This chapter should be cited as follows:
Reddy M, Rolnik DL, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416343

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 2

Health and risk in pregnancy and childbirth

Volume Editors: Professor Claudia Hanson, Karolinska Institutet, Sweden
Dr Nicola Vousden, King’s College, London, UK

Chapter

Preventing Pre-eclampsia and its Complications

First published: June 2022

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SYNOPSIS

There is considerable literature devoted to the prevention of pre-eclampsia in order to minimize the risk of the associated maternal and perinatal complications. The primary therapies of interest include lifestyle changes, aspirin, calcium, vitamin supplementation, and anticoagulant therapy with heparin. This chapter will focus on these interventions and also briefly explore emerging therapies for the prevention of pre-eclampsia. The evidence for these prophylactic therapies will be assessed according to populations grouped by risk. Therefore, prior to reading this chapter, it is important to understand the different methods of defining risk in pre-eclampsia, which are addressed in Chapter 5.

Current evidence supports two main interventions. Firstly, in women at increased risk, the use of low-dose aspirin (150 mg/day), ideally commenced prior to 16 weeks’ gestation is associated with a decreased incidence of preterm pre-eclampsia. Secondly, in populations with low dietary calcium intake, calcium supplementation (at least 1 g/day) may be of benefit. At this stage, there is insufficient evidence to support the use of vitamin C and E supplementation, heparin, fish oil, folic acid and other micronutrient supplementation for the sole prevention of pre-eclampsia.

LOW-DOSE ASPIRIN

Potential mechanism of action

Low-dose aspirin (LDA) is an irreversible cyclooxygenase (COX) inhibitor, which supresses the production of prostaglandins, prostacyclin, and thromboxane A2, thereby inhibiting platelet activation and aggregation.¹ Whilst we understand the pharmacodynamics of aspirin, the mechanisms by which aspirin prevents pre-eclampsia remain uncertain. The hypotheses suggested by in vitro studies include (1) improvement in trophoblastic invasion (placentation), (2) reduced placental infarction due to the anti-thrombotic effect of aspirin, and (3) endothelial stabilization due to the anti-inflammatory effects of COX inhibition.²

Evidence in women at increased risk

A plethora of the literature has been dedicated to the use of aspirin to prevent pre-eclampsia and its complications in high-risk women. Early randomized control trials (RCTs) in the late 1900s and early 2000s demonstrated mixed results with some suggesting significant benefit and others showing modest to no benefit with aspirin prophylaxis.^3,4,5 The Collaborative Low-dose Aspirin Study in Pregnancy (CLASP) is the largest of these RCTs, in which 9,364 women at high risk for pre-eclampsia (defined by maternal history alone) or with confirmed pre-eclampsia were randomized to 60 mg of aspirin or placebo between 12 and 32 weeks’ gestation.³ The results of the CLASP trial demonstrated no difference in the incidence of pre-eclampsia or associated complications in both the high-risk population group and those with confirmed pre-eclampsia or fetal growth restriction. A subsequent individual patient data meta-analysis published in 2007 included 31 RCTs assessing the use of anti-platelet agents for the primary prevention of pre-eclampsia, of which 24 used aspirin alone.⁵ In this meta-analysis, aspirin prophylaxis was associated with only a 10% reduction in the incidence of pre-eclampsia (relative ratio [RR] 0.90, 95% confidence interval [CI] 0.84–0.97). However, across the 31 studies, 15 different definitions of pre-eclampsia were used, the dose of aspirin ranged from 50–150 mg, and 59% of the women received prophylaxis after 20 weeks’ gestation. It is therefore likely that the conclusions drawn from these early trials are impeded by heterogeneity in the included study populations, the doses of aspirin used, the timing of aspirin prophylaxis and the definitions of pre-eclampsia.

More recently the 2017 landmark trial, Aspirin for Evidence-Based Pre-eclampsia Prevention (ASPRE), demonstrated significant reduction in the rate of preterm pre-eclampsia when 150 mg of aspirin was prescribed to women at high risk for pre-eclampsia prior to 15 weeks’ gestation.⁶ In this study of 1,776 participants, women underwent screening for preterm pre-eclampsia using a validated competing risks model, which combines maternal characteristics and medical history, mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PLGF).^7,8 Women identified as high risk (calculated risk ≥1 in 100) by this algorithm were randomized to 150 mg of aspirin or placebo from 11–14 + 6 weeks’ gestation until 36 weeks’ gestation or until birth, whichever came first. The results of the ASPRE trial demonstrated a 62% reduction in the rate of preterm pre-eclampsia with delivery prior to 37 weeks’ gestation (adjusted odds ratio [aOR] 0.38, 95% confidence interval [CI] 0.20–0.74). These results are in the setting of high levels of compliance (80% of the study population took more than 85% of the prescribed doses). The findings of ASPRE have since been supported by an updated meta-analysis of 16 studies including approximately 19,000 participants, in which aspirin commenced prior to 16 weeks’ gestation at a daily dose ≥100 mg was associated with a 67% reduction in the rate of preterm pre-eclampsia requiring delivery before 37 weeks’ gestation (relative risk [RR] 0.33, 95% CI 0.19–0.57).⁹

