Verschillende reumatische aandoeningen kunnen invloed hebben op de vruchtbaarheid bij mannen en vrouwen. Vooral een hoge ziekteactiviteit kan negatieve effecten hebben hierop. Het goed behandelen van een actieve ziekte is dan ook gunstig voor vrouwen en mannen met een kinderwens. Echter kunnen bepaalde medicijnen ook invloed hebben op de vruchtbaarheid. In deze module wordt beschreven welke medicamenten bij reumatische aandoeningen een nadelig effect kunnen hebben ten aanzien van de vruchtbaarheid wanneer deze gebruikt worden bij actieve kinderwens.

Deelvraag 1: Welke medicatie kan gebruikt worden bij een vrouw met een kinderwens ten aanzien van vruchtbaarheid?

Description of studies

A total of 18 studies were found on pre-conceptional exposure to antirheumatic drugs and the effects on fertility, miscarriages and congenital malformations: 1 randomized controlled trial (RCT), 11 cohort studies, 2 case-control studies and 4 case-series. 18 studies reported the effects of antirheumatic drugs on fertility outcomes. The drugs described in the studies were: NSAIDs (3 studies), Glucocorticoids (1 study), Sulfasalazine (1 study), Methotrexate (MTX) (2 studies), Cyclophosphamide (16 studies) and TNF inhibitors (1 study). The outcome measures to determine (in)fertility that were mainly analysed in the studies were sustained amenorrhea, premature menopause and time to pregnancy (TTP). No studies were found on pre-conceptional use of other antirheumatic drugs. 

Results

Fertility

Two cohort studies and one case-control study reported on the pre-conceptional exposition to NSAIDs in women with rheumatoid arthritis (RA). Pre-conceptional NSAIDs use was significantly associated with longer TTP (HR 0.66, 95%CI 0.46 to 0.94, p=0.022) (Brouwer, Hazes, Laven, & Dolhain, 2015). Moreover, sub-fertile patients used NSAIDs more often than fertile patients, adjusted for DAS28 score (n=104 vs. n=141, p = 0.007) (Brouwer et al., 2015). Also, luteinized unruptured follicle (LUF) syndrome occurred more often in women exposed to NSAIDs in a continuous per-ovulatory regimen than in women not exposed to NSAIDs (women with RA using NSAIDs vs. healthy women exposed to NSAIDs for noninflammatory conditions, p<0.001) (Micu, Micu, & Ostensen, 2011). 

Preconceptional prednisone use was found to be associated with longer TTP in women with RA, with higher dosage significantly extending the TTP (HR 0.50, 95%CI 0.33 to 0.76, p=0.001) (Brouwer et al., 2015). 

In women with RA the use of pre-conceptional sulfasalazine or methotrexate (MTX) was not significantly associated with a longer TTP (HR 0.83 95%CI 0.62 to 1.13, p=0.234 and HR1.35 95%CI 0.99 to 1.84, p=0.059 respectively) (Brouwer et al., 2015).

Contreras et al. (2005) studied the effect of pre-conceptional exposure to Cyclophosphamide (CYC) on sustained amenorrhea in an RCT (Contreras, Tozman, Nahar, & Metz, 2005). Fifty-nine women with lupus nephritis were randomly assigned to receive IVCYC, Mycophenolate mofetil (MMF) or Azathioprine (AZA). Significantly more women receiving IVCYC experienced sustained amenorrhea compared to women receiving MMF (32% vs. 6%, p-value = 0.03) or AZA (32% vs. 8%, p-value = 0.03). Multiple cohort studies reported a higher incidence of sustained amenorrhea, premature menopause, or infertility in women with systemic lupus erythematodes (SLE) exposed to CYC compared to women not-exposed (Alarfaj & Khalil, 2014; Appenzeller, Blatyta, & Costallat, 2008; Brunner et al., 2006; Contreras et al., 2005; Harward, Mitchell, Pieper, Copl, et al., 2013; Mayorga, Alpízar-Rodríguez, Prieto-Padilla, Romero-Díaz, & Cravioto, 2015; McDermott & Powell, 1996; Singh, Misra, & Aggarwal, 2016). Moreover, Appenzeller et al. (2008) found associations between sustained amenorrhea, treatment duration (p=0.001) and total IVCYC dose (p=0.002) (Appenzeller et al., 2008). These associations were also found in studies of Boumpas et al (1995) and Harward et al. (2013). Boumpas (1993), reported that patients exposed to long-term CYC were more likely to develop sustained amenorrhea than patients exposed to short term CYC treatment (39% vs 12%, Fisher exact test, p-value = 0.07) (Boumpas et al., 1993). Harward (2013) found that women with amenorrhea had a cumulative dose of CYC more than two-fold higher (p = 0.04) than those women with continuing menstruation (Harward, Mitchell, Pieper, Copl, et al., 2013). A significant association between age at first exposure to CYC treatment initiation and premature ovarian failure was found in 4 cohort studies, with older age being associated with ovarian failure (Harward, Mitchell, Pieper, Copl, et al., 2013; Mayorga et al., 2015; McDermott & Powell, 1996; Mok, Lau, & Wong, 1998).

