Gestational Hypertension and Preeclampsia ACOG.46

INTERIM UPDATE
ACOG PRACTICE BULLETIN

Downloaded from http://journals.lww.com/greenjournal by YI4yXheCXs6ZA0UDgFSYdifZcIEnNexHdKEsNsUAdQ7jCILFn/VrrY6f6iq4pIWbTr1qVwzYlJ6QNxFxXPHu7d5G2eGRL6VVJ63Ki4Aj2Mu0X1EDWaNuHZfJfhcFDtB+HE3wIRZ0xb1AqBVoMsKfDyweg7ewnLo+hD/oF++4Yq9G/V+n9GMd1w== on 07/22/2021
Clinical Management Guidelines for Obstetrician–Gynecologists

NUMBER 222 (Replaces Practice Bulletin No. 202, December 2018)
Committee on Practice Bulletins—Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and
Gynecologists’ Committee on Practice Bulletins—Obstetrics in collaboration with Jimmy Espinoza, MD, MSc; Alex Vidaeff, MD,
MPH; Christian M. Pettker, MD; and Hyagriv Simhan, MD.
INTERIM UPDATE: The content of this Practice Bulletin has been updated as highlighted (or removed as necessary) to
include limited, focused editorial corrections to platelet counts, diagnostic criteria for preeclampsia (Box 2), and pre-
eclampsia with severe features (Box 3).
Gestational Hypertension and

Preeclampsia
Hypertensive disorders of pregnancy constitute one of the leading causes of maternal and perinatal mortality
worldwide. It has been estimated that preeclampsia complicates 2–8% of pregnancies globally (1). In Latin
America and the Caribbean, hypertensive disorders are responsible for almost 26% of maternal deaths,
whereas in Africa and Asia they contribute to 9% of deaths. Although maternal mortality is much lower in
high-income countries than in developing countries, 16% of maternal deaths can be attributed to hypertensive
disorders (1, 2). In the United States, the rate of preeclampsia increased by 25% between 1987 and 2004 (3).
Moreover, in comparison with women giving birth in 1980, those giving birth in 2003 were at 6.7-fold increased
risk of severe preeclampsia (4). This complication is costly: one study reported that in 2012 in the United States,
the estimated cost of preeclampsia within the first 12 months of delivery was $2.18 billion ($1.03 billion for
women and $1.15 billion for infants), which was disproportionately borne by premature births (5). This
Practice Bulletin will provide guidelines for the diagnosis and management of gestational hypertension and
preeclampsia.
Background Definitions and Diagnostic Criteria for

Hypertensive Disorders of Pregnancy
Risk Factors Preeclampsia (With and Without
A variety of risk factors have been associated with Severe Features)
increased probability of preeclampsia (Box 1) (6–
12). Nonetheless, it is important to remember that Preeclampsia is a disorder of pregnancy associated with
most cases of preeclampsia occur in healthy nullipa- new-onset hypertension, which occurs most often after 20
rous women with no obvious risk factors. Although weeks of gestation and frequently near term. Although
the precise role of genetic–environmental inter- often accompanied by new-onset proteinuria, hypertension
actions on the risk and incidence of preeclampsia is and other signs or symptoms of preeclampsia may present
unclear, emerging data suggest the tendency to in some women in the absence of proteinuria (17). Reli-
develop preeclampsia may have some genetic com- ance on maternal symptoms may be occasionally problem-
ponent (13–16). atic in clinical practice. Right upper quadrant or epigastric
VOL. 135, NO. 6, JUNE 2020 OBSTETRICS & GYNECOLOGY e237
© 2020 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
sponsive to acetaminophen and not accounted for by
Box 1. Risk Factors for Preeclampsia alternative diagnoses or visual disturbances (Box 2). Ges-
tational hypertension is defined as a systolic blood pres-
Nulliparity sure of 140 mm Hg or more or a diastolic blood pressure
Multifetal gestations of 90 mm Hg or more, or both, on two occasions at least
Preeclampsia in a previous pregnancy 4 hours apart after 20 weeks of gestation in a woman
Chronic hypertension with a previously normal blood pressure (21). Women
Pregestational diabetes with gestational hypertension with severe range blood
Gestational diabetes pressures (a systolic blood pressure of 160 mm Hg or
Thrombophilia
higher, or diastolic blood pressure of 110 mm Hg or
higher) should be diagnosed with preeclampsia with
Systemic lupus erythematosus
severe features. These severe ranges of blood pressure
Prepregnancy body mass index greater than 30
or any of the severe features listed in Box 3 increase
Antiphospholipid antibody syndrome the risk of morbidity and mortality (22).
Maternal age 35 years or older
Kidney disease
Assisted reproductive technology
Obstructive sleep apnea Box 2. Diagnostic Criteria for
Preeclampsia
Blood pressure
pain is thought to be due to periportal and focal parenchy- c Systolic blood pressure of 140 mm Hg or more or
mal necrosis, hepatic cell edema, or Glisson’s capsule diastolic blood pressure of 90 mm Hg or more on
two occasions at least 4 hours apart after 20
distension, or a combination. However, there is not always weeks of gestation in a woman with a previously
a good correlation between the hepatic histopathology and normal blood pressure
laboratory abnormalities (18). Similarly, studies have
c Systolic blood pressure of 160 mm Hg or more or
found that using headache as a diagnostic criterion for diastolic blood pressure of 110 mm Hg or more.
preeclampsia with severe features is unreliable and non- (Severe hypertension can be confirmed within
specific. Thus, an astute and circumspect diagnostic a short interval (minutes) to facilitate timely
approach is required when other corroborating signs and antihypertensive therapy).
symptoms indicative of severe preeclampsia are missing and
(19, 20). Of note, in the setting of a clinical presentation
similar to preeclampsia, but at gestational ages earlier than Proteinuria
20 weeks, alternative diagnoses should to be considered,
c 300 mg or more per 24 hour urine collection (or
including but not limited to thrombotic thrombocytopenic this amount extrapolated from a timed collection)
purpura, hemolytic–uremic syndrome, molar pregnancy, or
renal disease or autoimmune disease. c Protein/creatinine ratio of 0.3 mg/dL or more or
Although hypertension and proteinuria are consid- c Dipstick reading of 2+ (used only if other quan-
ered to be the classical criteria to diagnose preeclampsia, titative methods not available)
other criteria are also important. In this context, it is Or in the absence of proteinuria, new-onset hyper-
recommended that women with gestational hypertension tension with the new onset of any of the following:
in the absence of proteinuria are diagnosed with pre- c Thrombocytopenia: Platelet count less than
eclampsia if they present with any of the following 100 ,000 3 109/L
severe features: thrombocytopenia (platelet count less c Renal insufficiency: Serum creatinine concen-
than 100 ,000 3 109/L); impaired liver function as indi- trations greater than 1.1 mg/dL or a doubling of
the serum creatinine concentration in the
cated by abnormally elevated blood concentrations of absence of other renal disease
liver enzymes (to twice the upper limit of normal con- c Impaired liver function: Elevated blood concen-
centration); severe persistent right upper quadrant or epi- trations of liver transaminases to twice normal
gastric pain and not accounted for by alternative concentration
diagnoses; renal insufficiency (serum creatinine concen- c Pulmonary edema
c New-onset headache unresponsive to medication
tration greater than 1.1 mg/dL or a doubling of the serum and not accounted for by alternative diagnoses or
creatinine concentration in the absence of other renal visual symptoms
disease); pulmonary edema; or new-onset headache unre-
e238 Practice Bulletin Gestational Hypertension and Preeclampsia OBSTETRICS & GYNECOLOGY

may need to be confirmed within a shorter interval (mi-
Box 3. Preeclampsia with Severe nutes) than 4 hours to facilitate timely antihypertensive
Features therapy (27). Gestational hypertension occurs when
hypertension without proteinuria or severe features de-
c Systolic blood pressure of 160 mm Hg or more, or velops after 20 weeks of gestation and blood pressure
diastolic blood pressure of 110 mm Hg or more levels return to normal in the postpartum period (21). It
on two occasions at least 4 hours apart (unless
antihypertensive therapy is initiated before this appears that this diagnosis is more of an exercise of
time) nomenclature than a pragmatic one because the manage-
c Thrombocytopenia (platelet count less than ment of gestational hypertension and that of preeclamp-
100 ,000 3 109/L sia without severe features is similar in many aspects, and
c Impaired liver function that is not accounted for both require enhanced surveillance. Outcomes in women
by alternative diagnoses and as indicated by with gestational hypertension usually are good, but the
abnormally elevated blood concentrations of liver notion that gestational hypertension is intrinsically less
enzymes (to more than twice the upper limit
concerning than preeclampsia is incorrect. Gestational
normal concentrations), or by severe persistent
right upper quadrant or epigastric pain unre- hypertension is associated with adverse pregnancy out-
sponsive to medications comes (17) and may not represent a separate entity from
c Renal insufficiency (serum creatinine concentra- preeclampsia (28). Up to 50% of women with gestational
tion more than 1.1 mg/dL or a doubling of the hypertension will eventually develop proteinuria or other
serum creatinine concentration in the absence of end-organ dysfunction consistent with the diagnosis of
other renal disease)
preeclampsia, and this progression is more likely when
c Pulmonary edema the hypertension is diagnosed before 32 weeks of gesta-
c New-onset headache unresponsive to medication tion (29, 30). Although investigators have reported
and not accounted for by alternative diagnoses
a higher perinatal mortality rate in women with nonpro-
c Visual disturbances teinuric hypertension compared with proteinuric pre-
eclampsia (31), in a cohort of 1,348 hypertensive
pregnant patients, the women with proteinuria progressed
Proteinuria during pregnancy is defined as 300 mg/ more frequently to severe hypertension and had higher
dL of protein or more in a 24-hour urine collection (21, rates of preterm birth and perinatal mortality; however,
23) or a protein -to-creatinine ratio of 0.30 or more (24). women without proteinuria had a higher frequency of
When quantitative methods are not available or rapid thrombocytopenia or liver dysfunction (17). Women with
decisions are required, a urine protein dipstick reading gestational hypertension who present with severe-range
can be substituted. However, dipstick urinalysis has high blood pressures should be managed with the same
false–positive and false–negative test results. A test result approach as for women with severe preeclampsia. Ges-
of 1+ proteinuria is false–positive in 71% of cases tational hypertension and preeclampsia may also be un-
compared with the 300 mg cutoff on 24-hour urine col- distinguishable in terms of long-term cardiovascular
lection, and even 3+ proteinuria test results may be false– risks, including chronic hypertension (32).
positive in 7% of cases. Using the same 24-hour urine
collection standard, the false–negative rate for dipstick Hemolysis, Elevated Liver Enzymes, and
urinalysis is 9% (25). If urinalysis is the only available Low Platelet Count Syndrome
means of assessing proteinuria then overall accuracy is The clinical presentation of hemolysis, elevated liver
better using 2+ as the discriminant value (25, 26). enzymes, and low platelet count (HELLP) syndrome is
one of the more severe forms of preeclampsia because it
Gestational Hypertension has been associated with increased rates of maternal
Gestational hypertension is defined as a systolic blood morbidity and mortality (33). Although different diag-
pressure 140 mm Hg or more or a diastolic blood pres- nostic benchmarks have been proposed (34), many clini-
sure of 90 mm Hg or more, or both, on two occasions at cians use the following criteria (35) to make the
least 4 hours apart after 20 weeks of gestation, in diagnosis: lactate dehydrogenase (LDH) elevated to
a woman with a previously normal blood pressure (21). 600 IU/L or more, aspartate aminotransferase (AST)
Gestational hypertension is considered severe when the and alanine aminotransferase (ALT) elevated more than
systolic level reaches 160 mm Hg or the diastolic level twice the upper limit of normal, and the platelets count
reaches 110 mm Hg, or both. On occasion, especially less than 100,000 3 109/L. Although HELLP syndrome
when faced with severe hypertension, the diagnosis is mostly a third-trimester condition, in 30% of cases it is
VOL. 135, NO. 6, JUNE 2020 Practice Bulletin Gestational Hypertension and Preeclampsia e239

first expressed or progresses postpartum. Furthermore, placebo arm of both studies. It is also noteworthy that
HELLP syndrome may have an insidious and atypical there is a significant proportion of patients who had
onset, with up to 15% of the patients lacking either abrupt-onset eclampsia without warning signs or symp-
hypertension or proteinuria (36). In HELLP syndrome, toms (40). In a nationwide analysis of cases of eclampsia
the main presenting symptoms are right upper quadrant in the United Kingdom, it was noted that in 38% of
pain and generalized malaise in up to 90% of cases and eclamptic cases the seizure occurred without any prior
nausea and vomiting in 50% of cases (35, 37). documentation of either hypertension or proteinuria in
the hospital setting (46). Thus, the notion that preeclamp-
Eclampsia sia has a natural linear progression from preeclampsia
Eclampsia is the convulsive manifestation of the hyper- without severe features to preeclampsia with severe fea-
tensive disorders of pregnancy and is among the more tures and eventually to eclamptic convulsions is
severe manifestations of the disease. Eclampsia is inaccurate.
defined by new-onset tonic-clonic, focal, or multifocal Nervous system manifestations frequently encoun-
seizures in the absence of other causative conditions such tered in preeclampsia are headache, blurred vision,
as epilepsy, cerebral arterial ischemia and infarction, scotomata, and hyperreflexia. Although uncommon,
intracranial hemorrhage, or drug use. Some of these temporary blindness (lasting a few hours to as long as
alternative diagnoses may be more likely in cases in a week) also may accompany preeclampsia with severe
which new-onset seizures occur after 48–72 hours post- features and eclampsia (47). Posterior reversible enceph-
partum (38) or when seizures occur during administration alopathy syndrome (PRES) is a constellation of a range
of magnesium sulfate. of clinical neurologic signs and symptoms such as vision
Eclampsia is a significant cause of maternal death, loss or deficit, seizure, headache, and altered sensorium
particularly in low-resource settings. Seizures may lead or confusion (48). Although suspicion for PRES is
to severe maternal hypoxia, trauma, and aspiration increased in the setting of these clinical features, the
pneumonia. Although residual neurologic damage is rare, diagnosis of PRES is made by the presence of vasogenic
some women may have short-term and long-term con- edema and hyperintensities in the posterior aspects of the
sequences such as impaired memory and cognitive brain on magnetic resonance imaging. Women are par-
function, especially after recurrent seizures or uncor- ticularly at risk of PRES in the settings of eclampsia and
rected severe hypertension leading to cytotoxic edema or preeclampsia with headache, altered consciousness, or
infarction (39). Permanent white matter loss has been visual abnormalities (49). Another condition that may
documented on magnetic resonance imaging (MRI) after be confused with eclampsia or preeclampsia is reversible
eclampsia in up to one fourth of women, however, this cerebral vasoconstriction syndrome (50). Reversible
does not translate into significant neurologic deficits cerebral vasoconstriction syndrome is characterized by
(39). reversible multifocal narrowing of the arteries of the
Eclampsia often (78–83% of cases) is preceded by brain with signs and symptoms that typically include
premonitory signs of cerebral irritation such as severe thunderclap headache and, less commonly, focal neuro-
and persistent occipital or frontal headaches, blurred logic deficits related to brain edema, stroke, or seizure.
vision, photophobia, and altered mental status. However, Treatment of women with PRES and reversible cerebral
eclampsia can occur in the absence of warning signs or vasoconstriction syndrome may include medical control
symptoms (40, 41). Eclampsia can occur before, during, of hypertension, antiepileptic medication and long-term
or after labor. Of note, a significant proportion of women neurologic follow-up.
(20–38%) do not demonstrate the classic signs of pre-
eclampsia (hypertension or proteinuria) before the sei- Pathophysiology
zure episode (42). Headaches are believed to reflect the Several mechanisms of disease have been proposed in
development of elevated cerebral perfusion pressure, preeclampsia (1, 51, 52) including the following: chronic
cerebral edema, and hypertensive encephalopathy (43). uteroplacental ischemia (53), immune maladaptation
The term preeclampsia implies that the natural (53), very low-density lipoprotein toxicity (53), genetic
history of patients with persistent hypertension and imprinting (53), increased trophoblast apoptosis or necro-
significant proteinuria during pregnancy is to have sis (54, 55), and an exaggerated maternal inflammatory
tonic–clonic seizures if no prophylaxis if instituted. response to deported trophoblasts (56, 57). More
However, the results of two randomized placebo- recent observations suggest a possible role for imbalan-
controlled trials indicate that seizure occurred in only ces of angiogenic factors in the pathogenesis of pre-
a small proportion of patients with preeclampsia (1.9%) eclampsia (58). It is possible that a combination of
(44) or severe preeclampsia (3.2%) (45) allocated to the some of these purported mechanisms may be responsible

