European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review article

Oral contraceptives use and risk of cervical cancer—A systematic

review & meta-analysis
Smita Asthana, Vishal Busa, Satyanarayana Labani*
Scientist E, Division of Epidemiology and Biostatistics, National Institute of Cancer Prevention and Research, Indian Council of Medical Research, India

A R T I C L E I N F O A B S T R A C T

Article history: Background: Role of Oral Contraceptive (OC) as a risk factor for cervical cancer remained controversial and
Received 1 October 2019 unclear.
Received in revised form 3 February 2020 Objective: To evaluate risk of cervical cancer in OC users and non-users through a comprehensive
Accepted 13 February 2020
systematic review.
Search strategy: Literature search conducted in databases from January 1990 till August 2019 using
Keywords: various search terms.
Cervical cancer
Selection criteria: Primary research studies that evaluated and assessed the association of OC use with
Meta-analysis
OC pills
cervical cancer with study design of case control or cohort types published in English language.
Risk Data collection and analysis: PRISMA guided review was done by two independent researchers. Effect size
Systematic review estimated by pooled Odds ratio with 95 % Confidence Interval (CI) in random effect models on OC pill use
for the risk of cervical cancer.
Results: Review included 19 studies. Overall risk of invasive cancer on OC use was found to be significant
with unknown status of HPV OR (95 % CI) as 1.51 (1.35, 1.68) and for unknown HPV as 1.66 (1.24, 2.21).
Adenocarcinoma, squamous cell carcinoma and carcinoma in situ had significant association with OR
(95 % CI) of 1.77 (1.4, 2.24), 1.29 (1.18, 1.42) and 1.7 (1.18, 2.44) respectively.
Conclusion: OC pills use had a definite associated risk for developing cervical cancer specially for
Adenocarcinoma and longer duration of OC pills use.
© 2020 Elsevier B.V. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Selection process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Qualitative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Risk overall and in various to histological types . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Risk associated with the duration of uses of oral contraceptives . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Risk estimated in different study designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Risk in relation to studies published before 2000 and after 2000 . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Risk associated with HPV positive women for OC pill use and cervical cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

* Corresponding author at: Division of Epidemiology and Biostatistics, Indian Council of Medical Research- NICPR, I-7, Sector-39, Noida, UP, India.
E-mail address: satyanarayanalabani@yahoo.com (S. Labani).

https://doi.org/10.1016/j.ejogrb.2020.02.014
0301-2115/© 2020 Elsevier B.V. All rights reserved.
164 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175

