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Abstract: Estimation of the influence of oral supplementation with low dose of L-arginine on biophysical profile, foeto-placental circulation and neonatal outcome in preeclampsia. Randomized, placebo-controlled, double-blind, clinical trial. Oral therapy with 3 g of L-arginine daily or placebo as a supplement to standard therapy. Eighty-three preeclamptic women, randomly assigned to the L-arginine (n=42) or placebo (n=41) groups; [n=30 (L-arginine) and n=31 (placebo) ended the study, respectively]. Foetal gain chances due to ultrasound biometry, biophysical profile, Doppler velocimetry of pulsatility indices of umbilical and middle cerebral arteries, cerebro-placental ratio, as well as differences in duration of pregnancy and clinical data of newborn. L-arginine treatment transitory accelerated foetal gain and improved biophysical profile. Starting from 3rd week of therapy, the umbilical artery pulsatility indices values were significantly lower in L-arginine than in placebo group. Moreover, treatment with L-arginine caused significant increase of middle cerebral artery pulsatility indices and cerbro-placental ratio values. Latency was longer in L-arginine group. Neonates delivered in the L-arginine group revealed higher Apgar score. Supplementary treatment with oral L-arginine seems to be promising in improving foetal well-being and neonatal outcome as well as in prolonging pregnancy complicated with preeclampsia. However, these benefits require confirmation in more-powered, larger studies.
Preeclampsia, described clinically as occurrence of hypertension and proteinuria after 20 weeks' of gestation in previously normotensive women, complicates approximately 6–8% of all gestations and is a leading cause of foetal growth restriction, infant mortality, premature birth and maternal complications (Duley 2003).
Despite identification of some predisposing factors, the aetiology of this multisystem disorder remains largely unclear (Roberts & Lain 2002; Davison et al. 2004). The classical concept is that primary pathophysiology of preeclampsia is placental and it begins with abnormal trophoblastic implantation and subsequent reduction in placental perfusion, which may result in foetal hypoxemia and intrauterine growth restriction. However, according to current thinking, development of preeclampsia is inherently related to systemic maternal endothelial cell injury and subsequent decrease of secretion of endothelium-dependent vasodilators, which promotes vasospasm and activates coagulation cascade (Davidge 1998; Dekker & van Geijn 1996). Nitric oxide (NO), a potent endothelial-derived vasodilator synthesized by constitutive nitric oxide synthase (NOS-3) from L-arginine was shown to be responsible for physiological vascular adaptation to gestational stimulation of renin-aldosterone axis and increase of blood volume (Begum et al. 1996; Lyall & Greer 1996). Decreased synthesis and/or bioavailability of NO, has been suggested to play the role in preeclampsia (Buhimschi et al. 1998; Lowe 2000). For example, pharmacological inhibition of NOS in pregnant rats precipitates preeclampsia-like symptoms, that can be reversed by infusion of L-arginine (Yallampalli & Garfield 1993; Helmbrecht et al. 1996). Additionally, in patients with preeclampsia, plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of NO synthesis were found to be elevated (Fickling et al. 1993; Savvidou et al. 2003). There were several attempts to treat NO deficiency with use of exogenous NO i.e. application of NO donors (Chattopadhyay 1997; Lees et al. 1998; Nakatsuka et al. 2002). Yet it should be noted, that prolonged use of NO donors may impair by itself endothelial function (Warnholtz et al. 2002). In this regard, stimulation of synthesis of endogenous NO, by use of substrate for NOS, L-arginine seems safer. Several authors have demonstrated such a possibility in patients suffering from preeclampsia, by administration of large amounts of L-arginine over a short period of time (Facchinetti et al. 1999), although others denied any effects (Staff et al. 2004). Apart from these acute effects, long-term oral administration of L-arginine has been associated with a significant improvement in NO-dependent vasodilatation in animal models of endothelial dysfunction and in patients with compromised endothelium-dependent vasodilatation (Alexander et al. 2004; Palloshi et al. 2004). Recently, we have shown that in preeclamptic patients prolonged dietary treatment with low dose of L-arginine significantly decreased maternal blood pressure and increased bioavailability of endothelial NO (Rytlewski et al. 2005).
