Advertisement
Mayo Clinic Proceedings Home

My Treatment Approach to Management of the Pregnant Patient With Inflammatory Bowel Disease

      Abstract

      Inflammatory bowel disease (IBD) is frequently diagnosed in women of childbearing age. Of paramount concern are questions about the effect of the disease on a woman's ability to conceive and carry the pregnancy safely to term, as well as the effect of the disease and its therapies on the health of the fetus. For health care providers, there is also the issue of medication dose adjustments and management of flares during pregnancy. Growing experience with IBD in pregnancy suggests that most women will have good outcomes; however, concerns and uncertainty remain for both the patient and the physician. This article outlines our approach to the treatment of these patients with respect to preconception counseling and management during pregnancy and the postpartum period.

      Abbreviations and Acronyms:

      AZA/6-MP (azathioprine/6-mercaptopurine), IBD (inflammatory bowel disease), PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes), UC (ulcerative colitis)
      Inflammatory bowel disease (IBD) can affect women during their childbearing years. This presents several unique treatment considerations in women with IBD who are contemplating pregnancy, attempting to conceive, or are pregnant. Most women will have a successful pregnancy, but close management of IBD during this time is crucial to a good outcome. This article will review the many issues that providers face in each stage of managing the pregnant patient with IBD.

      Preparing for Pregnancy

      Providers should ensure that a patient's vaccinations (hepatitis A and B, pneumonia, influenza, and tetanus/diphtheria/pertussis), colon cancer surveillance, and cervical dysplasia screening are up to date.
      • Moscandrew M.
      • Mahadevan U.
      • Kane S.
      General health maintenance in IBD.
      Routine laboratory tests should include a complete blood cell count and vitamin B12, folic acid, and iron levels. In addition, physicians should consider checking vitamin D and tissue transglutaminase levels, particularly if a patient is having difficulty conceiving, because abnormal levels can be seen in patients with IBD and are associated with infertility.
      • Pappa H.M.
      • Grand R.J.
      • Gordon C.M.
      Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease.
      • Liu N.Q.
      • Hewison M.
      Vitamin D, the placenta and pregnancy.
      • Choi J.M.
      • Lebwohl B.
      • Wang J.
      • et al.
      Increased prevalence of celiac disease in patients with unexplained infertility in the United States.
      Patients should ideally have established care with a primary care provider, a gastroenterologist, and an obstetrician who is comfortable with their medications. Also, their disease activity should be stable with maintenance therapy before conception. Medications that are absolutely contraindicated in pregnancy (eg, methotrexate and thalidomide) should be discontinued a minimum of 3 months, ideally 6 months, before conception, and alternative medical regimens should be started. Although the patient is usually focused on the risk of medications to the fetus, attention should be given to the risks of disease flare if medications are stopped. Ultimately, patients should have a pregnancy medication plan that they are comfortable with. Patients should be counseled that there is a 1.6% to 5.2% chance of the child developing IBD if a single parent has IBD
      • Yang H.
      • McElree C.
      • Roth M.P.
      • Shanahan F.
      • Targan S.R.
      • Rotter J.I.
      Familial empirical risks of inflammatory bowel disease: differences between Jews and non-Jews.
      ; this chance increases to 33% if both parents have IBD.
      • Bennett R.A.
      • Rubin P.H.
      • Present D.H.
      Frequency of inflammatory bowel disease in offspring of couples presenting with inflammatory bowel disease.
      • Laharie D.
      • Debeugny S.
      • Peeters M.
      • et al.
      Inflammatory bowel disease in spouses and their offspring.

      Getting Pregnant

      Active disease may reduce fertility,
      • Hudson M.
      • Flett G.
      • Sinclair T.S.
      • Brunt P.W.
      • Templeton A.
      • Mowat N.A.
      Fertility and pregnancy in inflammatory bowel disease.
      so disease quiescence should ideally be achieved before attempting conception. The rates of fertility in women with stable IBD are generally similar to those in age-matched controls.
      • Olsen K.O.
      • Juul S.
      • Berndtsson I.
      • Oresland T.
      • Laurberg S.
      Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample.
      The one major exception is women who have undergone previous pelvic surgery, particularly an ileal pouch–anal anastomosis, which is associated with a 3-fold increase in infertility.
      • Waljee A.
      • Waljee J.
      • Morris A.M.
      • Higgins P.D.
      Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis.
      If calculated attempts to conceive are unsuccessful after 6 months and disease remission is confirmed and laboratory parameters are normal, the patient should be referred to a reproductive endocrinologist for evaluation and assistance in management. In our experience, the medications commonly used to assist the reproductive process do not significantly affect IBD activity.

