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Medications for preventing hypertensive disorders in high-risk pregnant women: a systematic review and network meta-analysis
Systematic Reviews volume 11, Article number: 135 (2022)
To determine the relative effectiveness of medications for preventing hypertensive disorders in high-risk pregnant women and to provide a ranking of medications using network meta-analysis.
All randomized controlled trials comparing the most commonly used medications to prevent hypertensive disorders in high-risk pregnant women that are nulliparity and pregnant women having family history of preeclampsia, history of pregnancy-induced hypertension in previous pregnancy, obstetric risks, or underlying medical diseases. We received the search results from the Cochrane Pregnancy and Childbirth’s Specialised Register of Controlled Trials, searched on 31st July 2020. At least two review authors independently selected the included studies and extracted the data and the methodological quality. The comparative risk ratios (RR) and 95% confidence intervals (CI) were analyzed using pairwise and network meta-analyses, and treatment rankings were estimated by the surface under the cumulative ranking curve for preventing preeclampsia (PE), gestational hypertension (GHT), and superimposed preeclampsia (SPE). Safety of the medications is also important for decision-making along with effectiveness which will be reported in a separate review.
This network meta-analysis included 83 randomized studies, involving 93,864 women across global regions. Three medications, either alone or in combination, probably prevented PE in high-risk pregnant women when compared with a placebo or no treatment from network analysis: antiplatelet agents with calcium (RR 0.19, 95% CI 0.04 to 0.86; 1 study; low-quality evidence), calcium (RR 0.61, 95% CI 0.47 to 0.80; 13 studies; moderate-quality evidence), antiplatelet agents (RR 0.69, 95% CI 0.57 to 0.82; 31 studies; moderate-quality evidence), and antioxidants (RR 0.77, 95% CI 0.63 to 0.93; 25 studies; moderate-quality evidence). Calcium probably prevented PE (RR 0.63, 95% CI 0.46 to 0.86; 11 studies; moderate-quality evidence) and GHT (RR 0.89, 95% CI 0.84 to 0.95; 8 studies; high-quality evidence) in nulliparous/primigravida women. Few included studies for the outcome of superimposed preeclampsia were found.
Antiplatelet agents, calcium, and their combinations were most effective medications for preventing hypertensive disorders in high-risk pregnant women when compared with a placebo or no treatment. Any high-risk characteristics for women are important in deciding the best medications. The qualities of evidence were mostly rated to be moderate.
Systematic review registration
Hypertensive disorders in pregnancy (HDP) are one of the five common complications during pregnancy, causing maternal and fetal deaths globally. The incidence of HDP ranges from 1 to 35% worldwide, with a wide variation across regions [1,2,3]. Due to the lack of a clear understanding of the underlying etiology of HDP, the antiplatelet agents, anticoagulants, antioxidants, nitric oxide, and calcium, which have been widely studied for their possible use in reducing or preventing HDP, were systematically reviewed [4,5,6,7,8,9]. To date, there have been two network meta-analyses. One was a conference abstract, which reported that calcium supplements reduced the risk of preeclampsia (PE) compared to aspirin, fish oil, and vitamin C or E . Additionally, another network meta-analysis found that either vitamin D or calcium supplements may be effective .
A recent study demonstrated the superiority of Doppler and serum markers over conventional risk factor-based screening , and a new screening algorithm has recently demonstrated the effectiveness of aspirin prophylaxis in high-risk women [13, 14]. However, aspirin has been shown to be effective for high-risk women not only based on new screening algorithms but also on more traditional ways of defining high-risk, as shown in a Cochrane review . In addition, these screening methods require experienced technicians and are not routinely available in health facilities in low-or middle-income countries where HDP are common.
Pregnant women with a history of hypertensive disorders in a previous pregnancy, those having chronic kidney disease, autoimmune disease, diabetes mellitus, or chronic hypertension, as well as nulliparous women, advanced age, or obese women, and those having multiple pregnancies, or family history of PE, were considered as risk factors of being advised to take aspirin for prevention of PE by the National Institute for Health and Care Excellence (NICE) 2019 and the American College of Obstetricians and Gynecologists’ Committee [15, 16]. To date, only aspirin has been recommended for PE prophylaxis in women with risk factors in the NICE guideline and the US Preventive Services Task Force recommendation [15, 17], not the other medications reported in previous systematic reviews [4,5,6,7,8,9]. The objectives of this analysis were to determine the relative effectiveness and provide a ranking of the available medications for preventing hypertensive disorders in high-risk pregnant women classified by the NICE 2019 using a network meta-analysis.
We included all randomized controlled trials or cluster-randomized trials comparing the most commonly used medications by any route or doses in high-risk women during pregnancy for preventing hypertensive disorders. Only one main publication/report of the studies was selected to be reviewed and analyzed. Eligibility criteria were the studies that included pregnant women, at any gestational age, and at high risk of developing hypertensive disorders based on one of these following risk factors: nulliparity, family history of PE, history of pregnancy-induced hypertension in a previous pregnancy, obstetric risks (advanced maternal age, obesity, or multiple pregnancies), and underlying medical diseases (polycystic ovarian syndrome, autoimmune diseases, chronic renal diseases, diabetes, or chronic hypertension) in which medications were commenced only during pregnancy.
