Version May 2024
INTRODUCTION — Preeclampsia refers to a syndrome characterized by the new onset of hypertension plus proteinuria, end-organ dysfunction, or both after 20 weeks of gestation in a previously normotensive individual (table 1). In individuals with preexisting (chronic) hypertension, accelerating hypertension plus proteinuria, end-organ dysfunction, or both after 20 weeks suggests superimposed preeclampsia.
Preeclampsia is a common risk factor for maternal and perinatal morbidity and mortality worldwide. Standard prenatal care, including close follow-up of high-risk patients after midgestation, increases the chance that preeclampsia will be detected early in the course of disease. Early diagnosis followed by appropriate management, including delivery, may prevent some of the serious sequelae of the disease, such as eclamptic seizures and multiorgan failure.
Since there is no curative treatment other than delivery, an intervention that could prevent preeclampsia would have a significant impact on maternal and neonatal health worldwide. Many different strategies to prevent preeclampsia have been investigated in randomized trials. It is not surprising that most simple approaches have been unsuccessful, given the complexities in pathogenesis and the likelihood that multiple etiologies or pathways result in the clinical syndrome. Low-dose aspirin prophylaxis is the most useful preventive pharmacologic intervention, but the magnitude of benefit is variable and depends on a number of factors.
This topic will review several interventions that have been evaluated for prevention of preeclampsia. Other important aspects of preeclampsia are discussed separately:
●(See "Preeclampsia: Clinical features and diagnosis".)
●(See "Preeclampsia: Antepartum management and timing of delivery".)
●(See "Preeclampsia: Pathogenesis".)
●(See "Early pregnancy prediction of preeclampsia".)
EFFECTIVE INTERVENTIONS
Low-dose aspirin — Low-dose aspirin reduces the frequency of preeclampsia, as well as related adverse pregnancy outcomes (preterm birth, growth restriction), by approximately 10 to 20 percent when taken by patients at moderate to high risk of the disease. It has an excellent maternal/fetal safety profile, thus it is a reasonable preventive strategy for these patients. (See 'Safety' below.)
Rationale — The observation that preeclampsia is associated with increased platelet turnover and increased platelet-derived thromboxane levels led to randomized trials evaluating low-dose aspirin therapy in patients thought to be at increased risk of the disease [1-6]. As opposed to higher dose aspirin therapy, low-dose aspirin (60 to 150 mg/day) diminishes platelet thromboxane synthesis while maintaining vascular wall prostacyclin synthesis [6-8]. Although not well studied, the beneficial effect of low-dose aspirin for prevention of preeclampsia may also be partly related to modulation of inflammation, which is exaggerated in patients with preeclampsia [9].
Evidence of efficacy — Evidence from meta-analyses of randomized trials clearly shows that prophylactic administration of aspirin to pregnant patients has a modest ability (RR 0.57 to 0.92) to reduce the risk of developing preeclampsia and its sequelae [10]. For example:
●A 2019 meta-analysis reported the following main outcomes for prophylactic use of antiplatelet agents, primarily low-dose aspirin (50 to 162 mg per day), compared with either placebo or no antiplatelet agent (74 trials, >40,000 patients across the range of low, moderate, or high risk of preeclampsia) [11]:
•Reduction in proteinuric preeclampsia – 16 fewer cases per 1000 patients treated (risk ratio [RR] 0.82, 95% CI 0.77-0.88). The analysis did not specifically evaluate occurrence of preterm versus term preeclampsia.
•Reduction in fetal or neonatal death – 5 fewer deaths per 1000 patients treated (RR 0.85, 95% CI 0.76-0.95).
•Reduction in overall preterm birth <37 weeks – 16 fewer cases per 1000 patients treated (RR 0.91, 95% CI 0.87-0.95).
•Reduction in small for gestational age newborns – 7 fewer cases per 1000 patients treated (RR 0.84, 95% CI 0.76-0.92).
•Reduction in composite serious adverse maternal and neonatal outcomes – 20 fewer cases per 1000 patients treated (RR 0.90, 95% CI 0.85-0.96).
The intervention may have slightly increased the risk of postpartum hemorrhage >500 mL (RR 1.06, 95% CI 1.00-1.12) but did not have a statistically significant effect on risk of abruption (RR 1.21, 95% CI 0.95-1.54).
Although others have shown that preterm births <32 weeks decreased by approximately 60 percent (1.2 versus 2.9 percent, odds ratio [OR] 0.42, 95% CI 0.19-0.93) [12], this meta-analysis did not find a large or clear reduction (RR 0.92, 95% CI 0.83-1.02) [11]. It also found that antiplatelet agents probably make little or no difference in the risk of HELLP syndrome (hemolysis, elevated liver enzymes, low platelets; RR 0.77, 95% CI 0.44-1.36), severe maternal morbidity (RR 1.00, 95% CI 0.72-1.39), or admission to a newborn special care unit (RR 0.95, 95% CI 0.90-1.00) [11].
