Clinical Procedures for the Prevention of Preeclampsia in Pregnant Women: A Systematic Review

Moura, Nádya Santos; Gomes, Maria Luziene Sousa; Rodrigues, Ivana Rios; Rolnik, Daniel Lorber; Costa, Fabrício Silva; Oriá, Mônica Oliveira Batista

doi:10.1055/s-0040-1714135

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Brasil

Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet. 42 (10) • Oct 2020 • https://doi.org/10.1055/s-0040-1714135 copy

Clinical Procedures for the Prevention of Preeclampsia in Pregnant Women: A Systematic Review

Procedimentos clínicos para a prevenção de pré-eclâmpsia em gestantes: Uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective

To identify the most effective procedures recommended for the prevention of preeclampsia.

Data Sources

A systematic review was performed in the following databases: Pubmed/MEDLINE, CINAHL, Web of Science, Cochrane and LILACS via the Virtual Health Library (VHL). A manual search was also performed to find additional references. The risk of bias, the quality of the evidence, and the classification of the strength of the recommendations were evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

Selection of Studies

In the initial search in the databases, the total number of articles retrieved was 351, and 2 were retrieved through the manual search; after duplicate articles were removed, 333 citations remained. After a thorough review of the titles and abstracts, 315 references were excluded. Accordingly, 18 articles were maintained for selection of the complete text (phase 2). This process led to the exclusion of 6 studies. In total, 12 articles were selected for data extraction and qualitative synthesis.

Data Collection

The articles selected for the study were analyzed, and we inserted the synthesis of the evidence in the online software GRADEpro Guideline Development Tool (GDT) (McMaster University and Evidence Prime Inc. All right reserved. McMaster University, Hamilton, Ontário, Canada); thus, it was possible to develop a table of evidence, with the quality of the evidence and the classification of the strength of the recommendations.

Data Synthesis

In total, seven studies recommended the individual use of aspirin, or aspirin combined with calcium, heparin or dipyridamole. The use of calcium alone or in combination with phytonutrients was also highlighted. All of the studies were with women at a high risk of developing preeclampsia.

Conclusion

According to the studies evaluated, the administration of aspirin is still the best procedure to be used in the clinical practice to prevent preeclampsia.

Keywords
pregnant women; preeclampsia; prevention and control; maternal health; pregnancy complications

