L-Arginine supplementation in pregnancy: a systematic review of maternal and fetal outcomes

Figures & data

Figure 1. Flow diagram of the study selection.

Table 1. Main human study characteristics.

Author	Year	Study design	Population	N	Administration	Intervention	Duration of treatment
Battaglia C et al.	1999	RCT	ART	17/17	Oral	GnRHa + pFSH GnRHa + pFSH + 16 g L-Arg/day	8–10 days
Battaglia C et al.	2002	RCT	ART	18/19	Oral	GnRHa + pFSH + 16 g L-Arg GnRHa + pFSH + placebo	8–10 days
So S et al.	2020	RCT	ART	36/37/36	Oral	AS2000 group, L-Arg, 2 g + folate 400 μg + vitamin E 10 mg; AS1000 group L-Arg 1 g + folate 200 μg	Maximum 3 months
Neri I et al.	1996	RCT	IUGR	9/9/9	Intravenous	L-Arg infusion for 30 min (30 g/100 ml)	1 day
Sieroszewski P et al.	2004	Clinical trial	IUGR	78/30	Oral	L-Arg 3 g /day for 20 days	20 days
Xiao XM et al.	2005	Clinical trial	IUGR	30/36/30	Intravenous	20 g/day of L-Arg/routine therapy/control	7 days
Shen SF et al.	2011	RCT	IUGR	30/30	Intravenous	15 g of L-Arg in 500 ml 5% glucose, daily /control	1 day
Singh S et al.	2015	Clinical trial	IUGR	60/30/30	Oral	L-Arg 3 g daily for 21 days	21 days
Ropacka M et al.	2007	RCT	HDP and IUGR	124/78	Oral	L-Arg 3 g daily/placebo	Until delivery
Winer N et al.	2009	RCT	severe IUGR	21/22	Oral	14 g/day of L-Arg/placebo	Until delivery
Staff AC et al.	2004	RCT	PE	15/15	Oral	4 g of L-Arg/placebo	2 days
Neri I et al.	2004	RCT	HDP	7/7	Intravenous	Infusion of L-Arg 20 g/500 ml/placebo	1 day
Rytlewski K et al.	2005	Clinical trial	PE	30/31	Oral	3 g L-Arg/routine therapy/control	1–4 weeks after PE diagnosis and continued until 36 weeks of pregnancy
Neri I et al.	2006	RCT	HDP	80/80	Intravenous	L-Arg (20 g/500 ml) or placebo IV	5 days
Rytlewski K et al.	2006	RCT	PE	30/31	Oral	3 g L-Arg/routine therapy/control	3 weeks
Hladunewich MA et al.	2006	RCT	PE	22/23	Oral or intravenous	L-Arg orally (3.5 g every 6 h), or intravenously (10 g every 8h) when medications could not be taken orally	Median of 6 days before delivery (range 3–17)
Facchinetti F et al.	2007	RCT	HDP	40/40	Intravenous	L-Arg (20 g/500 ml intravenously daily, for 5 days followed by 4 g/day orally for 2 weeks) or placebo	5 days
Valdivia-Silva JE et al.	2009	RCT	PE	50/46	Oral	L-Arg 1 g 3 times a day	3 weeks
Neri I et al.	2010	RCT	CH	40/40	Oral	L-Arg 4 g/day /placebo	10–12 weeks
Monari F et al.	2021	RCT	CH and previous placenta vascular disorders	30/49	Oral	L-Arg 3 g (+Mg 350 mg and Sal extract 100 mg) + LDA 100 mg/day vs. only LDA 100 mg/day	Entire pregnancy
Vadillo-Ortega F et al.	2011	RCT	PE high risk population	228 222 222	Oral	6.6 g of L-Arg + antioxidant vitamins/placebo	Until delivery
Camarena Pulido EE et al.	2016	RCT	high risk pregnancies	50/50	Oral	3 g of L-Arg a day/placebo	From 20 to 39 weeks
Rytlewski K et al.	2008	RCT	threatened PTB	30/31	Oral	3 g of L-Arg/placebo	Since 1–4 weeks after admission to hospital until delivery
Facchinetti F et al.	1996	Clinical trial	threatened PTB	10	Intravenous	L-Arg was infused for 30 min 30 g/100 ml	1 day
Petrella E et al.	2014	Clinical trial	Overweight/obese	10/12	Intravenous	L-Arg (20 g/500 ml in 3h)	1 day

Table 2. Main findings of human studies.