      After Conception

      Effect of IBD on Pregnancy

      Most studies suggest that women with IBD have higher rates of pregnancy complications compared with age-matched controls. Complications include increased risk of preterm delivery, low birth weight, spontaneous abortion, and peripartum complications, including preeclampsia.
      • Stephansson O.
      • Larsson H.
      • Pedersen L.
      • et al.
      Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden.
      • Mahadevan U.
      • Sandborn W.J.
      • Li D.K.
      • Hakimian S.
      • Kane S.
      • Corley D.A.
      Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.
      Disease activity at conception and during pregnancy is associated with higher rates of adverse pregnancy outcomes,
      • Morales M.
      • Berney T.
      • Jenny A.
      • Morel P.
      • Extermann P.
      Crohn's disease as a risk factor for the outcome of pregnancy.
      • Nielsen O.H.
      • Andreasson B.
      • Bondesen S.
      • Jarnum S.
      Pregnancy in ulcerative colitis.
      but even patients with quiescent disease are at elevated risk for complications throughout their pregnancy compared with the general population.
      • Mahadevan U.
      • Sandborn W.J.
      • Li D.K.
      • Hakimian S.
      • Kane S.
      • Corley D.A.
      Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.
      Furthermore, maternal complications, such as venous thromboembolism and malnutrition, occur more frequently in women with IBD.
      • Nguyen G.C.
      • Boudreau H.
      • Harris M.L.
      • Maxwell C.V.
      Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United States.
      • Bröms G.
      • Granath F.
      • Linder M.
      • Stephansson Olof
      • Elmberg M.
      • Kieler H.
      Complications from inflammatory bowel disease during pregnancy and delivery.
      Therefore, we recommend that all women with IBD be followed as high-risk obstetric patients.
      The decision regarding mode of delivery should be made on an individual basis between the patient and her obstetric provider. Generally, patients with active perianal disease should be encouraged to have a cesarean delivery owing to the risk of exacerbating disease. Although cesarean delivery for the patient with an ileal pouch–anal anastomosis is recommended in some centers, studies have suggested that vaginal delivery may be safe.
      • Scott H.J.
      • McLeod R.S.
      • Blair J.
      • O'Connor B.
      • Cohen Z.
      Ileal pouch-anal anastomosis: pregnancy, delivery and pouch function.
      • Ravid A.
      • Richard C.S.
      • Spencer L.M.
      • et al.
      Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis.
      Patients without these conditions can be safely considered for vaginal delivery. We caution women against delaying or refusing cesarean delivery if labor is prolonged and the obstetrician recommends delivery. Forceps delivery and uncontrolled tears can affect pelvic floor function. In the patient with compromised bowel habits, this can have a substantial impact in the future.

