Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Celecoxib has been used in human pregnancy as a tocolytic. The animal data are suggestive of a low risk for congenital malformations. Moreover, a brief 2003 editorial on the potential for nonsteroidal anti-inflammatory drug (NSAID)-induced developmental toxicity concluded that NSAIDs, and specifically those with greater COX-2 affinity, had a lower risk of this toxicity in humans than aspirin (1). The use of first-generation NSAIDs during the latter half of pregnancy has been associated with oligohydramnios and premature closure of the ductus arteriosus (e.g., see Indomethacin) (2). Persistent pulmonary hypertension of the newborn may occur if NSAIDs are used in the 3rd trimester close to delivery (2,3). These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (4) and in animals (5). Similar effects should be expected if celecoxib is used during the 3rd trimester or close to delivery. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including celecoxib, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (6,7). Moreover, as noted above, NSAIDs have been associated with spontaneous abortions (SABs) and congenital malformations. The absolute risk for these defects, however, appears to be low. If celecoxib is used in pregnancy for the treatment of rheumatoid arthritis, healthcare professionals are encouraged to call the toll-free number (877-311-8972) for information about patient enrollment in the OTIS Rheumatoid Arthritis study.
FETAL RISK SUMMARY
Celecoxib is a second-generation NSAID that inhibits prostaglandin synthesis via the inhibition of cyclooxygenase-2 (COX-2). It is in the same NSAID subclass (COX-2 inhibitors) as rofecoxib and valdecoxib. In therapeutic concentrations, it does not inhibit, as do first-generation NSAIDs, the cyclooxygenase-1 (COX-1) isoenzyme. Celecoxib is indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis (8).
Celecoxib was not mutagenic or clastogenic in Chinese hamster ovary cells or clastogenic in an in vivo micronucleus test in rat bone marrow. Administration to female rats of oral doses that were about six times the maximum recommended human dose based on AUC at 200 mg twice a day (MRHD) resulted in preimplantation and postimplantation losses and reduced embryo–fetal survival, a natural consequence of its inhibition of prostaglandin synthesis (8).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, a dose-related increase in diaphragmatic hernias was observed in one of two studies at doses about six times the MRHD. No teratogenic effects occurred in pregnant rabbits at doses equal to the MRHD, but at doses about two times the MRHD, an increased incidence of fetal alterations (fused ribs and fused, misshapen sternebrae) was observed. No evidence of delayed labor or parturition at doses up to about seven times the MRHD was observed in rats (8).
Two studies in pregnant rabbits were designed to test the hypothesis that celecoxib was effective in preventing preterm delivery and did not adversely affect fetal ductus arteriosus patency (9,10). In the first study, the rabbits received a daily dose that was about 0.5 times the MRHD for differing periods starting at day 13 of gestation (9). Concentrations of prostanoids, cytokines, and nitric oxide were altered by the treatment, resulting in decrease in the incidence compared with controls of preterm parturition. In the second study, no adverse effect on the fetal ductus arteriosus was observed (10).
No reports describing the placental transfer of celecoxib have been located. The molecular weight (about 381) is low enough that passage to the fetus should be expected. Celecoxib metabolism is mediated by the cytochrome P450 2C9 enzyme, resulting in at least three inactive metabolites (8). Women, in whom metabolism by this enzyme is known or suspected to be deficient, may have abnormally high plasma levels of celecoxib and, thus, more of the drug will be available for placental transfer.
