Abstract Threatened abortion is a common problem in early pregnancy. This early vaginal bleeding happens in about 25% of pregnant women. The medications including progesterone, uterine muscle relaxant or human chorionic gonadotropin have essential effects in developing pregnancy, but the clinical data are insufficient to prescribe them. In recent decades, medicinal herbs can help us to present new treatments. Grape (Vitis vinifera L.) can protect the fetus from the perspective of Persian medicine. So, we hypothesize about the salutary effects of grape in miscarriage prevention. We found five standard expected mechanisms of grape to prevent threatened abortion: immunomodulatory and anti-inflammatory, anti-oxidant, anti-contraction, hormonal and anti-stress activities. Grape reduces nitric oxide, prostaglandin E2, expression of nuclear factor κB and other pro-inflammatory cytokines like IL (Interleukin)-1β, IL-6, IL-8, and tumor necrosis factor-α. It also elevates anti-inflammatory mediators and expression of peroxisome proliferator-activated receptor-γ. Grape polyphenols have a crucial role in fetus protection with high antioxidant power and other functions such as prevention of stress-triggered abortion with proanthocyanidins, or hormonal effects and inhibition of uterine contractions with resveratrol. So according to these studies, grape probably has effects on the immune and endocrine factors involved in threatened miscarriage.

1. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
131
doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
Persian Medicine
The potential role of grape (Vitis vinifera L.) in prevention of
threatened abortion via immunomodulatory and anti-inflammatory
abilities: a hypothesis
Malihe Tabarrai1
, Mozhgan Mehriardestani2
, Sharareh Hekmat2
, Fatemeh Nejatbakhsh1
, Fatemeh
Moradi1,
*
1
Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran,
Iran. 2
Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences,
Tehran, Iran.
*Corresponding to: Fatemeh Moradi, Department of Traditional Medicine, School of Persian Medicine, Tehran
University of Medical Sciences, Tehran, Iran. E-mail: dfmoradi@gmail.com.
Highlights
This paper proposed a hypothesis that grape (Vitis vinifera L.) could control threatened abortion due to its
immunomodulatory and anti-inflammatory, anti-oxidant, anti-contraction, hormonal and anti-stress activities.
Traditionality
According to the records of traditional Persian medicine literatures, Grape (Vitis vinifera L.) had the function of
fetal protection. Grape and grape molasses could produce good blood humor, the basic substances and fluids found
in human body. As mentioned in Makhzan al-Advieh (1670 A.D.-1749 A.D.) and Tohfat al-Momenin (16th century),
the leaf extract of Grapevine could prevent abortion. Rhazes, a great scientist of the 9th century A.D., also poineted
out that unripe grapes juice could fortify the stomach of pregnant women and prevent the fetus from abortion in
Al-Hawi (854 A.D.-925 A.D.) .

2. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
132
doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
Abstract
Threatened abortion is a common problem in early pregnancy. This early vaginal bleeding happens in about 25% of
pregnant women. The medications including progesterone, uterine muscle relaxant or human chorionic
gonadotropin have essential effects in developing pregnancy, but the clinical data are insufficient to prescribe them.
In recent decades, medicinal herbs can help us to present new treatments. Grape (Vitis vinifera L.) can protect the
fetus from the perspective of Persian medicine. So, we hypothesize about the salutary effects of grape in
miscarriage prevention. We found five standard expected mechanisms of grape to prevent threatened abortion:
immunomodulatory and anti-inflammatory, anti-oxidant, anti-contraction, hormonal and anti-stress activities.
Grape reduces nitric oxide, prostaglandin E2, expression of nuclear factor κB and other pro-inflammatory cytokines
like IL (Interleukin)-1β, IL-6, IL-8, and tumor necrosis factor-α. It also elevates anti-inflammatory mediators and
expression of peroxisome proliferator-activated receptor-γ. Grape polyphenols have a crucial role in fetus
protection with high antioxidant power and other functions such as prevention of stress-triggered abortion with
proanthocyanidins, or hormonal effects and inhibition of uterine contractions with resveratrol. So according to
these studies, grape probably has effects on the immune and endocrine factors involved in threatened miscarriage.
Keywords: Vitis vinifera L., Grape, Oxidation, Immunomodulation, Inflammation, Abortion, Persian medicine
Concepts:
Humor: Humors are basic substances and fluids found in human body. The 4 humors are black bile, yellow bile,
phlegm, and blood.
Abbreviations:
hCG, Human chorionic gonadotropin; Th, T helper; IL, Interleukin; TNF-α, Tumor necrosis factor-α; IFN-γ,
Interferon-γ; NO, Nitric oxide; PGs, Prostaglandins; ICAM, Intracellular adhesion molecules; VCAM,
Vascular cell adhesion molecule; PGF2α, Prostaglandin F2α; PGE2, Prostaglandin E2; COX-2,
Cyclooxygenase-2; iNOS, Inducible nitric oxide synthase; EGF, Epidermal growth factor; PDGF,
Platelet-derived growth factor; SLE, Systemic lupus erythematosus.
Acknowledgments:
This study has been partially supported by Tehran University of Medical Sciences (Grant No.