      Effect of Pregnancy on IBD

      Women are not at increased risk for disease flare while pregnant or during the postpartum period compared with the nonpregnant patient with IBD.
      • Mahadevan U.
      • Sandborn W.J.
      • Li D.K.
      • Hakimian S.
      • Kane S.
      • Corley D.A.
      Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.
      • Nielsen O.H.
      • Andreasson B.
      • Bondesen S.
      • Jarnum S.
      Pregnancy in ulcerative colitis.
      • Nielsen O.H.
      • Andreasson B.
      • Bondesen S.
      • Jacobsen O.
      • Jarnum S.
      Pregnancy in Crohn's disease.
      Earlier studies had reported higher rates of disease flares in pregnancy and the peripartum period, but this observation was likely confounded by medication cessation during pregnancy or while breastfeeding and resumption of tobacco smoking after delivery.
      • Mahadevan U.
      • Sandborn W.J.
      • Li D.K.
      • Hakimian S.
      • Kane S.
      • Corley D.A.
      Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.
      In the national pregnancy registry Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO), we observed a significantly higher rate of disease activity in patients with ulcerative colitis (UC) compared with Crohn disease.
      • Mahadevan U.
      • Martin C.
      • Sandler R.S.
      • et al.
      PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract].
      This same effect has been reported in a European study as well.
      • Pedersen N.
      • Bortoli A.
      • Duricova D.
      • et al.
      European Crohn-Colitis Organisation (ECCO) Study Group of Epidemiology Committee (EpiCom)
      The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women.
      Although the reasons for this are unclear (perhaps owing to secretion of pro-UC cytokines by the placenta), we are particularly mindful of disease activity in our patients with UC.
      If a patient develops a disease flare during her pregnancy, the evaluation and management of symptoms are similar to those of the nonpregnant patient with IBD. Stool studies should undergo laboratory testing to exclude infection, particularly Clostridium difficile, which is more prevalent during the peripartum period.
      • Unger J.A.
      • Whimbey E.
      • Gravett M.G.
      • Eschenbach D.A.
      The emergence of Clostridium difficile infection among peripartum women: a case-control study of a C. difficile outbreak on an obstetrical service.
      If imaging is needed, ultrasound or magnetic resonance imaging is preferred over computed tomography to avoid exposing the developing fetus to radiation. Contrast agents, such as gadolinium, should be avoided in the first trimester because this compound has been associated with teratogenic effects in animal models.
      • Okuda Y.
      • Sagami F.
      • Tirone P.
      • Morisetti A.
      • Bussi S.
      • Masters R.E.
      Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (3): study of embryo-fetal toxicity in rabbits by intravenous administration [in Japanese].
      We have used contrast imaging successfully in the second and third trimesters, but after discussion with our radiology colleagues. Endoscopic evaluation should be performed by unsedated flexible sigmoidoscopy if possible. A full colonoscopy is rarely required during pregnancy, but, if so, it should be performed with anesthesia support and fetal monitoring. Surgery should be considered for severe bleeding, medically refractory disease, or obstruction, if needed. The American College of Obstetricians and Gynecologists recommends that nonemergency operations should be performed during the second trimester, when preterm contractions and spontaneous abortion are least likely.
      ACOG Committee on Obstetric Practice
      ACOG Committee Opinion No. 474: nonobstetric surgery during pregnancy.

      Medications

      Most medications used for the treatment of IBD are considered compatible with pregnancy and breastfeeding. In general, the act of stopping medications and precipitating a possible disease flare poses a greater risk to the fetus than any potential adverse effects of most medications themselves. Therefore, we advise patients to have a thoughtful discussion with their gastroenterologist before making any changes to their treatment regimen. It has been our experience that patients who have a medication plan before conception are much more adherent to recommended therapies than patients who attempt to create a treatment plan after conception. We generally address the issue of conception during routine office visits so that the patient knows to contact us before conception and is comfortable with their therapy. We also emphasize that they should check with their gastroenterologist before discontinuing any IBD medications, even if this was a recommendation made by their obstetrician or pediatrician.

      Methotrexate and Thalidomide

      The 2 exceptions to IBD medications being safely continued in pregnancy are methotrexate and thalidomide, which are both Food and Drug Administration category X agents and are absolutely contraindicated in pregnancy. We do not routinely manage patients taking thalidomide, but for the many patients taking methotrexate as monotherapy or as combination therapy with biological agents, we advise discontinuing the drug at least 6 months before attempting conception. Methotrexate is also excreted in breast milk and can interfere with cellular metabolism
      • Johns D.G.
      • Rutherford L.D.
      • Leighton P.C.
      • Vogel C.L.
      Secretion of methotrexate into human milk.
      ; therefore, it is contraindicated in breastfeeding.

      Aminosalicylates

      Most aminosalicylates are category B and are considered safe in pregnancy. These include most formulations of mesalamine, such as Pentasa and Lialda (both from Shire US Inc), as well as sulfasalazine and balsalazide. Osalazine, Asacol, and Asacol HD (Actavis) are category C agents. Both Asacol and Asacol HD contain dibutyl phthalate in the coating, which has been associated with congenital anomalies in animals.

      Asacol(R) [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2013.