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, 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 (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 2006 case–control study found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the 1st trimester (14). A population-based pregnancy registry (N = 36,387) was developed by linking three databases in Quebec. (See Naprosyn for other study details.) Case infants were those with any congenital anomaly diagnosed in the first year of life and were compared with matched controls. There were 93 infants (8.8%) with congenital defects from 1056 mothers who had filled prescriptions for NSAIDs in the 1st trimester. In controls, there were 2478 infants (7%) with anomalies from 35,331 mothers who had not filled such a prescription. The adjusted odds ratio (OR) was 2.21 (95% CI 1.72–2.85). The adjusted OR for cardiac septal closure was 3.34 (95% CI 1.87–5.98). There also was a significant association with anomalies of the respiratory system 9.55 (95% CI 3.08–29.63), but this association disappeared when cases coded as “unspecified anomaly of the respiratory system” were excluded. For the cases involving septal closure, 61% were atrial septal defects and 31% were ventricular septal defects. There were no significant associations for oral clefts or defects involving other major organ systems. The five most common NSAIDs were naproxen (35%), ibuprofen (26%), rofecoxib (15%), diclofenac (9%), and celecoxib (9%). Among these agents, the only significant association was for ibuprofen prescriptions in the 1st trimester and congenital defects (p <0.01) (14).
An in vitro study demonstrated that celecoxib had significant uterine relaxant effects (15). Celecoxib was more potent, in this regard, than nimesulide or meloxicam. A 2002 randomized, double-blind, placebo-controlled study compared the tocolytic effects of celecoxib (100 mg orally every 12 hours for 4 doses) and indomethacin (100 mg rectally, then 50 mg orally every 6 hours for 7 doses) (16). The subjects, 12 in each group, were in preterm labor at 24 to 34 weeks’ gestation. Partial premature constriction of the fetal ductus arteriosus occurred in the indomethacin group, but not in the celecoxib group. A transient decrease in amniotic fluid volume was observed in both groups, but more so with indomethacin. Both drugs were equally effective in the maintenance of tocolysis, but the authors concluded that the safety of celecoxib was superior to that of indomethacin (16).
A randomized trial in 2007 compared the tocolytic effects of celecoxib (200 mg/day) and IV magnesium sulfate, each given for 48 hours (17). Gestational ages were 24–34 weeks and each group had 52 women. No statistical difference (81% vs. 87%) in the arrest of labor was found and there were no severe maternal or neonatal complications (17).
BREASTFEEDING SUMMARY
Celecoxib is excreted into human breastmilk (18–20). A 40-year-old woman who was breastfeeding her 5-month-old daughter was admitted to the hospital for surgery. In the postoperative period, she received four doses of celecoxib (100 mg twice/day) in addition to other medications. Starting about 5 hours after her last dose, four milk samples were obtained by hand expression over a 24-hour interval. The elimination half-life range was 4.0–6.5 hours. These data suggest that celecoxib would be eliminated from breast milk about 24 hours after the last dose. Although maternal plasma was not obtained, the estimated milk:plasma ratios (based on reported adult plasma levels) were 0.27–0.59. The infant did not resume breastfeeding until 48 hours after the last dose. If she had nursed, the estimated maximum infant dose would have been about 40 mcg/kg/day (18).
A 2004 study of five breastfeeding women taking celecoxib, three at steady state (200 mg once daily) and two after a single 200-mg dose, measured a mean milk concentration of 66 mcg/L and a mean milk:plasma ratio of 0.23 (19). The mean absolute infant dose was 9.8 mcg/kg/day and the relative infant dose was 0.30% of the mother’s weight-adjusted dose. Plasma concentrations in two infants at 17 and 22 months of age, who were nursing every 3–4 hours during the day and once at night, were below the limit of detection (10 mcg/L) (19).
Six lactating women, who stopped nursing after taking celecoxib, were included in a 2005 report (20). After a single 200-mg dose, the median absolute infant dose was 13 mcg/kg/day and the relative infant dose was 0.23% of the mother’s weight-adjusted dose.
Several first-generation NSAIDs are considered low risk during nursing (e.g., see Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, and Tolmetin) and, based on the available data, celecoxib, at the doses studied, can be similarly classified. Although only 3 of the 12 patients studied were breastfeeding when taking celecoxib, the authors of the studies concluded that celecoxib was unlikely to pose a risk to a nursing infant.
References
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