Colchicine in pregnancy

Overview

It is very important for all patients with FMF to take colchicine regularly at all times. This treatment:

• controls auto-inflammation very effectively
• prevents development of amyloidosis

Most FMF patients are diagnosed in childhood or young adulthood.

Many patients are concerned about the effect on child-bearing potential both of FMF itself and of FMF treatment.

Some women with FMF enjoy a period free from attacks while pregnant. Others actually experience severe attacks during pregnancy that are worse than their usual attacks. These attacks may endanger the pregnancy itself, by causing miscarriage, if the FMF is not treated.

Colchicine use during the reproductive years has been studied extensively, and the results of all studies are clear:

• Colchicine is safe in pregnancy and breastfeeding.
  

• Colchicine has no effect on fertility in women or in men.

• Women should continue taking colchicine regularly, in the dose prescribed throughout the period when they are trying to conceive, and throughout pregnancy and breastfeeding.

• Men who are trying to conceive should continue taking colchicine regularly, in the dose prescribed.

 

 

In contrast, untreated FMF has been associated with:

• increased risk of miscarriage and infertility in women
• impaired functioning of the testicles, which may affect sperm production
• increased risk of premature birth and low weight babies

The chances of successful pregnancy outcome are actually better in patients who are careful to take their colchicine.

For many patients this information provides sufficient reassurance.

For those who wish to understand more, the evidence on which this advice is based is summarised below:

Review of the medical literature on colchicine in pregnancy

Colchicine has been used as standard treatment for FMF since 1972. Since then, 40 years have passed and hundreds of pregnant women with FMF have taken colchicine throughout pregnancy and given birth to healthy children. Several major research studies on colchicine in pregnancy have been  published during this period of time.  The results of these studies are extremely reassuring for women with FMF and are summarised below.

This comprehensive review of the medical literature is up to date as of December 2012:

Fertility and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy.
Ehrenfeld M et al. Br J Obstet Gynaecol. 1987 Dec;94(12):1186-91
Researchers in Israel examined the obstetric course of 36 women with FMF. All women received long term colchicine for between 3 and 12 years. Rates of miscarriage and infertility were similar to those seen in women with FMF before colchicine treatment was standard. All the 16 babies born to mothers who took colchicine throughout pregnancy were healthy. The authors concluded:

• “it is not advised that colchicine be discontinued before a planned pregnancy”

Colchicine Prophylaxis in Familial Mediterranean fever: reappraisal after 15 years
Ben-Chetrit E and Levy M. Semin Arthritis Rheum. 1991 Feb;20(4):241-6.
Researchers in Israel reviewed the course of 45 patients treated with colchicine for FMF over a period of over 15 years. Patients were seen at regular 6 month intervals at the FMF clinic. There were 23 men and 22 women. FMF started between ages 2 to 35 years (mean age 11). Length of illness ranged from 16 to 52 years (mean 29). The age at which colchicine was started ranged from 4 to 51 years (mean 24).  All patients received colchicine for 15 – 18 years.
Eleven women took colchicine during pregnancy and delivered 15 normal babies at term.
The authors stated:

• “Our experience showed no direct adverse reaction of colchicine on female fertility and pregnancy”
• “we do not recommend discontinuation of colchicine before or during pregnancy”
• “ colchicine in vivo probably does not affect sperm motility”

Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever
Rabinovitch O et al. Am J Reprod Immunol. 1992 Oct-Dec;28(3-4):245-6.
Researchers in Israel studied 225 completed pregnancies in 116 women with FMF. Patients taking colchicine (131 of the pregnancies) were compared with untreated patients. Colchicine treatment before and during pregnancy was not associated with increased frequency of abnormalities in the babies. Long term follow up (6-10 years) of these children showed completely normal growth and development. The authors concluded:

• “Colchicine treatment does not apparently harm mother or child”

Familial Mediterranean fever in the col­chicine era: the fate of one family
Zemer D et al.  Am J Med Genet 1993;45:340-4.
This paper was by researchers in Israel who had followed more than 2000 patients over 25 years, spanning the pre-colchicine and the beginning of the colchicine era. They described the fate of one family of Sephardi-Jewish Israelis from Tunisia, which illustrated the common outcomes of FMF before colchicine treatment was standard.
Out of 9 children, 5 were diagnosed with FMF in childhood, before colchicine was introduced.

• One of the three sisters already had amyloidosis in her kidneys at age 17 when she was first offered colchicine treatment in 1974. She did not take the colchicine regularly, and stopped taking it completely when she became pregnant. She had a healthy baby but developed kidney failure and died 3 years later, aged 25.
• Another sister started colchicine in 1974 at age 24, when she too already had amyloidosis in her kidneys. She stopped colchicine 2 years later when she became pregnant, and had a miscarriage. She had 2 healthy babies after this, despite stopping colchicine during pregnancy. She continued taking colchicine regularly after that and her kidney failure remained stable.
• The third sister started taking colchicine regularly at age 10, in 1974. She had 4 healthy children and took colchicine regularly including throughout the pregnancies. She had no FMF attacks since colchicine was started, and her kidney function remained normal.
• The authors concluded that the third sister represented the ideally treated FMF patient.

