Received: 14 September 2016 | Accepted: 28 December 2016

DOI: 10.1111/jpn.12679

ORIGINAL ARTICLE

Arginine for gestating sows and foetal development:

A systematic review

J. Y. P. Palencia1 | M. A. G. Lemes1 | C. A. P. Garbossa2 | M. L. T. Abreu1 | L. J. Pereira3 |

M. G. Zangeronimo4

1
Animal Science Department, Federal
University of Lavras, Lavras, Minas Gerais,
Brazil
2
Federal Rural University of Amazon –
Campus Paragominas, Paragominas, Pará,
Brazil
3
Health Sciences Department, Federal
University of Lavras, Lavras, Minas Gerais,
Brazil
4
Veterinary Medicine Department, Federal
University of Lavras, Lavras, Minas Gerais,
Brazil
Correspondence
M. G. Zangeronimo, Veterinary Medicine
Department, Federal University of Lavras,
Lavras-MG, Brazil.
Email: zangeronimo@dmv.ufla.br
Summary
The use of functional amino acids during pregnancy has been linked to improved re-
production in mammals. In this context, arginine is a precursor in the synthesis of nu-
merous molecules, such as nitric oxide and polyamines, which play an important role
during reproduction. However, contradictory studies are found in the literature, par-
ticularly regarding the amount of supplementation and the period of pregnancy in
which it is used. The objective of this study was to evaluate the effects of dietary argi-
nine supplementation for pregnant sows on foetal development via a systematic re-
view. The search for papers was performed during the month of December 2015, in
the databases ISI Web of Science, Science Direct, Scopus, and SciELO. From a total of
5675 returned studies, only 13 papers were selected after applying selection criteria.
Most (47%) of the studies that evaluated the effects of dietary arginine supplementa-
tion on foetal development in pigs used 1% arginine. Supplementation was initiated in
the first third of pregnancy in 47% of tests, including in both primiparous and multipa-
rous sows. These studies showed positive results for embryo survival and foetal devel-
opment, evidenced by the increase in placental weight and the number and weight of
piglets born alive. Of all evaluated studies, 53% showed benefits on foetal develop-
ment. It is concluded that supplementing dietary arginine in gestating sows can benefit
embryo survival and foetal development. However, to establish a supplementation
plan with this amino acid, aspects related to the period of pregnancy, supplementation
levels, and source of arginine must be well defined.

KEYWORDS
foetal weight, functional amino acid, litter, reproduction, swine conceptus

1 | INTRODUCTION
In pigs, as well as in other species, proper growth and pre-­natal devel-
opment are essential for post-­natal growth performance (Ashworth,
Toma, & Hunter, 2009). Thus, losses during the period before birth are
hardly corrected later in life, limiting productivity and profitability to
the producer (Schinckel, Einstein, Stewart, Schwab, & Olynkf, 2010).
Therefore, the care of pregnant sows is important, especially consid-
ering nutrition.
For many years, the concept of functional amino acids has been
used in swine nutrition (Mateo et al., 2007). The use of these nutrients
during pregnancy has been widely studied due to their participation in
metabolic pathways related to animal reproductive functions. Among
the functional amino acids, arginine plays a significant role (Wu, 2010;
Wu, Bazer, Johnson, et al., 2010). According to these authors, in addi-
tion to participation in muscle tissue protein synthesis, arginine is also a
precursor of biologically active molecules, such as polyamines and nitric
oxide, which favour embryonic and foetal growth and development.

204 | © 2017 Blackwell Verlag GmbH wileyonlinelibrary.com/journal/jpn J Anim Physiol Anim Nutr. 2018;102:204–213.

