Carica papaya Leaves Might Cause Miscarriage

Abstract

Background: The use of Carica papaya leaves in folklore medicine for its antimalarial and antidiabetic activities is on the increase globally. Aim: This was undergone to investigate if C. papaya leaves have the propensity to induce miscarriage during pregnancy. Methods: Fresh and healthy leaves of C. papaya free from the disease were harvested from the culture garden of the Institute of Agricultural Research and Training, Moor Plantation, Ibadan. They were dried and extracted using Soxhlet apparatus and ethanol as the solvent. The toxicity test was carried out using the standard method. Thirty each of fertile male and female Wistar rats were taken for this study. After seven days of acclimatization, the female rats were separated into different cages and had estrus synchronization using Diethylstilbestrol dissolved in paraffin oil and administered at the dose of 1 mg/kg body weight. The male rats were then introduced into those each cages for mating process. After getting the confirmation of pregnancy test, the pregnant rats were grouped into the group of four. First group (Group A) was treated with normal saline, other groups (B, C, D) were treated with undiluted leaf extract of C. papaya for 24, 48 and 72 hours Original Research Article Airaodion et al.; ARJGO, 2(2): 1-9, 2019; Article no.ARJGO.51661 2 respectively. The animals were then observed daily if they littered. In vitro effects of the leaves on isolated rat uteri were determined following the standard method. Results: Ethanolic leaf extract of C. papaya was safe in rats at the tested oral doses (500-2000 mg/kg). There was no mortality within the study period. In the in vitro experiment, C. papaya leaf extract elicited dose-dependent multiple contractions of the pregnant rat's uterus. 20% of animals treated with C. papaya leaf extract for 24 hours did no litter which suggestive that miscarriage has occurred. In the animals treated for 48 hours, only 60% littered which is also suggestive that miscarriage has occurred in the remaining 40% that did not litter. In the group treated with C. papaya leaf extract for 72 hours, 80% of the animals did not litter. Conclusion: The results of this study suggest that papaya leaves contain active agents which could be toxic to the uterus. Thus, care should be taken in its use during pregnancy. However, this does not automatically translate to the same effect in humans; therefore, its effect on pregnant women can be further confirmed.

Full text

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*Corresponding author: E-mail: augustineairaodion@yahoo.com;
Asian Research Journal of Gynaecology and Obstetrics
2(2): 1-9, 2019; Article no.ARJGO.51661
Carica papaya Leaves Might Cause Miscarriage
Augustine I. Airaodion
1*
, John A. Ekenjoku
2
, Emmanuel O. Ogbuagu
2
,
Victor N. Okoroukwu
3
and Uloaku Ogbuagu
1
1
Department of Biochemistry, Federal University of Technology, Owerri, Imo State, Nigeria.
2
Department of Pharmacology and Therapeutics, Gregory University, Uturu, Abia State, Nigeria.
3
Department of Pharmacology and Therapeutics, Abia State University, Uturu, Nigeria.
Authors’ contributions
This work was carried out in collaboration with all authors. Author AIA conceptualized and designed
the study and also wrote the manuscript. Author EOO managed the analyses of the study. Author
VNO managed the literature searches. Author UO wrote the protocol while Author JAE performed the
statistical analysis. All authors read and approved the final manuscript.
Article Information
Editor(s):
(1)
Dr. Rajbala Singh, Assistant Professor, Siddhartha Institute of Pharmacy, Dehradun, Uttarakhand, India.
Reviewers:
(1) U. O. Ududua, University of Port Harcourt, Nigeria.
(2)
E. Siva Rami Reddy, Tantia University, India.
Complete Peer review History:
https://sdiarticle4.com/review-history/51661
Received 31 August 2019
Accepted 11 October 2019
Published 22 October 2019
ABSTRACT
Background:
The use of Carica papaya leaves in folklore medicine for its antimalarial and
antidiabetic activities is on the increase globally.
Aim: This was undergone to investigate if C. papaya leaves have the propensity to induce
miscarriage during pregnancy.
Methods: Fresh and healthy leaves of C. papaya free from the disease were harvested from the
culture garden of the Institute of Agricultural Research and Training, Moor Plantation, Ibadan. They
were dried and extracted using Soxhlet apparatus and ethanol as the solvent. The toxicity test was
carried out using the standard method. Thirty each of fertile male and female W istar rats were taken
for this study. After seven days of acclimatization, the female rats were separated into different
cages and had estrus synchronization using Diethylstilbestrol dissolved in paraffin oil and
administered at the dose of 1 mg/kg body weight. The male rats were then introduced into those
each cages for mating process. After getting the confirmation of pregnancy test, the pregnant rats
were grouped into the group of four. First group (Group A) was treated with normal saline, other
groups (B, C, D) were treated with undiluted leaf extract of C. papaya for 24, 48 and 72 hours
Original Research Article