The studies were eligible if they used any of these groups of medications (antiplatelet agents, anticoagulants, antioxidants, nitric oxide, or calcium supplements) for preventing HDP and compared them against each other, placebo, or no treatment/conventional management. We considered medications routinely prescribed during pregnancy, such as ferrous, folic, or multivitamin supplementation, as conventional standard treatments. The medications prescribed before conception and continued during pregnancy were excluded. Two-arm or multi-arm trials that compared drug(s) in different dosages or regimens in the same medication group were included, if the comparison of medication groups could be made after the drug(s) in the same medication group were combined. Both primary outcomes (PE, gestational hypertension (GHT), and chronic hypertension with superimposed preeclampsia (SPE)) and secondary outcomes (placental abruption, postpartum hemorrhage, neonatal intraventricular hemorrhage, and neonate with small gestational age or growth restriction) were included in the protocol registered in PROSPERO . However, in this network meta-analysis, the primary outcomes on relative effectiveness were focused, and the secondary outcomes on safety will be reported in other separate review with network meta-analysis.
Information sources and search strategy
We received the search results from the database of the Cochrane Pregnancy and Childbirth’s Specialised Register of Controlled Trials, on 31st July 2020, using the topic area of “hypertension, prevention,” as the assigned search. This is a database, containing the results of over 30 years of searching for trials related to pregnancy and childbirth as a whole.
The full search methods, including individual strategies for each database search, can be found within the Trials Register section of the group’s webpage (https://pregnancy.cochrane.org/pregnancy-and-childbirth-groups-trials-register). The register is stored in the Cochrane Register of Studies. Each review receives its own specific search results, and no language was restricted.
Selection and data collection process
Two review authors (TL, YY) screened the titles and abstracts of all search results independently, considering the criteria for included studies using the RAYYAN web-based application. Any discrepancies were solved by discussion. Two pairs of review authors (TL-YY, TL-CK) assessed the full texts independently to decide which of all the potential studies would be included using an electronic checklist form. We resolved any disagreements through discussion or in consultation with an independent reviewer (EO, RM), if required. A study flow diagram of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) was used to present the number of records identified, excluded, or included.
We reviewed all included reports; however, if more than one reports come from the same study, we chose one main primary report as the main cited reference which the data were extracted for this review to avoid the data duplication. At least two of the review authors (TL, YY, CK, RM, EO) independently assessed the risk of bias for each study, using the criteria in the Cochrane Handbook for Systematic Reviews of Interventions . TL and CK independently extracted the data.
Study risk-of-bias assessment and certainty assessment
The criteria for assessing risk of bias included random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, other bias, and overall risk of bias. TL and CK assessed the quality of the evidence, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods . Any disagreements were resolved by discussion, and the information was entered into Review Manager 5 software, for risk of bias . The summary of findings of each outcome was presented using the template of GRADE network meta-analysis–summary of findings (NMA-SoF) tables for multiple treatment comparisons compared with placebo .
We evaluated the assumption of transitivity epidemiologically, by comparing the clinical and methodological characteristics of sets of studies grouped by treatment comparisons. The drugs in the same two-arm or multiple-arm trials that are in the same groups of medication of interest in this review were grouped to be the same treatment node, regardless of regimens or doses. When the trials had more than one drugs in different treatment nodes in one arm, we defined them as the combinations group of medications. A network plot was drawn with the nodes representing interventions, the size of the nodes representing sample sizes, and the thickness of the lines connecting between nodes indicating the number of direct comparisons between pairs of interventions. A separate network plot was presented for primary outcomes on PE, GHT, and SPE.
We evaluated the inconsistency of the evidence on the network using the global inconsistency test  and the Dias’s side-splitting approach . The heterogeneity of pairwise studies in the meta-analysis was assessed using the I2 statistic. If substantial heterogeneity, I2 > 50%, was identified, subgroup analysis considering different high-risk characteristics was explored [23, 25]. The comparative risk ratios (RR) and 95% confidence interval (CI) were estimated for pooled direct evidence, using a random-effects model and network meta-analysis using multivariate random-effects models. We estimated the surface under the cumulative ranking curve (SUCRA) to provide a hierarchy of the medications in numerical presentations. The SUCRA values ranged from 0 to 100%, with values close to 0 indicating a higher likelihood that a medication is in one of the bottom ranks, while values close to 100% indicate a higher likelihood that a medication is in one of the top ranks . We also assessed the publication bias using a comparison-adjusted funnel plot and the Egger’s test, if at least 10 studies with the same comparisons and outcome were found because the power of the test is usually low to differentiate the chance of real asymmetry in fewer than 10 studies [27, 28].
The data were analyzed using STATA 15, with the “network” commands (The StataCorp, Texas, USA). Multivariate random-effects models were used to analyze both direct and indirect pairwise comparisons and network meta-analysis. The visualizations of RR and 95% CI of effect size of pairwise and network meta-analyses as well as ranking treatments among medications were operated in R software (R version 3.6.1, R Core Team 2019, Vienna, Austria), with “tidyverse,” “ggplot2,” “gridExtra,” and “RColorBrewer” packages. We reported this systematic review in accordance with the recommendations in PRISMA 2020 .
From 84 studies, there were 6998 women with outcomes of interest among 93,971 included women (7.4%). One included study, conducted in Columbia, comparing 100 mg aspirin with a placebo did not disclose the drug groups (drug 1, n = 54) and drug 2, n = 43) in the results of the study; hence, we could not use the data from this study for the analysis . The results of search and selection process are presented in the PRISMA flow diagram as shown in Fig. 1.
