DOI:http://dx.doi.org/10.7314/APJCP.2014.15.14.

5517
Risk of Cancer and Combined Oral Contraceptive among Iranian Women

RESEARCH ARTICLE

Risk of Cancer with Combined Oral Contraceptive Use among

Iranian Women
Afasaneh Vaisy*, Shirin Lotfinejad, Faegh Zhian

Abstract
Oral contraceptive use is the most common type of contraception. More than 300 million women worldwide
take oral contraceptives every day. However, there is a concern about the relationship with the incidence
of cancer. This analytical retrospective study aimed to investigate the relationship between the incidence of
cervical and breast cancers and oral contraceptive use in 128 Iranian patients with cervical cancer, 235 with
breast cancer and equal numbers of controls. Data were collected through interviews with an organized set of
questions. Details were also extracted from patient files. Data were analyzed using Student’s t-test, chi-square and
Fisher’s exact tests, and Pearson’s correlation analysis. The result revealed correlations between both cervical
and breast cancers and history of contraceptive pills use. While cervical cancer significantly correlated with
duration of use of pills, breast cancer had significant correlations with the type of oral contraceptive and age at
first use. No significant relationships were found between the two types of cancer and age at discontinuation of
oral contraceptives, patterns of use, and intervals from the last use. The use of oral contraceptives may triple
the incidence of cervical cancer and doubles the incidence of breast cancer. Therefore, performing Pap smears
every six months and breast cancer screening are warranted for long-term oral contraceptive users.
Keywords: Cancer risk - cervical cancer - breast cancer - oral contraceptive use - Iran

Asian Pac J Cancer Prev, 15 (14), 5517-5522

Introduction and accidents (Taheri et al., 2012).

The relationship between oral contraceptive and
In 1999, the world population reached 6 billion, cancer incidence is controversial. However, researchers,
an increase of approximately 4.4 billion since 1900. physicians, and patients are concerned about the possible
Contraceptive technology has been a medical success, increased incidence of breast and cervical cancers and due
and for the majority of users, contraception enhances the to the reports regarding the elevated rates of these cancers
quality of life, allowing couples to choose whether and in recent decades (Arbyn et al., 2011). The increased
when they have children. Oral contraceptives have been incidence of these two cancers in the U.S. and many other
studied since 1960; they are used every day around the parts of the world in the past 50 years has coincided with
world for the prevention of unintended pregnancies. Also the wide use of contraceptive pills which started in 1960.
oral contraceptives are the most effective and reversible In Iran, the pills were introduced in 1973 and according to
method of contraception, and is one of the main methods the country’s family planning statistics, 2,105,000 women
used to time the spacing between children (Farajzadegan were using this contraception method in 2010 [Health
et al., 2000). Oral contraceptive pills are among the most Ministry of Iran 2009). Worldwide 31% of cancers in
popular contraceptive methods (Ehsanpour et al., 2013). women are in the breast or uterine cervix. Cancer of the
Since the introduction of OC in the early 1960s more than uterine cervix is one of the leading causes of cancer death
300 million women are thought to have used it (Zhou et al., among women. (Zechariah et al., 2014). Various studies
2014). Despite OCP benefit Many studies have examined in 187 countries during 1980-2010 have highlighted
the potential association between OC use and cancer. (Wei cervical cancer as an important cause of mortality in
et al., 2014). Oral contraceptives may influence the risk women aged 15 years and older. Moreover, the incidence
of certain cancers (Gierisch et al., 2013). As other parts rate of this cancer has been found to have dramatically
of the world, cancers are major public health problems increased from 378,000 cases in 1980 to 465,000 cases
in Iran. According to reports of the Iranian Ministry of in 2010 (Foreman et al., 2011). Alston and researchers
Health and Medical Education (MOHME), cancer is the of Manchester University have indicated a 40% increase
third cause of death in following coronary heart disease in the incidence of cervical cancer among young women

Department of Midwifery, Mahabad Branch Islamic Azad University and Department of Pathology, Faculty of Medicin, Urmia
University of Medical Sciences, Pathologist, Mahabad, Iran *For correspondence: [email protected]

