Skip to main content
. 2022 Nov 2;62(4):e48–e88. doi: 10.1093/rheumatology/keac551

Table 2.

Summary of maternal exposure to conventional synthetic DMARDs, antimalarials and corticosteroids

Drug Studies (type and number) Pregnancy exposures (exposures per trimester) Foetal losses/total pregnancy outcomes Pregnancy duration and birth weight Malformations/total births Recommendation (GRADE/Strength of agreement)
HCQ 31 ct [17–25, 27, 28, 30–39, 44–53]

  • 4701

  • (1st ≥3075, 2nd/3rd ≥583)

 95/936 No significant adverse effect noted 162/3126
Overall, no increase in rate of major malformations attributable to drug

  1. HCQ remains the antimalarial of choice in women planning a pregnancy with rheumatic disease in need of treatment, and should be continued during pregnancy at dose of ≤400 mg/day (GRADE 1B, SOA 100%)

  2. HCQ is compatible with breastmilk exposure (GRADE 1B, SOA 99.5%)
1 rct [29]
1 nrt [26]
2 cc [42, 43]
3 cs [54–56]
6 cr [57–62]
2 sr [40, 41]
Pred/MP 3 rct [84–86]

  • 2733

  • (1st ≥995, 2nd/3rd ≥637)

 70/518 No significant adverse effect attributable to drug

  • 63/697

  • No increase in rate of major malformations attributable to drug

  1. Prednisolone is compatible with pregnancy and is the preferred corticosteroid in the treatment of maternal rheumatological disease in pregnancy and requires shared care with obstetric teams to monitor maternal blood pressure and blood glucose (GRADE 1B, SOA 100%)

  2. Where possible, the dose of prednisolone should be <20 mg/day and tapered to the minimum effective dose to control maternal disease, in conjunction with steroid-sparing drugs compatible with pregnancy (GRADE 1C, SOA 99.5%)

  3. Prednisolone is compatible with breastmilk exposure (GRADE 1B, SOA 100%)

  4. Methylprednisolone has similar rates of placental transfer to prednisolone and would therefore be expected to be compatible with pregnancy and breastmilk exposure (GRADE 2C, SOA 99%)
3 cc [43, 87, 88]
22 ct [31, 46, 48, 51–53, 71, 73–81, 89–95]
12 cs [55, 72, 96–105]
16 cr [55, 57, 59–61, 96–117]
1 Cochr [82]
1 sr [83]
MTX 2 cc [172, 181] 766 80/479 Insufficient data; only one study reported birthweight in a cohort of n = 23 [37], with two studies reporting pregnancy duration (n = 43) [37, 181]

  • 36/265

  • Individual case reports of MTX embryopathy, but larger studies show limited numbers of cases of foetal malformation

  1. MTX at any dose should be avoided in pregnancy and stopped at least one month in advance of planned conception, when it should be switched to another pregnancy-compatible drug to ensure maintenance of maternal disease suppression (GRADE 1A, SOA 98%)

  2. In women treated with low-dose (≤25 mg/week) MTX within one month prior to conception, folic acid supplementation (5 mg/day) should be continued up to 12 weeks of pregnancy (GRADE 1B, SOA 99.5%)

  3. In unintended pregnancy on low-dose MTX (≤25 mg/week), there is minimal risk to the foetus; the drug should be stopped immediately, folic acid supplementation (5 mg/day) continued, and a careful evaluation of foetal risk with early referral to a foetal medicine department considered (GRADE 1C, SOA 100%)

  4. Although only minute amounts of MTX are excreted into breastmilk, MTX cannot be recommended in breastfeeding because of theoretical risks and insufficient data on outcomes (GRADE 2C, SOA 99%)
8 ct [37, 50, 52, 91, 179, 180, 182, 183] (1st trimester ≥239, 2nd/3rd trimester ≥8)
1 cs [173]
5 cr [174–178]
SSZ 3 ct [46, 50, 52] 178 NR No significant adverse effect noted

  • Rate not specifically quantified in the majority of papers.

  • Overall, no increase in rate of major malformations attributable to drug

  1. SSZ is compatible throughout pregnancy, with folic acid 5 mg/day recommended in the periconception period and during the first trimester (GRADE 1B, SOA 100%)

  2. SSZ is compatible with breastmilk exposure in healthy, full-term infants (GRADE 1C, SOA 99.5%)
1 cs [55] (NR)
2 cr [62, 193]
LEF 6 ct [50, 91, 194, 199–201] 814 138/811 No significant adverse effect noted

  • 42/525

  • Overall, no increase in rate of major malformations attributable to drug, but most cases stopped in 1st trimester and received cholestyramine washout

  1. LEF may not be a human teratogen but there remains insufficient evidence to support use at the time of conception or during pregnancy (GRADE 1B, SOA 98%)

  2. Women on LEF considering pregnancy should stop and undergo a standard cholestyramine washout procedure, and switch to alternative medication compatible with pregnancy (GRADE 1B, SOA 98.8%)

