Pharmacological and Non-Pharmacological Intervention to Prevent Preeclampsia: A Systematic Literature Review

Fatimatasari - Fatimatasari, Fatimah Fatimah, Angela C.B Trude, Herlin Herlin Fitriana Kurniawati, Rosmita Nuzuliana


Preeclampsia is a disorder of pregnancy that increases risk for long-term health consequences for both mother and child, and if left untreated is one of the main causes of maternal and fetal mortality. However, delivery of the placenta is the only cure, making prevention options for this condition needed but little consensus exist on their effectiveness. Thus, we conducted a systematic literature review on the effectiveness of pharmacological interventions and dietary supplementations to prevent preeclampsia. We used MEDLINE and ProQuest to conduct a systematic search for peer-review publications on prevention of preeclampsia. We selected studies conducted in human and published in English from 2010 through 2020 on: i) types of interventions; ii) quality of studies and limitations. We selected 22 articles to be reviewed. Three types of pharmacological interventions and eight types of dietary supplementations were identified. Nitric Oxide-donors with Isosorbide Mononitrate (IMN), and aspirin have been shown to be effective, while selenium, calcium, vitamin D, DHA-rich fish oil-concentrate, copper, phytonutrient, Nitric Oxide-donors with Penthaerythrityl Tetranitrate (PETN), folic acid, vitamins C and E and magnesium have not been proved effective to prevent preeclampsia. Although all studies presented good quality of evidence, they had several limitations, the most common limitations are lack of initial therapy, lack of dosage, and inadequate sample size to detect small effect. Despite the growing evidence of treatments to prevent preeclampsia, their effect is not large. More research is needed in the field before prevention treatments are prescribed in clinical settings.


systematic literature review; preventive intervention; preeclampsia

Full Text:



Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A-B, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Heal. 2014 Jun;2(6):e323-33.

Saleem S, Mc Clure EM, Goudar SS, Patel A, Esamai F, Garces A, et al. A prospective study of maternal, fetal and neonatal deaths in low- and middle-income countries. Bull World Health Organ. 2014 Aug;92(8):605–12.

Abalos E, Cuesta C, Grosso AL, Chou D, Say L. European Journal of Obstetrics & Gynecology and Reproductive Biology Global and regional estimates of preeclampsia and eclampsia : a systematic review. Eur J Obstet Gynecol [Internet]. 2013;170(1):1–7. Available from:

Lestariningsih S, Budi Susila Duarsa A. Hubungan Preeklampsia Dalam Kehamilan Dengan Kejadian Bblr Di Rsud Jenderal Ahmad Yani Kota Metro Tahun 2011. J Kesehat Masy Andalas. 2013;8(1):34.

Mallisa B, Towidjojo VD. Hubungan Antara Preeklampsia Dengan Kejadian Bayi Berat Badan Lahir Rendah ( Bblr ) Di RSUD Undata Palu. Med Tadulako, J Ilm Kedokt [Internet]. 2014;1(3):1–7.Available from:

Hermes W, Franx A, Van Pampus MG, Bloemenkamp KWM, Bots ML, Van Der Post JA, et al. Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: A cohort study. Am J Obstet Gynecol [Internet]. 2013;208(6):474.e1-474.e8. Available from:

Veerbeek JHW, Hermes W, Breimer AY, Van Rijn BB, Koenen S V., Mol BW, et al. Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension. Hypertension. 2015;65(3):600–6.

Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: Prospective evidence from the child health and development studies cohort. Hypertension. 2010;56(1):166–71.

Heida KY, Franx A, Van Rijn BB, Eijkemans MJC, Boer JMA, Verschuren MWM, et al. Earlier Age of Onset of Chronic Hypertension and Type 2 Diabetes Mellitus After a Hypertensive Disorder of Pregnancy or Gestational Diabetes Mellitus. Hypertension. 2015;66(6):1116–22.

Auger N, Fraser WD, Schnitzer M, Leduc L, Healy-Profitós J, Paradis G. Recurrent pre-eclampsia and subsequent cardiovascular risk. Heart. 2017;103(3):235–43.

Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJP. Pre-eclampsia is associated with increased risk of stroke in the adult offspring the helsinki birth cohort study. Stroke. 2009;40(4):1176–80.