Secondary analyses of the ASPRE data has also shown a 68% reduction in the cumulative length of neonatal intensive care unit (NICU) stays and a trend towards lower rates of perinatal death.¹⁰ The treatment effect of aspirin appeared to be consistent across various subgroups according to maternal characteristics and medical history, with the exception of those with chronic hypertension (aOR 1.29, 95% CI, 0.33–5.12).¹¹ Interestingly, in another secondary analysis of data from ASPRE, chronic hypertension as well as a very high-risk screening result (≥1 in 50) and low PLGF (<0.712 MoM) were associated with a residual risk of preterm pre-eclampsia despite aspirin prophylaxis.¹²

Evidence in an unselected population – the role of universal prophylaxis

Whilst primary prevention with aspirin has been extensively examined in women at increased risk of pre-eclampsia, the evidence for universal aspirin prophylaxis in pregnancy and the efficacy in an unselected population group is limited. The ASPIRIN study was a multicenter RCT in which normotensive nulliparous women were randomized to 81 mg of aspirin or placebo between 6 and 14 weeks' gestation.¹³ In 11,976 women across low-middle income countries, a secondary analysis demonstrated that aspirin reduced the rate of preterm birth (<34 weeks) due to a hypertensive disorder of pregnancy by 62% (RR 0.38, 95% CI 0.17–0.85). However, the trial was designed to address a possible reduction in the rate of preterm birth (spontaneous and iatrogenic delivery) and showed only a 11% reduction in the primary outcome of delivery before 37 weeks (RR 0.89, 95% CI 0.81–0.98). There was also no reduction in the overall rates of hypertensive disorders of pregnancy.

Studies have also demonstrated the feasibility of aspirin treatment in a low-risk nulliparous population.¹⁴ In the “Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test (TEST)” study, 546 women were randomized to routine aspirin, no aspirin or prescription of aspirin using a screen-and-treat approach with the competing risks model. In this population, 52% of those approached agreed to participate in a trial with routine aspirin prophylaxis, and compliance rates were 90% with no differences between the routine aspirin group and the screen-and-treat group. Interestingly, this study also demonstrated the feasibility of the screen-and-treat approach with a 98% success rate in obtaining the uterine artery pulsatility index and a median time to obtaining a screening result of 7.6 days (9–26 days). However, this study is of a small size and there remains concerns about compliance and the acceptability of universal aspirin use in pregnancy, and possible increases in adverse events such as minor bleeding episodes, intrapartum and postpartum hemorrhage and neonatal intracranial bleeding if aspirin were universally given to all pregnant women.¹⁵ Such an approach of universal treatment specifically for the prevention of pre-eclampsia has not been properly assessed in adequately powered RCTs.

Furthermore, although a cost-effectiveness study suggests that routine aspirin use would be more cost-effective than no intervention or a screen-and-treat approach, such an analysis assumes that adherence to treatment and effectiveness would be similar between the different approaches, which is highly unlikely.^16,17,18 In fact, if there was a 20% lower compliance rate with universal prophylaxis, the screen-and-treat approach would be more cost-effective.¹⁸ As a corollary of similar population-wide interventions, it is known that adherence rates to folic acid supplementation for the prevention of neural tube defects is only 30–35%.¹⁹ Cost-effectiveness studies have also found that a screen-and-treat approach would be highly cost-effective.^20,21 This is predominately driven by a reduction in the short- and long-term costs of preterm birth and neonatal morbidity. In a decision model using the Canadian population, the use of the screen-and-treat approach with the competing risks model was associated with 1096 fewer cases of preterm pre-eclampsia and a saving of C$14.39 million in comparison to using a history-based screening approach.²⁰ Similarly, in a smaller cost-effectiveness study in Australia, the use of the competing risks model was associated with a AUD$1.4 million saving in comparison to a current practice.²¹

Safety, dosing, and timing of therapy

The numerous RCTs studying the use of low-dose aspirin in pregnancy have demonstrated that it is safe to use beyond the first trimester.^3,6,22,23 Low-dose aspirin is not associated with an increased risk of congenital anomalies, and in most studies has not been shown to increase maternal or fetal bleeding events.^15,22,23 With regards to dosing, studies suggest that the effect of aspirin is dose dependent and the greatest efficacy is at doses ≥100 mg.²⁴ With regards to timing of prophylaxis, it appears that low-dose aspirin is more effective if commenced prior to 16 weeks’ gestation.²⁵ However, in the same systematic review, commencement of aspirin after 16 weeks’ gestation was associated with a non-significant 20% reduction in the incidence of pre-eclampsia. Furthermore, in an individual patient data meta-analysis of 32,217 women, the effect of aspirin did not differ if treatment was commenced before or after 16 weeks’ gestation.²⁶ Therefore, from a clinical perspective, although not ideal, there may still be some benefit to the commencement of aspirin after 16 weeks’ gestation. Table 1 summarizes current recommendations by widely used guidelines.

CALCIUM

At a population level, there is an inverse relationship between dietary calcium intake and the incidence of pre-eclampsia.^32,33,34 Such ecological evidence, however, is insufficient to recommend supplementation at the individual patient level. The evidence for calcium supplementation in preventing pre-eclampsia has demonstrated mixed results. The disparity in findings again relates to heterogeneity in whether the population groups assessed were high risk or low risk for pre-eclampsia, background dietary calcium intake, and dosage and timing of calcium supplementation.

