Indomethacin and Antibiotics in Examination-Indicated Cerclage: A Randomized Controlled Trial To the Editor:
Dr. Miller and colleagues1 present important data on the use of indomethacin and cefazolin in the setting of examination-indicated cerclage. This randomized controlled trial is welldesigned, and the clinical data are uniquely rich. It was intriguing to find that, although median latency from cerclage placement to delivery was no different between groups, post hoc analysis revealed a lower number of deliveries within 28 days of cerclage placement in patients receiving indomethacin and cefazolin. I have two concerns that may have influenced the results. First, it seems that more than one third of the patients were candidates for 17a-hydroxyprogesterone caproate2 and at least half were candidates for vaginal progesterone.3 Considering the proven benefit of these two agents to prolong gestation, it would be helpful to know whether their use differed between groups. If there was greater use of progesterone in the intervention group, that may have confounded the authors’ results. My second concern relates to the authors’ analysis of perinatal outcomes in Table 3.1 The authors appear to estimate neonatal morbidities as a percentage of all deliveries. This may lead to survivor bias in the analysis, because surviving neonates are more likely to experience morbidities than are nonsurvivors. This may account for the apparent lack of increased morbidity in the nonintervention arm, which had a lower number of survivors. Financial Disclosure: The author did not report any potential conflicts of interest.
Richard M. Burwick, MD, MPH Division of Maternal Fetal Medicine, Oregon Health & Science University, Portland, OR
REFERENCES 1. Miller ES, Grobman WA, Fonseca L, Robinson BK. Indomethacin and antibiotics in examination-indicated cerclage. Obstet Gynecol 2014;123:1311–16.
VOL. 124, NO. 3, SEPTEMBER 2014
2. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–85. 3. Romero R, Nicolaides K, CondeAgudelo A, Tabor A, O’Brien JM, Cetingoz E, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206:124. e1–19.
REFERENCE 1. Miller ES, Grobman WA, Fonseca L, Robinson BK. Indomethacin and antibiotics in examination-indicated cerclage. Obstet Gynecol 2014;123:1311–16.
Increase in Prescription Opioid Use During Pregnancy Among Medicaid-Enrolled Women To the Editor:
In Reply: We appreciate Dr. Burwick’s favorable comments concerning our article1 and are happy to address his methodologic concerns. We agree with him that progesterone use has the potential to confound our results. However, there were no differences in the study arms in terms of progesterone eligibility or in the proportions of women receiving antenatal progesterone: nine women (34.6%) in the intervention arm compared with eight women (33.3%) in the nonintervention arm. There also was no evidence that survivor bias affected the results. Although we did estimate neonatal morbidities as a percentage of all deliveries, we also created a composite outcome that included death and morbidity together. This composite outcome did not differ between the intervention and nonintervention arms. In addition, a post hoc analysis performed to evaluate morbidities only among survivors demonstrated no significant differences between the groups in any of the neonatal morbidities. Financial Disclosure: The authors did not report any potential conflicts of interest.
Emily S. Miller, MD, MPH Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois William A. Grobman, MD, MBA Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
We commend Desai and team1 for the study and results of their study. The analysis of a data set this large is invaluable in helping guide recommendations regarding best practices. However, the authors did not provide information about potential confounding conditions. Specifically, how were patients with preconception opioid dependency identified and handled? If included, these patients would cause an overestimation of an opioid’s prescription. Patients in detox or methadone programs would begin with an a priori elevated filling rate. Also, opioid-dependent patients (not in programs) may exhibit drug-seeking behavior and also should be treated as outliers in the cohort. Further, how did the authors address comorbidities for which opioid prescription is indicated, such as sickle cell disease? Inclusion of these patients potentially could contribute to the trend observed in this report. Further, research on opioid teratogenicity is limited. Most studies (including the authors’ first two references) report weak statistical evidence of teratogenicity with opiate use in pregnancy and also lack the necessary controlling for confounders. Other studies contend that long-term exposure to opiates can result in fetal complications.2 Unfortunately, there is no consensus on what constitutes “long-term.” Our major concern is that the suggested overestimation of prescribed opioids during pregnancy may lead to excessive prescription concerns. This, in turn, may create a barrier for adequate pain relief during pregnancy and cause unnecessary suffering. We suggest that a more focused methodology that addresses confounding variables would better illuminate any trend in opioid prescriptions during pregnancy.
Letters to the Editor
637
Financial Disclosure: The authors did not report any potential conflicts of interest.
Daniel Cho, MPH St. George’s University, School of Medicine, Grenada, West Indies Shadi Rezai, MD Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, Bronx, New York Tiffani T. Phan St. George’s University, School of Medicine, Grenada, West Indies Cassandra E. Henderson, MD Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, Bronx, New York
REFERENCES 1. Desai RJ, Hernandez-Diaz S, Bateman BT, Huybrechts KF. Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol 2014;123:997–1002. 2. Parrish MR, Morrison JC. Sickle cell crisis and pregnancy. Semin Perinatol 2013; 37:274–9.
