part of treatment (4 trials), at
discretion of investigator (2 trials), given for specific clinical criteria (1 trial), or discouraged (1 trial)
primary outcome was composite of early-onset (< 34 weeks) or severe preeclampsia, late pregnancy loss
(≥ 20 weeks gestation), placental abruption leading to delivery, or birth of small-for-gestational-age
neonate (< 5th percentile)
comparing LMWH vs. control
primary composite outcome in 14% vs. 22% (p = 0.09)
early-onset or severe preeclampsia in 7% vs. 12% (not significant)
late pregnancy loss in 3% vs. 4% (not significant)
placental abruption leading to delivery in 1% vs. 2% (not significant)
birth of small-for-gestational-age neonate in 6% vs. 9% (p = 0.042, NNT 34)
28-day neonatal mortality 1% vs. 2% (p = 0.07)
in subgroup analyses according to patient history or treatment
LMWH associated with decreased risk of composite outcome
in women with history of preeclampsia (p = 0.003) or placental abruption (p < 0.0001) and in
women without thrombophilia (p < 0.0001)
when used in combination with daily aspirin (p = 0.009)
no significant differences in composite outcome

in women with prior small-for-gestational-age neonate or pregnancy loss or in women with
thrombophilia
without concurrent aspirin treatment
Reference - Lancet 2016 Nov 26;388(10060):2629, editorial can be found in Lancet 2016 Nov
26;388(10060):2570
addition of enoxaparin to standard high-risk care does not appear to reduce risk of preeclampsia or small-
for-gestational-age infant in high-risk women (level 2 [mid-level] evidence)
160 women with singleton pregnancy (6-16 weeks gestation) who had high risk for preeclampsia and/or
small for gestational age (SGA) were randomized to standard high-risk care plus enoxaparin 40 mg
subcutaneously daily vs. standard high-risk care alone until 36 weeks gestation
standard high-risk care was care coordinated by high-risk antenatal clinic and included aspirin 100
mg/day until 36 weeks gestation and calcium 1,000-1,500 mg/day until 36 weeks gestation in women
with previous pre-eclampsia
93.1% did not miscarry and were included in analyses
comparing standard high-risk care plus enoxaparin vs. standard high-risk care alone
preeclampsia in 8.3% vs. 6.5% (adjusted odds ratio [OR] 1.24, 95% CI 0.33-4.64)
SGA infant < 5th percentile in 20.8% vs. 16.9% (adjusted OR 1.48, 95% CI 0.61-3.62)
no significant differences in severe preeclampsia, SGA < 3rd percentile, SGA < 10th percentile,
antepartum hemorrhage and placental abruption, stillbirth, postpartum hemorrhage, preterm birth,
neonatal death, or neonatal intensive care admission
Reference - Am J Obstet Gynecol 2017 Mar;216(3):296.e1
selected trials showing benefit in women with history of specific obstetrical complications
addition of enoxaparin to aspirin may decrease risk of preeclampsia and placental complications in
second pregnancy in women with history of severe preeclampsia (level 2 [mid-level] evidence)
224 women with previous severe preeclampsia without fetal loss during first pregnancy were
randomized to enoxaparin 4,000 units subcutaneously once daily starting immediately after positive
test for second pregnancy vs. no enoxaparin
all women were negative for antiphospholipid antibodies at baseline and received aspirin 100 mg/day
comparing enoxaparin vs. no enoxaparin
composite placental complications in 8.9% vs. 25% (p = 0.004, NNT 7)
preeclampsia in 5.8% vs. 16.7% (p < 0.05, NNT 10)
placental abruption in 0.9% vs. 1.9% (not significant)
birth weight < 5th percentile in 2.9% vs. 8.6% (not significant)
fetal loss after 20 weeks in 2.9% vs. 5.9% (not significant)
Reference - NOH-PE trial ( Thromb Haemost 2011 Dec;106(6):1053)

prophylactic enoxaparin may reduce preeclampsia in women with previous placental abruption (level 2
160 women with previous placental abruption without fetal loss during first pregnancy and negative
for antiphospholipid antibodies were randomized to enoxaparin 4,000 units once daily
subcutaneously started at positive pregnancy test vs. no enoxaparin
comparing enoxaparin vs. no enoxaparin
preeclampsia in 7.5% vs. 22.5% (p = 0.009, NNT 2)
composite placental complications in 12.5% vs. 31.3% (p = 0.04, NNT 6)
abruptio placenta in 1.3% vs. 3.8% (not significant)
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)
Reference - NOH-AP trial ( Thromb Haemost 2010 Oct;104(4):771)
L-arginine
L-arginine may be useful for preventing preeclampsia and its complications in high-risk women (SOGC Grade
B, Level I)(2)
L-arginine plus antioxidant supplementation during pregnancy reduces risk of preeclampsia and preterm
delivery in high-risk women (level 1 [likely reliable] evidence)
based on randomized trial
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
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 30% 23% (p = 0.052 13% (p < 0.001

eclampsia vs. placebo) 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 6% 7% 5%
preterm delivery
Cesarean 68.4% 66.6% 67.9%

delivery
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)
Reference - BMJ 2011 May 19;342:d2901 full-text, editorial can be found in BMJ 2011 May 19;342:d2777
Antioxidants
Concomitant vitamin C and E
supplemental vitamin C and E are not recommended and may be associated with worse pregnancy
outcomes(6)
concomitant vitamin C and vitamin E supplementation during pregnancy may reduce risk of placental
abruption (level 2 [mid-level] evidence), but increases risk of term premature rupture of membranes (level
1 [likely reliable] evidence) and may not reduce risk of preeclampsia, stillbirth, or neonatal mortality (level
based on Cochrane review with statistical limitations
systematic review of 21 randomized or quasi-randomized trials evaluating vitamin E alone or in
combination with other supplements in 22,129 pregnant women
all trials included in meta-analyses compared vitamin C plus vitamin E vs. placebo or no treatment
(control)
most trials evaluated daily supplementation with vitamin C 1,000 mg plus vitamin E 400 units
statistical limitations for conclusion (outcomes with level 2 evidence) included
no significant differences in high-quality trials (placental abruption)
heterogeneity (preeclampsia)
confidence intervals including clinically meaningful differences (stillbirth and neonatal mortality)
supplementation with vitamin C plus vitamin E associated with
decreased risk of placental abruption in analysis of 7 trials with 14,922 women
risk ratio (RR) 0.64 (95% CI 0.44-0.93)
NNT 198-1,587 with placental abruption in 0.9% of control group
results not significant in any of 5 included high-quality trials
increased risk of term premature rupture of membranes in analysis of 2 trials with 2,504 women
RR 1.77 (95% CI 1.37-2.28)
NNH 11-38 with term premature rupture of membranes in 7% of control group
no significant differences between groups in

