Session Information
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose:
There is limited evidence relating to the impact of disease modifying anti-rheumatic drugs (DMARDs) upon male fertility and on pregnancies conceived by men with rheumatic disease. Safety concerns of reduced fertility and increased risk of adverse pregnancy outcomes frequently limits the prescription of these drugs in men wishing to conceive. These concerns however, arise based mainly from animal or in vitro experimental data and should be weighed against the beneficial effects of DMARD treatment in controlling active inflammatory disease that itself increases the chance of conception. Given that human in-vivo data pertaining to fertility and peri-conception safety is limited we conducted a systematic review of available evidence to update information on this subject and guide counselling in this situation.
Methods:
A systematic search of PubMed and Embase was carried out in September 2016 to find relevant peer-reviewed papers, using keywords for fertility / spermatogenesis / conception, men, and disease modifying or biologic drugs commonly prescribed in patients with rheumatic disease. Exclusion criteria included review articles, abstracts, animal and in-vitro studies, studies of cancer chemotherapy or pre/peri-pubertal exposure only, and non-English language papers. The search yielded 644 papers, and the titles/abstracts were screened independently by MM and JF, duplicates removed and 174 potentially relevant papers selected for full text review.
Results:
A total of 74 papers were included in the final analysis. Papers included 19 case reports, 15 case series, 2 mechanistic studies, 36 cohort studies, 1 RCT and 1 meta-analysis and covered the impact on fertility of over 553 male exposures to relevant drugs, and over 948 pregnancies conceived during paternal exposure to these drugs. Only 26 papers had a comparator group. Results for the individual drugs are shown in table 1. Overall there was no firm evidence of harm to fertility or pregnancy outcomes with paternal exposure to anti TNF, azathioprine, cyclosporine A, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil or rituximab. The quality of evidence for all drugs (using the GRADE approach) is ‘low’ or ‘very low’. There was no evidence found pertaining to the effects of male exposure to IVIG, tacrolimus, golimumab or abatacept on fertility or pregnancy outcomes. Many papers noted a correlation between active inflammatory disease and poor sperm quality, with seminal parameters improving when disease was well controlled.
Conclusion:
These results present provide further reassurance as to the safety of DMARDs, in particular methotrexate, for men trying to conceive and will be useful when counselling men about risks of anti-rheumatic drugs to fertility and pregnancies, and following accidental conception.
Table 1: Results of Systematic Study of Paternal Exposure in men trying to conceive.
|
Drug |
No. studies of fertility / conception (total male exposures) |
No. studies of pregnancy outcomes (total pregnancies exposed) |
Outcome / conclusions |
|
Anti-TNF: adalimumab |
6 (30) |
2 (>6) |
Improved control of inflammatory disease with anti-TNF therapy was generally associated with improved semen parameters. There were 2 case reports noting a co-incident decrease in sperm quality with anti-TNF therapy, and 2 small studies (total 13 exposures) suggesting a possible non-significant link between infliximab and reduced sperm motility or abnormal morphology, but there were multiple confounding factors and limitations to these studies. These papers were all too small to draw firm conclusions about safety in pregnancy, but none reported rates of adverse pregnancy outcomes that were significantly higher than would be expected. |
|
Anti TNF: certolizumab |
0 |
2 (>33) |
|
|
Anti TNF: etanercept |
5 (9) |
4 (>45) |
|
|
Anti TNF: infliximab |
6 (78) |
8 (>39) |
|
|
Anti TNF: combined (Wallenius 2015) |
|
1 (110) |
|
|
Azathioprine |
7 (>28) |
7 (>331) |
The majority of papers were reassuring about the effect of azathioprine on semen parameters. The majority of papers do not raise a concern regarding pregnancy outcomes; only 1 paper reported a slightly higher malformation rate in exposed vs unexposed pregnancies. However, even in this paper, none of the 19 exposures that had occurred within 3 months of conception resulted in a malformation. |
|
Cyclophosphamide |
10 (>103) |
2 (>15) |
Universal reporting of reduced sperm counts and fertility which improves on stopping cyclophosphamide in most cases. Pregnancy data is inconclusive with only one paper reporting 5 positive conceptions, 7 pregnancy losses and 2 live births, but this was a survey and likely susceptible to selection and recall bias. |
|
Cyclosporin A |
2 (>2) |
1 (1) |
The very limited available evidence did not suggest an effect of Cyclosporin A on fertility. There was only a case report of one successful pregnancy and birth. |
|
Hydroxychloroquine (HCQ) |
1 (1) |
1 (12) |
There was only one case report of the effect of HCQ on fertility, with multiple confounders. A national registry cohort study reported malformations in 1/12 babies with paternal exposure to HCQ <3 months prior to conception, lower that the western population malformation rate of 2-4%. |
|
Leflunomide |
|
2 (2) |
In one case report the father was on leflunomide for 6 months prior to conception and during the pregnancy with no barrier protection used. One healthy baby was born. The second report was inconclusive. |
|
Methotrexate (MTX) |
7 (48) |
12 (302) |
Aside from 2 case reports of oligospermia, the other 5 larger studies concluded that there was no impact of MTX on fertility. There is also now a reasonable body of reassuring evidence relating to paternal MTX exposure: only one small cohort study reported a major malformation amongst the 3 paternal exposures to MTX, whereas the other 11 papers (299 exposures) reported no link with adverse pregnancy outcomes or congenital malformations. |
|
Mycophenolate mofetil (MMF) |
1 (4) |
0 |
There was only one cohort study of men with SLE, including 4 MMF exposures. This suggested a link between impaired fertility and active SLE, but not MMF exposure. |
|
Rituximab |
0 |
1 (11) |
Pregnancy outcome data is limited but reassuring: Of the 11 reported exposures (2 weeks-1year prior to conception), there were 2 miscarriages, 7 live births and 2 ongoing pregnancies at the time of publication. |
|
Sulfasalazine |
29 (250) |
9 (>151) |
The vast majority of data comes from inflammatory bowel disease patients. Almost all studies noted poor sperm parameters in patients treated with sulfasalazine, but in most cases these resolved on stopping treatment. It must also be noted that infertility is not universal and most papers reported no adverse pregnancy outcomes attributed to sulfasalazine exposure. |
To cite this abstract in AMA style:
Flint JD, Mouyis M, Giles I. A Systematic Review of the Impact of Anti-Rheumatic Drugs upon Male Fertility and Paternal Exposure Peri-Conception [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-systematic-review-of-the-impact-of-anti-rheumatic-drugs-upon-male-fertility-and-paternal-exposure-peri-conception/. Accessed .« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-systematic-review-of-the-impact-of-anti-rheumatic-drugs-upon-male-fertility-and-paternal-exposure-peri-conception/