●A 2021 meta-analysis by the United States Preventive Services Task Force (USPSTF) reported similar data: lower risk of preeclampsia (RR 0.85, 95% CI 0.75-0.95), perinatal mortality (RR 0.79, 95% CI 0.66-0.96), preterm birth <37 weeks (RR 0.80, 95% CI 0.67-0.95), fetal growth restriction (RR 0.82, 95% CI 0.68-0.99), and no significant increase in bleeding related harms [13]. In the larger trials, absolute risk reductions for preeclampsia ranged from -1 to -6 percent and absolute risk reduction for perinatal mortality ranged from -0.5 to -1.1 percent. The analysis did not specifically evaluate occurrence of preterm versus term preeclampsia. Trial participants were individuals at increased risk based on clinical risk factors or measurements associated with higher disease incidence than in the general population.
●In a 2018 meta-analysis specifically evaluating the effects of low-dose aspirin on development of preterm versus term preeclampsia, there was a significant reduction in occurrence of preterm preeclampsia (before 37 weeks of gestation: RR 0.62, 95% CI 0.45-0.87) but not at term (RR 0.92, 95% CI 0.70-1.21) [14]. In the largest trial (ASPRE), high-risk individuals were identified by multivariable first-trimester screening and randomly assigned to receive aspirin (150 mg daily) or placebo starting at 11 to 13 weeks of gestation and continuing until 36 weeks of gestation [15]. The aspirin group had a 62 percent reduction in preterm preeclampsia <37 weeks (1.6 versus 4.3 percent, OR 0.38, 95% CI 0.20-0.74); the reduction in term preeclampsia was not significant (6.6 versus 7.2 percent, OR 0.95, 95% CI 0.57-1.57).
Candidates
Selecting patients at high risk of developing preeclampsia — We recommend low-dose aspirin prophylaxis for patients at high risk of developing preeclampsia, based on the evidence described above (See 'Evidence of efficacy' above.). The greatest benefit appears to be in patients at moderate to high risk of developing the disease [11,15-23].
There is some variation among international guidelines regarding the specific criteria that confer high and moderate risk (table 2). In the United States, the USPSTF high-risk criteria are typically used [24] and endorsed by the American College of Obstetricians and Gynecologists (ACOG) [25]. The incidence of preeclampsia is estimated to be at least 8 percent for pregnant patients with any one of these high-risk factors:
●Previous pregnancy with preeclampsia, especially early onset and with an adverse outcome.
●Type 1 or 2 diabetes mellitus.
●Chronic hypertension.
●Multifetal gestation.
●Kidney disease.
●Autoimmune disease with potential vascular complications (antiphospholipid syndrome, systemic lupus erythematosus).
Clinicians have expanded use of low-dose aspirin to other conditions in which the incidence of preeclampsia is estimated to be at least 8 percent. These include sickle cell disease and inflammatory bowel disease.
Although the USPSTF and ACOG have not addressed the 2017 American College of Cardiology/American Heart Association revised hypertension definitions with respect to pregnant patients, in a secondary analysis of patients with prior preeclampsia or pregestational diabetes, the subgroup of these high risk patients with stage I hypertension (systolic 130 to 139 mmHg or diastolic 80 to 89 mmHg) had a high frequency of preeclampsia that was lower in those treated with low-dose aspirin prophylaxis versus placebo (24 versus 39 percent) [26]. The subgroup of normotensive high risk patients was at lower risk for preeclampsia, and the risk was similar in the aspirin and placebo groups (14.6 versus 15.1 percent). In patients with stage I hypertension and no other risk factors for preeclampsia, a potential beneficial effect of low-dose aspirin needs to be established in prospective trials before a recommendation for routine prophylaxis can be made.
The management of patients with moderate risk factors is less straightforward. The USPSTF and ACOG recommend low-dose aspirin for preeclampsia prevention in patients with two or more moderate risk factors. The incidence of preeclampsia is estimated to be less than 8 percent in those with only one moderate risk factor, but increases with multiple moderate risk factors. Importantly, not all moderate risk factors are associated with the same magnitude of preeclampsia risk, and the frequency of these risk factors varies in different populations. In addition, the risk reduction benefits of low-dose aspirin have not been evaluated in each of these subgroups.
We generally follow the USPSTF criteria and recommend low-dose aspirin for preeclampsia prevention to patients with two or more of the following moderate risk factors [24]:
●Nulliparity.
●Obesity (body mass index >30 kg/m2).
●Family history of preeclampsia in mother or sister.
●Age ≥35 years.
●Sociodemographic characteristics (Black persons, lower income level [recognizing that these are not biological factors]).
●Personal risk factors (eg, previous pregnancy with low birth weight or small for gestational age newborn, previous adverse pregnancy outcome [eg, stillbirth], interval >10 years between pregnancies).
●In vitro conception
The USPSTF and ACOG also suggest considering low-dose aspirin for patients with only one moderate risk factor [24]. This consideration was motivated by concerns for disparities in outcomes for people with less access to medical care and to potentially reduce the racial disparity in the prevalence of preeclampsia in disadvantaged groups.
