Letters 3. To measure improvement, the authors used a 100-mm visual analog scale and not one of the validated tools for measuring effectiveness in nausea and vomiting in pregnancy.3 4. The sample size of the study (18/arm) is grossly suboptimal to discern effects. It has been shown repeatedly that randomized controlled trails with small sample sizes are more sensitive to bias against the null hypothesis. 5. There are still major unresolved issues around maternal and fetal safety of ondansetron that must be acknowledged.4 Specifically, new studies show increased cardiovascular malformation risks.5
Ondansetron Compared With Doxylamine and Pyridoxine for Treatment of Nausea in Pregnancy: A Randomized Controlled Trial To the Editor: Oliveira and colleagues compared, in a double-blind, placebo-controlled trial, ondansetron with doxylamine–pyridoxine for treating symptoms of morning sickness.1 The authors should be congratulated for conducting a study in an area that sees very few studies. There are, however, major issues in the methodology of the study that diminish its clinical interpretation: 1. The authors compare ondansetron with the doxylamine–pyridoxine combination, which are the components of the only U.S. Food and Drug Administration (FDA)– approved drug for this condition. Yet, they did not use the delayedrelease form of doxylamine– pyridoxine, which is critical for its efficacy, but rather an immediaterelease form.2 2. Even more serious, Oliveira et al used only 12.5 mg of doxylamine, which is half of the dose of the H1 blocker contained in the FDA-approved medication Diclegis.2 Guidelines for Letters. Letters posing a question or challenge to an article appearing in Obstetrics & Gynecology should be submitted within 8 weeks of the article’s publication online. Letters received after 8 weeks will rarely be considered. Letters should not exceed 350 words, including signatures and 5 references. A word count should be provided. The maximum number of authors permitted is four, and a corresponding author should be designated (and contact information listed). Letters will be published at the discretion of the Editor. The Editor may send the letter to the authors of the original paper so their comments may be published simultaneously. The Editor reserves the right to edit and shorten letters. A signed author agreement form is required from all authors before publication. Letters should be submitted using the Obstetrics & Gynecology online submission and review system, Editorial Manager (http://ong.edmgr.com).
490
Financial Disclosure: The authors have been supported by research grants from Duchesnay Inc. producer of Diclegis. Dr. Koren was the co-private investigator of the Diclegis Phase 3 trial.
Gideon Koren, MD, FRCPC Caroline Maltepe, BSc Svetlana Madjunkova, MD The Motherisk program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada
REFERENCES 1. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Madjunkova S, Maltepe C, Koren G. The delayed-release combination of doxylamine and pyridoxine (DiclegisÒ/DiclectinÒ) for the treatment of nausea and vomiting of pregnancy. Paediatr Drugs 2014;16: 199–211. 3. Ebrahimi N, Maltepe C, Bournissen FG, Koren G. Nausea and vomiting of pregnancy: using the 24-hour pregnancyunique quantification of emesis (PUQE-24) scale. J Obstet Gynaecol Can 2009;31: 803–7. 4. Koren G. Treating morning sickness in the United States-changes in prescribing are needed. Am J Obstet Gynecol 2014; 211:602–6. 5. Danielsson B, Wikner BN, Källén B. Use of ondansetron during pregnancy and
VOL. 125, NO. 2, FEBRUARY 2015
congenital malformations in the infant. Reprod Toxicol 2014;50:134–7.
Odansetron Compared With Doxylamine and Pyridoxine for Treatment of Nausea in Pregnancy: A Randomized Controlled Trial To the Editor: It is with interest that I read the article by Oliveira et al.1 The authors compare odansetron with doxylamine plus pyridoxine in the treatment of nausea in pregnancy and conclude that odansetron is superior, suggesting its use as first-line therapy for nausea in pregnancy. However, because the study uses only the lowest dose and lowest frequency of both doxylamine and pyridoxine, it may be premature to conclude that odansetron is superior. In the American College of Obstetricians and Gynecologists Practice Bulletin No. 52,2 the authors recommend doxylamine and pyridoxine as first-line therapy and suggest a dosage and frequency titration based on the patient’s symptoms. In addition, the combination of doxylamine and pyridoxine has been approved by the U.S. Food and Drug Administration (FDA) as safe for treatment of nausea in pregnancy.3 The FDA has not approved odansetron as safe in pregnancy and has issued warnings about dysrhythmias.4 Before suggesting the first-line use of a medication that is not approved by the FDA and has potential risks, there needs to be a more extensive comparison of all suggested dosages and dosing frequencies and resolution of any safety concerns. Financial Disclosure: The author did not report any potential conflicts of interest.
