Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of L-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials

Journal of Human Hypertension volume 28, pages 230–235 (2014)Cite this article

Subjects

Abstract

Pre-eclampsia is a significant health issue in pregnancy, complicating between 2–8% of pregnancies. L-arginine is an important mediator of vasodilation with a potential preventative role in pregnancy related hypertensive diseases. We aimed to systematically review randomised trials in the literature assessing the role of L-arginine in prevention and treatment of pre-eclampsia. We searched the Cochrane Controlled Trials Register, PUBMED, and the Australian and International Clinical Trials Registry, to identify randomised trials involving pregnant women where L-arginine was administered for pre-eclampsia to improve maternal and infant health outcomes. We identified eight randomised trials, seven of which were included. The methodological quality was fair, with a combined sample size of 884 women. For women at risk of pre-eclampsia, L-arginine was associated with a reduction in pre-eclampsia (RR: 0.34, 95% CI: 0.21–0.55), when compared with placebo and a reduction in risk of preterm birth (RR: 0.48 and 95% CI: 0.28 to 0.81). For women with established hypertensive disease, L-arginine was associated with a reduction in pre-eclampsia (RR: 0.21; 95% CI: 0.05–0.98). L-arginine may have a role in the prevention and/or treatment of pre-eclampsia. Further well-designed and adequately powered trials are warranted, both in women at risk of pre-eclampsia and in women with established disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Sibai B, Dekker G, Kupferminc M . Pre-eclampsia. Lancet 2005; 365 (9461): 785–799.

    Article  Google Scholar 

  2. Duley L . The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33 (3): 130–137.

    Article  Google Scholar 

  3. López-Jaramillo P, Arenas WD, García RG, Rincon MY, López M . The role of the L-arginine-nitric oxide pathway in pre-eclampsia. Ther Adv Cardiovasc Dis 2008; 2 (4): 261–275.

    Article  Google Scholar 

  4. Murad F . Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic GMP signal transduction system. Adv Pharmacol 1994; 26: 19–33.

    Article  CAS  Google Scholar 

  5. Benyó Z, Görlach C, Wahl M . Involvement of thromboxane A2 in the mediation of the contractile effect induced by inhibition of nitric oxide synthesis in isolated rat middle cerebral arteries. J Cereb Blood Flow Metab 1998; 18 (6): 616–618.

    Article  Google Scholar 

  6. Wang W, Diamond SL . Does elevated nitric oxide production enhance the release of prostacyclin from shear stressed aortic endothelial cells? Biochem Biophys Res Commun 1997; 233 (3): 748–751.

    Article  CAS  Google Scholar 

  7. Riddell DR, Owen JS . Nitric oxide and platelet aggregation. Vitam Horm 1999; 57: 25–48.

    Article  CAS  Google Scholar 

  8. Böger RH, Diemert A, Schwedhelm E, Lüneburg N, Maas R, Hecher K . The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. Gynecol Obstet Invest 2010; 69 (1): 1–13.

    Article  Google Scholar 

  9. Goss SP, Kalyanaraman B, Hogg N . Antioxidant effects of nitric oxide and nitric oxide donor compounds on low-density lipoprotein oxidation. Methods Enzymol 1999; 301: 444–453.

    Article  CAS  Google Scholar 

  10. Morris NH, Eaton BM, Dekker G . Nitric oxide, the endothelium, pregnancy and pre-eclampsia. BJOG 1996; 103 (1): 4–15.

    Article  CAS  Google Scholar 

  11. McCord N, Ayuk P, McMahon M, Boyd RC, Sargent I, Redman C . System y+ arginine transport and NO production in peripheral blood mononuclear cells in pregnancy and preeclampsia. Hypertension 2006; 47 (1): 109–115.

    Article  CAS  Google Scholar 

  12. Neri I, Piccinini F, Marietta M, Facchinetti F, Volpe A . Platelet responsiveness to L-arginine in hypertensive disorders of pregnancy. Hypertens Pregnancy 2000; 19 (3): 323–330.

    Article  CAS  Google Scholar 

  13. Lowe DT . Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric Oxide 2000; 4 (4): 441–458.

    Article  CAS  Google Scholar 

  14. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF . Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354 (9193): 1896–1900.

    Article  CAS  Google Scholar 

  15. Centre TNC. Review Manager (RevMan) In: Collaboration TC (ed). Copenhagen: Review Manager (RevMan) 2011.

  16. Facchinetti F, Saade GR, Neri I, Pizzi C, Longo M, Volpe A . L-arginine supplementation in patients with gestational hypertension: a pilot study. Hypertens Pregnancy 2007; 26 (1): 121–130.

    Article  CAS  Google Scholar 

  17. Hladunewich MA, Derby GC, Lafayette RA, Blouch KL, Druzin ML, Myers BD . Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial. Obstet Gynecol 2006; 107 (4): 886–895.

