Tumor necrosis factor-α inhibitor therapy and fetal risk: A systematic literature review

Table 1 Summary of reports of maternal exposure to anti-tumor necrosis factor agents during pregnancy

Ref.	Study type	Disease	Anti-TNF-αagent	Exposure to other drugs	Exposures in pregnancies with documented outcome	Maternal exposure: Pregnancy stage	Live births (n)	SA/SB (n)	PTB/PMB (n)	LBW/SGA (n)	CA (n)	Pregnancy outcomes: Details/complications
Chambers et al[18]	Prospective	RA	IFX	NS	4	T1	3	1 SA	2
Mahadevan et al[19]	Prospective	CD: (4) UC: (1)	IFX	NS	5	T2/T3 other exposure details NS	5
Berthelot et al[20]	Case series	Rheumatologic disease	IFX	-1	3	C/T1: 1 C/T1/T2: 2	3
Chakravarty et al[21]	Case series	RA	IFX	Some pts	1	Pregnancy, not otherwise specified	1
Correia et al[22]	Case series	CD	IFX	Yes: 1	2	C/T1/T2/T3	2		1	1 SGA		1 preterm/premature birth due to placental detachment (31 wk, 1.6 kg with acute respiratory failure requiring mechanical ventilation × 24 h and intensive care × 40 d; healthy at 8 mo follow-up)
				No: 1
Hyrich et al[23]	Case series	Rheumatologic disease	IFX	Some pts	3	C/T1	2	1 SA
Kane et al[24]	Case series	CD	IFX	Some pts	3	T1/T2/T3: 2 T2/T3: 1	3		1
Katz et al[25]	Case series	CD: (82)	IFX	Some pts	100	C: 53	68	10	1	1	3	CA (3):
		UC: (1)				T1: 30		SA		LBW		1 full-term with tetralogy of Fallot
		RA: (8)				> 3 mo						1 intestinal malrotation
		JRA: (2)				prior to C: 7		1				1 developmental delay and hypothyroidism
		Unknown:(3)				Unknown: 6		SB				1 complicated neonatal course:
												Respiratory distress/jaundice/seizure. Mother was also exposed to several antibiotics for pulmonary and urinary infections, azathioprine, hydrocortisone, and total parental nutrition early in pregnancy
												Miscarriages (14):
												10 SA
												1 SB (mother exposed to leflunomide)
												3 unknown type
Mahadevan et al[26]	Case series	CD	IFX	Some pts	10	T1: 1	10		3	1		1 neonatal jaundice (resolved)
						T3: 1				LBW		1 complicated neonatal course: term delivery at 39 wk with respiratory distress/desaturation/gastric ulcer day 5; healthy at 6 mo follow-up
						C/T1/T2/T3: 8
Rosner et al[27]	Case series	Rheumatologic disease	IFX	Yes	3	C/T1/T2/T3	3		1			1 premature rupture of membranes
Schnitzler et al[28]	Case series	CD/UC/IC	IFX	NS	10	C/T1/T2	9	1	2
								SB
Weber-Schoenderfer et al[29]	Case series	NS	IFX	NS	25	T1	22	2	4		2	CA (2):
								SA				1 ventricular septal defect
												1 growing hemangioma requiring therapy
Zelinkova et al[30]	Case series	CD: (3)	IFX	Some pts	4	C/T1/T2: 3	4		1		1	CA (1):
		UC: (1)				C/T1/T2/T3: 1						L hand polydactyly (Infant also had respiratory depression after anesthetics that resolved spontaneously. Mother was taking methotrexate 2 mo prior to conception without folic acid supplement.)
Akinci et al[31]	Case report	Rheumatologic disease	IFX	Yes	1	C/T1/T2/T3	1
Angelucci et al[32]	Case report	CD	IFX	Yes	1	C/T1	1		1	1
										LBW
Angelucci et al[33]	Case report	CD	IFX	Yes	1	T1	1
Antoni et al[34]	Case report	Psoriatic Arthritis	IFX	NS	1	C/T1	1
Arai et al[35]	Case report	CD	IFX	Yes	1	C/T1/T2	1
Aratari et al[36]	Case report	CD	IFX	Yes	1	T2	1			1
										SGA
Burt et al[37]	Case report	CD	IFX	Yes	1	C/T1	1		1
Chaparro et al[38]	Case report	CD	IFX	NS	1	C/T1/T2/T3	1		1
Cheent et al[39]	Case report	CD	IFX	NS	1	C/T1/T2/T3	1		1			Infant developed disseminated BCG after vaccination at 3 mo and died at 4.5 mo
Epping et al[40]	Case report	CD	IFX	Yes	1	C/T1/T2/T3	1
Hou et al[41]	Case report	CD	IFX	NS	1	C/T1/T2/T3	1