Overview preeclampsia in analysis of/14
and Recommendations trials with 20,878 women, results limited by significant heterogeneity
Background
stillbirth (RR 1.17, 95% CI 0.88-1.56) in analysis of 9 trials with 19,023 women
neonatal death (RR 0.81, 95% CI 0.58-1.13) in analysis of 9 trials with 18,617 infants
pre-term birth in analysis of 11 trials with 20,565 women, results limited by significant heterogeneity
intrauterine growth restriction in analysis of 11 trials with 20,202 women
preterm premature rupture of membranes in analysis of 5 trials with 1,999 women, results limited by
abdominal pain in 7.9% with vitamin C plus vitamin E vs. 4.8% with placebo (p = 0.0059, NNH 32) in 1 trial
with 1,877 women
no clear differences in subgroups of women based on timing of beginning supplementation or baseline
risk of adverse pregnancy outcomes
Reference - Cochrane Database Syst Rev 2015 Sep 7;(9):CD004069
largest trials in Cochrane review
concomitant vitamin C and vitamin E supplementation does not reduce risk of preeclampsia or its
complications (level 1 [likely reliable] evidence)
based on randomized trial
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 and 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
9,969 (98%) women who completed trial included in analysis
comparing vitamin C and E 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)
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
Reference - N Engl J Med 2010 Apr 8;362(14):1282 full-text
supplementation with vitamins C and E beginning at 9-16 weeks gestation may not increase risk
of spontaneous preterm birth (level 2 [mid-level] evidence)
based on secondary analysis of randomized trial above
10,154 nulliparous women at low risk for preeclampsia randomized to begin vitamin C 1,000
mg plus vitamin E 400 units daily vs. placebo daily between weeks 9 and 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
9,969 (98%) women who completed trial included in analysis
supplementation with vitamins C and E beginning at 9-16 weeks gestation not associated with
increased risk of spontaneous preterm birth
Reference - Obstet Gynecol 2010 Sep;116(3):653 full-text
vitamin C and vitamin E supplementation during second and third trimesters in pregnant women at
high risk of preeclampsia associated with increased risk of low-birth-weight infants but not other
perinatal morbidities (level 2 [mid-level] evidence)
based on randomized trial with low adherence
2,410 pregnant women at increased risk of preeclampsia were randomized to antioxidants
(vitamin C 1,000 mg and vitamin E 400 units) vs. placebo daily from second trimester until delivery
65% of study cohort took at least 80% of assigned tablets
for neonatal outcomes, compared to placebo
vitamins C and E associated with increased risk of low birth weight (< 2.5 kg) (risk ratio 1.15,
95% CI 1.02-1.3)
vitamins C and E not associated with increased risk of
stillbirth (1% in supplemented vs. 0.5% in placebo)
small-for-gestational-age infants
antepartum death
survival at 28 days
preterm birth
admission to neonatal intensive care unit, mechanical ventilation, respiratory distress
syndrome, or intraventricular hemorrhage
Reference - VIP trial ( Lancet 2006 Apr 8;367(9517):1145), editorial can be found in Lancet 2006
Apr 8;367(9517):1119, commentary can be found in Lancet 2006 Jul 15;368(9531):198
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)
based on randomized trial with wide confidence intervals
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
modified intention-to-treat analysis included 749 (98%) pregnancies > 20 weeks gestation
preeclampsia defined as gestational hypertension with proteinuria
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%
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
Reference - DAPIT trial ( Lancet 2010 Jul 24;376(9737):259 full-text), commentary can be found in Lancet
2010 Jul 24;376(9737):214
h d
Other antioxidants
antioxidant supplementation may not affect risk of preeclampsia or clinical outcomes (level 2 [mid-level]
evidence)
based on Cochrane review with heterogeneity and wide confidence intervals
systematic review and meta-analysis of 10 randomized trials of antioxidants for prevention of
preeclampsia in 6,533 women
5 trials met all quality criteria (allocation concealment, full blinding, < 3% excluded)
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
Reference - Cochrane Database Syst Rev 2008 Jan 23;(1):CD004227 (review updated 2008 Feb 4)
phytonutrient supplement not associated with reduced risk of preeclampsia (level 2 [mid-level] evidence)
based on randomized trial with high loss to follow-up
684 women (mean age 27 years) randomized to phytonutrient supplement (primarily blended fruit and
vegetable juice powder concentrate including vitamins C and E) vs. placebo daily starting at week 12
gestation through delivery
39% completed trial and included in analyses (most dropouts due to withdrawal from trial)
comparing supplement vs. placebo
preeclampsia in 15.9% vs. 16.3% (not significant)
placenta-related obstetrical complications in 8.3% vs. 15.5% (not significant)
respiratory distress syndrome in 5.3% vs. 15.4% in high-risk stratified group (not significant)
Reference - J Perinatol 2013 Aug;33(8):593
insufficient evidence to support vitamin E supplementation in pregnancy

systematic review of 4 randomized or quasi-randomized trials of vitamin E in 566 pregnant women with
or at high risk for preeclampsia
no significant differences in stillbirth, neonatal death, perinatal death, preterm birth, intrauterine growth
restriction, or birth weight
Reference - Cochrane Database Syst Rev 2005 Apr 18;(2):CD004069 (review updated 2010 May 7)
Other dietary and supplement considerations

diet and nutrition counseling may reduce risk of preeclampsia in pregnant women (level 2 [mid-level]
evidence)
systematic review of 18 randomized trials evaluating association between dietary or lifestyle
interventions and risk of preeclampsia in 8,712 pregnant women
interventions included diet and nutrition counseling (6 trials), essential fatty acid supplementation (6
trials), and mixed interventions including diet, physical activity, and lifestyle changes (6 trials)
control interventions included routine antenatal care for dietary and mixed interventions and placebo
for essential fatty acid supplementation
analyses limited by heterogeneity in patient population (baseline body mass index, gestational diabetes
Overview andand
status, Recommendations
preeclampsia risk) /and
Background
interventions (individual components, doses, intensity, patient
compliance, and timing/delivery)
diet and nutrition counseling associated with reduced risk of preeclampsia compared to control
interventions in analysis of 6 studies with 2,695 women
risk ratio 0.67 (95% CI 0.53-0.85)
NNT 20-61 with preeclampsia in 11% of control group
no significant difference in sensitivity analysis excluding 3 trials with women who had gestational
diabetes
no significant difference in risk of preeclampsia with mixed interventions or fatty acid supplementation
Reference - Acta Obstet Gynecol Scand 2014 Oct;93(10):973
vitamin D supplementation at higher than recommended doses may not reduce risk of preeclampsia
compared to lower doses in pregnant women (level 2 [mid-level] evidence)
based on Cochrane review with wide confidence interval
systematic review of 30 randomized trials evaluating different regimens of vitamin D supplementation
alone or in combination with minerals or other vitamins in 7,289 pregnant women
no significant difference in risk of preeclampsia comparing
vitamin D > 600 units/day to ≤ 600 units/day (risk ratio [RR] 0.96, 95% CI 0.65-1.42) in analysis of 5
trials with 1,553 women, not significant, but CI includes possibility of benefit or harm
vitamin D ≥ 4,000 units/day to < 4,000 units/day (RR 0.87, 95% CI 0.62-1.22) in analysis of 4 trials with
1,903 women, not significant, but CI includes possibility of benefit or harm
no or few adverse events were reported and were similar between groups
Reference - Cochrane Database Syst Rev 2019 Oct 3;10:CD013446
daily coenzyme Q10 supplementation may reduce risk of preeclampsia (level 2 [mid-level] evidence)
based on randomized trial without intention to treat analysis
235 pregnant women (mean age 17.5 years) randomized at gestational week 20 to coenzyme Q10 200
mg/day vs. placebo until delivery
83.8% completed follow-up (attended ≥ 2 visits)
65.5% analyzed (patients taking < 80% coenzyme Q10 softgels excluded)
overall rate of preeclampsia 20%
preeclampsia developed in 14.4% with coenzyme Q10 vs. 25.6% with placebo (p = 0.035, NNT 9)
Reference - Int J Gynaecol Obstet 2009 Apr;105(1):43
higher total dietary fiber intake in early pregnancy may reduce risk for preeclampsia (level 2 [mid-level]
evidence)
1,538 pregnant women completed food frequency questionnaire to assess fiber intake during 3 months
prior to pregnancy and during early pregnancy
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)
Reference - Am J Hypertens 2008 Aug;21(8):903
insufficient evidence to recommend garlic for preventing preeclampsia

