Risk Factor: B*
Class: Central nervous system drugs/ Nonsteroidal anti-inflammatory drugs
Fetal Risk Summary
Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID). It is indicated for the relief of the signs and symptoms of moderate-to-severe rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, and acute painful shoulder (bursitis and/or tendinitis). Indomethacin is in the same subclass (acetic acids) as three other NSAIDs (diclofenac, sulindac, and tolmetin).
Shepard reviewed four reproduction studies on the use of indomethacin in mice and rats (1). Fused ribs, vertebral abnormalities, and other skeletal defects were seen in mouse fetuses, but no malformations were observed in rats except for premature closure of the ductus arteriosus in some fetuses. A 1990 report described an investigation on the effects of several nonsteroidal anti-inflammatory agents on mouse palatal fusion both in vivo and in vitro (2). All of the compounds were found to induce some degree of cleft palate, although indomethacin was associated with the lowest frequency of cleft palate of the five agents tested (diclofenac, indomethacin, mefenamic acid, naproxen, and sulindac).
Indomethacin crosses the placenta to the fetus with concentrations in the fetus equal to those in the mother (3). Twenty-six women, between 23 and 37 weeks’ gestation, who were undergoing cordocenteses for varying indications, were given a single 50-mg oral dose approximately 6 hours before the procedure. Mean maternal and fetal indomethacin levels were 218 and 219 ng/mL, respectively, producing a mean ratio of 0.97. The mean amniotic fluid level, 21 ng/mL, collected during cordocenteses, was significantly lower than the maternal and fetal concentrations. Neither fetal nor amniotic fluid concentrations varied with gestational age.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 114 newborns had been exposed to indomethacin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Seven (6.1%) major birth defects were observed (five expected), two of which were cardiovascular defects (one expected). No anomalies were observed in five other defect categories (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A combined 2001 population-based observational cohort study and a case-control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (4). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with spontaneous abortions (SABs) (see Ibuprofen for details).
Indomethacin is occasionally used in the treatment of premature labor (5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26, 27,28,29,30,31,32,33,34,35,36 and 37). The drug acts as a prostaglandin synthesis inhibitor and is an effective tocolytic agent, including in those cases resistant to b-mimetics. Niebyl (30) reviewed this topic in 1981. Daily doses ranged from 100 to 200 mg usually by the oral route, but rectal administration was used as well. In most cases, indomethacin, either alone or in combination with other tocolytics, was successful in postponing delivery until fetal lung maturation had occurred. More recent reviews on the use of indomethacin as a tocolytic agent appeared in 1992 (34) and 1993 (35). The latter review concluded that the prostaglandin synthesis inhibitors, such as indomethacin, may be the only effective tocolytic drugs (35).
In a 1986 report, 46 infants exposed in utero to indomethacin for maternal tocolysis were compared with two control groups: (a) 43 infants exposed to other tocolytics and (b) 46 infants whose mothers were not treated with tocolytics (31). Indomethacin-treated women received one or two courses of 150 mg orally over 24 hours, all before 34 weeks’ gestation. No significant differences were observed between the groups in Apgar scores, birth weight, or gestational age at birth. Similarly, no differences were found in the number of neonatal complications such as hypocalcemia, hypoglycemia, respiratory distress syndrome, need for continuous positive airway pressure, pneumothorax, patent ductus arteriosus, sepsis, exchange transfusion for hyperbilirubinemia, congenital anomalies, or mortality.
