Int. J. Pharm. Sci. Rev. Res., 55(2), March - April 2019; Article No.

13, Pages: 70 - 77 ISSN 0976 – 044X

Research Article

Teratogenic Effects of Pantoprazole on the Pregnant Rats and Their Fetuses during Gestation

Marwa Alaa El Din Sarry El Din 1*, Abd El Wahab El Ghareeb2, Said Abdel Rahman Mostafa3, Heba Ali Abd El-Rahman2
1* Department of Biotechnology, Faculty of Science, Cairo University, Egypt.
2 Department of Zoology, Faculty of Science, Cairo University, Egypt.
3 Department of Chemistry, Faculty of Science, Cairo University, Egypt.

*Corresponding author’s E-mail: [email protected]

Received: 10-02-2019; Revised: 20-03-2019; Accepted: 03-04-2019.

ABSTRACT
This study was undertaken to evaluate the teratogenic effects of the proton pump inhibitor (PPI) drug (pantoprazole) which was on
a daily basis orally-administered to the pregnant albino rats (Rattus norvegicus). The virgin female rats were mated with the male
and the pregnant rats were orally-administered a human equivalent dose (4.11 mg/kg) of Pantoprazole from 6th to 19th gestation
days. On the 19th day of gestation, females were sacrificed and fetuses were removed from the uterus and evaluated for mortality
rate, growth parameters, morphological and skeletal malformation and the oxidative stress markers were evaluated. Results
showed decreased in corrected mother weight gain of pregnant rats and fetal growth retardation. Hematomas were detected
morphologically in the fetuses and high incidence of resorption in treated animals. Fetal skeletal anomalies summarized as less
degree of ossification in most bones, costal separation, curved and wavy ribs. Biochemical studies in both pregnant rats and their
fetuses showed that pantoprazole induced a reduction in the level of reduced glutathione (GSH) which is an important intracellular
(non-enzymatic antioxidant), and depletion in the superoxide dismutase (SOD) (enzymatic antioxidant) activity compared to control
group. Also, elevation in the level of catalase (CAT) and Lipid peroxide Malondialdehyde (MDA) (Biomarkers of oxidative stress)
compared to control group. All of these prove the teratogenic effect of the pantoprazole. Thus, we suggest the need for a great
caution to handle pantoprazole especially during pregnancy.
Keywords: Pregnant albino rats, Skeletal abnormalities, Gastroesophageal reflux disease (GERD), Liver, Placenta, Pantoprazole and
Oxidative stress.

INTRODUCTION to treat certain stomach and esophagus problems (such

as acid reflux). It helps heal acid damage to the stomach

T he birth defects could be obvious or latent at birth,

owing to the conjugation effects of internal and
external factors during the prenatal developmental
processes. 1,2 Teratogenic agents like chemicals (drugs),
irradiation and contagious substances. Potentially almost
and esophagus; helps prevent ulcers, and may help
prevent cancer of the esophagus. Pantoprazole is rapidly
and completely absorbed after oral administration. It is
almost exclusively metabolized in the liver through the
cytochrome P450 (CYP) system. The main metabolic
any medication used by the mother during pregnancy
pathway is demethylation, by CYP2C19, with subsequent
could be deleterious to the fetus, causing an anatomic
sulfation; other metabolic pathways include oxidation by
defect (teratogenic).
CYP3A4. 6
Most pregnant women have symptoms of
FDA Pharmaceutical Pregnancy Category (B) for
gastroesophageal reflux disease (GERD), a condition that
pantoprazole in animal reproduction studies is not
develops when the reflux of stomach contents causes
available for risk to the fetus classification. But there are
troublesome symptoms and/or complications, especially
no enough clinical trials or studies are available regarding
heartburn at some point. These symptoms may start at
the safety of Pantoprazole use during pregnancy. 7 The
any time during a pregnancy and they often get worse
present study is carried out to evaluate the teratogenic
throughout the pregnancy.3, 4 General management plan
potential of the proton pump inhibitor drug
would include the following: dietary and lifestyle
(Pantoprazole) on the female rats orally administrated
modification as avoidance of tobacco, alcohol, chocolate,
with (4.11mg/kg) from 6th day up to 19th days of
and citrus juice 5 and/or medical treatment if heartburn is
gestation. To evaluate the teratogenic effect of the drug,
not controlled by lifestyle measures as Antacids,
the following parameters were investigated, mortality
Histamine H2-receptor Antagonists, Prokinetic and Proton
rate, growth parameters, morphological and skeletal
Pump Inhibitors PPIs.
malformation. In addition, the oxidative stress markers
Proton Pump Inhibitors PPIs provide faster relief than were evaluated.
prokinetics or H2-blocking agents and have good evidence
for long-term healing of esophageal erosion (including
Barrett’s esophagus). Pantoprazole belongs to a class of
drugs known as proton pump inhibitors (PPIs). It is used
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MATERIALS AND METHODS Oxidative stress investigation

