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Female reproductive health and inflammatory bowel disease: A practice-based review

      Abstract

      Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.

      Keywords

      1. Introduction

      Inflammatory bowel disease (IBD), namely ulcerative colitis and Crohn's disease, is a pair of chronic, benign diseases of increasing incidence worldwide. Sex differences in incidence and prevalence have been reported in IBD as in other immune-mediated disorders such as rheumatoid arthritis, scleroderma, multiple sclerosis, and systemic lupus erythematosus [
      • Molodecky N.A.
      • Soon I.S.
      • Rabi D.M.
      • et al.
      Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
      ,
      • Ngo S.T.
      • Steyn F.J.
      • McCombe PA.
      Gender differences in autoimmune disease.
      . Gender may influence patients’ perception of the disease, their body image, and their clinical symptoms [
      • Greuter T.
      • Manser C.
      • Pittet V.
      • et al.
      Gender differences in inflammatory bowel disease.
      ].
      Currently, the prevalence of IBD in the Western world is almost 0.5% [
      • Molodecky N.A.
      • Soon I.S.
      • Rabi D.M.
      • et al.
      Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
      ,
      • Ngo S.T.
      • Steyn F.J.
      • McCombe PA.
      Gender differences in autoimmune disease.
      . According to population-based studies, there is slight predominance of females among all patients with Crohn's disease (CD) [
      • Shah S.C.
      • Khalili H.
      • Gower-Rousseau C.
      • et al.
      Sex-based differences in incidence of inflammatory bowel diseases-pooled analysis of population-based studies from western countries.
      ]. A few studies found a small male prevalence in ulcerative colitis (UC) [
      • Gower-Rousseau C.
      • Vasseur F.
      • Fumery M.
      • et al.
      Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD).
      ]. IBD onset, in Western populations, occurs most frequently in the second to fourth decades of life [
      • Kappelman M.D.
      • Rifas–Shiman S.L.
      • Kleinman K.
      • et al.
      The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States.
      ], although for UC a second peak in incidence in the 60-79 years age group has been reported [
      • Langholz E.
      • Munkholm P.
      • Nielsen O.H.
      • et al.
      Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987.
      ]. After 25 years of age, women have a 16% to 47% higher risk of CD than men do, according to an age-stratified meta-analysis [
      • Shah S.C.
      • Khalili H.
      • Gower-Rousseau C.
      • et al.
      Sex-based differences in incidence of inflammatory bowel diseases-pooled analysis of population-based studies from western countries.
      ].
      To help gastroenterologists, gynecologists and even neonatologists who see women with IBD, this article reviews the current state of knowledge regarding the management of IBD at different stages of a woman's life, including puberty, pregnancy and menopause.

      2. Puberty and menstruation

      IBD can affect the onset and progression of puberty. Girls with IBD may have delayed puberty and secondary amenorrhea [
      • Kirschner B.S.
      • Rich BH.
      Puberty and pediatric-onset inflammatory bowel disease.
      ,
      • Shamir R.
      • Phillip M.
      • Levine A.
      Growth retardation in pediatric Crohnʼs disease: pathogenesis and interventions.
      . Delayed puberty may be due to malnutrition and to the negative effects of pro-inflammatory cytokines such as interleukin (IL) 1 and tumor necrosis factor (TNF) α on sex hormone production [
      • Kirschner B.S.
      • Rich BH.
      Puberty and pediatric-onset inflammatory bowel disease.
      ].
      IBD symptoms can exacerbate during the menses [
      • Lahat A.
      • Falach-Malik A.
      • Haj O.
      • et al.
      Change in bowel habits during menstruation: are IBD patients different?.
      ], and this can be a confounding element in discriminating dysmenorrhea from intestinal disease relapse. The exacerbation of symptoms may be due to endometrial prostaglandins, which increase inflammation and intestinal motility [
      • Lahat A.
      • Falach-Malik A.
      • Haj O.
      • et al.
      Change in bowel habits during menstruation: are IBD patients different?.
      ], or to the presence in the gastrointestinal tract of estrogen receptors that are involved in visceral hypersensitivity and motility [
      • Lahat A.
      • Falach-Malik A.
      • Haj O.
      • et al.
      Change in bowel habits during menstruation: are IBD patients different?.
      ].

      3. Sexuality

      According to the World Health Organization, sexual health is the “state of physical, emotional, mental and social well-being in relation to sexuality” [

      WHO Sexual health [Internet]. [cited 2018 Sep 19]. Available from: http://www.who.int/topics/sexual_health/en/n.d.

      ]. Sexual health can be affected by IBD, especially when the disease is in an active phase [

      WHO Sexual health [Internet]. [cited 2018 Sep 19]. Available from: http://www.who.int/topics/sexual_health/en/n.d.

      ,
      • Bel L.G.J.
      • Vollebregt A.M.
      • Van der Meulen-de Jong A.E.
      • et al.
      Sexual dysfunctions in men and women with inflammatory bowel disease.
      ,
      • Marín L.
      • Mañosa M.
      • Garcia-Planella E.
      • et al.
      Sexual function and patients’ perceptions in inflammatory bowel disease: a case-control survey.
      ]. In a questionnaire survey [
      • Rivière P.
      • Zallot C.
      • Desobry P.
      • et al.
      Frequency of and factors associated with sexual dysfunction in patients with inflammatory bowel disease.
      ], 54% of IBD women reported sexual dysfunction; these rates were higher than those reported by healthy controls (28%).
      Body image can be negatively influenced by surgical scars, stoma, and weight variation due to excessive steroid use, malabsorption or perianal disease [
      • Szydlarska D.
      • Jakubowska A.
      • Rydzewska G.
      Assessment of sexual dysfunction in patients with inflammatory bowel disease.
      ,
      • Muller K.R.
      • Prosser R.
      • Bampton P.
      • et al.
      Female gender and surgery impair relationships, body image, and sexuality in inflammatory bowel disease: patient perceptions.
      . These manifestations can interfere with sexual satisfaction, decrease libido and cause dyspareunia [
      • Berndtsson I.
      • Oresland T.
      • Hultén L.
      Sexuality in patients with ulcerative colitis before and after restorative proctocolectomy: a prospective study.
      ]. IBD patients also may have more anxiety and depression than healthy persons, as reported in a Turkish survey [
      • Ateş Bulut E.
      • Törüner M.
      The influence of disease type and activity to sexual life and health quality in inflammatory bowel disease.
      ]. These emotional moods impact on women's sexual well-being and desire [
      • Roseira J.
      • Magro F.
      • Fernandes S.
      • et al.
      Sexual quality of life in inflammatory bowel disease: a multicenter, national-level study.
      ]. Socioeconomic factors, social status, age, comorbidities and complications of IBD also alter sexual function in both women and men [
      • Roseira J.
      • Magro F.
      • Fernandes S.
      • et al.
      Sexual quality of life in inflammatory bowel disease: a multicenter, national-level study.
      ]. Therefore, the clinical management of IBD women should include assessment and counseling for psychological status and sexual health, which are important elements of quality of life.

      4. Preconception period

      According to a multinational survey [
      • Chakravarty E.
      • Clowse M.E.B.
      • Pushparajah D.S.
      • et al.
      Family planning and pregnancy issues for women with systemic inflammatory diseases: patient and physician perspectives.
      ], most female IBD patients feel that issues of family planning and pregnancy are not adequately addressed by their physicians during medical consultations. Indeed, knowledge of family planning and pregnancy issues is poor in nearly one half of women with IBD [
      • Purewal S.
      • Chapman S.
      • Czuber-Dochan W.
      • et al.
      Systematic review: the consequences of psychosocial effects of inflammatory bowel disease on patients′ reproductive health.
      ].
      Up to 19% of IBD women are voluntarily childless [
      • Purewal S.
      • Chapman S.
      • Czuber-Dochan W.
      • et al.
      Systematic review: the consequences of psychosocial effects of inflammatory bowel disease on patients′ reproductive health.
      ]. IBD women with poor knowledge about family planning and pregnancy are more likely to be voluntarily childless than knowledgeable IBD women [
      • Purewal S.
      • Chapman S.
      • Czuber-Dochan W.
      • et al.
      Systematic review: the consequences of psychosocial effects of inflammatory bowel disease on patients′ reproductive health.
      ,
      • Laube R.
      • Yau Y.
      • Selinger C.P.
      • et al.
      Knowledge and attitudes towards pregnancy in females with inflammatory bowel disease: an international, multi-centre study.
      ,
      • Huang V.W.
      • Chang H.J.
      • Kroeker K.I.
      • et al.
      Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease?.
      ].
      Preconception counseling, preferably starting at the time of IBD diagnosis, significantly reduces the frequency of voluntary childlessness [
      • Laube R.
      • Yau Y.
      • Selinger C.P.
      • et al.
      Knowledge and attitudes towards pregnancy in females with inflammatory bowel disease: an international, multi-centre study.
      ,
      • Huang V.W.
      • Chang H.J.
      • Kroeker K.I.
      • et al.
      Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease?.
      ,
      • Mahadevan U.
      • Robinson C.
      • Bernasko N.
      • et al.
      Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
      ,
      • Ellul P.
      • Zammit S.C.
      • Katsanos K.H.
      • et al.
      Perception of reproductive health in women with inflammatory bowel disease.
      ], the risk of nonadherence to treatment [
      • Julsgaard M.
      • Nørgaard M.
      • Hvas C.L.
      • et al.
      Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis.
      ], and the risk of IBD relapses during pregnancy [
      • de Lima A.
      • Zelinkova Z.
      • Mulders A.
      • et al.
      Preconception care reduces relapse of inflammatory bowel disease during pregnancy.
      ]. It's suitable IBD pregnancy clinic that was co-managed by obstetricians and IBD subspecialists [
      • Laube R.
      • Yau Y.
      • Selinger C.P.
      • et al.
      Knowledge and attitudes towards pregnancy in females with inflammatory bowel disease: an international, multi-centre study.
      ].
      The American Gastroenterological Association's IBD Parenthood Project Working Group recommends that pregnancies be scheduled only after 3-6 months of stable clinical remission, 3 months after withdrawal of a teratogenic drug (e.g. methotrexate), and about 6 months after the last administration of any experimental drug [
      • Mahadevan U.
      • Robinson C.
      • Bernasko N.
      • et al.
      Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
      ]. Oral hormonal contraceptives have an acceptable safety profile in women with IBD [
      • Zapata L.B.
      • Paulen M.E.
      • Cansino C.
      • et al.
      Contraceptive use among women with inflammatory bowel disease: a systematic review.
      ], but progestogen-only contraceptives are preferred to reduce the risk of venous thromboembolism [
      • Dragoman M.V.
      • Tepper N.K.
      • Fu R.
      • et al.
      A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception.
      ]. However, the effectiveness of oral formulations can be reduced by ileal malabsorption in extensive ileal CD and in those who had multiple abdominal surgeries [
      • Gawron L.M.
      • Sanders J.
      • Steele K.P.
      • et al.
      Reproductive planning and contraception for women with inflammatory bowel diseases.
      ].
      Having a sick child is one of the biggest concerns of women with IBD, and therefore this risk requires special attention during preconception counseling. In a Danish national study, 12% of all cases of CD and 9% of all cases of UC had familial inheritance [
      • Moller F.T.
      • Andersen V.
      • Wohlfahrt J.
      • et al.
      Familial risk of inflammatory bowel disease: a population-based cohort study 1977–2011.
      ]. For the child of a parent with CD, the relative risk of developing IBD was 6- to 7.5-fold higher than that of a child whose parents do not have CD. Similarly, the relative risk that a child develops UC was 4-fold higher when a parent has UC than when both parents are healthy. Having two or more affected first-degree relatives further increased the incidence rate ratio, to 9.77 for CD and 6.63 for UC. Nevertheless, the absolute risk for a child whose siblings have IBD to develop IBD was less than 3% [
      • Moller F.T.
      • Andersen V.
      • Wohlfahrt J.
      • et al.
      Familial risk of inflammatory bowel disease: a population-based cohort study 1977–2011.
      ]; this is the datum that needs to be extensively discussed with patients.
      In a prospective case-control study, women with IBD had similar pregnancy outcomes to women without IBD, in terms of the frequency of abortions, preterm deliveries, cesarean sections, congenital abnormalities and low-birth weight [
      • Bortoli A.
      • Pedersen N.
      • Duricova D.
      • et al.
      Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006: pregnancy outcome in IBD.
      ]. According to a meta-analysis, women who start pregnancy with active IBD have higher risks of low-birth-weight babies (risk ratio [RR] = 2.0) and small-for-gestational-age babies (RR = 1.3) than women who start pregnancy when in clinical remission [
      • Gonzalez-Suarez B.
      • Sengupta S.
      • Moss AC.
      Impact of inflammatory bowel disease activity and thiopurine therapy on birth weight: a meta-analysis.
      ].
      Similarly, the effects of pregnancy on IBD should be discussed. According to a meta-analysis, the risk of relapse or persistent disease activity during pregnancy is higher when conception had occurred during active disease than during remission, with risk ratios of 2.0 for both CD and UC [
      • Abhyankar A.
      • Ham M.
      • Moss A.C.
      Meta-analysis: the impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease.
      ] and in multiparous women, a history of disease flares during a prior pregnancy associated with relapse during a subsequent gestation [
      • Rottenstreich A.
      • Fridman Lev S.
      • Rotem R.
      • et al.
      Disease flare at prior pregnancy and disease activity at conception are important determinants of disease relapse at subsequent pregnancy in women with inflammatory bowel diseases.
      ]. In a prospective study that compared women who started pregnancy with IBD to non-pregnant IBD [
      • Pedersen N.
      • Bortoli A.
      • Duricova D.
      • et al.
      The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-epicom study of 209 pregnant women.
      ], pregnant women with UC were at higher risk of relapse during the course of study than non-pregnant UC women, while no difference was observed between the two groups of women with CD. In UC, relapse was mostly recorded in the first and second trimesters and in the postpartum period. Pregnancy may also exert a positive effect on IBD in the long term. Two studies observed a lower rate of relapse in the years following pregnancy than in the period before pregnancy in both UC and CD [
      • Castiglione F.
      • Pignata S.
      • Morace F.
      • et al.
      Effect of pregnancy on the clinical course of a cohort of women with inflammatory bowel disease.
      ,
      • Riis L.
      • Vind I.
      • Politi P.
      • et al.
      Does pregnancy change the disease course? a study in a European cohort of patients with inflammatory bowel disease.
      .
      Misconceptions about drug safety during pregnancy and breastfeeding may influence patient choice and negatively affect the pregnancy or the health of the mother and infant. Up to 40% of women reported not adhering to medical prescriptions prior to or during pregnancy (even for drugs with proven safety profiles), because they considered the substances potentially dangerous for fertility or for the baby [
      • Laube R.
      • Yau Y.
      • Selinger C.P.
      • et al.
      Knowledge and attitudes towards pregnancy in females with inflammatory bowel disease: an international, multi-centre study.
      ,
      • Julsgaard M.
      • Nørgaard M.
      • Hvas C.L.
      • et al.
      Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis.
      ,
      • Nielsen M.J.
      • Nørgaard M.
      • Holland-Fisher P.
      • et al.
      Self-reported antenatal adherence to medical treatment among pregnant women with Crohn's disease: adherence in pregnant women with Crohn's disease.
      ,
      • Gallinger Z.R.
      • Rumman A.
      • Nguyen GC.
      Perceptions and attitudes towards medication adherence during pregnancy in inflammatory bowel disease.
      . Moreover, according to a study in Australia [
      • Kashkooli S.B.
      • Andrews J.M.
      • Roberts M.B.
      • et al.
      Inflammatory bowel disease-specific pregnancy knowledge of gastroenterologists against general practitioners and obstetricians..
      ], obstetricians and gynecologists often expressed concerns about starting IBD medications around conception and during pregnancy, and did not feel adequately trained about the safety of IBD medications. IBD-expert gastroenterologists should discuss pregnancy and breastfeeding issues with patients when starting or changing medications, and they should support obstetricians and gynecologists in the management of pregnant women with IBD.