Only one study reported on pre-conceptional exposure to TNF inhibitors. In this cohort study 9 women with RA exposed to certolizumab pegol and 6 women with RA exposed to etanercept were compared to 10 women with RA who discontinued all bDMARDs at pre-conceptional counselling. Mean TTP was significantly shorter in the cases than controls (5.9 (3.8) vs 11.0 (6.5) months, p-value = 0.04) (Shimada et al., 2019).

Level of evidence of the literature

The level of evidence regarding the effect of pre-conceptional NSAIDs, glucocorticoids, csDMARDs and bDMARDs use on the outcome measure fertility started at low GRADE, because included studies were mainly observational. Because comparative and non-comparative studies were included, risk of bias is probable and the literature should therefore be downgraded with at least one level to a very low GRADE.

The level of evidence regarding the effect of pre-conceptional use of the csDMARD CYC on the outcome measure fertility was downgraded by 1 level because of applicability (bias due to indirectness) to moderate GRADE. 

For all other antirheumatic drugs no GRADE could be applied as no (comparative) studies were found with regard to their effects on fertility. 

Deelvraag 2: Welke anti-inflammatoire medicatie kan gebruikt worden bij een man met een kinderwens ten aanzien van vruchtbaarheid?

Description of studies
A brief description of included studies, main outcomes and quality assessment can be found in the evidence table. No GRADE conclusions were formulated in this review.

Results
Sulfasalazine
Twenty-two studies with data on in total 329 exposed men to sulfasalazine were identified. Sperm analysis abnormalities were reported in 40-100% of those patients exposed to sulfasalazine (doses ranged from 2 to 4 mg per day). The most common sperm abnormality reported was asthenozoospermia (decreased motility) followed by decreased sperm counts and abnormal morphology. Data extracted from case reports and small case-series showed that oligospermia and asthenozoospermia were severe enough to cause male infertility. In all studies where follow up samples were available, sperm quality improved after sulfasalazine was withdrawn for 3 months. The majority of these studies were published between 1979-1987 and included patients diagnosed with Inflammatory bowel disease (IBD) (Di Paolo et al. 2001; Zelissen et al. 1988; Riley et al. 1987; Cosentino et al. 1984; Freixa et al. 1984; O'Morain et al. 1984; Ragni et al. 1984; Hudson et al. 1982; Freeman et al. 1982; Tobias et al. 1982; Toovey et al. 1981; Levi et al. 1979; Toth 1979; McIntyre et al. 1984; Iglesias-cortit et al. 1985; Cann et al. 1984; Ganatra et al. 2018; Shaffer et al. 1984; Traub et al. 1979; Chatzinoff et al. 1988; Birnie et al. 1981; Heineman et al. 1981). Importantly, most of these studies are case reports and case series.

Antimalarials (chloroquine, hydroxychloroquine)
Four studies that included data from 37 healthy men were identified. One study reported sperm quality parameters and three studies evaluated the ability of chloroquine to cross the blood-testis barrier (Ejebe et al. 2008; Hargreaves et al. 1998; Adeeko et al. 1994; Ette et al. 1988). As it is the case for other human tissues and fluids, chloroquine can be found on seminal plasma even after long-term withdrawal. One in-vitro study reported that high concentrations of chloroquine in seminal plasma inhibited sperm motility. No studies reporting these outcomes were identified for hydroxychloroquine.

