- Email: [email protected]
Abortion: what is the problem?
Comment
David S Stephens Emory University School of Medicine, Atlanta, GA 30322, USA; and VA Medical Center, Atlanta, GA 30033, USA [email protected] I declare that I have no conflicts of interest. I thank Nancy Messonier for her helpful comments. 1
2
3
Santolaya ME, O’Ryan M, Valenzuela MT, et al, for the V72P10 Meningococcal B Adolescent Vaccine Study group. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet 2012; published online Jan 18. DOI:10.1016/S0140-6736(11)61713-3. Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine 2001; 20 (suppl 1): S58–67. Gasparini R, Panatto D. Meningococcal glycoconjugate vaccines. Hum Vaccin 2011; 7: 170–82.
4 5 6
7 8
9
10
Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001; 344: 1378–88. Stephens DS, Greenwood B, Brandizaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 2007; 369: 2196–210. Lennon D, Jackson C, Wong S, Horsfall M, Stewart J, Reid S. Fast tracking the vaccine licensure process to control an epidemic of serogroup B meningococcal disease in New Zealand. Clin Infect Dis 2009; 49: 597–605. Stephens DS. Outer-membrane-vesicle vaccines: old but not forgotten. Lancet Infect Dis 2011; 11: 421–22. Mascioni A, Bentley BE, Camarda R, et al. Structural basis for the immunogenic properties of the meningococcal vaccine candidate LP2086. J Biol Chem2009; 284: 8738–46. Boccadifuoco G, Donnelly J, Medini D, et al. Estimating the potential strain coverage in Europe of a multicomponent vaccine targeting serogroup B meningococci. Meningitis and Septicemia in Children and Adults Conference 2011. London, UK; Nov 8–9, 2011. Abstract V36. Maiden MC, Ibarz-Pavon AB, Urwin R, et al. Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity. J Infect Dis 2008; 197: 737–43.
Abortion: what is the problem? Published Online January 19, 2012 DOI:10.1016/S01406736(12)60038-5
AFP/Getty Images
See Articles page 625
The publication of Gilda Sedgh and colleagues’ article in The Lancet coincides with the anniversary of the Roe v Wade US Supreme Court decision that effectively legalised abortion in all 50 states. In the nearly three decades that have followed this landmark decision, there has been no letup in the controversy surrounding abortion. In fact, discussion of abortion has become so fraught with symbolic and real controversy that even the scientific literature has not been spared. In The Lancet, Gilda Sedgh and colleagues1 present an article on global abortion rates and trends that will generate debate on tricky methodological issues in tallying the frequency of an act that is often highly stigmatised,
Signs placed by pro-abortion campaigners outside Congress building in Montevideo, Uruguay, Dec 27, 2011
594
frequently illegal, and commonly secret. This study1 should also draw attention to the impact of healthcare access, politics, and religion, and how these factors intersect to produce global patterns of death from abortion. The article by Sedgh and colleagues1 documents stagnation in global abortion rates between 2003 and 2008 (29 and 28 abortions per 1000 women aged 15–44 years, respectively), effectively ending the nearly decade-long decline that preceded 2003 and suggesting recent growth in the number of women with unmet need for contraception. They also found that the share of abortions worldwide that were unsafe has risen, from 44% in 1995 to 49% in 2008, indicating little progress in tackling this preventable source of maternal mortality.1 Despite the greater availability of national-level data, the estimates by Sedgh and colleagues are likely to be conservative, particularly in legally restricted settings where there is tremendous incentive to conceal abortion use and provision. Even in countries with liberal abortion laws, estimation of abortion incidence is problematic and relies on the use of many data sources and applications of adjustment factors.2 The challenges are even greater in restrictive settings where the use of indirect methods of measurement is required.3 As Sedgh and colleagues1 note, this dilemma is further complicated by new challenges such as the growth of private sector procedures and increased use of medical abortion. www.thelancet.com Vol 379 February 18, 2012
Comment
