Gestational Hypertension & Preeclampsia ACOG Practice Guideline #222

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. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics in collaboration with Jimmy Espinoza, MD, MSc; Alex Vidaeff, MD, MPH; Christian M. Pettker, MD; and Hyagriv Simhan, MD.

INTERIM UPDATE: The content of this Practice Bulletin has been updated as highlighted (or removed as necessary) to include limited, focused editorial corrections to platelet counts, diagnostic criteria for preeclampsia (Box 2), and pre- eclampsia with severe features (Box 3).

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

Background 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 3 109/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 1.1 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 hypertension is 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 0.3 mg/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 3 109/L

c Renal insufficiency: Serum creatinine concen- trations greater than 1.1 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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Proteinuria during pregnancy is defined 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 col- lection, 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 defined as a systolic blood pressure 140 mm Hg or more or a diastolic blood pres- sure 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 confirmed within a shorter interval (mi- nutes) than 4 hours to facilitate timely antihypertensive therapy (27). Gestational hypertension occurs when hypertension without proteinuria or severe features de- velops 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 manage- ment of gestational hypertension and that of preeclamp- sia 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 out- comes (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 gesta- tion (29, 30). Although investigators have reported a higher perinatal mortality rate in women with nonpro- teinuric hypertension compared with proteinuric pre- eclampsia (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. Ges- tational hypertension and preeclampsia may also be un- distinguishable 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 diag- nostic benchmarks have been proposed (34), many clini- cians 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 3 109/L. Although HELLP syndrome is mostly a third-trimester condition, in 30% of cases it is

Box 3. Preeclampsia with Severe Features

c 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)

c Thrombocytopenia (platelet count less than 100,000 3 109/L

c 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 unre- sponsive to medications

c Renal insufficiency (serum creatinine concentra- tion more than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease)

c Pulmonary edema c New-onset headache unresponsive to medication and not accounted for by alternative diagnoses

c Visual disturbances

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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 (1.9%) (44) or severe preeclampsia (3.2%) (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 A2 (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 3 109/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 3 109/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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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 preeclamp- sia (74). The most commonly accepted explanation for hyperuricemia in preeclampsia, besides increased pro- duction, is the increased reabsorption and decreased excretion of uric acid in the proximal renal tubules.

Fetal Consequences As a result of impaired uteroplacental blood flow 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 first or early second trimester (75, 76) limit the blood flow to the uteroplacental unit. Additional mechanisms for chronic uteroplacental ischemia include placental vascular insults (77, 78). Among women with preeclampsia, clinical manifes- tations that follow from this uteroplacental ischemia include fetal growth restriction, oligohydramnios, pla- cental abruption, and nonreassuring fetal status demon- strated 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 hyperten- sive 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 first 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 benefit from these interventions.

In general, the sensitivity and specificity for the prediction of early-onset preeclampsia using first- trimester (80–82) and second-trimester biochemical (81, 83) or biophysical parameters (84–87) 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 identified some angiogenic factors (soluble fms-like tyrosine kinase- [sFlt-1], placental growth factor [PlGF], and soluble en- doglin) in the second trimester as likely tools for the prediction of early-onset preeclampsia. However, no sin- gle test reliably predicts preeclampsia and further pro- spective investigation is required to demonstrate clinical utility. In the first 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, identified 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 mod- eling derived from a nested case2control study applied to a large cohort of almost 7,800 patients in which PlGF was measured only in the case2control group. The cal- culated positive predictive value was only 21.2%, indi- cating that approximately 79% of the women in the screen-positive group would not develop hypertensive disorders during pregnancy (82). Of note, a similar algo- rithm underperformed in a subsequent randomized trial performed by the same research group (89). Thus, bio- markers 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 interven- tion has been proved unequivocally effective at elimi- nating the risk of preeclampsia. With regard to nutritional interventions, evidence is insufficient to demonstrate effectiveness for vitamins C and E (90), fish 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 significant 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

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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 A2 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 A2 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

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