Asian Pacific Journal of Cancer Prevention, Vol 15, 2014 5517

Afasaneh Vaisy et al
in recent decades (Foley et al., 2011) An evaluation of Control group
statistics in Eastern Europe suggested the augmented The control group included women without cervical
incidence of cervical cancer in the Baltic states (Estonia cancer who referred to obstetrics and gynecology clinics
and Latvia), Romania, and Bulgaria, especially among of Imam Khomeini and Imam Hussein Hospitals (Urmia,
women born during 1940-60 (Antoine et al., 2011). Of Iran). They did not have a history of malignancy or
the 503 thousand registered new cases of cervical cancer contraindications to oral contraceptives. The subjects were
in 2008, 85% belonged to developing countries. In fact, all Iranian, Muslim, married, and 20-65 years old.
there is a significant difference in incidence of this disease After obtaining informed consent, 20-minute
between developed and developing countries (Arbyn et interviews were performed with all participants. Data
al., 2011). Statistics has also revealed a similar trend in about marital status, age, sexual activity, age at first
Asia, particularly since 1970. The increased incidence has marriage and first pregnancy, number of pregnancies,
even been seen in countries like India, Japan, and Korea deliveries, and miscarriages, history of abortion or induced
that used to have the lowest rates of breast cancer (Beiki abortion, history of cervical lesions and cryotherapy and
et al., 2012). In Turkey, breast cancer ranks first with an cauterization, history of Pap smears, number of marriages,
incidence of 41.6% and cervical cancer is the tenth most age at menarche, menstrual cycle regularity, menopause,
common cancer with an incidence of 4.4%. (Karadag et use of contraceptive methods, family history of cancer,
al., 2014). Likewise, the rates in Australia in 1982 (530 and history of diseases were collected from both groups.
cases) were more than doubled by 2009. Actually, 37 new Besides, the case and control groups were matched for
cases of the disease are registered in the country every day age, socioeconomic status, number of children, age at first
[Australian Institute of Health and Welfare., 2012]. The marriage and first pregnancy, history of miscarriage and
incidence of breast cancer is rapidly growing in China, abortion, and history of sexually transmitted diseases.
Latin America, and Africa and has been doubled or even
tripled in Malaysia and Singapore during the recent Breast cancer
decades (Bhoo-Pathy et al., 2012). Breast cancer is one A total of 235 patients with breast cancer (the case
of the most common cancers of women in India with high group) and 235 healthy controls were selected.
fatality rate. (Das et al., 2012). Breast cancer has been
increased in South East Asia countries (Matalqah et al., Case group
2012). Breast cancer is one of the most common cancers Convenience sampling was used to select subjects from
and the first-leading cause of cancer deaths among women women who referred to chemotherapy and radiotherapy
in the world. Indeed, breast cancer is ranked as the first departments of Imam Khomeini and Omid Hospitals
malignancy among Iranian women cancer [Ahmadinejad (Urmia, Iran) for examination or follow-up.
et al., 2013) Increments in the incidence of cervical and
breast cancers have also been proved in Iran [Center for Control group
Disease Control & Prevention. Iran]. The country has The control group was selected through a public
recently witnessed a 150% increase in mortality rate due notice and also from daily referrals to obstetrics and
to breast cancer, especially among women under 50 years gynecology clinics of the mentioned hospitals. After
of age (Taghavi et al., 2012) However, the relation between breast examinations by a trained general surgeon, only the
the increased incidence of breast and cervical cancers and healthy subjects were included and those with suspected
use of oral contraceptives, as a health issue, is still vague breast cancer were referred to relevant specialists for
for both the physicians and patients. The results of research further examinations.
on this subject can thus help early prevention and timely Both groups were interviewed and data about age,
treatment and diagnosis in high-risk individuals. marital status, education, socioeconomic status, history of
breast feeding, family history of cancer, history of benign
Materials and Methods breast masses, number of children, age at menarche,
menopause, menstrual cycle, use of contraceptive
This analytical case-control study assessed the effects methods, and history of diseases, alcohol use, hormone-
of contraceptive pills on the incidence of cervical and therapy for menopausal complications, infertility,
breast cancers. smoking, and chest radiography were collected.
The case and control groups were matched for age,
Cervical cancer economic status, weight, and number of children. In
Overall, 128 patients with cervical cancer and 128 both groups, single women and those with history of
healthy controls were studied. first pregnancy after 25 years of age, history of chest
radiography, family history of breast cancer, weighing
Case group over 80 kg, lack of breast feeding, history of hormonal
The case group included women who referred to infertility treatment, and alcohol and cigarette use were
Gorgani Radiotherapy Center and Cancer Institute (both excluded. Finally, more women were excluded to make
affiliated to Imam Khomeini Hospital, Urmia, Iran) where both groups equal size.
their cancer had been diagnosed. They were all receiving The collected data were analyzed using Student’s t-
treatment and had no contraindications to contraceptive test, Fisher’s exact and chi-squared test, and Pearson’s
pills. correlation analysis in SPSS for Windows XP (SPSS Inc.,

