- Email: [email protected]
Maternal effects of antenatal corticosteroid administration
1586 Letters
our gynecologic colleagues are unable to perform laparoscopic surgery safely and without expensive instrumentation, then they are going to have to retrain. If they continue to use expensive and disposable equipment, hospitals will no longer be able to support them. Some gynecologic surgeons must swallow their pride and stop performing difficult laparoscopic surgery if they are not yet qualified. There are innumerable courses offered on a monthly basis by the American Association of Gynecologic Laparoscopists and others. More important, these surgeons need to find proctors to guide them. It is the responsibility of the surgeon to know what he or she is capable of doing safely. I am particularly offended by the myth of market share. It became obvious in the general surgical world that laparoscopic cholecystectomy was demanded by the patients and that all general surgeons needed to learn this laparoscopic approach or they would be left behind. This led to significant complications and deaths, which placed the laparoscopic procedure in jeopardy. In gynecology, however most of our procedures are still being performed vaginally or abdominally instead of laparoscopically. The idea that surgeons are selling laparoscopic procedures to their patients, knowing full well that they cannot be completed laparoscopically, and then completing the procedure traditionally is a sad indictment of our specialty. I do not believe for one minute that this practice is followed by any significant percentage of our gynecologic colleagues. If this is Hopkins’ personal experience, the quality assurance policy at his institution is not doing its job. The myth that the operation is as good with the laparoscope is no myth. Let’s compare the Burch colposuspension. How could one possibly suggest that the visualization of the space of Retzius is not significantly greater when it is performed laparoscopically? Certainly the placement of sutures is far superior. There is little bleeding with the laparoscopic Burch colposuspension relative to the open approach. The 5-year data presented by Ross1 clearly show that results achieved with the laparoscopic Burch procedure are comparable to those achieved with the open Burch procedure. Hopkins considers the intraperitoneal laparoscopic approach to be more dangerous than the open retroperitoneal approach for the Burch procedure. He forgets, however, that there is a 15% incidence of enterocele after Burch colposuspension and that closing the cul-de-sac from the retropubic space might be a little difficult. Laparoscopic sacrocolpopexy is performed in the identical fashion as open sacrocolpopexy. However, it is done through five small incisions instead of an incision that runs from the umbilicus to the symphysis pubis. I find it comical that one might suggest that the recovery is the same. There is little bleeding in the retroperitoneal space with the laparoscopic procedure, and direct visualization of the sacral promontory makes suture placement safe. In summary I believe that Hopkins, who may be a wonderful surgeon when dealing with open procedures, obviously does not have enough laparoscopic experience to make these statements or has been exposed to colleagues who have little or no experience. Those of us who do a
June 2001 Am J Obstet Gynecol
significant amount of laparoscopic surgery are proud of our work. We are proud of our minimal complication rate and our patients’ quick recoveries. I am afraid that most of the criticism of the laparoscopically assisted vaginal hysterectomy is not related to the procedure as much as to patient selection and surgical experience. The requisite experience cannot be acquired in a 3-day course or from a medical supply salesman. We must put in the time to develop laparoscopic skills, and they must be practiced regularly. David J. Levine, MD Department of Obstetrics and Gynecology, St Luke’s Hospital, 224 S Woods Mill Rd, Suite 435 S, Chesterfield, MO 63017 REFERENCE
1. Ross JW. Multichannel urodynamic evaluation of laparoscopic Burch colposuspension genuine stress incontinence. Obstet Gynecol 1998;91:55-9.
