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Correlation between Fertility Drug and the Likelihood of Gynecological Cancer - A Systematic Review.
Journal of Women's Health Care

Journal of Women's Health Care
Open Access

ISSN: 2167-0420

+44-7360-538437

Review Article - (2021)

Correlation between Fertility Drug and the Likelihood of Gynecological Cancer - A Systematic Review.

Simi MS**
 
*Correspondence: Simi MS*, Department of Computer Science and Engineering, Adi Shankara Institute of Engineering and Technology, India, Email:

Author info »

Abstract

Background: There is increasing use of fertility drugs for ovulation induction and ovarian stimulation in assisted reproductive treatment like In Vitro Fertilization. For the treatment of subfertility, several medications are used to grow more eggs these drugs used to stimulate their ovaries may fuel cancer risk. In this review, recent literature regarding the correlation between fertility drug and cancer risk is reviewed to find out whether the medicines used to stimulate ovulation increase the risk of any gynecological cancer in women.

Main body: Broad controversy exists in the literature about fertility treatment-induced cancer, although clinical trials are generally more focused. In order to present comprehensive strategies, the author has attempted to synthesize findings from Forty-seven research papers. The purpose of this study is to present a systematic review of the available evidence-based research paper concerning the relationship between fertility drug and gynecological cancers.

Conclusion: The result of this study shows support for the correlation between fertility drugs and certain cancer risk, the correlation should continue to be monitored because the included studies had several limitations and multiple differences in the way they were conducted. However, we suggest the need to counsel women about their potential risk of Uterine/ Endometrial cancer and Breast Cancer in the future before any treatment procedure.

Keywords

Cancer, Clomiphene citrate, Female infertility, Fertility drugs, Gonadotropin, Ovulation induction

Abbrevations

WHO: World Health Organization; IVF:  In Vitro Fertilization; CC: Clomiphene Citrate; HMG:  Human Menopausal Gonadotropin; FSH: Follicle Stimulating Hormone; HCG: Human Chorionic Gonadotropin; ART:  Artificial Reproduction Technology; IRR: Individual Research Result; OI: Ovulation Induction.  

Background

Reproductive health is a priority global health area, According to WHO One in every four couples in developing nations had been seen as influenced by infertility. The rate of primary female infertility is ranged from 1.9 to 2.6% and secondary female infertility ranged from 7.3 to 17% with the highest rates in Central and Eastern Europe, followed by South Asia at 12.2% and Sub-Saharan Africa. This data consolidated information between 1990 and 2010, providing a 5-year projection of infertility [1]. According to this data, the highest rates of infertility were concentrated through Africa and Central/Eastern Europe [2]. Simi et al. explored the significance of early detection of female infertility in [3-5]. World Health Organization ICD-11 describes female infertility as a Disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse [6]. All clinical studies will begin after at least one year according to the World Health Organization (WHO).

In recent years, an incredible interest has been arisen to find the correlation between infertility treatments and cancer development, mainly breast, uterus, and ovarian cancer [7]. The importance of understanding any existing correlation between fertility medications and cancer risk is crucial because the use of these treatments has become very common, with approximately 1 million in vitro fertilization (IVF) cycles reported per year worldwide furthermore to an obscure number of ovulation induction cycles. This paper evaluates the association of fertility drugs and gynecological cancer risk [8,9].

Ovulation-inducing agents have been broadly used to treat infertility issues, either alone such as anti-estrogens (e.g. clomiphene citrate [CC] ), or as part of IVF cycles including human menopausal gonadotropin (hMG), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG). Infertile women with normal ovulatory function, who have been exposed to excessive CC and/or gonadotropin administration, continually raised estrogen and progestogen concentrations, and numerous ovulatory cycles may be more prone to changes in the ovarian tissue than those with ovulatory disorders. This review systematically analyzes the 47 most significant research papers published on this topic to summarize the correlation between infertility drugs and gynecological cancers.

This study aimed to create a comprehensive picture of the association between infertility drug and the risk of ovarian, endometrial, cervical, and breast cancer in women. The highlight of this paper was we only concentrate on cohort or case-control study of large population and single cancer researches [10].

