correspondence Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. Drs. Forlino and Vetro contributed equally to this letter, as did Drs. Stratakis and Zuffardi. This letter was published on February 26, 2014, at NEJM.org. 1. Beuschlein F, Fassnacht M, Assié G, et al. Constitutive acti-
vation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 2014;370:1019-28.
2. Almeida MQ, Stratakis CA. Carney complex and other condi-
tions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 2010;24:907-14. 3. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000;26: 89-92. DOI: 10.1056/NEJMc1309730
Genetic Diagnosis through Whole-Exome Sequencing To the Editor: Yang et al. (Oct. 17 issue)1 report the application of whole-exome sequencing in 250 patients with a potentially genetic disease, which resulted in a molecular diagnosis in 25% of them. A total of 30 patients had medically actionable incidental findings in a total of 16 genes; 18 of these patients had genotypes that the American College of Medical Genetics and Genomics has recommended be reported to the ordering physician.2 As noted in the editorial by Jacob,3 reporting these incidental findings is a gray area. We advocate a role for a team of specialized professionals to interpret such findings. For example, Yang et al. identified the PKP2 p.S140F mutation in 2 patients (0.8%), which is similar to findings in 26 of 6503 persons (0.4%; P = 0.28) in the GO Exome Sequencing Project (ESP5400) of the National Heart, Lung, and Blood Institute (http://evs.gs.washington.edu/EVS). This mutation has been reported as pathogenic (www .arvcdatabase.info),4 but we found no evidence in a large family with arrhythmogenic cardiomyopathy that it causes susceptibility to disease.5 Furthermore, the finding that 3 of 250 patients had a TTN nonsense or frameshift mutation is similar to findings in 2 of 249 controls,6 which brings into question whether these TTN mutations are truly medically actionable. These examples show the importance of consulting multidisciplinary experts, such as specialized cardiologists, molecular geneticists, and clinical geneticists. Paul A. van der Zwaag, M.D., Ph.D. Jan D.H. Jongbloed, Ph.D. J. Peter van Tintelen, M.D., Ph.D. University of Groningen Groningen, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported.
1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome se-
quencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502-11. 2. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. 3. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013;369:1557-8. 4. van der Zwaag PA, Jongbloed JD, van den Berg MP, et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat 2009;30:1278-83. 5. Groeneweg JA, van der Zwaag PA, Jongbloed JD, et al. Leftdominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype? Heart Rhythm 2013;10:548-59. 6. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366:619-28. DOI: 10.1056/NEJMc1315908
To the Editor: We are concerned that the pioneering approach by Yang et al. to clinical wholeexome sequencing, although demonstrably effective, does not permit families to obtain testing for a serious genetic disease without also undergoing testing for many unrelated genetic disorders and carrier status for certain autosomal recessive conditions. This approach denies families the right to refuse undesired genetic screening and denies children the right to decide for themselves whether to undergo genetic testing for conditions that do not occur before midlife.1 By initially filtering for variants reported in the Human Gene Mutation Database (www.biobase -international.com/product/hgmd), Yang et al. selected changes in thousands of genes unrelated to the phenotype for which the testing was performed, greatly increasing the number of variants shunted into their analytical filtering. There is an alternative approach that produces fewer adventitious findings: filter the large initial set of genomic variants according to allele frequency2 and the suspected pattern or patterns of inheritance with the use of parental and other family
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1067
The
n e w e ng l a n d j o u r na l
data,3 and leave annotation with HGMD and the functional and pathogenetic interpretation to the end of the process. Jan M. Friedman, M.D., Ph.D. Shelin Adam, M.Sc. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Burke W, Matheny Antommaria AH, Bennett R, et al. Rec-
ommendations for returning genomic incidental findings? We need to talk! Genet Med 2013;15:854-9. 2. Dorschner MO, Amendola LM, Turner EH, et al. Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 2013;93:631-40. 3. Adams DR, Sincan M, Fuentes Fajardo K, et al. Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat 2012;33:599-608. DOI: 10.1056/NEJMc1315908
To the Editor: In his editorial about clinical whole-exome sequencing, Jacob states, “One of the most encouraging findings of Yang et al. is that 126 of the 129 claims sent to insurance companies were paid.” I find it curious that he made this statement in the setting of concern for costeffectiveness and clinical relevance for these expensive tests. Without a clear relationship between the result of a test and its effect on patient treatment decisions, it is at best unclear whether an insurer should spend its limited resources on procedures with questionable effects on health outcomes. Health plans struggle with decisions related to coverage of the increasing number of genomic tests, many of which are bundled and are of unclear clinical importance. Covering the cost of a test without careful evaluation may not be the most prudent approach for a payer. J. Marc Rosen, M.D., M.P.H. Hawaii Medical Service Association Honolulu, HI [email protected] No potential conflict of interest relevant to this letter was reported.
