Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Personalized Genomic Medicine and Prenatal Genetic Testing Siobhan M. Dolan, MD, MPH
Just 30 years ago, Merkatz et al1 reported an association between low maternal serum alpha-fetoprotein and trisomy 18, proving in principal that information about a fetus could be learned prenatally. Today, genetic testing directly on fetal Related article page 1210 cells can provide a complete karyotype, and use of chromosomal microarray analysis (CMA) can generate information regarding more than 80 syndromes caused by microdeletions and microduplications.2 Noninvasive prenatal testing on cell-free fetal DNA in maternal serum is also being integrated into prenatal care, providing, as early as the first trimester, highly sensitive screening for the common trisomies, sex chromosome aneuploidies, and syndromes such as velocardiofacial syndrome (22q11 deletion).3 Progress in prenatal genetic testing and the integration of complex genetic technologies into care has been rapid, challenging patients and clinicians attempting to keep abreast of the latest developments in genomic medicine. A variety of fundamental questions remain unanswered regarding newly available prenatal genetic tests. How are these advances being translated into clinical care? How will this example of personalized genomic medicine be integrated into routine prenatal care for the 4 million pregnant women who give birth in the United States each year? With so many options available, how can clinicians determine the optimal testing strategy for each woman to truly personalize the experience? What educational tools can assist patients as well as clinicians trying to navigate the complexities of these new tests? Although the technology for prenatal testing has developed rapidly, proven approaches for understanding each woman’s personal interest in the multitude of available prenatal tests, considering her values and preferences, are not well established. Numerous complex factors interact in decision making during prenatal care, challenging how each woman weighs the risks and benefits of screening and diagnostic testing prenatally. For example, how important is timing? What is the agerelated risk of aneuploidy? How troubling is the risk of miscarriage? Is there a family history that is relevant? What is the range of acceptable pregnancy outcomes? Identifying and addressing such questions can require extensive time and expertise beyond that available to many clinicians who provide prenatal care. In this issue of JAMA, Kuppermann and colleagues 4 present important results from a clinical trial evaluating the effect of an intervention designed to facilitate informed
decision making by pregnant women (with widely varying levels of health literacy and numeracy) confronted by the myriad genetic screening and testing options. The primary outcome measured was use of invasive prenatal genetic testing obtained via medical record review. The intervention consisted of an interactive computer-based decision-support guide that explained the testing options and facilitated values clarification regarding testing. Additionally, testing was free to women in the intervention group. Secondary outcomes included testing strategy undergone, knowledge, risk comprehension, decisional conflict, and decision regret measured at 24- to 36-weeks’ gestation. Compared with women in the usual care control group (n=353, women who received care according to standard practice in their centers and for whom the study did not pay out-of-pocket expenses for prenatal genetic testing), women in the intervention group (n=357) were less likely to undergo invasive testing (5.9% vs 12.3%) and were more likely to forgo genetic testing altogether (25.6% vs 20.4%). The finding that women with better understanding of the information about various prenatal testing options were less likely to undertake invasive prenatal testing is important, and it contradicts the notion that more information is always desired. It is possible that the nature of prenatal testing is different than other health care decisions, but the public may be increasingly aware that the numerous medical advances of the last decade have also created greater complexity in decision making. This finding also suggests that prenatal genetic testing decisions require a complex calculus that considers the timing of the testing, the certainty of the results, and the risks related to undergoing invasive genetic testing during pregnancy. The ideal prenatal test would have no associated risk of miscarriage and would provide diagnostic information about a large number of the most common conditions. Because such a test is not currently available, women must navigate a complicated series of screening and diagnostic tests that provide risk prediction in some cases and diagnostic information in others. New technologies in prenatal genomic testing, such as noninvasive prenatal testing and chromosomal microarray analysis, are increasing the possibility of obtaining more information, but this added information often comes with more uncertainty about its clinical relevance. More uncertainty adds additional complexity to the historical considerations around prenatal diagnosis.5 When faced with trade-offs and difficult decisions, clinical
jama.com
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
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Opinion Editorial
