European evidenced-based consensus on reproduction in inflammatory bowel disease

Inflammatory bowel diseases (IBD) typically affect patients in their reproductive years. It has been shown that reproductive issues are of key concern to IBD patients, 1 especially women. 2 In this respect, it is important to note that IBD patients remain voluntary childless more frequently than non-IBD controls. 1 , 3 , 4 A recent study reported that IBD patients refrain from having children due the concerns about the adverse reproductive outcome. 1 Fear of side-effects of the medication on the child and medical advice given by physicians, were the most important reasons for voluntary childlessness in this study. The treatment of IBD patients wishing to conceive is surrounded with uncertainties both for the parents to be and the treating physician. This guideline is developed to address these uncertainties and to promote a European perspective on reproduction in inflammatory bowel disease patients. The strategy to reach consensus involved the following steps: The development of questions that should be covered by these pregnancy guidelines. Participants were asked to review these questions and when necessary to adjust or add questions. The participants met in London in November to agree on the questions The participants performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as their own files. The evidence level was graded ( Table 1 ) according to the Oxford Centre for Evidence-Based medicine 5 . Provisional statements of the participants were written and the participants met in Prague in February 2010 to agree on the statements. This was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined as agreement by > 80% of the participants. Each recommendation was graded as stated above. The final document on each topic was written by the designated participants. Consensus guideline statements in bold are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not to read in isolation. The final document was edited by the first author. In some areas the level of evidence is generally low, which reflects the lack of prospective trials in this specific area. Consequently expert opinion is included where appropriate. This document includes the ECCO opinion on drug safety during pregnancy and lactation. This approach is carefully chosen because the FDA made an announcement in May 2008, stating that they will replace the A, B, C, D, and X classification system with a narrative framework consisting of 3 sections although the system is easy to use, it might oversimplify the complexity of weighing risks to the fetus against the need to adequately manage maternal medical conditions 6 . The system does not fully address the fact that the benefits of treatment of some conditions (e.g., diabetes, asthma, pregnancy-induced hypertension, and psychiatric conditions) might outweigh the risk of fetal drug exposure. ECCO Statement 2 A There is no evidence that ulcerative colitis or inactive Crohn's disease affects fertility [EL3a, RG B]; however active Crohn's disease may lead to reduced fertility. Therefore it is advisable to strive for clinical remission to optimise the chances of conception [EL3b, RG B]. Patients with quiescent IBD are as fertile as the general population. Patients with IBD have fewer children than the general population, but this may partly be because of voluntary childlessness. 7 , 8 It is suggested that active Crohn's disease (CD) reduces fertility by several mechanisms, including inflammation involving the fallopian tubes and ovaries and perianal disease causing dyspareunia. 9 ECCO Statement 2 B There is no evidence that medication for IBD affects fertility in females [EL4, RG C]. In males sperm quality may be affected by sulphasalazine, methotrexate, and infliximab [EL4, RG C]. Sulfasalazine therapy causes a reversible decrease in sperm motility and count in male patients. The effect is dose related and it is unaffected by supplemental folic acid. 10 – 13 Azathioprine (AZA) did not influence sperm quality in 18 male IBD patients who used AZA at least 3 months. 14 Methotrexate (MTX) given for psoriasis produces oligospermia, this will improve within a few months after stopping the drug. 15 Infliximab (IFX) seems to affect semen quality by reducing motility in a small group of patients; however sperm concentration increased after infusion. 16 , 17 The outcome of 10 pregnancies indirectly exposed to IFX through the male partner resulted in 9 lives births, 1 miscarriage and no congenital malformations were reported. 17 For anti-TNF alpha it is unknown whether the fetus will be affected by exposure to anti-TNF alpha through semen and therefore barrier methods are advised during pregnancy [EL 5, RG D]. ECCO Statement 2 C Pelvic surgery may lead to impotence or ejaculatory problems in men [EL4, RG C]. Men who undergo ileoanal pouch surgery for ulcerative colitis (UC) may experience retrograde ejaculation and erectile dysfunction. 