Study characteristics and risk of bias
Among 83 studies with the outcomes of interest in this network meta-analysis, 77 studies reported PE [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107], 39 studies reported gestational hypertension [31, 34, 36, 37, 39, 40, 42, 50, 51, 57, 58, 60, 61, 63, 66, 68, 69, 71, 72, 77, 81,82,83, 86, 88, 90, 91, 94, 96, 97, 102, 103, 106,107,108,109,110,111,112], and four studies reported SPE [56, 58, 112, 113]. The incidences of PE, GHT, and SPE in control groups using a placebo or no treatment were 7.8% (3559/45,449), 14.9% (4463/30,002), and 1.4% (45/3174), respectively. Risks-of-bias domain is summarized across all studies and presented in Fig. 2; 38 studies were judged to have a low risk of bias [34, 38, 42,43,44,45, 50, 51, 53, 58,59,60,61,62,63,64, 67, 68, 70, 72,73,74, 78, 80, 82, 86,87,88,89, 91, 94, 95, 101,102,103, 105, 106, 108]. There was no evidence of global inconsistency in the network analysis for all primary outcomes on PE, GHT, and SPE.
Results of synthesis and certainty of evidence
The network diagram of 77 studies for preventing PE in all high-risk women is presented in Fig. 3. Antiplatelet agents were the most frequently investigated medications, in 38 of 77 studies (49.4%), followed by antioxidants in 25 studies (32.4%), calcium in 14 studies (18.2%), and various combinations in nine studies (11.7%). Pooled effect sizes, from direct estimates as well as network meta-analysis, are presented in Fig. 4. Calcium, antiplatelet agents, and combinations of antiplatelet agents with calcium probably had a moderately preventive effect for PE when compared with a placebo or no treatment as the evidence from network analysis accounted for antiplatelet agents with calcium (RR 0.19, 95% CI 0.04 to 0.86; 1 study; 334 participants; low-quality evidence); calcium (RR 0.61, 95% CI 0.47 to 0.80; 13 studies; 26,021 participants; moderate-quality evidence); antiplatelet agents (RR 0.69, 95% CI 0.57 to 0.82; 31 studies; 41,953 participants; moderate-quality evidence); and antioxidants (RR 0.77, 95% CI 0.63 to 0.93; 25 studies; 24,768 participants; moderate-quality evidence).
Antiplatelet agents with calcium in all high-risk women reported in one study showed highest SUCRA (89.9%) (Fig. 5). For the consistency of evidence on the network, the global inconsistency test was not significant (P = 0.459). The direct and indirect comparison estimates of each treatment pair by the Dias’s side splitting are presented in Fig. 4, and no significant treatment pairs were detected by the Dias’s inconsistency tests. The summary of findings for medication to prevent PE in all high-risk women is presented in Table 1. Certainty of evidence of the medications compared with a placebo or no treatment to prevent PE ranged from very low to moderate. Due to substantial heterogeneity (I2 59.0%), subgroup analyses based on the high-risk subgroup population were performed, and the findings are shown in the summary of findings for subgroups on prevention of PE (Additional file 1: Appendices 1–3).
The network diagram of 39 studies for preventing gestational hypertension is presented in Fig. 6. Antiplatelet agents were the most frequently investigated medications in 19 out of 39 studies (48.7%), followed by antioxidants in 10 studies (25.6%) and calcium in nine studies (23.1%). Pooled effect sizes from direct estimates as well as network meta-analysis (Fig. 7) suggested antiplatelet agents (RR 0.78, 95% CI 0.62 to 0.99 from direct estimates and RR 0.80, 95% CI 0.64 to 1.00 from network meta-analysis; 19 studies; 16,813 participants; moderate-quality evidence) or calcium (RR 0.77, 95% CI 0.59 to 1.00 from direct estimates and RR 0.78, 95% CI 0.61 to 1.00 from network meta-analysis; 9 studies; 24,534 participants; moderate-quality evidence) may prevent GHT. It is the uncertain effect of a combination of antiplatelet agents with anticoagulants in network meta-analysis estimate (RR 0.21, 95% CI 0.04 to 1.20; 1 study; 20 participants; very low-quality evidence) with highest SUCRA (90.1%) to prevent GHT in all high-risk women, as shown in Fig. 8.
For the consistency of evidence on the network, the global inconsistency test was not significant (P = 0.512). The direct and indirect comparison estimates of each treatment pair by the Dias’s side splitting are presented in Fig. 7, and no significant treatment pairs were detected by the Dias’s inconsistency tests. Summary of findings for medication to prevent gestational hypertension in all high-risk women is presented in Table 2. Certainty of evidence of the medications compared with a placebo or no treatment to prevent GHT ranged from very low to moderate. Due to substantial heterogeneity (I2 63.2%), the subgroup analyses based on the high-risk subgroup population were performed, and the findings are shown in the table of summary of findings for subgroups on prevention of gestational hypertension (Additional file 1: Appendices 4–6).
The network diagram of four studies for preventing SPE in all high-risk women is presented in Fig. 9. Pooled effect sizes from the network meta-analysis of four studies suggested the uncertainty of the evidence on antiplatelet agents when compared with a placebo or no treatment in network meta-analysis (RR 0.72, 95% CI 0.46 to 1.14; 3 study; 6298 participants; low-quality evidence). The summary of findings for medications in the prevention of SPE is presented in Table 3. Certainty of evidence of the medications compared with a placebo or no treatment to prevent SPE was very low or low. The inconsistency test using side-splitting approach was significant for SPE.