Funding . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Acknowledgements . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
References . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Introduction they have included data on HPV infected women [12]. Another meta-
analysis result specified that use of OC pills was a potential risk for all
Cervical cancer offers the greatest potential for prevention, stages of cervical cancer which implies an initiator effect. Such
early detection, and cure. It is one of the major cancers in women variations among study results created ambiguity in the association
living in less developed regions with an estimated 570,000 new of OC use and incidence of cervical cancer [14]. Few reviews on the
cases in 2018 (84 % of the cases worldwide). In 2018, approximately topic are quite old and non-comparable with current literature
311,000 women died from cervical cancer; more than 85 % of these [13,12–15]. Though recent systematic reviews showed no positive
deaths occurring in low and middle-income countries [1]. Cervical relation between OC pills use and cervical cancer, but they had
cancer is preventable and curable in the very early stages of the limitations to serious selection bias [11,12]. There exists a need for a
disease. Fortunately, it has a very well-known natural history comprehensive review on the issue. Thus, a comprehensive
characterized by a long premalignant phase which provides a good systematic review on OC pills use and cervical cancer was performed.
opportunity for preventive interventions. On the other hand,
controlling its risk factors can also reduce the burden of disease. Methods
Though evidence from the developed world clear cut shows a
reduction in cervical cancer incidence due to the implementation The systematic review was conducted and reported to find the
of the cervical screening program, the situation in developing cervical cancer risk associated with OC pills use. The study is
countries is much complex owing to the fact conducting a conducted in accord with PRISMA guidelines [16]. An extensive
nationwide screening program is still impossible Creating aware- literature search conducted in PubMed, IndMed, Google Scholar
ness about risk factors in the communities is a more feasible option and Cochrane databases restricted to January 1990 till August 2019.
for the control of this disease. In addition to various associated risk In addition to above-mentioned databases cross-references from
factors of CaCx, increasing usage of OC pills had drawn special included studies were also evaluated in order to find relevant
attention because of possible adverse health effects which could be studies. Institutional Review Board or Ethical Committee approval
an important concern of public health importance. People are was not needed. The protocol of the study was registered with
trying to weigh the risks and benefits of their usage and were Prospero Registration number: CRD 42019097173.
advised to use them cautiously [2].
Forty percent (85 million) of all pregnancies globally, were Search strategy
unintended [3]. Data from United Nations Population Prospects for
185 countries reported an increase in both demand and the actual Keywords/core terms appropriate to the databases used:
prevalence of contraceptive practice [4]. Oral contraceptive pills as (contraceptives OR OC pills OR hormonal pills OR combined oral
a means of contraception are widely used because they are contraceptives OR combined pills) AND (cervical neoplasm OR cervical
considered safe and effective for many women. More than 100 dysplasia OR carcinoma in situ OR uterine cervical neoplasms OR
million women currently use OC worldwide and by almost 12 cervical neoplasia OR cervical cancer OR Invasive cervical cancer).
million women in the United States [5]. There are considerable Articles/titles/abstracts with these keywords were screened by two
improvements in terms of modification in preparations of OC, independent reviewers applying pre-planned inclusion criteria to find
currently available may have implications for the incidence of out relevant studies to be included in the systematic review.
adverse events for non-contraceptive health conditions and
reproductive health care access [6]. Inclusion criteria
OC pills use as a risk factor for cervical cancer is not well
established. A recent study on the risk factor of cervical cancer stated This study includes all the primary research studies if a) it was
the role of oral contraceptives as controversial [7]. Another study published only in English b) studies that evaluated and assessed
stated long term use of oral contraceptives as a definite co-factor for the association of OC use with cervical cancer (Invasive cervical
cervical cancer but its role as a causal factor could not be established cancer and Carcinoma In-situ) c) studies in which relative risks/
[8]. Two large prospective studies found evidence for a considerable odds ratios can be derived d) studies that analysed this association
increase in cervical cancer risk in OC pill users [9]. A study on oral in relation to duration of use e) studies that are published after
contraceptive use found risk factors for cervical intra-epithelial January 1990 and forward. Studies with HPV status unknown and
neoplasia in univariate analysis but when adjusted for human HPV positive were included.
papillomavirus infection, it was found to be an insignificant risk [10].
Few systematic reviews also tried to evaluate the association Exclusion criteria
between use of OC pills and cervical cancer [11–15]. A study
concluded that there were a very few cancer-related risks with usage Studies that assessed only pre-cancerous lesions (CINs) were
of OC pills when compared to its benefits, so the net effect is excluded. Studies that were published in a language other than
negligible [13]. A study had evaluated results in relation to HPV status English and earlier reviews, case-series, case reports, editorial
of subjects, which is known cause of cervical cancer and this may lead letters, comments, and responses. We also excluded studies that
to confounder bias [15]. One of them included only case-control included other forms of contraceptives.
studies in their analysis and excluded available cohort studies [11].
Other review synthesized evidence from six case-control studies and Selection process
three cohort studies, but it had methodological limitations of its own.
Though they conducted literature search from 1990 till 2012, they Conducted searches identified 1255 citations for OC pill use and
had included data from 2000 onwards in their analysis, moreover associated cervical cancer risk by two independent investigators
 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
(SA and VB). Full-text articles were identified and assessed for
eligibility after applying the inclusion and exclusion criteria.
Critical appraisal of each study found eligible was done by both
investigators. The agreement of the selected studies checked any
disagreement sorted out with the inputs from the third investiga-
tor (LS). The quality of the primary studies was assessed by two
independent investigators. After completion of reviewing when
there was disagreement of opinion for the articles, a third reader
evaluated whether the articles in doubt were eligible. A total of 19
studies were selected for inclusion in the study in which HPV
status was unknown [17–35] and 15 studies with HPV positive
women (Web Fig. 1). Information on year of publication, place of
study, sample size age group, cases or exposure ascertainment
details of control or non-exposed group, confounder adjusted, OR/
RR, duration of use, matching of control, and significance of study
were part of data extraction sheet. Further data on adjustment for
confounding factors like age, education, smoking, parity, number
of sexual partners, etc., were also part of data extraction sheet.
The source for the selection of controls identified. Adjustments
for confounding factors such as smoking, alcohol, age, body
mass index (BMI), and geographical region were noted. Moose
Fig. 1. PRISMA flow chart for OC pills use and cervical cancer risk in women with HPV status unknown.
165
guidelines were followed for the conduct of systematic review and
meta-analysis [36].
Meta-analysis
RevMan 5.3 package used for meta-analysis the random-effects
model was used pooling of data for each subgroup. The effect size
of interest was the Odds Ratio (OR) for the effect of OC pill use and
associated risk of cervical cancer. Risk estimates of effect size along
with 95 % CI for overall and between subgroups were calculated.
Forest plots were drawn to summarize information from individual
studies and the pooled effect size for the subject under study. The
variation across studies due to heterogeneity is described by a
statistic called I2. For different models, I2 values revealed the
presence of heterogeneity, and this was supported by a Q test with
statistical significance. The estimates given in the form of RR were
also combined without any conversion owing to the fact that rare
diseases like cancer RR equate OR. A decision over selecting a
model was made after assessing the level of heterogeneity. An I2 of
more than 50 % was considered heterogeneous. The method of
visual assessment of funnel plots was adopted to measure the bias
 166
Table 1
Description of the included studies according to study variable.