Calcineurin Inhibitors (ciclosporine, sirolimus, tacrolimus)
Fifteen studies including a total of 263 cases and 229 controls were identified. All of these cases were receiving sirolimus or ciclosporine for organ transplantation (mainly kidney transplantation). In all 11 studies included, sperm quality abnormalities and reproductive hormonal alterations (low testosterone and high FSH/LH levels) were reported after sirolimus exposure (Zuber et al. 2008; Skrzypek et al. 2007; Deutsch et al. 2007; Kaczmarek et al. 2004; Lee et al. 2005; Misro et al. 1999; Sajad Hussain et al. 2015; Boobes et al. 2010; Bererhi et al. 2003; Fritsche et al. 2004; Tondolo et al. 2005). In addition, reversible infertility associated to sirolimus was reported in three studies. Despite the lack of reproductive safety information for tacrolimus in humans, in these studies, patients were switched from sirolimus to tacrolimus and their sperm quality improved.

Nine post kidney transplant patients exposed to ciclosporine provided semen samples and no relevant sperm quality abnormalities were reported. From this group of patients, 3 out of 4 patients were able to conceive while being exposed to ciclosporine (Misro et al. 1999; Haberman et al. 1991). A prospective study that included pre- and post-kidney transplantation data of 10 men, reported that hypogonadism was present before initiating treatment with ciclosporine. After 12 months of ciclosporine exposure levels of testosterone exceeded pre-transplant levels (Samojlik et al. 1992). Sexual hormone levels were normal and comparable among 21 ciclosporine and 16 tacrolimus exposed renal transplant male patients (Kantarci et al. 2004). Similar results were reported by others (Peces et al. 1994). Sperm concentration was inversely correlated to the ciclosporine whole blood levels in one study (Eid et al. 1996).

Colchicine
Eight studies including a total of 166 cases were identified. Most of these studies were published before 2000. Colchicine exposure (1-2 mg/day) was associated with low sperm counts and motility in 5 studies (Kirchin et al. 1999; Sarica et al. 1995; Ben-Chetrit et al. 1993; Merlin 1972; Kaya Aksoy et al. 2019). Abnormal sperm analysis were reported in 40-58% of patients exposed to colchicine (Kaya Aksoy et al. 2019; Sarica et al. 1995). One study reported normal cytogenic sperm analysis in 2 patients diagnosed with gout exposed to colchicine (Kastrop et al. 1999), one study reported no significant sperm analysis abnormalities in patients previously exposed to colchicine (Levy et al. 1977) and lastly, one study reported no significant sperm abnormalities in healthy volunteers exposed to colchicine (Bremner et al. 1976). A possible adverse effect on sperm quality associated with disease activity was discussed in the most recent study by Kaya et al (Kaya Aksoy et al. 2019). The authors of this study conclude that sperm abnormalities in male patients with familial Mediterranean fever are not infrequent and may be associated with both inflammation due to uncontrolled disease and colchicine therapy.

Cyclophosphamide
Twenty studies were identified, most of them included patients that were exposed to cyclophosphamide (CYC) to treat nephrotic syndromes associated with glomerulonephritis (73%). Most of these studies reported fertility outcomes from young adults that were exposed to CYC during their childhood. Unfortunately, the mean age of these participants was not reported in many studies. From these studies, a clear negative effect on sperm quality and reproductive hormones, mainly causing low sperm counts and high FSH levels, from CYC was found (Suehiro et al. 2008; Soares et al. 2007; Anserini et al. 2002; Bogdanovic et al. 1990; Perrone et al. 1989; Watson et al. 1985; Ogata et al. 1982; Fukutani et al. 1981; Trompeter et al. 1981; Marina et al. 1979; Hsu et al. 1979; Etteldorf et al. 1976; Pennisi et al. 1975; Kirkland et al. 1976; Kumar et al. 1972; Penso et al. 1974; Feng et al. 1972; Masala et al. 1997; Fairley et al. 1972). Reversibility (improvement in sperm counts after CYC withdrawal) with a possible dose-dependent effect was a repetitive finding in some studies. Because of substantial methodological problems (selection bias, loss of follow up, no baseline samples) reversibility and a dose-dependent effect cannot be interpreted as conclusive evidence.

Interleukin inhibitors
No studies were identified.

