Table I.

Summary of study characteristics and main findings for sperm quality, sexual function and reproductive hormones outcomes.

Reference Country	Number of cases and controls (with mean age in years)	Disease	Key findings	Effect on fertility	Effect on reproductive hormones	Effect on sexual function	NOS quality assessment
							Study type
Aminosalicylic acid and similar agents
Di Paolo et al. (2001) Italy	42 (NR) NR	IBD	All sperm samples had abnormalities, mainly in motility. Sperm quality improved after stopping SSZ or switching to 5-ASA.	−	−	NR	H CS
Zelissen et al. (1988) The Netherlands	11 (32.3) NR	IBD	Oligospermia was detected in 72% of samples. After switching to 5-ASA, all samples showed improvement in sperm counts.	−	*	NR	L CS
Riley et al. (1987) UK	15 (NR) NR	IBD	Oligospermia was detected on 40% of samples. After switching to mesalazine, samples showed improvement in sperm counts.	−	NR	NR	H CS
Cosentino et al. (1984) USA	10 (30) 19 (NR)	IBD	Mean number of sperm count and of normal morphology was significantly lower. In five patients who stopped SSZ, improvement in sperm quality was observed.	−	*	NR	H Ch
Freixa et al. (1984) Spain	10 (NR) 0	Healthy participants	Prostaglandin levels in seminal plasma decreased by 36% secondary to SSZ exposure.	−	NR	NR	L CS
O'Morain et al. (1984) UK	39 (NR) 9 (NR)	IBD	SSZ exposure was associated with significant decrease in sperm counts, motility and increase in abnormal sperm morphology.	−	*	NR	L CC
Ragni et al. (1984) Italy	7 (NR) 7 (30.1)	IBD	Sperm motility was reduced in all cases and serum testosterone levels were significantly lower in exposed cases.	−	−	NR	L CC
Hudson et al. (1982) UK	8 (NR) 10 (NR)	IBD	Sperm head size was significantly larger in cases than in controls.	−	NR	NR	L CS
Freeman et al. (1982) UK	11 (28.8) 6 (36)	IBD	Lower progressive motility in SSZ-exposed group.	−	NR	NR	L CC
Tobias et al. (1982) South Africa	1 (39) 0	IBD	Case report: reversible infertility after stopping SSZ, patient on high dose GCs.	−	*	NR	NA CR
Toovey et al. (1981) UK	28 (NR) 4 (NR)	IBD	Exposed samples showed reduced sperm motility and density and altered morphology. After withdrawal, sperm density and motility improved significantly but not sperm morphology.	−	*	NR	H CS
Levi et al. (1979) UK	4 (30) 0	IBD	Case series: One of the first case series where authors reported semen analysis abnormalities in SSZ-exposed patients.	−	NR	NR	NR Case series
Toth (1979) UK	6 (NR) 0	IBD	Head, midpiece and tail abnormalities were detected in spermatozoa of SSZ-exposed patients.	−	NR	NR	L CS
McIntyre and Lennard-Jones (1984) UK	3 (NR) 0	IBD	Case series: Sperm abnormalities detected after SSZ-exposed patients were sent to the infertility clinic. Sperm quality improved after switching therapy to balsalazide.	−	NR	NR	NA Case series
Iglesias-cortit et al. (1985) Spain	6 (NR) 0	Healthy participants	Sperm motility decreased 15% after exposure to SSZ.	−	NR	NR	L CS
Cann and Holdsworth (1984) Austria	1 (33) 0	IBD	Case report: SSZ-exposed patient who was diagnosed with infertility and achieved a successful pregnancy after switching therapy from SSZ to 5-ASA.	−	NR	NR	NA CR
Ganatra et al. (2018) India	61 (NR) 0	IBD	26.23% of SSZ-exposed patients developed oligospermia. This is the first article to comment on the possible effect by disease activity.	−	NR	NR	L CS
Shaffer et al. (1984) UK	1 (32) 0	IBD	Case report: oligospermia associated with exposure to SSZ.	−	NR	NR	NA CR
Traub et al. (1979) UK	1 (25) 0	IBD	Case report: pregnancy achieved after stopping SSZ therapy.	−	NR	NR	NA CR
Chatzinoff et al. (1988) USA	1 (32) 0	IBD	Case report: SSZ-induced infertility case confirmed by sperm penetration assay (sperm analysis was normal).	−*	NR	NR	NA CR
