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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) Cite this article

Abstract

Objectives

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.

Methods

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.

Results

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.

Conclusion

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

PROSPERO CRD42018096276

Peer Review reports

Background

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 [10]. Additionally, another network meta-analysis found that either vitamin D or calcium supplements may be effective [11].

A recent study demonstrated the superiority of Doppler and serum markers over conventional risk factor-based screening [12], 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 [4]. 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.

Methods

Eligibility criteria

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 [18]. 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 [19]. 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 [20]. Any disagreements were resolved by discussion, and the information was entered into Review Manager 5 software, for risk of bias [21]. 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 [22].

Effect measures

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 [23] and the Dias’s side-splitting approach [24]. 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 [26]. 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 [29].

Results

Study selection

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 [30]. The results of search and selection process are presented in the PRISMA flow diagram as shown in Fig. 1.

Fig. 1
figure 1

PRISMA study flow diagram

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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.

Fig. 2
figure 2

Risk-of-bias graph presented as percentages across all included studies

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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).

Fig. 3
figure 3

Network plot of medications for preventing preeclampsia. CON, control; ANC, anticoagulants; ANO, antioxidants; ANP, antiplatelet agents; CAL, calcium; N, nitric oxide; CAL-ANO, calcium plus antioxidants; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-NO, antiplatelet agents plus nitric oxide; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CAL, anticoagulants plus antiplatelet plus calcium

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Fig. 4
figure 4

Direct, indirect, and network meta-analysis estimates of medications for preventing preeclampsia. CON, control; ANC, anticoagulants; ANO, antioxidants; ANP, antiplatelet agents; CA, calcium; NO, nitric oxide; CAL-ANO, calcium plus antioxidants; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-NO, antiplatelet agents plus nitric oxide; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CAL, anticoagulants plus antiplatelet plus calcium

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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).

Fig. 5
figure 5

Cumulative rankograms of medications for preventing preeclampsia. CON, control; ANC, anticoagulants; ANO, antioxidants; ANP, antiplatelet agents; CAL, calcium; NO, nitric oxide; CAL-ANO, calcium plus antioxidants; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-NO, antiplatelet agents plus nitric oxide; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CAL, anticoagulants plus antiplatelet plus calcium

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Table 1 Summary of findings for medications to prevent preeclampsia
Full size table

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.

Fig. 6
figure 6

Network plot of medications for preventing gestational hypertension. CON, control; ANO, antioxidants; ANP, antiplatelet agents; CAL, calcium; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CA, anticoagulants plus antiplatelet plus calcium

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Fig. 7
figure 7

Direct, indirect, and network meta-analysis estimates of medications for preventing gestational hypertension. CON, control; ANO, antioxidants; ANP, antiplatelet agents; CAL, calcium; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CAL, anticoagulants plus antiplatelet plus calcium

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Fig. 8
figure 8

Cumulative rankograms of medications for preventing gestational hypertension. CON, control; ANO, antioxidants; ANP, antiplatelet agents; CAL, calcium; ANC-ANP, anticoagulants plus antiplatelet agents; ANP-CAL, antiplatelet agents plus calcium; ANC-ANP-CAL, anticoagulants plus antiplatelet plus calcium

Full size image

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).

Table 2 Summary of findings for medications to prevent gestational hypertension
Full size table

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.

Fig. 9
figure 9

Network plot of medications for preventing superimposed preeclampsia. CON, control; ANO, antioxidants; ANP, antiplatelet agents

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Table 3 Summary of findings for medications to prevent superimposed preeclampsia
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Reporting biases

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).

Discussion

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 [114], and the NICE recommendation for the use of 75–150 mg aspirin [15]. 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 [115]. 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 [10], and the latter defined nulliparous women as low-risk women [11]. The probability of being the most effective treatment for calcium in our review was higher than that in the study of Sanchez-Ramos (2017) [10]. 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 [116]. 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.

Conclusions

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.

Abbreviations

CI:

Confidence interval

GHT:

Gestational hypertension

GRADE:

Grading of Recommendations Assessment, Development and Evaluation

HDP:

Hypertensive disorders in pregnancy

NICE:

National Institute for Health and Care Excellence

NMA-SoF:

Network meta-analysis–summary of findings

PE:

Preeclampsia

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analyses

RR:

Risk ratios

SUCRA:

Surface under the cumulative ranking curve

SPE:

Superimposed preeclampsia

References

  1. 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.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. 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.

    PubMed Central  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. ACOG. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122–31.

    Article  Google Scholar 

  7. 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.

    PubMed  Google Scholar 

  8. Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev. 2008;2008(1):CD004227.

    PubMed Central  Google Scholar 

  9. Zullino S, Buzzella F, Simoncini T. Nitric oxide and the biology of pregnancy. Vascul Pharmacol. 2018;110:71–4.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  PubMed Central  CAS  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Google Scholar 

  15. NICE. Hypertension in pregnancy: diagnosis and management. London: NICE; 2019. p. 55.

    Google Scholar 

  16. ACOG No202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1–25.

  17. 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.

    Article  Google Scholar 

  18. PROSPERO. Guidance notes for registering a systematic review protocol with PROSPERO. York: University of York; 2016.

    Google Scholar 

  19. 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.

    Google Scholar 

  20. 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.

    Article  Google Scholar 

  21. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

  22. 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.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932–44.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

  26. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Google Scholar 

  28. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8:e76654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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.

    Google Scholar 

  31. 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.

  32. 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.

    Article  Google Scholar 

  33. 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.

    Google Scholar 

  34. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int. 2013;30:260–79.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    CAS  Google Scholar 

  36. 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.

  37. 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.

    Article  CAS  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Bassaw B, Roopnarinesingh S, Roopnarinesingh A, Homer H. Prevention of hypertensive disorders of pregnancy. J Obstet Gynaecol. 1998;18:123–6.