Potential mechanism of action

In vitro studies have demonstrated that calcium has an anti-inflammatory effect and reduces the endothelial activation and dysfunction resulting from trophoblastic debris in pre-eclampsia.³⁵ This may be mediated through the effect of calcium on the nitric oxide synthetase pathway, and the subsequent increased production of nitric oxide.³⁵ Other hypotheses suggest that dietary calcium intake may reduce the incidence of pre-eclampsia by inhibiting parathyroid activity, thereby decreasing intracellular calcium and causing vasodilatation.³⁶

Evidence in women at increased risk

The evidence for calcium supplementation in high-risk women predominately arises from the 2018 Cochrane review and the 2019 Calcium and Pre-eclampsia (CAP) trial.^34,37 Both of these trials have significant limitations and as such it remains unclear whether calcium supplementation is beneficial in high-risk women.

The Cochrane review included five studies (n = 587) in which women at high risk for pre-eclampsia received 2 g/day of elemental calcium or placebo. Although the pooled analysis demonstrated a significant risk reduction (pooled RR 0.22, 95% CI 0.12–0.42), these findings should be interpreted with caution. Firstly, the effect size may be significantly over-estimated due to the small sample sizes of the primary studies (n = 15–125) and possible publication bias. Secondly, three of the five studies were conducted in low calcium intake populations, which reduces the generalizability of the results and may suggest that the benefit is greatest in those with dietary deficiencies. Lastly, the definitions of “high risk” varied between the individual studies, which also reduces the applicability of these findings to the wider population.

The CAP study was a double-blind RCT, which aimed to assess whether 500 mg of calcium supplementation before pregnancy and in early pregnancy prevents pre-eclampsia in a population group of women at a high-risk for pre-eclampsia and with a generally low dietary calcium intake. In this study of 1,355 women with a history of pre-eclampsia, there was no difference in the incidence of pre-eclampsia between the treatment or placebo group (RR 0.80, 95% CI 0.61–1.06). However, the compliance rates were low (only 50% of the population took at least 80% of the expected tablets), which may limit the validity of these results. Interestingly, in a subgroup analysis of participants with adequate compliance (defined as >80%), the rate of pre-eclampsia was significantly lower in the calcium group in comparison to the placebo controls (RR 0.66, 95% CI 0.44–0.98). Another limitation of this study was the dosage of calcium used, which at 500 mg appeared to be lower than the doses prescribed in previous trials.

Evidence in women at low risk

Although one study found no significant difference in the rate of pre-eclampsia with 1.5 g/day oral calcium supplementation (RR 0.91, 95% CI 0.69–1.19; 357 women),³⁸ the 2018 Cochrane review found that oral calcium supplementation (of at least 1 g/day) in low-risk women decreased the incidence of pre-eclampsia (RR 0.59, 95% CI 0.41–0.83; eight trials; 15,143 women), and gestational hypertension (RR 0.71, 95% CI 0.57–0.89; eight trials; 15,143 women).³⁴ Furthermore, there were no differences in the rates of preterm birth or perinatal mortality between treatment groups, though these findings were contradictory to that of other systematic reviews.^34,39 It is important to note that the benefits of calcium supplementation in women at low risk of pre-eclampsia are most likely restricted to those with low dietary calcium intake.^34,39 Furthermore, potential harms in this population have not been ruled out. For example, in a supplementation trial of 1.5 g of calcium daily in The Gambia, calcium treatment was associated with lower bone mineral content throughout lactation.⁴⁰ An alternative to supplementation may be to increase dietary calcium intake, by three to four dairy servings per day (as one serving corresponds to 250–300 mg of calcium). Table 2 summarizes the current guideline recommendations for the use of calcium in pre-eclampsia prevention.

ANTI-THROMBOTIC THERAPY – HEPARIN

Potential mechanism of action

Features of pre-eclamptic pathophysiology include impaired trophoblast invasion, thrombosis within the uteroplacental circulation and endothelial dysfunction. It is hypothesized that the anticoagulant properties of heparin may minimize the formation of thrombotic lesions and thereby reduce placental infarction.⁴² Low molecular weight heparin (LMWH) has also been shown to promote differentiation and invasion of trophoblasts, decrease vascular resistance and improve endothelial function.^42,43 Whilst these hypotheses may hold true in in vitro studies, in vivo studies are lacking and both the efficacy and mechanisms by which heparin may prevent pre-eclampsia remain uncertain.

Evidence in women at increased risk

Existing evidence for anticoagulant therapy in preventing pre-eclampsia and its complications predominately targets those at increased risk of the disorder. To our knowledge, there are no studies assessing the role of anticoagulation therapy in the prevention of pre-eclampsia in an unselected population. Furthermore, most studies have focused on LMWH and have demonstrated mixed results. This is likely due to study variation with regards to the definition of “high-risk” status and the definition of the outcomes. Guidelines for heparin use in the prevention of pre-eclampsia predominately cite the 2013 Cochrane review and three subsequent trials.^44,45,46,47 More recently, Cruz-Lemini et al. have published an updated review and meta-analysis, which includes the latter landmark trials.⁴²