95-04-86-33380).
Competing interests:
The authors declare that they have no conflict of interest.
Citation:
Malihe Tabarrai, Mozhgan Mehriardestani, Sharareh Hekmat, et al. The potential role of grape (Vitis vinifera L.)
in prevention of threatened abortion via immunomodulatory and anti-inflammatory abilities: a hypothesis.
Traditional Medicine Research, 2019, 4(3): 131-139.
Executive Editor: Cui-Hong Zhu. Submitted: 20 February 2019, Accepted: 27 March 2019, Online: 8 April 2019.

3. HYPOTHESIS
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doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
Background
Threatened abortion in International Classification of
Diseases 10th
revision (2019) is defined: “Uterine
bleeding from a gestation of fewer than 20 weeks
without any cervical dilatation. It is characterized by
vaginal bleeding, lower back discomfort, or midline
pelvic cramping and a risk factor for miscarriage” [1].
Threatened miscarriage is a prevalent disorder and
almost a quarter of pregnant women are diagnosed
with significant vaginal bleeding in early pregnancy.
Finally, about 50% of these pregnancies lead to
abortion [2]. The medications including progesterone,
hCG (human chorionic gonadotropin) or uterine
muscle relaxant are prescribed empirically for
threatened abortion. Although some of these
medications have important physiological roles in
pregnancy development, the clinical data are
insufficient to advise them [3]. In this regard,
medicinal herbs could help us to discover new
treatments [4]. There are few in vivo or in vitro studies
on medicinal herbs for miscarriage prevention. While
throughout the world, many pregnant women use
medicinal herbs to prevent threatened abortion [5-9].
One of the medicinal herbs that can have functions on
the immune and endocrine factors involved in
threatened abortion is grape (Vitis vinifera L.). There
are several phenolic compounds, flavonoids, and
stilbenes in different grape components including seed,
fruit, skin, pomace, and stem [10]. For example,
resveratrol, a polyphenol found only in grapes and not
available in other vegetables and fruits, was shown to
exert an antioxidant activity on some prenatal
metabolic disorders like low protein diet, maternal
obesity, gestational diabetes mellitus and hypoxia [11,
12]. In addition to antioxidant properties, many
investigations have been conducted on the grape
pharmacological activities such as anticancer,
anti-inflammatory, antibacterial and antidiabetic effects
with skin, liver, heart and neural system protection
[10].
From the viewpoint of the Persian medicine,
pregnancy loss has three main causes, including
trauma, maternal factors, and fetal factors [13, 14]. The
discontinuation of uterine bleeding is crucial in early
pregnancy, because even if it does not lead to abortion,
it causes weakness in fetus and variety of
mild-to-severe illnesses in newborn after birth [15].
Therefore, Persian physicians controlled bleeding
during pregnancy and administrated tonic foods and
“fetus protection” medicines to strengthen mother and
fetus. Undeniably, main cause of abortion cannot be
resolved during pregnancy in most cases, because most
treatments is not safe in pregnant woman. So, the main
treatment for this condition is after miscarriage and
before proceeding to the next pregnancy. In Persian
medicine references such as The Canon of
Medicine (written by Avicenna, 980 A.D.-1037 A.D.)
and Great Elixir (written by Mohammad Azam Khan,
1814 A.D.-1902 A.D.), there were many medications
and foodstuffs for reduce bleeding in early pregnancy
[13, 16], and the grape was one of the remedies for
fetal protection [17, 18]. This hypothesis discusses the
possible role of grape in fetus protection and abortion
prevention.
The hypothesis
It is hypothesized that grape can prevent or control
threatened abortion with its immunomodulatory,
anti-inflammatory and antioxidant activities and
inhibiting uterine contractions.
Evaluation of the hypothesis
Grape in Persian medicine
Grape has been named Enab in Persian medicine.
Grape is one of the best fruits, because it has high
nutrition and is a body booster. Grape and grape
molasses also produces good blood humor (Humors
are basic substances and fluids found in human body,
including black bile, yellow bile, phlegm, and blood.)
[17]. Grapevine called Karm in Persian medicine texts.
In the traditional Persian medicine references as
Makhzan al-Advieh (written by Aghili, 1670
A.D.-1749 A.D.) and Tohfat al-Momenin (written by
Mohammad Momen, 16th century), it was mentioned
that its leaf extract could prevent abortion. Unripe
grape reduces laxity of tissues and strengthen the body.
The paste of unripe grape, in addition to protecting the
fetus, fortifies the viscera and decreases
inflammation of stomach [17, 18]. Rhazes, a great
scientist of the 9th century A.D., in Al-Hawi (written
by Rhazes, 854 A.D.-925 A.D.) noted that verjuice
(unripe grapes juice, used as vinegar) could fortify the
stomach of pregnant women and prevent the fetus from
abortion [19].
Mechanisms of threatened abortion
Although inflammation has a necessary role in
successful implantation and healthy development of
pregnancy, excessive inflammation and immune
suppression are the crucial mechanisms of miscarriage.
Also, inflammation has more adverse pregnancy
outcomes like preeclampsia [20, 21].
