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To The Editor: Re: Literature Highlights, Journal Sogc, March 1995, Page 279.
' ' '
L E T T E R S
TO
T H E
To THE EDITOR: RE: LITERATURE HIGHLIGHTS, JOURNAL MARCH
' ' '
fetal anomalies five times more frequently. In addition, what is not emphasized in the paper is that indomethacin was used in these infants as a tocolytic of last resort, only after other tocolytics had been used and had failed. Thus, in no way can these two small groups of infants be considered comparable. Although useful as an hypothesis generating paper, this work should not be inferred to be conclusive in any way. In fact, multiple prospective randomized controlled studies have demonstrated no such effect. 2 " These have been performed across a range of gestational ages using clinically appropriate doses of indomethacin in labouring women. The data in fact support a protective effect of indomethacin in intraventricular haemorrhage. In addition, the use of indomethacin has not been shown to be associated with IVH when used to close the ductus arteriosus in preterm neonates. 11 This question will likely not be answered satisfactorily until a large controlled study of indomethacin is performed and, contrary to Dr. Mitchell's somewhat gloomy prognosis that such a study will not be performed, such a study is currently underway in Vancouver and Calgary to address this issue. Necrotizing enterocolitis is another complication of prematurity that has been blamed on, among other things, a mystery virus, the season of the year, fluorescent lighting, plastic and PVC intravenous lines, and now indomethacin. It is clear from animal data that indomethacin can cause focal perforation of the ileum in rats, and it has been reported anecdotally in humans exposed to weeks of indomethacin therapy. 14 The dose of indomethacin that causes these complications is almost always a dose that would be considered excessive by any standard. The randomized placebo controlled studies of indomethacin as a tocolytic, as well as the largest retrospective studies, have repeatedly failed to demonstrate an association between necrotizing enterocolitis and the use of indomethacin in preterm infants. 1;' 16
SOGC,
1995, PAGE 279.
I was somewhat disturbed to see the Literature Highlights section of your prestigious organ being used to cast aspersions upon the use of indomethacin as a tocolytic. Professor Mitchell selectively discusses three papers from the last few years to support his contention that us youngsters are just plain foolish for thinking that indomethacin might be a safe and effective tocolytic. Unfortunately, the vast majority of the evidence in the literature fail to support his apocalyptic predictions for the use of this drug. Indomethacin has a few clearly demonstrated effects during pregnancy: 1. it prolongs gestation in women presenting with preterm labour by seven to ten days. 2. it temporarily reduces amniotic fluid volume when given over prolonged periods of time. 3. it is associated with premature reversible intrauterine constriction of the fetal ductus arteriosus when given for prolonged periods of time in advanced gestations. Other suggested effects of indomethacin, such as increasing the incidence of necrotizing enterocolitis and intraventricular haemorrhage, are not supported by either the animal or human literature. Intraventricular haemorrhage (IVH) has been proposed to be more common in infants being exposed to indomethacin in only one study. 1 This retrospective study is the only one to have demonstrated such an association and compared just 57 exposed infants to 57 controls who had other types of tocolytic. The median dose of indomethacin given was 425mg, but ranged as high as 6,000mg (equivalent to 60 days of continuous tocolytic therapy). Just over half of the indomethacin exposed infants were exposed for longer than four days (itself 2 days more than the recommended course length). Three of the control infants were delivered electively for maternal indications. More control infants were delivered by Caesarean section, and intra-uterine growth restriction (IUGR) was present in the indomethacin exposed group twice as frequently, and
JOURNAL SOGC
EDITOR
Finally, the effects of indomethacin on the ovine fetus are being studied intensively at our centre by myself and Dr. Rurak. We have administered indomethacin at doses comparable to those seen by the human fetus over
118 7
DECEMBER 1995