Thus, the aim of present study was to determine whether the treatment with low-dose oral L-arginine might affect the condition of the foetus, as well as the neonatal outcome, in patients with pregnancies complicated by preeclampsia, in randomized, double-blind, placebo-controlled, clinical trial.
Materials and Methods
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- Materials and Methods
Patients. The investigation was carried out in the High-Risk Pregnancy Unit at Department of Gynaecology and Obstetrics of the Jagiellonian University Medical College in Krakow, Poland, over a period of 4 years (2000–2003). All patients with preeclampsia, according to strict ACOG criteria (Technical Bulletin no. 225, July 1996.): onset of hypertension during late gestation with systolic (>140) or diastolic (>90) mmHg pressure on at least two occasions and urinary protein excretion greater than 300 mg/24 hr after 20th week of pregnancy, were candidates for inclusion in the study. Pregnancies were singletons. Furthermore, these patients were normotensive during the first trimester and had no history of chronic hypertension. They were not admitted to the study if any of the following criteria were present: smoking, chronic illnesses such as hypertension, coronary heart disease, renal disease, diabetes mellitus, prophylactic treatments such as low dose aspirin, severe foetal malformations detected by ultrasound examination. Other exclusion criterion, after randomization was urgent delivery before the beginning of L-arginine supplementation.
Study protocol. The protocol for the use of L-arginine in preeclampsia was approved by the Ethics Committee of the Jagiellonian University (KE/99/02/L/272.) and all patients gave written consent information.
Eighty-three patients were assigned to groups with use of random number table. Group assignments were blinded to the patients, doctors and nursing personnel. On the day of admission all patients received combined therapy: intravenous infusion of magnesium sulphate in total dose of 8–10 g (4 g loading dose, followed by a continuous infusion of 2 g per hr) and the same hypotensive treatment containing dihydralazine (4×25 mg) and methyldopa (250 mg). Then, the patients received daily: magnesium sulphate given at a rate of approximately 2 g per hour to total daily dose of 6 g. During the course of the study the doses of hypotensive drugs were decreased or increased whenever blood pressure was lower than 130/90 mm Hg or was higher than 150/100 mm Hg, respectively. Steroid treatment (dexamethasone 4 doses a 6 mg for every 12 hr in total dose of 24 mg/48 hr) to accelerate lung maturation was used in all patients between 26th and 34th week of pregnancy.
Treatment with L-arginine [Curtis Healthcare, Poznan, Poland, 3 g (3×2 tablets at 0.5) per day, (n=42)] or placebo [3×2 tablets at 0.5 g, containing lactose, magnesium stearate and aerosil (microcrystalline silica), (n=41)] began 1–2 weeks after admission to hospital. The tablets of L-arginine and placebo were identical; the placebo was identical to the vehicle used in L-arginine tablets. All patients were supplemented with L-arginine until delivery, and monitored according to standard procedure. The decision about the time and the mode of delivery in each case depended on the conditions of the mother and foetus as well as on the efficacy of antihypertensive therapy, and was made unanimously by independent consultants and clinical staff. In every case, the assignment of patient was blinded to the persons responsible for decisions.
Sonographic analysis of foetal growth. Foetal body weight was assessed average, every 2 weeks according to Hadlock et al. (1990) with use of Acuson 128 XP/10 equipped with convex 3.5 MHz ultrasound transducer. Measurements were done only by two physicians, most experienced in ultrasound examinations. Increase of the estimated foetal body weight (EFBWinc) was calculated according to formula:
Foetal biophysical profile. Foetal biophysical profile was assessed according to Manning et al. (1980) and the following parameters were estimated before treatment as well as consecutively in 10–20 day intervals up to delivery: non-stress test (NST), foetal movements (FM), foetal tone (FT), breathing movements (BM), amniotic fluid index (AFI).
