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

arginine, L-citrulline, nitric oxide donors, maternal mortality, maternal
morbidity, perinatal morbidity, perinatal mortality and randomis(z)ed
controlled trial. The reference lists of retrieved studies were searched by
hand and no date or language restrictions placed (Date of last search
November 2012).
Study selection
All published randomised controlled trials in which L-arginine was
administered alone or in combination with any other agent for the
prevention or treatment of pre-eclampsia, eclampsia or hypertensive
disorders in pregnancy were considered. Trials were excluded if L-arginine
was administered for the prevention or treatment of fetal growth
restriction in the absence of hypertension, or where studies were available
in abstract form only.
The primary outcomes were the development of pre-eclampsia or
eclampsia (as defined by the trial authors). Secondary maternal outcomes
included maternal death, placental abruption, HELLP syndrome (Hemolysis,
elevated liver enzymes and low platelets) syndrome, renal insufficiency,
pulmonary oedema or thrombocytopaenia (all as defined by the trial
authors) and mode of birth. Secondary infant outcomes included perinatal
death, stillbirth (intrauterine death of a fetus before birth), infant death
(death of a live born infant within 28 days of birth), preterm birth before 37
and 34 weeks’ gestation, intrauterine growth restriction (IUGR), neonatal
intensive care unit admission and complications related to prematurity,
including respiratory distress syndrome, chronic lung disease, cerebro-
vascular hemorrhage, periventricular leucomalacia, retinopathy of pre-
maturity and necrotising enterocolitis (all as defined by the trial authors).
Evaluation of studies for inclusion
Studies under consideration were evaluated independently for appropri-
ateness for inclusion and methodological quality without consideration of
their results by all authors, according to the QUORUM guidelines for
systematic reviews of randomised trials.14 There was no blinding of
authorship.
Assessment of studies
The assessment of quality considered the generation of the randomisation
sequence (with a random number table or computer generated sequence
judged as adequate), concealment of allocation (with central telephone
randomization or sealed opaque envelopes judged as adequate), blinding
(including participants, caregivers and outcome assessors) and complete-
ness of follow-up (with o20% loss to follow-up for primary outcomes
judged as adequate). This was conducted by two authors independently
(RG and TDW).
Data synthesis
We carried out statistical analysis using Review Manager.15 We used a
fixed-effect model for combining data where trials were judged to be
sufficiently similar. Heterogeneity was considered if I2 statistic was 450%,
and the analysis repeated using a random-effects model. Primary analyses
utilised intention-to-treat principles, with calculation of risk ratios (RR) for
dichotomous data and weighted mean difference (WMD) for continuous
data, both with a 95% confidence interval (95% CI).
RESULTS
Our search strategy identified fourteen reports all of which were
reviewed. Eight published randomised controlled trials were
identified, seven of which were included in the analysis.
Description of included studies
Seven randomised controlled trials were included (Table 1), in
which women received L-arginine supplements, involving a
combined sample size of 884 women who were considered to
be at risk of pre-eclampsia or had established hypertensive
disease (chronic hypertension, gestational hypertension or pre-
eclampsia).16–22 Six trials included women with established
disease, including pre-eclampsia,17–19 gestational hypertension16,22
