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Gestational Hypertension and Preeclampsia ACOG Practice Bulletin Number 222 1605448006
Ginecologia y Obstetricia
Universidad Xochicalco
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INTERIM UPDATE
ACOG PRACTICE BULLETIN
Clinical Management Guidelines for Obstetrician–Gynecologists
NUMBER 222 (Replaces Practice Bulletin No. 202, December 2018)
Committee on Practice Bulletins—Obstetrics 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% ofmaternal 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-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 billion ($1 billion for women and $1 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
Risk Factors
A variety of risk factors have been associated with increased probability of preeclampsia (Box 1) (6– 12). Nonetheless, it is important to remember that most cases of preeclampsia occur in healthy nullipa- rous women with no obvious risk factors. Although the precise role of genetic–environmental inter- actions on the risk and incidence of preeclampsia is unclear, emerging data suggest the tendency to develop preeclampsia may have some genetic com- ponent (13–16).
Definitions and Diagnostic Criteria for
Hypertensive Disorders of Pregnancy
Preeclampsia (With and Without
Severe Features)
Preeclampsia is a disorder of pregnancy associated with new-onset hypertension, which occurs most often after 20 weeks of gestation and frequently near term. Although often accompanied by new-onset proteinuria, hypertension and other signs or symptoms of preeclampsia may present in some women in the absence of proteinuria (17). Reli- ance on maternal symptoms may be occasionally problem- atic in clinical practice. Right upper quadrant or epigastric
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pain is thought to be due to periportal and focal parenchy- mal necrosis, hepatic cell edema, or Glisson’s capsule distension, or a combination. However, there is not always a good correlation between the hepatic histopathology and laboratory abnormalities (18). Similarly, studies have found that using headache as a diagnostic criterion for preeclampsia with severe features is unreliable and non- specific. Thus, an astute and circumspect diagnostic approach is required when other corroborating signs and symptoms indicative of severe preeclampsia are missing (19, 20). Of note, in the setting of a clinical presentation similar to preeclampsia, but at gestational ages earlier than 20 weeks, alternative diagnoses should to be considered, including but not limited to thrombotic thrombocytopenic purpura, hemolytic–uremic syndrome, molar pregnancy, renal disease or autoimmune disease. Although hypertension and proteinuria are consid- ered to be the classical criteria to diagnose preeclampsia, other criteria are also important. In this context, it is recommended that women with gestational hypertension in the absence of proteinuria are diagnosed with pre- eclampsia if they present with any of the following severe features: thrombocytopenia (platelet count less than 100,000 3109 /L); impaired liver function as indi- cated by abnormally elevated blood concentrations of liver enzymes (to twice the upper limit of normal con- centration); severe persistent right upper quadrant or epi- gastric pain and not accounted for by alternative diagnoses; renal insufficiency (serum creatinine concen- tration greater than 1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease); pulmonary edema; or new-onset headache unre-
sponsive to acetaminophen and not accounted for by alternative diagnoses or visual disturbances (Box 2).Ges- tational hypertensionis defined as a systolic blood pres- sure of 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). Women with gestational hypertension with severe range blood pressures (a systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher) should be diagnosed with preeclampsia with severe features. These severe ranges of blood pressure or any of the severe features listed in Box 3 increase the risk of morbidity and mortality (22).
