Alimentary Pharmacology and Therapeutics

Review article: the safety of therapeutic drugs in male inflammatory bowel disease patients wishing to conceive K. Sands*, R. Jansen†, S. Zaslau† & D. Greenwald‡

*EW Sparrow Hospital Urology Residency, Michigan State University College of Osteopathic Medicine, Lansing, MI, USA. † Division of Urology, West Virginia University, Morgantown, WV, USA. ‡ Department of Surgery, Stanford University, Stanford, CA, USA.

Correspondence to: Dr R. Jansen, Department of Surgery, School of Medicine, Robert C. Byrd Health Sciences Center, West Virginia University, One Medical Center Drive, PO Box 9238, Morgantown, WV 26506, USA. E-mail: [email protected]

Publication data Submitted 8 April 2013 First decision 27 April 2013 Resubmitted 5 October 2013 Resubmitted 6 February 2014 Resubmitted 6 June 2014 Resubmitted 13 June 2014 Resubmitted 9 October 2014 Resubmitted 4 February 2015 Accepted 5 February 2015 This uncommissioned review article was subject to full peer-review.

SUMMARY Background Many therapeutic drugs are used by patients with inflammatory bowel disease, often around the time of conception. The pregnancy outcomes of males and females exposed to these therapeutics needs to be examined and this information is necessary to counsel patients appropriately. Aim To review the literature describing male infertility and inflammatory bowel disease to educate practitioners of the impact of inflammatory bowel disease on male reproduction and the impact of therapeutics on pregnancy outcomes. Methods We performed a PubMed search using the search terms ‘male infertility,’ ‘Crohn’s disease,’ ‘inflammatory bowel disease,’ ‘ulcerative colitis,’ ‘ciprofloxacin AND infertility,’ ‘metronidazole AND infertility,’ ‘sulfasalazine AND infertility,’ ‘azathioprine AND infertility,’ ‘methotrexate AND infertility,’ ‘ciclosporin AND infertility,’ ‘corticosteroids AND infertility,’ ‘infliximab AND male fertility,’ ‘infliximab AND infertility,’ ‘infliximab AND foetus,’ ‘infliximab AND paternal exposure’ and ‘infliximab AND sperm.’ References from selected papers were reviewed and used if relevant. Results Over half of male patients with IBD have some degree of infertility, compared to 8–17% of the general population. Semen parameters including total count, motility and morphology may be adversely affected by therapeutics. IBD medications in males do not increase foetal risk with the possible exception of azathioprine and mercaptopurine; however, increased foetal risk is seen in other drugs if taken by female patients. Conclusions It is recognised that male infertility is often impacted with therapeutic drugs used to treat inflammatory bowel disease; however, the effects of the paternal drug exposure at the time of conception and exposure in utero should be considered to counsel patients appropriately. Aliment Pharmacol Ther

ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13142

1

K. Sands et al. INTRODUCTION Patients with inflammatory bowel disease who wish to conceive face a number of issues which must be taken into consideration. Underlying pathophysiologic features of inflammatory bowel disease lead to reduced fertility and pregnancy rates. In some cases, therapeutics carry not only fertility risks to the patient but also teratogenic risks to the foetus. Exploration of the impact of inflammatory bowel disease and associated treatments on male fertility potential is necessary to optimise pregnancy outcomes. Infertility is strictly defined as a couple’s inability to conceive after 1 year of unprotected sexual intercourse. The rate of infertility in the general population is 8– 17% for two healthy adults.1 In one population-based study, male factor infertility was found to be the sole cause in 26% of infertile couples.2 In patients with inflammatory bowel disease (IBD), male infertility is thought to be more prevalent compared to the general population3; it is unclear whether this is due to the disease process directly or perhaps resulting from a decreased desire to have children.4, 5 A systematic review by Tavernier et al. of females with Crohn’s disease (CD) revealed a 17–44% reduction in fertility, which they attributed to voluntary childlessness rather than a physiological cause.5, 6 They also found that there was a similar reduction in fertility of male patients with CD of 18–50%, although there was no difference in reproductive capacity.5 Farthing et al. published a small study of patients with CD, finding oligospermia in 46% of the subjects.7, 8 Narendranathan et al. surveyed 106 patients with CD and 62 patients with UC. Compared to 140 healthy agematched controls, pregnancy rates were lower for males with inflammatory bowel disease vs. controls.9 However, they did not detect a significant difference in fecundability between patients with IBD and healthy controls, thus failing to show a direct cause of decreased male fertility.7, 9, 10 In patients with ulcerative colitis (UC), Tavernier et al. found that in male patients there was no evidence of reduced fertility and most studies showed no reduced fertility in females.5, 6, 9 Sato et al. found that only 6% of male patients with IBD did not use medication and that patients in their study believed that medication use and continued remission were more important than withdrawing their treatment regimen when attempting to conceive.11 The prevalences of various factors affecting fertility are listed in Table 1.

2

A study by Burnell et al. looked at 70 males with CD (age range 19–79) and 70 males without the disease. Marriage rates were the same in both groups. Subjects with CD had significantly fewer children than matched controls, even when looking at only those who were married. The mechanism was not clear, as the decreased fertility may have been due to ill health or perhaps a direct manifestation of the disease – again, no causal relationship could be defined.12 A summary of the effects of CD on pregnancy and birth rates is shown in Table 2.

