Hipertensión gestacional y preeclampsia

Boletín de práctica 
número 222
junio 2020

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Número 222 (Reemplaza al Boletín de Prácticas No. 202, Diciembre 2018)

Boletines del Comité de Práctica—Obstetricia

Este Boletín de Práctica fue desarrollado por el Comité de Boletines de Práctica—Obstetricia del
Colegio Estadounidense de Obstetras y Ginecólogos en colaboración con Jimmy Espinoza, MD,
MSc; Alex Vidaeff, MD, MPH; Christian M. Pettker, MD; y Hyagriv Simhan, MD.

ACTUALIZACIÓN PROVISIONAL: El contenido de este Boletín de práctica se actualizó como se

destaca (o se eliminó según sea necesario) para incluir correcciones editoriales limitadas y
enfocadas a los recuentos de plaquetas, criterios de diagnóstico para la preeclampsia ( Caja 2 ),
y preeclampsia con rasgos severos ( Caja 3 ).
RESUMEN: Los trastornos hipertensivos del embarazo constituyen una de las principales causas
de mortalidad materna y perinatal a nivel mundial. Se ha estimado que la preeclampsia complica
entre el 2% y el 8% de los embarazos en todo el mundo. 1 . En América Latina y el Caribe, los
trastornos hipertensivos son responsables de casi el 26% de las muertes maternas, mientras que
en África y Asia contribuyen al 9% de las muertes. Aunque la mortalidad materna es mucho más
baja en los países de ingresos altos que en los países en desarrollo, el 16 % de las muertes
maternas pueden atribuirse a trastornos hipertensivos 1 2 . En los Estados Unidos, la tasa de

preeclampsia aumentó un 25 % entre 1987 y 2004 3 . Además, en comparación con las mujeres
que dieron a luz en 1980, las que dieron a luz en 2003 tenían un riesgo 6,7 veces mayor de
preeclampsia grave. 4 . Esta complicación es costosa: un estudio informó que en 2012 en los
Estados Unidos, el costo estimado de la preeclampsia dentro de los primeros 12 meses
posteriores al parto fue de $2180 millones ($1030 millones para las mujeres y $1150 millones para
los bebés), que fue desproporcionadamente asumido por los nacimientos prematuros 5 . Este
Boletín de práctica proporcionará pautas para el diagnóstico y manejo de la hipertensión
gestacional y la preeclampsia.

Fondo
Factores de riesgo

Una variedad de factores de riesgo se han asociado con una mayor probabilidad de preeclampsia
Caja 1 6 7 8 9 10 11 12 . No obstante, es importante recordar que la mayoría de los
casos de preeclampsia ocurren en mujeres nulíparas sanas sin factores de riesgo evidentes.
Aunque el papel preciso de las interacciones genético-ambientales en el riesgo y la incidencia de la
preeclampsia no está claro, los datos emergentes sugieren que la tendencia a desarrollar
preeclampsia puede tener algún componente genético 13 14 15dieciséis
.

Caja 1.

Factores de riesgo para la preeclampsia

• nuliparidad
 • gestaciones multifetales

• Preeclampsia en un embarazo anterior

• hipertensión crónica

• diabetes pregestacional

• Diabetes gestacional

• trombomlia

• Lupus eritematoso sistémico

• Índice de masa corporal antes del embarazo superior a 30

• Síndrome de anticuerpos antifosfolípidos

• Edad materna de 35 años o más

• Nefropatía

• tecnología de reproducción asistida

• Apnea obstructiva del sueño

De5niciones y criterios diagnósticos de los trastornos hipertensivos

del embarazo

Preeclampsia (con y sin características graves)

La preeclampsia es un trastorno del embarazo asociado con hipertensión de inicio reciente, que
ocurre con mayor frecuencia después de las 20 semanas de gestación y con frecuencia cerca del
término. Aunque a menudo se acompaña de proteinuria de inicio reciente, la hipertensión y otros
signos o síntomas de preeclampsia pueden presentarse en algunas mujeres en ausencia de
proteinuria. 17 . En ocasiones, la conmanza en los síntomas maternos puede ser problemática en la
práctica clínica. Se cree que el dolor en el cuadrante superior derecho o epigástrico se debe a
necrosis periportal y parenquimatosa focal, edema de células hepáticas o distensión de la cápsula
de Glisson, o una combinación. Sin embargo, no siempre existe una buena correlación entre la
histopatología hepática y las anomalías de laboratorio. 18 . De manera similar, los estudios han
encontrado que usar el dolor de cabeza como criterio de diagnóstico para la preeclampsia con
características graves no es conmable ni especímco. Por lo tanto, se requiere un enfoque de
diagnóstico astuto y circunspecto cuando faltan otros signos y síntomas que lo corroboren,
indicativos de preeclampsia grave. 19 20 . Cabe destacar que, en el contexto de una presentación
clínica similar a la preeclampsia, pero a edades gestacionales menores de 20 semanas, se deben
considerar diagnósticos alternativos, que incluyen, entre otros, púrpura trombocitopénica
trombótica, síndrome urémico hemolítico, embarazo molar, enfermedad renal o enfermedad
autoinmune.
Aunque la hipertensión y la proteinuria se consideran los criterios clásicos para diagnosticar la
preeclampsia, también son importantes otros criterios. En este contexto, se recomienda que a las
mujeres con hipertensión gestacional en ausencia de proteinuria se les diagnostique preeclampsia
si presentan alguna de las siguientes características graves: trombocitopenia (recuento de
plaquetas inferior a 100 000 × 10 9/L); alteración de la función hepática indicada por
concentraciones sanguíneas anormalmente elevadas de enzimas hepáticas (hasta el doble del
límite superior de la concentración normal); dolor severo persistente en el cuadrante superior
derecho o epigástrico y no explicado por diagnósticos alternativos; insumciencia renal
(concentración de creatinina sérica superior a 1,1 mg/dl o una duplicación de la concentración de
creatinina sérica en ausencia de otra enfermedad renal); edema pulmonar; o dolor de cabeza de
inicio reciente que no responde al paracetamol y no se explica por diagnósticos alternativos o
alteraciones visuales Caja 2 . La hipertensión gestacional se demne como una presión arterial
sistólica de 140 mm Hg o más o una presión arterial diastólica de 90 mm Hg o más, o ambas, en
dos ocasiones con al menos 4 horas de diferencia después de 20 semanas de gestación en una
mujer con un embarazo previamente normal. presión arterial 21 . Las mujeres con hipertensión
gestacional con rango severo de presión arterial (una presión arterial sistólica de 160 mm Hg o
superior, o una presión arterial diastólica de 110 mm Hg o superior) deben recibir un diagnóstico
de preeclampsia con características graves. Estos rangos severos de presión arterial o cualquiera
de las características severas enumeradas en Caja 3 aumentar el riesgo de morbilidad y
mortalidad 22 .

Caja 2.

Criterios de diagnóstico para la preeclampsia

Presión arterial

• Presión arterial sistólica de 140 mm Hg o más o presión arterial diastólica de 90 mm

Hg o más en dos ocasiones con al menos 4 horas de diferencia después de 20
semanas de gestación en una mujer con presión arterial previamente normal

• Presión arterial sistólica de 160 mm Hg o más o presión arterial diastólica de 110 mm

Hg o más. (La hipertensión grave se puede conmrmar en un intervalo corto (minutos)
para facilitar la terapia antihipertensiva oportuna).
y

proteinuria

• 300 mg o más por recolección de orina de 24 horas (o esta cantidad extrapolada de

una recolección cronometrada) o

• Proporción proteína/creatinina de 0.3 mg/dL o más o

• Lectura de tira reactiva de 2+ (usado solo si no hay otros métodos cuantitativos

disponibles)

O en ausencia de proteinuria, hipertensión de inicio reciente con el inicio reciente de

cualquiera de los siguientes:

• Trombocitopenia: Recuento de plaquetas inferior a 100 000 × 10 9 /L

• Insumciencia renal: concentraciones de creatinina sérica superiores a 1,1 mg/dl o una

duplicación de la concentración de creatinina sérica en ausencia de otra enfermedad
renal

• Deterioro de la función hepática: concentraciones sanguíneas elevadas de

transaminasas hepáticas al doble de la concentración normal

• Edema pulmonar

• Cefalea de inicio reciente que no responde a la medicación y no se explica por

diagnósticos alternativos o síntomas visuales

Caja 3.