      5. Fertility

      Fertility can be an important issue for IBD women, even though studies indicate that, in the inactive phase of disease, fertility is normal and infertility rates are low.
      Despite normal fertility in quiescent IBD, other studies have documented an increase in voluntary childlessness. A questionnaire study of mostly white, IBD women from Illinois, United States, found that respondents had fewer children than the general population [
      • Marri S.R.
      • Ahn C.
      • Buchman AL.
      Voluntary childlessness is increased in women with inflammatory bowel disease.
      ]. The Scottish survey found that 36% of CD women were voluntarily childless compared with 7% of women in the general population [
      • Hudson M.
      • Flett G.
      • Sinclair T.S.
      • et al.
      Fertility and pregnancy in inflammatory bowel disease.
      ]. These findings were confirmed in a systematic review of eleven studies that found a 17-44% reduction in fertility in CD compared with controls, mostly due to voluntary choice [
      • Tavernier N.
      • Fumery M.
      • Peyrin-Biroulet L.
      • et al.
      Systematic review: fertility in non-surgically treated inflammatory bowel disease.
      ]. The reasons for voluntary childlessness are thought to be: fears of disease transmission and of the possible impact of pregnancy on the disease course, concerns about drug safety, and consequences of pain and other symptoms on sexual activity [
      • Selinger C.P.
      • Eaden J.
      • Selby W.
      • et al.
      Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views.
      ,
      • Mountifield R.
      • Bampton P.
      • Prosser R.
      • et al.
      Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions.
      .
      Another indicator of fertility is the time to pregnancy. In a Danish population study [
      • Friedman S.
      • Nielsen J.
      • Nøhr E.A.
      • et al.
      Comparison of time to pregnancy in women with and without inflammatory bowel diseases.
      ], women with CD were 1.54 times more likely to self-report a time to pregnancy of >12 months than were women without IBD. Women who had had CD surgery were 2.54 times more likely to report a prolonged time to pregnancy.

      5.1 Drugs and fertility

      There are no reported effects of IBD medications on the fertility of IBD women. Mesalazine, corticosteroids, thiopurines, and anti-TNFα agents have not been shown to negatively impact female fertility [
      • Janssen N.M.
      • Genta MS.
      The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and pactation.
      ]. Methotrexate, a second-line immunosuppressive treatment for IBD, does not appear to cause infertility in women, but because it has teratogenic effects, its use is contraindicated during both pregnancy and the preconception period [
      • Kroser J.
      • Srinivasan R.
      Drug therapy of inflammatory bowel disease in fertile women.
      ].
      Some IBD patients are treated with the therapeutic antibodies vedolizumab (anti-alpha4beta7 integrin) and ustekinumab (anti-IL-12 and anti-IL-23) or with the janus kinase inhibitor tofacitinib, but data on the effects of these drugs on female fertility are lacking. So far, there is only one case report of a woman with CD who became pregnant while taking ustekinumab [
      • Cortes X.
      • Borrás-Blasco J.
      • Antequera B.
      • et al.
      Ustekinumab therapy for Crohn's disease during pregnancy: a case report and review of the literature.
      ]. According to the American Gastroenterological Association's IBD Parenthood Project Working Group, tofacitinib should not be used as a first-line treatment for IBD women who are planning to conceive due to the limited safety data in humans and the increase of fetal malformations in animal studies [
      • Mahadevan U.
      • Robinson C.
      • Bernasko N.
      • et al.
      Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
      ].

      5.2 Surgery and fertility

      Active IBD may diminish fertility secondarily through surgery [
      • Ban L.
      • Tata L.J.
      • Humes D.J.
      • et al.
      Decreased fertility rates in 9639 women diagnosed with inflammatory bowel disease: a United Kingdom population-based cohort study.
      ]. According to the Scottish questionnaire study [
      • Riis L.
      • Vind I.
      • Politi P.
      • et al.
      Does pregnancy change the disease course? a study in a European cohort of patients with inflammatory bowel disease.
      ], women with CD who had IBD surgery were more likely to have infertility than those treated with medical therapy (12% vs. 5%, respectively). One study found that ileal pouch–anal anastomosis (IPAA), which is the surgical intervention of choice for UC, severely decreased fertility in UC women [
      • Ørding Olsen K.
      • Juul S.
      • Berndtsson I.
      • et al.
      Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample.
      ]. A systematic review found that the infertility rate in 945 UC women was 12% before surgery but 26% after IPAA [
      • Cornish J.A.
      • Tan E.
      • Teare J.
      • et al.
      The effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review.
      ]. A meta-analysis revealed a three-fold greater infertility rate in women who had restorative proctocolectomy with IPAA than patients who only had received medical treatment only (48% vs. 15%) [
      • Waljee A.
      • Waljee J.
      • Morris A.M.
      • et al.
      Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis.
      ]. Another meta-analysis of women with UC or familial adenomatous polyposis (FAP), found that the infertility rate one year after IPAA was 63% and that the relative risk of infertility 12 months after IPAA was 3.91 [
      • Rajaratnam S.G.
      • Eglinton T.W.
      • Hider P.
      • et al.
      Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review.
      ].
      The main causes of reduced fertility after IPAA are post-operative adhesions and fallopian tube scarring due to deep pelvic dissection [
      • Rajaratnam S.G.
      • Eglinton T.W.
      • Hider P.
      • et al.
      Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review.
      ,
      • Öresland T.
      • Palmablad S.
      • Ellström M.
      • et al.
      Gynaecological and sexual function related to anatomical changes in the female pelvis after restorative proctocolectomy.
      . Considering the negative impact of IPAA on fertility, the laparoscopic surgical approach is recommended by the European Crohn's and Colitis Organisation (ECCO) [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ]. Compared to open surgery, laparoscopy was found to be less detrimental to fertility in a single-center study of 63 women with UC or FAP [
      • Beyer-Berjot L.
      • Maggiori L.
      • Birnbaum D.
      • et al.
      A total laparoscopic approach reduces the infertility rate after ileal pouch-anal anastomosis: a 2-center study.
      ]. This finding was contradicted by another study of 519 women with IBD or FAP who had laparoscopic or open IPAA in which high rates of infertility after surgery (61% vs. 65%) were found [
      • Palomba S.
      • Sereni G.
      • Falbo A.
      • et al.
      Inflammatory bowel diseases and human reproduction: a comprehensive evidence-based review.
      ]. However, in this study, the median time to conception was shorter for patients who had laparoscopic surgery (3.5 vs. 9 months). A surgical option to preserve fertility is the two-stage intervention with preliminary total colectomy and temporary ileostomy followed, after childbearing age, by IPAA as the second stage [
      • Rajaratnam S.G.
      • Eglinton T.W.
      • Hider P.
      • et al.
      Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review.
      ].