S. Study ID Year Origin, Period Sample Age Case/exposure Control/Non-exposure Confounders Adjusted OR/RR OR/RR Matching of Significance
no of Publication range. size group (user v/s (Duration control.
Mean non- of use)
+- SD/ user).
Range
/Median
(in
years)
— 3.07, 1.84- <60

S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
1. Afasaneh V Iran. Cases 20-65 Cervical cancer women without age, Oral contraceptive leads to
et al (2014). 128; (49.05; cases from cervical cancer from 5.11. months socioeconomic triple the incidence of cervical
Controls 47.75) registry gynaecology and 0.9, 0.51- status, age at cancer.
128 obstetrics department 1.78 first marriage,
clinics >97 history of
months sexually
5.2, 2.28- transmitted
11.8 diseases
2. Margaret U et. South Africa Cases 18–79 Histologically Control patients age, calendar year of diagnosis, 1.01, 0.66- < 5 years – women who had used oral and/
al (2012) 1995 - 2006. 2,182; confirmed cases diagnosed with education, smoking, alcohol, 1.56 (OC 1.03, 0.81- or injectable contraceptives
All of cervical cancer cancers without parity/age at first birth, and only). 1.30 within the last 10 y had a
Controls from hospital history of OC pills use. number of sexual partners. >5 years significantly elevated risk of
1,492. 1.00, 0.78- cervical cancer
1.27
3. Vanakankovit Thailand Cases Histologically Healthy women as the 1.45, 0.79- for >3 – Long-term use of oral
N et. al (2008) 60; confirmed cases control group from 2.64 years 2.57, contraceptive might be a
Control s of cervical cancer population. 1.22-5.49 cofactor that increases the risk
180 from hospital. of cervical carcinoma.
4. Lacey JV Jr et. USA, Cases 18-69. Histologically Controls from Age, ethnicity, Income, HPV [AC] 1.8, For >6 individually Current use of OCs was
al (1999) + 1992 -1996. 124 (AC), confirmed cases population. status., No of sexual partners. years matched (2:1) associated with cervical
139 of AC and SCC 0.7–4.3 for age, clinic, adenocarcinoma in situ, but
(SCC); diagnosed at [CIS] 17.1, [AC] 1.2, OCs were not associated with
controls Clinical centre. 1.5-188.2 0.6–2.6 AC or with SCC from the same
307 population.
[SCC] 0.8, [CIS] 6.2, ethnicity. Whether the association
0.3–2.0 0.7-52.7 between OCs and
[CIS] 1.6, [SCC] O.9, adenocarcinoma in situ reflects
0.3-8.5 0.4–2.0 detection bias, selection bias,
[CIS] 1.1, residual confounding by HPV,
0.3-5.0 or a true association.
5. Ylitalo N et al Sweden. Cases 30–49 CIS cases from selected from cohort School, marital status, sexual 3.64, 1.91- For matched by Current use of OCs was
(1999) * 1969 -1995. 422; Cancer registry. randomly who had no intercourse, parity, Age at 6.93 <2 years date of entry associated with a 4-fold
Control s history of prior CIS or menarche, 1.66, 0.78- into the cohort, increased risk with increase
422 ICC. 3.79 by year of birth with increasing duration of use.
>5 years Our results further indicate a
2.37, 1.30– relation with OC use and the
4.33 risk for cervical carcinoma in
>10 years situ.
2.93, 1.44-
5.98
6. Parazzini F et. Italy, Cases 17-60, Histologically Non- related patients age, education, calendar year at 1.21, 0.82- <24 — In this study, the risk of invasive
Al (1998) 1981 -1993. 592; 48; 16- confirmed admitted in same interview, parity, number of 1.74 months epithelial cervical cancer
Controls 60, 48 invasive cervical hospital. partners, smoking habits and 1.17, 0.75- tended to be elevated in ever-
616 cancers from number of Pap smears 1.82 users of OC and to increase with
Hospital. >24 duration of use, but the trend in
months risk was not significant.
 1.31, 0.72-
2.39
7. Thomas DB et. (8) Thailand, Kenya Cases 42; 44 Women with Controls were selected age, hospital, number of live [AC], 1.6, For >97 Controls not For both types combined, risk
Al (1996) + Mexico Philippines 271 adenocarcinoma from among women births, history of an induced 1.2-2.1 months matched to increased with duration of oral
Australia Chile Israel +106; and adeno- admitted in Hospital abortion, and number of prior Pap [ASC] 1.1, [AC] 2.4, individual contraceptive use, was highest
Colombia. 1979-1988 Controls squamous with no use of OC use. smears. 0.7-1.8 1.4-4.0 cases. in recent and current users, and
2887 carcinomas from Both: 1.5, [ASC]1.6, declined with time since
Hospitals.???? 1.1-1.9 0.6-4.1 cessation of use. Women who
Both: 2.2, have used oral contraceptives
1.4-3.5. should be considered at
< 60 increased risk of adenomatous
months cervical carcinomas.