of
m e dic i n e
pathogenic and that treatment or management that would affect medical care would be available for the related condition. We routinely consult with disease and gene experts when reporting variants that are challenging to interpret. The c.419C→T (p.S140F) mutation in PKP2 was identified in several reports as pathogenic in patients with arrhythmogenic right ventricular dysplasia and cardiomyopathy and in affected family members.2,3 This change was not detected in 950 controls (1900 chromosomes) and was not present in the database of single-nucleotide polymorphisms and the 1000 Genome Project database. It was reported in the ESP5400 database (in 11 of 2685 European persons), which includes patients with lung, heart, and blood disorders and thus should not be considered a normal population control. There is a need for periodic rereviewing of databases that contain information linking potentially medically actionable mutations to clinical outcomes. In response to Friedman and Adam: we designed our reporting process in tiers, with findings related to the phenotype and medically actionable incidental findings in tier 1 and findings unrelated to the phenotype in tier 2, which required a separate consent form in order to disclose results. We offer an opt-out for carrier-status reporting, but in our experience with 2000 patients, only 5% have opted out. Our filtering strategy is designed for a high level of sensitivity, which is vital in clinical testing, in which the return of a larger number of variants from the analytic pipeline to the molecular diagnostician for downstream analysis is preferable to a more stringent filter that may remove a potentially important finding. Christine M. Eng, M.D. Yaping Yang, Ph.D. Sharon E. Plon, M.D., Ph.D. Baylor College of Medicine Houston, TX [email protected] Since publication of their article, the authors report no further potential conflict of interest.
DOI: 10.1056/NEJMc1315908 1. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
The Authors Reply: We agree with van der Zwaag and colleagues that the reporting of medically actionable findings is challenging. The medical genetics community is in the early stages of developing guidelines.1 Our threshold for reporting medically actionable findings was that the variant would be either known or predicted to be 1068
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. 2. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36:1162-4. 3. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29:1670-80. DOI: 10.1056/NEJMc1315908
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
The Editorialist Replies: In response to Rosen: the clinical usefulness of exome sequencing has been shown for rare and undiagnosed disease, providing a tremendous increase in the rate of diagnosis, as compared with traditional approaches. A definite diagnosis, even without changes in clinical care, usually provides important information and comfort to the patient and family and ends the need to travel from provider to provider looking for a diagnosis. Genetic diagnosis by means of next-generation sequencing may also prove to be economical owing to the elimination of a diagnostic odyssey involving multiple gene tests, conducted serially and resulting in substantial delays. In my experience, genome sequencing has proved to be a relatively small cost, as compared with the financial and human cost of multiple unnecessary tests (some of which are inva-
sive), and it avoids having the patient undergo repeated tests by different providers. Illumina has recently announced1 its newest sequencing platform, which promises a whole-genome sequence for $1,000, a cost that is less than those of many single-gene tests. That said, formal tests of costeffectiveness have not, to my knowledge, been carried out. Howard J. Jacob, Ph.D. Medical College of Wisconsin Milwaukee, WI [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Illumina introduces the HiSeq X Ten Sequencing System.