A 1989 study compared indomethacin, 100-mg rectal suppository followed by 25 mg orally every 4 hours for 48 hours, with IV ritodrine in 106 women in preterm labor with intact membranes who were at a gestational age of 32 weeks or less (36). Fifty-two women received indomethacin and 54 received ritodrine. Thirteen (24%) of the ritodrine group developed adverse drug reactions severe enough to require discontinuance of the drug and a change to magnesium sulfate: cardiac arrhythmia (N=1), chest pain (N=2), tachycardia (N=3), and hypotension (N=7). None of the indomethacin-treated women developed drug intolerance (p
The tocolytic effects of indomethacin and magnesium sulfate (MgSO4) were compared in a study of women in labor at less than 32 weeks’ gestation (37). A total of 49 women were treated with indomethacin, 100 mg per rectum followed by 25 mg orally every 4 hours for 48 hours, whereas 52 women were administered IV MgSO4. Women who had responded to the initial treatment were then changed to oral terbutaline. All women received betamethasone and vitamin K and some received IV phenobarbital as prophylaxis against hyaline membrane disease and neonatal intracranial hemorrhage. Both indomethacin and MgSO4 were effective in delaying delivery more than 48 hours, 90% vs. 85%, respectively, and combined with terbutaline, in extending the gestation, 22.9 vs. 22.7 days, respectively (37). Renal function of the newborns delivering at (48 hours (indomethacin, N=5; MgSO4, N=8) as measured by blood urea nitrogen, creatinine, and urine output during the first 2 days after birth were statistically similar between the groups. Other neonatal outcomes, including the incidence of respiratory distress syndrome, intraventricular hemorrhage (all grades), and intraventricular hemorrhage (grades 3 and 4), were also similar. Tocolytic therapy was discontinued in 8 (15%) of the women treated with MgSO4 because of maternal adverse reactions compared with none in the indomethacin group (p
Complications associated with the use of indomethacin during pregnancy may include premature closure of the ductus arteriosus, which may result in primary pulmonary hypertension of the newborn and, in severe cases, neonatal death (5,6,7,8 and 9,34,35,38,39,40,41,42,43,44 and 45). Ductal constriction is dependent on the gestational age of the fetus, starting as early as 27 weeks (46,47), and increasing markedly at 2732 weeks (47,48), and occur with similar frequencies in singleton and multiple gestations (48). Further, constriction is independent of fetal serum indomethacin levels (46,47). Primary pulmonary hypertension of the newborn is caused by the shunting of the right ventricular outflow into the pulmonary vessels when the fetal ductus arteriosus narrows. This results in pulmonary arterial hypertrophy (45). Persistent fetal circulation occurs after birth secondary to pulmonary hypertension shunting blood through the foramen ovale, bypassing the lungs and still patent ductus arteriosus, with resultant difficulty in adequate oxygenation of the neonate (45).
Using fetal echocardiography, researchers described the above effects in a study of 13 women (14 fetuses, 1 set of twins) between the gestational ages of 26.5 and 31.0 weeks (45). The patients were treated with 100150 mg of indomethacin orally per day. Fetal ductal constriction occurred in 7 of 14 fetuses 9.525.5 hours after the first dose and was not correlated with either gestational age or maternal indomethacin serum levels. In two other cases not included in the present series, ductal constriction did not occur until several weeks after the start of therapy. Tricuspid regurgitation was observed in 3 of the fetuses with ductal constriction. This defect was caused by the constriction-induced elevated pressure in the right ventricular outflow tract producing mild endocardial ischemia with papillary muscle dysfunction (45). All cases of constriction, including 2 of the 3 with tricuspid regurgitation, resolved within 24 hours after indomethacin was discontinued. The third tricuspid case returned to normal 40 hours after resolution of the ductal constriction. No cases of persistent fetal circulation were observed in the 11 newborns studied. Some have questioned the methods used in the above study and whether the results actually reflected fetal ductal constriction (49). In response, the authors of the original paper defended their techniques based on both animal and human experimental findings (50).
A 1987 report described a patient with premature labor who was treated for 29 days between 27 and 32 weeks’ gestation with a total indomethacin dose of 6.2 g (51). The woman delivered a female infant who had patent ductus arteriosus that persisted for 4 weeks. A macerated twin fetus, delivered at the same time as the surviving infant, was thought to have died before the initiation of treatment.
Administration of indomethacin to the mother results in reduced fetal urine output. Severe oligohydramnios, meconium staining, constriction of the ductus arteriosus, and death were reported in the offspring of three women treated for preterm labor at 3233 weeks’ gestation (52). Indomethacin doses were 100 mg (one case) and 400 mg (two cases) during the first 24 hours followed by 100 mg/day for 25 days. Two of the fetuses were stillborn, and the third died within 3 hours of birth. A second report described a woman with preterm labor at 24 weeks’ gestation who was treated with IV ritodrine and indomethacin, 300 mg/day, for 8 weeks (53). A reduction in the amount of amniotic fluid was noted at 28 weeks’ gestation (after 4 weeks of therapy), and severe oligohydramnios was present 4 weeks later. Filling of the fetal bladder could not be visualized at this time. The infant, who expired 47 hours after birth, had the characteristic facies of Potter’s syndrome (i.e., oligohydramnios sequence), but autopsy revealed a normal urinary tract with normal kidneys. Both cardiac ventricles were hypertrophic and the lungs showed no evidence of pulmonary hypertension.
In a 1987 study involving eight patients with polyhydramnios and premature uterine contractions, indomethacin, administered by oral tablets or vaginal suppositories in a dose of 2.23.0 mg/kg/day, resolved the condition in each case (54). Four of the patients had diabetes mellitus. The gestational age of the patients at the start of treatment ranged between 21.5 and 34 weeks. The duration of therapy, which was stopped between 34.5 and 38 weeks’ gestation, ranged from 2 to 11 weeks. The average gestational age at birth was 38.6 weeks and none was premature. All infants were normal at birth and at follow-up for 26 months. In addition to the reduced urine output, indomethacin was thought to have minimized the amount of fluid produced by the amnion and chorion (54).