systematic review of randomized trials of garlic for prevention of preeclampsia and its complications
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
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)
Other medications
treatment of mild gestational diabetes, including the use of insulin to achieve blood glucose goals, during
pregnancy may reduce risk for preeclampsia and serious perinatal complications (level 2 [mid-level]
evidence)
based on randomized trial with baseline differences between groups
1,000 women with singleton or twin pregnancy (1,030 live births) in Australia and United Kingdom with
glucose intolerance at 24-34 weeks gestation were randomized to be informed they had glucose
intolerance of pregnancy (intervention group) vs. informed they did not have gestational diabetes mellitus
(GDM) (control group)
glucose intolerance defined as venous plasma glucose level < 140 mg/dL (7.8 mmol/L) after
overnight fast and 140-198 mg/dL (7.8-11 mmol/L) 2 hours after 75 g oral glucose load (World Health
Organization criteria)
women with 2-hour glucose level > 198 mg/dL (11 mmol/L) were diagnosed with GDM and were not
randomized
women with glucose intolerance of pregnancy and their providers were blinded to true results until
after birth
interventions provided to those informed of glucose intolerance of pregnancy were
individualized dietary advice from a dietitian
instructions on self-monitoring glucose levels 4 times daily until recommended range (fasting 63-
99 mg/dL [3.5-5.5 mmol/L], preprandial < 99 mg/dL [5.5 mmol/L], and 2-hour postprandial < 126
mg/dL [7 mmol/L]) for 2 weeks then daily at rotating times
insulin therapy, with dose adjusted based on glucose levels
control group could have testing for GDM at discretion of attending clinician if indications arose
≥ 20% of control group included women with normal glucose tolerance tests
primary outcome of serious perinatal complications was composite of death, shoulder dystocia, bone
fracture, and nerve palsy
intervention group was slightly older (mean 30.9 years vs. 30.1 years), less likely to be primiparous (43%
vs. 49%), less likely to be white (73% vs. 78%), and more likely to be Asian (19% vs. 14%); analyses
adjusted for these factors
comparing intervention group vs. control
preeclampsia in 11.8% vs. 18.2% (p = 0.0053, NNT 16)
serious perinatal complications in 1% vs. 4% (p = 0.01, NNT 34, 95% CI 20-103)
perinatal deaths 0 vs. 5 (not significant)
shoulder dystocia in 7 cases (1%) vs. 16 cases (3%) (not significant)
bone fracture in 0 vs. 1 (not significant)
nerve palsies in 0 vs. 3 (not significant)
admission to neonatal nursery in 71% vs. 61% (p = 0.01, NNH 10)
induction of labor in 39% vs. 29% (p < 0.001, NNH 10)
macrosomia in 10% vs. 21% (p < 0.001, NNT 9)
no significant difference in rates of jaundice requiring phototherapy (9% vs. 9%) or cesarean delivery
(31% vs. 32%)
Reference - N Engl J Med 2005 Jun 16;352(24):2477, editorial can be found in N Engl J Med 2005 Jun
16;352(24):2544, commentary can be found in CMAJ 2005 Aug 2;173(3):250 full-text, BMJ 2005 Aug
13;331(7513):361 full-text, N Engl J Med 2005 Oct 13;353(15):1629, or in ACP J Club 2005 Nov-
Dec;143(3):65
progesterone does not prevent preeclampsia or perinatal mortality (level 1 [likely reliable] evidence)
systematic review of 4 randomized trials evaluating progesterone in 1,445 women for prevention of
preeclampsia
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
insufficient evidence to recommend use of diuretics for preventing preeclampsia

