Indomethacin Pregnancy and Breastfeeding Warnings
Indomethacin Pregnancy Warnings
Indomethacin has been assigned to pregnancy category C by the FDA. Animal studies have failed to reveal evidence of teratogenicity or fetal harm except at doses which result in significant maternal toxicity. There are no controlled data in early human pregnancy. Indomethacin has been used in the management of premature labor. However, fetal hemodynamic changes, premature closure of the ductus arteriosus resulting in neonatal primary pulmonary hypertension, and neonatal oliguric renal failure, oligohydramnios, hemorrhage, and intestinal perforation have been reported as a result of this tocolytic therapy. Indomethacin is only recommended for use during pregnancy when benefit outweighs risk.
Indomethacin crosses the placenta. In one study, 26 pregnant patients were administered indomethacin 50 mg orally one time approximately six hours prior to scheduled cordocentesis, at a gestational age of 23.6 to 36.6 weeks. At the time of the procedure, maternal serum indomethacin concentrations ranged from 42 to 690 ng/mL (mean 218 ng/mL) while fetal concentrations ranged from 87 to 496 ng/mL (mean 219 ng/mL). The mean maternal to fetal serum concentration ratio was 0.97. There was no correlation between gestational age and maternal/fetal ratio. Amniotic fluid concentrations averaged 21 ng/mL. Indomethacin has been used successfully in the treatment of premature labor as well as polyhydramnios. In several studies, indomethacin was as effective and better tolerated than beta-agonists for premature labor. However, while earlier reports and studies suggested indomethacin was safe for the fetus or neonate, especially when use was confined to pregnancies of 34 weeks gestation or less, more recent data suggest a substantial increase in the risk of serious fetal or neonatal side effects. Eronen (1993) studied the effects of indomethacin or nylidrin on the fetal and neonatal ductus arteriosus and tricuspid valve function. A total of 84 pregnancies (94 fetuses) with premature labor between 22.9 and 34.0 weeks gestation were evaluated. Ductal constriction occurred in 46/49 (86%) of fetuses (gestational age 24.0 to 34.0 weeks) treated with indomethacin. The gestational age of the fetuses without ductal constriction ranged from 24.3 to 28.6 weeks. Eleven fetuses with ductal constriction also had tricuspid regurgitation. Data from this study suggest increasing reactivity of the ductus with increasing gestational age; although, ductal constriction occurred in one fetus at 22.9 weeks gestation. In addition to hemodynamic changes, other serious sequelae of maternal indomethacin use have been documented. One study compared 57 infants delivered at or before 30 weeks gestation whose mothers received indomethacin for the treatment of premature labor with 57 infants whose mothers had not received indomethacin. The total dose of indomethacin ranged from 50 to 6000 mg (median 425 mg) and the duration of therapy ranged from 1 to 79 days (median 3 days). Necrotizing enterocolitis occurred in 29% of infants exposed to indomethacin compared with an 8% incidence in the control group (p=0.005). Intracranial hemorrhage occurred in 28% of infants in the indomethacin group compared with only 9% in the control group (p=0.02). Maternal use of indomethacin has resulted in reduced fetal urine output and subsequent oligohydramnios, neonatal renal failure, fetal pleural effusion, and ileal perforation. In addition, at least two cases of neonatal lower limb ischemia have been reported following prolonged intrauterine exposure to indomethacin. Fetal echocardiograms after 24 hours of maternal indomethacin therapy and then weekly, thereafter, if long-term therapy is necessary, have been recommended. In addition, assessment of amniotic fluid volume is also recommended.
Indomethacin Breastfeeding Warnings
In vitro data suggest that indomethacin passes into human milk by simple diffusion. The excretion of indomethacin into human milk was evaluated in 16 women treated with doses ranging from 0.94 to 4.29 mg/kg/day. All but one patient was less than 10 days post partum. Milk concentrations ranged from less than 20 mcg/L to 115 mcg/L and did not correlate with maternal dose. The median milk to maternal plasma concentration ratio was 0.37. Plasma samples were obtained from seven nursing infants. In six infants, indomethacin plasma concentrations were below the level of detection (less than 20 mcg/L). In one infant, the plasma concentration was 47 mcg/L at approximately 1.2 hours after nursing. Seizures have been reported in a seven-day-old infant whose mother was treated with indomethacin in doses up to 200 mg per day during the puerperium. In the absence of a definitive cause, the authors speculated that the seizures were related to indomethacin exposure via breast milk. Causality in this case is unknown.
Indomethacin is excreted in the milk of lactating mothers. Indomethacin not recommended by the manufacturer for use in nursing mothers.
References for pregnancy information
- Moise KJ, Ching-Nan Ou, Cano LE, Rognerud C, Carpenter RJ "Placental transfer of indomethacin in the human pregnancy." Am J Obstet Gynecol 162 (1990): 549-54
- Morales WJ, Smith SG, Angel JL, O'Brien WF, Knuppel RA "Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study." Obstet Gynecol 74 (1989): 567-72
- Eronen M "The hemodynamic effects of antenatal indomethacin and a beta- sympathomimetic agent on the fetus and the newborn: a randomized study." Pediatr Res 33 (1993): 615-9
- Eronen M, Pesonen E, Kurki T, Teramo K, Ylikorkala O, Hallman M "Increased incidence of bronchopulmonary dysplasia after antenatal administration of indomethacin to prevent preterm labor." J Pediatr 124 (1994): 782-8
- Shen O, Rabinowitz R, Lavie O, Aboulafia Y, Diamant YZ "Good fetal outcome following prolonged indomethacin induced anhydramnios. case report." J Perinat Med 23 (1995): 233-6
- "Product Information. Indocin (indomethacin)." Merck & Co, Inc, West Point, PA.