The summary on the tests of heterogeneity, effect of intervention, and tests of publication bias for direct comparisons in a network meta-analysis are presented for all primary outcomes (Additional file 1: Appendix 7). Publication biases, using comparison-adjusted funnel plot for preventing PE and GHT, were found with a P-value of Egger’s test < 0.001 (Additional files 2 and 3).
This network meta-analysis found that antiplatelet agents, calcium, antioxidants, and their combinations were more effective medications for preventing hypertensive disorders in pregnancy than a placebo or no treatment in different women’s contexts. It was uncertain that one medication was superior to the others. The qualities of evidence were rated to be moderate, due to the limitation of risk of bias, publication bias, or imprecision. There is the potential for medication combinations, such as antiplatelet agents with calcium, anticoagulants with antiplatelet agents, or calcium with antioxidants, to be slightly better, but evidence was limited with only few current studies and large confidence intervals. More studies investigating these combination treatments are needed.
The effectiveness of antiplatelet agents and calcium on prevention of PE was similar to the findings of two previous systematic reviews and a meta-analysis [4, 7]. Doses of antiplatelet agents used in the included studies in this network meta-analysis ranged from 50 to 150 mg daily aspirin or 300 mg dipyridamole. For calcium, the daily doses ranged from 1000 to 2000 mg elemental calcium. Our findings support the WHO guidelines of 2011, which strongly recommends 1.5–2.0 g elemental calcium/day in areas where dietary calcium intake is low, or 75 mg of aspirin for the prevention of PE in women at high risk of developing the condition with moderate quality of evidence , and the NICE recommendation for the use of 75–150 mg aspirin . The majority of antioxidants used were a combination of daily 1000 mg vitamin C plus 200–400 mg vitamin E. Our network meta-analysis found a preponderance of evidence that antioxidants could reduce PE and gestational hypertension, although this finding was opposite to the finding of a previous systematic review . The combinations of antiplatelet agents with calcium or antioxidants with calcium, and antiplatelet agents with anticoagulants, had high cumulative probabilities for being the highest rank for preventing PE and/or GHT with low- to moderate-quality evidence, even though the studies were small. More research on combining antiplatelet agents with calcium may be needed.
The findings of our network meta-analysis were consistent with the results of two previous network meta-analyses, which found that calcium supplementation could reduce the risk of PE; however, these systematic reviews did not rate the quality of evidence using GRADE [10, 11]. In addition, the first review did not clearly describe risk characteristics of women in the results , and the latter defined nulliparous women as low-risk women . The probability of being the most effective treatment for calcium in our review was higher than that in the study of Sanchez-Ramos (2017) . The effectiveness of antiplatelet agents in our review supports the suggestion of using aspirin prophylaxis for PE from a previous systematic review and meta-analysis . However, the qualities of evidence for the outcomes in our review were rated as ranging from very low to moderate. These were then downgraded, due to the risk of bias, imprecision, and publication bias regarding a GRADE approach.
There were limitations of this network meta-analysis. First, a wide range of high-risk pregnant women were included, resulting in the heterogeneous findings of included studies. This may be explained by different responses to the medications in various risk characteristics. Second, we focused on the studies conducted in hospital settings using high-risk factors suggested by NICE 2019, not Doppler, laboratory tests, or serum markers for screening risk of hypertensive disorders in pregnancy. Third, the subgroup analysis on intervention (different drugs in the same group of medication in the intervention arm, different doses of the same drug, or gestational age at the time the medication was given) and gestational age at the time the outcome occurred was not performed in this network meta-analysis. Fourth, this review presented parts of the results on relative effectiveness of medications, and safety outcomes will be reported in a separate review. Both aspects of effectiveness and safety are essential to consider the benefits outweigh the risks of medications to pregnant women. Lastly, PE with preterm birth was not included as the outcome in this network analysis.
Antiplatelet agents, calcium, antioxidants, and their combinations were more effective medications than a placebo or no treatment for preventing hypertensive disorders in different risks of pregnant women’s context. It was uncertain that one medication was superior to the others. The combinations of antiplatelet agents with calcium or anticoagulants were in one of the top ranks to prevent PE; however, the evidence was limited due to imprecision and heterogeneity leading to different clinical decisions in a future study. Calcium was in one of the top ranks to prevent GHT in nulliparous or primigravida women. Further network meta-analyses considering different drugs in the same groups of medications, different doses of the same drug, gestational age at the time the medications are given, and gestational age at the time the outcome occurred are required, so as to identify the most effective regimen of drugs for preventing hypertensive disorders in pregnancy.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Grading of Recommendations Assessment, Development and Evaluation
Hypertensive disorders in pregnancy
National Institute for Health and Care Excellence
Network meta-analysis–summary of findings
Preferred Reporting Items for Systematic reviews and Meta-Analyses
Surface under the cumulative ranking curve
Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013;170:1–7.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet. 2006;367:1066–74.
Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2:e323–33.
Duley L, Meher S, Hunter KE, Seidler AL, Askie LM. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2019;2019(10):CD004659.
Mastrolia SA, Novack L, Thachil J, Rabinovich A, Pikovsky O, Klaitman V, et al. LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia. a systematic review and meta-analysis. Thromb Haemost. 2016;116:868–78.