systematic review of 5 randomized trials comparing thiazide diuretics with placebo or no intervention for
preventing preeclampsia in 1,836 women
allocation concealment not reported in 4 trials; 1 trial with allocation concealment had differential loss to
follow up
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
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)
Reference - Cochrane Database Syst Rev 2010 Jul 7;(7):CD004451
insufficient evidence for use of nitric oxide donors for preventing preeclampsia and its complications
systematic review of 6 randomized trials of nitric oxide donor or precursors in 310 women at risk for
preeclampsia
4 of 6 trials had good quality
4 trials compared nitric oxide donors (glyceryl trinitrate) or precursors (L-arginine) to placebo or no
intervention in 170 women
1 trial (36 women) compared nitric oxide donor to nifedipine
1 trial (76 women) comparing nitric oxide donor to antiplatelet agents
no significant differences in any efficacy analysis but wide confidence intervals make conclusions
unreliable
Reference - Cochrane Database Syst Rev 2007 Apr 18;(2):CD006490 (review updated 2010 Jan 18)
Other considerations
in pregnant women with preexisting diabetes, real time continuous glucose monitoring (CGM) may reduce
Overview
risk of and Recommendations
hypertensive / Background
disorders of pregnancy compared to intermittent self-monitoring blood glucose
(SMBG) (level 2 [mid-level] evidence)
based on Cochrane review of trials with methodologic or procedural limitations
systematic review of 12 randomized or quasi-randomized trials evaluating effect of blood glucose
monitoring techniques on maternal and neonatal outcomes in 944 pregnant women with preexisting type
1 or type 2 diabetes
70% had type 1 diabetes, 12% had type 2 diabetes, and 18% not specified
hypertensive disorders of pregnancy included composite of pregnancy-induced hypertension,
preeclampsia, and eclampsia
4 trials compared CGM to SMBG
all trials had ≥ 1 limitation including
unclear allocation concealment
lack of blinding
baseline differences
low compliance
CGM associated with
reduced hypertensive disorders in analysis of 2 trials with 384 women
risk ratio (RR) 0.58 (95% CI 0.39-0.85)
NNT 6-23 with hypertensive disorders of pregnancy in 29% of intermittent monitoring group
nonsignificant reduction in preeclampsia (RR 0.65, 95% CI 0.39-1.08) in analysis of 4 trials with
609 women
no significant difference in pregnancy induced hypertension (RR 0.67, 95% CI 0.38-1.16) in analysis of
2 trials with 384 women
Reference - Cochrane Database Syst Rev 2019 May 23;5:CD009613
Screening
United States Preventive Services Task Force (USPSTF) recommends screening for preeclampsia in
pregnant women with blood pressure measurements throughout pregnancy (USPSTF Grade B
recommendation) ( JAMA 2017 Apr 25;317(16):1661), editorial can be found in JAMA 2017 Apr
25;317(16):1629
systematic review supporting USPSTF recommendation for screening can be found in JAMA 2017 Apr
25;317(16):1668
Society of Obstetricians and Gynaecologists of Canada (SOGC) screening recommendations(2)
screen all women in early pregnancy for clinical risk markers of preeclampsia (SOGC Grade C, Level II-2)
screening using biomarkers or Doppler ultrasound velocimetry of uteroplacental circulation not routinely
recommended as it has not been shown to improve pregnancy outcomes (SOGC Grade C, Level II-2)
insufficient evidence to support hyperuricemia as predictive of preeclampsia
systematic review of 5 studies evaluating serum uric acid measurement before 25 weeks gestation and
risk of preeclampsia in 572 women
44 women developed preeclampsia
pooling of data not appropriate due to heterogeneity and poor reporting of methodology between studies
incidence of preeclampsia ranged from 3.4% to 40.1%
sensitivity of serum uric acid ranged from 0% to 55.6%, specificity ranged from 76.9% to 94.9%
Reference - Acta Obstet Gynecol Scand 2006;85(5):519
algorithm may detect women in first trimester at risk for pregnancy-associated hypertension
population-based cohort of 7,797 women with singleton pregnancies
34 developed early preeclampsia (preeclampsia requiring delivery before 34 weeks)
123 developed late preeclampsia (with delivery ≥ 34 weeks)
algorithm based on maternal variables including mean arterial pressure, uterine artery pulsatility index,
pregnancy-associated plasma protein-A, and placental growth factor
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
Reference - Hypertension 2009 May;53(5):812, editorial can be found in Hypertension 2009

May;53(5):747
ratios of maternal plasma levels of angiogenic or antiangiogenic factors at 30-34 weeks gestation appear
to have limited utility for prediction of preeclampsia (level 2 [mid-level] evidence)
based on prognostic cohort study without validation
1,269 women with singleton pregnancies were assessed at 30-34 weeks gestation for plasma
concentrations of placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1
(sVEGFR-1), and soluble endoglin (sEng)
all women delivered at > 34 weeks gestation
3.2% developed preeclampsia, including 1.8% with severe preeclampsia
for detection of preeclampsia, multiple of median (MoM) < 0.3 was identified as optimal cutoff for ratios
of plasma levels of PIGF to sVEGFR-1 and PIGF to sEng in receiver operator characteristic analysis
prognostic performance of PIGF to sVEGFR-1 ratio for detection of preeclampsia was
sensitivity 58%
specificity 83%
consistent performance of PIGF to sVEGFR-1 ratio for prediction of severe preeclampsia

consistent results for prognostic performance of PIGF to sEng ratio for detection of preeclampsia or
severe preeclampsia
Reference - Am J Obstet Gynecol 2013 Apr;208(4):287.e1-287.e15
DynaMed commentary -- The comparison of pretest probability and positive and negative predictive
values demonstrates limited utility of test for either a positive or negative result.
urinalysis
National Academy of Clinical Biochemistry (NACB) laboratory medicine practice guideline recommends
against routinely screening for hypertension or preeclampsia with urine dipstick testing at point of care
(NACB 2006)
routine urinalysis during pregnancy (in absence of hypertension) does not appear useful for predicting
preeclampsia (level 2 [mid-level] evidence)
based on prognostic cohort study without adjustments for possible cofounders
1,000 pregnant women had urine sample collected at first antenatal visit
913 women completed study
35 women 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
abnormal flow velocity on first-trimester uterine artery Doppler ultrasound appears to have high
specificity but low sensitivity for preeclampsia and fetal growth restriction in low-risk women (level 2
based on systematic review of diagnostic studies with unclear reference standards
systematic review of 18 diagnostic studies evaluating first-trimester uterine artery Doppler ultrasound
for prediction of maternal and fetal complications in 55,974 pregnant women
uterine artery Doppler ultrasound performed between 11 and 14 weeks gestation in all studies
reference standards in all studies were classified as appropriate by authors, but were not described
(standards for growth restriction reported to vary across studies)
pooled diagnostic performance of abnormal flow velocity on uterine artery Doppler ultrasound
for early-onset preeclampsia in analysis of 7 studies with 38,611 low-risk women
sensitivity 47.8% (95% CI 39%-56.8%)
specificity 92.1% (95% CI 88.6%-94.6%)
for late-onset preeclampsia in analysis of 3 studies with 33,879 low-risk women

sensitivity 21.5% (95% CI 18%-25.4%)
specificity 90.3% (95% CI 89.8%-90.8%)
for early-onset fetal growth restriction in analysis of 4 studies with 26,276 low-risk women
sensitivity 39.2% (95% CI 26.3%-53.8%)
specificity 93.1% (95% CI 90.6%-95%)
for fetal growth restriction at any gestational age in analysis of 6 studies with 30,454 low-risk
women
sensitivity 15.4% (95% CI 12.4%-18.9%)
specificity 93.3% (95% CI 90.9%-95.1%)
Reference - Ultrasound Obstet Gynecol 2014 May;43(5):500 full-text
see Prenatal Ultrasound Screening for details
Quality Improvement
Choosing Wisely
American College of Obstetricians and Gynecologists recommend against routinely recommending activity
restriction or bed rest during pregnancy for any indication (Choosing Wisely 2016 Aug 24)
Choosing Wisely Australia

Society of Obstetric Medicine of Australia and New Zealand recommends against repeat testing for
proteinuria in established preeclampsia. (Choosing Wisely Australia 2017 Sep 25)
Guidelines and Resources

Guidelines
International guidelines
World Health Organization recommendations on
drug
Overview treatment
and for severe hypertension
Recommendations in pregnancy can be found at WHO 2018
/ Background
prevention and treatment of preeclampsia and eclampsia can be found at WHO 2011 PDF
International Society for the Study of Hypertension in Pregnancy (ISSHP) guideline on classification,
diagnosis, and management of hypertensive disorders of pregnancy can be found in Pregnancy Hypertens
2018 Jul;13:291
United States guidelines