Author	Year	Population	Main outcome	Main finding
Battaglia C et al.	1990	ART	Uterine and follicular Doppler flow and ovarian response to gonadotrophin in poor responder women	Lower cancelation rate, increased oocytes collected, and transferred embryos, increased plasma, and follicular fluid concentrations of arginine, citrulline, NO2^−/NO3^−, and IGF-1. Significant Doppler flow improvement in the L-Arg-supplemented group
Battaglia C et al.	2002	ART	Hormonal, ultrasonographic and Doppler evaluations, and plasma and follicular fluid nitrite/nitrate concentrations	L-Arg may be detrimental to embryo quality and pregnancy rate during controlled ovarian hyperstimulation cycles
So S et al.	2020	ART	hCG-positive rate or CPR in 3 months	Higher hCG-positive rate and CPR in L-Arg group. In the subgroup of male infertility, the hCG-positive rate and CPR were significantly increased by L-Arg
Neri I et al.	1996	IUGR	Utero-placental circulation	L-Arg infusion affects utero-placental circulation in patients with IUGR associated with increased uterine resistances
Sieroszewski P et al.	2004	IUGR	US estimated weight	L-Arg improved the estimated fetal weight and birthweight
Xiao et al.	2005	IUGR	Birtweight and maternal NO serum levels	L-Arg increased maternal NO2^−/NO3^− levels and mean birthweight
Shen SF et al.	2011	IUGR	Parameters of fetal growth and development monitored by B-ultrasound at regular intervals	L-Arg reduced the expression of Bax, and enhanced the expression of bcl-2, associated with reduced placental apoptosis, and improved placental function and fetal development
Singh S et al.	2015	IUGR	Birthweight and maternal NO serum levels	L-Arg can be used to increase maternal NO levels, enhancing birthweight, and decreasing neonatal morbidity
Ropacka M et al.	2007	HDP and IUGR	Feto-maternal hemodynamic	L-Arg reduced incidence of abnormal umbilical artery blood flow and uterine artery early—diastolic notching
Winer N et al.	2009	severe IUGR	Birth weight and neonatal morbidity	L-Arg is not effective for severe vascular IUGR
Staff AC et al.	2004	PE	Diastolic blood pressure	Oral L-Arg supplementation did not reduce mean diastolic blood pressure after 2 days of treatment compared with placebo in pre-eclamptic patients with gestational length varying from 28 to 36 weeks
Neri et I al.	2004	HDP	Fetal heart variables by a computerized non-stress test (NST)	L-Arg infusion did not affect cardiac variables and fetal movements but showed an acute hypotensive effect of systolic and diastolic values
Rytlewski K et al.	2005	PE	SBP, DBP, MAP	L-Arg significantly lowered SBP, DPB, and MAP and elevated 24-h urinary excretion of NOx and mean plasma levels of l-citrulline. Exogenous L-Arg did not influence plasma concentrations of L-Arg, L-ornithine and methylated arginines
Neri I et al.	2006	HDP	Systolic and diastolic blood pressure	L-Arg showed an anti-hypertensive role, both SBP and DBP were reduced
Rytlewski K et al.	2006	PE	Fetal condition and neonatal outcome	L-Arg improved fetal well-being and neonatal outcome and prolonged pregnancy complicated with PE
Hladunewich MA et al.	2006	PE	MAP, glomerular filtration rate, proteinuria assessed on 3rd and 10th days postpartum by inulin clearance and albumin:creatinine ratio	L-Arg improve markedly blood pressure and kidney function the 10th day postpartum without hasten the recovery
Facchinetti et al.	2007	HDP	Time from randomization to delivery (Latency)	L-Arg seems promising in prolonging pregnancy and reducing blood pressure
Valdivia-Silva JE et al.	2009	PE	Fetal growth retardation	L-Arg markedly improved fetal growth
Neri et al.	2010	CH	BP change after 10-12 weeks of treatment and percentage of women on antihypertensive treatment at delivery, maternal, and fetal outcome	BP did not change after 10–12 weeks of treatment. Lower % of women received antihypertensive drugs in the L-Arg group. The incidence of superimposed PE indicated delivery before the 34th weeks and certain neonatal complications tended to be higher in the placebo group
Monari et al.	2021	CH and previous placenta vascular disorders	Improvements of perinatal outcomes in LDA + L-Arg group, considering	Promising results on BP values, uterine artery PI and the lower need to start a new antihypertensive treatment
Vadillo-Ortega et al.	2011	PE high-risk population	PE	Reduced the incidence of PE
Camarena Pulido et al.	2016	PE high-risk pregnancies	The resulting impact in reducing pregnancy medicalization	L-Arg reduced the cases of PE and led to higher birthweight and less PTB
Rytlewski et al.	2008	threatened PTB	Feto-placental circulation in women with threatened preterm labor.	Oral supplementation with low doses of L-Arg changed feto-placental blood flow distribution in patients with threatened preterm labor
Facchinetti et al.	1996	threatened PTB	Spontaneous uterine contractility	L-Arg significantly reduced the number of contractions, together with an increase of both serum growth hormone and nitrates levels
Petrella et al.	2014	Overweight/obese	Insulin signaling and endothelial function	In overweight/obese women, no responses to L-Arg were found in the 1st or 2nd trimesters. In the 1st trimester, insulin levels were significantly reduced in both groups after L-Arg infusion. Insulin levels during weeks 24–27 were suppressed only in normal-weight women after L-Arg infusion

