Objective
We sought to examine the fetal safety of colchicine.
Study Design
This was a prospective observational comparative cohort study regarding colchicine exposure during pregnancy including contacts to 2 Teratology Information Services in Israel from 1994 through 2006.
Results
In all, 238 colchicine-exposed pregnancies (97.0% first trimester) and 964 pregnancies with nonteratogenic exposure were followed up. Treatment indications were: familial Mediterranean fever (87.3%), Behçet disease (7.5%), or other (5.2%). The rate of major congenital anomalies was comparable between the groups (10/221 [4.5%] vs 35/908 [3.9%]; P = .648). There were no cytogenetic anomalies in the colchicine group. The median gestational age at delivery was earlier (39 [38-40] vs 40 [38-41] weeks; P < .001), the rate of preterm deliveries was higher (32/214 [15.0%] vs 51/867 [5.9%]; P < .001), and the median birthweight was lower (3000 [2688-3300] vs 3300 [2900-3600] g; P < .001) in the colchicine group.
Conclusion
The present study suggests that colchicine does not appear to be a major human teratogen, and, probably, has no cytogenetic effect.
Colchicine is an alkaloid that may interfere with microtubule formation, thereby affecting mitosis and other microtubule-dependent functions. Since 1972 colchicine has become the drug of choice for the prophylaxis and treatment of familial Mediterranean fever (FMF). It is also used in the treatment of gout, Behçet disease, psoriasis, and other diseases. Colchicine crosses the human placenta. Colchicine or its derivative demecolcine was teratogenic in mice and rabbits but not in monkeys. Its safe use in human pregnancy has been reported in a number of cases and studies. Three of the studies are reassuring but relatively small. Ehrenfeld et al reported on 16 healthy infants born to mothers who had taken colchicine. Ben-Chetrit and Levy focused on efficacy and safety of colchicine treatment, and reported on 11 women who took colchicine during their pregnancies and delivered 15 normal babies at term. Rabinovitch et al reported no increase in abnormality rate of the newborns, but found 2 cases of trisomy 21 in a series of 131 pregnancies exposed to colchicine, interpreted as a chance finding. The largest series on colchicine-treated patients to date was published by Berkenstadt et al. However, the study did not have a comparison group. The study included couples where the affected partner was either the woman or the man. The primary endpoint of interest was the rate of chromosomal abnormalities, although nonchromosomal abnormalities were also reported. The rate of nonchromosomal abnormalities in viable pregnancies in the study was unusually low (0.9%). In summary, human experience on the use of colchicine during pregnancy focusing on nonchromosomal anomalies with an appropriate comparison group is limited.
A 1965 report described 3 pregnancies, 2 of which ended abnormally, 1 with Down syndrome, fathered by a man who was under treatment by colchicine for gout. In a lymphocyte culture study from 3 patients with gout under colchicine treatment from the same laboratory, a significant increase of aneuploid cells was observed. Of 54 parents of registered patients with Down syndrome in their laboratory, 2 fathers were under colchicine treatment. Two additional cases of trisomy 21 were reported in a series of 131 colchicine-exposed pregnancies. Based on these reports, karyotyping is offered, in Israel, as in other countries, to couples who are under colchicine treatment.
FMF is an autosomal recessive disease that mainly affects people of Jewish, Armenian, Arabic, or Turkish ancestry. It affects patients of childbearing age. The disease manifests clinically by recurrent crises of fever and polyserositis, leading to abdominal, thoracic, or articular pain. Erysipelas-like erythema and myalgia are less frequent symptoms. FMF in pregnancy has been associated with a higher miscarriage rate, particularly in the pre-colchicine era. Colchicine can control the acute attacks of FMF and prevent the development of amyloidosis. Overall, colchicine treatment improves the prognosis of patients with FMF and increases their reproductive ability. The disease has recently been found to be an independent risk factor for preterm delivery, but not for congenital malformations.
The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after in utero exposure to colchicine compared to a comparison group counseled for nonteratogenic exposures. Special emphasis was given to assess the rate of cytogenetic anomalies. Secondary endpoints of interest were pregnancy outcome, birthweight, and gestational age at delivery.
