The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: ...
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Human Reproduction Update, Vol.26, No.6, pp. 961–1001, 2020
Advance Access Publication on August 3, 2020 doi:10.1093/humupd/dmaa022
The effect of paternal exposure to
immunosuppressive drugs on sexual
function, reproductive hormones,
fertility, pregnancy and offspring
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outcomes: a systematic review
L.F. Perez-Garcia 1,*, R.J.E.M. Dolhain1, S. Vorstenbosch2,
W. Bramer3, E. van Puijenbroek2,4, J.M.W. Hazes1, and B. te Winkel2
1
Department of Rheumatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands 2Netherlands
Pharmacovigilance Centre Lareb, 5237 MH ’s-Hertogenbosch, The Netherlands 3Medical Library, Erasmus MC, University Medical
Center, 3000 CA Rotterdam, The Netherlands 4Groningen Research Institute of Pharmacy, PharmacoTherapy, Epidemiology and
Economics, University of Groningen, 9712 CP Groningen, The Netherlands
*Correspondence address. Department of Rheumatology, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam,
the Netherlands. E-mail: l.perez@erasmusmc.nl https://orcid.org/0000-0002-8958-9493
Submitted on March 4, 2020; resubmitted on April 17, 2020; editorial decision on April 30, 2020
TABLE OF CONTENTS
................................................................................................................................
• Introduction
• Methods
Protocol and registration
Eligibility criteria
Information sources and search terms
Study selection and data extraction
Risk of bias in individual studies
Synthesis of results
Additional analysis
• Results
Study selection and characteristics
Description of participants
Description of interventions
Risk of bias within studies
• Outcomes
Aminosalicylic acid and similar agents
Antimalarials (chloroquine and hydroxychloroquine)
Calcineurin inhibitors (ciclosporine, sirolimus and tacrolimus)
Colchicine
Cyclophosphamide
Interleukin inhibitors
Methotrexate
Mycophenolate acid products
C The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com962 Perez-Garcia et al.
NSAIDs
Retinoids (acitretin, etretinate and isotretinoin)
Systemic corticosteroids
Thiopurines
Tumour necrosis factor- inhibitors
Verdolizumab
Other selective immunosuppressants
Immunosuppressive drugs without available information
Treatment of antisperm antibodies
• Discussion
Summary of evidence
Findings
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Strengths and limitations
Research recommendations
• Conclusion
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-a 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 inconclu-
sive. 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.
Key words: immunosuppressive agents / semen analysis / male infertility / sexual health / sexual dysfunction / hypogonadism / teratoge-
nicity / pregnancy / paternal exposure / gonadal steroid hormones
Introduction ..
.. pre-conceptional period (3 or 6 months before pregnancy) (Schirm
Men with immune-mediated diseases (IMDs) and a wish to become a .. et al., 2004; Crijns et al., 2012; Engeland et al., 2013). Many factors are
..
father represent an important neglected population. The question on .. contributing to a substantial number of men with a wish to become a
how they should be treated to improve (or at least not impair) their .. father being exposed to immunosuppressive drugs; some IMDs can af-
..
chances of achieving a successful pregnancy and a healthy offspring .. fect men at a young age (i.e. juvenile idiopathic arthritis), then the
remains a challenge for physicians and researchers all around the world. .. prevalence of other IMDs increases during the peak of the male repro-
..
Based on data from Denmark, the Netherlands and Norway, it is .. ductive lifespan (i.e. rheumatoid arthritis (RA) or inflammatory bowel
estimated that 5.6–7.6% of fathers could be exposed to non-steroidal .. disease (IBD)), and furthermore in many parts of the world, men are
..
anti-inflammatory drugs (NSAIDs) or anti-rheumatic drugs during the .. becoming fathers at an older age (Khandwala et al., 2017).
.Immunosuppressive exposure and male sexual health 963
..
It is known that immunosuppressive drugs can affect male sexual .. publications were included if paternal exposure of immunosuppressive
health and reproduction via multiple mechanisms: by altering repro- .. drugs took place in the 6 months before or around the time of con-
..
ductive hormone secretion and/or action, by disrupting spermatogen- .. ception, and in case of studies reporting sexual function or fertility
esis or sperm motility and by causing sexual dysfunction (Sasaki et al., ... parameters (i.e. semen analysis, sexual dysfunction and testosterone
2011). .. levels), publications were included if male exposure of immunosup-
..
Furthermore, many of the available immunosuppressive drugs, such .. pressive drugs was taken into consideration. For both categories, no
as methotrexate or sulfasalazine, were approved by the Food and
.. restrictions were made regarding the comparison groups.
..
Drug Administration (FDA) and/or the European Medicines Agency ..
..
(EMA) before it was required to perform mandatory evaluations of .. Information sources and search terms
male reproductive toxicity (FDA, 2015; EMA, 2017) ..
.. A search strategy was developed by an experienced medical librarian
On the contrary, to get approval, new drugs are facing more strict .. (W.B.) using a structured methodology (Bramer et al., 2018a,b). The
protocols. Testicular toxicity is first evaluated in animal studies. When ..
.. searches combined keywords regarding male sexual function and fertil-
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evidence suggests adverse events on the male reproductive system, .. ity, pregnancy outcomes and offspring health with a list of immunosup-
complex trials in humans should follow. Importantly, in animal studies, ..
.. pressive drugs collected by experts in the fields of Rheumatology,
the FDA considers histopathological evaluation to be an appropriate .. Gastroenterology, Dermatology and Nephrology. Our full electronic
endpoint. In the case of human studies, semen analyses at baseline, at
..
.. search strategy is provided in Supplementary Table S1.
one spermatogenic cycle after exposure and at 13 weeks after drug .. Subsequently, a systematic literature search was performed in the
discontinuation) become the most important marker of fertility. For
..
