- Email: [email protected]
Randomized trial of oral indomethacin and terbutaline sulfate for the long-term suppression of preterm labor
Randomized trial of oral indomethacin and terbutaline sulfate for the long-term suppression of preterm labor Harold A. Bivins, Jr., MD, Roger B. Newman, MD, Derek A. Fyfe, MD, PhD, Berry A. Campbell, MD, and Sue L. Stramm, RN Charleston, South Carolina OBJECTIVE: Our purpose was to determine the efficacy and safety of long-term oral tocolysis with indomethacin or terbutaline sulfate. STUDY DESIGN: Seventy-one patients at 26 to 32 weeks' gestation admitted for preterm labor were prospectively randomized to receive oral indomethacin or terbutaline sulfate after successful intravenous tocolysis. Patients were monitored weekly for cervical change, maternal side effects, amniotic fluid volume, and constriction of the fetal ductus arteriosus. Patients receiving indomethacin were converted to terbutaline at 34 weeks or with the occurrence of fetal ductal constriction or oligohydramnios. RESULTS: Of 71 patients randomized six were excluded after randomization. Thirty-three patients were randomized to indomethacin and thirty-two to terbutaline. There were no differences in the percentage of patients achieving 34 weeks of gestation. No differences in neonatal outcome were noted. Nine (27%) fetuses receiving indomethacin had constriction of the fetal ductus arteriosus, and 13 (38%) had oligohydramnios. Most patients on terbutaline reported ~-mimetic side effects (53%), but only one required discontinuation of therapy. CONCLUSION: Both indomethacin and terbutaline sulfate are effective tocolytics, but major fetal side effects are common with long-term indomethacin use. (AM J OSSTET GYNECOL 1993; 169: 1065-70.)
Key words: Indomethacin, terbutaline sulfate, tocolysis, ductus arteriosus, oligohydramnios
Preterm labor and delivery is a major cause of neonatal morbidity and mortality, especially at very early gestational ages. I Although much attention has been given to the prevention of preterm labor, the mainstay of management remains effective treatment once preterm labor has begun. Agents that have been used in the treatment of preterm labor include alcohol, 13agonists, magnesium sulfate, nifedipine,2 and prostaglandin inhibitors. 3 Oral J3-agonists are currently the mainstay oflong-term therapy; however, they have been associated with undesirable and potentially life-threatening side effects for the mother:-6 The formation and release of prostaglandins is believed to be an important promoter of uterine contractions in both term and preterm gestations. 7 Prostaglandin inhibitors, most notably indomethacin, have been used successfully for both short- and long-term tocolysis. s-12 However, adverse fetal effects from indomethacin exposure continue to be reported in the literature.
From the Division of Maternal-Fetal Medicine, Departments of Obstetrics and Cynecology and Pediatric Cardiology, Medical University of South Carolina. Presented at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8-13,1993. Reprint requests: Harold A. Bivins, Jr., MD, 4750 Waters Ave., Suite 202, Savannah, CA 31404. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/6/48966
The purpose of this prospective, randomized trial was to determine the efficacy and safety of long-term tocolysis with either oral indomethacin or terbutaline sulfate. The primary outcome variable to determine efficacy was attainment of 34 weeks' gestation. Maternal side effects were recorded, and the incidence of oligohydramnios and fetal ductus arteriosus constriction were used to measure fetal risk. Material and methods
Seventy-one women with singleton pregnancies between 26 and 32 weeks of gestation admitted for an initial epiosde of preterm labor at the Medical University of South Carolina were randomized. After successful tocolysis with intravenous magnesium sulfate for at least 12 hours these patients were presented with the preterm labor treatment protocol that had been approved by the Institutional Review Board of the Medical University of South Carolina. After giving informed consent, patients were randomized by means of a randomization list derived from a random number table to either receive oral indomethacin, 25 mg every 6 hours or terbutaline sulfate, 5 mg every 4 hours, for long-term tocolysis. Patients qualified for the preterm labor treatment protocol if they had a single, live intrauterine pregnancy with appropriately diagnosed preterm labor. Preterm labor was defined as at least four contractions in
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20 minutes associated with progressive cervical change or a single examination with a cervix that was ~ 2 cm dilated or ~ 80% effaced. The cervix had to be < 4 cm dilated, and amniotic membranes had to be intact for inclusion in the study protocol. Exclusion criteria included multifetal gestations, suspicion of chorioamnionitis, abruptio placentae, placenta previa, fetal anomaly, premature rupture of membranes, preeclampsia, intrauterine growth retardation, oligohydramnios, allergy to aspirin, or insulin-dependent diabetes mellitus. Oligohydramnios was defined as an amniotic fluid index :5 7 cm, which is 2 SDs below the mean. 13 All patients had a baseline ultrasonographic examination to confirm gestational age, rule out anomalies, and measure amniotic fluid index. An amniotic fluid index was obtained thereafter on a weekly basis for all patients. Ultrasonographic examinations were performed with an Acuson 128XP (Acuson, Mountain View, Calif.) and a Hitachi EUB 315 (Hitachi, Tokyo). A baseline and weekly fetal echocardiograms were performed on all patients exposed to indomethacin, to assess fetal heart anatomy and to measure ductus arteriosus blood velocities to confirm patency. Fetal echocardiography was performed by a board-certified pediatric cardiologist in the Children's Hospital at the Medical University of South Carolina in a manner similar to that described by Huhta et al. 14 Fetal ductal constriction was defined as the presence of a fetal ductal systolic velocity of > lA m/sec in conjunction with a diastolic velocity of > 0.35 m/sec. Fetal echocardiography was performed with an Acuson 128XP with a 3.5 to 5 MHz transducer and pulsed Doppler capability. Fetal echocardiograms were not performed on the patients randomized to terbutaline sulfate because of the cost and because there is no evidence in the literature that terbutaline sulfate causes ductal constriction. All patients were followed on a weekly basis with assessment of cervical dilatation, effacement, and adverse maternal symptoms from tocolytic ingestion. Patients on indomethacin were changed to terbutaline sulfate if they had evidence of fetal ductal constriction, oligohydramnios, or achievement of 34 weeks of gestation. Patients on terbutaline sulfate were changed to indomethacin if they had intolerable ~-mimetic adverse affects. Terbutaline was discontinued at 37 weeks of gestation. Recurrent preterm labor was defined as cervical change associated with uterine contractions while on an oral tocolytic. Recurrent preterm labor was treated again with intravenous magnesium sulfate for 24 hours, and if successful, reinstitution of oral tocolysis as previously assigned. Of the 71 patients randomized, six were excluded after randomization because of no follow-up (3), multifetal gestation (1), and fetal anomaly (2). Two other patients in the terbutaline sulfate group admittedly stopped their medication after discharge from the hos-