PALENCIA et al.
However, studies evaluating the effects of arginine supplementa-
tion for gestating sows on the intrauterine development of the litter
have conflicting results (Li et al., 2015; Novak et al., 2012; Quesnel
et al., 2014). It is known that, in addition to dietary levels of arginine,
lysine, and protein (Li et al., 2014), gestational age for supplementa-
tion (Li et al., 2010), the parity of the sow (Li et al., 2015), the litter size
(Strathe, Strathe, Theil, Hansen, & Kebreab, 2015), and environmental
conditions (Laspiur & Trottier, 2001) may also influence the results. To
date, there is no consensus about the best way to use this amino acid
in diets of gestating sows. Thus, the objective of this study was to ver-
ify the effects of dietary arginine supplementation for gestating sows
on foetal development, using a systematic review of scientific papers.
2 | MATERIALS AND METHODS
2.1 | Research strategy
Two researchers separately conducted an electronic search in the
database PubMed in December 2015 using the following key-
words: arginine, piglets, gestation, sow, and reproduction, forming
six combinations between them in an effort to find the greatest
number of articles. To confirm the results and obtain additional
papers, the same strategy was used in the databases ISI Web of
Science, Science Direct, Scopus, and SciELO. During the search,
filters were used according to their availability in each database.
Thus, books, book chapters, reviews, and articles involving arginine
were chosen, while excluding those evaluating its effects on other
species.
2.2 | Selection of studies
Only studies in which arginine was used as a functional amino acid
for gestating sows, and that evaluated a parameter related to intrau-
terine growth of the conceptus, were selected. There was no date
or language restriction. The researchers were careful to make sure
that all papers were in accordance with the selected criteria for inclu-
sion. In cases of discrepancies between papers, all of the criteria were
­reviewed and discussed among researchers.
2.3 | Quality criteria
The criteria were adapted based on other systematic reviews (Ferreira
et al., 2013; Pereira, Oliveira, Mesquita, Costa, & Pereira, 2011; Silva
et al., 2014) and on the author’s experience. The parameters used
were as follows:
(i) Randomization: randomized trials received a score of 2, while
non-randomized studies or those in which this was not clearly de-
scribed received a score of 1.
(ii) Blind evaluation: trials in which the assessment was conducted
by a blinded examiner received a score of 2; when this was not
clearly described in the text they received a score of 1.
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(iii) Control group: trials using a control group received a score of 2
and those that did not have a control group or did not mention it
in the text received a score of 1.
(iv) Sample size: up to 30 sows per treatment scored 1 and 31, or
more sows received a score of 2.
(v) Breed or genetic line: trials that mentioned breed or genetic line
received a score of 2 and those that did not mention it received a
score of 1.
(vi) Environmental characterization: trials that mentioned environ-
mental parameters were given a score of 2 and those that did not
mention it scored 1.
(vii) Isonitrogenous diet: trials with an isonitrogenous diet scored 2 and
those in which it was not used or mentioned received a score of 1.
(viii) Parity: trials that characterized the sows as primiparous and mul-
tiparous received a score of 2 and those that did not received a
score of 1.
Additional variables such as trial period, the amount of supple-
mented arginine, and analysed variables were used for descriptive pur-
poses, without scoring, to contribute to the discussion.
3 | RESULTS
The results of the search of each database according to the keywords
used and their combinations are shown in Table 1. When the data-
base PubMed was used, a total of 175 articles were found, of which
83% were excluded for being literature reviews or book chapters or
were not related to the purpose of this review. The Science Direct,
ISI, and Scopus databases only added four new articles. The search in
the SciELO database did not produce any results. After the selection
criteria, only 13 articles were selected.
Table 2 shows the general information of the selected papers.
While the selected articles were published in the last 10 years, there
was no date restriction during the search and selection of studies.
Most studies (41%) involved primiparous sows, 35% worked with
multiparous sows, and 24% involved both categories. The number of
animals ranged between papers, with a minimum of nine animals per
treatment and a maximum of 89 animals. Forty-­seven per cent of the
trials supplemented with 1% arginine, while the others supplemented
amounts ranging from 0.4% to 1.3% of arginine. Regarding the supple-
mentation period, 47% of the works studied arginine in the first third
of pregnancy, 18% studied it in the final third, and 35% studied it in
two phases, the middle and final thirds of pregnancy. Only one trial
evaluated this amino acid in the middle third alone.
The feed intake was controlled in almost all trials, varying the
amount of feed by the different phases of pregnancy. Only one trial
did not state the offered amount of feed. Data collection occurred
mostly (65%) at birth. Some trials (Bérard & Bee, 2010; Li et al., 2010,
2014; Novak et al., 2012) evaluated the effects of arginine by sacrific-
ing females on the 25th or 75th day of gestation. Several parameters
were assessed, including parameters related to animal breeding, sow
productivity, piglet performance, and gene expression assays.
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206 | PALENCIA et al.