Press release by Illumina, January 14, 2014 (http://investor .illumina.com/phoenix.zhtml?c=121127&p=irol-newsArticle&ID =1890696&highlight). DOI: 10.1056/NEJMc1315908
Fertility Treatments and Multiple Births in the United States To the Editor: Kulkarni et al. (Dec. 5 issue)1 state that increases in the rates of multiple pregnancy associated with fertility treatments are mostly due to aging of treated patients and clinical utilization of fertility-enhancing drugs aside from in vitro fertilization (IVF) treatments.1 In 2000, we pointed out that even under professional infertility care, such treatments resulted in rates of 20.0% for twin births and 8.8% for higherorder births (triplets or more), for a combined multiple-pregnancy rate of 28.8%.2 Among general obstetrician–gynecologists, who perform most non-IVF treatments, the rates of multiple births can be expected to be even higher. Thus, we have recommended a shift away from non-IVF treatments to IVF treatments, which allow better control by limiting transferred embryos.2 Paradoxically, for most patients with infertility, much of the insurance industry still mandates treatment with intrauterine insemination before IVF is approved. The medical profession and insurance providers would be well advised to focus on nonIVF treatments, which are a major source of medical complications and increased costs associated with infertility treatments in the United States, rather than focusing on reducing twin pregnancies in association with IVF.3-5
Norbert Gleicher, M.D. Vitaly A. Kushnir, M.D. David Barad, M.D. Center for Human Reproduction New York, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treat-
ments and multiple births in the United States. N Engl J Med 2013;369:2218-25. 2. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2-7. 3. Gleicher N, Barad DH. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril 2009; 91:2426-31. 4. Gleicher N. The irrational attraction of elective singleembryo transfer (eSET). Hum Reprod 2013;28:294-7. 5. Idem. For some IVF patients, twins are the best outcome. Contemp ObGyn 2013;58:40-46. DOI: 10.1056/NEJMc1400242
To the Editor: Using the method described by Kulkarni et al., we estimated the contribution of fertility treatments to multiple births for each maternal age group in 1998 and 2011 (Table 1). The percentage of multiple births attributable to medically assisted conception increased with maternal age. The largest relative changes were ob-
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1069
vation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 2014;370:1019-28.
2. Almeida MQ, Stratakis CA. Carney complex and other condi-
tions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 2010;24:907-14. 3. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000;26: 89-92. DOI: 10.1056/NEJMc1309730
Genetic Diagnosis through Whole-Exome Sequencing To the Editor: Yang et al. (Oct. 17 issue)1 report the application of whole-exome sequencing in 250 patients with a potentially genetic disease, which resulted in a molecular diagnosis in 25% of them. A total of 30 patients had medically actionable incidental findings in a total of 16 genes; 18 of these patients had genotypes that the American College of Medical Genetics and Genomics has recommended be reported to the ordering physician.2 As noted in the editorial by Jacob,3 reporting these incidental findings is a gray area. We advocate a role for a team of specialized professionals to interpret such findings. For example, Yang et al. identified the PKP2 p.S140F mutation in 2 patients (0.8%), which is similar to findings in 26 of 6503 persons (0.4%; P = 0.28) in the GO Exome Sequencing Project (ESP5400) of the National Heart, Lung, and Blood Institute (http://evs.gs.washington.edu/EVS). This mutation has been reported as pathogenic (www .arvcdatabase.info),4 but we found no evidence in a large family with arrhythmogenic cardiomyopathy that it causes susceptibility to disease.5 Furthermore, the finding that 3 of 250 patients had a TTN nonsense or frameshift mutation is similar to findings in 2 of 249 controls,6 which brings into question whether these TTN mutations are truly medically actionable. These examples show the importance of consulting multidisciplinary experts, such as specialized cardiologists, molecular geneticists, and clinical geneticists. Paul A. van der Zwaag, M.D., Ph.D. Jan D.H. Jongbloed, Ph.D. J. Peter van Tintelen, M.D., Ph.D. University of Groningen Groningen, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported.