Ehr J von, Versen-Hoynck F von. Implications of maternal conditions and pregnancy course on offspring’s medical problems in adult life. Arch Gynecol Obstet. 2016;294(4):673–9.

Pinheiro T V., Brunetto S, Ramos JGL, Bernardi JR, Goldani MZ. Hypertensive disorders during pregnancy and health outcomes in the offspring: A systematic review. J Dev Orig Health Dis. 2016;7(4):391–407.

Bezerra Maia e Holanda Moura S, Marques Lopes L, Murthi P, Da Silva Costa F. Prevention of preeclampsia. J Pregnancy. 2012;2012.

Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, et al. Checklist for Randomized Controlled Trials. Joanna Briggs Inst [Internet]. 2017;1–9. Available from:

Zhou SJ, Yelland L, Mcphee AJ, Quinlivan J, Gibson RA, Makrides M. Fish-oil supplementation in pregnancy does not reduce the risk of gestational diabetes or preeclampsia 1 – 3. 2012;1378–84.

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(1):99–111.

Abramovici A, Gandley RE, Clifton RG, Leveno KJ, Myatt L, Wapner RJ, et al. Prenatal Vitamin C and e supplementation in smokers is associated with reduced placental abruption and preterm birth: A secondary analysis. Bjog An Int J Obstet Gynaecol. 2015;122(13):1740–7.

Abramovici A, Jauk V, Wetta MPHL, Cantu J, Edwards R, Biggio J, et al. Low-Dose Aspirin , Smoking Status , and the Risk of Spontaneous Preterm Birth. 2015;1(212).

Cantu JA, Jauk VR, Owen J, Biggio JR, Abramovici AR, Edwards RK, et al. Is low-dose aspirin therapy to prevent preeclampsia more efficacious in non-obese women or when initiated early in pregnancy ? J Matern Neonatal Med. 2015;00(00):1–5.

Moore G, Allshouse A, Post A, Galan H, Heyborne K. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. 2016;35(5):328–31.

Odibo AO, Goetzinger KR, Odibo L, Tuuli MG. Early prediction and aspirin for prevention of pre-eclampsia ( EPAPP ) study : a randomized controlled trial. 2015;(April):414–8.

Roberts JM, Myatt L, Spong CY, Thom EA. Vitamins C and E to Prevent Complications of Pregnancy- Associated Hypertension. 2011;362(14):1282–91.

Parrish MR, Martin JN, Lamarca BB, Ellis B, Parrish SA, Owens MY, et al. Randomized, placebo controlled, double blind trial evaluating early pregnancy phytonutrient supplementation in the prevention of preeclampsia. J Perinatol [Internet]. 2013;33(8):593–9. Available from:

Kashanian M, Hasti H, Masoomeh F, Mitra N, Narges S. Evaluating the effects of copper supplement during pregnancy on premature rupture of membranes and pregnancy outcome. J Matern Neonatal Med. 2016;0(0):000.

Razik MA, El-Berry S, Abosereah M, Edris Y, Sharafeldeen A. Prophylactic treatment for preeclampsia in high-risk teenage primigravidae with nitric oxide donors: A pilot study. J Matern Neonatal Med. 2016;29(16):2617–20.

Schleussner E, Lehmann T, Kähler C, Schneider U. Impact of the nitric oxide-donor pentaerythrityl- tetranitrate on perinatal outcome in risk pregnancies : 2014;42(4):507–14.

Ayala DE, Ucieda R, Hermida RC. Chronotherapy With Low-Dose Aspirin for Prevention of Complications in Pregnancy. 2012;1–20.

Scazzocchio E, Oros D, Diaz D. Impact of aspirin on trophoblastic invasion in women with abnormal uterine artery Doppler at 11−14 weeks: A randomized controlled study (ASAP). Ultrasound Obs Gynecol. 2017;49:435–41.

Kiondo P, Wamuyu-Maina G, Wandabwa J, Bimenya GS, Tumwesigye NM, Okong P. The effects of vitamin C supplementation on pre-eclampsia in Mulago Hospital, Kampala, Uganda: A randomized placebo controlled clinical trial. BMC Pregnancy Childbirth. 2014;14(1):1–10.