6/8/114040 doi:10.1067/mob.2001.114040
Reply To the Editors: Levine’s letter actually highlighted the problems that I outlined in my article, and it strengthens my conviction that too little has been published regarding laparoscopic surgery. Levine’s letter is a nice anecdotal report that contains no data or references. Levine may be a wonderful laparoscopic surgeon, and he should publish his data. That would be a contribution to the scarce data on laparoscopic surgery. Even a report of no complications, however, is only a testimony to the individual surgeon. One of the points of my article was to highlight that few institutional, regional, or national data are available regarding outcomes and complications of laparoscopic surgery. Rather, like Levine, everyone wants this to be good, and we therefore are left mainly with anecdotal letters such as his. Michael P. Hopkins, MD Professor and Director, Department of Obstetrics and Gynecology, Aultman Health Foundation, 200 Sixth St SW, Canton, OH 44710 6/8/114039 doi:10.1067/mob.2001.114039
Maternal effects of antenatal corticosteroid administration To the Editors: The benefits of antenatal glucocorticoid treatment to premature infants are clear, but the efficacy and safety of repeated dosing remain undetermined. The study by McKenna et al (McKenna DS, Wittber GM, Nagaraja HN, Samuels P. The effects of repeat doses of antenatal corticosteroids on maternal adrenal function. Am J Obstet Gynecol 2000;183:669-73) clearly demonstrated suppression of basal and stimulated maternal cortisol after antenatal betamethasone treatment. Although McKenna et al also alluded to possible adverse effects on the neonatal adrenal glands, they did not investigate this possibility directly. McKenna et al also commented that maternal suppression of cortisol was due to the lack of adrenal protein kinase enzyme. Recent studies have clearly shown that in fact kinase is not lacking; rather,
Letters 1587
Volume 184, Number 7 Am J Obstet Gynecol
its activation is suppressed by maternal antenatal steroid treatment. Protein kinase A is activated in response to corticotropin and induces cholesterol transport to cytochrome P-450 side-chain cleavage enzyme (P-450scc), the rate-limiting step in conversion of cholesterol to pregnenolone. Prolonged protein kinase A activation also induces the expression of cytochrome P-450 17αhydroxylase (P-450c17), which is rate limiting for cortisol biosynthesis. Thus it is suppression of pituitary release of corticotropin in response to exogenous glucocorticoid treatment that dramatically decreases levels of cytochrome P-450c17, and subsequently cortisol, in both maternal and fetal rabbit adrenal glands.1 Our recent studies also show that a slight decrease in cytochrome P-450scc may contribute to overall maternal and fetal adrenal suppression but indicate that cytochrome P-450c17 is the primary determinant of cortisol biosynthesis, in agreement with our observations in the human H295R adrenal cell culture model.2 Parker et al3 also demonstrated suppression of cortisol and dehydroepiandrosterone sulfate in cord blood after betamethasone administration but also showed more prolonged suppression of dehydroepiandrosterone sulfate than of cortisol. This makes sense in light of the chronologic pattern of adrenal steroidogenesis, with hydroxylase activity of P-450c17 (conversion of pregnenolone to 17-OH-pregnenolone) being higher than lyase activity (conversion of 17-OH-pregnenolone to dehydroepiandrosterone), and again is in agreement with observations in H295R cells.2 In conclusion, we congratulate McKenna et al on their insightful study of maternal suppression of cortisol after antenatal betamethasone treatment. This study certainly highlights once again that antenatal glucocorticoid use should be examined thoroughly to determine the safety and efficacy of repeated treatments. Finally, although both maternal and neonatal adrenal suppression occur and are reversible, it is less clear whether antenatal multiple courses of glucocorticoids might have prenatal programming effects. Future studies should focus on these long-term effects on the individual’s well being. Jacqueline M. Cale, BS, and Ian M. Bird, PhD Department of Obstetrics and Gynecology, Division of Perinatal Research, University of Wisconsin-Madison, 7E Meriter Hospital Park, 202 S Park St, Madison, WI 53715 REFERENCES
1. Pratt L, Magness RR, Phernetton T, Hendricks SK, Abbott DH, Bird IM. Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome. Am J Obstet Gynecol 1999;180: 995-1005. 2. Bird IM, Mason JI, Rainey WE. Battle of the kinases: integration of adrenal responses to cAMP, DG, and Ca2+ at the level of steroidogenic cytochromes P450 and 3bHSD expression in H295R cells. Endocr Res 1998;24:345-54. 3. Parker CR, Atkinson MW, Owen J, Andrews WW. Dynamics of the fetal adrenal, cholesterol, and apolipoprotein B responses to antenatal betamethasone therapy. Am J Obstet Gynecol 1996; 174:562-5.