experience suggests that women and their partners respond along a spectrum regarding the amount of information desired and the risks they are willing to incur to obtain that information. Women who want to know the most they can about their pregnancy are often best served by undergoing invasive testing (chorionic villus sampling or amniocentesis) without antecedent screening because this provides them with the most certain information about the fetal karyotype. While undergoing an invasive procedure, some women agree to add CMA and welcome additional information about copy-number variants now available in the genomic era, whereas others decline when they learn about possible variants of uncertain significance.6 In a qualitative study, women reported that they initially perceived prenatal CMA testing as bonus information. However, after receiving CMA results indicating variants of uncertain significance without clear prognostic significance, women reported so much anxiety and concern about the health of the fetus for the duration of the pregnancy, that the results were ultimately experienced as unwanted “toxic knowledge.”7 CMA can also reveal incidental findings without clinical significance for the pregnancy, as in a report showing that the majority of findings on prenatal CMA in routine clinical practice were benign familial variants.6 CMA results have been most useful in the evaluation of a structural abnormality noted on ultrasound, 8 in which more information to explain the ultrasound finding was perceived as helpful. These observations all suggest that the context, timing, and certainty of genomic information influence the clinical utility for women. Women who adamantly decline invasive prenatal testing under any circumstance may do so because they are fearful of the actual procedure, have great concern about the risk of miscarriage, or feel that the results will not affect their decisions throughout the pregnancy. In the genomic era, a challenging scenario for these women is the presumption that noninvasive prenatal testing will offer them a way to avoid invasive prenatal testing, only to receive screening test results that show increased risk of aneuploidy, leading them right back to the difficult decision about invasive prenatal diagnostic testing. The majority of women are somewhere between wanting the most sophisticated testing and declining all testing. While seeking reassurance through prenatal testing, they acknowledge that difficult information may be revealed. Many admit not knowing exactly what decisions might be made based on receiving difficult information until they have it. For these women, providing information about testing options, with scenarios that illustrate the risks and benefits of each test as well as assisting with values clarification, is important before embarking on any particular testing strategy. For some women, the risk of intellectual disability in their child represents a major concern and an increasing number of testing panels are available that seek genetic causes of intellectual disability and might be appropriate for consideration. For other women, a trisomy associated with a structural anomaly, such as a serious cardiac 1204
defect, would influence their decision about a pregnancy or inform their plans for delivery. For some women, a familial condition such as albinism might not be a major concern because they have seen a family member live and thrive with the condition. Whereas for others, avoiding transmission of a BRCA mutation would be of paramount importance, especially if they have watched their mother or sister die of breast or ovarian cancer. Each of these scenarios raises important ethical questions. In prenatal genetic testing, there is no right answer, only the answer that is right for each woman. To date, models for fully informing women about prenatal testing options have been difficult to develop and time-consuming to administer. The challenge of providing personalized risk assessment is evident in the control group in the study by Kuppermann et al, 4 in which many clinicians relied on maternal age older than 35 years as a cutoff for offering additional testing, even though this recommendation is out of date.9 Although genetic counseling is ideal for advising women about the risks and benefits of various testing options, tools such as “Prenatal Testing: Exploring Your Options,” (a decision aid used in the study by Kuppermann et al, which can be updated by experts to reflect changes in practice) are needed to meet the needs of all pregnant women. This decision-support guide joins other electronic prenatal decision-support tools, including “The Pregnancy and Health Profile, 10 ” in demonstrating that use of an electronic decision-support tool can be feasible and effective in clinical care. Although these decision aids are lengthy, requiring approximately 45 to 60 minutes to complete, they can be used in the office setting and can assist clinicians in personalizing prenatal genomic medicine. Informed decision making for all pregnant women, with the help of electronic decision aids, is an obligation of the health care system. In the study by Kuppermann et al,4 financial barriers to genetic testing were minimized, but the real-world experience is often fraught with financial barriers.11 Costs of prenatal testing will be relevant for patients and clinicians, as well as insurers. Additional approaches are needed to evaluate ways to optimize choice of prenatal genetic testing while considering the costs related to testing and counseling. Further research is also needed to determine how to make these tools readily accessible to women of varying literacy and numeracy levels and also in ways that are culturally competent. Prenatal genetic testing in the era of personalized genomic medicine is not a “one size fits all” proposition and will continue to present challenges and require research on optimal translation to clinical practice. Pre- and posttest genetic counseling, as well as access to genetics professionals, are optimal methods for conveying the risks and benefits of various testing strategies. Learning more about women’s values and preferences and providing educational tools for women to use in their clinicians’ offices, are essential for widespread implementation. Only through such efforts can the promise of personalized genomic medicine be fully realized during the prenatal period.12