Reference	Study Design	Objective	Sample	Procedure	Main results
Rolnik et al (2017)⁵5 Rolnik DL,Wright D, Poon LC, O’Gorman N, Syngelaki A, Matallana CP, et al. Aspirin versus placebo in pregnancies at high risk for pretermpreeclampsia. N Engl J Med. 2017;377(07):613–622. Doi: 10.1056/NEJMoa1704559 https://doi.org/10.1056/NEJMoa1704559...	Randomized controlled trial	To evaluate whether low-dose aspirin during pregnancy reduces the risk of developing preeclampsia (PE) before 37 weeks of pregnancy in high-risk women according to an individual-risk calculation algorithm.	798 participants in the aspirin group; 822 in the placebo group.	Aspirin at a dose of 150 mg per day, administered from the 11th to the 14th gestational weeks until the 36th week.	Preterm PE occurred in 13 out of the 798 participants (1.6%;) in the aspirin group, compared with 35 out of 822 (4.3%;) participants in the placebo group, a 62%; reduction (adjusted odds ratio [OR] in the aspirin group: 0.38; 95%; confidence interval (95%;CI): 0.20-0.74; p = 0.004).
Camarena Pulido et al (2016)¹⁰10 Camarena Pulido EE, García Benavides L, Panduro Barón JG, Pascoe Gonzalez S, Madrigal Saray AJ, García Padilla FE, et al. Efficacy of Larginine for preventing preeclampsia in high-risk pregnancies: A double-blind, randomized, clinical trial. Hypertens Pregnancy. 2016;35(02):217–225. Doi: 10.3109/10641955.2015.1137586 https://doi.org/10.3109/10641955.2015.11...	Randomized controlled trial	To estimate the effectiveness and safety of L-arginine to prevent PE in high-risk patients.	L-arginine group (n = 50); placebo group (n = 50).	L-arginine 3 g once daily orally in 600 mg capsules. Beginning at the 20th week of gestation with follow-up every 3 weeks during pregnancy and 2 weeks after birth.	The incidence of severe PE was higher in the placebo group (n = 7) than in the L-arginine group (n = ;, p = 0 . 02; 95%;CI: 0.001-0.031)
Costantine et al (2016)³3 Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016;214(06):720.e1–720.e17. Doi: 10.1016/j.ajog.2015.12.038 https://doi.org/10.1016/j.ajog.2015.12.0...	Randomized controlled trial	To evaluate the maternal-fetal safety and pharmacokinetic parameters of pravastatin when used in pregnant women at high risk of developing PE.	Pravastatin group (n = 11); placebo group (n = 10).	Pravastatin 10 mg, 1 capsule orally per day until birth. Beginning in the 1st trimester (weeks 12 to 16) and follow-up until birth.	There were 4 cases of PE in the placebo group and none in the pravastatin group, with 5 preterm births before 37 weeks in the placebo group compared with 1 in the pravastatin group.
Talari et al (2014)⁹9 Talari H, Mesdaghinia E, Abedzadeh Kalahroudi M. Aspirin and preeclampsia prevention in patients with abnormal uterine artery blood flow. Iran Red Crescent Med J. 2014;16(08):e17175. Doi: 10.5812/ircmj.17175 https://doi.org/10.5812/ircmj.17175...	Randomized controlled trial	To determine whether the treatment with acetylsalicylic acid (ASA) reduces the incidence of PE among pregnant women with abnormal uterine artery flow.	Aspirin group (n = 40); placebo group (n = 40).	Aspirin 80 mg, 1 tablet daily after lunch. Beginning between 12 and 16 weeks of gestation, with no clear follow-up time.	The aspirin group presented an ∼ 11-fold reduced risk of developing PE. There was a significant difference between the aspirin and placebo groups in the incidence of PE (2.5%; versus 22.5%; respectively).