The 2013 Cochrane review (nine trials, 979 women) found that prophylactic doses of heparin (of any type) compared with no treatment, decreased the rates of perinatal mortality (2.9% vs. 8.6%; RR 0.40, 95% CI 0.20–0.78), preterm delivery before 34 weeks (8.9% vs. 19.4%; RR 0.46, 95% CI 0.29–0.73), and small for gestational age (SGA) infants (7.6% vs. 19.0%; RR 0.41, 95% CI 0.27–0.61) in women at high risk of placental-mediated complications.⁴⁴ In another review that focused on LMWH only (six trials, 848 women), LMWH, compared with no treatment, reduced the risk of "severe" or early‑onset pre-eclampsia (1.7% vs. 13.4%; RR 0.16, 95% CI 0.07–0.36), preterm delivery before 37 weeks (32.1% vs. 47.7%; RR 0.77, 95% CI 0.62–0.96), and SGA infants (10.1% vs. 29.4%; RR 0.42, 95% CI 0.29–0.59), without a significant effect on perinatal mortality (1.9% vs. 5.3%; RR 0.41, 95% CI 0.17–1.02).⁴⁸

In contrast to the above meta-analyses, the three subsequent trials have not demonstrated a significant improvement in outcomes with heparin use. The Heparin-Pre-eclampsia trial, which randomized 249 women with a history of severe pre-eclampsia to 4000 units of enoxaparin plus aspirin or aspirin alone, demonstrated no difference in the primary outcome of placental-mediated complications, and no difference in the rates of pre-eclampsia.⁴⁷ Similarly, the Enoxaparin for the Prevention of Pre-eclampsia and Intrauterine growth restriction (EPPI) trial, which defined the “high-risk group” as those with a history of preterm pre-eclampsia or SGA showed no difference in the rate of pre-eclampsia/SGA with heparin use (OR 1.19; 95% CI 0.53–2.64; n = 149).⁴⁶ The Thrombophilia in Pregnancy Prophylaxis Study (TIPPS), randomized 292 women with a thrombophilia and an increased risk of placental-mediated pregnancy complications and/or venous thromboembolism (VTE) to dalteparin or no dalteparin.⁴⁵ The study also observed no difference in the primary composite outcome of major VTE, severe or early-onset pre-eclampsia, SGA, or pregnancy loss.

Interestingly, the recently updated meta-analysis by Cruz-Lemini et al. included the above trials and still demonstrated a benefit of prophylactic heparin in high-risk populations.⁴² In particular, LMWH was associated with lower odds of pre-eclampsia (OR 0.62, 95% CI 0.43–0.90; 15 studies; 2,795 women), SGA (OR 0.61, 95% CI 0.44–0.83; 15 studies; 2,799 women), and perinatal death (OR 0.49, 95% CI 0.25–0.94; 7 studies; 1,393 women). The effect of LMWH on the incidence of pre-eclampsia also appeared to be greater if treatment was commenced prior to 16 weeks’ gestation. These results should be interpreted with caution given that most included studies had small sample sizes, low to moderate quality, and there was significant clinical heterogeneity between the studies.

Safety

LMWH in prophylactic subcutaneous doses is associated with minimal risks for the mother and, theoretically, none for the fetus as it does not cross the placenta.⁴⁹ In a meta-analysis of 64 studies (2,777 women), major allergic reactions were uncommon (1.2%) and no women developed heparin-induced thrombocytopaenia.⁴⁹ LMWH in prophylactic doses was associated with very low risks of antenatal bleeding (0.42%), intrapartum bleeding (0.92%), and wound hematoma after either cesarean section or vaginal birth (0.65%).⁴⁹ In the TIPPS trial, LMWH was associated with an increase in minor bleeding episodes compared with no treatment.⁴⁵ LMWH to prevent recurrent early-onset pre-eclampsia and/or fetal growth restriction could be stopped at 34–36 weeks’ gestation, such that the potential intrapartum and postpartum side effects of LMWH are minimized. Table 3 summarizes the current guideline recommendations for the use of heparin in the prevention of pre-eclampsia.

VITAMINS C AND E

Potential mechanism of action

In pre-eclampsia, it is hypothesized that impaired placentation results in placental ischemia and reperfusion injuries, which in turn cause oxidative stress and the subsequent clinical manifestations of disease. In women with pre-eclampsia, there is evidence of oxidative stress in the placenta and maternal circulation with increased production of reactive oxygen species and decreased concentrations of antioxidant defence mechanisms such as vitamins C and E. Antioxidants play an important role in the removal and inactivation of free radicals and other oxidative products, which would otherwise trigger the endothelial dysfunction and end-organ damage in pre-eclampsia. It is therefore hypothesized that treatment with antioxidants such as vitamins C and E may reduce the oxidative stress in pre-eclampsia and thereby reduce the manifestations of disease.

Evidence in women at increased risk

In a meta-analysis of five trials (n = 3,005) of women at high risk for pre-eclampsia, antioxidant therapy (usually combined therapy with vitamins C 1000 mg/day and E 400 IU/day) did not significantly reduce the incidence of pre-eclampsia (RR 0.56, 95% CI 0.29–1.11).⁵¹ Since this meta-analysis, at least four further randomized control trials have been conducted in high-risk population groups.^52,53,54,55 All four studies (n = 2,840) showed that treatment with vitamin C and E had no significant effect on the incidence of gestational hypertension or pre-eclampsia.

