Birth Outcomes in Children Fathered by Men Treated with Anti-TNF-α Agents Before Conception

Larsen, Michael Due; Friedman, Sonia; Magnussen, Bjarne; Nørgård, Bente Mertz

doi:10.1038/ajg.2016.405

Cited by 35 publications

(35 citation statements)

References 28 publications

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“…In men with RMD who are planning to father a pregnancy, we strongly recommend continuation of HCQ, azathioprine, 6‐mercaptopurine, colchicine, and tumor necrosis factor inhibitors ( ).…”

Section: Results/recommendationsmentioning

confidence: 99%

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

Sammaritano

Bermas

Chakravarty

et al. 2020

Arthritis & Rheumatology

425

520

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Objective To develop an evidence‐based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD). Methods We conducted a systematic review of evidence relating to contraception, ART, fertility preservation, HRT, pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary. Results This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD, except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre‐pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy‐compatible medications, and ongoing physician‐patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD. Conclusion This guideline provides evidence‐based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low‐level data. We intend that this guideline be used to inform a shared decision‐making process between patients and their physicians on issues related to reproductive health that incorporates patients’ values, preferences, and comorbidities.

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“…In men with RMD who are planning to father a pregnancy, we strongly recommend continuation of HCQ, azathioprine, 6‐mercaptopurine, colchicine, and tumor necrosis factor inhibitors ( ).…”

Section: Results/recommendationsmentioning

confidence: 99%

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

Sammaritano

Bermas

Chakravarty

et al. 2020

Arthritis & Rheumatology

425

520

View full text Add to dashboard Cite

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“…Some of the included studies also presented results for exposure at any time before conception. Comparison between ‘exposure 3 months prior to conception’ and ‘exposure at any time before conception’ was possible in publications of the Danish registry data ( Larsen et al , 2016 ; Egeberg et al , 2017 ; Nørgaard and Andersen, 2019 ). See Supplementary Table S5 for outcomes after exposures any time before conception.…”

Section: Discussionmentioning

confidence: 99%

“…Eight small studies and one large population-based cohort were identified ( Lamboglia et al , 2009 ; Paschou et al , 2009 ; Saougou et al , 2013 ; Clowse et al , 2015 ; Larsen et al , 2016 ; Hoxha et al , 2017 ; Uyaroglu et al , 2017 ; Lichtenstein et al , 2018 ; Micu et al , 2019 ). In total, 61 males, 121 pregnancies and 372 children were included.…”

Section: Discussionmentioning

confidence: 99%

The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: a systematic review

Perez-Garcia

Dolhain

Vorstenbosch

et al. 2020

Human Reproduction Update

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BACKGROUND Information regarding the possible influence of immunosuppressive drugs on male sexual function and reproductive outcomes is scarce. Men diagnosed with immune-mediated diseases and a wish to become a father represent an important neglected population since they lack vital information to make balanced decisions about their treatment. OBJECTIVE AND RATIONALE The aim of this research was to systematically review the literature for the influence of paternal immunosuppressive drug use on many aspects of male sexual health, such as sexual function, fertility, pregnancy outcomes and offspring health outcomes. SEARCH METHODS A systematic literature search was performed in the bibliographic databases: Embase (via Elsevier embase.com), MEDLINE ALL via Ovid, Cochrane Central Register of Trials (via Wiley) and Web of Science Core Collection. Additionally, Google Scholar and the Clinical trial registries of Europe and the USA were searched. The databases were searched from inception until 31 August 2019. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes and offspring health with a list of immunosuppressive drugs. Studies were included if they were published in English and if they included original data on male human exposure to immunosuppressive drugs. A meta-analysis was not possible to perform due to the heterogeneity of the data. OUTCOMES A total of 5867 references were identified, amongst which we identified 161 articles fulfilling the eligibility criteria. Amongst these articles, 50 included pregnancy and offspring outcomes and 130 included sexual health outcomes. Except for large Scandinavian cohorts, most of the identified articles included a small number of participants. While a clear negative effect on sperm quality was evident for sulfasalazine and cyclophosphamide, a dubious effect was identified for colchicine, methotrexate and sirolimus. In three articles, exposure to tumour necrosis factor-α inhibitors in patients diagnosed with ankylosing spondylitis resulted in improved sperm quality. The information regarding pregnancy and offspring outcomes was scant but no large negative effect associated with paternal immunosuppressive drug exposure was reported. WIDER IMPLICATIONS Evidence regarding the safety of immunosuppressive drugs in men with a wish to become a father is inconclusive. The lack of standardisation on how to evaluate and report male sexual function, fertility and reproduction as study outcomes in men exposed to immunosuppressive drugs is an important contributor to this result. Future research on this topic is needed and should be preferably done using standardised methods.

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“…A total of 63/67 had no malformations or were described as 'healthy'. In addition, three cohort studies (7,22,23) reported 432 peri-conceptional paternal exposures to a variety of anti-TNF medications (adalimumab, etanercept, certolizumab and infliximab), reporting no association with adverse pregnancy outcomes or congenital malformations.…”

Section: Pregnancy Outcomesmentioning

confidence: 99%

Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence

Mouyis

Flint

Giles

2019

Seminars in Arthritis and Rheumatism

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There is limited evidence relating to the impact of disease modifying anti-rheumatic drugs (DMARDs) upon male fertility and peri-conception paternal exposure in men with rheumatic disease. Therefore, we conducted a systematic review of available evidence to update information on this subject and guide paternal counselling. A systematic search of PubMed and Embase was carried out up to September 2017, 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. The search yielded 724 papers, and the titles/abstracts were screened independently by 2 authors, duplicates removed and 233 potentially relevant papers selected for full text review. A total of 84 papers were included in the final analysis which covered the impact on fertility of over 611 male exposures to relevant drugs, and over 5986 pregnancies conceived during paternal exposure to (or within 3 months of stopping) these drugs. Aside from the known adverse impact of cyclophosphamide and sulfasalazine on spermatogenesis, overall there was no firm evidence of harm to fertility or pregnancy outcomes with paternal exposure to anti-TNF therapies, abatacept, rituximab, azathioprine, cyclosporine A, hydroxychloroquine, leflunomide, methotrexate or mycophenolate mofetil. There was no evidence found pertaining to the effects of male exposure to IVIG, tacrolimus, golimumab, anakinra or belimumab on fertility or pregnancy outcomes. These results provide further reassurance as to the safety of many DMARDs 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.

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Birth Outcomes in Children Fathered by Men Treated with Anti-TNF-α Agents Before Conception

Abstract: Our results are overall reassuring regarding the safety of paternal preconceptional use of anti-TNF-α agents. The result regarding SGA should, however, be interpreted with caution as we found an increased risk, although not significantly increased.

Cited by 35 publications

References 28 publications

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: a systematic review

Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence

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