A case report described a 33-year-old woman with a low serum a-fetoprotein level at 16 weeks’ gestation and symptomatic polyhydramnios and preterm labor at 26 weeks’ gestation who was treated with indomethacin, 25 mg orally every 4 hours, after therapeutic decompression had removed 3000 mL of amniotic fluid (55). During the 9 weeks of therapy, periodic fetal echocardiography was conducted to ensure that the fetal ductus arteriosus remained patent. Fetal urine output declined significantly (
In two women treated for premature labor, indomethacin-induced oligohydramnios was observed 1 week and 3.5 weeks after starting therapy (56). Treatment was continued for 3 weeks in one patient and for 8 weeks in the other, with therapy discontinued at 31 and 32 weeks’ gestation, respectively. Within a week of stopping indomethacin, amniotic fluid volume had returned to normal in both patients. Ultrasonography revealed that both fetuses had regular filling of their bladders. The newborns, delivered 34 weeks after indomethacin treatment was halted, had normal urine output. Neither premature closure of the ductus arteriosus nor pulmonary hypertension was observed. Another case of reversible indomethacin-induced oligohydramnios was reported in 1989 (57). The woman was treated from 2028 weeks’ gestation with indomethacin, 100200 mg/day, plus various other tocolytic agents for premature labor. Ten days after indomethacin therapy was stopped, the volume of amniotic fluid was normal. She was eventually delivered of a 2905-g female infant at 36 weeks’ gestation. Development was normal at 1 year of age.
The effects of tocolytic therapy on amniotic fluid volume were the subject of a 1989 study (58). Of 27 women meeting the criteria for the study, 13 were treated either with indomethacin alone (N=9) or indomethacin combined with ritodrine (N=2), terbutaline (N=1), or magnesium sulfate (N=1). Indomethacin dosage varied from 100 to 200 mg/day with a mean duration of treatment of 15.3 days (range 544 days). Four other patients were treated with ibuprofen, another nonsteroidal antiinflammatory agent. Fourteen of the 17 patients (82.3%) either had a decrease in amniotic fluid volume to low-normal levels or had oligohydramnios compared with none of the 10 women treated only with terbutaline, ritodrine, or magnesium sulfate (p
A study published in 1988 described the treatment with indomethacin, 100150 mg/day, for premature labor in eight women at 2732 weeks’ gestation (59). Fetal urine output fell from a mean pretreatment value of 11.2 to 2.2 mL/hour at 5 hours, then stabilized at 1.8 mL/hour at 12 and 24 hours. Mean output 24 hours after stopping indomethacin was 13.5 mL/hour. No correlation was found between maternal indomethacin serum levels and hourly fetal urine output. Three of the four fetuses treated with indomethacin every 4 hours had ductal constriction at 24 hours that apparently resolved after therapy was halted. All newborns had normal renal function in the neonatal period.
Fetal adverse effects described during treatment of premature labor with indomethacin in recent studies include primary pulmonary hypertension (four cases) (32,60), ductal constriction with or without tricuspid regurgitation (33,61,62,63 and 64), and a significantly increased incidence compared with controls, in infants less than 30 weeks’ gestational age, of intracranial hemorrhage, necrotizing enterocolitis, and patent ductus arteriosus requiring ligation (65,66). A possible interaction between cocaine abuse and indomethacin resulting in fetal anuria, generalized massive edema, and neonatal gastrointestinal hemorrhage has also been reported (67).
A number of reports have described the use of indomethacin for the treatment of symptomatic polyhydramnios in singleton and multiple pregnancies (68,69,70,71,72,73,74,75,76,77,78 and 79), including a 1991 review of this indication (80). Indomethacin-induced constriction of the ductus arteriosus and tricuspid regurgitation were observed in some of the studies (67,69,71,77). In one report, indomethacin was used to treat polyhydramnios as a result of feto-fetal transfusion syndrome in two sets of twins (77). One twin survived from each pregnancy, but one was oliguric (urine output 0.5 mL/kg/hour) and the other was anuric requiring peritoneal dialysis. The authors speculated that the renal failure in both infants was secondary to indomethacin. A unilateral pleural effusion developed in one twin fetus after 28 days of indomethacin therapy for polyhydramnios, possibly because of ductus arteriosus constriction (79). The condition resolved completely within 48 hours of stopping the drug.
