Ibuprofen
Name: IBUPROFEN
Class: Nonsteroidal Anti-inflammatory
Risk Factor: BM*
Fetal Risk Summary
Ibuprofen is a nonsteroidal antiinflammatory drug (NSAID) indicated for the reduction of fever and mild to moderate pain. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ketoprofen, naproxen, and oxaprozin). No evidence of developmental abnormalities was observed in reproduction studies in rats and rabbits at doses slightly less then the maximum human clinical dose (1).
No published reports linking the use of ibuprofen with congenital defects have been located. The manufacturer has received information by a voluntary reporting system on the use of ibuprofen in 50 pregnancies (2). Seven of these cases were reported retrospectively and 43 prospectively. The results of the retrospective cases included one fetal death (cause of death unknown, no abnormalities observed) after 3rd trimester exposure, and one spontaneous abortion without abnormality. Five infants with defects were observed, including an anencephalic infant exposed during the 1st trimester to ibuprofen and Bendectin (doxylamine succinate and pyridoxine hydrochloride), petit mal seizures progressing to grand mal convulsions, cerebral palsy (the fetus had also been exposed to other drugs), a hearsay report of microphthalmia with nasal cleft and mildly rotated palate, and tooth staining (2) (M.M. Westland, personal communication, The Upjohn Company, 1981). A cause and effect relationship between the drug and these defects is doubtful.
Prospectively, 23 of the exposed pregnancies ended in normal outcomes, 1 infant was stillborn, and 1 ended in spontaneous abortion, both without apparent abnormality (2). Seven of the pregnancies were electively terminated, 3 had unknown outcomes, and 8 of the pregnancies were still progressing at the time of the report.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 3,178 newborns had been exposed to ibuprofen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 143 (4.5%) major birth defects were observed (129 expected). Specific data were available for six defect categories, including (observed/expected) 33/30 cardiovascular defects, 7/5 oral clefts, 3/2 spina bifida, 11/9 polydactyly, 5/5 limb reduction defects, and 4/8 hypospadias. These data do not support an association between the drug and congenital defects.
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 (3). The studies were based on data from the Danish birth registry and the North Jutland county's hospital discharge registry collected between 1991 and 1998. Only those women who had received a prescription for a NSAID at doses equivalent to 400 mg or 600 mg of ibuprofen were classified as exposed (NSAID doses equivalent to 200 mg of ibuprofen are over-the-counter in Denmark). The cohort involved 1,462 pregnant women who had received a NSAID prescription in the interval from 30 days before conception to birth and a Reference group of 17,259 pregnant women who had not been prescribed any drugs during pregnancy. In both groups, only pregnancies lasting longer than 28 weeks' were included. There were 1,106 women (76%) who had received a NSAID prescription between 30 days before conception and the end of the 1st trimester. The prevalences of congenital malformations in infants of these women and the Reference group were(N=46, 4.2%, 95% confidence interval [CI] 3.0%–5.3% vs. (N=564, 3.3%, 95% CI 3.0%–3.5%), respectively; adjusted odds ratio (OR) 1.27 (95% CI 0.93–1.75). A total of 997 women received a NSAID prescription in the 2nd and/or 3rd trimesters. In this group, the OR for preterm delivery was 1.05 (95% CI 0.80–1.39) and for low birth weight (excluding preterm infants) 0.79 95% CI (0.45–1.38). Adjusting the data for the use of indomethacin (the tocolytic of choice in Denmark) did not affect the results. There was no evidence of a specific grouping of defects or of a dose-response relationship for adverse birth outcome. Based on the analysis, the authors concluded that NSAIDs were not associated with adverse birth outcome (3).
