- Email: [email protected]
Base excess during cord occlusion
Letters 1811
Volume 189, Number 6 Am J Obstet Gynecol
to match them with a group of nonexposed pregnant women who do smoke or drink. This would enhance the generalizability of the study’s findings to the general population as well. In fact, following up a secondary group of women on nonteratogens, such as antibiotics or over-the-counter analgesics, matched for all potential confounders for all exposed women in the study would provide a much-needed internal control. Inclusion of a disease-matched group might correct for the impact of maternal depression itself on birth outcomes such as low birth weight. As we have found, comparing those exposed to SSRIs with a group of women on other antidepressants such as the tricyclics would better differentiate the effect of the drug from that of the disease itself.3 The authors suggest that studies done by Teratogen Information Services (TIS) are flawed because they are naturalistic. We believe that TIS studies do provide a valuable tool for physicians and their pregnant patients to make well-informed decisions. We feel they provide a balanced approach for studies in teratology because data are gathered prospectively and there are ample possible control groups that can be included. It is more likely for TIS than psychiatric clinics to prospectively collect large numbers of women with depression. Progress in this field will come with multicenter, collaborative studies and the use of a combination of different methods to close gaps in our knowledge about drugs and disease conditions on maternal and fetal health. Natasha Pinto, BSc, and Gideon Koren, MD Motherisk Program, Department of Population Health Sciences, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; e-mail: [email protected] REFERENCES 1. Hendrick V, Smith LM, Sui R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812-5. 2. Burke KC, Burke JD Jr, Rae DS, Regier DA. Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations. Arch Gen Psychiatry 1991;48:789-95. 3. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003;48:106-10.
doi:10.1016/S0002-9378(03)00914-1
Reply To the Editors: We appreciate the letter from Pinto and Koren and agree that more research is needed on the safety of antidepressants during pregnancy. The two cases of major malformations (Hirschprung’s disease and cavum septum pellucidum) were each exposed to an antidepressant (sertraline 50 mg/day and sertraline 150 mg/day, respectively) during the entire pregnancies. We agree that the inclusion of women on antidepressants during pregnancy who smoke and drink, matched with nonexposed pregnant women, might
enhance the generalizability of the studies. On the other hand, nicotine and alcohol exposures might present substantial confounders in studies with relatively small numbers, such as those typically reported from psychiatric clinics. Inclusion of a disease-matched group is another good idea because it helps distinguish between the impact of medications versus the impact of depression on birth outcomes. Our group has completed such a study and recently submitted the results for publication. We wholeheartedly believe that Teratogen Information Services provide an invaluable service to physicians and their pregnant patients. The majority of the information regarding antidepressants in pregnancy has been drawn from these services and we rely on this information daily. As Pinto and Koren point out, Teratogen Information Services are able to collect larger numbers of exposures than psychiatric clinics can. On the other hand, psychiatric clinics may be able to obtain more detailed data on variables such as the course of treatment over the pregnancy. The field certainly benefits from the diversity of methods, each with its particular strengths. Victoria Hendrick, MD, and Lynne Smith, MD UCLA Neuropsychiatric Institute, Department of Psychiatry and Hospital, 300 Medical Plaza Building, Suite 2345, Los Angeles, CA 90095; e-mail: [email protected]