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
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Editorial Opinion
ARTICLE INFORMATION Author Affiliation: Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York. Corresponding Author: Siobhan M. Dolan, MD, MPH, Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine/ Montefiore Medical Center, Block 634, 1300 Morris Park Ave, Bronx, NY 10461 (siobhanmdolan@yahoo .com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol. 1984;148(7): 886-894. 2. American College of Obstetricians and Gynecologists. Committee opinion No. 581: the use
of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013;122:1374-1377. 3. American College of Obstetricians and Gynecologists. Committee opinion No. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534. 4. Kuppermann M, Pena S, Bishop JT, et al. Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.11479. 5. Rapp R. Testing Women, Testing the Fetus. New York, NY: Routledge; 1999. 6. Klugman S, Suskin B, Spencer BL, et al. Clinical utility of chromosomal microarray analysis in prenatal diagnosis: report of first 6 months in clinical practice. J Matern Fetal Neonatal Med. 2014; 27(13):1333-1338. 7. Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ. Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med. 2013;15(2): 139-145.
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8. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23): 2175-2184. 9. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109:217-227. 10. Edelman EA, Lin BK, Doksum T, et al. Implementation of an electronic genomic and family health history tool in primary prenatal care. Am J Med Genet C Semin Med Genet. 2014;166C(1): 34-44. 11. O'Brien BM, Kloza EM, Halliday JV, Lambert-Messerlian GM, Palomaki GE. Maternal plasma DNA testing: experience of women counseled at a prenatal diagnosis center [published online August 19, 2014]. Genet Test Mol Biomarkers. doi:10.1089/gtmb.2014.0125 12. Phimister EG, Feero WG, Guttmacher AE. Realizing genomic medicine. N Engl J Med. 2012; 366(8):757-759.
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
1205
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Personalized Genomic Medicine and Prenatal Genetic Testing Siobhan M. Dolan, MD, MPH
Just 30 years ago, Merkatz et al1 reported an association between low maternal serum alpha-fetoprotein and trisomy 18, proving in principal that information about a fetus could be learned prenatally. Today, genetic testing directly on fetal Related article page 1210 cells can provide a complete karyotype, and use of chromosomal microarray analysis (CMA) can generate information regarding more than 80 syndromes caused by microdeletions and microduplications.2 Noninvasive prenatal testing on cell-free fetal DNA in maternal serum is also being integrated into prenatal care, providing, as early as the first trimester, highly sensitive screening for the common trisomies, sex chromosome aneuploidies, and syndromes such as velocardiofacial syndrome (22q11 deletion).3 Progress in prenatal genetic testing and the integration of complex genetic technologies into care has been rapid, challenging patients and clinicians attempting to keep abreast of the latest developments in genomic medicine. A variety of fundamental questions remain unanswered regarding newly available prenatal genetic tests. How are these advances being translated into clinical care? How will this example of personalized genomic medicine be integrated into routine prenatal care for the 4 million pregnant women who give birth in the United States each year? With so many options available, how can clinicians determine the optimal testing strategy for each woman to truly personalize the experience? What educational tools can assist patients as well as clinicians trying to navigate the complexities of these new tests? Although the technology for prenatal testing has developed rapidly, proven approaches for understanding each woman’s personal interest in the multitude of available prenatal tests, considering her values and preferences, are not well established. Numerous complex factors interact in decision making during prenatal care, challenging how each woman weighs the risks and benefits of screening and diagnostic testing prenatally. For example, how important is timing? What is the agerelated risk of aneuploidy? How troubling is the risk of miscarriage? Is there a family history that is relevant? What is the range of acceptable pregnancy outcomes? Identifying and addressing such questions can require extensive time and expertise beyond that available to many clinicians who provide prenatal care. In this issue of JAMA, Kuppermann and colleagues 4 present important results from a clinical trial evaluating the effect of an intervention designed to facilitate informed