Araújo CAL de, de Sousa Oliveira L, Gusmão IMB de, Guimarães A, Ribeiro M, Alves JGB. Magnesium supplementation and preeclampsia in low-income pregnant women – a randomized double-blind clinical trial. BMC Pregnancy Childbirth [Internet]. 2020;20(208):1–6. Available from:

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;362:1–8.

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 ). YMOB. 2010;202(3):239.e1-239.e10.

McCance DR, Holmes VA, Maresh MJA, Patterson CC, Walker JD, Pearson DWM, et al. Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): A randomised placebo-controlled trial. Lancet [Internet]. 2010;376(9737):259–66. Available from:

Hofmeyr GJ, Betrán AP, Singata-Madliki M, Cormick G, Munjanja SP, Fawcus S, et al. Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2019 Jan 26;393:330–9.

Rolnik DL, O’Gorman N, Roberge S, Bujold E, Hyett J, Uzan S, et al. Early screening and prevention of preterm pre-eclampsia with aspirin: time for clinical implementation. Ultrasound Obstet Gynecol. 2017;50(5):551–6.

Rolnik DL, Wright D, Poon LC, O’Gorman N. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. 2017;613–22.

Villa P, Kajantie E, Ra¨ikkonen K, Pesonen A-K, Inen EH, Vainio M, et al. Aspirin in the prevention of pre-eclampsia in high-risk women : a randomised placebo- controlled PREDO Trial and a meta-analysis of randomised trials. 2013;64–74.

Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int. 2013;30(1–2):260–79.

Wen SW, Champagne J, Rennicks White R, Coyle D, Fraser W, Smith G, et al. Effect of folic acid supplementation in pregnancy on preeclampsia: The folic acid clinical trial study. J Pregnancy. 2013;2013.

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 An Int J Obstet Gynaecol. 2009;116(6):780–8.

Wen SW, Guo Y, Rodger M, White RR. Folic Acid Supplementation in Pregnancy and the Risk of Pre-Eclampsia — A Cohort Study. 2016;1–11.

Odibo AO, Goetzinger KR, Odibo L, Tuuli MG. Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: A randomized controlled trial. Ultrasound Obstet Gynecol. 2015;46(4):414–8.

Villa PM, Kajantie E, Räikkönen K, Pesonen AK, Hämäläinen E, Vainio M, et al. Aspirin in the prevention of pre-eclampsia in high-risk women: A randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG An Int J Obstet Gynaecol. 2013;120(1):64–74.

S.J. Z, L. Y, A.J. M, J. Q, R.A. G, M. M. Fish-oil supplementation in pregnancy does not reduce the risk of gestational diabetes or preeclampsia. Am J Clin Nutr [Internet]. 2012;95(6):1378–84. Available


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 [Internet]. 2010;202(3):239.e1-239.e10. Available from:

Abramovici A, Jauk V, Wetta L, Cantu J, Edwards R, Biggio J, et al. Low-dose aspirin, smoking status, and the risk of spontaneous preterm birth. Am J Perinatol. 2015;32(5):445–50.

Schleussner E, Lehmann T, Kähler C, Schneider U, Schlembach D, Groten T. Impact of the nitric oxide-donor pentaerythrityltetranitrate on perinatal outcome in risk pregnancies: A prospective, randomized, double-blinded trial. J Perinat Med. 2014;42(4):507–14.

Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ. Vitamins C and E to Prevent Complications of Pregnancy- Associated Hypertension. N Engl J Med. 2010;362(14):1282–91.

Kashanian M, Hadizadeh H, Faghankhani M, Nazemi M, Sheikhansari N. Evaluating the effects of copper supplement during pregnancy on premature rupture of membranes and pregnancy outcome. J Matern Neonatal Med [Internet]. 2018;31(1):39–46. Available from:

Cantu JA, Jauk VR, Owen J, Biggio JR, Abramovici AR, Edwards RK, et al. Is low-dose aspirin therapy to prevent preeclampsia more efficacious in non-obese women or when initiated early in pregnancy? J Matern Neonatal Med [Internet]. 2015;28(10):1128–32. Available from:

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 [Internet]. 2009;105(1):43–5. Available from:

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(3):477–82.