6/8/114489 doi:10.1067/mob.2001.114489
Reply To the Editors: We sincerely appreciate Cale and Bird’s clarification of the mechanisms of secondary adrenal insufficiency related to exogenous steroids. Their comments underscore the importance of collaboration between basic scientists and clinicians in maternal-fetal medicine. The suggestion that chronic antenatal exposure to high doses of glucocorticoids may result in adverse fetal cellular programming is particularly worrisome. This issue must be systematically studied, because the full extent of these potential effects may not be apparent for many years. The use of repeated courses of antenatal corticosteroids became routine for many obstetricians after the 1994 National Institutes of Health Consensus Development Conference, despite the lack of evidence attesting to the efficacy and safety of this practice. We applaud the National Institutes of Health’s second consensus statement on antenatal steroids and their recommendation that “repeat courses of antenatal corticosteroids, including rescue therapy, should be reserved for patients enrolled in clinical trials.”1 David S. McKenna, MD Department of Obstetrics and Gynecology, Wright Patterson Air Force Base, 74th Medical Group/SGOG, 4881 Sugar Maple Dr, Dayton, OH 45433
Philip Samuels, MD Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor, Means Hall, 1654 Upham Dr, Columbus, OH 43120 REFERENCE
1. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement Online [serial online] 2000 Aug 17-18; [cited 2001 Jan 19]; 17(2):1-10. Available from: URL: http://odp.od.nih.gov/ consensus/cons/112/112_intro.htm.
6/8/114488 doi:10.1067/mob.2001.114488
Further concerns about the National Institute of Child Health and Human Development guidelines for interpretation of electronic fetal heart rate monitoring To the Editors: We read with interest the paper by Devoe et al (Devoe L, Golde S, Kilman Y, Morton D, Shea K, Waller J. A comparison of visual analyses of intrapartum fetal heart rate tracings according to the new National Institute of Child Health and Human Development guidelines with computer analyses by an automated fetal heart rate monitoring system. Am J Obstet Gynecol 2000;183: 361-6.), keeping in mind the concerns raised in 1998, after the publication of the National Institute of Child and Human Development guidelines for electronic fetal heart rate monitoring.1 We argued at that time that some definitions in these guidelines were still ambiguous and that this ambiguity could have a negative impact on agreement. We also noted some difficulties in interpreting κ values.1 Devoe et al concluded that the National Institute of Child Health and Human Development guidelines “did not increase agreements on most fetal heart rate features
our gynecologic colleagues are unable to perform laparoscopic surgery safely and without expensive instrumentation, then they are going to have to retrain. If they continue to use expensive and disposable equipment, hospitals will no longer be able to support them. Some gynecologic surgeons must swallow their pride and stop performing difficult laparoscopic surgery if they are not yet qualified. There are innumerable courses offered on a monthly basis by the American Association of Gynecologic Laparoscopists and others. More important, these surgeons need to find proctors to guide them. It is the responsibility of the surgeon to know what he or she is capable of doing safely. I am particularly offended by the myth of market share. It became obvious in the general surgical world that laparoscopic cholecystectomy was demanded by the patients and that all general surgeons needed to learn this laparoscopic approach or they would be left behind. This led to significant complications and deaths, which placed the laparoscopic procedure in jeopardy. In gynecology, however most of our procedures are still being performed vaginally or abdominally instead of laparoscopically. The idea that surgeons are selling laparoscopic procedures to their patients, knowing full well that they cannot be completed laparoscopically, and then completing the procedure traditionally is a sad indictment of our specialty. I do not believe for one minute that this practice is followed by any significant percentage of our gynecologic colleagues. If this is Hopkins’ personal experience, the quality assurance policy at his institution is not doing its job. The myth that the operation is as good with the laparoscope is no myth. Let’s compare the Burch colposuspension. How could one possibly suggest that the visualization of the space of Retzius is not significantly greater when it is performed laparoscopically? Certainly the placement of sutures is far superior. There is little bleeding with the laparoscopic Burch colposuspension relative to the open approach. The 5-year data presented by Ross1 clearly show that