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pital and did not return until delivery. Their outcome data were included in the statistical analysis. The one multifetal gestation was inadvertently randomized but was removed from the study when it was discovered by the principal investigator. The fetal anomalies excluded were a neural tube defect and an atrioventricular defect not discovered by prerandomization ultrasonography. Three patients randomized to terbutaline sulfate did not return for prenatal care and could not be found to obtain delivery outcome or neonatal data. As stated earlier, these patients were excluded from data analysis. Both groups were compared for various maternal and fetal outcomes, including attainment of 34 weeks, duration of therapy, gestational age at delivery, incidence of recurrent preterm labor, any constriction of the fetal ductus arteriosus, oligohydramnios requiring cessation of indomethacin therapy, and adverse maternal symptoms from long-term terbutaline sulfate or indomethacin therapy. The unpaired Student t test, X2 test with Yates' correction, and Fisher's exact test were used to compare the data from the two treatment groups. Correlation coefficient was used to analyze the relationship between decreasing amniotic fluid index and the days exposed to indomethacin. Statistical significance was defined as a p value of < 0.05. Results
The two treatment groups were similar, except that the indomethacin group had significantly more cervical effacement on admission (Table I). There were no statistically significant differences in the two groups with respect to maternal outcome, which is summarized in Table H. Adverse maternal side effects were not reported by any patient in the indomethacin group, but 16 (53.3%) patients randomized to terbutaline sulfate reported symptoms of tachycardia and jitteriness. Only one of these patients required discontinuation of terbutaline sulfate because of intolerable maternal tachycardia (pulse > 120 beats/min). No intolerable gastrointestinal symptoms were reported by patients taking indomethacin. Sixteen (48.5%) patients who were randomized to indomethacin were changed to oral terbutaline sulfate before they reached 34 weeks' gestation. This was because of oligohydramnios in seven patients, fetal ductus arteriosus constriction in seven patients, and both in two patients. As stated earlier, one patient originally randomized to terbutaline sulfate was required to change to indomethacin because of intolerable maternal tachycardia. This difference was statistically significant
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Table I. Patient characteristics after randomization Patient characteristic
Maternal age (yr, mean ± SD) Race White Black Parity (mean ± SD) Prior pregnancy with preterm labor Gestational age at admission (wk, mean ± SD) Initial cervical dilatation (cm, mean ± SD) Initial cervical effacement (%, mean ± SD)
Terbutaline (n = 32)
Indomethacin (n = 33)
Significance
21.6 ± 4.6
22.3 ± 5.1
p = 0.559
9 (28.1%) 23 (71.9%) 1.3 ± 1.1 18 (56.2%) 30.6 ± 1.6 1.9 ± 1.0 53.3 ± 12.1
6 (18.2%) 27 (81.8%) 1.6 ± 1.4 17 (51.5%) 30.0 ± 2.1 2.0 ± 1.0 62.9± 17.9
Terbutaline (n = 32)
Indomethacin (n = 33)
40.9 ± 20.4 36.5 ± 2.18 27 (84.4%) 32 (100%) 31 (96.9%) 11 (36.7%)
42.9 ± 25.0 36.1 ± 2.86 25 (75.8%) 33 (100%) 29 (87.9%) 19 (57.6%)
P = 0.725 P = 0.561 P = 0.577
32 (97.0) 1 (3.0%)
P = 0.613 P = 0.613
P = 0.511
P = 0.511 P = 0.476 P = 0.893
P = 0.151 P = 0.707
P = 0.014*
*Statistically significant at 0.05 level.
Table 11. Maternal outcome Variable
Initial treatment to delivery (days, mean ± SD) Gestational age at delivery (wk, mean ± SD) Attained 34th week of gestation (No.) Delivery delayed >48 hr (No.) Delivery delayed >7 days (No.) Recurrent preterm labor (No.) Delivery route (No.) Vaginal Cesarean section
who were exposed to indomethacin. Six of these patients had their dose of indomethacin reduced to 25 mg twice a day. A repeat ultrasonographic examination in 4 to 7 days revealed that four of these six patients had reaccumulation of amniotic fluid; they were continued on indomethacin. Two patients continued to have oligohydramnios and were changed to oral terbutaline. The remaining patients (nine) who had oligohydramnios while on indomethacin subsequently had reaccumulation of amniotic fluid when the indomethacin was withdrawn. There appeared to be no correlation between the fall in the amniotic fluid index and the number of days on indomethacin (r = - 0.24, P = 0.41). One patient in the terbutaline group had oligohydramnois associated with intrauterine growth retardation. Constriction of the fetal ductus arteriosus was noted in nine (26.5%) patients treated with oral indomethacin. These patients were immediately changed to oral terbutaline sulfate. A repeat fetal echocardiogram in 24 hours revealed a reversal of this constriction in all patients. Constriction of the fetal ductus arteriosus appeared to occur in a random fashion ranging between I to 24 days of indomethacin exposure and between 27 and 33 weeks' gestation. Only four of the nine (44.4%) fetuses with ductal constriction had simultaneous tricuspid valve regurgitation. The neonatal outcomes are presented in Table Ill. There were no statistically significant differences in the two study groups. There were no infants with persistent
30 (93.8%) 2 (6.2%)
Significance
P = 0.355 P = 0.131
fetal circulation, primary pulmonary hypertension, patent ductus arteriosus, necrotizing enterocolitis, or intraventricular hemorrhage.
Comment Indomethacin, a potent inhibitor of prostaglandin synthesis, has been used since the early 1970s as a tocolytic agent for the suppression of preterm labor.3 The initial enthusiasm for indomethacin decreased after reports of increased fetal side effects appeared in the literature. These fetal side effects were primarily premature closure of the fetal ductus arteriosus leading to primary pulmonary hypertension 15. 19 and oligohydramnios.1 9-23 Controlled studies of the efficacy of indomethacin for the suppression of preterm labor were reported by Niebyl et a1. 9 in 1980. Their prospective, randomized, double-blind study reported on 15 patients treated with indomethacin compared with 15 placebo controls. Tocolysis was continued only for 24 hours and was therefore considered short-term therapy. Indomethacin was markedly more effective than placebo during the 24hour treatment interval, and a statistically significant difference was found in temporarily delaying labor in spite of a relatively small number of patients. Neonatal outcome was not significantly different from the placebo group in this study, and no neonatal side effects were observed. A similar study by Zuckerman et al. 10 reported that a short course of indomethacin was successful in preventing preterm delivery for 7 days when
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Table Ill. Summary of neonatal outcome parameters Terbutaline
Indomethacin
(n = 32)
(n = 33)
2633 ± 474 7.8 ± 1.4 0.34 ± 1.60
2581 ± 570 7.6 ± 1.8 1.51 ± 4.89
p= P= P=
0.691 0.521 0.202
I
P=
0.999
Neonatal outcome Birth weight (gm, mean ± SDi 5 min Apgar score (mean ± SDi Stay in neonatal intensive care unit (days, mean ± SDi Neonates requiring ventilation (No.) Primary pulmonary hypertension (No.) Patent ductus arteriosus (No.) Intraventricular hemorrhage (No.) Necrotizing enterocolitis (No.) Neonatal deaths (No.)
