Department of Perinatology and Gynecology, Medical University in Pozna, Poland

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The effect of L-arginine treatment on the neonatal outcome

from pregnancies complicated by intrauterine growth restriction

and gestational hypertension

ANNA DERA, MARIOLA ROPACKA, JOANNA KOWALSKA, WIESAW MARKWITZ,

PIOTR NYCZ, GRZEGORZ H. BRBOROWICZ

Abstract

Objective: Gestational hypertension and what follows fetal hypotrophy are associated with elevated prenatal mortality and morbidity. The main

aim of this study was to evaluate the effect of L-arginine administration on the outcome of neonates from pregnancies complicated by

hypotrophy and gestational hypertension. Methods: The study was undertaken in Pozna Medical University, Department of Perinatology

and Gynecology. The study group included 69 randomly chosen pregnant women diagnosed with gestational hypertension or whose fetuses

were diagnosed with intrauterine growth restriction (IUGR). Some women were affected by both of these pathologies. 42 women received

3 g of L-arginine daily as a supplement to standard therapy and 27 women received placebo (control group) as well as routine therapy. The

ultrasound and clinical examination were done on the first day of hospitalization, and then every two weeks in both groups. Results: In the

group treated with L-arginine we observed higher birth weight at delivery (p < 0.05), gestational age (p < 0.05), and Apgar score at 1 and 5

minute (respectively p < 0.005, p < 0.001) compared to placebo group. There was significantly lower number of cesarean sections in the group

receiving L-arginine than in the group receiving placebo (respectively p < 0.01). There were no significant differences in IUGR (at entry and

at delivery) between two groups. We also observed that the incidence of fetal complication such as ICH and RDS in the L-arginine group is

significant lower (respectively p < 0.05, p < 0.005) compared to placebo group. Conclusion: Our study demonstrated that L-arginine admi-

nistration to pregnant women with gestational hypertension and IUGR may improve fetal condition and neonatal outcome after delivery

(significantly decrease serious complication such as ICH, RDS) by prolonging pregnancy (latency) and what follows delivering a child with

higher birth weight, better Apgar score as well as acid-base parameters and decrease the rate of cesarean sections. However, these benefits

require confirmation by larger, more-powered study.

Key words: gestational hypertension, IUGR, L-arginine, neonatal outcome

Introduction

Gestational hypertension as well as IUGR are known to

be significant complications of pregnancy and are known to be

associated with inadequate uteroplacental blood flow. They are

the leading cause of premature birth as well as increased

infant mortality and morbidity [1]. The pathomechanism of

IUGR is an impaired fetomaternal circulation which leads to

decreased distribution of oxygen and of nutritional substances

to the fetus. Intrauterine growth restriction constitutes an

important clinical problem associated with increased prenatal

morbidity [2], higher incidence of neuro-developmental im-

pairment [3], and increased risk of adult disease, such as dia-

betes and cardiovascular disease [4, 5]. The primary patho-

physiology of hypertension is placental and it begins with

abnormal trophoblastic implantation and subsequent reduction

in placental perfusion, which may result in fetal hypoxemia

and IUGR [6]. Measurements of maternal placental blood flow

and volume blood flow in the umbilical circulation clearly sug-

gest that blood flows are reduced on both sides of the pla-

cental exchange barrier in association with hypertension and

IUGR. The reduction in placental blood flows contribute to

fetal hypoxia in IUGR. Nitric oxide (NO) is an important re-

gulator of placental perfusion, as it plays a role in placental

vascular endothelial function being a potent vasodilator and

antiplatelet agent [6]. Nitric oxide is synthesized from the

physiologic precursor L-arginine by the stereo-specific enzy-

me NO synthase in what is called the L-arginine/NO pathway,

and L-arginine is the only substrate for the production of NO.

It has been demonstrated that inhibition of nitric oxide syn-

thesis affect fetal growth [7-10] and that plasma concen-

trations of L-arginine is lower in pregnancies complicated by

fetal growth restriction [11, 12]. The involvement of the L-ar-

ginine pathway in the regulation of vascular tone suggests a

possible role in the pathogenesis of hypertension and IUGR

sustained by placenta insufficiency. Knowing the properties

and effect of L-arginine we may predict its action [13]. Recent-

ly, several reports have been published on the use of L-argi-

nine for treating intrauterine growth restriction (IUGR),

indicating different conclusions [14-16]. Several authors have

demonstrated a positive effect of L-arginine on uteroplacental

circulation and at the same time fetal outcome but there are

others who denied the hypotensive effect of L-arginine [17].

There are numerous treatment methods for these two patho-

logies but the results and outcomes are not always satisfac-

tory. The aim of this study was to determine whether L-argi-

nine given in a daily dose of 6,0 g might improve the outcome

of neonates from pregnancies complicated by gestational

hypertension and IUGR.

Material and methods

Participants

We included 69 women with singleton pregnancies com-

plicated by gestational hypertension and/or IUGR over 25

-th

week of gestation. The gestational age was confirmed by a first

trimester ultrasound scan. Ultrasonographic examinations as

well as blood tests were performed after receiving written

consent from the patient. The study protocol was approved by

the Ethic Committee of the Pozna Medical University.