S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
Both: 1.5,
1.1-2.1
8. Zhan Ye et. al Multi-national, Cases 37.5; Histologically Selected from new hospital, age, marital status, 1.34, <60 Controls were use of combined oral
(1995) * Mexico, Chile, 1528; 40.6 confirmed cases admissions to each number of pregnancies, history of 1.16-1.54 months not matched to contraceptives was associated
Thailand. Controls of CIS. participating hospital. induced abortion, number of Pap 1.35, 1.13- individual with an increased risk of
12827 smears. 1.63 cases. cervical carcinoma in situ.
>61 Which increased with duration
months of oral contraceptive use.
2.04,
1.67-2.50
9 Ursin G et. al + USA (Los Angeles Cases <35 Cases of Identified from education, annual household 2.1, <5 years Controls compared with never use, ever
(1994) county) 1977 - 1991. 195; years. adenocarcinoma neighbourhood where income, number of sexual (1.1-3.8.) 1.0, matched on use of oral contraceptives was
Controls from population- the case lived at the partners before age 20, number of 0.4-2.3 age, race, and associated with twice as great a
386 based tumour time of diagnosis known episodes of genital warts. >5 years neighbourhood. risk of adenocarcinoma of the
registry. 1.9, cervix.
0.9-4.2
>10 years
2.5, 1.1-5.8
>12 years The highest risk was observed
4.4, 1.8- for oral contraceptive use for
10.8 more than 12 years.
10. Kjaer SK et. al Denmark 1987 -1988. Cases 20 to 49. Histologically Controls from potential confounders (excluding CIS1.4, For >6 Matched on age Risks for users vs non-users
(1993) *+ (CIS) 586 diagnosed population. human papillomavirus) 0.9-21 years to cases. were marginally increased, but
(ICC) 59; Squamous CIS ICC1.3, CIS 1.9, not statistically significant.
Controls and Squamous 0.5-3.3 1.1-3.1
614 invasive cancer. ICC 1.3,
0.5-3.5
>10 years we found asignificant trend
CIS 1.7, towards a higher risk for CIS
1.0-2.4 with increasing duration of use
11. Geoffrey Berry Thailand Kenya Mexico Cases Histologically Controls not using OC age, number of pregnancies, and 1.31 1.19- <60 Matched for Our study suggests that a causal
PI et. al (1993) Philippines Australia 2361; confirmed cases pills, who are number of prior Pap smears 1.45. months same year of relationship may exist between
+ Nigeria Chile Israel Controls of Squamous OCC hospitalised for other Adjusted also for centre. 1.39, birth and place use of combined oral
Colombia 1979 – 1988 13,644 from conditions. 1.1-1.71 of residence as contraceptives and squamous-
gynaecological >97 cases cell cervical carcinoma.
and tumour Months
clinics. 1.37,
1.19-1.57
12. Thomas DB (Australia, The Cases Histologically Women admitted to age, age at first sexual relations, 1.19,0.99- <60 controls were An observed trend of increasing
(1991) Germany, Israel) and in 709; detected new other than obstetric number of sexual partners, h/o 1.44 months not matched to risk of invasive cervical cancer
8 developing countries Controls cases of cervical and gynaecologic treated for vaginal discharge, and 1.25, individual with duration of use may not
Chile, China Colombia, 3935 cancer in wards, who met the a history of having had at least one 0.90-1.72 cases. represent a causal relationship
Kenya, Mexico Nigeria, Hospitals of same age and Pap smear, and is the subject of further
Philippines Thailand). these centres. residential criteria for study.
1979 -1988. case, don’t use OC pills.
>60
months

167
 168
Table 1 (Continued)
S. Study ID Year Origin, Period Sample Age Case/exposure Control/Non-exposure Confounders Adjusted OR/RR OR/RR Matching of Significance
no of Publication range. size group (user v/s (Duration control.
Mean non- of use)
+- SD/ user).
Range
/Median
(in
years)
1.53, 1.11-