or chronic hypertension,21 and one included women considered to
be at risk of pre-eclampsia.20
& 2014 Macmillan Publishers Limited
L-arginine in the prevention and treatment of pre-eclampsia
T Dorniak-Wall et al
231
L-arginine was given as an oral supplement in four of the
18–21
trials in doses ranging from 3 to 14 g daily. Two trials used a
combination of intravenous and oral therapy, and one trial used
intravenous therapy only. In general there was limited reporting of
important maternal and infant clinical outcomes, with some
studies only reporting changes in maternal blood pressure.
Methodological quality of included studies
The overall quality of the studies was considered fair. The
generation of the randomisation sequence using a random-
number table or computer-generated sequence was specifically
stated for five of the trials but was unclear in two.18,19 Allocation
concealment was adequate in three of the trials.18,20,22 All of the
studies were described as double-blinded. Overall the studies had
a low risk of bias, with the highest risk of bias being attributed to
incomplete outcome data (Figures 1 and 2). Five of the included
trials described adequately the flow of participants.
Excluded studies
Winer et al.23 was excluded, as the aim of the study was to treat
intrauterine growth restriction, and women were specifically
excluded if there was evidence of pre-eclampsia.
L-arginine for the prevention of pre-eclampsia in women at risk
One study was identified and included.20 This study20 compared
L-arginine and antioxidant vitamins with placebo and antioxidants
alone. L-arginine was associated with a reduction in pre-eclampsia
(1 study, 450 women, RR 0.34, 95% CI: 0.21–0.55), when compared
with placebo (Figure 3). L-arginine supplementation was asso-
ciated with a reduction in the risk of preterm birth before 37
weeks gestation. (1 study, 672 women, RR: 0.48 and 95% CI: 0.28 to
0.81) (Figure 4). There were no statistically significant differences
in other outcomes.
L-arginine for the treatment of established hypertensive disease
Six trials compared L-arginine with placebo.16–19,21,22 For some
studies, there was limited or no reporting of pre-specified clinical
maternal or infant outcomes.17–19,22
For women with established disease at trial entry, L-arginine was
associated with a reduction in the incidence of pre-eclampsia (one
study, 46 women, RR: 0.21; 95% CI: 0.05–0.98), although women
who were enrolled in the trial all had a diagnosis of gestational
hypertension) (Figure 5). L-arginine was not associated with a
reduction in Cesarean section for women (Figure 6), nor a
difference in perinatal death, NICU admission or preterm birth
(o34 or 37 weeks) for their infants.
There were no data able to be included and therefore no
estimable effect for any of the remaining secondary maternal or
infant outcomes.
DISCUSSION
The results of our systematic review indicate that L-arginine
supplementation in pregnant women with either established
hypertension or who are considered at risk of pre-eclampsia is
associated with a significant reduction in the risk of pre-eclampsia,
although data are limited with an available sample size for this
outcome of only 884. Although L-arginine may represent a
promising therapy, there is currently limited information available
to assess its impact on other maternal and infant health outcomes.
The precise mechanism whereby L-arginine may modify risk of
pre-eclampsia remains uncertain. However, there is observational
evidence from human studies to support a role for L-arginine in
the treatment of cardiovascular disease. The production of nitric
Journal of Human Hypertension (2014) 230 – 235
 L-arginine in the prevention and treatment of pre-eclampsia
T Dorniak-Wall et al
232
Table 1. Summary of studies included

