Journal of Human Hypertension (2014) 28, 230–235

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ORIGINAL ARTICLE
The role of L-arginine in the prevention and treatment of
pre-eclampsia: a systematic review of randomised trials
T Dorniak-Wall1, RM Grivell1,2, GA Dekker1,3, W Hague1,2 and JM Dodd1,2

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.

Journal of Human Hypertension (2014) 28, 230–235; doi:10.1038/jhh.2013.100; published online 31 October 2013
Keywords: pregnancy; L-arginine; pre-eclampsia; hypertensive disease

INTRODUCTION impaired nitric oxide synthesis and bioavailability have been

Pre-eclampsia is a pregnancy specific hypertensive disorder, which
can complicate the second half of pregnancy for between 2 and 8%
of women.1 The disorder more commonly affects women in their
first ongoing pregnancy, but maternal history of pre-eclampsia,
essential hypertension, autoimmune disorders, diabetes and a
multifetal pregnancy are all considered to increase a woman’s risk
of developing the condition.1 Hypertensive disorders of pregnancy
contribute significantly to both maternal and perinatal mortality
and morbidity on a global scale.2
Although the precise pathophysiology of pre-eclampsia remains
unknown, it is evident that there is abnormal placentation and
defective trophoblast invasion resulting in the utero-placental unit
being under perfused.1 This in turn is associated with endothelial
damage and production of vasoactive factors, which promote
vasoconstriction.1 In response, nitric oxide is synthesised from the
amino acid L-arginine, by the family of nitric oxide synthase
enzymes, which are calcium dependent.3
Nitric oxide has a potent vasodilator effect, mediating vascular
smooth muscle relaxation through cyclic guanosine monopho-
sphate (cGMP) pathways.4 Other recognised effects of nitric oxide
include the inhibition of thromboxane production,5 stimulation of
prostacyclin production,6 inhibition of platelet aggregation,7 while
also reducing both the release of oxygen-derived free radical
species,8 and oxidation of low-density lipoprotein cholesterol.9
The increase in nitric oxide production within the vascular
endothelium and its normal bioactivity are critical mechanisms
whereby the normal physiological haemodynamic adaptations to
pregnancy occur.3 Endothelial dysfunction and subsequent
hypothesized to occur in the setting of pre-eclampsia.3 The
production of nitric oxide is regulated by methyl derivatives of
L-arginine, in particular Asymmetric Dimethylarginine (ADMA),
which is an active inhibitor of nitric oxide synthase.8
L-arginine is a semi-essential amino acid, and during pregnancy,
under circumstances of increased nitric oxide production,
endogenous synthesis is insufficient.10 L-arginine concentrations
have been demonstrated to be significantly reduced in women
with pre-eclampsia when compared with healthy women without
the disease,11 with others suggesting alteration in substrate
transport.12 However, it appears that the ratio of ADMA to
L-arginine (rather than the absolute concentration of L-arginine)
may be more critical in determining nitric oxide synthase
activity and the subsequent production of oxygen free radicals,
thus creating a perpetuating cycle of nitric oxide synthase
dysfunction.13
The aim of this study was to conduct a systematic review of the
literature and meta-analysis, to evaluate the available evidence for
the use of L-arginine in the prevention and treatment of pre-
eclampsia, and the effect on clinical maternal and infant health
outcomes.
MATERIALS AND METHODS
Sources
We searched PUBMED, the Cochrane Controlled Trials Register (CENTRAL),
and the International Clinical Trials Register, using the free text search
terms pregnancy, pre-eclampsia, eclampsia, hypertension, L-arginine,

1
The University of Adelaide, Robinson Institute and Discipline of Obstetrics & Gynaecology, Adelaide, South Australia, Australia; 2The Women’s and Children’s Hospital,
Department of Perinatal Medicine, North Adelaide, South Australia, Australia and 3The Lyell McEwin Hospital, Department of Obstetrics & Gynaecology, Elizabeth, South Australia,
Australia. Correspondence: Dr RM Grivell, The University of Adelaide, Robinson Institute and Discipline of Obstetrics & Gynaecology, Women’s and Children’s Hospital, 77 King
William Road, North Adelaide, South Australia 5006, Australia.
E-mail: rosalie.grivell@adelaide.edu.au
Received 15 July 2013; accepted 9 September 2013; published online 31 October 2013