Kirstie Cunningham, MD, FACOG Department of Family Medicine, Morehouse School of Medicine, Atlanta, Georgia
REFERENCES 1. LG Oliveira, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Nausea and vomiting of pregnancy. ACOG Practice Bulletin No. 52. American College of Obstetrics and Gynecology. Obstet Gynecol 2004;103:803–14. 3. Nuangchamnong N, Niebyl J. Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview. Int J Womens Health 2014;6:401–9.
Financial Disclosure: The authors did not report any potential conflicts of interest. The views expressed herein are the authors’ and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. Research data derived from an approved Naval Medical Center, San Diego, CA IRB protocol.
Lauren Oliveira, DO, RDMS Naval Medical Center, Portsmouth, Virginia
4. Koren G. Treating morning sickness in the United States-changes in prescribing are needed. Am J Obstet Gynecol 2014; 211:602–6.
Shannon Capp, MD Naval Medical Center, San Diego, California
REFERENCES In Reply: We thank Dr. Koren and colleagues and Dr. Cunningham for their interest in our study1 and their thoughtful commentary. We would like to take this opportunity to address the concerns raised in their letters. Our study was designed to compare ondansetron with pyridoxine and doxylamine. The doses and formulations chosen were based on the current recommendations by the American College of Obstetricians and Gynecologists’ Practice Bulletin 52.2 We did not set out to compare ondansetron with Diclegis and therefore did not use the delayedrelease formulation. We chose to use the visual analog scale because it correlates well with numeric and verbal descriptors of nausea, has been externally validated, and has been used in a number of clinical settings.3,4 The fact that the visual analog scale has not been validated in the pregnant population was mentioned as a limitation in our study. With regard to the small sample size, we did a power analysis a priori and did a test for missing data bias a posteriori. The bias against the null hypothesis across many studies is somewhat due to publication selection for positive results, making it an unlikely bias in a single study. In our case, the data clearly show statistical significance and we believe in our data. Maternal and fetal safety are of the upmost concern to all of the investigators. Our study was not designed to establish the safety of ondansetron in pregnancy, but we did acknowledge the recent findings of Pasternik et al, which did not find an association with ondansetron and significant adverse fetal outcomes such as major birth defects, spontaneous abortion, or preterm delivery.5
1. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Nausea and vomiting of ACOG Practice Bulletin No. can College of Obstetricians cologists. Obstet Gynecol 803–14.
pregnancy. 52. Ameriand Gyne2004;103:
3. Hendey GW, Donner NF, Fuller K. Clinically significant changes in nausea as measured on a visual analog scale. Ann Emerg Med 2005;45:77–81. 4. Meek R, Kelly A, Hu X. Use of the visual analog scale to rate and monitor severity of nausea in the emergency department. Acad Emerg Med 2009; 16:1304–10. 5. Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med 2013;368:814–23.
Relevance of Random Biopsy at the Transformation Zone When Colposcopy Is Negative To the Editor: We read with interest the article by Huh et al 1 on random biopsy in women with negative colposcopy results. We completely agree that colposcopic practice is not perfect, and the colposcopist is not a perfect doctor. But the colposcopist remains a very important doctor. As recommended by European Guidelines, 2 the key for improving the standard of care for patients with cervical intraepithelial lesions is the skill of the colposcopist, who also has the
responsibility of facilitating shared decision-making through patient information before, during, and after the examination. This study stimulates every colposcopist to optimize disease detection, performing biopsies without seeing lesions, so an increase in biopsies is expected. The colposcopist will be responsible for managing these additional lesions, and this requires a further optimization and standardization. So the key question remains the training of the colposcopist, and our hope is that health systems will invest resources in this field. Recently, Cruickshank et al 3 reported that, if colposcopic examination results are normal, women with low-grade cervical cytology, even with a positive HPV test, can return to routine recall; this is surely an advantage from both a psychological and economic point of view. Our suggestion for improving the detection of highrate disease is to use a low threshold of abnormality at colposcopy (any acetowhitening); this also will favor better training for the colposcopist, 4 rather than adding nondirected biopsies. Financial Disclosure: The authors did not report any potential conflicts of interest.
Uri Wiesenfeld, MD Francesco Paolo Mangino, MD Franco Giovanni Toffoletti, MD Giuseppe Ricci, MD Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy
REFERENCES 1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol 2014;124:670–8. 2. Jordan J, Martin-Hirsch P, Arbyn M, Schenck U, Baldauf JJ, Da Silva D, et al. European guidelines for clinical management of abnormal cervical cytology, part 2. Cytopathology 2009;20:5–16. 3. Cruickshank M, Cotton S, Sharp L, Smart L, Walker L, Little J, et al. Management of women with low grade cytology: how reassuring is a normal colposcopy examination? BJOG 2014. [Epub ahead of print]. 4. Bentley J. Colposcopic management of abnormal cervical cytology and histology [in English, French]. J Obstet Gynaecol Can 2012;34:1188–202.
