110 Short paper
Oral contraceptives, human papillomavirus and cervical cancer Carlo La Vecchiaa,b and Stefania Bocciac Oncogenic human papillomavirus is the key determinant of cervical cancer, but other risk factors interact with it to define individual risk. Among these, there is oral contraceptive (OC) use. A quantitative review of the link between OCs and cervical cancer was performed. Longterm (> 5 year) current or recent OC use has been related to an about two-fold excess risk of cervical cancer. Such an excess risk, however, levels off after stopping use, and approaches unity 10 or more years after stopping. The public health implications of OC use for cervical cancer are limited. In any case, such implications are greater in middle-income and low-income countries, as well as in central and eastern Europe and Latin America, where cervical cancer screening and control remain inadequate. European Journal of Cancer Prevention
c 2014 Wolters Kluwer Health | Lippincott 23:110–112 Williams & Wilkins.
Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Worldwide, the prevalence of HPV has been estimated at 10–15%, with higher rates in subSaharan Africa, eastern Europe and Latin America (Forman et al., 2012). HPV16 and HPV18 are the most common oncogenic types in Europe and North America (although with considerable variation across countries and age groups), but other types are common in Africa (De Vuyst et al., 2009) and Latin America (HPV45) and in eastern Asia (HPV58) (Guan et al., 2012). Cervical cancer accounts for over 85% of HPV-related cancers worldwide, corresponding to about 530 000 cases per year (Forman et al., 2012).
that OCs do not increase the acquisition or persistence of HPV infection, but rather favour its progression to cervical cancer. This confirms the observation from an Italian case–control study, which suggested that OCs have a promoting effect on the process of cervical carcinogenesis, with a decrease in risk shortly after stopping use (Parazzini et al., 1998).
Although HPV is a necessary component cause of cervical cancer, other factors play a role in cervical carcinogenesis, including cigarette smoking (La Vecchia et al., 1986) and oral contraceptive (OC) use (La Vecchia and Bosetti, 2003; Cibula et al., 2010). To address the combined effect and interactions between HPV and OCs for cervical cancer risk, a pooled analysis was conducted by the International Agency for Research on Cancer (IARC) on the role of OCs among HPVpositive women (Moreno et al., 2002), including 1676 cervical cancer cases and 255 controls from eight case– control studies on invasive cancers and two studies on in-situ cancers. No excess risk was observed among women who had used OCs for 5 years or less, but the relative risk (RR) rose to 2.8 for those who had used OCs for 5–9 years and to 4.0 for those who had used it for 10 years or more. There was no correlation between HPV positivity and OC use among the controls. This indicates c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-8278
European Journal of Cancer Prevention 2014, 23:110–112 Keywords: cervical cancer, epidemiology, human papillomavirus, oral contraceptions, risk a Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, bDepartment of Clinical Sciences and Community Health, University of Milan, Milan and cSection of Hygiene, Institute of Public Health, Universita` Cattolica del Sacro Cuore, Rome, Italy
Correspondence to Carlo La Vecchia, MD, Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, via G. La Masa, 19-20156 Milano, Italy Tel: + 39 02 39014527; fax: + 39 02 33200231; e-mail: [email protected] Received 29 October 2013 Accepted 26 November 2013
A subsequent meta-analysis of 28 studies showed an excess cervical cancer risk with long-term OC use, with RRs of 1.3–1.6 for 5–9 years and 2.3–2.5 for 10 years or more (Smith et al., 2003). The RRs were similar in users of progestogen-only injectable contraceptives, and in separate strata of HPV-positive women. The International Collaboration of Epidemiological Studies of Cervical Cancer (Appleby et al., 2007) provided the most valid information on the effect of OC use, duration and time since stopping OC use on cervical cancer risk, on the basis of a collaborative reanalysis of individual data on 16 573 women with cervical cancer and 35 509 without cervical cancer. After allowance for a large number of covariates, including age, number of sexual partners, age at first intercourse, parity, smoking and screening, the RR was 1.9 [95% floating confidence interval (FCI) 1.7–2.1] for current users of at least 5 years, whereas no significant association was observed for shorter use. The RR, however, declined after stopping use to 1.3 (95% FCI 1.2–1.4) 2–9 years after stopping, and no residual excess risk was observed 10 or more years after stopping (RR = 0.9, Table 1). For cervical intraepithelial neoplasia 3/carcinoma in situ, the RR was 2.23 (95% FCI 2.0–2.5) for current long-term (> 5 years) current users, and the RR DOI: 10.1097/CEJ.0000000000000000
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Oral contraceptives, HPV and cervical cancer La Vecchia and Boccia 111
Relative risk and 95% floating confidence interval of invasive cervical cancer by duration of use and time since last oral contraceptive use
Table 1
Duration of use Never < 5 years
5 + years
Time since last use
Cases/controls
Mean duration of use in cases (years)
RRa
95% FCI
Current user 2–9 years 10 + years Current user 2–9 years 10 + years
7356/21 682 225/1022 443/1397 631/1960 880/1466 747/1510 412/1654
– 3.1 3.0 2.8 11.1 9.3 8.1
1.00 1.09 1.02 0.93 1.90 1.28 0.94
(0.96–1.04) (0.99–1.30) (0.88–1.14) (0.83–1.13) (1.71–2.12) (1.15–1.40) (0.80–1.11)
FCI, floating confidence interval; RR, relative risk. a Stratified by age, study or study centre, age at first intercourse, lifetime number of sexual partners, number of full-term pregnancies, smoking and screening status (Appleby et al., 2007).
