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Teruel C, López-San Román A, Bermejo F, et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines. Am J Gastroenterol. 2010;105:2003-2008.

It is not known whether thiopurine exposure in men leads to decreased fertility and/or adverse pregnancy outcomes. Only a few small reports have investigated this issue. Teruel et al tackled this important question by retrospectively interviewing consecutive men about the outcome of pregnancies they fathered in seven inflammatory bowel disease (IBD) centers throughout Madrid, Spain, between May, 2007 and December, 2008. These men were asked to respond to a structured questionnaire, and any remaining clinical questions were answered by chart review. Pregnancies where the mother was exposed to immunomodulators and those who terminated electively for reasons other than severe malformation or disease of the fetus were excluded. Pregnancies in the “thiopurine-exposed” group included those whose father was exposed to thiopurines either at the time or within 3 months of conception. All other men were considered “nonexposed” controls. Time needed to conceive was recorded, and any attempt for more than 1 year was defined as fertility impairment. Pregnancies were considered successful if the result was the delivery of a living child, and in this scenario, birth weight, period of gestation, and presence of any congenital malformations or infant neoplasms were also recorded. In a case with any negative outcome, i.e., unsuccessful pregnancy, low birth weight (<2500 g), preterm labor (gestation between 20 and 37 weeks), congenital malformations, or infant neoplasm, interviews were conducted to determine whether the issue was considered “maternal,” “paternal,” or “both.” Data analyzed included frequencies of fertility impairment or any of the negative outcomes. Smoking status was obtained from the questionnaire, whereas disease activity was determined by chart review.

A total of 46 pregnancies fathered by thiopurine-exposed men (20% on 6-mercaptopurine [6-MP]; the rest, azathioprine) with a median exposure time of 35 months before conception and 84 pregnancies in the unexposed-control group were analyzed for fertility and pregnancy outcomes. Men and women in the exposed group were slightly older (mean age: 34.2 versus 32.7 years for men; 32.7 versus 31.2 for women). A higher proportion of thiopurine-exposed men had Crohn's disease (82.6% versus 53.6%), were taking concurrent biologic therapy (five in the exposed group; none in control), and had moderate disease (18% versus 12% in the 36 patients whose disease activity was obtained). Also, in the exposed group, men had longer duration of disease until conception (8 versus 5 years). On the other hand, fewer of the exposed patients were on mesalamine, sulfasalazine, or steroids. Lastly, the proportion of smokers was not statistically different between the two groups.

It was found that even though the rate of fertility impairment was higher (odds ratio [OR] 1.92, 95% confidence interval [CI]: 0.54–6.88) and the time to conception was longer in the exposed group, neither difference was statistically significant, and in the five cases of impaired fertility where parental investigation had been performed, none of the cases in the exposed group was attributed to an issue with the father. In addition, there was no difference in unsuccessful pregnancy rates (OR 0.79, 95% CI: 0.22–2.85), and in the successful ones, there was no statistically significant difference in preterm labor (OR 1.3, 95% CI: 0.22–7.61) or low birth weight (OR 1.06, 95% CI: 0.25–4.54) despite a mild trend for higher frequencies of both in the exposed group. However, the mean birth weight was significantly lower in the exposed group (3063 versus 3248 g). There was no difference in congenital malformations between the two groups (OR 0.82, 95% CI: 0.08–9) and no infant neoplasm was noted in either group. The authors then performed a logistic regression analysis with data regarding fertility impairment and unsuccessful pregnancies (frequencies of the other endpoints were too small) using as covariates tobacco exposure and other factors that were unequally distributed (paternal age, mesalamine use, sulfasalazine use). Information on disease activity was too sparse to be included as a variable. Multivariate analyses for both unsuccessful pregnancy and fertility impairment yielded no statistical significant differences in either outcome between the two groups. The authors conclude that there is no demonstrable adverse effect on fertility or pregnancy outcomes from paternal exposure to thiopurines within 3 months of conception.

COMMENT

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  3. REFERENCES

Given the effect of thiopurine on DNA synthesis, there has been a long-standing concern regarding potential negative effects of thiopurines on fertility and pregnancy outcomes. Although not plentiful, there is a small body of data on outcomes when mothers are exposed to thiopurines during pregnancy. The latest report with the largest cohort of women exposed to thiopurines demonstrated no increased risk of infertility, interrupted pregnancies, or congenital abnormalities.1 Likewise, an older report from 2004 demonstrated no increase in adverse pregnancy outcomes in 101 women exposed to thiopurines.2 However, there are some reports of increased risk of congenital malformations, perinatal mortality, preterm labor, and/or low birth weight.3–6 Similar data on pregnancy outcomes where fathers are exposed are even more scarce. Some small reports have suggested changes in fertility7 or increased rates of congenital abnormalities,8, 9 while others demonstrated the absence of a negative outcome.10, 11

Although still a small set of patients, this report by Teruel et al contains the largest (46 pregnancies) thus far of any investigation of fertility and fetal outcomes in pregnancies fathered by males exposed to thiopurines. The authors were careful to account for smoking, which is known to cause changes in fertility as well as pregnancy outcomes, in their multivariate analysis. They also followed the offspring in both groups for long periods of time (>3 years), although observation of children in the exposed group was shorter than those in the control group (median length of time: 42 versus 108 months). However, one weakness of this study is the lack of disease activity data in most participants and the higher disease activity in the exposed group (suggested by the need for thiopurines and even biologic therapy in some and higher acuity of disease in those whose disease activity was able to be assessed). In fact, the limited information on clinical activity was not adequate to include it as a variable in the multivariate analysis. Despite these deficiencies and a hint of more severe disease in the exposed group, there were no statistically significant differences in rates of fertility or any of the negative pregnancy outcomes. However, given this study was not powered to detect modest differences, interpretation has to be made carefully.

What appears consistent between this study and some previous reports on pregnancy outcomes when mothers are exposed to thiopurines4, 5 is a lower mean birth weight and/or a trend for increased rates of lower birth weights. However, in this study (and perhaps also in others), it is not possible to make a causal link between this outcome and parental exposure to thiopurines given there were more patients with Crohn's disease and disease activity appeared to be more severe in the thiopurine-exposed patient group. Since Crohn's disease and IBD disease activity, at least in the mother, have been shown in some, but not all, studies to be associated with premature delivery and low birth weight,12, 13 IBD subtype and disease severity may be confounders for low birth weight.

In summary, given data from this study, there is no clear sign that thiopurine use in men leads to fertility impairment or negative pregnancy outcomes, although the study was underpowered to detect modest associations. These findings agree with previous statements that there are no firm data to base recommendations to withhold thiopurine use in males planning to have children.10

REFERENCES

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  2. COMMENT
  3. REFERENCES
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    Norgard B, Pedersen L, Christensen LA, et al. Therapeutic drug use in women with Crohn's disease and birth outcomes: a Danish nationwide cohort study. Am J Gastroenterol. 2007; 102: 14061413.
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    Ligumsky M, Badaan S, Lewis H, et al. Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol. 2005; 40: 444449.
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    Norgard B, Pedersen L, Jacobsen J, et al. The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception. Aliment Pharmacol Ther. 2004; 19: 679685.
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    Fedorkow DM, Persaud D, Nimrod CA. Inflammatory bowel disease: a controlled study of late pregnancy outcome. Am J Obstet Gynecol. 1989; 160: 9981001.
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    Dominitz JA, Young JC, Boyko EJ. Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study. Am J Gastroenterol. 2002; 97: 641648.
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