Author Setting Population Interventions Outcomes

Hladunewich, USA Inclusion: pregnant women with hypertension and L-arginine 3.5 g orally every 6 h Pre-eclampsia
2006 proteinuria or 10 g IV every 8 h if
Exclusion: underlying renal disease. medications could not be taken
Sample size: 45 orally. versus placebo.
Rytlewski, 2006 Poland Inclusion: pregnant women with pre-eclampsia 3 g oral L-arginine or placebo for Pre-eclampsia and
Exclusion: smokers, underlying chronic illnesses 3 weeks as a supplement to neonatal
Sample size: 83 standard therapy. outcome.
Staff, 2004 Not Inclusion: pregnant women with Pre-eclampsia and 4 g of L-arginine given 3x daily. Alteration in
mentioned proteinuria, gestational age at study start from 28 þ 0 diastolic BP
to 36 þ 0 weeks,
Exclusion criteria: none mentioned.
Sample size: 30
Facchinetti, Italy Inclusion: gestational age between 24–36 weeks, L-arginine intravenously for 5 Blood pressure
2007 onset of hypertension after the 20th week of days (20 g per 500 ml) followed and latency.
pregnancy by 4 g per day oral l-arginine for
Exclusion criteria: hypertension before 20 week of 2 weeks
pregnancy, severe hypertension or pre-eclampsia, versus placebo saline infusion
antiphospholipid syndrome, heart, kidney or liver and oral placebo.
disorders or diabetes.
Sample size: 74
Neri, 2006 Not Inclusion criteria: maternal age range 16–45 L-arginineintravenously for Changes in blood
mentioned years, gestational age from 24 to 36 weeks, diagnosis 5 days (20 g per 500 ml) pressure after
of gestational hypertension without versus placebo infusion treatment
proteinuria in patients being normotensive until the
20th week of pregnancy.
Exclusion criteria: hypertension,
proteinuria, severe pre-eclampsia, chronic
hypertension, renal or cardiac disease, known fetal
malformations, chromosome abnormalities and
multiple pregnancies.
Sample size:123
Neri, 2010 Italy Inclusion criteria: Singleton pregnancy, mild chronic Oral supplementation of BP changes after
hypertension Gestational ageo16 weeks. L-arginineof 4 g per day versus 10–12 weeks
Exclusion criteria: known cardiac or renal maternal placebo. treatment.
diseases,fetal malformations, chromosomal
abnormalities, maternal medication use (exception of
iron and folate).
Sample size: 79.
Vadillo-Ortego, Mexico Inclusion criteria: Pregnant women at increased risk of 2 L-arginine þ antioxidant Development of
2011 pre-eclampsia supplement bars a day versus pre-eclampsia or
Exclusion criteria: multiple gestation, known major antioxidant alone bars. eclampsia.
fetal anomalies, significant pre-existing disease
relatives, and pre-existing maternal disease needing
drug treatment.
Sample size: 450.

Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Figure 1. Risk of bias graph.

oxide is regulated by methyl derivatives of L-arginine, in particular
ADMA, which is an active inhibitor of nitric oxide synthase.8 ADMA
has been considered a marker of endothelial dysfunction and a
prognostic indicator of future cardiovascular disease risk,24 with
increased concentrations demonstrated in conditions associated
with endothelial dysfunction and atherosclerosis.25 Further,
supplementation with L-arginine in these conditions has been
associated with increased basal nitric oxide production.26
There is little information reported in the literature relating
to safety of L-arginine, and supplementation appears to be

Journal of Human Hypertension (2014) 230 – 235 & 2014 Macmillan Publishers Limited
 L-arginine in the prevention and treatment of pre-eclampsia
T Dorniak-Wall et al
233
associated with few side effects. Oral and intravenous adminis- tolerated, with no significant adverse effects documented, even in
tration of L-arginine involving healthy volunteers, patients with doses as high as 20 g daily.27,28 Vadillo–Ortega report that
cardiovascular disease and in pregnant women appears to be well L-arginine administration was associated with an increase in
pregnancy associated dyspepsia, nausea, dizziness, headache and
palpitations, when compared with placebo, although no partici-

Blinding of participants and personnel (performance bias)

pants withdrew from the study due to side effects.20
Evidence specifically relating to the mechanistic actions of
L-arginine in pregnancy is more limited. Animal studies involving

Blinding of outcome assessment (detection bias)

rats and mice have induced features of pre-eclampsia, including
Random sequence generation (selection bias)
hypertension, proteinuria and fetal growth restriction following
inhibition of nitric oxide synthase activity.29 NG-nitro-L-arginine
methyl ester (L-NAME) is an important inhibitor of nitric oxide

Incomplete outcome data (attrition bias)