results achieved with the laparoscopic Burch procedure are comparable to those achieved with the open Burch procedure. Hopkins considers the intraperitoneal laparoscopic approach to be more dangerous than the open retroperitoneal approach for the Burch procedure. He forgets, however, that there is a 15% incidence of enterocele after Burch colposuspension and that closing the cul-de-sac from the retropubic space might be a little difficult. Laparoscopic sacrocolpopexy is performed in the identical fashion as open sacrocolpopexy. However, it is done through five small incisions instead of an incision that runs from the umbilicus to the symphysis pubis. I find it comical that one might suggest that the recovery is the same. There is little bleeding in the retroperitoneal space with the laparoscopic procedure, and direct visualization of the sacral promontory makes suture placement safe. In summary I believe that Hopkins, who may be a wonderful surgeon when dealing with open procedures, obviously does not have enough laparoscopic experience to make these statements or has been exposed to colleagues who have little or no experience. Those of us who do a
June 2001 Am J Obstet Gynecol
significant amount of laparoscopic surgery are proud of our work. We are proud of our minimal complication rate and our patients’ quick recoveries. I am afraid that most of the criticism of the laparoscopically assisted vaginal hysterectomy is not related to the procedure as much as to patient selection and surgical experience. The requisite experience cannot be acquired in a 3-day course or from a medical supply salesman. We must put in the time to develop laparoscopic skills, and they must be practiced regularly. David J. Levine, MD Department of Obstetrics and Gynecology, St Luke’s Hospital, 224 S Woods Mill Rd, Suite 435 S, Chesterfield, MO 63017 REFERENCE
1. Ross JW. Multichannel urodynamic evaluation of laparoscopic Burch colposuspension genuine stress incontinence. Obstet Gynecol 1998;91:55-9.
6/8/114040 doi:10.1067/mob.2001.114040
Reply To the Editors: Levine’s letter actually highlighted the problems that I outlined in my article, and it strengthens my conviction that too little has been published regarding laparoscopic surgery. Levine’s letter is a nice anecdotal report that contains no data or references. Levine may be a wonderful laparoscopic surgeon, and he should publish his data. That would be a contribution to the scarce data on laparoscopic surgery. Even a report of no complications, however, is only a testimony to the individual surgeon. One of the points of my article was to highlight that few institutional, regional, or national data are available regarding outcomes and complications of laparoscopic surgery. Rather, like Levine, everyone wants this to be good, and we therefore are left mainly with anecdotal letters such as his. Michael P. Hopkins, MD Professor and Director, Department of Obstetrics and Gynecology, Aultman Health Foundation, 200 Sixth St SW, Canton, OH 44710 6/8/114039 doi:10.1067/mob.2001.114039
Maternal effects of antenatal corticosteroid administration To the Editors: The benefits of antenatal glucocorticoid treatment to premature infants are clear, but the efficacy and safety of repeated dosing remain undetermined. The study by McKenna et al (McKenna DS, Wittber GM, Nagaraja HN, Samuels P. The effects of repeat doses of antenatal corticosteroids on maternal adrenal function. Am J Obstet Gynecol 2000;183:669-73) clearly demonstrated suppression of basal and stimulated maternal cortisol after antenatal betamethasone treatment. Although McKenna et al also alluded to possible adverse effects on the neonatal adrenal glands, they did not investigate this possibility directly. McKenna et al also commented that maternal suppression of cortisol was due to the lack of adrenal protein kinase enzyme. Recent studies have clearly shown that in fact kinase is not lacking; rather,
Letters 1587
Volume 184, Number 7 Am J Obstet Gynecol
its activation is suppressed by maternal antenatal steroid treatment. Protein kinase A is activated in response to corticotropin and induces cholesterol transport to cytochrome P-450 side-chain cleavage enzyme (P-450scc), the rate-limiting step in conversion of cholesterol to pregnenolone. Prolonged protein kinase A activation also induces the expression of cytochrome P-450 17αhydroxylase (P-450c17), which is rate limiting for cortisol biosynthesis. Thus it is suppression of pituitary release of corticotropin in response to exogenous glucocorticoid treatment that dramatically decreases levels of cytochrome P-450c17, and subsequently cortisol, in both maternal and fetal rabbit adrenal glands.1 Our recent studies also show that a slight decrease in cytochrome P-450scc may contribute to overall maternal and fetal adrenal suppression but indicate that cytochrome P-450c17 