In the case-control portion of the above study, cases were defined as first recorded SAB in women who had received a prescription for NSAIDs in the 12 weeks before the date of discharge from the hospital after the SAB (63 of 4,268 women who had SABs) (3). The controls were 29,750 primiparous women who had live births, 318 of whom had received a prescription for NSAIDs in the 1st trimester. The data was analyzed for the time from receiving a NSAID prescription in the weeks before the SAB (or missed abortion), adjusted for maternal age. The OR (95% CI) for 1 week, 2–3 weeks, 4–6 weeks, 7–9 weeks, and 10–12 weeks before the SAB were 6.99 (2.75–17.74), 3.00 (1.21–7.44), 4.38 (2.66–7.20), 2.69 (1.81–4.00), and 1.26 (0.85–1.87), respectively. The results indicated that NSAIDs were associated with SAB because the OR decreased as the interval from assumed NSAID exposure to SAB increased (3).
The use of ibuprofen as a tocolytic agent has been associated with reduced amniotic fluid volume (4,5 and 6). Fourteen (82.3%) of 17 women treated with a NSAID had decreased amniotic fluid volume (4). Of the 17 women, ibuprofen, 1200–2400 mg/day, was used alone in 3 pregnancies and was combined with ritodrine in one. The other 13 women were treated with indomethacin (see also Indomethacin). One woman who was treated with ibuprofen for 44 days had a return to a normal amniotic fluid volume after the drug was stopped (time for reversal not specified).
Ibuprofen, 600 mg every 6 hours, was used as a tocolytic in a woman with a triplet pregnancy at approximately 26 weeks' gestation (5). Terbutaline and magnesium sulfate were combined with ibuprofen at various times for tocolysis. Oligohydramnios in each sac (pockets <1 cm) was documented by ultrasonogram on the 20th day of therapy and ibuprofen therapy was stopped. Therapy was restarted 5 days later when normal fluid volume for the three fetuses was observed but oligohydramnios was again evident after 4 days and ibuprofen was discontinued. Tocolysis was then maintained with terbutaline and normal fluid volumes were observed 5 days after the second course of ibuprofen. The triplets were eventually delivered by elective cesarean section at 35 weeks' gestation, but no details on the infants were given.
A brief 1992 abstract described the results of using ibuprofen, 1200–2400 mg/day, as a tocolytic agent in 52 pregnancies (61 fetuses) up to 32 weeks' gestation (6). Amniotic fluid volumes were evaluated every 1–2 weeks. No cases of true oligohydramnios were observed, although 3 cases of low-normal fluid occurred that resolved after discontinuation of ibuprofen. Periodic Doppler echocardiography during therapy revealed a non-dose-related mild constriction of the ductus arteriosus in 4 (6.6%) of the fetuses. Ductal constriction was observed in 3 of the fetuses within 1 week of starting ibuprofen. Normal echocardiograms were obtained in all 4 cases within 1 week of discontinuing therapy.
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (7). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (7). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (8) and in animals (9). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ibuprofen, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (10,11). Moreover, as noted above, NSAIDs have also been associated with spontaneous abortions.
[*Risk Factor D if used in 3rd trimester or near delivery.]
Breast Feeding Summary
Ibuprofen is excreted into human milk. Two studies were unable to detect the drug (12,13 and 14), but a third study using a more sensitive assay (lower limit 2.5 ng/mL) was able to quantify ibuprofen in milk (15). In 12 patients taking 400 mg every 6 hours for 24 hours, an assay capable of detecting 1 µg/mL failed to demonstrate ibuprofen in the milk (12,13). In a second report, a woman was treated with 400 mg twice daily for 3 weeks (14). Milk levels shortly before and up to 8 hours after drug administration were all less than 0.5 µg/mL.
The third study involved a lactating woman who underwent maxillary surgery (15). After surgery, she took ibuprofen 400 mg six times over a 42.5-hour interval for postoperative pain. Ten breast milk samples were collected during this same period. Ibuprofen was detected (13 ng/mL) 30 minutes after the first dose. The maximum milk concentration, 181 ng/mL, was found 20.5 hours after the first dose (about 5 hours after the third dose). Although the infant was not nursing, the infant's weight adjusted dose would have been an estimated 0.0008% of the mother's dose (15).
The American Academy of Pediatrics considers ibuprofen to be compatible with breast feeding (16).
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