Colchicine Use During Breastfeeding

Abstract

Objective:

This study evaluated the outcome of infants exposed to colchicine during lactation.

Subjects and Methods:

A prospective observational cohort study design was used. Mothers who contacted Beilinson Teratology Information Service (BELTIS) regarding use of colchicine while breastfeeding were followed up by phone interview. Data on lactation, neonatal symptoms, and outcome 1–3 years after initial consultation were obtained. Mothers breastfeeding while taking colchicine (n=37) and their infants (n=38) were compared with a matched control group of mothers using a drug known to be safe during lactation (n=75) and their infants (n=76).

Results:

Follow-up was obtained for 59 of 76 (78%) women who contacted BELTIS regarding use of colchicine. Of the 59 women, 37 breastfed while taking colchicine, five did not take colchicine, 16 did not breastfeed, and one declined to participate. The mean duration of breastfeeding was similar in both groups. Adverse neonatal symptoms were seen in three of 38 colchicine-exposed infants versus four of 76 of control group infants (p=0.68). Delayed development or neurological abnormalities were seen in two infants in both study groups (p=0.60). None of the colchicine-exposed infants showed abnormal growth.

Conclusions:

No increase in adverse long-term outcomes was found in colchicine-exposed breastfed infants. Our data support continuation of breastfeeding in women treated with colchicine.

Introduction

Colchicine is a well-known drug that in the past was used primarily to relieve pain associated with gout.¹ Colchicine may be used to treat Behçet's syndrome or scleroderma but, since 1972, has mainly been used for treatment of familial Mediterranean fever (FMF), for which the drug is considered the treatment of choice.¹

FMF, a hereditary inflammatory disorder common in the Mediterranean population, is characterized by recurrent febrile polyserositis attacks, most commonly resulting in abdominal pain and fever.¹ Colchicine can control the acute attacks associated with FMF and prevent the development of amyloidosis, which is the major disease complication.¹ FMF requires lifelong treatment to control symptoms and to prevent development of amyloidosis. In the past, women with FMF were counseled against taking colchicine while nursing.^2,3 As a result of discontinuation of the drug, the patients commonly had disease exacerbation.⁴ To prevent severe symptom aggravation, women with FMF need to continue colchicine treatment during pregnancy and after delivery.

As there are limited data on the effect of colchicine on breastfed infants, the aim of the present study was to evaluate the outcome of infants exposed to colchicine during breastfeeding.

Subjects and Methods

A prospective observational cohort study design^5,6 was used to assess the safety of colchicine use during lactation. Data were obtained from the Beilinson Teratology Information Service (BELTIS), which is a free public service for questions related to the effects of drugs during pregnancy and lactation. Mothers who sought information regarding use of colchicine during lactation during the period January 2008–March 2012 were eligible to participate in the study. During the initial query to BELTIS, information was obtained using a standard questionnaire. Items covered included maternal age, parity, number of gestations, smoking habits, alcohol or drug use, use of medications, gestational age, infant's gender, weight, length, and head circumference at birth, examination at birth, complications at birth, and data regarding breastfeeding. During the initial call the mothers were told that information regarding colchicine and breastfeeding was limited but, however, that the existing data supported infant safety during lactation. Safety during lactation was based on the absence of reported side effects^1,4,7–9 and in accordance with the recommendation of the American Academy of Pediatrics that classifies colchicine as compatible with breastfeeding.¹⁰

All queries were regularly followed up after obtaining maternal consent during the initial phone call. The follow-up telephone interview was performed 6–48 months after the initial query using a structured questionnaire focusing on possible adverse effects to the mothers and their infants. Data regarding duration of breastfeeding, drug dose, infant growth, and development were recorded. Growth of children was followed by comparing growth percentiles of length, weight, and head circumference. Data on development were based on maternal assessment, on any abnormalities noted on routine pediatric visits, and on achievement of basic developmental milestones such as age at which walking started. Specific data related to possible gastrointestinal side effects and infant irritability were also recorded. The study group was composed of breastfeeding mothers taking colchicine (37 mothers) and their infants (n=38) and was compared with a control group of breastfeeding mothers (75 mothers) who contacted BELTIS regarding use of a medication known to be safe for use during lactation (amoxicillin) and their infants (n=76). The control group mothers when contacting BELTIS were unaware that amoxicillin was safe for use during lactation. The control group was matched to the study group for year of birth (±1 year), gestational age (±2 weeks), and maternal age (±2 years). The control group was followed up similarly to the study group. The study was approved by the Rabin Medical Center Research Ethics Board.

Statistical analysis

Continuous variables were compared by group using analysis of variance with Bonferroni's correction for multiple comparisons. Data that did not have Gaussian distributions were compared using the Mann–Whitney U test. Discrete variables were compared, by group, using Pearson's chi-squared test or Fisher's exact test, as appropriate. A value of p≤0.05 was considered statistically significant. The data were analyzed using BMDP statistical software (1993; Chief Editor, W.J. Dixon; University of California Press, Los Angeles, CA).