In Reply: We appreciate the interest by Cho et al in our recent research report.1 In response to their concern that our study may have overestimated “legitimate” prescription opioid use in pregnancy owing to drug-seeking behavior by opioid-dependent women included in the cohort, we would note that a majority of the prescription opioid use
638
Letters to the Editor
observed in our study consisted of single, short-duration prescription fills (median cumulative days of exposure: 5 days, interquartile range: 3–13 days). Therefore, the observed trends and high prevalence of use are unlikely to be due to opioids dispensed to abusing patients, but rather reflect increasing use of opioids during pregnancy for acute pain. We also would note that the prevalence of chronic pain conditions for which chronic opioid therapy may be indicated was very low (0.20% for sickle cell disease and 0.03% for chronic pancreatitis, for instance), again suggesting that it is the treatment of acute pain that is driving the observed high prevalence of opioid use. We concur with Cho et al that the research on teratogenicity and other adverse effects of opioids in pregnancy is limited. However, some studies do suggest risk,2,3 and the absence of conclusive evidence should not serve as evidence of absence of risk. Although we would reiterate that the purpose of our study is not to create a barrier to adequate pain relief, the markedly high prevalence of opioid use in our Medicaid cohort (;22%) suggests the need for a critical appraisal of how these medications are being used in pregnancy and the urgent need for further research examining the safety of these medications for mothers and their offspring. Financial Disclosure: The authors did not report any potential conflicts of interest.
Rishi J. Desai, MS, PhD Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston, Massachusetts Sonia Hernandez-Diaz, MD, DrPH Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, Brian T. Bateman, MD, MSc Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School and, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Krista F. Huybrechts, MS, PhD Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
REFERENCES 1. Desai RJ, Hernandez-Diaz S, Bateman BT, Huybrechts KF. Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol 2014;123:997–002. 2. Yazdy MM, Mitchell AA, Tinker SC, Parker SE, Werler MM. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013;122: 838–44. 3. Broussard CS, Rasmussen SA, Reefhuis J, Friedman J, Jann MW, Riehle-Colarusso T, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011;204:314. e1–11.
OBSTETRICS & GYNECOLOGY
Dr. Miller and colleagues1 present important data on the use of indomethacin and cefazolin in the setting of examination-indicated cerclage. This randomized controlled trial is welldesigned, and the clinical data are uniquely rich. It was intriguing to find that, although median latency from cerclage placement to delivery was no different between groups, post hoc analysis revealed a lower number of deliveries within 28 days of cerclage placement in patients receiving indomethacin and cefazolin. I have two concerns that may have influenced the results. First, it seems that more than one third of the patients were candidates for 17a-hydroxyprogesterone caproate2 and at least half were candidates for vaginal progesterone.3 Considering the proven benefit of these two agents to prolong gestation, it would be helpful to know whether their use differed between groups. If there was greater use of progesterone in the intervention group, that may have confounded the authors’ results. My second concern relates to the authors’ analysis of perinatal outcomes in Table 3.1 The authors appear to estimate neonatal morbidities as a percentage of all deliveries. This may lead to survivor bias in the analysis, because surviving neonates are more likely to experience morbidities than are nonsurvivors. This may account for the apparent lack of increased morbidity in the nonintervention arm, which had a lower number of survivors. Financial Disclosure: The author did not report any potential conflicts of interest.
Richard M. Burwick, MD, MPH Division of Maternal Fetal Medicine, Oregon Health & Science University, Portland, OR
REFERENCES 1. Miller ES, Grobman WA, Fonseca L, Robinson BK. Indomethacin and antibiotics in examination-indicated cerclage. Obstet Gynecol 2014;123:1311–16.
VOL. 124, NO. 3, SEPTEMBER 2014
2. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–85. 3. Romero R, Nicolaides K, CondeAgudelo A, Tabor A, O’Brien JM, Cetingoz E, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206:124. e1–19.
REFERENCE 1. Miller ES, Grobman WA, Fonseca L, Robinson BK. Indomethacin and antibiotics in examination-indicated cerclage. Obstet Gynecol 2014;123:1311–16.