for triggering the clinical spectrum of preeclampsia. For Hepatic Changes
example, there is clinical (59, 60) and experimental evi- Hepatic function may be significantly altered in women
dence (61, 62) suggesting that uteroplacental ischemia with preeclampsia with severe features. Alanine amino-
leads to increased circulating concentrations of antiangio- transferase and AST may be elevated. Aspartate amino-
genic factors and angiogenic imbalances (63). transferase is the dominant transaminase released into the
peripheral circulation in liver dysfunction due to pre-
Vascular Changes eclampsia and is related to periportal necrosis. The fact
In addition to hypertension, women with preeclampsia or that AST is increased to a greater extent than ALT, at
eclampsia typically lack the hypervolemia associated with least initially, may help in distinguishing preeclampsia
normal pregnancy; thus, hemoconcentration is a frequent from other potential causes of parenchymal liver disease
finding (64). In addition, the interaction of various vaso- in which ALT usually is higher than AST. Increased
active agents, such as prostacyclin (vasodilator), throm- serum levels of LDH in preeclampsia are caused by
boxane A2 (potent vasoconstrictor), nitric oxide (potent hepatic dysfunction (LDH derived from ischemic, or
vasodilator), and endothelins (potent vasoconstrictors) re- necrotic tissues, or both) and hemolysis (LDH from red
sults in another significant change described in preeclamp- blood cell destruction). Increase in bilirubin secondary to
sia: intense vasospasm. Attempts to correct the contraction significant hemolysis may develop only in the late stages
of the intravascular space in preeclampsia with vigorous of the disease. Similarly, alterations in hepatic synthetic
fluid therapy are likely to be ineffective and could be function, as reflected by abnormalities of prothrombin
dangerous because of the frequent capillary leak and time, partial prothrombin time, and fibrinogen, usually
decreased colloid oncotic pressure often associated with
develop in advanced preeclampsia. Evaluation of these
preeclampsia. Aggressive fluid therapy may result in ele-
coagulation parameters is probably only useful when the
vation of the pulmonary capillary wedge pressure and
platelet count is below 150 ,000 3 109/L, there is signif-
increased risk of pulmonary edema. A study using inva-
icant liver dysfunction, or there is suspected placental
sive hemodynamic monitoring in women with preeclamp-
abruption (70).
sia found that before intravenous fluid therapy, women
with preeclampsia had hyperdynamic ventricular function
with low pulmonary capillary wedge pressure (65). How- Renal Changes
ever, after aggressive fluid therapy, the pulmonary capil- The histopathologic renal changes classically described
lary wedge pressure increased significantly above normal in preeclampsia as glomerular endotheliosis consist of
levels (65) with increased risk of pulmonary edema. swollen, vacuolated endothelial cells with fibrils, swollen
mesangial cells, subendothelial deposits of protein re-
Hematologic Changes absorbed from the glomerular filtrate, and tubular casts
Various hematologic changes also may occur in women (71, 72). Proteinuria in preeclampsia is nonselective, as
with preeclampsia, especially in preeclampsia with a result of increased tubular permeability to most large-
severe features. Thrombocytopenia and hemolysis may molecular-weight proteins (albumin, globulin, transfer-
occur and may reach severe levels as part of HELLP rin, and hemoglobin). Urinary calcium decreases because
syndrome. Thrombocytopenia results from increased of an increased tubular reabsorption of calcium.
platelet activation, aggregation, and consumption (66) In women with preeclampsia, contraction of the
and is a marker of disease severity. A platelet count less intravascular space secondary to vasospasm leads to
than 150 ,000 3 109/L is found in approximately 20% of worsening renal sodium and water retention (73). The
patients with preeclampsia, varying from 7% in cases normal increase in renal blood flow and glomerular fil-
without severe manifestations to 50% in cases with tration rate and the expected decrease in serum creatinine
severe manifestations (67). However, reduced platelet may not occur in women with preeclampsia, especially if
counts significant liver dysfunction, or there is suspected the disease is severe. Preeclampsia with severe features
are not found in all cases of preeclampsia or eclampsia may include acute renal deterioration as part of the clin-
(68). Interpretation of hematocrit levels in preeclampsia ical spectrum. Oliguria in severe preeclampsia is a conse-
should take into consideration that hemolysis and hemo- quence of intrarenal vasospasm with an approximate
concentration may occur (69). In some cases, the hemat- 25% reduction in glomerular filtration rate. In these pa-
ocrit may not appear decreased despite hemolysis tients, transient oliguria (less than 100 mL over 4 hours)
because of baseline hemoconcentration. Lactate dehydro- is a common observation in labor or the first 24 hours of
genase is present in erythrocytes in high concentration. the postpartum period. Plasma concentrations of uric acid
High serum concentrations of LDH (more than 600 IU/L) normally increase in late pregnancy, and this is thought
may be a sign of hemolysis (34, 35). to be due to increased rates of fetal or placental

production, or both, decreased binding to albumin, and insults may be different between early-onset and late-
a decrease in uric acid clearance. The serum uric acid onset preeclampsia. Even so, there is limited evidence
concentration increases to a greater extent in preeclamp- that an accurate prediction of early-onset preeclampsia
sia (74). The most commonly accepted explanation for can be followed by interventions that improve maternal
hyperuricemia in preeclampsia, besides increased pro- or fetal outcome.
duction, is the increased reabsorption and decreased Regardless of the index or combinations of indices
excretion of uric acid in the proximal renal tubules. used, uterine artery Doppler studies alone have a low
predictive value for the development of early-onset
Fetal Consequences preeclampsia and an even lower value for late-onset
As a result of impaired uteroplacental blood flow preeclampsia (88). Extensive work has identified some
secondary to failure of physiologic transformation of angiogenic factors (soluble fms-like tyrosine kinase-
the spiral arteries or placental vascular insults, or both, [sFlt-1], placental growth factor [PlGF], and soluble en-
manifestations of preeclampsia also may be seen in the doglin) in the second trimester as likely tools for the
fetal–placental unit (63). Abnormalities in the placental prediction of early-onset preeclampsia. However, no sin-
bed and subsequent failure of physiologic transformation gle test reliably predicts preeclampsia and further pro-
of the spiral arteries in the first or early second trimester spective investigation is required to demonstrate
(75, 76) limit the blood flow to the uteroplacental unit. clinical utility. In the first trimester of pregnancy, it has
Additional mechanisms for chronic uteroplacental been reported that a combination of low maternal serum
ischemia include placental vascular insults (77, 78). concentrations of PlGF, high uterine artery pulsatility
Among women with preeclampsia, clinical manifes- index, and other maternal parameters, identified 93.1%
tations that follow from this uteroplacental ischemia of patients who would develop preeclampsia requiring
include fetal growth restriction, oligohydramnios, pla- delivery before 34 weeks of gestation (82). However,
cental abruption, and nonreassuring fetal status demon- the results of this study are based on mathematical mod-
strated on antepartum surveillance. Consequently, fetuses eling derived from a nested case2control study applied
of women with preeclampsia are at increased risk of to a large cohort of almost 7,800 patients in which PlGF
spontaneous or indicated preterm delivery. was measured only in the case2control group. The cal-
culated positive predictive value was only 21.2%, indi-
Clinical Considerations cating that approximately 79% of the women in the
screen-positive group would not develop hypertensive
and Recommendations disorders during pregnancy (82). Of note, a similar algo-
rithm underperformed in a subsequent randomized trial
< Are there screening methods that are useful to performed by the same research group (89). Thus, bio-
identify women at risk of developing hyperten- markers and ultrasonography cannot accurately predict
sive disorders of pregnancy? preeclampsia and should remain investigational.
Several studies have evaluated the role of biochemical < Are there prevention strategies for reducing
markers or a combination of biochemical and biophysical the risk of hypertensive disorders of
markers in the prediction of preeclampsia in the first and pregnancy?
second trimesters of pregnancy (79). Regardless of the
parameters used, screening for preeclampsia in low-risk Strategies to prevent preeclampsia have been studied
women is associated with very low positive predictive extensively over the past 30 years. To date, no interven-
values ranging from 8% to 33% (79). Thus, most tion has been proved unequivocally effective at elimi-
screen–positive patients will not develop the disease nating the risk of preeclampsia. With regard to nutritional
and any prophylactic intervention in the screen-positive interventions, evidence is insufficient to demonstrate
group would unnecessarily expose a large number of effectiveness for vitamins C and E (90), fish oil (91),
patients who would not benefit from these interventions. garlic supplementation (92), vitamin D (93), folic acid
In general, the sensitivity and specificity for the (94) or sodium restriction (95) for reducing the risk of
prediction of early-onset preeclampsia using first- preeclampsia. A meta-analysis of 13 trials (15,730
trimester (80–82) and second-trimester biochemical (81, women) reported a significant reduction in preeclampsia
83) or biophysical parameters (84–87) are better than for with calcium supplementation, with the greatest effect
late-onset preeclampsia. The reason for this is still among women with low-baseline calcium intake (96).
unclear but it is possible that the timing of the insults Yet, this is not the case in the United States or other
to the fetal supply line or the fetal response to these developed countries. Likewise, data do not support

effectiveness of bed rest and, thus, it should not routinely The use of metformin for the prevention of pre-
be recommended (97). eclampsia has been suggested. In a meta-analysis of five
Investigators hypothesized that an imbalance in randomized controlled trials comparing metformin treat-
prostacyclin and thromboxane A2 metabolism was ment (n5611) with placebo and control (n5609), no
involved in the pathogenesis of preeclampsia, leading to difference in the risk of preeclampsia was found (com-
the initial studies of aspirin for preeclampsia prevention bined/pooled risk ratio, 0.86; 95% CI, 0.33–2.26);
because of its preferential inhibition of thromboxane A2 at P5.76; I2566%) (102). Because preeclampsia was a sec-
lower doses (98, 99). In a recent meta-analysis of aggre- ondary outcome in most studies in this meta-analysis, the
gate data from 45 randomized trials, only a modest reduc- effect of metformin needs to be assessed by a study de-
tion in preeclampsia was noted when low-dose aspirin was signed to evaluate the reduction in the prevalence of pre-
started after 16 weeks of gestation (relative risk [RR], eclampsia as a primary endpoint. In the meantime, the
0.81; 95% CI, 0.66–0.99) but a more significant reduction use of metformin for the prevention of preeclampsia re-
in severe preeclampsia (RR, 0.47; 95% CI, 0.26–0.83) and mains investigational, as is the use of sildenafil and sta-
fetal growth restriction (RR, 0.56; 95% CI, 0.44–0.70) was tins (103–105). These drugs are not recommended for
demonstrated when low-dose aspirin was started before 16 this indication outside of the context of clinical trials.
weeks of gestation (100). In contrast, in pooled individual
data from 31 high-quality randomized trials, the beneficial < What is the optimal treatment for women with
effects of low-dose aspirin were consistent, whether treat- gestational hypertension or preeclampsia?
ment was started before or after 16 weeks of gestation
(101). Women with any of the high-risk factors for pre-
eclampsia (previous pregnancy with preeclampsia, multi- Delivery Versus Expectant Management
fetal gestation, renal disease, autoimmune disease, type 1 At the initial evaluation, a complete blood count with
or type 2 diabetes mellitus, and chronic hypertension) and platelet estimate, serum creatinine, LDH, AST, ALT, and
those with more than one of the moderate-risk factors (first testing for proteinuria should be obtained in parallel with
pregnancy, maternal age of 35 years or older, a body mass a comprehensive clinical maternal and fetal evaluation.
index [BMI; calculated as weight in kilograms divided by In the settings of diagnostic dilemmas, such as in the
height in meters squared] of more than 30, family history evaluation of possible preeclampsia superimposed upon
of preeclampsia, sociodemographic characteristics, and chronic hypertension, a uric acid test may be considered.
personal history factors) should receive low-dose (81 Fetal evaluation should include ultrasonographic evalu-
mg/day) aspirin for preeclampsia prophylaxis initiated ation for estimated fetal weight and amount of amniotic
between 12 weeks and 28 weeks of gestation (optimally fluid, as well as fetal antepartum testing. Subsequent
before 16 weeks of gestation) and continuing until deliv- management will depend on the results of the evaluation
ery (Table 1). and gestational age. The decision to deliver must balance
In a recent multicenter, double blind, placebo- the maternal and fetal risks.
controlled trial, pregnant women at increased risk of Continued observation is appropriate for a woman
preterm preeclampsia (less than 37 weeks of gestation) with a preterm fetus if she has gestational hypertension or
were randomly assigned to receive aspirin, at a higher preeclampsia without severe features (21). There are no
dose (150 mg/day), or placebo from 11 weeks to 14 randomized controlled trials in this population, but retro-
weeks of gestation until 36 weeks of gestation (89). spective data suggest that without severe features, the
Preterm preeclampsia occurred in 1.6% of the partici- balance should be in favor of continued monitoring until
pants in the aspirin group, as compared with 4.3% in the delivery at 37 0/7 weeks of gestation in the absence of
placebo group (odds ratio, 0.38; 95% CI, 0.2020.74; abnormal antepartum testing, preterm labor, preterm prel-
P5.004). The authors also reported that there were no abor rupture of membranes (also referred to as premature
significant differences in the incidence of neonatal rupture of membranes) or vaginal bleeding, for neonatal
adverse outcomes between groups. The authors con- benefit (106). The risks associated with expectant man-
cluded that low-dose aspirin in women at high risk of agement in the late preterm period include the develop-
preeclampsia was associated with a lower incidence for ment of severe hypertension, eclampsia, HELLP
preterm preeclampsia. However, there were no differ- syndrome, placental abruption, fetal growth restriction
ences in the rates of term preeclampsia between study and fetal death; however, these risks are small and coun-
groups. Of note, as a possible study limitation, the prev- terbalanced by the increased rates of admission to the
alence of preterm preeclampsia in the placebo group neonatal intensive care unit, neonatal respiratory compli-
was one half of that expected for a high-risk population cations and neonatal death that would be associated with
based on first-trimester parameters (89). delivery before 37 0/7 weeks of gestation (39). In the