      Currently, Asacol HD is commercially available, but Asacol is no longer manufactured. Delzicol (Warner Chilcott), a new formulation of Asacol without dibutyl phthalate, was recently released and is a category B agent. Women receiving sulfasalazine who are pregnant or attempting to conceive should take supplemental folic acid, 2 mg daily, to prevent folate deficiency. Mesalamine suppositories and enemas are well tolerated and can be used during pregnancy. There is no evidence to suggest that the use of medicinal enemas during pregnancy is associated with an increased rate of miscarriage or preterm labor.

      Corticosteroids

      Prednisone and budesonide are category C agents but can be used in the setting of disease flares. There may be a small increased risk of orofacial clefts in infants exposed to corticosteroids during the first trimester, but there does not seem to be a major teratogenic risk.
      • Park-Wyllie L.
      • Mazzotta P.
      • Pastuszak A.
      • et al.
      Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.
      Prednisone (or more specifically its metabolite prednisolone) is minimally excreted in breast milk,
      • Ost L.
      • Wettrell G.
      • Björkhem I.
      • Rane A.
      Prednisolone excretion in human milk.
      and prednisone and budesonide are considered compatible with breastfeeding.

      Thiopurines

      Azathioprine/6-mercaptopurine (AZA/6-MP) has demonstrated teratogenicity in animal studies,
      • Polifka J.E.
      • Friedman J.M.
      Teratogen update: azathioprine and 6-mercaptopurine.
      although no consistent pattern of birth defects has been identified in humans.
      • Coelho J.
      • Beaugerie L.
      • Colombel J.F.
      • et al.
      CESAME Pregnancy Study Group (France)
      Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study.
      • Casanova M.J.
      • Chaparro M.
      • Domenech E.
      • et al.
      Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease.
      Nonetheless, these agents are pregnancy category D. In our practice, if AZA/6-MP is monotherapy, we will continue it throughout pregnancy. If the patient is taking a thiopurine as part of combination therapy with an anti–tumor necrosis factor agent, we will consider stopping it in the patient with long-standing remission. It should be recognized that stopping AZA/6-MP during pregnancy may not change outcomes given that fetal exposure during organogenesis has already occurred by the time the patient realizes she is pregnant, so the risk of flaring should be weighed against the unclear benefit of stopping thiopurines. We do not administer AZA/6-MP for the first time during pregnancy given the (very small) risk of pancreatitis or bone marrow suppression. Azathioprine/6-MP is excreted at low levels in breast milk, with maximal excretion during the first 4 hours of drug ingestion.
      • Christensen L.A.
      • Dahlerup J.F.
      • Nielsen M.J.
      • Fallingborg J.F.
      • Schmiegelow K.
      Azathioprine treatment during lactation.
      Azathioprine/6-MP is believed to be compatible with lactation, but mothers are advised to wait 4 hours after taking the medication before breastfeeding. This is not always possible with a newborn, in which case we still give patients the option of breastfeeding because transfer is minimal.