Preeclampsia con características graves

• Systolic blood pressure of 160 mm Hg or more, or diastolic blood pressure of 110 mm

Hg or more on two occasions at least 4 hours apart (unless antihypertensive therapy is
initiated before this time)

• Thrombocytopenia (platelet count less than 100 ,000 × 10 9/L

 • Impaired liver function that is not accounted for by alternative diagnoses and as
indicated by abnormally elevated blood concentrations of liver enzymes (to more than
twice the upper limit normal concentrations), or by severe persistent right upper
quadrant or epigastric pain unresponsive to medications

• Renal insuvciency (serum creatinine concentration more than 1.1 mg/dL or a doubling
of the serum creatinine concentration in the absence of other renal disease)

• Pulmonary edema

• New-onset headache unresponsive to medication and not accounted for by alternative

diagnoses

• Visual disturbances

Proteinuria during pregnancy is demned as 300 mg/dL of protein or more in a 24-hour urine
collection 21 23 or a protein -to-creatinine ratio of 0.30 or more 24 . When quantitative methods
are not available or rapid decisions are required, a urine protein dipstick reading can be substituted.
However, dipstick urinalysis has high false–positive and false–negative test results. A test result of
1+ proteinuria is false–positive in 71% of cases compared with the 300 mg cutoff on 24-hour urine
collection, and even 3+ proteinuria test results may be false–positive in 7% of cases. Using the
same 24-hour urine collection standard, the false–negative rate for dipstick urinalysis is 9% 25 . If
urinalysis is the only available means of assessing proteinuria then overall accuracy is better using
2+ as the discriminant value 25 26 .

Gestational Hypertension
Gestational hypertension is demned as a systolic blood pressure 140 mm Hg or more or a diastolic
blood pressure of 90 mm Hg or more, or both, on two occasions at least 4 hours apart after 20
weeks of gestation, in a woman with a previously normal blood pressure 21 . Gestational
hypertension is considered severe when the systolic level reaches 160 mm Hg or the diastolic level
reaches 110 mm Hg, or both. On occasion, especially when faced with severe hypertension, the
diagnosis may need to be conmrmed within a shorter interval (minutes) than 4 hours to facilitate
timely antihypertensive therapy 27 . Gestational hypertension occurs when hypertension without
proteinuria or severe features develops after 20 weeks of gestation and blood pressure levels
return to normal in the postpartum period 21 . It appears that this diagnosis is more of an exercise
of nomenclature than a pragmatic one because the management of gestational hypertension and
that of preeclampsia without severe features is similar in many aspects, and both require enhanced
surveillance. Outcomes in women with gestational hypertension usually are good, but the notion
that gestational hypertension is intrinsically less concerning than preeclampsia is incorrect.
Gestational hypertension is associated with adverse pregnancy outcomes 17 and may not
represent a separate entity from preeclampsia 28 . Up to 50% of women with gestational
hypertension will eventually develop proteinuria or other end-organ dysfunction consistent with the
diagnosis of preeclampsia, and this progression is more likely when the hypertension is diagnosed
before 32 weeks of gestation 29 30 . Although investigators have reported a higher perinatal
mortality rate in women with nonproteinuric hypertension compared with proteinuric preeclampsia
31 , in a cohort of 1,348 hypertensive pregnant patients, the women with proteinuria progressed

more frequently to severe hypertension and had higher rates of preterm birth and perinatal
mortality; however, women without proteinuria had a higher frequency of thrombocytopenia or liver
dysfunction 17 . Women with gestational hypertension who present with severe-range blood
pressures should be managed with the same approach as for women with severe preeclampsia.
Gestational hypertension and preeclampsia may also be undistinguishable in terms of long-term
cardiovascular risks, including chronic hypertension 32 .

Hemolysis, Elevated Liver Enzymes, and Low Platelet Count

Syndrome
The clinical presentation of hemolysis, elevated liver enzymes, and low platelet count (HELLP)
syndrome is one of the more severe forms of preeclampsia because it has been associated with
increased rates of maternal morbidity and mortality 33 . Although different diagnostic benchmarks
have been proposed 34 , many clinicians use the following criteria 35 to make the diagnosis:
lactate dehydrogenase (LDH) elevated to 600 IU/L or more, aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the
platelets count less than 100 ,000 × 10 9/L. Although HELLP syndrome is mostly a third-trimester
condition, in 30% of cases it is mrst expressed or progresses postpartum. Furthermore, HELLP
syndrome may have an insidious and atypical onset, with up to 15% of the patients lacking either
hypertension or proteinuria 36 . In HELLP syndrome, the main presenting symptoms are right
upper quadrant pain and generalized malaise in up to 90% of cases and nausea and vomiting in
50% of cases 35 37 .

Eclampsia

Eclampsia is the convulsive manifestation of the hypertensive disorders of pregnancy and is

among the more severe manifestations of the disease. Eclampsia is demned by new-onset tonic-
clonic, focal, or multifocal seizures in the absence of other causative conditions such as epilepsy,
cerebral arterial ischemia and infarction, intracranial hemorrhage, or drug use. Some of these
alternative diagnoses may be more likely in cases in which new-onset seizures occur after 48–72
hours postpartum 38 or when seizures occur during administration of magnesium sulfate.

Eclampsia is a signimcant cause of maternal death, particularly in low-resource settings. Seizures

may lead to severe maternal hypoxia, trauma, and aspiration pneumonia. Although residual
neurologic damage is rare, some women may have short-term and long-term consequences such
as impaired memory and cognitive function, especially after recurrent seizures or uncorrected
severe hypertension leading to cytotoxic edema or infarction 39 . Permanent white matter loss has
been documented on magnetic resonance imaging (MRI) after eclampsia in up to one fourth of
women, however, this does not translate into signimcant neurologic demcits 39 .
Eclampsia often (78–83% of cases) is preceded by premonitory signs of cerebral irritation such as
severe and persistent occipital or frontal headaches, blurred vision, photophobia, and altered
mental status. However, eclampsia can occur in the absence of warning signs or symptoms 40
41 . Eclampsia can occur before, during, or after labor. Of note, a signimcant proportion of women

(20–38%) do not demonstrate the classic signs of preeclampsia (hypertension or proteinuria)

before the seizure episode 42 . Headaches are believed to rewect the development of elevated
cerebral perfusion pressure, cerebral edema, and hypertensive encephalopathy 43 .

The term preeclampsia implies that the natural history of patients with persistent hypertension and
signimcant proteinuria during pregnancy is to have tonic–clonic seizures if no prophylaxis if
instituted. However, the results of two randomized placebo-controlled trials indicate that seizure
occurred in only a small proportion of patients with preeclampsia (1.9%) 44 or severe
preeclampsia (3.2%) 45 allocated to the placebo arm of both studies. It is also noteworthy that
there is a signimcant proportion of patients who had abrupt-onset eclampsia without warning signs
or symptoms 40 . In a nationwide analysis of cases of eclampsia in the United Kingdom, it was
noted that in 38% of eclamptic cases the seizure occurred without any prior documentation of
either hypertension or proteinuria in the hospital setting 46 . Thus, the notion that preeclampsia
has a natural linear progression from preeclampsia without severe features to preeclampsia with
severe features and eventually to eclamptic convulsions is inaccurate.

Nervous system manifestations frequently encountered in preeclampsia are headache, blurred

vision, scotomata, and hyperrewexia. Although uncommon, temporary blindness (lasting a few
hours to as long as a week) also may accompany preeclampsia with severe features and
eclampsia 47 . Posterior reversible encephalopathy syndrome (PRES) is a constellation of a range
of clinical neurologic signs and symptoms such as vision loss or demcit, seizure, headache, and
altered sensorium or confusion 48 . Although suspicion for PRES is increased in the setting of
these clinical features, the diagnosis of PRES is made by the presence of vasogenic edema and
hyperintensities in the posterior aspects of the brain on magnetic resonance imaging. Women are
particularly at risk of PRES in the settings of eclampsia and preeclampsia with headache, altered
consciousness, or visual abnormalities 49 . Another condition that may be confused with
eclampsia or preeclampsia is reversible cerebral vasoconstriction syndrome 50 . Reversible
cerebral vasoconstriction syndrome is characterized by reversible multifocal narrowing of the
arteries of the brain with signs and symptoms that typically include thunderclap headache and, less
commonly, focal neurologic demcits related to brain edema, stroke, or seizure. Treatment of women
with PRES and reversible cerebral vasoconstriction syndrome may include medical control of
hypertension, antiepileptic medication and long-term neurologic follow-up.
Pathophysiology

Several mechanisms of disease have been proposed in preeclampsia 1 51 52 including the

following: chronic uteroplacental ischemia 53 , immune maladaptation 53 , very low-density
lipoprotein toxicity 53 , genetic imprinting 53 , increased trophoblast apoptosis or necrosis 54
55 , and an exaggerated maternal inwammatory response to deported trophoblasts 56 57 . More

recent observations suggest a possible role for imbalances of angiogenic factors in the
pathogenesis of preeclampsia 58 . It is possible that a combination of some of these purported
mechanisms may be responsible for triggering the clinical spectrum of preeclampsia. For example,
there is clinical 59 60 and experimental evidence 61 62 suggesting that uteroplacental
ischemia leads to increased circulating concentrations of antiangiogenic factors and angiogenic
imbalances 63 .

