Harms Systematic review
Systematic review suggests TNF-α inhibitors may be rational options for pregnant patients with inflammatory bowel disease 10.1136/eb-2013-101536 Barrett G Levesque,1 Marlene E Pountney-Levesque2 1
Division of Gastroenterology, University of California San Diego, La Jolla, California, USA; 2North County Health Center, San Diego, California, USA Correspondence to: Barrett G Levesque, Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr #0956, La Jolla, CA 92093, USA; [email protected]
Commentary on: Nielsen OH, Loftus EV, Jess T. Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Med 2013;11:174.
Context The diagnosis of inflammatory bowel disease (IBD) overlaps with the reproductive years in many patients’ lives. Therefore, there is an important need for valid data to support medical decision-making around conception planning and pregnancy in IBD. Given that tumour necrosis factor α (TNF-α) inhibitors are highly effective options for inducing and maintaining a clinical remission, their risks and benefits need to be well understood in the context of maternal and fetal outcomes. This systematic review addresses the risk of adverse birth outcomes due to maternal TNF-α inhibitor therapy.
Methods This was a well-conducted review of all currently available studies of the risks of TNF-α therapy in pregnant patients. Study types included case– control studies, case series and case reports. Investigators assessed adverse birth outcomes by measuring the frequency of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformation and childhood infections. The TNF-α inhibitors included in the review were infliximab, adalimumab and certolizumab. Heterogeneity and publication bias were qualitatively assessed. The review clearly stated the aim of the study, outcome measures, search strategy and study selection, and adhered to the guidelines established by the Meta-analysis of Observational Studies and Epidemiology Group (the MOOSE criteria). Meta-analysis was not performed due to the heterogeneity of the study designs.
Findings Fifty-eight studies met inclusion criteria, reporting at least 1533 pregnant women exposed to TNF-α inhibitors. The majority of the included studies were single-patient case reports (n=32) or small case series with 2–33
pregnancies (n=15). The remaining studies were moderate-to-large case series with 66–556 pregnancies (n=7) or case–control studies (n=4). Early case report and case series of pregnant patients treated with infliximab found risks that either were not supported by later larger case series or prospective registries. Among 142 pregnancies in the TREAT registry, the risk of congenital malformations was not higher than the general population. Among 1232 women in the PIANO registry, with 357 receiving TNF-α inhibitors, there was a small increased risk of preterm birth among women on combination therapy (RR=2.4, 95% CI 1.3 to 4.3), but not with biological therapy alone (RR=0.8, 95% CI 0.5 to 1.3). Similarly, the large GETAID group’s CESAME study did not find an increased risk of adverse maternal events among women receiving biologics compared with those not receiving them. Among the four case–control studies, none found a statistically significant increased risk of adverse outcomes with biological therapy. Overall, the systematic review did not find an increased risk of adverse outcomes in mothers or newborns due to TNF-α inhibitors.
Commentary The safety and efficacy of anti-TNF-α inhibitors in the treatment of Crohn’s disease during pregnancy is ultimately defined by their ability to increase the chance of healthy pregnancies and healthy children. Overall, although current studies may be underpowered to detect rare risks of anti-TNF therapy, the growing number of available case series and case– control trials covering the last 15 years of use have shown no reproducible evidence of harm to mothers or children. There is still a need for ongoing prospective studies such as PIANO to further investigate their safety over the long term and in larger numbers of patients. Given that the use of TNF-α inhibitors could be considered a marker for patients with moderate-to-severe disease, the lack of frequent adverse events is particularly reassuring to patients and their clinicians. The review lacks data on the differential incidence of maternal infections, such as pyelonephritis or chorioamnionitis, which are potential concerns surrounding immunosuppression during pregnancy. In addition, the studies often lack information regarding whether or not women temporarily stopped anti-TNF therapy on learning of their pregnancy, before restarting after the first trimester. The review addresses the uncertainty regarding when or if there is an ideal time to temporarily stop biologics that may cross the placenta. However, given the difference in TNF-α inhibitor pharmacokinetics among individual patients due to body mass index, albumin and disease activity,1 it is unclear that a ‘one-time-fits-all’ approach to stopping therapy exists. Studies of therapeutic monitoring could help identify goal concentrations to target for time points in pregnancy that may be associated with low placental transfer, favourable outcomes and low potential to stimulate immunogenicity in the mother. Competing interests BGL reports personal fees from Prometheus Labs, personal fees from Santarus Inc, personal fees from UCB Pharma, personal fees from Warner Chilcott and personal fees from Salix, outside the submitted work.
Reference 1. Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91:635–46.