Evidence in women at low risk

Similar to the high-risk population, studies in low-risk women have also demonstrated no benefit with vitamins C and E treatment. In a 2012 Cochrane review, among low-risk women given vitamins C (1000 mg/day) and E (400 IU/day) therapy from either the first or early second trimester, vitamins C and E did not significantly decrease the incidence of pre-eclampsia (RR 0.85, 95% CI 0.48–1.51; 4 trials; 2,441 women).⁵¹ This has been confirmed in subsequent trials, the largest of which is an American multicenter study of 10,514 low-risk nulliparous women randomized to vitamins C and E or placebo between 9 and 16 weeks’ gestation.⁵⁶ In this study, treatment with vitamins C and E did not prevent severe hypertension (RR 1.07, 95% CI 0.91–1.25) or pre-eclampsia (RR 1.07, 95% CI 0.93–1.24).

Safety

In both low-risk and high-risk population groups, there is evidence that vitamins C and E treatment for the prevention of pre-eclampsia may be associated with harm. In the International trial of antioxidants in the prevention of pre-eclampsia study (INTAPP), treatment with vitamins C and E was associated with a higher rate of premature pre-labor rupture of membranes (RR 1.97, 95% CI 1.31–2.98) and perinatal mortality (RR 2.2, 95% CI 1.02–4.73).⁵³ These findings were identified during the interim analysis leading to suspension of the trial. Interestingly, other studies have also reported higher rates of low birthweight neonates (RR 1.15, 95% CI 1.02–1.30) and the need for intravenous hypertensive therapy (RR 1.94, 95% CI 1.07–3.53) in women treated with vitamins C and E.⁵⁷ Current guideline recommendations on the use of vitamins C and E for the prevention of pre-eclampsia are shown in Table 4.

DIETARY CHANGES

A variety of dietary and lifestyle interventions can reduce the risk of pre-eclampsia (overall RR 0.81, 95% CI 0.69–0.94; 18 trials; 8,712 women).⁵⁸ The effect appears to be greatest with dietary change alone (RR 0.67, 95% CI 0.53–0.85; six trials; 2,695 women) in contrast to mixed interventions of diet, physical activity, and lifestyle (RR 0.93, 95% CI 0.66–1.32; six trials, 1438 women).⁵⁸ A single case-control study also demonstrated a lower risk of pre-eclampsia with a heart healthy diet.⁵⁹ However, this has not been investigated in the setting of a RCT. Nutritional education counseling was associated with a reduction in the rate of preterm birth (RR 0.46, 95% CI 0.21–0.98; two trials; 449 women), and a reduction in the incidence of low birth weight infants (RR 0.04, 95% CI 0.01–0.14; one trial; 300 women).⁶⁰ Specifically, within undernourished women, nutritional advice was found to increase birthweight (mean difference 489.8 g, 95% CI 427.9–551.6; two trials, 320 women).

Specific dietary changes – salt

Dietary salt restriction (with confirmed compliance) does not affect the incidence of gestational hypertension (RR 0.98, 95% CI 0.49–1.94; two trials, 242 women) or pre-eclampsia specifically (RR 1.11, 95% CI 0.46–2.66; two trials, 603 women).⁶¹ However, this evidence is based on small studies of low quality and therefore the results should be interpreted with caution.

Specific dietary changes – protein

Balanced protein/energy supplementation in pregnancy did not affect pre-eclampsia incidence (RR 1.48, 95% CI 0.82–2.66; two trials; 463 women), but does appear to reduce the rates of stillbirth (RR 0.60, 95% CI 0.39–0.94; five trials; 3,408 women) and SGA neonates (RR 0.79, 95% CI 0.69–0.90; seven trials; 4,408 women).⁶⁰ In contrast, high protein supplementation may have been associated with harm by increasing the risk of SGA neonates (RR 1.58, 95% CI 1.03–2.41; one trial, 505 women), although weight at an age of 1 year did not differ between the high and low/no supplementation groups.⁶⁰ Isocaloric protein supplementation was found to not benefit pregnant women or their infants; it did not affect birthweight (mean difference 108.3 g, 95% CI 220.9–437.4) or weekly maternal gestational weight gain (mean difference 110.5 g/week, 95% CI 82.9–303.8; two trials, 184 women).⁶⁰

Specific dietary changes – probiotics

No trials of probiotics were identified, but the consumption of milk-based probiotics was associated with a lower risk of severe pre-eclampsia in a Norwegian population-based cohort study of 33,399 primiparous women (aOR 0.79, 95% CI 0.66–0.96).⁶² Given that such evidence comes from observational studies, confounding may be present and the results should be interpreted with caution.

Specific dietary changes – flavonoids

A preventative strategy with considerable potential appeal to women is administration of flavonoids, antioxidants found in citrus fruits, dark chocolate, and tea. The idea is based on the inverse relationship between higher chocolate intake and lower blood pressure in pregnancy in a prospective cohort study of 2,291 women.⁶³ Two small trials have found conflicting effects of flavanol-rich chocolate on blood pressure in pregnancy; one trial (90 women) found that blood pressure was lower when high cocoa content chocolate was ingested from 11–13 weeks’ gestation,⁶⁴ whereas another trial (44 women) found that blood pressure and endothelial function were unchanged among normotensive women at baseline.⁶⁵ A third trial of 131 women also demonstrated that daily ingestion of high flavanol chocolate was associated with an improvement in the uterine artery Doppler pulsatility index.⁶⁶