American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines on
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 full-text, commentary can be found in Chest 2012 Aug;142(2):545
American College of Obstetricians and Gynecologists (ACOG)

ACOG Practice Bulletin 202 on gestational hypertension and preeclampsia can be found in Obstet
Gynecol. 2019 Jan;133(1):e1
ACOG Practice Bulletin 203 on chronic hypertension in pregnancy can be found in Obstet Gynecol. 2019
Jan;133(1):e26-e50
ACOG Practice Bulletin 207 on thrombocytopenia in pregnancy can be found in Obstet Gynecol 2019
Mar;133(3):e181
ACOG Committee Opinion 767 on emergent therapy for acute-onset, severe hypertension during
pregnancy and postpartum period can be found in Obstet Gynecol 2019 Feb;133(2):e174
ACOG Practice Bulletin 170 on critical care in pregnancy can be found in Obstet Gynecol 2019
May;133(5):e303
National Partnership for Maternal Safety consensus bundle on severe hypertension during pregnancy and
postpartum period can be found in J Midwifery Womens Health 2017 Jul;62(4):493
Society of Maternal-Fetal Medicine (SMFM) statement on benefit of antihypertensive therapy for mild-to-
moderate chronic hypertension during pregnancy can be found in Am J Obstet Gynecol 2015 Jul;213(1):3
United States Preventive Services Task Force (USPSTF) recommendations on
screening for preeclampsia can be found at USPSTF 2017 Apr or in JAMA 2017 Apr 25;317(16):1629
evidence report and systematic review supporting USPSTF recommendation on screening for
preeclampsia can be found in JAMA 2017 Apr 25;317(16):1668
aspirin to prevent preeclampsia-related complications and death can be found at USPSTF 2014 Sep or in
Ann Intern Med 2014 Dec 2;161(11):819, commentary can be found in Nat Rev Nephrol 2014
Nov;10(11):613
American College of Cardiology/American Heart Association/American Academy of Physician
Assistants/Association of Black Cardiologists/American College of Preventive Medicine/American
Geriatrics Society/American Pharmacists Association/American Society of Hypertension/American Society
for Preventive Cardiology/National Medical Association/Preventive Cardiovascular Nurses Association
(ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA) guideline on prevention, detection,
evaluation, and management of high blood pressure in adults can be found in Hypertension 2018
Jun;71(6):e13
Eighth Joint National Committee (JNC 8) 2014 evidence-based guideline on management of high blood
pressure in adults can be found in JAMA 2014 Feb 5;311(5):507, correction can be found in JAMA 2014 May
7;311(17):1809, editorial can be found in JAMA 2014 Feb 5;311(5):472, commentary can be found in
Hypertension 2016 May;67(5):1053
comparison of JNC 8 to JNC 7 guidelines can be found in JAMA 2014 Apr 9;311(14):1424, correction can be
found in JAMA 2014 Aug 27;312(8):848, commentary can be found in JAMA 2014 Aug 27;312(8):846
United Kingdom guidelines

National Institute for Health and Care Excellence (NICE) guideline on diagnosis and management of
hypertensive / Background
disorders during pregnancy can be found at NICE 2019 Mar:NG133 PDF, summary can be
found in BMJ 2010 Aug 25;341:c2207
National Institute for Health and Care Excellence (NICE) guideline on cesarean section can be found at NICE
2011 Nov:CG132 PDF, summary can be found in BMJ 2011 Nov 23;343:d7108
Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 56 on maternal collapse
in pregnancy and puerperium can be found at RCOG 2011 Jan PDF
Action on Preeclampsia (APEC) preeclampsia community guidelines (PRECOG) on

screening of preeclampsia in community (PRECOG1) can be found at APEC 2004 PDF or in BMJ 2005
Mar 12;330(7491):576 full-text, editorial can be found in BMJ 2005 Mar 12;330(7491):549
assessing onset of preeclampsia in hospital day unit (PRECOG2) can be found at APEC 2009 PDF,
summary can be found in BMJ 2009 Sep 9;339:b3129
Canadian guidelines
Hypertension Canada guideline on management of hypertension in pregnancy can be found in Can J Cardiol
2018 May;34(5):526
Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical practice guideline on diagnosis,
evaluation, and management of hypertensive disorders of pregnancy: executive summary can be found in J
Obstet Gynaecol Can 2014 May;36(5):416
European guidelines
European Society of Cardiology (ESC) guidelines for management of cardiovascular diseases during
pregnancy can be found in Eur Heart J 2018 Sep 7;39(34):3165
French Society of Hypertension (Société Française d'Hypertension Artérielle [SFHTA]) consensus statement
on hypertension and pregnancy can be found in Presse Med 2016 Jul-Aug;45(7-8 Pt 1):682 [French]
Norwegian Society of Obstetrics and Gynecology (Norsk Gynekologisk Forening [NGF]) guideline on
hypertensive disorders of pregnancy and eclampsia can be found in Eur J Obstet Gynecol Reprod Biol 2016
Jun;201:171
French Society of Anesthesia and Intensive Care/French National College of Gynecology and
Obstetrics/French Society of Perinatal Medicine/French Society of Neonatology (Société Française
d'Anesthésie et de Réanimation/Collège National des Gynécologues et Obstétriciens Français/Société
Française de Médecine Périnatale/Société Française de Néonatalogie [SFAR/CNGOF/SFMP/SFNN])
guideline on multidisciplinary management of severe preeclampsia (PE) can be found in Ann Fr Anesth
Reanim 2009 Mar;28(3):275
Russian Federation of Anaesthesiologists and Reanimatologists (FAR) guideline on emergency care for
eclampsia and its complications can be found in Anesteziol Reanimatol 2013 Sep-Oct;(5):75 [Russian]
Italian Society of Hypertension (Societa Italiana dell'Ipertensione Arteriosa [SIIA]) recommendations on
clinical management of hypertension in pregnancy can be found in High Blood Press Cardiovasc Prev 2013
Sep;20(3):123, correction can be found in High Blood Press Cardiovasc Prev 2013 Sep;20(3):249
Italian expert guideline on sFlt-1/PlGF ratio and preeclampsia can be found in Eur J Obstet Gynecol Reprod
Biol 2016 Nov;206:70 PDF
Mexican 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]
National Health System of Mexico clinical practice guideline on detection, diagnosis and treatment of
hypertensive diseases of pregnancy can be found atSecretaría de Salud-México 2017 PDF [Spanish]
Central and South American guidelines

Brazilian
Overview expert
and guideline on arterial
Recommendations hypertension in pregnancy can be found in Arq Bras Cardiol 2016
/ Background
Sep;107(3 Suppl 3):49 full-text [English, Portuguese]
Australian and New Zealand guidelines