James et al[42]	Case report	CD	IFX	Yes	1	T2	1
Kinder et al[43]	Case report	RA	IFX	Yes	1	C/T1	0	1
								SA
Østensen et al[44]	Case report	RA	IFX	Yes	1	C/T1	1					Oligohydramnios detected on 18 wk ultrasound that resolved with discontinuation of Nimesulide
Puig et al[45]	Case report	Psoriasis	IFX	Yes	1	C/T1/T2/T3	1
Srinivasan et al[46]	Case report	CD	IFX	Yes	12	C/T1	1		1			Preterm premature birth (24 wk) complicated by intracerebral and intrapulmonary hemorrhages and neonate died at 3 d
												Mother was also exposed to metronidazole, azathioprine, and mesalamine for fistulizing CD
Steenholdt et al[47]	Case report	UC	IFX	Yes	1	C/T1/T2/T3	1
Stengel et al[48]	Case report	CD	IFX	Yes	1	C/T1/T2/T3	1
Tursi et al[49]	Case report	CD	IFX	NS	1	C/T1/T2/T3	1		1
Vasiliauskas et al[50]	Case report	CD	IFX	NS	1	C/T1/T2/T3	1
Wilbaux et al[51]	Case report	AS	IFX	NS	1	C/T1	1
Xirouchakis et al[52]	Case report	CD	IFX	Yes	1	C/T1	1		1			Preterm (29 wk) birth with neonatal hospitalization × 30 d post-delivery. Baby in “good condition” at follow-up
Johnson et al[53,54]	Prospective	CD and RA	ADA	NS	94	T1	80	13	12		7	CA (7) ( live births):
						Other exposure details NS		SA			(among live births)	1 undescended testicle
												1 microcephaly
												1 congenital hip dysplasia with inguinal hernia
												1 congenital hypothyroidism
												1 ventricular septal defect
												1 bicuspid aortic valve and agenesis of corpus callosum (twin sibling had patent ductus arteriosus)
												1 congenital hydronephrosis
												CA (9) (all pregnancies):
												In addition to above 7 defects were:
												1 spina bifida and hydrocephalus (resulted in elective termination)
												1 ectopia cordis and caudal regression (twin pregnancy resulting in a spontaneous abortion)
Berthelot et al[20]	Case series	Rheumatologic disease	ADA	-3	2	C/T1: 1	2
						C/T1/T2/T3: 1
Hyrich et al[23]	Case series	Rheumatologic disease	ADA	Some pts	3	C/T1	2	1 SA
Johnson et al[53,54]	Case series	CD and RA	ADA	NS	122	T1	122				5	5 CA (5):
						other exposure details NS						2 chromosomal abnormalities
												1 atrial septal defect and peripheral pulmonic stenosis
												1 ventricular septal defect
												1 congenital hip dysplasia
Weber-Schoenderfer et al[29]	Case series	NS	ADA	NS	28	T1	24	2	4			1 infant with autosomal dominant disease (not otherwise specified); paternal inheritance
								SA
Abdul Wahab et al[55]	Case report	CD	ADA	Yes	1	C/T1/T2/T3	2			1		Twin-to-twin transfusion syndrome
							(twins)			SGA		(1 small due to discordance)
Ben-Horin et al[56]	Case report	CD	ADA	NS	1	C/T1/T2/T3	1
Bosworth et al[57]	Case report	CD	ADA	Yes	1	C/T1/T2/T3	1		1
Coburn et al[58]	Case report	CD	ADA	Yes	1	T2/T3	1
Dessinioti et al[59]	Case report	Psoriasis	ADA	NS	1	C/T1	1			1		Infant reported as “normal” at 12 mo follow-up
										LBW
Jurgens et al[60]	Case report	CD	ADA	NS	1	C/T1	1
Kraemer et al[61]	Case report	Takayasau’s Arteritis	ADA	Yes	1	C/T1/T2/T3	1
Mishkin et al[62]	Case report	CD	ADA	Yes	1	C/T1/T2/T3	1
		RA	ADA	NS	1	C/T1	1		1
Roux et al[63]	Case report
Vesga et al[64]	Case report	CD	ADA	Yes	1	C/T1/T2/T3	1
Wibaux et al[51]	Case report	AS	ADA	Yes	1	C/T1/T2	1				1	CA (1):
												Primary craniosynostosis requiring surgery
Kane et al[65]	Case series	CD	CTZ	NS	14	NS	5	1		1
								SA		SGA
Mahadevan et al[66]	Case report	CD	CTZ	Yes	1	T2/T3	1
Ousallah et al[67]	Case report	CD	CTZ	NS	1	C/T1/T3	1
Steinberg et al[68]	Case report	CD	CTZ	Yes	1	T2	1