Materials and Methods

This paper presented a review of the scientific literature concerning the relationship between the use of fertility drugs and the risk of gynecological cancers. We searched digital databases including Pubmed, MEDLINE, and Google. The survey was completed using keywords such as "infertility", "ovarian stimulation consequences", " ovarian cancer risk", "gynecological cancer and fertility drug", "gynecological cancer risk", " Endometrial Cancer", "fertility drugs", "infertility treatment and cancer risk", variously associated together (Table 1).  The criteria for entering the study included either case-control or cohort study. Initially 84 articles were selected by checking the keywords. The fertility drug used is In vitro fertilization (IVF) Procedure and clomiphene citrate, the gonadotropins, human chorionic gonadotropin (hCG), and human menopausal gonadotropin (hMG), alone or in combination. 46 were selected for the research paper based on relevance and clear findings. Figure 1 shows the flowchart of the inclusion methodology.

Reference & Year Country Study Duration Study Population Study Design Medication Research Finding(s)
Trabert et al [4] -2013 United States 1965-88
with follow-up through 2010
9825 Cohort Clomiphene citrate gonadotropins No correlation between fertility drugs and ovarian cancer risk.
Overweight is associated with Ovarian cancer risk
However, their study suggests that Use of fertility drug and failure to attain pregnancy was related
to ovarian cancer risk
Modan et al [5]-1998 Israel 1964-
1974
2496 Cohort Clomiphene citrate
hMG
suggest that treatment with ovulation- inducing drugs doesn't increase the risk for ovarian cancer
Bjørnholt et al [6]- 2015 Denmar k 1963-
2006
96545 Cohort Gonadotrophi ns clomiphene citrate
human chorionic gonadotrophin s
No correlation between fertility drugs and ovarian cancer risk.
But they observed an increased risk for serious borderline ovarian tumors after the use of progesterone.
Stewart et al [7] -2013 Australi a 1982-
2002
21646 Cohort IVF No Evidence for ovarian cancer growth following IVF in women who conceive an offspring.
Meanwhile unsuccessful women have some risk.
Sanner et al. [8]-2009 Sweden 1961-75 2768 Cohort clomiphene citrate gonadotropins An increased risk of ovarian cancer gonadotropins and borderline tumors after
clomiphene treatment.
Franceschi et al [9] 1994 Italy Since 1992 195 cases
1339
controls
Case- Control gonadotropins No association between ovulation stimulation drugs and
cancer risk.
Asante et al [10]- 2013 USA 1999-
2012
1900
cases- 1028
control- 872
Case- control gonadotropins No Correlation between fertility drug use and risk of ovarian tumors
Kurta et al [11] 2012 USA 2003-
2008
902 cases Controls, N=1802 Case- control clomiphene citrate follicle-
stimulating
No Correlation between fertility drug use and risk of ovarian
Tumors
          hormone (FSH), human chorionic gonadotropin (hCG),
gonadotropin, and human menopausal gonadotropin (hMG)
 
Leeuwen et al [12]- 2011 Netherla nds 1983-
1995
19146 Cohort IVF Ovarian stimulation for IVF may increase the risk of borderline
ovarian tumors
Rizzuto et al [13]-
2019
  1990-
2013
4,684,724 Cohort and Case- control IVF Infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated
with infertility drugs.
Brinton et al [22]-
2004
  1965-88 12,193 Cohort clomiphene citrate gonadotropins No Correlation between fertility drug use and risk of ovarian tumors
Parazzini et al [24]-
2001
Italy 1992-99 Cases 1031
Controls 2411
Case- control no information was available Observed a moderate association between fertility drugs and
ovarian cancer risk
Vassard et al. [39]-
2019
Denmar k 1994-
2015
Cases 58472
Controls 625330
Case- control IVF Observed an association between ART treatment and the risk of ovarian cancer among women with
endometriosis
Lundberg et al. [47]-
2019
Sweden women born 1942â??
1992
2,882,847 Cohort Not specified Ovarian cancer incidence was higher in women diagnosed with
endometriosis
Williams CL et al. [52] -2018 Great Britain 1991-
2010
255â??786 Cohort ART Increased risks of invasive and borderline
ovarian cancer were found

Table 1: Study of Fertility drug effect and ovarian cancer.

advances

Figure 1: Flow chart demonstrating methodology of articles searched, filtered & included.