1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome se-
quencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502-11. 2. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. 3. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013;369:1557-8. 4. van der Zwaag PA, Jongbloed JD, van den Berg MP, et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat 2009;30:1278-83. 5. Groeneweg JA, van der Zwaag PA, Jongbloed JD, et al. Leftdominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype? Heart Rhythm 2013;10:548-59. 6. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366:619-28. DOI: 10.1056/NEJMc1315908
To the Editor: We are concerned that the pioneering approach by Yang et al. to clinical wholeexome sequencing, although demonstrably effective, does not permit families to obtain testing for a serious genetic disease without also undergoing testing for many unrelated genetic disorders and carrier status for certain autosomal recessive conditions. This approach denies families the right to refuse undesired genetic screening and denies children the right to decide for themselves whether to undergo genetic testing for conditions that do not occur before midlife.1 By initially filtering for variants reported in the Human Gene Mutation Database (www.biobase -international.com/product/hgmd), Yang et al. selected changes in thousands of genes unrelated to the phenotype for which the testing was performed, greatly increasing the number of variants shunted into their analytical filtering. There is an alternative approach that produces fewer adventitious findings: filter the large initial set of genomic variants according to allele frequency2 and the suspected pattern or patterns of inheritance with the use of parental and other family
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1067
The
n e w e ng l a n d j o u r na l
data,3 and leave annotation with HGMD and the functional and pathogenetic interpretation to the end of the process. Jan M. Friedman, M.D., Ph.D. Shelin Adam, M.Sc. University of British Columbia Vancouver, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Burke W, Matheny Antommaria AH, Bennett R, et al. Rec-
ommendations for returning genomic incidental findings? We need to talk! Genet Med 2013;15:854-9. 2. Dorschner MO, Amendola LM, Turner EH, et al. Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 2013;93:631-40. 3. Adams DR, Sincan M, Fuentes Fajardo K, et al. Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat 2012;33:599-608. DOI: 10.1056/NEJMc1315908
To the Editor: In his editorial about clinical whole-exome sequencing, Jacob states, “One of the most encouraging findings of Yang et al. is that 126 of the 129 claims sent to insurance companies were paid.” I find it curious that he made this statement in the setting of concern for costeffectiveness and clinical relevance for these expensive tests. Without a clear relationship between the result of a test and its effect on patient treatment decisions, it is at best unclear whether an insurer should spend its limited resources on procedures with questionable effects on health outcomes. Health plans struggle with decisions related to coverage of the increasing number of genomic tests, many of which are bundled and are of unclear clinical importance. Covering the cost of a test without careful evaluation may not be the most prudent approach for a payer. J. Marc Rosen, M.D., M.P.H. Hawaii Medical Service Association Honolulu, HI [email protected] No potential conflict of interest relevant to this letter was reported.
of
m e dic i n e
pathogenic and that treatment or management that would affect medical care would be available for the related condition. We routinely consult with disease and gene experts when reporting variants that are challenging to interpret. The c.419C→T (p.S140F) mutation in PKP2 was identified in several reports as pathogenic in patients with arrhythmogenic right ventricular dysplasia and cardiomyopathy and in affected family members.2,3 This change was not detected in 950 controls (1900 chromosomes) and was not present in the database of single-nucleotide polymorphisms and the 1000 Genome Project database. It was reported in the ESP5400 database (in 11 of 2685 European persons), which includes patients with lung, heart, and blood disorders and thus should not be considered a normal population control. There is a need for periodic rereviewing of databases that contain information linking potentially medically actionable mutations to clinical outcomes. In response to Friedman and Adam: we designed our reporting process in tiers, with findings related to the phenotype and medically actionable incidental findings in tier 1 and findings unrelated to the phenotype in tier 2, which required a separate consent form in order to disclose results. We offer an opt-out for carrier-status reporting, but in our experience with 2000 patients, only 5% have opted out. Our filtering strategy is designed for a high level of sensitivity, which is vital in clinical testing, in which the return of a larger number of variants from the analytic pipeline to the molecular diagnostician for downstream analysis is preferable to a more stringent filter that may remove a potentially important finding. Christine M. Eng, M.D. Yaping Yang, Ph.D. Sharon E. Plon, M.D., Ph.D. Baylor College of Medicine Houston, TX [email protected] Since publication of their article, the authors report no further potential conflict of interest.