Table 1. Clinical Risk Factors and Aspirin Use*
Level of Risk Risk Factors Recommendation
High† History of preeclampsia, especially when Recommend low-dose aspirin if the patient
accompanied by an adverse outcome has one or more of these high-risk factors
Multifetal gestation
Chronic hypertension
Type 1 or 2 diabetes
Renal disease
Autoimmune disease (ie, systemic lupus
erythematosus, the antiphospholipid
syndrome)
Moderatez Nulliparity Consider low-dose aspirin if the patient has
more than one of these moderate-risk
factors§
Obesity (body mass index greater than 30)
Family history of preeclampsia (mother or
sister)
Sociodemographic characteristics (African
American race, low socioeconomic status)
Age 35 years or older
Personal history factors (eg, low birth
weight or small for gestational age, previous
adverse pregnancy outcome, more than 10-
year pregnancy interval)
Low Previous uncomplicated full-term delivery Do not recommend low-dose aspirin
*Includes only risk factors that can be obtained from the patient’s medical history. Clinical measures, such as uterine artery
Doppler ultrasonography, are not included.
†
Single risk factors that are consistently associated with the greatest risk of preeclampsia. The preeclampsia incidence rate
would be approximately 8% or more in a pregnant woman with one or more of these risk factors.
z
A combination of multiple moderate-risk factors may be used by clinicians to identify women at high risk of preeclampsia. These
risk factors are independently associated with moderate risk of preeclampsia, some more consistently than others.
§
Moderate-risk factors vary in their association with increased risk of preeclampsia.
Modified from LeFevre, ML. U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and
mortality from preeclampsia: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2014;161(11):819–
26.
HYPITAT trial, women with gestational hypertension eclampsia. The frequency of these tests may be modified
and preeclampsia without severe features after 36 weeks based on clinical findings and patient symptoms. Fol-
of gestation were allocated to expectant management or lowing the initial documentation of proteinuria and the
induction of labor. The latter option was associated with establishment of the diagnosis of preeclampsia, addi-
a significant reduction in a composite of adverse mater- tional quantifications of proteinuria are no longer neces-
nal outcome including new-onset severe preeclampsia, sary. Although the amount of proteinuria is expected to
HELLP syndrome, eclampsia, pulmonary edema, or increase over time with expectant management, this
placental abruption (RR, 0.71; 95% CI, 0.59–0.86) change is not predictive of perinatal outcome and should
(107). In addition, no differences in rates of neonatal not influence the management of preeclampsia (108,
complications or cesarean delivery were reported by the 109). Women should be advised to immediately report
authors (107). any persistent, concerning, or unusual symptoms. In
Continued monitoring of women with gestational women with gestational hypertension without severe fea-
hypertension or preeclampsia without severe features tures, when there is progression to preeclampsia with
consists of serial ultrasonography to determine fetal severe features, this progression usually takes 1–3 weeks
growth, weekly antepartum testing, close monitoring of after diagnosis, whereas in women with preeclampsia
blood pressure, and weekly laboratory tests for pre- without severe features, the progression to severe

preeclampsia could happen within days (72). Gestational The expectant management of preeclampsia with
hypertension and preeclampsia are known risk factors for severe features before 34 0/7 weeks of gestation is based
fetal death and antenatal testing is indicated. However, on strict selection criteria of those appropriate candidates
limited-to-no data exist regarding when to start testing, and is best accomplished in a setting with resources
the frequency of testing, and which test to use. In women appropriate for maternal and neonatal care (116).
with gestational hypertension or preeclampsia without Because expectant management is intended to provide
severe features at or beyond 37 0/7 weeks of gestation, neonatal benefit at the expense of maternal risk, expec-
delivery rather than expectant management upon diagno- tant management is not advised when neonatal survival is
sis is recommended. not anticipated. During expectant management, delivery
Preeclampsia with severe features can result in acute is recommended at any time in the case of deterioration
and long-term complications for the woman and her of maternal or fetal condition, which may include some
newborn. Maternal complications include pulmonary of the criteria in Box 4. Indications for expedited delivery
edema, myocardial infarction, stroke, acute respiratory irrespective of gestational age after maternal stabilization
distress syndrome, coagulopathy, renal failure, and are described in Box 4 (115).
retinal injury. These complications are more likely to If delivery is indicated at less than 34 0/7 weeks of
occur in the presence of preexistent medical disorders. gestation, administration of corticosteroids for fetal lung
The clinical course of preeclampsia with severe features maturation is recommended (115); however, delaying
is characterized by progressive deterioration of maternal delivery for optimal corticosteroid exposure may not
and fetal condition. Therefore, delivery is recommended always be advisable. Maternal or fetal deterioration
when gestational hypertension or preeclampsia with may preclude completion of the course of steroid treat-
severe features (Box 3) is diagnosed at or beyond 34 0/ ment. Previously, fetal growth restriction was considered
7 weeks of gestation, after maternal stabilization or with an indication for delivery. In the setting of normal fetal
labor or prelabor rupture of membranes. Delivery should parameters (eg, amniotic fluid volume, Doppler findings,
not be delayed for the administration of steroids in the antenatal fetal testing), continuation of expectant man-
late preterm period. agement may be reasonable in the absence of other,
In women with preeclampsia with severe features at aforementioned maternal and fetal criteria.
less than 34 0/7 weeks of gestation, with stable maternal
and fetal condition, expectant management may be
Inpatient Versus
considered. Two randomized controlled trials of delivery
versus expectant management of preterm preeclampsia
Outpatient Management
with severe features demonstrated that expectant man- Ambulatory management at home is an option only for
agement is associated with higher gestational age at women with gestational hypertension or preeclampsia
delivery and improved neonatal outcomes (110, 111). without severe features and requires frequent fetal and
These observations were reiterated by a Cochrane sys- maternal evaluation. Hospitalization is appropriate for
tematic review (112). The limited available randomized women with severe features and for women in whom
data are consistent with observational evidence suggest- adherence to frequent monitoring is a concern. Because
ing that expectant management of early preeclampsia assessment of blood pressure is essential for this clinical
with severe features prolongs pregnancy by 1–2 weeks, condition, health care providers are encouraged to follow
has low maternal risk, and improves neonatal outcomes the recommendations from regulatory bodies regarding
(113). In contrast, in a multicenter randomized controlled the proper technique for blood pressure measurement.
trial in Latin America, the authors found no neonatal Having a blood pressure cuff that is too small or too large
benefit with expectant management of preeclampsia with may result in erroneous evaluations. To reduce inaccurate
severe features from 28 weeks to 34 weeks of gestation readings, an appropriate size cuff should be used (length
(114). These different results may reflect the limitations 1.5 times upper arm circumference or a cuff with
in neonatal intensive care in low-resource settings. a bladder that encircles 80% or more of the arm). The
Embarking on a course of expectant management blood pressure level should be taken with an
necessitates adherence to principles of shared decision appropriately-sized cuff with the patient in an upright
making with discussions of maternal and fetal risks and position after a 10-minute or longer rest period. For
benefits, appropriate resources (levels of care), and patients in the hospital, the blood pressure can be taken
ongoing vigilant surveillance. Close maternal and fetal with either the patient sitting up or in the left lateral
clinical monitoring is necessary, and laboratory testing recumbent position with the patient’s arm at the level of
(complete blood count including platelets, liver enzymes, the heart (117). The patient should not use tobacco or
and serum creatinine) should be performed serially (115). caffeine for 30 minutes preceding the measurement

gestation and amniotic fluid volume assessment at least
Box 4. Conditions Precluding Expectant once weekly. In addition, an antenatal test one-to-two
Management times per week for patients with gestational hypertension
or preeclampsia without severe features is recommended.
Maternal Maternal evaluation consists primarily of frequent
c Uncontrolled severe-range blood pressures (per-
evaluation for either the development of or worsening of
sistent systolic blood pressure 160 mm Hg or preeclampsia. In women with gestational hypertension or
more or diastolic blood pressure 110 mm Hg or preeclampsia without severe features, weekly evaluation
more not responsive to antihypertensive of platelet count, serum creatinine, and liver enzyme levels
medication is recommended. In addition, for women with gestational
c Persistent headaches, refractory to treatment hypertension, once weekly assessment of proteinuria is
c Epigastric pain or right upper pain unresponsive recommended. However, these tests should be repeated
to repeat analgesics sooner if disease progression is a concern. In addition,
c Visual disturbances, motor deficit or altered women should be asked about symptoms of preeclampsia
sensorium with severe features (eg, severe headaches, visual changes,
c Stroke epigastric pain, and shortness of breath). Blood pressure
c Myocardial infarction measurements and symptom assessment are recommended
c HELLP syndrome serially, using a combination of in-clinic and ambulatory
c New or worsening renal dysfunction (serum cre- approaches, with at least one visit per week in-clinic.
atinine greater than 1.1 mg/dL or twice baseline)
c Pulmonary edema
Intrapartum Management
c Eclampsia
In addition to appropriate management of labor and delivery,
c Suspected acute placental abruption or vaginal
bleeding in the absence of placenta previa the two main goals of management of women with
preeclampsia during labor and delivery are 1) prevention
Fetal of seizures and 2) control of hypertension.
c Abnormal fetal testing
c Fetal death Seizure Prophylaxis
c Fetus without expectation for survival at the time The prevention of eclampsia is empirically based on the
of maternal diagnosis (eg, lethal anomaly, concept of timely delivery, as previously discussed, once
extreme prematurity) preeclampsia has been diagnosed. A significant body of
c Persistent reversed end-diastolic flow in the evidence attests to the efficacy of magnesium sulfate to
umbilical artery prevent seizures in women with preeclampsia with severe
Abbreviation: HELLP, hemolysis, elevated liver enzymes, features and eclampsia. In the Magpie study, a random-
and low platelet count. ized placebo-controlled trial with 10,110 participants
In some cases, a course of antenatal steroids can be con-
sidered depending on gestational age and maternal
(two thirds originating from developing countries), the
severity of illness. seizure rate was reduced overall by more than one half
Data from Balogun OA, Sibai BM. Counseling, manage- with this treatment. It is interesting to note that the
ment, and outcome in women with severe preeclampsia
at 23 to 28 weeks’ gestation. Clin Obstet Gynecol
reduction in the rate of eclampsia was not statistically
2017;60:183–9. significant in the subset of women enrolled in high-
resource countries in the Western world (RR, 0.67; 95%
CI, 0.19–2.37) (44). In a subsequent systematic review
because these agents can temporarily lead to increased that included the Magpie study and five other studies,
blood pressure (118). magnesium sulfate compared with placebo more than
If home management is selected, frequent fetal and halved the risk of eclampsia (RR, 0.41; 95% CI, 0.29–
maternal evaluation are required. No randomized trials 0.58), reduced the risk of placental abruption (RR, 0.64;
have determined the best tests for fetal or maternal 95% CI, 0.50–0.83), and reduced the risk of maternal
evaluation. Among women with gestational hypertension mortality albeit nonsignificantly (RR, 0.54; 95% CI,
or preeclampsia without severe features, expectant man- 0.26–1.10). There were no differences in maternal mor-
agement up to 37 0/7 weeks of gestation is recommen- bidity or perinatal mortality. A quarter of women reported
ded, during which frequent fetal and maternal evaluation adverse effects with magnesium sulfate, primarily hot
is recommended. Fetal monitoring consists of ultraso- flushes, and the rate of cesarean delivery was increased
nography to determine fetal growth every 3–4 weeks of by 5% when magnesium sulfate was used (119).