Vascular Changes

In addition to hypertension, women with preeclampsia or eclampsia typically lack the hypervolemia
associated with normal pregnancy; thus, hemoconcentration is a frequent mnding 64 . In addition,
the interaction of various vasoactive agents, such as prostacyclin (vasodilator), thromboxane A 2
(potent vasoconstrictor), nitric oxide (potent vasodilator), and endothelins (potent
vasoconstrictors) results in another signimcant change described in preeclampsia: intense
vasospasm. Attempts to correct the contraction of the intravascular space in preeclampsia with
vigorous wuid therapy are likely to be ineffective and could be dangerous because of the frequent
capillary leak and decreased colloid oncotic pressure often associated with preeclampsia.
Aggressive wuid therapy may result in elevation of the pulmonary capillary wedge pressure and
increased risk of pulmonary edema. A study using invasive hemodynamic monitoring in women
with preeclampsia found that before intravenous wuid therapy, women with preeclampsia had
hyperdynamic ventricular function with low pulmonary capillary wedge pressure 65 . However,
after aggressive wuid therapy, the pulmonary capillary wedge pressure increased signimcantly
above normal levels 65 with increased risk of pulmonary edema.

Hematologic Changes
Various hematologic changes also may occur in women with preeclampsia, especially in
preeclampsia with severe features. Thrombocytopenia and hemolysis may occur and may reach
severe levels as part of HELLP syndrome. Thrombocytopenia results from increased platelet
activation, aggregation, and consumption 66 and is a marker of disease severity. A platelet count
less than 150 ,000 × 10 9/L is found in approximately 20% of patients with preeclampsia, varying
from 7% in cases without severe manifestations to 50% in cases with severe manifestations 67 .
However, reduced platelet counts signimcant liver dysfunction, or there is suspected are not found
in all cases of preeclampsia or eclampsia 68 . Interpretation of hematocrit levels in preeclampsia
should take into consideration that hemolysis and hemoconcentration may occur 69 . In some
cases, the hematocrit may not appear decreased despite hemolysis because of baseline
hemoconcentration. Lactate dehydrogenase is present in erythrocytes in high concentration. High
serum concentrations of LDH (more than 600 IU/L) may be a sign of hemolysis 34 35 .

Hepatic Changes

Hepatic function may be signimcantly altered in women with preeclampsia with severe features.
Alanine aminotransferase and AST may be elevated. Aspartate aminotransferase is the dominant
transaminase released into the peripheral circulation in liver dysfunction due to preeclampsia and
is related to periportal necrosis. The fact that AST is increased to a greater extent than ALT, at least
initially, may help in distinguishing preeclampsia from other potential causes of parenchymal liver
disease in which ALT usually is higher than AST. Increased serum levels of LDH in preeclampsia are
caused by hepatic dysfunction (LDH derived from ischemic, or necrotic tissues, or both) and
hemolysis (LDH from red blood cell destruction). Increase in bilirubin secondary to signimcant
hemolysis may develop only in the late stages of the disease. Similarly, alterations in hepatic
synthetic function, as rewected by abnormalities of prothrombin time, partial prothrombin time, and
mbrinogen, usually develop in advanced preeclampsia. Evaluation of these coagulation parameters
is probably only useful when the platelet count is below 150 ,000 × 10 9/L, there is signimcant liver
dysfunction, or there is suspected placental abruption 70 .

Renal Changes
The histopathologic renal changes classically described in preeclampsia as glomerular
endotheliosis consist of swollen, vacuolated endothelial cells with mbrils, swollen mesangial cells,
subendothelial deposits of protein reabsorbed from the glomerular mltrate, and tubular casts 71
72 . Proteinuria in preeclampsia is nonselective, as a result of increased tubular permeability to

most large-molecular-weight proteins (albumin, globulin, transferrin, and hemoglobin). Urinary

calcium decreases because of an increased tubular reabsorption of calcium.

In women with preeclampsia, contraction of the intravascular space secondary to vasospasm leads
to worsening renal sodium and water retention 73 . The normal increase in renal blood wow and
glomerular mltration rate and the expected decrease in serum creatinine may not occur in women
with preeclampsia, especially if the disease is severe. Preeclampsia with severe features may
include acute renal deterioration as part of the clinical spectrum. Oliguria in severe preeclampsia is
a consequence of intrarenal vasospasm with an approximate 25% reduction in glomerular mltration
rate. In these patients, transient oliguria (less than 100 mL over 4 hours) is a common observation
in labor or the mrst 24 hours of the postpartum period. Plasma concentrations of uric acid normally
increase in late pregnancy, and this is thought to be due to increased rates of fetal or placental
production, or both, decreased binding to albumin, and a decrease in uric acid clearance. The
serum uric acid concentration increases to a greater extent in preeclampsia 74 . The most
commonly accepted explanation for hyperuricemia in preeclampsia, besides increased production,
is the increased reabsorption and decreased excretion of uric acid in the proximal renal tubules.

Fetal Consequences

As a result of impaired uteroplacental blood wow secondary to failure of physiologic transformation

of the spiral arteries or placental vascular insults, or both, manifestations of preeclampsia also may
be seen in the fetal–placental unit 63 . Abnormalities in the placental bed and subsequent failure
of physiologic transformation of the spiral arteries in the mrst or early second trimester 75 76
limit the blood wow to the uteroplacental unit. Additional mechanisms for chronic uteroplacental
ischemia include placental vascular insults 77 78 . Among women with preeclampsia, clinical
manifestations that follow from this uteroplacental ischemia include fetal growth restriction,
oligohydramnios, placental abruption, and nonreassuring fetal status demonstrated on antepartum
surveillance. Consequently, fetuses of women with preeclampsia are at increased risk of
spontaneous or indicated preterm delivery.
Clinical Considerations and Recommendations
Are there screening methods that are useful to identify women at risk of developing hypertensive
disorders of pregnancy?

Several studies have evaluated the role of biochemical markers or a combination of biochemical
and biophysical markers in the prediction of preeclampsia in the mrst and second trimesters of
pregnancy 79 . Regardless of the parameters used, screening for preeclampsia in low-risk women
is associated with very low positive predictive values ranging from 8% to 33% 79 . Thus, most
screen–positive patients will not develop the disease and any prophylactic intervention in the
screen-positive group would unnecessarily expose a large number of patients who would not
benemt from these interventions.

In general, the sensitivity and specimcity for the prediction of early-onset preeclampsia using mrst-
trimester 80 81 82 and second-trimester biochemical 81 83 or biophysical parameters 84
85 86 87 are better than for late-onset preeclampsia. The reason for this is still unclear but it is

possible that the timing of the insults to the fetal supply line or the fetal response to these insults
may be different between early-onset and late-onset preeclampsia. Even so, there is limited
evidence that an accurate prediction of early-onset preeclampsia can be followed by interventions
that improve maternal or fetal outcome.
Regardless of the index or combinations of indices used, uterine artery Doppler studies alone have
a low predictive value for the development of early-onset preeclampsia and an even lower value for
late-onset preeclampsia 88 . Extensive work has identimed some angiogenic factors (soluble fms-
like tyrosine kinase-[sFlt-1], placental growth factor [PlGF], and soluble endoglin) in the second
trimester as likely tools for the prediction of early-onset preeclampsia. However, no single test
reliably predicts preeclampsia and further prospective investigation is required to demonstrate
clinical utility. In the mrst trimester of pregnancy, it has been reported that a combination of low
maternal serum concentrations of PlGF, high uterine artery pulsatility index, and other maternal
parameters, identimed 93.1% of patients who would develop preeclampsia requiring delivery before
34 weeks of gestation 82 . However, the results of this study are based on mathematical modeling
derived from a nested case−control study applied to a large cohort of almost 7,800 patients in
which PlGF was measured only in the case−control group. The calculated positive predictive value
was only 21.2%, indicating that approximately 79% of the women in the screen-positive group
would not develop hypertensive disorders during pregnancy 82 . Of note, a similar algorithm
underperformed in a subsequent randomized trial performed by the same research group 89 .
Thus, biomarkers and ultrasonography cannot accurately predict preeclampsia and should remain
investigational.