Balance of Th (T helper) 1/Th2 to shift toward Th2
is essential for maintaining a healthy gestation [20, 21].
Th2 cells are involved in humoral immunity. Th2
cytokines [IL (interleukin)-4, IL-5, IL-6, IL-9, and
IL-10] cause fetal immune protection. On the other
side, Th1 cells produce IL-2, IFN-γ (interferon-γ), and
TNF-α (tumor necrosis factor-α) and have an essential
role in autoimmune diseases and fetal immune
impairment. So, the primary factor causing abortion is

4. HYPOTHESIS
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doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
strengthening of Th1 cell-mediated immunity [21, 22].
Progesterone also can enhance Th2 immune reaction
and attenuate Th1 immune reaction. It seems
progesterone is a more important factor in the
prevention and treatment of miscarriage because
progesterone modulates the maternal immune system
and suppresses the inflammatory response. It also
develops a uterus, nourishes eggs, improves
uteroplacental circulation, supports the luteal phase
and decreases contraction of uterus smooth muscle
after implantation. So, insufficient secretion of
progesterone plays a vital role in threatened abortion
and recurrent miscarriage [22-24].
Estrogens also are needed for maintenance and
continuance of pregnancy [25]. They could inhibit the
immune response of the mother to the fetus and so
prevent miscarriage [26]. Estrogens increase
expression of the progesterone and strengthen the
progesterone activities [27]. Furthermore, hCG from
trophoblastic cells decrease the immune activity of
lymphocytes and protect the fetus from maternal
immune attack [22]. Some disorders like
hypercoagulable state also result in abortion through
immunological rejection or placental damage [3].
Oxidative stress or toxic agent are incriminated for
initiation of spontaneous abortion. Therefore,
antioxidants with detoxifying and repairing oxidation
damaged can be useful in miscarriage [21, 28, 29].
NO (nitric oxide) and PGs (prostaglandins) have
different effects on abortion and pregnancy periods and
the mechanisms of action are not precisely clear. PGs
and NO donors are administrated for cervical ripening
before first-trimester surgical termination of pregnancy
[30, 31]. In preterm labor and also during cervical
ripening in late pregnancy, NO is increased in cervical
fluid [32].
However, in early pregnancy, NO is required for
embryonic development. On the other side, Serum NO
concentration in threatened abortion looks like normal
pregnancy [31]. However, elevation in serum level of
NO in recurrent abortion [33] and decreased NO in
missed abortion [31] have been detected. PGs are also
needed for successful embryonic implantation. They
can suppress rejection of the fetal allograft [34]. Use of
nonsteroidal anti-inflammatory drugs around the time
of conception leads to abnormal implantation and
miscarriage [3, 35]. However, on the other side,
inadequate inhibition of uterine PGs may be correlated
with abortion [30].
In addition to the above mentioned, more factors are
involved in abortion mechanisms such as: activation of
cytotoxic T cells, natural killer cells [20-22, 36];
elevation of Th17 and related cytokines like IL-17,
IL-23 [21, 36], ICAM-1 (intracellular adhesion
molecules-1), VCAM-1 (vascular cell adhesion
molecule-1), IL-2 [22, 37], T-cell immunoglobulin
mucin-3 and adipsin [36]; decreased activation of
regulatory T cells [21, 36], TGF-β, [37, 38]; premature
or aberrant activation of NF-κB [21], etc.
Putative mechanisms of grape to prevent
threatened abortion
Grape polyphenols have many biological activities that
could prevent and treat several diseases. The most
critical polyphenolic compounds in grape are
flavonoids, flavanols, anthocyanins, resveratrol,
quercetin, epicatechin, etc. [39, 40]. Polyphenolic
compounds of grape, like resveratrol, have been shown
to exhibit immunomodulatory, anti-inflammatory and
antioxidant effects and also inhibit uterine contractions
[11, 41-43]. These properties during pregnancy could
prevent or control threatened miscarriage (Figure 1).
Figure 1 Expected mechanisms of grape to prevent threatened abortion

5. HYPOTHESIS
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Immunomodulatory and anti-inflammatory
activities. The elevation of anti-inflammatory cytokine
(such as IL-4 and IL-10) and reduction of
proinflammatory cytokines (like IL-1β, IL-6, IL-8,
IL-17, TNF-α and IFN-γ) are involved in preventing
abortion [21]. Elevation of TNF-α, and IL-6 had been
seen respectively to cause spontaneous and recurrent
abortion [21, 37]. On the other hand, decreased TNF-α
and IFN-γ and increased IL-4 and IL-10 levels could
inhibit the fetal allograft [22, 37].
Grape and its related compounds have complex
functions in anti-inflammatory properties. Raisin (both
fruit and seed) inhibits IL-8 secretion through various
mechanisms [44]. Grape juice inhibits expression of
TNF [45]. Grape seed and grape marc reduce IL-1β,
IL-8, and TNF-α [46]. Grape skin or flesh inhibit
TNF-α and IFN-γ and enhance significantly IL-4 [11].