5518 Asian Pacific Journal of Cancer Prevention, Vol 15, 2014

 DOI:http://dx.doi.org/10.7314/APJCP.2014.15.14.5517
Risk of Cancer and Combined Oral Contraceptive among Iranian Women
Chicago, IL, USAP values less than 0.05 were considered duration of use was more than 97 months (Table 2).
significant. ii) Breast cancer: The case and control groups had
used oral contraceptives for 94.5 and 100.2 months,
Results respectively (p>0.05) (Table 2).

The mean ages of patients with cervical cancer and Age at first use of contraceptive pills
their controls were 49.05 and 47.75 years, respectively. i) Cervical cancer: The relationship between cervical
The mean age of patients with breast cancer and their cancer and age at first use of contraceptive pills was not
controls were 47.63 and 46.45 years, respectively. significant.
Therefore, the case and control groups in both cancer ii) Breast cancer: In the case group, there was a
types were matched in terms of age. significant difference between the initiation of oral
contraceptives before and after the age of 25 years. The
History of oral contraceptives use odds of developing the disease increased by starting the
i) Cervical cancer: Overall, 63.3% of the case group pills at an age older than 25 years. The OR of suffering
and 35.9% of the control group had used contraceptive from breast cancer was 1.99 (95%CI: 1.2-3.3) in those who
pills. Chi-squared test revealed significant difference had started oral contraceptives after the age of 25 years
between the two groups (p<0.001). The odds ratio (OR) and increased to 6.47 (95%CI: 2.46-17.04) in subjects
and 95% confidence interval (CI) for cervical cancer was who had started the pills after 30 years of age.
estimated at 3.072 and 1.84-5.11, respectively (Table 1).
ii) Breast cancer: The majority of the case and control Type of contraceptive pills
groups (70.2% and 52.8%, respectively) had used oral i) Cervical cancer: There was no significant relationship
contraceptives. Chi-squared test results suggested a between the incidence of cervical cancer and type of pills
significant difference between the two groups (p=0.001; used.
OR=2.110; 95%CI: 1.44-3.08) (Table 1). ii) Breast cancer: The case and control groups had
a significant difference in terms of the type of oral
Duration of oral contraceptives use contraceptives (p=0.002), i.e. the patients had more
i) Cervical cancer: Most subjects in the case group frequently used high-dose birth control pills or high-
(40.7%) had used contraceptive pills for more than dose estrogen. While individuals who had used low-dose
97 months. In the control group, however, the highest contraceptive pills had an OR of 1.18 for developing the
relative frequency belonged to 13-60 months use (p<0.05; disease, the odds increased to 2.83 in those who had used
OR=3.072). The odds increased to 5.2 times when the high-dose pills.