T A B L E 1 Detailed results of the search

Combinationa
in each database according to the
Database Search 1 2 3 4 5 6 Totalb keywords used

PubMed Total number 40 93 4 18 17 3 175

Selected number 9 4 3 6 6 2 30
Repeated number 0 0 0 0 0 0 0
Science Total number 1646 1721 324 402 156 59 4308
Direct Selected number 3 0 3 1 2 1 10
Repeated number 4 0 4 2 1 1 12
ISI Web of Total number 132 522 59 20 8 4 745
Science Selected number 0 0 0 1 0 0 1
Repeated number 8 5 5 4 5 3 30
Scopus Total number 74 324 34 9 3 3 447
Selected number 0 0 0 0 0 0 0
Repeated number 7 6 4 1 1 1 20
Number of papers selectedc 13
a
1. Arginine and sows; 2. arginine and piglet; 3. arginine and sows and piglet; 4. arginine and sows and
reproduction; 5. arginine and sows and reproduction and gestation; 6. arginine and sows and reproduc-
tion and gestation and piglet.
b
Total number of found articles may be greater than the number of papers used due to the fact that the
same paper appears multiple times in the same database with different keywords.
c
Final number of papers selected.

The quality of the selected articles was evaluated (Table 3) accord-
ing to the established criteria. The maximum score achieved was 15
points (Li et al., 2015; Mateo, Wu, Moon, Carroll, & Kim, 2008) of a
possible 18, while the minimum score was 11 points (Garbossa et al.,
2015; Quesnel et al., 2014; Wu et al., 2012). Seventy-­seven per cent
of the papers reported that their studies were randomized. No article
reported a blind evaluation of the parameters studied. All papers had
a control group and described the breed/animal genetic line, and all
except one (Wu et al., 2012) reported the parity of sows. Only 23% of
the studies (Gao et al., 2012; Li et al., 2015; Novak et al., 2012) used
more than 30 sows per treatment and received a score of 2 for that
parameter. Regarding the environment, only three (Che, Yang, Fang,
Lin, & Wu, 2013; Li et al., 2015; Mateo et al., 2008) evaluated an en-
vironmental variable during the conduction of the trial. Regarding the
experimental diets, 62% of the trials supplemented L-­arginine HCl,
while others used the pure L-­arginine (Table 2). Fifty-­four per cent of
the trials used isonitrogenous diets.
The main results obtained from the use of arginine in diets of ges-
tating sows, and the general considerations regarding these results, are
presented in Table 4. The weight of the placenta was evaluated in eight
studies, of which 38% reported a significant increase with supplemen-
tal doses of 0.4%, 0.8%, or 1.0% L-­arginine HCl only during the first
third of gestation. Regarding the number of foetuses or total number
of piglets, depending on the evaluation of the trial, 15 results were ob-
tained of which only 13% improved with respect to this parameter. In
another 13% of trials these variables worsened, and in the rest of the
trials (74%) there were no significant effects of arginine supplementa-
tion. The number of live foetuses or piglets was measured in 16 trials,
and 44% had a positive effect from arginine supplementation (ranging
from an increase of 0.4% to 1.3% in the first third or the last two-­thirds
of gestation—Tables 2 and 4), 12% had a negative effect, and 44% had
no significant effects. Ten results evaluated the total weight of the foe-
tuses or piglets, and the majority (70%) indicated that arginine supple-
mentation has no effect on this variable, while two studies observed
increases in piglet weight and one study reported a decrease. Arginine
supplementation improved the live weight of piglets or foetuses in eight
of 17 results (47%) that evaluated this variable. However, 41% of the
trials did not show a significant effect, and 12% had a negative effect.
Overall, arginine supplementation in the diets of gestating sows
benefitted foetal development in 53% of trials. The other trials did not
show a beneficial effect: 29% did not show a statistical difference, and
18% showed a negative effect.
The effects of dietary arginine supplementation on the plasma
concentration of amino acids were evaluated in eight studies (Table 5).
In all these studies there was an influence of dietary arginine on some
plasma amino acid of the sows. Plasma arginine increased in all stud-
ies, followed by ornithine (seven studies), proline (five studies), and
citrulline (one study). On the other hand, there were decreases in
aspartate and glutamate (two studies), glutamine (three studies), and
alanine (six studies).
4 | DISCUSSION
Systematic reviews are an important tool for the scientific community
in general and can offer a comprehensive and complete view of study
results over time, allowing for new knowledge and the emergence
of new research topics. In addition, the evaluation criteria allow for
 TABLE 2 Summary of the general data of the selected papers to evaluate the effect of arginine supplementation during gestation in sows
PALENCIA et al.