The rising use and probable substantial undercount of medical abortion suggests that more women, particularly in restrictive environments, might be finding ways to obtain such procedures, even without medical assistance.4 Indeed, since many medical abortions in restrictive environments are likely to be considerably safer than surgical services in those same places, some procedures that are classified as unsafe by reason of location may actually be quite safe. This development calls for a re-evaluation of the operative definition of unsafe abortion that was used in this analysis: “a procedure for termination of an unintended pregnancy done either by people lacking the necessary skills or in an environment that does not conform to minimum medical standards, or both”.5 The definition was developed by WHO in 1992,5 before widespread access to or knowledge about medical abortion regimens, for which a typical surgical environment is not necessary and for which the extent of skilled training is different from that needed for surgery. Medical abortions can take place in private homes and be safe. Indeed, nearly all of the medical abortions that have taken place in the USA since Food and Drug Administration approval of the procedure in 2000 have occurred in private homes, but were certainly not unsafe. This paradox underscores the need for revision of both our concept and the definition of what truly constitutes an unsafe abortion. Beneath the manifest problems in documenting abortions and parsing them into safe and unsafe categories lies profound irony. Unsafe abortion is one of the five major contributors to maternal mortality: causing one in every seven or eight maternal deaths in 2008.6 Yet, when abortion is provided with proper medical techniques and care, the risk of death is negligible and nearly 14 times lower than that of childbirth.7 Almost the entire global burden of deaths due to abortion occurs in Africa, Asia, and Latin America.6 Somehow, we typically act as if this were neither surprising nor troubling. But there are no regional biological differences in women that could account for this discrepancy; there is no procedure to prevent death from abortion that is unknown to practitioners where the toll is high; and there are no costly technologies needed to avoid these deaths. If a lack exists, it is a lack of caring: a willingness to sacrifice lives to an ideological moral high ground, to social acceptability, or to the maintenance of a political comfort zone. www.thelancet.com Vol 379 February 18, 2012
The contribution of Sedgh and colleagues1 points to the weakness of some arguments in favour of restriction of abortion services. First, legal restrictions on abortion do not lead to decreased use of the procedure; in fact, there may be an inverse relation. The lowest subregional rate of abortion reported (12 per 1000 women aged 15–44 years) was in western Europe, where laws are among the least restrictive. Some of the highest subregional rates (ranging from 29 to 39 per 1000 women aged 15–44 years) were in Latin America, where laws are among the most restrictive. In recognition of this reality, the government of Mexico City voted in 2007 to legalise abortion for the first 12 weeks of pregnancy. For the rest of the country, abortion remains illegal, clandestine, and often unsafe, despite its high frequency. The data continue to confirm what we have known for decades: that women who wish to terminate unwanted pregnancies will seek abortion at any cost, even when it is illegal or involves risk to their own lives. It is time to move beyond the outdated rhetoric of the 1994 International Conference on Population and Development,8 in which governments conceded that abortion should be safe where it is legal. Sedgh and colleagues’ study1 shows that it is precisely where abortion is illegal that it must become safer. The public health community will not be able to address maternal mortality adequately and attainment of Millennium Development Goals is questionable until we directly confront the issue of unsafe abortion. With regard to abortion mortality, we may need to resurrect the wisdom of the 1960s: “if we are not part of the solution, we are part of the problem”. *Beverly Winikoff, Wendy R Sheldon Gynuity Health Projects, New York, NY 10010, USA bwinikoff@gynuity.org We declare that we have no conflicts of interest. 1
2
3
Sedgh G, Singh S, Shah IH, Åhman E, Henshaw SK, Bankole A. Induced abortion: incidence and trends worldwide from 1995 to 2008. Lancet 2012; published online Jan 19. DOI:10.1016/S0140-6736(11)61786-8. Sedgh G, Henshaw SK. Measuring the incidence of abortion in countries with liberal laws. In: Singh S, Remez L, Tartaglione A, eds. Methodologies for estimating abortion incidence and abortion-related morbidity: a review. New York: Guttmacher Institute and Paris: International Union for the Scientific Study of Population, 2010: 23–33. Ahman E, Shah IH. Generating national unsafe abortion estimates: challenges and choices. In: Singh S, Remez L, Tartaglione A, eds. Methodologies for estimating abortion incidence and abortion-related morbidity: a review. New York: Guttmacher Institute and Paris: International Union for the Scientific Study of Population, 2010: 13–22.