Allocation concealment (selection bias)

synthase, and, in pregnant rats, infusion with this induces

Selective reporting (reporting bias)

hypertension and other pre-eclampsia-like features. Importantly,
these features appear to be reversible following treatment with L-
arginine,29 with the L-NAME-treated animals who were then
treated with L-arginine having less urinary protein excretion,
significant blood pressure reduction as well as restored abnormal
glomeruli lesions; all thought to be due to L-arginine acting
through the nitric oxide synthase pathway.
In human studies involving pregnant women, Davidge and
colleagues evaluated plasma and urine nitrite and nitrate
concentrations in women with pre-eclampsia, indicating a
reduction in the production of nitric oxide when compared with
nulliparous women without pre-eclampsia.30 Several studies have
identified an increase in the concentrations of the nitric oxide
Facchinetti 2007 + + + + + ? synthase inhibitor, ADMA, among pregnant women with pre-
eclampsia,31,32 although this has not been universally reported.33
However, Savvidou and colleagues correlated increasing ADMA
Hladunewich 2006 + + + + + +
concentrations with abnormal Doppler flow in the maternal
uterine arteries at 23–25 weeks’ gestation among women who
Neri 2006 + – + ? + + subsequently develop pre-eclampsia,34 although this association
was not evident when measures were obtained in the first
Neri 2010 + + + + + ? trimester of pregnancy.35
The development of effective strategies for the prevention of
pre-eclampsia has proven difficult to date. There is currently
Rytlewski 2006 + ? + + – ? limited information available about the benefits and harms of
L-arginine supplementation in the prevention of pre-eclampsia.
Staff 2004 ? ? + ? ? ? Evaluation of any protective effects of L-arginine in the prevention
of pre-eclampsia is urgently required, through the conduct of high
Vadillo-Ortega 2011 + + + – – ?
quality randomised trials with adequate power to detect
important differences in clinically relevant health outcomes.
Figure 2. Risk of bias summary diagram.

L-arginine Placebo Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Vadillo-Ortega 2011 29 228 67 222 100.0% 0.34 [0.21, 0.55]

Total (95% Cl) 228 222 100.0% 0.34 [0.21, 0.55]

Total events 29 67
Heterogeneity: Not applicable
0.01 0.1 1 10 100
Test for overall effect: Z = 4.41 (P < 0.0001)
Favours L-arginine Favours placebo

Figure 3. Forest plot of comparison: L-arginine versus placebo for women at risk of pre-eclampsia, outcome: Pre-eclampsia or eclampsia.

L-arginine Placebo Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Vadillo-Ortega 2011 24 228 44 222 100.0% 0.48 [0.28, 0.81]
Total (95% CI) 228 222 100.0% 0.48 [0.28, 0.81]
Total events 24 44
Heterogeneity: Not applicable
Test for overall effect: Z = 2.71 (P = 0.007) 0.01 0.1 1 10 100
Favours L-arginine Favours placebo

Figure 4. Forest plot of comparison: L-arginine versus placebo for women at risk of pre-eclampsia, outcome: preterm birth (o37 weeks).

& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 230 – 235
 L-arginine in the prevention and treatment of pre-eclampsia
T Dorniak-Wall et al
234
L-arginine Placebo Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Facchinetti 2007 3 27 7 19 100.0% 0.21 [0.05, 0.98]

Total (95% CI) 27 19 100.0% 0.21 [0.05, 0.98]

Total events 3 7
Heterogeneity: Not applicable
Test for overall effect: Z=1.99 (P = 0.05) 0.01 0.1 1 10 100
Favours L-arginine Favours placebo

Figure 5. Forest plot of comparison: L-arginine versus placebo for women with established disease, outcome: Pre-eclampsia.

L-arginine Placebo Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H Random, 95% CI
Faccbinetti 2007 23 39 17 35 62.1% 1.52 [0.61, 3.82]
Staff 2004 9 15 12 15 37.9% 0.38 [0.07, 1.92]
Total (95% CI) 54 50 100.0% 0.89 [0.24, 3.39]
Total events 32 29
Heterogeneity: Tau2 = 0.52; Chi2 = 2.15, df = 1 (P = 0.14); I2 = 53%
0.01 0.1 1 10 100
Test for overall effect Z = 0.16 (P = 0.87)
Favours L-arginine Favours placebo

Figure 6. Forest plot of comparison: L-arginine versus placebo for women with established disease, outcome: cesarean section.