Are there prevention strategies for reducing the risk of hypertensive disorders of pregnancy?

Strategies to prevent preeclampsia have been studied extensively over the past 30 years. To date,
no intervention has been proved unequivocally effective at eliminating the risk of preeclampsia.
With regard to nutritional interventions, evidence is insuvcient to demonstrate effectiveness for
vitamins C and E 90 , msh oil 91 , garlic supplementation 92 , vitamin D 93 , folic acid 94 or
sodium restriction 95 for reducing the risk of preeclampsia. A meta-analysis of 13 trials (15,730
women) reported a signimcant reduction in preeclampsia with calcium supplementation, with the
greatest effect among women with low-baseline calcium intake ( 96 ). Yet, this is not the case in
the United States or other developed countries. Likewise, data do not support effectiveness of bed
rest and, thus, it should not routinely be recommended 97 .
Investigators hypothesized that an imbalance in prostacyclin and thromboxane A 2 metabolism
was involved in the pathogenesis of preeclampsia, leading to the initial studies of aspirin for
preeclampsia prevention because of its preferential inhibition of thromboxane A 2 at lower doses
98 99 . In a recent meta-analysis of aggregate data from 45 randomized trials, only a modest

reduction in preeclampsia was noted when low-dose aspirin was started after 16 weeks of
gestation (relative risk [RR], 0.81; 95% CI, 0.66–0.99) but a more signimcant reduction in severe
preeclampsia (RR, 0.47; 95% CI, 0.26–0.83) and fetal growth restriction (RR, 0.56; 95% CI, 0.44–
0.70) was demonstrated when low-dose aspirin was started before 16 weeks of gestation 100 . In
contrast, in pooled individual data from 31 high-quality randomized trials, the benemcial effects of
low-dose aspirin were consistent, whether treatment was started before or after 16 weeks of
gestation 101 . Women with any of the high-risk factors for preeclampsia (previous pregnancy with
preeclampsia, multifetal gestation, renal disease, autoimmune disease, type 1 or type 2 diabetes
mellitus, and chronic hypertension) and those with more than one of the moderate-risk factors (mrst
pregnancy, maternal age of 35 years or older, a body mass index [BMI; calculated as weight in
kilograms divided by height in meters squared] of more than 30, family history of preeclampsia,
sociodemographic characteristics, and personal history factors) should receive low-dose (81
mg/day) aspirin for preeclampsia prophylaxis initiated between 12 weeks and 28 weeks of
gestation (optimally before 16 weeks of gestation) and continuing until delivery Table 1 .
In a recent multicenter, double blind, placebo-controlled trial, pregnant women at increased risk of
preterm preeclampsia (less than 37 weeks of gestation) were randomly assigned to receive aspirin,
at a higher dose (150 mg/day), or placebo from 11 weeks to 14 weeks of gestation until 36 weeks
of gestation 89 . Preterm preeclampsia occurred in 1.6% of the participants in the aspirin group, as
compared with 4.3% in the placebo group (odds ratio, 0.38; 95% CI, 0.20−0.74; P=.004). The authors
also reported that there were no signimcant differences in the incidence of neonatal adverse
outcomes between groups. The authors concluded that low-dose aspirin in women at high risk of
preeclampsia was associated with a lower incidence for preterm preeclampsia. However, there
were no differences in the rates of term preeclampsia between study groups. Of note, as a possible
study limitation, the prevalence of preterm preeclampsia in the placebo group was one half of that
expected for a high-risk population based on mrst-trimester parameters 89 .
The use of metformin for the prevention of preeclampsia has been suggested. In a meta-analysis
of mve randomized controlled trials comparing metformin treatment (n=611) with placebo and
control (n=609), no difference in the risk of preeclampsia was found (combined/pooled risk ratio,
0.86; 95% CI, 0.33–2.26); P=.76; I 2=66%) 102 . Because preeclampsia was a secondary outcome in
most studies in this meta-analysis, the effect of metformin needs to be assessed by a study
designed to evaluate the reduction in the prevalence of preeclampsia as a primary endpoint. In the
meantime, the use of metformin for the prevention of preeclampsia remains investigational, as is
the use of sildenaml and statins 103 104 105 . These drugs are not recommended for this indication
outside of the context of clinical trials.

What is the optimal treatment for women with gestational hypertension or preeclampsia?

Delivery Versus Expectant Management

At the initial evaluation, a complete blood count with platelet estimate, serum creatinine, LDH, AST,
ALT, and testing for proteinuria should be obtained in parallel with a comprehensive clinical
maternal and fetal evaluation. In the settings of diagnostic dilemmas, such as in the evaluation of
possible preeclampsia superimposed upon chronic hypertension, a uric acid test may be
considered. Fetal evaluation should include ultrasonographic evaluation for estimated fetal weight
and amount of amniotic wuid, as well as fetal antepartum testing. Subsequent management will
depend on the results of the evaluation and gestational age. The decision to deliver must balance
the maternal and fetal risks.
Continued observation is appropriate for a woman with a preterm fetus if she has gestational
hypertension or preeclampsia without severe features 21 . There are no randomized controlled
trials in this population, but retrospective data suggest that without severe features, the balance
should be in favor of continued monitoring until delivery at 37 0/7 weeks of gestation in the
absence of abnormal antepartum testing, preterm labor, preterm prelabor rupture of membranes
(also referred to as premature rupture of membranes) or vaginal bleeding, for neonatal benemt 106 .
The risks associated with expectant management in the late preterm period include the
development of severe hypertension, eclampsia, HELLP syndrome, placental abruption, fetal
growth restriction and fetal death; however, these risks are small and counterbalanced by the
increased rates of admission to the neonatal intensive care unit, neonatal respiratory complications
and neonatal death that would be associated with delivery before 37 0/7 weeks of gestation 39 .
In the HYPITAT trial, women with gestational hypertension and preeclampsia without severe
features after 36 weeks of gestation were allocated to expectant management or induction of
labor. The latter option was associated with a signimcant reduction in a composite of adverse
maternal outcome including new-onset severe preeclampsia, HELLP syndrome, eclampsia,
pulmonary edema, or placental abruption (RR, 0.71; 95% CI, 0.59–0.86) 107 . In addition, no
differences in rates of neonatal complications or cesarean delivery were reported by the authors
107 .

Continued monitoring of women with gestational hypertension or preeclampsia without severe

features consists of serial ultrasonography to determine fetal growth, weekly antepartum testing,
close monitoring of blood pressure, and weekly laboratory tests for preeclampsia. The frequency of
these tests may be modimed based on clinical mndings and patient symptoms. Following the initial
documentation of proteinuria and the establishment of the diagnosis of preeclampsia, additional
quantimcations of proteinuria are no longer necessary. Although the amount of proteinuria is
expected to increase over time with expectant management, this change is not predictive of
perinatal outcome and should not inwuence the management of preeclampsia 108 109 . Women
should be advised to immediately report any persistent, concerning, or unusual symptoms. In
women with gestational hypertension without severe features, when there is progression to
preeclampsia with severe features, this progression usually takes 1–3 weeks after diagnosis,
whereas in women with preeclampsia without severe features, the progression to severe
preeclampsia could happen within days 72 . Gestational hypertension and preeclampsia are
known risk factors for fetal death and antenatal testing is indicated. However, limited-to-no data
exist regarding when to start testing, the frequency of testing, and which test to use. In women with
gestational hypertension or preeclampsia without severe features at or beyond 37 0/7 weeks of
gestation, delivery rather than expectant management upon diagnosis is recommended.
Preeclampsia with severe features can result in acute and long-term complications for the woman
and her newborn. Maternal complications include pulmonary edema, myocardial infarction, stroke,
acute respiratory distress syndrome, coagulopathy, renal failure, and retinal injury. These
complications are more likely to occur in the presence of preexistent medical disorders. The
clinical course of preeclampsia with severe features is characterized by progressive deterioration
of maternal and fetal condition. Therefore, delivery is recommended when gestational hypertension
or preeclampsia with severe features Box 3 is diagnosed at or beyond 34 0/7 weeks of gestation,
after maternal stabilization or with labor or prelabor rupture of membranes. Delivery should not be
delayed for the administration of steroids in the late preterm period.