VOL. 125, NO. 2, FEBRUARY 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
491
Ondansetron Compared With Doxylamine and Pyridoxine for Treatment of Nausea in Pregnancy: A Randomized Controlled Trial To the Editor: Oliveira and colleagues compared, in a double-blind, placebo-controlled trial, ondansetron with doxylamine–pyridoxine for treating symptoms of morning sickness.1 The authors should be congratulated for conducting a study in an area that sees very few studies. There are, however, major issues in the methodology of the study that diminish its clinical interpretation: 1. The authors compare ondansetron with the doxylamine–pyridoxine combination, which are the components of the only U.S. Food and Drug Administration (FDA)– approved drug for this condition. Yet, they did not use the delayedrelease form of doxylamine– pyridoxine, which is critical for its efficacy, but rather an immediaterelease form.2 2. Even more serious, Oliveira et al used only 12.5 mg of doxylamine, which is half of the dose of the H1 blocker contained in the FDA-approved medication Diclegis.2 Guidelines for Letters. Letters posing a question or challenge to an article appearing in Obstetrics & Gynecology should be submitted within 8 weeks of the article’s publication online. Letters received after 8 weeks will rarely be considered. Letters should not exceed 350 words, including signatures and 5 references. A word count should be provided. The maximum number of authors permitted is four, and a corresponding author should be designated (and contact information listed). Letters will be published at the discretion of the Editor. The Editor may send the letter to the authors of the original paper so their comments may be published simultaneously. The Editor reserves the right to edit and shorten letters. A signed author agreement form is required from all authors before publication. Letters should be submitted using the Obstetrics & Gynecology online submission and review system, Editorial Manager (http://ong.edmgr.com).
490
Financial Disclosure: The authors have been supported by research grants from Duchesnay Inc. producer of Diclegis. Dr. Koren was the co-private investigator of the Diclegis Phase 3 trial.
Gideon Koren, MD, FRCPC Caroline Maltepe, BSc Svetlana Madjunkova, MD The Motherisk program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada
REFERENCES 1. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Madjunkova S, Maltepe C, Koren G. The delayed-release combination of doxylamine and pyridoxine (DiclegisÒ/DiclectinÒ) for the treatment of nausea and vomiting of pregnancy. Paediatr Drugs 2014;16: 199–211. 3. Ebrahimi N, Maltepe C, Bournissen FG, Koren G. Nausea and vomiting of pregnancy: using the 24-hour pregnancyunique quantification of emesis (PUQE-24) scale. J Obstet Gynaecol Can 2009;31: 803–7. 4. Koren G. Treating morning sickness in the United States-changes in prescribing are needed. Am J Obstet Gynecol 2014; 211:602–6. 5. Danielsson B, Wikner BN, Källén B. Use of ondansetron during pregnancy and
VOL. 125, NO. 2, FEBRUARY 2015
congenital malformations in the infant. Reprod Toxicol 2014;50:134–7.
Odansetron Compared With Doxylamine and Pyridoxine for Treatment of Nausea in Pregnancy: A Randomized Controlled Trial To the Editor: It is with interest that I read the article by Oliveira et al.1 The authors compare odansetron with doxylamine plus pyridoxine in the treatment of nausea in pregnancy and conclude that odansetron is superior, suggesting its use as first-line therapy for nausea in pregnancy. However, because the study uses only the lowest dose and lowest frequency of both doxylamine and pyridoxine, it may be premature to conclude that odansetron is superior. In the American College of Obstetricians and Gynecologists Practice Bulletin No. 52,2 the authors recommend doxylamine and pyridoxine as first-line therapy and suggest a dosage and frequency titration based on the patient’s symptoms. In addition, the combination of doxylamine and pyridoxine has been approved by the U.S. Food and Drug Administration (FDA) as safe for treatment of nausea in pregnancy.3 The FDA has not approved odansetron as safe in pregnancy and has issued warnings about dysrhythmias.4 Before suggesting the first-line use of a medication that is not approved by the FDA and has potential risks, there needs to be a more extensive comparison of all suggested dosages and dosing frequencies and resolution of any safety concerns. Financial Disclosure: The author did not report any potential conflicts of interest.
Kirstie Cunningham, MD, FACOG Department of Family Medicine, Morehouse School of Medicine, Atlanta, Georgia
REFERENCES 1. LG Oliveira, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Nausea and vomiting of pregnancy. ACOG Practice Bulletin No. 52. American College of Obstetrics and Gynecology. Obstet Gynecol 2004;103:803–14. 3. Nuangchamnong N, Niebyl J. Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview. Int J Womens Health 2014;6:401–9.