.. bibliographic databases: Embase (via Elsevier embase.com), MEDLINE
further reassurance of testicular safety, the FDA recommends con- .. ALL (via Ovid), Cochrane Central Register of Trials (via Wiley) and
..
ducting randomised, double-blind, placebo-controlled, parallel-arm tri- .. Web of Science Core Collection. Additionally, Google Scholar and the
als including 200 men in a 1:1 ratio (drug:placebo) (FDA, 2015). ..
.. Clinical trial registries of Europe and the USA were searched. We also
For men of reproductive age, the decision on which immunosup- .. included references from the primary search publications, in case these
pressive drug to prescribe is not straightforward. Information regarding ..
.. were missed in our search and when relevant data were missing, we
the possible effects on male sexual health and reproduction is still lack- .. contacted authors for further information. These databases were
ing for most of the commonly used immunosuppressive drugs. ..
.. searched from inception until 31 August 2019.
The objective of our study is to provide this information in the form ..
of a ‘state of the art’ systematic review. Our goal is to review the
..
.. Study selection and data extraction
available information about the influence of paternal immunosuppres- ..
.. All articles were imported into EndNote X9. After removal of dupli-
sive drug exposure on many aspects of male sexual and reproductive ..
health, such as sexual function, reproductive hormones, fertility, preg- .. cates with the method described by Bramer et al. (2016), two
.. reviewers (L.F.P.-G. and B.t.W.) independently screened titles,
nancy and offspring outcomes. ..
.. abstracts and full-text of the records for eligibility. Disagreements were
.. resolved by consensus with the help of a third reviewer (R.J.E.M.D.).
..
.. Two reviewers (L.F.P.-G. and B.t.W.) extracted relevant information
Methods .. for each studied outcome from the included articles.
..
..
Protocol and registration ..
.. Risk of bias in individual studies
The protocol for this systematic review was registered with the ..
International Prospective Register of Systematic Reviews (Registration
.. The methodological quality of the studies was assessed with the
.. Newcastle–Ottawa Scale (NOS), developed for case–control and co-
no. CRD42018096898, https://www.crd.york.ac.uk/prospero/display_ ..
record.php?RecordID¼96898) and undertaken according to the
.. hort studies (Wells et al., 2013). In the case of cross-sectional studies,
.. an adapted scale was used (Modesti et al., 2016). Using these meth-
Preferred Reporting Items for Systematic Reviews and Meta-analyses ..
.. ods, points were awarded to each publication, related to the selection
protocols (PRISMA-P) guidelines (Moher et al., 2015). .. of the study group, the comparability of the study groups and the as-
..
.. certainment of the outcomes. The score ranges from 0 to 9, with
Eligibility criteria .. scores >5 representing good-quality studies. The results are presented
..
The literature search was limited to the English language and human .. in Tables I and II. Case reports were not graded. Quality assessment
subjects. Case–control studies, cohort studies, cross-sectional studies,
.. was done by L.F.P-G. for the sexual function, reproductive hormones
..
case reports and case series were included. In vitro studies using hu- .. and fertility data, and by B.t.W. and S.V. for pregnancy and child out-
..
man material were also included. Conference abstracts published after .. come data.
April 2016 were included. Publications without original data, such as .. Regarding pregnancy and child outcomes data, the following ‘rules’
..
reviews, were excluded. Publications concerning the use of immuno- .. were applied. Ascertainment exposure/outcome was graded ‘1’
suppressive drugs for the treatment of any form of cancer were .. (structured questionnaire equals structured interview). The question
..
excluded. .. ‘outcome not present at the start’ was always graded ‘0’. Follow-up
The outcome data should include at least one of the following out- .. length was considered long enough for congenital anomalies if at least
..
comes: sexual function, reproductive hormones, fertility, pregnancy .. 1-year follow-up was reported. For long-term outcomes, the follow-
outcomes or offspring outcomes. For pregnancy outcomes,
.. up needed to last until children were 18 years of age. In cases whereTable I Summary of study characteristics and main findings for sperm quality, sexual function and reproductive hormones outcomes.
964
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Aminosalicylic acid and similar agents
Di Paolo et al. (2001) 42 (NR) IBD All sperm samples had abnormalities, NR H
Italy NR mainly in motility. Sperm quality im- CS
proved after stopping SSZ or switch-
ing to 5-ASA.
Zelissen et al. (1988) 11 (32.3) IBD Oligospermia was detected in 72% of * NR L
The Netherlands NR samples. After switching to 5-ASA, all CS
samples showed improvement in
sperm counts.
Riley et al. (1987) 15 (NR) IBD Oligospermia was detected on 40% NR NR H
UK NR of samples. After switching to mesala- CS
zine, samples showed improvement
in sperm counts.
Cosentino et al. (1984) 10 (30) IBD Mean number of sperm count and of * NR H
USA 19 (NR) normal morphology was significantly Ch
lower. In five patients who stopped
SSZ, improvement in sperm quality
was observed.
Freixa et al. (1984) 10 (NR) Healthy Prostaglandin levels in seminal plasma NR NR L
Spain 0 participants decreased by 36% secondary to SSZ CS
exposure.
O’Morain et al. (1984) 39 (NR) IBD SSZ exposure was associated with * NR L
UK 9 (NR) significant decrease in sperm counts, CC
motility and increase in abnormal
sperm morphology.
Ragni et al. (1984) 7 (NR) IBD Sperm motility was reduced in all NR L
Italy 7 (30.1) cases and serum testosterone levels CC
were significantly lower in exposed
cases.
Hudson et al. (1982) 8 (NR) IBD Sperm head size was significantly NR NR L
UK 10 (NR) larger in cases than in controls. CS
(continued)
Perez-Garcia et al.