doi:10.1016/S0002-9378(03)00915-3
Base excess during cord occlusion To the Editors: The article of Fujii et al1 suggests that the degree of ovine fetal hippocampal damage after umbilical cord occlusion was correlated with the degree of ischemia and reperfusion but not with acidemic or hypoxic parameters. Although the authors’ conclusion of enhanced sensitivity of hippocampal neurons appears valid, there are concerns with the quantification of base excess (BE) during this protocol and the potential extrapolation to human newborn infants. The authors report a BE during the control period of +7.2 mEq/L. This value is increased compared with reports of other laboratories and may suggest a question as to the calibration of pH and PCO2 determinations and formulas used for the BE determination. For example, Nijland et al2 demonstrated a baseline BE (extracellular fluid) of +0.3 mEq/L. With the completion of 10 minutes of complete cord occlusion, Fujii et al reported a BE of ÿ9.9 mEq/L. However, calculation of extracellular BE by use of the Siggard Anderson nomogram, and with an assumed hemoglobin of 10 g, results in a BE of ÿ5 mEq/L. BE is highly correlated with lactate levels in a nearly 1:1 molar ratio.3 Because Fujii et al measured an increase in lactate from 1.7 to 7.0 mmol/L, these results would suggest a BE change of 5 to 6 mEq/L compared with 17 mEq/mL. This rate of BE change, approximately 1 mEq/L per 2 minutes of complete umbilical cord occlusion, is consistent with evidence from human and animal studies.4 Despite these calculations, the results of the authors of the current study are most important
1812 Letters
because both the reported and recalculated BE values indicate hippocampal damage in the ovine fetus before BE levels associated with fetal asphyxia. These results suggest the potential that hippocampal-related cognitive, memory, or behavioral functions may be influenced by levels of asphyxia without accompanying cerebral palsy or newborn encephalopathy. Michael G. Ross, MD, MPH Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Box 3, 1000 W Carson St, Torrance, CA 90509-2910; e-mail: [email protected] REFERENCES 1. Fujii EY, Takahashi N, Kodama Y, Roman C, Ferriero DM, Parer JT. Hemodynamic changes during complete umbilical cord occlusion in feta sheep related to hippocampal neuronal damage. Am J Obstet Gynecol 2003;188:413-8. 2. Nijland R, Jongsma HW, Nijhuis JG, van den Berg PP, Oeseburg B. Arterial oxygen saturation in relation to metabolic acidosis in fetal lambs. Am J Obstet Gynecol 1995;172:810-9. 3. Morgan TJ, Clark C, Endre ZH. Accuracy of base excess—an in vitro evaluation of the Van Slyke equation. Crit Care Med 2000;28: 2932-2936. 4. Ross MG, Gala R. Use of umbilical artery base excess: algorithm for the timing of hypoxic injury. Am J Obstet Gynecol 2002;187:1-9.
December 2003 Am J Obstet Gynecol
vitro relationship with human adult blood also fits for fetal sheep blood. And the rate of BE change, 1 mEq/L per 2 minutes occlusion, does not seem to fit to our complete occlusion confirmed by zero flow of umbilical artery. Ross reminded me the importance of the treatment of physiologic data and gave me the chance to review our own data. Although I could not fully explain the questions, I assume the conclusion in our paper, hippocampal damage correlated only with the degree of ischemia and reperfusion, would not be affected by these concerns. Eriko Y. Fujii, MD, PhD Gynecology, Maternal- Fetal Medicine, National Center for Child Health and Development, 2-10-1 Okura Setagaya, Tokyo, 157-8535, Japan; e-mail: [email protected] REFERENCES 1. Ball RH, Parer JT, Caldwell LE, Johnson J. Regional blood flow and metabolism in ovine fetuses during severe cord occlusion. Am J Obstet Gynecol 1994;171:1549-55. 2. Mallard EC, Gunn AJ, Williams CCE, Johnston BM, Gluckman PD. Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep. Am J Obstet Gynecol 1992;167:1423-30.
