- Email: [email protected]
Positive predictive values and false-positive results in noninvasive prenatal screening
ajog.org risk cohort, in this case the women with ICP. In that population, we identified that delivery at 36 weeks’ gestation would minimize perinatal mortality. The other apparent concern was the potential negative impact of intervention. We would certainly agree that there are morbidity tradeoffs with delivery at 36 or 37 weeks’ gestation such as increased risk of respiratory immaturity.3 Such tradeoffs between morbidity and mortality would need to be considered. The other concern about intervention is the negative impact of induction of labor. While it is true that traditionally it was thought that induction of labor would increase the risk of cesarean delivery,4 there is increasing evidence to suggest that that may not be true.5 Even the HYPITAT trial that randomized a high-risk group, women with preeclampsia, to induction vs expectant management did not find a higher risk of cesarean delivery in those who were induced.6 Unfortunately, ICP has been understudied and because it is a relatively rare complication of pregnancy, we have less information to make informed decisions about management. That being said, a recent decision analysis also found that 36 weeks was the optimal gestational age for delivery.7 We appreciate the interest in our study and hope that it provides additional information to clinicians and patients alike who are trying to manage the diagnosis of ICP to minimize the negative fetal and neonatal impacts. -
Letters to the Editors University of California, San Diego San Diego, CA Jessica Page, MD Obstetrics and Gynecology University of Utah Salt Lake City, UT The authors report no conflict of interest.
REFERENCES
Aaron B. Caughey, MD, PhD Obstetrics and Gynecology Oregon Health and Science University Portland, OR [email protected]
1. Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol 2015;212:667.e1-5. 2. Page JM, Snowden JM, Cheng YW, Doss A, Rosenstein MG, Caughey AB. The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age. Am J Obstet Gynecol 2013;209:375.e1-7. 3. Cheng YW, Kaimal AJ, Bruckner TA, Halloran DR, Caughey AB. Perinatal morbidity associated with late preterm deliveries compared with deliveries between 37 and 40 weeks of gestation. BJOG 2011;118: 1446-54. 4. Caughey AB, Nicholson JM, Cheng YW, Lyell DJ, Washington AE. Induction of labor and cesarean delivery by gestational age. Am J Obstet Gynecol 2006;195:700-5. 5. Darney BG, Snowden JM, Cheng YW, et al. Elective induction of labor at term compared to expectant management: maternal and neonatal outcomes. Obstet Gynecol 2013;122:761-9. 6. Koopmans CM, Bijlenga D, Groen H, Vijgen SM, Aarnoudse JG, Bekedam DJ; HYPITAT Study Group. Induction of labor versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet 2009;374:979-88. 7. Lo JO, Shaffer BL, Allen A, Little SE, Cheng YW, Caughey AB. Intrahepatic cholestasis of pregnancy: what is the optimal gestational age for delivery? J Matern Fetal Neonatal Med. ePub. 2014.
