Effect of L-Arginine Supplementation in treatment of Intrauterine Fetal Growth Restriction

Introduction

The genetic potential of the fetus is limited by Fetal growth restriction (FGR)^[1]. The estimated fetal weight (EFW) must be under the 10^th percentile for the usual standard of gestational age in order to diagnose FGR ^[2]. Risk of adverse perinatal outcomes and long-term complications is increased with FGR, according to epidemiological research^[4,5]

The primary endogenous vasodilator involved in controlling placental circulation is nitric oxide (NO)^[5]. Placental trophoblast invasion and vascular tone and resistance regulation are both influenced by it ^[6].

Three different forms of nitric oxide synthase (NOS) are involved in the production of NO from L-Arginine: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). One of the primary roles of the NO generated by vascular endothelial cells—which is mostly caused by the action of eNOS—is to regulate blood perfusion and expand blood vessels ^[7].

One competitive inhibitor of NOS that decreases NO generation is asymmetric dimethylarginine, or ADMA. There are nine isoforms of the protein L-Arginine methyltransferase (PRMT), the most common of which is PRMT1, which is responsible for ADMA synthesis in humans^[8].

Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH)—DDAH1 and DDAH2—are responsible for ADMA degradation. The primary metabolic locations of ADMA are consistent with the extensive in vivo expression of DDAH1, while DDAH2 is mostly present in placental tissues. Endothelial dysfunction, participation in cardiovascular illnesses, pre-eclampsia (PE), and reduced vasodilation due to inhibited NOS activity are all outcomes of high ADMA levels ^[9]

Angiogenic factors, such as vascular endo-thelial growth factor (VEGF) and placental growth factor (PLGF), promote angio-genesis in the placenta and are essential for the development and maintenance of the placenta's function. In its role as angiogenesis regulator, NO promotes the production of VEGF and the proliferation of endothelial cells ^[10].

The aim of the research was to evaluate the impact of L-Arginine supplementation in treatment of Intra-uterine FGR at MMUH, Primary outcome improvement in growth velocity, Secondary outcome improvement in amniotic fluid or Doppler parameters if impaired.

Patients and Methods

This clinical research was done In the Department of Obstetrics and Gynecology, Minia Maternity University Hospital between January-December 2023 for 4 weeks after taking medical history, Clinical examination and informed written consent from all subjects and after being approved by the local ethical Committee; on cases with their fetal weight below 10^th percentile for their gestational age with the following criteria:

Inclusion Criteria: Singleton pregnancy, Gestational age among ±28 Weeks and ± 34 weeks, Average liquor or reduced liquor and Normal or impaired Doppler indices

Exclusion criteria: Any maternal medical disorders e.g. (Hypertension, Diabetes, PE, Systemic lupus erythromatosis and etc.), pre-mature rupture of membrane and Presence of any congenital fetal mal-formation.

This randomized control research was done in the Department of Obstetrics and Gynecology Minia University. The research involved 60 randomly selected pregnant women identified as having IUGR.

Group (A): 30 cases received L-Arginine (BLUE OX® GINSENG fortified with ZINC. Dietary Supplement. Vanillin Taste. – Red Ginseng – L-Arginine – Wheat Germ Oil – Lecithin – Zinc Gluconate, Manuf. By: Nutrixia For: NEW CHAPTER, Sole Agent: MARVEL, Made in Egypt). Dose: 300 mg. 3 times Per day (case group)

Group (B): 30 cases received only Placebo (control group)  

Methods:

Patients of both groups were subjected to the following: Complete history taking (Personal history, Past medical history and Obstetric history), Complete clinical examination (General examination, Esti-mation of gestational age) and Laboratory Investigations (CBC, Random blood sugar, Kidney functions test, Liver function tests and Coagulation profile)

The follow-up of both groups include: Weekly Obstetric ultrasound and Colour Doppler Blood Flow.

After birth neonates were evaluated: Birth weight [Time Frame: 15 min] and Apgar score [Time Frame: at one and five minutes after birth]

Ethical considerations: The procedure for utilizing L-Arginine was approved by the Institutional Ethical Committee. During enrollment, all subjects provided complete informed consent in straightforward language.

Statistical Analysis

The statistical analysis was done utilizing the SPSS statistical software, version 16.0 (SPSS Inc., Chicago, IL, USA).  All of the data were reported as mean ± standard. A P value that was less than 0.05 was considered significant. For the data that were normally distributed, the student t-test was utilized.

Discussion

With its effects extending beyond the newborn phase to include the adult phenotype and quality of life, IUGR, a syndrome characterized by pathological limitations on fetal development in utero, remains a significant public health concern ^[11].

IUGR is a term utilized to describe the rate at which a fetus develops in relation to its potential growth for a foetus of a particular race and gender. ^[12].

