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The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age
The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age Stephen T. Vermillion, MD, James A. Scardo, MD, Andrew G. Lashus, MD, and Henry B. Wiles, MD Charleston, South Carolina OBJECTIVE: Our purpose was to determine whether continuing exposure to indomethacin tocolysis is associated with an increased incidence of constriction of the human fetal ductus arteriosus with advancing gestational age. STUDY DESIGN: Fetal echocardiograms were reviewed in 61 cases in which the pregnant women were treated for preterm labor with indomethacin (25 mg orally every 6 hours). Density function anaylsis and regression analysis were used to assess the effect of indomethacin tocolysis on ductal constriction with advancing gestational age. RESULTS: A total of 193 fetal echocardiograms were obtained for 72 fetuses. Ductal constriction developed in 50% of the fetuses ranging from 24.7 to 35.0 weeks' gestation. Fetuses with indomethacininduced ductal constriction demonstrated a greater increase in systolic flow velocities with advancing gestational age compared with the nonconstricted group (p < 0.05). Constriction was detected at a mean gestational age of 30.9 + 2.3 weeks at an average of 5.1 + 6.0 days after initiation of therapy. Ductal constriction occurred by 31 weeks' gestation in 70% of the affected fetuses. After discontinuation of indomethacin therapy, all follow-up echocardiograms demonstrated a return to nonconstricted ductal flow velocities. No significant adverse neonatal outcomes were attributed to indomethacin use. CONCLUSIONS: A dramatic yet reversible increase in the incidence of indomethacin-induced ductal constriction occurs at 31 weeks' gestation. However, ductal constriction can occur at any gestational age. With indomethacin tocolysis, weekly fetal echocardiography is warranted for the duration of therapy, (Am J Obstet Gynecol 1997;177:256-61,)
Key words: Indomethacin, ductal constriction, tocolysis
Indomethacin, a prostaglandin synthetase inhibitor, gained popularity in the early 1970s as an effective tocolytic agent for preterm labor. 1 This popularity, however, decreased after several case reports indicating an increase in the incidence of fetal and neonatal complications associated with indomethacin use. 2-5 Such complications included hyperbilirubinemia, necrotizing enterocolitis, intraventricular hemorrhage, and oligohydramnios. Of particular concern were reports of fetal ductus arteriosns constriction with resultant pulmonary hypertension. In the mid-1980s several authors reported supportive clinical trials for the safety and efficacy ofindomethacin when used for short-term tocolysis at a gestational age of <34 weeks.6, 7 Moise s was the first to evaluate serial fetal echocardiography for patients on a regimen of long-term
indomethacin therapy. He concluded that indomethacin therapy should be limited to gestational ages <32 weeks because of the increased incidence of ductal constriction occurring beyond that gestational age. This study prorides the basis on which most clinicians use long-term indomethacin therapy for the suppression of preterm labor. To further validate the results of this single study a retrospective analysis was undertaken to determine whether long-term indomethacin tocolysis is associated with an increased incidence or severity of fetal ductus arteriosus constriction with advancing gestational age. We analyzed both systolic and diastolic ductal flow velocities in both the constricted a n d nonconstricted groups. Additionally, differences between multiple and singleton gestations were evaluated, as were neonatal outcomes.
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Division of Pediatric Cardiology, Department of Pediatrics, Medical University of South Carolina. John R. McCain Presentation, presented as Invited Guest at the Fifty-ninth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 25-28, 199Z Reprint requests: Stephen T. Vermillion, MD, Department of Obstetrics and Gynecology, 171 Ashley Ave., Charleston, SC 29425. Copyright © 1997 by Mosby-Year Book, Inc. 0002-9378/97 $5.00 + 0 6/6/82720
The obstetric and neonatal records for all patients receiving indomethacin therapy for tocolysis between September 1991 and September 1995 at the Medical University of South Carolina in Charleston were reviewed. Only those patients meeting the following inclusion criteria were studied: All patients had accurate gestational age dating with ultrasonographic confirma-
256
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tion on initiation of indomethacin therapy. Only patients receiving an initial dosing of 50 mg rectally followed by 25 mg orally every 6 hours were included in the study. All subjects received continuous indomethacin for >24 hours' duration. Within 48 hours after initiation of therapy all patients underwent ultrasonographic amniotic fluid volume measurement and fetal echocardiograplay to assess fetal ductus arteriosus patency and flow velocity measurements. These studies were performed weekly thereafter until discontinuation of therapy. Any patients with known fetal cardiac anomalies were excluded from the study. Obstetric management and outcome data were obtained from outpatient and inpatient hospital records. Recorded real-time fetal echocardiograms were reviewed with members of the ped{atric cardiology faculty. Ductal constriction was defined as a systolic velocity >1.4 m/sec in conjunction with a diastolic flow velocity >0.35 m/sec. Any additional flow disturbances, including tricuspid regurgitation, were recorded. Neonatal outcome data were obtained from the Medical University of South Carolina perinatal database. Comparisons of adverse neonatal outcomes were made with a control population of non-indomethacin-exposedfetuses matched for gestational age at delivery. The frequency of ductal constriction at each gestational age was evaluated by density function analysis. Regression analysis and the t test were used to compare both systolic and diastolic flow velocities between constricted and nonconstricted groups. The X2 test was used to analyze neonatal outcomes and to compare the incidence of ductal constriction in singleton versus multifetal gestations. A p value < 0.05 was considered significant, Results Sixty-one women with 72 fetuses, including 9 multifetal pregnancies (7 twins, 2 triplets), were studied. Indometh-
acin tocolysis was initiated at a mean gestational age of 28.9 +- 3.2 weeks. All patients received betamethasone on admission; betamethasone was repeated in 24 hours and weekly thereafter until 34 weeks' gestation if delivery did not occur. A total of 193 fetal echocardiograms were reviewed (2.7 -+ 1.6 fetal echocardiograms per patient). Thirty-five cases of ductal constriction (50%) were noted, 18 of which were associated with tricuspid regurgitation. Ductal constriction was detected after a mean duration of 5,1 ± 6.0 days of indomethacin therapy, with a range from 1 to 27 days, Oligohydramnios occurred without ductal constriction in 2 cases, whereas both oligohydramnios and ductal constriction developed in 9 cases. Fig. 1 depicts the density function curve tor all affected fetuses. This demonstrates that the greatest incidence of ductal constriction occurred at 31 weeks' gestation. In addition, ductal constriction had already occurred by 31 weeks' gestation in 70% of the affected fetuses. Constriction was also noted to occur as early as 24.7 weeks' gestation. The regression analysis in Fig. 2 demonstrates a linear relationship between advancing gestational age and systolic flow velocity in both constricted and nonconstricted groups. In the constricted group advancing gestational age was associated with a more rapid increase in systolic flow velocity (p < 0.05). A comparison of the regression analyses for the constricted and nonconstricted groups with respect to diastolic flow velocity and advancing gestational age was not statistically significant (Fig. 3). Thirty-one of the 35 fetuses with' constriction underwent echocardiography and ultrasonographic amniotic fluid volume assessment within 8 days after discontinuation of therapy. All fetuses had a return to nonconstricted flow velocities without any significant flow disturbances. All 11 cases of oligohydramnios had reaccumulation of amniotic fluid to an amniotic fluid index > 5 cm.