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Freeman et al. (1982) 11 (28.8) IBD Lower progressive motility in SSZ-ex- NR NR L
UK 6 (36) posed group. CC
Tobias et al. (1982) 1 (39) IBD Case report: reversible infertility after * NR NA
South Africa 0 stopping SSZ, patient on high dose CR
GCs.
Toovey et al. (1981) 28 (NR) IBD Exposed samples showed reduced * NR H
UK 4 (NR) sperm motility and density and al- CS
tered morphology. After withdrawal,
Immunosuppressive exposure and male sexual health
sperm density and motility improved
significantly but not sperm
morphology.
Levi et al. (1979) 4 (30) IBD Case series: NR NR NR
UK 0 One of the first case series where Case series
authors reported semen analysis
abnormalities in SSZ-exposed
patients.
Toth (1979) 6 (NR) IBD Head, midpiece and tail abnormalities NR NR L
UK 0 were detected in spermatozoa of CS
SSZ-exposed patients.
McIntyre and 3 (NR) IBD Case series: NR NR NA
Lennard-Jones (1984) 0 Sperm abnormalities detected after Case series
UK SSZ-exposed patients were sent to
the infertility clinic. Sperm quality
improved after switching therapy to
balsalazide.
Iglesias-cortit et al. 6 (NR) Healthy Sperm motility decreased 15% after NR NR L
(1985) 0 participants exposure to SSZ. CS
Spain
Cann and Holdsworth 1 (33) IBD Case report: SSZ-exposed patient NR NR NA
(1984) 0 who was diagnosed with infertility and CR
Austria achieved a successful pregnancy after
switching therapy from SSZ to 5-ASA.
(continued)
965
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966
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Ganatra et al. (2018) 61 (NR) IBD 26.23% of SSZ-exposed patients de- NR NR L
India 0 veloped oligospermia. This is the first CS
article to comment on the possible ef-
fect by disease activity.
Shaffer et al. (1984) 1 (32) IBD Case report: oligospermia associated NR NR NA
UK 0 with exposure to SSZ. CR
Traub et al. (1979) 1 (25) IBD Case report: pregnancy achieved after NR NR NA
UK 0 stopping SSZ therapy. CR
Chatzinoff et al. (1988) 1 (32) IBD Case report: SSZ-induced infertility * NR NR NA
USA 0 case confirmed by sperm penetration CR
assay (sperm analysis was normal).
Birnie et al. (1981) 21 (32.8) IBD 86% of SSZ-exposed patients had ab- NR NR L
UK 0 normal semen analysis (72% had CS
oligospermia).
Heineman et al. (1981) 2 (32) IBD Case report: reversible oligospermia * NR NR NA
The Netherlands 0 in two cases exposed to SSZ. Both CS
cases achieved pregnancies after drug
withdrawal.
Antimalarials
Ejebe et al. (2008) 5 (NR) Healthy No differences in sperm quality * * NR L
Nigeria 10 (NR) participants parameters and reproductive hor- CS
mones were found between exposed
and non-exposed after exposure of
chloroquine 1 g/day for 2 days and
then 500 mg/day for 1 day.
Hargreaves et al. (1998) NR Healthy Chloroquine had a dual in vitro effect, þ NR NR CS
UK participants enhancing rapid motility at low con- L
centrations but inhibiting it at higher
concentrations. At 250 mg/ml chloro-
quine, all spermatozoa were static.
(continued)
Perez-Garcia et al.
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Adeeko and Dada 8 (NR) Healthy Chloroquine is present in seminal NR NR NR L
(1994) 0 (NR) participants plasma even after long time of no Ch
Nigeria exposure.
Ette et al. (1988) 4 (NR) Healthy Chloroquine crosses the BTB, proba- NR NR NR NA
Nigeria 0 (NR) participants bly by passive diffusion. Case series
Calcineurin inhibitors (CsP, ciclosporine; EVE, everolimus; SIR, sirolimus; TAC, tacrolimus)
Misro et al. (1999) NR Healthy In vitro study showing that ciclospor- NR NR H
India participants ine exerts deleterious effects on CS
Immunosuppressive exposure and male sexual health
CsP sperm, which become immotile and
nonviable.
Haberman et al. (1991) 9 (41.2) Kidney With the exemption of a low semen * * NR L
USA NR transplantation volume, ciclosporine A at 3 mg/kg/ CS
CsP day did not result in other sperm
quality or hormonal abnormalities.
Samojlik et al. (1992) 10 (NR) Kidney Pretreatment (pre-transplant) testos- NR þ NR L
USA 0 transplantation terone levels were below normal in CC
CsP 80%. After 12 months of treatment
with CsP and other immunosuppres-
sive drugs, testosterone levels signifi-
cantly increased in all 10 cases.
Eid et al. (1996) 34 (32) Kidney Sperm concentration was inversely * þ H
Egypt 31 (31) transplantation correlated to the CsP whole blood CC
CsP levels.
Kramer et al. (2005) 256 (NR) Kidney Testosterone levels increased from NR þ NR L
Germany 0 transplantation baseline in EVE and EVE-CsP groups. Ch
CsP–EVE
Kantarci et al. (2004) 37 (38.1) Kidney No statistical differences in baseline NR * NR L
Turkey 0 transplantation levels of serum FSH, LH, testosterone CS
CsP–TAC and PRL between CsP- and TAC-
treated patients. All results were in
normal ranges.
Peces et al. (1994) 19 (35) Kidney Serum levels of reproductive hor- NR * NR L
Spain 0 transplantation mones were normal in CsP exposed CS
CsP cases.