      5.3 In vitro fertilization

      In vitro fertilization (IVF) is frequently used to treat infertility. Several factors can impact the outcome of IVF, including poor embryo quality (e.g. advanced maternal age, diminished ovarian reserve), poor endometrial receptivity, or suboptimal embryo transfer [
      • Gorgun E.
      • Cengiz T.B.
      • Aytac E.
      • et al.
      Does laparoscopic ileal pouch-anal anastomosis reduce infertility compared with open approach?.
      ,
      Fertility problems: assessment and treatment
      NICE Clinical Guidelines, No. 156.
      .
      Numerous studies have examined the success of IVF in IBD patients. Another retrospective study found that the rates of live births after six IVF cycles were similar between UC women who had IPAA and those who did not (64% and 71%) [
      • Pabby V.
      • Oza S.S.
      • Dodge L.E.
      • et al.
      In vitro fertilization is successful in women with ulcerative Colitis and Ileal pouch anal anastomosis.
      ]. Afterward, the same research team identified younger age, shorter duration of disease, and clinical remission status or mild disease activity as independent predictors of successful IVF for UC patients; they also identified younger age, lower body mass index (BMI), and lower cycle day 3 follicle-stimulating hormone levels as independent predictors of successful IVF in CD patients [
      • Oza S.S.
      • Pabby V.
      • Dodge L.E.
      • et al.
      Factors associated with the success of in vitro fertilization in women with inflammatory bowel disease.
      ]. Previous exposure to biological therapies was associated with a lack of IVF success (no live birth) in UC patients only, but this finding must be cautiously interpreted given that only 3 UC patients used biological therapies. Among other factors studied, such as parity, causes of infertility, surgery and medications, none was found to affect the IVF success rate [
      • Oza S.S.
      • Pabby V.
      • Dodge L.E.
      • et al.
      Factors associated with the success of in vitro fertilization in women with inflammatory bowel disease.
      ].
      The largest cohort study reported so far was based on Danish nationwide registries, containing data on 432 UC, 182 CD and 52,489 non-IBD women who had assisted reproductive technology (ART) treatment over a 20-year period [
      • Nørgård B.M.
      • Larsen P.V.
      • Fedder J.
      • et al.
      Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction: a 20-year nationwide cohort study.
      ]. UC patients had a lower chance of live birth for each embryo transferred than non-IBD women (crude odds ratio [OR] = 0.79), and this reduced success remained after adjusting for comorbidities (using the Charlson index [
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ]), women's and partners’ ages, calendar year of treatment, type of ART used, infertility diagnosis, BMI, and tobacco or alcohol use (adjusted OR = 0.73). The impact of IBD activity was not included in the analysis, since, in Denmark, only patients with quiescent disease can access ART treatment. In the same study, children of women with UC were at increased risk of preterm birth (OR = 5.29). For women with CD, surgery before ART reduced the probability of a live birth for each embryo transferred compared to non-IBD patients (adjusted OR = 0.51). In a follow-up study, the same research team reported that the risk of unsuccessful ART within 18 months of the first cycle was higher for CD with a history of abdominal surgery (for a live birth, OR = 0.29), especially when the procedure had been performed less than 2 years before [
      • Friedman S.
      • Larsen P.V.
      • Fedder J.
      • et al.
      The efficacy of assisted reproduction in women with inflammatory bowel disease and the impact of surgery-a nationwide cohort study.
      ]. An increased risk of ART unsuccess was not observed for women with UC, irrespective of the type of surgery [
      • Nørgård B.M.
      • Larsen P.V.
      • Fedder J.
      • et al.
      Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction: a 20-year nationwide cohort study.
      ,
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • et al.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ,
      • Friedman S.
      • Larsen P.V.
      • Fedder J.
      • et al.
      The efficacy of assisted reproduction in women with inflammatory bowel disease and the impact of surgery-a nationwide cohort study.
      ].
      A recent study, also from Denmark, found that in a cohort of 13,560 UC women the use of ART treatments was three-fold higher among those who had IPAA than those who did not [
      • Pachler F.R.
      • Toft G.
      • Bisgaard T.
      • et al.
      Use and success of in vitro fertilisation following restorative proctocolectomy and ileal pouch-anal anastomosis. a nationwide 17-year cohort study.
      ]. However, the chances of success were comparable between the two groups of women and, in this paper, the authors concluded that an IBD diagnosis does not complicate the success of IVF.

      6. Pregnancy

      6.1 Nutritional status and gestational weight gain

      A woman's nutritional requirements increase during pregnancy [
      • Williamson CS.
      Nutrition in pregnancy.
      ], and a mother's diet can influence fetal development, pregnancy outcome and life course of her offspring [
      • Geraghty A.A.
      • Lindsay K.L.
      • Alberdi G.
      • et al.
      Nutrition during pregnancy impacts offspring's epigenetic status-evidence from human and animal studies.
      ,
      • Grieger J.A.
      • Clifton VL.
      A review of the impact of dietary intakes in human pregnancy on infant birthweight.
      . There are no specific nutritional recommendations for pregnant women with IBD [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ]. Preconception care, including attention to maternal nutritional status, can positively influence birth outcomes by protecting against preterm delivery (before 37 weeks of gestation), low birth weight (<2500 g), and small for gestational age (SGA) [
      • de Lima A.
      • Zelinkova Z.
      • Mulders A.
      • et al.
      Preconception care reduces relapse of inflammatory bowel disease during pregnancy.
      ,
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      .
      Patients with IBD are prone to malnutrition and diarrhea [
      • Vagianos K.
      • Bector S.
      • McConnell J.
      • et al.
      Nutrition assessment of patients with inflammatory bowel disease.
      ,
      • Goh J.
      • O'Morain CA.
      Review article: nutrition and adult inflammatory bowel disease.
      . Furthermore, they often restrict food intake, especially of dairy products and fiber-containing products, to avoid abdominal pain [
      • Vagianos K.
      • Bector S.
      • McConnell J.
      • et al.
      Nutrition assessment of patients with inflammatory bowel disease.
      ,
      • Nguyen G.C.
      • Boudreau H.
      • Harris M.L.
      • et al.
      Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United States.
      . Active IBD impairs nutrient absorption and leads to nutrient loss [
      • Goh J.
      • O'Morain CA.
      Review article: nutrition and adult inflammatory bowel disease.
      ]. The most common deficiencies reported are iron, folic acid, calcium, vitamins, protein, fat and zinc, which all require supplementation [
      • Kilby K.
      • Mathias H.
      • Boisvenue L.
      • et al.
      Micronutrient absorption and related outcomes in people with inflammatory bowel disease: a review.
      ,
      • Hébuterne X.
      • Filippi J.
      • Al-Jaouni R.
      • et al.
      Nutritional consequences and nutrition therapy in Crohn's disease.
      ,
      • Bischoff S.C.
      • Escher J.
      • Hébuterne X.
      • et al.
      ESPEN practical guideline: clinical nutrition in inflammatory bowel disease.
      ]. In a Finnish retrospective study, IBD women were three times more likely to have anemia during the third trimester than non-IBD controls [
      • Raatikainen K.
      • Mustonen J.
      • Pajala M.O.
      • et al.
      The effects of pre- and post-pregnancy inflammatory bowel disease diagnosis on birth outcomes.
      ].
      Serum iron and folate levels should be monitored regularly and in case of deficiency should be supplemented and checked at each visit [
      • Bischoff S.C.
      • Escher J.
      • Hébuterne X.
      • et al.
      ESPEN practical guideline: clinical nutrition in inflammatory bowel disease.
      ,
      Pregnancy, childbirth, postpartum and newborn care a guide for essential practice.
      . The World Health Organization advises once daily iron administration until three months after delivery or abortion, and twice daily in cases of anemia, which occurs in approximately in 25% of IBD patients and has been linked to adverse pregnancy outcomes [
      Pregnancy, childbirth, postpartum and newborn care a guide for essential practice.
      ]. Iron administration may worsen constipation, which often accompanies normal pregnancies, and may exacerbate abdominal pain [
      • Mahadevan U.
      • Robinson C.
      • Bernasko N.
      • et al.
      Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
      ].
      Folic acid supplementation should be encouraged, especially in CD patients on low-residue diets and those on medications such as sulfasalazine, which interferes with folic acid metabolism [
      • Mahadevan U.
      • Robinson C.
      • Bernasko N.
      • et al.
      Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
      ,
      • Habal F.M.
      • Huang VW.
      Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.
      . Calcium and vitamin D supplementation should be administered primarily to patients who have required steroid courses in the past and those who are currently taking steroids [
      • Habal F.M.
      • Huang VW.
      Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.
      ]. Inadequacy of trace minerals (e.g. selenium, copper, chromium) is rare in IBD patients except in those requiring parenteral nutrition [
      • Mullin GE.
      Micronutrients and inflammatory bowel disease.
      ].
      Another issue for fetal development and growth is an adequate gestational weight gain (GWG, i.e. the difference between pre-pregnancy weight and weight at birth) [
      • Bengtson M.B.
      • Aamodt G.
      • Mahadevan U.
      • et al.
      Inadequate gestational weight gain, the hidden link between maternal IBD and adverse pregnancy outcomes: results from the norwegian mother and child cohort study.
      ]. Inadequate GWG is a strong independent predictor of adverse pregnancy outcomes in IBD [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ]. Several studies have shown associations between inadequate GWG and the birth of both preterm and SGA babies [
      • Dzakpasu S.
      • Fahey J.
      • Kirby R.S.
      • et al.
      Contribution of prepregnancy body mass index and gestational weight gain to adverse neonatal outcomes: population attributable fractions for Canada.
      ,
      • Haugen M.
      • Brantsæter A.L.
      • Winkvist A.
      • et al.
      Associations of pre-pregnancy body mass index and gestational weight gain with pregnancy outcome and postpartum weight retention: a prospective observational cohort study.
      ,
      • Wen T.
      • Lv Y.
      Inadequate gestational weight gain and adverse pregnancy outcomes among normal weight women in China.
      ]. In a retrospective Canadian study, low GWG was more common in women with CD than in healthy controls [
      • Moser M.A.
      • Okun N.B.
      • Mayes D.C.
      • et al.
      Crohn's disease, pregnancy, and birth weight.
      ]. CD mothers delivered babies with significantly lower birth weight than did control mothers, and 24.6% of the babies born to CD mothers were classified as SGA [
      • Moser M.A.
      • Okun N.B.
      • Mayes D.C.
      • et al.
      Crohn's disease, pregnancy, and birth weight.
      ].
      The majority of IBD mothers with inadequate GWG have normal pre-pregnancy BMI. Inadequate GWG was slightly more frequent among UC than CD mothers in two cohort studies [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ,
      • Bengtson M.B.
      • Aamodt G.
      • Mahadevan U.
      • et al.
      Inadequate gestational weight gain, the hidden link between maternal IBD and adverse pregnancy outcomes: results from the norwegian mother and child cohort study.
      . CD and UC mothers with inadequate GWG had a 2.5-fold increased risk of preterm birth [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ]. Moreover, disease activity is associated with inadequate GWG among IBD mothers. In one cohort study, approximately 30% experienced flares during pregnancy [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ]. Flares happen in UC mothers more frequently than in CD mothers [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ,
      • Bengtson M.B.
      • Aamodt G.
      • Mahadevan U.
      • et al.
      Inadequate gestational weight gain, the hidden link between maternal IBD and adverse pregnancy outcomes: results from the norwegian mother and child cohort study.
      . Nevertheless, inadequate GWG similarly increased the risk of preterm birth for CD and UC mothers, independent of disease activity, suggesting that factors other than disease activity contribute to inadequate GWG in IBD [
      • Bengtson M.B.
      • Martin C.F.
      • Aamodt G.
      • et al.
      Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
      ].
      In a Norwegian cohort study, disease activity was not associated with inadequate GWG, and flares were similarly distributed among mothers with adequate and inadequate GWG [
      • Bengtson M.B.
      • Aamodt G.
      • Mahadevan U.
      • et al.
      Inadequate gestational weight gain, the hidden link between maternal IBD and adverse pregnancy outcomes: results from the norwegian mother and child cohort study.
      ].
      Although the causes of inadequate GWG remain unclear, these findings may be explained by the fact that IBD patients are prone to malnutrition before conceiving and even more so during the early period of pregnancy when there is rapid placental development. Nutritional intervention is required in cases of inadequate weight gain. For severely malnourished pregnant women, total parenteral nutrition can be lifesaving [
      • Caruso A.
      • De Carolis S.
      • Ferrazzani S.
      • et al.
      Pregnancy outcome and total parenteral nutrition in malnourished pregnant women.
      ]. Therefore, physicians treating pregnant IBD women should aim to maintain proper maternal nutritional status and disease quiescence.

      6.2 Medical therapy

      Most medications used in IBD, including conventional therapy and the first generation of biological therapies, are safe in pregnancy and their use reduces the risk of active disease [
      • Gallinger Z.R.
      • Rumman A.
      • Nguyen GC.
      Perceptions and attitudes towards medication adherence during pregnancy in inflammatory bowel disease.
      ]. Moreover, as new drugs with different mechanisms of action have been approved, more safety data must be obtained before these new drugs are used. This section summarizes current recommendations and risks of IBD medical therapy during pregnancy (Table 1).
      Table 1Use of IBD drugs during fertility and pregnancy.
      Medicine groupDrugsRecommendationRisk
      AminosalicylatesMesalazine Sulfasalazine Balsalazide OlsalazideMaintain pre-pregnancy doses. With sulfasalazine, supplement folate (>2 mg/day)Low
      CorticosteroidsAllReserve for active flaresLow
      AntibioticsMetronidazoleAvoid in the first trimesterLow
      CiprofloxacinAvoid in the first trimesterLow
      ImmunomodulatorsAzathioprineContinue as monotherapyLow
      6-MercaptopurineContinue as monotherapyLow
      MethotrexateStop >3 months before conceptionHigh
      CyclosporineUse only as rescue therapyUnclear
      Anti-TNFαInfliximabDiscontinue during 2nd-3rd trimestersLow
      AdalimumabDiscontinue during 2nd-3rd trimestersLow
      GolimumabDiscontinue during 2nd-3rd trimestersLow
      CertolizumabContinue useLow
      Anti-α4β7 integrinVedolizumabPersonalized decisionUnclear
      Anti-IL-12 and anti-IL-23UstekinumabPersonalized decisionUnclear
      Janus kinase inhibitorsTofacitinibContraindicatedHigh
      FilgotinibContraindicatedHigh
      UpadacitinibContraindicatedHigh
      Sphingosine-1-phosphate receptor modulatorOzanimodContraindicatedHigh

      6.2.1 Aminosalicylates

      Formulations of 5-aminosalicylic acid (5-ASA) are one of the most prescribed therapies for IBD. Their safe use in pregnancy has been reported in case series and population-based cohorts. According to a meta-analysis of seven studies, there was no increased risk of congenital abnormalities, stillbirths, spontaneous abortions, or preterm deliveries among the 642 women who used 5-ASA compared to the 1158 women who did not [
      • Rahimi R.
      • Nikfar S.
      • Rezaie A.
      • et al.
      Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis.
      ].
      There are different formulations of 5-ASA, with or without a dibutylphthalate coating, although the teratogenic effect of dibutylphthalate was not confirmed in humans. When sulfasalazine treatment is chosen, folate supplementation (folic acid >2 mg/day) is recommended [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ].