' ' ' a period of 72 hours whilst monitoring urinary flow, regional blood flow, and metabolic state. We have demonstrated clearly that regional blood flow is not altered to the kidney or the bowel in response to indomethacin infusion, despite a fall in urinary flow rate. Diaphragmatic blood flow alone increases in concert with increased fetal breathing, and lactate levels do tend to rise non-significantly in some animals. Fetal pH, pOz pCOz are not affected by indomethacin. It may well be that hypoxic infants respond to indomethacin in a different fashion, but until the hypoxic experiments are done with appropriate doses of indomethacin, it is impossible to draw conclusions from the animal data. The studies that are quoted by Professor Mitchell 17 ·18 both used excessively high doses of indomethacin, that would never be encountered in human obstetrical practice. Despite these reservations, Professor Mitchell will hear no argument from me if he maintains that tocolysis should not be used in the known presence of fetal hypoxia. It is clear that there are questions surrounding indomethacin, and the current randomized placebo study that is underway in Vancouver and Calgary will, it is hoped, answer concerns regarding both efficacy and safety. Indomethacin, as a tocolytic, should ideally be used as part of a clinically controlled trial, with the possible exception of transport situations, when it is clearly safer than the alternatives. We have chosen a dose of SOmg orally as a starting dose, and 25mg every six hours as a maintenance dose for 48 hours only. Repeat courses must be separated by at least 24 indomethacin-free hours. Indomethacin should not be used at greater than 32 weeks gestation because of the risk of ductal constriction. If these rules are followed, and tocolysis is employed in infants who can clearly tolerate continuing intra-uterine existence, there is no reason to suppose that indomethacin is an unsafe drug. On the other hand, there is every reason to suppose that preterm delivery is a morbid event. Before we rush to judgment on the use of indomethacin as a tocolytic, let us clearly and dispassionately review the facts, both from the human and the animal literature. Let us correctly perform the requisite studies and make a rational decision at the conclusion of those studies. Premature labour is not the common cold-it is a highly morbid event that is in need of effective therapy. If indomethacin is that therapy, we should
JOURNAL SOGC
find out as soon as possible for the benefit of our patients. If it is not helpful, or if it is unsafe, similarly this should be determined as rapidly as possible. That detennination has not yet been made. Yours sincerely, Martin PR Walker, BM, BS, FRCSC, Department of Obstetrics and Gynaecology, Division of Maternal Fetal Medicine, University of British Columbia and, BC Women's Hospital. REFERENCES 1.
2.
3.
Norton ME, Merrill J, Cooper BAB, Kuller JA, Clyman Rl. Neonatal complications after the administration of indomethacin for preterm labor. N Eng I J Med 1993;329:1602-7. Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment for preterm labor. Am J Obstet Gynecol1986;155:747-9. Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, Egner PG. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 1980;136:1 014-9.
4.
5.
6.
7.
8.
Gamissans 0, Balasch J, Fuchs F, Stubblefield PG (Eds). Preterm Birth: causes, prevention and management. Ney York: Macmillan; 1984; 14, Prostaglandin synthetase inhibitors in the treatment of preterm birth. p.223-48. Zuckerman H, Shalev E, Gil ad G, Katzuni E. Further study of the inhibition of preterm labor by indomethacin Part II double-blind study. J Perinat Med 1984;12:25-9. Spearing G. Alcohol, indomethacin, and salbutamol. A comparative trial of their use in preterm labor. Am J Obstet Gynecol 1979;53(2): 171-4. Besinger RE, Niebyl JR, Keyes WG, Johnson TRB. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol 1991 ;164:981-8. Kurki T, Eronen M, Lumme R, Ylikorkala 0. A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. Obstet Gynecol 1991;78:1093-7.
9.
Newton ER, Shields L, Ridgway LE, Berkus MD, Elliott BD. Combination antibiotics and indomethacin in idiopathic preterm labor: a randomized double-blind clinical trial. Am J Obstet Gynecol1991;165:1753-9. 10. Keirse MJNC, Chalmers I (Eds). Oxford Database of Perinatal Trials. Oxford: Oxford University Press; 1992; Indomethacin tocolysis in preterm labour. p. 4383. 11. Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993; 169:97-102.
