Use of colchicine in pregnancy: a systematic review and meta-analysis

Use of colchicine in pregnancy: a systematic review and meta-analysis Abstract Objectives Colchicine is an anti-inflammatory agent used in the treatment of several rheumatological conditions. The use of colchicine in pregnancy is controversial. The current study aimed to systematically review and meta-analyse the existing data in the literature regarding the safety of colchicine in pregnancy. Methods A systematic review was carried out using six electronic databases, identifying all relevant studies where colchicine was administered to pregnant women, and where pregnancy-related outcomes were measured. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Results Four studies were included for meta-analysis. Use of colchicine throughout pregnancy was not associated with an increased incidence of miscarriage or major foetal malformations. The incidence of miscarriage was significantly lower in women who took colchicine compared with those that did not. In women with FMF who took colchicine throughout the pregnancy, there was no significant difference in birthweight or gestational age compared with those who did not take colchicine. When not limited to FMF, colchicine use was associated with a significantly lower birthweight and gestational age compared with a control group including healthy women who did not take colchicine. Conclusions Colchicine therapy did not significantly increase the incidence of foetal malformations or miscarriage when taken during pregnancy. Colchicine therapy for FMF should not be withheld on this basis during pregnancy. colchicine, pregnancy, miscarriage, teratogenesis, malformation, foetus, familial Mediterranean fever Rheumatology key messages Colchicine is the standard treatment for familial Mediterranean fever, where it is used continuously. Colchicine use in pregnancy is controversial due to its anti-mitotic properties. Colchicine use was not associated with an increased risk of foetal malformations or miscarriage. Introduction Colchicine is an anti-inflammatory agent that is commonly used to treat gout, pseudogout, FMF and pericarditis. Colchicine is known to cross the placenta [1], and its use in pregnancy is controversial due to concerns over teratogenesis, which was first shown in animals exposed to high doses. Miscarriage and major malformations were noted in the offspring of mice injected with colchicine at a minimum dose of 0.5 mg/kg [2], a far higher dose than is typically prescribed in humans. High foetal mortality was also observed in the offspring of pregnant hamsters injected with a colchicine dose of 10 mg/kg [3]. Colchicine’s mechanism of action is 2-fold. It inhibits mitosis by preventing microtubule polymerization [4], which is the purported mechanism of teratogenesis in animals and toxicity in humans overdosing on the drug [5]. It also inhibits the diapedesis of neutrophils, that is, the migration of neutrophils from the microvasculature into the interstitial space. This mechanism is responsible for its clinical utility as an anti-inflammatory agent [6]. Current guidelines from Australia class colchicine as category D, which includes ‘drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage’ [7]. The United States Food and Drug Administration classes colchicine as category C, which encompasses drugs where foetal risk cannot be excluded. The manufacturer’s warning requests patients to discuss the use of the drug with their physician during pregnancy, but does not strictly contraindicate it [8]. Despite this, there is a growing trend towards continuing colchicine as a treatment for FMF in pregnancy to reduce the frequency of attacks and prevent systemic amyloidosis. There are no other proven and effective alternative therapies for FMF and it is essential to use the drug continuously in FMF to prevent renal failure due to amyloidosis. The objective of the current study was to systematically review and undertake a meta-analysis of the effect of colchicine on adverse foetal outcomes such as major malformations, miscarriages, preterm birth and low birthweight. Methods Search strategy and selection criteria Electronic searches were performed using Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club and Database of Abstracts of Review of Effectiveness. No date limitations were placed. Colchicine, pregnancy, embryo, foetus and teratogen* were combined as both key words and MeSH terms. After exclusion of duplicate results, abstracts were screened, and the full texts of those identified as potentially relevant were retrieved. Manual review of the reference lists was also performed to identify additional studies. Eligible studies for meta-analysis included those where patients were exposed to colchicine for any duration during pregnancy. Included publications were limited to human subjects and the English language. Unpublished data, conference presentations, editorials, case reports and correspondence were excluded. Studies where colchicine exposure was limited to the father were also excluded, as were those that lacked a control group and those where outcomes of patients exposed to colchicine were not presented separately. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Data extraction and critical appraisal Article texts, tables and figures were independently reviewed by three investigators (P.I., S.V. and D.G.). Discrepancies were resolved by discussion until a consensus was reached. The final results were reviewed by all authors. Statistical analysis Statistical analysis was conducted for two separate comparisons. Comparison A only included patients with FMF. Patients within the treatment arm received daily colchicine throughout all trimesters of the pregnancy. The control group comprised patients with FMF who did not receive colchicine at any point in their pregnancy. Comparison B comprised patients who were treated with colchicine for any indication and for any duration during the pregnancy. The control group comprised patients who did not receive any colchicine. This included patients with FMF and also healthy controls. The odds