Anela Puljic, MD Obstetrics and Gynecology
ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2015. 06.004
Positive predictive values and false-positive results in noninvasive prenatal screening TO THE EDITORS: We read with interest the article by Meck et al1 and were pleased to see an emphasis on the importance of positive predictive value (PPV). PPVs are more valuable to clinicians than detection rates. When the detection rate is close to 100% (as in the case for trisomy 21), it may provide a misleading view on noninvasive prenatal testing (NIPT) and suggest that it is actually a diagnostic test. However, several of the key findings presented in this study had been reported previously, but not referenced. High PPV for trisomy 21 and lower PPVs for trisomies 13 and monosomy X were reported by Dar et al.2 Likewise, the finding that twins can lead to false-positive calls has been discussed previously by Curnow et al.3 Although the inability to determine additional haplotypes might lead to an increase in false-positive calls with quantitative NIPT
methods, this limitation is eliminated when the SNP-based method is used. Meck et al1 assume that the use of chorionic villus sampling (CVS) is sufficiently accurate for the confirmation of NIPT results. We advise caution when CVS is used after NIPT. The diagnostic accuracy of CVS was established mostly on the basis of studies of women of advanced maternal age who were at risk for nonmosaic aneuploidy arising from meiotic nondisjunction.4 NIPT identifies women with aneuploid cells in the placenta that have arisen from both meiotic error and mitotic error. Mitotic errors often result in mosaicism. Therefore, placental mosaicism may be much more common in women with positive NIPT results. The presence of confined placental mosaicism accounted for at least 3.6% of high-risk calls in the study by Dar et al.2 In
OCTOBER 2015 American Journal of Obstetrics & Gynecology
595
ajog.org
Letters to the Editors 2 cases for which CVS appeared to confirm a high-risk call, further follow-up evaluation revealed that the fetus was actually normal. Others have reported similar findings. Therefore, we believe that, at this time, an abnormal CVS result should not be considered fully diagnostic. NIPTpositive, CVS-positive cases need confirmation through amniocentesis or ultrasound scans to prevent termination of a normal pregnancy. Pe’er Dar, MD Division of Fetal Medicine Department of Obstetrics and Gynecology and Women’s Health Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY Susan J. Gross, MD Natera Inc San Carlos, CA Peter Benn, DSc Division of Human Genetics Department of Genetics and Genome Sciences University of Connecticut Health Center Farmington, CT [email protected] S.J.G. is an employee of Natera and holds stock or options to hold stock in the company. P.B. is a paid consultant for Natera. P.D. receives research institutional funding from Natera.
REFERENCES 1. Meck JM, Kramer Dugan E, Matyakhina L, et al. Non-invasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. Am J Obstet Gynecol 2015;213:214.e1-5. 2. Dar P, Curnow KJ, Gross SJ, et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1-7. 3. Curnow KJ, Wilkins-Haug L, Ryan A, et al. Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphismbased noninvasive prenatal test. Am J Obstet Gynecol 2015;212:79.e1-9. 4. Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chorionic villus sampling (CVS): diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992. Prenat Diagn 1997;17:801-20. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.06.006
REPLY We wish to thank Dar et al for their comments, especially regarding the need for caution when using chorionic villus sampling (CVS) as follow up to abnormal noninvasive prenatal screening (NIPS). We agree that amniocentesis is, indeed, the better option than CVS for follow-up evaluation to NIPS. Because the “fetal” component of the cell-free DNA that is used in NIPS is actually trophoblast in origin like chorionic villi, aneuploidy suspected by that screening method is best confirmed by cytogenetic studies on amniotic fluid cells because chorionic villi may simply be mirroring the NIPS “false positives.” Confined placental mosaicism of the types that can result in a false-positive CVS cytogenetic result occurs in approximately 0.8% of pregnancies (309/52,673 pregnancies); a fraction of those would have a sufficiently high percentage of mosaicism to result in a positive NIPS result.1 In spite of the shortcoming of CVS as a method of determining the accuracy of NIPS, part of the intent of our article was to focus on the performance of NIPS from the viewpoint of a cytogenetics laboratory. In our experience, 32% of our NIPS follow-up diagnostic samples were CVS. This suggests that many patients who have early NIPS may not want to wait until 15 weeks gestation for clarification of a positive NIPS result by amniocentesis. Jeanne M. Meck, PhD GeneDx Gaithersburg, MD [email protected] Athena M. Cherry, PhD Stanford University School of Medicine Palo Alto, CA J.M.M. is a paid employee of GeneDx; A.M.C. is a paid employee of an academic institution (Stanford University School of Medicine) that performs prenatal cytogenetic testing.