      6.2.2 Corticosteroids

      Systemic, low-bioavailability steroids are commonly used to induce remission during IBD flares. All corticosteroids can cross the placental barrier, but their rapid conversion into less active metabolites results in low fetal blood concentrations [
      • Shannahan S.E.
      • Erlich J.M.
      • Peppercorn MA.
      Insights into the treatment of inflammatory bowel disease in pregnancy.
      ]. Budesonide, due to its low bioavailability, is considered to be safe during pregnancy but data are scarce.
      There have been concerns that corticosteroids have teratogenic effects, including orofacial malformations (cleft lip/palate). However, in a large population-based study including 51,973 pregnancies exposed to corticosteroids during the first trimester, no association with orofacial malformations was found [
      • Hviid A.
      • Mølgaard-Nielsen D.
      Corticosteroid use during pregnancy and risk of orofacial clefts.
      ].

      6.2.3 Metronidazole and ciprofloxacin

      The antibiotics metronidazole and ciprofloxacin are used to treat perianal CD [
      • Thia K.T.
      • Mahadevan U.
      • Feagan B.G.
      • et al.
      Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study.
      ] and pouchitis, sometimes as combination therapy [
      • Shen B.
      • Achkar J.P.
      • Lashner B.A.
      • et al.
      A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.
      ]. These medications do not increase the risk of spontaneous miscarriage or congenital anomalies [
      • Berkovitch M.
      • Pastuszak A.
      • Gazarian M.
      • et al.
      Safety of the new quinolones in pregnancy.
      ,
      • Piper J.M.
      • Mitchel E.F.
      • Ray WA.
      Prenatal use of metronidazole and birth defects: no association.
      . However, infants of women exposed to metronidazole in the second to third months of pregnancy had higher rates of cleft lip with or without cleft palate [
      • Czeizel A.E.
      • Rockenbauer M.
      Population-based case-control study of teratogenic potential of corticosteroids.
      ]. For these reasons, metronidazole and ciprofloxacin should be avoided in the first trimester, in accordance with ECCO guidelines [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ].

      6.2.4 Immunomodulators

      Thiopurines, including azathioprine and 6-mercaptopurine, are used as maintenance therapy in IBD. Thiopurines cross the placenta, but their discontinuation in women with well-controlled disease is not recommended. According to the Toronto Consensus Statements, thiopurines “should be continued throughout pregnancy” [
      • Nguyen G.C.
      • Seow C.H.
      • Maxwell C.
      • et al.
      The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy.
      ]. In a meta-analysis considering 3045 IBD pregnant women, the use of thiopurines was associated with preterm births (OR = 1.67), but not with congenital abnormalities or low birth weight [
      • Nguyen G.C.
      • Seow C.H.
      • Maxwell C.
      • et al.
      The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy.
      ]. A large Swedish registry study found an increased risk of preterm birth due to thiopurine use in IBD women with stable disease (OR = 2.41) and active disease (OR = 4.90) [
      • Bröms G.
      • Granath F.
      • Linder M.
      • et al.
      Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure.
      ].
      Methotrexate has strong teratogenic and abortive effects, and thus must be discontinued prior to conception. Women who plan to conceive should discontinue methotrexate and use contraception for at least 3 months before conception [
      • Nguyen G.C.
      • Seow C.H.
      • Maxwell C.
      • et al.
      The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy.
      ,
      • McDonald J.W.D.
      • Wang Y.
      • Tsoulis D.J.
      • et al.
      Methotrexate for induction of remission in refractory Crohn's disease.
      .
      Cyclosporine is a calcineurin and cytochrome P450 inhibitor. It demonstrated short-term efficacy and safety in the treatment of steroid-refractory acute UC, and can be used as rescue therapy for acute severe UC [
      • Herold K.C.
      • Lancki D.W.
      • Moldwin R.L.
      • et al.
      Immunosuppressive effects of cyclosporin a on cloned T cells.
      ,
      • Lichtiger S.
      • Present D.H.
      • Kornbluth A.
      • et al.
      Cyclosporine in severe ulcerative colitis refractory to steroid therapy.
      ,
      • Laharie D.
      • Bourreille A.
      • Branche J.
      • et al.
      Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.
      ,
      • Williams J.G.
      • Alam M.F.
      • Alrubaiy L.
      • et al.
      Comparison of infliximab and ciclosporin in steroid resistant ulcerative colitis: pragmatic randomised trial and economic evaluation (CONSTRUCT).
      ,
      • Lichtiger S.
      • Present DH.
      Preliminary report: cyclosporin in treatment of severe active ulcerative colitis.
      ]. No data on pregnant IBD women treated with cyclosporine are available. A meta-analysis of studies of pregnant transplant recipients did not find an increased rate of congenital malformations, but did find an increased risk of prematurity (OR = 1.52) [
      • Bar Oz B.
      • Hackman R.
      • Einarson T.
      • et al.
      Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis.
      ].

      6.2.5 Anti-TNFα agents

      The anti-TNFα agents infliximab, adalimumab and golimumab are commonly used in IBD. Certolizumab pegol, an anti-TNF agent not approved in Europe for IBD, is often used in CD patients with rheumatologic co-morbidity. These agents are IgG1 monoclonal antibodies. Infliximab, adalimumab and golimumab cross the placenta, starting from the second trimester, in a progressive way due to a specific FcRn receptor-mediated mechanism [
      • Seow C.H.
      • Leung Y.
      • Vande Casteele N.
      • et al.
      The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease.
      ]. Infliximab and adalimumab levels can be higher in infant and cord blood than in maternal peripheral blood [
      • Seow C.H.
      • Leung Y.
      • Vande Casteele N.
      • et al.
      The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease.
      ]. Certolizumab pegol, which is an Fab fragment of IgG1, does not cross the placenta.
      A meta-analysis of five cohort studies did not find any significant difference in unfavorable pregnancy outcomes between IBD pregnant women on and without anti-TNF therapy, suggesting that these therapies are safe [
      • Narula N.
      • Al-Dabbagh R.
      • Dhillon A.
      • et al.
      Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis.
      ]. However, ECCO guidelines suggest stopping anti-TNF therapy around gestational week 24 to minimize transplacental transfer [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ]. In some cases, early discontinuation may lead to disease relapse with consequences on management of the pregnancy. Therefore, the decision about stopping therapy should be based on both disease activity and the patient's risk profile [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ].
      Data from the Crohn's Therapy Resource Evaluation and Assessment Tool (TREAT) registry [
      • Lichtenstein G.R.
      • Feagan B.G.
      • Cohen R.D.
      • et al.
      Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREATTM registry.
      ] and the Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry [
      • Mahadevan U.
      • Martin C.F.
      • Sandler R.S.
      • et al.
      865 PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy.
      ] show no increased risk of congenital abnormalities, neonatal complications or preterm delivery and infections. The European retrospective multicenter TEDDY study [
      • Chaparro M.
      • Verreth A.
      • Lobaton T.
      • et al.
      Long-term safety of in utero exposure to anti-TNFα drugs for the treatment of inflammatory bowel disease: results from the multicenter european TEDDY study.
      ] evaluated 841 children of IBD mothers, including 388 children exposed to anti-TNFs in utero and 453 children not exposed. The study found similar rates of severe infection among the two groups (2.8% vs. 1.6% per person-year, respectively; hazard ratio, 1.2). Only pre-term delivery was significantly associated with a higher risk of severe infection. No differences in the frequencies of premature rupture of membranes, placenta previa, chorioamnionitis, eclampsia, or fetal growth were observed between the groups.
      Another study focused on the long-term outcomes of infants, comparing IBD mothers exposed to anti-TNFs with healthy non-IBD mothers [
      • Duricova D.
      • Dvorakova E.
      • Hradsky O.
      • et al.
      Safety of anti-TNFα therapy during pregnancy on long-term outcome of exposed children: a controlled, multicenter observation.
      ]. No differences in congenital abnormalities, perinatal complications or percentages of infants with low birth weight were found. Furthermore, the two groups of children had similar rates of infection and allergy, and similar growth and psychomotor development at a median follow-up of 36 months [
      • Duricova D.
      • Dvorakova E.
      • Hradsky O.
      • et al.
      Safety of anti-TNFα therapy during pregnancy on long-term outcome of exposed children: a controlled, multicenter observation.
      ].

      6.2.6 Vedolizumab

      Vedolizumab is a humanized, monoclonal IgG1 antibody against α4β7 integrin.
      Vedolizumab is transferred across the placenta to the fetal circulation like other IgG antibodies [
      • Moens A.
      • van Hoeve K.
      • Humblet E.
      • et al.
      Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab.
      ]. The safety of vedolizumab during pregnancy was assessed using data from six clinical trials (81 pregnancies) [
      • Mahadevan U.
      • Vermeire S.
      • Lasch K.
      • et al.
      Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease.
      ]. The analysis did not find any adverse effect of the drug on pregnancy outcomes.
      A multicenter, retrospective study of 24 pregnancies exposed to vedolizumab identified complications (premature rupture of membranes, pre-eclampsia, miscarriage and stillbirth) in six pregnancies [
      • Moens A.
      • van Hoeve K.
      • Humblet E.
      • et al.
      Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab.
      ]. Among the 23 live births, complications (prematurity, intrauterine growth retardation, congenital malformations and SGA) were seen in eight infants. Recently, a multicenter case-control study (CONCEIVE) compared pregnancy outcomes between vedolizumab-exposed women, anti-TNF-exposed women, and control women who had received neither drug [
      • Moens A.
      • van der Woude C.J.
      • Julsgaard M.
      • et al.
      Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNF or conventional therapy: results of the European CONCEIVE study.
      ]. Among the three groups, no significant differences in the rates of live births and of miscarriage were observed. Moreover, the groups had comparable neonatal outcomes regarding median gestational age, birth weight, median Apgar score, and incidences of congenital anomalies, infections and malignancies after 1 year.
      At present, due to the lack of data from prospective, controlled trials, an individualized decision should be made as to whether the benefits of vedolizumab to the mother outweigh the risks. Strict monitoring of any pregnant patient receiving vedolizumab has been recommended [
      • Cornish J.
      • Tan E.
      • Teare J.
      • et al.
      A meta-analysis on the influence of inflammatory bowel disease on pregnancy.
      ].

      6.2.7 Ustekinumab

      Ustekinumab is a human IgG1 antibody that inhibits the p40 subunit of IL-12 and IL-23. Research in pregnant cynomolgus macaques found low levels of active transplacental transport until the end of the second quarter of pregnancy [
      • Martin P.L.
      • Sachs C.
      • Imai N.
      • et al.
      Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23p40 monoclonal antibody, during pregnancy and lactation.
      ].
      Ustekinumab has been shown to be effective in the management of CD [
      • Feagan B.G.
      • Sandborn W.J.
      • Gasink C.
      • et al.
      Ustekinumab as induction and maintenance therapy for Crohn's disease.
      ]. Data regarding the use of ustekinumab in IBD women during pregnancy are limited to a conference presentation [
      • Scherl E.
      • Jacobstein D.
      • Murphy C.
      • et al.
      A109 pregnancy outcome in women exposed to ustekinumab in the Crohn's disease clinical development program.
      ] and a case report [
      • Klenske E.
      • Osaba L.
      • Nagore D.
      • et al.
      Drug levels in the maternal serum, cord blood and breast milk of a ustekinumab-treated patient with Crohn's Disease.
      ]. So far, no safety signals with neonatal outcomes have been reported. For three pregnant women treated with ustekinumab for psoriasis, gestation was uneventful and the pregnancies were completed without complications [
      • Galluzzo M.
      • D'Adamio S.
      • Bianchi L.
      • et al.
      Psoriasis in pregnancy: case series and literature review of data concerning exposure during pregnancy to ustekinumab.
      ]. The limited data available suggest that ustekinumab is unlikely to negatively impact on pregnancy outcomes. For the moment, personalized decision for the IBD population can be made; further data are required.