Birnie et al. (1981) UK	21 (32.8) 0	IBD	86% of SSZ-exposed patients had abnormal semen analysis (72% had oligospermia).	−	NR	NR	L CS
Heineman et al. (1981) The Netherlands	2 (32) 0	IBD	Case report: reversible oligospermia in two cases exposed to SSZ. Both cases achieved pregnancies after drug withdrawal.	−*	NR	NR	NA CS
Antimalarials
Ejebe et al. (2008) Nigeria	5 (NR) 10 (NR)	Healthy participants	No differences in sperm quality parameters and reproductive hormones 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.	*	*	NR	L CS
Hargreaves et al. (1998) UK	NR	Healthy participants	Chloroquine had a dual in vitro effect, enhancing rapid motility at low concentrations but inhibiting it at higher concentrations. At 250 µg/ml chloroquine, all spermatozoa were static.	+ −	NR	NR	CS L
Adeeko and Dada (1994) Nigeria	8 (NR) 0 (NR)	Healthy participants	Chloroquine is present in seminal plasma even after long time of no exposure.	NR	NR	NR	L Ch
Ette et al. (1988) Nigeria	4 (NR) 0 (NR)	Healthy participants	Chloroquine crosses the BTB, probably by passive diffusion.	NR	NR	NR	NA Case series
Calcineurin inhibitors (CsP, ciclosporine; EVE, everolimus; SIR, sirolimus; TAC, tacrolimus)
Misro et al. (1999) India	NR	Healthy participants CsP	In vitro study showing that ciclosporine exerts deleterious effects on sperm, which become immotile and nonviable.	−	NR	NR	H CS
Haberman et al. (1991) USA	9 (41.2) NR	Kidney transplantation CsP	With the exemption of a low semen volume, ciclosporine A at 3 mg/kg/day did not result in other sperm quality or hormonal abnormalities.	*	*	NR	L CS
Samojlik et al. (1992) USA	10 (NR) 0	Kidney transplantation CsP	Pretreatment (pre-transplant) testosterone levels were below normal in 80%. After 12 months of treatment with CsP and other immunosuppressive drugs, testosterone levels significantly increased in all 10 cases.	NR	+	NR	L CC
Eid et al. (1996) Egypt	34 (32) 31 (31)	Kidney transplantation CsP	Sperm concentration was inversely correlated to the CsP whole blood levels.	−	*	+	H CC
Kramer et al. (2005) Germany	256 (NR) 0	Kidney transplantation CsP–EVE	Testosterone levels increased from baseline in EVE and EVE-CsP groups.	NR	+	NR	L Ch
Kantarci et al. (2004) Turkey	37 (38.1) 0	Kidney transplantation CsP–TAC	No statistical differences in baseline levels of serum FSH, LH, testosterone and PRL between CsP- and TAC-treated patients. All results were in normal ranges.	NR	*	NR	L CS
Peces et al. (1994) Spain	19 (35) 0	Kidney transplantation CsP	Serum levels of reproductive hormones were normal in CsP exposed cases.	NR	*	NR	L CS
Sajad Hussain et al. (2015) India	1 (40)	Kidney transplantation SIR	Case report: patient was infertile while on Sirolimus he developed oligospermia with normal hormone levels after switching to tacrolimus he was able to conceive.	−*	*	NR	NA CR
Boobes et al. (2010) UAE	6 (43) 0	Kidney transplantation SIR	Case series: infertile patients with oligospermia, after discontinuing SRL, all patients had increased sperm counts and were able to conceive.	−*	NR	+	NA Case series
Zuber et al. (2008) France	25 (32) 67 (NR)	Kidney transplantation SIR	Sirolimus-exposed patients had lower sperm counts and motility. The fathered pregnancy rate was significantly lower in exposed patients than in non-exposed.	−	NR	NR	H CS
Skrzypek and Krause (2007) Germany	1 (29) 0	Kidney transplantation SIR	Recovery of spermatogenesis after cessation of sirolimus.	−*	−	NR	NR CR
Deutsch et al. (2007) Germany	1 (26)	Lung–heart transplantation SIR	Benign Leydig cell tumour in a patient exposed to sirolimus lead to testicular biopsy that showed testicular atrophy and signs of impaired spermatogenesis.	−*	−	NR	NA CR