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There were no adverse neonatal outcomes attributable to indomethacin therapy when compared with nonexposed controls (p > 0.05). There were no significant differences between singleton and muhifetal gestations with regard to the incidence or timing of ductal constriction (p > 0.05), Among twin gestations both fetuses demonstrated ductal constriction in 5 of 7 cases. One of the two sets of triplets demonstrated ductal constriction; however, only one of the three fetuses was affected. Comment
Indomethacin has been reported to be an effective agent in the treatment of preterm labor. 1'9 Concerns with premature closure of the fetal ductus arteriosus during indomethacin therapy have led to recommendations for serial fetal echocardiography. Additionally, the current recommendation restricting its use to pregnancies <32 weeks is because of the reported increased incidence of ductal constriction that occurs beyond that gestational age. s The current study was undertaken to determine the risk for ductal constriction with continuous indomethacin tocolysis with advancing gestational age. In a recent study by Moise ~ ductal constriction developed in 28% ofindomethacin-exposed fetuses, and 50% of the affected fetuses had constriction by 32 weeks' gestation. We identified a substantially higher incidence of ductal constriction, which developed in 50% of indomethacin-exposed fetuses, with the greatest incidence occurring at 31 weeks' gestation. Of the affected fetuses, 70% had demonstrated constriction by 31 weeks' gestation. Our findings lend further support to the recommendation for limiting the use of indomethacin beyond 31 to 32 weeks' gestation.
Earlier investigators provided supporting evidence for the safety of short-term indomethacin tocolysis before 34 weeks' gestation. 6' 7 Also, case reports of persistent fetal circulation in neonates as a result of fetal ductal constriction from antenatal indomethacin exposure were attributed to exposure in the late third trimester. 2-5 Animal studies support the concept of increasing sensitivity of the fetal ductus arteriosus with advancing gestational age with little effect on the premature ductus. 1°'11 Despite such evidence, both our study and Moise's studies demonstrated ductal constriction before 25 weeks' gestation. This suggests that indomethacin affects the ductus arteriosus at earlier gestational ages than previously suspected. Thus serial fetal echocardiography surveillance is indicated regardless of gestational age. Gerson et al. 12 evaluated neonatal outcomes of fetuses exposed continuously to indomethacin without fetal echocardiography evaluation. In their study irreversible pulmonary hypertension resulting from prolonged fetal ductal constriction developed in several fetuses. Because there was no fetal ductal evaluation, it is unknown at what interval constriction led to irreversible cardiac effects. In our study all fetuses with ductal constriction who underwent follow-up fetal echocardiographic evaluation (31 of 35 fetuses) after discontinuation of therapy demonstrated complete reversal of ductal constriction without any significant residual flow disturbances. The greatest interval between echocardiographic evaluations in identifying constriction was 8 days. This might suggest that weekly surveillance is adequate to detect constriction and be able to discontinue therapy without any significant fetal cardiac sequelae. Other ultrasonographic findings such as oligohydramnios or fetal tricuspid regurgitation have been suggested
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as predictive of fetal ductal constriction. A l t h o u g h indom e t h a c i n can cause decreased renal perfusion resulting in oligohydramnios, we f o u n d that oligohydramnios and ductal constriction o c c u r r e d i n d e p e n d e n t l y of each other. Also, all cases of oligohydramnios resolved after p r o m p t discontinuation of therapy. Ultrasonographic amniotic fluid v o l u m e assessment is thus warranted in addition to fetal e c h o c a r d i o g r a p h y regardless of fetal ductal flow velocities. With regard to tricuspid regurgitation it is technically easier to identify than ductal patency, la and some authors have suggested that it can be used to predict ductal constriction. In our study tricuspid regurgitation was associated with ductal constriction in 18 of 35 fetuses; however, it was not indicative of evolving or established ductal constriction. In twin gestations constriction occurred uniformly between fetuses but with variations in flow velocities. In the two triplet gestations constriction occurred in only one set, and in that set it occurred in only one of the three fetuses. All three fetuses in each set of triplets demonstrated wide variations in flow velocities. Similar inconsistencies in dnctal flow velocities between fetuses in multifetal gestations have been demonstrated by other authors. 8 In multiple gestations, therefore, it is important to perform fetal echocardiography on each fetus individually. O u r study c o n f i r m e d a positive linear relationship between ductal flow velocities and advancing gestational age as previously reported. 14 In particular, the constricted g r o u p of fetuses d e m o n s t r a t e d a m o r e rapid increase in systolic flow velocity that was earlier in onset w h e n c o m p a r e d with the nonconstricted group. This may suggest that systolic flow velocity is a m o r e sensitive indicator for those fetuses at increased risk o f indom e t h a c i n - i n d u c e d ductal constriction. Also, recognition of early increasing trends in systolic flow velocity may further aid clinicians in identifying those at-risk fetuses. Constriction of the fetal ductus arteriosus during ind o m e t h a c i n tocolysis can occur at any gestational age. However, ductal constriction has b e e n shown to be completely reversible with early identification and timely discontinuation of therapy. T h e dramatic increase in the incidence of ductal constriction that occurs after 31 weeks' gestation warrants caution w h e n i n d o m e t h a c i n is used beyond this gestational age. With close surveillance, including weekly fetal e c h o c a r d i o g r a p h y and amniotic fluid v o l u m e assessment, i n d o m e t h a c i n can be safely used for the t r e a t m e n t of p r e t e r m labor. We acknowledge J e a n M. Canty, BS, Melisa M. Holmes, MD, and R o g e r B. Newman, MD. REFERENCES
I. Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974;44: 787-92. 2. Manchester D, Mayolis HS, Sheldon RE. Possible association
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between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. AmJ Obstet Gynecol 1976;126:467-9. 3. Rubaitelli FF, Chiozza ML, Zanardo V, Cantarutti F. Effects on neonate of maternal treatment with indomethacin. J Pediatr 1979;94:161-5. 4. Arcilia KA, Thilenius OG, Ranninger K. Congenital heart failure from suspected ductal closure in utero. J Pediatr 1969;75:74-8. 5. Csaba IF, Sulyok E, Ertl T. Clinical note: relationship of maternal treatment with indomethacin to persistence of fetal circulation syndrome. J Pediatr 1978;92:484~ 6. Dudley DK, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. Am J Obstet Gynecol 1985;151:1814. 7. NiebylJR, Witter FR. Neonatal outcome after indornethacin treatment for premature labor. A m J Obstet Gynecol 1986; 155:747-9. 8. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use. Am J Obstet Gynecol 1993;168: 1350-3. 9. Zuckerman H, Shalev E, Gilad G, Katzuni E, Further study of the inhibition of premature labor by indomethacin. Part II. Double blind study. J Perinat Med 1984;12:25-9. 10. Klein KL, Scott WJ, Clark KE, Wilson JG. Indomethacin-placental transfer, cytotoxity, and teratology in the rat. AmJ Obstet Gynecol 1981;141:448-52. 11. Moise KJ, Huhta JC, Sharif DS, Ou C, Kirshon B, Wasserstrum N, Cano L. Indomethacin in the treatment of preterm labor. N EnglJ IVied 1988:319:327-31. 12. Gerson A, Abbasi S, Johnson A, Kalchbrenner M, Ashmead G, Bolognese R. Safety and efficacy of long-term tocolysis with indomethacin. Am J Perinatol 1990;7:71-4. 13. Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 14. Eronen M, Pesonen E, Kurki T, Ylikorkala O, Hallman M. The effects of indomethacin and a heta-sympathomimetic agent on the fetal ductus arteriosus during treatment of premature labor: a randomized double-blind study. Am J Obstet Gynecol 1991;164;141-6.
Discussion
DR. SUSANL. EPLEY, Orlando, Florida (Official Guest). Preterm delivery complicates at least 6% to 8% o f all births in the U n i t e d States. Complications f r o m prematurity account for 75% of all perinatal morbidity and mortality. Only a minority of patients at risk for p r e t e r m labor will be identified by epidemiologic studies. Thus tocolytic therapy remains the obstetrician's main weapon in r e d u c i n g p r e t e r m births, yet it is still uncertain whether tocolytic therapy i m p r o v e s perinatal outcome. T h e r e f o r e all tocolytic agents must be used thoughtfully. Fetal and maternal d r u g toxicity must be weighed against the benefits of p r o l o n g i n g pregnancy. Agents used for tocolysis have i n c l u d e d alcohol, magnesium sulfate, and [3-sympathomimetics. Significant maternal complications have b e e n associated with the use of all these drugs. Z u c k e r m a n et al. 1 first p r o p o s e d the use of i n d o m e t h a c i n , a prostaglandin synthase inhibitor, for t r e a t m e n t o f p r e m a t u r e labor. Prostaglandin release plays a key role in cervical ripening, f o r m a t i o n of myometrial gap junctions, and initiation of uterine contractions. 2 Multiple authors including Morales et al. s and
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Niebyl and Wither s have c o n f i r m e d i n d o m e t h a c i n to be an effective tocolytic with few maternal side effects. However, several studies have shown i n d o m e t h a c i n therapy to be a double-edged sword. I n d o m e t h a c i n is known to cross the h u m a n placenta freely, i n d e p e n d e n t of gestational age. 5 It inhibits prostaglandin synthesis in the developing fetus, thus affecting multiple organ systems. R e p o r t e d neonatal complications f r o m in u t e r o i n d o m e t h a c i n exposure have i n c l u d e d oligohydramnios, p r e m a t u r e closure of the ductus arteriosus, intraventricular h e m o r r h a g e , hyperbilirubinemia, necrotizing enterocolitis, isolated intestinal perforation, fetal platelet dysfunction, and impaired renal function. O n e of the most fearsome fetal complications has b e e n p r e m a t u r e closure of the ductus arteriosus. T h e ductus arteriosus allows shunting of the right ventricular stroke o u t p u t into the aorta, bypassing the high-resistance pulmonary vascular bed. P r e m a t u r e closure of the ductus arteriosus can result in persistent neonatal p u l m o n a r y hypertension. F u r t h e r m o r e , after initial constriction of the ductus arteriosus, the vessel's ability to constrict again may be limited as a result of early ischemic damage to the intimal layer of the vessel wall. Perhaps this explains the increased incidence of patent ductus arteriosus in neonates after in utero i n d o m e t h a c i n exposure. 6 In this retrospective review study Vermillion et al. have a t t e m p t e d to further e n h a n c e our knowledge of the risk of fetal constriction of the ductus arteriosus associated with in utero i n d o m e t h a c i n exposure. T h e i r data are consistent with previous studies showing that i n d o m e t h acin can induce constriction of the ductus arteriosus in the developing h u m a n fetus. They support the evidence that the h u m a n fetal ductus arteriosus is sensitive to the constrictive effects of i n d o m e t h a c i n as early as the late second trimester. Additionally, this article's focused review agrees with prior investigators that the ductus arteriosus becomes m o r e sensitive to the constrictive effect of i n d o m e t h a c i n as gestational age increases. This study offers some practical suggestions on how to follow up patients receiving indomethacin. Previously, Doppler e c h o c a r d i o g r a p h y has b e e n used to diagnose fetal ductus arteriosus constriction by revealing a characteristic increase in peak systolic and diastolic flow velocity measurements. 7 T h e authors have e x p a n d e d on the work of Moise s to propose weekly peak systolic flow measurements to identify and perhaps predict the fetus in w h o m ductal constriction will develop. They agree with o t h e r investigators who r e c o m m e n d limiting the use of indom e t h a c i n tocolysis to gestations of 31 to 32 weeks or more. T h e authors also make the intriguing original suggestion that fetuses who have closure of the ductus arteriosus have a m o r e rapid increase i.n systolic flow velocity on serial fetal e c h o c a r d i o g r a p h i c studies. This exciting new use of technology adds to the c o m p l e x issue of weighing the risks and benefits of i n d o m e t h a c i n tocolysis. I c o m m e n d the researchers for these impressive findings. In closing, I would ask the authors the following questions: (1) O n c e an elevated systolic ductal velocity is