Box 1. Risk Factors for Preeclampsia Nulliparity Multifetal gestations Preeclampsia in a previous pregnancy Chronic hypertension Pregestational diabetes Gestational diabetes Thrombophilia Systemic lupus erythematosus Prepregnancy body mass index greater than 30 Antiphospholipid antibody syndrome Maternal age 35 years or older Kidney disease Assisted reproductive technology Obstructive sleep apnea Box 2. Diagnostic Criteria for Preeclampsia Blood pressure c Systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure c Systolic blood pressure of 160 mm Hg or more or diastolic blood pressure of 110 mm Hg or more. (Severe hypertension can be confirmed within a short interval (minutes) to facilitate timely antihypertensive therapy). and
Proteinuria c 300 mg or more per 24 hour urine collection (or this amount extrapolated from a timed collection) or c Protein/creatinine ratio of 0/dL or more or c Dipstick reading of 2+ (used only if other quan- titative methods not available) Or in the absence of proteinuria, new-onset hyper- tension with the new onset of any of the following: c Thrombocytopenia: Platelet count less than 100 ,000 3109 /L c Renal insufficiency: Serum creatinine concen- trations greater than 1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease c Impaired liver function: Elevated blood concen- trations of liver transaminases to twice normal concentration c Pulmonary edema c New-onset headache unresponsive to medication and not accounted for by alternative diagnoses or visual symptoms
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first 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 hyper- tensive disorders of pregnancy and is among the more severe manifestations of the disease. Eclampsia is defined 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 post- partum (38) or when seizures occur during administration of magnesium sulfate. Eclampsia is a significant 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 con- sequences such as impaired memory and cognitive function, especially after recurrent seizures or uncor- rected 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 significant neurologic deficits (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 significant proportion of women (20–38%) do not demonstrate the classic signs of pre- eclampsia (hypertension or proteinuria) before the sei- zure episode (42). Headaches are believed to reflect 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 significant 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%) (44) or severe preeclampsia (3%) (45) allocated to the
placebo arm of both studies. It is also noteworthy that there is a significant proportion of patients who had abrupt-onset eclampsia without warning signs or symp- toms (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 preeclamp- sia has a natural linear progression from preeclampsia without severe features to preeclampsia with severe fea- tures and eventually to eclamptic convulsions is inaccurate. Nervous system manifestations frequently encoun- tered in preeclampsia are headache, blurred vision, scotomata, and hyperreflexia. 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 enceph- alopathy syndrome (PRES) is a constellation of a range of clinical neurologic signs and symptoms such as vision loss or deficit, 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 par- ticularly 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 neuro- logic deficits 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 necro- sis (54, 55), and an exaggerated maternal inflammatory response to deported trophoblasts (56, 57). More recent observations suggest a possible role for imbalan- ces of angiogenic factors in the pathogenesis of pre- eclampsia (58). It is possible that a combination of some of these purported mechanisms may be responsible
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for triggering the clinical spectrum of preeclampsia. For example, there is clinical (59, 60) and experimental evi- dence (61, 62) suggesting that uteroplacental ischemia leads to increased circulating concentrations of antiangio- genic 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 finding (64). In addition, the interaction of various vaso- active agents, such as prostacyclin (vasodilator), throm- boxane A 2 (potent vasoconstrictor), nitric oxide (potent vasodilator), and endothelins (potent vasoconstrictors) re- sults in another significant change described in preeclamp- sia: intense vasospasm. Attempts to correct the contraction of the intravascular space in preeclampsia with vigorous fluid 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 fluid therapy may result in ele- vation of the pulmonary capillary wedge pressure and increased risk of pulmonary edema. A study using inva- sive hemodynamic monitoring in women with preeclamp- sia found that before intravenous fluid therapy, women with preeclampsia had hyperdynamic ventricular function with low pulmonary capillary wedge pressure (65). How- ever, after aggressive fluid therapy, the pulmonary capil- lary wedge pressure increased significantly 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 3109 /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 significant 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 hemo- concentration may occur (69). In some cases, the hemat- ocrit may not appear decreased despite hemolysis because of baseline hemoconcentration. Lactate dehydro- genase 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 significantly altered in women with preeclampsia with severe features. Alanine amino- transferase and AST may be elevated. Aspartate amino- transferase is the dominant transaminase released into the peripheral circulation in liver dysfunction due to pre- eclampsia 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 significant hemolysis may develop only in the late stages of the disease. Similarly, alterations in hepatic synthetic function, as reflected by abnormalities of prothrombin time, partial prothrombin time, and fibrinogen, usually develop in advanced preeclampsia. Evaluation of these coagulation parameters is probably only useful when the platelet count is below 150,000 3109 /L, there is signif- icant 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 fibrils, swollen mesangial cells, subendothelial deposits of protein re- absorbed from the glomerular filtrate, 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, transfer- rin, 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 flow and glomerular fil- tration 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 clin- ical spectrum. Oliguria in severe preeclampsia is a conse- quence of intrarenal vasospasm with an approximate 25% reduction in glomerular filtration rate. In these pa- tients, transient oliguria (less than 100 mL over 4 hours) is a common observation in labor or the first 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
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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 aggre- gate data from 45 randomized trials, only a modest reduc- tion in preeclampsia was noted when low-dose aspirin was started after 16 weeks of gestation (relative risk [RR], 0; 95% CI, 0–0) but a more significant reduction in severe preeclampsia (RR, 0; 95% CI, 0–0) and fetal growth restriction (RR, 0; 95% CI, 0–0) 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 beneficial effects of low-dose aspirin were consistent, whether treat- 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- fetal 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 (first 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 ( mg/day) aspirin for preeclampsia prophylaxis initiated between 12 weeks and 28 weeks of gestation (optimally before 16 weeks of gestation) and continuing until deliv- ery (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% of the partici- pants in the aspirin group, as compared with 4% in the placebo group (odds ratio, 0; 95% CI, 0 2 0; P 5 .004). The authors also reported that there were no significant differences in the incidence of neonatal adverse outcomes between groups. The authors con- cluded that low-dose aspirin in women at high risk of preeclampsia was associated with a lower incidence for preterm preeclampsia. However, there were no differ- ences in the rates of term preeclampsia between study groups. Of note, as a possible study limitation, the prev- alence of preterm preeclampsia in the placebo group was one half of that expected for a high-risk population based on first-trimester parameters (89).