compared with placebo. As before, no neonatal side effects attributed to indomethacin were observed. In the current study indomethacin was as effective in preventing birth before 34 weeks' gestation as was oral terbutaline sulfate. In addition, no other parameter of pregnancy outcome related to premature delivery was different between the two groups. However, in spite of our inability to demonstrate any clinical superiority of one agent over the other, it is important to view this cautiously. The sample size necessary to insure a > 80% likelihood of avoiding a type II or f3-error in the evaluation of efficacy would have required > 400 patients per group. The decision was made to terminate the study because of the concerns of the investigators and the Institutional Review Board over the high rate of fetal side effects in the indomethacin group. The ductus arteriosus plays an important role in fetal circulation. The ductus arteriosus allows run-off of most of the right ventricular stroke output into the aorta, bypassing the high-resistance pulmonary vascular bed. Animal models support the concept that the fetal ductus arteriosus is controlled by prostaglandins. In lamb and rat fetuses prostaglandin inhibitors have been shown to cause marked ductal constriction late in gestation but to produce little change in the less mature fetuses. 17. 24 Constriction of the human fetal ductus arteriosus has been associated with in utero exposure to indomethacin. This was originally thought to occur mostly in fetuses> 34 weeks' gestation,25. 26 but a recent report by Moise et al. 27 using fetal echocardiography revealed evidence of ductal constriction in seven of 14 fetuses exposed to indomethacin at a mean gestational age of 29.3 ± 0.59 weeks. Echocardiographic evidence of fetal ductus arteriosus constriction is provided by measuring the ductal blood velocity with pulsed Doppler techniques. 14 Right ventricular dysfunction and tricuspid regurgitation also support ductal velocities in diagnosing fetal ductal constriction, but they are not always present with early ductal constriction. Our patients were followed up closely with weekly fetal echocardiograms. This close surveillance revealed that nine (26.5%) fetuses exposed to indomethacin had
o
o o o o
o
o
Significance
o
o o
o
constriction of their ductus arteriosus. Constriction of the ductus arteriosus appeared to occur in an unpredictable relationship to indomethacin exposure. All nine fetuses had normal echocardiograms within 24 hours of discontinuing indomethacin. Because of the unpredictability of ductal constriction, we recommend close surveillance of all fetuses exposed to prostaglandin inhibitors with echocardiography. Indomethacin freely crosses the placenta 28 and can affect fetal prostaglandin synthesis. Besides control over the fetal ductus arteriosus, prostaglandins also play an essential role in the renin-angiotensin-aldosterone system. Prostaglandins are also thought to play a key role in the regulation of renal blood flow and renal tubular sodium reabsorption. 29 Fetal anuria and resultant oligohydramnios have been associated with in utero indomethacin exposure.'9-22 Studies with pulsed Doppler measurements of fetal renal artery blood flow reveal no change in flow when the patient ingests indomethacin. 3o This would suggest an intrinsic renal cause for oligohydramnios in these patients. The renal effects of indomethacin are transient and do not appear to affect neonatal renal function." Studies on short-term indomethacin use did not observe a significant loss of amniotic fluid volume, but long-term studies have shown this complication.' I. 12 Gerson et al. 11 reported that oligohydramnios was reversible if the dose of indomethacin was reduced. Our study reveals a significant incidence of oligohydramnios in the indomethacin group compared with the terbutaline group. During the study period six patients with oligohdyramnios were treated with a reduced dosage of indomethacin (25 mg twice a day). Four of these patients had re accumulation of amniotic fluid and were continued on indomethacin. This finding is encouraging and warrants further study. The timing of oligohydramnios was also unpredictable, as was found with ductal constriction. At a minimum, weekly assessment of amniotic fluid volume is necessary in gestations being treated with indomethacin. In spite of a high frequency of fetal complications associated with indomethacin therapy, we observed no adverse neonatal outcomes in either treatment group,
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except for one neonate that required mechanical ventilation for 24 hours. None of the neonates experienced primary pulmonary hypertension, anuria, oliguria, or a patent ductus arteriosus. Indomethacin has also been implicated, in isolated cases, as a possible contributing cause of neonatal bleeding disorders such as intraventricular hemorrhage or necrotizing enterocolitis. Indomethacin has been used in very preterm neonates for closure of the patent ductus arteriosus with a decreased incidence of intraventricular hemorrhage and no increase in necrotizing enterocolitis when compared with surgical closure. 32 In our series there were no cases of intraventricular hemorrhage or necrotizing enterocolitis in either group. It must be noted that these complications are all much more common in very preterm infants and that in our study the mean gestational age at delivery was 36.1 ± 2.9 weeks and antepartum exposure to indomethacin ceased at 34 weeks by study design. Another aspect of long-term suppression of preterm labor with indomethacin that should be considered is the added cost of weekly fetal echo cardiograms and ultrasonography for amniotic fluid assessment. The total charge of an initial fetal echocardiogram including professional and hospital fees can be as high as $500, with repeat Doppler assessment of the fetal ductus arteriosus costing $200. A limited ultrasonographic examination for measuring the amniotic fluid index may cost between $50 and $100. These weekly charges may add significantly to the cost of medical care in these patients receiving indomethacin suppression for preterm labor. This must be seriously considered in light of the recent climate of medical cost containment. The availability of fetal echocardiography is expanding and is currently available at most tertiary care centers where pediatric cardiologists and maternal-fetal medicine specialists trained in fetal echocardiography are present. This comparative trial of indomethacin and terbutaline sulfate for the long-term suppression of preterm labor confirms and, in our opinion, better quantitates previous concerns over the fetal side effects of in utero exposure to indomethacin. Indomethacin appears to be as efficacious as oral terbutaline sulfate for the longterm suppression of preterm labor, but unfortunately indomethacin is associated with a high incidence of potentially serious fetal side effects. Indomethacin should be reserved as a second line tocolytic agent for the long-term suppression of preterm labor. When used, intensive fetal surveillance with fetal echocardiography and amniotic fluid volume assessment is mandatory on at least a weekly basis. Because these physiologic changes are known to occur rather rapidly and unpredictably, one could argue for more frequent periods of observation. Because the fetal ductal constric-