Airaodion et al.;
ARJGO, 2(2): 1-9, 2019; Article no.ARJGO.51661
2
respectively. The animals were then observed daily if they littered. In vitro effects of the leaves on
isolated rat uteri were determined following the standard method.
Results: Ethanolic leaf extract of C. papaya was safe in rats at the tested oral doses (500–2000
mg/kg). There was no mortality within the study period. In the in vitro experiment, C. papaya leaf
extract elicited dose-dependent multiple contractions of the pregnant rat's uterus. 20% of animals
treated with C. papaya leaf extract for 24 hours did no litter which suggestive that miscarriage has
occurred. In the animals treated for 48 hours, only 60% littered which is also suggestive that
miscarriage has occurred in the remaining 40% that did not litter. In the group treated with C.
papaya leaf extract for 72 hours, 80% of the animals did not litter.
Conclusion: The results of this study suggest that papaya leaves contain active agents which could
be toxic to the uterus. Thus, care should be taken in its use during pregnancy. However, this does
not automatically translate to the same effect in humans; therefore, its effect on pregnant women
can be further confirmed.
Keywords: Carica papaya; pregnancy; miscarriage; oxytocin; ethanolic leaf extract.
1. INTRODUCTION
Gestation is a vital part of the female
reproductive cycle all over the world. It is also
known as pregnancy. It normally consists of
three trimesters and care should be taken during
each trimester for safe delivery of the offspring
into the world. After gestation/pregnancy period,
oxytocin induces contraction for parturition (the
process of giving birth) to occur [1]. Oxytocin has
been reported to consist of nine amino acid
peptide hormone secreted by the posterior
pituitary that elicits milk ejection in female
animals and women. In pharmacological doses,
oxytocin can be used to induce uterine
contraction and maintain lactation [2].
Oxytocin is a typical neural hormone just as
vasopressin. The binding protein for oxytocin is
known as neurophysin I while that of vasopressin
is called neurophysin II. Both neurophysins are
analogous in structure. The hormone-
neurophysin complex stabilizes the hormone
within the neurosecretory granules. Oxytocin is
stored as neurosecretory granules and released
from axonal terminals by calcium-dependent
exocytosis [3,4]. Oxytocin is been best
recognized for its important roles in the female
reproductive system. It is released in increased
volume during labour and after stimulation of the
nipples. It is a facilitator for parturition and
breastfeeding. However, recent researches have
reported the role of oxytocin in various
behaviours, including social recognition, orgasm,
bonding, and maternal behaviours. oxytocin is
believed to be involved in a wide variety of
physiological and pathological functions such as
ejaculation, sexual activity, pregnancy, milk
ejection, penile erection, social bonding, uterine
contraction, maternal behaviour, stress and
probably many more [5]. Oxytocin is usually
administered via the intravenous to induce
contractions during childbirth. It is also available
as a nasal spray to induce lactation post-partum.
Oxytocin infusion near term will produce
contractions that decrease the fetal blood supply.
It is inactive orally because it is destroyed by
gastric and intestinal enzymes [1].
Oxytocin has also been reported to be useful in
stoppage bleeding postpartum. For this purpose,
it can be administered intravenously or
intramuscularly [6]. It is released into the
bloodstream in response to stretching of the
cervix and uterus during childbirth and with
stimulation of the nipples during lactation [7]. In
estrogen and progesterone primed rodents,
injections of prolactin cause the formation of milk
droplets and their secretion into the ducts but
oxytocin leads to contraction of the myoepithelial
cells lining the walls of the duct which results in
the ejection of milk through the nipple [6].
Membrane receptors for oxytocin are available in
uterine as well as mammary tissues. These
receptors have been found to increase in number
by estrogens and decrease by progesterone. The
concomitant rise in estrogen and fall in
progesterone occurring immediately before
childbirth might probably explain the onset of
lactation in some individuals before delivery [3,8].
The primer for the commencement of childbirth in
humans is oxytocin secretion by specific cells of
the fetus. The secreted oxytocin will activate
certain cells of the placenta to produce and
release prostaglandins. Oxytocin and
prostaglandins synergize to stimulate the uterine
myometria leading to a more vigorous and more
frequent contraction [9]. At that point, the
increasing emotional and physical stresses
caused by these contractions activate the