S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
2.12
13. Parazzini F et. Italy Since 1981. Cases 47; Women with a Patients admitted for age, marital status, education, 1.85, 1.00- <2 years – According to these results,
al (1990) 367; 22-59. histologically acute conditions in parity, number of sexual partners, 3 14 1.05, 0.84- women who had used OCs
Controls confirmed Milan and several age at first intercourse, cigarette 3.24 more frequently experienced
323. diagnosis of specialized University smoking, history of Pap smears ICC. The risk increased with
invasive cervical Clinics and use of barrier methods of duration of use and was
cancer. contraception doubled in OC users for more
than two years.
>2 years
2.47, 1.19-
5 13
14. Brinton LA + Panama, Costa Rica, Cases <70 Histologically Controls were age, number of sexual partners, Both; 1.21 <5 years age-matched The risk associated with oral
(1990) Colombia and Mexico. 759; diagnosed with randomly selected 1 age at first sexual intercourse, (0.9-1.6). 1.15, 0.8- (by five-year contraceptives significantly
1986 – 1987 Controls Invasive cervical from community and 1 years since last Pap smear, 1.6 groups). increased for AC whereas for
1430 cancer from Hospital. number of births, HPV 16/18 [AC] 2.4, >5 years SCC tumours the effect was
(In 2:1 ratio). detection status (negative, 1.3-4.6; 1.7, 1.1- minimal.
positive, equivocal, unknown), 2.6.
and years of education, unknown [SCC] 1.3,
0.8-1.5

Case-control studies

S. Study ID Origin, Sample size Age Case/exposure Control/Non- Confounders Adjusted OR/ OR/RR Matching of Significance
no Year of Period groupMean exposure RR (Duration control.
Publication range. +- SD/Range (user of use)
/Median v/s
(in years) non-
user).
1. Esther R et. Through 23 Total cohort 35-70 176,993 ever used OC 121,117 Never body mass index, marital 1.6, >5 years NA Duration of OC pills use was associated with a
Al (2016) centres in of 308,036; pills. used OC status, level education, 1.1- 2.0,1.3-3.0 significantly increased risk for 15 years versus
10 cases 609 pills. physical activity, smoking 2.3 never use.
European (184) ICC; 152.658 (Past users), habits, OC use and duration, CC >10 years
countries. control menopausal status with HT ICC 1.6, 1.0-2.6
1992-2000 1,218 17,384 (Current users). use. 1.5, >15 years
0.8- 1.8, 1.1-2.9
2.6 >10 years
ICC 1.5,
0.7-3.1
2. Vessey M England 17,032 25-39 years. Either current user of Women Non- social class, smoking, parity, 3.4, <48 NA The risk of cervical cancer was increased by OC
et. Al and any contraceptive for at exposure BMI, Influence of age at first 1.6- months use. All these effects increased with duration of
(2013) Scotland least 5 months. to any marriage. 8.9 2.3 0.8– use and declined with interval since last use.
1968 - 1974 contraceptive. 7.1
till 2010. >48
months
2.2, 0.6–
7.5
>73
months
 3.6,
1.2–11.1
3. Philip C et. UK. 1968 46,000 (23 29 (SD 6.6). Who were using oral Who had never age, parity, smoking, social 1.49, <48 NA Statistically significant trends of increasing risk
al (2007) over 000+23 contraceptives. user status, and ever use of HRT. 0.97- months of cervical cancer was seen with increasing
14-month 000) them. 2.28 1.10, duration of oral contraceptive use.
0.64-1.90
48-97
months
1.45,
0.84-2.49
97
months

S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
2.73, 1.61
4.61
4. Vessey M UK, 1968- 17,032 25-39 Who were using OCs, Who are not Age, social class, smoking, 4.2, <48 NA Combining data for cancers of the cervix,
et. al. 2004. diaphragm or an IUD. using any body mass index, parity, 1.8– months uterine body and ovary, the age adjusted RR for
(2006) form of height, age at first-term 12.0 2.9 0.9– women ever using OCs compared with those
contraceptives. pregnancy age at first 9.9 never doing so was 0.7 (95%CI, 0.5-0.8).
marriage. Beneficial effects of OCs on the gynaecological
cancers thus outweighed adverse effects.
49-96
months
3.3 1.2–
10.4
97+
months
6.1, 2.5-
17.9
5. Zondervan England 17,032 + 25-39 Women using any Cases were all social class, smoking, age at ICC < 2 years matched to cases These results suggest a possible effect
KT et. al and controls (in contraceptive for at women first birth, ever diaphragm 4.44, 5.45, 0.79- on exact year of of OC use on later stages of cervical
(1996) Scotland nested case least 5 months without diagnosed <45 use and ever condom use 1.04- 50.5 birth and clinic carcinogenesis, although residual confounding
1968 -1974. control). previous exposure. And yrs of age 13.6 attended at due to sexual factors or human papillomavirus
followed up for with invasive CIS 2-5 years recruitment to (HPV) infection cannot be ruled out.
incidence. carcinoma 1.73 2.77, 0.49- study.
((33), CIS (121) 1.00- 23.1
Controls 3.00
were randomly > 5 years
selected 4.65, 1.08-
from among 32.9
cohort
members.

