ajog.org
Letters to the Editors
Primum non nocere: stillbirth rate in intrahepatic cholestasis of pregnancy TO THE EDITORS: In reading the article written by Henderson et al,1 we question the selected background stillbirth rates used to compare to the estimated stillbirth rate in intrahepatic cholestasis of pregnancy (ICP) with expectant management. They found the unexplained stillbirth rate attributed to ICP with expectant management to be 1.2% (4/ 331) and compared it to published background rates of 1.1% (11/1000) and 0.6% (6/1000). Their analysis of stillbirths in ICP was limited to ones that were otherwise unexplained and >37 completed weeks’ gestation. They excluded stillbirths in pregnancies affected by ICP that were also complicated by congenital anomalies, preeclampsia, abruption, intrauterine growth restriction, or diabetes. However, the authors did not use the same criteria for their control group, which included stillbirths as early as 20 weeks’ gestation and incorporated attributed causes for stillbirth that were excluded in the group with ICP. An appropriate control group would have utilized stillbirth rates that were limited to term stillbirths, which have rates closer to 0.1-0.2% (1-2/1000).2,3 This background rate would potentially be lower by approximately 50% if limited to unexplained term stillbirths.3 Furthermore, we are surprised at the omission of several studies of perinatal outcomes in ICP that appear to meet the inclusion criteria, but are not included in the analysis of stillbirths. Many of the studies that have been included do not use bile acid level in the diagnosis of ICP, are retrospective, and are not adequately powered to robustly assess the frequency of stillbirth in ICP. It is noteworthy that the largest prospective national cohort study of severe ICP (ie, complicated by maternal serum bile acids 40 mmol/L) was published a little before the article by Henderson et al,1 and this did show a significant increase in stillbirth in ICP.4 In conclusion, although the authors attempt to answer an important clinical question they fail to do so by using inappropriate inclusion criteria for both the ICP and control groups. Richard H. Lee, MD Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine Los Angeles County-University of Southern California Medical Center Los Angeles, CA [email protected] Victoria L. Geenes, PhD Catherine Williamson, MD Women’s Health Academic Center, King’s College London London, United Kingdom The authors report no conflict of interest.
REFERENCES 1. Henderson CE, Shah RR, Gottimukkala S, Ferreira KK, Hamaoui A, Mercado R. Primum non nocere: how active management became
414 American Journal of Obstetrics & Gynecology MARCH 2015
modus operandi for intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2014;211:189-96. 2. MacDorman MF, Kirmeyer SE, Wilson EC. Fetal and perinatal mortality, United States, 2006. Natl Vital Stat Rep 2012;60:1-22. 3. Walsh CA, Vallerie AM, Baxi LV. Etiology of stillbirth at term: a 10year cohort study. J Matern Fetal Neonatal Med 2008;21:493-501. 4. Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 2014;59:1482-91. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.11.039
REPLY We thank Dr Lee et al for a thoughtful critique. Our systematic review was prompted by the same limitations in intrahepatic cholestasis of pregnancy literature that Lee et al noted: retrospective studies, underpowered study size, and lack of biochemical testing. Nevertheless, these papers continue to be cited as supportive evidence for active management in the absence of more robust studies. It is unfortunate that our literature review was complete and our manuscript was already in the publication pipeline by the time the article by Geenes et al,1 the largest prospective national cohort study of severe intrahepatic cholestasis of pregnancy, was first published online. Inclusion of the article by Geenes et al1 would have added support to our findings. However, we disagree with many of the other suppositions of Lee et al. When evaluating unexplained term stillbirth, it is appropriate to exclude cases with comorbid conditions known to be independent risks for fetal demise.2 The control group in the article by Geenes et al1 excluded complicated pregnancies, while their study group included complicated pregnancies. When only stillbirths occurring in uncomplicated pregnancies are considered, study groups of Geenes et al1 have similar stillbirth rates: 3/713 and 11/2205, respectively, P ¼ .79. We also disagree with the suggestion of Lee et al that an appropriate background stillbirth rate during our study period should be 1-2/1000. While we relied on public surveillance data for our background stillbirth rates, epidemiologic evidence cited by Lee et al indicates that during our study period stillbirth rates after 28 weeks of gestation varied between 2.97 and 4.95/1000.3 Cassandra E. Henderson, MD Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine Lincoln Medical and Mental Health Center Bronx, NY [email protected]