Doppler evaluation of umbilical artery and middle cerebral artery blood flow. Accurate Doppler measurement of blood flow in umbilical artery and middle cerebral artery, were done in all patients according to Takey & Campbell (2000), using Acuson 128 XP/10 apparatus equipped with convex 3.5 MHz ultrasound transducer, using intermittent exposure and the lowest power setting. Color Doppler imaging was used to optimize the insonation by pulsed Doppler examination. All angles of insonation were as close to 0 degrees as possible, and always less than 30 degrees. The output power was kept at a value of 50 mW/cm2; the high-pass filter was set at minimum, and 3–5 mm sample volumes were used for pulsed Doppler recording. Doppler studies were performed where mothers were in a semi-recumbent position, after a few minutes rest, in the period of foetal rest without breathing movements. Measurements were repeated for at least three separate cardiac cycles. In the course of obtaining of waveform from the mid portion (free-floating loop) of the umbilical cord, during foetal quiescence, the Doppler gate were placed within the walls of selected vessel, to avoid aliasing and the inclusion of both arteries in the same sample gate.
For measurements of the middle cerebral artery an axial view of the foetal head was obtained at the level of cerebral peduncles. The color Doppler was used to visualize the circle of Willis, and the Doppler sample volume was placed within approximately 1 cm of the origin of the middle cerebral artery which was identified as a major branch running anterolateral from the circle of Willis to ward the lateral edge of the orbit. Exposure of foetal brain to Doppler ultrasonography was kept to a minimum (1–5 min.). The first measurement was done prior to L-arginine or placebo administration, the next was done 2 weeks after the beginning of therapy. Then the measurements were consecutively repeated every 1 week until delivery. Each and every stored time point was an average of five measurements of blood flow waveforms, and for each time point pulsatility indices (PI) in umbilical (UA) as well as in middle cerebral artery (MCA) were estimated. Additionally, cerebro-placental ratio (CPR) was calculated (Gudmundsson et al. 1990; Arduini et al. 1992; Bahamo-Singh et al. 1999) according to the formula:
In every case, the assignment of patient was blinded to the person performing the measurements.
Postnatal clinical assessment. After delivery, independent and not involved in the trial neonatologist, assessed the following parameters: neonatal body weight, neonatal length, Apgar score after 1 min. and Apgar score after 5 min. Newborn intrauterine griowth restriction was defined as a body weight below 10th percentile of body weight, estimated with use of percentile nomograms for European population, corrected for gender and duration of gestation (Patterson 1991).
Statistics. Continuous variables, presented as means±standard deviation (S.D.), as well as confidence intervals (95%, CI), were tested for normality and frequency distribution and were compared using Student's t-test, non-parametric Mann-Whitney U-test, as well as ANOVA for multiple covariates with Tukey's post hoc test, whenever appropriate. Categorical variables were compared using the χ2 test. All statistical analyses were performed with STATISTICA v. 5.0 (StatSoft, Krakow, Poland).The power of tests were calculated using Power Analysis program (a part of Statistica v. 5.0). P<0.05 was considered statistically significant.
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Although initially 83 patients met the criteria for enrolment, only 61 women completed the study. Due to refusal, instability of maternal and/or foetal conditions and necessity of termination of pregnancy, 12 and 10 patients dropped out during the study from L-arginine and placebo groups, respectively. There were no observed or reported adverse effects attributable to the use of L-arginine.
There were no initial differences between the groups with regard to mean maternal age (29.3±6.7 versus 29.2±5.9 years) and body weight (74.9±12.0 versus 73.2±11.9 kg), mean gestational age on admission (29.3±3.4 versus 29.1± 3.4 weeks), creatinine clearance (136±46 versus 142±61 ml/min.) and previous history of pregnancies and labors between groups (table 1). There were no significant differences between groups at the beginning of the study in systolic, diastolic and mean arterial blood pressure, urine protein excretion (2.56±2.5 versus 2.89±3.0) (table 1). L-Arginine supplementation did not change urine protein excretion (2.9±2.3 versus 3.6±2.5), after 3 weeks of treatment.