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tion and reductions in amniotic fluid were uniformly reversible, fetal echocardiography and serial ultrasonography is probably not needed if indomethacin is used on a short-term basis only. REFERENCES 1. Fuchs F. Prevention of prematurity. AM] OBSTET GYNECOL 1976; 126:809-20. 2. Reed MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br] Obstet Gynaecol 1986;93:933-7. 3. Zuckerman H, Reiss U, Rubinstein 1. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974; 44:787-92. 4. Richards SR, Klingelberger CE. Intravenous ritodrine as a possible provocative predictive test in gestational diabetes: a case report.] Reprod Med 1987;32:798-800. 5. Benedetti T], Hargrove ]C, Rosene KA. Maternal pulmonary edema during premature labor inhibition. Ob stet Gynecol 1982;59(suppl):335-75. 6. Michalak D, Klein V, Marquette GP. Myocardial ischemia: a complication of ritodrine tocolysis. AM] OBSTET GYNECOL 1983;146:861-2. 7. Huszar G, Naftolin F. The myometrium and uterine cervix in normal and preterm labor. N Engl] Med 1984;311: 571-81. 8. Wigvist N, Lundstrom V, Green K. Premature labor and indomethacin. Prostaglandins 1975; 10:515-26. 9. Niebyl ]R, Blake DA, White RD, et al. The inhibition of premature labor with indomethacin. AM] OBSTET GYNECOL 1980; 136: 1014-9. 10. Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. n. Double-blind study.] Perinat Med 1984;12:25-9. 11. Gerson A, Abbasi S,] ohnson A, et al. Safety and efficacy of long-term tocolysis with indomethacin. Am ] Perinatol 1990:7:71-4. 12. Besinger RE, Niebyl ]R, Keyes WG, ]ohnson TRB. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment ofpreterm labor. AM] OBSTET GYNECOL 1991;164:981-8. 13. Moore TR, Cayle ]E. The amniotic fluid index in normal human pregnancy. AM] OBSTET GYNECOL 1990;162:116873. 14. Huhta]C, Moise K], Fisher D], SharifDS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 15. Arcilla RA, Thilenius OG, Ranniger K. Congestive heart failure f)'om suspected ductal closure in utero. Pediatrics 1969;75:74-8. 16. Manchester D, Margolis HS, Sheldon RE. Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. AM ] OBSTET GY~'mCOL 1976;126:467-50. 17. Levin DL, Mills L], Parkey M, Garriott], Campbell W. Constriction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe. Pediatrics 1979;94:647-50. 18. Goudie BM, Dossetor ]FB. Effect on the fetus of indomethacin given to suppress labour. Lancet 1979;2: 1187-8. 19. Itskovitz], Abramovici H, Brandes ]M. Oligohydramnion, meconium and perinatal death concurrent with indomethacin treatment in human pregnancy.] Reprod Med 1980; 24: 137-40. 20. Cantor B, Tyler '1', Nelson RM, Stein GH. Oligohydramnios and transient neonatal anuria: a possible association with the maternal use of prostaglandin synthetase inhibitors.] Reprod Med 1980;24:220-3. 21. Vanhaesebrouck P, Thiery M, Leroy]G, et al. Oligohydramnios, renal insufficiency, and ileal perforation in pre-
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22.
23.
24. 25. 26. 27.
tenn infants after intrauterine exposure to indomethacin. J Pediatr 1988;113:738-43. DeWit W, VanMourik I,Wiesenhaan PF. Prolonged maternal indomethacin therapy associated with oligohydramnios: case reports. Br J Obstet Gynaecol 1988;95: 303-5. Hickok DE, Hollenbach KA, Reilley SF, Nyberg DA. The association between decreased amniotic fluid volume and treatment with nonsteroidal anti-inflammatory agents for preterm labor. AM J OBSTET GVNECOL 1989;160:1525-31. Momma K, Takao A. In vivo constriction of the ductus arteriosus by nonsteroidal antiinflammatory drugs in nearterm and preterm fetal rats. Pediatr Res 1987;22:567-72. Dudley DKL, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. AM J OBSTET GVNECOL 1985;151:181-4. Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment for preterm labor. AM J OBSTET GYNECOL 1986;155:747-9. Moise Iq, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor: effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-31.
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28. Moise KJ, Ou C, Kirshon B, Cano LE, Rognerud C, Carpenter RJ. Placental transfer of indomethacin in the human pregnancy. AM J OBSTET GVNECOL 1990;162:54954. 29. Anderson RJ, Berl T, McDonald KM, Schrier RW. Prostaglandins: effects on blood pressure, renal blood flow, sodium and water excretion. Kidney Int 1976; 10: 205-15. 30. Mari G, Moise KJ, Deter RL, Kirshon B, Carpenter RJ. Doppler assessment of the renal blood flow velocity wavefonn during indomethacin therapy for pretenn labor and polyhydramnios. Obstet GynecoI1990;75:199-201. 31. Wurtzel D. Prenatal administration of indomethacin as a tocolytic agent: effect on neonatal renal function. Obstet Gynecol 1990;76:689-92. 32. Bandstra ES, Montalvo BM, Goldberg RN, et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988;82:53342.
Randomized trial of intraumbilical vein oxytocin in midtrimester pregnancy losses Harold A. Bivins, Jr., MD, Darrell A. Cope, MD, Roger B. Newman, MD, and Daniel P. Eller, MD Charleston, South Carolina OBJECTIVE: The purpose of this double-blind prospective randomized trial was to determine whether high-dose intraumbilical vein oxytocin injection shortens the third stage of labor in midtrimester pregnancy losses. STUDY DESIGN: Patients (n = 50) with spontaneous or induced midtrimester pregnancy losses (14 to 26 weeks' gestation) were randomized to receive either 100 IU of oxytocin in 20 ml of normal saline solution or 20 ml of normal saline solution alone as a placebo. The umbilical vein was injected as soon as the cord was clamped. Outcome data were collected. RESULTS: Of the 50 patients randomized, 45 completed the study. Five were excluded after randomization because of either cesarean delivery (1 patient) or en caul delivery (4 patients). Twenty-one patients received oxytocin, and 14 received placebo. Ten patients who were not injected because of technical failure were evaluated separately. There were no differences between the three groups with regard to gestational age, fetal weight, length of the third stage, blood loss, or need for operative removal of the placenta. CONCLUSION: Injection of high-dose oxytocin into the umbilical vein in second-trimester pregnancy losses does not shorten the third stage of labor or decrease the need for surgical intervention because of retained placenta. (AM J OBSTET GVNECOL 1993;169:1070-3.)