In women with preeclampsia with severe features at less than 34 0/7 weeks of gestation, with
stable maternal and fetal condition, expectant management may be considered. Two randomized
controlled trials of delivery versus expectant management of preterm preeclampsia with severe
features demonstrated that expectant management is associated with higher gestational age at
delivery and improved neonatal outcomes 110 111 . These observations were reiterated by a
Cochrane systematic review 112 . The limited available randomized data are consistent with
observational evidence suggesting that expectant management of early preeclampsia with severe
features prolongs pregnancy by 1–2 weeks, has low maternal risk, and improves neonatal
outcomes 113 . In contrast, in a multicenter randomized controlled trial in Latin America, the
authors found no neonatal benemt with expectant management of preeclampsia with severe
features from 28 weeks to 34 weeks of gestation 114 . These different results may rewect the
limitations in neonatal intensive care in low-resource settings.

Embarking on a course of expectant management necessitates adherence to principles of shared

decision making with discussions of maternal and fetal risks and benemts, appropriate resources
(levels of care), and ongoing vigilant surveillance. Close maternal and fetal clinical monitoring is
necessary, and laboratory testing (complete blood count including platelets, liver enzymes, and
serum creatinine) should be performed serially 115 .
The expectant management of preeclampsia with severe features before 34 0/7 weeks of
gestation is based on strict selection criteria of those appropriate candidates and is best
accomplished in a setting with resources appropriate for maternal and neonatal care ( 116 ).
Because expectant management is intended to provide neonatal benemt at the expense of maternal
risk, expectant management is not advised when neonatal survival is not anticipated. During
expectant management, delivery is recommended at any time in the case of deterioration of
maternal or fetal condition, which may include some of the criteria in Box 4 . Indications for
expedited delivery irrespective of gestational age after maternal stabilization are described in
Box 4 115 .

Box 4.
Conditions Precluding Expectant Management

Maternal

• Uncontrolled severe-range blood pressures (persistent systolic blood pressure 160 mm

Hg or more or diastolic blood pressure 110 mm Hg or more not responsive to
antihypertensive medication

• Persistent headaches, refractory to treatment

• Epigastric pain or right upper pain unresponsive to repeat analgesics

• Visual disturbances, motor demcit or altered sensorium

• Stroke

• Myocardial infarction

• HELLP syndrome

• New or worsening renal dysfunction (serum creatinine greater than 1.1 mg/dL or twice
baseline)

• Pulmonary edema

• Eclampsia

• Suspected acute placental abruption or vaginal bleeding in the absence of placenta

previa
 Fetal

• Abnormal fetal testing

• Fetal death

• Fetus without expectation for survival at the time of maternal diagnosis (eg, lethal
anomaly, extreme prematurity)

• Persistent reversed end-diastolic wow in the umbilical artery

Abbreviation: HELLP, hemolysis, elevated liver enzymes, and low platelet count.

In some cases, a course of antenatal steroids can be considered depending on

gestational age and maternal severity of illness.

Data from Balogun OA, Sibai BM. Counseling, management, and outcome in women with
severe preeclampsia at 23 to 28 weeks' gestation. Clin Obstet Gynecol 2017;60:183–9.

If delivery is indicated at less than 34 0/7 weeks of gestation, administration of corticosteroids for
fetal lung maturation is recommended 115 ; however, delaying delivery for optimal corticosteroid
exposure may not always be advisable. Maternal or fetal deterioration may preclude completion of
the course of steroid treatment. Previously, fetal growth restriction was considered an indication
for delivery. In the setting of normal fetal parameters (eg, amniotic wuid volume, Doppler mndings,
antenatal fetal testing), continuation of expectant management may be reasonable in the absence
of other, aforementioned maternal and fetal criteria.

Inpatient Versus Outpatient Management

Ambulatory management at home is an option only for women with gestational hypertension or
preeclampsia without severe features and requires frequent fetal and maternal evaluation.
Hospitalization is appropriate for women with severe features and for women in whom adherence
to frequent monitoring is a concern. Because assessment of blood pressure is essential for this
clinical condition, health care providers are encouraged to follow the recommendations from
regulatory bodies regarding the proper technique for blood pressure measurement. Having a blood
pressure cuff that is too small or too large may result in erroneous evaluations. To reduce
inaccurate readings, an appropriate size cuff should be used (length 1.5 times upper arm
circumference or a cuff with a bladder that encircles 80% or more of the arm). The blood pressure
level should be taken with an appropriately-sized cuff with the patient in an upright position after a
10-minute or longer rest period. For patients in the hospital, the blood pressure can be taken with
either the patient sitting up or in the left lateral recumbent position with the patient’s arm at the
level of the heart 117 . The patient should not use tobacco or caffeine for 30 minutes preceding the
measurement because these agents can temporarily lead to increased blood pressure 118 .

If home management is selected, frequent fetal and maternal evaluation are required. No
randomized trials have determined the best tests for fetal or maternal evaluation. Among women
with gestational hypertension or preeclampsia without severe features, expectant management up
to 37 0/7 weeks of gestation is recommended, during which frequent fetal and maternal evaluation
is recommended. Fetal monitoring consists of ultrasonography to determine fetal growth every 3–4
weeks of gestation and amniotic wuid volume assessment at least once weekly. In addition, an
antenatal test one-to-two times per week for patients with gestational hypertension or
preeclampsia without severe features is recommended.

Maternal evaluation consists primarily of frequent evaluation for either the development of or
worsening of preeclampsia. In women with gestational hypertension or preeclampsia without
severe features, weekly evaluation of platelet count, serum creatinine, and liver enzyme levels is
recommended. In addition, for women with gestational hypertension, once weekly assessment of
proteinuria is recommended. However, these tests should be repeated sooner if disease
progression is a concern. In addition, women should be asked about symptoms of preeclampsia
with severe features (eg, severe headaches, visual changes, epigastric pain, and shortness of
breath). Blood pressure measurements and symptom assessment are recommended serially, using
a combination of in-clinic and ambulatory approaches, with at least one visit per week in-clinic.

Intrapartum Management
In addition to appropriate management of labor and delivery, the two main goals of management of
women with preeclampsia during labor and delivery are 1) prevention of seizures and 2) control of
hypertension.

Seizure Prophylaxis

The prevention of eclampsia is empirically based on the concept of timely delivery, as previously
discussed, once preeclampsia has been diagnosed. A signimcant body of evidence attests to the
evcacy of magnesium sulfate to prevent seizures in women with preeclampsia with severe
features and eclampsia. In the Magpie study, a randomized placebo-controlled trial with 10,110
participants (two thirds originating from developing countries), the seizure rate was reduced overall
by more than one half with this treatment. It is interesting to note that the reduction in the rate of
eclampsia was not statistically signimcant 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 that included the Magpie study and mve other studies, magnesium sulfate compared with
placebo more than halved the risk of eclampsia (RR, 0.41; 95% CI, 0.29–0.58), reduced the risk of
placental abruption (RR, 0.64; 95% CI, 0.50–0.83), and reduced the risk of maternal mortality albeit
nonsignimcantly (RR, 0.54; 95% CI, 0.26–1.10). There were no differences in maternal morbidity or
perinatal mortality. A quarter of women reported adverse effects with magnesium sulfate, primarily
hot wushes, and the rate of cesarean delivery was increased by 5% when magnesium sulfate was
used 119 .

There is no consensus regarding the prophylactic use of magnesium sulfate for the prevention of
seizures in women with gestational hypertension or preeclampsia without severe features. Two
small randomized trials (total n=357) allocated women with preeclampsia without severe features
to either placebo or magnesium sulfate and reported no cases of eclampsia among women
allocated to placebo and no signimcant differences in the proportion of women that progressed to
severe preeclampsia 120 121 . However, given the small sample size, the results of these studies
cannot be used for clinical guidance 122 123 .
The rate of seizures in preeclampsia with severe features without magnesium sulfate prophylaxis
is four times higher than in those without severe features (4 in 200 versus 1 in 200). It has been
calculated that 129 women need to be treated to prevent one case of eclampsia in asymptomatic
cases, whereas in symptomatic cases (severe headache, blurred vision, photophobia, hyperrewexia,
epigastric pain), the number needed to treat is 36 124 . The evidence regarding the benemt-to-risk
ratio of magnesium sulfate prophylaxis is less supportive of routine use in preeclampsia without
severe features 122 . The clinical decision of whether to use magnesium sulfate for seizure
prophylaxis in patients with preeclampsia without severe features should be determined by the
physician or institution, considering patient values or preferences, and the unique risk-benemt trade-
off of each strategy. Although the benemt-to-risk ratio for routine prophylaxis is less compelling for
patients in high resource settings, it is recommended that magnesium sulfate should be used for
the prevention and treatment of seizures in women with gestational hypertension with severe
features and preeclampsia with severe features or eclampsia 124 125 .