    Article  CAS  Google Scholar 

  18. Rytlewski K, Olszanecki R, Korbut R, Zdebski Z . Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia. Eur J Clin Invest 2005; 35 (1): 32–37.

    Article  CAS  Google Scholar 

  19. Staff AC, Berge L, Haugen G, Lorentzen B, Mikkelsen B, Henriksen T . Dietary supplementation with L-arginine or placebo in women with pre-eclampsia. Acta Obstet Gynecol Scand 2004; 83 (1): 103–107.

    Google Scholar 

  20. Vadillo-Ortega F, Perichart-Perera O, Espino S, Avila-Vergara MA, Ibarra I, Ahued R et al. Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ 2011; 342: d2901.

    Article  Google Scholar 

  21. Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F . L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. J Matern Fetal Neonatal Med 2010; 23 (12): 1456–1460.

    Article  CAS  Google Scholar 

  22. Neri I, Jasonni VM, Gori GF, Blasi I, Facchinetti F . Effect of L-arginine on blood pressure in pregnancy-induced hypertension: a randomized placebo-controlled trial. J Matern Fetal Neonatal Med 2006; 19 (5): 277–281.

    Article  CAS  Google Scholar 

  23. Winer N, Branger B, Azria E, Tsatsaris V, Philippe HJ, Rozé JC et al. L-Arginine treatment for severe vascular fetal intrauterine growth restriction: a randomized double-bind controlled trial. Clin Nutr 2009; 28 (3): 243–248.

    Article  CAS  Google Scholar 

  24. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T . Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104 (22): 2673–2678.

    Article  CAS  Google Scholar 

  25. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; 99 (9): 1141–1146.

    Article  CAS  Google Scholar 

  26. Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol 1997; 29 (3): 479–485.

    Article  CAS  Google Scholar 

  27. Neri I, Mazza V, Galassi MC, Volpe A, Facchinetti F . Effects of L-arginine on utero-placental circulation in growth-retarded fetuses. Acta Obstet Gynecol Scand 1996; 75 (3): 208–212.

    Article  CAS  Google Scholar 

  28. Facchinetti F, Neri I, Genazzani AR . L-arginine infusion reduces preterm uterine contractions. J Perinat Med 1996; 24 (3): 283–285.

    Article  CAS  Google Scholar 

  29. Helmbrecht GD, Farhat MY, Lochbaum L, Brown HE, Yadgarova KT, Eglinton GS et al. L-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat. Am J Obstet Gynecol 1996; 175 (4 Pt 1): 800–805.

    Article  CAS  Google Scholar 

  30. Davidge ST, Stranko CP, Roberts JM . Urine but not plasma nitric oxide metabolites are decreased in women with preeclampsia. Am J Obstet Gynecol 1996; 174 (3): 1008–1013.

    Article  CAS  Google Scholar 

  31. Holden DP, Fickling SA, Whitley GS, Nussey SS . Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998; 178 (3): 551–556.

    Article  CAS  Google Scholar 

  32. Pettersson A, Hedner T, Milsom I . Increased circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in preeclampsia. Acta Obstet Gynecol Scand 1998; 77 (8): 808–813.

    Article  CAS  Google Scholar 

  33. King RG, Di Iulio JL, Gude NM, Brennecke SP . Effect of asymmetric dimethyl arginine on nitric oxide synthase activity in normal and pre-eclamptic placentae. Reprod Fertil Dev 1995; 7 (6): 1581–1584.

    Article  CAS  Google Scholar 

  34. Savvidou MD, Hingorani AD, Tsikas D, Frölich JC, Vallance P, Nicolaides KH . Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 2003; 361 (9368): 1511–1517.

    Article  CAS  Google Scholar 

  35. Prefumo F, Thilaganathan B, Whitley GS . First-trimester uterine artery resistance and maternal serum concentration of asymmetric dimethylarginine. Ultrasound Obstet Gynecol 2008; 31 (2): 153–157.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The University of Adelaide, Robinson Institute and Discipline of Obstetrics & Gynaecology, Adelaide, South Australia, Australia

    T Dorniak-Wall, R M Grivell, G A Dekker, W Hague & J M Dodd

  2. Department of Perinatal Medicine, The Women’s and Children’s Hospital, North Adelaide, South Australia, Australia

    R M Grivell, W Hague & J M Dodd

  3. Department of Obstetrics & Gynaecology, The Lyell McEwin Hospital, Elizabeth, South Australia, Australia

    G A Dekker

Authors
  1. T Dorniak-Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R M Grivell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G A Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W Hague
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J M Dodd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R M Grivell.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dorniak-Wall, T., Grivell, R., Dekker, G. et al. The role of L-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J Hum Hypertens 28, 230–235 (2014). https://doi.org/10.1038/jhh.2013.100

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2013.100

Keywords

  • pregnancy
  • L-arginine
  • pre-eclampsia
  • hypertensive disease

This article is cited by

Search

Advanced search

Quick links