Table 1. Absolute and Relative Frequency Distribution of Contraceptive Methods and Breast Cancer
Group Contraceptive method Case Control Total Result
Number Percent Number Percent Number Percent
Cervical cancer OCP 81 63.3 46 35.9 127 99.2 χ2=31.03
Other 24 18.7 65 50.8 89 69.5 p=0.0001
None 23 18 17 13.3 40 31.3 df=2
Brest cancer OCP 165 70.2 124 52.8 289 61.5 χ2=33.69
Other 63 26.8 92 39.1 155 32.95 p=0.001
None 7 3 19 8.1 26 5.55 df=2

Table 2. Risk of Cervical And Brest Cancer Acording to the use of Combination Oral Contraceptives
Variable Cervical cancer Brest cancer
Case 128 Control 128 OR (%95 CI) Case 235 Control235 OR (%95 CI)
No use 47 82 3.72 (1.84-5.11) 63 92
Any use 81 46 165 124 2.11 (0.46-3.33)
Duration of use <12 month 11 7 1.6 (0.46-3.33) 29 12 2.06 (1.31-3.01)
13-60 23 25 0.9 (0.51-1.78) 52 44 1.23 (0.78-1.93)
61- 96 14 6 2.4 (0.54-3.9) 17 11 1.58 (0.72-3.46)
>97 33 8 5.2 (2.28-11.8) 67 57 1.33 (0.88-2.02)
Age at first use 13-18 Year 11 8 1.41 (0.54-3.63) 20 22 0.88 (0.44-1.61)
19-24 38 20 2.28 (1.23-4.19) 64 69 0.9 (0.61-1.34)
25-30 19 10 2.05 (0.91-4.61) 50 28 1.99 (1.20-3.30)
>30 13 8 1.69 (0.84-4.24) 29 5 6.47 (2.46-17.4)
Time since last use >12 month 5 2 2.56 (0.48-13.44) 25 11 2.42 (1.63-5.04)
12-36 19 12 1.68 (0.78-3.63) 17 7 2.54 (1.03-6.24)
37-96 41 23 2.15 (1.19-3.85) 37 25 1.56 (0.91-2.70)
>97 16 9 1.88 (0.8-4.4) 86 81 1.09 (0.75-1.60)
Type of OCP HD 28 14 2.28 (1.13-4.57) 49 20 2.83 (1.62-4.93)
LD 51 32 1.98 (1.16-3.38) 116 106 1.18 (0.82-1.70)