Reference A B C D E F G H I
a
Mateo et al. (2007) Pri 28 24 1.0% 30–114 2.0 20.0 BIR LW and BF of the sow; plasma urea and amino acid; TNB, NBA, TBW,
and WBA
Mateo et al. (2008) Pri 18 20 1.0%b 30–114 2.0 20.0 BIR WBA
b
Bérard and Bee (2010) Pri 10 10 0.87% 14–28 3.0 26.1 75 GD Oestrogen sulphate and blood amino acids; PW NVF; WVF and
mummified foetuses; weight of heart, liver, kidney, brain; morphology
of the semitendinosus and rhomboid muscle
Li et al. (2010) Pri 10 10 0.4%a 0–25 2.0 8.0 25 GD Ammonia, urea, glucose, progesterone, oestrogen, and oestrogen
Pri 10 10 0.8%a 0–26 2.0 16.0 25 GD sulphate in the blood; PW; AmLV, AlLV for amino acids and
hormones. Corpus luteum number, total of embryos; length and
weight.
Gao et al. (2012) Pri, Mul 56 52 1.0%b 22–114 22–90 = 2.0 22.6 BIR BF and blood parameters of the sow (estradiol, progesterone, urea,
90–114 = 3.0 amino acids). TNB; MNV, stillbirth, mummified, PW, and WBA.

Liu et al. (2012) Mul 9 9 1.0%b 90–114 2.0 20.0 BIR Blood parameters (free amino acids, VEGF, eNOS, hormones). NNT,
NBA, TBW, WBA, parameter in the umbilical vein (RT-­PCR for VEGF,
eNOS); RT-­PCR (miR-­15b, miR-­16, miR-­221, miR-­222).
Novak et al. (2012) Mul 35 33 20 g 15–44 Not informed 20.0 Gestation PW, corpus luteum number, number and weight of the embryos; gene
expression of the embryo and placenta.
Wu et al. (2012) Mul 9 9 1.0%b 90–114 2.0 20.0 BIR Blood parameters and gene expression (NO, eNOS, VEGFA, PIGF1);
number and weight of piglets.
Che et al. (2013) Mul 20 20 1.0%b 30–90 1–30 = 2.0 18.3 BIR Blood parameters of the sow (amino acids, total protein, urea, IgG,
31–60 = 2.2 IgM). Born alive, stillbirth, mummified. Litter and individual weight.

61–90 = 2.6
91–114 = 3.2
Mul 20 20 1.0%b 30–114 1–30 = 2.0 18.3 BIR
31–60 = 2.2
61–90 = 2.6
91–114 = 3.2
Li et al. (2014) Pri 14 15 0.4%a 15 – 25 2.0 8.0 25 GD Blood parameters (amino acids, sodium, potassium, calcium, progester-
a one, estradiol, oestrogen, oestrogen sulphate), uterine weight, corpus
Pri 14 14 0.8% 15 – 25 2.0 16.0 25 GD
luteum number, PW, AmLV, and AlLV; placenta and endometrium
amino acids; amino acids and fructose in the AmLV and AlLV;
electrolytes in the ALF; progesterone, estradiol, oestrogen, oestrogen
sulphate in the ALF; NTF, NVF, foetal length, and weight.

(Continues)
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 | 208

TABLE 2 (Continued)

Reference A B C D E F G H I

Quesnel et al. (2014) Pri, Mul 23 24 0.77%a 77–114 3.3 25.4 BIR LW and BF of the sow; TNB, NBA, stillbirth, WBA
Li et al. (2015) Pri, Mul 86 89 1.3%a 1–30 1 -­3 = 1.8 22.8 BIR LW of the sow, BF, blood parameters (urea, ON, ammonia, endothelial
4 -­30 = 2.0 factor of growth, electrolytes, amino acids, and polyamines). TNB,
NBA, TBW, WBA, and dead.
31 -­84 = 2.2
85–107 = 3.5
108-­birth = 3.5
b
Mul 37 37 1.3% 1–30 1–3 = 1.8 22.8 BIR
41 1–14 4–30 = 2.0
40 15–30 31–84 = 2.2
85–107 = 3.5
108–birth =3.5
a
Garbossa et al. (2015) Pri, Mul 23 23 1.0% 25–53 1–28 = 2.3 21.3 BIR BF, PW. NBA, stillbirth, mummified; WBA, morphology of the
28–90 = 1.8 semitendinosus muscle; brain weight; post-­natal performance; pork
quality at the end of fattening period
91–110 = 2.8
111–114 = 2.6