What is known about the topic
 Hypertensive disorders of pregnancy contribute significantly to both
maternal and perinatal mortality and morbidity on a global scale.
 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.
 L-arginine (an amino acid which synthesises nitric oxide) may
represent a promising therapy, there is currently limited information
available to assess its impact on other maternal and infant health
outcomes.
What this study adds
 L-arginine supplementation in pregnant women with either estab-
lished hypertension or who are considered at risk of pre-eclampsia is
associated with a significant reduction in the risk of pre-eclampsia.
 Evaluation of any protective effects of L-arginine in the prevention of
pre-eclampsia is urgently required, through the conduct of high
quality randomised trials with adequate power to detect important
differences in clinically relevant health outcomes.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
1 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365(9461): 785–799.
2 Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;
33(3): 130–137.
3 López-Jaramillo P, Arenas WD, Garcı́a 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.
4 Murad F. Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic
GMP signal transduction system. Adv Pharmacol 1994; 26: 19–33.
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.
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.
7 Riddell DR, Owen JS. Nitric oxide and platelet aggregation. Vitam Horm 1999; 57:
25–48.
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 patho-
physiology of preeclampsia. Gynecol Obstet Invest 2010; 69(1): 1–13.
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.
10 Morris NH, Eaton BM, Dekker G. Nitric oxide, the endothelium, pregnancy and pre-
eclampsia. BJOG 1996; 103(1): 4–15.
11 McCord N, Ayuk P, McMahon M, Boyd RC, Sargent I, Redman C. System y þ
arginine transport and NO production in peripheral blood mononuclear cells in
pregnancy and preeclampsia. Hypertension 2006; 47(1): 109–115.
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.
13 Lowe DT. Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric
Oxide 2000; 4(4): 441–458.
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 state-
ment. Quality of Reporting of Meta-analyses. Lancet 1999; 354(9193): 1896–1900.
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 supple-
mentation in patients with gestational hypertension: a pilot study. Hypertens
Pregnancy 2007; 26(1): 121–130.
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.
18 Rytlewski K, Olszanecki R, Korbut R, Zdebski Z. Effects of prolonged oral supple-
mentation with l-arginine on blood pressure and nitric oxide synthesis in pre-
eclampsia. Eur J Clin Invest 2005; 35(1): 32–37.
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.
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.
21 Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F. L-arginine supple-
mentation in women with chronic hypertension: impact on blood pressure and
maternal and neonatal complications. J Matern Fetal Neonatal Med 2010; 23(12):
1456–1460.
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.
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.
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.
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.

Journal of Human Hypertension (2014) 230 – 235 & 2014 Macmillan Publishers Limited

26 Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B et al. Dietary
L-arginine supplementation normalizes platelet aggregation in hypercholester-
olemic humans. J Am Coll Cardiol 1997; 29(3): 479–485.
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.
28 Facchinetti F, Neri I, Genazzani AR. L-arginine infusion reduces preterm uterine
contractions. J Perinat Med 1996; 24(3): 283–285.
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.
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.
31 Holden DP, Fickling SA, Whitley GS, Nussey SS. Plasma concentrations
of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase,
& 2014 Macmillan Publishers Limited
L-arginine in the prevention and treatment of pre-eclampsia
T Dorniak-Wall et al
235
in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998; 178(3):
551–556.
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.
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.
34 Savvidou MD, Hingorani AD, Tsikas D, Frölich JC, Vallance P, Nicolaides KH.
Endothelial dysfunction and raised plasma concentrations of asymmetric dime-
thylarginine in pregnant women who subsequently develop pre-eclampsia.
Lancet 2003; 361(9368): 1511–1517.
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.
Journal of Human Hypertension (2014) 230 – 235