METHODS A PubMed search of the published literature utilising search terms ‘male infertility,’ ‘Crohn’s disease,’ ‘inflammatory bowel disease,’ ‘ulcerative colitis,’ ‘ciprofloxacin AND infertility,’ ‘metronidazole AND infertility,’ ‘sulfasalazine AND infertility,’ ‘sulfasalazine AND teratogen,’ ‘azathioprine AND infertility,’ ‘methotrexate AND infertility,’ ‘ciclosporin AND infertility,’ ‘corticosteroids AND infertility,’ ‘corticosteroids AND teratogen,’ ‘fluoroquinolones AND teratogen,’ ‘infliximab AND male fertility,’ ‘infliximab AND infertility,’ ‘infliximab AND foetus,’ ‘infliximab AND paternal exposure’ and ‘infliximab AND sperm.’ Additional articles were discovered through review of the reference lists of select pertinent articles. Due to the limited research on male infertility in inflammatory bowel disease, naturally, the data presented in this review were elucidated in studies utilising case reports, case series and small cohorts. The date of the last search was 16 May 2014. A total of 56 articles were analysed, with a wide range of study designs and reviews considered (Table 3). RESULTS Pathophysiology Several mechanisms have been described explaining male infertility seen in patients with IBD. The most commonly studied aetiology is impairment of spermatogenesis by therapeutic agents. Sulfasalazine Sulfasalazine has been used to treat IBD for over 60 years, either as initial treatment of CD or UC, or as maintenance treatment in UC. Sulfasalazine is metabolised by gut flora into sulfapyridine and 5-aminosalicylic acid, which act as anti-inflammatory agents. This medication has been shown to cause quantitative and qualitative abnormalities of sperm in over 80% of men on

Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD Table 1 | Factors affecting fertility Prevalence General population Rate of infertility among couples 8–10% Rate of infertility among couples 17% Sole male factor infertility (general population) Sperm defect/dysfunction 24% Other male infertility 2% Patients with CD without treatment Oligospermia 46% Oligospermia 48% Lack of motility 65% Pathological sperm morphology 90% Patients with UC during treatment with sulfasalazine Oligospermia 39.6% Abnormal morphology 41.7% Impaired motility 91.7%

n

Dates

Country

– 2803

2003 1985

UK UK

1 2

472 472

1985 1985

UK UK

2 2

13 29 29 29

1983 2003 2003 2003

UK UK UK UK

8 53, 54 53, 54 53, 54

16 16 16

1987 1987 1987

UK UK UK

22 22 22

Reference number

There is a paucity of infertility data, particularly relating to males, available on patients with untreated UC.

Table 2 | IBD effects on conception

Mean number of pregnancies Male patients with UC Male patients with CD Mean number of offspring Prior to diagnosis of CD Post-diagnosis of CD

Reference number

With disease

Controls

n

Significance

Dates

Country

1.77  0.18 1.75  0.12

NS* 2.14  0.11*

308 308

P < 0.07 P < 0.02

1989 1989

US US

9 9

1.2 0.8  1.1 0.4 0.3  0.7

1.5† 1.1  1.4‡ 0.8† 0.6  1.0‡

84 140 84 140

NS P < 0.006 P < 0.05 P < 0.006

2006 1986 2006 1986

US UK US UK

42 12 42 12

NS, not significant. * Age, sex and race matched neighbours. † Age matched controls. ‡ Healthy, same birth year controls.

treatment.10 In addition, Birnie et al. found that in a study of 21 men with CD receiving sulfasalazine treatment, 86% had abnormal semen analyses and 72% were found to have oligospermia.13 In forty male rats, Fukushima et al. found that there was a statistically significant decrease in percentage of progressively motile sperm in those treated with sulfasalazine 600 mg/kg for 28 days (8.3  2.5) when compared to controls (23.0  8.3). While percentage of motile sperm was significantly decreased, they did not find significant changes in histology or weight of reproductive organs. Possible mechanisms include competitive inhibition and subsequent impairment of folate metabolism, inhibition of gene expression for acrosomal membrane proteins CD59, MCP and DAF and decreased spermatic motility.14 Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Another proposed theory involves impairment of sperm parameters via reactive oxygen species (ROS), however in one study, no correlation was found between amount of reactive oxygen species produced and sperm density, motility or hamster oocyte penetration.15 Hormonal effects have not been observed, as patients on high doses of sulfasalazine have been shown to have normal testosterone levels.10 The sulfapyridine metabolite is thought to be directly responsible for the side effects of sulfasalazine treatment, including toxic effects on spermatozoa.16, 17 In one study, three groups of rats were fed sulfasalazine, sulfapyridine or 5-ASA. The groups ingesting sulfasalazine and sulfapyridine had decreased litter sizes compared to the 5-ASA group, leading the authors to link sulfapyri3

K. Sands et al. Table 3 | Characteristics of included studies Study type Animal studies Case control Case series Cohort study Cross-sectional Review

Number of studies

Total number of subjects

8 6 12 11 2 17

175 1149 191 2627 619 –

dine to infertility. Their study also showed no difference in reproductive organ weight and histology.18 This reversible infertility found in rats was also seen in human subjects with UC on sulfasalazine therapy. The authors found oligospermia in the sulfasalazine group, specifically linking it to sulfapyridine. When mesalazine was substituted, there was a consistent improvement in sperm counts, motility, morphology and successful conception.6, 10, 17, 19, 20 Patients treated with sulfasalazine have been shown to possess significantly more sperm with a larger head size (99th percentile) than that seen in non colitic oligospermic men. In these patients, after discontinuing sulfasalazine, concentrations of sperm with a large head size transiently increased further, then reduced, likely due to the lag effect of the drug and 74day period of spermatogenesis.18, 21 The effects of sulfasalazine on sperm have been shown to be reversible once the drug is discontinued.17 In one study, subjects who were taking sulfasalazine showed significantly decreased sperm counts, decreased sperm motility and increased number of abnormal forms, especially compared to subjects who were not on therapy or had discontinued sulfasalazine >3 months prior to the study. Resolution of abnormal semen analyses was noted after a few months and the median time to pregnancy following cessation of therapy was 2–5 months18 (Table 4). Riley et al. observed dose-dependent abnormalities in 16 ulcerative colitis patients on sulfasalazine