is the primary determinant of cortisol biosynthesis, in agreement with our observations in the human H295R adrenal cell culture model.2 Parker et al3 also demonstrated suppression of cortisol and dehydroepiandrosterone sulfate in cord blood after betamethasone administration but also showed more prolonged suppression of dehydroepiandrosterone sulfate than of cortisol. This makes sense in light of the chronologic pattern of adrenal steroidogenesis, with hydroxylase activity of P-450c17 (conversion of pregnenolone to 17-OH-pregnenolone) being higher than lyase activity (conversion of 17-OH-pregnenolone to dehydroepiandrosterone), and again is in agreement with observations in H295R cells.2 In conclusion, we congratulate McKenna et al on their insightful study of maternal suppression of cortisol after antenatal betamethasone treatment. This study certainly highlights once again that antenatal glucocorticoid use should be examined thoroughly to determine the safety and efficacy of repeated treatments. Finally, although both maternal and neonatal adrenal suppression occur and are reversible, it is less clear whether antenatal multiple courses of glucocorticoids might have prenatal programming effects. Future studies should focus on these long-term effects on the individual’s well being. Jacqueline M. Cale, BS, and Ian M. Bird, PhD Department of Obstetrics and Gynecology, Division of Perinatal Research, University of Wisconsin-Madison, 7E Meriter Hospital Park, 202 S Park St, Madison, WI 53715 REFERENCES
1. Pratt L, Magness RR, Phernetton T, Hendricks SK, Abbott DH, Bird IM. Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome. Am J Obstet Gynecol 1999;180: 995-1005. 2. Bird IM, Mason JI, Rainey WE. Battle of the kinases: integration of adrenal responses to cAMP, DG, and Ca2+ at the level of steroidogenic cytochromes P450 and 3bHSD expression in H295R cells. Endocr Res 1998;24:345-54. 3. Parker CR, Atkinson MW, Owen J, Andrews WW. Dynamics of the fetal adrenal, cholesterol, and apolipoprotein B responses to antenatal betamethasone therapy. Am J Obstet Gynecol 1996; 174:562-5.
6/8/114489 doi:10.1067/mob.2001.114489
Reply To the Editors: We sincerely appreciate Cale and Bird’s clarification of the mechanisms of secondary adrenal insufficiency related to exogenous steroids. Their comments underscore the importance of collaboration between basic scientists and clinicians in maternal-fetal medicine. The suggestion that chronic antenatal exposure to high doses of glucocorticoids may result in adverse fetal cellular programming is particularly worrisome. This issue must be systematically studied, because the full extent of these potential effects may not be apparent for many years. The use of repeated courses of antenatal corticosteroids became routine for many obstetricians after the 1994 National Institutes of Health Consensus Development Conference, despite the lack of evidence attesting to the efficacy and safety of this practice. We applaud the National Institutes of Health’s second consensus statement on antenatal steroids and their recommendation that “repeat courses of antenatal corticosteroids, including rescue therapy, should be reserved for patients enrolled in clinical trials.”1 David S. McKenna, MD Department of Obstetrics and Gynecology, Wright Patterson Air Force Base, 74th Medical Group/SGOG, 4881 Sugar Maple Dr, Dayton, OH 45433
Philip Samuels, MD Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor, Means Hall, 1654 Upham Dr, Columbus, OH 43120 REFERENCE
1. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement Online [serial online] 2000 Aug 17-18; [cited 2001 Jan 19]; 17(2):1-10. Available from: URL: http://odp.od.nih.gov/ consensus/cons/112/112_intro.htm.
6/8/114488 doi:10.1067/mob.2001.114488
Further concerns about the National Institute of Child Health and Human Development guidelines for interpretation of electronic fetal heart rate monitoring To the Editors: We read with interest the paper by Devoe et al (Devoe L, Golde S, Kilman Y, Morton D, Shea K, Waller J. A comparison of visual analyses of intrapartum fetal heart rate tracings according to the new National Institute of Child Health and Human Development guidelines with computer analyses by an automated fetal heart rate monitoring system. Am J Obstet Gynecol 2000;183: 361-6.), keeping in mind the concerns raised in 1998, after the publication of the National Institute of Child and Human Development guidelines for electronic fetal heart rate monitoring.1 We argued at that time that some definitions in these guidelines were still ambiguous and that this ambiguity could have a negative impact on agreement. We also noted some difficulties in interpreting κ values.1 Devoe et al concluded that the National Institute of Child Health and Human Development guidelines “did not increase agreements on most fetal heart rate features