Table 1. Comparison of selected inclusion data of patients enrolled in the analysis, outcomes of pregnancies and postnatal assessment of children born in L-arginine and placebo groups Confidence intervals (95%, CI) are shown in parentheses.
|Variables||L-Arginine (n=30)||Placebo (n=31)||P=|
|Maternal age (years±S.D.)||29.3±6.7 (26.9–31.7) ||29.2±5.9 (27.1–31.3) ||0.98 |
|Maternal weight (kg±S.D.)||74.9±12.0 (70.6–79.2) ||73.2±11.9 (69.0–85.1) ||0.5807 |
|Mean gestational age on admission (weeks±S.D.)||29.3±3.42 (27.1–30.5) ||29.1±3.41 (27.9–30.3) ||0.8459 |
|Creatinine clearance (ml/min.±S.D.)|| 136±46 (119.5–152.5)||142±61 (120.5–163.5) ||0.6668 |
|Urine protein excretion (g/24 hr±S.D.)||2.56±2.5 (1.66–3.46) ||2.89±3.0 (1.83–3.95) ||0.643 |
|SBP (mmHg±S.D.)|| 143.9±5.7 (141.87–145.93)||145.5±4.8 (143.8–147.2) ||0.2399 |
|DBP (mmHg±S.D.)||87.8±1.7 (87.2–88.4) ||87.7±0.9 (87.28–88.02) ||0.774 |
|MAP (mmHg±S.D.)|| 107.5±3.1 (106.64–107.36)||106.0±4.5 (105.54–106.46)||0.3591 Outcome of pregnancies and postnatal assessment Male/female [n(%)]|
| Neonatal death*[n(%)]||0 (0.00%)||2 (6.45%) ||0.4918 |
| Neonatal body weight at birth (gram±S.D.)||2358±900.9 (2021.6–2694.4)||2066±916.7 (1729.8–2402.3) ||0.2144 |
| IUGR [n(%)]||7 (23.3%)||14 (45.2%)||0.039* |
| Neonatal length at birth (cm±S.D.)|| 47.7±6.2 (45.48–49.92)||45.9±6.6 (43.58–48.22) ||0.2687 |
| Mean duration of pregnancy (weeks±S.D.)|| 36.0±2.9 (34.97–37.03)||34.8±3.5 (33.6–36.0) ||0.1442 |
| Latency (days) (from entry into study until time at delivery)||36.4±18.5 (29.6–43.2) ||25.2±15.6 (19.6–30.8) ||0.00537*|
Both in the placebo and in the L-arginine group there was a prevalence of female neonates; no cases of death in utero in the L-arginine or the placebo group were observed. Importantly, there were 2 cases of neonatal death due to prematurity and intracranial haemorrhages among children born by the placebo patients group and no cases of neonatal death in L-arginine group (table 1). There were higher rate of intrauterine growth restriction in placebo than in L-arginine group [14/31 (45.2%) versus 7/30 (23.3%), respectively, P=0.039]. Importantly, L-arginine significantly increased latency (time from entry into the study until delivery) (table 1).
During the first two weeks of treatment, the increase of estimated foetal body weight was significantly greater in L-arginine than in placebo group (281.4±95.6 versus 132.6± 100.6 g/week, P<0.05) (table 2). Interestingly, this effect was transient as during next two weeks of treatment there were no significant differences between the rates of estimated foetal body weight increase in L-arginine and placebo groups (table 2).
Table 2. Increase of estimated foetal body weight (EFBW, g/week) and values of Biophysical Profile up to fourth week of treatment with L-arginine (3 g per day) and placebo. Data are presented in means±S.D. Confidence intervals (95%, CI) are shown in parentheses as well as a percent value of achieved points in Biophysical Profile, dependent on duration of treatment.