therapy – oligospermia in 39.6%, increased number of abnormal forms in 41.7% and impairment of sperm motility in 91.7%. All of these effects were shown to regress 3 months after discontinuing the treatment. Sperm were also shown to normalise when subjects were switched to mesalazine therapy with mean sperm count, sperm motility and abnormal sperm forms significantly improving.22 Notably there is one case report of reversible infertility in a patient with UC on mesalazine therapy. The patient experienced decreased sperm quantity and motility, both of which normalised when mesalazine was stopped. The mechanism is unknown, but may be similar to that of sulfapyridine.23 A retrospective study by Shin et al. evaluated a group of 1225 subfertile men for prevalence of IBD in their reproductive clinic. Of the 1225 men, two men had been diagnosed with Crohn’s disease and six men with ulcerative colitis. Seven of the patients included had taken mesalazine, of which six had discontinued therapy. Semen parameters of these six patients were evaluated. Following cessation of mesalazine therapy, improvement in sperm motility and total motile sperm count were found to be statistically significant (P < 0.05). This improvement resulted in four of the six patients achieving pregnancy. The authors concluded that mesalazine cessation should only be pursued in patients with stable IBD.24 A review by Vermeire et al. concluded that treatment with sulfasalazine caused no increase in birth defects, still births, miscarriages, low birth weights or pre-term delivers as compared to the general population and untreated patients with IBD. They did caution against the use of mesalazine due to the inclusion of dibutyl phthalate and the association with male genitourinary malformations.6 As a result of newer derivatives of aminosalicylates that exclude the sulfapyridine moiety and are much better tolerated, the effect of sulfasalazine on decreased male fertility may be somewhat unintentionally mitigated. This could be due to changes in prescribing patterns secondary to more noticeable side effects of nausea, vomiting,

Table 4 | Effects of sulfasalazine on sperm Parameter

Sulfasalazine 2–4 g/day (n = 39)

Discontinued >3 months (n = 16) Controls (n = 9)

n

Dates Country Reference

24.0 (95% CI 16.3–32.9) 55.7 (95% CI 37.7–77.1) 49.3 64 1984 Mean sperm (P = 0.03) (NS) (95% CI 27.7–77.1) count (9106 sperm/ml) Progressively 29.6 (95% CI 22.8–36.4) 48.2 (95% CI 37.6–58.8) 48.6 64 1984 motile sperm (%) (P = 0.03) (NS) (95% CI 34.4–62.7) Abnormal 35.3 (95% CI 30.5–40.9) 22.9 (95% CI 18.2–28.8) 21.7 64 1984 morphology (%) (P = 0.008) (NS) (95% CI 15.8–29.6) 4

UK

18

UK

18

UK

18

Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD decreased appetite, headache and dizziness. The American College of Gastroenterology (ACG) Clinical Guideline on Crohn’s disease notes the common use of mesalazine and sulfasalazine in treatment regimens but does not recommend one over the other. In addition, they state that currently there are no published clinical trials of sufficient size to compare the efficacy of sulfasalazine to alternative 5-ASA therapies. The ACG Clinical Guideline on Ulcerative Colitis also notes the common use of sulfasalazine as the traditional first line treatment for mild to moderate disease. They also note that the major advantage of sulfasalazine over newer formulations is its lower cost rather than efficacy.25, 26

Methotrexate Methotrexate (MTX) is an inhibitor of dihydrofolate reductase and is used in multiple autoimmune disorders, including IBD. It is known to be teratogenic and mutagenic, but does not appear to affect testicular function. It has an association with oligospermia, likely due to its anti-folate mechanism, which results in decreased DNA synthesis rates and subsequent inhibition of cellular proliferation.10 One animal study on methotrexate showed altered spermatogenesis, cytotoxicity and degeneration of spermatocytes, Sertoli and Leydig cells. The oligospermia due to MTX is reversible when the drug is discontinued.7, 27 In a study on the effect of MTX on rat seminiferous tubules, microscopic analysis showed a dose-dependent and statistically significant decreased diameter of the tubules (18 vs. 22, P < 0.01), increased size of the interstitium, as well as a distortion in Leydig cell shape. Findings included vacuolisation/decondensation of the ‘chromatinmass’ in spermatocytes, change in head shape from round to oval, a significant reduction in the size of the Sertoli and Leydig cells, and partial thinning/disruption of the basement membrane. They concluded that these findings could contribute to changes in reproductive capacity of male rats but note that it may be reversible.28 Human studies have shown mixed effects. One study on the use of MTX in the treatment of psoriasis showed injury to the germinal epithelium and impaired spermatogenesis with no effect on Leydig cells or testosterone production. The proposed mechanism was again due to the anti-folate effect which disrupts DNA synthesis in spermatogonia and spermatocytes.27 Another review showed no abnormalities in semen, testicular histology or spermatogenic function with short-term follow-up.7 Noted in this study was the absence of adverse pregnancy outcomes related to the teratogenicity of methotrexate. The authors ascribed this to lack of long-term follow-up, Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

stating that male infertility or early arrested embryonic development may have occurred and not been observed. Although the effect of MTX on fertility is well documented, French and Koren in collaboration with the Motherisk Programme at the University of Toronto report that there have been ‘no reports of adverse pregnancy outcomes among men exposed to methotrexate before conception’.29 In addition, there is one report of a 41-year-old male taking MTX and infliximab at the time of conception resulting in a healthy 2.8 kg foetus.30 A prospective observational study by Weber-Shoendorfer et al. of 113 conceptions fathered by men on low dose methotrexate treatment compared to 412 non-exposed controls were not significantly different. The authors concluded that there was no increased risk posed by paternal methotrexate exposure and subsequently ‘it seems reasonable not to postpone family planning’.31