      6.2.8 Tofacitinib

      Tofacitinib is an oral inhibitor of janus kinases 1 and 3 that has recently been approved for the treatment of UC.
      Tofacitinib is a small molecule taken orally, so it is reasonable to assume that it can cross the placenta. According to the manufacturer, Pfizer, tofacitinib is teratogenic in animals, and causes malformations such as anasarca, membranous ventricular septal defects, and skeletal abnormalities [
      Xeljanz prescribing information..
      ]. The manufacturer recommends that women being treated with tofacitinib also take contraception.
      At the moment, data regarding its effects on human pregnancy are limited. Among 47 women who became pregnant while taking tofacitinib for rheumatoid arthritis or psoriasis, the rates of healthy newborns, fetal deaths and malformations were similar to those for the general population [
      • Clowse M.E.B.
      • Feldman S.R.
      • Isaacs J.D.
      • et al.
      Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis.
      ]. The safety for UC during pregnancy was assessed from data reported in five clinical trials, allowing the identification of 11 cases of maternal exposure and 14 cases of paternal exposure to the drug [
      • Mahadevan U.
      • Dubinsky M.C.
      • Su C.
      • et al.
      Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerative colitis.
      ]. No fetal deaths or congenital malformations had been reported.

      6.2.9 Small molecules in pipeline

      In the next few years many new small molecules will be used in the treatment of IBD. Other janus kinases inhibitors as Filgotinib and Upadacitinib, boths janus kinase 1 inhibitors, will shortly be used in CD and UC treatment respectively [
      • Vermeire S.
      • Schreiber S.
      • Petryka R.
      • et al.
      Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.
      ,
      • Sandborn W.J.
      • Feagan B.G.
      • Loftus E.V.
      • et al.
      Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease.
      . Sphingosine-1-phosphate receptor modulator as Ozanimod has been completed phase II studies in UC and CD [
      • Sandborn W.J.
      • Feagan B.G.
      • Wolf D.C.
      • et al.
      Ozanimod induction and maintenance treatment for ulcerative colitis.
      ,
      • Feagan B.G.
      • Sandborn W.J.
      • Danese S.
      • et al.
      Endoscopic and clinical efficacy demonstrated with oral ozanimod in moderately to severely active Crohnʼs disease.
      .Their lack of immunogenicity, the low half-life and the oral administration make the small molecules very attractive for patients and physicians. Actually, there are no data in pregnancy and they are contraindicated [
      • Gilardi D.
      • Gabbiadini R.
      • Allocca M.
      • et al.
      PKPD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD.
      ].

      6.3 Probiotics

      There are no literature data that support the use of probiotics during the gestation of patients with IBD both as a protection of the disease activity and as a prevention of the onset of the same in the unborn child.
      However, data from the recent study by Torres et al. suggests that, in the future, the study of the microbiota composition and its modulation during pregnancy in women with IBD could be a possible weapon to predict and prevent the development of the disease in the unborn child [
      • Torres J.
      • Hu J.
      • Seki A.
      • et al.
      Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.
      ].

      6.4 Impact of delivery mode on IBD outcome

      A few studies have analyzed the impact of delivery mode on the long-term outcomes of IBD. Two retrospective studies reported no significant differences in the rates of symptomatic flares after cesarean or vaginal delivery [
      • Cheng A.G.
      • Oxford E.C.
      • Sauk J.
      • et al.
      Impact of mode of delivery on outcomes in patients with perianal Crohn's disease.
      ,
      • Smink M.
      • Lotgering F.K.
      • Albers L.
      • et al.
      Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands.
      . Another study (161 cesarean, 199 vaginal delivery) found no association between the mode of delivery and IBD natural history over 4 years, considering the need for IBD-related hospitalization or surgery and the initiation of immunosuppressants or anti-TNFα therapy [
      • Ananthakrishnan A.N.
      • Cheng A.
      • Cagan A.
      • et al.
      Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases.
      ].
      According to a systematic review [
      • Foulon A.
      • Dupas J.L.
      • Sabbagh C.
      • et al.
      Defining the most appropriate delivery mode in women with inflammatory bowel disease: a systematic review.
      ], the mode of delivery was not associated with differences in the rate of new or relapsed perianal CD. However, two-thirds of women with active perianal disease experienced a worsening of symptoms after vaginal delivery. In patients with IPAA uncomplicated vaginal delivery moderately influenced pouch function, without a significant difference in terms of stool frequency or incontinence. However complicated vaginal delivery negatively impacted on pouch function.

      6.5 Choice of delivery mode

      No guidelines exist regarding the choice of delivery mode, standard vaginal delivery is commonly recommended by gastroenterologists in cases of quiescent or mild disease.
      Data on clinical outcomes following cesarean or vaginal delivery in women with IPAA are conflicting. On one hand, some cohort studies found no increased rates of adverse pregnancy outcome and no change in pouch function after vaginal delivery [
      • Juhasz E.S.
      • Fozard B.
      • Dozois R.R.
      • et al.
      Ileal pouch-anal anastomosis function following childbirth. an extended evaluation.
      ,
      • Hahnloser D.
      • Pemberton J.H.
      • Wolff B.G.
      • et al.
      Pregnancy and delivery before and after ileal pouch-anal anastomosis for inflammatory bowel disease: immediate and long-term consequences and outcomes.
      ,
      • Kitayama T.
      • Funayama Y.
      • Fukushima K.
      • et al.
      Anal function during pregnancy and postpartum after ileal pouch anal anastomosis for ulcerative colitis.
      ], including the rate of incontinence [
      • Seligman N.S.
      • Sbar W.
      • Berghella V.
      Pouch function and gastrointestinal complications during pregnancy after ileal pouch-anal anastomosis.
      ]. On the other hand, one study found that sphincter integrity and physiology and manometric pressures were more frequently altered by vaginal delivery in patients with IPAA than by cesarean section [
      • Remzi F.H.
      • Gorgun E.
      • Bast J.
      • et al.
      Vaginal delivery after ileal pouch-anal anastomosis: a word of caution.
      ]. As a consequence, cesarean delivery should be considered an option in patients with IPAA, in order to minimize the risk of anal sphincter injury.
      There are also conflicting data on the impact of delivery mode on perianal disease. Some retrospective studies raised concerns that vaginal delivery may trigger or worsen perianal disease [
      • Ilnyckyji A.
      • Blanchard J.F.
      • Rawsthorne P.
      • et al.
      Perianal Crohn's disease and pregnancy: role of the mode of delivery.
      ,
      • Brandt L.J.
      • Estabrook S.G.
      • Reinus JF.
      Results of a survey to evaluate whether vaginal delivery and episiotomy lead to perineal involvement in women with Crohn's disease.
      . Active perianal disease has been associated with a high risk of fourth-degree laceration during delivery [
      • Hatch Q.
      • Champagne B.J.
      • Maykel J.A.
      • et al.
      Crohn's disease and pregnancy: the impact of perianal disease on delivery methods and complications.
      ,
      • Grouin A.
      • Brochard C.
      • Siproudhis L.
      • et al.
      Perianal Crohn's disease results in fewer pregnancies but is not exacerbated by vaginal delivery.
      . Conversely, other studies reported that vaginal delivery did not exacerbate the disease in cases of inactive perianal disease, and that cesarean delivery did not reduce the risk of flares in women with previous perianal disease [
      • Cheng A.G.
      • Oxford E.C.
      • Sauk J.
      • et al.
      Impact of mode of delivery on outcomes in patients with perianal Crohn's disease.
      ,
      • Smink M.
      • Lotgering F.K.
      • Albers L.
      • et al.
      Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands.
      . Finally, a retrospective cohort study [
      • Burke K.E.
      • Haviland M.J.
      • Hacker M.R.
      • et al.
      Indications for mode of delivery in pregnant women with inflammatory bowel disease.
      ] found no difference in the incidence of cesarean delivery between women with and without CD, but a higher incidence of cesarean delivery was observed among women with perianal disease. Given these considerations, cesarean delivery is commonly recommended by gastroenterologists for patients with active perianal disease, while for other situations the decision should be made on a case by case basis, taking into account the past severity of the perianal disease and the previous surgery of the perianal area.
      Regarding ileostomy or colostomy, data are extremely limited. CD outcomes after deliveries have been reported in four women with ileostomy and one with sigmoidostomy: in all but one pregnancy, the delivery occurred by cesarean, and no stoma complication was observed [
      • Takahashi K.
      • Funayama Y.
      • Fukushima K.
      • et al.
      Pregnancy and delivery in patients with enterostomy due to anorectal complications from Crohn's disease.
      ]. Of note, ileostomy obstruction can occur in pregnancy, and small bowel obstruction is associated with maternal and fetal morbidity and mortality [
      • Meyerson S.
      • Holtz T.
      • Ehrinpreis M.
      • et al.
      Small bowel obstruction in pregnancy.
      ]. Ileostomy obstruction may be caused by post-surgical adhesions or by the enlarging gravid uterus. In this latter case, it can be treated conservatively according to a case report [
      • Spring A.
      • Lee M.
      • Patchett S.
      • et al.
      Ileostomy obstruction in the third trimester of pregnancy.
      ]. The mode of delivery for women with ileostomy or colostomy should be discussed on a case by case basis in consultation with the gynecologist and gastroenterologist.
      In conclusion, decision-making about the mode of delivery for women with IBD is influenced by many factors. In specific situations such as IPAA and perianal disease, the mode of delivery should be decided after a multidisciplinary discussion between gynecologists, gastroenterologists, and colorectal surgeons. In the absence of IPAA or perianal disease, the decision between vaginal and cesarean delivery should be based on obstetric indications and patient preference, as for women without IBD.