Evid Based Med April 2014 | volume 19 | number 2 | ebmed.19.2.e15
Systematic review suggests TNF-α inhibitors may be rational options for pregnant patients with inflammatory bowel disease 10.1136/eb-2013-101536 Barrett G Levesque,1 Marlene E Pountney-Levesque2 1
Division of Gastroenterology, University of California San Diego, La Jolla, California, USA; 2North County Health Center, San Diego, California, USA Correspondence to: Barrett G Levesque, Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr #0956, La Jolla, CA 92093, USA; [email protected]
Commentary on: Nielsen OH, Loftus EV, Jess T. Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Med 2013;11:174.
Context The diagnosis of inflammatory bowel disease (IBD) overlaps with the reproductive years in many patients’ lives. Therefore, there is an important need for valid data to support medical decision-making around conception planning and pregnancy in IBD. Given that tumour necrosis factor α (TNF-α) inhibitors are highly effective options for inducing and maintaining a clinical remission, their risks and benefits need to be well understood in the context of maternal and fetal outcomes. This systematic review addresses the risk of adverse birth outcomes due to maternal TNF-α inhibitor therapy.
Methods This was a well-conducted review of all currently available studies of the risks of TNF-α therapy in pregnant patients. Study types included case– control studies, case series and case reports. Investigators assessed adverse birth outcomes by measuring the frequency of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformation and childhood infections. The TNF-α inhibitors included in the review were infliximab, adalimumab and certolizumab. Heterogeneity and publication bias were qualitatively assessed. The review clearly stated the aim of the study, outcome measures, search strategy and study selection, and adhered to the guidelines established by the Meta-analysis of Observational Studies and Epidemiology Group (the MOOSE criteria). Meta-analysis was not performed due to the heterogeneity of the study designs.
Findings Fifty-eight studies met inclusion criteria, reporting at least 1533 pregnant women exposed to TNF-α inhibitors. The majority of the included studies were single-patient case reports (n=32) or small case series with 2–33
pregnancies (n=15). The remaining studies were moderate-to-large case series with 66–556 pregnancies (n=7) or case–control studies (n=4). Early case report and case series of pregnant patients treated with infliximab found risks that either were not supported by later larger case series or prospective registries. Among 142 pregnancies in the TREAT registry, the risk of congenital malformations was not higher than the general population. Among 1232 women in the PIANO registry, with 357 receiving TNF-α inhibitors, there was a small increased risk of preterm birth among women on combination therapy (RR=2.4, 95% CI 1.3 to 4.3), but not with biological therapy alone (RR=0.8, 95% CI 0.5 to 1.3). Similarly, the large GETAID group’s CESAME study did not find an increased risk of adverse maternal events among women receiving biologics compared with those not receiving them. Among the four case–control studies, none found a statistically significant increased risk of adverse outcomes with biological therapy. Overall, the systematic review did not find an increased risk of adverse outcomes in mothers or newborns due to TNF-α inhibitors.
Commentary The safety and efficacy of anti-TNF-α inhibitors in the treatment of Crohn’s disease during pregnancy is ultimately defined by their ability to increase the chance of healthy pregnancies and healthy children. Overall, although current studies may be underpowered to detect rare risks of anti-TNF therapy, the growing number of available case series and case– control trials covering the last 15 years of use have shown no reproducible evidence of harm to mothers or children. There is still a need for ongoing prospective studies such as PIANO to further investigate their safety over the long term and in larger numbers of patients. Given that the use of TNF-α inhibitors could be considered a marker for patients with moderate-to-severe disease, the lack of frequent adverse events is particularly reassuring to patients and their clinicians. The review lacks data on the differential incidence of maternal infections, such as pyelonephritis or chorioamnionitis, which are potential concerns surrounding immunosuppression during pregnancy. In addition, the studies often lack information regarding whether or not women temporarily stopped anti-TNF therapy on learning of their pregnancy, before restarting after the first trimester. The review addresses the uncertainty regarding when or if there is an ideal time to temporarily stop biologics that may cross the placenta. However, given the difference in TNF-α inhibitor pharmacokinetics among individual patients due to body mass index, albumin and disease activity,1 it is unclear that a ‘one-time-fits-all’ approach to stopping therapy exists. Studies of therapeutic monitoring could help identify goal concentrations to target for time points in pregnancy that may be associated with low placental transfer, favourable outcomes and low potential to stimulate immunogenicity in the mother. Competing interests BGL reports personal fees from Prometheus Labs, personal fees from Santarus Inc, personal fees from UCB Pharma, personal fees from Warner Chilcott and personal fees from Salix, outside the submitted work.
Reference 1. Ordas I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91:635–46.
Evid Based Med April 2014 | volume 19 | number 2 | ebmed.19.2.e15