Key words: Intraumbilical vein oxytocin, midtrimester pregnancy loss, retained placenta
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Medical University of South Carolina. Presented at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8-13,1993. Reprint requests: Harold A. Bivins, Jr., MD, 4750 Waters Ave., Suite 202, Savannah, CA 31404. Copyright © 1993 by Mashy-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/6/48965
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Midtrimester pregnancy losses are associated with an increased risk of prolonged third stage of labor, excessive blood loss, and retained placenta. l -4 This increases the need for operative intervention resulting in increased morbidity, medical costs, and maternal stress. Although controversial, the use of intraumbilical vein oxytocin has been reported to hasten the third stage of
Key words: Indomethacin, terbutaline sulfate, tocolysis, ductus arteriosus, oligohydramnios
Preterm labor and delivery is a major cause of neonatal morbidity and mortality, especially at very early gestational ages. I Although much attention has been given to the prevention of preterm labor, the mainstay of management remains effective treatment once preterm labor has begun. Agents that have been used in the treatment of preterm labor include alcohol, 13agonists, magnesium sulfate, nifedipine,2 and prostaglandin inhibitors. 3 Oral J3-agonists are currently the mainstay oflong-term therapy; however, they have been associated with undesirable and potentially life-threatening side effects for the mother:-6 The formation and release of prostaglandins is believed to be an important promoter of uterine contractions in both term and preterm gestations. 7 Prostaglandin inhibitors, most notably indomethacin, have been used successfully for both short- and long-term tocolysis. s-12 However, adverse fetal effects from indomethacin exposure continue to be reported in the literature.
From the Division of Maternal-Fetal Medicine, Departments of Obstetrics and Cynecology and Pediatric Cardiology, Medical University of South Carolina. Presented at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8-13,1993. Reprint requests: Harold A. Bivins, Jr., MD, 4750 Waters Ave., Suite 202, Savannah, CA 31404. Copyright © 1993 by Mosby-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/6/48966
The purpose of this prospective, randomized trial was to determine the efficacy and safety of long-term tocolysis with either oral indomethacin or terbutaline sulfate. The primary outcome variable to determine efficacy was attainment of 34 weeks' gestation. Maternal side effects were recorded, and the incidence of oligohydramnios and fetal ductus arteriosus constriction were used to measure fetal risk. Material and methods
Seventy-one women with singleton pregnancies between 26 and 32 weeks of gestation admitted for an initial epiosde of preterm labor at the Medical University of South Carolina were randomized. After successful tocolysis with intravenous magnesium sulfate for at least 12 hours these patients were presented with the preterm labor treatment protocol that had been approved by the Institutional Review Board of the Medical University of South Carolina. After giving informed consent, patients were randomized by means of a randomization list derived from a random number table to either receive oral indomethacin, 25 mg every 6 hours or terbutaline sulfate, 5 mg every 4 hours, for long-term tocolysis. Patients qualified for the preterm labor treatment protocol if they had a single, live intrauterine pregnancy with appropriately diagnosed preterm labor. Preterm labor was defined as at least four contractions in
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20 minutes associated with progressive cervical change or a single examination with a cervix that was ~ 2 cm dilated or ~ 80% effaced. The cervix had to be < 4 cm dilated, and amniotic membranes had to be intact for inclusion in the study protocol. Exclusion criteria included multifetal gestations, suspicion of chorioamnionitis, abruptio placentae, placenta previa, fetal anomaly, premature rupture of membranes, preeclampsia, intrauterine growth retardation, oligohydramnios, allergy to aspirin, or insulin-dependent diabetes mellitus. Oligohydramnios was defined as an amniotic fluid index :5 7 cm, which is 2 SDs below the mean. 13 All patients had a baseline ultrasonographic examination to confirm gestational age, rule out anomalies, and measure amniotic fluid index. An amniotic fluid index was obtained thereafter on a weekly basis for all patients. Ultrasonographic examinations were performed with an Acuson 128XP (Acuson, Mountain View, Calif.) and a Hitachi EUB 315 (Hitachi, Tokyo). A baseline and weekly fetal echocardiograms were performed on all patients exposed to indomethacin, to assess fetal heart anatomy and to measure ductus arteriosus blood velocities to confirm patency. Fetal echocardiography was performed by a board-certified pediatric cardiologist in the Children's Hospital at the Medical University of South Carolina in a manner similar to that described by Huhta et al. 14 Fetal ductal constriction was defined as the presence of a fetal ductal systolic velocity of > lA m/sec in conjunction with a diastolic velocity of > 0.35 m/sec. Fetal echocardiography was performed with an Acuson 128XP with a 3.5 to 5 MHz transducer and pulsed Doppler capability. Fetal echocardiograms were not performed on the patients randomized to terbutaline sulfate because of the cost and because there is no evidence in the literature that terbutaline sulfate causes ductal constriction. All patients were followed on a weekly basis with assessment of cervical dilatation, effacement, and adverse maternal symptoms from tocolytic ingestion. Patients on indomethacin were changed to terbutaline sulfate if they had evidence of fetal ductal constriction, oligohydramnios, or achievement of 34 weeks of gestation. Patients on terbutaline sulfate were changed to indomethacin if they had intolerable ~-mimetic adverse affects. Terbutaline was discontinued at 37 weeks of gestation. Recurrent preterm labor was defined as cervical change associated with uterine contractions while on an oral tocolytic. Recurrent preterm labor was treated again with intravenous magnesium sulfate for 24 hours, and if successful, reinstitution of oral tocolysis as previously assigned. Of the 71 patients randomized, six were excluded after randomization because of no follow-up (3), multifetal gestation (1), and fetal anomaly (2). Two other patients in the terbutaline sulfate group admittedly stopped their medication after discharge from the hos-