Airaodion et al.;
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3
mother's hypothalamus which signals for
oxytocin released by the posterior pituitary. The
elevated levels of oxytocin and prostaglandins
trigger the rhythmic expulsive contraction of true
labour [10].
Carica papaya belongs to the family of
Caricaceae, and different species of Caricaceae
have been used as a remedy against several
diseases [11,12]. C. papaya was originally
discovered in the southern part of Mexico, it is
presently distributed over the whole tropical area.
In particular, C. papaya fruit circulates widely,
and it is accepted as food or as a quasi-drug.
Many scientific investigations have been
conducted to evaluate the biological activities of
various parts of C. papaya, including fruits,
shoots, leaves, rinds, seeds, roots or latex. The
leaves of C. papaya have been shown to contain
many active components such as papain,
chymopapain, cystatin, à-tocopherol, ascorbic
acid, flavonoids, cyanogenic glucosides and
glucosinolates that can increase the total
antioxidant power in the blood and reduce lipid
peroxidation level [13].
Seed and fruit extracts of papaya have been
reported to elicit bactericidal activities [14]. The
leaves of papaya have been poultice into
nervous pains, elephantoid growths and it has
been smoked for asthma relief amongst
tropical tribal communities. The antiplasmodial
potency of ethanolic leaf extract of C. papaya
against Plasmodium berghei in infected Swiss
albino mice has also been reported [15]. C.
papaya leaf extracts have also been used for a
long time as an aboriginal remedy for various
disorders, including cancer and infectious
diseases.
C. papaya contains two vital biologically active
compounds namely: chymopapain and papain
which are widely used for digestive disorders
[16]. It showed that papaya derived caricain,
chymopapain, papain, and glycerin
endopeptidase might boost acidic pH conditions
and pepsin degradation. Another active
component of C. papaya is lipase, which is a
hydrolase, tightly bonded to the water-insoluble
fraction of crude papain and is thus considered
as a “naturally immobilized” biocatalyst [17].
According to folk medicine, C. papaya latex can
cure dyspepsia and also applicable to external
burns and scalds. Fruits, as well as seeds of
papaya, are excellent antihelminthic and
antiamoebic agents [18]. Dried and pulverized
leaves are sold for making tea; also the leaf
decoction is administered as a purgative for
horses and used for the treatment of genetic-
urinary system.
Fig. 1. Carica papaya Plant [15]