Even though nulliparous patients are the group comprising the largest proportion of preeclampsia cases, nulliparity alone is not an indication for prophylaxis. A meta-analysis of trials limited to low-risk nulliparous patients found no benefit [27] and major trials limited to unselected nulliparous patients also found little or no benefit from prophylactic low-dose aspirin therapy [28,29].
Other conditions (eg, thrombotic thrombocytopenic purpura [30,31], use of assisted reproductive techniques [32,33]) may also confer high or moderate risk for preeclampsia, but available data are limited. We individualize use of low-dose aspirin in such patients. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Pregnancy after an episode of TTP'.)
Other considerations
●Role of universal prophylaxis – ACOG has opined that in practice settings in which the majority of patients are at high or moderate risk for preeclampsia and would therefore be candidates for low-dose aspirin prophylaxis, universal implementation (eg, offering low-dose aspirin to all patients) may be medically reasonable [25].
●High-risk multiparous patients with no history of preeclampsia – Guidelines have not specifically addressed the management of multiparous patients who are at high risk for preeclampsia based on the risk factors described above, but who did not develop preeclampsia in previous pregnancies even though they did not take low-dose aspirin for preeclampsia prevention. We suggest low-dose aspirin prophylaxis for these patients as a prudent approach.
●Use of algorithms for candidate selection – Multimarker algorithms for identifying patients at high risk for preeclampsia have been published [34-38], but none are widely used in the United States, as they have not been validated in a variety of unselected populations. These algorithms typically include biochemical and imaging results, as well as historical risk factors. (See "Early pregnancy prediction of preeclampsia", section on 'Risk prediction models'.)
●Use of low-dose aspirin for treatment of established preeclampsia – Low-dose aspirin appears to be of little or no benefit in patients who already have developed preeclampsia [6,39,40]. At this late stage, aspirin does not prevent progression to more severe disease and may exacerbate bleeding in patients with thrombocytopenia related to preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count).
Timing of initiation — We initiate low-dose aspirin for preeclampsia prevention at ≥12 weeks of gestation, and ideally prior to 16 weeks [16,24,25,41-43], although adverse effects from earlier initiation (eg, preconception) have not been consistently documented [44,45] and others (eg, the International Federation of Gynecology and Obstetrics) recommend initiation of aspirin at 11 to 14 weeks [46].
Early therapy (before 16 weeks) may be important since the pathophysiologic features of preeclampsia develop early in pregnancy, weeks before clinical disease is apparent. However, available evidence is inconsistent about the benefits of early initiation of therapy (particularly before 11 weeks [47]), possibly because aspirin has major effects on prostacyclin production and endothelial function throughout gestation [48]. If aspirin is not initiated at the end of the first trimester, initiation after 16 weeks (but before symptoms develop) may also be effective [18]. The majority of trials have initiated therapy before 28 weeks.
No trials have directly compared early versus late initiation of aspirin therapy for preeclampsia prevention.
●In the 2019 meta-analysis discussed above, data suggested a slight benefit to initiating aspirin before rather than after 20 weeks of gestation (RR 0.85 and 0.90 at <16 and 16 to 19 weeks versus RR 0.99, 0.88, and 0.95 at 20 to 23, 24 to 27, and ≥28 weeks, respectively), but the confidence intervals for the risk ratios at the various gestational ages overlapped; thus, whether a real difference exists is uncertain [11].
Dose
●Typically 75 to 162 mg – There is no consensus regarding the optimal dose of aspirin for preeclampsia prevention. We use 81 mg daily, which is the commercially available dose in the United States and has proven efficacy. Based on the data described below, some authorities have advocated a higher dose of aspirin (100 to 150 mg) daily, which is also reasonable. In the United States, the higher dosing has been achieved by taking one and one-half 81 mg tablets daily (121.5 mg), or one 81 mg pill on "odd" days and two 81 mg pills on "even" days. Although no trials have evaluated the efficacy of doses >150 mg, which could be achieved easily by taking two 81 mg tablets or splitting a 325 mg tablet in half, the 162 mg dose is one of the pragmatic options suggested by the Society of Obstetricians and Gynaecologists of Canada [43] and others [46].
For prevention of myocardial infarction and stroke in nonpregnant individuals, aspirin appears to be equally effective at doses between 75 and 325 mg/day. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)
It is important to note that there has been no head-to-head comparison or individual patient data meta-analysis comparing <100 mg versus ≥100 mg aspirin doses; either of these research methods would provide more robust data regarding optimal dose.
•A 2017 meta-analysis suggested a dose-response effect for the prevention of preeclampsia, severe preeclampsia, and fetal growth restriction, with higher doses associated with a greater risk reduction [23]. In the ASPRE trial, 150 mg aspirin was used with a significant risk reduction of preterm preeclampsia [15].
•A 2018 meta-analysis in which subgroup analyses were available found that aspirin reduced the risk of preeclampsia only when it was initiated at ≤16 weeks of gestation and at a daily dose of ≥100 mg [14].
•In the 2019 meta-analysis discussed above, trials using doses >75 mg appeared to show a greater risk reduction for preeclampsia than trials using doses <75 mg, but further studies are warranted since the overall data were not conclusive [11].
Variations in dosing regimens among studies are at least partly based on different formulations available in various regions of the world.