Queensland Maternity and Neonatal Clinical Guidelines Program guideline on hypertensive disorders of
pregnancy can be found at Queensland Health 2016 Aug PDF
Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) guideline on management of
hypertensive disorders of pregnancy can be found at SOMANZ 2014 PDF, updated 2015 June or in Aust N Z
J Obstet Gynaecol 2015 Oct;55(5):e1 or Aust N Z J Obstet Gynaecol 2015 Feb;55(1):11
New South Wales (NSW) Ministry of Health policy on management of hypertensive disorders of pregnancy
can be found at NSW 2011 Oct 12 PDF
Review articles
review can be found in Am Fam Physician 2016 Jan 15;93(2):121 full-text
reviews of preeclampsia
review of preeclampsia can be found in Rev Bras Ginecol Obstet 2017 Sep;39(9):496 full-text
review of preeclampsia can be found in Lancet 2016 Mar 5;387(10022):999
review of preeclampsia can be found in Acta Anaesthesiol Belg 2014;65(4):137
review of preeclampsia can be found in Lancet 2010 Aug 21;376(9741):631
reviews on management of preeclampsia can be found in
Curr Pharm Biotechnol 2018;19(10):786
Anesthesiol Clin 2017 Mar;35(1):95
review of pathophysiology and clinical implications of pre-eclampsia can be found in BMJ 2019 Jul
15;366:l2381
review of prediction, prevention, and management of preeclampsia can be found in Nat Rev Nephrol 2014
Sep;10(9):531
review of pathophysiology, diagnosis, and management of preeclampsia can be found in Vasc Health
Risk Manag 2011;7:467 full-text
review on the pathophysiology of hypertension in preeclampsia can be found in Microvasc Res 2017
Jan;109:34
review of pathophysiology of preeclampsia can be found in Nat Rev Nephrol 2014 Aug;10(8):466
review of eclampsia can be found in Obstet Gynecol 2005 Feb;105(2):402
review of hypertensive disorders of pregnancy can be found in Ann Transl Med 2017 Jun;5(12):266 full-text
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 on recognition, prevention, and management of hypertension in pregnancy can be found in Obstet
Gynecol Clin North Am 2017 Jun;44(2):219
reviews of postpartum management of hypertension can be found in
BMJ Open 2017 Nov 28;7(11):e018696 full-text
BMJ 2013 Feb 25;346:f894
review of interpreting abnormal proteinuria in pregnancy can be found in Obstet Gynecol 2010 Feb;115(2 Pt
1):365
review of liver disease in pregnancy can be found in Lancet 2010 Feb 13;375(9714):594
review of therapeutic bed rest in pregnancy can be found in Obstet Gynecol 2013 Jun;121(6):1305, editorial
can be found in Obstet Gynecol 2013 Jun;121(6):1158
Agency for Healthcare Research and Quality (AHRQ) evidence report of vitamin D and calcium can be found
at AHRQ Evidence Report 2014 Sep:217 PDF
case presentation of preeclampsia can be found in BMJ 2012 Jul 19;345:e4437
case report of false-positive amphetamine toxicology screen results in three pregnant women using labetalol
Overview
can be and Recommendations
found / Background
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 from Association of Ontario Midwives PDF or in Spanish PDF, French PDF, Chinese PDF, Arabic PDF,
Farsi PDF
handout on preeclampsia and high blood pressure during pregnancy from American College of Obstetricians
and Gynecologists PDF
handout on high blood pressure during pregnancy from Centers for Disease Control and Prevention
handout on preeclampsia from American Heart Association PDF
handout on pregnancy-induced hypertension from American Academy of Family Physicians or in Spanish
handout on preeclampsia from Royal College of Obstetricians and Gynaecologists PDF
handout on preeclampsia and related disorders from Preeclampsia Foundation or in Spanish
ICD Codes
ICD-10 codes
O10 preexisting hypertension complicating pregnancy, childbirth and the puerperium
O10.0 preexisting essential hypertension complicating pregnancy, childbirth and the puerperium
O10.1 preexisting hypertensive heart disease complicating pregnancy, childbirth and the puerperium
O10.2 preexisting hypertensive renal disease complicating pregnancy, childbirth and the puerperium
O10.3 preexisting hypertensive heart and renal disease complicating pregnancy, childbirth and the
puerperium
O10.4 preexisting secondary hypertension complicating pregnancy, childbirth and the puerperium
O10.9 unspecified preexisting hypertension complicating pregnancy, childbirth and the puerperium
O11 preexisting hypertensive disorder with superimposed proteinuria
O12 gestational [pregnancy-induced] oedema and proteinuria without hypertension
O12.0 gestational oedema
O12.1 gestational proteinuria
O12.2 gestational oedema with proteinuria
O13 gestational [pregnancy-induced] hypertension without significant proteinuria
O14 gestational [pregnancy-induced] hypertension with significant proteinuria
O14.0 moderate preeclampsia
O14.1 severe preeclampsia
O14.9 preeclampsia, unspecified
ICD-10-CA modification in Canada: O14 code range revised as follows
O14.001 delivered, with or without mention of antepartum condition
O14.002 delivered, with mention of postpartum complication
O14.003 antepartum condition or complication
O14.004 postpartum condition or complication
O14.009 unspecified as to episode of care, or not applicable
O15 eclampsia
O15.0 eclampsia in pregnancy
O15.1 eclampsia in labour
O15.2 eclampsia in the puerperium
O15.9 eclampsia, unspecified as to time period
O16 unspecified maternal hypertension
P00.0 fetus and newborn affected by maternal hypertensive disorders
References
General references used
1. Leeman L, Fontaine P. Hypertensive disorders of pregnancy. Am Fam Physician 2016 Jan 15;93(2):121 full-
text
2. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P; Canadian Hypertensive Disorders of Pregnancy
Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy:
executive summary. J Obstet Gynaecol Can. 2014 May;36(5):416-41
3. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al; ESC Scientific Document Group. 2018 ESC
Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018 Sep
7;39(34):3165-3241
4. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 202: Gestational
Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):e1-e25
5. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 203: Chronic
Hypertension in Pregnancy. Obstet Gynecol. 2019 Jan;133(1):e26-e50
6. Brown MA, Magee LA, Kenny LC, et al; International Society for the Study of Hypertension in Pregnancy
(ISSHP). The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management
recommendations for international practice. Pregnancy Hypertens. 2018 Jul;13:291-310
Recommendation grading systems used