- Van den Veyver IB, Moise KJ, Jr Ou CN, Carpenter RJ, Jr "The effect of gestational age and fetal indomethacin levels on the incidence of constriction of the fetal ductus arteriosus." Obstet Gynecol 82 (1993): 500-3
- Vanhaesebrouck P, Thiery M, Leroy JG, et al. "Oligohydramnios, renal insufficiency, and ileal perforation in preterm infants after intrauterine exposure to indomethacin." J Pediatr 113 (1988): 738-43
- Koren G, Pastuszak A, Ito S "Drugs in pregnancy." N Engl J Med 338 (1998): 1128-37
- Norton ME, Merrill J, Cooper BAB, Kuller JA, Clyman RI "Neonatal complications after the administration of indomethacin for preterm labor." N Engl J Med 329 (1993): 1602-7
- Merrill JD, Clyman RI, Norton ME "Indomethacin as a tocolytic agent: the controversy continues." J Pediatr 124 (1994): 734-6
- Morales WJ, Madhav H "Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study." Am J Obstet Gynecol 169 (1993): 97-102
- Major CA, Lewis DF, Harding JA, Porto MA, Garite TJ "Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low-birth-weight neonate." Am J Obstet Gynecol 170 (1994): 102-6
- Murray HG, Stone PR, Strand L, Flower J "Fetal pleural effusion following maternal indomethacin therapy." Br J Obstet Gynaecol 100 (1993): 277-9
- Kirshon B, Moise KJ Jr, Mari G, Willis R "Long-term indomethacin therapy decreases fetal urine output and results in oligohydramnios." Am J Perinatol 8 (1991): 86-8
- Buderus S, Thomas B, Fahnenstich H, Kowalewski S "Renal failure in two preterm infants: toxic effect of prenatal maternal indomethacin treatment?" Br J Obstet Gynaecol 100 (1993): 97-8
- Eronen M, Pesonen E, Kurki T, Ylikorkala O, Hallman M "The effects of indomethacin and a B-sympathomimetic agent on the fetal ductus arteriosus during treatment of premature labor: a randomized double-blind study." Am J Obstet Gynecol 164 (1991): 141-6
- Goldenberg RL, Davis RO, Baker RC "Indomethacin-induced oligohydramnios." Am J Obstet Gynecol 160 (1989): 1196-7
- Moise KJ, Jr "Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use." Am J Obstet Gynecol 168 (1993): 1350-3
- Arad I, Baroz B, Amit Y, Ergaz Z, Peleg O "Neonatal limb ischemia following maternal indomethacin treatment in twin pregnancies." J Perinat Med 23 (1995): 487-91
- Ostensen M "Optimisation of antirheumatic drug treatment in pregnancy." Clin Pharmacokinet 27 (1994): 486-503
- Moise KJ, Huhta JC, Sharif DS, et al. "Indomethacin in the treatment of premature labor." N Engl J Med 319 (1988): 327-31
- Vanderheijden BJ, Carlus C, Narcy F, Bavoux F, Delezoide AL, Gubler MC "Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin." Am J Obstet Gynecol 171 (1994): 617-23
- Dudley DKL, Hardie MJ "Fetal and neonatal effects of indomethacin used as a tocolytic agent." Am J Obstet Gynecol 151 (1985): 181-4
- Niebyl JR, Witter FR "Neonatal outcome after indomethacin treatment for preterm labor." Am J Obstet Gynecol 155 (1986): 747-9
- Van den Veyver IB, Moise KJ, Jr "Prostaglandin synthetase inhibitors in pregnancy." Obstet Gynecol Surv 48 (1993): 493-502
- Moise KJ, Jr "Polyhydramnios: problems and treatment." Semin Perinatol 17 (1993): 197-209
References for breastfeeding information
- Committee on Drugs, 1992 to 1993 "The transfer of drugs and other chemicals into human milk." Pediatrics 93 (1994): 137-50
- Roberts RJ, Blumer JL, Gorman RL, et al "American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk." Pediatrics 84 (1989): 924-36
- Lebedevs TH, Wojnar-Horton RE, Yapp P, et al. "Excretion of indomethacin in breast milk." Br J Clin Pharmacol 32 (1991): 751-4
- "Product Information. Indocin (indomethacin)." Merck & Co, Inc, West Point, PA.
- Fairhead FW "Convulsions in a breast-fed infant after maternal indomethacin." Lancet 2 (1978): 576
- Eeg-Olofsson O, Malros I, Elwin C, Steen B "Convulsions in a breast-fed infant after maternal indomethacin." Lancet 2 (1978): 215
- Beaulacbaillargeon L, Allard G "Distribution of indomethacin in human milk and estimation of its milk to plasma ratio invitro." Br J Clin Pharmacol 36 (1993): 413-6
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