      Biological Agents

      In general, these agents are compatible with pregnancy and breastfeeding. Infliximab, adalimumab, and certolizumab are all Food and Drug Administration pregnancy category B. Natalizumab is pregnancy category C. Experience with this group of drugs is increasing. To date, there has not been a consistent pattern of adverse pregnancy outcomes or birth defects observed in exposed individuals. Infliximab and adalimumab are IgG1 antibodies that are actively transported across the placenta by the FcRn receptor on the placenta and are detectable in newborns for up to 6 months after birth. Certolizumab is a pegylated Fab' fragment that is not actively transported across the placenta during pregnancy, resulting in minimal drug levels detected in infant and cord blood. Natalizumab is an integrin receptor antagonist and IgG4 antibody that would be expected to actively cross the placenta as well. Available data, mostly in patients with multiple sclerosis, do not suggest an increase in birth defects.
      • Cristiano L.
      • Friend S.
      • Bozic C.
      • Bloomren G.
      Evaluation of pregnancy outcomes from the Tysabri (natalizumab) Pregnancy Exposure Registry.
      The PIANO registry has now enrolled more than 1200 pregnant patients with IBD, of whom more than 500 have been exposed to a biological agent.
      • Mahadevan U.
      • Martin C.
      • Sandler R.S.
      • et al.
      PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract].
      The risk of birth defects does not seem to be increased based on exposure to medication (biological agents, AZA/6-MP, or combination therapy) compared with those not exposed to these medications.
      There is significant debate over when to stop anti–tumor necrosis factor agents during pregnancy. The theoretical risks of drug transfer to the infant must be weighed against the risk to the mother and infant if a flare occurs during pregnancy. Because certolizumab has minimal placental transfer, it can be continued throughout pregnancy with no adjustment made to medication timing or infant immunization schedules. There is evidence of placental transfer of infliximab as early as 26 weeks' gestation, with detectable drug levels in cord blood at term birth.
      • Zelinkova Z.
      • de Haar C.
      • de Ridder L.
      • et al.
      High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy.
      We also know that the FcRn is functioning as early as week 13 of gestation, so transfer may occur even earlier. In our practice, we try to manipulate the timing of infliximab doses so that the patient receives her last predelivery infusion during week 30 to 32 of gestation, followed by an infusion immediately after delivery. This method generally works well because there is little interruption to therapy. Adalimumab, on the other hand, has a 2-week dosing schedule, so a patient is at greater risk for disease flare when a scheduled injection is delayed. Therefore, we will continue treatment through week 36 to 38 of gestation. For natalizumab, these patients often have limited therapeutic options, and antibody development would be devastating; therefore, we generally continue therapy until week 37 to 38 of gestation and avoid infusion delays. For infliximab, adalimumab, and natalizumab, we send letters to the pediatrician and advise the mother that there should be no live vaccines for the first 6 months of life (all other attenuated vaccines should be given on schedule) and that the infant should be monitored for infection. At 1 year, in a preliminary analysis of the PIANO registry, we have not observed an increase in the rate of infections in those exposed to biological agents, and there seems to be no impairment in achieving developmental milestones.
      • Mahadevan U.
      • Martin C.
      • Sandler R.S.
      • et al.
      PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract].
      Infliximab and adalimumab have been detected in breast milk in miniscule amounts.
      • Ben-Horin S.
      • Yavzori M.
      • Kopylov U.
      • et al.
      Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease.
      • Ben-Horin S.
      • Yavzori M.
      • Katz L.
      • et al.
      Adalimumab level in breast milk of a nursing mother.
      Breastfeeding is considered compatible with the use of biological agents.

      Recommendations

      There are several key points that providers should keep in mind when treating IBD in women who are interested in conceiving or are pregnant (Table). Women with IBD who have not had pelvic surgery have similar chances of conceiving as women without IBD. Once pregnant, women with IBD are at increased risk for adverse outcomes and should be observed as high-risk obstetric patients, even in remission. Ideally, women should strive to achieve quiescent or stable disease before conception and to maintain it during pregnancy to reduce the risk of miscarriage and preterm birth. Preconception counseling, a medical therapy plan that the patient is comfortable following, and good communication with the treatment team should be established before pregnancy. Most IBD medications may be safely continued during pregnancy and lactation. Biological agent therapy may need to be adjusted in the third trimester but is generally well tolerated without significant adverse fetal outcomes. An interdisciplinary approach among the gastroenterologist, obstetrician, and, eventually, pediatrician is needed to ensure a healthy baby and a healthy mother.
      TableKey Points of IBD Management of the Pregnant Patient
      PeriodKey points
      Preconception counselingCare should be established with a primary care provider, an obstetrician, and a gastroenterologist

      Medication that may be harmful to the fetus (eg, methotrexate) should be discontinued in favor of an alternative agent

      The patient should have a medication plan that she is comfortable with before conception and should understand the risks of NOT treating and the risks of the medication

      Disease activity should be stabilized and the patient should be receiving established maintenance therapy if appropriate

      Vaccinations and other health care maintenance should be up to date

      Laboratory values, such as complete blood cell count, B12, folic acid, iron, and vitamin D, should be checked and addressed if abnormal
      ConceptionRates of conception are similar in women with and without IBD (except in the setting of previous pelvic surgery)

      Increased disease activity may affect fertility and miscarriage rates; stable disease should be maintained

      Patients should be referred to a reproductive endocrinologist if concerted attempts to conceive are unsuccessful after 6 mo
      PregnancyIncreased disease activity may affect pregnancy outcome; stable disease should be maintained

