- Email: [email protected]
Resistance to targeted therapy in leukaemia
COMMENTARY
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The prospective investigation of pulmonary embolism diagnosis (PIOPED) investigators. Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED) investigators. JAMA 1990; 263: 2753–59. Wells PS, Hirsh J, Anderson DR, et al. A simple clinical model for the diagnosis of deep vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process. J Intern Med 1998; 243: 15–23. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorise patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83: 416–20. Anderson DR, Wells PS, Kovacs MJ, Kearon C, Dreyer J, Forgie MA. A randomised trial in patients with suspected deep vein thrombosis comparing a D-dimer/clinical probability strategy to clinical probability, prior to ultrasound imaging. D-dimer safely reduces the need for diagnostic imaging. Blood 2001; 98: 447a. Schutgens REG, Ackermark P, Haas FJLM, et al. The combination of low D-dimer concentration and a non-high clinical probability score is a safe strategy to exclude deep vein thrombosis. Blood 2001; 98: 448a. Anderson DR, Wells PS, Kovacs M, et al. Use of spiral computed tomography to exclude the diagnosis of pulmonary embolism in the emergency department. Blood 2001; 98: 447a. Hull R, Hirsh J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64: 622–25. Hull RD, Raskob GE, Coates G, Panju AA. Clinical validity of a normal perfusion lung scan in patients with suspected pulmonary embolism. Chest 1990; 97: 23–26.
The doctor’s role in advocacy See page 520 In his Rock Carling lecture last year, entitled “Fads in medical care policy and politics: the rhetoric and reality of managerialism”, Theodore Marmor spoke of the “linguistic muddle” and “conceptual confusion” that marked the organisation of medicine during the past decade. Business ideology infiltrated health care when costs spiralled and governments reconsidered their longstanding commitment to the welfare state. As professors were deposed by chief executive officers, and as the fog of human-resources jargon obscured an emptiness of serious thought, so mediocrity became the benchmark for running a health service. Priorities shifted. Quality was eroded by a concern for quantity, effectiveness gave way to efficiency, and notions of professionalism were subsumed by mission statements. Morale collapsed, cynicism became commonplace. But medicine is governed by an ethos, not a balance sheet, and doctors are now reasserting the values that politicians, managers, accountants, and lawyers have either dismissed or manipulated, according to their own partisan interests. This issue of The Lancet carries the results of a European-American project to produce a charter of fundamental principles and professional responsibilities for physicians. This unusual collaboration between the European Federation of Internal Medicine, American College of Physicians, American Society of Internal Medicine, and American Board of Internal Medicine sets clear standards for practice, which can be used by doctors to defend the interests of patients at the bedside and in the community. The Lancet is pleased to be supporting this initiative with colleagues at the Annals of Internal Medicine, who are also publishing the charter this week. Why does this charter matter? Doctors can no longer remain silent about their work, leaving advocacy to a small group of medical politicians. Doctors cannot assume that they have either the trust of the public or the support of governments unless they are willing to take 458
part in the public debate about what kind of society they want for the sick and impoverished. More doctors, irrespective of their specialty, responsibility, or seniority, need to enter the public arena of dispute. This idea is embodied in the charter’s principle of social justice, together with its parallel commitments to improving quality of care, enhancing access to health services, redistributing resources to those in most need, and strengthening the research base of medicine. Some doctors will argue that advocacy should be left to the few rather than be encouraged among the many. A doctor’s task, they might say, is to care, not to coerce. But advocacy can mean as little as writing a letter to a newspaper, posting a comment on a website, or asking a question at a meeting. Advocacy only means taking the problems that one faces day to day and pursuing their resolution outside their usual place of presentation. If every doctor who reads the physicians’ charter wrote a letter, posted a comment, or asked a question, the voice of medicine would be less easily dismissed or manipulated. Richard Horton The Lancet, London WC1X 8RR, UK 1
Marmor T. Fads in medical care policy and politics: the rhetoric and reality of managerialism. Rock Carling Fellowship, 2001. Norwich: The Stationery Office, on behalf of Nuffield Trust, 2001.
