Characteristics of studies and outcome of pregnancy exposure related to medications used to treat rheumatic diseases, SLR-period 2008–2015*
| Drug | Type of publication in numbers | References on cohorts and case controls | Total pregnancies† (prospective/retrospective) | Number of miscarriages of eligible pregnancies‡ (%) | Number of congenital malformations of live births§ (%) | Comments on miscarriages (MC) and/or congenital malformations (CM) compared with control groups and/or background data§ | Strength of evidence according to GRADE Oxford | |
|---|---|---|---|---|---|---|---|---|
| Non-selective COX inhibitors (classical NSAIDs) | 3 cohorts 3 case controls | 11–16 | 17 992 (7684/10 308) | 530/5609 (9.4) | 457/ 12 354 (3.7) | No difference MC or CM | ++++ | 2a |
| Selective COX II inhibitors (rofecoxib, celecoxib, etoricoxib) | 3 case controls | 14 15 17 | 215 (0/215) | 11/71 (15.5) | 9/114 (7.9) | Significance for slightly increased rate MC and CM questionable due to confounders | ++ | 3b |
| Glucocorticoids (any route/formulation) | 2 cohorts 5 case controls 17 case reports/series (1 abstract) | 16 18–23 | 3500¶ (94/3406) | 70/331 (21.1) | 34/3180 (1.1) | MC slightly increased confounded by disease indication, no difference CM compared with control groups | +++ | 2b |
| Antimalarials | 2 cohorts 4 case controls | 16 24–28 | 492 (170/322) | 20/170 (11.8) | 23/492 (4.7) | No difference MC or CM | ++++ | 2a |
| Sulfasalazine | 2 cohorts 2 case controls | 16 29–31 | 525 (227/298) | 12/186 (6.5) | 16/339 (4.7) | No difference MC or CM | +++ | 2a |
| Leflunomide | 2 cohorts (1 abstract) 1 case control 4 case reports/series | 16 32 33 | 129 (80/49) | 12/122 (9.8) | 5/129 (3.9) | No difference MC or CM | +++ | 2b |
| Azathioprine | 4 cohorts (1 abstract) 7 case controls 7 case reports/series (1 abstract) | 16 31 34–42 | 1327 (434/893) | 40/559 (7.2) | 65/1327 (4.9) | No significant difference MC or CM compared with disease-matched controls | ++++ | 2a |
| Methotrexate | 2 cohorts 2 case controls 8 case reports/series | 16 27 43 44 | 372 (332/40) | 140/329 (42.6) | 15/143 (10.5) | Increased rate MC Increased rate CM with specific pattern | ++++ | 2b |
| Cyclophosphamide | 2 cohorts 28 case reports/series (2 abstracts) | 45 46 | 276 (160/116) | No separate studies on MC published | 23/86 (26.7) | High rate CM No studies with control group available | +++ | 2b |
| Ciclosporin | 2 cohorts 1 case control 11 case reports/series (1 abstract) | 47–49 | 1126 (1010/116) | 137/953 (14.4) | 9/261 (3.4) | No difference MC or CM | ++++ | 2a |
| Tacrolimus | 1 cohort 1 case control 10 case reports/series | 47 49 | 505 (482/23) | 91/344 (26.5) | 3/107 (2.8) | MC increase confounded by disease indicationNo difference CM | +++ | 2b |
| Mycophenolate mofetil | 2 cohorts 1 register data 20 case reports/series (2 abstracts) | 47 50 | 333 (199/134) | 119/318 (37.4) | 48/174** (27.6) | In studies without control group high rate MC and CM with specific pattern | +++ | 2b |
| Colchicine | 1 cohort 1 case control 1 case series | 51 52 | 460 (238/222) | 30/417 (7.2) | 11/460 (2.4) | No difference MC or CM | +++ | 2b |
| IVIG | 3 cohorts 3 case reports/series | 53–55 | 96 (93/3) | 24/93 (25.8) | 0/96 | No increase of MC or CM compared with disease-matched controls | ++ | 3b |
| Tofacitinib | 1 case series (abstract) | – | 27 (27/0) | 7/27 (25.9) | 1/15 | In case series and with concomitant MTX exposure high rate MC, no indication of an increased rate CM | + | 4 |
| Infliximab | 9 cohorts (1 abstract) 4 case controls (1 abstract) 2 register data (1 abstract) 16case reports/series (3 abstracts) | 27 36 56–66 | 1161 (968/ 193) | 64/676 (9.5) | 20/756†† (2.6) | No difference MC or CM | ++++ | 2b |
| Adalimumab | 10 cohorts (2 abstracts) 5 case controls (1 abstract) 2 register data (1 abstract) 6 case reports/series (1 abstract) | 16 27 36 56–58 60–68 | 524 (266/258) | 23/191 (12.0) | 24/350†† (6.9) | No significant difference MC Increased rate CM in one study, no increase compared with disease-matched controls | +++ | 2b |