Specific dietary changes – omega-3 fatty acids

In the 2018 Cochrane review assessing the role of omega-3 fatty acid supplementation in pregnancy, fish oil supplementation may have shown a trend towards a decreased incidence of pre-eclampsia (RR 0.84, 95% CI 0.69–1.01; 20 trials; 8,306 women).⁶⁷ However, the majority of the included studies were of small sample size and evidence was of low quality. In a planned secondary analysis of the Omega-3 to Reduce the Incidence of Preterm Birth (ORIP) trial, there was no reduction in the incidence of pre-eclampsia with fish oil supplementation (adjusted RR 1.07, 95% CI 0.80–1.43; 5,486 women).⁶⁸

Specific dietary changes – micronutrient supplementation

Micronutrient deficiencies (other than calcium) are common in pregnancy. Deficiencies of folate, magnesium, zinc, and pyridoxine have been associated with an increase in hypertensive disorders of pregnancy and their complications.^69,70,71

The potential benefits of folic acid supplementation in the prevention of pre-eclampsia remains unclear. In observational studies, folic acid supplementation has been associated with lower rates of pre-eclampsia in both high- and low-risk women.⁷² However, in a RCT of 2,464 women at a high risk of pre-eclampsia, high-dose folic acid (4 g/day) from 8–16 weeks’ gestation did not reduce the incidence of pre-eclampsia (RR 1.10, 95% CI 0.90–1.37).⁷³ These findings have been supported by another RCT where high-dose folate was prescribed to high-risk women till birth rather than 16 weeks’ gestation (RR 0.96, 95% CI 0.76–1.19; 1576 women).⁷⁴

With regards to other micronutrients, magnesium supplementation, in women at low and high risk, did not affect the incidence of pre-eclampsia, low birthweight, or SGA infants.⁷⁰ Small trials of zinc supplementation have also failed to suggest benefit in preventing hypertensive disorders of pregnancy.⁷⁵ However, in studies conducted in areas of zinc deficiency, zinc levels appear to be lower in those affected by pre-eclampsia in comparison to controls.⁷⁶ There are few small studies assessing the role of selenium supplementation, which have demonstrated mixed results.^77,78 Current guideline recommendations on dietary changes and micronutrient supplementation for the prevention of pre-eclampsia are shown in Table 5.

PHYSICAL ACTIVITY

There are robust epidemiological data that weight gain between pregnancies (even in non-obese women) is associated with higher rates of pre-eclampsia and other pregnancy complications, such as cesarean delivery and gestational diabetes.⁷⁹

With regards to physical activity, studies assessing exercise and the prevention of pre-eclampsia are heterogenous with varying study quality and mixed results. In a systematic review of six case-control studies, physical activity was associated with a 23% reduction in the odds of pre-eclampsia (OR 0.77, 95% CI 0.64–0.91).⁸⁰ However, this protective effect was not observed in ten prospective cohort studies (OR 0.99, 95% CI 0.93–1.05).⁸⁰ Similarly in three RCTs of small sample size, no impact of exercise was seen on gestational hypertension or pre-eclampsia.^81,82,83 However, in an updated review of moderate- to high-quality RCTs, exercise intervention was associated with a lower incidence of gestational hypertension (OR 0.61, 95% CI 0.43, 0.85; 5316 women), pre-eclampsia (OR 0.59, 95% CI 0.37, 0.90; 3322 women) and gestational diabetes (OR 0.62, 95% CI, 0.52–0.75).⁸⁴ To achieve a 25% reduction in risk of pre-eclampsia, approximately 25 min of moderate intensity exercise is required for at least 3 days per week.⁸⁴

Physically demanding work is associated with a higher risk of gestational hypertension and pre-eclampsia in observational studies (OR 1.60, 95% CI 1.30–1.96; four observational studies; 5,837 women).⁸⁵ Although workload reduction is a common obstetric intervention, we were unable to identify randomized studies of workload or stress reduction on the incidence of pre-eclampsia. These are unlikely to be forthcoming given the nature of the interventions.

Increased rest at home (varying from 30 min to 6 h/day) in the third trimester of pregnancy decreased the incidence of pre-eclampsia (RR 0.05, 95% CI 0.00–0.83; one trial, 32 women for increased rest alone; RR 0.13, 95% CI 0.03–0.51 for rest plus a nutrient supplement; 1 trial, 74 women).⁸⁶ Other substantive outcomes (such as adverse effects of rest and women’s views) were not reported. Overall, these studies are of small sample size and prone to reporting bias. As such, there is a lack of adequate evidence to support bed rest. Furthermore, there remains a lack of clarity about the definition of bed rest and uncertainty about whether women would comply with activity restriction.⁸⁷

EMERGING THERAPIES

Whilst low-dose aspirin is an effective intervention in preventing early-onset pre-eclampsia, it has little to no effect on preventing term disorder. Given that late-onset pre-eclampsia (>34 weeks’ gestation) accounts for approximately 80% of disease burden,⁸⁸ there is a need for novel therapies that have a particular focus on this population group. In this section, we discuss therapies that have shown promise in the setting of prevention. There are other therapies such as melatonin, sildenafil, and sulphorophane that are currently under investigation for the treatment of pre-eclampsia. However, there are no studies assessing the role of these novel therapies in the setting of prevention.