declined to 1.36 10 or more years after stopping. Data were scantier when analyses were restricted to studies providing information on HPV status and to HPV-positive women only, but the pattern of risk was similar. Likewise, the pattern of risk was similar for users of progestogen-only injectable contraceptives. The pooled multivariate RR was 1.22, of borderline significance, for users for at least 5 years, in the absence of any excess risk 5 or more years after stopping OC use (Appleby et al., 2007). Available data, therefore, indicate that long-term (i.e. Z 10 years) OC use (and, most likely, injectable progestogens as well) increases the risk of cervical cancer in HPV-positive women. With current incidence rates of cervical cancer, this may translate to a cumulative risk at the age of 50 years of around 0.8% in low-income and middle-income countries and 0.4% in high-income countries (Appleby et al., 2007; Cibula et al., 2010). Understanding the role of HPV infection in cervical intraepithelial neoplasia and cervical cancer has led to the development of a prophylactic cancer vaccine (Crosbie et al., 2013). The efficacy of vaccination against HPV in the prevention of cervical cancer in HPV-naive women has been demonstrated within two randomized clinical trials (FUTURE II Study Group, 2007; Paavonen et al., 2009), and two vaccines are currently available, the quadrivalent type (HPV6, HPV11, HPV16 and HPV18; Merck, Whitehouse Station, New Jersey, USA) and the bivalent type (HPV16 and HPV18; GlaxoSmithKline, Rixensart, Belgium). Even though vaccination has been estimated to be cost-effective in different settings (Kim, 2011; La Torre, 2010), vaccination policies largely differ between countries, and in particular two administrations seem as effective as three (Crosbie et al., 2013). As OCs have a promoting effect on the process of cervical carcinogenesis that is initiated by HPV infection, in the future (i.e. after 2030) OCs will have little material effect on cervical carcinogenesis in countries where the vaccination policies cover a large proportion of women before the onset of sexual activity or HPV infection. Thus, any association between OCs and cervical cancer is likely to remain more relevant in low-income and
middle-income countries, as well as in eastern Europe and Latin America, where cervical screening and vaccination policies are largely inadequate, and cervical cancer rates are still exceedingly high (Franceschi et al., 2000; Bosetti et al., 2005, 2013; Chatenoud et al., 2010; La Vecchia et al., 2010).
Acknowledgements This work was supported by the Italian Association for Cancer Research (Grant No. 10068). Conflicts of interest
There are no conflicts of interest.