967
(continued)
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968
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Sajad Hussain et al. 1 (40) Kidney Case report: patient was infertile * * NR NA
(2015) transplantation while on Sirolimus he developed oli- CR
India SIR gospermia with normal hormone lev-
els after switching to tacrolimus he
was able to conceive.
Boobes et al. (2010) 6 (43) Kidney Case series: infertile patients with oli- * NR þ NA
UAE 0 transplantation gospermia, after discontinuing SRL, all Case series
SIR patients had increased sperm counts
and were able to conceive.
Zuber et al. (2008) 25 (32) Kidney Sirolimus-exposed patients had lower NR NR H
France 67 (NR) transplantation sperm counts and motility. The fa- CS
SIR thered pregnancy rate was signifi-
cantly lower in exposed patients than
in non-exposed.
Skrzypek and Krause 1 (29) Kidney Recovery of spermatogenesis after * NR NR
(2007) 0 transplantation cessation of sirolimus. CR
Germany SIR
Deutsch et al. (2007) 1 (26) Lung–heart Benign Leydig cell tumour in a patient * NR NA
Germany transplantation exposed to sirolimus lead to testicular CR
SIR biopsy that showed testicular atrophy
and signs of impaired
spermatogenesis.
Bererhi et al. (2003) 1 (36) Kidney Case report: low sperm count and * NR NR NA
France transplantation motility with abnormal morphology
SIR associated with sirolimus exposure.
These changes were reversed after
switching therapy to tacrolimus.*
Kaczmarek et al. (2004) 66 (NR) Heart Patients exposed to sirolimus had sig- NR NR H
Germany 66 (NR) transplantation nificantly lower serum testosterone CS
SIR levels and higher FHS/LH levels than
control group.
Lee et al. (2005) 32 (41) Kidney Patients exposed to sirolimus had sig- NR NR H
USA 34 (47) transplantation nificantly lower serum testosterone CS
SIR levels and higher FHS/LH levels than
control group.
Perez-Garcia et al.
(continued)
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Fritsche et al. (2004) 28 (46.5) Kidney Sirolimus daily dose and testosterone NR NR H
Germany 28 (45.5) transplantation concentrations were significantly in- CC
SIR versely correlated (r ¼ –0.383).
Tondolo et al. (2005) 59 (48) Kidney Significantly reduced levels of circulat- NR NR L
USA 0 transplantation ing testosterone amongst patients re- CS
SIR ceiving sirolimus alone compared to
those treated with calcineurin inhibi-
tors alone were identified.
Immunosuppressive exposure and male sexual health
Colchicine
Kastrop et al. (1999) 2 (40) Gout Cytogenic analysis of sperm (FISH) * NR NR NA
The Netherlands 0 revealed no damage secondary to col- CR
chicine use.
Kirchin et al. (1999) 1 (48) Retinal vasculitis Case report: reversible azoospermia. NR NR NA
UK 0 CR
Sarica et al. (1995) 62 (32.4) Behçet syndrome The longer the use of colchicine, the þ NR L
Turkey 0 more serious the adverse events on CS
sperm count
Ben-Chetrit et al. (1993) 15 (NR) Healthy In vitro study, high concentrations of NR NR H
Israel 0 participants colchicine may affect in vitro motility CC
of sperms, probably by its direct ef-
fect on the microtubules.
Levy and Eliakim (1977) 6 (34.6) FMF After being advised to stop treatment * NR NR L
Israel 0 with colchicine prior to attempt con- CS
ception, sperm analysis was within
normal limits in all six patients.
Bremner and Paulsen 7 (22) Healthy Colchicine caused no significant * * NR L
(1976) 0 participants changes in sperm quality or reproduc- CS
USA tive hormones levels after 3 or 6
months of treatment.
Merlin (1972) 1 (36) Gout Case report: azoospermia believed to NR NR NA
USA 0 be associated with colchicine use. CR
Colchicine was stopped and after 3
months, sperm count improved and
wife became pregnant.
969
(continued)
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970
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Kaya Aksoy et al. (2019) 72 (14.5) FMF Mean colchicine dose at the time of NR NR H
Turkey 0 sperm analysis was higher in patients Ch
with low sperm motility than that
with normal sperm motility.
Cyclophosphamide
Suehiro et al. (2008) 13 (NR) SLE The median serum inhibin B was NR L
Brazil NR lower in patients treated with CYC CS
compared with those without this
therapy.
Soares et al. (2007) 14 (NR) SLE Semen analysis demonstrated that NR H
Brazil NR patients who had undergone IV CC
CYC therapy had worse sperm
quality (count, motility and morphol-
ogy) compared with patients who
did not undergo this treatment.
Elevated FSH levels were detected in
patients who underwent IV CYC
therapy.
Anserini et al. (2002) 19 (NR) Bone marrow 10% of patients who received CYC NR NR NA
Italy 0 transplantation showed azoospermia, and recovery Case series
of spermatogenesis was observed in
60% of patients.
Bogdanovic et al. (1990) 17 (NA) Nephrotic Significant inverse correlation be- NR NR NA
Yugoslavia 0 syndrome tween sperm density and CYC dos- Case series
age and duration of treatment.
Perrone et al. (1989) 22 (NR) Nephrotic Altered spermatogenesis was found NR H
Italy 20 (NR) syndrome in 41.6% of adult patients treated CC
with CYC during childhood (1.8–5.5
mg/kg/day for 12 weeks). No signifi-
cant inverse correlation of total dose
of the drug with sperm density.
Watson et al. (1985) 30 (22) Nephrotic A significant inverse correlation was * L
Canada 18 (28) syndrome evident between sperm density and CC
CYC dosage. Recovery of sperm
count after prolonged interval after
treatment is possible.
Perez-Garcia et al.