All the experimental protocols and procedures used in this Autopsy samples that were taken from the placenta and
study were approved by the Cairo University, Faculty of liver of mother rats and fetuses in various groups were
Science Institutional Animal Care and Use Committee put away at - 40◦C for oxidative stress examination. Piece
(IACUC) (Egypt), (CU/I/S /103/17). of each tissue were weighted and homogenized in 10
mmol/L phosphate buffer saline (PBS) as 10 % (W/V) at
Drug Used
pH 7.4. The homogenates were centrifuged and the
Pantoprazole Tablets produced by PHARAONIA supernatants were taken for the estimation of:
PHARMACEUTICALS (PHARO PHARMA) - Alexandria - A.R.E. Glutathione Reduced (GSH), Catalase (CAT), Superoxide
Each tablet contains 40 mg of pantoprazole sodium Dismutase (SOD) and Lipid Peroxidatio (MDA) by
sesquihydrate. The tablets were soluble in water. calorimetric method using reagent kits obtained from Bio
Diagnostic (Egypt). 12-15
Animal Housing
Statistical analysis
Healthy adult female and male rats (Rattus norvegicus),
Wistar strain with an average age of approximately 2 to 2.5 All the values were presented as means (μ) ± standard
months and weighing170-180 grams were obtained from errors of the means (S.E.M) comparison between two
the animal house of the Faculty of Veterinary, Cairo different groups was carried out using the independent
university- Egypt and used for experimentation. student T test. GraphPad Software InStat (version 2) was
used to carry out the statistical tests.
The virgin female rats were mated with the male rats
(Two females caged together with one male) overnight RESULTS
under standard conditions (21 ± 1°C, 60±20% humidity,
Effect of pantoprazole on pregnant rats
and 12 h/12 h light/dark cycle). The first day of gestation
was determined by the presence of sperm in the vaginal The pregnant rats treated orally with 4.11mg/Kg (group B)
smear. 8 of pantoprazole during gestational period (6th - 19thday)
revealed no external symptoms of toxicity. No mortality
Experimental procedure and dosing
cases were recorded and we didn't score any dead case
In the present investigation, the recommended dose for through the experimental duration.
human is 40 mg/daily. The dose was modified to suit the
The corrected mother body weight gain of the treated
weight of rats. 9
group was decreased than that of the control group but
Ten pregnant rats, served as control group, was received not significant (P› 0.05) (Table 1).
equivalent amount of distilled water from the 6th day to
Table 1:
19 day of gestation, daily during gestation. Ten females
treated group was received orally 4.11 mg/ Kg day of Group Control Treated 4.11mg/Kg
pantoprazole. Item (A) (B)
Growth observations Corrected weight
20.79±10.19 9.05±2.83
gain (C.W.G)
On the 19th day of gestation, all pregnant rats were
weighted and dissected and uterus weighted then Uterus Weight
36.21±2.61 24.54±3.10a
opened to remove fetuses with their placenta. Fetuses (U.W)
and placentas were removed from the uterus then Placenta weight
weighted and evaluated for any external malformations 0.545±0.008 0.429±0.013a
(P.W)
(exencephaly, cleft palate, abdominal hernia, polydactyl,
post-implantation
open eyelid, etc.) was performed under a dissecting 1.25±1.25 19.48±9.31
(Po.I)
microscope and their weights, mortality rate (resorbed or
still birth) and growth parameters. The weights of the pre-implantation
27.75±7.08 27.11±6.84
pregnant rats were recorded at the 6th and 19th GD and (Pr.I)
the % of change in maternal weight through the gestation Fetus weight
was calculated as % change in maternal weight = (wt. of 2.97±0.094 1.71±0.067a
(F.W)
20th day- wt. of 1st day / wt. of 20th day) x 100. In
Viable fetus No.
addition to, post-implantation loss index calculated. 10 (VF)
7.5±0.734 7.0±0.966