A. Dera, M. Ropacka, J. Kowalska, W. Markwitz, P. Nycz, G.H. Brborowicz

36

Study groups

The study group included 69 women between 25 and 34 week

of pregnancy complicated by gestational hypertension, IUGR

or both.

Group 1 included pregnant women with gestational hy-

pertension, which was defined as an elevated blood pressure

(>140/90 mm Hg) in at least two measurements 6 hours apart

with or without proteinuria and edema, with an onset after 20

week of pregnancy. From this group we excluded all patients

with diabetes, chronic hypertension, renal disease and endo-

crinopathies.

Group 2 included pregnant women, which fetuses indi-

cated signs of growth restriction based on abdominal circum-

ference (AC) or calculated on the base of ultrasonographic

evaluation of estimated fetal birth weight (EFBW) below the

10 percentile.

Both groups were divided in subgroups based on the ad-

ministered therapy:

A. L-arginine (3.0 g per day)

B. Placebo (3.0 g per day)

All Doppler examinations were performed in the Ultra-

sonographic Lab of the Pozna Medical University Clinic of

Perinatology and Gynecology between the years 2003-2006.

Accurate Doppler measurements of blood flow in umbilical

artery and middle cerebral artery, were done in all patients

using Voluson 730 Expert apparatus equipped with convex 3.5

MHz ultrasound transducer. Doppler imagining 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. Measurements were repeat-

ed for at least three separate cardiac cycles. In the course of

obtaining of waveform from mid portion (free-floating loop) of

the umbilical cord, during quiescence, the Doppler gate were

placed within the walls of selected vessel, to avid aliasing and

the inclusion of both arteries in the same sample gate. For

measurement of the middle cerebral artery an axial view of the

fetal 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. The first measure-

ment was done prior to administration of therapy, one week

after and then every two weeks until delivery. We estimated

the average velocity of blood flow as well as pulsatility index

(PI), resistance index (RI), systolic/diastolic index (S/D).

Exclusion criteria

Singleton pregnancies < 25 week of gestation;

Multiple pregnancies;

Congenital malformations;

Gestational week which was not confirmed by first tri-

mester ultrasonography;

Maternal age

Effect of L-arginine treatment on the neonatal outcome from pregnancies complicated by IUGR and gestational hypertension

37

Table 2. Infant data at delivery

Arginine group (n = 42) Placebo group (n = 27) p

Sex (M/F) (%) 45.24/54.76 51.85/48.15 NS

Birth weight (g) 2261.43 764.85 1864.07 922.17 < .05

Gestational at delivery (wk) 36.21 2.53 34.29 3.42 < .05

Apgar score at 1 minute 8 (7-9) 5 (2-7) < .005

Apgar score at 5 minute 9 (8-10) 7 (2-7) < .001

pHa 7.25 0.09 7.17 0.12 < .05

BEa -3.17 4.75 -5.28 5.84 NS

pO

2

a 9.76 5.58 7.91 4.59 NS

pCO

2

a 56.86 14.23 56.28 9.87 NS

pHv 7.32 0.08 7.22 0.13 < .005

BEv -2.22 5.12 -5.38 4.81 < .005

pO

2

v 16.18 5.71 11.87 4.52 < .005

pCO

2

v 46.82 8.37 51.72 9.56 < .05

Placental weight (g) 488.57 167.03 432.03 163.55 NS

Cesarean section (%) 59.5 88.9 < .05

IUGR at delivery (%) 57.14 51.85 NS

Table 3. Neonatal outcome. Incidence in %

Arginine group (n = 42) Placebo group (n = 27) p

pHa < 7.20 (%) 30.95 48.15 NS

pHv < 7.20 (%) 7.14 25.93 < .05

Infection

incidence (%)

19.05 14.81 NS

ICH (%) 4.76 29.63 < .05

Grade 0 95.24 70.37 < .005

Grade 1 0 18.52 < .005

Grade 2 4.76 11.11 < .05

RDS (%) 23.81 62.96 < .005

ICH = intracranial haemorrhage

Infant mean birth weight, was significantly higher in the

L-arginine group compared with placebo (2261.43 764.85 vs.

1864.07 922.17), mean gestation age at delivery was signi-

ficant greater in the L-arginine group compared to placebo

(36.21 2.53 vs. 34.29 3.42) (Table 2). Mean values of Ap-

gar score recorded after 1st and 5th minute after delivery

were significantly higher in the L-arginine group as compared

to placebo (8(7-9) vs. 5(2-7) and 9(8-10) vs. 7(2-7) (Table 2).

There was no significant difference in the number of females

and males between groups. There was a significant reduction

in number of cesarean section in the L-arginine group (59.5%)

versus placebo (88.9%) (Table 2).