  3. If unintended conception occurs on LEF, the drug should be stopped immediately and a standard cholestyramine washout procedure given, with early referral to a foetal medicine department considered (GRADE 1B, SOA 99%)

  4. LEF is not recommended while breastfeeding (GRADE 1C, SOA 99.5%)
(1st ≥156, 2nd/3rd ≥24)
4 cr [195–198]
AZA 5 cc [88, 135, 172, 203, 204] 1757 130/642 No significant adverse effect noted

  • 18/487

  • Overall, no increase in rate of major malformations attributable to drug

  1. AZA is compatible throughout pregnancy (GRADE 1B, SOA 100%)

  2. AZA is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
(1st ≥1254, 2nd/3rd ≥580)
16 ct [31, 45, 50–52, 78, 90, 92, 93, 95, 205, 206, 212–215]
6 cs [55, 99, 102, 173, 207, 208]
2 cr [61, 107]
1 sr [83]
CsA 4 cc [43, 88, 135, 136] 401 9/132 Possible trend towards shorter pregnancy duration [92, 101, 136, 165] and low birth weight [88, 92, 165]

  • 2/26

  • Data confounded by concomitant AZA/MMF exposure

  1. CsA is compatible throughout pregnancy with monitoring of maternal blood pressure, renal function, blood glucose and drug levels (GRADE 1B, SOA 100%)

  2. CsA is compatible with breastmilk exposure (GRADE 2C, SOA 99.7%)
(1st ≥131, 2nd/3rd ≥136)
8 ct [50, 51, 92, 93, 95, 182, 219, 220]
3 cs [54, 101, 165]
TAC 1 ct [92, 93, 219, 223, 225–231] 515 108/451 Insufficient data to confirm lack of a significant adverse effect

  • 12/270

  • Overall, insufficient data, mainly in organ transplant cohorts

  1. TAC is compatible throughout pregnancy with monitoring of maternal blood pressure, renal function, blood glucose and drug levels (GRADE 2B, SOA 100%)

  2. TAC is compatible with breastmilk exposure (GRADE 2C, SOA 99.8%)
(1st ≥302, 2nd/3rd ≥135)
1 cs [99]
2 cr [107, 116]
CYC 1 cs [102] 20 2/16 Insufficient data

  • 0/13

  • Few data, from individual case reports or case series, available

  1. CYC is a known teratogen and gonadotoxic, and therefore should only be considered in pregnancy in cases of severe life/organ-threatening maternal disease when there is appreciable risk of maternal and foetal morbidity and mortality without this therapy (GRADE 1B, SOA 99.5%)

  2. CYC is not recommended while breastfeeding (GRADE 2C, SOA 100%)
4 cr [106, 111, 167, 168] (1st ≥6, 2nd/3rd ≥2)
1 ct [232]
MMF 7 ct [92, 95, 215, 242–245] 804 371/753 Evidence of reduced pregnancy duration and birth weight

  • 47/316

  • Data mainly from organ transplant cohorts, including one cohort of n = 221 demonstrating both reduced gestation and birth weight

  1. MMF remains contraindicated during pregnancy, and should be avoided in women planning pregnancy or switched to a pregnancy-compatible alternative at least 6 weeks before attempting to conceive (GRADE 1B, SOA 100%)

  2. In cases of unintended conception, switch MMF to a pregnancy-compatible alternative and refer to local experts for further advice and risk assessment (GRADE 1B, SOA 100%)

  3. MMF is not recommended while breastfeeding (GRADE 2C, SOA 99.7%)
(1st ≥796, 2nd/3rd ≥320)
3 cs [99, 208, 235]
12 cr [57, 60, 113, 114, 116, 236–241]
IVIG 1 cc [248] 403 10/178 No significant adverse effect noted

  • 22/121

  • Overall, no increase in rate of major malformations attributable to drug, albeit limited data available

  1. IVIG is compatible with pregnancy (GRADE 1B, SOA 99.5%)

  2. IVIG is compatible with breastmilk exposure (GRADE 2C, SOA 100%)
(1st ≥13, 2nd/3rd ≥77)
12 ct [48, 49, 74, 79, 127, 128, 133, 249–253]
1 Cochr [82]
1 cs [97]
3 cr [58, 110, 254]

All studies that provided quantitative and/or qualitative information on the safety of the relevant drug in pregnancy were included; however, numerical outcome data could only be collated from papers where the relevant outcome was clearly quantified. Details of how numerical data in this table were derived are shown in Supplementary Data S3, available at Rheumatology online. 

cc: case control; Cochr: Cochrane review; cr: case report; cs: case series; CsA: ciclosporin; ct: cohort; MP: methylprednisolone; NR: not reported; nrt: non-randomized trial; Pred: prednisolone; rct: randomised controlled trial; SOA: strength of agreement; sr: systematic review; TAC: tacrolimus.