Post-implantation loss index= No. of implantation sites-

Values are expressed as Mean ± SEM. The statistical
No. of live fetuses/ No. of implantation sites x100.
differences were analyzed by independent samples T test.
Skeletal examination a= P ≤ 0.05 compared with control.
Fetuses were preserved in 95% ethyl alcohol and were
stained with double staining of fetal skeletons for
cartilage (Alcian blue) and bone (Alizarin red) solution. 11
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The uterus from control group revealed normal The average weight of placenta of all treated pregnant
distribution of the implanted fetuses between the two rats group was significantly (P≤ 0.05) decreased as
horns (Fig.1) while the uterus of treated pregnant rats compared to control (Table 1).
treated showed asymmetrical distribution of fetuses in
Moreover, there was a significant decrease in uterus
the two uteri horns (Fig.1), resorption sites (late &early
weight (Table 1), non-significant increase in post-
embryonic resorption) were observed (Fig.1) and
implantation loss index and decreased in pre-
completely early resorbed uterus also revealed that called
implantation loss index after comparison with the control
pinpoint hemorrhagic implantation sites (Fig.1).
group (Table 1) were observed.

Figure 1: Photographs of uterus of pregnant rat at the 19th day of gestation.

From control group showing: (a) Normal symmetrical distribution of fetuses (F) in the two uteri horns. From treated
group showing: (b) Asymmetrical distribution of fetuses in the two uteri horns with resorbed site (arrow). (c) Uterine
horns showing pinpoint hemorrhagic implantation sites (early resorption= R). (d) Uterine horns showing clearly visible
embryonic early resorption sites(R). (e) Uterine horns showing clearly visible embryonic late resorption sites (LR).
Effect of pantoprazole on fetuses non-significant decrease (p > 0.05) in number of a live
fetus of the pregnant rats that treated with 4.11 mg/Kg of
The fetuses of the control mothers have normal
pantoprazole when compared with the control group
morphology, normal body weight (Fig.2) and appeared
(Table1).The malformations found in fetuses of treated
straight dorsally. Maternal administration of pantoprazole
group are summarized in hematoma (red patches at
caused growth retardation represented by a decrease in
different parts of the body) and whitish spots just under
fetal body weight (Fig.2). There was a significant (P≤ 0.05)
the left axilla (Fig.3).
reduction in fetus weight of treated group when
compared with the control group (Table 1). There was a

Figure 2: Photographs of fetus of mother at 19th day of gestation

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From control group (a) showing fetus exhibited normal morphology with correct size and length. Treated mother with
11.4 mg/Kg showing (b) growth retarted Fetuses.

Figure 3: Photographs of fetus of mother at 19th day of gestation

Treated mother with 11.4 mg/Kg showing: (a) Dorsal Hematoma (Orange arrow). (b) Ventral Hematoma (yellow arrows)
and Hematoma at tail (Blue arrow). (c) Hematoma at intra thoracic cage (Green arrow). (d) Whitish spots just under the
left axilla (Black arrows)
Skeletal anomalies pantoprazole showed high percentage of incomplete
ossification of all cranial bones (64.4%) from the
At the 19th day of gestation, the cleared cartilage and
examined fetuses (Fig.5), and the ribs anomalies
bone preparations of control rat fetuses have designated
represented in wavy , curved, rudimentary ribs,
that all parts of the axial skeleton, skull, vertebrae and
incomplete ossification degree and high percentage of
ribs as well as appendicular skeleton comprising the fore
un-ossified ribs (49.3%). (61.8%) of the sternum showed
and hind limbs, pectoral and pelvic girdles, ossification
unossified sternebrae (Fig.6). In addition, girdle and limbs
process has been obviously completed (Fig. 4). On the
showed incomplete degree of ossification.
other hand, fetuses maternally treated with 4.11mg/Kg of