1188
DECEMBER 1995
' ' ' review articles with no original data. One was retrospective and not randomized and two others had no randomized controls. Only two of the trials with a total of 33 patients in the treatment group compared indomethacin to a placebo. Only three of the eight RCTs showed a beneficial effect of indomethacin, measured as a delay in delivery. In only one of these was there any benefit for more than 24 to 48 hours and the control in this case was Nylidrin. Most of these studies were performed more than a decade ago and contain very few details about the incidence of neonatal intraventricular haemorrhage, necrotizing enterocolitis or renal abnormality. If one looks at the studies published in the last ten years in this restricted series, there were ten cases of documented persistent patent ductus arteriosus in the indomethacin treated group compared to two in the controls, and twenty cases of intraventricular haemorrhage compared to sixteen in the controls. Perhaps the most important statistic from all of these references is that in no study was the overall neonatal outcome significantly different in the indomethacin versus control groups. This, of course, enforces Dr. Walker's argument. However, it also begs the very important question of why we are administering this drug if there is no neonatal benefit. The question of pregnancy prolongation is moot. We are after a better baby! Dr. Walker mentions that evidence suggests indomethacin has a protective effect on intraventricular haemorrhage. This is a confusing issue. Indeed, indomethacin may be beneficial if given to the neonate. However, when administered to the fetus it appears to have the opposite effect. This is exactly analogous to the fetal and neonatal effects of indomethacin on the ductus arteriosus. A potential explanation for these paradoxical effects is provided in the Norton article and elsewhere. 1 All of these prospective data add up to an extremely small number of women (approximately 250) treated with indomethacin. The concerning retrospective data of Norton et al. and Major et al. discussed in the original column cannot be ignored. Other studies have come to similar conclusions 1 and there is a host of animal data suggesting fetal toxicity from prostaglandin synthesis inhibitors. I do not have much hope that the VancouverCalgary study will do anything more than add more inconclusive data to the literature. It may act as fodder for a subsequent meta-analysis but this in no way is a substitute for good scientific evidence.
12. Bivins HA, Newman RB, Fyfe DA, Campbell BA, Stramm SL. Randomized trial of oral indomethacin and terbutaline sulfate for the long-term supression of preterm labor. Am J Obstet Gynecol1993;169:1 065-70. 13. Davis JM, Hendricks-Munoz KD, Hagberg D, Manning JA. The effects of indomethacin on renal function and intracranial hemorrhage in infants with patent ductus arteriosus. Dev Pharmacal Ther 1990;14:15-9. 14. Vanhaesebrouck P, Theiry M, Leroy JG, Govaert P, de Praeter C, Coppens M, Cuvelier C, Dhont M. Oligohydramnios, renal insufficiency and ileal perforation in preterm infants after intrauterine exposure to indomethacin. J Pediatr 1988; 113:738-43. 15. Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala 0, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor. J Pediatr 1994;124:782-8. 16. Dudley DKL, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. Am J Obstet Gynecol 1985;151 :181-4. 17. Hooper SB, Harding R, Deayton J, Thorburn GD. Role of prostaglandins in the metabolic responses of the fetus to hypoxia. Am J Obstet Gynecol1992;166:1568-75. 18. Wlodek ME, Harding R, Thorburn GD. Effects of inhibition of prostaglandin synthesis on flow and composition of fetal urine, lung liquid, and swallowed fluid in sheep. Am J Obstet Gynecol 1994; 170:186-95.