References Appleby P, Beral V, Berrington de Gonzalez A, Colin D, Franceschi S, Goodhill A, et al. (2007). Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies. Lancet 370:1609–1621. Bosetti C, Malvezzi M, Chatenoud L, Negri E, Levi F, La Vecchia C (2005). Trends in cancer mortality in the Americas, 1970–2000. Ann Oncol 16: 489–511. Bosetti C, Bertuccio P, Malvezzi M, Levi F, Chatenoud L, Negri E, et al. (2013). Cancer mortality in Europe, 2005–2009, and an overview of trends since 1980. Ann Oncol 24:2657–2671. Chatenoud L, Bertuccio P, Bosetti C, Levi F, Curado MP, Malvezzi M, et al. (2010). Trends in cancer mortality in Brazil, 1980–2004. Eur J Cancer Prev 19:79–86. Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, et al. (2010). Hormonal contraception and risk of cancer. Hum Reprod Update 16:631–650. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC (2013). Human papillomavirus and cervical cancer. Lancet 382:889–899. De Vuyst H, Clifford G, Li N, Franceschi S (2009). HPV infection in Europe. Eur J Cancer 45:2632–2639. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. (2012). Global burden of human papillomavirus and related diseases. Vaccine 30 (Suppl 5):F12–F23. Franceschi S, Herrero R, La Vecchia C (2000). Cervical cancer screening in Europe. What next? Eur J Cancer 36:2272–2275. FUTURE II Study Group (2007). Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356: 1915–1927. Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. (2012). Human papillomavirus types in 115 789 HPV-positive women: a metaanalysis from cervical infection to cancer. Int J Cancer 131:2349–2359. Kim JJ (2011). The role of cost-effectiveness in U.S. vaccination policy. N Engl J Med 365:1760–1761. La Torre G (2010). Assessment of HPV vaccines: from the burden of dieases to the health technology assessment approach. Hum Vaccin 6:915–917.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
112 European Journal of Cancer Prevention 2014, Vol 23 No 2
La Vecchia C, Franceschi S, Decarli A, Fasoli M, Gentile A, Tognoni G (1986). Cigarette smoking and the risk of cervical neoplasia. Am J Epidemiol 123:22–29. La Vecchia C, Bosetti C (2003). Oral contraceptives and cervical cancer: public health implications. Eur J Cancer Prev 12:1–2. La Vecchia C, Bosetti C, Lucchini F, Bertuccio P, Negri E, Boyle P, et al. (2010). Cancer mortality in Europe, 2000–2004, and an overview of trends since 1975. Ann Oncol 21:1323–1360. Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, et al. (2002). Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case–control study. Lancet 359:1085–1092.
Paavonen J, Naud P, Salmero´n J, Wheeler CM, Chow SN, Apter D, et al. (2009). Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374:301–314. Parazzini F, Chatenoud L, La Vecchia C, Chiaffarino F, Ricci E, Negri E (1998). Time since last use of oral contraceptives and risk of invasive cervical cancer. Eur J Cancer 34:884–888. Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, et al. (2003). Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 361:1159–1167.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Oral contraceptives, human papillomavirus and cervical cancer Carlo La Vecchiaa,b and Stefania Bocciac Oncogenic human papillomavirus is the key determinant of cervical cancer, but other risk factors interact with it to define individual risk. Among these, there is oral contraceptive (OC) use. A quantitative review of the link between OCs and cervical cancer was performed. Longterm (> 5 year) current or recent OC use has been related to an about two-fold excess risk of cervical cancer. Such an excess risk, however, levels off after stopping use, and approaches unity 10 or more years after stopping. The public health implications of OC use for cervical cancer are limited. In any case, such implications are greater in middle-income and low-income countries, as well as in central and eastern Europe and Latin America, where cervical cancer screening and control remain inadequate. European Journal of Cancer Prevention
c 2014 Wolters Kluwer Health | Lippincott 23:110–112 Williams & Wilkins.
Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Worldwide, the prevalence of HPV has been estimated at 10–15%, with higher rates in subSaharan Africa, eastern Europe and Latin America (Forman et al., 2012). HPV16 and HPV18 are the most common oncogenic types in Europe and North America (although with considerable variation across countries and age groups), but other types are common in Africa (De Vuyst et al., 2009) and Latin America (HPV45) and in eastern Asia (HPV58) (Guan et al., 2012). Cervical cancer accounts for over 85% of HPV-related cancers worldwide, corresponding to about 530 000 cases per year (Forman et al., 2012).
that OCs do not increase the acquisition or persistence of HPV infection, but rather favour its progression to cervical cancer. This confirms the observation from an Italian case–control study, which suggested that OCs have a promoting effect on the process of cervical carcinogenesis, with a decrease in risk shortly after stopping use (Parazzini et al., 1998).