Grape powder extract reduces IL-1β, IL-6, IL-8, and
TNF-α. Grape-seed procyanidin extract reduces IL-6
and TNF-α and elevates anti-inflammatory cytokines
[47]. Grape-seed epicatechin inhibits IL-1β and IL-6
production [48]. Resveratrol decreases the levels of
IL-1β [42].
In inflammation, alongside pro-inflammatory
cytokines, other mediators such as NO and PGs elevate
[49]. Reduction of PGE2 (prostaglandin E2) and NO
due to reduction of COX-2 (cyclooxygenase-2) and
iNOS (inducible NO synthase) were observed in
threatened abortion treatment [21]. Piceatannol, a
grape polyphenol, acts to prevent and treat
inflammatory bowel diseases with reducing of
pro-inflammatory cytokines, NO and PGE2 [49]. Other
grape compounds including resveratrol, grape seed,
and grape juice inhibit expression of COX-2 and iNOS
and decrease prostaglandin D2 level [42, 45, 47, 50,
51].
Increasing expression of peroxisome
proliferator-activated receptor-γ is the other
mechanism that could block inflammation and
decrease oxidative stress. Grape powder extract and
anthocyanins may be a role in miscarriage prevention
or treatment with this mechanism [36, 47].
Furthermore, NF-κB plays a role in
proinflammatory genes expression. Inhibition of
NF-κB is significant in the treatment of several
diseases [21]. Several products from grape decrease
NF-κB activation [45-47, 52, 53].
Reduction of expression of ICAM-1 and VCAM-1
also was seen in the treatment of threatened abortion
[21]. Activin, a proanthocyanidin in grape seed extract,
attenuates the levels of ICAM-1 and VCAM-1
significantly. Raisins [54], red wine, grape juice [55]
and quercetin [56] decrease only the ICAM-1
expression. It seems that grape products reduce TNF-α
expression and then increase ICAM-1 expression [55]
via inhibition of NF-κB pathway [46, 47, 55].
In addition, in subchorionic hemorrhage, the
increase of EGF (epidermal growth factor) and PDGF
(platelet-derived growth factor) was seen [21]. Some
products of grape inhibit the levels of EGF and PDGF
[47, 50, 57, 58].
Anti-oxidant activities. Decreased antioxidant level in
pregnant body is thought to play a role in the etiology
of abortion [59], and some dietary supplements have
functions in preventing miscarriage with antioxidant
and anti-inflammatory activities [21, 60]. Even an
increased intake of antioxidants by men with sperm
disorders, can improve gestational outcomes in couples
with history of recurrent abortions [61]. Many research
suggest that grape seed has many health-promoting
benefits because of its antioxidant effects. The
antioxidant power of grape seed proanthocyanidins is
50 times greater than that of vitamin C and 20 times
greater than that of vitamin E [39]. Also, antioxidant
activity of grape molasses is more than grape and
raisins [62]. The high melatonin content in the seeds of
edible plants like grape, could protect fetus from
oxidative stress [63]. In pregnancy, red grapes seeds
extract shows prophylactic effects against oxidative
stress [29]. Flavonoids can protect DNA from
oxidation, especially in inflamed tissues [64]. So, when
a pregnant woman uses flavonoid in her diet, like
grape quercetin, she protects her fetus from
reproductive toxicants [65].
Anti-contraction. Uterine contractions are induced by
several factors such as PGF2α, oxytocin, acetylcholine,
carbachol, calcium channel activator, etc. Grape
resveratrol inhibits uterine contractions induced with
these mechanisms and could imitate calcium channel
blockers in the plasma membrane [66].
Hormonal activities. Progesterone acts with hormonal
and immunological mechanisms to maintain pregnancy
[23]. Grape leaves could affect progesterone [67, 68].
Although, estrogens are essential in the maintenance of
pregnancy [25], in the other, elevated estrogen is
linked to unexplained recurrent miscarriage [69, 70].
Grape antioxidants have both estrogenic and
antiestrogenic properties. Because the structure of
some grape antioxidants, like resveratrol, quercetin,
and catechin, are similar to the steroid hormones [50].
Anti-stress activities. Biological stress can increase
TNF-α and decrease TGF-β2 [38]. Decreased TNF-α
and increased TGF-β levels can also inhibit fetal
rejection [37]. So, the grape products which decreased
TNF-α probably had a role in stress-triggered abortion
prevention [11, 45-47]. On the other, CD8+ T cells
immunization could prevent the stress-triggered
abortion [38] and proanthocyanidins of grape seed
could stimulate CD8+ effector T cells [71].
Anti-candida activities. Although vaginal candidiasis
during pregnancy does not influence abortion,
treatment of candidiasis could prevent preterm labor
[41]. Resveratrol has fungicide effects [43]. Grape seed
extracts could inhibit Candida infections because of the
high level of flavanols. Epigallocatechin gallate, a
grape flavanol, has effect on the several fungi,

6. HYPOTHESIS
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doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
including Candida albicans [72].
Consequences of the hypothesis and
discussion
This proposed hypothesis offers grape may have
salutary effects on threatened abortion in pregnant
women or women who are going to become pregnant.
If the hypothesis is right, the grape can prevent
threatened abortion or reduce miscarriage rate with
different mechanisms and can be recommended as a
natural fetal protective product. Even so, it still
suggests that more investigations should be done to
identify grape’s various mechanisms involved in
abortion around and during pregnancy.