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pital and did not return until delivery. Their outcome data were included in the statistical analysis. The one multifetal gestation was inadvertently randomized but was removed from the study when it was discovered by the principal investigator. The fetal anomalies excluded were a neural tube defect and an atrioventricular defect not discovered by prerandomization ultrasonography. Three patients randomized to terbutaline sulfate did not return for prenatal care and could not be found to obtain delivery outcome or neonatal data. As stated earlier, these patients were excluded from data analysis. Both groups were compared for various maternal and fetal outcomes, including attainment of 34 weeks, duration of therapy, gestational age at delivery, incidence of recurrent preterm labor, any constriction of the fetal ductus arteriosus, oligohydramnios requiring cessation of indomethacin therapy, and adverse maternal symptoms from long-term terbutaline sulfate or indomethacin therapy. The unpaired Student t test, X2 test with Yates' correction, and Fisher's exact test were used to compare the data from the two treatment groups. Correlation coefficient was used to analyze the relationship between decreasing amniotic fluid index and the days exposed to indomethacin. Statistical significance was defined as a p value of < 0.05. Results
The two treatment groups were similar, except that the indomethacin group had significantly more cervical effacement on admission (Table I). There were no statistically significant differences in the two groups with respect to maternal outcome, which is summarized in Table H. Adverse maternal side effects were not reported by any patient in the indomethacin group, but 16 (53.3%) patients randomized to terbutaline sulfate reported symptoms of tachycardia and jitteriness. Only one of these patients required discontinuation of terbutaline sulfate because of intolerable maternal tachycardia (pulse > 120 beats/min). No intolerable gastrointestinal symptoms were reported by patients taking indomethacin. Sixteen (48.5%) patients who were randomized to indomethacin were changed to oral terbutaline sulfate before they reached 34 weeks' gestation. This was because of oligohydramnios in seven patients, fetal ductus arteriosus constriction in seven patients, and both in two patients. As stated earlier, one patient originally randomized to terbutaline sulfate was required to change to indomethacin because of intolerable maternal tachycardia. This difference was statistically significant
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Table I. Patient characteristics after randomization Patient characteristic
Maternal age (yr, mean ± SD) Race White Black Parity (mean ± SD) Prior pregnancy with preterm labor Gestational age at admission (wk, mean ± SD) Initial cervical dilatation (cm, mean ± SD) Initial cervical effacement (%, mean ± SD)
Terbutaline (n = 32)
Indomethacin (n = 33)
Significance
21.6 ± 4.6
22.3 ± 5.1
p = 0.559
9 (28.1%) 23 (71.9%) 1.3 ± 1.1 18 (56.2%) 30.6 ± 1.6 1.9 ± 1.0 53.3 ± 12.1
6 (18.2%) 27 (81.8%) 1.6 ± 1.4 17 (51.5%) 30.0 ± 2.1 2.0 ± 1.0 62.9± 17.9
Terbutaline (n = 32)
Indomethacin (n = 33)
40.9 ± 20.4 36.5 ± 2.18 27 (84.4%) 32 (100%) 31 (96.9%) 11 (36.7%)
42.9 ± 25.0 36.1 ± 2.86 25 (75.8%) 33 (100%) 29 (87.9%) 19 (57.6%)
P = 0.725 P = 0.561 P = 0.577
32 (97.0) 1 (3.0%)
P = 0.613 P = 0.613
P = 0.511
P = 0.511 P = 0.476 P = 0.893
P = 0.151 P = 0.707
P = 0.014*
*Statistically significant at 0.05 level.
Table 11. Maternal outcome Variable
Initial treatment to delivery (days, mean ± SD) Gestational age at delivery (wk, mean ± SD) Attained 34th week of gestation (No.) Delivery delayed >48 hr (No.) Delivery delayed >7 days (No.) Recurrent preterm labor (No.) Delivery route (No.) Vaginal Cesarean section
who were exposed to indomethacin. Six of these patients had their dose of indomethacin reduced to 25 mg twice a day. A repeat ultrasonographic examination in 4 to 7 days revealed that four of these six patients had reaccumulation of amniotic fluid; they were continued on indomethacin. Two patients continued to have oligohydramnios and were changed to oral terbutaline. The remaining patients (nine) who had oligohydramnios while on indomethacin subsequently had reaccumulation of amniotic fluid when the indomethacin was withdrawn. There appeared to be no correlation between the fall in the amniotic fluid index and the number of days on indomethacin (r = - 0.24, P = 0.41). One patient in the terbutaline group had oligohydramnois associated with intrauterine growth retardation. Constriction of the fetal ductus arteriosus was noted in nine (26.5%) patients treated with oral indomethacin. These patients were immediately changed to oral terbutaline sulfate. A repeat fetal echocardiogram in 24 hours revealed a reversal of this constriction in all patients. Constriction of the fetal ductus arteriosus appeared to occur in a random fashion ranging between I to 24 days of indomethacin exposure and between 27 and 33 weeks' gestation. Only four of the nine (44.4%) fetuses with ductal constriction had simultaneous tricuspid valve regurgitation. The neonatal outcomes are presented in Table Ill. There were no statistically significant differences in the two study groups. There were no infants with persistent
30 (93.8%) 2 (6.2%)
Significance
P = 0.355 P = 0.131
fetal circulation, primary pulmonary hypertension, patent ductus arteriosus, necrotizing enterocolitis, or intraventricular hemorrhage.
Comment Indomethacin, a potent inhibitor of prostaglandin synthesis, has been used since the early 1970s as a tocolytic agent for the suppression of preterm labor.3 The initial enthusiasm for indomethacin decreased after reports of increased fetal side effects appeared in the literature. These fetal side effects were primarily premature closure of the fetal ductus arteriosus leading to primary pulmonary hypertension 15. 19 and oligohydramnios.1 9-23 Controlled studies of the efficacy of indomethacin for the suppression of preterm labor were reported by Niebyl et a1. 9 in 1980. Their prospective, randomized, double-blind study reported on 15 patients treated with indomethacin compared with 15 placebo controls. Tocolysis was continued only for 24 hours and was therefore considered short-term therapy. Indomethacin was markedly more effective than placebo during the 24hour treatment interval, and a statistically significant difference was found in temporarily delaying labor in spite of a relatively small number of patients. Neonatal outcome was not significantly different from the placebo group in this study, and no neonatal side effects were observed. A similar study by Zuckerman et al. 10 reported that a short course of indomethacin was successful in preventing preterm delivery for 7 days when
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Table Ill. Summary of neonatal outcome parameters Terbutaline
Indomethacin
(n = 32)
(n = 33)
2633 ± 474 7.8 ± 1.4 0.34 ± 1.60
2581 ± 570 7.6 ± 1.8 1.51 ± 4.89
p= P= P=
0.691 0.521 0.202
I
P=
0.999
Neonatal outcome Birth weight (gm, mean ± SDi 5 min Apgar score (mean ± SDi Stay in neonatal intensive care unit (days, mean ± SDi Neonates requiring ventilation (No.) Primary pulmonary hypertension (No.) Patent ductus arteriosus (No.) Intraventricular hemorrhage (No.) Necrotizing enterocolitis (No.) Neonatal deaths (No.)