ratio (OR) or mean difference was used as a summary statistic, and reported with 95% CI. For the analysis of continuous data, medians and interquartile ranges were converted to mean values and standard deviations using the methods described by Hozo et al. [9] Meta-analyses were performed using random-effects models to take into account the anticipated clinical and methodological diversity between studies. The I2 statistic was used to estimate the percentage of total variation across studies due to heterogeneity rather than chance, with values exceeding 50% indicative of considerable heterogeneity. Statistical analysis was conducted with Review Manager Version 5.3.5 (Cochrane Collaboration, Software Update, Oxford, UK). All P-values were two-sided, and values <0.05 were considered statistically significant. Results Quantity and quality of trials The initial electronic database search yielded 1401 references. After exclusion of duplicates and irrelevant articles, 15 potentially relevant publications were retrieved for critical evaluation. Manual review of reference lists did not yield any additional references. After application of the selection criteria, four studies were ultimately included for statistical analysis (see supplementary figure available at Rheumatology Online and Table 1) [10–13]. Table 1 Study characteristics Reference  Study period  No. of pregnancies  Indication for colchicine  Daily dose of colchicine  Details of control groups  Ben-Chetrit et al. [10]  2004–08  179  FMF  1–1.5 mg  197 pregnancies with FMF, 312 healthy pregnancies  Diav-Citrin et al. [11]  1994–2006  238  FMF, Behçet’s disease and other  1 mg (median)  964 healthy pregnancies  Rabinovitch et al. [12]  1973–92  91a  FMF  1–2 mg  94 pregnancies with FMF  Yazicioglu et al. [13]  2002–12  42  FMF  NR  8 pregnancies with FMF  Reference  Study period  No. of pregnancies  Indication for colchicine  Daily dose of colchicine  Details of control groups  Ben-Chetrit et al. [10]  2004–08  179  FMF  1–1.5 mg  197 pregnancies with FMF, 312 healthy pregnancies  Diav-Citrin et al. [11]  1994–2006  238  FMF, Behçet’s disease and other  1 mg (median)  964 healthy pregnancies  Rabinovitch et al. [12]  1973–92  91a  FMF  1–2 mg  94 pregnancies with FMF  Yazicioglu et al. [13]  2002–12  42  FMF  NR  8 pregnancies with FMF  a Does not include a separate subgroup of 40 patients who ceased colchicine therapy during pregnancy. NR: not reported. All four studies were observational in nature. Two studies comprised only patients who had FMF [12, 13] and two included healthy patients in their control groups [10, 11]. In total, data were available for 554 pregnancies with colchicine exposure, and 1575 pregnancies where no colchicine exposure occurred. Colchicine doses between 1 and 2 mg daily were reported. Clinical outcomes Miscarriage In women with FMF (comparison A), those receiving colchicine throughout the pregnancy demonstrated a lower rate of miscarriage than those not receiving any colchicine. However, this difference did not reach statistical significance (see Table 2 and Fig. 1). Table 2 Comparison A: Colchicine vs no colchicine in FMF Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  3a  OR  0.69 (0.43, 1.11)  0.12  0  34/312 (10.9%) vs 50/299 (16.7%)  Major malformations  3  OR  0.59 (0.12, 2.93)  0.52  0  3/312 (1.0%) vs 3/299 (1.0%)  Pre-term birth  1  OR  —  —  —  —  Cesarean section  2  OR  1.61 (0.65, 4.03)  0.31  64  37/270 (13.7%) vs 27/291 (9.3%)  Gestational age, weeks  1  MD  —  —  —  —  Birthweight, g  2  MD  −96.72 (−218.90, 25.46)  0.12  0  2956.03 ± 661.87 vs 3104.52 ± 451.55  Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  3a  OR  0.69 (0.43, 1.11)  0.12  0  34/312 (10.9%) vs 50/299 (16.7%)  Major malformations  3  OR  0.59 (0.12, 2.93)  0.52  0  3/312 (1.0%) vs 3/299 (1.0%)  Pre-term birth  1  OR  —  —  —  —  Cesarean section  2  OR  1.61 (0.65, 4.03)  0.31  64  37/270 (13.7%) vs 27/291 (9.3%)  Gestational age, weeks  1  MD  —  —  —  —  Birthweight, g  2  MD  −96.72 (−218.90, 25.46)  0.12  0  2956.03 ± 661.87 vs 3104.52 ± 451.55  a Includes one study with zero event rate. MD: mean difference; OR, odds ratio. Fig. 1 View largeDownload slide Odds ratio of miscarriage after colchicine exposure in FMF Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine throughout pregnancy versus no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 1 View largeDownload slide Odds ratio of miscarriage after colchicine exposure in FMF Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine throughout pregnancy versus no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. In all women exposed to colchicine for any duration or indication compared with those who were not exposed at all (comparison B), there was a significantly lower rate of miscarriage (see Table 3 and Fig. 2). Table 3 Comparison B: colchicine vs no colchicine (in any) Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  4a  OR  0.65 (0.45, 0.93)  0.02  0  46/590 (7.8%) vs 157/1575 (10.0%)  Major malformations  4  OR  1.08 (0.56, 2.07)  0.82  0  14/573 (2.4%) vs 40/1519 (2.6%)  Pre-term birth  2  OR  2.48 (1.65, 3.71)  <0.001  1  57/345 (16.5%) vs 62/961 (6.5%)  Cesarean section  3  OR  1.47 (0.96, 2.26)  0.07  38  99/527 (18.8%) vs 196/1178 (16.6%)  Gestational age, weeks  2  MD  −1.00 (−1.05 −0.95)  <0.001  0  38.57 ± 1.88 vs 39.98 ± 0.55  Birthweight, g  3  MD  −209.62 (−381.58, −37.66)  0.02  80  2985.12 ± 413.96 vs 3281.30 ± 186.96  Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  4a  OR  0.65 (0.45, 0.93)  0.02  0  46/590 (7.8%) vs 157/1575 (10.0%)  Major malformations  4  OR  1.08 (0.56, 2.07)  0.82  0  14/573 (2.4%) vs 40/1519 (2.6%)  Pre-term birth  2  OR  2.48 (1.65, 3.71)  <0.001  1  57/345 (16.5%) vs 62/961 (6.5%)  Cesarean section  3  OR  1.47 (0.96, 2.26)  0.07  38  99/527 (18.8%) vs 196/1178 (16.6%)  Gestational age, weeks  2  MD  −1.00 (−1.05 −0.95)  <0.001  0  38.57 ± 1.88 vs 39.98 ± 0.55  Birthweight, g  3  MD  −209.62 (−381.58, −37.66)  0.02  80  2985.12 ± 413.96 vs 3281.30 ± 186.96  a Includes one study with zero event rate. MD: mean difference; OR, odds ratio. Fig. 2 View largeDownload slide Odds ratio of miscarriage after exposure to any amount of colchicine during pregnancy Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine of any duration and for any reason during pregnancy vs no colchicine for all pregnant women. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 2 View largeDownload slide Odds ratio of miscarriage after exposure to any amount of colchicine during pregnancy Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine of any duration and for any reason during pregnancy vs no colchicine for all pregnant women. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Major malformations In women with FMF (comparison A), there was no significant difference in the rate of major malformations between the babies of women who used colchicine throughout pregnancy compared with those who did not take the drug (see Table 2 and Fig. 3). Fig. 3 View largeDownload slide Odds ratio of major foetal malformation after colchicine use in FMF Forest plot of the odds ratio (OR) of major foetal malformation after exposure to colchicine throughout pregnancy vs no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 3 View largeDownload slide Odds ratio of major foetal malformation after colchicine use in FMF Forest plot of the odds ratio (OR) of major foetal malformation after exposure to colchicine throughout pregnancy vs no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. In comparison B, the rate of major malformations was similar between the babies of women who received colchicine for any duration or indication and those who did not receive any colchicine (see Table 3 and supplementary figure available at Rheumatology Online). Pre-term birth This end point was only analysed in comparison B due to the paucity of studies reporting the outcome. In women exposed to colchicine for any duration or indication, preterm birth was significantly more common compared with women who did not receive the drug. The mean gestational age was 40.0 (0.6) weeks for women who were not exposed to colchicine, and 38.6 (1.9) weeks for women who were. This difference reached statistical significance (see Table 3). Birthweight In comparison A, there was no significant difference in the birthweight of babies born to women who received colchicine during pregnancy compared with those who did not (see Table 2). In comparison B, birthweight among those exposed to colchicine was significantly lower (see Table 3). Discussion Colchicine is the primary treatment for FMF, as well as a useful adjunctive treatment in gout, pseudogout and pericarditis. In FMF, colchicine is taken lifelong in order to prevent painful flares of the disease, which if uncontrolled, can progress to systemic amyloidosis due to deposition of immune complexes [14]. The utility of colchicine in preventing relapses of FMF has led to controversy regarding its use in pregnant women, in light of animal studies suggesting foetal harm. In some institutions, routine foetal karyotyping via amniocentesis is offered to detect embyronal chromosomal abnormalities, although there is no evidence to support this practice [15]. While no randomized control trials have been published on the efficacy and safety of colchicine in pregnancy, several observational studies have been published, typically focusing on patients who are treated for FMF. A large retrospective cohort study from Israel recruited FMF patients and stratified them into three groups based on colchicine use in each of their pregnancies [10]. This included women who took colchicine in all pregnancies, those who took it in selected pregnancies, and those who never took colchicine in any pregnancies. No significant differences were observed between groups in regard to miscarriage or malformation rates. A prospective cohort study from a separate Israeli institution enrolled women who contacted a teratology information service or drug consultation centre [11]. Eighty per cent of patients who took colchicine continued it for the entire pregnancy, with 97% being exposed to colchicine for at least the first trimester. A variety of indications for colchicine were identified, and the outcomes were compared against a cohort of healthy pregnant controls. While no statistically significant differences were observed in the rates of miscarriage and major malformations, there were higher rates of preterm delivery observed in the colchicine group (15 vs 5.9%; P < 0.001; low birthweight) and median birthweight was lower (3000 g vs 3300 g; P < 0.001). A retrospective study of pregnant patients treated at the National FMF centre was performed by Rabinovitch and colleagues [12]. Three separate groups were included—those who continued colchicine throughout the pregnancy, those who discontinued colchicine during pregnancy, and those who did not take it at any stage. No significant differences in any of the listed outcomes were identified; however, the study was limited due to the lack of reporting of baseline characteristics of patients. Detailed statistical analysis was also not performed. The fourth included study was a retrospective analysis of 50 cases forming a 10-year experience from a Turkish FMF centre [13]. Forty-two of the patients were exposed to colchicine. No significant differences were observed in any of the listed endpoints; however, this may be due to the relatively low power of the study. The present systematic review and meta-analysis is unique, as it is the first to examine the impact of colchicine on pregnancy-related outcomes. Colchicine did not increase the risk of miscarriage; in fact, in comparison B, colchicine use appeared protective against miscarriage. This result was not replicated in the FMF group (comparison A); however, a trend showing borderline statistical significance was seen. The painful acute peritonitis of FMF can cause miscarriage, and thus prevention of relapses using colchicine may be protective against spontaneous abortions [15]. Although colchicine has been suspected to be teratogenic on the basis of animal studies [2, 3] and the theoretical risk of mitotic arrest, there was no evidence in either comparison to suggest that it