There is no consensus regarding the prophylactic use ically effective in prevention of eclampsia has not been
of magnesium sulfate for the prevention of seizures in established. Seizures occur even with magnesium at
women with gestational hypertension or preeclampsia a therapeutic level, whereas several trials using infusion
without severe features. Two small randomized trials rates of 1 g/hour, frequently associated with subtherapeu-
(total n5357) allocated women with preeclampsia with- tic magnesium levels, were able to significantly reduce
out severe features to either placebo or magnesium sul- the rate of eclampsia or recurrent convulsions (44, 130).
fate and reported no cases of eclampsia among women Further complicating aspects are that steady magnesium
allocated to placebo and no significant differences in the levels are reached more slowly during the antepartum
proportion of women that progressed to severe pre- period than postpartum period. Larger volume of distri-
eclampsia (120, 121). However, given the small sample bution and higher BMI also affect the dosage and dura-
size, the results of these studies cannot be used for clin- tion needed to reach adequate circulating levels. It has
ical guidance (122, 123). been reported in patients with a high BMI (especially
The rate of seizures in preeclampsia with severe greater than 35) that the antepartum level of magnesium
features without magnesium sulfate prophylaxis is four may remain subtherapeutic for as long as 18 hours after
times higher than in those without severe features (4 in infusion initiation when an intravenous loading dose of
200 versus 1 in 200). It has been calculated that 129 4.5 g followed by 1.8 g/hour is used (131). However,
women need to be treated to prevent one case of infusion rates in excess of 2 g/hour have been associated
eclampsia in asymptomatic cases, whereas in symptom- with increased perinatal mortality in a systematic review
atic cases (severe headache, blurred vision, photophobia, of randomized studies of magnesium sulfate used for
hyperreflexia, epigastric pain), the number needed to tocolysis (132). These data may be considered supportive
treat is 36 (124). The evidence regarding the benefit-to- for the regimen generally preferred in the United States
risk ratio of magnesium sulfate prophylaxis is less sup- (intravenous [IV] administration of a 4–6 g loading dose
portive of routine use in preeclampsia without severe over 20–30 minutes, followed by a maintenance dose of
features (122). The clinical decision of whether to use 1–2 g/hour). For women requiring cesarean delivery
magnesium sulfate for seizure prophylaxis in patients (before onset of labor), the infusion should ideally begin
with preeclampsia without severe features should be before surgery and continue during surgery, as well as for
determined by the physician or institution, considering 24 hours afterwards. For women who deliver vaginally,
patient values or preferences, and the unique risk- the infusion should continue for 24 hours after delivery.
benefit trade-off of each strategy. Although the benefit- In case of difficulties with establishing venous access,
to-risk ratio for routine prophylaxis is less compelling for magnesium sulfate can be administered by intramuscular
patients in high resource settings, it is recommended that (IM) injection, 10 g initially as a loading dose (5 g IM in
magnesium sulfate should be used for the prevention and each buttock), followed by 5 g every 4 hours. The
treatment of seizures in women with gestational hyper- medication can be mixed with 1 mL of xylocaine 2%
tension with severe features and preeclampsia with solution because the intramuscular administration is
severe features or eclampsia (124, 125). painful. The rate of adverse effects is also higher with the
Magnesium sulfate is more effective than phenytoin, intramuscular administration (44). The adverse effects of
diazepam, or nimodipine (a calcium-channel blocker magnesium sulfate (respiratory depression and cardiac
used in clinical neurology to reduce cerebral vasospasm) arrest) come largely from its action as a smooth muscle
in reducing eclampsia and should be considered the drug relaxant. Deep tendon reflexes are lost at a serum mag-
of choice in the prevention of eclampsia in the intra- nesium level of 9 mg/dL (7 mEq/L), respiratory depres-
partum and postpartum periods (119, 126, 127). Benzo- sion occurs at 12 mg/dL (10 mEq/L), and cardiac arrest at
diazepines and phenytoin are justified only in the context 30 mg/dL (25 mEq/L). Accordingly, provided deep ten-
of antiepileptic treatment or when magnesium sulfate is don reflexes are present, more serious toxicity is avoided.
contraindicated or unavailable (myasthenia gravis, hypo- (Table 2) Because magnesium sulfate is excreted almost
calcemia, moderate-to-severe renal failure, cardiac ische- exclusively in the urine, measuring urine output should
mia, heart block, or myocarditis). be part of the clinical monitoring, in addition to moni-
There are still sparse data regarding the ideal dosage toring of respiration status and tendon reflexes. If renal
of magnesium sulfate. Even the therapeutic range of 4.8– function is impaired, serum magnesium levels will
9.6 mg/dL (4–8 mEq/L) quoted in the literature is ques- increase quickly, which places the patient at risk of sig-
tionable (128, 129). Although there is a relationship nificant adverse effects. In patients with mild renal failure
between toxicity and plasma concentration of magne- (serum creatinine 1.0–1.5 mg/dL) or oliguria (less than
sium, with higher infusion rates increasing the potential 30 mL urine output per hour for more than 4 hours),
for toxicity, the accurate magnesium concentration clin- the loading dose of 4–6 g should be followed by

Table 2. Serum Magnesium Concentration women found no significant differences regarding either
and Toxicities efficacy or safety between hydralazine and labetalol or
between hydralazine and calcium channel blockers (135).
Serum Magnesium Concentration Thus, any of these agents can be used to treat acute
severe hypertension in pregnancy (135, 136). Although
mmol/L mEq/L mg/dL Effect
parenteral antihypertensive therapy may be needed ini-
2–3.5 4–7 5–9 Therapeutic range tially for acute control of blood pressure, oral medica-
.3.5 .7 .9 Loss of patellar reflexes
tions can be used as expectant management is continued.
Oral labetalol and calcium channel blockers have been
.5 .10 .12 Respiratory paralysis
commonly used. One approach is to begin an initial reg-
.12.5 .25 .30 Cardiac arrest
imen of labetalol at 200 mg orally every 12 hours and
Data from Duley L. Magnesium sulphate regimens for women
with eclampsia: messages from the Collaborative Eclampsia
increase the dose up to 800 mg orally every 8–12 hours
Trial. Br J Obstet Gynaecol 1996;103:103–5 and Lu JF, as needed (maximum total 2,400 mg/d). If the maximum
Nightingale CH. Magnesium sulfate in eclampsia and pre- dose is inadequate to achieve the desired blood pressure
eclampsia: pharmacokinetic principles. Clin Pharmacokinet
2000;38:305–14.
goal, or the dosage is limited by adverse effect, then
short-acting oral nifedipine can be added gradually.
a maintenance dose of only 1 gm/hour. Using a lower Monitoring for Disease Progression
loading dose, such as 4 g, may be associated with sub- Because the clinical course of gestational hypertension or
therapeutic levels for at least 4 hours after loading (133). preeclampsia without severe features can evolve during
In cases with renal dysfunction, laboratory determination labor, all women with gestational hypertension or pre-
of serum magnesium levels every 4 hours becomes nec- eclampsia without severe features who are in labor must be
essary. If the serum level exceeds 9.6 mg/dL (8 mEq/L), monitored for early detection of progression to severe
the infusion should be stopped and serum magnesium disease. This should include monitoring of blood pressure
levels should be determined at 2-hour intervals. The infu- and symptoms during labor and delivery as well as
sion can be restarted at a lower rate when the serum level immediately after delivery. Magnesium sulfate therapy
decreases to less than 8.4 mg/dL (7 mEq/L) (133). The should be initiated if there is progression to preeclampsia
serum concentration of magnesium is related to the occur- with severe features. The evidence regarding the benefit-to-
rence of adverse effects and toxicities (see Table 2) (128, risk ratio of magnesium sulfate prophylaxis is less support-
134). Patients at risk of impending respiratory depression ive of routine use in preeclampsia without severe features
may require tracheal intubation and emergency correction (122). The clinical decision of whether to use magnesium
with calcium gluconate 10% solution, 10 mL IV over sulfate for seizure prophylaxis in patients with preeclampsia
3 minutes, along with furosemide intravenously to accel- without severe features should be determined by the physi-
erate the rate of urinary excretion. cian or institution, considering patient values or preferences
and the unique risk-benefit trade-off of each strategy.
Antihypertensive Approach: Drugs
and Thresholds for Treatment Mode of Delivery
The objectives of treating severe hypertension are to The mode of delivery in women with gestational hyperten-
prevent congestive heart failure, myocardial ischemia, sion or preeclampsia (with or without severe features)
renal injury or failure, and ischemic or hemorrhagic should be determined by routine obstetric considerations.
stroke. Antihypertensive treatment should be initiated Vaginal delivery often can be accomplished, but with labor
expeditiously for acute-onset severe hypertension (sys- induction in preeclampsia with severe features this is less
tolic blood pressure of 160 mm Hg or more or diastolic likely with decreasing gestational age at diagnosis. The
blood pressure of 110 mm Hg or more, or both) that is likelihood of cesarean delivery at less than 28 weeks of
confirmed as persistent (15 minutes or more). The gestation could be as high as 97%, and at 28–32 weeks of
available literature suggests that antihypertensive agents gestation as high as 65% (137–139). For gestational hyper-
should be administered within 30–60 minutes. However, tension or preeclampsia without severe features, vaginal
it is recommended to administer antihypertensive therapy delivery is preferred (137–139). Retrospective studies com-
as soon as reasonably possible after the criteria for acute- paring induction of labor with cesarean delivery in women
onset severe hypertension are met. Intravenous hydral- with preeclampsia with severe features remote from term
azine or labetalol and oral nifedipine are the three agents concluded that induction of labor was reasonable and was
most commonly used for this purpose (see Table 3). A not harmful to low-birth-weight infants (140, 141). The
recent Cochrane systematic review that involved 3,573 decision to perform cesarean delivery should be

Table 3. Antihypertensive Agents Used for Urgent Blood Pressure Control in Pregnancy
Drug Dose Comments Onset of Action
Labetalol 10–20 mg IV, then 20–80 mg Tachycardia is less common with 1–2 minutes
every 10–30 minutes to a maxi- fewer adverse effects.
mum cumulative dosage of
300 mg; or constant infusion
1–2 mg/min IV
Avoid in women with asthma,
preexisting myocardial disease,
decompensated cardiac function,
and heart block and bradycardia.
Hydralazine 5 mg IV or IM, then 5–10 mg IV Higher or frequent dosage 10–20 minutes

every 20–40 minutes to a maxi- associated with maternal
mum cumulative dosage of 20 mg; hypotension, headaches, and
or constant infusion of abnormal fetal heart rate tracings;
0.5–10 mg/hr may be more common than other
agents.
Nifedipine 10–20 mg orally, repeat in May observe reflex tachycardia 5–10 minutes
(immediate release) 20 minutes if needed; then and headaches
10–20 mg every 2–6 hours;
maximum daily dose is 180 mg
Abbreviations: IM, intramuscularly; IV, intravenously.
individualized, based on anticipated probability of vaginal increased systemic and intracranial pressures during intu-
delivery and on the nature and progression of preeclampsia bation and extubation (145, 146). However, neuraxial
disease state. anesthesia and analgesia are contraindicated in the pres-
ence of a coagulopathy because of the potential for hem-
Anesthesia Considerations orrhagic complications (147). Thrombocytopenia also
With improved techniques over the past decades, regional increases the risk of epidural hematoma. There is no
anesthesia has become the preferred technique for women consensus in regard to the safe lower-limit for platelet
with preeclampsia with severe features and eclampsia for count and neuraxial anesthesia. The literature offers only
labor and delivery. A secondary analysis of women with limited and retrospective data to address this issue, but
preeclampsia with severe features in a randomized trial of a recent retrospective cohort study of 84,471 obstetric pa-
low-dose aspirin reported that epidural anesthesia was not tients from 19 institutions combined with a systematic
associated with an increased rate of cesarean delivery, review of the medical literature support the assertion that
pulmonary edema, or renal failure (142). Also, in a pro- the risk of epidural hematoma from neuraxial anesthetics in
spective study, the incidence and severity of hypotension a parturient patient with a platelet count of more than 70 3
did not appear to be increased with spinal anesthesia for 109/L is exceptionally low (less than 0.2%) (148). Extrap-
cesarean delivery in women with preeclampsia with severe olating this expanded data to previous recommendations
features (n565) compared with women without pre- (149) would suggest that epidural or spinal anesthesia is
eclampsia (143). considered acceptable, and the risk of epidural hematoma
When the use of spinal or epidural anesthesia in is exceptionally low, in patients with platelet counts of 70
women with preeclampsia with severe features was 3 109/L or more provided that the platelet level is stable,
compared in a randomized trial (144), the incidence of there is no other acquired or congenital coagulopathy, the
hypotension was higher in the spinal group (51% versus platelet function is normal, and the patient is not on any
23%) but was easily treated and of short duration (less antiplatelet or anticoagulant therapy (148, 149).
than 1 minute). General anesthesia carries more risk to Magnesium sulfate has significant anesthetic impli-
pregnant women than regional anesthesia does because cations because it prolongs the duration of nondepolariz-
of the risk of aspiration, failed intubation because of ing muscle relaxants. However, women with
pharyngolaryngeal edema, and stroke secondary to preeclampsia who require cesarean delivery should

continue magnesium sulfate infusion during the delivery. pressure, antihypertensive requirements, or other adverse
This recommendation is based on the observation that events for patients managed with NSAIDs in the post-
magnesium sulfate half-life is 5 hours and that discon- partum period (157, 158).
tinuation of the infusion of magnesium sulfate before
cesarean delivery would only minimally reduce magne- < What is the optimal treatment for eclampsia?
sium concentration at the time of delivery while possibly The initial steps in the management of a woman with
increasing the risk of seizure (150). Women with preeclampsia are basic supportive measures such as calling
eclampsia with severe features undergoing cesarean for help, prevention of maternal injury, placement in
delivery remain at risk of developing eclampsia. The lateral decubitus position, prevention of aspiration,
induction of general anesthesia and the stress of delivery administration of oxygen, and monitoring vital signs
may even reduce the seizure threshold and increase the including oxygen saturation. Only subsequently is atten-
likelihood of eclampsia in the immediate postpartum tion directed to the administration of magnesium sulfate.
period if the infusion of magnesium sulfate is stopped Most eclamptic seizures are self-limited. Magnesium
during delivery. sulfate is not necessary to arrest the seizure but to
prevent recurrent convulsions.
Postpartum Hypertension and During eclamptic seizures, there are usually pro-
Postpartum Headache longed fetal heart rate decelerations, even fetal brady-
Postpartum hypertension and preeclampsia are either cardia, and sometimes an increase in uterine contractility
persistent or exacerbated hypertension in women with and baseline tone. After a seizure, because of maternal
previous hypertensive disorders of pregnancy or a new- hypoxia and hypercarbia, the fetal heart rate tracing may
onset condition. It is important to increase the awareness show recurrent decelerations, tachycardia, and reduced
among health care providers and to empower patients to variability. However, only after maternal hemodynamic
seek medical advice if symptoms that precede eclampsia, stabilization should one proceed with delivery. Further-
hypertensive encephalopathy, pulmonary edema, or more, maternal resuscitation is usually followed by
stroke are noted in the postpartum period. Most women normalization of the fetal tracing.
who present with eclampsia and stroke in the postpartum Cochrane reviews, including data originating from
period have these symptoms for hours or days before developing countries, indicate a significant reduction in
presentation (151–154). Some common medications and recurrent seizures and eclampsia-related maternal mor-
substances used in the postpartum period may potentially tality with the use of magnesium sulfate. Magnesium
aggravate hypertension through three major mechanisms: sulfate administered intramuscularly or intravenously is
volume retention, sympathomimetic activation, and superior to phenytoin, diazepam, or lytic cocktail (usu-
direct vasoconstriction. Of particular interest are nonste- ally chlorpromazine, promethazine, and pethidine) and
roidal antiinflammatory drugs (NSAIDs), which are fre- also is associated with less maternal and neonatal
quently prescribed as postpartum analgesics. These morbidity (126, 159, 160). Thus, these data support the
medications decrease prostaglandins leading to a lack use of magnesium sulfate as the drug of choice to prevent
of vasodilation and increased sodium retention. Nonste- recurrent seizures in women with eclampsia. In the rare
roidal anti-inflammatory medications should continue to cases of an extremely agitated patient, IV clonazepam 1
be used preferentially over opioid analgesics; however, mg, diazepam 10 mg, or midazolam may be used for
women with chronic hypertension may theoretically sedation to facilitate the placement of the IV lines and
require intensification of blood pressure monitoring and Foley catheter, and the collection of blood specimens.
regimen adjustments when on these medications. Over- These drugs should be used cautiously and only if abso-
all, data support the safe use of NSAIDs in postpartum lutely necessary because they inhibit laryngeal reflexes,
patients with blood pressure issues. In a randomized trial increasing the risk of aspiration and also may depress the
comparing use of ibuprofen to acetaminophen in post- central respiratory centers leading to apnea.
partum patients with preeclampsia with severe features, Women with eclampsia should be delivered in
ibuprofen did not lengthen the duration of severe-range a timely fashion. However, eclampsia by itself is not an
blood pressures (155). In a cohort of 399 patients with indication for cesarean delivery. Once the patient is
preeclampsia with severe features, there was no associa- stabilized, the method of delivery should depend, in part,
tion of NSAID use with postpartum blood pressure ele- on factors such as gestational age, fetal presentation, and
vations (156). Further, another cohort study of the findings of the cervical examination. A high rate of
postpartum patients on magnesium for seizure prophy- failure may be anticipated with induction or augmenta-
laxis for preeclampsia did not show differences in blood tion in pregnancies less than 30 weeks of gestation if the