In addition to numerous useful properties of grape in
fetal protection, some findings do not support this
hypothesis at first glance. As mentioned above, in the
prevention of abortion, Th2 anti-inflammatory
cytokines like IL-4 and IL-10 increased and
pro-inflammatory Th1 cytokines such as IFN-γ
decreased [21, 22]. However, in two studies, grape
seed products increased IFN-γ (Th1 cytokine) and
suppressed the levels of IL-10 and IL-4 [71, 73]. These
deleterious grape seed effects can be justified by
several ways. Firstly, excessive inflammation is one of
the causes of abortion. Whereas, inflammation has a
pivotal role in successful embryonic implantation [21].
Secondly, in pregnancy, the relative changes of Th1
and Th2 cytokines are more important than the
absolute concentration changes between Th1 or Th2
productions [22]. Finally, although, there were higher
ratio of Th1/Th2 in recurrent miscarriage [74] and
higher Th1 and lower Th2 in threatened abortion [75],
in Kalinka study, no relation to Th1 and Th2
concentrations was found in threatened abortion [76].
So, maybe grape seed does not cause abortion.
As pointed out earlier, iNOS/NO or COX2/PGs
worked like a double-edged sword in pregnancy. iNOS
has accumulated in many autoimmune and chronic
inflammatory disorders like SLE (systemic lupus
erythematosus), but the exact function of iNOS is not
clear. For example, SLE could cause abortion with
immunological rejection or placental damage. In some
diseases, iNOS is elevated with proinflammatory Th1
reactions for limitation of bacterial invasion, local
immune reactions and so tissue destruction against Th1
responses [3, 77]. Maybe it can be said, controlling
excessive inflammation is also crucial in NO responses.
Moreover, grape decreases excessive inflammation
with several mechanisms as discussed in this article. In
the other words, hyperactivation of iNOS/NO or
COX2/PGs pathways can lead to abortion, not only
activation of them.
Conclusion
Based on the described mechanisms of action in above,
we can anticipate that grape protects fetus. Of course,
further clinical investigations are necessary. According
to Rhazes’ (865 A.D.-925 A.D.) opinion about the
priority of food therapy to drug therapy [78], we
suggest the design of a study with edible grape
products. In this regard, we recommend to evaluate
nutritional and therapeutic effect of grape foodstuff in
maternal diet in clinical study, such as grape seed oil,
grape juice or grape molasses. In the next steps, studies
can be designed with grape leaves extract in threatened
abortion.
References
1. Threatened Abortion. 2018/2019 ICD-10-CM
Diagnosis Code O20.0. available at:
https://www.icd10data.com/ICD10CM/Codes/O0
0-O9A/O20-O29/O20-/O20.0.
2. Cunningham GLK, Bloom SL, Spong CY, et al.
Williams Obstetrics. 24nd Edition. New York:
Mcgraw-Hill Professional Publishing. 2014. p.
354.
3. Tulandi T, Al-Fozan HM. Spontaneous abortion:
Management. Last updated: Aug 10, 2018.
Available at: https://www.uptodate.com/contents/
spontaneous-abortion-management?search=threat
ened%20abortion&source=search_result&selecte
dTitle=1~10&usage_type=default&display_rank=
1.
4. Rahimi R, Ghiasi S, Azimi H, et al. A review of
the herbal phosphodiesterase inhibitors; future
perspective of new drugs. Cytokine 2010, 49:
123-129.
5. Njamen D, Mvondo MA, Djiogue S, et al.
Phytotherapy and women's reproductive health:
the Cameroonian perspective. Planta Medica 2013,
79: 600-611.
6. Zhu X, Qi X, Hao J, et al. Pattern of drug use
during the first trimester among Chinese women:
data from a population-based cohort study. Eur J
Clin Pharmacol 2010, 66: 511-518.
7. Chuang CH, Chang PJ, Hsieh WS, et al. Chinese
herbal medicine use in Taiwan during pregnancy
and the postpartum period: a population-based
cohort study. Int J Nurs Stud 2009, 46: 787-795.
8. Kaingu CK, Oduma JA, Kanui TI. Practices of
traditional birth attendants in Machakos District,
kenya. J Ethnopharmacol 2011, 137: 495-502.
9. Amusan OO, Dlamini PS, Msonthi JD, et al.
Some herbal remedies from Manzini region of
Swaziland. J Ethnopharmacol 2002, 79: 109-112.
10. Nassiri-Asl M, Hosseinzadeh H. Review of the
pharmacological effects of Vitis vinifera (Grape)
and its bioactive constituents: an update.
Phytother Res 2016, 30: 1392-1403.
11. Mukherjee S, Das SK, Vasudevan D. Dietary
grapes (Vitis vinifera) feeding attenuates
ethanol-induced oxidative stress in blood and
modulates immune functions in mice. Indian J
Biochem Biophys 2012, 49: 379-385.

7. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
137
doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
12. Vega CC, Reyes-Castro LA, Rodriguez-Gonzalez
GL, et al. Resveratrol partially prevents oxidative
stress and metabolic dysfunction in pregnant rats
fed a low protein diet and their offspring. J
Physiol 2016, 594:1483-1499.
13. Cheshti MA. Exir Azam (Great Elixir). Tehran:
Iran University of Medical Science, Institute for
Islamic and Complementary Medicine; 2007. p.
728-733. (Persian).
14. Arzani MA. Tebb-e Akbari (Akbari Medicine).
Iran, Qom: Jalal al-Din; 2008. p. 948-951.
(Persian).
15. Baladi A. Tadbir al-Hobali val-Atfal val-Sebyan.
Tehran: Iran University of Medical Science,
Institute for Islamic and Complementary
Medicine; 2004. p. 128. (Arabic).
16. Ibn Sina AAH (Avicenna). Al-Qanun fi-Teb
(Canon of Medicine). Shams-od-Din E (editor).
Beirut: Al-Aalamy lel-Matbooat Institute; 2005.
Volume 3, p. 426-429. (Arabic).
17. Aghili SMH. Makhzan-Al' Advieh. Shams MR
(editor). Tehran: Tehran University publication;
2008, p. 357, 741. (Persian).
18. Momen Tonekaboni SM. Tohfe Momenin. Qom,
Iran: Noore Vahy; 2011. Volume 1, p. 320-321,
701. (Persian).
19. Razi AM (Rhazes). Al-Hawi fit-Teb (The book of
the collector of medicine; Liber Continent).
Taaimi HK (editor). Beirut: Dar Ihyaa al-Turaath
al-Arabi. 2002. Volume 21, p. 269. (Arabic).
20. Abdoli A. Salt and miscarriage: Is there a link?
Med Hypotheses 2016, 89: 58-62.
21. Monastra G, De Grazia S, Cilaker Micili S, et al.
Immunomodulatory activities of alpha lipoic acid
with a special focus on its efficacy in preventing
miscarriage. Expert Opin Drug Deliv 2016, 13:
1695-1708.
22. Liu F, Luo SP. Effect of Chinese herbal treatment
on Th1- and Th2-type cytokines, progesterone
and beta-human chorionic gonadotropin in early
pregnant women of threatened abortion. Chin J
Integr Med 2009, 15: 353-358.
23. Di Renzo GC, Giardina I, Clerici G, et al.
Progesterone in normal and pathological
pregnancy. Horm Mol Biol Clin Investig 2016, 27:
35-48.
24. Chernyshov VP, Vodyanik MA, Pisareva SP. Lack
of soluble TNF-receptors in women with
recurrent spontaneous abortion and possibility for
its correction. Am J Reprod Immunol 2005, 54:
284-291.
25. Albrecht ED, Aberdeen GW, Pepe GJ. The role of
estrogen in the maintenance of primate pregnancy.
Am J Obstet Gynecol 2000, 182: 432-438.
26. Gurka G, Rocklin RE. Reproductive immunology.
JAMA 1987, 258: 2983-2987.
27. Kastner P, Krust A, Turcotte B, et al. Two distinct
estrogen-regulated promoters generate transcripts
encoding the two functionally different human
progesterone receptor forms A and B. EMBO J
1990, 9: 1603-1614.
28. Gupta S, Agarwal A, Banerjee J, et al. The role of
oxidative stress in spontaneous abortion and
recurrent pregnancy loss: a systematic review.
Obstet Gynecol Surv 2007, 62: 335-347.
29. Mureşan A, Alb C, Suciu S, et al. Studies on
antioxidant effects of the red grapes seed extract
from Vitis vinifera, Burgund Mare, Recaş in
pregnant rats. Acta Physiologica Hungarica 2010,
97: 240-246.
30. Nakhai-Pour HR, Broy P, Sheehy O, et al. Use of
nonaspirin nonsteroidal anti-inflammatory drugs
during pregnancy and the risk of spontaneous
abortion. CMAJ 2011, 183: 1713-1720.
31. Paradisi R, Fabbri R, Battaglia C, et al. Nitric
oxide levels in women with missed and
threatened abortion: results of a pilot study. Fertil
Steril 2007, 88: 744-748.
32. Vaisanen-Tommiska M, Nuutila M, Aittomaki K,
et al. Nitric oxide metabolites in cervical fluid
during pregnancy: further evidence for the role of
cervical nitric oxide in cervical ripening. Am J
Obstet Gynecol 2003, 188: 779-785.
33. Makino A, Nakanishi T, Sugiura-Ogasawara M, et
al. No association of C677T
methylenetetrahydrofolate reductase and an
endothelial nitric oxide synthase polymorphism
with recurrent pregnancy loss. Am J Reprod
Immunol 2004, 52: 60-66.
34. Clark DA, Banwatt D, Chaouat G. Effect of
prostaglandin synthesis inhibitors on spontaneous
and endotoxin-induced abortion in mice. J Reprod
Immunol 1993, 24: 29-44.
35. Li DK, Ferber JR, Odouli R, et al. Use of
nonsteroidal antiinflammatory drugs during
pregnancy and the risk of miscarriage. Am J
Obstet Gynecol 2018, 219: 275.e1-275.e8.