In the current thesis demographic characteristics of the studied groups showed that, there was no significant difference in age, BMI, parity, gravidity and GA at assessment between both groups (P-value > 0.05). In Patients of group A mean age was 26.70 ± 3.96 years, mean BMI was 24.90±2.16 Kg/m², the mean GA was 32.13±0.78 week. While, in group B mean age was 27.87±3.88 years, mean BMI was 25.13±1.98 Kg/m², the mean GA was 32.10±0.80 week.

In agreement was a randomized control study by Mary et al., sought to assess how administering L-Arginine affected the outcome for the foetus in pregnancies impacted by IUGR. A total of sixty pregnant cases with IUGR were selected at random for the research. The case group consisted of 30 women who had conventional therapy plus 3 g of L-Arginine daily, whereas the control group involved 30 cases who received only routine therapy. There was not a significant distinction among the two groups concerning age, BMI, or gestational period. ^[13].

In the same line Winer et al., Data were gathered from 43 cases whose fetuses were found to have severe vascular IUGR below the third percentile. Of these patients, 21 were assigned to the L-Arginine group & 22 to the placebo group. The average ages of the two groups were 28.2±5.9 and 29.3±4.2 years, corres-pondingly; additionally, the average gestational age was 28.0±2.0 weeks, contrasted with 27.7±2.1 weeks, corres-pondingly. There was no significant variance among L-Arginine and the placebo group in demographic and obstetric data (P > 0.05) ^[14].

EFW after receiving L-Arginine treatment was statistically significantly higher than before treatment. Regarding EFW distributions, most pre-treatment cases (80％) have EFW ≤1500gm while after treatment most cases (83.3％) have EFW more than 1700gm.

In agreement was several studies Bhargavi et al.,^[11], Lampariello et al.,^[15], Hegda et al.,^[16], and Zhu et al.,^[17] demonstrated that EFW after receiving L-Arginine treatment was significantly higher than before treatment.

In the current study, Post-treatment EFW was statistically significantly higher than pre-treatment EFW in L-Arginine treated (1324.18±177.04 vs 1821.73±153.85; P-value ˂ 0.05). Also, in placebo group (1296.12±156.27vs 1645.17±160.49; P-value > 0.05).

These results were closed to those obtained by Chen et al.,^[12] who found that there were statistically significant higher in Post-treatment EFW when compared with pre-treatment EFW in L-Arginine-treated patients.

The current data displayed that, there was statistically significant higher post-treatment EFW in L-Arginine treated than placebo group (1821.73±153.85 vs 1645.17±160.49; P-value ˂ 0.05).

Similar findings were stated by Lampariello et al.,^[15] Nevertheless, in another research Winer et al.,^[14] stated no significance variance amongst the group received an L-Arginine supplement contrasted with control group.

Our results detected that, there was statistically significant greater birth weight in L-Arginine treated than placebo groups. 

Neonatal weights in group II A were 1.90 ± 0.3 kg, while in group II B they were 1.77 ± 0.53 kg (P (0.05)). The L-Arginine treatment group had a greater gestational age at birth (35.68 ± 2.80 in group II A contrasted with 34.0 ± 3.50 in group II B).

The newborn clinical characteristics of the population under study were comparable in the L-Arginine and placebo groups at birth, as stated by Winer et al.,^[14]. Groups did not differ in terms of birth weight.

Results for baby weight immediately after birth in patients given L-Arginine were as follows: 2.1 kgs (01), 2.2 kgs (01), 2.4 kgs (03), 2.5 kgs (20), 2.6 kgs (03), 2.7 kgs (13), 2.9 kgs (01), 03 kgs (41), 3.1 kgs (13), 3.2 kgs (14), 3.3 kgs (05).

Despite that NICU admission frequency in females who did not receive L-Arginine than those who received L-Arginine (33.3% vs 46.7%) but the difference was statistically insignificant. Also, IUFD was higher in females who did not receive L-Arginine than those who received L-L-Arginine but the difference was statistically insignificant. there was statistically insignificant variance in mode of delivery and fetal sex between females who did not receive L-Arginine and those who received L-Arginine. 

Singh et al.,^[18] reported that, In the control group, a greater number of neo-nates essential resuscitation and venti-lating than in the L-Arginine group. NICU hospitalization was necessary for 30.76 and 33.33% of newborns in the L-Arginine group and control trial, with hospital stays of 9.75 ± 6.0 and 11.38 ± 8.5 days, correspondingly, with no statistically significant distinction. The rate of neonatal death was lower in cases with IUGR treated with L-Arginine (15.3% vs 12.5%).

In accordance, Mary et al.,^[13] found that the prevalence of vaginal delivery was 76.67 percent in the case group and 73.33 percent in the control group. The P value was judged to be statistically insignificant (p>0.05).

In another investigation, Bhargavi et al.,^[11] displayed that Out of the total of 124 instances where L-Arginine was admini-stered, 85(69%) resulted in full-term deliveries while 39(31%) resulted in lower segment cesarean section.