595
Comment
4
5
6
Gomperts RJ, Jelinska K, Davies S, Gemzell-Danielsson K, Kleiverda G. Using telemedicine for termination of pregnancy with mifepristone and miosprostol in settings where there is no access to safe services. BJOG 2008; 115: 1171–75. WHO. The prevention and management of unsafe abortion. Report of a technical working group (WHO/MSM/92.5). Geneva: World Health Organization, 1992. WHO. Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2008, 6th edn. Geneva: World Health Organization, 2011.
7 8
Raymond EG, Grimes DA. The comparative safety of legal induced abortion and childbirth in the United States. Obstet Gynecol (in press). United Nations. Population and development: programme of action adopted at the International Conference on Population and Development. Cairo, Sept 5–13, 1994. New York NY: United Nations, 1995.
Dual inhibition of HER2 in breast cancer treatment Published Online January 17, 2012 DOI:10.1016/S01406736(12)60068-3 See Articles page 633 See Comment Lancet Oncol 2012; 13: 112
Science Photo Library
See Articles Lancet Oncol 2012; 13: 135
596
In The Lancet, José Baselga and colleagues1 present results from the phase 3 NeoALLTO trial, a pivotal investigation of dual anti-HER2 therapy for neoadjuvant treatment of breast cancer. The investigators used a straightforward approach to assess whether combination treatment with the antibody trastuzumab and the tyrosine kinase inhibitor lapatinib was better than single-agent treatment. 455 women were randomised to treatment with trastuzumab, lapatinib, or both drugs combined for 6 weeks, followed by addition of paclitaxel for 12 weeks and subsequent surgery. In terms of the primary endpoint, pathological complete response (pCR) at the time of surgery, dual blockade was significantly more efficacious (51·3% [95% CI 43·1–59·5]) than was lapatinib (24·7% [18·1–32·3]) or trastuzumab (29·5% [22·4–37·5]) alone. Because targeting of HER2 and
molecules important in downstream signalling is a paradigm for targeted anticancer therapy, NeoALLTO is a model for future research and clinical trial design. A crucial scientific strength of NeoALLTO is the study’s design. During the initial 6 week biological window, targeted anti-HER2 treatment was given without chemotherapy, enabling collection of samples for translational research, and early tumour response to be assessed without confounding by cytotoxic therapy. Such approaches should be used more often in pivotal trials of new drugs that target specific biological pathways, to enable unbiased efficacy assessments to be made. Equally important, such trials could help to identify clinically useful markers of early response, with the ultimate goal of tailoring neoadjuvant treatments for individual patients. In NeoALLTO,1 after 6 weeks the dual treatment strategy already had higher efficacy (tumour response rate 67%) than did treatment with lapatinib (53%) or trastuzumab (30%) alone. Differences in early tumour response had diminished by the time of surgery, however, potentially because of the addition of taxane or continuation of treatment. Factors such as optimum assessment timepoints and different mechanisms of action (eg, antibodies or tyrosine kinase inhibitors) are important to bear in mind, and careful consideration will be needed as to whether the best predictor of clinical outcomes is early or definite response, pCR, residual cancer burden, or all these together in a combined algorithm. The ultimate aim of breast cancer treatment is to save lives, not just to achieve responses to treatment. With targeted therapies being used in pathway-orientated trials such as NeoALTTO, what matters most in early response assessment needs to be established with respect to prediction of long-term survival under adjuvant treatment. www.thelancet.com Vol 379 February 18, 2012
David S Stephens Emory University School of Medicine, Atlanta, GA 30322, USA; and VA Medical Center, Atlanta, GA 30033, USA [email protected] I declare that I have no conflicts of interest. I thank Nancy Messonier for her helpful comments. 1
2
3
Santolaya ME, O’Ryan M, Valenzuela MT, et al, for the V72P10 Meningococcal B Adolescent Vaccine Study group. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet 2012; published online Jan 18. DOI:10.1016/S0140-6736(11)61713-3. Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine 2001; 20 (suppl 1): S58–67. Gasparini R, Panatto D. Meningococcal glycoconjugate vaccines. Hum Vaccin 2011; 7: 170–82.