August 1997 Am J Obstet Gynecol
found, should i n d o m e t h a c i n tocolysis always be immediately stopped? If so, at what ductal velocity m e a s u r e m e n t ? (2) M o m m a and Takao 9 r e p o r t e d the c o m b i n a t i o n of i n d o m e t h a c i n and b e t a m e t h a s o n e to be associated with an even greater degree of ductal constriction. H o w many of your patients received betamethasone? Did the corticosteroid-treated patients have a greater d e g r e e of ductal constriction? (3) O b t a i n i n g accurate ductal velocity measurements requires a skilled sonographer. Measurements are often highly d e p e n d e n t on fetal position. Was it possible to obtain m e a s u r e m e n t s on each fetus weekly? Who did these studies and how many studies had previously b e e n p e r f o r m e d by the sonographer?
REFERENCES
1. Zuckerman H, Reiss. U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974;44: 787-92. 2. Huszan G, Naftolin F. The myometrium and uterine cervix in normal and preterm labor. N EnglJ Med 1984;311:57181. 3. Morales WJ, Smith SG, Angel JL, O'Brien WP, Knuppel RA. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor; a randomized study. Obstet Gynecol 1989;74:567~72. 4. Niebyl JR, Wither RF. Neonatal outcome after indomethacin treatment for premature labor. Am J Obstet Gynecol 1986;155:747-9. 5. Van Den Veyver IB, Moise KJ Jr. Prostaglandin synthetase inhibitors in pregnancy. Obstet Gynecol Surv 1993;48:493502. 6. Clyman RI, Campbell D, Heymann MA, Mauray F. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin induced closure. Circulation 1985;71:141-5. 7. Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 8. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use. Am J Obstet Gynecol 1993;168: 1350-3. 9. Momma K, Takao A. Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats. Pediatr Res 1989;25:69-75. DR. RoNan~ V. W ~ E , Charlotte, N o r t h Carolina. Were any of the patients receiving [3-adrenergic r e c e p t o r agents or anything that could increase the fetal cardiac rate? We know that w h e n there is a situation involving fetal tachycardia there can be an increase in the systolic velocity. Parallel to that, can you tell us how many o f these constrictions were diagnosed on the basis of systolic only, diastolic only, or both? DR. StrNWT P. C n A ~ , Augusta, Georgia. How many patients with and without constriction received indomethacin for < 2 4 hours, 24 to 48 hours, and > 4 8 hours? Were any o t h e r tocolytics used and what was the indication f o r switching to i n d o m e t h a c i n ? If there is no clinical significance of the ductal constriction, why is there so m u c h c o n c e r n if the c o n s e q u e n c e is only some technical deviation in the systolic and diastolic flow?
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DR. VERNn,HON (Closing). In response to Dr. Epley's questions regarding elevated systolic velocity without constriction, I believe that if the situation is such that there is a clear benefit to continued tocolysis then therapy should be continued, provided there are not any obvious flow disturbances and that the patient is reliable and can be followed up for weekly echo surveillance. Further, not all fetuses with an elevated systolic velocity trend ultimately had ductal constriction, and those fetuses in whom constriction did develop had complete reversibility after p r o m p t identification and discontinuation of therapy within 1 week of a previously nonconstricted study. Second, all patients in the study received betamethasone on admission; betamethasone was repeated in 24 hours and weekly thereafter until 34 weeks' gestation if delivery did not occur. Finally, all ductal velocity measurements were obtainable on all fetuses studied, and all the studies were performed by one of two certified technicians in the pediatric cardiology echo laboratory. Further, all echo studies were initially reviewed by the pediatric cardiology attending faculty for accuracy. Concerning Dr. Wade's and Dr. Chauhan's questions regarding fetal tachycardia and the use of other tocolyt-
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ics, particularly [3-adrenergic receptor agents, all patients initially underwent tocolysis with magnesium sulfate. Only 8 patients had a trial of terbutaline, in which no patient received more than two doses. Six of the 8 patients were switched m indomethacin because of increasing uterine activity with terbutaline, whereas the remaining two were unable to tolerate terbutaline because of maternal tachycardia. Subsequently, none of these 8 subjects had fetal ductal constriction with indomethacin therapy. Of the 35 fetuses with ductal constriction 16 had the diagnosis made on the basis of systolic measurements alone, 15 had both systolic and diastolic measurements, and only 4 cases were diagnosed with diastolic measurements alone. W{th respect to the duration of therapy, patients with indomethacin therapy for <24 hours were not studied. Twenty-six patients received therapy for 24 to 48 hours, whereas 46 received indomethacin for >48 hours. Nnally, I would reemphasize that whereas ductal constriction is completely reversible after p r o m p t identification and discontinuation of indornethacin therapy, continued prolonged use with unrecognized constriction greatly increases the risk of that fetus for irreversible changes of the ductus arteriosus, including pulmonary hypertension.