| ||L-Arginine (n=30)||Placebo (n=31)||P=|
|Increase of EFBW (g per week)|
| During first two weeks of treatment||281.4±95.6 (247.2–315.6)||132.6±100.6 (97.2–168.0)||0.0238*|
| During second two weeks of treatment||142.4±86.5 (111.4–173.0)|| 209.9±65.7 (178.6–240.3)||0.4281 |
|Biophysical profile values|
| Before treatment|| 9.3±0.9 (8.98–9.62)|| 9.6±0.8 (9.32–9.88)||0.1737 |
| After first two weeks of treatment|| 9.5±0.9 (9.18–9.82)|| 8.8±1.3 (8.34–9.26)||0.0178*|
| After four weeks of treatment|| 9.5±0.9 (9.08–9.92)|| 8.1±1.7 (7.5–8.7)||0.0002*|
| Before treatment||8–10||30/30 (100%) ||31/31 (100%)||1 |
| After first two weeks of treatment||8–10||30/30 (100%) ||28/31 (89.3%)||0.2377 |
| ||6||0 (0%) || 3/31 (10.7%)||0.2377 |
| after four weeks of treatment||8–10||30/30 (100%) ||23/31 (74%) ||0.0047*|
| ||6–4||0 ||(6+2) 8/31 (26%)||0.0047*|
There were no significant differences between L-arginine and placebo groups in mean values of biophysical profile before therapy, but up to first two weeks of the treatment statistically important difference between groups has occurred (table 2). Yet it should be noted that values of biophysical profile significantly decreased during 4 weeks of treatment with placebo (9.6±0.8 versus 8.1±1.7; P<0.01 in paired t-test) (table 2), as well as the percentage of biophysical profile values of 8–10 (good foetal condition) are statistical higher in L-arginine group (P=0.0047).
There were no initial differences between L-arginine and placebo groups in pulsatility indexes in umbilical artery and middle cerebral artery (table 3). Importantly, L-arginine prevented increase of pulsatility indexes in umbilical artery observed after 3 and after 4 weeks of treatment in placebo group (table 3). Moreover, L-arginine treatment caused increase of pulsatility indexes in middle cerebral artery, which reached statistical significance after 2nd and after 4th week of treatment (table 3). There were no initial differences between L-arginine and placebo groups in cerebro-placental ratio values (table 3). In placebo patients, the cerebroplacental ratio values significantly decreased over time of 4 weeks of treatment. Importantly, L-arginine treatment significantly increased these values, as compared to placebo (table 3).
Table 3. Values of pulsatility indexes (PI) in umbilical artery and middle cerebral artery as well as values of cerebro-placental ratio before and up to fourth week of treatment with L-arginine (3 g per day) and placebo. Data are presented in means±S.D. Confidence intervals (95%, CI) are shown in parentheses.
| ||L-Arginine (n=30)||Placebo (n=31)||P=|
|PI in umbilical artery |
| Before treatment||1.16±0.32 (1.06–1.26)||1.29±0.30 (1.19–1.39)||0.3513 |
| After two weeks of treatment||1.07±0.34 (0.97–1.17)||1.22±0.31 (1.12–1.32)||0.3951 |
| After three weeks of treatment||1.05±0.44 (0.89–1.21)||2.21±0.36 (0.91–3.51)||0.00003*|
| After four weeks of treatment||1.06±0.28 (0.96–1.16)||1.56±0.18 (1.5–1.62) ||0.00003*|
|PI in middle cerebral artery |
| Before treatment||1.65±0.46 (1.49–1.81)||1.76±0.40 (1.62–1.9) ||0.5677 |
| After two weeks of treatment||1.99±0.39 (1.85–2.13)||1.55±0.28 (1.45–1.65)||0.00003*|
| After three weeks of treatment||1.78±0.41 (1.63–1.93)||1.61±0.47 (1.44–1.78)||0.9477 |
| After four weeks of treatment||1.67±0.18 (1.52–1.82)||1.43±0.19 (1.36–1.5) ||0.0007* |
|Cerebro-placental ratio (CPR) |
| Before treatment||1.50±0.48 (1.33–1.67)||1.41±0.54 (1.22–1.6) ||0.911 |
| After two weeks of treatment||1.96±0.29 (1.86–2.06)||1.33±0.18 (1.14–1.39)||0.00003*|
| After three weeks of treatment||2.06±0.36 (1.93–2.19)||1.21±0.44 (1.06–1.36)||0.0002* |
| After four weeks of treatment||1.71±0.19 (1.64–1.78)||1.09±0.18 (1.03–1.15)||0.00003*|
Mean values of Apgar score recorded after 1st and after 5th min. after delivery were significantly higher in the L-arginine group as compared to placebo [8.97±1.1 versus 7.74±1.8 and 9.6±0.7 versus 8.8±1.7, respectively, χ2 test, P<0.01) (table 4). There was higher incidence of low Apgar score (less than 8) in the group of placebo patients (3/30 versus 13/31 after 1 min. and 0/30 versus 6/31 after 5 min., t-test P<0.01) (Table 4).