*Studies that consider carcinoma in-situ. +Studies that consider adenocarcinoma, squamous carcinoma.
AC: adenocarcinoma, ASC: adeno-squamous carcinoma, CO: Cohort, CC: case-control, NCC: Nested Case-Control.

169
170 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175

in the meta-analysis after performing different models for various
subgroups.
Forest plots were drawn for risk assessment of subgroup
analysis of case-control versus cohort studies. Histological type
analysis included subgroups such as overall invasive carcinoma,
carcinoma in situ. adenocarcinoma, and squamous cell carcinoma.
Subgroup analysis of the duration of OC pill uses included < 2,2–5,
5–10 and >10 years of OC pill use. Cut-off for studies published
before and after the year 2000. The method of visual assessment of
funnel plots was used to measure the bias in the meta-analysis
after performing different models for various subgroups. For the
validity and reliability of each individual study, we used CASP
(critical appraisal skills program) Checklists [37] for case-control
and cohort studies. These checklists are effective in assessing the
quality of each individual study included in a systematic review as
it considers three major issues validity, results, and clinical
relevance.
Results
Forty-two articles obtained for full-text review after screening
abstracts of 224 articles. Of the screened, 19 studies were finally
included in the study with unknown HPV status. They were 14
case-control and 5 cohort studies (Fig. 1 and Web Fig. 1). Full details
of the 19 studies included in the analysis were given in Web Table 1.
Qualitative assessment
A separate analysis was also done on 15 studies for OC pill use
and risk of cervical cancer in HPV positive women [21,24,34,38–49]
and included as a web source. A summary of included studies for
study location along with the period of study, study design, sample
size, study setting, and case ascertainment for each primary study
were enlisted (Web Table 1). Quality assessment results of CASP
tool assessment given in Web Table 2 and Web Table 3. A summary
of studies included in analysis was prepared, according to the study
design Case-control [17–28,20–23,25–30,33,34] and Cohort
study [19,24,31,32,35], histology type [17,18,20,21,25,28], duration
of OC pills uses [17–35], and study published before 2000
[17,18,20–23,25,26,28,33,34] and after 2000 [19,24,27,29,32].
CASP checklist had shown that all the studies used reliable and
valid way in recruiting cases and controls. It also demonstrated
that most of studies have taken measures to minimise bias. It also
demonstrated that there were few short-comings within the
studies. Most of the studies except two [21,30] have failed to take
confounders into account. Furthermore, very few studies
[19,26,27,34] included are conducted in global population and
most of the studies are conducted in local population.
Risk overall and in various to histological types
The overall risk for all histological types considered was found
to be significant with OR (95 % CI) as 1.51 (1.35, 1.68). The maximum
risk was associated with adenocarcinoma (OR 1.77 95 % CI 1.40,
2.24), while the risk for squamous cell carcinoma was OR 1.29
(95 % CI 1.18, 1.42). Four studies showed association of increased
duration of OC with carcinoma-in-situ (CIS) (OR of 1.70 and 95 % CI
1.18, 2.44). Twelve studies evaluated the risk for invasive cervical
cancer (ICC) and found a significant relation with OC use (OR 1.59,
95 % CI 1.31, 1.93). Heterogeneity was very low and non-significant
among cervical adenocarcinoma group with I2 = 0 (Fig. 2).
Risk associated with the duration of uses of oral contraceptives
As shown in Fig. 3, a statistically insignificant risk was seen if the
use was <2 years with OR 1.27 (95 % CI 0.98, 1.65). Usage for 2-5years
had shown a significant risk with OR 1.34 (95 % CI 1.20,1.50). Women
who used for 5–10 years and >10 years had risks of ODDS ratio
(95 % CI) as 1.93 (1.56, 2.36) and 2.24 (1.45–3.48) respectively. For >10
years of duration, there was a 2-folded risk (Fig. 3).
Risk estimated in different study designs
Different risks found for different study design for both case-
control studies and cohort studies. For cohort studies associated
risk was higher with OR (95 % CI) as 2.32 (1.50, 3.60) as compared to
case control studies with OR (95 % CI) as 1.42 (1.25, 1.62). Both
design estimates had significant heterogeneity (P = 0.04)
(Web Fig. 2).

Table 2
Quality assessment of case-control studies using CASP checklist for case-control studies.

Study Q1 Q2 Q3 Q4 Q5 Q6a Q6b Q7 Q8 Q9 Q10 Q11

Afasaneh V et al Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes
Margaret U et. al Yes Yes Yes Yes Yes No No Yes Yes No No Yes
Vanakankovit N et. al Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes
Lacey JV Jr et. al Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes
Ylitalo N et al Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes
Parazzini F et. al Yes Yes Yes Yes Yes No No Yes Yes No No Yes
Thomas DB et. al Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes
Zhan Ye et. al Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes
Ursin G et. al Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes
Kjaer SK et. al Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes
Geoffrey Berry et. al Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes
Thomas DB (1991) Yes Yes Yes Yes Yes No No Yes Yes No Yes Yes
Parazzini F et. al (1990) Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes
Brinton LA Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes

Q1: Did the study address a clearly focused issue?

