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Lead Researcher, Associate Professor, College of Medicine, LyceumNorthwestern University
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Assistant Researchers, College of Medicine, Lyceum Northwestern University
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ABSTRACT
Randomized controlled trials of treatment with metformin vs. insulin with gestational diabetes
mellitus
Gestational Diabetes Mellitus is a major health risk both for the mother and the fetus. In the
various forms of gestational diabetes. The most important correlate perinatal correlate is
excessive fetal growth, which may result in both maternal and fetal birth trauma. The likelihood
of fetal death with appropriately treated gestational diabetes mellitus is not different from that in
the general population. The research work focused on determining the safety and effectiveness of
Metformin in gestational diabetes. It further aimed to give answers to the following questions:
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2. Is there a significant difference between the effectiveness of Metformin and Insulin in
The results showed that Metformin gave a higher safety and effectiveness as compared to insulin
in terms of the weight of the baby, risk of NICU admission rate, pre-eclampsia and frequency of
neonatal hypoglycaemia.
METHODS
Forest plot table 1: Test for Herogeneity: Chi-square = 85.2347; df = 7 p-value = 0.00065, forest
plot relative risk of insulin vs metformin by macrosmia show that patients who took metformin
showed better outcomes in terms of the babies’ weight. Forest plot table 2: Test for Herogeneity:
Neonatal Intensive Care unit admissions showed that patients from metformin group showed
better outcomes. Forest plot table 3: Test for Herogeneity: Chi-square = 191.8012; df = 6 p
value = 0.0031, relative risk of Insulin vs Metformin by neonatal hypoglycemia showed that
patients taking insulin are the ones that are higher in risk for having neonatal hypoglycemia.
Forest plot 4: Test for Herogeneity: Chi-square = 112.31 df = 6 p-value = >0.0001, relative risk
of insulin vs Metformin by preeclampsia, showed that patients who took insulin has higher risk
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Based from the results of the four forest plots, in which all of them showed p- values <0.5 means
that values of relative risk for Meta- analysis is significant and therefore conclude that
Metformin is safe and effective against gestational diabetes mellitus; there is a significant
difference between the effectiveness of Metformin and Insulin in gestational diabetes mellitus in
terms of neonatal hypoglycemia and pre-eclampsia, and Metformin is safer for gestational
CHAPTER I
INTRODUCTION
The worldwide prevalence of DM has risen dramatically over the past two decades, from an
estimated 30 million cases in 1985 to 382 million in 2013. The countries with the greatest
number of individuals with diabetes in 2013 are China (98.4 million), India (65.1 million),
United States (24.4 million), Brazil (11.9 million) and Russian Federation (10.9 million). Up to
80% of individuals with diabetes live in low income or medium income countries (Harrisons
250,000 women—are affected annually by various forms of gestational diabetes. Risk factors of
acquiring such disease are the following: Severe obesity, strong family history of Type 2
Diabetes and previous history of GDM, impaired glucose metabolism or glucosoria (Williams
Obstetrics). Different complications for both the mother and the fetus can arise such as large for
gestational age (LGA), macrosomia, shoulder dystocia, neonatal hypoglycaemia, and the need
for cesarean section which are all manageable and preventable. There have been numerous
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researches that were done regarding the different management of diabetes mellitus, both
Many pharmaceutical companies offer medications that are made up of herbal plants and
prepared chemically, however, there were no approved drugs that can offer absolute cure. Diet
modification is often used as first-line treatment, and if partly or wholly unsuccessful or where
glibenclamide (glyburide) and/or insulin) are offered. They can be prescribed with various
medication, but there should be a balance of therapeutic effect and safety to both the mother and
the fetus. Common drugs prescribed are Insulin and Metformin, several studies have been
conducted regarding the effect of the said drugs to the diabetic mother and it’s safety to the
developing fetus.
The researchers, as future clinicians whose purpose is to promote health and wellness for
both the mother and the fetus, therefore aimed at gathering and analyzing pertinent and reliable
data and then critically appraise the published evidences on the effectiveness and safety of the
5
CONCEPTUAL FRAMEWORK
Subjects were women diagnosed with Journals excluded based on titles and
Gestational Diabetes Mellitus requiring abstracts
drug treatment.
studies done from August 2016 until December 2017 were excluded
included.
