ajog.org We acknowledge the fact that late preterm delivery has its downsides and have stated in the Comment section that “the possible iatrogenic consequences of late preterm induced labor must be balanced against the probability of the prevention of intrauterine deaths.” In fact, our center actively participated in several multicenter randomized controlled trials within the Dutch Consortium, resulting in a conservative approach between 34 and 37 weeks of gestation in women with preterm premature rupture of membranes2 and in women with hypertensive disorders,3 preventing unnecessary iatrogenic late preterm births. However, in the absence of methods for fetal monitoring in ICP and given its devastating consequences, we propose earlier intervention in a small subset of cases with BA of 100 mmol/L or greater, in line with a recent presentation at the Society for Maternal-Fetal Medicine meeting in San Diego, CA.4 The statement of Rezai et al that spontaneous preterm birth occurred most frequently in the mild ICP group is not correct. We refer to Table 2, in which the spontaneous preterm birth rate is presented in the lower section under the heading, Adverse neonatal outcome, being 2.8% (3 of 108), 3.5% (3 of 86), and 19% (4 of 21) in the mild, moderate, and severe ICP groups, respectively. In the regression analysis, the highest BA levels were associated with spontaneous preterm birth. We hope we have clarified the comments raised by Rezai et al. -
Letters to the Editors Martijn A. Oudijk, MD, PhD Maria P. H. Koster, MD, PhD Department of Obstetrics University Medical Center Utrecht KE 04.123.1 PO Box 85090 Lundlaan 6 Utrecht 3508 AB, The Netherlands [email protected] The authors report no conflict of interest.
REFERENCES 1. Brouwers L, Koster MPH, Page-Christiaens GCML, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol 2015;212:100.e1-7. 2. van der Ham DP, Vijgen SM, Nijhuis JG, et al. Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial. PloS Med 2012;9:e1001208. 3. Broekuijsen, et al. Delivery versus expectant monitoring for late preterm hypertensive disorders of pregnancy (HYPITAT-II): a multicenter, open label, randomized controlled trial. Am J Obstet Gynecol 210(Suppl, Abstract 2). 4. Puljic 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 212(Suppl, Abstract 77). ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.03.041
Getting to safer and smarter medication use during pregnancy TO THE EDITORS: We commend the authors reporting on the Centers for Disease Control and Preventionesponsored meeting to develop a priority setting, evidence review, and consensus recommendation structure to advance safer medication use during pregnancy.1 However, several key issues received either scant or no mention in their report. The Food and Drug Administration (FDA) classification of drug use in gestation (categories A-D and X) was criticized as a system with which “oversimplification might result in incorrect conclusions.” Indeed, the FDA (itself represented at the meeting) recognized the need for a better approach and proposed major rule changes that would favor more nuanced and informative labeling in 2008. Unfortunately, despite being labeled an “agency priority” to be written and cleared “as efficiently as possible,” no published updates leading to a final rule have appeared since 2011.2 Is a conclusion anywhere in sight? Further, while systematic reviews are often helpful, a larger concern is that information will be occasionally limited and frequently incomplete. This seems an understatement regarding the still shameful lack of well-designed and adequately powered studies that focus on optimal prescribing, maternal efficacy, and fetal safety of drugs in pregnancy, which is a void that has been recognized for decades.3 A more explicit plea by the
authors for this needed research would have been welcome. Finally, although represented at the meeting, there was no mention of the National Institute of Child Health and Developmentesupported Obstetric-Fetal Pharmacology Research Units network, whose limited, but much needed, work focuses not on teratogenesis but more broadly on rational pharmacotherapy across the span of pregnancy, which includes safety, efficacy, dosing, and the risks of undertreated maternal disease.4 Again, our congratulations to the authors; we all look towards needed progress in this area. Jason G. Umans, MD, PhD Departments of Medicine and of Obstetrics and Gynecology Georgetown University Washington, DC Marshall D. Lindheimer, MD Departments of Medicine and of Obstetrics and Gynecology University of Chicago Chicago, IL The authors report no conflict of interest.