REFERENCE 1. Grati FR, Malvestiti F, Ferreira JCPB, et al. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 2014;16:620-4. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.06.007
Prenatal aneuploidy screening using cell free DNA TO THE EDITORS: We read with interest the document, “Prenatal aneuploidy screening using cell free DNA.”1 Whereas we support the aim of appropriate counseling on prenatal aneuploidy testing,2 we were surprised by the overall critical approach to the description of cell-free (cf) DNA technology. We applaud a critical comparison of cfDNA vs other available tests. However, the publication is presented to highlight limitations of cfDNA testing while downplaying its scientifically proven benefits. 596 American Journal of Obstetrics & Gynecology OCTOBER 2015
While discussing the accuracy of cfDNA aneuploidy screening, the statement neglects to mention the superior performance of this test. It describes a positive predictive value of cfDNA testing ranging from 45% to 96% and suggests this to be low, whereas with current screening, the positive predictive value is 5%. The document also lists the limitations of cfDNA testing in detail but ignores its clinical value, which has already been robustly shown in published literature. With cfDNA testing,
Letters to the Editors University of California, San Diego San Diego, CA Jessica Page, MD Obstetrics and Gynecology University of Utah Salt Lake City, UT The authors report no conflict of interest.
REFERENCES
Aaron B. Caughey, MD, PhD Obstetrics and Gynecology Oregon Health and Science University Portland, OR [email protected]
1. Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol 2015;212:667.e1-5. 2. Page JM, Snowden JM, Cheng YW, Doss A, Rosenstein MG, Caughey AB. The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age. Am J Obstet Gynecol 2013;209:375.e1-7. 3. Cheng YW, Kaimal AJ, Bruckner TA, Halloran DR, Caughey AB. Perinatal morbidity associated with late preterm deliveries compared with deliveries between 37 and 40 weeks of gestation. BJOG 2011;118: 1446-54. 4. Caughey AB, Nicholson JM, Cheng YW, Lyell DJ, Washington AE. Induction of labor and cesarean delivery by gestational age. Am J Obstet Gynecol 2006;195:700-5. 5. Darney BG, Snowden JM, Cheng YW, et al. Elective induction of labor at term compared to expectant management: maternal and neonatal outcomes. Obstet Gynecol 2013;122:761-9. 6. Koopmans CM, Bijlenga D, Groen H, Vijgen SM, Aarnoudse JG, Bekedam DJ; HYPITAT Study Group. Induction of labor versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet 2009;374:979-88. 7. Lo JO, Shaffer BL, Allen A, Little SE, Cheng YW, Caughey AB. Intrahepatic cholestasis of pregnancy: what is the optimal gestational age for delivery? J Matern Fetal Neonatal Med. ePub. 2014.
Anela Puljic, MD Obstetrics and Gynecology
ª 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2015. 06.004
Positive predictive values and false-positive results in noninvasive prenatal screening TO THE EDITORS: We read with interest the article by Meck et al1 and were pleased to see an emphasis on the importance of positive predictive value (PPV). PPVs are more valuable to clinicians than detection rates. When the detection rate is close to 100% (as in the case for trisomy 21), it may provide a misleading view on noninvasive prenatal testing (NIPT) and suggest that it is actually a diagnostic test. However, several of the key findings presented in this study had been reported previously, but not referenced. High PPV for trisomy 21 and lower PPVs for trisomies 13 and monosomy X were reported by Dar et al.2 Likewise, the finding that twins can lead to false-positive calls has been discussed previously by Curnow et al.3 Although the inability to determine additional haplotypes might lead to an increase in false-positive calls with quantitative NIPT
methods, this limitation is eliminated when the SNP-based method is used. Meck et al1 assume that the use of chorionic villus sampling (CVS) is sufficiently accurate for the confirmation of NIPT results. We advise caution when CVS is used after NIPT. The diagnostic accuracy of CVS was established mostly on the basis of studies of women of advanced maternal age who were at risk for nonmosaic aneuploidy arising from meiotic nondisjunction.4 NIPT identifies women with aneuploid cells in the placenta that have arisen from both meiotic error and mitotic error. Mitotic errors often result in mosaicism. Therefore, placental mosaicism may be much more common in women with positive NIPT results. The presence of confined placental mosaicism accounted for at least 3.6% of high-risk calls in the study by Dar et al.2 In
OCTOBER 2015 American Journal of Obstetrics & Gynecology
595
ajog.org
Letters to the Editors 2 cases for which CVS appeared to confirm a high-risk call, further follow-up evaluation revealed that the fetus was actually normal. Others have reported similar findings. Therefore, we believe that, at this time, an abnormal CVS result should not be considered fully diagnostic. NIPTpositive, CVS-positive cases need confirmation through amniocentesis or ultrasound scans to prevent termination of a normal pregnancy. Pe’er Dar, MD Division of Fetal Medicine Department of Obstetrics and Gynecology and Women’s Health Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY Susan J. Gross, MD Natera Inc San Carlos, CA Peter Benn, DSc Division of Human Genetics Department of Genetics and Genome Sciences University of Connecticut Health Center Farmington, CT [email protected] S.J.G. is an employee of Natera and holds stock or options to hold stock in the company. P.B. is a paid consultant for Natera. P.D. receives research institutional funding from Natera.