The title, abstract and full text screening was done by five
reviewers with disagreements resolved by the consensus of
the other members of the review team. 6
Figure 1.1 Conceptual Framework of Meta-Analysis on the Comparison of
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Figure 1.2 Paradigm of the Meta-Analysis on the Comparison of Metformin and Insulin in the
This study compared the results of the studies gathered regarding the effects of
Metformin and Insulin when used in the treatment of gestational diabetes, since both drugs are
capable to decrease glucose. The researchers have used the MESH terms Gestational diabetes,
Metformin and Insulin in PubMed, Cochrane and Elsevier search engines to gather journals that
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The main focus of the study was to come-up with an updated meta-analysis on
comparison between metformin and insulin for the management of gestational diabetes mellitus
utilizing a randomized control trial study. Studies were included if they met the following
criteria: subjects were women are diagnosed with Gestational Diabetes Mellitus requiring drug
treatment, randomized control trials that has results of efficacy of Metformin and Insulin for
gestational diabetes mellitus, studies done from August 2016 until December 2017. Trials had to
report on effects on adverse effects outcomes such Pre- eclampsia, Premature birth, Cesarean
section and Weight gain during pregnancy. Journals that were uplifted were from the Elsevier,
MEDLINE and PubMed. Whereas the following studies are excluded if these criteria are met:
reviews, letters and comments and studies that results to the effectiveness of metformin and
Study Selection
1. Subjects were women diagnosed with Gestational Diabetes Mellitus requiring drug
treatment.
2. Randomized control trials that has results of efficacy of Metformin and Insulin for
gestational diabetes mellitus, studies done from August 2016 until December 2017.
The randomized control trials had to report on the adverse effects outcomes, such as, Pre-
eclampsia, Premature birth, Cesarean section, and Weight gain during pregnancy. Whereas the
following studies are excluded if these criteria are met: Reviews, letters and comments and
studies that results to the effectiveness of metformin and insulin with other diseases.
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OBJECTIVES OF THE STUDY
General Objective
Specific Objectives
gestational diabetes.
gestational diabetes.
3. To be able to know if Metformin is more effective than Insulin for gestational diabetes.
DEFINITION OF TERMS
with onset or first recognition during pregnancy (illiams Obstetrics 24th edition)
webster.com/dictionary/hyperglycemia).
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INSULIN – It is the mainstay for treatment of virtually all type 1 and type 2 diabetes
patients (Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition,
pp. 1248).
systematically assess previous research studies to derive conclusions about that body of
research (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049418/)
METFORMIN – It is currently the most commonly used oral agent to treat type 2
diabetes and is generally accepted the first-line treatment for this condition (Goodman &
pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP)
syndrome that can affect virtually every organ system (Williams Obstetrics 24th edition,
pp. 729).
individuals who receive them in random order. The RCT is one of the simplest and most
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powerful tools in clinical research
(https://www.medicinenet.com/script/main/art.asp?articlekey=39532).
CHAPTER II
pregnancy. It is associated with maternal and neonatal adverse outcomes. Maintaining adequate
blood glucose level in GDM reduces morbidity for both the mother and baby. The initial
treatment for GDM consists of diet and exercise. If these measures fail to achieve glycemic
goals, insulin should be initiated. For several decades, insulin has been the most reliable
treatment strategy and the gold standard for GDM. Metformin on the other hand is an effective
insulin sensitizing agent and it appears that it may perhaps open a new door in managing GDM
(Singh et al,2016).
According to Saleh et. al. (2016), health education for dose adjustment of insulin is
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health education on the safe use of insulin in addition to the cost of the drug itself are chased.
Observably, oral therapy if safe and effective could be more satisfactory and desired.
Presently, Metformin is becoming more widely used in Australia among pregnancy specialists
and endocrinologists. There have been few observable risks identified with metformin over
insulin, slightly lower gestational age at delivery (pooled mean difference −0.16 weeks (−0.30 to
−0.02)), and more preterm birth (pooled risk ratio 1.50 (1.04 to 2.16)) and studies are emerging
which show benefits to mothers and the neonate (Gray, S. et. al. 2017).
Metformin is a biguanide compound, which exerts its clinical effect by both reducing
hepatic glucose output and by increasing insulin sensitivity. This results in a decreased glucose
level without an associated high risk of either hypoglycemia or weight gain. These characteristics
have established metformin as an ideal first-line treatment for people with type 2 diabetes
mellitus and, hypothetically, a particularly attractive drug for use in pregnancy. Confidence
regarding the use of metformin in pregnancy has been reinforced by the results of several
observational studies and randomized trials over the past decade (Feig, D. & Moses, R. 2011).