Increase in Prescription Opioid Use During Pregnancy Among Medicaid-Enrolled Women To the Editor:
In Reply: We appreciate Dr. Burwick’s favorable comments concerning our article1 and are happy to address his methodologic concerns. We agree with him that progesterone use has the potential to confound our results. However, there were no differences in the study arms in terms of progesterone eligibility or in the proportions of women receiving antenatal progesterone: nine women (34.6%) in the intervention arm compared with eight women (33.3%) in the nonintervention arm. There also was no evidence that survivor bias affected the results. Although we did estimate neonatal morbidities as a percentage of all deliveries, we also created a composite outcome that included death and morbidity together. This composite outcome did not differ between the intervention and nonintervention arms. In addition, a post hoc analysis performed to evaluate morbidities only among survivors demonstrated no significant differences between the groups in any of the neonatal morbidities. Financial Disclosure: The authors did not report any potential conflicts of interest.
Emily S. Miller, MD, MPH Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois William A. Grobman, MD, MBA Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
We commend Desai and team1 for the study and results of their study. The analysis of a data set this large is invaluable in helping guide recommendations regarding best practices. However, the authors did not provide information about potential confounding conditions. Specifically, how were patients with preconception opioid dependency identified and handled? If included, these patients would cause an overestimation of an opioid’s prescription. Patients in detox or methadone programs would begin with an a priori elevated filling rate. Also, opioid-dependent patients (not in programs) may exhibit drug-seeking behavior and also should be treated as outliers in the cohort. Further, how did the authors address comorbidities for which opioid prescription is indicated, such as sickle cell disease? Inclusion of these patients potentially could contribute to the trend observed in this report. Further, research on opioid teratogenicity is limited. Most studies (including the authors’ first two references) report weak statistical evidence of teratogenicity with opiate use in pregnancy and also lack the necessary controlling for confounders. Other studies contend that long-term exposure to opiates can result in fetal complications.2 Unfortunately, there is no consensus on what constitutes “long-term.” Our major concern is that the suggested overestimation of prescribed opioids during pregnancy may lead to excessive prescription concerns. This, in turn, may create a barrier for adequate pain relief during pregnancy and cause unnecessary suffering. We suggest that a more focused methodology that addresses confounding variables would better illuminate any trend in opioid prescriptions during pregnancy.
Letters to the Editor
637
Financial Disclosure: The authors did not report any potential conflicts of interest.
Daniel Cho, MPH St. George’s University, School of Medicine, Grenada, West Indies Shadi Rezai, MD Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, Bronx, New York Tiffani T. Phan St. George’s University, School of Medicine, Grenada, West Indies Cassandra E. Henderson, MD Department of Obstetrics and Gynecology, Lincoln Medical and Mental Health Center, Bronx, New York
REFERENCES 1. Desai RJ, Hernandez-Diaz S, Bateman BT, Huybrechts KF. Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol 2014;123:997–1002. 2. Parrish MR, Morrison JC. Sickle cell crisis and pregnancy. Semin Perinatol 2013; 37:274–9.
In Reply: We appreciate the interest by Cho et al in our recent research report.1 In response to their concern that our study may have overestimated “legitimate” prescription opioid use in pregnancy owing to drug-seeking behavior by opioid-dependent women included in the cohort, we would note that a majority of the prescription opioid use
638
Letters to the Editor
observed in our study consisted of single, short-duration prescription fills (median cumulative days of exposure: 5 days, interquartile range: 3–13 days). Therefore, the observed trends and high prevalence of use are unlikely to be due to opioids dispensed to abusing patients, but rather reflect increasing use of opioids during pregnancy for acute pain. We also would note that the prevalence of chronic pain conditions for which chronic opioid therapy may be indicated was very low (0.20% for sickle cell disease and 0.03% for chronic pancreatitis, for instance), again suggesting that it is the treatment of acute pain that is driving the observed high prevalence of opioid use. We concur with Cho et al that the research on teratogenicity and other adverse effects of opioids in pregnancy is limited. However, some studies do suggest risk,2,3 and the absence of conclusive evidence should not serve as evidence of absence of risk. Although we would reiterate that the purpose of our study is not to create a barrier to adequate pain relief, the markedly high prevalence of opioid use in our Medicaid cohort (;22%) suggests the need for a critical appraisal of how these medications are being used in pregnancy and the urgent need for further research examining the safety of these medications for mothers and their offspring. Financial Disclosure: The authors did not report any potential conflicts of interest.
Rishi J. Desai, MS, PhD Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston, Massachusetts Sonia Hernandez-Diaz, MD, DrPH Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, Brian T. Bateman, MD, MSc Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School and, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Krista F. Huybrechts, MS, PhD Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
REFERENCES 1. Desai RJ, Hernandez-Diaz S, Bateman BT, Huybrechts KF. Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol 2014;123:997–002. 2. Yazdy MM, Mitchell AA, Tinker SC, Parker SE, Werler MM. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013;122: 838–44. 3. Broussard CS, Rasmussen SA, Reefhuis J, Friedman J, Jann MW, Riehle-Colarusso T, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011;204:314. e1–11.
OBSTETRICS & GYNECOLOGY