●Morning versus evening administration – Some authors believe that aspirin may be more effective if taken at bedtime [49,50]; however, specifying timing of administration is not standard practice, and nighttime dosing may increase gastric irritation.
●Importance of good adherence – Good adherence with therapy is important; adherence <90 percent may not be effective [51,52]. Strategies to improve medication adherence include patient education, daily count-type pillboxes, and telemonitoring or mobile health applications for reminding [53].
Timing of discontinuation — There is no consensus on the optimal timing of aspirin discontinuation. In our practice, we continue low-dose aspirin until delivery. Some advocate discontinuation at 36 weeks of gestation or 5 to 10 days before expected delivery to diminish the risk of bleeding during delivery [2,5,54]; however, no adverse maternal or fetal effects related to use of low-dose aspirin at delivery have been proven.
●A randomized trial evaluated early aspirin discontinuation. Patients considered at high risk of preterm preeclampsia (≥1/170) based on a first-trimester screening algorithm were placed on aspirin 150 mg daily before 14 weeks of gestation [55]. At 24 to 28 weeks of gestation, those with an sFlt-1:PlGF ratio ≤38 (ie, the level that excludes preeclampsia) stopped taking aspirin. The risk of preterm preeclampsia was similar for both groups (early discontinuation group: 1.48 percent [7 in 473] versus 1.73 percent [8 in 463] in the control group; RR 0.86, 95% CI 0.31-2.34); the risk of term preeclampsia was also similar for both groups (early discontinuation: 6.3 versus 8.6 percent in the control group; RR 0.73, 95% CI 0.47-1.16). The discontinuation group had less minor antepartum bleeding (7.6 versus 12.3 percent; RR 0.62, 95% CI 0.42-0.92), but differences in the risks of all other adverse outcomes were not statistically significant. These findings warrant further study. They are not generalizable to other populations, such as the United States, where a lower dose of aspirin (81 mg) is commonly used and the population is more diverse (eg, White participants accounted for 93 percent of the trial population). A laboratory test to measure sFlt-1:PlGF was first approved by the US Food and Drug Administration in mid 2023 for use in pregnant patients hospitalized for a hypertensive disorder of pregnancy.
Safety — The short-term safety of low-dose aspirin use in the second and third trimesters is well established [11,56], and it appears to be safe in the first trimester as well (ie, no demonstrable increase in rates of miscarriage or congenital anomalies) [57,58]. Importantly, there is no clear increase in risk of fetal/neonatal intracranial bleeding (intraventricular hemorrhage: RR 0.99, 95% CI 0.72-1.36; other neonatal bleeding: RR 0.90, 95% CI 0.75-1.08; 20 trials, >32,000 neonates), but a small absolute increase in risk of postpartum hemorrhage is likely (143 hemorrhages >500 mL per 1000 patients, which represents 9 more hemorrhages per 1000 patients compared with nonuse of aspirin; RR 1.06, 95% CI 1.00-1.12) [11]. The comparative safety of different doses has not been evaluated, but a trial comparing the 150 mg dose with placebo reported similar rates of maternal bleeding (eg, vaginal, nasal, skin bruising, abruption) in both groups, suggesting a low risk of maternal harm with the 150 mg dose [15].
Longer term safety data are limited. In a meta-analysis of data from the Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) and the Italian Study of Aspirin in Pregnancy (ISAP) trials, in utero exposure to low-dose aspirin for prophylaxis or treatment of preeclampsia or fetal growth restriction was associated with lower postneonatal mortality until age 12 months, fewer hospital visits for developmental delay at 12 months, and improved gross and fine motor function at 18 months [59]. There were no differences in other neurodevelopmental outcomes (language, hearing and/or vision problems), respiratory problems, and the proportion of children with a short stature and/or low weight.
Treatment of chronic hypertension to lower blood pressure targets — In the 2022 Control of Mild Hypertension During Pregnancy Trial (CHAP), a strategy of treating pregnant patients with blood pressures ≥140/90 mmHg compared with a strategy of reserving treatment only for severe hypertension reduced the incidence of any preeclampsia (24.4 versus 31.1 percent; RR 0.79, 95% CI 0.69-0.89), preeclampsia with severe features (23.2 versus 29.1, RR 0.80, 95% CI 0.70-0.92), and medically-indicated preterm birth <35 weeks (12.2 versus 16.7 percent; RR 0.73, 95% CI 0.60-0.89), as well as the development of severe hypertension in pregnancy (36.1 versus 44.3 percent; RR 0.82, 95% CI 0.74-0.90) [60]. (See "Treatment of hypertension in pregnant and postpartum patients" and "Chronic hypertension in pregnancy: Prenatal and postpartum care".)