      Appropriate maintenance therapy should be continued throughout pregnancy

      The schedule of biological agent dosing may be adjusted to minimize placental transfer to the fetus during the third trimester

      Women with IBD should be followed as high-risk obstetric patients given the increased risk of complications during labor and delivery
      DeliveryGenerally, vaginal delivery is appropriate in women with IBD except those with active perianal disease

      Mode of delivery should remain an individualized decision between the patient and her obstetrician
      PostpartumMost medications can be safely continued while breastfeeding

      Live vaccines should not be given in the first 6 mo to infants exposed to anti–tumor necrosis factor agents during pregnancy (except certolizumab)

      All other vaccines can be given on schedule

      The pediatrician should be aware of anti–tumor necrosis factor or other biological agent exposure during pregnancy so that fevers and infections in the newborn can be appropriately managed
      IBD = inflammatory bowel disease.

      References

        • Moscandrew M.
        • Mahadevan U.
        • Kane S.
        General health maintenance in IBD.
        Inflamm Bowel Dis. 2009; 15: 1399-1409
        • Pappa H.M.
        • Grand R.J.
        • Gordon C.M.
        Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease.
        Inflamm Bowel Dis. 2006; 12: 1162-1174
        • Liu N.Q.
        • Hewison M.
        Vitamin D, the placenta and pregnancy.
        Arch Biochem Biophys. 2012; 523: 37-47
        • Choi J.M.
        • Lebwohl B.
        • Wang J.
        • et al.
        Increased prevalence of celiac disease in patients with unexplained infertility in the United States.
        J Reprod Med. 2011; 56: 199-203
        • Yang H.
        • McElree C.
        • Roth M.P.
        • Shanahan F.
        • Targan S.R.
        • Rotter J.I.
        Familial empirical risks of inflammatory bowel disease: differences between Jews and non-Jews.
        Gut. 1993; 34: 517-524
        • Bennett R.A.
        • Rubin P.H.
        • Present D.H.
        Frequency of inflammatory bowel disease in offspring of couples presenting with inflammatory bowel disease.
        Gastroenterology. 1991; 100: 1638-1643
        • Laharie D.
        • Debeugny S.
        • Peeters M.
        • et al.
        Inflammatory bowel disease in spouses and their offspring.
        Gastroenterology. 2001; 120: 816-819
        • Hudson M.
        • Flett G.
        • Sinclair T.S.
        • Brunt P.W.
        • Templeton A.
        • Mowat N.A.
        Fertility and pregnancy in inflammatory bowel disease.
        Int J Gynaecol Obstet. 1997; 58: 229-237
        • Olsen K.O.
        • Juul S.
        • Berndtsson I.
        • Oresland T.
        • Laurberg S.
        Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample.
        Gastroenterology. 2002; 122: 15-19
        • Waljee A.
        • Waljee J.
        • Morris A.M.
        • Higgins P.D.
        Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis.
        Gut. 2006; 55: 1575-1580
        • Stephansson O.
        • Larsson H.
        • Pedersen L.
        • et al.
        Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden.
        Inflamm Bowel Dis. 2011; 17: 795-801
        • Mahadevan U.
        • Sandborn W.J.
        • Li D.K.
        • Hakimian S.
        • Kane S.
        • Corley D.A.
        Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.
        Gastroenterology. 2007; 133: 1106-1112
        • Morales M.
        • Berney T.
        • Jenny A.
        • Morel P.
        • Extermann P.
        Crohn's disease as a risk factor for the outcome of pregnancy.
        Hepatogastroenterology. 2000; 47: 1595-1598
        • Nielsen O.H.
        • Andreasson B.
        • Bondesen S.
        • Jarnum S.
        Pregnancy in ulcerative colitis.
        Scand J Gastroenterol. 1983; 18: 735-742
        • Nguyen G.C.
        • Boudreau H.
        • Harris M.L.
        • Maxwell C.V.
        Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United States.
        Clin Gastroenterol Hepatol. 2009; 7: 329-334
        • Bröms G.
        • Granath F.
        • Linder M.
        • Stephansson Olof
        • Elmberg M.
        • Kieler H.
        Complications from inflammatory bowel disease during pregnancy and delivery.
        Clin Gastroenterol Hepatol. 2012; 10: 1246-1252
        • Scott H.J.
        • McLeod R.S.
        • Blair J.
        • O'Connor B.
        • Cohen Z.
        Ileal pouch-anal anastomosis: pregnancy, delivery and pouch function.
        Int J Colorectal Dis. 1996; 11: 84-87
        • Ravid A.
        • Richard C.S.
        • Spencer L.M.
        • et al.
        Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis.
        Dis Colon Rectum. 2002; 45: 1283-1288
        • Nielsen O.H.
        • Andreasson B.
        • Bondesen S.
        • Jacobsen O.
        • Jarnum S.
        Pregnancy in Crohn's disease.
        Scand J Gastroenterol. 1984; 19: 724-732
        • Mahadevan U.
        • Martin C.
        • Sandler R.S.
        • et al.
        PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract].
        Gastroenterology. 2012; 142 (S-149)
        • Pedersen N.
        • Bortoli A.
        • Duricova D.
        • et al.
        • European Crohn-Colitis Organisation (ECCO) Study Group of Epidemiology Committee (EpiCom)
        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
        • Unger J.A.
        • Whimbey E.
        • Gravett M.G.
        • Eschenbach D.A.
        The emergence of Clostridium difficile infection among peripartum women: a case-control study of a C. difficile outbreak on an obstetrical service.
        Infect Dis Obstet Gynecol. 2011; 2011: 267249
        • Okuda Y.
        • Sagami F.
        • Tirone P.
        • Morisetti A.
        • Bussi S.
        • Masters R.E.
        Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (3): study of embryo-fetal toxicity in rabbits by intravenous administration [in Japanese].
        J Toxicol Sci. 1999; 24: 79-87
        • ACOG Committee on Obstetric Practice
        ACOG Committee Opinion No. 474: nonobstetric surgery during pregnancy.
        Obstet Gynecol. 2011; 117: 420-421
        • Johns D.G.
        • Rutherford L.D.
        • Leighton P.C.
        • Vogel C.L.
        Secretion of methotrexate into human milk.
        Am J Obstet Gynecol. 1972; 112: 978-980
      1. Asacol(R) [package insert]. Rockaway, NJ: Warner Chilcott (US), LLC; 2013.