Resistance to targeted therapy in leukaemia See pages 481, 487 The development of STI571 for the treatment of chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL) is a significant advance in the field of molecular oncology.1,2 STI571 (imatinib; Gleevec or Glivec, Novartis Pharma AG) is the second oncogenetargeted small-molecule drug to produce impressive clinical results in human leukaemias (the first being alltrans retinoic acid, which specifically targets the PML/RAR␣ oncogene in acute promyelocytic leukaemia3), and is a harbinger of more to come. The efficacy of STI571 in stable-phase CML could be predicted from the results of earlier studies that showed that the ability of BCR/ABL to cause a CML-like disease in mice depended entirely on the activity of the BCR/ABL tyrosine-kinase. Less expected, however, was the substantial activity of the drug in patients with advanced phases of CML or Ph+ALL, leukaemias characterised by mutations in multiple genes in addition to BCR/ABL. Although responses in stable-phase CML have, so far, been quite durable, most patients with blast-phase CML or Ph+ALL develop resistance to STI571, and go into relapse after weeks or months of therapy. The mechanisms of drug resistance are diverse, but most patients are found to have mutations at the time of relapse that change aminoacids within the kinase domain of BCR/ABL. Gorre and colleagues4 reported that STI571 resistance was associated with mutations of one aminoacid, threonine 315 of ABL, a site previously shown in an elegant crystallographic study to be involved in the binding of STI571 to the kinase domain.5 In this issue of The Lancet, Nikolas von Bubnoff and co-workers report their results of the sequencing of the kinase domain of BCR/ABL in eight patients with clinical resistance to STI571: they identified five different point mutations in seven patients. Importantly, each of these
THE LANCET • Vol 359 • February 9, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
BCR/ABL mutations was found to transform murine haematopoietic cell-lines and to confer resistance to STI571. Interestingly, almost all of these mutations change aminoacids that have previously been predicted to make contact with STI571,5 a wonderful example of the convergence of basic science and clinical medicine. The mutations were not detected before STI571 therapy, although rare mutant cells could have been missed. This report, and others,6 show that resistance to STI571 is commonly associated with point mutations in BCR/ABL, and that these mutations can involve various sites. The importance of other mechanisms, such as BCR/ABL gene amplification, activation of other kinases, or upregulation of drug-resistance genes, such as MDR1, have not been established.7 These findings have substantial implications for therapy of these leukaemias. First, in advanced BCR/ABL+ leukaemias, there is a high frequency of DNA mutations and a reduced role of DNA repair. Thus, STI571-resistant clones can emerge very rapidly. Second, since the mutation sites in the kinase domain are diverse, it may be difficult to find a second ABL kinase inhibitor that is effective in all STI571-resistant clones. Put another way, these results suggest that treating STI571-resistant disease may be difficult, and efforts should be focused on preventing resistance from occurring. New strategies should aim to eliminate leukaemic cells as fast as possible. Combinations of ABL inhibitors, when available and if they have different contact sites, may be most useful when given together, much like modern antiretroviral therapy for HIV. Combinations of STI571 with other signal-transduction inhibitors acting on a critical downstream pathway, such as RAS or AKT, may be particularly useful as well. Finally, combinations of STI571 with techniques that are very effective at eliminating minimal residual disease, such as immunotherapy, should be evaluated. Wolf-K Hofmann and colleagues in this issue of The Lancet have taken a pharmacogenetic approach to understanding STI571 resistance. Microarray analysis on marrow cells from 19 patients with Ph+ALL was used to identify profiles associated with drug sensitivity versus primary resistance or rapid failure. A set of 95 genes, out of the 2500 evaluated, could be used to cluster sensitive and resistant cases. If validated on other patient sets, such algorithms might be used to select, or stratify, patients included in future clinical trials. Although such strategies are aiming at a moving target, Hoffman and colleagues’ report makes the powerful statement that gene profiling may well have the ability to predict the future for patients with cancer. This approach is a long way from practice, but the ability to predict who will do well and who will not will have a striking impact on cancer medicine. The panel of 95 genes identified here is likely to be refined over time as more patients are studied, more of the genome is queried, and STI571 is used in combination therapy rather than as a single agent. Also important will be the much harder task of understanding why every gene in the panel seems to have some relation to resistance. Overall, it is to be hoped that these studies give a glimpse of the future. Now that specific, targeted, therapies for leukaemias are available, learning how to use them to optimum advantage is the next step. I receive research funding from Novartis Pharma AG.
James D Griffin Leukemia Program, Dana-Farber Cancer Institute, Boston, MA 02115, USA (e-mail: [email protected])
THE LANCET • Vol 359 • February 9, 2002 • www.thelancet.com
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Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–42. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–37. Degos L, Wang ZY. All trans retinoic acid in acute promyelocytic leukemia. Oncogene 2001; 20: 7140–45. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–80. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289: 1938–42. Kreil S, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance in CML patients after STI571 (Glivec) therapy. Blood 2001; 98: 1823a (abstr). Weisberg E, Griffin JD. Mechanisms of resistance to imatinib (STI571) in preclinical models and in leukemia patients. Drug Resist Updat 2001; 4: 22–28.