Bererhi et al. (2003) France	1 (36)	Kidney transplantation SIR	Case report: low sperm count and motility with abnormal morphology associated with sirolimus exposure. These changes were reversed after switching therapy to tacrolimus.*	−*	NR	NR	NA
Kaczmarek et al. (2004) Germany	66 (NR) 66 (NR)	Heart transplantation SIR	Patients exposed to sirolimus had significantly lower serum testosterone levels and higher FHS/LH levels than control group.	NR	−	NR	H CS
Lee et al. (2005) USA	32 (41) 34 (47)	Kidney transplantation SIR	Patients exposed to sirolimus had significantly lower serum testosterone levels and higher FHS/LH levels than control group.	NR	−	NR	H CS
Fritsche et al. (2004) Germany	28 (46.5) 28 (45.5)	Kidney transplantation SIR	Sirolimus daily dose and testosterone concentrations were significantly inversely correlated (r = –0.383).	NR	−	NR	H CC
Tondolo et al. (2005) USA	59 (48) 0	Kidney transplantation SIR	Significantly reduced levels of circulating testosterone amongst patients receiving sirolimus alone compared to those treated with calcineurin inhibitors alone were identified.	NR	−	NR	L CS
Colchicine
Kastrop et al. (1999) The Netherlands	2 (40) 0	Gout	Cytogenic analysis of sperm (FISH) revealed no damage secondary to colchicine use.	*	NR	NR	NA CR
Kirchin et al. (1999) UK	1 (48) 0	Retinal vasculitis	Case report: reversible azoospermia.	−	NR	NR	NA CR
Sarica et al. (1995) Turkey	62 (32.4) 0	Behçet syndrome	The longer the use of colchicine, the more serious the adverse events on sperm count	−	+	NR	L CS
Ben-Chetrit et al. (1993) Israel	15 (NR) 0	Healthy participants	In vitro study, high concentrations of colchicine may affect in vitro motility of sperms, probably by its direct effect on the microtubules.	−	NR	NR	H CC
Levy and Eliakim (1977) Israel	6 (34.6) 0	FMF	After being advised to stop treatment with colchicine prior to attempt conception, sperm analysis was within normal limits in all six patients.	*	NR	NR	L CS
Bremner and Paulsen (1976) USA	7 (22) 0	Healthy participants	Colchicine caused no significant changes in sperm quality or reproductive hormones levels after 3 or 6 months of treatment.	*	*	NR	L CS
Merlin (1972) USA	1 (36) 0	Gout	Case report: azoospermia believed to be associated with colchicine use. Colchicine was stopped and after 3 months, sperm count improved and wife became pregnant.	−	NR	NR	NA CR
Kaya Aksoy et al. (2019) Turkey	72 (14.5) 0	FMF	Mean colchicine dose at the time of sperm analysis was higher in patients with low sperm motility than that with normal sperm motility.	−	NR	NR	H Ch
Cyclophosphamide
Suehiro et al. (2008) Brazil	13 (NR) NR	SLE	The median serum inhibin B was lower in patients treated with CYC compared with those without this therapy.	−	−	NR	L CS
Soares et al. (2007) Brazil	14 (NR) NR	SLE	Semen analysis demonstrated that patients who had undergone IV CYC therapy had worse sperm quality (count, motility and morphology) compared with patients who did not undergo this treatment. Elevated FSH levels were detected in patients who underwent IV CYC therapy.	−	−	NR	H CC
Anserini et al. (2002) Italy	19 (NR) 0	Bone marrow transplantation	10% of patients who received CYC showed azoospermia, and recovery of spermatogenesis was observed in 60% of patients.	−	NR	NR	NA Case series
Bogdanovic et al. (1990) Yugoslavia	17 (NA) 0	Nephrotic syndrome	Significant inverse correlation between sperm density and CYC dosage and duration of treatment.	−	NR	NR	NA Case series
Perrone et al. (1989) Italy	22 (NR) 20 (NR)	Nephrotic syndrome	Altered spermatogenesis was found in 41.6% of adult patients treated with CYC during childhood (1.8–5.5 mg/kg/day for 12 weeks). No significant inverse correlation of total dose of the drug with sperm density.	−	−	NR	H CC