36. Chen SJ, Liu YL, Sytwu HK. Immunologic
regulation in pregnancy: from mechanism to
therapeutic strategy for immunomodulation.
clinical and developmental immunology. Clin
Dev Immunol 2012, 2012: 258391.
37. Gorczynski RM, Hadidi S, Yu G, et al. The same
immunoregulatory molecules contribute to
successful pregnancy and transplantation. Am J
Reprod Immunol 2002, 48: 18-26.
38. Arck PC, Merali F, Chaouat G, et al. Inhibition of
immunoprotective CD8+ T cells as a basis for
stress-triggered substance P-mediated abortion in
mice. Cell Immunol 1996, 171: 226-230.
39. Shi J, Yu J, Pohorly JE, et al. Polyphenolics in
grape seeds-biochemistry and functionality. J Med
Food 2003, 6: 291-299.
40. Xia EQ, Deng GF, Guo YJ, et al. Biological
activities of polyphenols from grapes. Int J Mol
Sci 2010, 11: 622-646.

8. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
138
doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
41. Roberts CL, Algert CS, Rickard KL, et al.
Treatment of vaginal candidiasis for the
prevention of preterm birth: a systematic review
and meta-analysis. Syst Rev 2015, 4: 31.
42. Mart ֐n AR, Villegas I, La Casa C, et al.
Resveratrol, a polyphenol found in grapes,
suppresses oxidative damage and stimulates
apoptosis during early colonic inflammation in
rats. Biochem Pharmacol 2004, 67: 1399-1410.
43. McCarty MF. Potential utility of natural
polyphenols for reversing fat-induced insulin
resistance. Med Hypotheses 2005, 64: 628-635.
44. Di Lorenzo C, Sangiovanni E, Fumagalli M, et al.
Evaluation of the anti-inflammatory activity of
raisins (Vitis vinifera L.) in human gastric
epithelial cells: a comparative study. Int J Mol Sci
2016, 17: E1156 .
45. Campanholo V, Silva RM, Silva TD, et al. Oral
concentrated grape juice suppresses expression of
NF-kappa B, TNF-alpha and iNOS in
experimentally induced colorectal carcinogenesis
in Wistar rats. Asian Pac J Cancer Prev 2015, 16:
947-952.
46. Gessner D, Ringseis R, Siebers M, et al.
Inhibition of the pro‐inflammatory NF‐κB
pathway by a grape seed and grape marc meal
extract in intestinal epithelial cells. J Anim
Physiol Anim Nutr. 2012, 96: 1074-1083.
47. Terra X, Montagut G, Bustos M, et al. Grape-seed
procyanidins prevent low-grade inflammation by
modulating cytokine expression in rats fed a
high-fat diet. J Nutr Biochem 2009, 20: 210-218.
48. Mitjans M, del Campo J, Abajo C, et al.
Immunomodulatory activity of a new family of
antioxidants obtained from grape polyphenols. J
Agric Food Chem 2004, 52: 7297-7299.
49. Kim YH, Kwon H-S, Kim DH, et al. Piceatannol,
a stilbene present in grapes, attenuates dextran
sulfate sodium-induced colitis. Int
Immunopharmacol 2008, 8: 1695-1702.
50. Zhou K, Raffoul JJ. Potential anticancer
properties of grape antioxidants. J Oncol 2012,
2012: 803294.
51. Surh YJ, Chun KS, Cha HH, et al. Molecular
mechanisms underlying chemopreventive
activities of anti-inflammatory phytochemicals:
down-regulation of COX-2 and iNOS through
suppression of NF-κB activation. Mutat Res 2001,
480: 243-268.
52. Jiang M, Wu Y-L, Li X, et al. Oligomeric
proanthocyanidin derived from grape seeds
inhibited NF-κB signaling in activated HSC:
Involvement of JNK/ERK MAPK and PI3K/Akt
pathways. Biomed Pharmacother 2017, 93:
674-680.
53. Calabriso N, Massaro M, Scoditti E, et al. Red
grape skin polyphenols blunt matrix
metalloproteinase-2 and-9 activity and expression
in cell models of vascular inflammation:
protective role in degenerative and inflammatory
diseases. Molecules 2016, 21: E1147.
54. Kaliora AC, Kountouri AM, Karathanos VT, et al.
Effect of Greek raisins (Vitis vinifera L.) from
different origins on gastric cancer cell growth.
Nutr Cancer 2008, 60: 792-799.
55. Puglisi MJ, Vaishnav U, Shrestha S, et al. Raisins
and additional walking have distinct effects on
plasma lipids and inflammatory cytokines. Lipids
Health Dis 2008, 7: 14.
56. Kalfin R, Righi A, Del Rosso A, et al. Activin, a
grape seed-derived proanthocyanidin extract,
reduces plasma levels of oxidative stress and
adhesion molecules (ICAM-1, VCAM-1 and
E-selectin) in systemic sclerosis. Free Radic Res
2002, 36: 819-825.
57. Gessner D, Koch C, Romberg FJ, et al. The effect
of grape seed and grape marc meal extract on
milk performance and the expression of genes of
endoplasmic reticulum stress and inflammation in
the liver of dairy cows in early lactation. J Dairy
Sci 2015, 98: 8856-8868.