Figure 4: Photographs of the control fetal skeleton. (Alcian blue & Alizarin red stain).
a) Skull bones. Showing complete ossification of the cranial bones. Fr= frontal, Pr = parietal, N= nasal, Mx= maxilla, Ma=
mandible, IP= interparietal. b) Ribs and vertebral column. Showing complete ossification. C.V= cervical vertebrae, Th.V=
thoracic vertebrae, Th R= thoracic rib, L.V= lumbar vertebrae. c)The sternum. showing complete ossification of sternbrae
bones. d) Pectoral girdle and Forelimb. Showing complete ossification. Cl= clavicle, Sc= scapula, H= humerus, U= ulna, R=
radius, MC= metacarpals. e) Pelvic girdle and Hind limb. Showing complete ossification. I= ilium, IS= ischium, P=pubis,
Fe= femur, Ti= tibia, Fi= fibula and MT= metatarsus.

Figure 5: Photographs of the skull bones from treated group with 4.11 mg/Kg. Showing:

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. (a) Incomplete ossification of all cranial bones. b) Unossified cranial bones

Figure 6: Photographs of the ribs and vertebral column from treated group with 4.11 mg/Kg. Showing: a) un
ossification Curved ribs. (b) Incomplete ossification Wavy ribs and rudimentary ribs. (c) Costal separation. (d) Unossified
sternbrae bones.

Figure 7: Photographs of fetuses from treated group with 4.11 mg/Kg.

Showing: (a) incomplete ossification pectoral girdle and Forelimb. (b) Incomplete ossification Pelvic girdle and Hind limb.
Oxidative stress observations 2- Maternal liver tissue
Reduced glutathione (GSH) is an important intracellular Oral administrated of 4.11 mg/Kg pantoprazole during
antioxidant and redox potential regulator that plays a gestation revealed significant decrease in the level of
vital role in cellular protection from damage by free GSH, no significant decrease in the levels of antioxidant
radicals, peroxides and toxins. CAT serves to protect the enzymes CAT and no significant increase in the levels of
cell from the toxic effects of hydrogen peroxide by MDA was recorded when compared with control group.
catalyzing its decomposition into molecular oxygen and However, significant decrease (P≤0.05) in the level of SOD
water without the production of free radicals. In addition when compared with the control group (Table 3).
the level of MDA was elevated as an indicator of lipid
3- Fetal liver tissue
peroxidation and SOD quenches superoxide anion, thus
its activity inhibits the overall colorimetric reaction. The content of GSH was decrease insignificantly in the
hepatic tissue of fetuses treated with pantoprazole 4.11
1- Placenta tissue
mg/Kg. The fetuses of pregnant rats orally administrated
There was significant reduction (P≤ 0.05) in the level of with 4.11 mg/Kg and showed significant (P≤ 0.05)
GSH was observed when pregnant rats treated with 4.11 decrease in the activity of CAT and significant increase in
mg/Kg of pantoprazole during gestation compared with the MDA antioxidant enzyme level. In addition to
the control group, non-significant elevation in the significant reduction in the SOD levels when compared
catalase activity and MDA were observed and significant with the control group (Table 4).
reduction in the level SOD during gestation compared
with the control group (Table2).