Results

During the study period, 76 women contacted BELTIS regarding use of colchicine during lactation. Follow-up was obtained for 59 of 76 women (78%). Of the 59 mothers, 37 breastfed while taking colchicine, five did not take colchicine, 16 did not breastfeed, and one woman refused to participate. The 38 infants (one set of twins) exposed to colchicine during breastfeeding and their mothers were compared with a control group of 76 breastfed infants (one set of twins) and their mothers.

The study and control groups are described in Table 1. Maternal age and gestational age at birth of both study groups were similar. The colchicine-exposed infants compared with the control infants were of a lower birth weight (2,944±483 g versus 3,188±458 g; p=0.01) but did not differ significantly in birth head circumference percentile (46.2±15.9 versus 50.1±8.6; p=0.13). No infant in the colchicine-exposed group had a birth head circumference below the 3rd percentile for age.

Table 1.

Comparison of Maternal and Neonatal Characteristics of Colchicine-Exposed Versus Nonexposed Breastfed Infants

Characteristic	Colchicine-exposed breastfed infants (n=38)^a	Nonexposed breastfed infants (n=76)^b	p value
Maternal age (years)	30.1 (4.6)	30.7 (4.1)	0.48^c
Parity [n (SD)]	2.3 (1.2)	2.1 (1.1)	0.27^d
Alcohol use during pregnancy	0 (0%)	0 (0%)	1.00^e
Tobacco smoking during pregnancy	4 (10.5%)	1 (1.3%)	0.04^e
Daily colchicine dose (mg)	2.4 (0.8)	NA	NA
Additional drug use during lactation^f	8 (21%)	12 (16%)	0.60^e
Gestational age at birth (weeks)	39.1 (1.8)	39.2 (1.4)	0.75^c
Male gender	16 (42%)	39 (51%)	0.42^e
Birth weight (g)	2,944 (483)	3,188 (458)	0.01^c
Birth head circumference (percentile)	46.2 (15.9) (n=33)	50.0 (8.6) (n=62)	0.13^c

Data are mean (standard deviation) values, number (%), or number (standard deviation [SD]) as indicated.

n=38 unless otherwise specified.

n=76 unless otherwise specified.

Compared using analysis of variance.

Compared using the Mann–Whitney U test.

Compared using Fisher's exact test.

Drugs used other than colchicine or amoxicillin.

NA, not applicable.

Neonatal symptoms were seen in three of 38 colchicine-exposed infants (jaundice that delayed discharge, n=2; suspected seizures that were not confirmed under observation and with normal electroencephalography, n=1) versus four of 76 control group infants (jaundice that delayed discharge, n=4) (p=0.68).

Mean duration of follow-up for the colchicine versus the control group was 28.0±13.0 months versus 23.3±9.7 months (p=0.055), respectively. Infants were exclusively breastfed in 29 of 38 (76.3%) of the colchicine-exposed group versus 62 of 76 (81.6%) of the control group (p=0.15). The mean duration of breastfeeding in the colchicine-exposed group was 9.1±6.6 months (8.8±5.3 months for exclusively breastfed infants, 9.8±10.4 months for partially breastfed infants) and in the control group was 9.2±5.3 months (8.3±4.7 months for exclusively breastfed infants, 12.6±6.7 months for partially breastfed infants). Comparison of the duration of breastfeeding of the entire cohort of both groups did not show statistical significance (p=0.93).

Gastrointestinal symptoms are commonly noted in patients treated with colchicine; however, there were no cases in the colchicine-exposed infants versus two cases in the control infants (exacerbation of gastroesophageal reflux, n=1; fever, vomiting, and diarrhea, n=1) (p=0.29). Restlessness was noted in two control infants versus no colchicine-exposed infants.

Comparison of growth at follow-up showed no difference between colchicine-exposed and control children (Table 2). Developmental or neurological problems were identified at follow-up in two of 38 colchicine-exposed children versus two of 76 control group children (p=0.60). In the colchicine-exposed infants, one child had motor delay, and a second child had both motor and cognitive delay. In the control group one child had motor delay, and a second had both motor delay and hydrocephalus (identified at the age of 4 months).

Table 2.

Outcome of Infants Exposed to Colchicine During Breastfeeding Versus Control Infants

Outcome	Colchicine-exposed breastfed infants (n=38)^a	Nonexposed breastfed infants (n=76)^b	p value
Breastfeeding duration (months)	9.1 (6.6)	9.2 (5.3)	0.93^c
Exclusive breastfeeding	29 (76.3%)	62 (81.6%)	0.15^d
At follow-up (percentile)
Weight	38.3 (21.3) (n=37)	35.2 (29.6) (n=63)	0.58^c
Length	43.3 (20.7) (n=28)	37.8 (24.7) (n=50)	0.32^c
Head circumference	42.9 (20.4) (n=28)	37.6 (24.0) (n=50)	0.33^c
Any symptoms during breastfeeding	0 (0%)	4 (5.3%)	0.29^d
Gastrointestinal symptoms	0 (0%)	2 (2.6%)	0.55^d
Developmental/neurological problems	2 (5.3%)	2 (2.6%)	0.60^d

Data are mean (standard deviation) values or number (%) as indicated.

n=38 unless otherwise specified.

n=76 unless otherwise specified.