A probable drug interaction between indomethacin and b-blockers resulting in severe maternal hypertension was reported in two women in 1989 (81). One woman, with a history of labile hypertension of 6 years’ duration, was admitted at 30 weeks’ gestation for control of her blood pressure. She was treated with propranolol 80 mg/day with good response. Indomethacin was started because of premature uterine contractions occurring at 32 weeks’ gestation. An initial 200-mg rectal dose was followed by 25 mg orally/day. On the 4th day of therapy, the patient suffered a marked change in blood pressure, which rose from 135/85 mm Hg to 240/140 mm Hg, with cardiotocographic signs of fetal distress. A cesarean section was performed, but the severely growth-retarded newborn died 72 hours later. The second patient developed signs and symptoms of preeclampsia at 31 weeks’ gestation. She was treated with pindolol 15 mg/day with good blood pressure response. Two weeks later, indomethacin was started, as in the first case, for preterm labor. On the 5th day of therapy, blood pressure rose to 230/130 mm Hg. Signs of fetal distress were evident and a cesarean section was performed. The low-weight infant survived. In a brief letter referring to the above study, one author proposed that the mechanism of nonsteroidal antiinflammatory-induced hypertension may be related to the inhibition of prostaglandin synthesis in the renal vasculature (82). On the basis of this theory, the author recommended that all similar agents should be avoided in women with preeclampsia. Although the mechanism is unknown, one source has reviewed several cases of the interaction with the observation that indomethacin may inhibit the effects of b-blockers, as well as antihypertensives in general (83).
Severe complications after in utero exposure to indomethacin have been reported in three preterm infants (84). The three mothers had been treated with indomethacin, 200300 mg/day, for 4 weeks, 3 days, and 2 days immediately before delivery. Complications in the newborns included edema or hydrops, oliguric renal failure (
A single case of phocomelia with agenesis of the penis has been described, but the relationship between indomethacin and this defect is unknown (85). Inhibition of platelet aggregation may have contributed to postpartum hemorrhage in 3 of 16 women given a 100-mg indomethacin suppository during term labor (16).
In summary, the use of indomethacin as a tocolytic agent during the latter half of pregnancy may cause constriction of the fetal ductus arteriosus, with or without tricuspid regurgitation. These effects are usually transient and reversible if therapy is stopped an adequate time before delivery. Premature closure of the ductus arteriosus can result in primary pulmonary hypertension of the newborn that, in severe cases, may be fatal. Reduced fetal urine output should be expected when indomethacin is administered to the mother. This may be therapeutic in cases of symptomatic polyhydramnios, but the complications of this therapy may be severe. Oliguric renal failure, hemorrhage, and intestinal perforation have been reported in premature infants exposed immediately before delivery. Use of indomethacin with antihypertensive agents, particularly the b-blockers, has been associated with severe maternal hypertension and resulting fetal distress. Short courses of indomethacin, such as 2448 hours with allowance of at least 24 hours or more between the last dose and delivery, should prevent complications of this therapy in the newborn. Use of the smallest effective dose is essential, although maternal serum levels of indomethacin that are effective for tocolysis have not yet been defined (45) and, at least one complication, ductal constriction, is independent of fetal drug serum levels (46,47). Restriction of indomethacin tocolysis to gestational ages between 24 and 32 completed weeks, when therapy for premature labor is most appropriate, will also lessen the incidence of complications (35), although a higher rate of newborn complications has been observed when delivery occurred before 30 weeks’ gestation (65,66). Other uses of indomethacin, such as for analgesia or inflammation, have not been studied in pregnancy but should be approached with caution because of the effects described above. Moreover, women attempting to conceive should not use any prostaglandin synthesis inhibitor, including indomethacin, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (86,87). In addition, as noted above, NSAIDs have been associated with SABs.
[*Risk Factor D if used for longer than 48 hours or after 34 weeks’ gestation or close to delivery.]
Breast Feeding Summary
Indomethacin is excreted in human breast milk. Although an earlier Reference speculated that milk levels were similar to maternal plasma levels (88), a study published in 1991 reported a median milk:plasma ratio of 0.37 in 7 of 16 women taking 75300 mg/day (89). The other nine women did not have measurable drug levels in both milk and plasma. The investigators calculated that the total infant dose ingested (assuming 100% absorption) ranged from 0.07% to 0.98% (median=0.18%) of the weight-adjusted maternal dose (89).
A case report of possible indomethacin-induced seizures in a breast-fed infant has been published (88), although the causal link between the two events has been questioned (90). The mother was taking 200 mg/day (3 mg/kg/day). The American Academy of Pediatrics noted the above possible adverse reaction but considers indomethacin to be compatible with breast feeding (91).
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