patient is not in active labor and the Bishop score is Very close monitoring is required in HELLP syndrome
unfavorable. In these cases, it may be preferable to opt until delivery and in the postpartum period, with laboratory
for cesarean delivery without further delay. However, testing at least at 12-hour intervals. Aspartate aminotransfer-
patients that adequately progress in labor could be ase levels more than 2,000 IU/L or LDH more than
allowed to continue labor even after an eclamptic seizure. 3,000 IU/L suggest an increased mortality risk. In the natural
It has been proposed that when convulsions recur, history of HELLP syndrome there is an inverse relationship
a further 2–4 grams of magnesium sulfate could be between the trends in platelet values and liver enzymes level.
administered IV over 5 minutes (130). In cases refractory During the aggravation slope in the disease evolution,
to magnesium sulfate (still seizing at 20 minutes after the platelet count usually decreases at an average rate of
bolus or more than two recurrences), a health care pro- approximately 40% per day, whereas the liver enzymes
vider can use sodium amobarbital (250 mg IV in 3 mi- values tend to increase. The lowest observed platelet count
nutes), thiopental, or phenytoin (1,250 mg IV at a rate of occurs at a mean of 23 hours after delivery. The disease may
50 mg/minute). Endotracheal intubation and assisted ven- achieve peak intensity during the first 2 days after delivery,
tilation in the intensive care unit are appropriate in these including a downward trend in hematocrit. If the platelet
circumstances. Head imaging should also be considered count continues to drop and liver enzymes to increase after 4
because most of cases refractory to magnesium sulfate days postpartum, the validity of the initial diagnosis of
therapy may prove to have abnormal findings on brain HELLP syndrome should be reassessed. With supportive
imaging (161). care alone, 90% of patients with HELLP syndrome will have
platelet count more than 100,000 3 109/L and reversed
< What is the management of acute complica- trend (decrease) in liver enzymes values within 7 days after
tions for preeclampsia with HELLP? delivery. Not infrequently, a rebound phenomenon in platelet
count follows reaching values of 400,000–871,000 3 109/L
The clinical course of HELLP syndrome often is
(164). Women with HELLP syndrome are also at increased
characterized by progressive and sometimes sudden
risk of pulmonary edema, acute respiratory distress syn-
deterioration in maternal and fetal condition. Considering
drome and renal failure (165).
the serious nature of this entity, with increased rates of
maternal morbidity and mortality, many authors have < What are the risks of subsequent cardiovascu-
concluded that women with HELLP syndrome should be lar disease among women with hypertensive
delivered regardless of their gestational age. Because the disorders of pregnancy and are there preven-
management of patients with HELLP syndrome requires tion strategies that modify this risk?
the availability of neonatal and obstetric intensive care
units and personnel with special expertise, patients with Women with a history of preeclampsia continue to have an
HELLP syndrome who are remote from term should elevated risk of cardiovascular disease in subsequent years.
receive care at a tertiary care center (116, 162). Several systematic reviews and meta-analyses have linked
It has been hypothesized that the antiinflammatory preeclampsia with an increased risk of cardiovascular
and immunosuppressive effects of corticosteroids may disease (hypertension, myocardial infarction, congestive
modify some of the proinflammatory features of pre- heart failure), cerebrovascular events (stroke), peripheral
eclampsia with severe features and favorably affect the arterial disease, and cardiovascular mortality later in life,
clinical course. Several randomized controlled trials of with an estimated doubling of odds compared with women
high-dose corticosteroid treatment for antepartum or unaffected by preeclampsia (166–168). Meta-regression
postpartum stabilization of HELLP syndrome have been analysis reveals a graded relationship between the severity
conducted. The use of corticoids in the management of of preeclampsia or eclampsia and the risk of cardiac disease
HELLP syndrome compared with placebo or no treat- (mild: RR, 2.00; 95% CI, 1.83–2.19; moderate: RR, 2.99;
ment was reviewed in a Cochrane Database Systematic 95% CI, 2.51–3.58; severe: RR, 5.36; 95% CI, 3.96–7.27,
Review, which included 11 randomized trials (550 P,.0001) (169). The risk is even higher (4–8 times the risk
women) (163). There was no difference in the risk of for women with normal pregnancies) in women with recur-
maternal death, severe maternal morbidity, or perinatal rent preeclampsia (170) and women with early-onset pre-
or infant death. The only effect of treatment on individual eclampsia or preeclampsia requiring preterm delivery (171).
outcomes was improved platelet count (standardized More recent evidence suggests that all hypertensive condi-
mean difference [SMD] 0.67; 95% CI, 0.2421.10). tions in pregnancy are associated with later cardiovascular
The authors concluded that the evidence is insufficient disease with an approximately doubling of the rate of inci-
to support the use of corticosteroids for attenuation of the dent cardiovascular disease and a five times higher rate of
disease process in HELLP syndrome (163). hypertension (172).

The mechanisms that account for an increased risk of < In women with gestational hypertension or pre-
cardiovascular disease in women with a history of eclampsia without severe features at or beyond 37 0/7
preeclampsia are not yet well understood, but endothelial weeks of gestation, delivery rather than expectant
dysfunction, which has been linked to atherosclerosis, management upon diagnosis is recommended.
persists in women with a history of preeclampsia many < Magnesium sulfate should be used for the prevention
years after an affected pregnancy (173). A study of car- and treatment of seizures in women with gestational
diovascular risk factors present before and after preg- hypertension and preeclampsia with severe features
nancy suggested that nearly one half of the elevated or eclampsia.
risk of future hypertension after preeclampsia can be ex-
< Nonsteroidal anti-inflammatory medications should
plained by prepregnancy risk factors (174). Yet, it may continue to be used preferentially over opioid an-
be possible that the stress incurred to the cardiovascular algesics. Postpartum patients on magnesium for sei-
system during gestation triggers a biological response zure prophylaxis for preeclampsia did not show
that would otherwise not have occurred despite any differences in blood pressure, antihypertensive re-
genetic predisposition or risk factors (172). It remains quirements, or other adverse events for patients
unclear if cardiovascular changes associated with pre- managed with NSAIDs in the postpartum period.
eclampsia during pregnancy causally lead to cardiovas-
cular remodeling increasing the risk of cardiovascular The following recommendations are based on limited or
disease later in life or if preeclampsia is a manifestation inconsistent scientific evidence (Level B):
of an underlying increased risk of cardiovascular disease
(for example, a common genetic–environmental risk < Delivery is recommended when gestational hyperten-
sion or preeclampsia with severe features is diagnosed
factor(s) interaction [such as hyperlipidemia, obesity,
at or beyond 34 0/7 weeks of gestation, after maternal
diabetes mellitus, or renal disease] that predisposes
stabilization or with labor or prelabor rupture of
women to develop preeclampsia during pregnancy and
membranes. Delivery should not be delayed for the
cardiovascular diseases later in life) (175). Preventive
administration of steroids in the late preterm period.
strategies to be considered by patients and health care
providers may warrant closer long-term follow-up and < The expectant management of preeclampsia with
lifestyle modifications to better manage risk factors for severe features before 34 0/7 weeks of gestation is
cardiovascular disease (eg, achieving healthful weight, based on strict selection criteria of those appropriate
exercise, diet, smoking cessation), for which women candidates and is best accomplished in a setting with
and their primary care providers may maintain ongoing resources appropriate for maternal and neonatal care.
care and vigilance. Because expectant management is intended to pro-
vide neonatal benefit at the expense of maternal risk,
expectant management is not advised when neonatal
Summary of survival is not anticipated. During expectant man-
agement, delivery is recommended at any time in the
Recommendations case of deterioration of maternal or fetal condition.
< Antihypertensive treatment should be initiated expe-
The following recommendations are based on good and ditiously for acute-onset severe hypertension (systolic
consistent scientific evidence (Level A): blood pressure of 160 mm Hg or more or diastolic
blood pressure of 110 mm Hg or more, or both) that
< Women with any of the high-risk factors for pre-
eclampsia (previous pregnancy with preeclampsia, is confirmed as persistent (15 minutes or more). The
multifetal gestation, renal disease, autoimmune dis- available literature suggests that antihypertensive
ease, type 1 or type 2 diabetes mellitus, and chronic agents should be administered within 30–60 minutes.
hypertension) and those with more than one of the However, it is recommended to administer antihy-
moderate-risk factors (first pregnancy, maternal age pertensive therapy as soon as reasonably possible
of 35 years or older, a body mass index of more than after the criteria for acute-onset severe hypertension
30, family history of preeclampsia, sociodemographic are met.
characteristics, and personal history factors) should The following recommendations are based primarily on
receive low-dose (81 mg/day) aspirin for pre- consensus and expert opinion (Level C):
eclampsia prophylaxis, initiated between 12 weeks
and 28 weeks of gestation (optimally before 16 weeks < It is recommended that women with gestational
of gestation) and continuing until delivery. hypertension in the absence of proteinuria are

diagnosed with preeclampsia if they present with any 5. Stevens W, Shih T, Incerti D, Ton TGN, Lee HC,
of the following severe features: thrombocytopenia Peneva D, et al. Short-term costs of preeclampsia to the
United States health care system. Am J Obstet Gynecol
(platelet count less than 100 ,000 3 109/L); impaired
2017; 217:237–48.e16. (Level III)
liver function as indicated by abnormally elevated
blood concentrations of liver enzymes (to twice the 6. Conde-Agudelo A, Belizan JM. Risk factors for pre-
eclampsia in a large cohort of Latin American and Carib-
upper limit of normal concentration); severe persis- bean women. BJOG 2000;107:75–83. (Level II-3)
tent right upper quadrant or epigastric pain and not
accounted for by alternative diagnoses; renal insuf- 7. Sibai BM, Hauth J, Caritis S, Lindheimer MD,
MacPherson C, Klebanoff M, et al. Hypertensive disor-
ficiency (serum creatinine concentration more than ders in twin versus singleton gestations. National Institute
1.1 mg/dL or a doubling of the serum creatinine of Child Health and Human Development Network of
concentration in the absence of other renal disease); Maternal– Fetal Medicine Units. Am J Obstet Gynecol
pulmonary edema, or new-onset headache unre- 2000;182: 938–42. (Level II-3)
sponsive to acetaminophen and not accounted for by 8. Bartsch E, Medcalf KE, Park AL, Ray JG. Clinical risk
alternative diagnoses, or visual disturbances. factors for pre-eclampsia determined in early pregnancy:
systematic review and meta-analysis of large cohort stud-
< Women with gestational hypertension who present ies. High Risk of Preeclampsia Identification Group. BMJ
with severe-range blood pressures should be managed 2016;353:i1753. (Systematic Review and Meta-Analysis)
with the same approach as for women with severe
9. Ostlund I, Haglund B, Hanson U. Gestational diabetes
preeclampsia. and preeclampsia. Eur J Obstet Gynecol Reprod Biol
< Among women with gestational hypertension or 2004;113:12–6. (Level II-3)
preeclampsia without severe features, expectant 10. Alfirevic Z, Roberts D, Martlew V. How strong is the
management up to 37 0/7 weeks of gestation is rec- association between maternal thrombophilia and adverse
ommended, during which frequent fetal and maternal pregnancy outcome? A systematic review. Eur J Obstet
evaluation is recommended. Fetal monitoring consists Gynecol Reprod Biol 2002;101:6–14. (Systematic
of ultrasonography to determine fetal growth every Review)
3–4 weeks of gestation, and amniotic fluid volume 11. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM,
assessment at least once weekly. In addition, an Garovic VD. A systematic review and meta-analysis of
antenatal test one-to-two times per week for patients pregnancy outcomes in patients with systemic lupus er-
ythematosus and lupus nephritis. Clin J Am Soc Nephrol
with gestational hypertension or preeclampsia with- 2010;5:2060–8. (Systematic Review and Meta-analysis)
out severe features is recommended.
12. Zhang JJ, Ma XX, Hao L, Liu LJ, Lv JC, Zhang H. A
< Epidural or spinal anesthesia is considered acceptable, systematic review and meta-analysis of outcomes of preg-
and the risk of epidural hematoma is exceptionally low, nancy in CKD and CKD outcomes in pregnancy. Clin J
in patients with platelet counts 70 3 109/L or more Am Soc Nephrol 2015;10:1964–78. (Systematic Review
provided that the platelet level is stable, there is no other and Meta-Analysis)
acquired or congenital coagulopathy, the platelet func- 13. Chesley LC, Cooper DW. Genetics of hypertension in
tion is normal, and the patient is not on any antiplatelet pregnancy: possible single gene control of pre-eclampsia
or anticoagulant therapy. and eclampsia in the descendants of eclamptic women. Br
J Obstet Gynaecol 1986;93:898–908. (Level III)
14. Morgan T, Craven C, Lalouel JM, Ward K. Angiotensi-
References nogen Thr235 variant is associated with abnormal physi-
ologic change of the uterine spiral arteries in first-
1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. trimester decidua. Am J Obstet Gynecol 1999;180:95–
Pre-eclampsia. Lancet 2010;376:631–44. (Level III) 102. (Level III)
2. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look 15. Ward K, Hata A, Jeunemaitre X, Helin C, Nelson L,
PF. WHO analysis of causes of maternal death: a system- Namikawa C, et al. A molecular variant of angiotensino-
atic review. Lancet 2006;367:1066–74. (Systematic gen associated with preeclampsia. Nat Genet 1993;4:59–
Review) 61. (Level III)
16. Williams PJ, Broughton Pipkin F. The genetics of pre-
3. Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends
eclampsia and other hypertensive disorders of pregnancy.
in the rates of preeclampsia, eclampsia, and gestational Best Pract Res Clin Obstet Gynaecol 2011;25:405–17.
hypertension, United States, 1987-2004. Am J Hypertens (Level III)
2008;21:521–6. (Level II-3)
17. Homer CS, Brown MA, Mangos G, Davis GK. Non-pro-
4. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates teinuric pre-eclampsia: a novel risk indicator in women
in the United States, 1980-2010: age-period-cohort anal- with gestational hypertension. J Hypertens 2008;26:295–
ysis. BMJ 2013;347:f6564. (Level II-3) 302. (Level II-3)