    Article  CAS  PubMed  Google Scholar 

  40. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet. 1985;1:840–2.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  Google Scholar 

  49. Cong KJ, Chi SL, Liu GR. Calcium supplementation during pregnancy to reduce pregnancy induced hypertension. Beijing Med J. 1992;5:268.

    Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  Google Scholar 

  52. 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.

    CAS  PubMed  Google Scholar 

  53. 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.

    Article  PubMed  CAS  Google Scholar 

  54. 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.

    Article  Google Scholar 

  55. 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.

  56. Essinger S. The use of low-dose acetylsalicylic acid in prevention of pregnancy-induced hypertension. Rev Col Bras Cir. 1992;19:58–62.

    Google Scholar 

  57. 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.

    Google Scholar 

  58. 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.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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.

    Google Scholar 

  66. 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.

    Article  CAS  Google Scholar 

  67. 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.

    Article  CAS  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. 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.

    Article  Google Scholar 

  72. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Naghshineh E, Sheikhaliyan S. Effect of vitamin D supplementation in the reduce risk of preeclampsia in nulliparous women. Adv Biomed Res. 2016;5:7.

    PubMed  PubMed Central  Google Scholar 

  75. 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.

    Google Scholar 

  76. Nieder J, Claus P, Augustin W. Prevention of pre-eclampsia and fetal growth retardation by trapidil. Zentralbl Gynakol. 1995;117:23–8.

    CAS  PubMed  Google Scholar 

  77. 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.

    Article  Google Scholar 

  78. 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.

    Article  CAS  PubMed  Google Scholar 

  79. 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.

    CAS  Google Scholar 

  80. 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.

    Article  CAS  Google Scholar 

  81. Porreco RP, Hickok DE, Williams MA, Krenning C. Low-dose aspirin and hypertension in pregnancy. Lancet. 1993;341:312.

    Article  CAS  PubMed  Google Scholar 

  82. 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.

    Article  CAS  PubMed  Google Scholar 

  83. Purwar M, Kulkarni H, Motghare V, Dhole S. Calcium supplementation and prevention of pregnancy induced hypertension. J Obstet Gynaecol Res. 1996;22:425–30.

    Article  CAS  PubMed  Google Scholar 

  84. 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.

  85. 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.

    Google Scholar 

  86. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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.

    Article  CAS  PubMed  Google Scholar 

  88. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. 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.

    Article  CAS  PubMed  Google Scholar 

  92. 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.

    Article  CAS  PubMed  Google Scholar 

  93. 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.

    Article  CAS  Google Scholar 

  94. 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.

    Article  CAS  PubMed  Google Scholar 

  95. 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.

    Article  CAS  PubMed  Google Scholar 

  96. 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.

    CAS  Google Scholar 

  97. Šulović N, Kontić-Vučinić, Relic G, Šulović L. Did calcium management prevent preeclampsia? Abstract no: P33. Pregnancy Hypertens. 2011;1:287.

    Article  Google Scholar 

  98. 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.

    Google Scholar 

  99. Taherian AA, Taherian A, Shirvani A. Prevention of preeclampsia with low-dose aspirin or calcium supplementation. Arch Iran Med. 2002;5:151–6.

    CAS  Google Scholar 

  100. 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.

    Article  PubMed  Google Scholar 

  101. 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.

    Article  CAS  Google Scholar 

  102. 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.

    Article  CAS  PubMed  Google Scholar 

  103. 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.

    Article  CAS  Google Scholar 

  104. Wanchu M, Malhotra S, Khullar M. Calcium supplementation in pre-eclampsia. J Assoc Physicians India. 2001;49:795–8.

    CAS  PubMed  Google Scholar 

  105. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  106. 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.

    Article  CAS  Google Scholar 

  107. 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.

    Google Scholar 

  108. 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.

    Article  CAS  PubMed  Google Scholar 

  109. 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.

    Google Scholar 

  110. 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.

  111. 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.

    Article  CAS  PubMed  Google Scholar 

  112. 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.

    Article  CAS  PubMed  Google Scholar 

  113. 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.

    Article  CAS  PubMed  Google Scholar 

  114. World Health Organization. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Geneva: World Health Organization; 2011.

    Google Scholar 

  115. 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.

    Article  PubMed  CAS  Google Scholar 

  116. 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Department of Epidemiology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand

    Tippawan Liabsuetrakul

  2. Department of Health Policy, National Center for Child Health and Development, Setagaya-ku, Japan

    Yoshiko Yamamoto

  3. Department of Community Medicine and Preventive Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand

    Chanon Kongkamol

  4. Global Health Nursing, Graduate School of Nursing Science, St. Luke’s International University, Chuo-ku, Japan

    Erika Ota

  5. Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Rintaro Mori

  6. Department of Data Science, The Institute of Statistical Mathematics, Tokyo, Japan

    Hisashi Noma

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Contributions

All authors participated in the concept of the study and approved the protocol. TL prepared the protocol, conducted the screening and selection of studies, extracted the data, assessed the risks of bias and GRADE, entered the data, analyzed and interpreted the results, and prepared the draft for review. YY participated in screening and selecting the studies, extracting the data, assessing the risks of bias, and approved the draft of the review. CK participated in selection of studies, extracted as before the data, assessed risk of bias and GRADE, entered the data, and approved the draft for review. RM and EO participated in the data extraction, assessing risk of bias, and approved the draft for review. HN was involved in data analysis and interpretation. All authors have approved the final version of the review.

Corresponding author

Correspondence to Tippawan Liabsuetrakul.

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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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Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Appendix 1.

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.

Additional file 2.

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.

Additional file 3.

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

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Systematic Reviews

ISSN: 2046-4053