Thiopurines Azathioprine (AZA) and its active metabolite mercaptopurine are used to induce remission in patients with chronically active IBD. With these treatments, male fertility is not affected but treatment with these drugs remains controversial.6 Azathioprine does not decrease semen quality by sperm density, motility, morphology, ejaculate volume or total sperm count.32 Notably, in one mouse study, sperm production, quality and reproductive outcome were measured following prolonged mercaptopurine administration. Sperm was analysed after 45 days of treatment, and no impairment in sperm production or sperm morphology was identified. However, a significantly high rate of embryonic resorption occurred, which the authors determined indicated occult sperm damage. Another study observed an increase in spontaneous abortions when comparing mercaptopurine use in male mice vs. placebo (rates of 45–50% vs. 21%). As such, normal semen analyses do not exclude genetic abnormalities induced by these drugs and though true causality cannot be determined, occult sperm damage may carry a higher risk of teratogenicity in fathers on mercaptopurine within 3 months of conception.33, 34 A study of 130 conceptions by Teruel et al. in 2010 recommended no routine alteration to treatment regimens for male patients taking thiopurines while attempting to conceive. However, as noted in the author’s discussion of limitations, the power of the study was lacking in addition to the retrospective nature of their methods. The data presented in their paper did not provide definitive evidence for requiring a change to the treatment regimens 35 (Table 5). 5

K. Sands et al. Table 5 | Conception risks of thiopurine use in male patients Exposed (n = 46)

Control (n = 84)

Statistical analysis

7 (15.2%)

7 (8.3%)

P = 0.596

1 (0–60)

0 (0–48)

P = 0.73

35

5 (10.9%)

11 (13.1%)

P = 0.718

35

2 (4.3%) 38.9 (2.2)

2 (2.4%) 39.4 (1.4)

P = 0.769 P = 0.111

35 35

3 (6.5%) 3063 (533)

5 (6%) 3248 (493)

P = 0.939 P = 0.004

35 35

1 (2.2%)

2 (2.4%)

P = 0.872

35

7.4% (n = 54)

4.1% (n = 57 195)

OR 1.8 (95% CI, 0.7–5.0)

Possible association, no evidence for causality

36

Mercaptopurine Spontaneous abortion

Group 1* 4

Group 2* 6

Controls 11

Overall risk P = 0.59, RR 0.85 (0.47–1.55)

No change in treatment regimen

37

Foetal defect aborted Anembryonic pregnancy Embryonic demise Pre-term Full term Ectopic Twins Low birth weight Major defect Postnatal infections Neoplasia Major congenital abnormalities Mercaptopurine

1 1 1 1 32 1 3 2 2 1 0 3

1 0 0 3 27 0 0 2 0 0 1 1

0 0 0 3 59 0 0 3 2 0 0 2

Group 1A† (n = 13) 2 (15%)

Group 1B† (n = 37) 1 (2.7%)

Group 2 (n = 90) 2 (2.2%)

Azathioprine Fertility impairment Time to achieve pregnancy (median months, range) Unsuccessful pregnancies Premature births Pregnancy length (mean weeks, s.d.) Low birth weight Weight at birth (mean grams, s.d.) Congenital Malformations Azathioprine or mercaptopurine Congenital anomalies

Spontaneous abortions

Congenital anomalies

2 (15%)

Recommendations

Reference

No change in treatment regimen

35

37 37 37 37 37 37 37 37 37 37 37 37

Group 1A compared to Group 2 (P < 0.002, OR 19.6, 95% CI 31–122) Group 1A compared to Group 1B (P < 0.013, OR 16, 95% CI 16–161)

Discontinue mercaptopurine at least 3 months prior to planned conception

38

38

* Group 1: father who discontinued mercaptopurine prior to conception, Group 2: father who was taking mercaptopurine at time of conception. † Group 1A: Conceptions within 3 months of paternal mercaptopurine use, Group 1B: conceptions following >3 months after paternal discontinuation of mercaptopurine, Group 2: Controls.

6

Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD A Danish study of 54 pregnancies conceived, while the father was taking AZA or mercaptopurine revealed four children with congenital abnormalities (7.4%) compared to the control group of 57 195 pregnancies with a congenital abnormality rate of 4.1%. They concluded their adjusted odds ratio of 1.8 (95% CI, 0.7–5.0) may indicate an increased risk of congenital abnormalities, but could not determine if this association was causal. Interestingly, the four children in the exposed group were all males and none had been conceived by fathers that had received AZA or mercaptopurine prescriptions in the 3 months leading up to conception. These fathers had taken AZA or mercaptopurine between 9– 38 months prior to conception. Their study was an evaluation of a prescription database and compliance with treatment regimen could not be investigated. Nogard et al. recommend using caution in males taking AZA and mercaptopurine while attempting to conceive.36 Francella et al. investigated 154 pregnancies that resulted from 76 male patients taking mercaptopurine at the time of conception. They found no statistically significant difference in pregnancy outcomes from both males and females exposed to mercaptopurine [RR = 0.85 (0.47–1.55), P = 0.59).37 Their results differed from a smaller study of 57 men by Rajapakse who compared males with IBD who were taking mercaptopurine with those not taking mercaptopurine. Twenty-three men taking mercaptopurine at the time of conception who fathered fifty pregnancies were compared to thirty-four men who were mercaptopurine na€ıve prior to conception and fathered ninety children. The fifty pregnancies in the exposed group were further split into two sections, 1A and 1B. The first, 1A, was comprised of 13 pregnancies conceived within 3 months of paternal mercaptopurine use and the second, 1B, comprised of 37 pregnancies at least 3 months after discontinuation of mercaptopurine. The 1A group, those with recent mercaptopurine exposure, showed a 30.7% (4 out of 13) rate of complications including two spontaneous abortions, one child with a missing thumb and one child with ‘acrania combined with digital and limb abnormalities.’ The 1B group, those conceived following discontinuation at least 3 months after discontinuation of mercaptopurine, had a complication rate of 2.7% (1 of 37) which included spontaneous abortion. The control group, had a complication rate of 2.2% (2 of 90) which included two-first trimester spontaneous abortions and no congenital abnormalities. There was no statistical difference between the 1A and 1B group (P < 0.097); however, there was a statistically higher incidence of Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

