Antigout
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Although colchicine is teratogenic in animals, the human pregnancy experience suggests that the risk to the embryo–fetus is low, if it exists at all. The use of colchicine by the father before conception does not appear to represent a significant reproductive risk, but azoospermia may be a rare complication. Because some reports suggested a risk of chromosome abnormalities, routine amniocentesis was recommended in cases of familial Mediterranean fever (FMF) treated with colchicine (1). However, more recent data suggest that routine amniocentesis is not justified (2,3).
FETAL RISK SUMMARY
Colchicine is used in the treatment of gout and FMF. Seven animal studies, reviewed by Shepard (4), indicated that colchicine, or its derivative, demecolcine (desacetylmethylcolchicine), were teratogenic in mice and rabbits at low doses and embryocidal in mice, rats, and rabbits at higher doses. Mutagenic effects were also observed in rabbit blastocysts. No adverse fetal effects were observed in limited studies with pregnant monkeys (4).
A number of reports have described the use of colchicine or demecolcine in human pregnancy (2,3,5–23). In these reports, no evidence of teratogenicity or other forms of developmental toxicity was found when these agents were used at recommended doses. In a woman treated throughout pregnancy with colchicine 1 mg/day, drug concentrations in the mother and cord blood at 38 weeks’ gestation were 3.15 ng/mL and 0.47 ng/mL, respectively (23).
A 2011 case report described a successful 15 course of colchicine 1 mg/day, prednisolone 15 mg/day, and azathioprine 100 mg/day in a woman at 28 weeks’ gestation with idiopathic granulomatous mastitis (24). No information on the pregnancy outcome was provided.
The mutagenic effects of colchicine and the possible relationship of this drug to sperm abnormalities and congenital malformations were the subjects of several publications (25–32). A 1965 report described three pregnancies occurring in a woman between the ages of 24 and 27 years, two of which ended abnormally (25). Her first pregnancy resulted in an SAB of a macerated fetus at 4.5 months, her second in the delivery of a normal girl, and her third in the delivery of a male with atypical Down’s syndrome (trisomy 21), who died 24 hours after birth. The infant had palmar transverse folds on the hands, inner epicanthic folds, unspecified cardiac malformations, trigger thumbs, syndactyly in the second and third toes, hypognathous, cleft palate, low-set ears, and an incompletely developed scapha helix. The father was 27–30 years of age during these pregnancies and was being treated for gout on an intermittent basis with 1–2 mg/day of colchicine. Cultures of leukocytes obtained from him demonstrated mutagenic changes when exposed to colchicine, but blood and sperm samples, collected 3 months after the end of colchicine therapy, were normal. The investigators theorized that the colchicine therapy may have caused diploid spermatozoa that resulted in the production of triploid children (25).
A brief report, from the same laboratory as the reference above, described the analysis of lymphocyte cultures from three male patients being treated with colchicine (26). Compared with controls, a significant increase in the number of cells with abnormal numbers of chromosomes was found in the colchicine-exposed men. The investigators proposed that this finding indicated that these men were at higher risk of producing trisomic offspring than were nonexposed men. Of 54 children with Down’s syndrome in their clinic, two had been fathered by men being treated with colchicine (26). The validity of this proposed association between colchicine and Down’s syndrome was the subject of several references (27–30). One of the arguments against the association included the high possibility of Down’s syndrome and colchicine therapy occurring at the same time in an older population (28). Moreover, several references have described healthy children fathered by men who were being treated with colchicine (6–8,31,32).
A 2005 study analyzed the reproductive histories of 326 couples in which at least one of the partners had FMF (236 women—628 pregnancies; 90 men—273 pregnancies) (1). Among the 901 pregnancies, there were 891 singletons and 10 sets of twins. After excluding abortions and fetal deaths, there were 777 viable pregnancies to determine if colchicine was teratogenic. Amniocentesis to detect chromosomal abnormalities was conducted in 558 of the viable pregnancies. Seven numerical chromosomal abnormalities were found (4.99 expected, ns), six of which were unbalanced structural abnormalities (3.22 expected; ns). There were seven major malformations, also lower than expected. Although not significant, the authors concluded that the higher number of chromosomal abnormalities justified continuing the policy of routine amniocentesis in this patient population (1). However, two reports concluded that amniocentesis was not justified (2,3).