 

No study design restrictions and periods have been applied in this research. A general concern is that the medication of infertility has changed over the years. Specific fertility drugs that are currently in the commonplace, such as gonadotropins, were not broadly used until the late 1980s. Therefore, a few studies might not have caught exposure to this study. Furthermore, Cohort studies also have inherent advantages and limitations because in most of the studies data are collected via interview or answering the questionnaires, numerous cohort studies are restricted by an absence of long-term follow-up, prompting lower apparent occurrence of disease as cancers may occur many years after the medications. Reference lists of the most significant papers were likewise analyzed and examined the full versions of all relevant studies. The strength of this study includes the large size of the cohort and the long and complete follow-up, providing sufficient power for subgroup analyses (Tables 2-4) [11-13].

Reference &Year Country Study Duration Study Population Study Design Medication Research Finding(s)
Modan et al.
[5]- 1998
Israel 1964-
1974
2496 Cohort Clomiphene citrate
hMG
suggested that the chance of association between infertility drug and the development of endometrial cancer can't
be avoided
Reigstad et al.
[14]- 2017
Norway 2004-
2014
1,353,724 Cohort clomiphene citrate and ART
exposure
Clomiphene citrate appears associated with an increased risk of
Endometrial cancer.
Jensen et al.
[15]- 2009
Denmar k 1965-
1998
54,362 Cohort clomiphene citrate gonadotropi ns
human chorionic gonadotropin
Correlation between fertility drug (clomiphene citrate, human chorionic gonadotropin) and the risk
of uterine cancer was observed.
(Exception-: gonadotropin was not associated with risk)
Althuis et al
[16]- 2005
USA 1965-
1988
8,431 Cohort clomiphene citrate The association between clomiphene use and uterine cancer was
observed
Kessous et al
[17]- 2016
  1988-
2013
106,031 Cohort IVF and ovulation induction
(OI)
Observed an association between IVF history and uterine cancer
Brinton et al.
[18]-2013
USA 1965-88 12 193 Cohort Clomiphene gonadotropi ns No association between fertility drugs and
endometrial cancer risk
Venn et al.
[21]- 2001
Australi a   29,700 Cohort IVF Observed an increased incidence
of uterine cancer in women with a history of infertility
Sponholt z et al.
[20]- 2017
USA 1995-
2013
47,555 Cohort IUI Observed an association between
endometrial cancer and fertility drug
Parazzini et al.
[23]- 2010
Italy 1992-
2006
454 cases
908
Controls
case- control Clomiphene gonadotropi ns Observed an increase in the risk of endometrial
cancer with the duration of fertility drug usage.
Benshush an et al.
[25]- 2001
Israel 1989-
1992
128 cases
255
controls
case- control clomiphene citrate No evidence found for proving the association of ovulation-inducing agents, including clomiphene citrate and a higher risk of
endometrial cancer.
Silva et al
[54]- 2009
British 20 years 7355 Cohort clomiphene Women consuming
>or=2250mg of clomiphene having a 2.6- fold increase in the risk of
Uterine cancer

Table 2: Study of Fertility drugs effect and Uterine /endometrial cancer.