4 5 6
7 8
9
10
Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001; 344: 1378–88. Stephens DS, Greenwood B, Brandizaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 2007; 369: 2196–210. Lennon D, Jackson C, Wong S, Horsfall M, Stewart J, Reid S. Fast tracking the vaccine licensure process to control an epidemic of serogroup B meningococcal disease in New Zealand. Clin Infect Dis 2009; 49: 597–605. Stephens DS. Outer-membrane-vesicle vaccines: old but not forgotten. Lancet Infect Dis 2011; 11: 421–22. Mascioni A, Bentley BE, Camarda R, et al. Structural basis for the immunogenic properties of the meningococcal vaccine candidate LP2086. J Biol Chem2009; 284: 8738–46. Boccadifuoco G, Donnelly J, Medini D, et al. Estimating the potential strain coverage in Europe of a multicomponent vaccine targeting serogroup B meningococci. Meningitis and Septicemia in Children and Adults Conference 2011. London, UK; Nov 8–9, 2011. Abstract V36. Maiden MC, Ibarz-Pavon AB, Urwin R, et al. Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity. J Infect Dis 2008; 197: 737–43.
Abortion: what is the problem? Published Online January 19, 2012 DOI:10.1016/S01406736(12)60038-5
AFP/Getty Images
See Articles page 625
The publication of Gilda Sedgh and colleagues’ article in The Lancet coincides with the anniversary of the Roe v Wade US Supreme Court decision that effectively legalised abortion in all 50 states. In the nearly three decades that have followed this landmark decision, there has been no letup in the controversy surrounding abortion. In fact, discussion of abortion has become so fraught with symbolic and real controversy that even the scientific literature has not been spared. In The Lancet, Gilda Sedgh and colleagues1 present an article on global abortion rates and trends that will generate debate on tricky methodological issues in tallying the frequency of an act that is often highly stigmatised,
Signs placed by pro-abortion campaigners outside Congress building in Montevideo, Uruguay, Dec 27, 2011
594
frequently illegal, and commonly secret. This study1 should also draw attention to the impact of healthcare access, politics, and religion, and how these factors intersect to produce global patterns of death from abortion. The article by Sedgh and colleagues1 documents stagnation in global abortion rates between 2003 and 2008 (29 and 28 abortions per 1000 women aged 15–44 years, respectively), effectively ending the nearly decade-long decline that preceded 2003 and suggesting recent growth in the number of women with unmet need for contraception. They also found that the share of abortions worldwide that were unsafe has risen, from 44% in 1995 to 49% in 2008, indicating little progress in tackling this preventable source of maternal mortality.1 Despite the greater availability of national-level data, the estimates by Sedgh and colleagues are likely to be conservative, particularly in legally restricted settings where there is tremendous incentive to conceal abortion use and provision. Even in countries with liberal abortion laws, estimation of abortion incidence is problematic and relies on the use of many data sources and applications of adjustment factors.2 The challenges are even greater in restrictive settings where the use of indirect methods of measurement is required.3 As Sedgh and colleagues1 note, this dilemma is further complicated by new challenges such as the growth of private sector procedures and increased use of medical abortion. www.thelancet.com Vol 379 February 18, 2012
Comment
The rising use and probable substantial undercount of medical abortion suggests that more women, particularly in restrictive environments, might be finding ways to obtain such procedures, even without medical assistance.4 Indeed, since many medical abortions in restrictive environments are likely to be considerably safer than surgical services in those same places, some procedures that are classified as unsafe by reason of location may actually be quite safe. This development calls for a re-evaluation of the operative definition of unsafe abortion that was used in this analysis: “a procedure for termination of an unintended pregnancy done either by people lacking the necessary skills or in an environment that does not conform to minimum medical standards, or both”.5 The definition was developed by WHO in 1992,5 before widespread access to or knowledge