REFERENCES 1. Broussard CS, Frey MT, Hernandez-Dias S, et al. Developing a systematic approach to safer medication use during pregnancy: summary of
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Letters to the Editors a Centers for Disease Control and Prevention-convened meeting. Am J Obstet Gynecol 2014;211:208-14. 2. US Food and Drug Administration. Pregnancy and lactation labeling final rule. Available at: www.fda.gov/Drugs/DevelopmentApproval Process/DevelopmentResources/Labeling/ucm093307.htm; last updated 2/11/2011. Accessed Oct.12, 2014. 3. Barron WM, Lindheimer MD. Introduction. In: Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy, 3rd ed. St. Louis: Mosby; 2000:xi-xiii. 4. Obstetric-Fetal Pharmacology Research Units Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development Mission statement. Available at: www.nichd.nih.gov/research/supported/ Pages/opru_network.aspx. Accessed Oct. 12, 2014. NOTE ADDED IN PROOF: Approximately 8 1/2 weeks after submission of this letter, the FDA withdrew its decades old A-D,X drug labeling policy, by adopting the long awaited final rule, entitled, “Content and Format of labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling,” available online at https://s3. amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.12.035
REPLY We thank Drs Umans and Lindheimer for their interest in our meeting summary1 and welcome the opportunity to respond to their concerns. We agree with the authors about the need for more data to inform various aspects of medication treatment during pregnancy; this was evident to all the subject matter experts who attended the Centers for Disease Control and Prevention (CDC) meeting and is likely appreciated by the Journal’s readership. The agencies represented at the meeting have continued their efforts to address the current data gap. In an attempt to raise greater awareness among policy makers and the general public about safer medication use in pregnancy as a pressing public health issue, the CDC posted an infographic on the Treating for Two website, available at http://www.cdc.gov/ pregnancy/meds/treatingfortwo/infographic.html. While this infographic focuses on the lack of medication safety data, the CDC continues with its commitment to conduct research on the safety of medications in pregnant women. In addition, as mentioned by the authors, our National Institute of Child Health and Human Development colleagues have documented the parallel alarming dearth of pharmacokinetic/ pharmacodynamic data during pregnancy and continue to do important work in this area.2 The Food and Drug Administration (FDA) continues its efforts to consider ways to collect safety data on pregnant women, as was demonstrated by the May 2014 public meeting held at the FDA, “Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products during Pregnancy in the Post-Approval Setting.”3
116 American Journal of Obstetrics & Gynecology JULY 2015
Draft guidance on the scientific and ethical considerations for the inclusion of pregnant women in clinical trials is also being developed by the FDA. In regards to the final rule on pregnancy and lactation labeling, the rule-making process is complex and includes several layers of review. We are happy to note that the rule published on Dec. 4, 2014, and will be fully in effect on June 30, 2015 (http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DevelopmentResources/Labeling/ ucm093307.htm). Health care providers and regulators have to make decisions now with whatever data and guidance are currently available. Although further research on both safety and efficacy of medication use in pregnancy obviously is needed, the intent of the expert meeting and resulting summary publication was to focus on how to move forward collaboratively and use the decades of research that have accumulated thus far to provide better information to improve decision-making. We must continue to gather data and develop evidence-based guidance for better informed decisions, ultimately leading to healthier pregnancies and healthier babies. Cheryl S. Broussard, PhD Division of Birth Defects and Developmental Disabilities National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, GA Leyla Sahin, MD, FACOG Melissa S. Tassinari, PhD, DABT Division of Pediatric and Maternal Health, Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration Silver Spring, MD The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention or the Food and Drug Administration.
The authors report no conflict of interest.