A. Parity; B. number of animals in the control group; C. number of animals in the groups that received arginine; D. arginine dose and source; E. supplementation period (days); F. daily feed intake (kg) during
pregnancy period (days); G. arginine intake (g/day); H. day of collection; I. evaluated parameters.
PRI, primiparous; MUL, multiparous; LW, live weight; BF, backfat thickness; TNB, total number of viable foetuses or piglets born; NBA, number born alive; TBW, total birth weight; WBA, weight of born alive;
PW, placenta weight; NTF, number of total foetuses; NVF, number of viable foetuses; WVF, weight of viable foetuses; AmLV, amniotic liquid volume; AlLV, allantoic fluid volume; BIR, birth; GD, gestation day;
NO, nitric oxide; eNOS, endothelial nitric oxide synthase; VEGFA, endothelial growth factor a; PIGF1, placenta growth factor 1.
a
L-­arginine HCl; bL-­arginine.
PALENCIA et al.

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PALENCIA et al. | 209

T A B L E 3 Evaluation of the quality of

Reference A B C D E F G H Total
the papers according to the selection
criteria Li et al. (2015) 2 1 2 2 2 2 2 2 15
Mateo et al. (2008) 2 1 2 1 2 2 2 2 14
Che et al. (2013) 2 1 2 1 2 2 2 2 14
Gao et al. (2012) 2 1 2 2 2 2 1 2 14
Li et al. (2014) 2 1 2 1 2 2 1 2 13
Li et al. (2010) 2 1 2 1 2 2 1 2 13
Bérard and Bee (2010) 2 1 2 1 2 2 1 1 12
Liu et al. (2012) 2 1 2 1 2 2 1 1 12
Mateo et al. (2007) 2 1 2 1 2 2 1 2 13
Novak et al. (2012) 1 1 2 2 2 2 1 1 12
Garbossa et al. (2015) 1 1 2 1 2 2 1 1 11
Quesnel et al. (2014) 1 1 2 1 2 2 1 1 11
Wu et al. (2012) 2 1 2 1 2 1 1 1 11

A. Randomization: 2 for randomized and 1 for non-­randomized or unclear in the text; B. blind evalua-
tion: 2 for blind and 1 when not clear in the text; C. control group: 2 for trials using a control group and
1 for those without a control group or when unclear in the text; D. sample size: 2 for trials using more
than 30 sows per treatment and 1 for those using 30 or fewer sows; E. breed or genetic line; F. parity:
2 for trials that categorized females as primiparous or multiparous and 1 when the parity was not dis-
closed; G. environment characterization: 2 for trials that mentioned environmental parameters and 1
when it was not mentioned or unclear in the text; H. isonitrogenous diets: 2 for trials with isonitroge-
nous diets and 1 when it was not used or not mentioned in the text.

T A B L E 4 Effect of arginine
Reference A B C D E F
supplementation during gestation in sows
from selected studies Mateo et al. (2007) NE NS 2.3 NS 24.18 +
Mateo et al. (2008) NE NE NE NE NS IND
Bérard and Bee (2010) NS NS 3.7 NS 32.7 +
Li et al. (2010). Trial 1 NS −0.5 −0.4 NE 7.3 −
Li et al. (2010). Trial 2 NS −3.1 −3.1 NE −50.9 −
Gao et al. (2012) 16.11 1.3 1.1 8.28 10.75 +
Liu et al. (2012) NE NS NS NS 15.16 +
Novak et al. (2012) NS NE NS NE NS IND
Wu et al. (2012) NE NS NS NS 10.96 +
Che et al. (2013). Trial 1 NE NS NS NS NS IND
Che et al. (2013). Trial 2 NE NS 1.62 NS NS +
Li et al. (2014). Trial 1 33.98 NS 2.2 NE NS +
Li et al. (2014). Trial 2 20.97 NS 1.7 NE NS +
Quesnel et al. (2014) NE NS NS −20.1 −23.3 −
Garbossa et al. (2015) NS NS NS NE NS IND
Li et al. (2015). Trial 1 NE 1.16 1.24 8.25 8.03 +
Li et al. (2015). Trial 2 NE NS NS NS NS IND