Follow-up of children born after in-vitro fertilisation See page 461 The first baby born after in-vitro fertilisation (IVF) is now 23 years old. The first IVF baby to have a baby or father a baby could be expected in the near future. Yet follow-up studies of the health of children conceived by any of the IVF techniques have been few and logistically difficult. Epidemiological cohort and case-control studies are easy to criticise but difficult to undertake. To provide information useful in the counselling of infertile couples, researchers need persistence to follow up IVF children and their families. Bo Stromberg and colleagues report in this issue of The Lancet that children born in Sweden after IVF have three times the rate of cerebral palsy compared with children in the general population. This greater risk of cerebral palsy was found not only among children from IVF multiple pregnancies but also among singleton IVF infants born at term with normal birthweight. The latter finding is puzzling, but much remains in general to be understood about the pathophysiology of cerebral palsy. The prevalence of cerebral palsy is commonly cited as being 2·0–2·5 per 1000 livebirths.1 Although the prevalence for IVF children in this study (31/5680) exceeds this range, that for the controls is less than expected. If the high prevalence is a true result, then the question is whether the IVF process is deficient in some way for the development of the fetal motor system or that infertility itself is an independent factor. The results of this study are important. Few countries have the cross-discipline population registers to enable such a study to be undertaken. As with early reports suggesting increased rates of cancer among women treated by IVF,2 this report is easy to criticise but finding comparable and valid studies looking at the same or a similar question is more difficult. The high prevalence of cerebral palsy in the Stromberg data seems to be due to the high frequency of twin and higher multiple pregnancies. Senior figures in the US have recently pleaded for a reduction in twin and higher-order multiple pregnancies to minimise the shortterm and long-term damage to babies and mothers from multiple births resulting from the transfer of more than one embryo.3 No mention is made in the Stromberg paper of natural-cycle IVF compared with stimulated cycle IVF, gamete intrafallopian transfer, fresh or frozen embryo 459
For personal use. Only reproduce with permission from The Lancet Publishing Group.
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The prospective investigation of pulmonary embolism diagnosis (PIOPED) investigators. Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED) investigators. JAMA 1990; 263: 2753–59. Wells PS, Hirsh J, Anderson DR, et al. A simple clinical model for the diagnosis of deep vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process. J Intern Med 1998; 243: 15–23. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorise patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83: 416–20. Anderson DR, Wells PS, Kovacs MJ, Kearon C, Dreyer J, Forgie MA. A randomised trial in patients with suspected deep vein thrombosis comparing a D-dimer/clinical probability strategy to clinical probability, prior to ultrasound imaging. D-dimer safely reduces the need for diagnostic imaging. Blood 2001; 98: 447a. Schutgens REG, Ackermark P, Haas FJLM, et al. The combination of low D-dimer concentration and a non-high clinical probability score is a safe strategy to exclude deep vein thrombosis. Blood 2001; 98: 448a. Anderson DR, Wells PS, Kovacs M, et al. Use of spiral computed tomography to exclude the diagnosis of pulmonary embolism in the emergency department. Blood 2001; 98: 447a. Hull R, Hirsh J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64: 622–25. Hull RD, Raskob GE, Coates G, Panju AA. Clinical validity of a normal perfusion lung scan in patients with suspected pulmonary embolism. Chest 1990; 97: 23–26.
