Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (1). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (1,2). These drugs also have been shown to inhibit labor and prolong pregnancy, in both humans (3) (see also Indomethacin) and animals (4). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketoprofen, because of the findings in a variety of animal models indicating that these agents block blastocyst implantation (5,6). As noted below, nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with spontaneous abortions (SABs) and congenital malformations (see also Ibuprofen), but the risk for these defects appears to be low.
FETAL RISK SUMMARY
Ketoprofen is an NSAID that is indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, naproxen, and oxaprozin). The drug undergoes metabolism to an inactive metabolite but can be converted back to the parent compound. Plasma protein binding, mainly to albumin, is high (>99%) and the elimination half-life is about 2 hours (7).
Reproductive studies in mice and rats at about 0.2 times the maximum recommended human dose based on BSA revealed no teratogenic or embryotoxic effects (7). In rabbits, maternally toxic doses were embryotoxic but not teratogenic (7). Shepard (8) reviewed four animal studies that used mice, rats, and monkeys and found no adverse fetal effects or congenital malformations.
Consistent with the low molecular weight (about 254), ketoprofen crosses the human placenta. A 1998 study, using a human isolated perfused placenta, demonstrated transfer of the drug (9). The investigators had previously shown that the drug crosses to the fetus and is detectable in the newborn (10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 112 newborns had been exposed to ketoprofen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (2.7%) major birth defects were observed (five expected), including (expected/observed) 1/1 cardiovascular defect and 1/0.3 polydactyly. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, 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 (11). 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 with NSAIDs found a significant association with cardiac defects and orofacial clefts (12). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (13). (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 (14).
In a 2007 study, atosiban (an oxytocin inhibitor not available in the United States) was compared with ritodrine for the prevention of preterm labor (15). Ketoprofen was added to 51.1% of the atosiban group and 47.7% of the ritodrine group because the response to the single drug was unsatisfactory. The ketoprofen dose was 100 mg IV followed by 100–150 mg IV every 12 hours for a total duration up to 48 hours. Neonatal mortality and morbidity were unrelated to ketoprofen exposure (15).
BREASTFEEDING SUMMARY
No reports describing the use of ketoprofen during breastfeeding have been located. However, in a 2007 report, 18 non-breastfeeding women immediately after delivery were given IV ketoprofen (100 mg every 12 hours) and nalbuphine (0.2 mg/kg every 4 hours) for postpartum pain (16). The mean and maximum ketoprofen milk concentrations were 57 and 91 ng/mL, respectively. Assuming a milk volume of 150 mL/kg/day, the estimated mean and maximum infant doses were 8.5 and 13.6 mcg/kg/day, respectively. The relative infant dose as a percentage of the weight-adjusted maternal dose was 0.31% (16). (See Nalbuphine for additional data.)
The above data are consistent with the low molecular weight (about 254) of ketoprofen as well as the relatively short elimination half-life (about 2 hours) and the high plasma protein binding (>99%). Although the amounts measured in the above are low, an abstract from France reported that ketoprofen use during breastfeeding was associated with adverse renal and gastrointestinal effects (17). Based on this information, maternal use of other agents should be considered, such as ibuprofen, which is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Ibuprofen).
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.Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
4.Powell JG, Cochrane RL. The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.
5.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.
6.Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
7.Product information. Ketoprofen. Mylan Pharmaceuticals, 2011.
8.Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The Johns Hopkins University Press, 1989:364.
9.Lagrange F, Pehourcq F, Bannwarth B, Leng JJ, Saux MC. Passage of S-(+)- and R-(−)-ketoprofen across the human isolated perfused placenta. Fundam Clin Pharmacol 1998;12:286–91.
10.Labat L, Llanas B, Demotes-Mainard F, Lagrange F, Demarquez JL, Bannwarth B. Accumulation of S-ketoprofen in neonates after maternal administration of the racemate. Fundam Clin Pharmacol 1995;9:62. As cited in Lagrange F, Pehourcq F, Bannwarth B, Leng JJ, Saux MC. Passage of S-(+)- and R-(−)-ketoprofen across the human isolated perfused placenta. Fundam Clin Pharmacol 1998;12:286–91.
11.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.
12.Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.
13.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.
14.Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2003;68:3–4.
15.Grignaffini A, Soncini E, Ronzoni E, Lo Cane F, Anfuso S, Nardelli GB. Clinical practice evaluation of combination of atosiban, ritodrine and ketoprofen for inhibiting preterm labor. Minerva Ginecol 2007;59:481–9.
16.Jacqz-Aigrain E, Serreau R, Boissinot C, Popon M, Sobel A, Michel J, Sibony O. Excretion of ketoprofen and nalbuphine in human milk during treatment of maternal pain after delivery. Ther Drug Monit 2007;29:815–8.
17.Lacroix I, Soussan C, Portolan G, Montastruc JL. Drug-induced adverse reactions via breastfeeding: a study in the French Pharmacovigilance Database (abstract 26-01). Fundam Clin Pharmacol 2013;27(Suppl 1): 42–3. doi:10.1111/fep.12025. As cited by National Library of Medicine LactMed Database. Ketoprofen, 2013.