(continued)
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Ogata et al. (1982) 6 (NR) Nephrotic Histologic oligospermic changes were NR NR L
Japan 0 syndrome observed in three patients treated Case series
with high doses (10.6–16.2 g during
125–432 days).
Fukutani et al. (1981) 31 (33) Behcet syndrome Azoospermia and oligospermia found NR L
Japan 33 (NR) in 13 out of 17 patients treated with CS
CYC.
High mean FSH levels in CYC-treated
patients
Immunosuppressive exposure and male sexual health
Trompeter et al. (1981) 19 (22) Nephrotic Lower ejaculate volumes and sperm NR L
UK 17 (23) syndrome densities and higher percentage of im- CS
motile and abnormal forms in CYC
exposed group.
Marina and Barcelo 3 (NR) Nephrotic All patients showed abnormalities: oli- NR NR NA
(1979) 0 syndrome gospermia (1), azoospermia (1) and Case series
Spain aplasia of germinal epithelium (1).
Hsu et al. (1979) 16 (NR) Nephrotic Sperm quality abnormalities found in NR L
Canada 0 syndrome 63%. An increase in the total dosage Ch
and in duration of the treatment was
associated with a higher incidence of
testicular dysfunction.
Etteldorf et al. (1976) 12 (NR) Nephrotic Low doses (2–4 mg/kg/day) did not NR NA
USA 0 syndrome influence pituitary gonadal function Case series
(confirmed by biopsy).
Kirkland et al. (1976) 15 (NR) Nephrotic Serum testosterone levels were nor- NR * NR NA
USA 0 syndrome mal in CYC-treated patients Case series
Pennisi et al. (1975) 23 (NR) Nephrotic Sperm quality was uniformly de- NR L
USA 0 syndrome creased in CYC-treated patients and Case series
high FSH levels were common.
Kumar et al. (1972) 8 (NR) Nephrotic All eight biopsy specimens had evi- NR NR L
UK 0 syndrome dence of testicular atrophy, and it was CS
profound in 6.
(continued)
971
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972
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Penso et al. (1974) 7 (NR) Nephrotic Biopsies confirmed absent spermato- NR L
USA 0 syndrome genesis in azoospermic patients and CS
FSH elevation correlated with degree
of testicular damage.
Feng et al. (1972) 1 (18) Nephrotic First case report that reported azoo- NR NR NA
Singapore 0 syndrome spermia associated with CYC CR
exposure.
Masala et al. (1997) 15 (NR) Nephrotic All 15 patients received CYC and be- NR NR L
Italy 0 syndrome came azoospermic or oligospermic. CS
Five patients received testosterone
(100 mg intramuscularly every 15
days during CYC therapy). After CYC
treatment, normal sperm analysis was
reported in all five patients who re-
ceived testosterone (vs 1/10)
Fairley et al. (1972) 31 (31.2) NR Testicular biopsy was performed on NR NR L
Australia 0 five patients who were receiving CYC CS
and no spermatogenesis was found.
Methotrexate
Sussman and Leonard 1 (26) Psoriasis Case report: reversible oligospermia NR NR NA
(1980) 0 secondary to MTX. CR
USA
Van Scott and 2 (NR) Psoriasis Sperm count was reduced to 63–97% NR NR NA
Reinertson (1959) 0 at 2 weeks after a single IV injection Case series
USA of MTX.
El-Beheiry et al. (1979) 26 (33–52) Psoriasis The mean difference in sperm count, * NR NR L
Egypt 0 motility and abnormal forms before CS
and after methotrexate therapy was
not significant.
Five testicular biopsies performed
where no alterations were found.
(continued)
Perez-Garcia et al.
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Grunnet et al. (1977) 10 (23–46) Psoriasis Sperm abnormalities found in 40% of þ NR NR L
Denmark 0 MTX-treated patients but sperm CS
quality was better than in patients
treated with glucocorticoids.
Ley et al. (2018) 7 (28) IBD In all MTX-treated patients, basic se- DFI NR NR L
USA 1912 (NR) men analyses were within normal *sperm CC
limits
Pandhi et al. (2006) 1 (50) Psoriasis Case report: gynaecomastia and oli- NR NR NA
Immunosuppressive exposure and male sexual health
India gospermia secondary to MTX CR
NSAIDs
Kristensen et al. (2018) 14 (NR) Healthy Experiment: exposure to ibuprofen NR NR NA
Denmark 17 (NR) participants in adult testis explants caused a RCT
Ibuprofen state of compensated
hypogonadism.
Poratsoldin and Soldin 19 (NR) Healthy In vitro study: salicylate significantly NR NR H
(1992) 0 participants decreases sperm motility CS
USA Salicylate
Bendvold et al. (1985) 6 (NR) Healthy Treatment with naproxen significantly NR NR NR H
Sweden 0 participants reduces the concentration of all PGs CC
Naproxen present in human seminal fluid.
Albert et al. (2013) NA Healthy In vitro study: production of testoster- NR NR L
France participants one by Leydig cells was altered by ex- CS
Aspirin and posure to all these drugs
indo-
methacin
Knuth et al. (1989) 10 (25.1) Healthy Exposure to indomethacin led to * * NR L
Germany 12 (27.4) participants lower PGs levels in seminal plasma CS
Indomethacin but unchanged sperm quality parame-
ters and levels of reproductive
hormones.
(continued)
973
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974
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Retinoids
Liu et al. (2017) 31 (NR) Psoriasis After 3 months of treatment at doses * * NR H
China 14 (NR) Acitretin of 20 mg/day and 30 mg/day, sperm CC
quality did not differ between cases
and controls.
Schmitt-Hoffmann (et al. 24 (30) Healthy After 3 months of treatment at doses NR NR NR L
2011) 0 participants of 20 mg or 40 mg/day alitretinoin CC
Switzerland Acitretin and 4-oxo-alitretinoin were detected
in 11 of 12 semen
samples.Concentrations detected are
unlikely associated with
teratogenicity.