Reference &Year Country Study Duration Study Population Study Design Medication Research Finding(s)
Modan et al
[5]- 1998
Israel 1964-
1974
2496 Cohort Clomiphene citrate
Hmg
suggest that treatment with ovulation-inducing
drugs doesn't increase the risk for breast cancer
Brinton et al.
[19]- 2014
USA 1989-
2010
9,892 Cohort Clomiphene
gonadotropin
s
Observed an association
between gonadotropins
and
breast cancer risk among
nulligravid women
Burkman et al.
[26]- 2003
USA 1994-
1998
4,575 case
4,682
control
case-
control
human
menopausal
gonadotropin
(hMG)
clomiphene
citrate
Observed an adverse
effect of fertility drug on
the risk of breast cancer
Gauthier et al.
[27]- 2004
Europe 1990-
1991
98997 Cohort Clomid(CC),
Ondogyne
Neopergonal,
menotropin,
gonadotropin, chorionic
gonadotropin
Fertility drug does not
influence
breast cancer risk overall
Geva et al.
[28]- 2006
Israel 1964-
1984
120,895 Cohort
and nested case-control study.
clomiphene
citrate,
gonadotropin
s
Observed a Significant
Risk of breast cancer for
women treated with
clomiphene citrate
Jensen et al.
[29]- 2007
Denmar
k
  54,362 Cohort gonadotrophins,
clomiphene,
human
chorionic
gonadotrophin
No strong association between
breast cancer risk and use
of fertility drugs
Pappo et al.
[30]- 2008
Israel 1986-
2003
3,375 Cohort IVF Observed an association
between IVF therapy and
breast cancer development
Orgeas et al.
[31]- 2009
Sweden 1961-
1976
1135 Cohort clomiphene
citrate
gonadotropin
s
Observed that high-dose
clomiphene
citrate therapy may have
an elevated risk for
breast cancer
Stewart et al.
[51]- 2012
Australi
a
1983-
2002
21,025 Cohort IVF Observed that
Commencing IVF
treatment at a young age
is associated with an increased rate of breast cancer.
Ricci et al.
[32]- 1999
Italy 1983-
1991
3 415
cases 2916
controls
case- control Not specified No association between fertility drug treatment and breast cancer risk.
Krul et al.
[33]- 2015
Netherla nds 1983-95 12,589 Cohort IVF Observed an association between IVF therapy and breast cancer development
Reigstad et al.
[34]- 2015
Norway 1984-
2010
808,834 Cohort IVF Observed an association between IVF therapy and breast cancer development
Van den et al.
[35]- 2016
Netherla nds 1983-
1995
19,158 Cohort IVF No association between fertility drug treatment and breast cancer risk.
Cooley et al.
[36]-2012
USA   MCF- 10A, MCF-7
and HCC 1937 cell lines
cell lines hCG,
estrogen, progesterone and clomiphene citrate
Observed minimal direct effects of infertility treatment on breast cell multiplication
Bernstein et al.
[37]- 1995
USA 1983-
1988
744 case- control pair case- control human chorionic gonadotropin (hCG) Observed that hCG may be a means for reducing breast cancer risk.
Katz et al. [38] Israel 1984-
2002
7162 Case- Control IVF Observed that Women who start IVF after the age of 30 appear to be at increased risk of developing breast cancer

Table 3: Study of Fertility drugs effect and breast cancer.

Reference & Year Country Study Duration Population Study Design Medication Research Finding(s)
Kallen et al. [40] Sweden 1982-
2006
Case:24,058
Control: 1,394,061
Case- Control IVF Observed a lower risk for cervical cancer in IVF
recipients
Kristiansson
et al. [41]
Sweden 1981-
2001
Case: 8,716 Control:
64,0059
Cohort IVF Decreased incidence of cervical cancer
after IVF treatment
Dor et al. [42] Israel 1981-92 Total:5,026 Cohort Clomiphen e citrate hMG
GnRH
No association between fertility treatment and cervical cancer risk
Calderon- Margalit et al. [43] Israel 1974â??
2004
14463 Cohort Clomiphen e citrate No association between fertility drugs and cervical cancer risk
  Siristatidis et al. [44] Meta- Analysis 1966-
2012
109 969 Cohort IVF No association between fertility drugs and cervical cancer risk

Table 4: Study of Fertility drugs effect and Cervical Cancer.

Results and Discussion

For decades, researchers are trying to discovering the uncovered causes of cancer and the means of prevention. All the gynecological cancers are dangerous especially breast cancer has been the most common life-threatening cancers among women worldwide [14,15]. Infertility has long been perceived as a risk factor for different cancers, including breast, ovary, and

Gynecologic cancers. More recently, concern has been raised for the impacts of medications used to treat infertility, especially since these fertility drugs stimulate ovulation and raise different Hormone levels. Researchers worldwide have been involved with several pieces of research to clarify the effects of fertility drug exposures on the risk of various gynecologic cancers [16].

Analysis of Ovarian Cancer Studies

The Correlation between fertility drugs including those associated with in vitro fertilization (IVF) and cancers is an ongoing concern of both health providers and patients. Gynecological cancers are related to several hormonal and reproductive risk factors. The association among PCOS and endometrial cancer, as well as between endometriosis and ovarian cancer, are genuinely well defined [17-20].