18. Barton JR, Riely CA, Adamec TA, Shanklin DR, 31. Thornton CE, Makris A, Ogle RF, Tooher JM, Hennessy A.
Khoury AD, Sibai BM. Hepatic histopathologic condition Role of proteinuria in defining pre-eclampsia: clinical out-
does not correlate with laboratory abnormalities in comes for women and babies. Clin Exp Pharmacol Physiol
HELLP syndrome (hemolysis, elevated liver enzymes, 2010;37:466–70. (Level II-3)
and low platelet count). Am J Obstet Gynecol 1992; 32. Williams D. Long-term complications of preeclampsia.
167:1538–43. (Level III) Semin Nephrol 2011;31:111–22. (Level III)
19. Sperling JD, Dahlke JD, Huber WJ, Sibai BM. The role of 33. Barton JR, Sibai BM. Diagnosis and management of
headache in the classification and management of hyper- hemolysis, elevated liver enzymes, and low platelets syn-
tensive disorders in pregnancy. Obstet Gynecol 2015;126: drome. Clin Perinatol 2004;31:807–33, vii. (Level III)
297–302. (Level III)
34. Martin JN Jr, Blake PG, Perry KG Jr, McCaul JF,
20. Thangaratinam S, Gallos ID, Meah N, Usman S, Ismail KM, Hess LW, Martin RW. The natural history of HELLP
Khan KS. How accurate are maternal symptoms in predict- syndrome: patterns of disease progression and regres-
ing impending complications in women with preeclampsia? sion. Am J Obstet Gynecol 1991;164:1500–9; discus-
A systematic review and meta-analysis. TIPPS (Tests in Pre- sion 1509–13. (Level II-3)
diction of Preeclampsia’s Severity) Review Group. Acta Ob- 35. Sibai BM. The HELLP syndrome (hemolysis, elevated
stet Gynecol Scand 2011;90:564–73. (Systematic Review liver enzymes, and low platelets): much ado about noth-
and Meta-Analysis) ing? Am J Obstet Gynecol 1990;162:311–6. (Level III)
21. Report of the National High Blood Pressure Education 36. Martin JN Jr, Rinehart BK, May WL, Magann EF,
Program Working Group on High Blood Pressure in Preg- Terrone DA, Blake PG. The spectrum of severe pre-
nancy. Am J Obstet Gynecol 2000;183:S1–22. (Level III) eclampsia: comparative analysis by HELLP (hemolysis,
22. von Dadelszen P, Payne B, Li J, Ansermino JM, elevated liver enzyme levels, and low platelet count) syn-
Broughton Pipkin F, Cote AM, et al. Prediction of drome classification. Am J Obstet Gynecol 1999;180:
adverse maternal outcomes in pre-eclampsia: develop- 1373–84. (Level II-3)
ment and validation of the fullPIERS model. PIERS 37. Tomsen TR. HELLP syndrome (hemolysis, elevated liver
Study Group. Lancet 2011;377:219–27. (Level II-2) enzymes, and low platelets) presenting as generalized ma-
laise. Am J Obstet Gynecol 1995;172:1876–8; discussion
23. Kuo VS, Koumantakis G, Gallery ED. Proteinuria and its
assessment in normal and hypertensive pregnancy. Am J
Obstet Gynecol 1992;167:723–8. (Level II-3) 38. Brown CE, Cunningham FG, Pritchard JA. Convulsions
in hypertensive, proteinuric primiparas more than 24
24. Morris RK, Riley RD, Doug M, Deeks JJ, Kilby MD. hours after delivery. Eclampsia or some other cause?
Diagnostic accuracy of spot urinary protein and albumin J Reprod Med 1987;32:499–503. (Level III)
to creatinine ratios for detection of significant proteinuria
or adverse pregnancy outcome in patients with suspected 39. Zeeman GG. Neurologic complications of pre-eclampsia.
pre-eclampsia: systematic review and meta-analysis. BMJ Semin Perinatol 2009;33:166–72. (Level III)
2012;345:e4342. (Systematic Review and Meta-Analysis) 40. Sibai BM. Diagnosis, prevention, and management of
eclampsia. Obstet Gynecol 2005;105:402–10. (Level III)
25. Phelan LK, Brown MA, Davis GK, Mangos G. A pro-
spective study of the impact of automated dipstick urinal- 41. Cooray SD, Edmonds SM, Tong S, Samarasekera SP,
ysis on the diagnosis of preeclampsia. Hypertens Whitehead CL. Characterization of symptoms immedi-
Pregnancy 2004;23:135–42. (Level II-3) ately preceding eclampsia. Obstet Gynecol 2011;118:
26. North RA, Taylor RS, Schellenberg JC. Evaluation of
a definition of pre-eclampsia. Br J Obstet Gynaecol 42. Noraihan MN, Sharda P, Jammal AB. Report of 50 cases
1999;106:767–73 (Level II-2) of eclampsia. J Obstet Gynaecol Res 2005;31:302–9.
(Level III)
27. Bernstein PS, Martin JN Jr, Barton JR, Shields LE,
43. Belfort MA, Saade GR, Grunewald C, Dildy GA,
Dru- zin ML, Scavone BM, et al. National Partnership
Abedejos P, Herd JA, et al. Association of cerebral per-
for Maternal Safety: consensus bundle on severe hyper-
fusion pressure with headache in women with pre-eclamp-
tension during pregnancy and the postpartum period.
sia. Br J Obstet Gynaecol 1999;106:814–21. (Level II-3)
Obstet Gynecol 2017;130:347–57. (Level III)
44. Altman D, Carroli G, Duley L, Farrell B, Moodley J,
28. Pettit F, Brown MA. The management of pre-eclampsia: Neilson J, et al. Do women with preeclampsia, and their
what we think we know. Eur J Obstet Gynecol Reprod babies, benefit from magnesium sulphate? The Magpie
Biol 2012;160:6–12. (Level III) Trial: a randomised placebo-controlled trial. Magpie Trial
29. Sibai BM, Stella CL. Diagnosis and management of atyp- Collaboration Group. Lancet 2002;359:1877–90. (Level I)
ical preeclampsia-eclampsia. Am J Obstet Gynecol 2009; 45. Coetzee EJ, Dommisse J, Anthony J. A randomised con-
200:481.e1–7. (Level III) trolled trial of intravenous magnesium sulphate versus
30. Magee LA, von Dadelszen P, Bohun CM, Rey E, placebo in the management of women with severe
El- Zibdeh M, Stalker S, et al. Serious perinatal compli- pre- eclampsia. Br J Obstet Gynaecol 1998;105:300–3.
cations of non-proteinuric hypertension: an international, (Level I)
multicentre, retrospective cohort study. J Obstet Gynaecol 46. Douglas KA, Redman CW. Eclampsia in the United
Can 2003;25:372–82. (Level II-3) Kingdom. BMJ 1994;309:1395–400. (Level II-3)

47. Cunningham FG, Fernandez CO, Hernandez C. Blindness like tyrosine kinase-1 expression under reduced oxygen:
associated with preeclampsia and eclampsia. Am J Obstet an implication for the placental vascular development and
Gynecol 1995;172:1291–8. (Level III) the pathophysiology of preeclampsia. Endocrinology
48. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, 2004;145:4838–45. (Level III)
et al. A reversible posterior leukoencephalopathy syndrome. 62. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A,
N Engl J Med 1996;334:494–500. (Level III) et al. Increased expression of sFlt-1 in in vivo and in vitro
49. Wagner SJ, Acquah LA, Lindell EP, Craici IM, Wingo MT, models of human placental hypoxia is mediated by HIF-1.
Rose CH, et al. Posterior reversible encephalopathy syn- Am J Physiol Regul Integr Comp Physiol 2006;291:R1085–
drome and eclampsia: pressing the case for more aggressive 93. (Level III)
blood pressure control. Mayo Clin Proc 2011;86:851–6. 63. Espinoza J. Uteroplacental ischemia in early- and late-
(Level II-2) onset pre-eclampsia: a role for the fetus? Ultrasound Ob-
50. Singhal AB, Bernstein RA. Postpartum angiopathy and stet Gynecol 2012;40:373–82. (Level III)
other cerebral vasoconstriction syndromes. Neurocrit Care 64. Pritchard JA, Cunningham FG, Pritchard SA. The Park-
2005;3:91–7. (Level III) land Memorial Hospital protocol for treatment of eclamp-
51. Redman CW, Sargent IL. Latest advances in understand- sia: evaluation of 245 cases. Am J Obstet Gynecol 1984;
ing preeclampsia. Science 2005;308:1592–4. (Level III) 148:951–63. (Level III)
52. von Dadelszen P, Magee LA, Roberts JM. Subclassifica- 65. Hankins GD, Wendel GD Jr, Cunningham FG, Leveno KJ.
tion of preeclampsia. Hypertens Pregnancy 2003;22:143– Longitudinal evaluation of hemodynamic changes in
8. (Level III) eclampsia. Am J Obstet Gynecol 1984;150:506–12.
(Level III)
53. Dekker GA, Sibai BM. Etiology and pathogenesis of pre-
eclampsia: current concepts. Am J Obstet Gynecol 1998; 66. Burrows RF, Kelton JG. Thrombocytopenia at delivery:
179:1359–75. (Level III) a prospective survey of 6715 deliveries. Am J Obstet
Gynecol 1990;162:731–4. (Level II-3)
54. Crocker IP, Cooper S, Ong SC, Baker PN. Differences in
apoptotic susceptibility of cytotrophoblasts and syncytio- 67. Giles C, Inglis TC. Thrombocytopenia and macrothrom-
trophoblasts in normal pregnancy to those complicated bocytosis in gestational hypertension. Br J Obstet Gynae-
with preeclampsia and intrauterine growth restriction. col 1981;88:1115–9. (Level II-3)
Am J Pathol 2003;162:637–43. (Level III) 68. Sibai BM, Anderson GD, McCubbin JH. Eclampsia II.
55. Leung DN, Smith SC, To KF, Sahota DS, Baker PN. Clinical significance of laboratory findings. Obstet Gyne-
Increased placental apoptosis in pregnancies complicated col 1982;59:153–7. (Level III)
by preeclampsia. Am J Obstet Gynecol 2001;184:1249– 69. Gant NF, Cunningham FG. Management of preeclampsia.
50. (Level III) Semin Perinatol 1994;18:94–102. (Level III)
56. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CW. 70. Leduc L, Wheeler JM, Kirshon B, Mitchell P, Cotton DB.
Trophoblast deportation and the maternal inflammatory Coagulation profile in severe preeclampsia. Obstet Gyne-
response in pre-eclampsia. J Reprod Immunol 2003; 59: col 1992;79:14–8. (Level III)
71. Spargo B, McCartney CP, Winemiller R. Glomerular cap-
57. Chua S, Wilkins T, Sargent I, Redman C. Trophoblast illary endotheliosis in toxemia of pregnancy. Arch Pathol
deportation in pre-eclamptic pregnancy. Br J Obstet Gy- 1959;68:593–9. (Level III)
naecol 1991;98:973–9. (Level III)
72. Hennessy A, Makris A. Preeclamptic nephropathy.
58. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Nephrology (Carlton) 2011;16:134–43. (Level III)
et al. Soluble endoglin and other circulating antiangiogenic
factors in preeclampsia. CPEP Study Group [published erra- 73. Svenningsen P, Friis UG, Versland JB, Buhl KB, Moller
tum appears in N Engl J Med 2006;355: 1840]. N Engl J Frederiksen B, Andersen H, et al. Mechanisms of renal
Med 2006;355:992–1005. (Level II-2) NaCl retention in proteinuric disease. Acta Physiol (Oxf)
2013;207:536–45. (Level III)
59. Chaiworapongsa T, Espinoza J, Gotsch F, Kim YM,
Kim GJ, Goncalves LF, et al. The maternal plasma solu- 74. Sagen N, Haram K, Nilsen ST. Serum urate as a pre-
ble vascular endothelial growth factor receptor-1 concen- dictor of fetal outcome in severe pre-eclampsia. Acta
tration is elevated in SGA and the magnitude of the Obstet Gynecol Scand 1984;63:71–5. (Level III)
increase relates to Doppler abnormalities in the maternal 75. Espinoza J, Romero R, Mee Kim Y, Kusanovic JP,
and fetal circulation. J Matern Fetal Neonatal Med 2008; Has- san S, Erez O, et al. Normal and abnormal trans-
21:25–40. (Level II-3) formation of the spiral arteries during pregnancy.
60. Crispi F, Dominguez C, Llurba E, Martin-Gallan P, J Perinat Med 2006;34:447–58. (Level III)
Ca- bero L, Gratacos E. Placental angiogenic growth 76. Pijnenborg R, Vercruysse L, Hanssens M. The uterine
factors and uterine artery Doppler findings for charac- spiral arteries in human pregnancy: facts and controver-
terization of different subsets in preeclampsia and in sies. Placenta 2006;27:939–58. (Level III)
isolated intrauterine growth restriction. Am J Obstet 77. Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B.
Gynecol 2006;195: 201–7. (Level II-3) The frequency and severity of placental findings in
61. Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T, women with preeclampsia are gestational age dependent.
Osuga Y, et al. Cytotrophoblasts up-regulate soluble fms- Am J Obstet Gynecol 2003;189:1173–7. (Level II-3)