DR. MITCHELL REPLIES
To THE EDITOR: I am delighted for two reasons that Dr. Martin Walker has responded to my column. First, it proves that at least one person read it. Second, Dr. Walker is one of the country's brightest young perinatologists and extremely worthy of a minor spar concerning one of my favourite topics. Dr. Walker suggests that the three papers regarding indomethacin were selected and discussed in a biased fashion. Not so! The three papers came from the literature in November, 1993 to January, 1994 and were selected not only because of their similar publications dates but also because I feel they make a major point. The data were summarized exactly as presented, exactly as written in the original manuscripts. I will admit to adding some editorial comments to reinforce the important points. However, my interpretation of the available literature on indomethacin is quite different from Dr. Walker's. He cites eleven references of prospective randomized controlled studies which demonstrate the drug's safety. I re-reviewed these eleven and the following are the results as I read them. Two of the cited references were
JOURNAL SOGC
1189
DECEMBER 1995
L E T T E R S
TO
T H E
To THE EDITOR: RE: LITERATURE HIGHLIGHTS, JOURNAL MARCH
' ' '
fetal anomalies five times more frequently. In addition, what is not emphasized in the paper is that indomethacin was used in these infants as a tocolytic of last resort, only after other tocolytics had been used and had failed. Thus, in no way can these two small groups of infants be considered comparable. Although useful as an hypothesis generating paper, this work should not be inferred to be conclusive in any way. In fact, multiple prospective randomized controlled studies have demonstrated no such effect. 2 " These have been performed across a range of gestational ages using clinically appropriate doses of indomethacin in labouring women. The data in fact support a protective effect of indomethacin in intraventricular haemorrhage. In addition, the use of indomethacin has not been shown to be associated with IVH when used to close the ductus arteriosus in preterm neonates. 11 This question will likely not be answered satisfactorily until a large controlled study of indomethacin is performed and, contrary to Dr. Mitchell's somewhat gloomy prognosis that such a study will not be performed, such a study is currently underway in Vancouver and Calgary to address this issue. Necrotizing enterocolitis is another complication of prematurity that has been blamed on, among other things, a mystery virus, the season of the year, fluorescent lighting, plastic and PVC intravenous lines, and now indomethacin. It is clear from animal data that indomethacin can cause focal perforation of the ileum in rats, and it has been reported anecdotally in humans exposed to weeks of indomethacin therapy. 14 The dose of indomethacin that causes these complications is almost always a dose that would be considered excessive by any standard. The randomized placebo controlled studies of indomethacin as a tocolytic, as well as the largest retrospective studies, have repeatedly failed to demonstrate an association between necrotizing enterocolitis and the use of indomethacin in preterm infants. 1;' 16
SOGC,
1995, PAGE 279.
I was somewhat disturbed to see the Literature Highlights section of your prestigious organ being used to cast aspersions upon the use of indomethacin as a tocolytic. Professor Mitchell selectively discusses three papers from the last few years to support his contention that us youngsters are just plain foolish for thinking that indomethacin might be a safe and effective tocolytic. Unfortunately, the vast majority of the evidence in the literature fail to support his apocalyptic predictions for the use of this drug. Indomethacin has a few clearly demonstrated effects during pregnancy: 1. it prolongs gestation in women presenting with preterm labour by seven to ten days. 2. it temporarily reduces amniotic fluid volume when given over prolonged periods of time. 3. it is associated with premature reversible intrauterine constriction of the fetal ductus arteriosus when given for prolonged periods of time in advanced gestations. Other suggested effects of indomethacin, such as increasing the incidence of necrotizing enterocolitis and intraventricular haemorrhage, are not supported by either the animal or human literature. Intraventricular haemorrhage (IVH) has been proposed to be more common in infants being exposed to indomethacin in only one study. 1 This retrospective study is the only one to have demonstrated such an association and compared just 57 exposed infants to 57 controls who had other types of tocolytic. The median dose of indomethacin given was 425mg, but ranged as high as 6,000mg (equivalent to 60 days of continuous tocolytic therapy). Just over half of the indomethacin exposed infants were exposed for longer than four days (itself 2 days more than the recommended course length). Three of the control infants were delivered electively for maternal indications. More control infants were delivered by Caesarean section, and intra-uterine growth restriction (IUGR) was present in the indomethacin exposed group twice as frequently, and