Table 4. Apgar score after 1 min. and 5 min. Data are presented in means±S.D. Confidence intervals (95%, CI) are shown in parentheses.
|Variables||L-Arginine (n=30)||Placebo (n=31)||P=|
|Apgar score (after 1 min.)|| 8.97±1.1 (8.57–9.34)|| 7.74±1.8 (7.14–8.34)||0.0025*|
|Apgar score values 3–7|| 3 (10%)||13 (41.94%)||0.0063*|
|Apgar score values 8–10||27 (90%)||18 (58.06%)||0.0063*|
|Apgar score (after 5 min.)|| 9.6±0.7 (9.35–9.85)||8.8±1.0 (8.2–9.4)||0.0167*|
|Apgar score values 3–7||0 (0%)||6 (19.35%)||0.0138*|
|Apgar score values 8–10||30 (100%)||25 (80.65%)||0.0138*|
There were no differences between L-arginine and placebo groups in numbers of Caesarean sections due to other causes than threatening foetal asphyxia [5/30 (16.66%) versus 6/31 (19.36%), respectively]. Noteworthy, both in the placebo and in the L-arginine group there were high overall indicated Caesarean section rates [14/30 (46.67%) versus 21/31 (67.74%)]; the number of natural labours was significantly higher in L-arginine group [11/30 (36.67%) versus 4/31 (12.9%), χ2 test, P<0.05]. Neither vacuum extractor nor forceps were used during natural labours.
Interestingly, decrease of dosage of hypertensive drugs during the course of the study was possible in significantly greater number of patients taking L-arginine as compared to placebo group (50% of patients from L-arginine group versus 12.9% of patients from placebo group, χ2 test, P<0.05) (table 5). On the other hand, the increase of dosage of hypotensive drugs was necessary in greater number of placebo patients as compared to L-arginine group (16.7% of patients from L-arginine group versus 48.4% of patients from placebo group, χ2 test, P<0.05) (table 5). Noteworthy, among patients treated with placebo but not with L-arginine, there were 4 cases of placental abruption.
Table 5. Analysis of clinical course of antihypertensive treatment in patients, based on the possible decrease (improvement) or indicated increase (deterioration) of dosage of antihypertensive drugs (see Materials and Methods).
|Variables||L-Arginine (n=30)||Placebo (n=31)||P=|
|Improvement||15 (50%)|| 4 (12.9%)||0.0027*|
|Lack of reaction||10 (33.3%)||12 (38.7%)||0.6622 |
|Deterioration|| 5 (16.7%)||15 (48.4%)||0.0107*|
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A wide range of interventions has been suggested for the prevention and treatment of preeclampsia (Duley 2003; Peters & Flack 2004). Antihypertensive drugs were demonstrated to have benefit rather for mother than for foetus, and they represent still more symptomatic than causal treatment. Additionally, many, otherwise useful, antihypertensive drugs cannot be used in pregnancy either because they are teratogenic, like ACE inhibitors or because their adverse effects are augmented when administered in combination with magnesium sulphate, such as calcium channels blockers (Waisman et al. 1988). The main finding of this study is that in women with preeclampsia, addition of oral L-arginine but not placebo to standard treatment allow decrease of dosage of hypertensive drugs, as well as improved foetal condition and neonatal outcome without any adverse effects.