exerts any teratogenic effect in humans. The rate of major foetal malformations was not significantly different in either group. The development of teratogenesis may be dose dependent, as the weight-based adjusted doses administered to animals was over 100 times that which is typically prescribed in humans. In women treated for FMF throughout pregnancy with colchicine, there was no increased risk of low birthweight. In comparison B, however, there was a statistically significant difference between the birthweights of babies born to women taking colchicine during the pregnancy. There are several confounding factors that may have influenced this result. Firstly, a large proportion of patients in the control group of comparison B did not have FMF. Therefore, the difference in birth weight may be attributable to the disease rather than the intervention. The relatively high I2 value calculated for this end point reflects significant heterogeneity. Similarly, the increased risk of preterm delivery (defined as 36 weeks of gestation or fewer) in women exposed to colchicine may again reflect the influence of disease rather than colchicine. FMF has been identified as an independent risk factor for preterm delivery, but not for congenital malformations [16]. Reasons for preterm delivery, such as medical induction of pregnancy, were not reported in the majority of studies. The findings of the present meta-analysis suggest that colchicine is not associated with teratogenesis or miscarriage, which is in contrast to certain published international guidelines. There may be a risk of preterm delivery and low birthweight; however, it is unclear whether this is reflective of the natural history of FMF in pregnancy rather than an effect of colchicine. There are several limitations to the current study and the findings should be interpreted with caution. Firstly, the literature does not contain any randomized studies. Secondly, certain studies compared patients who received colchicine for FMF against healthy controls, thus potentially confounding the result. There remains a lack of available data on the use of colchicine for other medical conditions such as gout, pseudogout and pericarditis. In these conditions, where there are alternative treatment agents available, and a lower risk of long term complications, the role of colchicine in pregnancy remains unclear. There was a paucity of reporting of FMF disease activity throughout pregnancy, and thus associations between disease activity and adverse foetal outcomes could not be established. Conclusion The results from the present meta-analysis suggest that colchicine is not associated with an increased risk of miscarriage or foetal malformations. Colchicine therapy should not be withheld on the basis of increased teratogenic risk in FMF where there is a risk of disease relapse and systemic amyloidosis if the disease is untreated. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1 Michael O, Goldman RD, Koren G. Safety of colchicine therapy during pregnancy. Can Fam Physician  2003; 49: 967– 9. PubMed PMID: 12943352. Google Scholar PubMed  2 Shoji RMS. Preliminary notes on the teratogenic and embryocidal effects of colchicine on mouse embryos. Proc Jpn Acad  1966; 42: 822– 7. 3 Ferm V. Effect of transplacental mitotic inhibitors on the fetal hamster eye. Anat Rec  1964; 148: 129– 37. Google Scholar CrossRef Search ADS PubMed  4 Skoufias D, Wilson L. Mechanism of inhibition of microtubule polymerization by colchicine: inhibitory potencies of unliganded colchicine and tubulin-colchicine complexes. Biochemistry  1992; 31: 738– 46. Google Scholar CrossRef Search ADS PubMed  5 Smith M, Roberts D, Ritson S, Day R. Death and morbidity from supratherapeutic dosing of colchicine. Med J Aust  2011; 194: 612– 3. Google Scholar PubMed  6 Malawista S. The action of colchicine in acute gouty arthritis. Arthritis Rheum  1975; 18: 835– 45. Google Scholar CrossRef Search ADS PubMed  7 Australian Government, Department of Health, Therapeutic Goods Administration. Prescribing Medicines in Pregnancy Database 2016. https://www.tga.gov.au/prescribing-medicines-pregnancy-database (14 March 2017, date last accessed). 8 NPS MedicineWise. 2016. https://www.nps.org.au/medical-info/medicine-finder/colgout-tablets (14 March 2017, date last accessed) 9 Hozo S, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol  2005; 5: 13. Google Scholar CrossRef Search ADS PubMed  10 Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit E. Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arth Care Res  2010; 62: 143– 8. Google Scholar CrossRef Search ADS   11 Diav-Citrin O, Schectman S, Schwartz V et al.   Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol  2010; 203: 144.e1– 6. Google Scholar CrossRef Search ADS   12 Rabinovitch O, Zemer D, Kukia E, Sohar E, Maschiach S. Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever. Am J Reprod Immunol  1992; 28: 245– 6. Google Scholar CrossRef Search ADS PubMed  13 Yazicioglu A, Turgal M, Yucel O, Ozyuncu O, Beksac M. Pregnancy outcome in women with familial Mediterranean fever: A retrospective analysis of 50 cases with a 10-year experience. Arch Rheumatol  2014; 29: 94– 8. Google Scholar CrossRef Search ADS   14 Yasar O, Iskender C, Kaymak O et al.   Retrospective evaluation of pregnancy outcomes in women with familial Mediterranean fever. J Matern Fetal Neonatal Med  2014; 27: 733– 6. Google Scholar CrossRef Search ADS PubMed  15 Mijatovic V, Hompes PG, Wouters MG. Familial Mediterranean fever and its implications for fertility and pregnancy. Eur J Obstet Gynecol Reprod Biol  2003; 108: 171– 6. PubMed PMID: 12781406. Google Scholar CrossRef Search ADS PubMed  16 Ofir D, Levy A, Wiznitzer A, Mazor M, Sheiner E. Familial Mediterranean fever during pregnancy: an independent risk factor for preterm delivery. Eur J Obstet Gynecol Reprod Biol  2008; 141: 115– 8. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Use of colchicine in pregnancy: a systematic review and meta-analysis

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Abstract