In several years, researchers have investigated the association between borderline ovarian tumors and fertility drugs. Ovarian cancer is rare and the most deadly gynecological cancer worldwide [21-23]. Many pieces of research have shown that an increased risk of ovarian cancer is related to the intake of clomiphene citrate and gonadotropin [24].

Trabert et al. [4] reported that there is a correlation between Clomiphene citrate, gonadotropins, and ovarian cancer risk. They are also able to find Overweight is associated with ovarian cancer risk significantly. However, their study suggests that Use of fertility drugs and failure to attain pregnancy was related to ovarian cancer risk. A 1998 study by Modan et al. [5] suggested that fertility drug doesn’t increase the risk of cancer. Additionally another study by Bjørnholt et al. [6] provided the same result. Stewart et al. [7] concluded that there is no proof of an expanded danger of ovarian cancer growth following IVF in women who conceive an offspring. There is some vulnerability concerning the impact of IVF in ladies who remain nulliparous they have an increased chance of Risk.

Although some studies have shown an increased risk [25-28], most studies do not show an overall increase of ovarian cancer in women exposed to fertility drugs [28]. However, some suggest a possible increased risk within subgroups, including sub fertile women, and women who are not conceived even after the medication. Reviewing the recently documented literature [29-31], demonstrate a significantly increased risk of invasive and borderline ovarian cancer. Two studies suggested an increased risk of ovarian cancer associated with endometriosis [32,33].

Analysis of Uterine /Endometrial Cancer Studies

Endometrial cancer is one of the hormone-related cancers. Death rates for uterine cancer began to increase around 2000 in the wake of increasing occurrence rates. According to the recent statistics, excess weight increases endometrial cancer risk by 50%. The results of several cohort studies showed an increase in uterine cancer among women who used ovulation-inducing drugs [31-35]. In this study, we have selected 11 relevant types of research. Out of 11 nine studies shown a Correlation between fertility drugs and the risk of uterine/endometrial cancer.

Reviewing the literature yields suggested that the chance of association between infertility drugs and the development of endometrial cancer can't be avoided [36]. According to a cohort of 1,353,724 women, the incidence of endometrial cancer increases in women who have a history of clomiphene citrate drug usage more than 6 cycles. A cohort study that lasted for 33-years revealed that uterine cancer is associated with the usage of clomiphene citrate and one exception point they reported is gonadotropin was not associated with risk [15]. This is consistent with the finding of Althuis's study. Kessous et al. [37] have attempted to pursue the conclusion that, an association between IVF history and uterine cancer are existing. In a retrospective study, Sponholtz et al [20] communicate that fruitful women were less likely to develop endometrial cancer (IRR 0.77, 95% CI 0.57, 1.05) than nulliparous women.

A study by Venn et al. [21] the incidence of uterine cancer increases in women who have a history of infertility. The results of a case-control study stated the duration of the use of fertility drugs was positively associated with endometrial cancer risk. There have been a few studies that did not show any association between fertility drugs including clomiphene citrate and a higher risk of endometrial cancer [38-40]. A 20 years British cohort study of 7355 women concluded that consumption of more than 2,250 mg of clomiphene is associated with a 2.6-fold increase in the risk of uterus cancers relative to those who were not treated.

Analysis of Breast Cancer Studies

Breast cancer is the leading cause of cancer death in women aged 20 to 59 years [41-43]. From 2005 to 2014, in general, breast cancer incidence rates expanded. Although the relationship between breast cancer and ovulation-inducing drugs is not clear, it appears that these drugs increase breast cell multiplication. Some studies reported that breast cancer diagnosed within the initial 2 years following infertility treatment is similar in cancer characteristics compared with those happening in patients without earlier fruitlessness treatment [45,45].

Most recent studies have shown an association between the risk of breast cancer and fertility drug usage when comparing women undergoing fertility treatment [46-48]. Although few recent studies found no association of fertility drugs with breast cancer risk. Treatment with ovulation-inducing drugs is not associated with an increased risk of a breast cancer diagnosis is the conclusion of one early study. The use of gonadotropins, due to ovulation disorders, increases breast cancer risk among nulliparous women [49]. A case-control study of 4,575 cases and 4,862 controls aged between 35 to 64 found that extensive use of fertility drugs could initiate some negative effect; the relative risk of breast cancer in women with an hMG use for more than 6 months was between 207 to 3.8.           