In spite of significant differences between the two groups

in the scope of acid-base balance pointing out better outcome

of the newborns in the L-arginine group, the results in both

groups didnt indicate significant disturbances which could

influence the final state of the newborn (Table 2). Interesting

data was obtained from analysis of the infant condition directly

after the birth in the two groups. We observed significant

statistical decrease in the frequency of the newborn acidosis

in the L-arginine group compared to placebo (7.14% vs. 25.93%

p < 0.05). The incidence of ICH was significantly lower in

L-arginine group (4.76%), especially Grade 1 (Table 3). The

respiratory distress syndrome incidence was also higher in the

L-arginine group compared to placebo (23.81 % vs 62.96%,

p < 0.005) (Table 3).

The obtained results can not be only associated with admi-

nistration of L-arginine. One of the reasons of such a neonatal

outcome may be prematurity in both groups, apart from the

fact that in group 1 the infants were statistically more mature

which resulted in statistically greater birth weight in this

group. There was significantly lower fetal body weight at

A. Dera, M. Ropacka, J. Kowalska, W. Markwitz, P. Nycz, G.H. Brborowicz

38

delivery in the placebo group (p < 0.05) (Table 2). In the study

we didnt find significant differences in the incidence of IUGR

after delivery as well as in the weight of the placenta.

In ours examination, we didn't note any side effects or ne-

gative influence on neonate related to the taken doses of L-ar-

ginine. The study suggests that L-arginine administration to

pregnant women with gestational hypertension and IUGR, can

significant influence the state of the newborn after delivery and

significantly decrease serious complications such as ICH, RDS.

Discussion

Gestational hypertension and IUGR are clinically very

serous complications of pregnancy. Due to its adverse effect

on the pregnancy, fetus and neonatal outcome there have

been different approaches to treat these conditions which

have not always been satisfactory. Knowing that gestational

hypertension is associated with reduced placental perfusion

and what follows intrauterine growth restriction we would like

to try improving the uteroplacental circulation. Due to the fact

that fetoplacental vessels lack innervations the control of feto-

placental circulation is dependent on locally produced and

circulating vasoactive factors. eNO, as a potent vasodilator

may play a pivotal role in the control of fetoplacental vascular

tone, and it is regarded as a platelet anti-aggregating agent in

the uteroplacental circulation [17]. L-arginine reverses fetal

growth restriction induced by inhibition of nitric oxide synthe-

sis[4-6, 15] and by hypoxia. Nitric oxide improves uteroplacen-

tal blood flow and thereby increases oxygen delivery to the

fetus. This study was undertaken to demonstrate the effect of

L-arginine the only precursor of NO, on the pregnancy and

neonatal outcome by indirectly influencing the uteroplacental

circulation.

The aim of our study was to demonstrate the effect of

L-arginine treatment on the neonatal outcome from pregnan-

cies complicated by gestational hypertension and IUGR. In

this study we have demonstrated that administration of 6 g of

L-arginine daily to patients with gestational hypertension and

IUGR can be beneficial for the prevention of serious compli-

cation of the newborn after delivery. Our results indicated that

administration of L-arginine in the dose indicated above can

positively influence the gestational age at delivery and what

follows increase fetal birth weight and Apgar score at 1st and

5th minute, decrease the incidence of acidosis and serious

complications such as ICH and RDS.

To our knowledge there are several studies in which the

authors administrated L-arginine in either pregnancies com-

plicated by hypertension or IUGR. The difference from our

study was associated with the dose of L-arginine, duration of

treatment, mode of administration and various outcomes. The

most recent study done by Rytlewski et al. indicated that

administration of 3 g of L-arginine daily represents efficient

strategy to improve fetal condition and neonatal outcome in

women with preeclampsia. This study demonstrated similar

results such as decreased rate of IUGR, increased gestational

age at delivery; inc. estimated fetal birth weight during the

treatment and higher Apgar score. In this study there was no

difference in the rate of c-sections between groups but there

was increase in the rate of vaginal deliveries in the L-arginine

group [6]. Another study done by Facchinetti et al. indicated

that administration of L-arginine in the dose of 30 g iv daily

may benefit patients with preeclampsia [17]. On the other

hand, study done by Staff et al. where 12 g of L-arginine was

administered for up to 5 days to patients with preeclampsia

didnt reduce mean diastolic blood pressure [15]. Xiao et al.

administered 20 g of L-arginine iv daily for 7 days to patients

with IUGR indicating that the mean birth weight was signi-

ficantly higher compared to control group [18]. Sieroszewski

et al. recently demonstrated improvement of fetal growth and

increase in birth weight in patients with IUGR who received

3 g of L-arginine for 20 days.

All of his results indicate that L-arginine has a significant

positive effect on the neonatal outcome by improving the

uteroplacental circulation and decreasing the complications

associated with prematurity.

In summary we have demonstrated that oral administra-

tion of L-arginine to women with pregnancies complicated by

IUGR and hypertension may represent efficient and safe

strategy to improve the fetal condition and neonatal outcome.

These benefits should be confirmed by larger, more-powered

study.

Acknowledgments

The work was supported by KBN 3PO5E 072 24

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J Anna Dera

Department of Perinatology and Gynecology

Medical University in Pozna

60-535 Pozna, ul. Polna 33, Poland

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