REFERENCES 1. Broussard CS, Frey MT, Hernandez-Diaz S, et al. Developing a systematic approach to safer medication use during pregnancy: summary of a Centers for Disease Control and Prevention-convened meeting. Am J Obstet Gynecol 2014;211:208-14. 2. Parisi MA, Spong CY, Zajicek A, Guttmacher AE. We don’t know what we don’t study: the case for research on medication effects in pregnancy. Am J Med Genet Part C Semin Med Genet 2011;157:247-50. 3. Food and Drug Administration. Study approaches and methods to evaluate the safety of drugs and biological products during pregnancy in the post-approval setting; public meeting. Available at: http://www.fda. gov/drugs/newsevents/ucm386560.htm. Accessed Nov. 14, 2014. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2014.12.036
Letters to the Editors Martijn A. Oudijk, MD, PhD Maria P. H. Koster, MD, PhD Department of Obstetrics University Medical Center Utrecht KE 04.123.1 PO Box 85090 Lundlaan 6 Utrecht 3508 AB, The Netherlands [email protected] The authors report no conflict of interest.
REFERENCES 1. Brouwers L, Koster MPH, Page-Christiaens GCML, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol 2015;212:100.e1-7. 2. van der Ham DP, Vijgen SM, Nijhuis JG, et al. Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial. PloS Med 2012;9:e1001208. 3. Broekuijsen, et al. Delivery versus expectant monitoring for late preterm hypertensive disorders of pregnancy (HYPITAT-II): a multicenter, open label, randomized controlled trial. Am J Obstet Gynecol 210(Suppl, Abstract 2). 4. Puljic 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 212(Suppl, Abstract 77). ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2015.03.041
Getting to safer and smarter medication use during pregnancy TO THE EDITORS: We commend the authors reporting on the Centers for Disease Control and Preventionesponsored meeting to develop a priority setting, evidence review, and consensus recommendation structure to advance safer medication use during pregnancy.1 However, several key issues received either scant or no mention in their report. The Food and Drug Administration (FDA) classification of drug use in gestation (categories A-D and X) was criticized as a system with which “oversimplification might result in incorrect conclusions.” Indeed, the FDA (itself represented at the meeting) recognized the need for a better approach and proposed major rule changes that would favor more nuanced and informative labeling in 2008. Unfortunately, despite being labeled an “agency priority” to be written and cleared “as efficiently as possible,” no published updates leading to a final rule have appeared since 2011.2 Is a conclusion anywhere in sight? Further, while systematic reviews are often helpful, a larger concern is that information will be occasionally limited and frequently incomplete. This seems an understatement regarding the still shameful lack of well-designed and adequately powered studies that focus on optimal prescribing, maternal efficacy, and fetal safety of drugs in pregnancy, which is a void that has been recognized for decades.3 A more explicit plea by the
authors for this needed research would have been welcome. Finally, although represented at the meeting, there was no mention of the National Institute of Child Health and Developmentesupported Obstetric-Fetal Pharmacology Research Units network, whose limited, but much needed, work focuses not on teratogenesis but more broadly on rational pharmacotherapy across the span of pregnancy, which includes safety, efficacy, dosing, and the risks of undertreated maternal disease.4 Again, our congratulations to the authors; we all look towards needed progress in this area. Jason G. Umans, MD, PhD Departments of Medicine and of Obstetrics and Gynecology Georgetown University Washington, DC Marshall D. Lindheimer, MD Departments of Medicine and of Obstetrics and Gynecology University of Chicago Chicago, IL The authors report no conflict of interest.