Timed birth at 39 weeks in low-risk, nulliparous patients — The ARRIVE trial showed that low-risk nulliparas assigned to induction of labor at 39+0 to 39+4 weeks of gestation were less likely to develop a hypertensive disorder of pregnancy than those assigned to expectant management until 40+5 to 42+2 weeks (gestational hypertension or preeclampsia: 9.1 versus 14.1 percent; RR 0.64, 95% CI 0.56-0.74) [61]. Results for gestational hypertension versus preeclampsia were not provided. We emphasize that this approach for prevention of preeclampsia requires shared decision-making, and available evidence is inadequate to extrapolate to other populations, such as high-risk and/or parous patients. The risks and spectrum of benefits of induction of labor at 39 weeks is discussed in detail separately (see "Induction of labor with oxytocin").
POSSIBLY EFFECTIVE INTERVENTIONS — Low-dose aspirin prophylaxis is the generally accepted therapy for prevention of preeclampsia. The following interventions have been either offered to a particular subgroup of patients, on a case-by-case basis to highly selected patients, or on an investigational basis.
Calcium supplementation — Low dietary calcium intake is associated with hypertension in the general population. (See "Diet in the treatment and prevention of hypertension", section on 'Other dietary interventions'.)
Pregnant individuals should achieve the recommended daily allowance (RDA) for elemental calcium through diet and/or supplements. In the United States, the RDA for elemental calcium is 1000 mg/day in pregnant, lactating, or nonpregnant females 19 to 50 years of age (1300 mg for girls 14 to 18 years of age). The United States female population in the reproductive age range has an average calcium intake of 950 mg/day; thus, most are candidates for modest supplementation, which may be supplied by a prenatal vitamin [62]. However, individuals who have low dairy intake, other calcium deficient states, or live in an area of endemic calcium deficiency may benefit from higher calcium supplementation to reduce the risk of preeclampsia. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Calcium and vitamin D'.)
In populations where baseline dietary calcium intake is low, the World Health Organization (WHO) recommends 1500 to 2000 mg elemental calcium supplementation per day divided into three doses for pregnant individuals to reduce the risk of preeclampsia, particularly among those at higher risk of developing hypertension (2.5 g of calcium carbonate or 4.75 g of calcium citrate contains approximately 1 g elemental calcium) [63]. The WHO recommendation is based on positive results from systematic reviews (see following example), which should be interpreted with caution because of the possibility of small-study effect or publication bias.
●A 2022 meta-analysis evaluated calcium supplementation versus placebo/no therapy for preeclampsia prevention (30 randomized trials; >20,000 participants) [64]. Seventeen trials included patients considered to be at high risk of developing preeclampsia, 24 trials included patients with low baseline calcium intake (<900 mg/day), 18 trials used high-dose calcium supplementation (≥1 g elemental calcium/day), and six trials initiated calcium before 20 weeks of gestation but most of the remainder initiated the intervention soon after 20 weeks. Median adherence to calcium supplementation was >80 percent. One-third of trials were at high risk of bias. Major findings were:
•Calcium supplementation reduced the risk of developing preeclampsia (risk ratio [RR] 0.49, 95% CI 0.39-0.61). Other maternal and perinatal outcomes were not substantially different between the supplementation and placebo/no therapy groups.
•The risk reduction for preeclampsia was statistically significant in patients with low baseline calcium intake (RR 0.45, 95% CI 0.35-0.58) but not in those with adequate baseline intake (RR 0.62, 95% CI 0.37-1.06).
•The risk reduction occurred in low dose (<1 g) and high dose (≥1) supplementation trials (low dose RR 0.49, 95% CI 36-65; high dose: RR 0.49, 95% CI 0.36-0.66).
•The risk reduction with supplementation occurred in patients with low- and high-baseline preeclampsia risk (low risk: RR 0.46, 95% CI 0.42-0.76; high risk: RR 0.41, 95% CI 0.29-0.57).
A subsequent randomized trial specifically evaluated low (500 mg) versus high (1500 mg) calcium supplementation in over 20,000 nulliparous pregnant people residing in two countries with low dietary calcium intake [65]. Low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia (India: 3 versus 3.6 percent, RR 0.84, 95% CI 0.68-1.03; Tanzania: 3.0 versus 2.7 percent, RR 1.90, 95% CI 0.88-1.36). These findings suggest that a single 500 mg supplement is sufficient to reduce the risk of preeclampsia and would be less cumbersome than the current WHO recommendation of 1500 to 2000 mg per day divided into three doses.
Prepregnancy weight loss and appropriate gestational weight gain — In patients who are overweight or obese, prepregnancy weight loss has a variety of reproductive, pregnancy, and overall health benefits. In particular, cohort studies of females who underwent bariatric surgery suggest that weight loss in females with obesity significantly reduces the risk of preeclampsia [66]. In addition, a cohort study of individuals with preeclampsia found weight loss between pregnancies reduced the risk of recurrent preeclampsia in those who were normal weight, overweight, or obese [67]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Prepregnancy weight loss' and "Fertility and pregnancy after bariatric surgery", section on 'Preeclampsia and other hypertensive disorders of pregnancy'.)
Patients may reduce their risk of developing preeclampsia by not exceeding Institute of Medicine (now National Academy of Medicine) recommendations for gestational weight gain. Those who are overweight or obese are likely to benefit most [68]. (See "Gestational weight gain", section on 'Recommendations for gestational weight gain'.)