Souza et al (2014)¹⁴14 Souza EV, Torloni MR, Atallah AN, Santos GMS, Kulay L Jr, Sass N. Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial. Braz J Med Biol Res. 2014;47 (05):419–425. Doi: 10.1590/1414-431X20143629 https://doi.org/10.1590/1414-431X2014362...	Randomized controlled trial	To test the hypothesis that the administration of a combination of low-dose aspirin and calcium would reduce the risk of superimposed PE in women at a high risk of developing this condition due to chronic hypertension and abnormal uterine artery Doppler in the second trimester.	Aspirin and calcium group (n = 23); placebo group (n = 26).	Pills containing 100 mg of aspirin and clear plastic envelopes containing 2 g of elemental calcium in the form of calcium carbonate. The placebo and powder pills were combined with the study supplements for taste, color, and size. Follow-up since the patient's hospital admission (between weeks 20 to 27) up to 6 weeks postpartum.	The rate of superimposed PE was 28.6%; lower among women receiving aspirin and calcium than in the placebo group (52.2%; versus 73.1%; respectively); however, this difference did not reach statistical significance (p = 0 . 112).
Parrish et al (2013)²⁷27 ParrishMR, Martin JN Jr, Lamarca BB, Ellis B, Parrish SA,Owens MY, et al. Randomized, placebo controlled, double blind trial evaluating early pregnancy phytonutrient supplementation in the prevention of preeclampsia. J Perinatol. 2013;33(08):593–599. Doi: 10.1038/jp.2013.18 https://doi.org/10.1038/jp.2013.18...	Randomized controlled trial	To provide daily dietary supplements containing antioxidants and phytonutrients to pregnant women to reduce the incidence of PE.	Supplement group (n = 349); placebo group (n = 335).	Phytonutrient (the contents of the antioxidant supplement capsule consisted of a blend of fruit and vegetable juice powder concentrate). Each capsule contained 7.5 mg of β-carotene, 234 mg of vitamin C, 30 mg of vitamin E, 420 mg of folate, and 60 mg of calcium. From the 12^th week of gestation until birth.	No difference was observed in the incidence of PE between the phytonutrient and placebo groups: 15.9%; versus 16.3%;, respectively (relative risk [RR]: 0.97; 95%;CI: 0.56-1.69).
Roberge et al (2018)²⁵25 Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(03):287–293.e1. Doi: 10.1016/j.ajog.2017.11.561 https://doi.org/10.1016/j.ajog.2017.11.5...	Systematic review with meta-analysis	To examine the effect and the dose of aspirin on the prevention of preterm and term PE in relation to the gestational age at the beginning of the treatment.	16 studies (18,907 participants).	Aspirin alone or in combination with dipyridamole with another group receiving placebo or no treatment. Gestational age at the start of aspirin use: ≤16 and > 16 weeks of gestation. Daily dose of the drug: < 100 mg and ≥100 mg.	The administration of aspirin was associated with a reduction in the risk of developing preterm PE (RR: 0.62; 95%;CI: 0.45-0.87); however, there was no significant effect on term PE (RR: 0.92, 95%;CI: 0.70-1.21). The reduction in preterm PE was confined to the subgroup in which aspirin was initiated before or at 16 weeks gestation, and at a daily dose of ≥100 mg. There was no significant reduction in the risk of developing preterm PE in the subgroup in which aspirin was started before or at 16 weeks gestation and at a daily dose < 100 mg (RR: 0.59; 95%;CI: 0.29-1.19) or in the subgroup in which aspirin was initiated after 16 weeks of gestation, regardless of whether the dose was ≥100 mg (RR: 0.88; 95%;CI: 0.54-1.43) or < 100 mg (RR: 1.00; 95%;CI: 0.80-1.25).
Roberge et al (2017)¹⁹19 Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growthrestriction: systematic reviewandmeta-analysis. Am J Obstet Gynecol. 2017;216(02):110–120.e6. Doi: 10.1016/j.ajog.2016.09.076 https://doi.org/10.1016/j.ajog.2016.09.0...	Systematic review with meta-analysis	To estimate the impact of aspirin dosing on the prevention of PE, severe PE and restricted fetal growth (RFG).	45 studies (20,909 participants).	Aspirin with or without dipyridamole. The dose of aspirin ranged from 50 mg to 150 mg per day, including 2 studies that combined 300 mg of dipyridamole with aspirin. The follow-up period was not clear.	Aspirin, when started before the 16^th gestational week, was associated with a significant reduction in the prevalence of PE, severe PE, and RFG, with a significant dose-response relationship.