about medical abortion regimens, for which a typical surgical environment is not necessary and for which the extent of skilled training is different from that needed for surgery. Medical abortions can take place in private homes and be safe. Indeed, nearly all of the medical abortions that have taken place in the USA since Food and Drug Administration approval of the procedure in 2000 have occurred in private homes, but were certainly not unsafe. This paradox underscores the need for revision of both our concept and the definition of what truly constitutes an unsafe abortion. Beneath the manifest problems in documenting abortions and parsing them into safe and unsafe categories lies profound irony. Unsafe abortion is one of the five major contributors to maternal mortality: causing one in every seven or eight maternal deaths in 2008.6 Yet, when abortion is provided with proper medical techniques and care, the risk of death is negligible and nearly 14 times lower than that of childbirth.7 Almost the entire global burden of deaths due to abortion occurs in Africa, Asia, and Latin America.6 Somehow, we typically act as if this were neither surprising nor troubling. But there are no regional biological differences in women that could account for this discrepancy; there is no procedure to prevent death from abortion that is unknown to practitioners where the toll is high; and there are no costly technologies needed to avoid these deaths. If a lack exists, it is a lack of caring: a willingness to sacrifice lives to an ideological moral high ground, to social acceptability, or to the maintenance of a political comfort zone. www.thelancet.com Vol 379 February 18, 2012
The contribution of Sedgh and colleagues1 points to the weakness of some arguments in favour of restriction of abortion services. First, legal restrictions on abortion do not lead to decreased use of the procedure; in fact, there may be an inverse relation. The lowest subregional rate of abortion reported (12 per 1000 women aged 15–44 years) was in western Europe, where laws are among the least restrictive. Some of the highest subregional rates (ranging from 29 to 39 per 1000 women aged 15–44 years) were in Latin America, where laws are among the most restrictive. In recognition of this reality, the government of Mexico City voted in 2007 to legalise abortion for the first 12 weeks of pregnancy. For the rest of the country, abortion remains illegal, clandestine, and often unsafe, despite its high frequency. The data continue to confirm what we have known for decades: that women who wish to terminate unwanted pregnancies will seek abortion at any cost, even when it is illegal or involves risk to their own lives. It is time to move beyond the outdated rhetoric of the 1994 International Conference on Population and Development,8 in which governments conceded that abortion should be safe where it is legal. Sedgh and colleagues’ study1 shows that it is precisely where abortion is illegal that it must become safer. The public health community will not be able to address maternal mortality adequately and attainment of Millennium Development Goals is questionable until we directly confront the issue of unsafe abortion. With regard to abortion mortality, we may need to resurrect the wisdom of the 1960s: “if we are not part of the solution, we are part of the problem”. *Beverly Winikoff, Wendy R Sheldon Gynuity Health Projects, New York, NY 10010, USA bwinikoff@gynuity.org We declare that we have no conflicts of interest. 1
2
3
Sedgh G, Singh S, Shah IH, Åhman E, Henshaw SK, Bankole A. Induced abortion: incidence and trends worldwide from 1995 to 2008. Lancet 2012; published online Jan 19. DOI:10.1016/S0140-6736(11)61786-8. Sedgh G, Henshaw SK. Measuring the incidence of abortion in countries with liberal laws. In: Singh S, Remez L, Tartaglione A, eds. Methodologies for estimating abortion incidence and abortion-related morbidity: a review. New York: Guttmacher Institute and Paris: International Union for the Scientific Study of Population, 2010: 23–33. Ahman E, Shah IH. Generating national unsafe abortion estimates: challenges and choices. In: Singh S, Remez L, Tartaglione A, eds. Methodologies for estimating abortion incidence and abortion-related morbidity: a review. New York: Guttmacher Institute and Paris: International Union for the Scientific Study of Population, 2010: 13–22.