18 – 20 However, these studies have shown that overall there is no change or even an improvement in sexual function post 18 – The effect of or improvement of sexual function after surgery on fertility in men has not been ECCO Statement 2 and to a surgery for IBD the of in females RG B]. There is evidence to that to conceive within a has an increased with IBD who have 8 , 9 , 18 , – A systematic review that the fertility of with was reduced after and a that a increased risk of to medical have a of of and following surgery and this is the most for after There is a of literature on the of there are no studies that fertility following a than a there are no to the approach of with and during the and an in to The of the during pregnancy as and related , ECCO Statement 3 A conception at a of quiescent disease the risk of is the as in RG D]. at a of active disease is with during pregnancy [EL3b, RG B]. might affect the of IBD RG B]. conception during a of remission about a of patients during pregnancy which is to that in patients a of months. – the conception at a of active have and of will This the of patients to conceive at a when disease is in – It seems that pregnancy the overall of IBD because as the need for patients with a pregnancy fewer and the to be when with with , with to have a in the after with the pregnancy but specific as have not been or in , has an effect on the which may to these ECCO Statement 3 B The of should be by and However, a approach involving the the is [EL 5, RG D]. ECCO Statement 3 C ileoanal pouch or an in with IBD is as a for a but the should be made on an [EL RG D]. should be in active perianal disease or [EL4, RG C]. The of should be by but the should be with the the to the and a on the of a post with to and bowel is in patients with disease or in of some for patients it seems to for with quiescent or disease as no evidence be in the literature for , should be because a of perianal has been but is than an is as an for – The that a with an is and more on an and function for with a having The be to patients with an although they have an function they have and are at risk of disease and The literature is not on , , , There is a in risk that a with will need a and may be a for an pouch during fertile The risk of is at the first a with to of be on an to Patients with a or but the risk is increased for there should be a for A recent has that IBD patients have more problems with after with controls. ECCO Statement 3 C There is no increased risk of a in the remain on their therapy [EL RG C]. a of IBD experience a after but this risk is not when to the risk of having a not having a Patients with have a of of pouch function bowel and a decrease in in pregnancy and in the during the , , , ECCO Statement 4 A from parents with IBD have an increased risk of The risk is for Crohn's disease than for ulcerative colitis RG B]. The risk for children of both parents have IBD [EL4, RG C]. The of IBD is to of patients with IBD have affected with the , In the most important risk for IBD is having a with the The risk for a of a to affected is 13 to and for a of a this risk is this an overall in and of 10 for and for this a risk of for a of a and for a of a The risk for children of both parents have IBD and was shown to be at the of years. Patients with IBD and a to their disease at an than patients a and an increased in disease or and disease – In the of the disease does not or ECCO Statement 4 B with IBD and in with Crohn's disease may have an increased risk of adverse pregnancy outcome [EL RG C]. adverse and an increased of [EL RG B]. risk for adverse pregnancy outcome is of disease [EL RG although in Crohn's disease the of with the of the disease [EL RG D]. ECCO Statement 4 C as or to an [EL RG are not increased in at the risk for congenital is increased due to in the literature [EL RG D]. with IBD have an increased overall risk for adverse pregnancy The most are of with a risk of and than with a risk of , , most studies have shown increased of but is it not whether this is due to or by , , , , pregnancy are more in with to few studies have at the influence of IBD on a conception outcome and on the of of pregnancy and of and the of is and on the of of pregnancy and are a , , , does have an on pregnancy outcome. However, most of the studies did not this and the recent studies that the influence of the in the risk of but not in at and in congenital in with active for the and maternal IBD seems to have no adverse on the at In these the in the and were not more in of with the of congenital is due to in the included and the influence of the used However, might a risk for congenital to for malformations and congenital , – ECCO Statement 4 There are no on as of or increased risk for specific with to in drug exposure [EL 5, RG D]. ECCO Statement 4 with for who have been exposed in to anti-TNF not from for as no adverse have been and to were appropriate RG D]. ECCO Statement 4 as and should be when there is no anti-TNF in the which is in most in the of the first RG D]. the of the drug to of the dose of therapy should be as in the of pregnancy as RG D]. IFX is in the through the first 6 months of there are concerns about the system of and for the to there have been no reported adverse and to were as well as the of patients with to with and with for who have been exposed to anti-TNF in not from for This does not for as and which are in was reported of a child from a exposed to IFX during pregnancy that at months due to after a at 3 months. be to in the of the first when it is that no IFX or are or when there are no anti-TNF in the of the dose of IFX and should be as in the as to remission but to to the , , this for to be The of used for IBD treatment in as are not and will not influence however are ECCO Statement 5 A during pregnancy a risk of adverse and are to these [EL RG C]. medical treatment of IBD ( Table 1 ) should be in patients who to conceive in to the risk of during pregnancy [EL 5, RG D]. studies have that most pregnancies in with IBD will be the is in remission or has disease at the of – A by with more than patients with and patients with that pregnancies are in of with in and in of with in were in about of pregnancies and the of and were in the as in the population. In several studies that the of pregnancies is reduced and the of adverse of pregnancy is when pregnancies in with active inflammatory bowel – to IBD patients with inactive with a during pregnancy have with and , , , the of active disease in patients