JOURNAL SOGC
EDITOR
Finally, the effects of indomethacin on the ovine fetus are being studied intensively at our centre by myself and Dr. Rurak. We have administered indomethacin at doses comparable to those seen by the human fetus over
118 7
DECEMBER 1995
' ' ' a period of 72 hours whilst monitoring urinary flow, regional blood flow, and metabolic state. We have demonstrated clearly that regional blood flow is not altered to the kidney or the bowel in response to indomethacin infusion, despite a fall in urinary flow rate. Diaphragmatic blood flow alone increases in concert with increased fetal breathing, and lactate levels do tend to rise non-significantly in some animals. Fetal pH, pOz pCOz are not affected by indomethacin. It may well be that hypoxic infants respond to indomethacin in a different fashion, but until the hypoxic experiments are done with appropriate doses of indomethacin, it is impossible to draw conclusions from the animal data. The studies that are quoted by Professor Mitchell 17 ·18 both used excessively high doses of indomethacin, that would never be encountered in human obstetrical practice. Despite these reservations, Professor Mitchell will hear no argument from me if he maintains that tocolysis should not be used in the known presence of fetal hypoxia. It is clear that there are questions surrounding indomethacin, and the current randomized placebo study that is underway in Vancouver and Calgary will, it is hoped, answer concerns regarding both efficacy and safety. Indomethacin, as a tocolytic, should ideally be used as part of a clinically controlled trial, with the possible exception of transport situations, when it is clearly safer than the alternatives. We have chosen a dose of SOmg orally as a starting dose, and 25mg every six hours as a maintenance dose for 48 hours only. Repeat courses must be separated by at least 24 indomethacin-free hours. Indomethacin should not be used at greater than 32 weeks gestation because of the risk of ductal constriction. If these rules are followed, and tocolysis is employed in infants who can clearly tolerate continuing intra-uterine existence, there is no reason to suppose that indomethacin is an unsafe drug. On the other hand, there is every reason to suppose that preterm delivery is a morbid event. Before we rush to judgment on the use of indomethacin as a tocolytic, let us clearly and dispassionately review the facts, both from the human and the animal literature. Let us correctly perform the requisite studies and make a rational decision at the conclusion of those studies. Premature labour is not the common cold-it is a highly morbid event that is in need of effective therapy. If indomethacin is that therapy, we should
JOURNAL SOGC
find out as soon as possible for the benefit of our patients. If it is not helpful, or if it is unsafe, similarly this should be determined as rapidly as possible. That detennination has not yet been made. Yours sincerely, Martin PR Walker, BM, BS, FRCSC, Department of Obstetrics and Gynaecology, Division of Maternal Fetal Medicine, University of British Columbia and, BC Women's Hospital. REFERENCES 1.
2.
3.
Norton ME, Merrill J, Cooper BAB, Kuller JA, Clyman Rl. Neonatal complications after the administration of indomethacin for preterm labor. N Eng I J Med 1993;329:1602-7. Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment for preterm labor. Am J Obstet Gynecol1986;155:747-9. Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, Egner PG. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 1980;136:1 014-9.
4.
5.
6.
7.
8.
Gamissans 0, Balasch J, Fuchs F, Stubblefield PG (Eds). Preterm Birth: causes, prevention and management. Ney York: Macmillan; 1984; 14, Prostaglandin synthetase inhibitors in the treatment of preterm birth. p.223-48. Zuckerman H, Shalev E, Gil ad G, Katzuni E. Further study of the inhibition of preterm labor by indomethacin Part II double-blind study. J Perinat Med 1984;12:25-9. Spearing G. Alcohol, indomethacin, and salbutamol. A comparative trial of their use in preterm labor. Am J Obstet Gynecol 1979;53(2): 171-4. Besinger RE, Niebyl JR, Keyes WG, Johnson TRB. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol 1991 ;164:981-8. Kurki T, Eronen M, Lumme R, Ylikorkala 0. A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. Obstet Gynecol 1991;78:1093-7.
9.
Newton ER, Shields L, Ridgway LE, Berkus MD, Elliott BD. Combination antibiotics and indomethacin in idiopathic preterm labor: a randomized double-blind clinical trial. Am J Obstet Gynecol1991;165:1753-9. 10. Keirse MJNC, Chalmers I (Eds). Oxford Database of Perinatal Trials. Oxford: Oxford University Press; 1992; Indomethacin tocolysis in preterm labour. p. 4383. 11. Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993; 169:97-102.