Magnesium sulfate is more effective than phenytoin, diazepam, or nimodipine (a calcium-channel

blocker used in clinical neurology to reduce cerebral vasospasm) in reducing eclampsia and should
be considered the drug of choice in the prevention of eclampsia in the intrapartum and postpartum
periods 119 126 127 . Benzodiazepines and phenytoin are justimed only in the context of
antiepileptic treatment or when magnesium sulfate is contraindicated or unavailable (myasthenia
gravis, hypocalcemia, moderate-to-severe renal failure, cardiac ischemia, heart block, or
myocarditis).

There are still sparse data regarding the ideal dosage of magnesium sulfate. Even the therapeutic
range of 4.8–9.6 mg/dL (4–8 mEq/L) quoted in the literature is questionable 128 129 . Although
there is a relationship between toxicity and plasma concentration of magnesium, with higher
infusion rates increasing the potential for toxicity, the accurate magnesium concentration clinically
effective in prevention of eclampsia has not been established. Seizures occur even with
magnesium at a therapeutic level, whereas several trials using infusion rates of 1 g/hour, frequently
associated with subtherapeutic magnesium levels, were able to signimcantly reduce the rate of
eclampsia or recurrent convulsions 44 130 . Further complicating aspects are that steady
magnesium levels are reached more slowly during the antepartum period than postpartum period.
Larger volume of distribution and higher BMI also affect the dosage and duration needed to reach
adequate circulating levels. It has been reported in patients with a high BMI (especially greater than
35) that the antepartum level of magnesium may remain subtherapeutic for as long as 18 hours
after infusion initiation when an intravenous loading dose of 4.5 g followed by 1.8 g/hour is used
131 . However, infusion rates in excess of 2 g/hour have been associated with increased perinatal
mortality in a systematic review of randomized studies of magnesium sulfate used for tocolysis
132 . These data may be considered supportive for the regimen generally preferred in the United
States (intravenous [IV] administration of a 4–6 g loading dose over 20–30 minutes, followed by a
maintenance dose of 1–2 g/hour). For women requiring cesarean delivery (before onset of labor),
the infusion should ideally begin before surgery and continue during surgery, as well as for 24
hours afterwards. For women who deliver vaginally, the infusion should continue for 24 hours after
delivery. In case of divculties with establishing venous access, magnesium sulfate can be
administered by intramuscular (IM) injection, 10 g initially as a loading dose (5 g IM in each
buttock), followed by 5 g every 4 hours. The medication can be mixed with 1 mL of xylocaine 2%
solution because the intramuscular administration is painful. The rate of adverse effects is also
higher with the intramuscular administration 44 . The adverse effects of magnesium sulfate
(respiratory depression and cardiac arrest) come largely from its action as a smooth muscle
relaxant. Deep tendon rewexes are lost at a serum magnesium level of 9 mg/dL (7 mEq/L),
respiratory depression occurs at 12 mg/dL (10 mEq/L), and cardiac arrest at 30 mg/dL (25 mEq/L).
Accordingly, provided deep tendon rewexes are present, more serious toxicity is avoided. Table 2
Because magnesium sulfate is excreted almost exclusively in the urine, measuring urine output
should be part of the clinical monitoring, in addition to monitoring of respiration status and tendon
rewexes. If renal function is impaired, serum magnesium levels will increase quickly, which places
the patient at risk of signimcant adverse effects. In patients with mild renal failure (serum creatinine
1.0–1.5 mg/dL) or oliguria (less than 30 mL urine output per hour for more than 4 hours), the
loading dose of 4–6 g should be followed by a maintenance dose of only 1 gm/hour. Using a lower
loading dose, such as 4 g, may be associated with subtherapeutic levels for at least 4 hours after
loading 133 . In cases with renal dysfunction, laboratory determination of serum magnesium levels
every 4 hours becomes necessary. If the serum level exceeds 9.6 mg/dL (8 mEq/L), the infusion
should be stopped and serum magnesium levels should be determined at 2-hour intervals. The
infusion can be restarted at a lower rate when the serum level decreases to less than 8.4 mg/dL (7
mEq/L) 133 . The serum concentration of magnesium is related to the occurrence of adverse
effects and toxicities Table 2 128 134 . Patients at risk of impending respiratory depression may
require tracheal intubation and emergency correction with calcium gluconate 10% solution, 10 mL
IV over 3 minutes, along with furosemide intravenously to accelerate the rate of urinary excretion.
Antihypertensive Approach: Drugs and Thresholds for Treatment
The objectives of treating severe hypertension are to prevent congestive heart failure, myocardial
ischemia, renal injury or failure, and ischemic or hemorrhagic stroke. Antihypertensive treatment
should be initiated expeditiously for acute-onset severe hypertension (systolic blood pressure of
160 mm Hg or more or diastolic blood pressure of 110 mm Hg or more, or both) that is conmrmed
as persistent (15 minutes or more). The available literature suggests that antihypertensive agents
should be administered within 30–60 minutes. However, it is recommended to administer
antihypertensive therapy as soon as reasonably possible after the criteria for acute-onset severe
hypertension are met. Intravenous hydralazine or labetalol and oral nifedipine are the three agents
most commonly used for this purpose Table 3 . A recent Cochrane systematic review that
involved 3,573 women found no signimcant differences regarding either evcacy or safety between
hydralazine and labetalol or between hydralazine and calcium channel blockers 135 . Thus, any of
these agents can be used to treat acute severe hypertension in pregnancy 135 136 . Although
parenteral antihypertensive therapy may be needed initially for acute control of blood pressure, oral
medications can be used as expectant management is continued. Oral labetalol and calcium
channel blockers have been commonly used. One approach is to begin an initial regimen of
labetalol at 200 mg orally every 12 hours and increase the dose up to 800 mg orally every 8–12
hours as needed (maximum total 2,400 mg/d). If the maximum dose is inadequate to achieve the
desired blood pressure goal, or the dosage is limited by adverse effect, then short-acting oral
nifedipine can be added gradually.
Monitoring for Disease Progression

Because the clinical course of gestational hypertension or preeclampsia without severe features
can evolve during labor, all women with gestational hypertension or preeclampsia without severe
features who are in labor must be monitored for early detection of progression to severe disease.
This should include monitoring of blood pressure and symptoms during labor and delivery as well
as immediately after delivery. Magnesium sulfate therapy should be initiated if there is progression
to preeclampsia with severe features. The evidence regarding the benemt-to-risk ratio of
magnesium sulfate prophylaxis is less supportive of routine use in preeclampsia without severe
features 122 . The clinical decision of whether to use magnesium sulfate for seizure prophylaxis in
patients with preeclampsia without severe features should be determined by the physician or
institution, considering patient values or preferences and the unique risk-benemt trade-off of each
strategy.

Mode of Delivery

The mode of delivery in women with gestational hypertension or preeclampsia (with or without
severe features) should be determined by routine obstetric considerations. Vaginal delivery often
can be accomplished, but with labor induction in preeclampsia with severe features this is less
likely with decreasing gestational age at diagnosis. The likelihood of cesarean delivery at less than
28 weeks of gestation could be as high as 97%, and at 28–32 weeks of gestation as high as 65%
137 138 139 . For gestational hypertension or preeclampsia without severe features, vaginal

delivery is preferred 137 138 139 . Retrospective studies comparing induction of labor with
cesarean delivery in women with preeclampsia with severe features remote from term concluded
that induction of labor was reasonable and was not harmful to low-birth-weight infants 140 141 .
The decision to perform cesarean delivery should be individualized, based on anticipated
probability of vaginal delivery and on the nature and progression of preeclampsia disease state.

Anesthesia Considerations
With improved techniques over the past decades, regional anesthesia has become the preferred
technique for women with preeclampsia with severe features and eclampsia for labor and delivery.
A secondary analysis of women with preeclampsia with severe features in a randomized trial of
low-dose aspirin reported that epidural anesthesia was not associated with an increased rate of
cesarean delivery, pulmonary edema, or renal failure 142 . Also, in a prospective study, the incidence
and severity of hypotension did not appear to be increased with spinal anesthesia for cesarean
delivery in women with preeclampsia with severe features (n=65) compared with women without
preeclampsia 143 .

