DICLOFENAC

Fetal Risk Summary

Diclofenac is a nonsteroidal antiinflammatory drug (NSAID) used for the treatment of arthritis, acute and chronic pain, and primary dysmenorrhea. Similar to other agents in this class, it also has antipyretic activity. Diclofenac is in the same subclass (acetic acids) as three other NSAIDs (indomethacin, sulindac, and tolmetin).

In reproduction studies in mice, rats and rabbits, the drug was not teratogenic with doses up to those that produced maternal and fetal toxicity (1). Maternal toxic doses, however, were associated with dystocia, prolonged gestation, decreased fetal survival (1), and intrauterine growth retardation (1,2).

A 1990 report described an investigation on the effects of several nonsteroidal antiinflammatory agents on mouse palatal fusion both in vivo and in vitro (3). The compounds, including diclofenac, were found to induce cleft palate. In the rat, diclofenac, presumably by inhibiting prostaglandin synthesis, has been shown to inhibit implantation and placentation (2).

The tocolytic effect of diclofenac was demonstrated in a study that used mifepristone (RU 486) to induce preterm labor in rats (4). Diclofenac inhibited preterm delivery but had no effect on mifepristone-induced cervical maturation.

Diclofenac crosses the human placenta. In a 2000 study, 30 women undergoing termination of pregnancy at a mean gestational age of 10.2 weeks (range 8–12 weeks) were given two 50 mg oral doses at a mean 13.5 and 2.5 hours before the procedure (5). Diclofenac was detected in all maternal serum (mean 183.9 ng/mL) and fetal tissue (mean 279.2 ng/mL) samples, producing a mean maternal serum:fetal tissue ratio of 0.95 (range 0.05–4.26). Only 7 of the 30 amniotic fluid samples contained detectable diclofenac (range 0.6–3.5 ng/mL), whereas 17 of 30 coelomic fluid samples contained the drug (range 1.1–33.4 ng/mL) (5).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 51 newborns had been exposed to diclofenac during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One unspecified major birth defect was observed (two expected). No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. Although the number of exposures is small, these data do not support an association between the drug and congenital defects.

A 29-year-old woman at 33 weeks' gestation was diagnosed by clinical symptoms and ultrasound as having a spontaneous rupture of the right renal pelvis with a small amount of perinephric extravasation of urine (6). She was treated conservatively with diclofenac while hospitalized (50 mg twice daily; duration not specified) and delivered a healthy female infant 5 weeks later. A follow-up examination of her kidney by ultrasonography 5 days postpartum was normal.

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 (7). 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 (see Ibuprofen for details).

A 1998 report described a case of premature closure of the ductus arteriosus in a fetus who was exposed to diclofenac, 50 mg twice daily, for 2 weeks from the 34th week of gestation (8). The mother had taken the drug for musculoskeletal back pain and carpal tunnel syndrome. At 41 weeks' gestation, a fetal echocardiogram revealed the ductus defect, enlargement of the right side of the heart, and early cardiac failure (8). An emergency cesarean section was performed and the baby was successfully resuscitated (8).

Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy, as is inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (see also Indomethacin) (9). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (9). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including diclofenac, 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 been associated with SABs.

[*Risk Factor D if used in 3rd trimester or near delivery.]

Breast Feeding Summary

No reports describing the use of diclofenac during lactation have been located. The manufacturer states that diclofenac is excreted into the milk of nursing mothers but does not cite quantitative data (1). One reviewer classified diclofenac as one of several low-risk alternatives, because of its short adult serum half-life (1.1 hours) and toxicity profile compared with other similar agents, if a nonsteroidal antiinflammatory agent was required while nursing (12). Other reviewers have also stated that diclofenac can be safely used during breast feeding (13,14). Another NSAID in the same subclass as diclofenac is considered compatible with breast feeding by the American Academy of Pediatrics (see Indomethacin).

References

1. Product information. Voltaren. Geigy Pharmaceuticals, 1995.
2. Carp HJA, Fein A, Nebel L. Effect of diclofenac on implantation and embryonic development in the rat. Eur J Obstet Gynecol Reprod Biol 1988;28:273–7.
3. Montenegro MA, Palomino H. Induction of cleft palate in mice by inhibitors of prostaglandin synthesis. J Craniofac Genet Del Biol 1990;10:83–94.
4. Cabrol D, Carbonne B, Bienkiewicz A, Dallot E, Alj AE, Cedard L. Induction of labor and cervical maturation using mifepristone (RU 486) in the late pregnant rat. Influence of a cyclooxygenase inhibitor (diclofenac). Prostaglandins 1991;42:71–9.
5. Siu SSN, Yeung JHK, Lau TK. A study on placental transfer of diclofenac in first trimester of human pregnancy. Hum Reprod 2000;15:2423–5.
6. Royburt M, Peled Y, Kaplan B, Hod M, Friedman S, Ovadia J. Non-traumatic rupture of kidney in pregnancy—case report and review. Acta Obstet Gynecol Scan 1994;73:663–7.
7. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of nonsteroidal antiinflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70.
8. Adverse Drug Reactions Advisory Committee. Premature closure of the fetal ductus arteriosus after maternal use of nonsteroidal anti-inflammatory drugs. Med J Aust 1998;169:270–1.
9. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
10. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, editor. Reproductive Toxicology. 2nd ed. New York, NY:Raven Press, 1995:175–93.
11. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
12. Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.
13. Goldsmith DP. Neonatal rheumatic disorders. View of the pediatrician. Rheum Dis Clin North Am 1989;15:287–305.
14. Needs CJ, Brooks PM. Antirheumatic medication during lactation. Br J Rheumatol 1985;24:291–7.