DOI: 10.1056/NEJMc1315908 1. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
The Authors Reply: We agree with van der Zwaag and colleagues that the reporting of medically actionable findings is challenging. The medical genetics community is in the early stages of developing guidelines.1 Our threshold for reporting medically actionable findings was that the variant would be either known or predicted to be 1068
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. 2. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36:1162-4. 3. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29:1670-80. DOI: 10.1056/NEJMc1315908
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
The Editorialist Replies: In response to Rosen: the clinical usefulness of exome sequencing has been shown for rare and undiagnosed disease, providing a tremendous increase in the rate of diagnosis, as compared with traditional approaches. A definite diagnosis, even without changes in clinical care, usually provides important information and comfort to the patient and family and ends the need to travel from provider to provider looking for a diagnosis. Genetic diagnosis by means of next-generation sequencing may also prove to be economical owing to the elimination of a diagnostic odyssey involving multiple gene tests, conducted serially and resulting in substantial delays. In my experience, genome sequencing has proved to be a relatively small cost, as compared with the financial and human cost of multiple unnecessary tests (some of which are inva-
sive), and it avoids having the patient undergo repeated tests by different providers. Illumina has recently announced1 its newest sequencing platform, which promises a whole-genome sequence for $1,000, a cost that is less than those of many single-gene tests. That said, formal tests of costeffectiveness have not, to my knowledge, been carried out. Howard J. Jacob, Ph.D. Medical College of Wisconsin Milwaukee, WI [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Illumina introduces the HiSeq X Ten Sequencing System.
Press release by Illumina, January 14, 2014 (http://investor .illumina.com/phoenix.zhtml?c=121127&p=irol-newsArticle&ID =1890696&highlight). DOI: 10.1056/NEJMc1315908
Fertility Treatments and Multiple Births in the United States To the Editor: Kulkarni et al. (Dec. 5 issue)1 state that increases in the rates of multiple pregnancy associated with fertility treatments are mostly due to aging of treated patients and clinical utilization of fertility-enhancing drugs aside from in vitro fertilization (IVF) treatments.1 In 2000, we pointed out that even under professional infertility care, such treatments resulted in rates of 20.0% for twin births and 8.8% for higherorder births (triplets or more), for a combined multiple-pregnancy rate of 28.8%.2 Among general obstetrician–gynecologists, who perform most non-IVF treatments, the rates of multiple births can be expected to be even higher. Thus, we have recommended a shift away from non-IVF treatments to IVF treatments, which allow better control by limiting transferred embryos.2 Paradoxically, for most patients with infertility, much of the insurance industry still mandates treatment with intrauterine insemination before IVF is approved. The medical profession and insurance providers would be well advised to focus on nonIVF treatments, which are a major source of medical complications and increased costs associated with infertility treatments in the United States, rather than focusing on reducing twin pregnancies in association with IVF.3-5
Norbert Gleicher, M.D. Vitaly A. Kushnir, M.D. David Barad, M.D. Center for Human Reproduction New York, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treat-
ments and multiple births in the United States. N Engl J Med 2013;369:2218-25. 2. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2-7. 3. Gleicher N, Barad DH. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril 2009; 91:2426-31. 4. Gleicher N. The irrational attraction of elective singleembryo transfer (eSET). Hum Reprod 2013;28:294-7. 5. Idem. For some IVF patients, twins are the best outcome. Contemp ObGyn 2013;58:40-46. DOI: 10.1056/NEJMc1400242
To the Editor: Using the method described by Kulkarni et al., we estimated the contribution of fertility treatments to multiple births for each maternal age group in 1998 and 2011 (Table 1). The percentage of multiple births attributable to medically assisted conception increased with maternal age. The largest relative changes were ob-
n engl j med 370;11 nejm.org march 13, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1069