58. Godichaud S, Si-Tayeb K, Augé N, et al. The
grape-derived polyphenol resveratrol
differentially affects epidermal and
platelet-derived growth factor signaling in human
liver myofibroblasts. Int J Biochem Cell Biol
2006, 38: 629-637.
59. Katar-Yildirim C, Tokmak A, Yildirim C, et al.
Investigation of serum thiol/disulphide
homeostasis in patients with abortus imminens. J
Matern Fetal Neonatal Med 2018, 31: 2457-2462.
60. Costantino M, Guaraldi C, Costantino D.
Resolution of subchorionic hematoma and
symptoms of threatened miscarriage using vaginal
alpha lipoic acid or progesterone: clinical
evidences. Eur Rev Med Pharmacol Sci 2016, 20:
1656-1663.
61. Gil-Villa AM, Cardona-Maya W, Agarwal A, et al.
Role of male factor in early recurrent embryo loss:
do antioxidants have any effect? Fertil Steril 2009,
92: 565-571.
62. Karakaya S, El SN, Tas AA. Antioxidant activity
of some foods containing phenolic compounds.
Int J Food Sci Nutr 2001, 52: 501-508.
63. Manchester LC, Tan DX, Reiter RJ, et al. High
levels of melatonin in the seeds of edible plants:
possible function in germ tissue protection. Life
Sci 2000, 67: 3023-3029.
64. McCarty MF. Scavenging of peroxynitrite-derived
radicals by flavonoids may support endothelial
NO synthase activity, contributing to the vascular
protection associated with high fruit and
vegetable intakes. Med Hypotheses 2008, 70:
170-181.
65. Lesser MNR, Keen CL, Lanoue L. Reproductive
and developmental outcomes, and influence on

9. HYPOTHESIS
Submit a manuscript: https://www.tmrjournals.com/tmr
139
doi: 10.12032/TMR20190403113
TMR | May 2019 | vol. 4 | no. 3 |
maternal and offspring tissue mineral
concentrations, of (-)-epicatechin, (+)-catechin,
and rutin ingestion prior to, and during pregnancy
and lactation in C57BL/6J mice. Toxicol Rep
2015, 2: 443-449.
66. Hsia SM, Wang KL, Wang PS. Effects of
resveratrol, a grape polyphenol, on uterine
contraction and Ca2+
mobilization in rats in vivo
and in vitro. Endocrinology 2011, 152:
2090-2099.
67. Ernst M, Munkert J, Campa M, et al. Steroid
5β-reductase from leaves of Vitis vinifera:
molecular cloning, expression, and modeling. J
Agric Food Chem 2015, 63: 10112-10120.
68. Charbonneau A. Genomic organization of a
human 5β-reductase and its pseudogene and
substrate selectivity of the expressed enzyme.
Biochim Biophys Acta 2001, 1517: 228-235.
69. Gurbuz B, Yalti S, Ozden S, et al. High basal
estradiol level and FSH/LH ratio in unexplained
recurrent pregnancy loss. Arch Gynecol Obstet
2004, 270: 37-39.
70. Trout SW, Seifer DB. Do women with
unexplained recurrent pregnancy loss have higher
day 3 serum FSH and estradiol values? Fertil
Steril 2000, 74: 335-337.
71. Vaid M, Singh T, Prasad R, et al. Bioactive grape
proanthocyanidins enhance immune reactivity in
UV-irradiated skin through functional activation
of dendritic cells in mice. Cancer Prev Res 2013,
6: 242-252.
72. Simonetti G, Santamaria AR, et al. Evaluation of
anti-Candida activity of Vitis vinifera L. seed
extracts obtained from wine and table cultivars.
Biomed Res Int 2014, 2014: 127021.
73. Nair N, Mahajan S, Chawda R, et al. Grape seed
extract activates Th1 cells in vitro. Clin Diagn
Lab Immunol 2002, 9: 470-476.
74. Kwak-Kim J, Lee SK, Gilman-Sachs A. Elevated
Th1/Th2 cell ratios in a pregnant woman with a
history of RSA, secondary Sjogren's syndrome
and rheumatoid arthritis complicated with one
fetal demise of twin pregnancy. Am J Reprod
Immunol 2007, 58: 325-329.
75. Hudic I, Fatusic Z. Progesterone-induced
blocking factor (PIBF) and Th(1)/Th(2) cytokine
in women with threatened spontaneous abortion. J
Perinat Med 2009, 37: 338-342.
76. Kalinka J, Radwan M. The impact of
dydrogesterone supplementation on serum
cytokine profile in women with threatened
abortion. Am J Reprod Immunol 2006, 55:
115-121.
77. Kröncke KD, Fehsel K, Kolb-Bachofen V.
Inducible nitric oxide synthase in human diseases.
Clin Exp Immunol 1998, 113: 147-156
78. Zargaran A, Azizi A, Kordafshari G, et al. Rhazes
contribution to the role of nutrition in preventive
medicine and public health. Iran J Public Health
2014, 43: 1461-1462.