decision making by pregnant women (with widely varying levels of health literacy and numeracy) confronted by the myriad genetic screening and testing options. The primary outcome measured was use of invasive prenatal genetic testing obtained via medical record review. The intervention consisted of an interactive computer-based decision-support guide that explained the testing options and facilitated values clarification regarding testing. Additionally, testing was free to women in the intervention group. Secondary outcomes included testing strategy undergone, knowledge, risk comprehension, decisional conflict, and decision regret measured at 24- to 36-weeks’ gestation. Compared with women in the usual care control group (n=353, women who received care according to standard practice in their centers and for whom the study did not pay out-of-pocket expenses for prenatal genetic testing), women in the intervention group (n=357) were less likely to undergo invasive testing (5.9% vs 12.3%) and were more likely to forgo genetic testing altogether (25.6% vs 20.4%). The finding that women with better understanding of the information about various prenatal testing options were less likely to undertake invasive prenatal testing is important, and it contradicts the notion that more information is always desired. It is possible that the nature of prenatal testing is different than other health care decisions, but the public may be increasingly aware that the numerous medical advances of the last decade have also created greater complexity in decision making. This finding also suggests that prenatal genetic testing decisions require a complex calculus that considers the timing of the testing, the certainty of the results, and the risks related to undergoing invasive genetic testing during pregnancy. The ideal prenatal test would have no associated risk of miscarriage and would provide diagnostic information about a large number of the most common conditions. Because such a test is not currently available, women must navigate a complicated series of screening and diagnostic tests that provide risk prediction in some cases and diagnostic information in others. New technologies in prenatal genomic testing, such as noninvasive prenatal testing and chromosomal microarray analysis, are increasing the possibility of obtaining more information, but this added information often comes with more uncertainty about its clinical relevance. More uncertainty adds additional complexity to the historical considerations around prenatal diagnosis.5 When faced with trade-offs and difficult decisions, clinical
jama.com
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
1203
Opinion Editorial
experience suggests that women and their partners respond along a spectrum regarding the amount of information desired and the risks they are willing to incur to obtain that information. Women who want to know the most they can about their pregnancy are often best served by undergoing invasive testing (chorionic villus sampling or amniocentesis) without antecedent screening because this provides them with the most certain information about the fetal karyotype. While undergoing an invasive procedure, some women agree to add CMA and welcome additional information about copy-number variants now available in the genomic era, whereas others decline when they learn about possible variants of uncertain significance.6 In a qualitative study, women reported that they initially perceived prenatal CMA testing as bonus information. However, after receiving CMA results indicating variants of uncertain significance without clear prognostic significance, women reported so much anxiety and concern about the health of the fetus for the duration of the pregnancy, that the results were ultimately experienced as unwanted “toxic knowledge.”7 CMA can also reveal incidental findings without clinical significance for the pregnancy, as in a report showing that the majority of findings on prenatal CMA in routine clinical practice were benign familial variants.6 CMA results have been most useful in the evaluation of a structural abnormality noted on ultrasound, 8 in which more information to explain the ultrasound finding was perceived as helpful. These observations all suggest that the context, timing, and certainty of genomic information influence the clinical utility for women. Women who adamantly decline invasive prenatal testing under any circumstance may do so because they are fearful of the actual procedure, have great concern about the risk of miscarriage, or feel that the results will not affect their decisions throughout the pregnancy. In the genomic era, a challenging scenario for these women is the presumption that noninvasive prenatal testing will offer them a way to avoid invasive prenatal testing, only to receive screening test results that show increased risk of aneuploidy, leading them right back to the difficult decision about invasive prenatal diagnostic testing. The majority of women are somewhere between wanting the most sophisticated testing and declining all testing. While seeking reassurance through prenatal testing, they acknowledge that difficult information may be revealed. Many admit not knowing exactly what decisions might be made based on receiving difficult information until they have it. For these women, providing information about testing options, with scenarios that illustrate the risks and benefits of each test as well as assisting with values clarification, is important before embarking on any particular testing strategy. For some women, the risk of intellectual disability in their child represents a major concern and an increasing number of testing panels are available that seek genetic causes of intellectual disability and might be appropriate for consideration. For other women, a trisomy associated with a structural anomaly, such as a serious cardiac 1204