Table 3. Main characteristics of basic science studies.

Author	Year	Animal model	Indication/target	Administration	Intervention
Kelley D et al.	2013	Multiparous Quarter horse mares	Reproductive parameters	Oral	100 g L-Arg for 1 day during the last 3 weeks of pregnancy
Mateo et al.	2007	52 pregnant gilts (Camborough 22, Pig Improvement)	Reproductive performance	Oral	Corn-soybean-based diets supplemented with 1.0% L-Arg-HCl or 1.7% L-alanine
Mateo et al.	2008	38 first-parity sows (Camborough 22, Pig Improvement Co., Franklyn)	Lactation performance	Oral	1% L-Arg-HCl or 1.7% L-Ala
Li et al.	2015	Exp 1. 62 Landrace gilts (Parity 1) and 113 sows Exp 2. 155 multiparous Landrace sows (Parity ≥ 2)	Reproductive performance	Oral	Exp 1. corn- and soybean meal-based diet supplemented with 1.3% L-Arg HCl or 2.2% l-alanine. Exp 2. 1.3% L-Arg HCl supplementation between d 1 and 14 (n = 41), d 15 and 30 (n = 40), or d 1 and 30 (n = 37), control group 2.2% l-alanine supplementation between d 1 and 30 (n = 37).
Crane et al.	2016	Multiparous Rambouillet ewes naturally stimulated	Reproductive parameter	Intravenous	Injectable and oral Arg supplementation provided for 14 d post breeding
Sales F et al.	2016	Multiparous Romney ewes, with a diet supplement	Fetal growth	Intravenous	Intravenous bolus of either 345 μmol Arg HCl/kg BW or saline solution 3/day from day 100 to 140 of pregnancy
de Boo HA et al.	2005	Pregnant Romney ewes undergone placental embolization with Microspheres	Fetal growth restriction	Intravenous	L-Arg or mixed amino acid (AA) infusion
Vosatka et al.	1998	Wistar rats with or without exposure to maternal hypobaric hypoxia	Fetal growth restriction	Oral	0.2% L-Arg, 2% L-Arg, or 2% glycine in drinking water
Sun et al.	2018	Pregnant sheep with nutrient-restriction (fed 50% NRC requirements)	Fetal growth restriction	Oral	10 g/day of rumen-protected arginine and 2.5 g/day of N-carbamylglutamate
Sun et al.	2017	Pregnant sheep with nutrient-restriction (fed 50% NRC requirements)	Fetal growth restriction	Oral	20 g/day rumen-protected arginine or 5 g/day N-carbamylglutamate
Garbossa et al.	2015	Sows receiving dietary supplement	Fetal development	Oral	Control diet, control + 1% Arg, control + 20mg/kg ractopamine (Rac), and control diet + Arg + Rac from day 25 to 53 of gestation
Berard et al.	2010	Swiss Large White gilts with dietary supplement	Fetal development and myogenesis	Oral	26 g of L-Arg daily from 14 to 28 days of gestation/control
Quensel et al.	2014	Highly prolific crossbred Landrace × Large White sows under 3 dietary supplements	Fetal growth	Oral	Dextrose the week before insemination (190 g/d) and of L-Arg (25.5 g/d) from d 77 of pregnancy until term (DEXA, n = 26); a dietary supplementation of L-Arg only (25.5 g/d), from d 77 of pregnancy until term (ARGI, n = 24)