Watson et al. (1985) Canada	30 (22) 18 (28)	Nephrotic syndrome	A significant inverse correlation was evident between sperm density and CYC dosage. Recovery of sperm count after prolonged interval after treatment is possible.	−	−	*	L CC
Ogata et al. (1982) Japan	6 (NR) 0	Nephrotic syndrome	Histologic oligospermic changes were observed in three patients treated with high doses (10.6–16.2 g during 125–432 days).	−	NR	NR	L Case series
Fukutani et al. (1981) Japan	31 (33) 33 (NR)	Behcet syndrome	Azoospermia and oligospermia found in 13 out of 17 patients treated with CYC. High mean FSH levels in CYC-treated patients	−	−	NR	L CS
Trompeter et al. (1981) UK	19 (22) 17 (23)	Nephrotic syndrome	Lower ejaculate volumes and sperm densities and higher percentage of immotile and abnormal forms in CYC exposed group.	−	−	NR	L CS
Marina and Barcelo (1979) Spain	3 (NR) 0	Nephrotic syndrome	All patients showed abnormalities: oligospermia (1), azoospermia (1) and aplasia of germinal epithelium (1).	−	NR	NR	NA Case series
Hsu et al. (1979) Canada	16 (NR) 0	Nephrotic syndrome	Sperm quality abnormalities found in 63%. An increase in the total dosage and in duration of the treatment was associated with a higher incidence of testicular dysfunction.	−	−	NR	L Ch
Etteldorf et al. (1976) USA	12 (NR) 0	Nephrotic syndrome	Low doses (2–4 mg/kg/day) did not influence pituitary gonadal function (confirmed by biopsy).	−	−	NR	NA Case series
Kirkland et al. (1976) USA	15 (NR) 0	Nephrotic syndrome	Serum testosterone levels were normal in CYC-treated patients	NR	*	NR	NA Case series
Pennisi et al. (1975) USA	23 (NR) 0	Nephrotic syndrome	Sperm quality was uniformly decreased in CYC-treated patients and high FSH levels were common.	−	−	NR	L Case series
Kumar et al. (1972) UK	8 (NR) 0	Nephrotic syndrome	All eight biopsy specimens had evidence of testicular atrophy, and it was profound in 6.	−	NR	NR	L CS
Penso et al. (1974) USA	7 (NR) 0	Nephrotic syndrome	Biopsies confirmed absent spermatogenesis in azoospermic patients and FSH elevation correlated with degree of testicular damage.	−	−	NR	L CS
Feng et al. (1972) Singapore	1 (18) 0	Nephrotic syndrome	First case report that reported azoospermia associated with CYC exposure.	−	NR	NR	NA CR
Masala et al. (1997) Italy	15 (NR) 0	Nephrotic syndrome	All 15 patients received CYC and became azoospermic or oligospermic. 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 received testosterone (vs 1/10)	−	NR	NR	L CS
Fairley et al. (1972) Australia	31 (31.2) 0	NR	Testicular biopsy was performed on five patients who were receiving CYC and no spermatogenesis was found.	−	NR	NR	L CS
Methotrexate
Sussman and Leonard (1980) USA	1 (26) 0	Psoriasis	Case report: reversible oligospermia secondary to MTX.	−	NR	NR	NA CR
Van Scott and Reinertson (1959) USA	2 (NR) 0	Psoriasis	Sperm count was reduced to 63–97% at 2 weeks after a single IV injection of MTX.	−	NR	NR	NA Case series
El-Beheiry et al. (1979) Egypt	26 (33–52) 0	Psoriasis	The mean difference in sperm count, motility and abnormal forms before and after methotrexate therapy was not significant. Five testicular biopsies performed where no alterations were found.	*	NR	NR	L CS
Grunnet et al. (1977) Denmark	10 (23–46) 0	Psoriasis	Sperm abnormalities found in 40% of MTX-treated patients but sperm quality was better than in patients treated with glucocorticoids.	+	NR	NR	L CS
Ley et al. (2018) USA	7 (28) 1912 (NR)	IBD	In all MTX-treated patients, basic semen analyses were within normal limits	−DFI *sperm	NR	NR	L CC
Pandhi et al. (2006) India	1 (50)	Psoriasis	Case report: gynaecomastia and oligospermia secondary to MTX	−	NR	NR	NA CR