Metformin

In vitro and in vivo studies have demonstrated that metformin reduces the secretion of the anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT-1) and soluble endoglin, which play an important role in the endothelial dysfunction seen in pre-eclampsia.⁸⁹ The evidence for the potential benefit of metformin in pre-eclampsia arises from secondary analysis of studies in gestational diabetes, polycystic ovarian syndrome (PCOS), and obesity in pregnancy. To date, there are no randomized controlled trials assessing the role of metformin in preventing pre-eclampsia. Across 13 studies in women with gestational diabetes, metformin use was associated with lower rates of gestational hypertension in comparison to insulin (RR 0.56, 95% CI 0.37–0.85) and a trend toward lower rates of pre-eclampsia (RR 0.83, 95% CI 0.60–1.14).⁹⁰ There are two studies that have compared metformin with placebo in the obese population group. In the Efficacy of Metformin in Pregnant Obese Women (EMPOWaR) study of 449 women, a secondary analysis demonstrated no difference in pre-eclampsia rates between metformin and placebo use (3% vs.1%; OR 2.39, 95% CI 0.61–9.36).⁹¹ In contrast, a secondary analysis of the Metformin in Obese Nondiabetic Pregnant Women (MOP) trial, demonstrated lower rates of pre-eclampsia with metformin use in comparison to placebo (n = 450; 3% vs.11.3%; OR 0.24, 95% CI 0.10–0.61).⁹² More recently, a randomized control trial of 180 women with preterm pre-eclampsia demonstrated that metformin prolongs time to delivery (median difference 8.4 days, 95% CI 1.0–15.8 days).^93,94 Given the potential benefit of metformin, RCTs where prevention of pre-eclampsia is evaluated as the primary outcome are required.

Esomeprazole

In vitro and in vivo studies have shown that esomeprazole decreases the release of sFLT-1 and soluble endoglin in placental tissue and endothelial cells, promotes vasodilation of vessels, and decreases endothelial dysfunction.⁹⁵ In women with suspected or confirmed pre-eclampsia who were coincidentally using proton pump inhibitors (PPIs) such as esomeprazole, the concentrations of sFLT-1 appeared to be lower than in those not taking PPIs.^96,97 There is only one RCT that has evaluated the use of esomeprazole (40 mg/day) in prolonging pregnancy in preterm pre-eclampsia and has demonstrated no significant benefit (median difference 3 days, 95% CI −2.9–8.8 days; 120 women).⁹⁸ There are no studies to date that have assessed the role of esomeprazole in the prevention of pre-eclampsia. However, two phase II trials are currently in progress and their results might offer greater insight into the potential prophylactic role of esomeprazole in preventing pre-eclampsia.

L-arginine

Supplements containing L-arginine and "antioxidant vitamins" have been shown to reduce diastolic blood pressure or both systolic and diastolic blood pressure, and the incidence of pre-eclampsia in a population at high risk of the condition (two trials, 672 women).^99,100 Another systematic review supported that L-arginine supplements in high-risk women reduce the incidence of pre-eclampsia (RR 0.34, 95% CI 0.21–0.55) and preterm birth (RR 0.48, 95% CI 0.28–0.81).¹⁰¹ The protective effect was greater in women with established hypertensive disease (RR 0.21, 95% CI 0.05–0.98).¹⁰¹ Data from several small randomized trials suggests that L-arginine given to women with already diagnosed gestational hypertension (with or without proteinuria) or with fetal growth restriction can lead to improvement of maternal blood pressure and uteroplacental circulation.^{102,103,104,105} Optimal dosage needs to be defined and large randomized trials are required to further investigate its possible benefits.

Vitamin D

Vitamin D may play a protective role against pre-eclampsia through effects on immune modulation and vascular function.^106,107,108 In observational studies, vitamin D deficiency has been associated with an increased risk of pre-eclampsia (aOR 2.18, 95% CI 1.80–2.65).¹⁰⁹ In a meta-analysis of four RCTs, vitamin D supplementation has been shown to reduce the risk of pre-eclampsia in both high-risk and low-risk populations (499 women, RR 0.48, 95% CI 0.30–0.79).¹¹⁰ However, the comprising four trials are of small sample size (n = 54–165). Three of the four studies demonstrated no benefit, and one study suggested a risk reduction with vitamin D supplementation. Therefore, these results should be interpreted with caution and larger RCTs are required to determine a possible benefit.

Statins

Statins are lipid lowering drugs, which are most often used for the prevention of cardiovascular disease. In the setting of pregnancy, in vitro studies have shown that statins upregulate antioxidant pathways, inhibit the secretion of sFLT-1 and soluble endoglin from endothelial and trophoblast cells, and improve endothelial function.^111,112 Furthermore, in animal models of pre-eclampsia, administration of pravastatin has been shown to ameliorate the symptoms of disease.¹¹³ With regards to human trials, there are two pilot RCTs that have assessed the use of pravastatin for the prevention and treatment of pre-eclampsia. The first, by Costantine et al. assessed the potential prophylactic benefit of pravastatin (10 mg/day from 12–16 weeks till delivery) in 20 women at high risk for pre-eclampsia and demonstrated a non-significant trend towards lower sFLT-1 and higher PlGF concentrations in the treatment group.¹¹⁴ Furthermore, whilst no participants developed pre-eclampsia in the pravastatin group, four of the ten participants in the placebo group went on to develop the disorder. In contrast, the statins to ameliorate early-onset pre-eclampsia (StAmP) trial of 62 women with early-onset pre-eclampsia demonstrated no difference in sFLT-1 levels or outcomes between the pravastatin and placebo group.¹¹⁵ A third non-randomized trial in a select group of patients with antiphospholipid syndrome and pre-eclampsia demonstrated an improvement in the uterine artery pulsatility index and lower rates of perinatal death with pravastatin treatment.¹¹⁶ All three trials reported no adverse events with pravastatin use, which is concordant with preliminary epidemiological studies. Larger RCTs are currently underway to better assess the role of pravastatin in the prevention and treatment of pre-eclampsia.