Gao et al.	2012	Gestating pigs (Yorkshire × Landrace, n = 108) with dietary supplement	Fetal and placental growth	Oral	1.0% L-Arg HCl or 1.7% L-alanine
Li et al.	2010	Gilts (F1 crosses of Yorkshire 3 Landrace sows and Duroc 3 Hampshire boars) with dietary supplement	Fetal growth	Oral	0.0, 0.4, or 0.8% L-Arg (wt:wt) between d 0 and 25 of gestation (10 gilts/treatment)
Li et al.	2014	Gilts (F1 crosses of Yorkshire 3 Landrace sows and Duroc 3 Hampshire boars) with dietary supplement	Fetal growth	Oral	Fed 2/daily 1 kg of a corn- and soybean meal-based diet supplemented with 0.0, 0.4, or 0.8% L-Arg
Bass et al.	2017	97 Pregnant gilts and sows with dietary supplement	Fetal growth and lactation	Oral	Exp 1. control diet 19.8 g standardized ileal digestible Arg/d) or the CON + 1.0% L-Arg (ARG; 46.6 g SID Arg/d). Exp 2. CON or ARG, Sows received 2.73 kg feed/d with CON sows provided 17 g SID Arg/d and ARG sows for a total of 44 g SID Arg/d.
Madsen et al.	2017	30 Low birthweight piglets with dietary supplement	Growth performance	Oral	Milk replacer diets containing either no supplement (CON), CAR (0.40 g/piglet per day) or ARG (1.08 g/kg BW per day)
Zhang et al.	2016	48 Multiparous nutrient-restricted pregnant Hu sheep with dietary supplements	Nutrient restriction	Oral	N-carbamylglutamate (NCG) and rumen-protected L-Arg (RP-Arg)
Peine et al.	2018	32 Rambouillet ewes allocated to 60% restricted diet	Nutrient restriction	Oral	180 mg L-Arg/kg BW (based on initial BW)
Helmbrecht et al.	1996	Timed-pregnant Sprague-Dawley rats receiving L-NAME and dietary supplements	PE, IUGR	Oral	L-Arg (21 mg/kg per day) through delivery
Bursztyn et al.	2003	Pregnant rats with insulin-induced hypertension receiving dietary supplements	Hypertension	Oral	L-Arg given orally (in drinking water) at a dose of 2 g/L
Sharkey et al.	2001	SHHF/Mcc-fa^cp (spontaneous hypertension and heart failure) rats receiving dietary supplements	Placenta gene expression, Hypertension, IUGR	Oral	L-Arg in drinking water (0.5 mg/mL)
Altun et al.	2008	Stress-induced preeclamptic pregnant rats with dietary supplements	PE	Oral	21 mg kg^−1day^−1 L-Arg administered via orogastric route on the 18th and 19th days of pregnancy
Podjarny et al.	2001	Pregnant rats with insulin-induced hypertension with dietary supplements	Hypertension	Oral	2 g/L of L-Arg in the drinking water from day 11 of gestation until delivery
De Costa et al.	2014	Trypanosoma cruzi infected and pregnant Wistar rats with dietary supplements	Chagas disease	Oral	21 mg of L-Arg/kg body weight/day, diluted with distilled water. From this solution, 0.1 ml was given from the 4th day of pregnancy until the 18th day, once a day, in the morning until the day of the experiment

Table 4. Main findings of the basic science studies.