compared with placebo. As before, no neonatal side effects attributed to indomethacin were observed. In the current study indomethacin was as effective in preventing birth before 34 weeks' gestation as was oral terbutaline sulfate. In addition, no other parameter of pregnancy outcome related to premature delivery was different between the two groups. However, in spite of our inability to demonstrate any clinical superiority of one agent over the other, it is important to view this cautiously. The sample size necessary to insure a > 80% likelihood of avoiding a type II or f3-error in the evaluation of efficacy would have required > 400 patients per group. The decision was made to terminate the study because of the concerns of the investigators and the Institutional Review Board over the high rate of fetal side effects in the indomethacin group. The ductus arteriosus plays an important role in fetal circulation. The ductus arteriosus allows run-off of most of the right ventricular stroke output into the aorta, bypassing the high-resistance pulmonary vascular bed. Animal models support the concept that the fetal ductus arteriosus is controlled by prostaglandins. In lamb and rat fetuses prostaglandin inhibitors have been shown to cause marked ductal constriction late in gestation but to produce little change in the less mature fetuses. 17. 24 Constriction of the human fetal ductus arteriosus has been associated with in utero exposure to indomethacin. This was originally thought to occur mostly in fetuses> 34 weeks' gestation,25. 26 but a recent report by Moise et al. 27 using fetal echocardiography revealed evidence of ductal constriction in seven of 14 fetuses exposed to indomethacin at a mean gestational age of 29.3 ± 0.59 weeks. Echocardiographic evidence of fetal ductus arteriosus constriction is provided by measuring the ductal blood velocity with pulsed Doppler techniques. 14 Right ventricular dysfunction and tricuspid regurgitation also support ductal velocities in diagnosing fetal ductal constriction, but they are not always present with early ductal constriction. Our patients were followed up closely with weekly fetal echocardiograms. This close surveillance revealed that nine (26.5%) fetuses exposed to indomethacin had
o
o o o o
o
o
Significance
o
o o
o
constriction of their ductus arteriosus. Constriction of the ductus arteriosus appeared to occur in an unpredictable relationship to indomethacin exposure. All nine fetuses had normal echocardiograms within 24 hours of discontinuing indomethacin. Because of the unpredictability of ductal constriction, we recommend close surveillance of all fetuses exposed to prostaglandin inhibitors with echocardiography. Indomethacin freely crosses the placenta 28 and can affect fetal prostaglandin synthesis. Besides control over the fetal ductus arteriosus, prostaglandins also play an essential role in the renin-angiotensin-aldosterone system. Prostaglandins are also thought to play a key role in the regulation of renal blood flow and renal tubular sodium reabsorption. 29 Fetal anuria and resultant oligohydramnios have been associated with in utero indomethacin exposure.'9-22 Studies with pulsed Doppler measurements of fetal renal artery blood flow reveal no change in flow when the patient ingests indomethacin. 3o This would suggest an intrinsic renal cause for oligohydramnios in these patients. The renal effects of indomethacin are transient and do not appear to affect neonatal renal function." Studies on short-term indomethacin use did not observe a significant loss of amniotic fluid volume, but long-term studies have shown this complication.' I. 12 Gerson et al. 11 reported that oligohydramnios was reversible if the dose of indomethacin was reduced. Our study reveals a significant incidence of oligohydramnios in the indomethacin group compared with the terbutaline group. During the study period six patients with oligohdyramnios were treated with a reduced dosage of indomethacin (25 mg twice a day). Four of these patients had re accumulation of amniotic fluid and were continued on indomethacin. This finding is encouraging and warrants further study. The timing of oligohydramnios was also unpredictable, as was found with ductal constriction. At a minimum, weekly assessment of amniotic fluid volume is necessary in gestations being treated with indomethacin. In spite of a high frequency of fetal complications associated with indomethacin therapy, we observed no adverse neonatal outcomes in either treatment group,
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except for one neonate that required mechanical ventilation for 24 hours. None of the neonates experienced primary pulmonary hypertension, anuria, oliguria, or a patent ductus arteriosus. Indomethacin has also been implicated, in isolated cases, as a possible contributing cause of neonatal bleeding disorders such as intraventricular hemorrhage or necrotizing enterocolitis. Indomethacin has been used in very preterm neonates for closure of the patent ductus arteriosus with a decreased incidence of intraventricular hemorrhage and no increase in necrotizing enterocolitis when compared with surgical closure. 32 In our series there were no cases of intraventricular hemorrhage or necrotizing enterocolitis in either group. It must be noted that these complications are all much more common in very preterm infants and that in our study the mean gestational age at delivery was 36.1 ± 2.9 weeks and antepartum exposure to indomethacin ceased at 34 weeks by study design. Another aspect of long-term suppression of preterm labor with indomethacin that should be considered is the added cost of weekly fetal echo cardiograms and ultrasonography for amniotic fluid assessment. The total charge of an initial fetal echocardiogram including professional and hospital fees can be as high as $500, with repeat Doppler assessment of the fetal ductus arteriosus costing $200. A limited ultrasonographic examination for measuring the amniotic fluid index may cost between $50 and $100. These weekly charges may add significantly to the cost of medical care in these patients receiving indomethacin suppression for preterm labor. This must be seriously considered in light of the recent climate of medical cost containment. The availability of fetal echocardiography is expanding and is currently available at most tertiary care centers where pediatric cardiologists and maternal-fetal medicine specialists trained in fetal echocardiography are present. This comparative trial of indomethacin and terbutaline sulfate for the long-term suppression of preterm labor confirms and, in our opinion, better quantitates previous concerns over the fetal side effects of in utero exposure to indomethacin. Indomethacin appears to be as efficacious as oral terbutaline sulfate for the longterm suppression of preterm labor, but unfortunately indomethacin is associated with a high incidence of potentially serious fetal side effects. Indomethacin should be reserved as a second line tocolytic agent for the long-term suppression of preterm labor. When used, intensive fetal surveillance with fetal echocardiography and amniotic fluid volume assessment is mandatory on at least a weekly basis. Because these physiologic changes are known to occur rather rapidly and unpredictably, one could argue for more frequent periods of observation. Because the fetal ductal constric-
