AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2

March 1991

LONG-TERM INDOMETHACIN THERAPY DECREASES FETAL URINE OUTPUT AND RESULTS IN OLIGOHYDRAMNIOS Brian Kirshon, M.D., Kenneth J. Moise, Jr., M.D., Giancarlo Mari, M.D., and Rita Willis, R.N.

Four quadrant quantitative amniotic fluid volume (length, width, and depth) was performed in six fetuses prior to and during indomethacin therapy for preterm labor in patients with normal amniotic fluid volume prior to therapy. The dose of indomethacin was 25 mg oral ly every 6 hours. One patient had to have the dose reduced to 25 mg every 12 hours due to constriction of the ductus arteriosus. Fetal urine output was determined prior to and during indomethacin therapy. The mean pretherapy amniotic fluid volume of 341.5 ±43.2 mm declined to 97 ±9.3 mm at the time of discontinuation of indomethacin foroligohydramnios. This occurred after 15 days of 25 mg indomethacin orally every 6 hours in four patients and after 28 days at 25 mg indomethacin every 12 hours in the remaining patient. Fetal urine output prior to and following indomethacin was 4.93 ± 14 ml and 1.73 ± 0.6 ml/hr, respectively. Prolonged indomethacin therapy results in decreased fetal urine output with resultant oligohydramnios and appears to be the major limiting factor aside from ductal constriction to long-term indomethacin therapy.

Amniotic fluid volume is largely dependent on fetal urination in the second half of pregnancy. Maternal administration of indomethacin, a prostaglandin synthetase inhibitor, has been shown to decrease fetal urine output.l However, the duration of indomethacin therapy was less than 72 hours in that study and no subjective change in amniotic fluid volume was observed. The purpose of this study was to quantitate amniotic fluid volume in patients undergoing long-term indomethacin therapy. MATERIALS AND METHODS

Institutional review board approval was obtained for the study. Six fetuses from five pregnancies were treated with indomethacin. The indication for indomethacin therapy was preterm labor in all patients, one of whom also had a degenerating leiomyoma. The dose of indomethacin was 25 mg orally every 6 hours. In one patient the dose had to be reduced to 25 mg orally every 12 hours due to constriction of the ductus arteriosus at a dose of 25

mg every 6 hours. The fetal ductus arteriosus was examined by fetal echocardiography prior to therapy, within 24 hours of initiating therapy, and then weekly. If constriction of the ductus arteriosus was noted, indomethacin was discontinued and patency of the ductus arteriosus documented within 24 hours of discontinuation of the indomethacin. In the single patient who demonstrated fetal ductus arteriosus constriction on 25 mg orally every 6 hours, resolution of the constriction was noted on discontinuation of indomethacin. A reduced dose of 25 mg orally every 12 hours was not associated with constriction. Amniotic fluid volume was quantitated with a four quadrant ultrasound technique. The width, depth, and length of amniotic fluid in each of the four quadrants was measured and added together prior to indomethacin and again biweekly until oligohydramnios necessitated discontinuation of therapy. Oligohydramnios was defined as less than a 2 cm by 2 cm pocket of amniotic fluid.2 Fetal urine output was determined following the method of Campbell et al3 prior to and during indomethacin therapy.

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, Texas Reprint requests: Dr. Kirshon, Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030

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Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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ABSTRACT

OLIGOHYDRAMNIOS WITH INDOMETHACIN/Kirshon, Moise, Mari, Willis Table 1. Maternal Demographic Data, Duration of Indomethacin, and Newborn Data Newborn Data

Indomethacin Gravidity (G) Maternal Parity (P) Age (yr) Abortions (Ab)

AFI* (mm) Before After

GA* at Start of Therapy (weeks)

Duration of Therapy (days)

Weight Apgar Score (grams) (1/5 min)

32

G ^

360

94

26°/7

1 day/25 mg every 6 hours 28 days/25 mg twice daily

2500

8/9

31

G 2 Pi

16

G 2 P, Ab!

106 100 101 102 80

24V7

25 29 26

400 300 335 368 286

29°/ 7

21 12 14

2600 2100 3985 2895 2780

8/9 7/9 7/9 8/8 9/9

G3P3 G5 P3 Ab2

33V7

23°//

RESULTS

The mean amniotic fluid volume (length, depth, and width in millimeters added together from each quadrant) prior to therapy was 341.5 ± 43.2 mmHg which declined to 97 ± 9.3 mm at the time of discontinuation of indomethacin. The four patients given 25 mg orally every 6 hours received the indomethacin for a mean of 15 days, and the one patient on 25 mg orally every 12 hours had indomethacin discontinued after 28 days due to oligohydramnios. Amniotic fluid volume reaccumulated within 1 week after discontinuation of indomethacin. Fetal urine output prior to indomethacin was 4.93 ± 1.4 ml/hr and declined to 1.73 ± 0.6 ml/hr during indomethacin therapy. Maternal demographic data with duration of indomethacin and newborn data are presented in Table 1. DISCUSSION

Indomethacin has been demonstrated to be an effective agent for the treatment of preterm labor.45 The major concern regarding its use has been the potential for constriction of the fetal ductus arteriosus. Moise et al6 studied the effect of maternal indomethacin administration for preterm labor on the fetal ductus arteriosus in 14 fetuses and detected ductal constriction in seven fetuses. Three of the seven cases of ductal constriction were associated with tricuspid regurgitation. All cases with constriction and tricuspid regurgitation resolved on discontinuation of indomethacin. Studies in animals have demonstrated the need for prostaglandins to maintain in utero patency of the fetal ductus arteriosus.7 Some investigators8 have suggested that indomethacin is a safe tocolytic agent before 34 weeks' gestation, since the ductus is more sensitive to constriction beyond this time. Persistent fetal circulation thought to be related to ductal constriction in utero from indomethacin therapy has been reported.9'10 Despite this, no deleterious newborn cardiopulmonary effects were reported by Niebyl et al11 and Dudley and Hardie8 with short-term indomethacin tocolytic therapy.