Methotrexate
Six studies reporting fertility outcomes in patients exposed to methotrexate (MTX) were identified. These studies included a total of 47 cases (40 men diagnosed with psoriasis and 7 with IMD) and 1912 controls (all controls come from one study (Ley et al. 2018)). In patients exposed to MTX, a decreased sperm concentration was found in three studies, although it remains unclear what the effect of this is on fertility (Sussman et al. 1980; Van Scott et al. 1959; Pandhi et al. 2006). No differences in fertility outcomes were reported in two studies (one study reported five normal testicular biopsies after MTX exposure) (El-Beheiry et al. 1979; Ley et al. 2018) and the sperm quality of one group of patients diagnosed with psoriasis and exposed to MTX was better than patients treated with high dose glucocorticoids (Fischer’s exact probability test: p=0.04) (Grunnet et al. 1977).

Mycophenolate acid products
No studies were identified.

NSAIDs
For NSAIDs as a group, no studies were identified in our population of interest. Nonetheless, 6 studies that included healthy participants were identified. Exposure to salicylate decreased sperm motility and for naproxen one study concluded that sperm quality abnormalities were similar between pre- and post-exposed samples (Poratsoldin et al. 1992; Bendvold et al. 1985; Knuth et al. 1989). A study from Kristensen et al. concluded that ibuprofen exposure results in a state of compensated hypogonadism (Kristensen et al. 2018). One in vitro study using adult human testis explants demonstrated that exposure to indomethacin and aspirin altered the production of testosterone by Leydig cells (Albert et al. 2013). It is unclear what the effect of this is on fertility.

Systemic corticosteroids
Two studies were identified. In a study from 1956, seven patients diagnosed with rheumatoid arthritis (RA) were treated with 75 mg of cortisone over periods ranging from 23 to 334 days. Pre- and post-treatment testicular biopsies were performed in 6 patients in which no significant changes were reported (McDonald et al. 1956). In a small study that included 36 men with long standing active RA, the use of prednisone at doses ranging from 5 to 10 mg/day was associated with significantly lower testosterone levels and lower levels of FSH and LH compared to men with long standing RA but without prednisone treatment (Martens et al. 1994). Because of the scope of our SLR, studies that reported the effect of corticosteroids on the male reproductive health of healthy controls were excluded. A review on this topic can be found elsewhere (Drobnis et al. 2017). In this review, it was described that corticosteroids have been used to treat antisperm antibodies and even as an empirical treatment for male infertility in general. Trials of these methods have provided mixed results on semen quality and fertility, with improvement, no change and negative effects reported by different investigators.

Thiopurines
Four studies that included a total of 75 cases and 40 controls exposed to azathioprine were included (Dejaco et al. 2001; Farthing et al. 1983; Baumgarten et al. 1977; Grosen, Nersting, et al. 2019). Sperm quality, sperm DNA fragmentation index and the male endocrine reproductive axis appear not to be negatively affected by azathioprine exposure.

TNF inhibitors
We identified fifteen studies that evaluated the effect of TNF inhibitors on male sexual health. Thirteen studies reported fertility/sperm quality outcomes, and two studies reported sexual function as the outcome of interest (Oh et al. 2009)(Kreitenberg et al. 2015). In total, outcomes of interest (sexual function, reproductive hormones, fertility, and pregnancy and offspring outcomes) were reported in 156 men diagnosed with ankylosing spondylitis (AS), psoriasis, RA and IBD exposed to TNF inhibitors and in 225 men without TNF inhibitors that participated in these studies as controls.

Regarding sperm quality before and after TNF inhibitor use, one small randomized control trial (RCT) that included data of 20 men concluded that certolizumab pegol had no adverse event on sperm quality compared to placebo (Perrier d'Hauterive et al. 2012). In studies where a comparison between baseline samples before TNF inhibitor exposure and follow up samples were available, no differences on sperm quality were reported in five studies (Heppt et al. 2017; Micu et al. 2014; Almeida et al. 2013; Grosen, Bungum, Christensen, et al. 2019; Micu et al. 2019), in three studies sperm quality improved after exposure (Pascarelli et al. 2017; Ramonda et al. 2014; Villiger et al. 2010) and in one study sperm quality worsened after exposure (Mahadevan et al. 2005). A possible positive effect on sperm quality using TNF inhibitors could be the result of decreasing disease activity in patients with AS. These findings should not be extrapolated to other diseases until more research is available. Worth mentioning is that TNF plays an important role in spermatogenesis and testicular homeostasis; one of the main findings for this group of drugs is that disease activity itself might play a role in baseline sperm quality characteristics and on the subsequent effect that TNF inhibitors have on sperm quality. At least for patients diagnosed with AS, TNF inhibitors appeared to have a positive effect on sperm quality. As it is the case for most of the drugs included in this systematic review, further research is needed. One study showed that exposure to TNF inhibitors in a group of men diagnosed with AS resulted in improvement of sexual function scores (Oh et al. 2009).