      7. Breastfeeding

      IBD may flare during the postpartum period for various reasons: hormonal changes, the resumption of smoking or the discontinuation of therapies [
      • Kane S.
      • Lemieux N.
      The role of breastfeeding in postpartum disease activity in women with inflammatory bowel disease.
      ]. Fear of possible adverse effects on the newborn is the main reason why mothers discontinue therapy during breastfeeding or prefer bottle feeding over breastfeeding [
      • Mañosa M.
      • Navarro-Llavat M.
      • Marín L.
      • et al.
      Fecundity, pregnancy outcomes, and breastfeeding in patients with inflammatory bowel disease: a large cohort survey.
      ]. Physician recommendations and personal preferences are other reasons why women favor bottle feeding [
      • Ng S.W.
      • Mahadevan U.
      Management of inflammatory bowel disease in pregnancy.
      ].
      Physicians should educate patients to avoid drug safety misconceptions, and should emphasize the delicate balance between disease control and potential toxicity for the newborn.
      Whenever possible, breastfeeding should be encouraged in all women due to its benefits to both the mother and infant [
      • Jackson K.M.
      • Nazar AM.
      Breastfeeding, the immune response, and long-term health.
      ,
      • Koloski N.A.
      • Bret L.
      • Radford-Smith G.
      Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature.
      ,
      • Frolkis A.
      • Dieleman L.A.
      • Barkema H.W.
      • et al.
      Environment and the inflammatory bowel diseases.
      ]. Two systematic reviews found that children who breastfeed have lower risks of developing early-onset IBD [
      • Barclay A.R.
      • Russell R.K.
      • Wilson M.L.
      • et al.
      Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease.
      ,
      • Klement E.
      • Cohen R.V.
      • Boxman J.
      • et al.
      Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis.
      .
      Despite the fears of women, many drugs can be safely taken during breastfeeding (Table 2). Mesalazine, sulfasalazine and thiopurines can be detected in breast milk, but in relatively small amounts [
      • van der Woude C.J.
      • Ardizzone S.
      • Bengtson M.B.
      • et al.
      The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
      ]. For example, in a study of eight women, the level of sulfasalazine in milk was about half that in maternal serum (milk/serum ratio, 0.48) [
      • Esbjörner E.
      • Järnerot G.
      • Wranne L.
      Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation.
      ]. Bloody, watery diarrhea has been reported in two infants of UC mothers using 5-ASA [
      • Branski D.
      • Kerem E.
      • Gross-Kieselstein E.
      • et al.
      Bloody diarrhea-a possible complication of sulfasalazine transferred through human breast milk.
      ,
      • Nelis GF.
      Diarrhoea due to 5-aminosalicylic acid in breast milk.
      . In such cases, the treatment should be stopped. A case–control study that investigated 30 babies, half of whose mothers had taken azathioprine in pregnancy and during lactation, found that the exposed babies had normal physical and mental development without a greater risk of infection [
      • Angelberger S.
      • Reinisch W.
      • Messerschmidt A.
      • et al.
      Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding.
      ].
      Table 2Use of IBD drugs during breastfeeding.
      Medicine groupDrugsRecommendationRisk
      AminosalicylatesMesalazine Sulfasalazine Balsalazide OlsalazideDiscontinue in cases of infant diarrheaLow
      CorticosteroidsAllBreastfeed 4 h after takingLow
      AntibioticsMetronidazoleBreastfeed 12-24 h after takingLow
      CiprofloxacinBreastfeed 48 h after takingLow
      ImmunomodulatorsAzathioprineContinue useLow
      6-MercaptopurineContinue useLow
      MethotrexateContraindicatedHigh
      CyclosporineContraindicatedHigh
      Anti-TNFαInfliximabContinue useLow
      AdalimumabContinue useLow
      GolimumabNot recommendedUnclear
      CertolizumabContinue useLow
      Anti-α4β7 integrinVedolizumabNot recommendedUnclear
      Anti-IL-12 and anti-IL-23UstekinumabNot recommendedUnclear
      Janus kinase inhibitorTofacitinibNot recommendedUnclear
      FilgotinibNot recommendedUnclear
      UpadacitinibNot recommendedUnclear
      Sphingosine-1-phosphate receptor modulatorOzanimodNot recommendedUnclear
      Regarding corticosteroids, one study of six lactating women found low concentrations of prednisolone in breast milk, and concluded that breastfeeding can be safe if mothers wait for 4 hours after a dose [
      • Ost L.
      • Wettrell G.
      • Björkhem I.
      • et al.
      Prednisolone excretion in human milk.
      ].
      The antibiotics metronidazole and ciprofloxacin are excreted into breast milk [
      • Gardner D.K.
      • Gabbe S.G.
      • Harter C.
      Simultaneous concentrations of ciprofloxacin in breast milk and in serum in mother and breast-fed infant.
      ,
      • Nielsen O.H.
      • Maxwell C.
      • Hendel J.
      IBD medications during pregnancy and lactation.
      . Their long-term use should be avoided, while short-term use is possible with some precautions. The American Academy of Pediatrics recommends interrupting breastfeeding for 12–24 hours after a single 2 g oral dose of metronidazole, and for 48 hours after the last dose of ciprofloxacin, to allow their clearance [
      • Nielsen O.H.
      • Maxwell C.
      • Hendel J.
      IBD medications during pregnancy and lactation.
      ,
      Committee on drugs. The transfer of drugs and other chemicals into human milk.
      .
      Methotrexate and cyclosporine are contraindicated during breastfeeding. Methotrexate is excreted into breast milk [
      • Sachs H.C.
      Committee on drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics.
      ] and can accumulate in neonatal tissues with possible adverse effects including immune suppression, neutropenia and a potential link with carcinogenesis [
      • Sachs H.C.
      Committee on drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics.
      ]. As regards cyclosporine, current recommendations by the American Pediatric Association are to avoid breastfeeding due to potential alterations in cellular metabolism of newborns [
      • Sachs H.C.
      Committee on drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics.
      ].
      Infliximab, adalimumab and certolizumab are safe. These drugs have high molecular weights, so they likely transfer into breast milk in only small amounts. One study of three women found low amounts in breast milk [
      • Grosen A.
      • Julsgaard M.
      • Kelsen J.
      • et al.
      Infliximab concentrations in the milk of nursing mothers with inflammatory bowel disease.
      ]. In addition, when one of these three drugs is ingested by a breastfeeding baby, it should be inactivated by digestive enzymes in the gastrointestinal tract and therefore not absorbed [
      • Moffatt M.D.
      • Bernstein BC.
      Drug therapy for inflammatory bowel disease in pregnancy and the puerperium.
      ,
      • Ben–Horin S.
      • Yavzori M.
      • Katz L.
      • et al.
      Adalimumab level in breast milk of a nursing mother.
      . For golimumab, vedolizumab, ustekinumab and tofacitinib, safety data are lacking. Therefore, breastfeeding by women taking these drugs is not recommended.
      It is mandatory that physicians inform mothers about the risks of treatment during breastfeeding. Mothers must make their decisions consciously considering that, for many drugs, the benefits of breastfeeding outweigh the risks to the infant.

      8. Newborn vaccinations

      There are no specific recommendations for vaccinations of children born to IBD mothers taking conventional therapy. All vaccines should be administered according to each country's vaccination schedule.
      Intrauterine exposure to anti-TNFs, vedolizumab or ustekinumab does not affect antibody responses to inactivated vaccines (e.g. vaccines for diphtheria-tetanus-pertussis, poliomyelitis, Haemophilus influenzae type b, hepatitis B, and pneumococcal infection). Therefore, the British Society of Gastroenterology recommends that newborns complete their vaccination schedule [
      • Lamb C.A.
      • Kennedy N.A.
      • Raine T.
      • et al.
      British society of gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
      ]. Indeed, a study of 179 women found no significant differences in the rates of serological responses to Haemophilus influenzae type b and tetanus vaccines in infants of IBD women who were exposed or not to biologics during pregnancy [
      • Beaulieu D.B.
      • Ananthakrishnan A.N.
      • Martin C.
      • et al.
      Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines.
      ].
      European vaccine schedules recommended waiting until an infant is 6 months of age before giving a live vaccine (e.g. vaccines for measles-mumps-rubella, varicella) [

      European Centre for Disease Prevention and Control [Internet] 2021Available from: https://www.ecdc.europa.eu/en.

      ]. This recommendation holds true even for infants exposed to biologic therapy during the third trimester of gestation (i.e. after 27 weeks). This is because detectable drug levels can be found in infants up to 6 months after birth, and may lead to clinically relevant neonatal immunosuppression [
      • Cheent K.
      • Nolan J.
      • Shariq S.
      • et al.
      Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease.
      ,
      • Julsgaard M.
      • Christensen L.A.
      • Gibson P.R.
      • et al.
      Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection.
      . For this reason, the oral administration of live rotavirus vaccine (not mandatory in most countries), scheduled for the first 6 months of age, should not be given to newborns exposed in utero to biological drugs [
      • Restellini S.
      • Biedermann L.
      • Hruz P.
      • et al.
      Update on the management of inflammatory bowel disease during pregnancy and breastfeeding.
      ].

      9. Menopause

      The last period of a woman's life, in terms of hormonal activity, is menopause. There are conflicting data on whether the age of onset of menopause differs between IBD and non-IBD women, but a recent study found no difference [
      • Rolston V.S.
      • Boroujerdi L.
      • Long M.D.
      • et al.
      The influence of hormonal fluctuation on inflammatory bowel disease symptom severity- a cross-sectional cohort study.
      ]. Menopausal symptoms such as vulvovaginal discomfort (mainly vaginal dryness and dyspareunia) can worsen intestinal manifestations. These complaints could worsen sexual health and alter the quality of life of women with IBD [
      • Ona S.
      • James K.
      • Ananthakrishnan A.N.
      • et al.
      Association between vulvovaginal discomfort and activity of inflammatory bowel diseases.
      ].
      Hormone replacement therapy (HRT) may protect against disease activity and may provide relief from menopausal symptoms [
      • Kane S.V.
      • Reddy D.
      Hormonal replacement therapy after menopause is protective of disease activity in women with inflammatory bowel disease.
      ,
      • Principi M.
      • Barone M.
      • Pricci M.
      • et al.
      Ulcerative colitis: from inflammation to cancer. Do estrogen receptors have a role?.
      . According to a Cochrane review, HRT “may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with uterus)” [
      • Marjoribanks J.
      • Farquhar C.
      • Roberts H.
      • et al.
      Long term hormone therapy for perimenopausal and postmenopausal women.
      ]. Therefore, HRT is only suitable for short-term use in low-risk women [
      • Veerisetty S.S.
      • Eschete S.O.
      • Uhlhorn A.P.
      • et al.
      Women's health in inflammatory bowel Disease.
      ].

      10. Conclusions

      Women with IBD are particularly affected by issues involving puberty, sexuality, conception, pregnancy, breastfeeding up to menopause. Disease control is undoubtedly the key to ensuring women with IBD have a positive view of sexuality, body image and general well-being. To ensure that women with IBD can live their lives like healthy women, unaffected by intestinal disease, a multidisciplinary approach involving gastroenterologists, gynecologists and neonatologists is required. Studies on the safety of using the newest drugs during pregnancy and lactation are needed. The overall goal is to help IBD women achieve disease remission in the shortest time, so they can run through life safely.

      Declaration of Competing Interest

      None.

      Acknowledgment

      Valerie Matarese provided scientific editing.

      References

        • Molodecky N.A.
        • Soon I.S.
        • Rabi D.M.
        • et al.
        Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
        Gastroenterology. 2012; 142: 46-54
        • Ngo S.T.
        • Steyn F.J.
        • McCombe PA.
        Gender differences in autoimmune disease.
        Front Neuroendocrinol. 2014; 35: 347-369
        • Greuter T.
        • Manser C.
        • Pittet V.
        • et al.
        Gender differences in inflammatory bowel disease.
        Digestion. 2020; 101: 98-104
        • Shah S.C.
        • Khalili H.
        • Gower-Rousseau C.
        • et al.
        Sex-based differences in incidence of inflammatory bowel diseases-pooled analysis of population-based studies from western countries.
        Gastroenterology. 2018; 155: 1079-1089
        • Gower-Rousseau C.
        • Vasseur F.
        • Fumery M.
        • et al.
        Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD).
        Dig Liv Dis. 2013; 45: 89-94
        • Kappelman M.D.
        • Rifas–Shiman S.L.
        • Kleinman K.
        • et al.
        The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States.
        Clin Gastroenterol Hepatol. 2007; 5: 1424-1429
        • Langholz E.
        • Munkholm P.
        • Nielsen O.H.
        • et al.
        Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987.
        Scand J Gastroenterol. 1991; 26: 1247-1256
        • Kirschner B.S.
        • Rich BH.
        Puberty and pediatric-onset inflammatory bowel disease.
        in: Mamula P Markowitz JE Baldassano RN Pediatric Inflammatory Bowel Disease. Springer US, Boston, MA2008: 133-142
        • Shamir R.
        • Phillip M.
        • Levine A.
        Growth retardation in pediatric Crohnʼs disease: pathogenesis and interventions.
        Inflamm Bowel Dis. 2007; 13: 620-628
        • Lahat A.
        • Falach-Malik A.
        • Haj O.
        • et al.
        Change in bowel habits during menstruation: are IBD patients different?.
        Therap Adv Gastroenterol. 2020; 131756284820929806
      1. WHO Sexual health [Internet]. [cited 2018 Sep 19]. Available from: http://www.who.int/topics/sexual_health/en/n.d.