By far, none of studies on L-arginine administration in hypertension or in preeclampsia describe any adverse reactions attributable to use of L-arginine, at least in doses similar to used in our study (Boger & Bode-Boger 2001). Interestingly, as far as therapeutic action of L-arginine in preeclampsia is concerned, most reports focus on the arterial blood pressure. Infusion of 30 g of L-arginine was reported to reduce blood pressure and increase plasma levels of L-citruline and nitrite; noteworthy, these effects were significantly greater in uncomplicated than in preeclamptic pregnancies (Facchinetti et al. 1999). On the other hand, a recent study on preeclamptic patients denied hypotensive effect of L-arginine given in daily oral dose of 12 g up to 5 days (Staff et al. 2004). Importantly, in both studies L-arginine was given in high amounts over short periods of time. Our study represents a different approach according to the hypothesis of Boger & Bode-Boger (2001), directed towards selective, gradual improvement of endothelial function. Previously, we have demonstrated that oral treatment with low doses of L-arginine may decrease significantly blood pressure through increased synthesis and/or bioavailability of endothelial NO in preeclamptic patients (Rytlewski et al. 2005). To our knowledge, the present study is the first showing influence of that treatment on foetal conditions and neonatal outcome in preeclampsia.
In our study foetal well-being was estimated using Biophysical Profile and ultrasound measurements of blood flow in umbilical artery as well as in foetal middle cerebral artery (Conde-Agudelo et al. 2004). The Doppler velocimetry studies can provide valuable information regarding foetal well-being and neonatal prognosis in preeclampsia (Detti et al. 2004; Yalti et al. 2004). It has been demonstrated that in foetal hypoxaemia, there is a compensatory decrease of resistance in middle cerebral artery in response for increase of resistance in umbilical artery; this changes are reflected by decrease and increase of respective pulsatility indices (Vyas et al. 1990). Accordingly, cerebro-placental ratio i.e. ratio of middle cerebral artery pulsatibility indices to umbilical artery pulsatility indices has been demonstrated to correlate with foetal blood oxygenation and is considered as a valuable measure of foetal well-being (Gramellini 1992). As expected, in our study there was a gradual decrease of cerebro-placental ratio in the placebo group. Importantly, treatment with exogenous L-arginine caused significant increase of cerebro-placental ratio, which reached nearly physiological values. Clearly, in our hands exogenous L-arginine, but not placebo normalized foeto-placental blood flow distribution.
The question arises about the mechanisms of L-arginine action. As NO donors have been shown to improve foeto-placental distribution of blood flow in preeclampsia (Luzi et al. 1999), it may well be that foeto-placental effects of L-arginine depended on increased synthesis and/or action of endothelial NO, like it was demonstrated for L-arginine-elicited decrease of maternal arterial pressure (Rytlewski et al. 2005).
Preeclampsia increases the risk of intrauterine growth restriction, likely by impairment of foeto-maternal blood flow (Roberts et al. 2003). In our patients, treatment with exogenous L-arginine significantly increased newborn Apgar score and duration of pregnancy (Latency). However, the influence of exogenous L-arginine on foetal body weight and for incidence of intrauterine growth restriction was confounding. Taking into granted stable, long-lasting influence of L-arginine on cerebral-placental ratio in our patients, one could expect durable acceleration of foetal body growth. However, prolonged treatment with L-arginine increased foetal growth only transiently and body weights at birth did not differ significantly between L-arginine and placebo groups. Clearly, larger groups are needed to evaluate durability of these L-arginine effects. It should be noted however that even transient effect in preeclampsia may be of clinical importance – in the case of acute foetal asphyxia, especially shortly after beginning of the hypotensive treatment, supplementation with L-arginine may increase chances for delivery of child with higher weight and better outcome.
It should be noted that as far as foetal growth is concerned, other than NO-dependent changes of foeto-placental circulation may be involved. High intravenous doses of L-arginine have been used since the 1960s to stimulate growth hormone secretion (Merimee et al. 1967). However, oral administration of this amino acid, especially in low doses has no such effect (Boger & Bode-Boger 2001). Sieroszewski et al. (2004) recently demonstrated durable improvement of foetal growth and increase of birth weight in patients with intrauterine growth restriction treated with low doses of L-arginine for 20 days, however patients with preeclampsia were excluded from that study.
In summary, we have demonstrated that oral supplementation with L-arginine may represent efficient strategy to improve foetal conditions and neonatal outcome in women with preeclampsia. These benefits should be confirmed by larger, more-powered studies.