ACOG. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122–31.
Hofmeyr GJ, Lawrie TA, Atallah ÁN, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2018;10(10):CD001059.
Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev. 2008;2008(1):CD004227.
Zullino S, Buzzella F, Simoncini T. Nitric oxide and the biology of pregnancy. Vascul Pharmacol. 2018;110:71–4.
Sanchez-Ramos L, Roeckner JT, Kaunitz AM. Which agent most effectively prevents preeclampsia? a systematic review with multitreatment comparison (network meta-analysis) of large multicenter randomized controlled trials. Am J Obstet Gynecol. 2017;216:S504.
Khaing W, Vallibhakara SA-O, Tantrakul V, Vallibhakara O, Rattanasiri S, McEvoy M, et al. Calcium and vitamin D supplementation for prevention of preeclampsia: a systematic review and network meta-analysis. Nutrients. 2017;9:1141.
Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D, et al. Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE. Ultrasound Obstet Gynecol. 2018;51:743–50.
Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377:613–22.
Guy GP, Leslie K, Diaz Gomez D, Forenc K, Buck E, Khalil A, et al. Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study. Br J Obstet Gynecol. 2020;1:1–8.
NICE. Hypertension in pregnancy: diagnosis and management. London: NICE; 2019. p. 55.
ACOG No202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1–25.
US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, et al. Aspirin use to prevent preeclampsia and related morbidity and mortality: US Preventive Services Task Force recommendation statement. JAMA. 2021;326:1186–91.
PROSPERO. Guidance notes for registering a systematic review protocol with PROSPERO. York: University of York; 2016.
Higgins JPT, Savović J, Page MJ, Elbers RG, Sterne JAC. Chapter 8: assessing risk of bias in a randomized trial. In: Cochrane handbook for systematic reviews of interventions version 620/0/00 0:00:00 AM (updated February 2021). Cochrane: Cochrane; 2021. p. 1–25.
Puhan MA, Schünemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. Br Med J. 2014;349:g5630.
Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
Yepes-Nuñez JJ, Li SA, Guyatt G, Jack SM, Brozek JL, Beyene J, et al. Development of the summary of findings table for network meta-analysis. J Clin Epidemiol. 2019;115:1–13.
Higgins JPT, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3:98–110.
Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932–44.
Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 10: Analysing data and undertaking metaanalyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Available from: www.training.cochrane.org/handbook.
Mbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, et al. Approaches to interpreting and choosing the best treatments in network meta-analyses. Syst Rev. 2017;6:79.
Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. Br Med J. 2011;342:1–8.
Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8:e76654.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:89.
Hernandez F, Martinez MF, Camero A, Pinzon JA. Low dose aspirin as prophylactic therapy of pregnancy induced hypertension. Rev Colomb Obstet Ginecol. 1996;47:197–201.
Abo-Elwafa HA, Ahmed NS, Ameen M. The possible effect of gestational antioxidant on coagulopathy associated preeclampsia in women at risk of preeclampsia. 2011. A preprint published in university website 2011 at https://staffsites.sohag-univ.edu.eg/uploads/448/1538011756%20-%20BLOOD3_article_2.pdf.
Antartani R, Ashok K. Effect of lycopene in prevention of preeclampsia in high risk pregnant women. J Turk Ger Gynecol Assoc Artemis. 2011;12:35–8.
August P, Helseth G, Edersheim TG, Hutson JM, Druzin M. Sustained release, low-dose aspirin ameliorates but does not prevent preeclampsia (PE) in a high risk population. In: Proceedings of the 9th International Congress, International Society for the Study of Hypertension; 1994. Abstract no: 72. p. 280.
Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int. 2013;30:260–79.
Azami M, Azadi T, Farhang S, Rahmati S, Pourtaghi K. The effects of multi mineral-vitamin D and vitamins (C) supplementation in the prevention of preeclampsia: an RCT. Int J Reprod Biomed Yazd Iran. 2017;15:273–8.
Azar R, Turpin D. Effect of antiplatelet therapy in women at high risk for pregnancy-induced hypertension [abstract]. In: Cosmi EV, Di Renzo GC, editors. Perugia: Proceedings of 7th World Congress of Hypertension in Pregnancy; 1990. p. 257.
Bakhti A, Vaiman D. Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation. Hypertens Res - Clin Exp. 2011;34:1116–20.
Banerjee S, Jeyaseelan S, Guleria R. Trial of lycopene to prevent pre-eclampsia in healthy primigravidas: results show some adverse effects. J Obstet Gynaecol Res. 2009;35:477–82.
Bassaw B, Roopnarinesingh S, Roopnarinesingh A, Homer H. Prevention of hypertensive disorders of pregnancy. J Obstet Gynaecol. 1998;18:123–6.
Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet. 1985;1:840–2.
Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM. Vitamin C and E supplementation in women at high risk for preeclampsia: a double-blind, placebo-controlled trial. Am J Obstet Gynecol. 2005;192:520–1.
Belizan JM, Villar J, Gonzalez L, Campodonico L, Bergel E. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med. 1991;325:1399–405.
Byaruhanga RN, Chipato T, Rusakaniko S. A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. Int J Gynecol Obstet. 1998;60:129–35.
Camarena-Pulido EE, Benavides LG, Baron JGP, Gonzalez SP, Saray AJM, Padilla FEG, et al. Efficacy of l-arginine for preventing preeclampsia in high-risk pregnancies: a double-blind, randomized, clinical trial. Hypertens Pregnancy. 2016;35:217–25.
Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk National Institute of Child Health and human development network of maternal-fetal medicine units [see comments]. N Engl J Med. 1998;338:701–5.
Carpentier C, Bujold E, Camire B, Tapp S, Boutin A, Demers S. P08.03: low-dose aspirin for prevention of fetal growth restriction and pre-eclampsia in twins: the GAP pilot randomised trial. Ultrasound Obstet Gynecol. 2017;50:178.
Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W, Marozio L, et al. A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2004;112:142–4.
CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative G r. o. u. p. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619–29.
Cong KJ, Chi SL, Liu GR. Calcium supplementation during pregnancy to reduce pregnancy induced hypertension. Beijing Med J. 1992;5:268.
Crowther CA, Hiller JE, Pridmore B, Bryce R, Duggan P, Hague WM, et al. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: an Australian randomized trial Fracog and the act study group. Aust N Z J Obstet Gynaecol. 1999;39:12–8.
Davies NJ, Gazvani R, Farquharson RG, Walkinshaw SA. Low-dose aspirin in the prevntion of hypertensive disorders or pregnancy in relatively low-risk nulliparous women. Hypertens Pregnancy. 1995;14:49–55.
Dendrinos S, Kalogirou I, Makrakis E, Theodoridis T, Mahmound EA, Christopoulou-Cokkinou V, et al. Safety and effectiveness of tinzaparin sodium in the management of recurrent pregnancy loss. Clin Exp Obstet Gynecol. 2007;34:143–5.
de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, Investigators Fruit. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost. 2012;10:64–72.
ECPPA. ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. Br J Obstet Gynaecol. 1996;103:39–47.
Elmahaishi. The uses of low dose aspirin (150 mg/day) in primigravida reduces the severity and complications of pregnancy induced hypertension [abstract]. In: Washington DC: XVI FIGO World Congress of Obstetrics & Gynecology; 2000. p. 98.
Essinger S. The use of low-dose acetylsalicylic acid in prevention of pregnancy-induced hypertension. Rev Col Bras Cir. 1992;19:58–62.
Ferrier C, Koferl U, Durig P, Schneider H. LMW-heparin and low-dose aspirin for prevention of preeclampsia: preliminary data of a randomized prospective study [abstract]. Hypertens Pregnancy. 2000;19:82.
Golding J. A randomised trial of low dose aspirin for primiparae in pregnancy. The jamaica low dose aspirin study group. Br J Obstet Gynaecol. 1998;105:293–9.
Gris JC, Chauleur C, Molinari N, Mares P, Fabbro-Peray P, Quere I, et al. Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia: the pilot randomised controlled NOH-PE trial. Thromb Haemost. 2011;106:1053–61.
Groom KM, McCowan LM, Mackay LK, Chamley LW, Stone PR, Lee AC, et al. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet Gynecol. 2017;216:296.e1–14.
Gu W, Lin J, Hou YY, Lin N, Song MF, Zeng WJ, et al. Effects of low-dose aspirin on the prevention of preeclampsia and pregnancy outcomes: a randomized controlled trial from Shanghai, China. Eur J Obstet Gynecol Reprod Biol. 2020;248:156–63.
Haddad B, Winer N, Chitrit Y, Houfflin-Debarge V, Chauleur C, Bages K, et al. Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized controlled trial. Obstet Gynecol. 2016;128:1053–63.
Hauth JC, Goldenberg RL, Parker CR, Philips JB III, Copper RL, DuBard MB, et al. Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol. 1993;168:1083–93.
Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, et al. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;395:285–93.
Huria A, Gupta P, Kumar D, Sharma MK. Vitamin C and vitamin E supplementation in pregnant women at risk for pre-eclampsia: a randomized controlled trial. Internet J Health. 2010;10:1–5.
Kincaid-Smith P, North RA, Fairley KF, Kloss M, Ihle BU. Prevention of pre-eclampsia in high risk women with renal disease: a prospective randomized trial of heparin and dipyridamole. Nephrology. 1995;1:297–300.
Kumar A, Devi SG, Batra S, Singh C, Shukla DK. Calcium supplementation for the prevention of pre-eclampsia. Int J Gynecol Obstet. 2009;104:32–6.
Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337:69–76.
Liu FM, Zhao M, Wang M, Yang HL, Li L. Effect of regular oral intake of aspirin during pregnancy on pregnancy outcome of high-risk pregnancy-induced hypertension syndrome patients. Eur Rev Med Pharmacol Sci. 2016;20:5013–6.
Lopez-Jaramillo P, Delgado F, Jacome P, Teran E, Ruano C, Rivera J. Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. Obstet Gynecol. 1997;90:162–7.
Mahdy ZA, Siraj HH, Khaza’ai H, Mutalib MS, Azwar MH, Wahab MA, et al. Does palm oil vitamin E reduce the risk of pregnancy induced hypertension? Acta Medica (Hradec Kralove). 2013;56:104–9.
McCance DR, Holmes VA, Maresh MJ, Patterson CC, Walker JD, Pearson DW, et al. Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial. Lancet. 2010;376:259–66.
Mone F, Mulcahy C, McParland P, Breathnach F, Downey P, McCormack D, et al. Trial of feasibility and acceptability of routine low-dose aspirin versus early screening test indicated aspirin for pre-eclampsia prevention (test study): a multicentre randomised controlled trial. BMJ Open. 2018;8:e022056.
