Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Because ketorolac is a prostaglandin synthesis inhibitor, constriction of the ductus arteriosus in utero and fetal renal impairment are potential complications when multiple doses of the drug are administered during the latter half of pregnancy (1) (see also Indomethacin). Premature closure of the ductus can result in primary pulmonary hypertension of the newborn that, in severe cases, may be fatal (1,2). Other complications that have been associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibition of labor and prolongation of pregnancy. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketorolac, because of the findings in a variety of animal models indicating that these agents block blastocyst implantation (3,4). Moreover, as noted above, NSAIDs have been associated with spontaneous abortions (SABs) and congenital malformations (see also Ibuprofen). The risk for these defects, however, appears to be low.
In a “black box” warning, the FDA stated that ketorolac was contraindicated in labor and delivery because its prostaglandin synthesis inhibitory effect may adversely affect fetal circulation and inhibit uterine contractions.
FETAL RISK SUMMARY
Ketorolac is an NSAID indicated for the short-term (≤5 days) treatment of pain. The drug is also available as a solution for ocular pain. Ketorolac is in an NSAID subclass (pyrrolizine carboxylic acid) with no other members.
Ketorolac was not teratogenic in rats (1.0 times the human AUC) and rabbits (0.37 times the human AUC) treated with daily oral doses of the drug during organogenesis. Oral dosing in rats at 0.14 times the human AUC after day 17 of gestation caused dystocia and decreased pup survivability (5).
In a study using chronically catheterized pregnant sheep, an infusion of ketorolac completely blocked the ritodrine-induced increase of prostaglandin F2α, a potent uterine stimulant, in the uterine venous plasma (6,7). The researchers speculated that ritodrine stimulation of prostaglandin synthesis in pregnant uterine tissue might contribute to the tachyphylaxis sometimes observed with the tocolytic agent.
It is not known if ketorolac crosses the human placenta. The molecular weight (about 376) is low enough that passage to the embryo and fetus should be expected.
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 (8). 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 SABs. A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations, but did find a significant association with cardiac defects and orofacial clefts (9), In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (10). (See Ibuprofen for details on these three studies.)
A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater cyclooxygenase 2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (11).
A randomized, double-blind study published in 1992 compared single IM doses of ketorolac 10 mg, meperidine 50 mg, and meperidine 100 mg in multiparous women in labor (12). All patients also received a single dose of prochlorperazine (for nausea and vomiting) and ranitidine for acid reflux. Ineffective pain relief was observed in all three treatment groups, but both doses of meperidine were superior to ketorolac. Duration of labor was similar among the three groups, as was the occurrence of adverse effects, including maternal blood loss. One-minute Apgar scores were significantly greater in the ketorolac group compared with the meperidine groups, most likely because of the lack of respiratory depressant effects of ketorolac, but this difference was not observed at 5 minutes (12).
A 1997 abstract and later full report described the use of ketorolac for acute tocolysis in preterm labor (13,14). Women, at ≤32 weeks’ gestation, were randomized to receive either ketorolac (N = 45), 60 mg IM and then 30 mg IM every 4–6 hours, or magnesium sulfate (N = 43), 6 g IV and then 3–6 g/hour IV. Therapy was stopped if 48 hours lapsed, labor progressed (>4 cm), severe side effects occurred, or uterine quiescence was achieved. Ketorolac was significantly better than magnesium sulfate in the time required to stop uterine contractions (2.7 vs. 6.2 hours), but no difference was found between the two regimens for the other parameters (failed tocolysis, birth weight, gestational age at delivery, and neonatal morbidity). There was no difference in the incidence of maternal and neonatal adverse effects between the groups (13,14).
BREASTFEEDING SUMMARY
Ketorolac is excreted into breast milk (15). Ten women, 2–6 days postpartum, were given oral ketorolac, 10 mg four times daily for 2 days. Their infants were not allowed to breastfeed during the study. Four of the women had milk concentrations of the drug below the detection limit of the assay (<5 ng/mL) and were excluded from analysis. In the remaining six women, the mean milk:plasma ratios 2 hours after doses 1, 3, 5, and 7 ranged from 0.016 to 0.027, corresponding to mean milk concentrations ranging from 5.2 to 7.9 ng/mL. Based on a milk production of 400–1000 mL/day, the investigators estimated that the maximum amount of drug available to a nursing infant would range from 3.16 to 7.9 mcg/day (Note: The cited reference indicated 3.16–7.9 mg/day, but this appears to be an error), equivalent to 0.16%–0.40% of the mother’s dose on a weight-adjusted basis. These amounts were considered clinically insignificant (15).
The FDA has placed a “Black Box” warning on ketorolac, stating that drug is contraindicated during breastfeeding because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
References
1.Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
2.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.
3.Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.
4.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
5.Product information. Toradol. Roche Laboratories, 2000.
6.Rauk PN, Laifer SA. Ketorolac blocks ritodrine-stimulated production of PGF2α in pregnant sheep (abstract). Am J Obstet Gynecol 1992;166:274.
7.Rauk PN, Laifer SA. The prostaglandin synthesis inhibitor ketorolac blocks ritodrine-stimulated production of prostaglandin F2α in pregnant sheep. Obstet Gynecol 1993;81:323–6.
8.Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population-based observational study and case-control study. Br Med J 2001;322:266–70.
9.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.
10.Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population-based cohort study. Br Med J 2003;327:368–71.
11.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res (Part B) 2003;68:3–4.
12.Walker JJ, Johnston J, Fairlie FM, Lloyd J, Bullingham R. A comparative study of intramuscular ketorolac and pethidine in labour pain. Eur J Obstet Gynecol Reprod Biol 1992;46:87–94.
13.Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EF, Perry KG Jr, Morrison JC. Ketorolac is a safe and effective drug for acute tocolysis (abstract). Am J Obstet Gynecol 1997;176:S7.
14.Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EL, Perry KG Jr, Morrison JC. A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor. South Med J 1998;91:1028–32.
15.Wischnik A, Manth SM, Lloyd J, Bullingham R, Thompson JS. The excretion of ketorolac tromethamine into breast milk after multiple oral dosing. Eur J Clin Pharmacol 1989;36:521–4.