130 | MARCH 2013 | VOLUME 10 www.nature.com/nrgastro

NEWS & VIEWSIBD

Can TNF inhibitors be administered during the third trimester?Ole Haagen Nielsen and Tine Jess

As pregnancies frequently occur in patients with IBD, and given that TNF inhibitors are increasingly being used for treatment of this chronic intestinal disease, the discontinuation of biologic agents during the third trimester in patients with quiescent disease has been advocated owing to safety concerns.Nielsen, O. H. & Jess, T. Nat. Rev. Gastroenterol. Hepatol. 10, 130–131 (2013); published online 18 December 2012; doi:10.1038/nrgastro.2012.248

IBD affects both sexes in their peak repro-ductive age, and treatment of pregnant patients is a common clinical phenom enon. Pregnant women with IBD are known to have a greater risk of adverse pregnancy outcomes than the general population,1 but whether the diagnosis of IBD independently carries an increased risk of adverse out-comes, or if the increased risk of adverse outcomes is a consequence of active disease and/or treatment of IBD, is continuously debated. With respect to the TNF inhibi-tors (that is, the synthetic antibodies inflixi-mab, adalimumab and certolizumab pegol), which are increasingly used in clinical prac-tice, it is discussed whether discontinuation of TNF inhibitors is necessary among preg-nant patients. From a study of 28 pregnant women with IBD, Zelinkova et al.2 report that discontinuation of TNF inhibitors before gestational week 30 and resumption after pregnancy is a safe strategy in terms of disease control among mothers-to-be with quiescent disease.

An increased risk of adverse outcomes such as preterm birth, low birth weight, spontaneous abortions, still birth, congenital

abnormalities and cesarean sections are observed in active disease stages,3 whereas women with IBD in remission can expect to have a pregnancy comparable to that of women in the general population.4 Patients with IBD are, therefore, advised to conceive in quiescent stages of their disease; notably, however, the unplanned pregnancy rate worldwide is around 41%.5

Even though no firm evidence exists to support such a recommendation, dis-continuation of biologic therapy around week 30 of pregnancy has been advocated not only by Zelinkova et al.2 but by a number of sources, including a decision-making algorithm,6 because the trans placental transfer of IgG1 anti bodies (that is, inflixi-mab and adalimumab) increases over time during pregnancy, with maximum amounts being transferred during the third tri mester.7 Accordingly, Zelinkova et al.2 observed signifi cantly lower mean cord blood levels of infliximab among women receiving the drug ≥10 weeks before delivery than among women treated closer to delivery. Serum levels of infliximab have been reported to be higher in newborns than mothers at the time of birth, decreasing to non detectable levels after 2–7 months in these infants.7 Certolizumab pegol differs in this respect because it is a Fab’ fragment of a humanized anti-TNF antibody. Fab’ fragments cross the placenta minimally via passive diffusion compared with the active high-level trans-port across the placenta of full-length IgG antibodies (that is, infliximab and adali-mumab). Accordingly, it has been judged less necessary to stop certolizumab pegol treatment in the third trimester.

The American Gastroenterological Association has identified treatment with

biologic agents as ‘low risk’ in pregnancy and compatible with use during concep-tion and pregnancy. All three TNF inhibi-tors are classified as category B drugs according to the US FDA.8 In the case of discontinuation of biologic therapy, treat-ment in the third trimester could be bridged with gluco corticoids to control disease activity until delivery. This approach also has the benefit of minimizing the break from treatment and thus the time for anti-body development (consequently reducing the risk of allergic reactions once treatment is reintroduced postpartum for example).

From scrutinizing the available litera-ture of >600 reported pregnancies there is, however, no convincing association between treatment with TNF inhibitors for IBD in pregnancy and adverse pregnancy outcomes—such as spontaneous abortions, preterm deliveries, low birth weight, con-genital malformations, and/or infections—even when TNF inhibitors are administered in the third trimester. However, even though available data suggest that the rates of congenital malformations and adverse birth events are similar to the rates in the background population of pregnant women or women with IBD in general, it should be emphasized that immunosuppression of the offspring contraindicates the use of live vaccines until the biologic agent is no longer detectable in the child’s circula-tion (that is, up to 7 months postpartum). A report from the PIANO registry of 1,115 Ph

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‘‘Physicians and patients should weigh the potential risks and benefits concerning the various TNF inhibitors...’’

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NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 10 | MARCH 2013 | 131

NEWS & VIEWS

pregnant women with IBD, of whom 269 had Crohn’s disease and were treated with biologic agents, showed a slightly increased risk of infections at 12 months in children of mothers exposed to biologic agents (exclud-ing certolizumab pegol) in combination with thiopurines (relative risk 1.35; 95% CI 1.01–1.80).9 An elevated risk was not observed in the group exposed to biologic agents alone or if combined therapy with certolizumab pegol was administered. The observed infections were mild and mostly affected the ears and urinary tract.