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Table 2: Showing effect of pantoprazole on placenta The safety of using pantoprazole which is newer PPI in
tissue. pregnancy was proven in some animal experiments. 18 In
our study, oral administration of Pantoprazole to female
Group GA GB rat from 6th day up to 19th days of gestation did not
parameter (control) (4.11 mg/Kg) reveal any signs of maternal toxicity as vaginal bleeding
GSH (U/g) 0.46±0.074 0.0511±0.0063a also no dead cases were observed. While the study
showed a significant reduction in the placenta weight and
CAT (U/g) 0.053±0.003 0.0567±0.0053
fetal weight, high incidence of the resorption and high
MDA (U/g) 0.62±0.057 0.74±0.059 percent of the hematoma (dark spot) at different parts of
SOD (U/g) 42.28±2.19 25.72±4.71a the body (dorsal, ventral, intra thoracic cage and tail) also
whitish spots just under the left axilla appeared on the
Values are expressed as Mean ± SEM. The statistical fetal body as an external malformation when compared
differences were analyzed by with the control. In addition, there was non-significant
ANOVA followed by independent samples T test. a= P ≤ reduction in the maternal corrected body weight and
0.05 compared with control. non-significant increase in the percent of post-
implantation loss were observed. The previous finding
Table 3: Showing effect of pantoprazole on liver of may be occurred due to the direct action of the drug or its
pregnant rats at 19th day of gestation. metabolites on fetuses which can transfer via the
Group placental barrier.
GA GB
parameter (control) (4.11 mg/Kg) A study conducted in the 1960s reported that embryonic
GSH (U/g) 0.373±0.038 0.24±0.043a
exposure to antacids during the last trimester of
pregnancy would carry the risk of congenital
CAT (U/g) 0.157±0.017 0.098±0.0233 malformations. In animal studies, cimetidine has a weak
MDA (U/g) 1.27±0.36 1.54±0.086 antiandrogenic effect in animals, in the form of smaller
SOD (U/g) 113.05±18.61 26.62±4.03a size of male genital system. 19 However, ranitidine has no
such effect in animals. 20
Table 4: Showing effect of pantoprazole on liver of
fetuses at 19th day of gestation. According to FDA, all PPIs are categorized as class B drugs
except omeprazole due to its fetal toxicity which is
Group GA GB classified as a class C drug. 12 birth defects as
parameter (control) (4.11 mg/Kg) anencephaly and hydranencephaly were reported to FDA
in pregnant women undertaken omeprazole. (19) Other
GSH (U/g) 0.38±0.086 0.355±0.032
researchers reported taking 20-60 mg omeprazole/day
CAT (U/g) 0.15±0.012 0.056±0.001a has no risk of fetal congenital anomalies even if taken
MDA (U/g) 0.315±0.066 5.16±0.163a from the first trimester. (21-23) Regarding lansoprazole,
SOD (U/g) 39.8±2.77 21.36±3.07a animal studies using doses exceeding 40 times the
recommended human dose have no harm on fetus or
DISCUSSION & CONCLUSION fertility.
Heartburn is a normal consequence of pregnancy, Skeletal malformations are clinically important as they are
occurring in nearly two-thirds of women. Symptomatic associated with severe disability and may cause death. 24
GERD during pregnancy should be managed with lifestyle Incomplete ossification of the fetal skeleton may be a
modifications and dietary changes. Antacids are reason for fetal growth retardation and the consequential
considered the first-line medical therapy. If symptoms decrease in fetal weight. Un- ossification of several bones
persist, any of the Histamine2-receptor antagonists can may be due to alternations in calcium metabolism or
be used. These antagonists do not cause infantile sexual deviations in calcitonin levels in the developing fetus,
defects. Proton-pump inhibitors are reserved for women leading to weak bone development. (25) The present study
with intractable symptoms or complicated reflux disease. suggested that the oral administration of pantoprazole
(16)
to the pregnant rat induced a broad variety of
FDA classify the pantoprazole as category (B), the animal incompletely ossified, unossified skull bones, appearance
reproduction studies do not show any fetal risk. But there of costal separation, incomplete ossification of the
are no enough clinical trials or studies are available sternum, incompletely ossified, unossified bones of fore
regarding the safety of pantoprazole use during and hind limbs and absence of ossification of metacarpals
pregnancy in woman. (17) The present study is carried out and metatarsals.
to evaluate the teratogenic potential of the proton pump
While ROS are produced in large quantities continuously
inhibitor drug (Pantoprazole) on the female rats and their
throughout life, both from mitochondrial and cytosolic
offspring orally administrated with (4.11mg/kg) during
elements, antioxidant defense mechanisms are vital for
the gestation.
cellular homoeostasis. 26 Antioxidant activity is at the very
least a continuous two stage process, with several potent
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Int. J. Pharm. Sci. Rev. Res., 55(2), March - April 2019; Article No. 13, Pages: 70 - 77 ISSN 0976 – 044X

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