The effect of colchicine on sperm production is controversial. Hamsters and mice treated chronically with SC injections of demecolcine developed extensive damage to the germinal epithelium, resulting in azoospermia within 35–45 days (33). One study observed azoospermia in a 36-year-old patient induced by 1.2 mg/day of colchicine, but not with 0.6 mg/day (34). A second study, however, using 1.8–2.4 mg/day in seven healthy men 20–25 years old, measured no effect on sperm production or on serum levels of testosterone, luteinizing hormone, or follicle-stimulating hormone (35). The authors of this second report, however, could not exclude the fact that some men may be unusually sensitive to the drug, resulting in testicular toxicity (35). A 1998 review concluded that colchicine by itself may not have a significant direct adverse effect on sperm production or function (36).
BREASTFEEDING SUMMARY
Colchicine is excreted into breast milk (9–11). A 31-year-old woman, receiving long-term therapy with colchicine (0.6 mg twice daily) for FMF, was treated throughout a normal pregnancy, labor, and delivery (9). Milk, urine, and serum samples were obtained from her between 16 and 21 days after delivery. Colchicine was detected in three of five milk samples collected on days 16–20 with levels ranging from 1.2 to 2.5 ng/mL (test sensitivity 0.5 ng/mL). However, the authors could not determine whether their analysis was recovering all of the drug in the milk because of the high lipid content of the samples. Two serum samples collected on days 19 and 21 measured 0.7 and 1.0 ng/mL of the drug, indicating that the milk:plasma ratio exceeded 1.0. Daily urine colchicine concentrations (days 16–20) ranged from 70 to 390 ng/mL. No apparent effects were observed in the nursing infant over the first 6 months of life (9).
In four lactating women on long-term colchicine therapy (1–1.5 mg/day for at least 7 years) for FMF, serum and milk samples were drawn before a dose and at 1, 3, and 6 hours after a dose (10). Maximum breast milk drug concentrations ranged between 1.9 and 8.6 ng/mL, whereas maximum serum concentrations ranged from 3.6 to 6.46 ng/mL. The peak concentrations in milk and serum both occurred at 1 hour and the colchicine concentration time curves for milk and serum were parallel. No apparent effects in the nursing infants were observed over a 10-month period. The authors concluded that nursing was safe for women taking colchicine, but that waiting 12 hours after a dose to breastfeed would minimize exposure of the nursing infant (10).
Much higher colchicine milk concentrations were measured in a second study. A 21-year-old woman had taken colchicine (1 mg/day) throughout gestation and continued while breastfeeding her normal infant (11). On postpartum days 5 and 15, colchicine concentrations in the mother’s 24-hour urine sample were 276,000 and 123,000 ng/24 hours, respectively, while none was detected (test sensitivity 5 ng/mL) in the infant’s 12-hour urine collection. Milk samples were collected four times each on day 5 (2, 4, 15, and 21 hours after a dose) and day 15 (0, 4, 7, and 11 hours after a dose). Colchicine concentrations in the 2-hour and 4-hour samples on day 5 were 31 and 24 ng/mL, respectively, and below the level of detection at 15 and 21 hours. On day 15, levels at 0 and 11 hours were below detection, while those at 4 and 7 hours were 27 and 10 ng/mL, respectively. Assuming 100% of the dose in milk was absorbed, the infant’s estimated dose during the 8-hour period after a dose was 10% of the mother’s weight-adjusted dose. Although no adverse effects were observed in the infant, the authors recommended that a mother could minimize drug exposure from her milk by taking her dose at bedtime and waiting 8 hours to breastfeed (11).
Because of the absence of infant toxicity observed during nursing in one of the above cases (9), the American Academy of Pediatrics classified colchicine as compatible with breastfeeding (37).
References
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