Compared using the Mann–Whitney U test.

Compared using Fisher's exact test.

Discussion

Data on safety of colchicine during breastfeeding are essential as discontinuation of treatment is likely to induce disease exacerbation. To date, safety of colchicine treatment during lactation has been based mainly on case series, and our study is the first designed specifically to assess long-term safety using a controlled observational design. The results of the present study provide evidence supporting the safety of colchicine use during breastfeeding.

Colchicine is an alkaloid that works by binding to tubulin and blocking its polymerization.⁷ This blockade causes metaphase arrest in cells undergoing mitosis. Colchicine weakly binds to proteins but is lipophilic enough to be excreted in breastmilk, with peak levels within 1–2 hours after administration.^2,4 The concentration of colchicine in breastmilk was found to be similar or higher than the serum concentration.^1,4,11 The relative infant dose is has been estimated as being less than 10%^1,3,4 but may be up to 31.5%.²

Data regarding safety of colchicine for the breastfed infants are scarce, based on two case reports,^3,11 a single case series on four patients,⁴ one personal experience in a review,¹ and a clinical note about 111 newborns in a prospective observational cohort study.⁸ In a review by Ben-Chetrit and Levy,¹ no clinical adverse effects were reported. In both case reports^3,11 and in the case series by Ben-Chitrit et al.,⁴ no adverse effects were noted in the nursing infants. Diav-Citrin et al.⁸ performed a cohort study evaluating the effect of colchicine exposure during pregnancy on the rate of major congenital malformations and cytogenetic anomalies. The study was performed by two teratology information centers in Israel between the years 1994 and 2006. One hundred eleven of 181 women (61.3%) breastfed while taking colchicine. Details of outcome following breastfeeding were not provided as routine follow-up was not performed; however, the authors commented that there were no known adverse effects in the breastfed infants.⁷

Colchicine-exposed infants were of a lower birth weight compared with control infants (2,944 g versus 3,188 g; p=0.011). This difference may be related to chronic maternal disease. However, as colchicine may cause gastrointestinal side effects that may influence maternal weight gain during pregnancy, a possible colchicine-related effect cannot be excluded. Decreased birth weight is known to be related to an increased risk of adverse developmental outcome.¹² However, head circumference is a stronger marker of developmental outcome, and there was no significant difference in this variable between colchicine-exposed and control infants. A difference in weight at birth between colchicine-exposed and control infants was not observed at the time of follow-up. Thus, this finding may be less important as it is only a transient phenomenon. Growth of children was followed by comparing length, weight, and head circumference percentiles and not absolute values because infants were followed up at different ages. No abnormal growth parameters were identified in colchicine-exposed infants.

No infant had any colchicine-related adverse effects during breastfeeding, including irritability or abdominal pain. Not one of the severe known side effects of colchicine, such as blood dyscrasias, bone marrow depression, or hepatomegaly, was noted, either in the mothers or in their children. Long-term follow-up showed no increased risk of developmental or neurological problems in colchicine-exposed breastfed infants.

Some study limitations should be acknowledged. Although the patients were prospectively followed, data were based on maternal report after a variable time period; thus recall bias was possible. All mothers were able to report if growth was within normal limits; however, not all recalled the precise growth percentile. Follow-up duration was variable, and a longer follow-up period may have resulted in additional findings. There was a trend toward difference in the mean duration of the follow-up period. As the follow-up period was longer in colchicine-exposed infants, this might have led to an underestimation of the risks of the comparison of children, but not of the exposed infants. The sample size was insufficient to identify uncommon side effects.

The present study did not identify any adverse effects in children exposed to colchicine via breastmilk. This is in concordance with the expected low relative infant exposure, with previous reports, and with the classification of colchicine as compatible with breastfeeding by the American Academy of Pediatrics.¹⁰ As discontinuation of colchicine is associated with maternal FMF exacerbation, breastfeeding without continued treatment with colchicine is inadvisable. Use of colchicine for indications other than maternal FMF is usually not required as alternative treatments are available.

To minimize infant exposure, it has been recommended that the breastfeeding mother wait 8 hours after taking colchicine before feeding the baby.^2,3 However, as maximal exposure is between 1 and 2 hours,² we do not support this recommendation and just follow the general rule recommending taking colchicine immediately after breastfeeding. Because blood dyscrasias are possible side effects of colchicine treatment, it seems prudent to perform a complete blood count after a period of breastfeeding; however, there is no clear recommendation regarding the timing.

In conclusion, the present study assessing infant exposure to colchicine during breastfeeding did not identify any adverse drug effects and supports the safety of breastfeeding while continuing maternal treatment with colchicine.

Footnotes

Disclosure Statement

No competing financial interests exist.

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