78. Ogge G, Chaiworapongsa T, Romero R, Hussein Y, nancies at high risk for preterm preeclampsia. N Engl J Med
Kusanovic JP, Yeo L, et al. Placental lesions associated 2017;377:613–22. (Level I)
with maternal underperfusion are more frequent in 90. Rumbold A, Duley L, Crowther CA, Haslam RR. Anti-
early-onset than in late-onset preeclampsia. J Perinat oxidants for preventing pre-eclampsia. Cochrane Data-
Med 2011;39: 641–52. (Level II-2) base of Systematic Reviews 2008, Issue 1. Art. No.:
79. Espinoza J. Recent biomarkers for the identification of CD004227. (Systematic Review and Meta-Analysis)
patients at risk for preeclampsia: the role of uteroplacental 91. Zhou SJ, Yelland L, McPhee AJ, Quinlivan J, Gibson RA,
ischemia. Expert Opin Med Diagn 2012;6:121–30. (Level Makrides M. Fish-oil supplementation in pregnancy does
III) not reduce the risk of gestational diabetes or preeclampsia.
80. Bolin M, Wiberg-Itzel E, Wikstrom AK, Goop M, Am J Clin Nutr 2012;95:1378–84. (Level I)
Larsson A, Olovsson M, et al. Angiopoietin-1/angio- 92. Meher S, Duley L. Garlic for preventing pre-eclampsia
poietin-2 ratio for prediction of preeclampsia. Am J and its complications. Cochrane Database of Systematic
Hypertens 2009;22:891–5. (Level II-2) Reviews 2006, Issue 3. Art. No.: CD006065 (Systematic
81. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Review)
Mittal P, Vaisbuch E, et al. A prospective cohort study 93. Bodnar LM, Catoy JM, Simhan HN, Holick MF, Powers RW,
of the value of maternal plasma concentrations of angio- Roberts JM. Maternal vitamin D deficiency increases the risk
genic and anti-angiogenic factors in early pregnancy and of preeclampsia. J Clin Endocrinol Metab 2007;92:3517–22.
midtrimester in the identification of patients destined to (Level II-2)
develop preeclampsia. J Matern Fetal Neonatal Med
2009;22:1021–38. (Level II-2) 94. Wen SW, White RR, Rybak N, Gaudet LM, Robson S,
Hague W, et al. Effect of high dose folic acid supplemen-
82. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. tation in pregnancy on preeclampsia (FACT): double
First-trimester prediction of hypertensive disorders in preg- blind, phase III, randomised controlled, international,
nancy. Hypertension 2009;53:812–8. (Level II-2) multicentre trial. FACT Collaborating Group. BMJ
83. Espinoza J, Romero R, Nien JK, Gomez R, Kusanovic JP, 2018;362:k3478. (Level I)
Goncalves LF, et al. Identification of patients at risk for 95. Duley L, Henderson-Smart David J. Reduced salt intake
early onset and/or severe preeclampsia with the use of compared to normal dietary salt, or high intake, in preg-
uterine artery Doppler velocimetry and placental growth nancy. Cochrane Database of Systematic Reviews 1999,
factor [published erratum appears in Am J Obstet Gynecol Issue 3. Art. No.: CD001687. (Level III)
2007;196: 614]. Am J Obstet Gynecol 2007;196:326.13.
(Level II-2) 96. Hofmeyr GJ, Lawrie TA, Atallah AN, Torloni MR. Cal-
cium supplementation during pregnancy for preventing
84. Harrington K, Cooper D, Lees C, Hecher K, Campbell S. hypertensive disorders and related problems. Cochrane
Doppler ultrasound of the uterine arteries: the importance Database of Systematic Reviews 2018, Issue 10. Art.
of bilateral notching in the prediction of pre-eclampsia, No.: CD001059. DOI: 10.1002/14651858.CD001059.
placental abruption or delivery of a small-for-gestational- pub5. (Systematic Review)
age baby. Ultrasound Obstet Gynecol 1996;7:182–8.
97. Meher S, Abalos E, Carroli G. Bed rest with or without
(Level II-3)
hospitalisation for hypertension during pregnancy. Co-
85. Albaiges G, Missfelder-Lobos H, Lees C, Parra M, chrane Database of Systematic Reviews 2005, Issue 4.
Nicolaides KH. One-stage screening for pregnancy com- Art. No.: CD003514. (Systematic Review and Meta-Anal-
plications by color Doppler assessment of the uterine ar- ysis)
teries at 23 weeks’ gestation. Obstet Gynecol 2000;96:
98. Benigni A, Gregorini G, Frusca T, Chiabrando C,
559–64. (Level II-3)
Ballerini S, Valcamonico A, et al. Effect of low-dose
86. Papageorghiou AT, Yu CK, Cicero S, Bower S, aspirin on fetal and maternal generation of thromboxane
Nicolaides KH. Second-trimester uterine artery Doppler by platelets in women at risk for pregnancy-induced
screening in unselected populations: a review. J Matern hypertension. N Engl J Med 1989;321:357–62. (Level I)
Fetal Neonatal Med 2002;12:78–88. (Level III)
99. Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E,
87. Papageorghiou AT, Yu CK, Bindra R, Pandis G, Tamarkin M, et al. The use of aspirin to prevent
Nicolaides KH. Multicenter screening for pre-eclampsia pregnancy-induced hypertension and lower the ratio of
and fetal growth restriction by transvaginal uterine artery thromboxane A2 to prostacyclin in relatively high risk
Doppler at 23 weeks of gestation. Fetal Medicine Foun- pregnancies. N Engl J Med 1989;321:351–6. (Level I)
dation Second Trimester Screening Group. Ultrasound 100. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N,
Obstet Gynecol 2001;18:441–9. (Level II-3) Bujold E. The role of aspirin dose on the prevention of
88. Cnossen JS, Morris RK, Ter Riet G, Mol BW, van der preeclampsia and fetal growth restriction: systematic
Post JA, Coomarasamy A, et al. Use of uterine artery review and meta-analysis. Am J Obstet Gynecol 2017;
Doppler ultrasonography to predict preeclampsia and 216:110–20.e6. (Systematic Review and Meta-Analysis)
intrauterine growth restriction: a systematic review and 101. Meher S, Duley L, Hunter K, Askie L. Antiplatelet ther-
bivariable meta-analysis. CMAJ 2008;178:701–11. (Sys- apy before or after 16 weeks’ gestation for preventing
tematic Review and Meta-Analysis) preeclampsia: an individual participant data meta-analy-
89. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, sis. Am J Obstet Gynecol 2017;216:121–8.e2. (System-
de Paco Matallana C, et al. Aspirin versus placebo in preg- atic Review and Meta-Analysis)

102. Alqudah A, McKinley MC, McNally R, Graham U, MEXPRE Latin Study, a randomized, multicenter clinical
Watson CJ, Lyons TJ, et al. Risk of pre-eclampsia in trial. Am J Obstet Gynecol 2013;209:425.e1–8. (Level I)
women taking metformin: a systematic review and
115. Balogun OA, Sibai BM. Counseling, management, and
meta-analysis. Diabet Med 2018;35:160–72. (Systematic
outcome in women with severe preeclampsia at 23 to 28
Review and Meta-Analysis)
weeks’ gestation. Clin Obstet Gynecol 2017;60:183–9.
103. George EM, Granger JP. Mechanisms and potential ther- (Level III)
apies for preeclampsia. Curr Hypertens Rep 2011;13:269–
75. (Level III) 116. Levels of maternal care. Obstetric Care Consensus No. 9.
American College of Obstetricians and Gynecologists.
104. Samangaya RA, Mires G, Shennan A, Skillern L, Howe D, Obstet Gynecol 2019;134:e41–55. (Level III)
McLeod A, et al. A randomised, double-blinded, placebo-
controlled study of the phosphodiesterase type 5 inhibitor 117. Garovic VD. Hypertension in pregnancy: diagnosis and
sildenafil for the treatment of preeclampsia. Hypertens treatment. Mayo Clin Proc 2000;75:1071–6. (Level III)
Pregnancy 2009;28:369–82. (Level I) 118. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J,
105. Trapani A Jr, Goncalves LF, Trapani TF, Vieira S, Hill MN, et al. Recommendations for blood pressure mea-
Pires M, Pires MM. Perinatal and hemodynamic eval- surement in humans and experimental animals: part 1:
uation of sildenafil citrate for preeclampsia treatment: blood pressure measurement in humans: a statement for
a randomized controlled trial. Obstet Gynecol 2016; professionals from the Subcommittee of Professional and
128:253–9. (Level I) Public Education of the American Heart Association
Council on High Blood Pressure Research. Circulation
106. Sibai BM. Management of late preterm and early-term 2005;111:697–716. (Level III)
pregnancies complicated by mild gestational hyperten-
sion/pre-eclampsia. Semin Perinatol 2011;35:292–6. 119. Duley L, Gülmezoglu AM, Henderson-Smart DJ,
(Level III) Chou D. Magnesium sulphate and other anticonvulsants
for women with pre-eclampsia. Cochrane Database of Sys-
107. Koopmans CM, Bijlenga D, Groen H, Vijgen SM, tematic Reviews 2010, Issue 11. Art. No.: CD000025.
Aarnoudse JG, Bekedam DJ, et al. Induction of labour (Systematic Review and Meta-Analysis)
versus expectant monitoring for gestational hypertension
or mild pre-eclampsia after 36 weeks’ gestation (HYPI- 120. Witlin AG, Friedman SA, Egerman RS, Frangieh AY,
TAT): a multicentre, open-label randomised controlled Sibai BM. Cerebrovascular disorders complicating preg-
trial. HY- PITAT study group. Lancet 2009;374:979–88. nancy—beyond eclampsia. Am J Obstet Gynecol 1997;
(Level I) 176:1139–45; discussion 1145–8. (Level III)
108. Schiff E, Friedman SA, Kao L, Sibai BM. The importance 121. Livingston JC, Livingston LW, Ramsey R, Mabie BC,
of urinary protein excretion during conservative manage- Sibai BM. Magnesium sulfate in women with mild pre-
ment of severe preeclampsia. Am J Obstet Gynecol 1996; eclampsia: a randomized controlled trial. Obstet Gynecol
175:1313–6. (Level II) 2003;101:217–20. (Level I)
109. Newman MG, Robichaux AG, Stedman CM, Jaekle RK, 122. Cahill AG, Macones GA, Odibo AO, Stamilio DM. Mag-
Fontenot MT, Dotson T, et al. Perinatal outcomes in pre- nesium for seizure prophylaxis in patients with mild pre-
eclampsia that is complicated by massive proteinuria. Am eclampsia. Obstet Gynecol 2007;110:601–7. (Level III)
J Obstet Gynecol 2003;188:264–8. (Level II-3)
123. Sibai BM. Magnesium sulfate prophylaxis in preeclamp-
110. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. sia: lessons learned from recent trials. Am J Obstet Gy-
Aggressive or expectant management for patients with necol 2004;190:1520–6. (Level III)
severe preeclampsia between 28–34 weeks’ gestation:
a randomized controlled trial. Obstet Gynecol 1990;76: 124. Schrier RW. Body fluid volume regulation in health and
1070–5. (Level I) disease: a unifying hypothesis. Ann Intern Med 1990;113:
111. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggres-
sive versus expectant management of severe preeclampsia 125. Chien PF, Khan KS, Arnott N. Magnesium sulphate in the
at 28 to 32 weeks’ gestation: a randomized controlled treatment of eclampsia and pre-eclampsia: an overview of
trial. Am J Obstet Gynecol 1994;171:818–22. (Level I) the evidence from randomised trials. Br J Obstet Gynaecol
1996;103:1085–91. (Meta-Analysis)
112. Churchill D, Duley L, Thornton JG, Jones L. Interven-
tionist versus expectant care for severe pre-eclampsia 126. Duley L, Henderson-Smart DJ, Walker GJA, Chou D.
between 24 and 34 weeks’ gestation. Cochrane Database Magnesium sulphate versus diazepam for eclampsia. Co-
of Systematic Reviews 2013, Issue 7. Art. No.: chrane Database of Systematic Reviews 2010, Issue 12.
CD003106. (Systematic Review and Meta-Analysis) Art. No.: CD000127. (Systematic Review and Meta-Anal-
ysis)
113. Magee LA, Yong PJ, Espinosa V, Cote AM, Chen I,
von Dadelszen P. Expectant management of severe pre- 127. Belfort MA, Anthony J, Saade GR, Allen JC Jr. A com-
eclampsia remote from term: a structured systematic parison of magnesium sulfate and nimodipine for the pre-
review. Hypertens Pregnancy 2009;28:312–47. (Sys- vention of eclampsia. Nimodipine Study Group. N Engl J
tematic Review) Med 2003;348:304–11. (Level I)
114. Vigil-De Gracia P, Reyes Tejada O, Calle Minaca A, 128. Lu JF, Nightingale CH. Magnesium sulfate in eclampsia
Tellez G, Chon VY, Herrarte E, et al. Expectant manage- and preeclampsia: pharmacokinetic principles. Clin Phar-
ment of severe preeclampsia remote from term: the macokinet 2000;38:305–14. (Level III)