Asian Pacific Journal of Cancer Prevention, Vol 15, 2014 5519

Afasaneh Vaisy et al
Age at discontinuation of oral contraceptives on 373 patients and a control group (age <40 years) by
We did not find any significant relationship between Tavoani could not establish a relationship between useOral
cervical and breast cancers and age at discontinuation of of contraceptive and the incidence of cancer (Tavani et
oral contraceptives. al., 1993) Whiteman not only rejected oral contraceptive
use as a risk factor, but suggested it as a protective factor
Pill usage pattern (Whiteman et al., 2007)
There was no significant relationship between cervical We did not categorize the participants in different age
and breast cancers and the pattern of contraceptive pills groups in the present study. Furthermore, our findings were
use (regular or intermittent use). not indicative of increased risk of cervical or breast cancer
due to longer use of oral contraceptives. The findings
Discussion of Ehsanpour regarding breast cancer were consistent
with ours (Ehsanpour et al., 2013) Nevert heless, Kelsey
Our findings indicated that oral contraceptives use believed long-term use of Oral contraceptive to increase
tripled the incidence of cervical cancer and doubled the the risk of the disease (Kelsey et al., 1993). Stanford
incidence of breast cancer. The mean age of patients with also fo und the relative risk in women who used Oral
cervical and breast cancer was 49.05 and 47.63 years, contraceptive for more than 10 years to be 2.2 (Stanford
respectively. Thomas reported the age of affliction with et al., 1995).
cervical squamous cell carcinoma and adenocarcinoma The current study did not show any significant
as 46 and 42 years, respectively( David et al., 1996). The relation between age at first use of oral contraceptives
mean age of breast cancer prevalence was calculated as and incidence of cervical cancer. However, according
49.1 years by Shamsaldini (Shamseddine et al., 2002) to Thomas, the risk of developing adenocarcinoma
49.18 years by Najafzar (Najf Zare et al., 2013) and was higher in women that had started the pill before
51.3 years by Mosavi (Mousavi et al., 2006) Although 20 years or after 35 years of age (David et al., 1996) In
we excluded patients who aged over 65 years, the mean 2002, the World Health Organization announced that the
age of the subjects was still higher compared to other incidence of cancer would increase in women who start
studies. This difference can be justified by late diagnosis oral contraceptives before the age of 20 (OR=2.9) (WHO
of cancer due to the absence of screening programs for 2002).Since it is common for Iranian women to give
Iranian women. birth at younger ages, Oral contraceptive are rarely used
The OR of developing cervical cancer following the before 20 years of age. Differences in age at first delivery
use of Oral contraceptive (OR=3.072; 95%CI: 1.84- and use of contraceptive methods before 20 years of age
5.11) in the present study was similar to the results between Iran and other countries might have influenced
obtained by Zondravan (OR=3.34) (Zondervan et al., the above-mentioned results.
1996). Henderson(Henderson et al., 1994)argued that The findings of the present research pinpointed the
the risk of Cervical adenocarcinoma increases with Oral significant relation between age at first oral contraceptive
contraceptive use (OR=2.1). While Mcfarlin (Mc Farlane use and the incidence of breast cancer. In other words,
et al., 2008) confirmed such results, Becker (Becker et al., using pills before the age of 25 years was associated with
1994) concluded that Oral contraceptive have a protective higher odds of developing the disease. Faramni found
effect against dysplasia. Likewise, in a study on the higher odds of affliction with breast cancer in women
effects of oral contraceptives on abnormal changes in Pap who started these pill after 40 years of age (FRAUMENI
smears, Nowzadi (Sayednozadi et al., 2005) found the et al., 1982). Battis et al. deduced that starting oral
pills to have a protective effect against dysplasia. Among contraceptives before 18 years of age would decrease the
all contraceptive methods, OCP are the most common. age at the onset of cancer by four years (Bates et al., 2012).
Moreover, since some other methods and devices such as On the contrary, Whiteman did not find any relationship
diaphragms are not available in Iran, their effects cannot between age at first use of pills and the incidence of cancer
be evaluated. (Whiteman et al., 2007).
In the current study, use of contraceptive pills doubled The current study failed to establish a significant
the odds for affliction with breast cancer (OR=2.11; relationship between the incidence of cervical cancer and
95%CI: 1.44-3.08). A similar level of risk (OR=2.20) type of Oral contraceptive. Although Henderson reported
has also been reported in Isfahan, Iran [28]. In the study similar findings (Henderson et al., 1993). WHO concluded
by Shobairy (Shobeiri et al., 2010)] and Paul (Paul et al., that cervical cancer was more prevalent in women who
2011) calculated the as 2.83 and 3.02, respectively. Studies used pills with high doses of progesterone (David B
in Italy suggested an OR of 1.30 (La Vecchiaet al., 1995) Thomas and WHO., 1996) Conversely, Becker did not
In addition, Wang (Wang et al., 1992) Stanford (Stanford find any relationship between dysplasia and type of Oral
et al., 1995), Fassall (Fasal et al., 1975) and Comal (Kumle contraceptive used (Becker et al., 1994).
et al., 2002) affirmed the relationship between history of We found a significant relationship between breast
Oral contraceptive use and breast cancer. Marshi examined cancer and type of oral contraceptives, i.e. high-dose
4575 cancer cases and 4682 controls aged 35-65 years birth control OCP were more common among women
in Atlanta. In contrast to the mentioned studies, they did with breast cancer and the odds of developing the disease
not find Oral contraceptive to increase the incidence of was higher in those who had received higher doses of
cancer as the difference between the two groups was not estrogen. Likewise, Eliassen detected higher levels of
significant (March et al., 2002). In the same way, a study estrogen in women with breast cancer (Eliassen et al.,
5520 Asian Pacific Journal of Cancer Prevention, Vol 15, 2014
 DOI:http://dx.doi.org/10.7314/APJCP.2014.15.14.5517
Risk of Cancer and Combined Oral Contraceptive among Iranian Women
2006). A number of studies have also investigated the Investigation on the association between breast cancer and
role of progesterone in breast cancer. Alsakar discovered consumption patterns of combined oral contraceptive pills
a relationship between the incidence of cancer and use of in the women of Isfahan in 2011. Iran J Nurs Midwifery
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Eliassen AH, Missmer SA, Tworoger SS, et al (2006).
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Endogenous steroid hormone concentrations and risk of
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