World Health Organization (WHO) recommendation grading system
strength of recommendations
Strong - confident that desirable effects of adherence to recommendation outweigh undesirable
effects
Conditional - less certain about balance between benefits and harms or disadvantages of
implementing a recommendation
certainty of evidence
High - very confident that true effect lies close to that of estimate of effect
Moderate - true effect is likely to be close to estimate of effect, but possibility that it is substantially
different
Low - true effect may be substantially different from estimate of effect
Very low - true effect likely to be substantially different from estimate of effect
Reference - WHO recommendations on drug treatment for severe hypertension in pregnancy (WHO 2018)
American College of Obstetricians and Gynecologists (ACOG) levels of recommendations
Level A - based on good and consistent scientific evidence
Level B - based on limited or inconsistent scientific evidence
Level C - based primarily on consensus and expert opinion
References
Overview ACOG Practice Bulletin 202/on
and Recommendations gestational hypertension and preeclampsia (Obstet Gynecol 2019
Background
Jan;133(1):e1)
ACOG Practice Bulletin 203 on chronic hypertension in pregnancy (Obstet Gynecol 2019
Jan;133(1):e26)
Society of Obstetricians and Gynaecologists of Canada (SOGC) grades of recommendation

classifications of recommendations
Grade A - good evidence to recommend clinical preventive action
Grade B - fair evidence to recommend clinical preventive action
Grade 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
Grade D - fair evidence to recommend against clinical preventive action
Grade E - good evidence to recommend against clinical preventive action
Grade L - insufficient evidence (in quantity or quality) to make recommendation; however, other
factors may influence decision-making
levels of evidence
Level I - evidence obtained from ≥ 1 properly randomized controlled trial
Level II-1 - evidence from well-designed controlled trials without randomization
Level II-2 - evidence from well-designed cohort (prospective or retrospective) or case-control studies,
preferably from more than 1 center or research group
Level 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
Level III - opinions of respected authorities, based on clinical experience, descriptive studies, or
reports of expert committees
Reference - SOGC guideline on diagnosis, evaluation, and management of the hypertensive disorders of
pregnancy (J Obstet Gynaecol Can 2014 May;36(5):416)
American College of Chest Physicians (ACCP) grades

Grade 1 - strong recommendation based on clear risk/benefit balance
Grade 2 - weak recommendation based on unclear or close risk/benefit balance
Grade A - high-quality evidence based on consistent evidence from randomized trials without important
limitations or exceptionally strong evidence from observational studies
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
Grade C - low- or very low-quality evidence based on evidence for ≥ 1 critical outcome from observational
studies, case series, or randomized trials with serious flaws or indirect evidence
Reference - ACCP evidence-based clinical practice guideline on methodology for development of
antithrombotic therapy and prevention of thrombosis (Chest 2012 Feb;141(2 Suppl):53S full-text),
commentary can be found in Chest 2013 Apr;143(4):1190
United States Preventive Services Task Force (USPSTF) grades of recommendation

Grade A - USPSTF recommends the service with high certainty of substantial net benefit
Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate
certainty of moderate-to-substantial net benefit
Grade C - USPSTF recommends selectively offering or providing the service (based on professional
judgment and patient preference) with at least moderate certainty of small net benefit
Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no net
Overview andorRecommendations
benefit / Background
harms outweighing benefits
Grade I - insufficient evidence to assess balance of benefits and harms
Reference - USPSTF recommendation statement on screening for preeclampsia (JAMA 2017 Apr
25;317(16):1661), editorial can be found in JAMA 2017 Apr 25;317(16):1629
European Society of Cardiology (ESC) grading system for recommendations

classes of recommendations
Class I - evidence and/or general agreement that given treatment or procedure is beneficial, useful,
and effective
Class II - conflicting evidence and/or divergence of opinion about usefulness/efficacy of given
treatment or procedure
Class IIa - weight of evidence/opinion in favor of usefulness/efficacy
Class IIb - usefulness/efficacy less well established by evidence/opinion
Class III - evidence or general agreement that given treatment or procedure is not useful/effective,
and in some cases may be harmful
levels of evidence
Level A - data derived from multiple randomized clinical trials or meta-analyses
Level B - data derived from single randomized clinical trial or large nonrandomized studies
Level C - consensus of opinion of experts and/or small studies, retrospective studies, registries
Reference - ESC guidelines on management of cardiovascular diseases during pregnancy (Eur Heart J.
2018 Sep 7;39(34):3165)
Hypertension Canada grades of recommendations

Grade A - recommendations based on randomized trials (or systematic reviews of trials) with high levels
of internal validity and statistical precision for which study results can be directly applied to patients
because of similar clinical characteristics and clinical relevance of study outcomes
Grade B - recommendations based on randomized trials, systematic reviews, or prespecified subgroup
analyses of randomized trials that have lower precision, or if there is a need to extrapolate from studies
because of differing populations or reporting of validated intermediate/surrogate outcomes rather than
clinically important outcomes
Grade C - recommendations based on trials with lower levels of internal validity and/or precision, or trials
reporting unvalidated surrogate outcomes, or results from nonrandomized observational studies
Grade D - recommendations based on expert opinion alone
Reference - Hypertension Canada guideline on management of hypertension in pregnancy (Can J Cardiol
2018 May;34(5):526)
Synthesized Recommendation Grading System for DynaMed
DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid
relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided with the
recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see
where guidelines agree and where guidelines differ from each other and from the current evidence.
In DynaMed (DM), we synthesize the current evidence, current guidelines from leading authorities, and
clinical expertise to provide recommendations to support clinical decision-making in the Overview &
Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify
synthesized recommendations as Strong or Weak.
Strong
Overview andrecommendations
Recommendationsare used when, based on the available evidence, clinicians (without conflicts of
/ Background
interest) consistently have a high degree of confidence that the desirable consequences (health benefits,
decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
Weak recommendations are used when, based on the available evidence, clinicians believe that desirable
and undesirable consequences are finely balanced, or appreciable uncertainty exists about the
magnitude of expected consequences (benefits and harms). Weak recommendations are used when
clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their
judgments. Weak recommendations are also used when the range of patient values and preferences
suggests that informed patients are likely to make different choices.
DynaMed (DM) synthesized recommendations (in the Overview & Recommendations section) are determined
with a systematic methodology:
Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise and
≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and the
recommendations from guidelines.
Recommendations are phrased to match the strength of recommendation. Strong recommendations use
"should do" phrasing, or phrasing implying an expectation to perform the recommended action for most
patients. Weak recommendations use "consider" or "suggested" phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a
qualified group has explicitly deliberated on making such a recommendation. Group deliberation may
occur during guideline development. When group deliberation occurs through DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention, Comparison, Outcome)
framework for all outcomes of interest specific to the recommendation to be developed.
Systematic searches will be conducted for any clinical questions where systematic searches were not
already completed through DynaMed content development.
Evidence will be summarized for recommendation panel review including for each outcome, the
relative importance of the outcome, the estimated effects comparing intervention and comparison,
the sample size, and the overall quality rating for the body of evidence.
Recommendation panel members will be selected to include at least 3 members that together have
sufficient clinical expertise for the subject(s) pertinent to the recommendation, methodological
expertise for the evidence being considered, and experience with guideline development.
All recommendation panel members must disclose any potential conflicts of interest (professional,
intellectual, and financial), and will not be included for the specific panel if a significant conflict exists
for the recommendation in question.
Panel members will make Strong recommendations if and only if there is consistent agreement in a
high confidence in the likelihood that desirable consequences outweigh undesirable consequences
across the majority of expected patient values and preferences. Panel members will make Weak
recommendations if there is limited confidence (or inconsistent assessment or dissenting opinions)
that desirable consequences outweigh undesirable consequences across the majority of expected
patient values and preferences. No recommendation will be made if there is insufficient confidence to
make a recommendation.
All steps in this process (including evidence summaries which were shared with the panel, and
identification of panel members) will be transparent and accessible in support of the
recommendation.
Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in