doi:10.1016/S0002-9378(03)00920-7 doi:10.1016/S0002-9378(03)00919-0
Reply To the Editors: Ross was concerned about the increase of our control base excess (BE) compared with reports of other researchers, and he suggested that there might be some calibration or calculation problem in our measurement of pH, PCO2, and BE. We used the same facilities that the other researchers used in the university, and the same technician routinely calibrated the machines before the experiment. I should have mentioned in our article that blood samples were analyzed for pH, PCO2, PO2, and BE at 398C on a Corning analyzer 158. To compare our data with that of others, I recalculated pH and PCO2 at 378C by reversing the temperature correction and then figured out BE with the Siggaard- Anderson nomogram in each fetus. The control values resulted in pH 7.44 ± 0.05, PCO2 48 ± 6 mm Hg, and BE 6.3 ± 2.5 mEq/L, and the values at 10 minutes of occlusion resulted in pH 7.00 ± 0.06, PCO2 114 ± 13 mm Hg, and BE ÿ6.5 ± 4.0 mEq/L. The control BE level that was measured on the same analyzer by Ball et al1 was 5 ± 1 mEq/L in their article. In another 10 minutes of complete occlusion study by Mallard et al,2 the levels of control read pH 7.4, PCO2 57 mm Hg, and lactate 1 mmol/L, and the levels at 10 minutes of occlusion read pH 6.9, PCO2 115 mm Hg, and lactate 5.5 mmol/L in their figures. The BE levels of control and at 10 minutes of occlusion in their study would be estimated about 7.5 and ÿ12.5 mEq/L. Taking these examples together with our data, our control BE condition was not quite far from those in other studies performed on fetal sheep. I cannot comment about the application of the results by Morgan et al to our data, but I just wonder if the in
Fetal betamethasone treatment and neonatal outcome in preeclampsia and intrauterine growth restriction To the Editors: We were interested to read the article of Jobe et al.1 This study demonstrated that fetal betamethasone treatment induced lung maturation without apparent effect on fetal growth. In human preterm infants, repeated maternal antenatal corticosteroid (ANCS) therapy resulted in intrauterine growth restriction (IUGR).2 Maternal ANCS and postnatal surfactant administration are still the mainstays for the prevention and therapy of respiratory distress syndrome (RDS). According to the guidelines of the EURAIL working group (Europe Against Immature Lung) maternal ANCS treatment is indicated between the 26th and 34th weeks of pregnancy for the prevention of RDS.3 ANCS administration is effective if delivery occurs at least 24 hours after the first dose was given. Recent data suggest that in pregnancies complicated with preeclampsia (PE) and/or IUGR the incidence of RDS is not decreased; moreover, the effectiveness of ANCS is a controversial issue.4 We analyzed the perinatal data of 60 neonates born to mothers with severe PE and/or IUGR between the 24th and 32nd weeks of gestation from May 1, 1996, to December 31, 2002, at our perinatal unit. All fetuses were treated with a single intramuscular injection of betamethasone in a dose of 0.5 mg/kg estimated fetal weight for the prophylaxis of RDS because termination of pregnancy for combined maternal/fetal interest was inevitable and fetal lung maturity tests showed immature index values.
Volume 189, Number 6 Am J Obstet Gynecol
to match them with a group of nonexposed pregnant women who do smoke or drink. This would enhance the generalizability of the study’s findings to the general population as well. In fact, following up a secondary group of women on nonteratogens, such as antibiotics or over-the-counter analgesics, matched for all potential confounders for all exposed women in the study would provide a much-needed internal control. Inclusion of a disease-matched group might correct for the impact of maternal depression itself on birth outcomes such as low birth weight. As we have found, comparing those exposed to SSRIs with a group of women on other antidepressants such as the tricyclics would better differentiate the effect of the drug from that of the disease itself.3 The authors suggest that studies done by Teratogen Information Services (TIS) are flawed because they are naturalistic. We believe that TIS studies do provide a valuable tool for physicians and their pregnant patients to make well-informed decisions. We feel they provide a balanced approach for studies in teratology because data are gathered prospectively and there are ample possible control groups that can be included. It is more likely for TIS than psychiatric clinics to prospectively collect large numbers of women with depression. Progress in this field will come with multicenter, collaborative studies and the use of a combination of different methods to close gaps in our knowledge about drugs and disease conditions on maternal and fetal health. Natasha Pinto, BSc, and Gideon Koren, MD Motherisk Program, Department of Population Health Sciences, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; e-mail: [email protected] REFERENCES 1. Hendrick V, Smith LM, Sui R, Hwang S, Haynes D, Altshuler L. Birth outcomes after prenatal exposure to antidepressant medication. Am J Obstet Gynecol 2003;188:812-5. 2. Burke KC, Burke JD Jr, Rae DS, Regier DA. Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations. Arch Gen Psychiatry 1991;48:789-95. 3. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003;48:106-10.