A. Placenta weight (% of increase compared to the control group); B. number of foetuses or total piglets
born compared to the control; C. number of viable foetuses or piglets born alive compared to the
­control; D. difference in per cent in the weight of foetuses or total piglets born compared to the con-
trol; E. difference in per cent in the weight of viable foetuses or piglets born alive compared to the
control; F. benefits of using arginine.
NS, not significant; NE, not evaluated; IND, indifferent.

improvement of the methods and protocols used in the conduction However, items not related to the keywords used or that did not meet
of research. In this study, the authors endeavoured to ensure that the established criteria were disregarded (Ferreira et al., 2013; Silva
all scientific articles related to the topic were present in the review. et al., 2014).
 | 210

TABLE 5 Effect of arginine supplementation during gestation on plasma concentration of amino acids in sows from selected studies

Amino acidsa

Other AA
Reference A B C Arginine Proline Ornithine Citrulline Aspartate Glutamate Glutamine Alanine profileb

Mateo et al. (2007) 1% 30–114 30 NS NS NS NS NS NS NS NS NS

1% 30–114 70 79.9 31.29 44.76 NS NS NS −15.11 −91.49 NS
1% 30–114 110 76.68 28.72 52.63 NS NS NS −34.36 −35.33 NS
Bérard and Bee 0.87% 14–28 24 69.66 NS 45.91 NS NS NS −13.54 −15.1 Yes c
(2010)
Li et al. (2010) 0.4% 0–25 25 70.73 34.09 51.56 NE NS NS NE −53.27 NS
0.8% 0–25 25 104.07 40.91 45.31 NE −40 −31.08 NE −191.09 NS
Gao et al. (2012) 1% 22–114 40 87.1 32.04 46.96 NE NS NS NS NS NS
1% 22–114 70 128.81 35.68 60 NE NS NS NS NS NS
1% 22–114 90 100.05 42.67 82.05 NE NS NS NS NS NS
Liu et al. (2012) 1% 90–114 110 22.58 NS NE NE NS NS NE NE NE
Che et al. (2013) 1% 30–90 30 NS NS NS NE NE NE NE NS NE
1% 30–114 30 NS NS NS NE NE NE NE NS NE
1% 30–90 90 106.82 12.09 46.4 NE NE NE NE −93.24 NE
1% 30–114 90 108.64 13.19 45.6 NE NE NE NE −87.88 NE
1% 30–90 110 NS NS NS NE NE NE NE NS NE
1% 30–114 110 90.2 19.19 60.81 NE NE NE NE −96.32 NE
Li et al. (2014) 0.4% 14–25 25 94.41 NS 55.7 NS NS NS NS NS NS
0.8% 14–25 25 108.7 NS 50.63 NS −63.64 −59.3 −19.3 −154.92 NS
Li et al. (2015). Exp. 1.3% 1–30 1 NS NS NS NS NS NS NS NS NS
2 1.3% 1–30 14 54.14 NS 58.64 14.12 NS NS NS −24.87 NS
1.3% 1–30 28 48.42 31.6 55.43 NS NS NS NS −23.11 NS