REFERENCES 1. Meck JM, Kramer Dugan E, Matyakhina L, et al. Non-invasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. Am J Obstet Gynecol 2015;213:214.e1-5. 2. Dar P, Curnow KJ, Gross SJ, et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014;211:527.e1-7. 3. Curnow KJ, Wilkins-Haug L, Ryan A, et al. Detection of triploid, molar, and vanishing twin pregnancies by a single-nucleotide polymorphismbased noninvasive prenatal test. Am J Obstet Gynecol 2015;212:79.e1-9. 4. Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chorionic villus sampling (CVS): diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992. Prenat Diagn 1997;17:801-20. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.06.006
REPLY We wish to thank Dar et al for their comments, especially regarding the need for caution when using chorionic villus sampling (CVS) as follow up to abnormal noninvasive prenatal screening (NIPS). We agree that amniocentesis is, indeed, the better option than CVS for follow-up evaluation to NIPS. Because the “fetal” component of the cell-free DNA that is used in NIPS is actually trophoblast in origin like chorionic villi, aneuploidy suspected by that screening method is best confirmed by cytogenetic studies on amniotic fluid cells because chorionic villi may simply be mirroring the NIPS “false positives.” Confined placental mosaicism of the types that can result in a false-positive CVS cytogenetic result occurs in approximately 0.8% of pregnancies (309/52,673 pregnancies); a fraction of those would have a sufficiently high percentage of mosaicism to result in a positive NIPS result.1 In spite of the shortcoming of CVS as a method of determining the accuracy of NIPS, part of the intent of our article was to focus on the performance of NIPS from the viewpoint of a cytogenetics laboratory. In our experience, 32% of our NIPS follow-up diagnostic samples were CVS. This suggests that many patients who have early NIPS may not want to wait until 15 weeks gestation for clarification of a positive NIPS result by amniocentesis. Jeanne M. Meck, PhD GeneDx Gaithersburg, MD [email protected] Athena M. Cherry, PhD Stanford University School of Medicine Palo Alto, CA J.M.M. is a paid employee of GeneDx; A.M.C. is a paid employee of an academic institution (Stanford University School of Medicine) that performs prenatal cytogenetic testing.
REFERENCE 1. Grati FR, Malvestiti F, Ferreira JCPB, et al. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 2014;16:620-4. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.06.007
Prenatal aneuploidy screening using cell free DNA TO THE EDITORS: We read with interest the document, “Prenatal aneuploidy screening using cell free DNA.”1 Whereas we support the aim of appropriate counseling on prenatal aneuploidy testing,2 we were surprised by the overall critical approach to the description of cell-free (cf) DNA technology. We applaud a critical comparison of cfDNA vs other available tests. However, the publication is presented to highlight limitations of cfDNA testing while downplaying its scientifically proven benefits. 596 American Journal of Obstetrics & Gynecology OCTOBER 2015
While discussing the accuracy of cfDNA aneuploidy screening, the statement neglects to mention the superior performance of this test. It describes a positive predictive value of cfDNA testing ranging from 45% to 96% and suggests this to be low, whereas with current screening, the positive predictive value is 5%. The document also lists the limitations of cfDNA testing in detail but ignores its clinical value, which has already been robustly shown in published literature. With cfDNA testing,