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.
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 monophosphate (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 impaired nitric oxide synthesis and bioavailability have been 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
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, 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).
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, cerebrovascular hemorrhage, periventricular leucomalacia, retinopathy of prematurity and necrotising enterocolitis (all as defined by the trial authors).
Evaluation of studies for inclusion
Studies under consideration were evaluated independently for appropriateness 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 completeness of follow-up (with <20% loss to follow-up for primary outcomes judged as adequate). This was conducted by two authors independently (RG and TDW).
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 >50%, 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).
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, 17, 18, 19, 20, 21, 22 Six trials included women with established disease, including pre-eclampsia,17, 18, 19 gestational hypertension16, 22 or chronic hypertension,21 and one included women considered to be at risk of pre-eclampsia.20
L-arginine was given as an oral supplement in four of the trials18, 19, 20, 21 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.
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 associated 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
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 (<34 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.
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 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 associated with few side effects. Oral and intravenous administration of L-arginine involving healthy volunteers, patients with cardiovascular disease and in pregnant women appears to be well tolerated, with no significant adverse effects documented, even in doses as high as 20 g daily.27, 28 Vadillo–Ortega report that L-arginine administration was associated with an increase in pregnancy associated dyspepsia, nausea, dizziness, headache and palpitations, when compared with placebo, although no participants 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 rats and mice have induced features of pre-eclampsia, including 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 synthase, and, in pregnant rats, infusion with this induces 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 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 concentrations with abnormal Doppler flow in the maternal uterine arteries at 23–25 weeks’ gestation among women who subsequently develop pre-eclampsia,34 although this association was not evident when measures were obtained in the first trimester of pregnancy.35
The development of effective strategies for the prevention of pre-eclampsia has proven difficult to date. There is currently limited information available about the benefits and harms of L-arginine supplementation in the prevention 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.
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The authors declare no conflict of interest.
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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
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