have to be and it is conception during ECCO Statement 5 B used for the treatment of IBD are to be of risk during and are ECCO Statement 5 C The of and is not with malformations or adverse in IBD patients and their RG C]. Patients with should be with folic RG C]. In of and are ECCO Statement 5 to lack of adverse drug be as an RG D]. ECCO Statement 5 In the of patients, remission with medical treatment the risks of adverse drug However, the benefits and the risks be with the and have to made on an For a of safety of IBD used during pregnancy , and ECCO recommendation Table 1 . Sulfasalazine and are , – and , did not an increased risk for pregnancy adverse as miscarriage and trials have a of and the of active disease is to and and the recent did not A small in risk of congenital malformations has been shown in the by it have been the of disease treatment with is of and the to the fetus but are by to active in and are more by the and therefore reach in the fetus than the and the are for the treatment of maternal conditions on pregnancy shown in have not been in , , However, the risk for malformations is increased in of in the first of – this increased risk is and not by there are of due to the of in the pregnancy of with There is of patients with which did not an increased risk of adverse pregnancy outcome. AZA and are which with the of and AZA the and it fetal have been in in maternal and , exposure to AZA and has been reported in several of studies the safety of in females and males as no increased risk of malformations in the , , – The most pregnancy adverse are increased of and , in the of studies the adverse outcome have been by the disease than by the of AZA or risks for and in a few are and and by For it is reported that it the safety are not and therefore during pregnancy in IBD is not and are used for treatment and of after and to after Therefore most of on pregnancy outcome are from these patients. For a of 15 studies with patients did not an increased of congenital but for on the of in IBD is to small of that during , a of was congenital malformations were the were with and but it is to the of disease from the effect of drug are and in pregnancy and therefore barrier methods to pregnancy during therapy with are pregnancy were exposure to during the first may in and congenital including and conception should should be but not should be to and dose The of have a and about to reach or to exposure to it should be in both females and at least for months to of has been with malformations involving and with of IFX and both are and in the and IFX and are to be in fetal and in for several months after For this has not been but seems were in a and in 8 after pregnancies during which were IFX 8 with the at the of as in and were for 2 to 7 months. This as well as the evidence from the with exposed to IFX and from IFX where are for with exposure to IFX 17 that IFX is of risk in both for the and and does not to be a For were on 3 pregnancies in patients with in of these pregnancies and the were at 6 months. – or was in 14 with to pregnancies resulted in in the 10 pregnancies no is a of a the by the active of the of the in the are to be than IFX or A study of a of and a of this drug in the and with the to the The with are more but in and first clinical not an increased risk in and the have for treatment of of these may be in the treatment of and perianal disease and are risk in the is used for treatment of active as well as perianal This medication does not risk of or congenital , although of exposed to in the to months of pregnancy have shown of with or studies with have not shown an in or congenital However, studies by this medication have a for and and may in they are to have risk they should be in the first ECCO Statement 5 as [EL RG and RG should be and as 1 should be in IBD patients in of a pregnancy RG There are no specific in with IBD or specific as an in literature as a of pregnancy in IBD patients. The not specific conception is for – and although are be given in with small bowel ECCO Statement for surgery in with IBD are the as for In the be colitis not to medical In Crohn's disease and In the is a risk to the than [EL4, RG C]. for surgery in with IBD not from women. In patients, is a risk to the than In with or are for surgery and are no to for women. , – have included and A is generally to the risk of after In the of ulcerative colitis the for surgery is disease not by medical therapy and or disease on an to of surgery during pregnancy there is for a is in but there is some on in the first and when in the ECCO Statement 6 A does not affect disease in IBD [EL RG C]. was with an in disease in however medication was a was not with an increased risk for a in or ECCO Statement 6 B are to be [EL are to be [EL RG C]. are in small in the are however to be because of unknown in the with [EL4, RG C]. ECCO Statement 6 C are to be in the in small However, no adverse have been reported in the small of by on this the of in the to be carefully and drug and in and RG C]. For a of safety of IBD used during and ECCO recommendation Table 2 . Sulfasalazine is for The is in and is in however the is The safety of has been in prospective – and are both are not as appropriate during the and in a 4 after be , small of of and in a reported in several There is a in the and of and , that the exposure of the that exposure to is and therefore this should be There are no to the of in because in the are It is not whether is in In 4 with IFX the IFX not be in and the IFX was not in the of 3 , has been reported to be in in the of a however no are about in ECCO Statement 7 A on the effect of IBD on the sexual function are RG C]. A effect on sexual function is with but disease is RG C]. In