        • Bel L.G.J.
        • Vollebregt A.M.
        • Van der Meulen-de Jong A.E.
        • et al.
        Sexual dysfunctions in men and women with inflammatory bowel disease.
        J Sex Med. 2015; 12: 1557-1567
        • Marín L.
        • Mañosa M.
        • Garcia-Planella E.
        • et al.
        Sexual function and patients’ perceptions in inflammatory bowel disease: a case-control survey.
        J Gastroenterol. 2013; 48: 713-720
        • Rivière P.
        • Zallot C.
        • Desobry P.
        • et al.
        Frequency of and factors associated with sexual dysfunction in patients with inflammatory bowel disease.
        J Crohns Colitis. 2017; 11: 1347-1352
        • Szydlarska D.
        • Jakubowska A.
        • Rydzewska G.
        Assessment of sexual dysfunction in patients with inflammatory bowel disease.
        Prz Gastroenterol. 2019; 14: 104-108
        • Muller K.R.
        • Prosser R.
        • Bampton P.
        • et al.
        Female gender and surgery impair relationships, body image, and sexuality in inflammatory bowel disease: patient perceptions.
        Inflamm Bowel Dis. 2010; 16: 657-663
        • Berndtsson I.
        • Oresland T.
        • Hultén L.
        Sexuality in patients with ulcerative colitis before and after restorative proctocolectomy: a prospective study.
        Scand J Gastroenterol. 2004; 39: 374-379
        • Ateş Bulut E.
        • Törüner M.
        The influence of disease type and activity to sexual life and health quality in inflammatory bowel disease.
        Turk J Gastroenterol. 2019; 30: 33-39
        • Roseira J.
        • Magro F.
        • Fernandes S.
        • et al.
        Sexual quality of life in inflammatory bowel disease: a multicenter, national-level study.
        Inflamm Bowel Dis. 2020; 26: 746-755
        • Chakravarty E.
        • Clowse M.E.B.
        • Pushparajah D.S.
        • et al.
        Family planning and pregnancy issues for women with systemic inflammatory diseases: patient and physician perspectives.
        BMJ Open. 2014; 4e004081
        • Purewal S.
        • Chapman S.
        • Czuber-Dochan W.
        • et al.
        Systematic review: the consequences of psychosocial effects of inflammatory bowel disease on patients′ reproductive health.
        Aliment Pharmacol Ther. 2018; 48: 1202-1212
        • Laube R.
        • Yau Y.
        • Selinger C.P.
        • et al.
        Knowledge and attitudes towards pregnancy in females with inflammatory bowel disease: an international, multi-centre study.
        J Crohns Colitis. 2020; 14: 1248-1255
        • Huang V.W.
        • Chang H.J.
        • Kroeker K.I.
        • et al.
        Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease?.
        Can J Gastroenterol Hepatol. 2015; 29: 95-103
        • Mahadevan U.
        • Robinson C.
        • Bernasko N.
        • et al.
        Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group.
        Gastroenterology. 2019; 156: 1508-1524
        • Ellul P.
        • Zammit S.C.
        • Katsanos K.H.
        • et al.
        Perception of reproductive health in women with inflammatory bowel disease.
        J Crohns Colitis. 2016; 10: 886-891
        • Julsgaard M.
        • Nørgaard M.
        • Hvas C.L.
        • et al.
        Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis.
        Inflamm Bowel Dis. 2011; 17: 1573-1580
        • de Lima A.
        • Zelinkova Z.
        • Mulders A.
        • et al.
        Preconception care reduces relapse of inflammatory bowel disease during pregnancy.
        Clin Gastroenterol Hepatol. 2016; 14: 1285-1292
        • Zapata L.B.
        • Paulen M.E.
        • Cansino C.
        • et al.
        Contraceptive use among women with inflammatory bowel disease: a systematic review.
        Contraception. 2010; 82: 72-85
        • Dragoman M.V.
        • Tepper N.K.
        • Fu R.
        • et al.
        A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception.
        Int J Gynaecol Obstet. 2018; 141: 287-294
        • Gawron L.M.
        • Sanders J.
        • Steele K.P.
        • et al.
        Reproductive planning and contraception for women with inflammatory bowel diseases.
        Inflam Bowel Dis. 2016; 22: 459-464
        • Moller F.T.
        • Andersen V.
        • Wohlfahrt J.
        • et al.
        Familial risk of inflammatory bowel disease: a population-based cohort study 1977–2011.
        Am J Gastroenterol. 2015; 110: 564-571
        • Bortoli A.
        • Pedersen N.
        • Duricova D.
        • et al.
        Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006: pregnancy outcome in IBD.
        Aliment Pharmacol Ther. 2011; 34: 724-734
        • Gonzalez-Suarez B.
        • Sengupta S.
        • Moss AC.
        Impact of inflammatory bowel disease activity and thiopurine therapy on birth weight: a meta-analysis.
        World J Gastroenterol. 2017; 23: 8082-8089
        • Abhyankar A.
        • Ham M.
        • Moss A.C.
        Meta-analysis: the impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease.
        Aliment Pharmacol Ther. 2013; 38: 460-466
        • Rottenstreich A.
        • Fridman Lev S.
        • Rotem R.
        • et al.
        Disease flare at prior pregnancy and disease activity at conception are important determinants of disease relapse at subsequent pregnancy in women with inflammatory bowel diseases.
        Arch Gynecol Obstet. 2020; 301: 1449-1454
        • Pedersen N.
        • Bortoli A.
        • Duricova D.
        • et al.
        The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-epicom study of 209 pregnant women.
        Aliment Pharmacol Ther. 2013; 38: 501-512
        • Castiglione F.
        • Pignata S.
        • Morace F.
        • et al.
        Effect of pregnancy on the clinical course of a cohort of women with inflammatory bowel disease.
        Ital J Gastroenterol. 1996; 28: 199-204
        • Riis L.
        • Vind I.
        • Politi P.
        • et al.
        Does pregnancy change the disease course? a study in a European cohort of patients with inflammatory bowel disease.
        Am J Gastroenterol. 2006; 101: 1539-1545
        • Nielsen M.J.
        • Nørgaard M.
        • Holland-Fisher P.
        • et al.
        Self-reported antenatal adherence to medical treatment among pregnant women with Crohn's disease: adherence in pregnant women with Crohn's disease.
        Aliment Pharmacol Ther. 2010; 32: 49-58
        • Gallinger Z.R.
        • Rumman A.
        • Nguyen GC.
        Perceptions and attitudes towards medication adherence during pregnancy in inflammatory bowel disease.
        J Crohns Colitis. 2016; 10: 892-897
        • Kashkooli S.B.
        • Andrews J.M.
        • Roberts M.B.
        • et al.
        Inflammatory bowel disease-specific pregnancy knowledge of gastroenterologists against general practitioners and obstetricians..
        United Eur Gastroenterol J. 2015; 3: 462-470
        • Marri S.R.
        • Ahn C.
        • Buchman AL.
        Voluntary childlessness is increased in women with inflammatory bowel disease.
        Inflamm Bowel Dis. 2007; 13: 591-599
        • Hudson M.
        • Flett G.
        • Sinclair T.S.
        • et al.
        Fertility and pregnancy in inflammatory bowel disease.
        Int J Gynaecol Obstet. 1997; 58: 229-237
        • Tavernier N.
        • Fumery M.
        • Peyrin-Biroulet L.
        • et al.
        Systematic review: fertility in non-surgically treated inflammatory bowel disease.
        Aliment Pharmacol Ther. 2013; 38: 847-853
        • Selinger C.P.
        • Eaden J.
        • Selby W.
        • et al.
        Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views.
        J Crohns Colitis. 2013; 7: e206-e213
        • Mountifield R.
        • Bampton P.
        • Prosser R.
        • et al.
        Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions.
        Inflamm Bowel Dis. 2009; 15: 720-725
        • Friedman S.
        • Nielsen J.
        • Nøhr E.A.
        • et al.
        Comparison of time to pregnancy in women with and without inflammatory bowel diseases.
        Clin Gastroenterol Hepatol. 2020; 18: 1537-1544
        • Janssen N.M.
        • Genta MS.
        The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and pactation.
        Arc Int Med. 2000; 160: 610-619
        • Kroser J.
        • Srinivasan R.
        Drug therapy of inflammatory bowel disease in fertile women.
        Am J Gastroenterol. 2006; 101: S633-S639
        • Cortes X.
        • Borrás-Blasco J.
        • Antequera B.
        • et al.
        Ustekinumab therapy for Crohn's disease during pregnancy: a case report and review of the literature.
        J Clin Pharm Ther. 2017; 42: 234-236
        • Ban L.
        • Tata L.J.
        • Humes D.J.
        • et al.
        Decreased fertility rates in 9639 women diagnosed with inflammatory bowel disease: a United Kingdom population-based cohort study.
        Aliment Pharmacol Ther. 2015; 42: 855-866
        • Ørding Olsen K.
        • Juul S.
        • Berndtsson I.
        • et al.
        Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample.
        Gastroenterology. 2002; 122: 15-19
        • Cornish J.A.
        • Tan E.
        • Teare J.
        • et al.
        The effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review.
        Dis Colon Rectum. 2007; 50: 1128-1138
        • Waljee A.
        • Waljee J.
        • Morris A.M.
        • et al.
        Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis.
        Gut. 2006; 55: 1575-1580
        • Rajaratnam S.G.
        • Eglinton T.W.
        • Hider P.
        • et al.
        Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review.
        Int J Colorectal Dis. 2011; 26: 1365-1374
        • Öresland T.
        • Palmablad S.
        • Ellström M.
        • et al.
        Gynaecological and sexual function related to anatomical changes in the female pelvis after restorative proctocolectomy.
        Int J Colorect Dis. 1994; 9: 77-81
        • van der Woude C.J.
        • Ardizzone S.
        • Bengtson M.B.
        • et al.
        The second european evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
        J Crohns Colitis. 2015; 9: 107-124
        • Beyer-Berjot L.
        • Maggiori L.
        • Birnbaum D.
        • et al.
        A total laparoscopic approach reduces the infertility rate after ileal pouch-anal anastomosis: a 2-center study.
        Ann Surg. 2013; 258: 275-282
        • Palomba S.
        • Sereni G.
        • Falbo A.
        • et al.
        Inflammatory bowel diseases and human reproduction: a comprehensive evidence-based review.
        World J Gastroenterol. 2014; 20: 7123
        • Gorgun E.
        • Cengiz T.B.
        • Aytac E.
        • et al.
        Does laparoscopic ileal pouch-anal anastomosis reduce infertility compared with open approach?.
        Surgery. 2019; 166: 670-677
        • Fertility problems: assessment and treatment
        NICE Clinical Guidelines, No. 156.
        National Institute for Health and Care Excellence, London(UK)2017 (ISBN-13: 978-1-4731-0029-9)
        • Pabby V.
        • Oza S.S.
        • Dodge L.E.
        • et al.
        In vitro fertilization is successful in women with ulcerative Colitis and Ileal pouch anal anastomosis.
        Am J Gastroenterol. 2015; 110: 792-797
        • Oza S.S.
        • Pabby V.
        • Dodge L.E.
        • et al.
        Factors associated with the success of in vitro fertilization in women with inflammatory bowel disease.
        Dig Dis Sci. 2016; 61: 2381-2388
        • Nørgård B.M.
        • Larsen P.V.
        • Fedder J.
        • et al.
        Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction: a 20-year nationwide cohort study.
        Gut. 2016; 65: 767-776
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • et al.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Friedman S.
        • Larsen P.V.
        • Fedder J.
        • et al.
        The efficacy of assisted reproduction in women with inflammatory bowel disease and the impact of surgery-a nationwide cohort study.
        Inflamm Bowel Dis. 2017; 23: 208-217
        • Pachler F.R.
        • Toft G.
        • Bisgaard T.
        • et al.
        Use and success of in vitro fertilisation following restorative proctocolectomy and ileal pouch-anal anastomosis. a nationwide 17-year cohort study.
        J Crohns Colitis. 2019; 13: 1283-1286
        • Williamson CS.
        Nutrition in pregnancy.
        Nutr Bull. 2006; 31: 28-59
        • Geraghty A.A.
        • Lindsay K.L.
        • Alberdi G.
        • et al.
        Nutrition during pregnancy impacts offspring's epigenetic status-evidence from human and animal studies.
        Nutr Metab Insights. 2015; 8: 41-47
        • Grieger J.A.
        • Clifton VL.
        A review of the impact of dietary intakes in human pregnancy on infant birthweight.
        Nutrients. 2014; 7: 153-178
        • Bengtson M.B.
        • Martin C.F.
        • Aamodt G.
        • et al.
        Inadequate gestational weight gain predicts adverse pregnancy outcomes in mothers with inflammatory bowel disease: results from a prospective US pregnancy cohort.