Moreover, the success rate of a drug in achieving targeted glucose levels also depends on
disease severity as reflected by plasma glucose values. The rate of success for achieving
glycaemic control in metformin-treated patients ranged from 54 to 79 per cent (Tripathi, R., et al.
2017).
Meanwhile a study on the mean blood glucose level at overnight fasting and postprandial
and HbAlc level at delivery were similar in both groups throughout GDM treatment. The number
of patients who reached the goal of an approximately equal fasting and postprandial glycaemia
did not differ significantly between the two groups. Consequently, Metformin was found to be
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In general, Metformin is effective as insulin for the management of GDM. Metformin can
be used securely during pregnancy as it is not linked with congenital malformations or increased
hypoglycemia. Current studies show that metformin is safe and effective in treatment of
Metformin?” by Somani, P. (2016), metformin has established as an ideal first-line treatment for
type 2 diabetes mellitus, and hypothetically a particularly attractive drug for use in pregnancy. A
total of 32 on metformin (Intervention group) and 33 on insulin (Active control group) subjects
metformin until delivery and 25% of the metformin group received supplemental insulin. There
was no significant difference in mean birth weight between the groups. There were no significant
satisfaction (70.97%) was significantly better in the metformin group, whereas, better control of
Another study conducted by Singh favors metformin which can be used as a safe and
effective oral hypoglycaemic agent in GDM, especially in low-resource settings where cost,
Therefore, using oral hypoglycemic agents in controlling blood sugar almost parallels
with the effect of insulin. Hypothetically, metformin is an alternative to insulin in the treatment
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enhancing peripheral glucose uptake. Glycaemic control in GDM can be achieved by using
metformin orally without increasing risk of maternal hypoglycemia with satisfying neonatal
outcome.
CHAPTER III
RESEARCH METHODOLOGY
METHODS
Patient Involvement
The results of different randomized controlled trials from the year 2016- 2017 about the effects
of metformin in pregnancy were included in this study. Pregnant women who has, had and those
are at risk of having gestational diabetes mellitus were selected and they will be the contributory
factor for the appraisal and review of the effects of metformin in pregnancy for this study.
Search Methods
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We started with using keyword based searching (Metformin, Insulin and Gestational Diabetes
Mellitus) in multiple databases and identified types of study. The search strategy of choosing
randomized controlled trials (RCT) of treatment with Metformin vs. Insulin of women with
GDM. We also considered the date it was published and limited it to studies between August
2016 and 2017. The bibliographical databases searched were Elsevier, MEDLINE and PubMed
among others. The studies were not bounded by the country it was published in. The searches
were started August 2017 and were organized using the same search strategies to qualify studies
that fit the parameters given. We also included other form of references like journals,
supplementary files, and readings. To balance the sensitivity and precision, we asked the experts
what inclusion criteria should be considered aside from the parameters given, as well as
screening the reference list and citations from the articles found.
The title, abstract and full text screening was done by five reviewers with disagreements resolved
by the consensus of the other members of the review team. The risk of bias of the clinical trials
that were included was assessed by the Cochrane risk of bias tool which considers sequence
allocation, blinding of the assessors, loss to follow-up, selective reporting of outcomes and other
sources of bias. Each criterion was classified as either low or high risk of bias or unclear. Two
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CHAPTER IV
Events/
Sample Relative
Study Size Risk
17
Metaanalysis 231/1452 18.312
Considering 8 previous studies, our systematic review estimated that the relative risk of
having macrosomia babies for those patients who received insulin is approximately 18.312. This
means that the risk of having macrosomia babies are higher to those patients who received
insulin as compared to those patients in Metformin treatment. Hence, patients who took
Note that since the p-value is less than 0.05, the values of relative risk for metaanalysis is
Total
Events/ Relative
Study Sample Size Risk
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Meta-
analysis 349/1491 22.69971
Figure 4.2 Forest plot of relative risk of Insulin vs Metformin by NICU admission
Considering 7 previous studies, the NICU admission rate for metformin group are found
to be as compared to insulin group and hence, this meta-analysis showed that the relative risk of
NICU admission for insulin group is approximately 22.69971 which means that the risk of
babies from insulin group to be admitted in NICU are higher than those babies from the
metformin group. In terms of NICU admission rate, patients from metformin group showed
better outcomes.