Other selective immunosuppressants
All publications on other selective immunosuppressants contained mostly maternal exposure cases and briefly mentioned paternal exposures. The results for the paternal exposure were; one case report on leflunomide reported a healthy child (De Santis et al. 2005), two case series initiated by the pharmaceutical industry on abatacept (10 pregnancies) and tofacitinib (84 pregnancies) revealed no safety concerns concerning birth defects or complications for the child (Kumar et al. 2015; Mahadevan et al. 2018).

Deelvraag 1: Welke medicatie kan gebruikt worden bij een vrouw met een kinderwens ten aanzien van vruchtbaarheid?

A systematic review of the literature was performed to answer the following question: 

What is the effect of specified rheumatic medication, taken by females with inflammatory rheumatic disease before conception, on fertility?

P:           Females with inflammatory rheumatic diseases (connective tissue diseases and

Systemic autoimmune diseases included), defined as rheumatoid arthritis, (axial and peripheral) spondylo-arthritis, reactive arthritis, juvenile idiopathic arthritis(JIA)/juvenile arthritis, uveitis in JIA, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, mixed connective tissue disease, vasculitis, polymyalgia rheumatica, polymyositis, dermatomyositis, ANCA-associated vasculitis, polyarteritis nodosa, Behçet’s disease, gout and adult-onset Still’s disease;

I:            Disease-modifying antirheumatic drugs (DMARDs) and Non-steroidal anti-inflammatory drugs  (NSAIDs) including: classical NSAIDs, COX-2 selective NSAIDs, glucocorticoids, conventional synthetic DMARDs (methotrexate, sulfasalazine, leflunomide, azathioprine, mycophenolate mofetil), targeted synthetic DMARDs (tofacitinib, baricitinib), biological DMARDs (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, rituximab, belimumab, tocilizumab, anakinra, canakinumab, ustekinumab, secukinumab and ixekizumab) and other antirheumatic medication (cyclophosphamide, antimalarials, intravenous immunoglobulin, colchicine, ciclosporin, tacrolimus);

C:           No use of the specific antirheumatic medication 

O:          Effects on fertility

Relevant outcome measures

The guideline development group considered fertility as critical outcome measure for decision making; and reduced fertility and time to pregnancy (TTP) as important outcome measures for decision making. 

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies. 

Search and select (Methods)

The databases Medline (via OVID), Embase (via Embase.com) and the Cochrane Library were searched with relevant search terms until June 26^th 2019. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 4377 hits. Studies were selected based on the following criteria:

• A separate description of at least one, or multiple women with inflammatory rheumatic diseases;
• Intake of antirheumatic medication as defined in PICO;
• Description of at least one outcome measure, e.g. fertility, reduced fertility or TTP.

Research into safety of drugs during pregnancy in women with rheumatic diseases cannot be conducted in an experimental design due to ethical/safety concerns. The working group decided to include studies of all design (comparative and non-comparative design), because even a small amount of information on safety of rheumatic medication during pregnancy could be important. 

Initially, 59 studies were selected based on title and abstract screening. After reading the full text, 47 studies were excluded (see the exclusion table with reasons for exclusion) and 12 studies were included. After checking reference lists of some important review studies, another 6 studies were included. In total 18 studies were included. 

Conclusions regarding the literature were based on results reported in one RCT, cohort studies and case-control studies. Results of the case-series were included in the evidence tables.  

Results

A total number of 18 studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence table 1. The assessment of the risk of bias is summarized in the risk of bias table 1.

Deelvraag 2: Welke anti-inflammatoire medicatie kan gebruikt worden bij een man met een kinderwens ten aanzien van vruchtbaarheid?

No systematic search was performed for this clinical question because in 2020, a high quality systematic review was published on the effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes (Perez-Garcia, Dolhain, et al., 2020). In this review, publications were included which also described chronic conditions other than rheumatic diseases, such as IBD, psoriasis and transplantation patients. Although the evidence that emerges from this review is indirect evidence for the clinical question proposed in this chapter, the working group chose to incorporate this review. Summary of the literature for the present clinical question was given for the outcomes sexual function, semen quality, reproductive hormones and fertility.