Abstract Objectives Colchicine is an anti-inflammatory agent used in the treatment of several rheumatological conditions. The use of colchicine in pregnancy is controversial. The current study aimed to systematically review and meta-analyse the existing data in the literature regarding the safety of colchicine in pregnancy. Methods A systematic review was carried out using six electronic databases, identifying all relevant studies where colchicine was administered to pregnant women, and where pregnancy-related outcomes were measured. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Results Four studies were included for meta-analysis. Use of colchicine throughout pregnancy was not associated with an increased incidence of miscarriage or major foetal malformations. The incidence of miscarriage was significantly lower in women who took colchicine compared with those that did not. In women with FMF who took colchicine throughout the pregnancy, there was no significant difference in birthweight or gestational age compared with those who did not take colchicine. When not limited to FMF, colchicine use was associated with a significantly lower birthweight and gestational age compared with a control group including healthy women who did not take colchicine. Conclusions Colchicine therapy did not significantly increase the incidence of foetal malformations or miscarriage when taken during pregnancy. Colchicine therapy for FMF should not be withheld on this basis during pregnancy. colchicine, pregnancy, miscarriage, teratogenesis, malformation, foetus, familial Mediterranean fever Rheumatology key messages Colchicine is the standard treatment for familial Mediterranean fever, where it is used continuously. Colchicine use in pregnancy is controversial due to its anti-mitotic properties. Colchicine use was not associated with an increased risk of foetal malformations or miscarriage. Introduction Colchicine is an anti-inflammatory agent that is commonly used to treat gout, pseudogout, FMF and pericarditis. Colchicine is known to cross the placenta [1], and its use in pregnancy is controversial due to concerns over teratogenesis, which was first shown in animals exposed to high doses. Miscarriage and major malformations were noted in the offspring of mice injected with colchicine at a minimum dose of 0.5 mg/kg [2], a far higher dose than is typically prescribed in humans. High foetal mortality was also observed in the offspring of pregnant hamsters injected with a colchicine dose of 10 mg/kg [3]. Colchicine’s mechanism of action is 2-fold. It inhibits mitosis by preventing microtubule polymerization [4], which is the purported mechanism of teratogenesis in animals and toxicity in humans overdosing on the drug [5]. It also inhibits the diapedesis of neutrophils, that is, the migration of neutrophils from the microvasculature into the interstitial space. This mechanism is responsible for its clinical utility as an anti-inflammatory agent [6]. Current guidelines from Australia class colchicine as category D, which includes ‘drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage’ [7]. The United States Food and Drug Administration classes colchicine as category C, which encompasses drugs where foetal risk cannot be excluded. The manufacturer’s warning requests patients to discuss the use of the drug with their physician during pregnancy, but does not strictly contraindicate it [8]. Despite this, there is a growing trend towards continuing colchicine as a treatment for FMF in pregnancy to reduce the frequency of attacks and prevent systemic amyloidosis. There are no other proven and effective alternative therapies for FMF and it is essential to use the drug continuously in FMF to prevent renal failure due to amyloidosis. The objective of the current study was to systematically review and undertake a meta-analysis of the effect of colchicine on adverse foetal outcomes such as major malformations, miscarriages, preterm birth and low birthweight. Methods Search strategy and selection criteria Electronic searches were performed using Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club and Database of Abstracts of Review of Effectiveness. No date limitations were placed. Colchicine, pregnancy, embryo, foetus and teratogen* were combined as both key words and MeSH terms. After exclusion of duplicate results, abstracts were screened, and the full texts of those identified as potentially relevant were retrieved. Manual review of the reference lists was also performed to identify additional studies. Eligible studies for meta-analysis included those where patients were exposed to colchicine for any duration during pregnancy. Included publications were limited to human subjects and the English language. Unpublished data, conference presentations, editorials, case reports and correspondence were excluded. Studies where colchicine exposure was limited to the father were also excluded, as were those that lacked a control group and those where outcomes of patients exposed to colchicine were not presented separately. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Data extraction and critical appraisal Article texts, tables and figures were independently reviewed by three investigators (P.I., S.V. and D.G.). Discrepancies were resolved by discussion until a consensus was reached. The final results were reviewed by all authors. Statistical analysis Statistical analysis was conducted for two separate comparisons. Comparison A only included patients with FMF. Patients within the treatment arm received daily colchicine throughout all trimesters of the pregnancy. The control group comprised patients with FMF who did not receive colchicine at any point in their pregnancy. Comparison B comprised patients who were treated with colchicine for any indication and for any duration during the pregnancy. The control group comprised patients who did not receive any colchicine. This included patients with FMF and also healthy controls. The odds ratio (OR) or mean difference was used as a summary statistic, and reported with 95% CI. For the analysis of continuous data, medians and interquartile ranges were converted to mean values and standard deviations