A. Arginine dose; B. supplementation period (days); C. day of blood sampling.

a
Increase or decrease in AA concentration in the plasma compared to the control group.
b
change in the profile of the other AA.
c
alteration of: asparagine, serine, threonine, tyrosine, phenylalanine, leucine, and aminobutyrate. NS: Not significant; NE: not evaluated.
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PALENCIA et al.
To make a quality assessment, criteria including the presence or ab-
sence of randomization, blind evaluation, presence of a control group,
and number of animals per treatment were employed. These types of
criteria are important because they allow characterization of the study
and provide a sense of quality. None of the studies mentioned the use
of a blind evaluation, a procedure which should be standard in any
experiment to give credibility to the results (Jadad et al., 1996). The
environmental characterization in trials with arginine is also extremely
important, because, for example, in heat stress situations blood flow
is redirected from peripheral organs (Black, Mullan, Lorschy, & Giles,
1993). Thus, the metabolic requirement for arginine may be increased
as this compound is the primary substrate for nitric oxide synthesis
(Ignarro, Buga, Wood, Byrns, & Chaudhuri, 1987), which plays a key
role in vasodilation and blood flow (Lacasse, Farr, Davis, & Prosser,
1996). Therefore, it has been hypothesized that high environmen-
tal temperatures increase the use of arginine and, consequently, its
­dietary requirement (Laspiur & Trottier, 2001).
Considering the selected papers, arginine had beneficial effects on
pig foetus development in the majority (53%) of cases, mainly influ-
encing the weight of those born alive and, in some situations, the litter
size. Previous studies have associated these results with the fact that
arginine is a precursor for the synthesis of many important metabolic
molecules, including nitric oxide and polyamines, which participate in
foetal development (Bazer, Wang, Johnson, & Wu, 2015; Wu et al.,
2013). Nitric oxide has been linked to increased blood flow (Reynolds
et al., 2006), while polyamines stimulate angiogenesis, embryogene-
sis, and placental growth (Wu, Bazer, Hu, Johnson, & Spencer, 2005).
However, these effects may vary with different intrinsic characteristics
of the animal or of the diet.
Regarding parity, primiparous sows have different nutritional re-
quirements compared to multiparous sows, and young females are not
fully developed and have a lower reproductive performance (Eissen,
Kanis, & Kemp, 2000). Thus, parity could influence the effects of ar-
ginine supplementation during pregnancy. However, the trials pre-
sented in this review showed beneficial effects for both primiparous
and multiparous sows, demonstrating the potential of this amino acid
in improving reproductive performance of animals. Li et al. (2015)
found that supplementation of 1.3% of L-­arginine HCl during the
first 30 days of gestation of primiparous and multiparous sows led to
similar beneficial effects for both groups. However, no studies have
separately evaluated different levels of arginine for primiparous and
multiparous sows. Research in this direction would be interesting to
determine the optimal level of supplementation of this amino acid in
the diet, as primiparous sows have higher nutritional requirements
than multiparous sows.
Arginine source is also an important point to be considered, mainly
because there are different products with different concentrations of
arginine, leading to different responses. Currently, there are mainly two
sources of available arginine, L-­arginine 98% and L-­arginine HCl 83%
arginine. Considering the trials with beneficial effects on foetal devel-
opment, the majority (78%) worked with L-­arginine HCl, which may be
related to the lower cost of the product in relation to the pure source,
although it is necessary to increase the level of supplementation to
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| 211
ensure its effects. There were no studies comparing the two sources
of arginine in the diet of gestating sows, hindering any inference about
the best source to be used. However, the two sources are well toler-
ated by pigs (Wu et al., 2016).
Arginine supplementation levels varied in the selected papers
(0.4% to 1.3%), being that the most tested level (47% of trials) was 1%.
From these studies, 63% observed positive effects of arginine, 37%
no observed difference, and none observed negative effects. Only Li
et al. (2010) and Quesnel et al. (2014) observed negative effects of
arginine supplementation. In these studies, 0.8% or less of arginine
was tested. However, Li et al. (2014) observed positive effects on the
litter size when used 0.4% or 0.8% of arginine. But these authors used
the arginine supplementation only during the 15th and 25th days of
pregnancy. Supplementation of amino acids in the diet requires careful
control, mainly to avoid any imbalance, which could cause losses in an-
imal production. Within these amino acids, the relationship between
arginine and lysine should be considered, as both have the same trans-
port systems for intestinal absorption. The competition between these
nutrients could harm animal performance (Wu, Bazer, Burghardt, et al.,
2010). None of the papers used in this systematic review made it clear
if there was concern about the relationships between the amino acids
present in the diet. This feature must be considered in future research.
For the period of arginine supplementation, there is still no con-
sensus regarding the ideal time to supplement, although the research
points to the first third of pregnancy as the period which could obtain
the best results. In pigs, pregnancy is commonly divided into three
periods; the first (1st to 21st day) is characterized by maternal recog-
nition of pregnancy and embryo implantation in the uterus (Geisert,
Zavy, Moffatt, Blair, & Yellin, 1989). The other two periods (22nd to
75th day, and 76th day to the day of delivery) are characterized by
development and foetal growth. During the first third of pregnancy,
the formation of the placenta occurs, which is directly related to foe-
tal development (Jones, Powell, & Jansson, 2007), as the amount of
nutrients transported across the placenta depends on the size and
efficiency of this tissue (Vallet & Freking, 2007). Because arginine
and its metabolites are related to angiogenesis and improved blood
flow, it is assumed that supplementation during the first third of preg-
nancy could be more favourable for foetal development by allowing
greater placental development. Furthermore, it is in the first third of
pregnancy that the most embryonic deaths occur. Therefore, arginine
could improve embryo survival and, consequently, increase the size
of the litter.
The 2nd and 3rd third periods of gestation are characterized by
increased foetal development. The increase in the size or number of
foetuses at that stage can limit the availability of oxygen and nutri-
ents for the foetus, in addition to restricting the space for foetal de-
velopment (Fix et al., 2010; McPherson, Ji, Wu, Blanton, & Kim, 2004).
Arginine supplementation during these final stages could promote
foetal growth and reduce variation in birth weight. In this review, the
trials that supplemented arginine during the 2nd and 3rd periods of
gestation had an average increase of 12% in the foetal or live piglet
weight and an increase in one foetus or live piglet per litter, depend-
ing on the methodology of the study. The trials that supplemented