complications when comparing group 1A and group 1B (P < 0.013). In addition, there was a statistically significant increase in complications in group 1A compared to the controls, group 2 (P < 0.002). The authors concluded that there was indeed an increase in pregnancy complications resulting from paternal exposure to mercaptopurine within 3 months of conception.38 A meta-analysis by Akbari et al. of the above studies concluded that thiopurine use in female patients led to an increase in pre-term births when exposed at the time of conception and/or during the pregnancy. They did not find an association with low birth weight or congenital abnormalities. Furthermore, pooled analysis of paternal exposure to thiopurines at the time of conception were not found to be at risk of increased congenital abnormalities (OR 1.87; 95% CI 0.67–5.25; P = 0.236).39 Based on the data presented above regarding the use of mercaptopurine and AZA in male and female patients wishing to conceive, providers should counsel them that although fertility does not appear to be affected by these therapies, there is a possibility of an increased risk of congenital defects and pregnancy complications. No causal relationship has been delineated; however, the possibility cannot be excluded given the dearth of available research.

Ciclosporin Ciclosporin is an agent used for severe IBD. It is a fungal metabolite which acts as an immunosuppressor of T cells via blockage of IL-2 gene transcription.40 One study looking at its use in male mice showed presence of abnormal sperm, oligospermia, disorders of sperm motility, decreased testis weight and decreased testosterone concentrations.10 Dosing of 10 mg/kg/day showed decreased sperm motility and levels of sex hormones in another study; this is much higher than the normal dose used for IBD, and there are no studies analysing fertility rates in patients treated with a lower dose.10, 41 Interestingly, ciclosporin may actually serve as a treatment for autoimmune infertility. In one mouse study, its administration decreased the immune response to bilateral testicular injury, which may decrease immune sensitisation to testicular antigens and subsequent autoimmune orchitis.40 Systemic corticosteroids Corticosteroids are commonly used for acute treatment of IBD flares and induction of IBD remission. The use of exogenous steroids can cause a reversible decrease in sperm concentration and motility.4 In a study in patients 7

K. Sands et al. with CD, no correlation was identified between male infertility and steroid use.9 Another review looking at infertility linked with azathioprine noted that the addition of corticosteroids to AZA therapy did not worsen infertility caused by AZA.7

Monoclonal antibodies The exact aetiology of IBD is still under investigation; however, the cytokine tumour necrosis factor alpha (TNF-a) appears to have some influence on the development and progression of IBD. Therefore, newer therapeutics have evolved in recent years aimed at treatment of IBD through inhibition of TNF-a. In the USA, three TNF-a inhibitors are available, infliximab, adalimumab and certolizumab. Of the three, infliximab is the most studied. These medications are currently used for many inflammatory diseases such as ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, psoriasis and IBD. Infliximab is an anti-TNF-a monoclonal antibody used for severe IBD that is refractory to standard therapy. Although no specific study on infliximab and fertility in IBD patients has been performed, negative spermatic effects have been noted.7 Its use has been shown to significantly decrease sperm motility and morphology with just one infusion. These effects showed some dose–response, as there was further decrease with five infusions 8 weeks apart. This decreased motility and morphology may negatively affect fertility.10, 42 Infliximab use in 10 men caused increased semen volume, and may decrease sperm motility and the number of normal forms as well.41 However, a study of 26 men with spondylarthritis by Villiger et al. concluded that the sperm quality was comparable to healthy controls and therefore recommended the continuation of TNF-a inhibitors while attempting to conceive.43 Adalimumab (another monoclonal antibody against TNF-a), has not been studied for effects on male fertility.7 Paschou et al. reviewed the medical records of male patients in their clinic on infliximab over a period of 7 years. Their review of four male patients on infliximab with one on concomitant methotrexate had fathered six healthy children over this time without any fertility problems. While the effect of anti-TNF medications on male infertility is limited, even more limited is the research on children fathered by these patients.44 Puchner et al. found 60 cases of TNF-a use in males shortly before conception. Their review of the documented births of twenty-eight infants found no evidence 8

of reported anomalies or increases in miscarriages. They concluded, based on the published data available at the time, that there was no increase in risk to those foetuses conceived while the father was treated with anti-TNF medications. In addition, they concluded that there was positive effect of TNF-a inhibitor use on sperm motility and vitality.45 Millsop et al. also found that there was no need to withdraw therapy in men attempting to conceive as TNF-a inhibitor therapy should not adversely affect fertility.46 Ramonda et al. investigated the effect of TNF-a inhibitors in male spondylarthritis patients and concluded that TNF-a inhibitors do not damage testicular function or spermatogenesis, these medications are safe to use while attempting to conceive, and discontinuation is not likely necessary.47 Although few studies are readily available investigating the effects upon the foetus of male patients with IBD that are taking TNF-a inhibitors at the time of conception, other studies on patients taking these medications for other indications are easily extrapolated as the dosing and treatment regimen is similar. Much of the data are derived from case reports or small sample sizes.