129. Okusanya BO, Oladapo OT, Long Q, Lumbiganon P, Institute of Child Health and Human Development
Carroli G, Qureshi Z, et al. Clinical pharmacokinetic Maternal–Fetal Medicine Units Network. Am J Obstet
properties of magnesium sulphate in women with pre- Gynecol 1999;181:1096–101. (Level II-2)
eclampsia and eclampsia. BJOG 2016;123:356–66. (Sys-
143. Aya AG, Vialles N, Tanoubi I, Mangin R, Ferrer JM,
tematic Review)
Robert C, et al. Spinal anesthesia-induced hypotension:
130. Which anticonvulsant for women with eclampsia? Evi- a risk comparison between patients with severe pre-
dence from the Collaborative Eclampsia Trial [published eclampsia and healthy women undergoing preterm cesar-
erratum appears in Lancet 1995;346:258]. Lancet 1995; ean delivery. Anesth Analg 2005;101:869–75. (Level II-
345:1455–63. (Level I) 2)
131. Dayicioglu V, Sahinoglu Z, Kol E, Kucukbas M. The use 144. Visalyaputra S, Rodanant O, Somboonviboon W,
of standard dose of magnesium sulphate in prophylaxis of Tantivitayatan K, Thienthong S, Saengchote W. Spinal
eclamptic seizures: do body mass index alterations have versus epidural anesthesia for cesarean delivery in severe
any effect on success? Hypertens Pregnancy 2003;22: preeclampsia: a prospective randomized, multicenter
257–65. (Level II-3) study. Anesth Analg 2005;101:862–8. (Level I)
132. Crowther CA, Brown J, McKinlay CJD, Middleton P. 145. Hawkins JL, Koonin LM, Palmer SK, Gibbs CP. Anes-
Magnesium sulphate for preventing preterm birth in thesia-related deaths during obstetric delivery in the
threatened preterm labour. Cochrane Database of System- United States, 1979-1990. Anesthesiology 1997;86:277–
atic Reviews 2014, Issue 8. Art. No.: CD001060. (Sys- 84. (Level III)
tematic Review)
146. Huang CJ, Fan YC, Tsai PS. Differential impacts of
133. Alexander JM, McIntire DD, Leveno KJ, Cunningham
modes of anaesthesia on the risk of stroke among pre-
FG. Selective magnesium sulfate prophylaxis for the pre-
eclamptic women who undergo Caesarean delivery: a pop-
vention of eclampsia in women with gestational hyperten-
ulation-based study. Br J Anaesth 2010;105:818–26.
sion. Obstet Gynecol 2006;108:826–32. (Level II-3)
(Level II-3)
134. Duley L. Magnesium sulphate regimens for women with
eclampsia: messages from the Collaborative Eclampsia 147. Vandermeulen EP, Van Aken H, Vermylen J. Anticoagu-
Trial. Br J Obstet Gynaecol 1996;103:103–5. (Level III) lants and spinal-epidural anesthesia. Anesth Analg 1994;
79:1165–77. (Level III)
135. Duley L, Meher S, Jones L. Drugs for treatment of very
high blood pressure during pregnancy. Cochrane Data- 148. Lee LO, Bateman BT, Kheterpal S, Klumpner TT,
base of Systematic Reviews 2013, Issue 7. Art. No.: Housey M, Aziz MF, et al. Risk of epidural hematoma
CD001449. (Systematic Review and Meta-Analysis) after neuraxial techniques in thrombocytopenic parturi-
ents: a report from the Multicenter Perioperative Out-
136. Emergent therapy for acute-onset, severe hypertension comes Group. Multicenter Perioperative Outcomes
during pregnancy and the postpartum period. ACOG Group Investigators. Anesthesiology 2017;126:1053–63.
Committee Opinion No. 767. American College of Ob- (Systematic Review)
stetricians and Gynecologists. Obstet Gynecol 2019;133:
e174–80. (Level III) 149. van Veen JJ, Nokes TJ, Makris M. The risk of spinal
haematoma following neuraxial anaesthesia or lumbar
137. Alanis MC, Robinson CJ, Hulsey TC, Ebeling M, puncture in thrombocytopenic individuals. Br J Haematol
Johnson DD. Early-onset severe preeclampsia: induction 2010;148:15–25. (Level III)
of labor vs elective cesarean delivery and neonatal outcomes.
Am J Obstet Gynecol 2008;199:262.e1–6. (Level II-3) 150. Taber EB, Tan L, Chao CR, Beall MH, Ross MG. Phar-
macokinetics of ionized versus total magnesium in sub-
138. Blackwell SC, Redman ME, Tomlinson M, Landwehr JB Jr,
jects with preterm labor and preeclampsia. Am J Obstet
Tuynman M, Gonik B, et al. Labor induction for the preterm
Gynecol 2002;186:1017–21. (Level III)
severe pre-eclamptic patient: is it worth the effort? J Matern
Fetal Med 2001;10:305–11. (Level II-3) 151. Al-Safi Z, Imudia AN, Filetti LC, Hobson DT,
139. Sibai BM. Evaluation and management of severe pre- Bahado-Singh RO, Awonuga AO. Delayed postpartum
eclampsia before 34 weeks’ gestation. Publications Com- preeclampsia and eclampsia: demographics, clinical
mittee, Society for Maternal–Fetal Medicine. Am J Obstet course, and complications. Obstet Gynecol 2011;118:
Gynecol 2011;205:191–8. (Level III) 1102–7. (Level II-3)
140. Alexander JM, Bloom SL, McIntire DD, Leveno KJ. 152. Chames MC, Livingston JC, Ivester TS, Barton JR, Sibai
Severe preeclampsia and the very low birth weight infant: BM. Late postpartum eclampsia: a preventable disease?
is induction of labor harmful? Obstet Gynecol 1999;93: Am J Obstet Gynecol 2002;186:1174–7. (Level III)
485–8. (Level II-3) 153. Filetti LC, Imudia AN, Al-Safi Z, Hobson DT, Awonuga
141. Nassar AH, Adra AM, Chakhtoura N, Gomez-Marin O, AO, Bahado-Singh RO. New onset delayed postpartum
Beydoun S. Severe preeclampsia remote from term: labor preeclampsia: different disorders? J Matern Fetal Neona-
induction or elective cesarean delivery? Am J Obstet Gy- tal Med 2012;25:957–60. (Level II-3)
necol 1998;179:1210–3. (Level II-3) 154. Matthys LA, Coppage KH, Lambers DS, Barton JR, Sibai
142. Hogg B, Hauth JC, Caritis SN, Sibai BM, Lindheimer M, BM. Delayed postpartum preeclampsia: an experience of
Van Dorsten JP, et al. Safety of labor epidural anesthesia 151 cases. Am J Obstet Gynecol 2004;190:1464–6.
for women with severe hypertensive disease. National (Level II-3)

155. Blue NR, Murray-Krezan C, Drake-Lavelle S, Weinberg D, and low platelets. Am J Obstet Gynecol 1993;168:
Holbrook BD, Katukuri VR, et al. Effect of ibuprofen vs 1682–7; discussion 1687–90. (Level III)
acetaminophen on postpartum hypertension in preeclamp- 166. Behrens I, Basit S, Melbye M, Lykke JA, Wohlfahrt J,
sia with severe features: a double-masked, randomized con- Bundgaard H, et al. Risk of post-pregnancy hypertension
trolled trial. Am J Obstet Gynecol 2018;218:616.e1–8. in women with a history of hypertensive disorders of
(Level I) pregnancy: nationwide cohort study. BMJ 2017;358:
156. Viteri OA, England JA, Alrais MA, Lash KA, Villegas MI, j3078. (Level II–2)
Ashimi Balogun OA, et al. Association of nonsteroidal 167. Stuart JJ, Tanz LJ, Missmer SA, Rimm EB, Spiegelman
antiinflammatory drugs and postpartum hypertension in D, James-Todd TM, et al. Hypertensive disorders of preg-
women with preeclampsia with severe features. Obstet Gy- nancy and maternal cardiovascular disease risk factor
necol 2017;130:830–5. (Level II-3) development: an observational cohort study. Ann Intern
157. Wasden SW, Ragsdale ES, Chasen ST, Skupski DW. Med 2018;169:224–32. (Level II–2)
Impact of non-steroidal anti-inflammatory drugs on 168. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC,
hypertensive disorders of pregnancy. Pregnancy Hyper- Bell R. Cardiovascular disease risk in women with pre-
tens 2014;4:259–63. (Level II-3) eclampsia: systematic review and meta-analysis. Eur J
158. Anastasio HB, Campbell LE, Buermeyer A, Saccone G, Epidemiol 2013;28:1–19. (Systematic Review and Meta-
Moreno S, Cruz Y, et al. Nonsteroidal antiinflammatory Analysis)
drug administration and postpartum blood pressure in 169. McDonald SD, Malinowski A, Zhou Q, Yusuf S,
women with hypertensive disorders of pregnancy. Obstet Devereaux PJ. Cardiovascular sequelae of preeclamp-
Gynecol 2018;132:1471–6. (Level II–2) sia/eclampsia: a systematic review and meta-analyses. Am
159. Duley L, Henderson-Smart DJ, Chou D. Magnesium sul- Heart J 2008;156:918–30. (Systematic Review and Meta-
phate versus phenytoin for eclampsia. Cochrane Database Analysis)
of Systematic Reviews 2010, Issue 10. Art. No.: 170. Funai EF, Paltiel OB, Malaspina D, Friedlander Y,
CD000128. (Systematic Review and Meta-Analysis) Deutsch L, Harlap S. Risk factors for pre-eclampsia in
nulliparous and parous women: the Jerusalem perinatal
160. Duley L, Gülmezoglu AM, Chou D. Magnesium sulphate
study. Paediatr Perinat Epidemiol 2005;19:59–68. (Level
versus lytic cocktail for eclampsia. Cochrane Database of
II–2)
Systematic Reviews 2010, Issue 9. Art. No.: CD002960.
(Systematic Review and Meta-Analysis) 171. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Car-
diovascular health after maternal placental syndromes
161. Dunn R, Lee W, Cotton DB. Evaluation by computerized (CHAMPS): population-based retrospective cohort study.
axial tomography of eclamptic women with seizures Lancet 2005;366:1797–803. (Level II–3)
refractory to magnesium sulfate therapy. Am J Obstet
Gynecol 1986;155:267–8. (Level III) 172. Grandi SM, Vallee-Pouliot K, Reynier P, Eberg M, Platt RW,
Arel R, et al. Hypertensive disorders in pregnancy and the
162. Sibai BM. Diagnosis, controversies, and management of risk of subsequent cardiovascular disease. Paediatr Perinat
the syndrome of hemolysis, elevated liver enzymes, and Epidemiol 2017;31:412–21. (Level II–3)
low platelet count. Obstet Gynecol 2004;103:981–91.
(Level III) 173. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia,
a disease of the maternal endothelium: the role of antian-
163. Woudstra DM, Chandra S, Hofmeyr GJ, Dowswell T. giogenic factors and implications for later cardiovascular
Corticosteroids for HELLP (hemolysis, elevated liver en- disease. Circulation 2011;123:2856–69. (Level III)
zymes, low platelets) syndrome in pregnancy. Cochrane
174. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ.
Database of Systematic Reviews 2010, Issue 9. Art. No.:
Hypertension in pregnancy and later cardiovascular risk:
CD008148. (Systematic Review and Meta-Analysis)
common antecedents? Circulation 2010;122:579–84.
164. Neiger R, Contag SA, Coustan DR. The resolution of (Level II–2)
preeclampsia-related thrombocytopenia. Obstet Gynecol 175. Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V.
1991;77:692–5. (Level III) Pre-eclampsia and future cardiovascular risk among
165. Sibai BM, Ramadan MK. Acute renal failure in pregnan- women: a review. J Am Coll Cardiol 2014;63:1815–22.
cies complicated by hemolysis, elevated liver enzymes, (Level III)

Published online on May 21, 2020.
The MEDLINE database, the Cochrane Library, and the
American College of Obstetricians and Gynecologists’ Copyright 2020 by the American College of Obstetricians and
own internal resources and documents were used to Gynecologists. All rights reserved. No part of this publication
locate relevant articles published between January may be reproduced, stored in a retrieval system, posted on the
1985–June 2018. Studies were reviewed and evaluated internet, or transmitted, in any form or by any means, elec-
for quality according to the method outlined by the U.S. tronic, mechanical, photocopying, recording, or otherwise,
Preventive Services Task Force: without prior written permission from the publisher.
I Evidence obtained from at least one properly de- American College of Obstetricians and Gynecologists
signed randomized controlled trial. 409 12th Street SW, Washington, DC 20024-2188
II-1 Evidence obtained from well-designed controlled
trials without randomization. Gestational hypertension and preeclampsia. ACOG Practice
II-2 Evidence obtained from well-designed cohort or Bulletin No. 222. American College of Obstetricians and
case–control analytic studies, preferably from Gynecologists. Obstet Gynecol 2020;135:e237–60.
more than one center or research group.
II-3 Evidence obtained from multiple time series with
or without the intervention. Dramatic results in
uncontrolled experiments also could be regarded
as this type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to
the following categories:
Level A—Recommendations are based on good and
consistent scientific evidence.
Level B—Recommendations are based on limited or
inconsistent scientific evidence.
Level C—Recommendations are based primarily on
consensus and expert opinion.
This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use
of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of
care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the
treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such
course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or
technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its
publications may not reflect the most recent evidence. Any updates to this document can be found on acog.org or by calling
the ACOG Resource Center.
While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any
warranty of accuracy, reliability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the
products or services of any firm, organization, or person. Neither ACOG nor its officers, directors, members, employees, or agents
will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential
damages, incurred in connection with this publication or reliance on the information presented.
All ACOG committee members and authors have submitted a conflict of interest disclosure statement related to this published
product. Any potential conflicts have been considered and managed in accordance with ACOG’s Conflict of Interest Disclosure
Policy. The ACOG policies can be found on acog.org. For products jointly developed with other organizations, conflict of interest
disclosures by representatives of the other organizations are addressed by those organizations. The American College of Ob-
stetricians and Gynecologists has neither solicited nor accepted any commercial involvement in the development of the content of
this published product.


Gestational Hypertension and Preeclampsia ACOG.46

Uploaded by

Copyright:

Available Formats

Gestational Hypertension and Preeclampsia ACOG.46

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Gestational Hypertension and Preeclampsia ACOG.46

Uploaded by

Copyright:

Available Formats

INTERIM UPDATE

ACOG PRACTICE BULLETIN

Clinical Management Guidelines for Obstetrician–Gynecologists

Gestational Hypertension and

Background Definitions and Diagnostic Criteria for

VOL. 135, NO. 6, JUNE 2020 OBSTETRICS & GYNECOLOGY e237

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

Level of Risk Risk Factors Recommendation

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

Drug Dose Comments Onset of Action

Hydralazine 5 mg IV or IM, then 5–10 mg IV Higher or frequent dosage 10–20 minutes

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

© 2020 by the American College of Obstetricians

You might also like