Although HPV is a necessary component cause of cervical cancer, other factors play a role in cervical carcinogenesis, including cigarette smoking (La Vecchia et al., 1986) and oral contraceptive (OC) use (La Vecchia and Bosetti, 2003; Cibula et al., 2010). To address the combined effect and interactions between HPV and OCs for cervical cancer risk, a pooled analysis was conducted by the International Agency for Research on Cancer (IARC) on the role of OCs among HPVpositive women (Moreno et al., 2002), including 1676 cervical cancer cases and 255 controls from eight case– control studies on invasive cancers and two studies on in-situ cancers. No excess risk was observed among women who had used OCs for 5 years or less, but the relative risk (RR) rose to 2.8 for those who had used OCs for 5–9 years and to 4.0 for those who had used it for 10 years or more. There was no correlation between HPV positivity and OC use among the controls. This indicates c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-8278
European Journal of Cancer Prevention 2014, 23:110–112 Keywords: cervical cancer, epidemiology, human papillomavirus, oral contraceptions, risk a Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, bDepartment of Clinical Sciences and Community Health, University of Milan, Milan and cSection of Hygiene, Institute of Public Health, Universita` Cattolica del Sacro Cuore, Rome, Italy
Correspondence to Carlo La Vecchia, MD, Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, via G. La Masa, 19-20156 Milano, Italy Tel: + 39 02 39014527; fax: + 39 02 33200231; e-mail: [email protected] Received 29 October 2013 Accepted 26 November 2013
A subsequent meta-analysis of 28 studies showed an excess cervical cancer risk with long-term OC use, with RRs of 1.3–1.6 for 5–9 years and 2.3–2.5 for 10 years or more (Smith et al., 2003). The RRs were similar in users of progestogen-only injectable contraceptives, and in separate strata of HPV-positive women. The International Collaboration of Epidemiological Studies of Cervical Cancer (Appleby et al., 2007) provided the most valid information on the effect of OC use, duration and time since stopping OC use on cervical cancer risk, on the basis of a collaborative reanalysis of individual data on 16 573 women with cervical cancer and 35 509 without cervical cancer. After allowance for a large number of covariates, including age, number of sexual partners, age at first intercourse, parity, smoking and screening, the RR was 1.9 [95% floating confidence interval (FCI) 1.7–2.1] for current users of at least 5 years, whereas no significant association was observed for shorter use. The RR, however, declined after stopping use to 1.3 (95% FCI 1.2–1.4) 2–9 years after stopping, and no residual excess risk was observed 10 or more years after stopping (RR = 0.9, Table 1). For cervical intraepithelial neoplasia 3/carcinoma in situ, the RR was 2.23 (95% FCI 2.0–2.5) for current long-term (> 5 years) current users, and the RR DOI: 10.1097/CEJ.0000000000000000
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Oral contraceptives, HPV and cervical cancer La Vecchia and Boccia 111
Relative risk and 95% floating confidence interval of invasive cervical cancer by duration of use and time since last oral contraceptive use
Table 1
Duration of use Never < 5 years
5 + years
Time since last use
Cases/controls
Mean duration of use in cases (years)
RRa
95% FCI
Current user 2–9 years 10 + years Current user 2–9 years 10 + years
7356/21 682 225/1022 443/1397 631/1960 880/1466 747/1510 412/1654
– 3.1 3.0 2.8 11.1 9.3 8.1
1.00 1.09 1.02 0.93 1.90 1.28 0.94
(0.96–1.04) (0.99–1.30) (0.88–1.14) (0.83–1.13) (1.71–2.12) (1.15–1.40) (0.80–1.11)
FCI, floating confidence interval; RR, relative risk. a Stratified by age, study or study centre, age at first intercourse, lifetime number of sexual partners, number of full-term pregnancies, smoking and screening status (Appleby et al., 2007).
declined to 1.36 10 or more years after stopping. Data were scantier when analyses were restricted to studies providing information on HPV status and to HPV-positive women only, but the pattern of risk was similar. Likewise, the pattern of risk was similar for users of progestogen-only injectable contraceptives. The pooled multivariate RR was 1.22, of borderline significance, for users for at least 5 years, in the absence of any excess risk 5 or more years after stopping OC use (Appleby et al., 2007). Available data, therefore, indicate that long-term (i.e. Z 10 years) OC use (and, most likely, injectable progestogens as well) increases the risk of cervical cancer in HPV-positive women. With current incidence rates of cervical cancer, this may translate to a cumulative risk at the age of 50 years of around 0.8% in low-income and middle-income countries and 0.4% in high-income countries (Appleby et al., 2007; Cibula et al., 2010). Understanding the role of HPV infection in cervical intraepithelial neoplasia and cervical cancer has led to the development of a prophylactic cancer vaccine (Crosbie et al., 2013). The efficacy of vaccination against HPV in the prevention of cervical cancer in HPV-naive women has been demonstrated within two randomized clinical trials (FUTURE II Study Group, 2007; Paavonen et al., 2009), and two vaccines are currently available, the quadrivalent type (HPV6, HPV11, HPV16 and HPV18; Merck, Whitehouse Station, New Jersey, USA) and the bivalent type (HPV16 and HPV18; GlaxoSmithKline, Rixensart, Belgium). Even though vaccination has been estimated to be cost-effective in different settings (Kim, 2011; La Torre, 2010), vaccination policies largely differ between countries, and in particular two administrations seem as effective as three (Crosbie et al., 2013). As OCs have a promoting effect on the process of cervical carcinogenesis that is initiated by HPV infection, in the future (i.e. after 2030) OCs will have little material effect on cervical carcinogenesis in countries where the vaccination policies cover a large proportion of women before the onset of sexual activity or HPV infection. Thus, any association between OCs and cervical cancer is likely to remain more relevant in low-income and
middle-income countries, as well as in eastern Europe and Latin America, where cervical screening and vaccination policies are largely inadequate, and cervical cancer rates are still exceedingly high (Franceschi et al., 2000; Bosetti et al., 2005, 2013; Chatenoud et al., 2010; La Vecchia et al., 2010).