REFERENCES 1. Broussard CS, Frey MT, Hernandez-Dias S, et al. Developing a systematic approach to safer medication use during pregnancy: summary of
JULY 2015 American Journal of Obstetrics & Gynecology
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Letters to the Editors a Centers for Disease Control and Prevention-convened meeting. Am J Obstet Gynecol 2014;211:208-14. 2. US Food and Drug Administration. Pregnancy and lactation labeling final rule. Available at: www.fda.gov/Drugs/DevelopmentApproval Process/DevelopmentResources/Labeling/ucm093307.htm; last updated 2/11/2011. Accessed Oct.12, 2014. 3. Barron WM, Lindheimer MD. Introduction. In: Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy, 3rd ed. St. Louis: Mosby; 2000:xi-xiii. 4. Obstetric-Fetal Pharmacology Research Units Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development Mission statement. Available at: www.nichd.nih.gov/research/supported/ Pages/opru_network.aspx. Accessed Oct. 12, 2014. NOTE ADDED IN PROOF: Approximately 8 1/2 weeks after submission of this letter, the FDA withdrew its decades old A-D,X drug labeling policy, by adopting the long awaited final rule, entitled, “Content and Format of labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling,” available online at https://s3. amazonaws.com/public-inspection.federalregister.gov/2014-28241.pdf. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.12.035
REPLY We thank Drs Umans and Lindheimer for their interest in our meeting summary1 and welcome the opportunity to respond to their concerns. We agree with the authors about the need for more data to inform various aspects of medication treatment during pregnancy; this was evident to all the subject matter experts who attended the Centers for Disease Control and Prevention (CDC) meeting and is likely appreciated by the Journal’s readership. The agencies represented at the meeting have continued their efforts to address the current data gap. In an attempt to raise greater awareness among policy makers and the general public about safer medication use in pregnancy as a pressing public health issue, the CDC posted an infographic on the Treating for Two website, available at http://www.cdc.gov/ pregnancy/meds/treatingfortwo/infographic.html. While this infographic focuses on the lack of medication safety data, the CDC continues with its commitment to conduct research on the safety of medications in pregnant women. In addition, as mentioned by the authors, our National Institute of Child Health and Human Development colleagues have documented the parallel alarming dearth of pharmacokinetic/ pharmacodynamic data during pregnancy and continue to do important work in this area.2 The Food and Drug Administration (FDA) continues its efforts to consider ways to collect safety data on pregnant women, as was demonstrated by the May 2014 public meeting held at the FDA, “Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products during Pregnancy in the Post-Approval Setting.”3
116 American Journal of Obstetrics & Gynecology JULY 2015
Draft guidance on the scientific and ethical considerations for the inclusion of pregnant women in clinical trials is also being developed by the FDA. In regards to the final rule on pregnancy and lactation labeling, the rule-making process is complex and includes several layers of review. We are happy to note that the rule published on Dec. 4, 2014, and will be fully in effect on June 30, 2015 (http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DevelopmentResources/Labeling/ ucm093307.htm). Health care providers and regulators have to make decisions now with whatever data and guidance are currently available. Although further research on both safety and efficacy of medication use in pregnancy obviously is needed, the intent of the expert meeting and resulting summary publication was to focus on how to move forward collaboratively and use the decades of research that have accumulated thus far to provide better information to improve decision-making. We must continue to gather data and develop evidence-based guidance for better informed decisions, ultimately leading to healthier pregnancies and healthier babies. Cheryl S. Broussard, PhD Division of Birth Defects and Developmental Disabilities National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, GA Leyla Sahin, MD, FACOG Melissa S. Tassinari, PhD, DABT Division of Pediatric and Maternal Health, Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration Silver Spring, MD The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention or the Food and Drug Administration.
The authors report no conflict of interest.
REFERENCES 1. Broussard CS, Frey MT, Hernandez-Diaz S, et al. Developing a systematic approach to safer medication use during pregnancy: summary of a Centers for Disease Control and Prevention-convened meeting. Am J Obstet Gynecol 2014;211:208-14. 2. Parisi MA, Spong CY, Zajicek A, Guttmacher AE. We don’t know what we don’t study: the case for research on medication effects in pregnancy. Am J Med Genet Part C Semin Med Genet 2011;157:247-50. 3. Food and Drug Administration. Study approaches and methods to evaluate the safety of drugs and biological products during pregnancy in the post-approval setting; public meeting. Available at: http://www.fda. gov/drugs/newsevents/ucm386560.htm. Accessed Nov. 14, 2014. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2014.12.036