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4
2. METHODOLOGY
2.1 Collection and Extraction of Plant
Material
Fresh and healthy leaves of C. papaya free from
the disease were harvested from the Institute of
Agricultural Research and Training, Moor
Plantation, Ibadan, Nigeria and were identified by
a botanist. They were washed in running water to
remove contaminants. They were air-dried at
room temperature in open laboratory space for
14 days and milled into powder using an
electronic blender (Moulinex). The extraction was
done using Soxhlet apparatus and ethanol as the
solvent according to the method described by
Airaodion et al. [19,20]. About 25 g of the powder
was packed into the thimble of the Soxhlet
extractor. 250 mL of ethanol was added to a
round bottom flask, which was attached to the
Soxhlet extractor and condenser on a heating
mantle solvent was heated using the heating
mantle and began to evaporate moving through
the apparatus to the condenser. The condensate
dripped into the reservoir housing the thimble
containing the sample. Once the level of the
solvent reached the siphon, it poured back into
the round bottom flask and the cycle began
again. The process was allowed to run for a total
of 18 hours. Once the process was completed,
the ethanol was evaporated in a rotary
evaporator at 35
°
C with a yield of 2.98 g which
represents a percentage yield of 11.92%. The
extract was preserved in the refrigerator for
further analysis.
2.2 Oral Acute Toxicity Studies
Oral acute toxicity study was carried out
according to the method described by Miller and
Tainter [21]. Twenty-five rats were divided into
five groups (1–5) consisting of 5 rats per group.
Group A was given distilled water (10 ml/kg)
while groups B, C, D and E were separately
given 500, 1000, 1500, and 2000 mg/kg of the
extract respectively. Treatments were
administered orally by gastric intubation. The
animals were observed for 24 hours post-
treatment for signs of toxicity and then 48 hours
for possible death.
2.3 Experimental Design and Animal
Treatment
Thirty fertile male and thirty virgin female Wistar
rats weighing between 170 and 200 g were
purchased from the Central Animal House,
College of Medicine, University of Ibadan,
Nigeria. They were acclimatized for seven (7)
days during which they were fed ad libitum with
standard feed and drinking water and were
housed in clean cages placed in well-ventilated
housing conditions (under humid tropical
conditions) throughout the experiment. All the
animals received humane care according to the
criteria outlined in the ‘Guide for the Care and
Use of Laboratory Animals’ prepared by the
National Academy of Science and published by
the National Institute of Health. After the
acclimatization period, the female rats were
separated into its cages and had estrus
synchronization using Diethylstilbestrol dissolved
in paraffin oil and administered at the dose of 1
mg/kg body weight. A male was then introduced
into each cage for mating. On the 7
th
day, the
vaginal smear of each of the female rats was
made on a clean glass slide by carefully inserting
a cotton-tipped swab moistened with normal
saline into the vaginal cavity of the rats and rolled
gently against the wall before the withdrawal.
The smear was stained with Giemsa and
observed under the microscope to check for the
presence of protein coagulates. After
confirmation of pregnancy, the pregnant rats
were grouped into four in the following order:
Group A: Normal saline ad libitum (control)
Group B: Undiluted C. papaya leaf extract ad
libitum for 24 hours
Group C: Undiluted C. papaya leaf extract ad
libitum for 48 hours
Group D: Undiluted C. papaya leaf extract ad
libitum for 72 hours.
The animals were then observed daily till they
littered.
2.4 In vitro Effect of C. papaya Leaf
Extract on Isolated Rat Uteri
The method described by Airaodion et al. [22]
was adopted: Matured pregnant female rats were
sacrificed by stunning and decapitation. The
lower abdomen was opened and the two uterine
horns were harvested and transferred into De
Jalon solution that continuously bubbled with air
and maintained at 37
°
C (pH 7.4). The De Jalon
solution was constituted such that each liter
contained: NaCl (9 g), KCl (0.42 g), CaCl
2
(0.06
g), NaHCO
3
(0.5 g), and glucose (0.5 g). Each
uterine horn was suspended vertically in a 35 mL
organ bath using ligatures attached at one end to
a tissue holder and at the other end to an
isometric force-displacement transducer

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connected to a digital physiological recorder
(Medicaid Physiopac) for displaying isometric
contractions. Resting tension in the muscle strip
was readjusted, just sufficient to remove the
slack. The preparation was allowed to equilibrate
within 30 minutes of mounting. After recording
regular rhythmic contractions, dose-response
relationships were established for C. papaya leaf
extract and other standard drugs used. For all
administrations, a minimum time of 1 minute was
allowed for individual tissue responses before
being washed 3 times with De Jalon solution.
The test substances were administered as final
bath concentration (FBC).
Percentage (%) rise in Amplitude of Contraction
was calculated as:
Percentage (%) rise in Amplitude of Contraction
=
.