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Key words: Indomethacin, ductal constriction, tocolysis
Indomethacin, a prostaglandin synthetase inhibitor, gained popularity in the early 1970s as an effective tocolytic agent for preterm labor. 1 This popularity, however, decreased after several case reports indicating an increase in the incidence of fetal and neonatal complications associated with indomethacin use. 2-5 Such complications included hyperbilirubinemia, necrotizing enterocolitis, intraventricular hemorrhage, and oligohydramnios. Of particular concern were reports of fetal ductus arteriosns constriction with resultant pulmonary hypertension. In the mid-1980s several authors reported supportive clinical trials for the safety and efficacy ofindomethacin when used for short-term tocolysis at a gestational age of <34 weeks.6, 7 Moise s was the first to evaluate serial fetal echocardiography for patients on a regimen of long-term
indomethacin therapy. He concluded that indomethacin therapy should be limited to gestational ages <32 weeks because of the increased incidence of ductal constriction occurring beyond that gestational age. This study prorides the basis on which most clinicians use long-term indomethacin therapy for the suppression of preterm labor. To further validate the results of this single study a retrospective analysis was undertaken to determine whether long-term indomethacin tocolysis is associated with an increased incidence or severity of fetal ductus arteriosus constriction with advancing gestational age. We analyzed both systolic and diastolic ductal flow velocities in both the constricted a n d nonconstricted groups. Additionally, differences between multiple and singleton gestations were evaluated, as were neonatal outcomes.
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Division of Pediatric Cardiology, Department of Pediatrics, Medical University of South Carolina. John R. McCain Presentation, presented as Invited Guest at the Fifty-ninth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 25-28, 199Z Reprint requests: Stephen T. Vermillion, MD, Department of Obstetrics and Gynecology, 171 Ashley Ave., Charleston, SC 29425. Copyright © 1997 by Mosby-Year Book, Inc. 0002-9378/97 $5.00 + 0 6/6/82720
The obstetric and neonatal records for all patients receiving indomethacin therapy for tocolysis between September 1991 and September 1995 at the Medical University of South Carolina in Charleston were reviewed. Only those patients meeting the following inclusion criteria were studied: All patients had accurate gestational age dating with ultrasonographic confirma-
256
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257
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tion on initiation of indomethacin therapy. Only patients receiving an initial dosing of 50 mg rectally followed by 25 mg orally every 6 hours were included in the study. All subjects received continuous indomethacin for >24 hours' duration. Within 48 hours after initiation of therapy all patients underwent ultrasonographic amniotic fluid volume measurement and fetal echocardiograplay to assess fetal ductus arteriosus patency and flow velocity measurements. These studies were performed weekly thereafter until discontinuation of therapy. Any patients with known fetal cardiac anomalies were excluded from the study. Obstetric management and outcome data were obtained from outpatient and inpatient hospital records. Recorded real-time fetal echocardiograms were reviewed with members of the ped{atric cardiology faculty. Ductal constriction was defined as a systolic velocity >1.4 m/sec in conjunction with a diastolic flow velocity >0.35 m/sec. Any additional flow disturbances, including tricuspid regurgitation, were recorded. Neonatal outcome data were obtained from the Medical University of South Carolina perinatal database. Comparisons of adverse neonatal outcomes were made with a control population of non-indomethacin-exposedfetuses matched for gestational age at delivery. The frequency of ductal constriction at each gestational age was evaluated by density function analysis. Regression analysis and the t test were used to compare both systolic and diastolic flow velocities between constricted and nonconstricted groups. The X2 test was used to analyze neonatal outcomes and to compare the incidence of ductal constriction in singleton versus multifetal gestations. A p value < 0.05 was considered significant, Results Sixty-one women with 72 fetuses, including 9 multifetal pregnancies (7 twins, 2 triplets), were studied. Indometh-
acin tocolysis was initiated at a mean gestational age of 28.9 +- 3.2 weeks. All patients received betamethasone on admission; betamethasone was repeated in 24 hours and weekly thereafter until 34 weeks' gestation if delivery did not occur. A total of 193 fetal echocardiograms were reviewed (2.7 -+ 1.6 fetal echocardiograms per patient). Thirty-five cases of ductal constriction (50%) were noted, 18 of which were associated with tricuspid regurgitation. Ductal constriction was detected after a mean duration of 5,1 ± 6.0 days of indomethacin therapy, with a range from 1 to 27 days, Oligohydramnios occurred without ductal constriction in 2 cases, whereas both oligohydramnios and ductal constriction developed in 9 cases. Fig. 1 depicts the density function curve tor all affected fetuses. This demonstrates that the greatest incidence of ductal constriction occurred at 31 weeks' gestation. In addition, ductal constriction had already occurred by 31 weeks' gestation in 70% of the affected fetuses. Constriction was also noted to occur as early as 24.7 weeks' gestation. The regression analysis in Fig. 2 demonstrates a linear relationship between advancing gestational age and systolic flow velocity in both constricted and nonconstricted groups. In the constricted group advancing gestational age was associated with a more rapid increase in systolic flow velocity (p < 0.05). A comparison of the regression analyses for the constricted and nonconstricted groups with respect to diastolic flow velocity and advancing gestational age was not statistically significant (Fig. 3). Thirty-one of the 35 fetuses with' constriction underwent echocardiography and ultrasonographic amniotic fluid volume assessment within 8 days after discontinuation of therapy. All fetuses had a return to nonconstricted flow velocities without any significant flow disturbances. All 11 cases of oligohydramnios had reaccumulation of amniotic fluid to an amniotic fluid index > 5 cm.