Events/Sample Relative
Study Size Risk
Sikder et.al 154/550 28
Tertti et. al 18/69 26.086
Spaulonci et. al 13/94 13.829
Moosavi et. al 5/160 3.125
Saberi et. al 25/100 25
Ijas et. al 11/97 11.34021
Hassan et. al 30/150 20
Meta-analysis 256/1220 19.562
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Test for Herogeneity: Chi-square = 191.8012 df = 6 p-value = 0.0031
Figure 4.3 Forest plot of relative risk of Insulin vs Metformin by neonatal hypoglycemia
neonatal hypoglycemia and that incidence of neonatal hypoglycemia are significantly higher for
those patients in the insulin group. The systematic review estimated that the relative risk of
having neonatal hypoglycemia for babies from insulin group is approximately 19.562 . This
means that the risk of having neonatal hypoglycemia for babies from insulin group are
Events/Sample Relative
Study Size Risk
Fadl et. al 8/72 11.11
Tertti et. al 38/217 6.92
Elnour et. al 33/165 19.39
Pavao et. al 22/94 23.40
Moosavi et. al 28/160 18.33
Macklin et.al 5/20 25
Saleh et. al 25/137 18.2418
Meta-analysis 113/745 19.67
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Test for overal effect: z=0.3812 p-value = 0.0016
Overall, pre-eclampsia was significantly less in metformin treated groups and hence, the
incidence of suffering from pre-eclampsia are most common to insulin group. The relative risk of
suffering from pre-eclampsia for insulin group is estimated to be 19.67 indicating that the risk of
having suffering from pre-eclampsia for insulin group are significantly higher as compared to
CHAPTER V
The main focus of this chapter is to present the summary of all the procedures performed
in the meta-analysis, the results obtained, the conclusions and the recommendations for the
future researchers.
SUMMARY
The research work focused on determining the safety and effectiveness of Metformin in
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5. Is there a significant difference between the effectiveness of Metformin and Insulin in
Fourteen (14) studies on Metformin were retrieved from the meta-analysis, Treatments for
gestational diabetes: a systematic review and meta-analysis. The group gathered 2 new studies
The results showed that Metformin gave a higher safety and effectiveness as compared to insulin
in terms of the weight of the baby, risk of NICU admission rate, pre-eclampsia and frequency of
neonatal hypoglycaemia.
CONCLUSION
In this study it shows that using Metformin is more safe and effective compared to using Insulin
RECOMMENDATION
To further enhance and improve the study, the researchers recommend that the following
measures be done:
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1. To obtain more randomized controlled trials (RCTs) to supply new evidence in giving a
2. To consider additional neonatal parameters such as large for gestational age (LGA) and
APGAR score, as well as maternal parameters such as HbA1c and FBS levels before,
REFERENCES
https://www.merriam-webster.com/dictionary/hyperglycemia.
23
Arshad R, Khanam S, Shaikh F, Karim N. Feto-Maternal outcomes and Glycemic control
Borg, H., Ezat, S., (2016) Metformin Opposed to Insulin in the Management of
Cunninghan, G.F., Leveno, K.J., Bloom, S.L., Spong, C.Y., Dashe, J.S., Hoffman, B.L.,
Casey, B.M., Sheffield, J.S. (2014) Williams Obstetrics (24th edition). McGraw Hill
Education.
Gilman, Alfred Sr., Goodman, Louis S. () Goodman & Gilman's The Pharmacological
Gray, SG., McGuire TM., Cohen, N., Little, PJ. (March 24, 2017) The emerging role of
metformin in gestational diabetes mellitus. Volume 19, Issue 6, pp 765 – 772. doi:
10.1111/dom.12893.
Hassan JA, Karim N, Sheikh Z. Metformin prevents macrosomia and neonatal morbidity
24
Ija¨s H, Va¨a¨ra¨sma¨ki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T,
Medical definition of randomized controlled trial (2016, May 13). Retrieved February 28,
Comparison of newborn outcomes in women with gestional diabetes mellitus treated with
Rowan J, Hague W, Gao W, Battin M, Moore P. Metfromin versus Insulin for the
Saleh, Hend S., Abdelsalam, Walid A., Mowafy, Hala E., Abd Elhameid, Azza A. (July
12, 2016) Clinical Study: Could Metformin Manage Diabetes Mellitus instead of
http://dx.doi.org/10.1155/2016/3480629
Singh, N., Madhu, M., Vanamail, P., Malik, N., Kumar, S. (September 25, 2017) Effiacy
DOI: 10.4103/ijmr.IJMR_1358_15.
25
Somani, Prashant S., Sahana, Pranab K., Chaudhuri, P., Nilanjan, S. (August 8, 2016)
Spaulonci CP, Bernardes LS, Trindade TC, et al. Randomized trial of metformin vs
7.