The doctor’s role in advocacy See page 520 In his Rock Carling lecture last year, entitled “Fads in medical care policy and politics: the rhetoric and reality of managerialism”, Theodore Marmor spoke of the “linguistic muddle” and “conceptual confusion” that marked the organisation of medicine during the past decade. Business ideology infiltrated health care when costs spiralled and governments reconsidered their longstanding commitment to the welfare state. As professors were deposed by chief executive officers, and as the fog of human-resources jargon obscured an emptiness of serious thought, so mediocrity became the benchmark for running a health service. Priorities shifted. Quality was eroded by a concern for quantity, effectiveness gave way to efficiency, and notions of professionalism were subsumed by mission statements. Morale collapsed, cynicism became commonplace. But medicine is governed by an ethos, not a balance sheet, and doctors are now reasserting the values that politicians, managers, accountants, and lawyers have either dismissed or manipulated, according to their own partisan interests. This issue of The Lancet carries the results of a European-American project to produce a charter of fundamental principles and professional responsibilities for physicians. This unusual collaboration between the European Federation of Internal Medicine, American College of Physicians, American Society of Internal Medicine, and American Board of Internal Medicine sets clear standards for practice, which can be used by doctors to defend the interests of patients at the bedside and in the community. The Lancet is pleased to be supporting this initiative with colleagues at the Annals of Internal Medicine, who are also publishing the charter this week. Why does this charter matter? Doctors can no longer remain silent about their work, leaving advocacy to a small group of medical politicians. Doctors cannot assume that they have either the trust of the public or the support of governments unless they are willing to take 458
part in the public debate about what kind of society they want for the sick and impoverished. More doctors, irrespective of their specialty, responsibility, or seniority, need to enter the public arena of dispute. This idea is embodied in the charter’s principle of social justice, together with its parallel commitments to improving quality of care, enhancing access to health services, redistributing resources to those in most need, and strengthening the research base of medicine. Some doctors will argue that advocacy should be left to the few rather than be encouraged among the many. A doctor’s task, they might say, is to care, not to coerce. But advocacy can mean as little as writing a letter to a newspaper, posting a comment on a website, or asking a question at a meeting. Advocacy only means taking the problems that one faces day to day and pursuing their resolution outside their usual place of presentation. If every doctor who reads the physicians’ charter wrote a letter, posted a comment, or asked a question, the voice of medicine would be less easily dismissed or manipulated. Richard Horton The Lancet, London WC1X 8RR, UK 1
Marmor T. Fads in medical care policy and politics: the rhetoric and reality of managerialism. Rock Carling Fellowship, 2001. Norwich: The Stationery Office, on behalf of Nuffield Trust, 2001.
Resistance to targeted therapy in leukaemia See pages 481, 487 The development of STI571 for the treatment of chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL) is a significant advance in the field of molecular oncology.1,2 STI571 (imatinib; Gleevec or Glivec, Novartis Pharma AG) is the second oncogenetargeted small-molecule drug to produce impressive clinical results in human leukaemias (the first being alltrans retinoic acid, which specifically targets the PML/RAR␣ oncogene in acute promyelocytic leukaemia3), and is a harbinger of more to come. The efficacy of STI571 in stable-phase CML could be predicted from the results of earlier studies that showed that the ability of BCR/ABL to cause a CML-like disease in mice depended entirely on the activity of the BCR/ABL tyrosine-kinase. Less expected, however, was the substantial activity of the drug in patients with advanced phases of CML or Ph+ALL, leukaemias characterised by mutations in multiple genes in addition to BCR/ABL. Although responses in stable-phase CML have, so far, been quite durable, most patients with blast-phase CML or Ph+ALL develop resistance to STI571, and go into relapse after weeks or months of therapy. The mechanisms of drug resistance are diverse, but most patients are found to have mutations at the time of relapse that change aminoacids within the kinase domain of BCR/ABL. Gorre and colleagues4 reported that STI571 resistance was associated with mutations of one aminoacid, threonine 315 of ABL, a site previously shown in an elegant crystallographic study to be involved in the binding of STI571 to the kinase domain.5 In this issue of The Lancet, Nikolas von Bubnoff and co-workers report their results of the sequencing of the kinase domain of BCR/ABL in eight patients with clinical resistance to STI571: they identified five different point mutations in seven patients. Importantly, each of these
THE LANCET • Vol 359 • February 9, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