595
Comment
4
5
6
Gomperts RJ, Jelinska K, Davies S, Gemzell-Danielsson K, Kleiverda G. Using telemedicine for termination of pregnancy with mifepristone and miosprostol in settings where there is no access to safe services. BJOG 2008; 115: 1171–75. WHO. The prevention and management of unsafe abortion. Report of a technical working group (WHO/MSM/92.5). Geneva: World Health Organization, 1992. WHO. Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2008, 6th edn. Geneva: World Health Organization, 2011.
7 8
Raymond EG, Grimes DA. The comparative safety of legal induced abortion and childbirth in the United States. Obstet Gynecol (in press). United Nations. Population and development: programme of action adopted at the International Conference on Population and Development. Cairo, Sept 5–13, 1994. New York NY: United Nations, 1995.
Dual inhibition of HER2 in breast cancer treatment Published Online January 17, 2012 DOI:10.1016/S01406736(12)60068-3 See Articles page 633 See Comment Lancet Oncol 2012; 13: 112
Science Photo Library
See Articles Lancet Oncol 2012; 13: 135
596
In The Lancet, José Baselga and colleagues1 present results from the phase 3 NeoALLTO trial, a pivotal investigation of dual anti-HER2 therapy for neoadjuvant treatment of breast cancer. The investigators used a straightforward approach to assess whether combination treatment with the antibody trastuzumab and the tyrosine kinase inhibitor lapatinib was better than single-agent treatment. 455 women were randomised to treatment with trastuzumab, lapatinib, or both drugs combined for 6 weeks, followed by addition of paclitaxel for 12 weeks and subsequent surgery. In terms of the primary endpoint, pathological complete response (pCR) at the time of surgery, dual blockade was significantly more efficacious (51·3% [95% CI 43·1–59·5]) than was lapatinib (24·7% [18·1–32·3]) or trastuzumab (29·5% [22·4–37·5]) alone. Because targeting of HER2 and
molecules important in downstream signalling is a paradigm for targeted anticancer therapy, NeoALLTO is a model for future research and clinical trial design. A crucial scientific strength of NeoALLTO is the study’s design. During the initial 6 week biological window, targeted anti-HER2 treatment was given without chemotherapy, enabling collection of samples for translational research, and early tumour response to be assessed without confounding by cytotoxic therapy. Such approaches should be used more often in pivotal trials of new drugs that target specific biological pathways, to enable unbiased efficacy assessments to be made. Equally important, such trials could help to identify clinically useful markers of early response, with the ultimate goal of tailoring neoadjuvant treatments for individual patients. In NeoALLTO,1 after 6 weeks the dual treatment strategy already had higher efficacy (tumour response rate 67%) than did treatment with lapatinib (53%) or trastuzumab (30%) alone. Differences in early tumour response had diminished by the time of surgery, however, potentially because of the addition of taxane or continuation of treatment. Factors such as optimum assessment timepoints and different mechanisms of action (eg, antibodies or tyrosine kinase inhibitors) are important to bear in mind, and careful consideration will be needed as to whether the best predictor of clinical outcomes is early or definite response, pCR, residual cancer burden, or all these together in a combined algorithm. The ultimate aim of breast cancer treatment is to save lives, not just to achieve responses to treatment. With targeted therapies being used in pathway-orientated trials such as NeoALTTO, what matters most in early response assessment needs to be established with respect to prediction of long-term survival under adjuvant treatment. www.thelancet.com Vol 379 February 18, 2012