2013;15:246-251
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APPENDICES
n=72
27
Metformin vs. insulin in gestational diabetes. A randomized
study characterizing metformin patients needing additional
Insulin
28
Pharmaceutical care of patients with gestational diabetes
Mellitus
29
Randomized trial of metformin vs insulin in the management of gestational diabetes
Pregnancy outcome
The 2 groups did not differ in terms of the frequency of preeclampsia (10/46 [21.7%] in
group 1 and 7/46 [15.2%] in Of those, preeclampsia was superimposed to chronic
hypertension in 5 patients that had chronic hypertension in group 1 (5/14, 35.7%) and in
3 patients (3/12, 25%) in group 2 (P ¼.683).
30
Metformin-compared-with-insulin-in-the-management-of-gestational-diabetes-mellitus-
A-randomized-clinical-trial
31
Comparison-of-Newborn-Outcomes-in-Women-with-Gestational-Diabetes-Mellitus-
Treated-with-Metformin-or-Insulin-A-Randomised-Blinded-Trial
32
Metformin-should-be-considered-in-the-treatment-of-gestational-diabetes-a-prospective-
randomised-study
Metformin-prevents-macrosomia-and-neonatal
33
Metformin-versus-insulin-treatment-in-gestational-diabetes-in-pregnancy-in-a-
developing-country.-A-randomized-control-trial
34
Clinical Study
Could Metformin Manage Gestational Diabetes
Mellitus instead of Insulin?
Hend S. Saleh,
35
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CURRICULUM
VITAE
37
PERSONAL DATA:
Sex: Male
Nationality: Filipino
Status: Single
Email: luizulueta7@gmail.com
Educational Background:
38
PERSONAL DATA:
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015- Present
39
PERSONAL DATA:
Name: Chukaew,Saovaleeporn
Sex: Female
Nationality: Thai
Birth date: May 11, 1985
Age: 33 years old
Status: Single
Religion: Buddhist
Contact Numb er: 09213264613
Email: bo_062-3@hotmail.com
EDUCATIONAL BACKGROUND:
Tertiary:
Secondary:
Primary:
40
PERSONAL DATA
Name: Merielle C. Fernando
Address: Pangapisan North Lingayen, Pangasinan
Sex: Female
Nationality: Filipino
Birthdate: August 13, 1992
Age: 25 years old
Status: Single
Religion: Roman Catholic
Contact Number: 09366163110
Email: merielle.fernando@gmail.com
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015 – Present
41
PERSONAL DATA
Name: Hersi Khalif Abdirahman
Address: Tapuac, Dagupan City, Pangasinan
Sex: Male
Nationality: Somali
Birthdate: December 26, 1992
Age: 25 years old
Status: Single
Religion: Muslim
Contact Number: 09260170969
Email: khalifazeeg@gmail.com
EDUCATIONAL BACKGOROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015 – Present
42
PERSONAL DATA:
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015 – Present
43
PERSONAL DATA:
Name: Michael Francis M. Mangahas
Address: Poblacion East, Sta. Ignacia, Tarlac
Sex: Male
Nationality: Filipino
Birthdate: March 24, 1994
Age: 23 years old
Status: Single
Religion: Roman Catholic
Contact Number: 09279730716
Email: mfmmangahas.sbcm@gmail.com
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015 – Present
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PERSONAL DATA:
Name: Mohamed mohamed hussein
Address: Amado street, Dagupan city, Pangasinan
Sex: Male
Nationality: Somali
Birthdate: April/07/1990
Age: 27 years old
Status: Single
Religion: Islam
Contact Number: 09273245277
Email: baashi571@gmail.com
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2013 – Present
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PERSONAL DATA:
Name: RIKKIEMAE MARIA Z. PANLASIGUI
Address: 18 Bacar, Magsingal, Ilocos Sur
Sex: Female
Nationality: Filipino
Birth date: May 16, 1994
Age: 23 years old
Status: Single
Religion: Roman Catholic
Contact no: 09277742990
Email: rikkiemaemaria@gmail.com
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2015 – Present
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PERSONAL DATA:
Name: RAHUT, RANEE
Address: Amado, Dagupan City, Pangasinan
Sex: Female
Nationality: Thai
Birth date: December 19, 1990
Age: 27 years old
Status: Single
Religion: Buddhist
Contact Number: 09273073537
Email: ranee14@hotmail.com
EDUCATIONAL BACKGROUND:
Post – Graduation: 3rd year student, Doctor of Medicine
Lyceum Northwestern University Dr. Francisco Q. Duque Medical
Foundation
2014 – Present
47