BCR/ABL mutations was found to transform murine haematopoietic cell-lines and to confer resistance to STI571. Interestingly, almost all of these mutations change aminoacids that have previously been predicted to make contact with STI571,5 a wonderful example of the convergence of basic science and clinical medicine. The mutations were not detected before STI571 therapy, although rare mutant cells could have been missed. This report, and others,6 show that resistance to STI571 is commonly associated with point mutations in BCR/ABL, and that these mutations can involve various sites. The importance of other mechanisms, such as BCR/ABL gene amplification, activation of other kinases, or upregulation of drug-resistance genes, such as MDR1, have not been established.7 These findings have substantial implications for therapy of these leukaemias. First, in advanced BCR/ABL+ leukaemias, there is a high frequency of DNA mutations and a reduced role of DNA repair. Thus, STI571-resistant clones can emerge very rapidly. Second, since the mutation sites in the kinase domain are diverse, it may be difficult to find a second ABL kinase inhibitor that is effective in all STI571-resistant clones. Put another way, these results suggest that treating STI571-resistant disease may be difficult, and efforts should be focused on preventing resistance from occurring. New strategies should aim to eliminate leukaemic cells as fast as possible. Combinations of ABL inhibitors, when available and if they have different contact sites, may be most useful when given together, much like modern antiretroviral therapy for HIV. Combinations of STI571 with other signal-transduction inhibitors acting on a critical downstream pathway, such as RAS or AKT, may be particularly useful as well. Finally, combinations of STI571 with techniques that are very effective at eliminating minimal residual disease, such as immunotherapy, should be evaluated. Wolf-K Hofmann and colleagues in this issue of The Lancet have taken a pharmacogenetic approach to understanding STI571 resistance. Microarray analysis on marrow cells from 19 patients with Ph+ALL was used to identify profiles associated with drug sensitivity versus primary resistance or rapid failure. A set of 95 genes, out of the 2500 evaluated, could be used to cluster sensitive and resistant cases. If validated on other patient sets, such algorithms might be used to select, or stratify, patients included in future clinical trials. Although such strategies are aiming at a moving target, Hoffman and colleagues’ report makes the powerful statement that gene profiling may well have the ability to predict the future for patients with cancer. This approach is a long way from practice, but the ability to predict who will do well and who will not will have a striking impact on cancer medicine. The panel of 95 genes identified here is likely to be refined over time as more patients are studied, more of the genome is queried, and STI571 is used in combination therapy rather than as a single agent. Also important will be the much harder task of understanding why every gene in the panel seems to have some relation to resistance. Overall, it is to be hoped that these studies give a glimpse of the future. Now that specific, targeted, therapies for leukaemias are available, learning how to use them to optimum advantage is the next step. I receive research funding from Novartis Pharma AG.
James D Griffin Leukemia Program, Dana-Farber Cancer Institute, Boston, MA 02115, USA (e-mail: [email protected])
THE LANCET • Vol 359 • February 9, 2002 • www.thelancet.com
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Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–42. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–37. Degos L, Wang ZY. All trans retinoic acid in acute promyelocytic leukemia. Oncogene 2001; 20: 7140–45. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–80. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289: 1938–42. Kreil S, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance in CML patients after STI571 (Glivec) therapy. Blood 2001; 98: 1823a (abstr). Weisberg E, Griffin JD. Mechanisms of resistance to imatinib (STI571) in preclinical models and in leukemia patients. Drug Resist Updat 2001; 4: 22–28.
Follow-up of children born after in-vitro fertilisation See page 461 The first baby born after in-vitro fertilisation (IVF) is now 23 years old. The first IVF baby to have a baby or father a baby could be expected in the near future. Yet follow-up studies of the health of children conceived by any of the IVF techniques have been few and logistically difficult. Epidemiological cohort and case-control studies are easy to criticise but difficult to undertake. To provide information useful in the counselling of infertile couples, researchers need persistence to follow up IVF children and their families. Bo Stromberg and colleagues report in this issue of The Lancet that children born in Sweden after IVF have three times the rate of cerebral palsy compared with children in the general population. This greater risk of cerebral palsy was found not only among children from IVF multiple pregnancies but also among singleton IVF infants born at term with normal birthweight. The latter finding is puzzling, but much remains in general to be understood about the pathophysiology of cerebral palsy. The prevalence of cerebral palsy is commonly cited as being 2·0–2·5 per 1000 livebirths.1 Although the prevalence for IVF children in this study (31/5680) exceeds this range, that for the controls is less than expected. If the high prevalence is a true result, then the question is whether the IVF process is deficient in some way for the development of the fetal motor system or that infertility itself is an independent factor. The results of this study are important. Few countries have the cross-discipline population registers to enable such a study to be undertaken. As with early reports suggesting increased rates of cancer among women treated by IVF,2 this report is easy to criticise but finding comparable and valid studies looking at the same or a similar question is more difficult. The high prevalence of cerebral palsy in the Stromberg data seems to be due to the high frequency of twin and higher multiple pregnancies. Senior figures in the US have recently pleaded for a reduction in twin and higher-order multiple pregnancies to minimise the shortterm and long-term damage to babies and mothers from multiple births resulting from the transfer of more than one embryo.3 No mention is made in the Stromberg paper of natural-cycle IVF compared with stimulated cycle IVF, gamete intrafallopian transfer, fresh or frozen embryo 459
For personal use. Only reproduce with permission from The Lancet Publishing Group.