using the methods described by Hozo et al. [9] Meta-analyses were performed using random-effects models to take into account the anticipated clinical and methodological diversity between studies. The I2 statistic was used to estimate the percentage of total variation across studies due to heterogeneity rather than chance, with values exceeding 50% indicative of considerable heterogeneity. Statistical analysis was conducted with Review Manager Version 5.3.5 (Cochrane Collaboration, Software Update, Oxford, UK). All P-values were two-sided, and values <0.05 were considered statistically significant. Results Quantity and quality of trials The initial electronic database search yielded 1401 references. After exclusion of duplicates and irrelevant articles, 15 potentially relevant publications were retrieved for critical evaluation. Manual review of reference lists did not yield any additional references. After application of the selection criteria, four studies were ultimately included for statistical analysis (see supplementary figure available at Rheumatology Online and Table 1) [10–13]. Table 1 Study characteristics Reference  Study period  No. of pregnancies  Indication for colchicine  Daily dose of colchicine  Details of control groups  Ben-Chetrit et al. [10]  2004–08  179  FMF  1–1.5 mg  197 pregnancies with FMF, 312 healthy pregnancies  Diav-Citrin et al. [11]  1994–2006  238  FMF, Behçet’s disease and other  1 mg (median)  964 healthy pregnancies  Rabinovitch et al. [12]  1973–92  91a  FMF  1–2 mg  94 pregnancies with FMF  Yazicioglu et al. [13]  2002–12  42  FMF  NR  8 pregnancies with FMF  Reference  Study period  No. of pregnancies  Indication for colchicine  Daily dose of colchicine  Details of control groups  Ben-Chetrit et al. [10]  2004–08  179  FMF  1–1.5 mg  197 pregnancies with FMF, 312 healthy pregnancies  Diav-Citrin et al. [11]  1994–2006  238  FMF, Behçet’s disease and other  1 mg (median)  964 healthy pregnancies  Rabinovitch et al. [12]  1973–92  91a  FMF  1–2 mg  94 pregnancies with FMF  Yazicioglu et al. [13]  2002–12  42  FMF  NR  8 pregnancies with FMF  a Does not include a separate subgroup of 40 patients who ceased colchicine therapy during pregnancy. NR: not reported. All four studies were observational in nature. Two studies comprised only patients who had FMF [12, 13] and two included healthy patients in their control groups [10, 11]. In total, data were available for 554 pregnancies with colchicine exposure, and 1575 pregnancies where no colchicine exposure occurred. Colchicine doses between 1 and 2 mg daily were reported. Clinical outcomes Miscarriage In women with FMF (comparison A), those receiving colchicine throughout the pregnancy demonstrated a lower rate of miscarriage than those not receiving any colchicine. However, this difference did not reach statistical significance (see Table 2 and Fig. 1). Table 2 Comparison A: Colchicine vs no colchicine in FMF Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  3a  OR  0.69 (0.43, 1.11)  0.12  0  34/312 (10.9%) vs 50/299 (16.7%)  Major malformations  3  OR  0.59 (0.12, 2.93)  0.52  0  3/312 (1.0%) vs 3/299 (1.0%)  Pre-term birth  1  OR  —  —  —  —  Cesarean section  2  OR  1.61 (0.65, 4.03)  0.31  64  37/270 (13.7%) vs 27/291 (9.3%)  Gestational age, weeks  1  MD  —  —  —  —  Birthweight, g  2  MD  −96.72 (−218.90, 25.46)  0.12  0  2956.03 ± 661.87 vs 3104.52 ± 451.55  Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  3a  OR  0.69 (0.43, 1.11)  0.12  0  34/312 (10.9%) vs 50/299 (16.7%)  Major malformations  3  OR  0.59 (0.12, 2.93)  0.52  0  3/312 (1.0%) vs 3/299 (1.0%)  Pre-term birth  1  OR  —  —  —  —  Cesarean section  2  OR  1.61 (0.65, 4.03)  0.31  64  37/270 (13.7%) vs 27/291 (9.3%)  Gestational age, weeks  1  MD  —  —  —  —  Birthweight, g  2  MD  −96.72 (−218.90, 25.46)  0.12  0  2956.03 ± 661.87 vs 3104.52 ± 451.55  a Includes one study with zero event rate. MD: mean difference; OR, odds ratio. Fig. 1 View largeDownload slide Odds ratio of miscarriage after colchicine exposure in FMF Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine throughout pregnancy versus no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 1 View largeDownload slide Odds ratio of miscarriage after colchicine exposure in FMF Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine throughout pregnancy versus no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. In all women exposed to colchicine for any duration or indication compared with those who were not exposed at all (comparison B), there was a significantly lower rate of miscarriage (see Table 3 and Fig. 2). Table 3 Comparison B: colchicine vs no colchicine (in any) Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  4a  OR  0.65 (0.45, 0.93)  0.02  0  46/590 (7.8%) vs 157/1575 (10.0%)  Major malformations  4  OR  1.08 (0.56, 2.07)  0.82  0  14/573 (2.4%) vs 40/1519 (2.6%)  Pre-term birth  2  OR  2.48 (1.65, 3.71)  <0.001  1  57/345 (16.5%) vs 62/961 (6.5%)  Cesarean section  3  OR  1.47 (0.96, 2.26)  0.07  38  99/527 (18.8%) vs 196/1178 (16.6%)  Gestational age, weeks  2  MD  −1.00 (−1.05 −0.95)  <0.001  0  38.57 ± 1.88 vs 39.98 ± 0.55  Birthweight, g  3  MD  −209.62 (−381.58, −37.66)  0.02  80  2985.12 ± 413.96 vs 3281.30 ± 186.96  Outcome  No. of Studies  Estimate  OR/MD (95% CI)  P-value  I2 (%)  Raw values (colchicine vs no colchicine)  Miscarriage  4a  OR  0.65 (0.45, 0.93)  0.02  0  46/590 (7.8%) vs 157/1575 (10.0%)  Major malformations  4  OR  1.08 (0.56, 2.07)  0.82  0  14/573 (2.4%) vs 40/1519 (2.6%)  Pre-term birth  2  OR  2.48 (1.65, 3.71)  <0.001  1  57/345 (16.5%) vs 62/961 (6.5%)  Cesarean section  3  OR  1.47 (0.96, 2.26)  0.07  38  99/527 (18.8%) vs 196/1178 (16.6%)  Gestational age, weeks  2  MD  −1.00 (−1.05 −0.95)  <0.001  0  38.57 ± 1.88 vs 39.98 ± 0.55  Birthweight, g  3  MD  −209.62 (−381.58, −37.66)  0.02  80  2985.12 ± 413.96 vs 3281.30 ± 186.96  a Includes one study with zero event rate. MD: mean difference; OR, odds ratio. Fig. 2 View largeDownload slide Odds ratio of miscarriage after exposure to any amount of colchicine during pregnancy Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine of any duration and for any reason during pregnancy vs no colchicine for all pregnant women. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 2 View largeDownload slide Odds ratio of miscarriage after exposure to any amount of colchicine during pregnancy Forest plot of the odds ratio (OR) of miscarriage after exposure to colchicine of any duration and for any reason during pregnancy vs no colchicine for all pregnant women. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Major malformations In women with FMF (comparison A), there was no significant difference in the rate of major malformations between the babies of women who used colchicine throughout pregnancy compared with those who did not take the drug (see Table 2 and Fig. 3). Fig. 3 View largeDownload slide Odds ratio of major foetal malformation after colchicine use in FMF Forest plot of the odds ratio (OR) of major foetal malformation after exposure to colchicine throughout pregnancy vs no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. Fig. 3 View largeDownload slide Odds ratio of major foetal malformation after colchicine use in FMF Forest plot of the odds ratio (OR) of major foetal malformation after exposure to colchicine throughout pregnancy vs no colchicine for women with FMF. The estimate of the OR of each trial corresponds to the middle of the squares, and the horizontal line shows the 95% CI. The summary OR is depicted by the diamond. In comparison B, the rate of major malformations was similar between the babies of women who received colchicine for any duration or indication and those who did not receive any colchicine (see Table 3 and supplementary figure available at Rheumatology Online). Pre-term birth This end point was only analysed in comparison B due to the paucity of studies reporting the outcome. In women exposed to colchicine for any duration or indication, preterm birth was significantly more common compared with women who did not receive the drug. The mean gestational age was 40.0 (0.6) weeks for women who were not exposed to colchicine, and 38.6 (1.9) weeks for women who were. This difference reached statistical significance (see Table 3). Birthweight In comparison A, there was no significant difference in the birthweight of babies born to women who received colchicine during pregnancy compared with those who did not (see Table 2). In comparison B, birthweight among those exposed to colchicine was significantly lower (see Table 3). Discussion Colchicine is the primary treatment for FMF, as well as a useful adjunctive treatment in gout, pseudogout and pericarditis. In FMF, colchicine is taken lifelong in order to prevent painful flares of the disease, which if uncontrolled, can progress to systemic amyloidosis due to deposition of immune complexes [14]. The utility of colchicine in preventing relapses of FMF has led to controversy regarding its use in pregnant women, in light of animal studies suggesting foetal harm. In some institutions, routine foetal karyotyping via amniocentesis is offered to detect embyronal chromosomal abnormalities, although there is no evidence to support this practice [15]. While no randomized control trials have been published on the efficacy and safety of colchicine in pregnancy, several observational studies have been published, typically focusing on patients who are treated for FMF. A large retrospective cohort study from Israel recruited FMF patients and stratified them into three groups based on colchicine use in each of their pregnancies [10]. This included women who took colchicine in all pregnancies, those who took it in selected pregnancies, and those who never took colchicine in any pregnancies. No significant differences were observed between groups in regard to miscarriage or malformation rates. A prospective cohort study from a separate Israeli institution enrolled women who contacted a teratology information service or drug consultation centre [11]. Eighty per cent of patients who took colchicine continued it for the entire pregnancy, with 97% being exposed to colchicine for at least the first trimester. A variety of indications for colchicine were identified, and the outcomes were compared against a cohort of healthy pregnant controls. While no statistically significant differences were observed in the rates of miscarriage and major malformations, there were higher rates of preterm delivery observed in the colchicine group (15 vs 5.9%; P < 0.001; low birthweight) and median birthweight was lower (3000 g vs 3300 g; P < 0.001). A retrospective study of pregnant patients treated at the National FMF centre was performed by Rabinovitch and colleagues [12]. Three separate groups were included—those who continued colchicine throughout the pregnancy, those who discontinued colchicine during pregnancy, and those who did not take it at any stage. No significant differences in any of the listed outcomes were identified; however, the study was limited due to the lack of reporting of baseline characteristics of patients. Detailed statistical analysis was also not performed. The fourth included study was a retrospective analysis of 50 cases forming a 10-year experience from a Turkish FMF centre [13]. Forty-two of the patients were exposed to colchicine. No significant differences were observed in any of the listed endpoints; however, this may be due to the relatively low power of the study. The present systematic review and meta-analysis is unique, as it is the first to examine the impact of colchicine on pregnancy-related outcomes. Colchicine did not increase the risk of miscarriage; in fact, in comparison B, colchicine use appeared protective against miscarriage. This result was not replicated in the FMF group (comparison A); however, a trend showing borderline statistical significance was seen. The painful acute peritonitis of FMF can cause miscarriage, and thus prevention of relapses using colchicine may be protective against spontaneous abortions [15]. Although colchicine has been suspected to be teratogenic on the basis of animal studies [2, 3] and the theoretical risk of mitotic arrest, there was no evidence in either