Antibiotics The use of antibiotics in treatment of inflammatory bowel disease is well documented. Most notably, the use of ciprofloxacin, metronidazole or a combination of the two is a common treatment for fistulising and perianal disease in patients with CD. Foote showed that the effect of metronidazole at 10 mg/mL appears not to be toxic to sperm.48 Several studies of ciprofloxacin in rats have shown statistically significant decreases in fertility. Zobeiri et al. showed that changes in germinal epithelium due to prolonged treatment with ciprofloxacin may cause intracytoplasmic changes resulting in decreased fertility. They also reported a dose-dependent decrease in serum testosterone, luteinising hormone (LH) and follicle stimulating hormone (FSH) thus potentially affecting spermatogenesis.49 In a study in rats, Khaki et al. showed a statistically significant decrease in total sperm count, motility and viability in rats treated with 12.5 mg/kg vs. controls. They also found a significant decrease in spermatogonia, spermatocytes, spermatids and sperm within the seminiferous tubules.50 Given the limited studies, in certain patients deemed appropriate to treat with ciprofloxacin, metronidazole or a combination, some component of male infertility attributed to this treatment regimen cannot be excluded. Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD Table 6 | Quantitative risks of drug therapy n Sulfasalazine Sperm count Abnormal morphology Sperm motility Abnormal semen analysis Oligospermia Adverse haematological reaction % progressively motile sperm Mesalazine Interstitial nephritis Adverse haematological reaction Azathioprine (mercaptopurine) Sperm density Sperm motility Normal morphology Ejaculate volume Total sperm count Leukopenia (15 million per mL, total motility >40%, progressive motility >32%, vitality (% of live spermatozoa) >58% and >4% normal sperm morphology.

TREATMENT OF INFERTILITY IN MALE IBD PATIENTS The treatment of male infertility in IBD is dependent on the aetiology (Table 7). In general, it is recommended to control the patient’s IBD and optimise their nutritional status. If the patient is zinc deficient, zinc supplementation may restore testicular function, thus increasing sperm count and Leydig cell function.53, 55 It is recommended for patients to limit alcohol and tobacco use; in the setting of male infertility, tobacco and alcohol cessation may improve fertility.7 In the case of persistent infertility following nutritional deficiency correction and pharmacological optimisation, referral to a urological surgeon is recommended for further evaluation and work-up. In patients taking medications which may damage sperm quality, cessation may restore fertility.56 However, the risk of stopping the medication to potentially regain fertility must be weighed against the health benefits derived from the medication.48 In patients on sulfasalazine, it is recommended that patients switch to mesalazine at least 4 months prior to attempting conception.19, 20, 22, 42 It has also been recommended that men stop methotrexate at least 4 months prior to attempted conception.7 Corticosteroids should only be used for short periods of time to control active disease, after which they should be discontinued to avoid any potential effect on fertility.4 Although men on AZA or mercaptopurine within 3 months of conception may carry a higher risk of teratogenicity due to occult sperm damage, no strong enough evidence exists to recommend stopping AZA or mercaptopurine.34 In the case of immunologically mediated infertility, immunosuppression is the key in treatment. There is no evidence suggesting that stopping Infliximab or Adalimumab will benefit male fertility.57 Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD History IBD History: Years Since Diagnosis, # of Flares, Severity Medical and Surgical Therapies Sexual History: Coital Frequency, Duration of Infertility, STD History, Congential/Developmental History

Physical Exam

No plausible anatomical cause

Plausible Anatomical Cause/Abnormal Testicular Exam1

Modify IBD Risk Factors: Tobacco and alcohol cessation, evaluate pharacological influence, Nutritional Status

Scrotal ultrasound

Abnormal2

Correct anatomical defect

Normal3

Semen analysis

Normal Sperm Parameters4

Abnormal

Evaluate FSH, LH, Testosterone, Prolactin

1.5 mL, total sperm count >39 million per ejaculate, sperm concentration of >15 million per mL, total motility >40%, progressive motility >32%, vitality (% of live spermatozoa) >58% and >4% normal sperm morphology. 5Post-ejaculatory urinalysis is used as an aid in evaluating for retrograde ejaculation. If a significant proportion of the total sperm count is discovered in the postejaculatory urinalysis, further evaluation and treatment should be undertaken. IBD, inflammatory bowel disease; STD, sexually transmitted disease; FSH, follicle stimulating hormone; LH, luteinising hormone; WBC, white blood cells; Ab, antibodies.

Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

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K. Sands et al. Table 7 | Risk factors for infertility Infertility risk factor

Side effects

Key recommendation

Reference number

Sulfasalazine

Oligospermia, increased abnormal forms, decreased motility

19, 20, 22, 42

AZA/mercaptopurine

Potential for occult sperm damage and possible teratogenicity

Corticosteroids

Decrease in sperm concentration and motility Oligospermia, teratogen

Switch to mesalazine (mesalamine) at least 4 months prior to conception Counsel on possibility of teratogenicity due to sperm damage Limit to short-term use Stop methotrexate at least 4 months prior to conception Zinc supplementation

7, 27

Tobacco cessation Alcohol cessation

7 7

Methotrexate

Nutritional status Smoking tobacco Alcohol Consumption

Decreased testicular/ leydig cell function General male infertility Decreased sperm quality