When the use of spinal or epidural anesthesia in women with preeclampsia with severe features
was compared in a randomized trial 144 , the incidence of hypotension was higher in the spinal
group (51% versus 23%) but was easily treated and of short duration (less than 1 minute). General
anesthesia carries more risk to pregnant women than regional anesthesia does because of the risk
of aspiration, failed intubation because of pharyngolaryngeal edema, and stroke secondary to
increased systemic and intracranial pressures during intubation and extubation 145 146 . However,
neuraxial anesthesia and analgesia are contraindicated in the presence of a coagulopathy because
of the potential for hemorrhagic complications 147 . Thrombocytopenia also increases the risk of
epidural hematoma. There is no consensus in regard to the safe lower-limit for platelet count and
neuraxial anesthesia. The literature offers only limited and retrospective data to address this issue,
but a recent retrospective cohort study of 84,471 obstetric patients from 19 institutions combined
with a systematic review of the medical literature support the assertion that the risk of epidural
hematoma from neuraxial anesthetics in a parturient patient with a platelet count of more than 70 ×
10 9/L is exceptionally low (less than 0.2%) 148 . Extrapolating this expanded data to previous
recommendations 149 would suggest that epidural or spinal anesthesia is considered acceptable,
and the risk of epidural hematoma is exceptionally low, in patients with platelet counts of 70 × 10
9
/L or more provided that the platelet level is stable, there is no other acquired or congenital
coagulopathy, the platelet function is normal, and the patient is not on any antiplatelet or
anticoagulant therapy 148 149 .
Magnesium sulfate has signimcant anesthetic implications because it prolongs the duration of
nondepolarizing muscle relaxants. However, women with preeclampsia who require cesarean
delivery should continue magnesium sulfate infusion during the delivery. This recommendation is
based on the observation that magnesium sulfate half-life is 5 hours and that discontinuation of
the infusion of magnesium sulfate before cesarean delivery would only minimally reduce
magnesium concentration at the time of delivery while possibly increasing the risk of seizure 150 .
Women with preeclampsia with severe features undergoing cesarean delivery remain at risk of
developing eclampsia. The induction of general anesthesia and the stress of delivery may even
reduce the seizure threshold and increase the likelihood of eclampsia in the immediate postpartum
period if the infusion of magnesium sulfate is stopped during delivery.

Postpartum Hypertension and Postpartum Headache

Postpartum hypertension and preeclampsia are either persistent or exacerbated hypertension in

women with previous hypertensive disorders of pregnancy or a new-onset condition. It is important
to increase the awareness among health care providers and to empower patients to seek medical
advice if symptoms that precede eclampsia, hypertensive encephalopathy, pulmonary edema, or
stroke are noted in the postpartum period. Most women who present with eclampsia and stroke in
the postpartum period have these symptoms for hours or days before presentation 151 152 153
154 . Some common medications and substances used in the postpartum period may potentially

aggravate hypertension through three major mechanisms: volume retention, sympathomimetic

activation, and direct vasoconstriction. Of particular interest are nonsteroidal antiinwammatory
drugs (NSAIDs), which are frequently prescribed as postpartum analgesics. These medications
decrease prostaglandins leading to a lack of vasodilation and increased sodium retention.
Nonsteroidal anti-inwammatory medications should continue to be used preferentially over opioid
analgesics; however, women with chronic hypertension may theoretically require intensimcation of
blood pressure monitoring and regimen adjustments when on these medications. Overall, data
support the safe use of NSAIDs in postpartum patients with blood pressure issues. In a
randomized trial comparing use of ibuprofen to acetaminophen in postpartum patients with
preeclampsia with severe features, ibuprofen did not lengthen the duration of severe-range blood
pressures 155 . In a cohort of 399 patients with preeclampsia with severe features, there was no
association of NSAID use with postpartum blood pressure elevations 156 . Further, another cohort
study of postpartum patients on magnesium for seizure prophylaxis for preeclampsia did not show
differences in blood pressure, antihypertensive requirements, or other adverse events for patients
managed with NSAIDs in the postpartum period 157 158 .
What is the optimal treatment for eclampsia?

The initial steps in the management of a woman with eclampsia are basic supportive measures
such as calling for help, prevention of maternal injury, placement in lateral decubitus position,
prevention of aspiration, administration of oxygen, and monitoring vital signs including oxygen
saturation. Only subsequently is attention directed to the administration of magnesium sulfate.
Most eclamptic seizures are self-limited. Magnesium sulfate is not necessary to arrest the seizure
but to prevent recurrent convulsions.

During eclamptic seizures, there are usually prolonged fetal heart rate decelerations, even fetal
bradycardia, and sometimes an increase in uterine contractility and baseline tone. After a seizure,
because of maternal hypoxia and hypercarbia, the fetal heart rate tracing may show recurrent
decelerations, tachycardia, and reduced variability. However, only after maternal hemodynamic
stabilization should one proceed with delivery. Furthermore, maternal resuscitation is usually
followed by normalization of the fetal tracing.

Cochrane reviews, including data originating from developing countries, indicate a signimcant
reduction in recurrent seizures and eclampsia-related maternal mortality with the use of
magnesium sulfate. Magnesium sulfate administered intramuscularly or intravenously is superior
to phenytoin, diazepam, or lytic cocktail (usually chlorpromazine, promethazine, and pethidine) and
also is associated with less maternal and neonatal morbidity 126 159 160 . Thus, these data
support the use of magnesium sulfate as the drug of choice to prevent recurrent seizures in
women with eclampsia. In the rare cases of an extremely agitated patient, IV clonazepam 1 mg,
diazepam 10 mg, or midazolam may be used for sedation to facilitate the placement of the IV lines
and Foley catheter, and the collection of blood specimens. These drugs should be used cautiously
and only if absolutely necessary because they inhibit laryngeal rewexes, increasing the risk of
aspiration and also may depress the central respiratory centers leading to apnea.

Women with eclampsia should be delivered in a timely fashion. However, eclampsia by itself is not
an indication for cesarean delivery. Once the patient is stabilized, the method of delivery should
depend, in part, on factors such as gestational age, fetal presentation, and the mndings of the
cervical examination. A high rate of failure may be anticipated with induction or augmentation in
pregnancies less than 30 weeks of gestation if the patient is not in active labor and the Bishop
score is unfavorable. In these cases, it may be preferable to opt for cesarean delivery without
further delay. However, patients that adequately progress in labor could be allowed to continue
labor even after an eclamptic seizure.
It has been proposed that when convulsions recur, a further 2–4 grams of magnesium sulfate
could be administered IV over 5 minutes 130 . In cases refractory to magnesium sulfate (still
seizing at 20 minutes after the bolus or more than two recurrences), a health care provider can use
sodium amobarbital (250 mg IV in 3 minutes), thiopental, or phenytoin (1,250 mg IV at a rate of 50
mg/minute). Endotracheal intubation and assisted ventilation in the intensive care unit are
appropriate in these circumstances. Head imaging should also be considered because most of
cases refractory to magnesium sulfate therapy may prove to have abnormal mndings on brain
imaging ( 161 ).

What is the management of acute complications for preeclampsia with HELLP?

The clinical course of HELLP syndrome often is characterized by progressive and sometimes
sudden deterioration in maternal and fetal condition. Considering the serious nature of this entity,
with increased rates of maternal morbidity and mortality, many authors have concluded that
women with HELLP syndrome should be delivered regardless of their gestational age. Because the
management of patients with HELLP syndrome requires the availability of neonatal and obstetric
intensive care units and personnel with special expertise, patients with HELLP syndrome who are
remote from term should receive care at a tertiary care center 116 162 .