recommendation drafting or development, with explicit confirmation that Strong recommendations are
adequately supported.
Recommendations are published only after consensus is established with agreement in phrasing and
strength of recommendation by all editors.
If consensus cannot be reached then the recommendation can be published with a notation of
"dissenting commentary" and the dissenting commentary is included in the topic details.
If recommendations are questioned during peer review or post publication by a qualified individual, or
reevaluation is warranted based on new information detected through systematic literature surveillance,
the recommendation is subject to additional internal review.
DynaMed
Overview andEditorial Process/ Background
Recommendations
DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
All editorial team members and reviewers have declared that they have no financial or other competing
interests related to this topic, unless otherwise indicated.
DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster
University and F1000.
Special acknowledgements
Elliot M. Levine, MD, FACOG (Assistant Professor, Department of Obstetrics and Gynecology, Rush University
Medical Center; Site Director of Informatics and Director of Informatics and Research, Department of
Obstetrics and Gynecology, Advocate Illinois Masonic Medical Center)
Dr. Levine declares no relevant financial conflicts of interest.
Amir Qaseem, MD, PhD, MHA, FACP (Vice President of Clinical Policy, American College of Physicians;
Pennsylvania, United States; President Emeritus, Guidelines International Network (GIN); Germany)
Dr. Qaseem declares no relevant financial conflicts of interest.
Alan Ehrlich, MD, FAAFP (Executive Editor; Associate Professor of Family Medicine, University of
Massachusetts Medical School; Massachusetts, United States)
Dr. Ehrlich declares no relevant financial conflicts of interest.
DynaMed topics are written and edited through the collaborative efforts of the above individuals. Deputy
Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice.
Recommendations Editors are actively involved in development and/or evaluation of guidelines.
Editorial Team role definitions
Topic Editors define the scope and focus of each topic by formulating a set of clinical
questions and suggesting important guidelines, clinical trials, and other data to be
addressed within each topic. Topic Editors also serve as consultants for the internal
DynaMed Editorial Team during the writing and editing process, and review the final
topic drafts prior to publication.
Section Editors have similar responsibilities to Topic Editors but have a broader role
that includes the review of multiple topics, oversight of Topic Editors, and systematic
surveillance of the medical literature.
Recommendations Editors provide explicit review of DynaMed Overview and

Recommendations sections to ensure that all recommendations are sound,
supported, and evidence-based. This process is described in "Synthesized
Recommendation Grading."
Deputy Editors are employees of DynaMed and oversee DynaMed internal publishing
groups. Each is responsible for all content published within that group, including
supervising topic development at all stages of the writing and editing process, final
review of all topics prior to publication, and direction of an internal team.
How to cite
National
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Recommendations or "Vancouver
/ Background style" (International
Committee of Medical Journal Editors):
DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T116522, Hypertensive
Disorders of Pregnancy; [updated 2018 Dec 01, cited place cited date here]. Available from
https://www.dynamed.com/topics/dmp~AN~T116522. Registration and login required.

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Hypertensive Disorders of Pregnancy

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Overview and Recommendations / Background

[+]Updated 2019 Nov 07 01:12 PM (ET)

Hypertension is the most common medical condition complicating

Topic Editor Elliot M. Levine, MD, FACOG

Recommendations Editor Amir Qaseem, MD, PhD, MHA, FACP

Deputy Editor Alan Ehrlich, MD

Overview and Recommendations

Preeclampsia with severe features is characterized by severe hypertension or non-severe hypertension in

In women with gestational hypertension or preeclampsia:

urinalysis for measurement of proteinuria (Strong recommendation)

Give corticosteroids to women receiving expectant management at ≤ 34 weeks gestation to beneﬁt

uteroplacental dysfunction, possibly indicated by any of the following

hypertension known before pregnancy or present < 20 weeks gestation, including

American College of Obstetricians and Gynecologists (ACOG) recommendations for classiﬁcation of

preeclampsia superimposed on chronic hypertension, deﬁned as preeclampsia with history of

Society of Obstetricians and Gynaecologists of Canada (SOGC) recommendations for classiﬁcation of

fetoplacental indications, such as

severe complications of preeclampsia that warrant delivery include

maternal cardiorespiratory involvement, such as

maternal hepatic complications, such as

fetoplacental complications, such as

Reference - Obstet Gynecol 2009 Jun;113(6):1299

Reference - Med J Aust 2005 Apr 4;182(7):332 full-text

chronic hypertension reported in 0.9%-1.5% of pregnant women(5)

mean incidence of preeclampsia about 3.6%

severe preeclampsia expected to occur in about 0.39% of deliveries in United Kingdom

additional possible risk factors based on individual studies

Reference - BMJ 2011 Apr 7;342:d1875 full-text

nonspeciﬁc risk factors for severe complications of preeclampsia include(2)

Reference - BMJ 2016 Apr 19;353:i1753 full-text

Medical risk factors

at 34 weeks gestation with

Reference - Reprod Biol Endocrinol 2013 Jun 26;11:56 full-text

medical conditions in pregnancy

Reference - PLoS One 2013;8(8):e71387 full-text

migraine headaches associated with increased risk of hypertensive disorders in pregnancy

rheumatologic disorders associated with increased risk of preeclampsia

vitamin D insufﬁciency during pregnancy associated with increased risk of preeclampsia

no signiﬁcant differences with use of SSRIs

Obstetric risk factors

short duration of sexual relationship with current partner(2)

antepartum risk factors

Reference - Obstet Gynecol 2014 Oct;124(4):763

excessive maternal weight gain in pregnancy

vaginal bleeding in early pregnancy(2)

chronic hypertension associated with increased risk of preeclampsia

Family history risk factors

Reference - Obstet Gynecol 2014 Aug;124(2 Pt 1):265

other maternal serum angiogenesis-related biomarkers associated with preeclampsia in case-control

New-onset postpartum preeclampsia

Reference - Am J Obstet Gynecol 2014 Apr;210(4):338.e1

Possible risk factors

see Thrombophilia in Pregnancy for details

Factors not associated with increased risk

inhaled corticosteroids do not appear to be associated with increased risk of pregnancy-induced

Etiology and Pathogenesis

cardiovascular maladaptation and vasoconstriction(1)

endothelial dysfunction implicated in case-control study (JAMA 2001 Mar 28;285(12):1607)

History and Physical

History of present illness (HPI)

eclampsia may be preceded by premonitory symptoms, such as(1, 4)

Past medical history (PMH)

Family history (FH)