males and females sexual function seems to be or even increased after surgery [EL RG B]. There are of the of IBD of , It is that and disease affect and patients with IBD are reported to have a of as and may a and has been to be more with IBD and is a for sexual with IBD reduced sexual and to There is evidence on the affect of surgery on the sexual function of with IBD with some studies a in and sexual after surgery and studies no an in dyspareunia. – In seems to be , from or retrograde sexual function seems to be or even increased after – This be to in general after surgery in to increased sexual for of which has been shown to have a on sexual , ECCO Statement 7 B There are no to an effect of IBD on the of RG D]. not the of IBD RG C]. There are no studies the of in with are from the small and on of or may to in patients who have inflammatory or Therefore it be that the of may be reduced in with who have small bowel disease and The general advice for using that have been or for more than is to for prospective study and some studies no effect of on the of – ECCO Statement 7 C IBD is a however the effect is RG C]. patients with conditions as IBD and at risk for RG is and in In an IBD a clinical the of should be made on an has been with a in the of In the literature a was that may a in the of IBD through a of the effect of risk that be specific to IBD patients is therapy is of the most risk to C, of and decrease of and and of and – The risk with with the treatment but is in the first of use, especially in who have a , who have as a of or have to because these them at risk for – is a due to IBD is a in an IBD a clinical the of should be made on an ECCO Statement 7 for should be performed in the with IBD [EL 4 RG of should be given for IBD a to or risk are RG B]. the risk of by and is a of maternal in developed The of risk is in the first 6 of the IBD patients, with active are at increased risk for , IBD patients have an increased risk of to their non-IBD for and for an in a dose reduces the risk of in medical and patients by has been shown to be and in the population. Therefore of the of is IBD patients a to is should undergo a of risk for in pregnancy or This should be the is to for and after ECCO Statement 7 It is that with IBD their and they have [EL RG B]. should be given to with to [EL 5 RG D]. There is evidence of an in of in the , and in patients. Therefore it has been that with IBD who are on therapy at , There is to this for a of was in an study where of with IBD were to have to of controls. This was by study which in of with IBD to of and ( . This study therapy by an increased in in on for > 6 months to not were in a study which with of However, the in in these studies did not to an in 2 studies no in with IBD with or , The of in this was there is no consensus on the necessary of it is that with IBD are about the risks and as the have a of for the of that are with of It is therefore that with in should be advised to have this for ECCO in Consensus on the and of in inflammatory bowel ECCO Statement 7 RG and RG are generally to be in these should be done when there is a and should be performed in the RG D]. are and should be with RG C]. ECCO Statement 7 and exposure should be to a RG C]. should be in with in and RG D]. patients should be in or during and after the to RG D]. of fetal should be is and after the RG D]. ECCO Statement 7 should be to appropriate drug using most and in pregnancy and using the dose to the effect RG C]. should be to [EL 5, RG D]. evidence the and safety of in the with the increased risk of following due to the of maternal and to Therefore should have their the and the dose of drug necessary for an effect should be patients in the or should be in the to the risk of and to these in pregnancy should be for does to a to or – and studies have shown that is and with no evidence for this , small of in pregnancy no evidence of adverse outcome. , retrograde in pregnancy has been reported in several – studies that is in pregnancy with no increased of congenital fetal or of However, there may be a risk of , – although this did not the overall pregnancy outcome in these dose should be to a and in the of studies the dose did not the of 10 however this was not the and several and a small study on 6 has the of The of and in the appropriate outweigh the The risk of of for is have no but a and should be is used in for and It is the but studies of and no from during the first was reported. that for 1 after maternal This be as a of however this effect is and not a when used is by the of for in is during and is although note and as is in but to the it to following during is However, it has not been in in the first and and therefore is not for during this of are and but the concentration is The and should be during the first the for the but fetal to about to of maternal after or maternal and are but there is exposure was for 4 after of a 15 , ECCO Statement 8 A for and should be for patients with IBD to and optimise conception RG D]. ECCO Statement 8 B and therapy is in should by a with experience in treating active IBD in pregnancy RG D]. It was shown in a small that the of IBD patients with conception medication for which on the safety of the is In reproductive lead to the medication in of these patients. Therefore the group it is important to wishing to conceive for suggested in 1 a in the the group that these are in need of by a with experience in treating active IBD in This should and The to the following of The following have given by the following – The following have the following The following have an from the following The following have as for the following for females who to of IBD in pregnancy of IBD in pregnancy of IBD during of IBD during