Exercise — Exercise has several health benefits and is a potential strategy for reducing the risk of developing preeclampsia in individuals who are not candidates for low-dose aspirin prophylaxis, but exercise for this indication warrants further investigation. In a meta-analysis of randomized trials of exercise-related interventions in selected pregnant individuals, exercise-only interventions generally reduced the odds of developing preeclampsia (odds ratio [OR] 0.59, 95% CI 0.37-0.94) [69]. Some benefit began to accrue when exercise was performed at a frequency of at least three days/week or at least 25 minutes per session, but 140 minutes per week of brisk walking, water aerobics, stationary cycling, or resistance training would be required for a 25 percent reduction in preeclampsia. Surprisingly, interventions combining exercise and cointerventions (such as counseling) were less effective than exercise alone (OR 0.97, CI 0.78-1.21), possibly because patients in the counseling trials were often unsupervised during exercise and poorly compliant.
In another meta-analysis of randomized trials comparing supervised exercise during pregnancy with standard antenatal care or unsupervised exercise, the intervention reduced the incidence of hypertensive disorders of pregnancy (3 versus 5 percent; OR 0.54, 95% CI 0.40-0.72) [70]. Structured exercise (combination of aerobic, strength, and flexibility workouts) and yoga were both effective. (See "Exercise during pregnancy and the postpartum period", section on 'Prescribing exercise for pregnant individuals'.)
Other — For patients undergoing fertility therapy with in vitro fertilization or ovulation induction alone, various techniques can be employed to reduce the chances of multiple gestation, especially triplets or more. (See "Strategies to control the rate of high order multiple gestation".)
INVESTIGATIONAL APPROACHES
Statins — Statins are generally discontinued in pregnancy, with some exceptions, such as patients with homozygous familial hypercholesterolemia or established cardiovascular disease and at very high risk of myocardial infarction or stroke [71]. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)
Endothelial dysfunction and inflammation are key components of both adult cardiovascular disease and preeclampsia. Because inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (ie, statins) are effective for primary and secondary prevention of cardiovascular mortality and morbidity, these drugs may also reduce the risk of preeclampsia. Data from animal studies [72-76] and a single small pilot trial in humans [77] support this hypothesis. However, in a multicenter randomized trial of over 1100 patients with singleton pregnancies at high risk for term preeclampsia, pravastatin 20 mg daily beginning at 35+0 to 36+6 weeks and continuing until birth did not reduce the incidence of preeclampsia (hazard ratio 1.08, 95% CI 0.78-1.49) or other adverse pregnancy outcomes compared with placebo [78]. The justification for the very short duration of therapy in this trial is not clear, and few preventive trials of any strategy have initiated therapy at this late gestational age; therefore, the negative results are not surprising. Appropriately powered randomized trials are warranted to determine whether earlier initiation of therapy, use of higher doses, or use of more potent statins might be effective [79].
Anticoagulation — The placenta of patients with preeclampsia displays characteristic features of uteroplacental ischemia, including increased syncytial knots and intervillous fibrin, distal villous hypoplasia, villous infarcts, decidual necrosis, and spiral artery abnormalities including acute atherosis, mural hypertrophy, and luminal thrombosis/fibrous obliteration. (See "The placental pathology report", section on 'Preeclampsia'.)
The use of prophylactic anticoagulation in selected high-risk patients, particularly those with known thrombophilic genetic variants plus a history of placenta-mediated adverse pregnancy outcome (eg, early severe preeclampsia) has been suggested to prevent recurrence [80-85]. However, available limited data do not support this practice.
●In a 2016 meta-analysis using individual patient data from eight randomized trials of low molecular weight heparin (LMWH) therapy versus no LMWH for patients with any prior placenta-mediated pregnancy complications (term or preterm preeclampsia, late pregnancy loss, placental abruption, birth of a small for gestational age [SGA] neonate), the intervention did not significantly reduce the incidence of the primary composite outcome (early-onset or severe preeclampsia, SGA newborn <5th percentile, abruption, pregnancy loss ≥20 weeks of gestation): 62/444 (14 percent) versus 95/443 (22 percent), absolute difference -8 percent, 95% CI -17.3 to 1.4, relative risk (RR) 0.64, 95% CI 0.36-1.11 [86]. There were also no significant differences in the secondary outcomes of preeclampsia, severe preeclampsia, early-onset preeclampsia, and severe or early-onset preeclampsia. An unexplained observation from this meta-analysis was that the results obtained from single-center trials contrasted starkly with those from the multicenter trials, with the former demonstrating significant benefit from LMWH while the latter did not.
●In patients with hereditary thrombophilias, another meta-analysis found that use of LMWH did not improve live birth weight or other pregnancy outcomes compared with low-dose aspirin alone; however, the findings were based on a few trials with methodological limitations [87].
Since publication of these meta-analyses, two additional multicenter, randomized trials were published in which low molecular heparin in high-risk patients did not reduce preeclampsia recurrence and other adverse pregnancy outcomes [88,89]. Although these data do not demonstrate benefits of LMWH, concerns remain regarding heterogeneity between single-center and multicenter trials, inclusion of different placenta-mediated processes and phenotypes that may have different pathogenic pathways, differences in LMWH treatment protocols (dose, initiation/duration of treatment, combination therapy), analysis of multiple subgroups, multiple assessed outcomes, and possible lack of power to answer all of the relevant clinical questions, thus further investigation to needed to address these deficiencies.
