Association between oral contraceptive use and pancreatic cancer risk: A systematic review and meta-analysis

Table 1 Characteristics of included studies

Study design	Ref.	Country	Sample size1	Exposure assessment	Outcome assessment	Risk estimate (95%CI)2	Adjustments	NOS score
Case-control
	Bueno de Mesquita et al[20], 1992	Netherlands	82 cases and 252 controls	Interviewer administered questionnaire	Clinical diagnosis (histological verification, clinicians, laboratory records, registries)	OR = 0.83 (0.31-2.23)	Age, response status and life-time smoking of cigarettes	7
	Ji et al[21], 1996	China	184 cases and 680 controls	Interviewer administered questionnaire	Rapid reporting system within cancer registry	OR = 1.78 (0.91-3.47)	Age, income, education, smoking, BMI, green tea drinking, respondent status, age at first birth, intake of dietary vitamin C	7
	Kreiger et al[10], 2001	Canada	52 cases and 233 controls	Mailed questionnaire	Cancer registry	OR = 0.36 (0.13-0.96); P = 0.031	Age, smoking status, BMI, tofu, dietary fat, coffee consumption, age at menarche, age at menopause, parity, estrogen replacement therapy age at first full term pregnancy	8
	Duell et al[22], 2005	United States	241 cases and 818 controls	Interviewer administered questionnaire	Physician, SEER and histologic confirmation	OR = 0.95 (0.65-1.4)	Age, education, smoking	8
	Duell et al[23], 2009	Australia, Canada, The Netherlands, Poland	367 cases and 821 controls	Interviewer administered questionnaire	Clinicians, hospital records, pathology records, cancer registries	OR = 0.74 (0.43-1.26)	Smoking, schooling, age, center, type of interview	8
	Zhang et al[24], 2010	United States	284 cases and 1096 controls	Interviewer administered questionnaire	Pathology report confirmation	3	-	6
	Lucenteforte et al[8], 2011	Italy	285 cases and 713 controls	Interviewer administered questionnaire	Histologically confirmed	OR = 1.04 (0.55-1.98)	Study/center, age, education, area of residence, year of interview, history of diabetes, tobacco smoking	7
	Azeem et al[11], 2015	Czech Republic	129 cases and 97 controls	Interviewer administered questionnaire	Hospital diagnosis	OR = 0.21 (0.07-0.69)	Not specified (other monitored factors)	5
	Masoudi et al[9], 2017	Iran	153 cases and 202 controls	Interviewer administered questionnaire	Pathological reports	OR = 1.07 (0.62-1.84)	Smoking status, BMI, diabetes	6
	Archibugi et al[25], 2020	Italy	253 cases and 506 controls	Interviewer administered questionnaire	Histologically proven diagnosis	OR = 0.52 (0.31-0.89)	Age, BMI, first degree family history of pancreatic cancer, history of diabetes > 1 yr, history of chronic pancreatitis, heavy alcohol intake, smoking habit	7
Cohort
	Skinner et al[26], 2003	United States	243 cases and 115474 non-cases	Mailed questionnaire	Self-reported confirmed via medical records, pathology reports, death certificates, physicians, next of kin interview	RR = 1.21 (0.91-1.61)	Age, time period, cigarette smoking, diabetes, BMI, height, parity	8
	Teras et al[27], 2005	United States	1959 cases among 387981 participants	Self-administered questionnaire	National Death Index and death certificates	3	-	8
	Navarro Silvera et al[28], 2005	Canada	187 cases and 89645 noncases	Self-administered questionnaire	Canadian Cancer Database and the National mortality database	HR = 1.10 (0.81-1.50)	Age, cigarette smoking intensity, cigarette smoking duration, BMI, height, study center, randomization group, parity	8
	Prizment et al[29], 2007	United States	228 cases and 37231 noncases	Self-administered questionnaire	National Death Index and State Health Registry of Iowa	HR = 0.90 (0.62-1.30)	Age	7
	Dorjgochoo et al[30], 2009	China	78 cases among 66661 participants	In-person interview and a self-reported questionnaire	Shanghai Cancer registry and Shanghai Vital Statistics Registry	HR = 0.83 (0.45-1.55)	Education, age at menarche, number of live births, cumulative breast feeding months, BMI, exercised regularly in past 5 yr, smoking, menopausal status, first-degree family history of cancer, other contraceptive methods	9
	Duell et al[31], 2013	Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom	304 cases among 328610 participants	Self-administered questionnaire	Population cancer registries, health insurance records, hospital-based and pathology registries	3	-	8
	Lee et al[32], 2013	United States	323 cases among 118164 participants	Self-administered questionnaire	California Cancer Registry	3	-	8
	Kabat et al[33], 2017	United States	1003 cases and 157295 non-cases	Self-administered questionnaire	Self-reports verified by physician adjudicators through records of hospitalizations, surgeries, pathology reports and procedures	HR = 0.92 (0.80-1.06)	Age, smoking status, pack-years of smoking, BMI, educational level, ethnicity, allocation to study component, diabetes	7
	Andersson et al[34],2018	Sweden	110 cases and 16921 noncases	On-site questionnaires and examinations	Swedish Cancer register confirmed by pathology records, autopsy	HR = 0.68 (0.44-1.06)	Age, smoking, alcohol consumption, BMI	8
	Butt et al[35], 2018	Denmark	235 cases among 1.9 million women	National Register of Medicinal Product Statistics	Danish Cancer Register and Danish National Patient Register	RR = 0.90 (0.68-1.19)	Age, year, education, PCOS, endometriosis, parity	9
	Michels et al[36], 2018	United States	1000 cases and 195536 noncases	Mailed questionnaire	Cancer registries	HR = 1.11 (0.97-1.28)	Age, race, BMI, smoking status, alcohol use, number of cigarettes smoked per day	8