        Dig Dis Sci. 2017; 62: 2063-2069
        • Vagianos K.
        • Bector S.
        • McConnell J.
        • et al.
        Nutrition assessment of patients with inflammatory bowel disease.
        JPEN J Parenter Enteral Nutr. 2007; 31: 311-319
        • Goh J.
        • O'Morain CA.
        Review article: nutrition and adult inflammatory bowel disease.
        Aliment Pharmacol Ther. 2003; 17: 307-320
        • Nguyen G.C.
        • Boudreau H.
        • Harris M.L.
        • et al.
        Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United States.
        Clin Gastroenterol Hepatol. 2009; 7: 329-334
        • Kilby K.
        • Mathias H.
        • Boisvenue L.
        • et al.
        Micronutrient absorption and related outcomes in people with inflammatory bowel disease: a review.
        Nutrients. 2019; 11: 1388
        • Hébuterne X.
        • Filippi J.
        • Al-Jaouni R.
        • et al.
        Nutritional consequences and nutrition therapy in Crohn's disease.
        Gastroentérol Clin Biol. 2009; 33: S235-S244
        • Bischoff S.C.
        • Escher J.
        • Hébuterne X.
        • et al.
        ESPEN practical guideline: clinical nutrition in inflammatory bowel disease.
        Clin Nutr. 2020; 39: 632-653
        • Raatikainen K.
        • Mustonen J.
        • Pajala M.O.
        • et al.
        The effects of pre- and post-pregnancy inflammatory bowel disease diagnosis on birth outcomes.
        Aliment Pharmacol Ther. 2011; 33: 333-339
      2. Pregnancy, childbirth, postpartum and newborn care a guide for essential practice.
        World Health Organization, 2015 (PMID:26561684 Bookshelf ID: NBK326678)
        • Habal F.M.
        • Huang VW.
        Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.
        Aliment Pharmacol Ther. 2012; 35: 501-515
        • Mullin GE.
        Micronutrients and inflammatory bowel disease.
        Nutr Clin Pract. 2012; 27: 136-137
        • Bengtson M.B.
        • Aamodt G.
        • Mahadevan U.
        • et al.
        Inadequate gestational weight gain, the hidden link between maternal IBD and adverse pregnancy outcomes: results from the norwegian mother and child cohort study.
        Inflamm Bowel Dis. 2017; 23: 1225-1233
        • Dzakpasu S.
        • Fahey J.
        • Kirby R.S.
        • et al.
        Contribution of prepregnancy body mass index and gestational weight gain to adverse neonatal outcomes: population attributable fractions for Canada.
        BMC Pregnancy Childbirth. 2015; 15: 21
        • Haugen M.
        • Brantsæter A.L.
        • Winkvist A.
        • et al.
        Associations of pre-pregnancy body mass index and gestational weight gain with pregnancy outcome and postpartum weight retention: a prospective observational cohort study.
        BMC Pregnancy Childbirth. 2014; 14: 201
        • Wen T.
        • Lv Y.
        Inadequate gestational weight gain and adverse pregnancy outcomes among normal weight women in China.
        Int J Clin Exp Med. 2015; 8: 2881-2886
        • Moser M.A.
        • Okun N.B.
        • Mayes D.C.
        • et al.
        Crohn's disease, pregnancy, and birth weight.
        Am J Gastroenterol. 2000; 95: 1021-1026
        • Caruso A.
        • De Carolis S.
        • Ferrazzani S.
        • et al.
        Pregnancy outcome and total parenteral nutrition in malnourished pregnant women.
        Fetal Diagn Ther. 1998; 13: 136-140
        • Rahimi R.
        • Nikfar S.
        • Rezaie A.
        • et al.
        Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis.
        Reprod Toxicol. 2008; 25: 271-275
        • Shannahan S.E.
        • Erlich J.M.
        • Peppercorn MA.
        Insights into the treatment of inflammatory bowel disease in pregnancy.
        Therap Adv Gastroenterol. 2019; 12175628481985223
        • Hviid A.
        • Mølgaard-Nielsen D.
        Corticosteroid use during pregnancy and risk of orofacial clefts.
        CMAJ. 2011; 183: 796-804
        • Thia K.T.
        • Mahadevan U.
        • Feagan B.G.
        • et al.
        Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study.
        Inflamm Bowel Dis. 2009; 15: 17-24
        • Shen B.
        • Achkar J.P.
        • Lashner B.A.
        • et al.
        A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.
        Inflamm Bowel Dis. 2001; 7: 301-305
        • Berkovitch M.
        • Pastuszak A.
        • Gazarian M.
        • et al.
        Safety of the new quinolones in pregnancy.
        Obstet Gynecol. 1994; 84: 535-538
        • Piper J.M.
        • Mitchel E.F.
        • Ray WA.
        Prenatal use of metronidazole and birth defects: no association.
        Obstet Gynecol. 1993; 82: 348-352
        • Czeizel A.E.
        • Rockenbauer M.
        Population-based case-control study of teratogenic potential of corticosteroids.
        Teratology. 1997; 56: 335-340
        • Nguyen G.C.
        • Seow C.H.
        • Maxwell C.
        • et al.
        The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy.
        Gastroenterology. 2016; 150: 734-757
        • Bröms G.
        • Granath F.
        • Linder M.
        • et al.
        Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure.
        Inflamm Bowel Dis. 2014; 20: 1091-1098
        • McDonald J.W.D.
        • Wang Y.
        • Tsoulis D.J.
        • et al.
        Methotrexate for induction of remission in refractory Crohn's disease.
        Cochrane Database Syst Rev. 2014; CD003459
        • Herold K.C.
        • Lancki D.W.
        • Moldwin R.L.
        • et al.
        Immunosuppressive effects of cyclosporin a on cloned T cells.
        J Immunol. 1986; 136: 1315-1321
        • Lichtiger S.
        • Present D.H.
        • Kornbluth A.
        • et al.
        Cyclosporine in severe ulcerative colitis refractory to steroid therapy.
        N Engl J Med. 1994; 330: 1841-1845
        • Laharie D.
        • Bourreille A.
        • Branche J.
        • et al.
        Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.
        Lancet. 2012; 380: 1909-1915
        • Williams J.G.
        • Alam M.F.
        • Alrubaiy L.
        • et al.
        Comparison of infliximab and ciclosporin in steroid resistant ulcerative colitis: pragmatic randomised trial and economic evaluation (CONSTRUCT).
        Health Technol Assess. 2016; 20: 1-320
        • Lichtiger S.
        • Present DH.
        Preliminary report: cyclosporin in treatment of severe active ulcerative colitis.
        Lancet. 1990; 336: 16-19
        • Bar Oz B.
        • Hackman R.
        • Einarson T.
        • et al.
        Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis.
        Transplantation. 2001; 71: 1051-1055
        • Seow C.H.
        • Leung Y.
        • Vande Casteele N.
        • et al.
        The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease.
        Aliment Pharmacol Ther. 2017; 45: 1329-1338
        • Narula N.
        • Al-Dabbagh R.
        • Dhillon A.
        • et al.
        Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis.
        Inflamm Bowel Dis. 2014; 20: 1862-1869
        • Lichtenstein G.R.
        • Feagan B.G.
        • Cohen R.D.
        • et al.
        Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREATTM registry.
        Am J Gastroenterol. 2012; 107: 1409-1422
        • Mahadevan U.
        • Martin C.F.
        • Sandler R.S.
        • et al.
        865 PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy.
        Gastroenterology. 2012; 142 (S-149)
        • Chaparro M.
        • Verreth A.
        • Lobaton T.
        • et al.
        Long-term safety of in utero exposure to anti-TNFα drugs for the treatment of inflammatory bowel disease: results from the multicenter european TEDDY study.
        Am J Gastroenterol. 2018; 113: 396-403
        • Duricova D.
        • Dvorakova E.
        • Hradsky O.
        • et al.
        Safety of anti-TNFα therapy during pregnancy on long-term outcome of exposed children: a controlled, multicenter observation.
        Inflamm Bowel Dis. 2019; 25: 789-796
        • Moens A.
        • van Hoeve K.
        • Humblet E.
        • et al.
        Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab.
        J Crohns Colitis. 2019; 13: 12-18
        • Mahadevan U.
        • Vermeire S.
        • Lasch K.
        • et al.
        Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease.
        Aliment Pharmacol Ther. 2017; 45: 941-950
        • Moens A.
        • van der Woude C.J.
        • Julsgaard M.
        • et al.
        Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNF or conventional therapy: results of the European CONCEIVE study.
        Aliment Pharmacol Ther. 2020; 51: 129-138
        • Cornish J.
        • Tan E.
        • Teare J.
        • et al.
        A meta-analysis on the influence of inflammatory bowel disease on pregnancy.
        Gut. 2007; 56: 830-837
        • Martin P.L.
        • Sachs C.
        • Imai N.
        • et al.
        Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23p40 monoclonal antibody, during pregnancy and lactation.
        Birth Defects Res B Dev Reprod Toxicol. 2010; 89: 351-363
        • Feagan B.G.
        • Sandborn W.J.
        • Gasink C.
        • et al.
        Ustekinumab as induction and maintenance therapy for Crohn's disease.
        N Engl J Med. 2016; 375: 1946-1960
        • Scherl E.
        • Jacobstein D.
        • Murphy C.
        • et al.
        A109 pregnancy outcome in women exposed to ustekinumab in the Crohn's disease clinical development program.
        J Can Assoc Gastroenterol. 2018; 1: 166
        • Klenske E.
        • Osaba L.
        • Nagore D.
        • et al.
        Drug levels in the maternal serum, cord blood and breast milk of a ustekinumab-treated patient with Crohn's Disease.
        J Crohns Colitis. 2019; 13: 267-269
        • Galluzzo M.
        • D'Adamio S.
        • Bianchi L.
        • et al.
        Psoriasis in pregnancy: case series and literature review of data concerning exposure during pregnancy to ustekinumab.
        J Dermatol Treat. 2019; 30: 40-44
      3. Xeljanz prescribing information..
        Pfizer Inc, 2021 ([Internet][accessedAvailable from: http://labeling.pfizer. com/ShowLabeling.aspx?id=959)
        • Clowse M.E.B.
        • Feldman S.R.
        • Isaacs J.D.
        • et al.
        Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis.
        Drug Saf. 2016; 39: 755-762
        • Mahadevan U.
        • Dubinsky M.C.
        • Su C.
        • et al.
        Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerative colitis.
        Inflamm Bowel Dis. 2018; 24: 2494-2500
        • Vermeire S.
        • Schreiber S.
        • Petryka R.
        • et al.
        Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.
        Lancet. 2017; 389: 266-275
        • Sandborn W.J.
        • Feagan B.G.
        • Loftus E.V.
        • et al.
        Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn's disease.
        Gastroenterol. 2020; 158: 2123-2138
        • Sandborn W.J.
        • Feagan B.G.
        • Wolf D.C.
        • et al.
        Ozanimod induction and maintenance treatment for ulcerative colitis.
        N Engl J Med. 2016; 374: 1754-1762
        • Feagan B.G.
        • Sandborn W.J.
        • Danese S.
        • et al.
        Endoscopic and clinical efficacy demonstrated with oral ozanimod in moderately to severely active Crohnʼs disease.
        Am J Gastroenterol. 2017; 112: S371
        • Gilardi D.
        • Gabbiadini R.
        • Allocca M.
        • et al.
        PKPD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD.
        Expert Rev Gastroenterol Hepatol. 2020; 14: 797-806
        • Torres J.
        • Hu J.
        • Seki A.
        • et al.
        Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.
        Gut. 2020; 69: 42-51
        • Cheng A.G.
        • Oxford E.C.
        • Sauk J.
        • et al.
        Impact of mode of delivery on outcomes in patients with perianal Crohn's disease.
        Inflamm Bowel Dis. 2014; 20: 1391-1398
        • Smink M.
        • Lotgering F.K.
        • Albers L.
        • et al.
        Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands.
        BMC Gastroenterol. 2011; 11: 6
        • Ananthakrishnan A.N.
        • Cheng A.
        • Cagan A.
        • et al.
        Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases.
        Dig Dis Sci. 2015; 60: 471-477
        • Foulon A.
        • Dupas J.L.
        • Sabbagh C.
        • et al.
        Defining the most appropriate delivery mode in women with inflammatory bowel disease: a systematic review.
        Inflamm Bowel Dis. 2017; 23: 712-720
        • Juhasz E.S.
        • Fozard B.
        • Dozois R.R.
        • et al.
        Ileal pouch-anal anastomosis function following childbirth. an extended evaluation.
        Dis Colon Rectum. 1995; 38: 159-165
        • Hahnloser D.
        • Pemberton J.H.
        • Wolff B.G.
        • et al.
        Pregnancy and delivery before and after ileal pouch-anal anastomosis for inflammatory bowel disease: immediate and long-term consequences and outcomes.
        Dis Colon Rectum. 2004; 47: 1127-1135