Rossi and Pellegrino 1 (39) Psoriasis Case report: 39-year old diagnosed NR NR NA
(2009) 0 Acitretin with psoriasis reported erectile dys- CR
Italy function after starting treatment with
acitretin (25 mg/day). After 2 weeks
of drug withdrawal, patient reported
normalisation of sexual activity.
Parsch et al. (1990) 5 (34) Psoriasis After 3 months of treatment at doses * * NR H
Germany 6 (34) Acitretin of 25–50 mg/day, sperm quality did CC
not differ between cases and controls
Çinar et al. (2016) 81 (22.6) Acne After 6 months of treatment at doses þ * NR H
Turkey 0 Isotretinoin of 120 mg/day, all the sperm quality CS
parameters changed positively and re-
productive hormone levels did not
differ.
Torok et al. (1987) 13 (27) Acne After 4 months of treatment at doses of þ NR NR H
Hungary 0 Isotretinoin 1 mg/kg/day, sperm motility increased CS
significantly and the other sperm quality
parameters did not differ.
Coleman and 1 (29) Acne Case report of ejaculatory failure as- NR NR NA
MacDonald (1994) 0 Isotretinoin sociated with isotretinoin (1 mg/kg/ CR
UK day).
(continued)
Perez-Garcia et al.
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Healy et al. (2018) 47 (NR) Acne Independent drug safety website NR NR H
UK 0 Isotretinoin (RxISK.org) data: isotretinoin com- Ch
monly associated with SD.
Systemic glucocorticoids
McDonald and Heckel 4 (NR) RA Case series: biopsies performed after * NR NR NA
(1956) 7 (NR) exposure to 75 mg of cortisone, and Case series
USA no negative effect was observed.
Martens et al. (1994) 36 (62) RA Compared to healthy controls, RA NR NR L
Immunosuppressive exposure and male sexual health
USA 70 (68) patients taking prednisone had signifi- CS
cantly lower testosterone levels and
slightly elevated levels of FSH and LH.
Thiopurines (AZA, Azathioprine)
Dejaco et al. (2001) 23 (32) IBD Semen analyses of 23 patients with * NR NR L
Austria 0 (NR) AZA IBD showed no negative association CS
between AZA therapy and sperm
quality.
Farthing and Dawson 5 (NR) IBD 80% of patients had oligospermia. NR NR NA
(1983) 0 AZA Case series
UK
Baumgarten et al. (1977) 7 (NR) Kidney No correlation between poor sper- * * NR NA
USA 0 transplantation matogenesis and AZA was reported. Case series
AZA
Grosen et al. (2019c) 40 (27.6) IBD Sperm motility was decreased in DFI * NR H
Denmark 40 (23.3) AZA patients, DFI was similar. *sperm Ch
TNF-a inhibitors (INF, infliximab; ETN, etanercept; CZP, certolizumab pegol; ADA, adalimumab; GOL, golimumab)
Heppt et al. (2017) 27 (37.5) Psoriasis Compared with baseline, no signifi- * NR NR L
Germany 0 ETN cant differences in mean total sperm Ch
ADA number, sperm concentration, total
and progressive motility nor other se-
men parameters were noticed during
follow-up.
(continued)
975
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976
Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
Pascarelli et al. (2017) 10 (NR) Healthy *In vitro study: TNF-a had a detrimen- þ NR NR L
Italy 0 participants tal effect on sperm function and CS
ETN in vitro etanercept counteracted this
toxic action of TNF-a.
Ramonda et al. (2014) 10 (28.7) SpA Improvement in semen parameters þ * NR H
Italy 20 (27.4) ADA after 12 months of TNF-a inhibitor CC
treatment was reported.
Micu et al. (2014) 23 (34.7) AS Exposure of 20 patients to three dif- * NR NR L
Rumania 42 (34.8) ETN (2) ferent types of anti-TNFs did not CC
ADA (14) have a negative impact on sperm
INF(4) quality after 3–6 months and in six
cases after 12 months of treatment.
Almeida et al. (2013) 10 (33) AS Sperm abnormalities were compara- * * NR H
Brazil 24 (28.5) ETN (2) ble in patients and controls after 6 CC
ADA (8) months of TNF-a inhibitor therapy.
Villiger et al. (2010) 15 (29.5) SpA Impaired sperm quality was especially þ * NR L
Switzerland 102 (30) ETN found in the group of anti-TNF na- CC
ADA ive patients with active disease.
INF Sperm quality tended to improve
within the five paired samples for
sperm vitality (P ¼ 0.08) and sperm
motility (P ¼ 0.08).
Mahadevan et al. (2005) 10 (31) IBD Sperm motility, or the percentage of NR NR H
USA 0 INF sperm that show flagellar motion, was CS
below normal in study patients after
INF treatment.
Perrier d’Hauterive et al. 10 (NR) Healthy CZP treatment was found to have no * NR NR NA
(2012) 10 (NR) participants effect on the semen quality variables RCT
Belgium CZP assessed vs placebo
Grosen et al. (2019a) 28 (30.8) IBD A statistically significant reduction in *sperm NR NR H
Denmark 17 (27.5) INF (38) DFI was observed after the start of þDFI Ch
ADA(7) anti-TNF-a therapy (median DFI
12.8 off therapy versus 10.0 on
therapy, P ¼ 0.02).
(continued)
Perez-Garcia et al.
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Reference Country Number of Disease Key findings Effect on Effect on repro- Effect on sexual NOS quality
cases and con- fertility ductive function assessment
trols (with hormones Study type
mean age in
years)
...................................................................................................................................................................................................................................................................................................