Letters to the Editors
Primum non nocere: stillbirth rate in intrahepatic cholestasis of pregnancy TO THE EDITORS: In reading the article written by Henderson et al,1 we question the selected background stillbirth rates used to compare to the estimated stillbirth rate in intrahepatic cholestasis of pregnancy (ICP) with expectant management. They found the unexplained stillbirth rate attributed to ICP with expectant management to be 1.2% (4/ 331) and compared it to published background rates of 1.1% (11/1000) and 0.6% (6/1000). Their analysis of stillbirths in ICP was limited to ones that were otherwise unexplained and >37 completed weeks’ gestation. They excluded stillbirths in pregnancies affected by ICP that were also complicated by congenital anomalies, preeclampsia, abruption, intrauterine growth restriction, or diabetes. However, the authors did not use the same criteria for their control group, which included stillbirths as early as 20 weeks’ gestation and incorporated attributed causes for stillbirth that were excluded in the group with ICP. An appropriate control group would have utilized stillbirth rates that were limited to term stillbirths, which have rates closer to 0.1-0.2% (1-2/1000).2,3 This background rate would potentially be lower by approximately 50% if limited to unexplained term stillbirths.3 Furthermore, we are surprised at the omission of several studies of perinatal outcomes in ICP that appear to meet the inclusion criteria, but are not included in the analysis of stillbirths. Many of the studies that have been included do not use bile acid level in the diagnosis of ICP, are retrospective, and are not adequately powered to robustly assess the frequency of stillbirth in ICP. It is noteworthy that the largest prospective national cohort study of severe ICP (ie, complicated by maternal serum bile acids 40 mmol/L) was published a little before the article by Henderson et al,1 and this did show a significant increase in stillbirth in ICP.4 In conclusion, although the authors attempt to answer an important clinical question they fail to do so by using inappropriate inclusion criteria for both the ICP and control groups. Richard H. Lee, MD Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine Los Angeles County-University of Southern California Medical Center Los Angeles, CA [email protected] Victoria L. Geenes, PhD Catherine Williamson, MD Women’s Health Academic Center, King’s College London London, United Kingdom The authors report no conflict of interest.
REFERENCES 1. Henderson CE, Shah RR, Gottimukkala S, Ferreira KK, Hamaoui A, Mercado R. Primum non nocere: how active management became
414 American Journal of Obstetrics & Gynecology MARCH 2015
modus operandi for intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2014;211:189-96. 2. MacDorman MF, Kirmeyer SE, Wilson EC. Fetal and perinatal mortality, United States, 2006. Natl Vital Stat Rep 2012;60:1-22. 3. Walsh CA, Vallerie AM, Baxi LV. Etiology of stillbirth at term: a 10year cohort study. J Matern Fetal Neonatal Med 2008;21:493-501. 4. Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 2014;59:1482-91. ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2014.11.039
REPLY We thank Dr Lee et al for a thoughtful critique. Our systematic review was prompted by the same limitations in intrahepatic cholestasis of pregnancy literature that Lee et al noted: retrospective studies, underpowered study size, and lack of biochemical testing. Nevertheless, these papers continue to be cited as supportive evidence for active management in the absence of more robust studies. It is unfortunate that our literature review was complete and our manuscript was already in the publication pipeline by the time the article by Geenes et al,1 the largest prospective national cohort study of severe intrahepatic cholestasis of pregnancy, was first published online. Inclusion of the article by Geenes et al1 would have added support to our findings. However, we disagree with many of the other suppositions of Lee et al. When evaluating unexplained term stillbirth, it is appropriate to exclude cases with comorbid conditions known to be independent risks for fetal demise.2 The control group in the article by Geenes et al1 excluded complicated pregnancies, while their study group included complicated pregnancies. When only stillbirths occurring in uncomplicated pregnancies are considered, study groups of Geenes et al1 have similar stillbirth rates: 3/713 and 11/2205, respectively, P ¼ .79. We also disagree with the suggestion of Lee et al that an appropriate background stillbirth rate during our study period should be 1-2/1000. While we relied on public surveillance data for our background stillbirth rates, epidemiologic evidence cited by Lee et al indicates that during our study period stillbirth rates after 28 weeks of gestation varied between 2.97 and 4.95/1000.3 Cassandra E. Henderson, MD Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine Lincoln Medical and Mental Health Center Bronx, NY [email protected]