NSAIDs
Kristensen et al. (2018) Denmark	14 (NR) 17 (NR)	Healthy participants Ibuprofen	Experiment: exposure to ibuprofen in adult testis explants caused a state of compensated hypogonadism.	NR	−	NR	NA RCT
Poratsoldin and Soldin (1992) USA	19 (NR) 0	Healthy participants Salicylate	In vitro study: salicylate significantly decreases sperm motility	−	NR	NR	H CS
Bendvold et al. (1985) Sweden	6 (NR) 0	Healthy participants Naproxen	Treatment with naproxen significantly reduces the concentration of all PGs present in human seminal fluid.	NR	NR	NR	H CC
Albert et al. (2013) France	NA	Healthy participants Aspirin and indo methacin	In vitro study: production of testosterone by Leydig cells was altered by exposure to all these drugs	NR	−	NR	L CS
Knuth et al. (1989) Germany	10 (25.1) 12 (27.4)	Healthy participants Indomethacin	Exposure to indomethacin led to lower PGs levels in seminal plasma but unchanged sperm quality parameters and levels of reproductive hormones.	*	*	NR	L CS
Retinoids
Liu et al. (2017) China	31 (NR) 14 (NR)	Psoriasis Acitretin	After 3 months of treatment at doses of 20 mg/day and 30 mg/day, sperm quality did not differ between cases and controls.	*	*	NR	H CC
Schmitt-Hoffmann (et al. 2011) Switzerland	24 (30) 0	Healthy participants Acitretin	After 3 months of treatment at doses of 20 mg or 40 mg/day alitretinoin and 4-oxo-alitretinoin were detected in 11 of 12 semen samples.Concentrations detected are unlikely associated with teratogenicity.	NR	NR	NR	L CC
Rossi and Pellegrino (2009) Italy	1 (39) 0	Psoriasis Acitretin	Case report: 39-year old diagnosed with psoriasis reported erectile dysfunction after starting treatment with acitretin (25 mg/day). After 2 weeks of drug withdrawal, patient reported normalisation of sexual activity.	NR	NR	−	NA CR
Parsch et al. (1990) Germany	5 (34) 6 (34)	Psoriasis Acitretin	After 3 months of treatment at doses of 25–50 mg/day, sperm quality did not differ between cases and controls	*	*	NR	H CC
Çinar et al. (2016) Turkey	81 (22.6) 0	Acne Isotretinoin	After 6 months of treatment at doses of 120 mg/day, all the sperm quality parameters changed positively and reproductive hormone levels did not differ.	+	*	NR	H CS
Torok et al. (1987) Hungary	13 (27) 0	Acne Isotretinoin	After 4 months of treatment at doses of 1 mg/kg/day, sperm motility increased significantly and the other sperm quality parameters did not differ.	+	NR	NR	H CS
Coleman and MacDonald (1994) UK	1 (29) 0	Acne Isotretinoin	Case report of ejaculatory failure associated with isotretinoin (1 mg/kg/day).	NR	NR	−	NA CR
Healy et al. (2018) UK	47 (NR) 0	Acne Isotretinoin	Independent drug safety website (RxISK.org) data: isotretinoin commonly associated with SD.	NR	NR	−	H Ch
Systemic glucocorticoids
McDonald and Heckel (1956) USA	4 (NR) 7 (NR)	RA	Case series: biopsies performed after exposure to 75 mg of cortisone, and no negative effect was observed.	*	NR	NR	NA Case series
Martens et al. (1994) USA	36 (62) 70 (68)	RA	Compared to healthy controls, RA patients taking prednisone had significantly lower testosterone levels and slightly elevated levels of FSH and LH.	NR	−	NR	L CS
Thiopurines (AZA, Azathioprine)
Dejaco et al. (2001) Austria	23 (32) 0 (NR)	IBD AZA	Semen analyses of 23 patients with IBD showed no negative association between AZA therapy and sperm quality.	*	NR	NR	L CS
Farthing and Dawson (1983) UK	5 (NR) 0	IBD AZA	80% of patients had oligospermia.	−	NR	NR	NA Case series
Baumgarten et al. (1977) USA	7 (NR) 0	Kidney transplantation AZA	No correlation between poor spermatogenesis and AZA was reported.	*	*	NR	NA Case series