The author of this cohort study provided the information that there is no evidence of an association between fertility drug and breast cancer risk but a family history of cancer can affect. An Israelian study on the effect of ovulation-inducing drugs discloses that for barren ladies treated with clomiphene citrate, breast cancer risk is elevated. They have adopted a cohort and nested case-control study of 20 years to reach into this conclusion. A Danish cohort study of 54,362 women with infertility problems, however, did show no strong association between breast cancer and ovulation-inducing fertility drugs, but they suggested a long term follow up of among nulliparous women exposed to gonadotropin, this suggestion support the result of Brinton et al. [19].

Some previous studies have also revealed an increased risk of breast cancer in women who used fertility drugs [50,51]. Orgeas et al. [31] convey that cancer risk is associated with high-dose clomiphene citrate for women treated with nonovulatory causes. An IVF cohort study of women aged 20-44 years reported that risk of breast cancer was associated with women they had their first delivery at a late age (HR=1.56,95% CI 1.01-2.40) [51]. A breast cell proliferation study supported minimal direct effects of infertility treatment on breast cell multiplication.

The result of a registry-based cohort study of 808,834 women showed that the risk of breast cancer increased in individuals who gave birth following IVF [95 % CI 1.07-1.71] [34]. These data agree with a recent 2 IVF cohort studies comprised of 12589 women [52]. A 12-year long cohort study of 19,158 IVF treated women revealed that the risk of breast cancer in IVF-treated women was not significantly different from that in the general population and from the risk in the non-IVF group. The result of a case-control study of 18 years showed that an increased risk of breast cancer was associated with women who undergo IVF treatment after the age of 30 years [38]. Meanwhile, many researchers could not show a positive relationship between fertility treatment and breast cancer.

Analysis of Cervical Cancer studies

A few studies assessing the risk of cervical cancer following fertility treatment have consistently shown no increased risk of cervical cancer compared to both the general population and infertile women as controls. A subset of studies has discovered a decreased incidence of cervical cancer in IVF patients, although the mechanism behind this phenomenon is unclear but perhaps related to better access to care with more frequent cervical cytology screening in women experiencing fertility medication. Twenty four years of case-control study disclose that they can find a lower risk of cervical cancer in IVF treated women [40]. A cohort study of Swedish women showed that IVF treated women had a decreased rate of cervical cancer [41]. Overall the results of the present study suggest that fertility drug is not a risk factor for cervical cancer [53-57].

Conclusion

This study intended to learn the association between the use of fertility drug and gynecological cancers. Because of the correlation between hormonal and reproductive factors, women's cancers have been got much more attention to found the association between the use of fertility drugs and cancer in recent years. Even though this association is hypothetically justifiable, the unpredictable and various elements that are engaged with the beginning of cancer growth make it hard to decide the precise relationship between the use of these medications and cancer by fertility treatment. According to the results of this study, there is no absolute correlation between the use of fertility drugs and cervical cancer, and only some observational studies have studied and pointed to this relationship so we suggest a long term follow-up for reaching the conclusion. As reported by this review 82% of studies show a strong association between the ovulation-inducing drug and Uterine /Endometrial Cancer. In the case of breast cancer, 63% research paper says we cannot completely neglect the association between fertility drug and risk of cancer. Generally, most studies show that fertility treatments do not increase the risks of ovarian cancer but at the same time some most recent studies show the association. There is, however, limited evidence that the use of fertility treatments may quietly increase the risk of borderline ovarian cancer. So the correlation between fertility drug and gynecological cancers is still an open question.

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Competing Interests

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Funding

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Authors' Contributions

MS analyzed and interpreted the 47 research data regarding the correlation between fertility treatment and Gynecological cancers.

Acknowledgements

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References

Author Info

Simi MS**
 
Department of Computer Science and Engineering, Adi Shankara Institute of Engineering and Technology, kerala, India
 

Citation: Simi MS (2021). Correlation between Fertility Drug and the Likelihood of Gynecological Cancer - A Systematic Review. J Women's Health Care 10:548. doi: 10.35248/2167-0420.21.10.548.

Received: 06-Aug-2021 Published: 30-Aug-2021

Copyright: © 2021 Simi MS. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

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