Johal T, Lees CC, Everett TR, Wilkinson IB. The nitric oxide pathway and possible therapeutic options in pre-eclampsia. Br J Clin Pharmacol. 2014;78(2):244–57.

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 [Internet]. 2019;69:103–10. Available from:

Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for Prevention of Preeclampsia. Drugs. 2017;77(17):1819–31.

Everett T, Johal T, Lees C. Nitric Oxide Donors in Preeclampsia. In: Cardiovascular Therapies. Cambridge University Main; 2018. p. 1689–99.

Meher S, Duley L. Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;(2).

GJ H, TA L, An A, MR T. Cochrane Database of Systematic Reviews Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (Review). 2018;(10).

DeSousa J, Tong M, Wei J, Chamley L, Stone P, Chen Q. The anti-inflammatory effect of calcium for preventing endothelial cell activation in preeclampsia. J Hum Hypertens. 2016 May;30(5):303–8.

Song X, Li B, Li Z, Wang J, Zhang D. High serum copper level is associated with an increased risk of preeclampsia in Asians: A meta-analysis. Nutr Res. 2017 Mar;39:14–24.

Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy. Oxid Med Cell Longev. 2011;2011.

Moussa HN, Hosseini Nasab S, Haidar ZA, Blackwell SC, Sibai BM. Folic acid supplementation: what is new? Fetal, obstetric, long-term benefits and risks. Futur Sci OA. 2016;2(2).

Gugun AM. Hiperhomosisteinemia dan Faktor Risiko Kelainan Vaskuler. Vol. 8, Mutiara Medika. 2008. p. 97–105.

Liu C, Liu C, Wang Q, Zhang Z. Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis. Arch Gynecol Obstet [Internet]. 2018;298(4):697–704. Available from:

Hua X, Zhang J, Guo Y, Shen M, Gaudet L, Janoudi G, et al. Effect of folic acid supplementation during pregnancy on gestational hypertension/preeclampsia: A systematic review and meta-analysis. Hypertens Pregnancy. 2016 Oct;35(4):447–60.

Yang X, Chen H, Du Y, Wang S, Wang Z. Periconceptional folic acid fortification for the risk of gestational hypertension and pre-eclampsia: a meta-analysis of prospective studies. Matern Child Nutr. 2016 Oct;12(4):669–79.

Bird JK, Calder PC, Eggersdorfer M. The role of n-3 long chain polyunsaturated fatty acids in cardiovascular disease prevention, and interactions with statins. Nutrients. 2018;10(6).

Kashanian M, Baradaran HR, Bahasadri S, Alimohammadi R. Risk factors for pre-eclampsia: a study in Tehran, Iran. Arch Iran Med. 2011 Nov;14(6):412–5.

Kharb S, Goel K, Bhardwaj J, Nanda S. Role of Magnesium in Preeclampsia. Biomed Biotechnol Res J. 2018;2:178–80.

Bullarbo M, Mattson H, Broman AK, Ödman N, Nielsen TF. Magnesium Supplementation and Blood Pressure in Pregnancy: A Double-Blind Randomized Multicenter Study. J Pregnancy. 2018;2018.

Tara F, Maamouri G, Rayman MP, Ghayour-mobarhan M. Selenium Supplementation and The Incidence of Preeclampsia in Pregnant Iranian Women : A Randomized, Double-Blinded,Placebo-Controlled Pilot Trial. Taiwan J Obstet Gynecol. 2010;49(2):181–7.

Xu M, Guo D, Gu H, Zhang L, Lv S. Selenium and Preeclampsia: a Systematic Review and Meta-analysis. Biol Trace Elem Res. 2016;171(2):283–92.

Rumbold A, Ota E, Miyazaki C, Crowther caroline A. Vitamin E supplementation in pregnancy. Cochrane Database Syst Rev. 2016;(2):CD004069.

Rumbold A, Ota E, Nagata C, Shahrook S, Crowther caroline A. Vitamin C supplementation in pregnancy ( Review ) Summary Of Findings For The Main Comparison. 2016;(9).



  • There are currently no refbacks.

Jurnal Ners dan Kebidanan Indonesia (JNKI) indexed by:


Lisensi Creative Commons

  View My Stats