Roberge et al (2016)²⁰20 Roberge S, Demers S, Nicolaides KH, Bureau M, Côté S, Bujold E. Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2016;47(05):548–553. Doi: 10.1002/uog.15789 https://doi.org/10.1002/uog.15789...	Systematic review with meta-analysis	To estimate the impact of low-molecular-weight heparin (LMWH) or unfractionated heparin on the low dose of aspirin initiated before or at16 weeks of gestation in relation to the prevalence of PE and birth of newborns small for gestational age (SGA).	8 studies (885 participants).	Three RCTs used dalteparin, two used enoxaparin, another two did not specify the type of LMWH, and one used unfractionated heparin. The dose of aspirin ranged from 75 mg to 100 mg/day. The follow-up period was not made clear.	In women with a history of PE, the addition of LMWH or unfractionated heparin to a low dose of aspirin reduced the risk of developing PE (3 RCTs, n = 379; RR: 0.54; 95%;CI: 0.31-0.92; p = . 03), and SGA (2 RCTs, n = 363; RR: 0.54; 95%;CI: 0.32-0.91; p = . 02).
Gan et al (2016)²¹21 Gan J, He H, Qi H. Preventing preeclampsia and its fetal complications with low-dose aspirin in East Asians and non-East Asians: A systematic review and meta-analysis. Hypertens Pregnancy. 2016;35(03):426–435. Doi: 10.1080/10641955.2016.1178772 https://doi.org/10.1080/10641955.2016.11...	Systematic review with meta-analysis	To comparatively evaluate the efficacy of low-dose aspirin in the prevention of PE and related fetal complications in East Asian and non-East Asian pregnant women at risk of developing PE.	21 high-quality RCTs were included in the meta-analysis, 3 studies from East Asia, and 18 non-East Asian studies.	Aspirin in low doses (75 mg). The follow-up period was not made clear.	Low-dose aspirin significantly reduced the risk of developing PE in East Asian (OR = 0.20; 95%;CI: 0.11-0.35) and non-East Asian women (OR = 0.84; 95%;CI: 0.77-0.92).
Rodger et al (2014)²⁶26 Rodger MA, Carrier M, Le Gal G, Martinelli I, Perna A, Rey E, et al; Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group. Meta-analysis of low-molecularweight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123(06):822–828. Doi: 10.1182/blood- 2013-01-478958 https://doi.org/10.1182/blood-2013-01-47...	Systematic review with meta-analysis	To compare LMWH versus non-LMWH for the prevention of recurrent placental-mediated pregnancy complications.	6 studies (848 participants).	LMWH versus non-LMWH. The follow-up period was not made clear.	The primary outcome, being a composite of PE, birth of a an SGA newborn (percentile < 10), placental abruption, or termination of pregnancy > 20 weeks, was significantly reduced by LMWH, with an RR reduction of 0.52 (95%;CI: 0.32-0.86; p < 0.01)
Hofmeyr et al (2014)¹³13 Hofmeyr GJ, Belizán JM, von Dadelszen P; Calcium and Preeclampsia (CAP) Study Group. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG. 2014;121(08):951–957. Doi: 10.1111/1471-0528.12613 https://doi.org/10.1111/1471-0528.12613...	Systematic review	To determine the lowest effective dose of calcium supplementation to reduce the effects of preeclampsia.	9 studies.	Low-dose calcium. The follow-up period was not made clear.	The 4 trials with low risk of bias, all with women at a high risk of developing PE, showed a consistent reduction in PE (365 women; RR: 0.25; 95%;CI: 0.12-0.50). However, in three of these trials there was co-intervention with linoleic acid (two trials) or antioxidants.