¹For samples including both sexes only data for women were presented.

²Ever use of oral contraceptives vs never use.

³Not reported, derived from available published data.

CI: Confidence interval; NOS: Newcastle-Ottawa Scale; OR: Odds ratio; RR: Relative risk; HR: Hazard ratio; BMI: Body mass index; PCOS: Polycystic ovary syndrome.

Table 2 Association between the use of oral contraceptives and risk of pancreatic cancer: Subgroup analysis

Characteristic	Subgroup	Number of studies	RR (95%CI)	I2 within each subgroup	Test for subgroups differences
Study design	Case-control	10	0.85 (0.64-1.14)	60% (P = 0.008)	P = 0.92
	Cohort	11	0.84 (0.70-1.00)	85% (P < 0.00001)
Source of controls in case-control studies	Population	6	0.75 (0.47-1.21)	63% (P = 0.02)	P = 0.47
	Hospital	4	0.94 (0.64-1.39)	61% (P = 0.06)
Number of pancreatic cancer cases	< 200	8	0.80 (0.56-1.14)	66% (P = 0.004)	P = 0.77
	≥ 200	13	0.85 (0.71-1.00)	83% (P < 0.00001)
Assessed study quality	NOS ≤ 7	9	0.93 (0.75-1.17)	56% (P = 0.02)	P = 0.33
	NOS > 7	12	0.80 (0.66-0.98)	84% (P < 0.00001)
Geographic region1	Europe	7	0.67 (0.51-0.88)	55% (P = 0.04)	P = 0.07
	Americas	10	0.91 (0.74-1.11)	86% (P < 0.00001)
	Asia	3	1.14 (0.76-1.73)	27% (P = 0.25)
Menopausal status	Premenopausal	1	0.90 (0.68-1.19)	N/A	0.90
	Postmenopausal	4	0.88 (0.79-0.98)	17% (P = 0.31)

¹One study was multicentric and conducted in all three geographic regions so it was not included in the subgroup analysis by geographic region.

CI: Confidence interval; NOS: Newcastle-Ottawa Scale; RR: Relative risk.