Pregnancy and medications for inflammatory bowel disease: An updated narrative review

Table 1 Summary of prospective and nationwide studies regarding the safety of biologics and small molecules for pregnant women with inflammatory bowel disease

Biologics/small molecules	ECCO’s guideline[25]	Summary of recent prospective and nationwide studies
TNF inhibitors (monotherapy)	Low risk	The PIANO registry predominantly including patients treated with TNF inhibitors found no increased risks of adverse maternal or fetal outcomes at birth or in the first year of life in pregnant women with IBD treated with biologics[20]. Two French nationwide studies reported no significant differences in the risk of pregnancy outcomes between pregnancies exposed to anti-TNF monotherapy and unexposed controls[21]. The risk of serious infection during the first 5 yr of life was not significantly different between children exposed to anti-TNF monotherapy and the unexposed population[22]
TNF inhibitors with thiopurines	Thiopurine discontinuation may be considered	The PIANO registry predominantly including patients treated with TNF inhibitors found no increased risks of adverse maternal or fetal outcomes at birth or in the first year of life in pregnant women with IBD treated with biologics combined with thiopurines[20]. Two French nationwide studies reported that patients on combination therapy were more likely to have preterm birth than unexposed controls[21]. Children exposed to combination therapies had a higher risk of serious infection during the first year of life[22]
Vedolizumab	Low risk, limited data	In 50 vedolizumab-exposed pregnancies, the rates of live birth, miscarriage, and congenital malformations were 86%, 14%, and 0%, respectively. Infant vedolizumab level was not associated with the risk of infection during the first year of life[28]. The first prospective study comparing 24 pregnant women treated with vedolizumab, 82 with TNF inhibitors, and 224 with conventional therapy showed that the rate of spontaneous abortion (21%) was higher in the vedolizumab group than in the other groups[29]. In this study, disease activity at conception may affect the result. A Czech prospective study including 39 pregnant women with IBD exposed to vedolizumab during pregnancy showed that 90% of pregnancies ended in a live birth, 5% in spontaneous abortion, and 5% in therapeutic abortion. No significant differences in the risk of pregnancy outcomes were observed between vedolizumab- and TNF inhibitor-exposed populations[24]
Ustekinumab	Low risk, limited data	A Czech prospective study including 54 pregnant women treated with ustekinumab showed that 80% and 20% of patients resulted in live births and spontaneous abortions, respectively. The risk of pregnancy outcomes was not significantly different between ustekinumab- and anti-TNF-exposed controls[24]. An Israeli prospective study including 27 pregnancies exposed to ustekinumab, 52 exposed to TNF inhibitors, and 50 unexposed controls showed no significant differences in the rates of obstetrical maternal complications, preterm delivery, LBW, and first-year newborn hospitalization[23]. The manufacturer’s global safety database including 408 ustekinumab-exposed pregnancies with IMIDs showed that the rates of adverse pregnancy outcomes were comparable to those of United States general population[31]
JAK inhibitors	Contraindicated (no mention of upadacitinib)	Data from interventional studies of tofacitinib identified 11 patients with UC exposed to tofacitinib before/at the time of conception or during pregnancy and showed that 36% of patients delivered healthy newborns, 18% had a medical termination, and no cases of neonatal death, fetal death, or congenital malformation were reported[33]
Ozanimod	Contraindicated	N/A
Calcineurin inhibitors	Low risk, limited data	N/A

ECCO: European Crohn’s and Colitis Organization; IBD: Inflammatory bowel disease; IMIDs: Immune-mediated inflammatory diseases; JAK: Janus kinase; LBW: Low birth weight; TNF: Tumor necrosis factor; UC: Ulcerative colitis; N/A: Not applicable.

Table 2 Summary of systematic review and meta-analyses regarding the safety profiles of biologics and small molecules for pregnant women with inflammatory bowel disease

Biologics/small molecules	ECCO’s guideline[25]	Summaries of recent systematic review and meta-analysis
TNF inhibitors (monotherapy)	Low risk	There was an increased risk of preterm births, LBW, and cesarian section in patients with IBD treated with TNF inhibitors[27]. This study was limited in its understanding of whether anti-TNF monotherapy or its combination with thiopurines is associated with these risks
TNF inhibitors with thiopurines	Thiopurine discontinuation may be considered on an individualized basis	Meta-analyses including recent prospective studies that assess the risk of combination therapy for pregnant women with IBD are lacking
Vedolizumab	Low risk, limited data	Women treated with vedolizumab had an increased risk of preterm births and early pregnancy loss compared with those unexposed to vedolizumab during pregnancy. No differences were observed in the number of live births or congenital abnormalities[26,30]. The systematic review and meta-analyses’ results may be biased by disease activity
Ustekinumab	Low risk, limited data	A meta-analysis including two case studies showed that women treated with ustekinumab had an increased risk of early pregnancy loss compared with those treated with TNF inhibitors[26]. The prevalence of adverse pregnancy events was likely to be overestimated due to the small number of studies in this meta-analysis
JAK inhibitors	Contraindicated (no mention of upadacitinib)	N/A
Ozanimod	Contraindicated	N/A
Calcineurin inhibitors	Low risk, limited data	A meta-analysis including 4450 CNI-treated patients (4372 solid organ transplant recipients and 78 patients with IMIDs including IBD) showed that the rates of preterm delivery, LBW, and preeclampsia were 3–4 times greater than the rates in the general population. The risk of neonatal prematurity was higher in solid organ transplant recipients than in patients with IMIDs due to the higher risk of preeclampsia in solid organ transplant recipients. CNIs may be safer for pregnant women with immune-mediated diseases than for solid organ transplant recipients[38]

CNI: Calcineurin inhibitor; ECCO: European Crohn’s and Colitis Organization; IBD: Inflammatory bowel disease; IMIDs: Immune-mediated inflammatory diseases; JAK: Janus kinase; LBW: Low birth weight; TNF: Tumor necrosis factor; UC: Ulcerative colitis; N/A: Not applicable.