Safety of biologic therapies during pregnancy in women with rheumatic disease

Table 1 Current European Medicines Agency recommendations about licensed biologic therapies and pregnancy (from http://www.ema.europa.eu/ema/)

Biologic drug	Recommendations for women of childbearing potential	Recommendations for the infant exposed in utero
Infliximab1	Adequate contraception for at least 6 mo after the last infusion	Neither live vaccines administration nor breast-feeding is recommended while treated and for 6 mo following the mother’s last infliximab infusion during pregnancy
Etanercept	To use appropriate contraception during therapy and for 3 wk after discontinuation of therapy	Neither live vaccines administration nor breast-feeding is recommended while treated and for 16 wk after the mother’s last dose of Enbrel is generally not recommended
Adalimumab2	Adequate contraception for at least 5 mo after the last injection	Neither live vaccines administration nor breast-feeding is recommended while treated and for 5 mo following the mother’s last injection during pregnancy
Golimumab	Adequate contraception for at least 6 mo after the last injection	Neither live vaccines administration nor breast-feeding is recommended while treated and for 6 mo following the mother’s last injection during pregnancy
Certolizumab	Adequate contraception for at least 5 mo after the last injection	Neither live vaccines administration nor breast-feeding is recommended while treated and for 5 mo following the mother’s last injection during pregnancy
Anakinra	Not recommended during pregnancy and in women of childbearing potential not using contraception	No data
Tocilizumab	Adequate contraception for at least 3 mo after the last infusion	A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman
		Advice about live vaccine use in newborns is not given
Rituximab	Adequate contraception for at least 12 mo after the last infusion	No breast-feeding is recommended while treated and for 12 mo following the mother’s last infusion during pregnancy
		Advice about live vaccine use in newborns is not given
Abatacept	Adequate contraception for at least 14 wk after the last dose	No breast-feeding is recommended while treated and for 14 wk following the mother’s last infusion during pregnancy
		Advice about live vaccine use in newborns is not given

¹Remicade^®, Inflectra^® and Remsima^®;

²Humira^® and Trudexa^®.

Table 2 Tumor necrosis factor inhibitors use during pregnancy and the conception period

Ref./registry	No. of pregnancies	Disease	Biologic drugs	Pregnancy stage	Pregnancy outcome
Lichtenstein et al[61] TREAT registry	36	CD	IFX	Any exposure	11.1% miscarriage (NS), 8.3% neonatal complications (NS)
Katz et al[62] Infliximab safety database	96	CD, UC, RA	IFX	7 prior to conception, 53 conception, 30 T1, 6 unknown	67% live births, 15% miscarriages, and 19% elective termination. Results similar to those expected for the general United States population or pregnant women with CD not exposed to infliximab
Garcia et al[50] BIOBADASER	14	RA, AS, PsA	IFX, ETN, ADA	First trimester	7 live births, 1 miscarriage, 3 therapeutic termination, 3 therapeutic termination, 2 on-going pregnancies, 0 malformations
Strangfeld et al[10] RABBIT	37		IFX, ETN, ADA, ANK	22 first-trimester (2 restarted biologic after week 20) 15 prior to conception	Similar miscarriage (4.5% vs 6.6%); 0 marformations
Johnson et al[17] OTIS	175	RA, PsA, AS, CPs	ETN	139 first trimester 67 disease matched	Similar live births (93.5% vs 88.1%); more miscarriage (14% vs 5% vs 1.1%); malformations (9.4% vs 4.5%)
Verstappen et al[11] BSRBR	140	RA, PsA, JIA, AS, SLE, AOSD	IFX, ETN, ADA	59 prior conception 71 at conception 10 controls never exposed	In post-conception exposures vs never exposed: less live births (59% vs 100%; P = 0.012), more miscarriages (27% vs 10%; P = 0.437), elective terminations (11% vs 10%; P = 0.587)
Chambers et al[14] OTIS	239	RA, CD	ADA	94 first trimester 58 disease-matched controls 87 non-disease controls	Similar live births (85% vs 91.4% vs 89.7%), miscarriages (4.3% vs 9%); similar preterm deliveries (15% vs 17% vs 4%); malformations (9.6% vs 5.4% vs 5%)

Experience from national registries. CD: Crohn’s disease; UC: Ulcerative colitis; RA: Rheumatoid arthritis; PsA: Psoriatic arthritis; JIA: Juvenile idiopathic arthritis; AS: Ankylosing spondylitis; SLE: Systemic lupus erythematosus; AOSD: Adult onset still disease; CPs: Cutaneous psoriasis; BSRBR: British society for rheumatology biologics register; NS: Non-significant; T1: First-trimester; IFX: Infliximab; ETN: Etanercept; ADA: Adalimumab.

Table 3 Others biological agents use during pregnancy and the conception period

Ref./study	No. of pregnancies	Disease	Biologic drugs	Pregnancy stage	Pregnancy outcome
Berger et al[56] Fischer-Betz et al[57] Case report	3	AOSD	ANK	Through pregnancy	3 healthy live birth, full-term deliveries
Rubbert-Roth et al[58] Case series from clinical trials	33	RA	TCZ	Non-data	26/32 treated wit TCZ + MTX, 6/32 TCZ monotherapy or concomitant with DMARD other than MTX 10/33 healthy live birth at term; 1/33 (1 infant died of ARDS 3 d after emergency cesarean section for intrapartum fetomaternal hemorrhage due to placenta previa; 13/33 elective terminations, 7/33 miscarriages
Chakravarty et al[59]	153	NHL, RA, SLE, Others1	RTX	132 prior to the conception	90 live births: 68 full-term deliveries; 22 preterm; 1 neonatal death at 6 wk; 2 malformations (clubfoot in one twin, and cardiac malformation in a singleton birth)
Biogen Idec/Genentech/Roche rituximab global drug safety database				21 after the concption	11 newborns had hematologic abnormalities (none with infections); 4 neonatal infections (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis)
Ojeda-Uribe et al[22]	1	RA	ABT	First trimester	No complications. One healthy live birth

¹Idiopathic purpura thrombocytopenic, autoimmune haemolytic anaemia, multiple sclerosis, thrombotic thrombocytopenia. Purpura, Castleman disease, mixed connective tissue disease, and renal transplantation. AOSD: Adult onset still disease; RA: Rheumatoid arthritis; NHL: No hodgkin lymphoma; SLE: Systemic lupus erythematosus; ANK: Anakinra; TCZ: Tocilizumab; RTX: Rituximab; ABT: Abatacept; ARDS: Acute respiratory distress syndrome.