Familial Mediterranean fever and its implications for fertility and pregnancy
Mijatovic Vet al. Eur J Obstet Gynecol Reprod Biol. 2003 Jun 10;108(2):171-6.
Researchers in the Netherlands reviewed the implications of FMF for fertility and pregnancy. They discussed the reasons why untreated FMF could lead to problems with fertility in both men and women. They reviewed the results of the studies mentioned above, which showed that colchicine does not affect fertility and is safe in pregnancy in FMF. They also mentioned a study of patients who took long-term colchicine for gout, all of whom had healthy babies while on treatment. The authors concluded:

• “it is advocated to continue colchicine treatment in FMF patients at conception and throughout pregnancy”

Reproductive system in familial Mediterranean fever: an overview
Ben-Chetrit E. and Levy M. Ann Rheum Dis. 2003 October; 62(10): 916–919.
Researchers in Israel reviewed the available knowledge of the effects of FMF on reproduction. They discussed the reasons why untreated FMF could lead to problems with fertility in both men and women. They mentioned the risks associated with FMF attacks during pregnancy: During FMF attacks there is pain and inflammation inside the abdomen which may lead to early contractions of the uterus and miscarriage. Some women require a higher dose of colchicine than usual in order to control attacks during pregnancy. The authors concluded that:

• “colchicine treatment improved female fertility and pregnancy outcome in FMF”
•  “breast feeding while taking colchicine is quite safe  (despite the fact that pharmaceutical company leaflets may recommend against it)”

Safety of colchicine therapy during pregnancy
Ong M et al. Can Fam Physician. 2003 August; 49: 967–969.
This review by Canadian physicians summarises the findings from the studies discussed above. The authors concluded that:

• “current evidence supports the safety of colchicine use throughout pregnancy at recommended doses”
• “discontinuing the drug during pregnancy might be detrimental for a woman with FMF”

Familial Mediterranean fever during pregnancy: an independent risk factor for preterm delivery
Ofir D et al. Eur J Obstet Gynecol Reprod Biol. 2008 Dec;141(2):115-8. Epub 2008 Sep 3.
Researchers in Israel compared all pregnancies of women with and without FMF between 1988-2006. There were 175,572 deliveries, including 239 in patients with FMF. The women with FMF were slightly more likely to give birth prematurely, to require fertility treatments, and to suffer recurrent miscarriages.

However there were no differences between the health of the babies born to women with FMF and those born to other women.
It is important to note that this study was not designed to assess the safety of colchicine, so the women with FMF were assessed altogether. Some took colchicine during pregnancy and others did not. However, they were not compared on the basis of whether or not they took colchicine during pregnancy.  It was therefore unclear whether the FMF itself or the colchicine caused the differences between the women with FMF and those without.
The authors concluded that:

• “FMF increases the risk of pre-term delivery”
• “health outcomes for babies born to mothers with FMF are comparable to the general population”

Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified?
Ben-Chetrit E. et al. Arthritis Care Res (Hoboken). 2010 Feb;62(2):143-8.
Researchers in Israel compared the outcome of 179 pregnancies in 61 women taking colchicine for FMF with 197 pregnancies in 49 women with FMF who did not take colchicine and 312 pregnancies in 84 healthy women who were not taking medication. The number of miscarriages was slightly higher in the pregnancies where women with FMF did not take colchicine. This difference was not statistically significant. Apart from this there were no differences in pregnancy outcomes between the 3 groups.

The authors stated that prior to this study they recommended amniocentesis to all women taking colchicine. This was because of legal issues connected to the pharmaceutical company warnings, and because of results from animal studies where a much higher dose of colchicine was used than is ever given to humans.
They noted that in Turkey, where FMF is quite common, physicians do not recommend amniocentesis to patients on colchicine.
As a result of the good outcomes of this large number of pregnancies with colchicine, the authors concluded that:

• “treatment with colchicine during pregnancy in patients with FMF is beneficial in controlling the disease while not affecting the pregnancy outcome”
• “there is no justification for recommending amniocentesis in women taking colchicine solely because of this treatment”

Pregnancy outcome after in utero exposure to colchicine
Diav-Citrin O et al. Am J Obstet Gynecol. 2010 Aug;203(2):144.e1-6. Epub 2010 Jul 1.
Researchers in the Israeli Teratology Information Service, together with other doctors at University hospitals in Israel followed the course of 238 pregnancies in women taking colchicine, from 1994-2006. Most women (87%) were taking colchicine as treatment for FMF. Some were taking it for other reasons such as a disease called Behcet disease. They compared the outcomes with 964 pregnancies in the same time period in women who were not taking medications.

Major birth defects and genetic abnormalities occurred with the same frequency in the babies whose mothers took colchicine as in those whose mothers took no medication.
Pre-term and early births were slightly more common in the colchicine group, and their babies had slightly lower birth weights.
Most of the mothers in the colchicine group breast-fed their babies while taking the medication (111 out of 181- 61.3%). No colchicine-related side effects were reported in these babies.
The authors concluded that:

• “ this study supports the safety of colchicine use in pregnant women and does not imply an increase in genetic risk”

The impact of familial Mediterranean fever on women’s health
Dotters-Katz S et al. Obstet Gynecol Surv. 2012 Jun;67(6):357-6.
This review article by physicians in the US evaluated the findings of all the studies mentioned here. The authors concluded that:

• “colchicine treatment in pregnancy reduces the frequency and severity of attacks of FMF and leads to improved pregnancy outcomes”
• “based on the outcomes of the large study above (Diav-Citrin et al 2010), amniocentesis is not presently recommended on the basis of colchicine exposure”

Pregnancy outcome in women with familial Mediterranean fever
Nabil H et al. J Obstet Gynaecol. 2012 Nov;32(8):756-9.
Researchers in Turkey studied 74 infertile women with FMF. Several had other conditions apart from FMF which may have contributed to fertility problems. Most of the patients were taking colchicine. 26 of the patients became pregnant, and pregnancy outcomes were similar to those expected in the general population. The authors concluded that:

• “favourable pregnancy outcome occurs in patients with FMF treated with colchicine before and after pregnancy”