The use of metformin for the prevention of pre- eclampsia has been suggested. In a meta-analysis of five randomized controlled trials comparing metformin treat- ment (n 5 611) with placebo and control (n 5 609), no difference in the risk of preeclampsia was found (com- bined/pooled risk ratio, 0; 95% CI, 0–2); P 5 .76; I 25 66%) (102). Because preeclampsia was a sec- ondary outcome in most studies in this meta-analysis, the effect of metformin needs to be assessed by a study de- signed to evaluate the reduction in the prevalence of pre- eclampsia as a primary endpoint. In the meantime, the use of metformin for the prevention of preeclampsia re- mains investigational, as is the use of sildenafil and sta- tins (103–105). 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 evalu- ation for estimated fetal weight and amount of amniotic fluid, 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 retro- spective 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 prel- abor rupture of membranes (also referred to as premature rupture of membranes) or vaginal bleeding, for neonatal benefit (106). The risks associated with expectant man- agement in the late preterm period include the develop- ment of severe hypertension, eclampsia, HELLP syndrome, placental abruption, fetal growth restriction and fetal death; however, these risks are small and coun- terbalanced by the increased rates of admission to the neonatal intensive care unit, neonatal respiratory compli- cations and neonatal death that would be associated with delivery before 37 0/7 weeks of gestation (39). In the
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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 significant reduction in a composite of adverse mater- nal outcome including new-onset severe preeclampsia, HELLP syndrome, eclampsia, pulmonary edema, or placental abruption (RR, 0; 95% CI, 0–0) (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 pre-
eclampsia. The frequency of these tests may be modified based on clinical findings and patient symptoms. Fol- lowing the initial documentation of proteinuria and the establishment of the diagnosis of preeclampsia, addi- tional quantifications of proteinuria are no longer neces- sary. 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 influence 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 fea- tures, 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
Table 1 Risk Factors and Aspirin Use*
Level of Risk Risk Factors Recommendation
High† History of preeclampsia, especially when accompanied by an adverse outcome
Recommend low-dose aspirin if the patient 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. zA 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. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2014;161(11):819– 26.
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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 man- agement up to 37 0/7 weeks of gestation is recommen- ded, during which frequent fetal and maternal evaluation is recommended. Fetal monitoring consists of ultraso- nography to determine fetal growth every 3–4 weeks of
gestation and amniotic fluid 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 significant body of evidence attests to the efficacy of magnesium sulfate to prevent seizures in women with preeclampsia with severe features and eclampsia. In the Magpie study, a random- ized 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 significant in the subset of women enrolled in high- resource countries in the Western world (RR, 0; 95% CI, 0–2) (44). In a subsequent systematic review that included the Magpie study and five other studies, magnesium sulfate compared with placebo more than halved the risk of eclampsia (RR, 0; 95% CI, 0– 0), reduced the risk of placental abruption (RR, 0; 95% CI, 0–0), and reduced the risk of maternal mortality albeit nonsignificantly (RR, 0; 95% CI, 0–1). There were no differences in maternal mor- bidity or perinatal mortality. A quarter of women reported adverse effects with magnesium sulfate, primarily hot flushes, and the rate of cesarean delivery was increased by 5% when magnesium sulfate was used (119).