Financial Disclosure: The authors did not report any potential conflicts of interest. The views expressed herein are the authors’ and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. Research data derived from an approved Naval Medical Center, San Diego, CA IRB protocol.
Lauren Oliveira, DO, RDMS Naval Medical Center, Portsmouth, Virginia
4. Koren G. Treating morning sickness in the United States-changes in prescribing are needed. Am J Obstet Gynecol 2014; 211:602–6.
Shannon Capp, MD Naval Medical Center, San Diego, California
REFERENCES In Reply: We thank Dr. Koren and colleagues and Dr. Cunningham for their interest in our study1 and their thoughtful commentary. We would like to take this opportunity to address the concerns raised in their letters. Our study was designed to compare ondansetron with pyridoxine and doxylamine. The doses and formulations chosen were based on the current recommendations by the American College of Obstetricians and Gynecologists’ Practice Bulletin 52.2 We did not set out to compare ondansetron with Diclegis and therefore did not use the delayedrelease formulation. We chose to use the visual analog scale because it correlates well with numeric and verbal descriptors of nausea, has been externally validated, and has been used in a number of clinical settings.3,4 The fact that the visual analog scale has not been validated in the pregnant population was mentioned as a limitation in our study. With regard to the small sample size, we did a power analysis a priori and did a test for missing data bias a posteriori. The bias against the null hypothesis across many studies is somewhat due to publication selection for positive results, making it an unlikely bias in a single study. In our case, the data clearly show statistical significance and we believe in our data. Maternal and fetal safety are of the upmost concern to all of the investigators. Our study was not designed to establish the safety of ondansetron in pregnancy, but we did acknowledge the recent findings of Pasternik et al, which did not find an association with ondansetron and significant adverse fetal outcomes such as major birth defects, spontaneous abortion, or preterm delivery.5
1. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial. Obstet Gynecol 2014;124:735–42. 2. Nausea and vomiting of ACOG Practice Bulletin No. can College of Obstetricians cologists. Obstet Gynecol 803–14.
pregnancy. 52. Ameriand Gyne2004;103:
3. Hendey GW, Donner NF, Fuller K. Clinically significant changes in nausea as measured on a visual analog scale. Ann Emerg Med 2005;45:77–81. 4. Meek R, Kelly A, Hu X. Use of the visual analog scale to rate and monitor severity of nausea in the emergency department. Acad Emerg Med 2009; 16:1304–10. 5. Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med 2013;368:814–23.
Relevance of Random Biopsy at the Transformation Zone When Colposcopy Is Negative To the Editor: We read with interest the article by Huh et al 1 on random biopsy in women with negative colposcopy results. We completely agree that colposcopic practice is not perfect, and the colposcopist is not a perfect doctor. But the colposcopist remains a very important doctor. As recommended by European Guidelines, 2 the key for improving the standard of care for patients with cervical intraepithelial lesions is the skill of the colposcopist, who also has the
responsibility of facilitating shared decision-making through patient information before, during, and after the examination. This study stimulates every colposcopist to optimize disease detection, performing biopsies without seeing lesions, so an increase in biopsies is expected. The colposcopist will be responsible for managing these additional lesions, and this requires a further optimization and standardization. So the key question remains the training of the colposcopist, and our hope is that health systems will invest resources in this field. Recently, Cruickshank et al 3 reported that, if colposcopic examination results are normal, women with low-grade cervical cytology, even with a positive HPV test, can return to routine recall; this is surely an advantage from both a psychological and economic point of view. Our suggestion for improving the detection of highrate disease is to use a low threshold of abnormality at colposcopy (any acetowhitening); this also will favor better training for the colposcopist, 4 rather than adding nondirected biopsies. Financial Disclosure: The authors did not report any potential conflicts of interest.
Uri Wiesenfeld, MD Francesco Paolo Mangino, MD Franco Giovanni Toffoletti, MD Giuseppe Ricci, MD Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy
REFERENCES 1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol 2014;124:670–8. 2. Jordan J, Martin-Hirsch P, Arbyn M, Schenck U, Baldauf JJ, Da Silva D, et al. European guidelines for clinical management of abnormal cervical cytology, part 2. Cytopathology 2009;20:5–16. 3. Cruickshank M, Cotton S, Sharp L, Smart L, Walker L, Little J, et al. Management of women with low grade cytology: how reassuring is a normal colposcopy examination? BJOG 2014. [Epub ahead of print]. 4. Bentley J. Colposcopic management of abnormal cervical cytology and histology [in English, French]. J Obstet Gynaecol Can 2012;34:1188–202.
VOL. 125, NO. 2, FEBRUARY 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
491