doi:10.1016/S0002-9378(03)00914-1
Reply To the Editors: We appreciate the letter from Pinto and Koren and agree that more research is needed on the safety of antidepressants during pregnancy. The two cases of major malformations (Hirschprung’s disease and cavum septum pellucidum) were each exposed to an antidepressant (sertraline 50 mg/day and sertraline 150 mg/day, respectively) during the entire pregnancies. We agree that the inclusion of women on antidepressants during pregnancy who smoke and drink, matched with nonexposed pregnant women, might
enhance the generalizability of the studies. On the other hand, nicotine and alcohol exposures might present substantial confounders in studies with relatively small numbers, such as those typically reported from psychiatric clinics. Inclusion of a disease-matched group is another good idea because it helps distinguish between the impact of medications versus the impact of depression on birth outcomes. Our group has completed such a study and recently submitted the results for publication. We wholeheartedly believe that Teratogen Information Services provide an invaluable service to physicians and their pregnant patients. The majority of the information regarding antidepressants in pregnancy has been drawn from these services and we rely on this information daily. As Pinto and Koren point out, Teratogen Information Services are able to collect larger numbers of exposures than psychiatric clinics can. On the other hand, psychiatric clinics may be able to obtain more detailed data on variables such as the course of treatment over the pregnancy. The field certainly benefits from the diversity of methods, each with its particular strengths. Victoria Hendrick, MD, and Lynne Smith, MD UCLA Neuropsychiatric Institute, Department of Psychiatry and Hospital, 300 Medical Plaza Building, Suite 2345, Los Angeles, CA 90095; e-mail: [email protected]
doi:10.1016/S0002-9378(03)00915-3
Base excess during cord occlusion To the Editors: The article of Fujii et al1 suggests that the degree of ovine fetal hippocampal damage after umbilical cord occlusion was correlated with the degree of ischemia and reperfusion but not with acidemic or hypoxic parameters. Although the authors’ conclusion of enhanced sensitivity of hippocampal neurons appears valid, there are concerns with the quantification of base excess (BE) during this protocol and the potential extrapolation to human newborn infants. The authors report a BE during the control period of +7.2 mEq/L. This value is increased compared with reports of other laboratories and may suggest a question as to the calibration of pH and PCO2 determinations and formulas used for the BE determination. For example, Nijland et al2 demonstrated a baseline BE (extracellular fluid) of +0.3 mEq/L. With the completion of 10 minutes of complete cord occlusion, Fujii et al reported a BE of ÿ9.9 mEq/L. However, calculation of extracellular BE by use of the Siggard Anderson nomogram, and with an assumed hemoglobin of 10 g, results in a BE of ÿ5 mEq/L. BE is highly correlated with lactate levels in a nearly 1:1 molar ratio.3 Because Fujii et al measured an increase in lactate from 1.7 to 7.0 mmol/L, these results would suggest a BE change of 5 to 6 mEq/L compared with 17 mEq/mL. This rate of BE change, approximately 1 mEq/L per 2 minutes of complete umbilical cord occlusion, is consistent with evidence from human and animal studies.4 Despite these calculations, the results of the authors of the current study are most important
1812 Letters
because both the reported and recalculated BE values indicate hippocampal damage in the ovine fetus before BE levels associated with fetal asphyxia. These results suggest the potential that hippocampal-related cognitive, memory, or behavioral functions may be influenced by levels of asphyxia without accompanying cerebral palsy or newborn encephalopathy. Michael G. Ross, MD, MPH Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Box 3, 1000 W Carson St, Torrance, CA 90509-2910; e-mail: [email protected] REFERENCES 1. Fujii EY, Takahashi N, Kodama Y, Roman C, Ferriero DM, Parer JT. Hemodynamic changes during complete umbilical cord occlusion in feta sheep related to hippocampal neuronal damage. Am J Obstet Gynecol 2003;188:413-8. 2. Nijland R, Jongsma HW, Nijhuis JG, van den Berg PP, Oeseburg B. Arterial oxygen saturation in relation to metabolic acidosis in fetal lambs. Am J Obstet Gynecol 1995;172:810-9. 3. Morgan TJ, Clark C, Endre ZH. Accuracy of base excess—an in vitro evaluation of the Van Slyke equation. Crit Care Med 2000;28: 2932-2936. 4. Ross MG, Gala R. Use of umbilical artery base excess: algorithm for the timing of hypoxic injury. Am J Obstet Gynecol 2002;187:1-9.