Naghshineh E, Sheikhaliyan S. Effect of vitamin D supplementation in the reduce risk of preeclampsia in nulliparous women. Adv Biomed Res. 2016;5:7.
Nasrolahi SH, Alimohammady SH, Zamani M. The effect of antioxidants (vitamin e and c) on preeclampsia in primiparous women. J Gorgan Univ Med Sci. 2006;8:17–21.
Nieder J, Claus P, Augustin W. Prevention of pre-eclampsia and fetal growth retardation by trapidil. Zentralbl Gynakol. 1995;117:23–8.
Parazzini F, Benedetto C, Frusca T, Gregorini G, Bocciolone L, Marozio L, et al. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Italian study of aspirin in pregnancy. Lancet. 1993;341:396–400.
Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol. 2000;183:1008–12.
Picciolo C, Roncaglia N, Neri I, Pasta F, Arreghini A, Facchinetti F. Nitric oxide in the prevention of pre-eclampsia. Prenat Neonatal Med. 2000;5:212–5.
Ponmozhi G, Keepanasseril A, Mathaiyan J, Manikandan K. Nitric oxide in the prevention of pre-eclampsia (NOPE): a double-blind randomized placebo-controlled trial assessing the efficacy of isosorbide mononitrate in the prevention of pre-eclampsia in high-risk women. J Obstet Gynecol India. 2019;69:S103–10.
Porreco RP, Hickok DE, Williams MA, Krenning C. Low-dose aspirin and hypertension in pregnancy. Lancet. 1993;341:312.
Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH, for the Vitamins in Pre-eclampsia trial consortium. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet. 2006;367:1145–54.
Purwar M, Kulkarni H, Motghare V, Dhole S. Calcium supplementation and prevention of pregnancy induced hypertension. J Obstet Gynaecol Res. 1996;22:425–30.
Railton A, Davey DA. Aspirin and dipyridamole in the prevention of pre-eclampsia: effect on plasma 6 keto PGF1alpha and TxB2 and clinical outcome of pregnancy. In: Vienna: Proceedings of 1st European Congress on Prostaglandins in Reproduction; 1988. p. 48.
Ranjkesh F, Laluha F, Pakniat H, Kazemi H, Golshahi T, Esmaeili S. Effect of omeg-3 supplementation on preeclampsia in high risk pregnant women. J Qazvin Univ Med Sci. 2011;15:28–33.
Rayman MP, Searle E, Kelly L, Johnsen S, Bodman-Smith K, Bath SC, et al. Effect of selenium on markers of risk of pre-eclampsia in UK pregnant women: a randomised, controlled pilot trial. Br J Nutr. 2014;112:99–111.
Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost. 2009;7:58–64.
Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010;362:1282–91.
Rodger MA, Hague WM, Kingdom J, Kahn SR, Karovitch A, Sermer M, et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014;384:1673–83.
Rogers MS, Fung HYM, Hung CY. Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension. Hypertens Pregnancy. 1999;18:165–72.
Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS, for the Acts Study G r. o. u. p. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med. 2006;354:1796–806.
Seki H, Kuromaki K, Takeda S, Kinoshita K, Satoh K. Trial of prophylactic administration of TXA2 synthetase inhibitor, ozagrel hydrochloride for preeclampsia. Hypertens Pregnancy. 1999;18:157–64.
Sharma JB, Kumar A, Kumar A, Malhotra M, Arora R, Prasad S, et al. Effect of lycopene on pre-eclampsia and intra-uterine growth retardation in primigravidas. Int J Gynecol Obstet. 2003;81:257–62.
Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N Engl J Med. 1993;329:1213–8.
Spinnato JA, Freire S, Silva JL, Cunha Rudge MV, Martins-Costa S, Koch MA, et al. Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstet Gynecol. 2007;110:1311–8.
Subtil D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G, et al. Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the essai regional aspirine mere-enfant study (part 1). BJOG Int J Obstet Gynaecol. 2003;110:475–84.
Šulović N, Kontić-Vučinić, Relic G, Šulović L. Did calcium management prevent preeclampsia? Abstract no: P33. Pregnancy Hypertens. 2011;1:287.
Sun H, Cai Y, Ma Z, Yuan J, Zhang L, Yang H, et al. Preventive effect of low-dose aspirin on preeclampsia occured in preeclampsia high-risk pregnant women and its mechanism. J Jilin Univ Med Ed. 2020;46:138–43.
Taherian AA, Taherian A, Shirvani A. Prevention of preeclampsia with low-dose aspirin or calcium supplementation. Arch Iran Med. 2002;5:151–6.
Tara F, Maamouri G, Rayman MP, Ghayour-Mobarhan M, Sahebkar A, Yazarlu O, et al. Selenium supplementation and the incidence of preeclampsia in pregnant Iranian women: a randomized, double-blind, placebo-controlled pilot trial. Taiwan J Obstet Gynecol. 2010;49:181–7.
Teran E, Hernandez I, Nieto B, Tavara R, Ocampo JE, Calle A. Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. Int J Gynecol Obstet. 2009;105:43–5.
Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali MM, Zavaleta N, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006;194:639–49.
Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc N, Anthony J, et al. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG Int J Obstet Gynaecol. 2009;116:780–8.
Wanchu M, Malhotra S, Khullar M. Calcium supplementation in pre-eclampsia. J Assoc Physicians India. 2001;49:795–8.