Acknowledgements This work was supported by the Italian Association for Cancer Research (Grant No. 10068). Conflicts of interest
There are no conflicts of interest.
References Appleby P, Beral V, Berrington de Gonzalez A, Colin D, Franceschi S, Goodhill A, et al. (2007). Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies. Lancet 370:1609–1621. Bosetti C, Malvezzi M, Chatenoud L, Negri E, Levi F, La Vecchia C (2005). Trends in cancer mortality in the Americas, 1970–2000. Ann Oncol 16: 489–511. Bosetti C, Bertuccio P, Malvezzi M, Levi F, Chatenoud L, Negri E, et al. (2013). Cancer mortality in Europe, 2005–2009, and an overview of trends since 1980. Ann Oncol 24:2657–2671. Chatenoud L, Bertuccio P, Bosetti C, Levi F, Curado MP, Malvezzi M, et al. (2010). Trends in cancer mortality in Brazil, 1980–2004. Eur J Cancer Prev 19:79–86. Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, et al. (2010). Hormonal contraception and risk of cancer. Hum Reprod Update 16:631–650. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC (2013). Human papillomavirus and cervical cancer. Lancet 382:889–899. De Vuyst H, Clifford G, Li N, Franceschi S (2009). HPV infection in Europe. Eur J Cancer 45:2632–2639. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. (2012). Global burden of human papillomavirus and related diseases. Vaccine 30 (Suppl 5):F12–F23. Franceschi S, Herrero R, La Vecchia C (2000). Cervical cancer screening in Europe. What next? Eur J Cancer 36:2272–2275. FUTURE II Study Group (2007). Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356: 1915–1927. Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. (2012). Human papillomavirus types in 115 789 HPV-positive women: a metaanalysis from cervical infection to cancer. Int J Cancer 131:2349–2359. Kim JJ (2011). The role of cost-effectiveness in U.S. vaccination policy. N Engl J Med 365:1760–1761. La Torre G (2010). Assessment of HPV vaccines: from the burden of dieases to the health technology assessment approach. Hum Vaccin 6:915–917.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
112 European Journal of Cancer Prevention 2014, Vol 23 No 2
La Vecchia C, Franceschi S, Decarli A, Fasoli M, Gentile A, Tognoni G (1986). Cigarette smoking and the risk of cervical neoplasia. Am J Epidemiol 123:22–29. La Vecchia C, Bosetti C (2003). Oral contraceptives and cervical cancer: public health implications. Eur J Cancer Prev 12:1–2. La Vecchia C, Bosetti C, Lucchini F, Bertuccio P, Negri E, Boyle P, et al. (2010). Cancer mortality in Europe, 2000–2004, and an overview of trends since 1975. Ann Oncol 21:1323–1360. Moreno V, Bosch FX, Munoz N, Meijer CJ, Shah KV, Walboomers JM, et al. (2002). Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case–control study. Lancet 359:1085–1092.
Paavonen J, Naud P, Salmero´n J, Wheeler CM, Chow SN, Apter D, et al. (2009). Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374:301–314. Parazzini F, Chatenoud L, La Vecchia C, Chiaffarino F, Ricci E, Negri E (1998). Time since last use of oral contraceptives and risk of invasive cervical cancer. Eur J Cancer 34:884–888. Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, et al. (2003). Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 361:1159–1167.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