No differences in sperm quality
parameters were found between
groups.
Montagna et al. (2005) 3 (40) AS Case series reporting asthenoazoo- * NR NR NA
Italy 0 INF spermia in two out of three patients Case series
using infliximab.
Wildi and Haraoui 1 (35) AS Case report: oligoasthenozoospermia * NR NR NA
(2012) 0 ADA and decreased motility reversed after CR
Immunosuppressive exposure and male sexual health
Canada stopping drug.
Younis et al. (2014) 1 (50) AS Case report: low sperm count, con- * NR NR NA
Israel INF centration increased after stopping CR
IFX.
Micu et al. (2019) 5 (NR) SpA Normospermia before and after * NR NR L
Romania 0 ADA TNF-a therapy initiation. Ch
Kreitenberg et al. (2015) 1 (58) RA Case report: priapism associated with NR NR NA
USA ADA adalimumab. CR
Oh et al. (2009) 22 (37.8) AS Anti-TNF-a-treated patients showed NR NR þ L
Korea 0 ETN significant improvements in four out Ch
ADA of the five IIEF domains.
INF
Verdolizumab
Grosen et al. (2019b) 15 (33) IBD Sperm quality and DFI were similar * * NR L
Denmark 33 (23) amongst cases and controls after CC
exposure to verdolizumab.
Verdolizumab was detected in semi-
nal plasma at levels that correspon-
dent to 0.3–1.1% of serum levels.
H, high; L, low; NA, not applicable; NR, not reported; *, no differences reported; þ, positive effect; , negative effect; *, reversible negative effect upon withdrawal; CC, case–control study; Ch, cohort study; CR, case report; CS, cross-sec-
tional study; RCT, randomised controlled trial.
977
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978
Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
Calcineurin inhibitors (CsP, ciclosporine; SIR, sirolimus; TAC, tacrolimus)
Hospital Case report 3 months prior to Ciclosporine LB 1 NS NR BD L
Germany 1 male conception 0
Schopf
2017
(Schopf, 2017)
Hospital Case series Long term 1 Tacrolimus, LB 3 NR BW BD L
Sweden NR 2 Ciclosporine 3967 0
Holmgren 3 children
2004
(Holmgren et al.,
2004)
TC* Case series Long term Ciclosporine LB 167 PB BW BD L
China 1981–2007 7 3274 6 395 1
Xu 164 males
2009
(Xu et al., 2009)
Hospital Case series Long term 1 Sirolimus, LB 2 PB BW BD L
Turkey 1997–2010 1 Tacrolimus 0 >3500 0
Ecevit 2 males
2017
(Ecevit et al., 2012)
TPR* Case series Long term Sirolimus LB 28 NR NR BD L
USA 1991-2017 SA 1 1
Moritz 29
2017 pregnancies
(Moritz et al., 2017)
PBR* Denmark Cohort 3 months prior to Ciclosporine/no NA PB LBW BD H
Egeberg 2004–2010 conception and during immunosuppressants 4 (6.0)/18 968 (4.5)Table II Continued
Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
Colchicine
Hospital Case series 3 months prior to Colchicine LB 3 NR NR NR L
Israel 3 pregnancies conception
Levy
Immunosuppressive exposure and male sexual health
1977
(Levy and Eliakim
1977)
Ehrenfeld Case series 3 months prior to Colchicine LB 9 NR NR NR L
1985 11 years conception SA 3
(Ehrenfeld et al., 1986) 12 (8)
children (fathers)
Ben-Chetrit Cohort 3 months prior to Colchicine SA NR NR NR L
2004 1995–2003 conception 10 (6)/6 (9)
(Ben-Chetrit et al., 158/64
2004) Pregnancies
Cyclophosphamide
Hospital Case report Long term Cyclophosphamide LB 1 NR NR BD L
Turkey 1 child 1
Balci
1983
(Balci and Sarikayalar,
1983)
Interleukin inhibitors
TIS Case series Long term Tocilizumab LB 1 NR NR BD L
Germany 2011–2014 SA 1 0
Weber-Schoendorfer 2 pregnancies
2016
(Weber-Schoendorfer
and Schaefer, 2016)
(continued)
979
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980
Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
MAH SD* Case series Long term Anakinra NA NR NR BD L
Youngstein Until 2012 Canakinumab NA NR NR 0
2017 6 (5) BD
(Youngstein et al., children (fathers) 0
2017) 5 (3)
children (fathers)
MAH SD Case series At the time of Secukinumab LB 29 (54) PB NR BD L
Warren Until 2017 conception SA 4 (7) 1 (2) 1 (2)
2018 54 pregnancies ET 1 (2)
(Warren et al., 2018) PL 20 (37)
Methotrexate
Hospital Case report 6 months LB 1 PT BW BD NA
USA 1 male prior to conception 0 2730 0
Perry
1983
(Perry, 1983)
Hospital Case report 6 months LB 1 NR BW BD NA
USA 1 male prior to conception 3500 0
Griggs
2006
(Griggs and Schwartz,
2006)
Hospital Case report At the time of LB 1 NR BW BD NA
Italy 1 male conception 2800 0
Lamboglia
2009
(Lamboglia et al.,
2009)
TIS Case series 3 months prior to LB 36 GA BW BD L
France 1997–2009 conception SA 3 39.2 6 1.1 3393 6 407 0
Beghin 42 pregnancies (40 ET 3 PB
2011 fathers) 1
(Beghin et al., 2011)
Perez-Garcia et al.