It has been hypothesized that the antiinwammatory and immunosuppressive effects of

corticosteroids may modify some of the proinwammatory features of preeclampsia with severe
features and favorably affect the clinical course. Several randomized controlled trials of high-dose
corticosteroid treatment for antepartum or postpartum stabilization of HELLP syndrome have been
conducted. The use of corticoids in the management of HELLP syndrome compared with placebo
or no treatment was reviewed in a Cochrane Database Systematic Review, which included 11
randomized trials (550 women) ( 163 ). There was no difference in the risk of maternal death,
severe maternal morbidity, or perinatal or infant death. The only effect of treatment on individual
outcomes was improved platelet count (standardized mean difference [SMD] 0.67; 95% CI,
0.24−1.10). The authors concluded that the evidence is insuvcient to support the use of
corticosteroids for attenuation of the disease process in HELLP syndrome ( 163 ).
Very close monitoring is required in HELLP syndrome until delivery and in the postpartum period,
with laboratory testing at least at 12-hour intervals. Aspartate aminotransferase levels more than
2,000 IU/L or LDH more than 3,000 IU/L suggest an increased mortality risk. In the natural history
of HELLP syndrome there is an inverse relationship between the trends in platelet values and liver
enzymes level. During the aggravation slope in the disease evolution, platelet count usually
decreases at an average rate of approximately 40% per day, whereas the liver enzymes values tend
to increase. The lowest observed platelet count occurs at a mean of 23 hours after delivery. The
disease may achieve peak intensity during the mrst 2 days after delivery, including a downward
trend in hematocrit. If the platelet count continues to drop and liver enzymes to increase after 4
days postpartum, the validity of the initial diagnosis of HELLP syndrome should be reassessed.
With supportive care alone, 90% of patients with HELLP syndrome will have platelet count more
than 100 ,000× 10 9/L and reversed trend (decrease) in liver enzymes values within 7 days after
delivery. Not infrequently, a rebound phenomenon in platelet count follows reaching values of 40 0
,000–871 ,000 × 10 9/L ( 164 ). Women with HELLP syndrome are also at increased risk of
pulmonary edema, acute respiratory distress syndrome and renal failure ( 165 ).

What are the risks of subsequent cardiovascular disease among women with hypertensive
disorders of pregnancy and are there prevention strategies that modify this risk?

Women with a history of preeclampsia continue to have an elevated risk of cardiovascular disease
in subsequent years. Several systematic reviews and meta-analyses have linked preeclampsia with
an increased risk of cardiovascular disease (hypertension, myocardial infarction, congestive heart
failure), cerebrovascular events (stroke), peripheral arterial disease, and cardiovascular mortality
later in life, with an estimated doubling of odds compared with women unaffected by preeclampsia
( 166 167 168 ). Meta-regression analysis reveals a graded relationship between the severity of
preeclampsia or eclampsia and the risk of cardiac disease (mild: RR, 2.00; 95% CI, 1.83–2.19;
moderate: RR, 2.99; 95% CI, 2.51–3.58; severe: RR, 5.36; 95% CI, 3.96–7.27, P<.0001) ( 169 ). The
risk is even higher (4–8 times the risk for women with normal pregnancies) in women with
recurrent preeclampsia ( 170 ) and women with early-onset preeclampsia or preeclampsia requiring
preterm delivery ( 171 ). More recent evidence suggests that all hypertensive conditions in
pregnancy are associated with later cardiovascular disease with an approximately doubling of the
rate of incident cardiovascular disease and a mve times higher rate of hypertension ( 172 ).
The mechanisms that account for an increased risk of cardiovascular disease in women with a
history of preeclampsia are not yet well understood, but endothelial dysfunction, which has been
linked to atherosclerosis, persists in women with a history of preeclampsia many years after an
affected pregnancy ( 173 ). A study of cardiovascular risk factors present before and after
pregnancy suggested that nearly one half of the elevated risk of future hypertension after
preeclampsia can be explained by prepregnancy risk factors ( 174 ). Yet, it may be possible that the
stress incurred to the cardiovascular system during gestation triggers a biological response that
would otherwise not have occurred despite any genetic predisposition or risk factors ( 172 ). It
remains unclear if cardiovascular changes associated with preeclampsia during pregnancy
causally lead to cardiovascular remodeling increasing the risk of cardiovascular disease later in life
or if preeclampsia is a manifestation of an underlying increased risk of cardiovascular disease (for
example, a common genetic–environmental risk factor(s) interaction [such as hyperlipidemia,
obesity, diabetes mellitus, or renal disease] that predisposes women to develop preeclampsia
during pregnancy and cardiovascular diseases later in life) ( 175 ). Preventive strategies to be
considered by patients and health care providers may warrant closer long-term follow-up and
lifestyle modimcations to better manage risk factors for cardiovascular disease (eg, achieving
healthful weight, exercise, diet, smoking cessation), for which women and their primary care
providers may maintain ongoing care and vigilance.

Summary of Recommendations
The following recommendations are based on good and consistent scienti_c evidence (Level A):

• Women with any of the high-risk factors for preeclampsia (previous pregnancy with
preeclampsia, multifetal gestation, renal disease, autoimmune disease, type 1 or type 2 diabetes
mellitus, and chronic hypertension) and those with more than one of the moderate-risk factors
(mrst pregnancy, maternal age of 35 years or older, a body mass index of more than 30, family
history of preeclampsia, sociodemographic characteristics, and personal history factors) should
receive low-dose (81 mg/day) aspirin for preeclampsia prophylaxis, initiated between 12 weeks
and 28 weeks of gestation (optimally before 16 weeks of gestation) and continuing until
delivery.
• In women with gestational hypertension or preeclampsia without severe features at or beyond
37 0/7 weeks of gestation, delivery rather than expectant management upon diagnosis is
recommended.

• Magnesium sulfate should be used for the prevention and treatment of seizures in women with
gestational hypertension and preeclampsia with severe features or eclampsia.

• Nonsteroidal anti-inwammatory medications should continue to be used preferentially over

opioid analgesics. Postpartum patients on magnesium for seizure prophylaxis for preeclampsia
did not show differences in blood pressure, antihypertensive requirements, or other adverse
events for patients managed with NSAIDs in the postpartum period.

The following recommendations are based on limited or inconsistent scienti_c evidence (Level
B):

• Delivery is recommended when gestational hypertension or preeclampsia with severe features

is diagnosed at or beyond 34 0/7 weeks of gestation, after maternal stabilization or with labor or
prelabor rupture of membranes. Delivery should not be delayed for the administration of
steroids in the late preterm period.

• The expectant management of preeclampsia with severe features before 34 0/7 weeks of
gestation is based on strict selection criteria of those appropriate candidates and is best
accomplished in a setting with resources appropriate for maternal and neonatal care. Because
expectant management is intended to provide neonatal benemt at the expense of maternal risk,
expectant management is not advised when neonatal survival is not anticipated. During
expectant management, delivery is recommended at any time in the case of deterioration of
maternal or fetal condition.

• Antihypertensive treatment should be initiated expeditiously for acute-onset severe

hypertension (systolic blood pressure of 160 mm Hg or more or diastolic blood pressure of 110
mm Hg or more, or both) that is conmrmed as persistent (15 minutes or more). The available
literature suggests that antihypertensive agents should be administered within 30–60 minutes.
However, it is recommended to administer antihypertensive therapy as soon as reasonably
possible after the criteria for acute-onset severe hypertension are met.

The following recommendations are based primarily on consensus and expert opinion (Level C):
• It is recommended that women with gestational hypertension in the absence of proteinuria are
diagnosed with preeclampsia if they present with any of the following severe features:
thrombocytopenia (platelet count less than 100 ,000 × 10 9/L); impaired liver function as
indicated by abnormally elevated blood concentrations of liver enzymes (to twice the upper limit
of normal concentration); severe persistent right upper quadrant or epigastric pain and not
accounted for by alternative diagnoses; renal insuvciency (serum creatinine concentration
more than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of
other renal disease); pulmonary edema, or new-onset headache unresponsive to acetaminophen
and not accounted for by alternative diagnoses, or visual disturbances.

• Women with gestational hypertension who present with severe-range blood pressures should be
managed with the same approach as for women with severe preeclampsia.

• Among women with gestational hypertension or preeclampsia without severe features,

expectant management up to 37 0/7 weeks of gestation is recommended, during which
frequent fetal and maternal evaluation is recommended. Fetal monitoring consists of
ultrasonography to determine fetal growth every 3–4 weeks of gestation, and amniotic wuid
volume assessment at least once weekly. In addition, an antenatal test one-to-two times per
week for patients with gestational hypertension or preeclampsia without severe features is
recommended.

• Epidural or spinal anesthesia is considered acceptable, and the risk of epidural hematoma is
exceptionally low, in patients with platelet counts 70 × 10 9/L or more provided that the platelet
level is stable, there is no other acquired or congenital coagulopathy, the platelet function is
normal, and the patient is not on any antiplatelet or anticoagulant therapy.

References

1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;
376: 631– 44. (Level III)
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