defect, would influence their decision about a pregnancy or inform their plans for delivery. For some women, a familial condition such as albinism might not be a major concern because they have seen a family member live and thrive with the condition. Whereas for others, avoiding transmission of a BRCA mutation would be of paramount importance, especially if they have watched their mother or sister die of breast or ovarian cancer. Each of these scenarios raises important ethical questions. In prenatal genetic testing, there is no right answer, only the answer that is right for each woman. To date, models for fully informing women about prenatal testing options have been difficult to develop and time-consuming to administer. The challenge of providing personalized risk assessment is evident in the control group in the study by Kuppermann et al, 4 in which many clinicians relied on maternal age older than 35 years as a cutoff for offering additional testing, even though this recommendation is out of date.9 Although genetic counseling is ideal for advising women about the risks and benefits of various testing options, tools such as “Prenatal Testing: Exploring Your Options,” (a decision aid used in the study by Kuppermann et al, which can be updated by experts to reflect changes in practice) are needed to meet the needs of all pregnant women. This decision-support guide joins other electronic prenatal decision-support tools, including “The Pregnancy and Health Profile, 10 ” in demonstrating that use of an electronic decision-support tool can be feasible and effective in clinical care. Although these decision aids are lengthy, requiring approximately 45 to 60 minutes to complete, they can be used in the office setting and can assist clinicians in personalizing prenatal genomic medicine. Informed decision making for all pregnant women, with the help of electronic decision aids, is an obligation of the health care system. In the study by Kuppermann et al,4 financial barriers to genetic testing were minimized, but the real-world experience is often fraught with financial barriers.11 Costs of prenatal testing will be relevant for patients and clinicians, as well as insurers. Additional approaches are needed to evaluate ways to optimize choice of prenatal genetic testing while considering the costs related to testing and counseling. Further research is also needed to determine how to make these tools readily accessible to women of varying literacy and numeracy levels and also in ways that are culturally competent. Prenatal genetic testing in the era of personalized genomic medicine is not a “one size fits all” proposition and will continue to present challenges and require research on optimal translation to clinical practice. Pre- and posttest genetic counseling, as well as access to genetics professionals, are optimal methods for conveying the risks and benefits of various testing strategies. Learning more about women’s values and preferences and providing educational tools for women to use in their clinicians’ offices, are essential for widespread implementation. Only through such efforts can the promise of personalized genomic medicine be fully realized during the prenatal period.12
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
jama.com
Editorial Opinion
ARTICLE INFORMATION Author Affiliation: Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York. Corresponding Author: Siobhan M. Dolan, MD, MPH, Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine/ Montefiore Medical Center, Block 634, 1300 Morris Park Ave, Bronx, NY 10461 (siobhanmdolan@yahoo .com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol. 1984;148(7): 886-894. 2. American College of Obstetricians and Gynecologists. Committee opinion No. 581: the use
of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013;122:1374-1377. 3. American College of Obstetricians and Gynecologists. Committee opinion No. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534. 4. Kuppermann M, Pena S, Bishop JT, et al. Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.11479. 5. Rapp R. Testing Women, Testing the Fetus. New York, NY: Routledge; 1999. 6. Klugman S, Suskin B, Spencer BL, et al. Clinical utility of chromosomal microarray analysis in prenatal diagnosis: report of first 6 months in clinical practice. J Matern Fetal Neonatal Med. 2014; 27(13):1333-1338. 7. Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ. Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med. 2013;15(2): 139-145.
jama.com
8. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23): 2175-2184. 9. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109:217-227. 10. Edelman EA, Lin BK, Doksum T, et al. Implementation of an electronic genomic and family health history tool in primary prenatal care. Am J Med Genet C Semin Med Genet. 2014;166C(1): 34-44. 11. O'Brien BM, Kloza EM, Halliday JV, Lambert-Messerlian GM, Palomaki GE. Maternal plasma DNA testing: experience of women counseled at a prenatal diagnosis center [published online August 19, 2014]. Genet Test Mol Biomarkers. doi:10.1089/gtmb.2014.0125 12. Phimister EG, Feero WG, Guttmacher AE. Realizing genomic medicine. N Engl J Med. 2012; 366(8):757-759.
JAMA September 24, 2014 Volume 312, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 06/10/2015
1205