Q2: Did the authors use an appropriate method to answer their question?
Q3: Were the cases recruited in an acceptable way?
Q4: Were the controls selected in an acceptable way?
Q5: Was the exposure accurately measured to minimise bias?
Q6a: Aside from the experimental intervention, were the groups treated equally?
Q6b: Have the authors taken account of the potential confounding factors in the design and/or in their analysis?
Q7: How large was the treatment effect?
Q8: How precise was the estimate of the treatment effect?
Q9: Do you believe the results?
Q10: Can the results be applied to the local population?
Q11: Do the results of this study fit with other available evidence?
 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175 171

Table 3
Quality assessment of cohort studies using CASP checklist for cohort studies.

Study Q1 Q2 Q3 Q4 Q5a Q5b Q6a Q6b Q7 Q8 Q9 Q10 Q11 Q12

Esther R et. al Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes
Vessey M et. al Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes
Philip C et. al Yes Yes Yes Yes Yes No Yes No Yes Yes No No Yes No
Vessey M et. al (2006) Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes
Zondervan KT et. al Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes

Q1. Did the study address a clearly focused issue?

Q2. Was the cohort recruited in an acceptable way?
Q3. Was the exposure accurately measured to minimise bias?
Q4. Was the outcome accurately measured to minimise bias?
Q5(a) Have the authors identified all important confounding factors?
Q5(b) Have they take account of the confounding factors in the design and/or analysis?
Q6(a) Was the follow up of subjects complete enough?
Q6(b)Was the follow up of subjects long enough?
Q7. What are the results of this study?
Q8. How precise are the results?
Q9. Do you believe the results?
Q10. Can the results be applied to the local population?
Q11. Do the results of this study fit with other available evidence?
Q12. What are the implications of this study for practice?

Risk in relation to studies published before 2000 and after 2000
The risk of cervical cancer with OC use is shown in Web Fig. 3.
Both the subgroups had a significant risks of cervical cancer with
OC use. The studies published after 2000 had higher risk with
OR = 1.90 (95 % CI 1.33, 2.72, I2 = 69 %, P = 0.004) as compared to
studies published before 2000 (OR = 1.40, 95 % CI 1.24, 1.58,
I2 = 45 %, P = 0.05).
Risk associated with HPV positive women for OC pill use and cervical
cancer
Significant risk found in HPV Positive women for oral contra-
ceptives causing cervical cancer with a OR 1.66 [95 % CI 1.24–2.2].
From this we concluded that use of oral contraceptive pills is an
independent risk factor in causing cervical cancer (Fig. 4).
The funnel plot shows the observed effect sizes are more or less
symmetrically distributed around the combined effect size. Five
studies, which consisted of less than 27 % of the overall number,
were outside the pseudo 95 % confidence limits. Aside from those
studies, the rest of the funnel was symmetrical. However, absence
of studies towards left corner of the plot and hence minimal
publication bias cannot be rule out which can be ignored as it may
not have much influence on the outcome (Web Fig. 4).
Discussion
This comprehensive systematic review along with meta-
analysis revealed positive association between use of OC pills
and cervical cancer. The association of longer duration of OC pills
use found a higher risk with proportionate increase in duration of
use. Risk according to histologic specific types of cervical
carcinoma such as adenocarcinoma and squamous cell carcinoma
was also evaluated separately. It was higher among adenocarci-
noma as compared to squamous cell carcinoma. Risk of cervical
cancer with the use of OC pills was present in both women with
unknown HPV status and positive for HPV infection. Limitation of
the current systematic review is the non-availability of primary
studies on type specific contraceptive use and its relation to
cervical cancer. Strength of the current review was various
subgroup analysis performed in addition to year of publication,
duration of OC pills uses, past use of OC pills and specific
histologic type.
Our results on significant association between OC use and CaCx
are consistent with that results of other systematic reviews
[8,14,15]. A review that pooled 28 studies, all published before
1990 and found an overall significant increase in the risk of cervical
cancer when comparing ever versus never users [15]. A collabora-
tive reanalysis of individual data for cervical cancer from 24
epidemiological studies in a case-control setup also found higher
risk for OC pills user which was higher for less developed countries
[8]. Delgado-Rodriguez et al. also found identical results on
invasive cancer data which was pooled from 18 studies and
concluded OC pill use is a risk factor for all stages of cervical cancer.
This study observed significant linear dose-response effect was
observed in dysplasia, carcinoma in situ, and invasive cervical
cancer [14]. One of the earlier reviews also included Cervical
intraepithelial neoplasia grade 3 [15]. It could be possible that risk
differs between invasive cancers and pre-cancerous lesions as CIN
conditions has a potential to revert back. Two recent reviews
differed with our results and found no association of OC Pills with
cervical cancer [11,12]. Our study had a prominent advantage over
earlier studies that it is comprehensive and assessed both case-
control studies and cohort studies whereas earlier systematic
review included only case-control studies [11] whereas the other
study included only few studies and hence deficient in data [12].
Further, both the earlier reviews included only studies
published in 2000 and later [11,12]. One study, though collected
data from earlier years also, included data only from 2000
onwards, thus there are chances of selection bias and throwing
away important data [12]. Current review computed risk from
studies published after 2000 was slightly higher (2 folds) as
compared from (one and half fold risk) to studies published before
2000 but both of them were significant. The cut off for year 2000
was taken into consideration for analysis, owing to the fact that
there was a difference in combination of combined OC pills that
varied over the period of time. The cut-off variations might give
different effect sized as it is arbitrary in nature. We analysed risk of
cervical cancer for women who used pills during late 80 s and 90 s
in comparison to women who used pills from the year early 2000
onwards. However, an earlier review had also adopted the similar
cut off of year 2000 in their analysis [12].
Two recent systematic reviews concluded that risk associated
with increasing duration of use is not significant [11,12]. Increase of
the duration of OC pills use might have an increase in risk due to
chronic exposure to risk factors as observed from primary studies.
Systematic reviews earlier also demonstrated same findings as that
of ours the increase in the duration of use was associated with an
increased risk of cervical cancer [15]. One review had shown no
relation for duration less than 5 years’ exposure but had shown the
172 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175