Reference	Outcomes	Potential absolute effects^* * The risk in the intervention group (and its 95%; confidence interval) is based on the risk assumed for the comparison group and the relative effect of the intervention (and its 95%; confidence interval). (95%;CI)		Relative effect (95%;CI)	Number of participants (studies)	Certainty in evidence (GRADE)
Reference	Outcomes	Comparison group - risk	Intervention group - risk	Relative effect (95%;CI)	Number of participants (studies)	Certainty in evidence (GRADE)
Rolnik et al (2017)⁵5 Rolnik DL,Wright D, Poon LC, O’Gorman N, Syngelaki A, Matallana CP, et al. Aspirin versus placebo in pregnancies at high risk for pretermpreeclampsia. N Engl J Med. 2017;377(07):613–622. Doi: 10.1056/NEJMoa1704559 https://doi.org/10.1056/NEJMoa1704559...	Preterm preeclampsia occurred in 13 out of the 798 participants (1.6%;) in the aspirin group, compared with 35 out of 822 (4.3%;) in the placebo group, when aspirin was started between the 11th and 14th gestational weeks and continued until the 36th week.	4 per 100	2 per 100 (1 to 3)	OR: 0.38 (0.20 to 0.74)	1620 (RCT)	⊕⊕⊕⊕ HIGH
Camarena Pulido et al (2016)¹⁰10 Camarena Pulido EE, García Benavides L, Panduro Barón JG, Pascoe Gonzalez S, Madrigal Saray AJ, García Padilla FE, et al. Efficacy of Larginine for preventing preeclampsia in high-risk pregnancies: A double-blind, randomized, clinical trial. Hypertens Pregnancy. 2016;35(02):217–225. Doi: 10.3109/10641955.2015.1137586 https://doi.org/10.3109/10641955.2015.11...	The incidence of severe preeclampsia was greater in the placebo group (n = 7) than in the L-arginine group (n = 1; p = 0 . 02; 95%;CI: 0.001-0.031). Follow-up: since 1^st trimester until birth.	23 per 100	0 per 100 (0 to 1)	Not estimable	96 (RCT)	⊕⊕⊕⊕ HIGH
Costantine et al (2016)³3 Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol. 2016;214(06):720.e1–720.e17. Doi: 10.1016/j.ajog.2015.12.038 https://doi.org/10.1016/j.ajog.2015.12.0...	Four subjects in the placebo group developed preeclampsia (3 out of 4 with severe illness) compared with none in the pravastatin group. Follow-up: variation from the 1st week to the 40th week.	40 per 100	0 per 100 (0 to 0)	Not estimable	21 (RCT)	⊕⚪⚪⚪ VERY LOW^a a Inaccurate due to not presenting confidence interval. ^b b Highly suspicious due to sample size, form of sample selection, and for presenting statistically significant results.
Talari et al (2014)⁹9 Talari H, Mesdaghinia E, Abedzadeh Kalahroudi M. Aspirin and preeclampsia prevention in patients with abnormal uterine artery blood flow. Iran Red Crescent Med J. 2014;16(08):e17175. Doi: 10.5812/ircmj.17175 https://doi.org/10.5812/ircmj.17175...	There was a significant difference between the aspirin and placebo groups in the incidence of preeclampsia (2.5%; versus 22.5%; respectively). The aspirin group presented an ∼ 11-fold reduced risk of developing preeclampsia.	25 per 100	79 per 100 (31 to 97)	OR: 11.323 (1.360 to 94.248)	80 (RCT)	⊕⊕⊕⊕ HIGH
Souza et al (2014)¹⁴14 Souza EV, Torloni MR, Atallah AN, Santos GMS, Kulay L Jr, Sass N. Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial. Braz J Med Biol Res. 2014;47 (05):419–425. Doi: 10.1590/1414-431X20143629 https://doi.org/10.1590/1414-431X2014362...	The rate of superimposed preeclampsia was 28.6%; lower among women receiving aspirin and calcium when compared to the placebo group (52.2 versus 73.1%; respectively); however, this difference did not reach statistical significance (p = . 112). Follow-up: variation from hospital admission to birth.	73 per 100	0 per 100 (0 to 0)	Not estimable	49 (RCT)	⊕⊕⊕⊕ HIGH^a a Inaccurate due to not presenting confidence interval. ^b b Highly suspicious due to sample size, form of sample selection, and for presenting statistically significant results.