Only very small amounts of infliximab and adalimumab are transferred in the breast milk of nursing mothers; the concen-trations are roughly 1:200 of the level in the mothers blood,10 and are unlikely to result in any systemic immune suppression of the infant. Nonetheless, possible local effects of such an exposure on the intestine of the offspring and potential immune sensi-tization or tolerization towards the bio-logic agent can not be excluded and merits further investigation. Administration of certolizumab pegol is compatible with breastfeeding.

Physicians and patients should weigh the potential risks and benefits concern-ing the various TNF inhibitors in the IBD armamentarium, using up-to-date evidence in this area. Given the limited number of studies with proper control groups, evi-dence is still insufficient to prove the abso-lute safety of TNF inhibitor use during pregnancy in patients with IBD. As a result, in our view, the use of biologic therapy during pregnancy should be limited to cases in which uncontrolled activity of IBD could expose both the mother and child to risks greater than the potential risks from the use of TNF inhibitors. If a patient has been prescribed biologic therapy, stopping this treatment in the third trimester should primarily be considered if the patient has quies cent disease, in accordance with results from Zelinkova et al.2 The inten-tional use of biologic therapy throughout pregnancy might, on the other hand, be

considered in situations in which IBD is not quiescent at the end of the second tri-mester, as the documented benefit of TNF inhibitors for active inflammatory and fis-tulizing IBD is unprecedented. However, it should be kept in mind that concomitant therapy with biologic agents and thio-purines might cause a marginal increased risk of infections in the offspring, and gastroenterologists must take this matter into consideration accordingly when pre-scribing biologic therapy throughout the pregnancy. Further studies are needed to elucidate the risk of combination therapy on the neonatal immune system.

Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark (O. H. Nielsen). National Health Surveillance and Research, Statens Serum Institute, 5 Artillerivej, DK-2300 Copenhagen S, Denmark (T. Jess). Correspondence to: O. H. Nielsen ohn@dadlnet.dk

Competing interestsThe authors declare no competing interests.

1. Cornish, J. et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 56, 830–837 (2007).

2. Zelinkova, Z. et al. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease

and neonatal exposure. Clin. Gastroenterol. Hepatol. http://dx.doi.org/10.1016/ j.cgh.2012.10.024.

3. Dominitz, J. A., Young, J. C. & Boyko, E. J. Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study. Am. J. Gastroenterol. 97, 641–648 (2002).

4. Reddy, D., Murphy, S. J., Kane, S. V., Present, D. H. & Kornbluth, A. A. Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes. Am. J. Gastroenterol. 103, 1203–1209 (2008).

5. Singh, S., Sedgh, G. & Hussain, R. Unintended pregnancy: worldwide levels, trends, and outcomes. Stud. Fam. Plann. 41, 241–250 (2010).

6. Habal, F. M. & Huang, V. W. Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient. Aliment. Pharmacol. Ther. 35, 501–515 (2012).

7. Zelinkova, Z. et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy. Aliment. Pharmacol. Ther. 33, 1053–1058 (2011).

8. Mahadevan, U. et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organisation: pregnancy and pediatrics. Am. J. Gastroenterol. 106, 214–223 (2011).

9. Mahadevan, U. et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract]. Gastroenterology 142 (Suppl. 5), S149 (2012).

10. Ben-Horin, S. et al. Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease. J. Crohns Colitis 5, 555–558 (2011).

Key point

In patients with quiescent IBD, discontinuation of TNF inhibitors should be considered in the third trimester—although no evidence exists that these drugs cause any adverse pregnancy outcomes if administered throughout the pregnancy. Any live vaccines to the offspring are contraindicated until the TNF inhibitor is no longer detectable in the child’s circulation.

LIVER CANCER

Intrahepatic cholangiocarcinoma —appearances can be deceivingMalcolm R. Alison and Wey-Ran Lin

The phenotype and behaviour of primary tumours in the liver is widely believed to reflect their cell of origin. A new study in mice shows that this relationship is not always the case—the cells of origin of intrahepatic cholangiocarcinomas might be hepatocytes rather than the expected cholangiocytes or bipotential hepatic progenitor cells.Alison, M. R. & Lin, W.-R. Nat. Rev. Gastroenterol. Hepatol. 10, 131–133 (2013); published online 15 January 2013; doi:10.1038/nrgastro.2012.258

The role of stem cells in cancer has become a major focus of interest in oncology research, largely because of the realization that in most cases tumour growth is sus-tained by a specific population of stem cells, the so-called cancer stem cells. The origin of these cancer stem cells in any tumour type is presently unclear, but one obvious possi-bility is that they are derived directly from mutated normal stem cells. This assumption

is a logical one given that normal stem cells already have the attributes of self-renewal, clonogenicity and multipotentiality.

In a hierarchically organized tissue such as the small intestine, we can be reasonably sure that tumours arise from either normal stem cells or their immediate transit-amplifying descendants, but not from the terminally differentiated cells located on the villi. The situation is less clear in the

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