Wen SW, White RR, Rybak N, Gaudet LM, Robson S, Hague W, et al. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ. 2018;362:k3478.
Xu H, Perez-Cuevas R, Xiong X, Reyes H, Roy C, Julien P, et al. An international trial of antioxidants in the prevention of preeclampsia (INTAPP). Am J Obstet Gynecol. 2010;202:239.e1–10.
Zhao YM, Xiao LP, Hu H, Yang XN, Xu YQ, Guo LM. Low-dose aspirin prescribed at bed time for the prevention of pre-eclampsia in high-risk pregnant women. Reprod Contracept. 2012;32:355–9.
Caspi E, Raziel A, Sherman D, Arieli S, Bukovski I, Weinraub Z. Prevention of pregnancy-induced hypertension in twins by early administration of low-dose aspirin: a preliminary report. Am J Reprod Immunol. 1994;31:19–24.
D’Anna R, Santamaria A, Corrado F, Benedetto AD, Petrella E, Facchinetti F. Myo-inositol in the prevention of gestational diabetes and its complications. Pregnancy Hypertens. 2015;5:6.
Frusca T, Gregorini G, Ballerini S, Marchesi D, Bruni M. Low dose aspirin in preventing preeclampsia and IUGR. In: Proceedings of 6th World Congress of Hypertension in Pregnancy. Montreal; 1988. p. 232.
Lopez-Jaramillo P, Narvaez M, Weigel RM, Yepez R. Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. Br J Obstet Gynaecol. 1989;96:648–55.
Viinikka L, Hartikainen-Sorri AL, Lumme R, Hiilesmaa V, Ylikorkala O. Low dose aspirin in hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn. Br J Obstet Gynaecol. 1993;100:809–15.
Kalpdev A, Saha SC, Dhawan V. Vitamin C and e supplementation does not reduce the risk of superimposed PE in pregnancy. Hypertens Pregnancy. 2011;30:447–56.
World Health Organization. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Geneva: World Health Organization; 2011.
Tenório MB, Ferreira RC, Moura FA, Bueno NB, Goulart MOF, Oliveira ACM. Oral antioxidant therapy for prevention and treatment of preeclampsia: meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2018;28:865–76.
Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218:287–93.e1.
This study was made possible through a grant offered by the Training Scholarship Program from the Faculty of Medicine, Prince of Songkla University, Thailand, the training programs from the KKU-WHO Long-Term Institutional Development HUBs, Thailand, and the Department of Health Policy, National Centre for Child Health and Development, Japan. We would like to thank the Editorial Team of Cochrane Pregnancy and Childbirth for their comments. We gratefully thank Assistant Professor Edward McNeil, Prince of Songkla University, for his assistance on graphic presentation of ranking treatments with SUCRA and forest plots in R software and the International Affairs Office, Faculty of Medicine, Prince of Songkla University for the English editing.
Educational grants were provided to the principal author to attend the training programs and workshops on network meta-analysis. The funding body has not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Ethics approval and consent to participate
The protocol of this systematic review and network meta-analysis was approved by Institute Ethics Committee, Faculty of Medicine, Prince of Songkla University in consideration of exempt determination REC.61-139-18-1.
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The authors declare that they have no competing interests.
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Summary of findings for medications to prevent pre-eclampsia in subgroup: the studies including high-risk women with underlying diseases. Appendix 2. Summary of findings for medications to prevent pre-eclampsia in subgroup: the studies including high-risk women with no underlying diseases or mixed nulliparous women and women with no underlying diseases. Appendix 3. Summary of findings for medications to prevent pre-eclampsia in subgroup: the studies including nulliparous or primigravida women. Appendix 4. Summary of findings for medications to prevent gestational hypertension in subgroup: studies including high-risk women with underlying diseases or mixed other high-risk women. Appendix 5. Summary of findings for medications to prevent gestational hypertension in subgroup: the studies including high-risk women with no underlying diseases or mixed nulliparous women and women with no underlying diseases. Appendix 6. Summary of findings for medications to prevent gestational hypertension in subgroup: the studies including nulliparous or primigravida women. Appendix 7. Findings on the tests of heterogeneity, effect of intervention and tests of publication bias for direct comparisons in a network meta-analysis.
Publication biases using comparison-adjusted funnel plot for preventing preeclampsia. 01: anticoagulants; 02: anticoagulants plus antiplatelet agents; 03: anticoagulants plus antiplatelet plus calcium; 04: antioxidants; 05: antiplatelet agents; 06: antiplatelet agents plus calcium; 07: antiplatelet agents plus nitric oxide; 08: calcium; 09: calcium plus antioxidants; 10: control; 11: nitric oxide.
Publication biases using comparison-adjusted funnel plot for preventing gestational hypertension. 01: anticoagulants plus antiplatelet agents; 02: anticoagulants plus antiplatelet plus calcium; 03: antioxidants; 04: antiplatelet agents; 05: antiplatelet agents plus calcium; 06: calcium; 07: control.
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Liabsuetrakul, T., Yamamoto, Y., Kongkamol, C. et al. Medications for preventing hypertensive disorders in high-risk pregnant women: a systematic review and network meta-analysis. Syst Rev 11, 135 (2022). https://doi.org/10.1186/s13643-022-01978-5
- Hypertension prevention
- Hypertensive disorders in pregnancy
- High-risk pregnant women
- Network meta-analysis