comparison to suggest that it exerts any teratogenic effect in humans. The rate of major foetal malformations was not significantly different in either group. The development of teratogenesis may be dose dependent, as the weight-based adjusted doses administered to animals was over 100 times that which is typically prescribed in humans. In women treated for FMF throughout pregnancy with colchicine, there was no increased risk of low birthweight. In comparison B, however, there was a statistically significant difference between the birthweights of babies born to women taking colchicine during the pregnancy. There are several confounding factors that may have influenced this result. Firstly, a large proportion of patients in the control group of comparison B did not have FMF. Therefore, the difference in birth weight may be attributable to the disease rather than the intervention. The relatively high I2 value calculated for this end point reflects significant heterogeneity. Similarly, the increased risk of preterm delivery (defined as 36 weeks of gestation or fewer) in women exposed to colchicine may again reflect the influence of disease rather than colchicine. FMF has been identified as an independent risk factor for preterm delivery, but not for congenital malformations [16]. Reasons for preterm delivery, such as medical induction of pregnancy, were not reported in the majority of studies. The findings of the present meta-analysis suggest that colchicine is not associated with teratogenesis or miscarriage, which is in contrast to certain published international guidelines. There may be a risk of preterm delivery and low birthweight; however, it is unclear whether this is reflective of the natural history of FMF in pregnancy rather than an effect of colchicine. There are several limitations to the current study and the findings should be interpreted with caution. Firstly, the literature does not contain any randomized studies. Secondly, certain studies compared patients who received colchicine for FMF against healthy controls, thus potentially confounding the result. There remains a lack of available data on the use of colchicine for other medical conditions such as gout, pseudogout and pericarditis. In these conditions, where there are alternative treatment agents available, and a lower risk of long term complications, the role of colchicine in pregnancy remains unclear. There was a paucity of reporting of FMF disease activity throughout pregnancy, and thus associations between disease activity and adverse foetal outcomes could not be established. Conclusion The results from the present meta-analysis suggest that colchicine is not associated with an increased risk of miscarriage or foetal malformations. Colchicine therapy should not be withheld on the basis of increased teratogenic risk in FMF where there is a risk of disease relapse and systemic amyloidosis if the disease is untreated. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1 Michael O, Goldman RD, Koren G. Safety of colchicine therapy during pregnancy. Can Fam Physician  2003; 49: 967– 9. PubMed PMID: 12943352. Google Scholar PubMed  2 Shoji RMS. Preliminary notes on the teratogenic and embryocidal effects of colchicine on mouse embryos. Proc Jpn Acad  1966; 42: 822– 7. 3 Ferm V. Effect of transplacental mitotic inhibitors on the fetal hamster eye. Anat Rec  1964; 148: 129– 37. Google Scholar CrossRef Search ADS PubMed  4 Skoufias D, Wilson L. Mechanism of inhibition of microtubule polymerization by colchicine: inhibitory potencies of unliganded colchicine and tubulin-colchicine complexes. Biochemistry  1992; 31: 738– 46. Google Scholar CrossRef Search ADS PubMed  5 Smith M, Roberts D, Ritson S, Day R. Death and morbidity from supratherapeutic dosing of colchicine. Med J Aust  2011; 194: 612– 3. Google Scholar PubMed  6 Malawista S. The action of colchicine in acute gouty arthritis. Arthritis Rheum  1975; 18: 835– 45. Google Scholar CrossRef Search ADS PubMed  7 Australian Government, Department of Health, Therapeutic Goods Administration. Prescribing Medicines in Pregnancy Database 2016. https://www.tga.gov.au/prescribing-medicines-pregnancy-database (14 March 2017, date last accessed). 8 NPS MedicineWise. 2016. https://www.nps.org.au/medical-info/medicine-finder/colgout-tablets (14 March 2017, date last accessed) 9 Hozo S, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol  2005; 5: 13. Google Scholar CrossRef Search ADS PubMed  10 Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit E. Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arth Care Res  2010; 62: 143– 8. Google Scholar CrossRef Search ADS   11 Diav-Citrin O, Schectman S, Schwartz V et al.   Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol  2010; 203: 144.e1– 6. Google Scholar CrossRef Search ADS   12 Rabinovitch O, Zemer D, Kukia E, Sohar E, Maschiach S. Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever. Am J Reprod Immunol  1992; 28: 245– 6. Google Scholar CrossRef Search ADS PubMed  13 Yazicioglu A, Turgal M, Yucel O, Ozyuncu O, Beksac M. Pregnancy outcome in women with familial Mediterranean fever: A retrospective analysis of 50 cases with a 10-year experience. Arch Rheumatol  2014; 29: 94– 8. Google Scholar CrossRef Search ADS   14 Yasar O, Iskender C, Kaymak O et al.   Retrospective evaluation of pregnancy outcomes in women with familial Mediterranean fever. J Matern Fetal Neonatal Med  2014; 27: 733– 6. Google Scholar CrossRef Search ADS PubMed  15 Mijatovic V, Hompes PG, Wouters MG. Familial Mediterranean fever and its implications for fertility and pregnancy. Eur J Obstet Gynecol Reprod Biol  2003; 108: 171– 6. PubMed PMID: 12781406. Google Scholar CrossRef Search ADS PubMed  16 Ofir D, Levy A, Wiznitzer A, Mazor M, Sheiner E. Familial Mediterranean fever during pregnancy: an independent risk factor for preterm delivery. Eur J Obstet Gynecol Reprod Biol  2008; 141: 115– 8. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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RheumatologyOxford University Press

Published: Feb 1, 2018

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