212 | PALENCIA et al.
arginine in the first third of pregnancy obtained an increase of 10% in
weight and an additional 2.2 foetuses or live piglets.
Increases in plasma arginine concentration were observed when
arginine was added in the diet. However, Wu, Bazer, Cudd, et al.
(2007) demonstrated that 40% of the dietary arginine is metabolized
in the small intestine and liver in other substances as ornithine, for
example. In fact, increases in ornithine were observed in several stud-
ies. Moreover, the competition with other amino acids by sites of in-
testinal absorption has limited the use of dietary arginine in animal
nutrition. In addition to L-­arginine studies, the supplementation of
arginine precursors has been also studied in recent years. According
to Wu, Bazer, Davis, et al. (2007), arginine, glutamine, glutamate, pro-
line, aspartate, asparagine, ornithine, and citrulline are interconvertible
via complex interorgan metabolism in most mammals, including the
pig. Moreover, Zhang et al. (2014) demonstrated that 500 mg/kg of
N-­carbamylglutamate (NCG) throughout the gestation significantly
improved the reproductive performance of the gilts. The authors asso-
ciated this result to the increase in plasma arginine and the angiogenic
factors expression in the placenta. Also, supplementation of 0.1%
NCG or 1% of L-­arginine HCL between days 90 and 114 of gestation
significantly improved the litter weight at birth (Liu et al., 2012) and
birth weight of piglets (Wu et al., 2012). These results indicate that
arginine precursors can also improve the reproductive performance
of sows avoiding, in this case, problems with the intestinal absorp-
tion of other amino acids caused by the excess of arginine in the diet.
However, the comparison between the addition of different arginine
precursors with arginine is scarce on the literature, mainly on repro-
ductive performance of sows.
This study determined that arginine supplementation during ges-
tation improves parameters associated with the reproductive perfor-
mance of sows and foetal development. However, some studies found
no effects of arginine supplementation or even showed negative
results. This may be related to the biochemistry of the amino acids,
interrelationship between nutrition and reproductive physiology,
control of environmental variables, unknown content of crude or true
protein in the basal diet, and differences in experimental protocols
utilized. The studies evaluated in the present review point that re-
cent researches on dietary arginine or their metabolites as NCG which
stimulate in vivo arginine synthesis in gestating sows can be consid-
ered one of the great advances in pig nutrition research. Therefore,
future studies are necessary to evaluate the effects of arginine sup-
plementation in gestating sows and confirm the results previously
­reported in the literature.
5 | CONCLUSION
Dietary arginine supplementation in gestating sows can benefit em-
bryo survival and foetal development. Adequate provision of arginine
to a gestation diet is necessary to maximize embryonic and foetal
survival in gilts and sows. However, to establish a supplementation
plan with this amino acid, aspects related to the period of pregnancy,
supplementation levels, and source of arginine must be well defined.
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AC KNOW L ED G EM ENTS
The authors thank CAPES, FAPEMIG and CNPq (process number
305478/2015-0) by financial support for research.
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How to cite this article: Palencia JYP, Lemes MAG, Garbossa
CAP, Abreu MLT, Pereira LJ, Zangeronimo MG. Arginine for
gestating sows and foetal development: A systematic
review. J Anim Physiol Anim Nutr. 2018;102:204–213.
https://doi.org/10.1111/jpn.12679