December 2003 Am J Obstet Gynecol
vitro relationship with human adult blood also fits for fetal sheep blood. And the rate of BE change, 1 mEq/L per 2 minutes occlusion, does not seem to fit to our complete occlusion confirmed by zero flow of umbilical artery. Ross reminded me the importance of the treatment of physiologic data and gave me the chance to review our own data. Although I could not fully explain the questions, I assume the conclusion in our paper, hippocampal damage correlated only with the degree of ischemia and reperfusion, would not be affected by these concerns. Eriko Y. Fujii, MD, PhD Gynecology, Maternal- Fetal Medicine, National Center for Child Health and Development, 2-10-1 Okura Setagaya, Tokyo, 157-8535, Japan; e-mail: [email protected] REFERENCES 1. Ball RH, Parer JT, Caldwell LE, Johnson J. Regional blood flow and metabolism in ovine fetuses during severe cord occlusion. Am J Obstet Gynecol 1994;171:1549-55. 2. Mallard EC, Gunn AJ, Williams CCE, Johnston BM, Gluckman PD. Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep. Am J Obstet Gynecol 1992;167:1423-30.
doi:10.1016/S0002-9378(03)00920-7 doi:10.1016/S0002-9378(03)00919-0
Reply To the Editors: Ross was concerned about the increase of our control base excess (BE) compared with reports of other researchers, and he suggested that there might be some calibration or calculation problem in our measurement of pH, PCO2, and BE. We used the same facilities that the other researchers used in the university, and the same technician routinely calibrated the machines before the experiment. I should have mentioned in our article that blood samples were analyzed for pH, PCO2, PO2, and BE at 398C on a Corning analyzer 158. To compare our data with that of others, I recalculated pH and PCO2 at 378C by reversing the temperature correction and then figured out BE with the Siggaard- Anderson nomogram in each fetus. The control values resulted in pH 7.44 ± 0.05, PCO2 48 ± 6 mm Hg, and BE 6.3 ± 2.5 mEq/L, and the values at 10 minutes of occlusion resulted in pH 7.00 ± 0.06, PCO2 114 ± 13 mm Hg, and BE ÿ6.5 ± 4.0 mEq/L. The control BE level that was measured on the same analyzer by Ball et al1 was 5 ± 1 mEq/L in their article. In another 10 minutes of complete occlusion study by Mallard et al,2 the levels of control read pH 7.4, PCO2 57 mm Hg, and lactate 1 mmol/L, and the levels at 10 minutes of occlusion read pH 6.9, PCO2 115 mm Hg, and lactate 5.5 mmol/L in their figures. The BE levels of control and at 10 minutes of occlusion in their study would be estimated about 7.5 and ÿ12.5 mEq/L. Taking these examples together with our data, our control BE condition was not quite far from those in other studies performed on fetal sheep. I cannot comment about the application of the results by Morgan et al to our data, but I just wonder if the in
Fetal betamethasone treatment and neonatal outcome in preeclampsia and intrauterine growth restriction To the Editors: We were interested to read the article of Jobe et al.1 This study demonstrated that fetal betamethasone treatment induced lung maturation without apparent effect on fetal growth. In human preterm infants, repeated maternal antenatal corticosteroid (ANCS) therapy resulted in intrauterine growth restriction (IUGR).2 Maternal ANCS and postnatal surfactant administration are still the mainstays for the prevention and therapy of respiratory distress syndrome (RDS). According to the guidelines of the EURAIL working group (Europe Against Immature Lung) maternal ANCS treatment is indicated between the 26th and 34th weeks of pregnancy for the prevention of RDS.3 ANCS administration is effective if delivery occurs at least 24 hours after the first dose was given. Recent data suggest that in pregnancies complicated with preeclampsia (PE) and/or IUGR the incidence of RDS is not decreased; moreover, the effectiveness of ANCS is a controversial issue.4 We analyzed the perinatal data of 60 neonates born to mothers with severe PE and/or IUGR between the 24th and 32nd weeks of gestation from May 1, 1996, to December 31, 2002, at our perinatal unit. All fetuses were treated with a single intramuscular injection of betamethasone in a dose of 0.5 mg/kg estimated fetal weight for the prophylaxis of RDS because termination of pregnancy for combined maternal/fetal interest was inevitable and fetal lung maturity tests showed immature index values.