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tion and reductions in amniotic fluid were uniformly reversible, fetal echocardiography and serial ultrasonography is probably not needed if indomethacin is used on a short-term basis only. REFERENCES 1. Fuchs F. Prevention of prematurity. AM] OBSTET GYNECOL 1976; 126:809-20. 2. Reed MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br] Obstet Gynaecol 1986;93:933-7. 3. Zuckerman H, Reiss U, Rubinstein 1. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974; 44:787-92. 4. Richards SR, Klingelberger CE. Intravenous ritodrine as a possible provocative predictive test in gestational diabetes: a case report.] Reprod Med 1987;32:798-800. 5. Benedetti T], Hargrove ]C, Rosene KA. Maternal pulmonary edema during premature labor inhibition. Ob stet Gynecol 1982;59(suppl):335-75. 6. Michalak D, Klein V, Marquette GP. Myocardial ischemia: a complication of ritodrine tocolysis. AM] OBSTET GYNECOL 1983;146:861-2. 7. Huszar G, Naftolin F. The myometrium and uterine cervix in normal and preterm labor. N Engl] Med 1984;311: 571-81. 8. Wigvist N, Lundstrom V, Green K. Premature labor and indomethacin. Prostaglandins 1975; 10:515-26. 9. Niebyl ]R, Blake DA, White RD, et al. The inhibition of premature labor with indomethacin. AM] OBSTET GYNECOL 1980; 136: 1014-9. 10. Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. n. Double-blind study.] Perinat Med 1984;12:25-9. 11. Gerson A, Abbasi S,] ohnson A, et al. Safety and efficacy of long-term tocolysis with indomethacin. Am ] Perinatol 1990:7:71-4. 12. Besinger RE, Niebyl ]R, Keyes WG, ]ohnson TRB. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment ofpreterm labor. AM] OBSTET GYNECOL 1991;164:981-8. 13. Moore TR, Cayle ]E. The amniotic fluid index in normal human pregnancy. AM] OBSTET GYNECOL 1990;162:116873. 14. Huhta]C, Moise K], Fisher D], SharifDS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987;75:406-12. 15. Arcilla RA, Thilenius OG, Ranniger K. Congestive heart failure f)'om suspected ductal closure in utero. Pediatrics 1969;75:74-8. 16. Manchester D, Margolis HS, Sheldon RE. Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. AM ] OBSTET GY~'mCOL 1976;126:467-50. 17. Levin DL, Mills L], Parkey M, Garriott], Campbell W. Constriction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe. Pediatrics 1979;94:647-50. 18. Goudie BM, Dossetor ]FB. Effect on the fetus of indomethacin given to suppress labour. Lancet 1979;2: 1187-8. 19. Itskovitz], Abramovici H, Brandes ]M. Oligohydramnion, meconium and perinatal death concurrent with indomethacin treatment in human pregnancy.] Reprod Med 1980; 24: 137-40. 20. Cantor B, Tyler '1', Nelson RM, Stein GH. Oligohydramnios and transient neonatal anuria: a possible association with the maternal use of prostaglandin synthetase inhibitors.] Reprod Med 1980;24:220-3. 21. Vanhaesebrouck P, Thiery M, Leroy]G, et al. Oligohydramnios, renal insufficiency, and ileal perforation in pre-
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24. 25. 26. 27.
tenn infants after intrauterine exposure to indomethacin. J Pediatr 1988;113:738-43. DeWit W, VanMourik I,Wiesenhaan PF. Prolonged maternal indomethacin therapy associated with oligohydramnios: case reports. Br J Obstet Gynaecol 1988;95: 303-5. Hickok DE, Hollenbach KA, Reilley SF, Nyberg DA. The association between decreased amniotic fluid volume and treatment with nonsteroidal anti-inflammatory agents for preterm labor. AM J OBSTET GVNECOL 1989;160:1525-31. Momma K, Takao A. In vivo constriction of the ductus arteriosus by nonsteroidal antiinflammatory drugs in nearterm and preterm fetal rats. Pediatr Res 1987;22:567-72. Dudley DKL, Hardie MJ. Fetal and neonatal effects of indomethacin used as a tocolytic agent. AM J OBSTET GVNECOL 1985;151:181-4. Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment for preterm labor. AM J OBSTET GYNECOL 1986;155:747-9. Moise Iq, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor: effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-31.
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28. Moise KJ, Ou C, Kirshon B, Cano LE, Rognerud C, Carpenter RJ. Placental transfer of indomethacin in the human pregnancy. AM J OBSTET GVNECOL 1990;162:54954. 29. Anderson RJ, Berl T, McDonald KM, Schrier RW. Prostaglandins: effects on blood pressure, renal blood flow, sodium and water excretion. Kidney Int 1976; 10: 205-15. 30. Mari G, Moise KJ, Deter RL, Kirshon B, Carpenter RJ. Doppler assessment of the renal blood flow velocity wavefonn during indomethacin therapy for pretenn labor and polyhydramnios. Obstet GynecoI1990;75:199-201. 31. Wurtzel D. Prenatal administration of indomethacin as a tocolytic agent: effect on neonatal renal function. Obstet Gynecol 1990;76:689-92. 32. Bandstra ES, Montalvo BM, Goldberg RN, et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988;82:53342.
Randomized trial of intraumbilical vein oxytocin in midtrimester pregnancy losses Harold A. Bivins, Jr., MD, Darrell A. Cope, MD, Roger B. Newman, MD, and Daniel P. Eller, MD Charleston, South Carolina OBJECTIVE: The purpose of this double-blind prospective randomized trial was to determine whether high-dose intraumbilical vein oxytocin injection shortens the third stage of labor in midtrimester pregnancy losses. STUDY DESIGN: Patients (n = 50) with spontaneous or induced midtrimester pregnancy losses (14 to 26 weeks' gestation) were randomized to receive either 100 IU of oxytocin in 20 ml of normal saline solution or 20 ml of normal saline solution alone as a placebo. The umbilical vein was injected as soon as the cord was clamped. Outcome data were collected. RESULTS: Of the 50 patients randomized, 45 completed the study. Five were excluded after randomization because of either cesarean delivery (1 patient) or en caul delivery (4 patients). Twenty-one patients received oxytocin, and 14 received placebo. Ten patients who were not injected because of technical failure were evaluated separately. There were no differences between the three groups with regard to gestational age, fetal weight, length of the third stage, blood loss, or need for operative removal of the placenta. CONCLUSION: Injection of high-dose oxytocin into the umbilical vein in second-trimester pregnancy losses does not shorten the third stage of labor or decrease the need for surgical intervention because of retained placenta. (AM J OBSTET GVNECOL 1993;169:1070-3.)
Key words: Intraumbilical vein oxytocin, midtrimester pregnancy loss, retained placenta
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Medical University of South Carolina. Presented at the Thirteenth Annual Meeting of the Society of Perinatal Obstetricians, San Francisco, California, February 8-13,1993. Reprint requests: Harold A. Bivins, Jr., MD, 4750 Waters Ave., Suite 202, Savannah, CA 31404. Copyright © 1993 by Mashy-Year Book, Inc. 0002-9378/93 $1.00 + .20 6/6/48965
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Midtrimester pregnancy losses are associated with an increased risk of prolonged third stage of labor, excessive blood loss, and retained placenta. l -4 This increases the need for operative intervention resulting in increased morbidity, medical costs, and maternal stress. Although controversial, the use of intraumbilical vein oxytocin has been reported to hasten the third stage of