| Etanercept | 3 cohorts 3 case controls (1 abstract) 2 register data (1 abstract) 11case reports/series (3 abstracts) | 16 27 57 58 64 65 | 332 (213/119) | 12/74 (16.2) | 9/251†† (3.6) | No difference MC or CM | +++ | 2b |
| Certolizumab | 2 cohorts 1 case control 2 case reports/series | 61 63 65 | 362 (243/119) | 52/339 (15.3) | 12/267†† (4.5) | No increased rate MC or CM No studies with control group available | ++ | 3b |
| Golimumab | 1 cohort 1 case series (abstract) | 65 | 50 (38/12) | 13/47 (27.7) | 0/26†† | With concomitant MTX exposure high rate MC, no indication of an increased rate CMNo studies with control group available | + | 4 |
| All TNF inhibitors, including studies not differentiating between them | 10 cohorts (3 abstracts) 5 case controls (1 abstract) 2 register data (1 abstract) 32 case reports/series (7 abstracts) | 16 27 36 56–68 | 2492 (1734/758) | 265/2258 (11.7) | 75/2110 (3.6) | No difference in MC or CM in pregnancies exposed to TNF inhibitors compared with controls | +++ | 2b |
| Rituximab | 1 register data 20 case reports/series | – | 256 (72/184) | 48/210 (22.9) | 6/172 (3.5) | Increased rate MC confounded by disease indication, no increased rate CMNo studies with control group available | ++ | 4 |
| Anakinra | 1 register data 3 case reports | – | 40 (not reported) | 4/40 (10.0) | 2/34 (5.9) | No increased rate MC or CM No studies with control group available | + | 4 |
| Abatacept | 1 case series‡‡ 1 case report | – | 152 (94/58) | 40/151 (26.5) | 7/87 (8.0) | With concomitant MTX exposure high rate MC and CMNo studies with control group available | ++ | 4 |
| Tocilizumab | 1 register data 2 case series (2 abstracts) | – | 218 (180/38) | 47/218 (21.6) | 5/128 (3.9) | With concomitant MTX exposure high rate MC, no indication of an increased rate CM | ++ | 4 |
| Ustekinumab | 1 register data 4 case reports/series (1 abstract) | – | 108 (104/4) | 15/108 (13.9) | 1/58 (1.7) | No increased rate MC or CM No studies with control group available | ++ | 4 |
| Belimumab | 1 register data 1 case series (abstract) | – | 153 (152/1) | 41/153 (26.8) | 7/ 71 (9.9) | High rate MC and CM Concomitant medication possible confounderNo studies with disease-matched controls available | ++ | 4 |
Strength of evidence based on previous consensus papers1 ,2 and new SLR and registry data.
*As the update publication did not include all non-biologic drugs, an additional search for the period 2006–2008 was performed for 10 drugs; NSAIDs, glucocorticoids, MTX, cyclophosphamide, sulfasalazine, antimalarials, azathioprine, colchicine, ciclosporin and IVIG.
†Total reported pregnancies for a given drug, where CM and/or MC are reported, and where the pregnancies have been exposed in the window of susceptibility for the reported outcome.
‡Nominator represents exposed pregnancies with MC as outcome. Denominator represents the total number of exposed pregnancies where MC is reported.
§Nominator represents exposed pregnancies with CM in live births as outcome; mainly major CM but in some publications major and minor CM are not differentiated. Denominator represents the total number of exposed pregnancies resulting in live births.
¶One cohort of 2295 pregnancies looks only at isolated clefts.
**Nominator includes CM in elective terminations in addition to CM in live births. Denominator includes elective terminations with anomalies in addition to live births.
††Several publications report congenital malformations for women using different TNF inhibitors; nominator/denominator reflects numbers in which each TNF inhibitor is reported separately.
‡‡Publication after 15 April (replacing earlier abstract).
IVIG, intravenous immunoglobulin; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; SLR, systematic literature review; TNF, tumour necrosis factor.