Metformin — Metformin is an oral hypoglycemic agent used to treat type 2 diabetes and gestational diabetes. It has multiple sites of action and pre-clinical studies indicate a reduction in secretion of anti-angiogenic factors from the placenta and mitigation of endothelial dysfunction.
●In pregnant patients with obesity but no diabetes, a placebo-controlled randomized trial evaluating use of metformin to decrease maternal and fetal weight gain found it reduced the rate of preeclampsia by 76 percent (odds ratio [OR] 0.24, 95% CI 0.10-0.61) [90].
●In high-risk insulin-resistant patients, a meta-analysis of trials comparing metformin with insulin also demonstrated a reduction in preeclampsia (OR 0.68, 95% CI 0.48-0.95), but no difference in the overall rate of hypertensive disorders of pregnancy (OR 0.86, 95% CI 0.33-2.26) [91].
●Subsequently, in a multicenter randomized trial that assigned 502 pregnant patients with type 2 diabetes to receive either metformin or placebo added to insulin, metformin did not reduce the combined outcome of gestational hypertension, worsening chronic hypertension, or preeclampsia (23 percent in both groups) [92].
Other — A number of other agents are being investigated for primary prevention of preeclampsia or secondary prevention/mitigation of adverse outcomes in established preeclampsia [93]. In addition to those mentioned above, omeprazole and sulfasalazine are being studied in clinical trials.
PROBABLY INEFFECTIVE INTERVENTIONS
Vitamin C and E supplements — We recommend not prescribing antioxidant supplementation with vitamin C and/or E for prevention of preeclampsia. Multiple large, randomized, multicenter trials including patients at both high and low risk of developing preeclampsia have consistently demonstrated that it is not effective [94-101]. Meta-analyses of nine such trials involving a total of almost 20,000 patients confirmed this finding and also found that supplementation was associated with a slightly increased risk of gestational hypertension (relative risk [RR] 1.11, 95% CI 1.05-1.17), but this could have been the result of multiple statistical comparisons [102,103]. Similarly, two trials included in a meta-analysis noted that supplementation was associated with an increased risk of prelabor rupture of membranes (RR 1.73, 95% CI 1.34-2.23) [103] but not preterm prelabor rupture of membranes.
Vitamin D supplements — A 2016 meta-analysis of vitamin D supplementation in pregnancy concluded supplementation may reduce the risk of preeclampsia (8.9 versus 15.5 percent, RR 0.52, 95% CI 0.25-1.05), but these findings were based on only two low-quality trials involving a total of 219 patients [104]. The combination of vitamin D and calcium resulted in a lower risk of preeclampsia than not receiving this intervention (RR 0.51, 95% CI 0.32-0.80, three trials, 1114 patients, moderate quality), but this may have been related to calcium supplementation in calcium-deficient patients. A dose of 600 international units (the recommended dietary allowance) appears to be sufficient as it results in similar preeclampsia risk as higher doses [105]. (See 'Calcium supplementation' above.)
Folic acid supplementation — The body of data does not indicate a consistent decreased or increased risk for hypertensive disorders of pregnancy (preeclampsia, gestational hypertension) with folic acid supplementation [106,107], even at high doses (4 mg daily) [108]. Regardless, periconceptional folic acid supplementation is recommended to reduce the occurrence of neural tube defects. (See "Preconception and prenatal folic acid supplementation".)
Fish oil supplements — In a 2018 Cochrane meta-analysis of randomized trials, compared with placebo or no marine omega-3 fatty acid intervention, marine omega-3 fatty acid supplementation (food, supplements) during pregnancy showed a trend toward a reduction in preeclampsia (RR 0.84, 95% CI 0.69-1.01, 20 trials, n >8300 patients), but the evidence was low quality [109]. When only trials at low risk of bias were analyzed, the trend disappeared (RR 1.00, 95% CI 0.81-1.25). In another review [110], only three trials of marine omega-3 fatty acid supplementation in patients with singleton gestations at high risk of preeclampsia or growth restriction were considered well-designed, and none reported a reduction in these outcomes [111-113].
Diet — Only a few small randomized trials have evaluated the role of dietary modifications in the prevention of preeclampsia. No beneficial results have been demonstrated from these interventions, which include nutritional advice, protein and energy supplements, protein and energy restriction (in patients with obesity), magnesium supplementation, and salt restriction [114-116].
A systematic review of observational data suggested that dietary patterns higher in vegetables, fruits, whole grains, nuts, legumes, fish, and vegetable oils and lower in meat, refined grains, and added sugar were associated with reduced risk of preeclampsia and gestational hypertension [117]. Although there are limitations in observational data, a healthy diet is beneficial over the long-term regardless of pregnancy status and not associated with any harms.