(continued)
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Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
JuMBO registry Case series At the time of LB 6 NR NR BD L
Germany Up to 2018 conception SA 2 1
Drenches 9 pregnancies ET 1
2018
(Drenches et al.,
2018)
Immunosuppressive exposure and male sexual health
PBR* Cohort 3 months prior to SA 0 PB SGA BD L
Norway 2004–2011 conception 0 0 0
UK 5
2012 singleton pregnancies
(Engeland et al., 2013)
TIS Cohort 3 months prior to LB 87/349 (84.7) GA BW BD L
Germany 1995–2012 conception SA 15/40 (10.2) 39.1/39 3380/3330 major
Weber-Schoendorfer 113/412 pregnancies ET 11/21 (5.1) PB 1 (1.1)/4 (1.1)
2014 8 (9.2)/54 (15.1) minor
(Weber-schoendorfer 4 (4.6)/18 (5.0)
et al., 2014) genetic
1 (1.1)/2 (0.55)
all
OR (95% CI)
1.02 (0.4–2.5)
PBR Cohort 3 months prior to Methotrexate/no NA PB SGA BD H
Denmark 1997–2013 conception methotrexate 13 (6.7)/57 088 (5.6) 6 (3.1)/34 236 (3.4) 10 (5.2)/48 466 (4.8)
Winter 193/1 013 801 OR (95% CI) OR (95% CI) OR (95% CI)
2017 live born children 1.27 (0.63–2.56) 0.92 (0.37–2.31) 1.16 (0.62–2.18)
(Winter et al., 2017) (singleton) Adj. OR (95% CI) Adj. OR (95% CI) Adj. OR (95% CI)
Eck 1.38 (0.68–2.81) 0.98 (0.39–2.50) 1.10 (0.57–2.13)
2017
(Eck et al., 2017)
Egeberg
2017
(Egeberg et al., 2017)
(continued)
981
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982
Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
Andersen Cohort 3 months prior to Methotrexate/no SA GA BW NA L
2018 1997–2015 conception and during methotrexate 46 (8.9)/122 929 (9.0) 39.7 (38.7–41.0)/40.0 3510 (3198–3915)/
(Andersen et al., 520/1 363 543 fathers the first trimester Adj. HR (95% CI) (39.0–41.0) 3540 (3200–3890)
2018) 0.99 (0.67–1.46) NA NA
Andersen
2019
(Andersen et al.,
2019)
Mycophenolate acid products
TPR* Cohort Long term MPA/no MPA LB (90.2)/(91.9) GA BW BD H
USA 1991–2017 SA (9.2)/(6.2) 39 6 2.5/39 6 2.3 3323 6 635/3362 6 (3.5)/(3.1)
Moritz 295/1092 ET 0/(0.6) PT 592
2017 pregnancies SB (0.7)/(0.7) (12.8)/(12.8) LBW
(Moritz et al., 2017) OT 0/(0.6) (8.5)/(6.6)
PBR* Cohort Long term MPA/no MPA LB GA BW BD H
Norway 1995–2015 154 (99.4)/191 (97.9) 38.8 6 2.5/39.1 6 3381 6 681/3429 6 6 (3.9)/5 (2.6)
Midtvedt 155 (112)/195 (133) SB 2.7 714
2017 children (fathers) 1 (0.6%)/4 (2.1%)
(Midtvedt et al., 2017)
Åsberg
2017
(Åsberg et al., 2017)
PBR* Cohort 3 months prior to Mycophenolate mofe- NA PB LBW BD H
Denmark 2004–2010 conception and during til/no 0/18 972 (4.5) 0/22 089 (5.3) 0/31 238 (7.5)
Egeberg 6/417 628 the first trimester immunosuppressants
2017 children
(Egeberg et al., 2017)
Hospital Cohort Long term MPA/no MPA LB 28/21 BW BD L
Spain 1988–2015 SA 6/2 3298 6 646/3148 6 0/1
Lopez-Lopez 28 (20)/21 (13) 401
2018 children (fathers)
(Lopez-Lopez et al.,
2018)
(continued)
Perez-Garcia et al.
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Data source Type of study Exposure period Inclusion Pregnancy outcome Gestational age Birth weight Birth defects Quality
Country Study period Cases Live births (LB) (GA in weeks, (BW in gram, (BD, n (%)) assessment
Author Number of cases Controls Spontaneous mean 6 SD) mean 6 SD)
Year of publication Number of controls abortions (SA) Preterm birth Low birth weight
Unit cases ETOP* (ET) (PB, n (%)) (LBW, n (%))
Stillbirths (SB) Small for
Pending/LTFU* (PL) gestational age
Neonatal death (ND) (SGA, n (%))
Other (OT)
n (%)
...................................................................................................................................................................................................................................................................................................
Other selective immunosuppressants
TIS Case report At the time of Leflunomide LB 1 GA BW BD NA
Italy 1 pregnancy conception 38 3350 0
De Santis
Immunosuppressive exposure and male sexual health
2005
(De Santis et al., 2005)
MAH SD* Case series At the time of Abatacept LB 9 NR NR BD L
Kumar 1995–2014 conception ET 1 0
2015 10 pregnancies
(Kumar et al., 2015)
MAH SD Case series At the time of Tofacitinib LB 55 (65.5) NR NR BD L
Mahadevan Until 2017 conception SA 7 (8.3) 0
2018 84 pregnancies PL 21 (25)
(Mahadevan et al., ND 1 (1.2)
2018)
Clowse
2016
(Clowse et al., 2016)
Retinoids
Hospital Case series Long term Etretinate LB 3 NR NR BD L
UK 1974–2004 0
Katugampola 3 (2)
2006 children (fathers)
(Katugampola and
Finlay, 2006)
PBR* Cohort 3 months prior to Isotretinoin/NR NR PB NR BD L
Norway 2004–2011 conception 7 1
Engeland 80 OR (95% CI)
2012 singleton pregnancies 1.8 (0.81–3.8)
(Engeland et al., 2013)
(continued)
983
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