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Fig, 3. Diastolic flow velocity by gestational age.
Fig. 2. Systolicflow velocity by gestational age.
There were no adverse neonatal outcomes attributable to indomethacin therapy when compared with nonexposed controls (p > 0.05). There were no significant differences between singleton and muhifetal gestations with regard to the incidence or timing of ductal constriction (p > 0.05), Among twin gestations both fetuses demonstrated ductal constriction in 5 of 7 cases. One of the two sets of triplets demonstrated ductal constriction; however, only one of the three fetuses was affected. Comment
Indomethacin has been reported to be an effective agent in the treatment of preterm labor. 1'9 Concerns with premature closure of the fetal ductus arteriosus during indomethacin therapy have led to recommendations for serial fetal echocardiography. Additionally, the current recommendation restricting its use to pregnancies <32 weeks is because of the reported increased incidence of ductal constriction that occurs beyond that gestational age. s The current study was undertaken to determine the risk for ductal constriction with continuous indomethacin tocolysis with advancing gestational age. In a recent study by Moise ~ ductal constriction developed in 28% ofindomethacin-exposed fetuses, and 50% of the affected fetuses had constriction by 32 weeks' gestation. We identified a substantially higher incidence of ductal constriction, which developed in 50% of indomethacin-exposed fetuses, with the greatest incidence occurring at 31 weeks' gestation. Of the affected fetuses, 70% had demonstrated constriction by 31 weeks' gestation. Our findings lend further support to the recommendation for limiting the use of indomethacin beyond 31 to 32 weeks' gestation.
Earlier investigators provided supporting evidence for the safety of short-term indomethacin tocolysis before 34 weeks' gestation. 6' 7 Also, case reports of persistent fetal circulation in neonates as a result of fetal ductal constriction from antenatal indomethacin exposure were attributed to exposure in the late third trimester. 2-5 Animal studies support the concept of increasing sensitivity of the fetal ductus arteriosus with advancing gestational age with little effect on the premature ductus. 1°'11 Despite such evidence, both our study and Moise's studies demonstrated ductal constriction before 25 weeks' gestation. This suggests that indomethacin affects the ductus arteriosus at earlier gestational ages than previously suspected. Thus serial fetal echocardiography surveillance is indicated regardless of gestational age. Gerson et al. 12 evaluated neonatal outcomes of fetuses exposed continuously to indomethacin without fetal echocardiography evaluation. In their study irreversible pulmonary hypertension resulting from prolonged fetal ductal constriction developed in several fetuses. Because there was no fetal ductal evaluation, it is unknown at what interval constriction led to irreversible cardiac effects. In our study all fetuses with ductal constriction who underwent follow-up fetal echocardiographic evaluation (31 of 35 fetuses) after discontinuation of therapy demonstrated complete reversal of ductal constriction without any significant residual flow disturbances. The greatest interval between echocardiographic evaluations in identifying constriction was 8 days. This might suggest that weekly surveillance is adequate to detect constriction and be able to discontinue therapy without any significant fetal cardiac sequelae. Other ultrasonographic findings such as oligohydramnios or fetal tricuspid regurgitation have been suggested
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as predictive of fetal ductal constriction. A l t h o u g h indom e t h a c i n can cause decreased renal perfusion resulting in oligohydramnios, we f o u n d that oligohydramnios and ductal constriction o c c u r r e d i n d e p e n d e n t l y of each other. Also, all cases of oligohydramnios resolved after p r o m p t discontinuation of therapy. Ultrasonographic amniotic fluid v o l u m e assessment is thus warranted in addition to fetal e c h o c a r d i o g r a p h y regardless of fetal ductal flow velocities. With regard to tricuspid regurgitation it is technically easier to identify than ductal patency, la and some authors have suggested that it can be used to predict ductal constriction. In our study tricuspid regurgitation was associated with ductal constriction in 18 of 35 fetuses; however, it was not indicative of evolving or established ductal constriction. In twin gestations constriction occurred uniformly between fetuses but with variations in flow velocities. In the two triplet gestations constriction occurred in only one set, and in that set it occurred in only one of the three fetuses. All three fetuses in each set of triplets demonstrated wide variations in flow velocities. Similar inconsistencies in dnctal flow velocities between fetuses in multifetal gestations have been demonstrated by other authors. 8 In multiple gestations, therefore, it is important to perform fetal echocardiography on each fetus individually. O u r study c o n f i r m e d a positive linear relationship between ductal flow velocities and advancing gestational age as previously reported. 14 In particular, the constricted g r o u p of fetuses d e m o n s t r a t e d a m o r e rapid increase in systolic flow velocity that was earlier in onset w h e n c o m p a r e d with the nonconstricted group. This may suggest that systolic flow velocity is a m o r e sensitive indicator for those fetuses at increased risk o f indom e t h a c i n - i n d u c e d ductal constriction. Also, recognition of early increasing trends in systolic flow velocity may further aid clinicians in identifying those at-risk fetuses. Constriction of the fetal ductus arteriosus during ind o m e t h a c i n tocolysis can occur at any gestational age. However, ductal constriction has b e e n shown to be completely reversible with early identification and timely discontinuation of therapy. T h e dramatic increase in the incidence of ductal constriction that occurs after 31 weeks' gestation warrants caution w h e n i n d o m e t h a c i n is used beyond this gestational age. With close surveillance, including weekly fetal e c h o c a r d i o g r a p h y and amniotic fluid v o l u m e assessment, i n d o m e t h a c i n can be safely used for the t r e a t m e n t of p r e t e r m labor. We acknowledge J e a n M. Canty, BS, Melisa M. Holmes, MD, and R o g e r B. Newman, MD. REFERENCES
I. Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974;44: 787-92. 2. Manchester D, Mayolis HS, Sheldon RE. Possible association
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between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. AmJ Obstet Gynecol 1976;126:467-9. 3. Rubaitelli FF, Chiozza ML, Zanardo V, Cantarutti F. Effects on neonate of maternal treatment with indomethacin. J Pediatr 1979;94:161-5. 4. Arcilia KA, Thilenius OG, Ranninger K. Congenital heart failure from suspected ductal closure in utero. J Pediatr 1969;75:74-8. 5. Csaba IF, Sulyok E, Ertl T. Clinical note: relationship of maternal treatment with indomethacin to persistence of fetal circulation syndrome. J Pediatr 1978;92:484~ 6. Dudley DK, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. Am J Obstet Gynecol 1985;151:1814. 7. NiebylJR, Witter FR. Neonatal outcome after indornethacin treatment for premature labor. A m J Obstet Gynecol 1986; 155:747-9. 8. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use. Am J Obstet Gynecol 1993;168: 1350-3. 9. Zuckerman H, Shalev E, Gilad G, Katzuni E, Further study of the inhibition of premature labor by indomethacin. Part II. Double blind study. J Perinat Med 1984;12:25-9. 10. Klein KL, Scott WJ, Clark KE, Wilson JG. Indomethacin-placental transfer, cytotoxity, and teratology in the rat. AmJ Obstet Gynecol 1981;141:448-52. 11. Moise KJ, Huhta JC, Sharif DS, Ou C, Kirshon B, Wasserstrum N, Cano L. Indomethacin in the treatment of preterm labor. N EnglJ IVied 1988:319:327-31. 12. Gerson A, Abbasi S, Johnson A, Kalchbrenner M, Ashmead G, Bolognese R. Safety and efficacy of long-term tocolysis with indomethacin. Am J Perinatol 1990;7:71-4. 13. Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 14. Eronen M, Pesonen E, Kurki T, Ylikorkala O, Hallman M. The effects of indomethacin and a heta-sympathomimetic agent on the fetal ductus arteriosus during treatment of premature labor: a randomized double-blind study. Am J Obstet Gynecol 1991;164;141-6.
Discussion
DR. SUSANL. EPLEY, Orlando, Florida (Official Guest). Preterm delivery complicates at least 6% to 8% o f all births in the U n i t e d States. Complications f r o m prematurity account for 75% of all perinatal morbidity and mortality. Only a minority of patients at risk for p r e t e r m labor will be identified by epidemiologic studies. Thus tocolytic therapy remains the obstetrician's main weapon in r e d u c i n g p r e t e r m births, yet it is still uncertain whether tocolytic therapy i m p r o v e s perinatal outcome. T h e r e f o r e all tocolytic agents must be used thoughtfully. Fetal and maternal d r u g toxicity must be weighed against the benefits of p r o l o n g i n g pregnancy. Agents used for tocolysis have i n c l u d e d alcohol, magnesium sulfate, and [3-sympathomimetics. Significant maternal complications have b e e n associated with the use of all these drugs. Z u c k e r m a n et al. 1 first p r o p o s e d the use of i n d o m e t h a c i n , a prostaglandin synthase inhibitor, for t r e a t m e n t o f p r e m a t u r e labor. Prostaglandin release plays a key role in cervical ripening, f o r m a t i o n of myometrial gap junctions, and initiation of uterine contractions. 2 Multiple authors including Morales et al. s and
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Niebyl and Wither s have c o n f i r m e d i n d o m e t h a c i n to be an effective tocolytic with few maternal side effects. However, several studies have shown i n d o m e t h a c i n therapy to be a double-edged sword. I n d o m e t h a c i n is known to cross the h u m a n placenta freely, i n d e p e n d e n t of gestational age. 5 It inhibits prostaglandin synthesis in the developing fetus, thus affecting multiple organ systems. R e p o r t e d neonatal complications f r o m in u t e r o i n d o m e t h a c i n exposure have i n c l u d e d oligohydramnios, p r e m a t u r e closure of the ductus arteriosus, intraventricular h e m o r r h a g e , hyperbilirubinemia, necrotizing enterocolitis, isolated intestinal perforation, fetal platelet dysfunction, and impaired renal function. O n e of the most fearsome fetal complications has b e e n p r e m a t u r e closure of the ductus arteriosus. T h e ductus arteriosus allows shunting of the right ventricular stroke o u t p u t into the aorta, bypassing the high-resistance pulmonary vascular bed. P r e m a t u r e closure of the ductus arteriosus can result in persistent neonatal p u l m o n a r y hypertension. F u r t h e r m o r e , after initial constriction of the ductus arteriosus, the vessel's ability to constrict again may be limited as a result of early ischemic damage to the intimal layer of the vessel wall. Perhaps this explains the increased incidence of patent ductus arteriosus in neonates after in utero i n d o m e t h a c i n exposure. 6 In this retrospective review study Vermillion et al. have a t t e m p t e d to further e n h a n c e our knowledge of the risk of fetal constriction of the ductus arteriosus associated with in utero i n d o m e t h a c i n exposure. T h e i r data are consistent with previous studies showing that i n d o m e t h acin can induce constriction of the ductus arteriosus in the developing h u m a n fetus. They support the evidence that the h u m a n fetal ductus arteriosus is sensitive to the constrictive effects of i n d o m e t h a c i n as early as the late second trimester. Additionally, this article's focused review agrees with prior investigators that the ductus arteriosus becomes m o r e sensitive to the constrictive effect of i n d o m e t h a c i n as gestational age increases. This study offers some practical suggestions on how to follow up patients receiving indomethacin. Previously, Doppler e c h o c a r d i o g r a p h y has b e e n used to diagnose fetal ductus arteriosus constriction by revealing a characteristic increase in peak systolic and diastolic flow velocity measurements. 7 T h e authors have e x p a n d e d on the work of Moise s to propose weekly peak systolic flow measurements to identify and perhaps predict the fetus in w h o m ductal constriction will develop. They agree with o t h e r investigators who r e c o m m e n d limiting the use of indom e t h a c i n tocolysis to gestations of 31 to 32 weeks or more. T h e authors also make the intriguing original suggestion that fetuses who have closure of the ductus arteriosus have a m o r e rapid increase i.n systolic flow velocity on serial fetal e c h o c a r d i o g r a p h i c studies. This exciting new use of technology adds to the c o m p l e x issue of weighing the risks and benefits of i n d o m e t h a c i n tocolysis. I c o m m e n d the researchers for these impressive findings. In closing, I would ask the authors the following questions: (1) O n c e an elevated systolic ductal velocity is