Nitric oxide donors — Patients with preeclampsia may be deficient in nitric oxide, which mediates vasodilatation and inhibits platelet aggregation. However, a systematic review concluded that there is no high-quality evidence that administration of nitric oxide donors (nitroglycerin) prevents preeclampsia [118].
L-arginine, the substrate for synthesis of nitric oxide, has been investigated as a means of preventing preeclampsia. In a small randomized trial that tested this approach in patients with a history of preeclampsia in a previous pregnancy (a group who would be expected to have a recurrence rate of between 5 and 20 percent), supplementation with medical food-bars containing L-arginine plus antioxidant vitamin was associated with a significant reduction in the incidence of preeclampsia compared with placebo (29 [13/228] versus 67 percent [30/222]; RR 0.17, 95% CI 0.12-0.21) and compared with use of antioxidant vitamins alone (29 [13/228] versus 50 percent [23/222]; RR 0.09, 95% CI 0.05-0.14) [119]. The mean gestational age at delivery was >38 weeks, regardless of treatment assignment, and there were no significant differences between groups in mean infant birth weight, proportion of SGA infants, or rate of abruption. Thus, it appears that most of these patients had mild preeclampsia, and the experimental treatment did not have an important impact on meaningful clinical outcomes.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Preeclampsia (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Low-dose aspirin (preferred approach) – Low-dose aspirin reduces the risk of developing preterm preeclampsia. (See 'Low-dose aspirin' above.)
•Candidates
-For patients at high-risk of developing preeclampsia, we suggest low-dose aspirin prophylaxis (Grade 2B). At least a modest (≥10 percent) reduction in the overall incidence of preeclampsia and its sequelae (growth restriction, preterm birth) is possible. The risk for preterm preeclampsia is reduced more than that for term preeclampsia. We base our selection of high-risk patients on United States Preventive Services Task Force /American College of Obstetricians and Gynecologists criteria (table 2). (See 'Selecting patients at high risk of developing preeclampsia' above and 'Other considerations' above and 'Evidence of efficacy' above.)
We do not prescribe low-dose aspirin for patients at low risk of developing preeclampsia (eg, healthy nulliparous patients) because pregnancy outcomes such as birth weight, fetal growth restriction, and length of gestation are similar to those in untreated patients. (See 'Selecting patients at high risk of developing preeclampsia' above and "Spontaneous preterm birth: Overview of interventions for risk reduction", section on 'Low-dose aspirin'.)
•Administration and dose – We use aspirin 81 mg daily for prevention of preeclampsia in patients at high risk. Emerging evidence suggests a benefit of doses of 100 to 150 mg, and possibly 162 mg. (See 'Dose' above.)
We begin aspirin in the 12th or 13th week of gestation and ideally prior to 16 weeks of gestation. We continue aspirin until delivery; some have suggested discontinuation at 36 weeks or 5 to 10 days prior to delivery to theoretically to diminish the risk of bleeding during delivery. (See 'Timing of initiation' above and 'Timing of discontinuation' above and 'Safety' above.)
If aspirin is not initiated at the end of the first trimester, initiation after 16 weeks (but before symptoms develop) may also be effective. (See 'Timing of initiation' above.)
●Other approaches
•Antihypertensive therapy for chronic hypertension – Treatment of mild chronic hypertension during pregnancy reduces the incidence of preeclampsia with severe features and development of severe hypertension. (See "Treatment of hypertension in pregnant and postpartum patients" and "Chronic hypertension in pregnancy: Prenatal and postpartum care".)
•Calcium – In populations with low calcium intake, the World Health Organization recommends 1500 to 2000 mg elemental calcium supplementation per day for pregnant individuals to reduce the risk of preeclampsia, particularly those at higher risk of developing hypertension. For healthy females in the United States, we agree with the recommended daily allowance for elemental calcium advised in the United States: 1000 mg/day in pregnant and lactating individuals 19 to 50 years of age (1300 mg for girls 14 to 18 years old). We do not prescribe a higher intake via diet and/or supplements for patients at high risk of developing preeclampsia, as even 500 mg/day may be adequate for this purpose. (See 'Calcium supplementation' above.)
•Preconception weight loss, appropriate gestational weight gain – Preconception weight loss and appropriate gestational weight gain can reduce the risk of developing preeclampsia. Weight loss in patients who are overweight or obese is recommended for a variety of reproductive, pregnancy, and health benefits. (See 'Prepregnancy weight loss and appropriate gestational weight gain' above.)
•Low molecular weight heparin – Available data do not conclusively support use of low molecular weight heparin prophylaxis in addition to low-dose aspirin to reduce the risk of preeclampsia or its sequelae, although these data are not definitive, and there are methodologic concerns with the published trials. (See 'Anticoagulation' above.)
•Timed birth at 39 weeks – In the ARRIVE trial, nulliparas assigned to induction of labor at 39+0 to 39+4 weeks of gestation were less likely to develop a hypertensive disorder of pregnancy than those assigned to expectant management until 40+5 to 42+2 weeks. Delivery at 39 weeks for this indication should be a shared decision. (See 'Timed birth at 39 weeks in low-risk, nulliparous patients' above.)
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