1188
DECEMBER 1995
' ' ' review articles with no original data. One was retrospective and not randomized and two others had no randomized controls. Only two of the trials with a total of 33 patients in the treatment group compared indomethacin to a placebo. Only three of the eight RCTs showed a beneficial effect of indomethacin, measured as a delay in delivery. In only one of these was there any benefit for more than 24 to 48 hours and the control in this case was Nylidrin. Most of these studies were performed more than a decade ago and contain very few details about the incidence of neonatal intraventricular haemorrhage, necrotizing enterocolitis or renal abnormality. If one looks at the studies published in the last ten years in this restricted series, there were ten cases of documented persistent patent ductus arteriosus in the indomethacin treated group compared to two in the controls, and twenty cases of intraventricular haemorrhage compared to sixteen in the controls. Perhaps the most important statistic from all of these references is that in no study was the overall neonatal outcome significantly different in the indomethacin versus control groups. This, of course, enforces Dr. Walker's argument. However, it also begs the very important question of why we are administering this drug if there is no neonatal benefit. The question of pregnancy prolongation is moot. We are after a better baby! Dr. Walker mentions that evidence suggests indomethacin has a protective effect on intraventricular haemorrhage. This is a confusing issue. Indeed, indomethacin may be beneficial if given to the neonate. However, when administered to the fetus it appears to have the opposite effect. This is exactly analogous to the fetal and neonatal effects of indomethacin on the ductus arteriosus. A potential explanation for these paradoxical effects is provided in the Norton article and elsewhere. 1 All of these prospective data add up to an extremely small number of women (approximately 250) treated with indomethacin. The concerning retrospective data of Norton et al. and Major et al. discussed in the original column cannot be ignored. Other studies have come to similar conclusions 1 and there is a host of animal data suggesting fetal toxicity from prostaglandin synthesis inhibitors. I do not have much hope that the VancouverCalgary study will do anything more than add more inconclusive data to the literature. It may act as fodder for a subsequent meta-analysis but this in no way is a substitute for good scientific evidence.
12. Bivins HA, Newman RB, Fyfe DA, Campbell BA, Stramm SL. Randomized trial of oral indomethacin and terbutaline sulfate for the long-term supression of preterm labor. Am J Obstet Gynecol1993;169:1 065-70. 13. Davis JM, Hendricks-Munoz KD, Hagberg D, Manning JA. The effects of indomethacin on renal function and intracranial hemorrhage in infants with patent ductus arteriosus. Dev Pharmacal Ther 1990;14:15-9. 14. Vanhaesebrouck P, Theiry M, Leroy JG, Govaert P, de Praeter C, Coppens M, Cuvelier C, Dhont M. Oligohydramnios, renal insufficiency and ileal perforation in preterm infants after intrauterine exposure to indomethacin. J Pediatr 1988; 113:738-43. 15. Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala 0, Hallman M. Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor. J Pediatr 1994;124:782-8. 16. Dudley DKL, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. Am J Obstet Gynecol 1985;151 :181-4. 17. Hooper SB, Harding R, Deayton J, Thorburn GD. Role of prostaglandins in the metabolic responses of the fetus to hypoxia. Am J Obstet Gynecol1992;166:1568-75. 18. Wlodek ME, Harding R, Thorburn GD. Effects of inhibition of prostaglandin synthesis on flow and composition of fetal urine, lung liquid, and swallowed fluid in sheep. Am J Obstet Gynecol 1994; 170:186-95.
DR. MITCHELL REPLIES
To THE EDITOR: I am delighted for two reasons that Dr. Martin Walker has responded to my column. First, it proves that at least one person read it. Second, Dr. Walker is one of the country's brightest young perinatologists and extremely worthy of a minor spar concerning one of my favourite topics. Dr. Walker suggests that the three papers regarding indomethacin were selected and discussed in a biased fashion. Not so! The three papers came from the literature in November, 1993 to January, 1994 and were selected not only because of their similar publications dates but also because I feel they make a major point. The data were summarized exactly as presented, exactly as written in the original manuscripts. I will admit to adding some editorial comments to reinforce the important points. However, my interpretation of the available literature on indomethacin is quite different from Dr. Walker's. He cites eleven references of prospective randomized controlled studies which demonstrate the drug's safety. I re-reviewed these eleven and the following are the results as I read them. Two of the cited references were
JOURNAL SOGC
1189
DECEMBER 1995