.()
x 100
2.5 Statistical Analysis
Data were subjected to analysis of variance
using Graph Pad Prism. Results were presented
as Mean ± standard deviation. One way analysis
of variance (ANOVA) was used for comparison of
the means followed by Tukey’s (HSD) multiple
comparison test. Differences between
means were considered to be significant at
p<0.05.
3. RESULTS
3.1 Acute Toxicity Studies
Ethanolic leaf extract of C. papaya was safe in
rats at the tested oral doses (500–2000 mg/kg).
There was no mortality within the study
period. However, there were behavioural
changes such as depression, reduced
motor activity and ataxia. There was also a
slight increase in urine output.
All animals in the control group littered which is
an indication that no abortion occurred as shown
in Table 1. 20% of animals treated with C.
papaya leaf extract for 24 hours did no litter
which suggests that miscarriage has occurred. In
the animals treated for 48 hours, only 60%
littered which is also suggestive that
miscarriage has occurred in the remaining
40% that did not litter. In the group treated
with C. papaya leaf extract for 72 hours, 80% of
the animals did not litter.
Table 1. In vivo activity of fresh C. papaya leaves extract on pregnant rats’ uteri
Treatment
groups
Number
of rats per
group
Pregnancy
test
Type of treatment
Number
that
littered
Percentage (%)
that littered
A 5 Positive Normal Saline 5 100
B 5 Positive Undiluted C. papaya leaf
extract ad libitum for 24
hours
4 80
C 5 Positive Undiluted C. papaya leaf
extract ad libitum for 48
hours
3 60
D 5 Positive Undiluted C. papaya leaf
extract ad libitum for 72
hours
1 20
Table 2. In vitro effect of C. papaya leaf extract on isolated pregnant rats’ uteri
Volume administered
(mL)
Basal amplitude of
contraction (mm)
The amplitude of
contraction with C.
papaya leaf extract
(mm)
Percentage (%) rise in
amplitude of
contraction
0.05 5.00 21.17
±
2.04 323.40
0.10 5.00 27.83
±
2.83 456.60
0.20 5.00 29.14
±
0.89 482.80
0.30 5.00 30.86
±
1.27 517.20
0.40 5.00 31.11
±
2.11 522.20

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6
Fig. 2. Comparative effects of oxytocin and C. papaya leaf extract on an isolated pregnant rat
uterus
The table showed that all doses of C. papaya
leaf extract administered significantly induced
contractions of the isolated rat uteri and this
contraction increases as the dosage increases.
The effect of C. papaya leaf extract on an
isolated pregnant rat uterus compared with that
of standard uterotonic agent oxytocin showed
that C. papaya leaf extract was giving slightly
higher effect oxytocin at all doses.
4. DISCUSSION
Miscarriage is the natural death of an embryo or
fetus before it can survive independently
[23,24]. It is also known as spontaneous abortion
and pregnancy loss [22]. Some use the cutoff of
20 weeks of gestation to describe miscarriage,
after which fetal death is known as a stillbirth
[25]. The most common symptom of a
miscarriage is vaginal bleeding with or without
pain. Miscarriage has been linked to several
factors. The nutrition of a pregnant woman plays
a major role in the status of the fetus. C. papaya
leaves have been reported to possess
antimalarial [15] as well as antidiabetic [26]
properties. Consequently, it is used as a remedy
to these ailments even in pregnancy. This study
sought to investigate if it can induce miscarriage
in an earlier pregnancy.
The result of the acute toxicity test of this study
showed that C. papaya leaves are not toxic to
health as no death was observed after 48 hours
of administration of 500 to 2000 mg/kg body
weight. The change in behaviour observed in the
animals might be an indication that consumption
of C. papaya leaves in high amount could lead to
depression. Increase in urine output observed in
the acute toxicity studies could also be
suggestive that C. papaya leaves might inhibit
antidiuretic hormone (vasopressin), a hormone
involved in the regulation of micturition.
All the pregnant rats administered C. papaya leaf
extract appeared physically healthy throughout
this study. All animals in the control group littered
which is an indication that no abortion occurred
as shown in table 1. Only 80% of animals treated
with C. papaya leaf extract for 24 hours littered
which suggests that miscarriage has occurred in
20% of animals in that group. In the animals
treated for 48 hours, only 60% littered which is
also suggestive that miscarriage has occurred in
0
5
10
15
20
25
30
35
A B C D E
Contraction (mm)
Volume of Drug Administered (mL)
Oxytocin
C. papaya