Fig. 2. Risk for different histological types for cervical cancer in users versus non-users of oral contraceptives (women with unknown HPV status).

significant association with use >5 years or >10 years [8]. Regarding
the association with past use of oral contraceptive pills and risk of
cervical cancer, studies included in our review suggested that
there was no association when compared to current users
[17–20,22–24,28,29]. Few studies in the review shown a higher risk
of cervical cancer in those with use in the last 48 months
subsequently declining to levels close to no risk [31–34]. These
studies shown a lower the risk with cessation of OC use.
There are three primary studies that evaluated risk for both
adenocarcinoma and squamous cell carcinoma separately. Two of
those studies found that risk for both adenocarcinoma and
squamous cell carcinoma was high and significant [17,25]. Another
primary study though found elevated risk but it was statistically
insignificant [21]. None of the other earlier reviews considered the
evaluation according to histological categories. The risk of OC pills
use found more associated with adenocarcinoma as compared to
squamous cell carcinoma may be due to the fact that with OC pills
use causes hyperplasia of the endometrium. The reason could be
hormonal imbalance such as excess estrogenic without progester-
one due to influence of OC pills. The hormonal influence leads to
lack of ovulation further leading to decrease in, progesterone, and
the endometrial remains unshed. The endometrium cells in
response to estrogenic may cause endometrial hyperplasia, which
crowd together and become abnormal. This hyperplasia, may lead
to cancer and since this phenomenon occur in endometrium its
more of adenocarcinomas [50].
Pooling of data from fifteen studies on HPV positive women
found risk that was similar to risk in women in which HPV status
was unknown [15]. Our findings are consistent with pooled
review of HPV positive women. Among low (<5 years) or median
 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175 173

Fig. 3. Risk for cervical cancer in users versus non-users of oral contraceptives with increase in duration of use (women with unknown HPV status).
174 S. Asthana et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 247 (2020) 163–175
Fig. 4. Forest plot showing risk of cervical cancer in women with known HPV positive status using oral contraceptive pills.
(5–10 years) duration of use of OC Pills, the association was absent
with cervical cancer irrespective of HPV infection. In the longer
duration (>10 years) of OC use, the association was reported as
significant after adjusting for HPV status. The affect in this group
was significant increase to the extent of doubling the risk with an
effect modification of HPV positivity. Though our results show
significant association in both the groups of higher duration of OC
use. In conclusion, use of OC pills for longer duration had definite
higher risk for developing cervical cancer. Further, cohort studies
are needed for use of specific type of OC pills and risk of cervical
cancer.
Author contributions
SA and VB conducted the literature search, selected studies, and
extracted data. LS assessed the methodologic quality of studies. SA
conceived and planned the review, assessed the methodologic
quality of studies, verified the data, and drafted and revised the
manuscript. LS provided methodologic advice, data interpretation,
content expertise, and finalising the manuscript. All authors
reviewed and approved the final manuscript.
Funding
All authors disclose no financial and personal relationships with
other people ororganizations that could inappropriately bias their work.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
We thank Dr Rahul Modi, Speciality Registrar, division of
gynaecological oncology, Tata memorial hospital, Mumbai for
reviewing the manuscript.
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