August 1997 Am J Obstet Gynecol
found, should i n d o m e t h a c i n tocolysis always be immediately stopped? If so, at what ductal velocity m e a s u r e m e n t ? (2) M o m m a and Takao 9 r e p o r t e d the c o m b i n a t i o n of i n d o m e t h a c i n and b e t a m e t h a s o n e to be associated with an even greater degree of ductal constriction. H o w many of your patients received betamethasone? Did the corticosteroid-treated patients have a greater d e g r e e of ductal constriction? (3) O b t a i n i n g accurate ductal velocity measurements requires a skilled sonographer. Measurements are often highly d e p e n d e n t on fetal position. Was it possible to obtain m e a s u r e m e n t s on each fetus weekly? Who did these studies and how many studies had previously b e e n p e r f o r m e d by the sonographer?
REFERENCES
1. Zuckerman H, Reiss. U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974;44: 787-92. 2. Huszan G, Naftolin F. The myometrium and uterine cervix in normal and preterm labor. N EnglJ Med 1984;311:57181. 3. Morales WJ, Smith SG, Angel JL, O'Brien WP, Knuppel RA. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor; a randomized study. Obstet Gynecol 1989;74:567~72. 4. Niebyl JR, Wither RF. Neonatal outcome after indomethacin treatment for premature labor. Am J Obstet Gynecol 1986;155:747-9. 5. Van Den Veyver IB, Moise KJ Jr. Prostaglandin synthetase inhibitors in pregnancy. Obstet Gynecol Surv 1993;48:493502. 6. Clyman RI, Campbell D, Heymann MA, Mauray F. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin induced closure. Circulation 1985;71:141-5. 7. Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 8. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use. Am J Obstet Gynecol 1993;168: 1350-3. 9. Momma K, Takao A. Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats. Pediatr Res 1989;25:69-75. DR. RoNan~ V. W ~ E , Charlotte, N o r t h Carolina. Were any of the patients receiving [3-adrenergic r e c e p t o r agents or anything that could increase the fetal cardiac rate? We know that w h e n there is a situation involving fetal tachycardia there can be an increase in the systolic velocity. Parallel to that, can you tell us how many o f these constrictions were diagnosed on the basis of systolic only, diastolic only, or both? DR. StrNWT P. C n A ~ , Augusta, Georgia. How many patients with and without constriction received indomethacin for < 2 4 hours, 24 to 48 hours, and > 4 8 hours? Were any o t h e r tocolytics used and what was the indication f o r switching to i n d o m e t h a c i n ? If there is no clinical significance of the ductal constriction, why is there so m u c h c o n c e r n if the c o n s e q u e n c e is only some technical deviation in the systolic and diastolic flow?
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DR. VERNn,HON (Closing). In response to Dr. Epley's questions regarding elevated systolic velocity without constriction, I believe that if the situation is such that there is a clear benefit to continued tocolysis then therapy should be continued, provided there are not any obvious flow disturbances and that the patient is reliable and can be followed up for weekly echo surveillance. Further, not all fetuses with an elevated systolic velocity trend ultimately had ductal constriction, and those fetuses in whom constriction did develop had complete reversibility after p r o m p t identification and discontinuation of therapy within 1 week of a previously nonconstricted study. Second, all patients in the study received betamethasone on admission; betamethasone was repeated in 24 hours and weekly thereafter until 34 weeks' gestation if delivery did not occur. Finally, all ductal velocity measurements were obtainable on all fetuses studied, and all the studies were performed by one of two certified technicians in the pediatric cardiology echo laboratory. Further, all echo studies were initially reviewed by the pediatric cardiology attending faculty for accuracy. Concerning Dr. Wade's and Dr. Chauhan's questions regarding fetal tachycardia and the use of other tocolyt-
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ics, particularly [3-adrenergic receptor agents, all patients initially underwent tocolysis with magnesium sulfate. Only 8 patients had a trial of terbutaline, in which no patient received more than two doses. Six of the 8 patients were switched m indomethacin because of increasing uterine activity with terbutaline, whereas the remaining two were unable to tolerate terbutaline because of maternal tachycardia. Subsequently, none of these 8 subjects had fetal ductal constriction with indomethacin therapy. Of the 35 fetuses with ductal constriction 16 had the diagnosis made on the basis of systolic measurements alone, 15 had both systolic and diastolic measurements, and only 4 cases were diagnosed with diastolic measurements alone. W{th respect to the duration of therapy, patients with indomethacin therapy for <24 hours were not studied. Twenty-six patients received therapy for 24 to 48 hours, whereas 46 received indomethacin for >48 hours. Nnally, I would reemphasize that whereas ductal constriction is completely reversible after p r o m p t identification and discontinuation of indornethacin therapy, continued prolonged use with unrecognized constriction greatly increases the risk of that fetus for irreversible changes of the ductus arteriosus, including pulmonary hypertension.
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