RESOURCE-CONSTRAINED SETTINGS

Pre-eclampsia and its complications are far more prevalent in low-income and low/middle-income countries with 99% of the serious morbidity from pre-eclampsia occurring in these resource-poor settings.¹¹⁷ There are also significant barriers to the implementation of screening and prevention strategies in these populations, which exacerbates the inequalities in disease prevalence and outcomes. Factors that determine the potential impact of an intervention on prevention of pre-eclampsia include its availability, acceptability, and cost‑effectiveness, as well as the strength of the infrastructure of a health-care system. The latter is where resource-constrained settings face the greatest difficulty. Until these barriers are addressed, the prevention of pre-eclampsia will remain a significant challenge. In this section, we will focus on the two interventions that have been shown to be of greatest benefit in the prevention of pre-eclampsia.

Low-dose aspirin

The use of aspirin to reduce the incidence of preterm pre-eclampsia requires (1) screening and risk stratification and (2) commencement of 150 mg of aspirin ideally prior to 16 weeks’ gestation. This poses several challenges in resource-constrained settings. From a screening perspective, it may be difficult to implement the complete first-trimester combined test for pre-eclampsia with uterine artery Doppler studies and biochemical markers. As such, a more pragmatic approach, which uses maternal history and risk factors and mean arterial pressure to calculate individual-patient risks, may be more appropriate. From a treatment perspective, limitations in infrastructure in resource-constrained settings may delay commencement of treatment, which in turn may affect efficacy. In 2013, only 24% of women in low-resource countries had an antenatal visit prior to 12 weeks’ gestation in comparison to 82% in high-resource settings.¹¹⁸ An essential aspect of implementing aspirin prophylaxis in resource-constrained settings involves increasing education regarding the benefits of early initiation of antenatal care, and improving infrastructure and staffing to provide such care. Furthermore, the availability, accessibility, and affordability of aspirin needs to be addressed.

Calcium

The current recommendations support the use of calcium supplementation for the prevention of pre-eclampsia in those with low dietary calcium intake. Global trends typically show lower intake of calcium in low-resource countries (ranging from 300 to 600 mg/day) compared with high-resource countries (e.g., 969 mg for France).¹¹⁹ Therefore, calcium supplementation is likely to be of greatest benefit in the resource-constrained population. However, in a study of women receiving antenatal care in Brazilian public hospitals, over 90% of women consumed less than 1 g of calcium per day, yet less than 6% of women received a prescription for calcium supplements.¹²⁰ Similar results were observed in a teaching public hospital in Argentina.¹²¹ Barriers to calcium supplementation include procurement and storage of the drug, education regarding potential benefits of supplementation, and cost. Of note, both low-dose aspirin and calcium are listed in the World Health Organization’s model list of essential medicines and therefore “are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the individual and the community can afford”.⁴¹ Alternative strategies to calcium supplementation may also include increased dietary intake and public health interventions such as food fortification.

SUMMARY

Pre-eclampsia and its complications represent an important cause of maternal and perinatal morbidity and mortality. Optimizing primary prevention efforts in the peri-conceptional and antenatal period are essential to reduce this burden. This chapter summarizes the current evidence‑based recommendations regarding lifestyle changes and drugs that have been shown to help prevent pre-eclampsia and its complications. Current evidence supports the use of low-dose aspirin in high-risk population groups with the greatest benefit at doses ≥100 mg and when commenced prior to 16 weeks’ gestation. There may also be some benefit in calcium supplementation particularly in those with a dietary deficiency. Whilst these interventions may prevent preterm pre-eclampsia, our ability to prevent the more prevalent late-onset disorder is limited. As such, research into alternative therapeutic agents that target term pre-eclampsia is essential.

PRIORITIES FOR FUTURE RESEARCH

This chapter identifies gaps in knowledge regarding the prevention of pre-eclampsia. Whilst interventions such as aspirin prophylaxis have been shown to be effective in preventing preterm pre-eclampsia, they have minimal benefit in reducing the incidence of term pre-eclampsia. As such, it is essential that we identify interventions targeted at preventing term pre-eclampsia, which is where most disease burden lies. Furthermore, aspirin does not prevent all cases of preterm pre-eclampsia among women who are deemed to be at high risk, and a recent study has identified the main risk factors for developing preterm pre-eclampsia despite aspirin prophylaxis.¹² Interventions targeted at this population group are also required.

The effectiveness of prevention efforts relies on the development of infrastructure, and dissemination of knowledge among health-care providers and women with subsequent uptake of given recommendations. To help identify barriers and help achieve these objectives, there is a need for further implementation research, particularly in resource-constrained settings.

PRACTICE RECOMMENDATIONS

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