Grosen et al. (2019c) Denmark	40 (27.6) 40 (23.3)	IBD AZA	Sperm motility was decreased in patients, DFI was similar.	−DFI *sperm	*	NR	H Ch
TNF-α inhibitors (INF, infliximab; ETN, etanercept; CZP, certolizumab pegol; ADA, adalimumab; GOL, golimumab)
Heppt et al. (2017) Germany	27 (37.5) 0	Psoriasis ETN ADA	Compared with baseline, no significant differences in mean total sperm number, sperm concentration, total and progressive motility nor other semen parameters were noticed during follow-up.	*	NR	NR	L Ch
Pascarelli et al. (2017) Italy	10 (NR) 0	Healthy participants ETN	*In vitro study: TNF-α had a detrimental effect on sperm function and in vitro etanercept counteracted this toxic action of TNF-α.	+	NR	NR	L CS
Ramonda et al. (2014) Italy	10 (28.7) 20 (27.4)	SpA ADA	Improvement in semen parameters after 12 months of TNF-α inhibitor treatment was reported.	+	*	NR	H CC
Micu et al. (2014) Rumania	23 (34.7) 42 (34.8)	AS ETN (2) ADA (14) INF(4)	Exposure of 20 patients to three different types of anti-TNFs did not have a negative impact on sperm quality after 3–6 months and in six cases after 12 months of treatment.	*	NR	NR	L CC
Almeida et al. (2013) Brazil	10 (33) 24 (28.5)	AS ETN (2) ADA (8)	Sperm abnormalities were comparable in patients and controls after 6 months of TNF-α inhibitor therapy.	*	*	NR	H CC
Villiger et al. (2010) Switzerland	15 (29.5) 102 (30)	SpA ETN ADA INF	Impaired sperm quality was especially found in the group of anti-TNF naive patients with active disease. Sperm quality tended to improve within the five paired samples for sperm vitality (P = 0.08) and sperm motility (P = 0.08).	+	*	NR	L CC
Mahadevan et al. (2005) USA	10 (31) 0	IBD INF	Sperm motility, or the percentage of sperm that show flagellar motion, was below normal in study patients after INF treatment.	−	NR	NR	H CS
Perrier d’Hauterive et al. (2012) Belgium	10 (NR) 10 (NR)	Healthy participants CZP	CZP treatment was found to have no effect on the semen quality variables assessed vs placebo	*	NR	NR	NA RCT
Grosen et al. (2019a) Denmark	28 (30.8) 17 (27.5)	IBD INF (38) ADA(7)	A statistically significant reduction in DFI was observed after the start of anti-TNF-α therapy (median DFI 12.8 off therapy versus 10.0 on therapy, P = 0.02). No differences in sperm quality parameters were found between groups.	*sperm +DFI	NR	NR	H Ch
Montagna et al. (2005) Italy	3 (40) 0	AS INF	Case series reporting asthenoazoospermia in two out of three patients using infliximab.	−*	NR	NR	NA Case series
Wildi and Haraoui (2012) Canada	1 (35) 0	AS ADA	Case report: oligoasthenozoospermia and decreased motility reversed after stopping drug.	−*	NR	NR	NA CR
Younis et al. (2014) Israel	1 (50)	AS INF	Case report: low sperm count, concentration increased after stopping IFX.	−*	NR	NR	NA CR
Micu et al. (2019) Romania	5 (NR) 0	SpA ADA	Normospermia before and after TNF-α therapy initiation.	*	NR	NR	L Ch
Kreitenberg et al. (2015) USA	1 (58)	RA ADA	Case report: priapism associated with adalimumab.	NR	NR	−	NA CR
Oh et al. (2009) Korea	22 (37.8) 0	AS ETN ADA INF	Anti-TNF-α-treated patients showed significant improvements in four out of the five IIEF domains.	NR	NR	+	L Ch
Verdolizumab
Grosen et al. (2019b) Denmark	15 (33) 33 (23)	IBD	Sperm quality and DFI were similar amongst cases and controls after exposure to verdolizumab. Verdolizumab was detected in seminal plasma at levels that correspondent to 0.3–1.1% of serum levels.	*	*	NR	L CC

H, high; L, low; NA, not applicable; NR, not reported; *, no differences reported; +, positive effect; −, negative effect; −*, reversible negative effect upon withdrawal; CC, case–control study; Ch, cohort study; CR, case report; CS, cross-sectional study; RCT, randomised controlled trial.