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7
the remaining 40% that did not litter. In the
group treated with C. papaya leaf extract for 72
hours, 80% of the animals did not litter. This
might be an indication that C. papaya leaf
extract induced miscarriage in 80% of the
animals in that group. Animals that did not litter in
their respective group were observed to be
depressed which is one of the reported
symptoms of miscarriage [27]. This result
contradicts the findings of Airaodion et al. who
treated animals with Chrysophyllum albidum [22]
and Ananas comosus fruit juices [28,9]
respectively.
All doses of C. papaya leaf extract administered
significantly induced contractions of the isolated
rat uteri (p<0.05) with 0.05, 0.1, 0.2. 0.3 and 0.4
raised the amplitudes of contractions from 5 mm
to 21.17 ± 2.04, 27.83 ± 2.83, 29.14 ± 0.89,
30.86 ± 1.27, and 31.11 ± 2.11 respectively. The
contractions induced by papaya leaves
compared favourably with that of the standard
drug oxytocin. This result corresponds with the
findings of Airaodion et al. who treated animals
with Chrysophyllum albidum fruit juice [22] and
Ananas comosus fruit juice [28] respectively.
In the in vitro experiment, C. papaya leaf
extract elicited dose-dependent multiple
contractions of the pregnant rat's uterus. These
effects were significantly different (p<0.05)
from the basal contractions, with 0.40 mL of
extract eliciting the highest increase in the
amplitude of 522.20% (Table 2). This result also
corresponds with the findings of Airaodion et al.
who treated animals with Chrysophyllum albidum
[22] and Ananas comosus fruit juices [28]
respectively.
The effect of C. papaya leaf extract on an
isolated pregnant rat uterus compared with that
of standard uterotonic agent oxytocin showed
that C. papaya leaf extract was giving slightly
higher effect oxytocin at all doses (Fig. 2). This
contradicts the study of Airaodion et al. [22] who
reported greater effect for oxytocin at all doses
when animals were treated with Chrysophyllum
albidum fruit juice. It also contradicts another
finding of Airaodion et al. [28] who reported
greater effect for oxytocin at low doses but the
lower effect at high doses when animals were
treated with Ananas comosus fruit juice. Papaya
leaf extract when administered to the isolated
pregnant rat uteri induced multiple uterine
contractions like that of oxytocin. This result
suggests that C. papaya leaf extract may contain
bioactive principles capable of inducing uterine
contractions and as such could be used to
facilitate labour or as an abortifacient. This might
be due to the ability of the content of C. papaya
leaves to bind to histaminergic (H
2
) receptors
present in the rat uterus [29], promoting calcium
flux in the smooth muscles [9].
5. CONCLUSION
C. papaya leaf extract induced multiple
contractions of the pregnant rat uteri following in
vitro and in vivo administrations. This suggests
that papaya leaves contain active agents which
could be isolated and processed into pure
uterotonic agents. Thus, it is recommended that
care should be taken in the use of C. papaya
leaves during pregnancy and its use in folklore
medicine during pregnancy should be
discouraged. However, the results observed
in this study does not automatically translate to
the same effect in humans, therefore, its
effect on pregnant women can be further
confirmed.
CONSENT
It is not applicable.
ETHICAL APPROVAL
Animal ethic Committee approval has been
collected and preserved by the author.
COMPETING INTERESTS
Authors have declared that no competing
interests exist.
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