¹Specified no exposure to disease-modifying antirheumatic drugs, methotrexate, or non-steroidal anti-inflammatory drugs;

²Case reported by Srinivasan et al[46] was also documented by Katz et al[25];

³Specified no exposure to disease-modifying antirheumatic drugs, methotrexate, or non-steroidal anti-inflammatory drugs. TNF: Tumor necrosis factor; CD: Crohn’s disease; UC: Ulcerative colitis; IC: Indeterminate colitis; RA: Rheumatoid arthritis; JRA: Juvenile rheumatoid arthritis; AS: Ankylosing spondylitis; IFX: Infliximab; ADA: Adalimumab; CTZ: Certolizumab pegol; NS: Not specified; Pts: Patients; C: Within < 3 mo prior to conception; T1: First trimester (LMP to 13 wk); T2: Second trimester (14 to 27 wk); T3: Third trimester (28 to 40 wk); SA: Spontaneous abortion; SB: Stillbirth; Preterm birth (< 37 wk gestation); PMB: Premature birth (< 37 wk gestation and prior to organ development); LBW: Low birth weight (< 2500 g); SGA: Small for gestational age (smaller than average size given the number of weeks of pregnancy).

Table 2 Summary of anti-tumor necrosis factor exposures and birth outcomes n (%)

Anti-TNF exposure	Birth outcomes, n (with relative percents)
	Fetal exposures	Live births	SA	SB	PTB/ PMB	LBW/SGA	CA
IFX/ADA/CTZ total	472	405 (85.8)	32 (8.2)	2 (0.6)	41 (19.9)	8 (6.1)	19 (4.1)
IFX1	194	155 (79.9)	15 (10.6)	2 (1.1)	21 (26.9)	5 (4.4)	6 (4.0)
IFX in IBD2	151	117 (77.5)	11 (8.9)	2 (1.4)	16 (36.4)	5 (4.8)	4 (3.5)
ADA1	261	242 (92.7)	16 (6.9)	0 (0.0)	20 (15.9)	2 (28.6)	13 (5.4)
ADA in IBD2	224	210 (93.8)	13 (5.8)	0 (0.0)	15 (17.0)	2 (28.6)	12 (5.7)
CTZ1	17	8 (47.1)	1 (5.9)	0 (0.0)	0 (0.0)	1 (12.5)	0 (0.0)
CTZ in IBD2	17	8 (47.1)	1 (5.9)	0 (0.0)	0 (0.0)	1 (12.5)	0 (0.0)
Outcome percents in general US population[69-73]		64.60%	16.50%	0.60%	12.30%	8.20%	3.00%-5.00%

¹Exposure in all reported medical conditions;

²Exposure in inflammatory bowel disease (IBD) patients. TNF: Tumor necrosis factor; IFX: Infliximab; ADA: Adalimumab; CTZ: Certolizumab pegol; SA: Spontaneous abortion (fetal death at < 20 wk); SB: Stillbirth (fetal death at > 20 wk or > 350 g if gestational age unknown); PTB: Preterm birth (< 37 wk gestation); PMB: Premature birth (< 37 wk gestation and prior to completion of organ development); LBW: Low birth weight (< 2500 g); SGA: Small for gestational age (smaller than average size given number of pregnancy weeks).

Table 3 Summary of congenital abnormalities reported

Congenital abnormalities (n = 19)	Affected (n)	Anti-TNF exposure
Ventricular septal defect	3	IFX (1), ADA (2)
Chromosomal abnormalities	2	IFX
Congenital hip dysplasia	2	IFX (1), ADA (1)
Intestinal malrotation	1	IFX
Congenital hypothyroidism	1	IFX
Hemangiomas	1	IFX
L hand polydactyly	1	IFX
Tetralogy of Fallot	1	IFX
Patent ductus arteriosus	1	ADA
Atrial septal defect and peripheral pulmonic stenosis	1	ADA
Bicuspid aortic valve and agenesis of corpus callosum	1	ADA
Primary craniosynostosis	1	ADA
Microcephaly	1	ADA
Congenital hydronephrosis	1	ADA
Undescended testes	1	ADA

IFX: Infliximab; ADA: Adalimumab; TNF: Tumor necrosis factor.