Does paternal use of azathioprine pose a risk of teratogenicity?

Fråga: Does paternal use of azathioprine pose a risk of teratogenicity? Is there any reason to discourage family building during azathioprine therapy? If so, how long should one wait after treatment?

Sammanfattning: The limited published data in human do not indicate an increased risk for infertility or for infants with congenital abnormalities after paternal exposure to thiopurines. Waiting at least 6 months after exposure to thiopurines is necessary to allow for recovery and production of new sperm that have not been exposed to the drug. However, the decision to discontinue therapy prior to attempting conception must be weighed against the absence of data confirming a teratogenic effect of these drugs, as well as against the risks of withdrawing therapy on the patient´s underlying chronic disease. High-resolution ultrasound during pregnancy could be offered to confirm normal development of the fetus.

Svar: This question has been dealt in previous Drugline documents (1,2).

Drug treatment of the male prior to conception could affect the outcome of subsequent progeny either through drug induced defect in the spermatozoon itself, such as an effect on the DNA or chromosomal proteins (mutagenic) or due to an effect caused by the presence of the drug in the seminal fluid (teratogenic)(3).

Azathioprine and its active metabolite, 6-mercaptopurine (6-MP) are immune-modulatory drugs that are widely used in organ transplantation and in the management of autoimmune diseases like pemphigus. 6-MP goes into the tissues and is metabolized further to inactive methylated metabolites and to 6-thioguanine nucleotides (6-TGN) which incorporated into DNA. Azathioprine itself disappears from the blood after a few minutes. 6-MPs elimination half-life is 30 minutes to 4 hours. Methylated metabolites of 6-MP and TGN has a much longer half-lives of approximately 5 days and can be detected for weeks after the treatment (4,5). The onset of action for azathioprine and 6-mercaptopurine is slow, about 4-6 months, and the steady state is reached after 4 month.

These drugs are purine analogs that inhibit purine metabolism and they are therefore considered to have mutagenic potentials.

The concerns is based on data from animal model as 6-MP has been shown to cause chromosomal damage and aberrations in the spermatocytes of male mice (6) and data from two retrospective cohort studies reported an increased risk of congenital abnormalities after paternal use of azathioprine (7,8). The conclusions were based on observation of congenital abnormalities which were found in 30% (4/13) and 9% (4/45) of exposed group compared by 0/90 and 4% (2334/57195) in control group respectively. The authors of the first study recommended discontinuation of therapy 3 months before conception based on the probable turn over time for spermatozoas. The second study suggest even more long term teratogenic potential of azathioprine as the time interval between the father´s last prescription for azathioprine and the time of conception was 938 months.

However, the fact that the exposed group in the first study consisted of only 13 pregnancies and the rate of adverse outcome among the control pregnancies is considerably less than would be expected in the general population, and the fact that the conclusion of the second study has been based on indirect items; prescribtion records and birth registry which is less accurate approximiation of reality than a direct analysis of the target population, the results of both studies should be interpreted with caution.

On the other hand, other authors have not observed negative outcomes of pregnancies fathered by males exposed to thiopurines and therefore do not recommend interrupting thiopurines therapy routinely in males attempting conception. These studies were well controlled and of better methodological designs than the previously mentioned studies.

A retrospective cohort study in 37 pregnancies that were paternally exposed to thiopurines at the moment of conception did not detect negative outcomes with respect to spontaneous abortions or major malformations (9). One more retrospective study included 46 conceptions fathered by thiopurines-exposed males for IBD was unable to detect a higher proportion of adverse gestational outcomes; unsuccessful pregnancies, premature births, low birth weight or congenital malformations in exposed pregnancies, as compared with IBD non-exposed ones (10). There is one prospective study recently published where the authors saw no need for termination of a pregnancy only because of paternal treatment with thiopurines and no need for delaying in family planning in case of inevitable paternal therapy(11). The study observed a higher overall rate of all birth defects in the exposed group 11% (11/100) compared to the controls 7.7% (25/323) but this finding was considered to be non significant. The rate of major birth defects in the exposed group 3% (3/100) versus 2.2% (7/320) was not significantly increased and complies with the prevalence rates observed in the general population(2%-3%). No chromosomal or genetic abnormalities were observed among the exposed infants/fetuses.

Furthermore, male fertility was investigated in 23 patients with IBD during azathioprine treatment. Semen analyses showed no negative association between azathioprine therapy and semen quality. During the study period, 6 patients receiving azathioprine fathered 7 healthy children. No fetal abnormalities were found at delivery (12).

Generally, when there are concerns of spermatoxicity of a certain drug, men are advised to discontinue the drug for at least three months prior to pursuing pregnancy, to allow for recovery of spermatogenesis and to avoid any potential teratogenicity. This time has to be prolonged in case of thiopurines to allow for the elimination of 6-MR which has very long half life.