Kirshon et al1 examined the effect of short-term indomethacin therapy on fetal urine output. Eight pregnancies ranging from 26 to 32 weeks' gestation were treated for preterm labor with oral indomethacin. A dramatic decline in fetal urine output occurred during indomethacin therapy. Similar findings have been demonstrated in newborn lambs12 and human adults.13 The pathogenesis of the decline in urine output is probably due to an enhanced antidiuretic hormone (ADH) effect because the E class prostaglandins antagonize the peripheral action of ADH by blocking its stimulation of cyclic adenosine monophosphate.14 Novy et al15 examined the effects of indomethacin inhibition of prostaglandin synthesis in the baboon fetus and demonstrated marked oligohydramnios after maternal indomethacin therapy. With the knowledge that amniotic fluid is largely dependent on fetal urination and urine output decreases following indomethacin therapy,1 we demonstrated the efficacy of indomethacin in reducing amniotic fluid volume in polyhydramnios.16 This current study was performed to assess amniotic fluid volume with prolonged indomethacin therapy when normal amniotic fluid volume was present prior to therapy. It is therefore evident that prolonged indomethacin therapy leads to oligohydramnios and would appear to be the major limiting factor aside from ductal constriction to long-term indomethacin therapy. Even at a lower dosage of indomethacin, oligohydramnios still occurs, albeit after a longer period of time. It is reassuring, however, that reaccumulation of amniotic fluid occurs after discontinuation of indomethacin.

REFERENCES

Kirshon B, Moise KJ Jr, Wasserstrum N, et al: Influence of short term indomethacin therapy on fetal urine output. Obstet Gynecol 72:51-53, 1988 Manning FA: Fetal biophysical assessment by ultrasound. In Creasn, Resnik (eds): Maternal Fetal Medicine: Principles

and Practice. 2nd ed. Philadelphia: WB Saunders, 1989, p 360 Campbell S, Wladimiroff JW, Dewhust CJ: The antenatal 87

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AFI: Amniotic fluid index, or four-quadrant volume of amniotic fluid; GA: gestational age.

AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2 March 1991

5. 6. 7.

8. 9.

10. Scaba IF, Sulyok E, Ertl T: Clinical note: Relationship of maternal treatment with indomethacin to persistence of fetal circulation syndrome. J Pediatr 92:484, 1978 11. Niebyl JR, Witter FR: Neonatal outcome after indomethacin treatment for premature labor. Am J Obstet Gynecol 155:747-749, 1986 12. Winther JB, Hoskins E, Printz MP, et al: Influence of indomethacin on renal function in conscious newborn lambs. Biol Neonate 38:76, 1980 13. Brater DC: Effects of indomethacin on salt and water homeostasis. Clin Pharmacol Ther 25:322, 1979 14. Anderson R, Berl T, McDonald D, et al: Prostaglandins: Effects on blood pressure, renal bloodflow,sodium and water excretion. Kidney Int 10:205, 1976 15. Novy MJ, Cook MJ, Manaugh L: Indomethacin block of normal onset of parturition in primates. Am J Obstet Gynecol 118:412, 1974 16. Kirshon B, Moise KJ Jr, Mari G, Willis R: Indomethacin therapy for the treatment of polyhydramnios. Proceedings of the Society of Perinatal Obstetricians, New Orleans, January 1989 Downloaded by: National University of Singapore. Copyrighted material.

4.

measurement of fetal urine production. J Obstet Gynaecol Br Common 80:680, 1973 Niebyl JR, Blake DA, White RD, et al: The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 136:1014, 1980 Zuckerman H, Shaler E, Gilad G, et al: Further study of the inhibition of premature labor by indomethacin. Part 1. J Perinat Med 12:19, 1984 Moise KJ Jr, Huhta JC, Sharif DS, Ou C, Kirshon B, Wasserstrum N, Cano L: Indomethacin in the treatment of premature labor. N Engl J Med 319:327-331, 1988 Sideris EB, Yokochi K, Van Helder T, Coseani F, Olley PM: Effects of indomethacin and prostaglandin E2I2 and D2 on the fetal circulation. Adv Prostaglandin Thromboxane Leukotriene Res 12:477-482, 1983 Dudley DKL, Hardie MJ: Fetal and neonatal effects of indomethacin used as a tocolytic agent. Am J Obstet Gynecol 151:181-184, 1985 Manchester KD, Margolis HS, Sheldon RE: Possible pulmonary hypertension of the newborn. Am J Obstet Gynecol 126:467-469, 1976

Long-term indomethacin therapy decreases fetal urine output and results in oligohydramnios.

Four quadrant quantitative amniotic fluid volume (length, width, and depth) was performed in six fetuses prior to and during indomethacin therapy for ...
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