COUNSELLING MALE IBD PATIENTS AT THE TIME OF CONCEPTION In patients with inflammatory bowel disease desiring to have children, it becomes important to counsel them appropriately on the risks and benefits of the currently accepted treatment regimens. A survey of male IBD patients by Sato et al. revealed that maintaining remission of their disease while attempting to conceive was important to them.11 These patients, with an already increased propensity for infertility due to their disease state, may find themselves drastically more infertile with treatment with sulfasalazine. Careful consideration of plans to have children in the near future should be taken into account when starting certain medications. Due to the possible teratogenicity of certain medications, they should be avoided in patients undergoing treatment for IBD desiring to produce children in the near future. Although the aetiology of male infertility and the consequences of particular drug regimens especially in the IBD patient population is multifactorial, it is our opinion that based on the evidence presented in this paper, that continued treatment of male IBD patients with sulfasalazine, methotrexate, ciclosporin, TNF-a inhibitors or systemic corticosteroids at the time of conception is both reasonable and preferred. Caution and extensive counselling are warranted for males currently being treated by azathioprine and mercaptopurine as the data are mixed regarding increased congenital anomalies. A recent meta-analysis found no statistically significant increase in congenital abnormalities following paternal exposure at the time of concep12

33, 34

4

49, 50

tion; however, limitations include retrospective analysis and limited data collection in the available human studies.39 In addition, control of the chronic inflammatory state may improve fertility in these patients. If infertility should be of concern, further evaluation by an urologist is recommended (Figure 1).

LIMITATIONS Limitations of the studies reviewed in this paper include small study sizes, anecdotal evidence, medication sequelae, lack of reliable pharmacoepidemiology and the multifactorial nature of infertility itself. With these considerations, we understand that there is much research to be undertaken with respect to infertile male patients with IBD. Future areas of research could include analysis of pre-, peri- and post-treatment fertility for patients with and without IBD, utilising head to head comparisons of different drug regimens with controls. CONCLUSION It is recognised that male infertility is often impacted with therapeutic drugs used to treat inflammatory bowel disease, however, the effect of the paternal drug exposure at the time of conception and exposure in utero should also be considered to counsel patients appropriately. AUTHORSHIP Guarantor of the article: Robert Jansen Author contributions: I, Robert Jansen, as Guarantor of the article, take responsibility of the creation and editing Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Review: safety of drugs in males with IBD of the article. All authors contributed to the writing and compilation of this paper.

ACKNOWLEDGEMENT Declaration of personal and funding interests: None.

REFERENCES 1. Alstead EM, Nelson-Piercy C. Inflammatory bowel disease in pregnancy. Gut 2003; 52: 159–61. 2. Hull MG, Glazener CM, Kelly NJ, et al. Population study of causes, treatment and outcome of infertility. Br Med J (Clin Res Ed) 1985; 291: 1693–7. 3. Rossato M, Foresta C. Antisperm antibodies in inflammatory bowel disease. Arch Intern Med 2004; 164: 2283. 4. Heetun ZS, Byrnes C, Neary P, O’Morain C. Review article: reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26: 513–33. 5. Tavernier N, Fumery M, PeyrinBiroulet L, Colombel J-F, GowerRousseau C. Systematic review: fertility in non-surgically treated inflammatory bowel disease. Aliment Pharmacol Ther 2013; 38: 847–53. 6. Vermeire S, Carbonnel F, Coulie PG, et al. Management of inflammatory bowel disease in pregnancy. J Crohns Colitis 2012; 6: 811–23. 7. Feagins LA, Kane SV. Sexual and reproductive issues for men with inflammatory bowel disease. Am J Gastroenterol 2009; 104: 768–73. 8. Farthing MJ, Dawson AM. Impaired semen quality in Crohn’s disease–drugs, ill health, or undernutrition? Scand J Gastroenterol 1983; 18: 57–60. 9. Narendranathan M, Sandler RS, Suchindran CM, Savitz DA. Male infertility in inflammatory bowel disease. J Clin Gastroenterol 1989; 11: 403–6. 10. Serghini M, Fekih M, Karoui S, et al. Fertility and inflammatory bowel diseases. Tunis Med 2010; 88: 623–8. 11. Sato A, Naganuma M, Asakura K, et al. Conceptions outcomes and opinions about pregnancy for men with inflammatory bowel disease. J Crohns Colitis 2010; 4: 183–8. 12. Burnell D, Mayberry J, Calcraft BJ, Morris JS, Rhodes J. Male fertility in Crohn’s disease. Postgrad Med J 1986; 62: 269–72. 13. Birnie GG, McLeod TI, Watkinson G. Incidence of sulphasalazineinduced male infertility. Gut 1981; 22: 452–5. 14. Fukushima T, Kato M, Adachi T, et al. Effects of sulfasalazine on sperm acrosome reaction and gene expression Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

in the male reproductive organs of rats. Toxicol Sci 2005; 85: 675–82. Wu FC, Aitken RJ, Ferguson A. Inflammatory bowel disease and male infertility: effects of sulfasalazine and 5-aminosalicylic acid on spermfertilizing capacity and reactive oxygen species generation. Fertil Steril 1989; 52: 842–5. Toovey S, Hudson E, Hendry WF, Levi AJ. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut 1981; 22: 445–51. Linares V, Alonso V, Domingo JL. Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity. Expert Opin Drug Saf 2011; 10: 253–63. O’Morain C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984; 25: 1078–84. Kjaergaard N, Christensen LA, Lauritsen JG, Rasmussen SN, Hansen SH. Effects of mesalazine substitution on salicylazosulfapyridine-induced seminal abnormalities in men with ulcerative colitis. Scand J Gastroenterol 1989; 24: 891–6. Di Paolo MC, Paoluzi OA, Pica R, et al. Sulphasalazine and 5aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects. Dig Liver Dis 2001; 33: 563–9. Hudson E, Dore C, Sowter C, Toovey S, Levi AJ. Sperm size in patients with inflammatory bowel disease on sulfasalazine therapy. Fertil Steril 1982; 38: 77–84. Riley SA, Lecarpentier J, Mani V, et al. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut 1987; 28: 1008–12. Chermesh I, Eliakim R. Mesalazineinduced reversible infertility in a young male. Dig Liver Dis 2004; 36: 551–2. Shin T, Kobori Y, Suzuki K, et al. Inflammatory bowel disease in subfertile men and the effect of mesalazine on fertility. Syst Biol Reprod Med 2014; 60: 373–6. Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn’s disease in adults. Am J Gastroenterol 2009; 104: 465–83.

26. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105: 501–23. 27. Sussman A, Leonard JM. Psoriasis, methotrexate, and oligospermia. Arch Dermatol 1980; 116: 215–7. 28. Saxena AK, Dhungel S, Bhattacharya S, Jha CB, Srivastava AK. Effect of chronic low dose of methotrexate on cellular proliferation during spermatogenesis in rats. Arch Androl 2004; 50: 33–5. 29. French AE, Koren G. Effect of methotrexate on male fertility. Can Fam Physician 2003; 49: 577–8. 30. Lamboglia F, D’Inca R, Oliva L, Bertomoro P, Sturniolo GC. Patient with Severe Crohn’s Disease Became a Father While on Methotrexate and Infliximab Therapy. Inflamm Bowel Dis 2009; 15: 648–9. 31. Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, Meister R, Schaefer C. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology 2014; 53: 757–63. 32. Dejaco C, Mittermaier C, Reinisch W, et al. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001; 121: 1048–53. 33. Ligumsky M, Badaan S, Lewis H, Meirow D. Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol 2005; 40: 444–9. 34. Kane SV. What’s good for the goose should be good for the gander–6-MP use in fathers with inflammatory bowel disease. Am J Gastroenterol 2000; 95: 581–2. 35. Teruel C, Lopez-San Roman A, Bermejo F, et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines. Am J Gastroenterol 2010; 105: 2003–8. 36. Norgard B, Pedersen L, Jacobsen J, Rasmussen SN, Sorensen HT. The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception. Aliment Pharmacol Ther 2004; 19: 679–85. 13

K. Sands et al. 37. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003; 124: 9–17. 38. Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000; 95: 684–8. 39. Akbari M, Shah S, Velayos F, Mahadevan U, Cheifetz A. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm Bowel Dis 2013; 19: 15–22. 40. Sakamoto Y, Matsumoto T, Kumazawa J. Cell-mediated autoimmune response to testis induced by bilateral testicular injury can be suppressed by cyclosporin A. J Urol 1998; 159: 1735–40. 41. Mahadevan U, Terdiman JP, Aron J, Jacobsohn S, Turek P. Infliximab and semen quality in men with inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 395–9. 42. Mahadevan U. Fertility and pregnancy in the patient with inflammatory bowel disease. Gut 2006; 55(8): 1198– 206. 43. Villiger PM, Caliezi G, Cottin V, Forger F, Senn A, Ostensen M. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis 2010; 69: 1842–4.

14

44. Paschou S, Voulgari PV, Vrabie IG, Saougou IG, Drosos AA. Fertility and Reproduction in Male Patients with Ankylosing Spondylitis Treated with Infliximab. J Rheumatol 2009; 36: 351–4. 45. Puchner R, Danninger K, Puchner A, Pieringer H. Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clin Exp Rheumatol 2012; 30: 765–7. 46. Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication effects on male fertility. Dermatol Ther 2013; 26: 337–46. 47. Ramonda R, Foresta C, Ortolan A, et al. Influence of tumor necrosis factor a inhibitors on testicular function and semen in spondyloarthritis patients. Fertil Steril 2014; 101: 359–65. 48. Foote RH. Effects of metronidazole, ipronidazole, and dibromochloropropane on rabbit and human sperm motility and fertility. Reprod Toxicol 2002; 16: 749–55. 49. Zobeiri F, Sadrkhanlou R, Salami S, Mardani K. Long-term effect of ciprofloxacin on testicular tissue: evidence for biochemical and histochemical changes. Int J Fertil Steril 2013; 6: 294–303. 50. Khaki A, Heidari M, Novin MG, Khaki AA. Adverse effects of ciprofloxacin on testis apoptosis and sperm parameters in rats. Iran J Reprod Med 2008; 6: 71–6. 51. Cunliffe RN, Scott BB. Review article: monitoring for drug side-effects in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16: 647–62.

52. Jarrow J, Sharlip I, Belker A, et al. Male Infertility Best Practices Policy of the American Urological Association: optimal Evaluation of the Infertile Patient and Management of Obstructive Azoospermia, AUA Update Series. 2002; Lesson 38, Volume XXI. http:// www.auanet.org/common/pdf/ education/clinical-guidance/MaleInfertility-d.pdf 53. El-Tawil AM. Zinc deficiency in men with Crohn’s disease may contribute to poor sperm function and male infertility. Andrologia 2003; 35: 337–41. uchsel R, 54. Sch€ olmerich J, Wietholtz H, B€ K€ ottgen E, L€ ohle E, Gerok W. Zinc and vitamin A deficiency in gastrointestinal diseases. Leber Magen Darm 1984; 14: 288–95. 55. Abbasi AA, Prasad AS, Rabbani P, DuMouchelle E. Experimental zinc deficiency in man. Effect on testicular function. J Lab Clin Med 1980; 96: 544–50. 56. Mountifield R, Bampton P, Prosser R, Muller K, Andrews JM. Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions. Inflamm Bowel Dis 2009; 15: 720–5. 57. Dimitrova D, Kalaydjiev S, Mendizova A, Piryova E, Nakov L. Circulating antibodies to human spermatozoa in patients with ulcerative colitis. Fertil Steril 2005; 84: 1533–5.

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