Materials and Methods
The present prospective comparative observational study enrolled pregnant women who contacted the Israeli Teratology Information Service (TIS), Jerusalem, or the Drug Consultation Center at Assaf Harofeh Medical Center, Zerifin, Israel, in regard to gestational exposure to colchicine from 1994 through 2006. The 2 centers offer counseling services in regard to environmental exposures during pregnancy, and use a similar methodology for data collection. The exposed group was compared to a group of women who contacted the Israeli TIS during pregnancy in regard to exposures known not to be teratogenic in a similar time frame (comparison group). Paternal-only exposures to colchicine were not included in the study. Details of exposure were collected during pregnancy, at the initial contact to the TIS and before pregnancy outcome was known, using a structured questionnaire. Verbal consent to participate in the study was given by the woman at initial contact. Since the study was observational it was exempt from institutional review board approval. In addition, the following information was recorded: maternal demographics, medical and obstetric histories, and exposure details (dose, duration, and timing in pregnancy). Retrospective cases were not included in the study. Pregnant women who contacted the TIS after an anomaly had been identified on prenatal testing were also excluded. After the expected date of delivery, pregnancy outcome was actively sought after in the exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the pregnancy outcome, gestational age at delivery, birthweight, congenital anomalies, and neonatal complications. In addition, colchicine and other exposures were ascertained. In Israel, each neonate undergoes at least 2 physical examinations before being discharged from the hospital. The interview was conducted after these physical examinations. Data collection methods were similar in the exposed and comparison groups. Major anomalies were defined as structural anomalies in the offspring that have serious medical, surgical, or cosmetic consequences. Children with minor anomalies (eg, mild hypospadias not requiring an intervention) or functional problems without any morphological changes (eg, systolic heart murmur with normal echocardiography finding, slight developmental delay) or complications of preterm delivery were not considered as having major anomalies. All septal defects were considered major anomalies in the present study. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included in our study, since antenatal screening for major anomalies is routinely performed in Israel. Thus, the analysis of major congenital anomalies was performed among live-born infants and elective terminations of pregnancy due to prenatally diagnosed anomalies. In the case of multiple births, each live-born offspring was included in the analysis.
Statistical analysis
Categorical data were compared by χ 2 or Fisher’s exact tests and are expressed as ratios or percentage. Continuous data did not follow normal distribution and were compared using the Mann-Whitney test, and are presented using median with interquartile range (IQR). Statistical calculations were done using SPSS Version 16 (SPSS, Inc., Chicago, IL), while study sample size was calculated using Epi Info 2000 software (Centers for Disease Control and Prevention, Atlanta Epidemiology Program Office, Atlanta, GA).
Results
During the study period there were 310 calls in regard to women who took colchicine in pregnancy. A total of 238 colchicine-exposed pregnancies were prospectively followed up in the present study (225 from the Israeli TIS, Jerusalem, and 13 from the Drug Consultation Center at Assaf Harofeh Medical Center). The follow-up rate in the colchicine group was 76.8% (238/310). The 72 cases lost to follow-up (23.2%) were due to technical reasons (eg, telephone disconnection or change of address) and not due to refusal to complete the questionnaire. The exposure was at least in the first trimester of pregnancy in 97.0% of the colchicine group. The median daily dose (IQR between the 25th-75th percentiles) of colchicine was 1.0 mg (1.0–1.5). The medication was taken throughout pregnancy in 79.7% of the colchicine-exposed pregnancies. The indications for the treatment with colchicine in the exposed group were as follows: FMF in 87.3%, Behçet disease in 7.5%, and other in 5.2% including scleroderma (1.3%), arthritis (0.8%), gout (0.4%), erythema nodosum (0.4%), systemic lupus erythematosus (0.4%), Paget disease (0.4%), accidental ingestion (0.4%), and missing (0.8%). The comparison group consisted of 964 pregnancies of women counseled for nonteratogenic exposure by the Israeli TIS.
A comparison of maternal characteristics and obstetric history between the 2 groups is presented in Table 1 . The median maternal age was 1 year younger and the gestational age at initial contact was earlier in the colchicine group compared to the comparison group. A higher proportion of the colchicine-treated women called in regard to their first pregnancy and a lower proportion called in regard to their 2nd-4th pregnancy. The rate of heavy cigarette smokers was higher in the colchicine-exposed group. There were no significant differences between the groups in the history of miscarriages or elective terminations of pregnancy.
| Characteristic | Colchicine group n = 238 | Comparison group n = 964 | P value |
|---|---|---|---|
| Median maternal age, y (IQR) | 29 (25–32) | 30 (27–34) | < .001 |
| Pregnancy order, n (%) | |||
| 1 | 89/215 (41.4) | 234/921 (25.4) | < .001 |
| 2-4 | 97/215 (45.1) | 552/921 (59.9) | < .001 |
| ≥5 | 29/215 (13.5) | 135/921 (14.7) | .665 |
| Parity, n (%) | |||
| 0 | 104/217 (47.9) | 280/918 (30.5) | < .001 |
| 1-3 | 95/217 (43.8) | 569/918 (62.0) | < .001 |
| ≥4 | 18/217 (8.3) | 69/918 (7.5) | .698 |
| Previous miscarriage, n (%) | |||
| 0 | 181/215 (84.2) | 734/916 (80.1) | .173 |
| 1 | 33/215 (15.3) | 172/916 (18.8) | .240 |
| ≥2 | 1/215 (0.5) | 10/916 (1.1) | .701 |
| Previous ETOP ≥1 | 20/215 (9.3) | 82/915 (9.0) | .875 |
| Gestational age at initial contact median, wk (IQR) | 8 (6–13) | 10 (7–18) | < .001 |
| Cigarette/d, n (%) | |||
| 0 | 178/206 (86.4) | 675/717 (94.1) | < .001 |
| <10 | 8/206 (3.9) | 16/717 (2.2) | .189 |
| ≥10 | 20/206 (9.7) | 26/717 (3.6) | < .001 |
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