Box 4. Conditions Precluding Expectant Management Maternal c Uncontrolled severe-range blood pressures (per- sistent systolic blood pressure 160 mm Hg or more or diastolic blood pressure 110 mm Hg or more not responsive to antihypertensive medication c Persistent headaches, refractory to treatment c Epigastric pain or right upper pain unresponsive to repeat analgesics c Visual disturbances, motor deficit or altered sensorium c Stroke c Myocardial infarction c HELLP syndrome c New or worsening renal dysfunction (serum cre- atinine greater than 1 mg/dL or twice baseline) c Pulmonary edema c Eclampsia c Suspected acute placental abruption or vaginal bleeding in the absence of placenta previa
Fetal c Abnormal fetal testing c Fetal death c Fetus without expectation for survival at the time of maternal diagnosis (eg, lethal anomaly, extreme prematurity) c Persistent reversed end-diastolic flow in the umbilical artery Abbreviation: HELLP, hemolysis, elevated liver enzymes, and low platelet count. In some cases, a course of antenatal steroids can be con- sidered depending on gestational age and maternal severity of illness. Data from Balogun OA, Sibai BM. Counseling, manage- ment, and outcome in women with severe preeclampsia at 23 to 28 weeks’ gestation. Clin Obstet Gynecol 2017;60:183–9.
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and Gynecologists. Published by Wolters Kluwer Health, Inc.
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 5 357) allocated women with preeclampsia with- out severe features to either placebo or magnesium sul- fate and reported no cases of eclampsia among women allocated to placebo and no significant differences in the proportion of women that progressed to severe pre- eclampsia (120, 121). However, given the small sample size, the results of these studies cannot be used for clin- ical 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 symptom- atic cases (severe headache, blurred vision, photophobia, hyperreflexia, epigastric pain), the number needed to treat is 36 (124). The evidence regarding the benefit-to- risk ratio of magnesium sulfate prophylaxis is less sup- portive 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- benefit trade-off of each strategy. Although the benefit- 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 hyper- tension 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 intra- partum and postpartum periods (119, 126, 127). Benzo- diazepines and phenytoin are justified only in the context of antiepileptic treatment or when magnesium sulfate is contraindicated or unavailable (myasthenia gravis, hypo- calcemia, moderate-to-severe renal failure, cardiac ische- mia, heart block, or myocarditis). There are still sparse data regarding the ideal dosage of magnesium sulfate. Even the therapeutic range of 4– 9 mg/dL (4–8 mEq/L) quoted in the literature is ques- tionable (128, 129). Although there is a relationship between toxicity and plasma concentration of magne- sium, with higher infusion rates increasing the potential for toxicity, the accurate magnesium concentration clin-
ically 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 subtherapeu- tic magnesium levels, were able to significantly 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 distri- bution and higher BMI also affect the dosage and dura- tion 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 g followed by 1 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 difficulties 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 reflexes are lost at a serum mag- nesium level of 9 mg/dL (7 mEq/L), respiratory depres- sion occurs at 12 mg/dL (10 mEq/L), and cardiac arrest at 30 mg/dL (25 mEq/L). Accordingly, provided deep ten- don reflexes 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 moni- toring of respiration status and tendon reflexes. If renal function is impaired, serum magnesium levels will increase quickly, which places the patient at risk of sig- nificant adverse effects. In patients with mild renal failure (serum creatinine 1–1 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
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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 pro- spective 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 5 65) compared with women without pre- eclampsia (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 intu- bation and extubation (145, 146). However, neuraxial anesthesia and analgesia are contraindicated in the pres- ence of a coagulopathy because of the potential for hem- orrhagic 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 pa- tients 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 3 109 /L is exceptionally low (less than 0%) (148). Extrap- olating 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 3109 /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 significant anesthetic impli- cations because it prolongs the duration of nondepolariz- ing muscle relaxants. However, women with preeclampsia who require cesarean delivery should
Table 3 Agents Used for Urgent Blood Pressure Control in Pregnancy
Drug Dose Comments Onset of Action
Labetalol 10 – 20 mg IV, then 20–80 mg every 10–30 minutes to a maxi- mum cumulative dosage of 300 mg; or constant infusion 1 – 2 mg/min IV
Tachycardia is less common with fewer adverse effects.
1 – 2 minutes
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 every 20–40 minutes to a maxi- mum cumulative dosage of 20 mg; or constant infusion of 0–10 mg/hr
Higher or frequent dosage associated with maternal hypotension, headaches, and abnormal fetal heart rate tracings; may be more common than other agents.