Parrish et al (2013)²⁷27 ParrishMR, Martin JN Jr, Lamarca BB, Ellis B, Parrish SA,Owens MY, et al. Randomized, placebo controlled, double blind trial evaluating early pregnancy phytonutrient supplementation in the prevention of preeclampsia. J Perinatol. 2013;33(08):593–599. Doi: 10.1038/jp.2013.18 https://doi.org/10.1038/jp.2013.18...	No difference was observed in the incidence of preeclampsia between the phytonutrient and placebo groups (15.9%; versus 16.3%; respectively). Follow-up: variation from the 12th week to birth.	33 per 100	32 per 100 (18 to 55)	OR: 0.97 (0.56 to 1.69)	267 (RCT)	⊕⊕⊕⊕ HIGH
Roberge et al (2018)²⁵25 Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(03):287–293.e1. Doi: 10.1016/j.ajog.2017.11.561 https://doi.org/10.1016/j.ajog.2017.11.5...	The administration of aspirin was associated with a reduction in the risk of developing preterm preeclampsia (RR: 0.62; 95%;CI: 0.45-0.87); however, there was no significant effect on term preeclampsia (RR: 0.92; 95%;CI: 0.70-1.21).	0 per 100	0 per 100 (0 to 0)	OR: 0.62 (0.45 to 0.87)	(16 RCTs)	⊕⊕⊕⊕ HIGH
Roberge et al (2017)¹⁹19 Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growthrestriction: systematic reviewandmeta-analysis. Am J Obstet Gynecol. 2017;216(02):110–120.e6. Doi: 10.1016/j.ajog.2016.09.076 https://doi.org/10.1016/j.ajog.2016.09.0...	Aspirin was associated with a significant reduction in the prevalence of preeclampsia, severe preeclampsia and fetal growth restriction, with a significant dose-response relationship when initiated before the 16th week of gestation.	0 per 100	0 per 100 (0 to 0)	OR: 0.57 (0.43 to 0.75)	(45 RCTs)	⊕⊕⊕⊕ HIGH
Roberge et al (2016)²⁰20 Roberge S, Demers S, Nicolaides KH, Bureau M, Côté S, Bujold E. Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2016;47(05):548–553. Doi: 10.1002/uog.15789 https://doi.org/10.1002/uog.15789...	The addition of low-molecular-weight heparin or unfractionated heparin to low dose aspirin reduced the risk of developing preeclampsia.	0 per 100	0 per 100 (0 to 0)	OR: 0.54 (0.31 to 0.92)	(8 RCTs)	⊕⊕⊕⚪ MODERATE^c c Due to the heterogeneity of the selected studies.
Gan et al (2016)²¹21 Gan J, He H, Qi H. Preventing preeclampsia and its fetal complications with low-dose aspirin in East Asians and non-East Asians: A systematic review and meta-analysis. Hypertens Pregnancy. 2016;35(03):426–435. Doi: 10.1080/10641955.2016.1178772 https://doi.org/10.1080/10641955.2016.11...	The low dose of aspirin (75 mg) significantly reduced the risk of developing preeclampsia in East Asian and non-East Asian women.	0 per 100	0 per 100 (0 to 0)	OR: 0.20 (0.11 to 0.35)	(21 RCTs)	⊕⊕⊕⚪ MODERATE
Rodger et al (2014)²⁶26 Rodger MA, Carrier M, Le Gal G, Martinelli I, Perna A, Rey E, et al; Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group. Meta-analysis of low-molecularweight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123(06):822–828. Doi: 10.1182/blood- 2013-01-478958 https://doi.org/10.1182/blood-2013-01-47...	The primary outcome, being a composite of preeclampsia, birth of a newborn small for gestational age (percentile < 10), placental abruption, or termination of pregnancy > 20 weeks, were significantly reduced by low-molecular-weight heparin, with an RR reduction of 0.52 (95%;CI: 0.32-0.86; p <.01)	0 per 100	0 per 100 (0 to 0)	OR: 0.52 (0.32 to 0.86)	(6 RCTs)	⊕⚪⚪⚪ VERY LOW^a a Inaccurate due to not presenting confidence interval. ^b b Highly suspicious due to sample size, form of sample selection, and for presenting statistically significant results.
Hofmeyr et al (2014)¹³13 Hofmeyr GJ, Belizán JM, von Dadelszen P; Calcium and Preeclampsia (CAP) Study Group. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG. 2014;121(08):951–957. Doi: 10.1111/1471-0528.12613 https://doi.org/10.1111/1471-0528.12613...	The four trials with low risk of bias, all in women at a high risk of developing preeclampsia, showed a consistent reduction in the incidence of preeclampsia, even with calcium started at the end of the pregnancy.	0 per 100	0 per 100 (0 to 0)	RR: 0.38 (0.28 to 0.52)	(9 RCTs)	⊕⊕⚪⚪ Low

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