Author	Year	Main outcome	Main finding
Kelley et al.	2013	Plasma Arg concentrations, follicular dynamics, and ovarian and uterine artery blood flow after foaling	Reduced uterine fluid accumulation, while not altering follicular development. L-arg supplementation can be a breeding management tool during the postpartum period to increase reproductive success
Mateo et al.	2008	Reproductive performance of pregnant gilts	L-Arg determined a marked increase of live-born piglets by 2 per litter in gilts
Mateo et al.	2007	Lactation performance of 38 first-parity sows	Potential beneficial effects of dietary Arg supplementation in improving lactation performance of first-parity sows
Li et al.	2015	Reproductive performance of gilts and sows	Dietary Arg supplementation during early gestation increased the number of piglets born alive and live litter birth weight
Crane et al.	2016	Reproductive performance	Supplemental Arg during the first 14 days of pregnancy was ineffective on lambing rates while infusion positively impacted weaning rates
Sales F et al.	2016	Fetal skeletal muscle growth, the abundance and activation of mTOR protein, and postnatal muscle growth of the offspring	Arg increases female lamb weight and muscle weight after birth: changes are associated with altered mTOR protein abundance
de Boo HA et al.	2005	Protein metabolism	Amino acid infusion increased protein accretion better than Arg alone
Vosatka et al.	1998	Fetal growth and hypoxia-induced uricemia	L-Arg ameliorates maternal hypoxia-induced fetal growth restriction in rats
Sun et al.	2018	Fetal growth	Arg and NCG supplementation decreases fetal IUGR by improving metabolic homeostasis and affecting expression of fetal somatotropic axis genes.
Sun et al.	2017	Effects during gestation	The beneficial effect of dietary Arg and NCG supplementation on mammalian reproduction is associated with complex metabolic networks.
Garbossa et al.	2015	Fetal muscle development performance and carcass characteristics of the progeny	L-Arg increased the size of muscular fiber in the semitendinosus muscle of piglets originating from sows. The combination of ractopamine and Arg did not have additive effect and increased the stillbirth
Berard et al.	2010	Porcine fetal development and myogenesis	L-Arginine supplemented during early gestation enhanced fetal survival
Quensel et al.	2014	Within-litter variation of piglet birth weight (BW0)	L-Arg during the last third of pregnancy reduced within-litter changes of birthweight
Gao et al.	2012	Pregnancy outcomes	Dietary Arg supplementation enhances placental growth and estrogen levels in the maternal circulation
Li et al.	2010	Embryonic/fetal survival and growth in gilts	Dietary supplementation with 0.8% L-arginine between day 0 and 25 of gestation, while increasing placental vascularity, adversely affects the reproductive performance of gilts
Li et al.	2014	Embryonic growth and survival	Dietary supplementation with L-Arg at 14–25 days of gestation enhances embryonic/fetal survival in swine
Bass et al.	2017	Piglet birth weight and preweaning performance	Late pregnancy supplementation with L-Arg had no effect on number of pigs born alive, piglet birth weight, or lactation performance
Madsen et al.	2017	Growth performance, carcass composition, organ, and Semitendinosus muscle (STM) development	ARG and CAR supplements were beneficial for muscle maturation
Zhang et al.	2016	Maternal endocrine status; maternal, fetal, and placental antioxidation capability; and placental development	Dietary supplementation of NCG and Arg influence maternal endocrine status, improve the maternal–fetal–placental antioxidation capability, and promote fetal and placental development
Peine et al.	2018	Postnatal growth and development	Arg supplementation during the last two-thirds of gestation can mitigate offspring, but not maternal negative consequences associated with restricted maternal nutrition
Helmbrecht et al.	1996	PE, IURG, and renal glomerular capillary endothelial lesions	L-Arg significantly lowered systolic blood pressure at late pregnancy, increased birthweight, decreased the degree of proteinuria and decreased the proportion of injured glomeruli.
Bursztyn et al.	2003	Endothelial NO synthase in kidney	L-Arg treatment significantly reduced blood pressure, serum creatinine, and excretion of NO metabolites. Expression of endothelial NO synthase in kidneys was doubled
Sharkey et al.	2001	Hypertension and feto/placenta weight	L-Arg prevented the elevation of Blood Pressure, particularly during the third trimester; avoid placenta overweight without effect of fetal growth
Altun et al.	2008	Effect of oral L-Arg treatment on stress-induced hypertensive rats	L-Arg supplementation decreased hypertension, proteinuria and ADMA levels
Podjarny et al.	2001	Fetal growth and blood pressure	L-Arg reversed insulin-induced hypertension and improved fetal weight not affecting plasma insulin/glucose
De Costa et al.	2014	Parasitemia, corticosterone levels, NO production, fetal morphological measurements, heart, and placenta histology	L-Arg supplementation decreased corticosterone and parasitemia, enhanced nitrite concentrations, fetal weight, length and placental weight. Cardiac tissue showed reduced amastigote burdens in the L-Arg group. The placental parasitism was similar between groups