Table 4.

Summary of pregnancy outcomes after paternal exposure

Drug	Studies included (type and number)	Pregnancy exposures	Adverse pregnancy outcomes (foetal losses or malformations)	Recommendation (GRADE/Strength of agreement)
HCQ	1 ct [52]	13	No increase	Paternal exposure to HCQ is compatible with pregnancy (GRADE 2C, SOA 99.3%)
	1 cs [404]
CS	5 ct [52, 405–407, 411]	4507	No increase	Paternal exposure to prednisolone is compatible with pregnancy (GRADE 1B, SOA 99.3%)
	2 cs [404, 408]
SSZ	3 ct [52, 407, 412]	237	No increase	Men who take SSZ may have reduced fertility. There is little evidence to suggest that SSZ should be stopped pre-conception, unless conception is delayed by >12 months when stopping SSZ should be considered along with other causes of infertility (GRADE 1C, SOA 99.0%)
	1 cc [409]
LEF	1 ct [52]	2	No increase	Paternal exposure to LEF is compatible with pregnancy (GRADE 2C, SOA 99.3%)
	1 cr [413]
AZA	9 ct [52, 185, 187, 216, 405–407, 414, 415]	3282a	No increase	Paternal exposure to AZA is compatible with pregnancy (GRADE 1B, SOA 99.3%)
	1 cc [409]
	2 cs [404, 408]
MTX	10 ct [52, 184–189, 405, 407]	2289	No increase	Paternal exposure to low-dose (≤25 mg/week) MTX is compatible with pregnancy (GRADE 1B, SOA 99.3%)
	3 cs [404, 410],   1 cr [428]
CsA	3 ct [185, 406, 416]	501a	No increase	Paternal exposure to CsA is compatible with pregnancy (GRADE 1C, SOA 99.3%)
	2 cs [408, 410]
TAC	3 ct [406, 416, 417]	41a	No increase	Paternal exposure to TAC is compatible with pregnancy (GRADE 2C, SOA 99.3%)
CYC	No data meeting inclusion criteria		Known to affect male fertility; evidence of an adverse impact on germ cell development and male-mediated teratogenicity from animal studies	Due to the adverse effect of CYC on male fertility, semen cryopreservation is recommended for men prior to paternal exposure (GRADE 1C, SOA 99.5%)
MMF	3 ct [185, 246, 247]	292	No increase	Paternal exposure to MMF is compatible with pregnancy (GRADE 2C, SOA 99.3%)
	3 cs [406, 416, 426]
TNFi	13 ct [52, 263, 293, 298, 306, 405, 412, 427, 430–434]	751	No increase	Paternal exposure to TNFi is compatible with pregnancy (GRADE 1C, SOA 99.3%)
	2 cs [404, 410]
	2 cr [428, 429]
	1 cc [409]
RTX	1 ct [343]	11	No increase	Paternal exposure to RTX is compatible with pregnancy (GRADE 2C, SOA 99.3%)
IL-6i	1 ct [359]	15 (TOC)	No increase	Paternal exposure to IL-6i is compatible with pregnancy (GRADE 2C, SOA 99.3%)
IL-1i	1 ct [369]	5 (ANA)	No increase	Paternal exposure to IL-1i is compatible with pregnancy (GRADE 2C, SOA 99.3%)
		6 (CAN)
ABA	1 ct [375]	10	No increase	Paternal exposure to ABA is compatible with pregnancy (GRADE 2C, SOA 99.3%)
IL-17i	2 ct [387, 389]	54 (SEC)	No increase	Paternal exposure to IL-17i is compatible with pregnancy (GRADE 2C, SOA 99.3%)
		34 (IXE)
JAKi	1 ct [398]	87 (TOF)	No increase	Paternal exposure to JAKi is compatible with pregnancy (GRADE 2C, SOA 99.3%)

All studies that provided quantitative and/or qualitative information on the safety of the relevant drug following paternal exposure were included. Details of how numerical data in this table were derived are shown in Supplementary Data S3, available at Rheumatology online. 

^aMinimum number of pregnancy exposures to drug; additional exposures were described in some studies but could not be separated from grouped study data.

ABA: abatacept; ANA: anakinra; BEL: belimumab; CAN: canakinumab; cc: case control; cr: case report; cs: case series; CS: corticosteroids; CsA: ciclosporin; ct: cohort; IL-1i: IL-1 inhibitors; IL-6i: IL-6 inhibitors; IL-17i: IL-17 inhibitors; IXE: ixekizumab; JAKi: Janus kinase inhibitors; NR: not reported; RTX: rituximab; SEC: secukinumab; SOA: strength of agreement; TAC: tacrolimus; TNFi: TNF-alpha inhibitor; TOC: tocilizumab; TOF: tofacitinib; UST: ustekinumab.