10 – 20 minutes
Nifedipine (immediate release)
10 – 20 mg orally, repeat in 20 minutes if needed; then 10 – 20 mg every 2–6 hours; maximum daily dose is 180 mg
May observe reflex tachycardia and headaches
5 – 10 minutes
Abbreviations: IM, intramuscularly; IV, intravenously.
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continue magnesium sulfate infusion during the delivery. This recommendation is based on the observation that magnesium sulfate half-life is 5 hours and that discon- tinuation of the infusion of magnesium sulfate before cesarean delivery would only minimally reduce magne- sium concentration at the time of delivery while possibly increasing the risk of seizure (150). Women with pre- eclampsia 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 (151–154). 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 nonste- roidal antiinflammatory drugs (NSAIDs), which are fre- quently prescribed as postpartum analgesics. These medications decrease prostaglandins leading to a lack of vasodilation and increased sodium retention. Nonste- roidal anti-inflammatory medications should continue to be used preferentially over opioid analgesics; however, women with chronic hypertension may theoretically require intensification of blood pressure monitoring and regimen adjustments when on these medications. Over- all, 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 post- partum 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 associa- tion of NSAID use with postpartum blood pressure ele- vations (156). Further, another cohort study of postpartum patients on magnesium for seizure prophy- laxis for preeclampsia did not show differences in blood
pressure, antihypertensive requirements, or other adverse events for patients managed with NSAIDs in the post- partum 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 atten- tion 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 pro- longed fetal heart rate decelerations, even fetal brady- cardia, 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. Further- more, maternal resuscitation is usually followed by normalization of the fetal tracing. Cochrane reviews, including data originating from developing countries, indicate a significant reduction in recurrent seizures and eclampsia-related maternal mor- tality with the use of magnesium sulfate. Magnesium sulfate administered intramuscularly or intravenously is superior to phenytoin, diazepam, or lytic cocktail (usu- ally 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 abso- lutely necessary because they inhibit laryngeal reflexes, 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 findings of the cervical examination. A high rate of failure may be anticipated with induction or augmenta- tion in pregnancies less than 30 weeks of gestation if the
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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 car- diovascular risk factors present before and after preg- nancy suggested that nearly one half of the elevated risk of future hypertension after preeclampsia can be ex- plained 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 pre- eclampsia during pregnancy causally lead to cardiovas- cular 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 modifications 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 scientific evidence (Level A):
<Women with any of the high-risk factors for pre-
eclampsia (previous pregnancy with preeclampsia, multifetal gestation, renal disease, autoimmune dis- ease, type 1 or type 2 diabetes mellitus, and chronic hypertension) and those with more than one of the moderate-risk factors (first 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 pre- eclampsia 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 pre-
eclampsia without severe features at or beyond 37 0/ 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-inflammatory medications should
continue to be used preferentially over opioid an- algesics. Postpartum patients on magnesium for sei- zure prophylaxis for preeclampsia did not show differences in blood pressure, antihypertensive re- quirements, or other adverse events for patients managed with NSAIDs in the postpartum period.
The following recommendations are based on limited or inconsistent scientific evidence (Level B):
<Delivery is recommended when gestational hyperten-
sion 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 pro- vide neonatal benefit at the expense of maternal risk, expectant management is not advised when neonatal survival is not anticipated. During expectant man- agement, delivery is recommended at any time in the case of deterioration of maternal or fetal condition.
<Antihypertensive treatment should be initiated expe-
ditiously 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 confirmed 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 antihy- pertensive 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
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diagnosed with preeclampsia if they present with any of the following severe features: thrombocytopenia (platelet count less than 100,000 3109 /L); impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (to twice the upper limit of normal concentration); severe persis- tent right upper quadrant or epigastric pain and not accounted for by alternative diagnoses; renal insuf- ficiency (serum creatinine concentration more than 1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease); pulmonary edema, or new-onset headache unre- sponsive 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 rec- ommended, 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 fluid volume assessment at least once weekly. In addition, an antenatal test one-to-two times per week for patients with gestational hypertension or preeclampsia with- out 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 3109 /L or more provided that the platelet level is stable, there is no other acquired or congenital coagulopathy, the platelet func- tion is normal, and the patient is not on any antiplatelet or anticoagulant therapy.
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