        • Park-Wyllie L.
        • Mazzotta P.
        • Pastuszak A.
        • et al.
        Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.
        Teratology. 2000; 62: 385-392
        • Ost L.
        • Wettrell G.
        • Björkhem I.
        • Rane A.
        Prednisolone excretion in human milk.
        J Pediatr. 1985; 106: 1008-1011
        • Polifka J.E.
        • Friedman J.M.
        Teratogen update: azathioprine and 6-mercaptopurine.
        . 2002; 65: 240-261
        • Coelho J.
        • Beaugerie L.
        • Colombel J.F.
        • et al.
        • CESAME Pregnancy Study Group (France)
        Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study.
        Gut. 2011; 60: 198-203
        • Casanova M.J.
        • Chaparro M.
        • Domenech E.
        • et al.
        Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease.
        Am J Gastroenterol. 2013; 108: 433-440
        • Christensen L.A.
        • Dahlerup J.F.
        • Nielsen M.J.
        • Fallingborg J.F.
        • Schmiegelow K.
        Azathioprine treatment during lactation.
        Aliment Pharmacol Ther. 2008; 28: 1209-1213
        • Cristiano L.
        • Friend S.
        • Bozic C.
        • Bloomren G.
        Evaluation of pregnancy outcomes from the Tysabri (natalizumab) Pregnancy Exposure Registry.
        Neurology. 2013; 80 (meeting abstracts 1):P02.127
        • Zelinkova Z.
        • de Haar C.
        • de Ridder L.
        • et al.
        High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy.
        Aliment Pharmacol Ther. 2011; 33: 1053-1058
        • Ben-Horin S.
        • Yavzori M.
        • Kopylov U.
        • et al.
        Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease.
        J Crohns Colitis. 2011; 5: 555-558
        • Ben-Horin S.
        • Yavzori M.
        • Katz L.
        • et al.
        Adalimumab level in breast milk of a nursing mother.
        Clin Gastroenterol Hepatol. 2010; 8: 475-476