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Management of the Pregnant IBD patient Jennifer Shroff, MD Pregnancy and IBD • Peak incidence of IBD occurs during the childbearing years • Questions about fertility, pregnancy, and breast-feeding are common Fertility in IBD • Voluntary childlessness – – – – Fear of infertility Concerns about inheritance Fear that IBD medications are harmful to fetus Fear about disease flares during pregnancy • Preconception counseling important – Clarify misconceptions about pregnancy – Promotes healthier behaviors (smoking/alcohol cessation, use of folic acid, etc) – Reduces IBD flares during pregnancy by promoting adherence to medication Marri SR, et al. Inflamm Bowel Dis 2007 Selinger CP, et al. J Crohns Colitis 2013 De Lima A, et al. CGH 2016 Fertility in IBD • Those with quiescent disease seem to have normal fertility – However, previous abdominal/pelvic surgery (especially ileal pouch anal anastomosis—IPAA) can reduce fertility 2 to 3-fold • Increased risk hydrosalpinx, fimbria destruction, tubal obstruction • Fertility reduction may be less if IPAA is done laparoscopically • Active disease can reduce fertility • Malnutrition, decreased libido, dyspareunia, depression, pelvic inflammation Rajaratnam SG, et al. Int J Colorectal Dis 2011 Timmer A, et al. BMC Gastroenterol 2008 Fertility in IBD • In-vitro fertilization (IVF) in women with IBD as successful as general infertility population – Retrospective study – IVF in women with IBD (CD and UC) as successful as in the general infertility population – UC patients with history of IPAA achieved live births following IVF at comparable rates to women with UC without IPAA and to women without IBD Oza S, et al. CGH 2015 Pabby V, et al. Am J Gastroenterol. 2015 Heritability of IBD • If one parent has IBD, the offspring has a 2-5% risk of developing IBD – Lower heritability of UC than CD • If both parents have IBD, the offspring >30% chance of developing IBD • Higher risk of heritability of CD – Mother to child risk is higher – Female offspring more likely to inherit – High degree disease concordance (similar age at diagnosis and disease location) Halme L, et al. World J Gastroenterol. 2006 Adverse outcomes • • • • Spontaneous abortions Preterm birth (<37 weeks gestation) Low birth weight (<2500 grams or 5.5 pounds) Small for gestational age (fetal weight below the 10th percentile for gestational age as determined by ultrasound) • Complications of labor/delivery – Pre-eclampsia, pre-term premature rupture of membranes, venous thromboembolism (usually seen with active/flaring disease) • Risk of congenital anomalies does not seem to be increased Cornish J, et al. Gut 2007 Nguyen, GC et al. Toronto Consensus Statements. Gastroenterology 2016 Adverse outcomes • Should be followed as high-risk obstetric patients • DISEASE ACTIVITY AT CONCEPTION IS THOUGHT TO BE STRONGEST PREDICTOR OF ADVERSE OUTCOMES – Goal to be in remission at least 3-6 months prior to conception Broms G, et al. Inflamm Bowel Dis 2014 Abhyankar A, et al. Aliment Pharmacol Ther 2013 Risk of IBD flare during pregnancy • Risk of flare of UC during pregnancy – 1/3 flare if no active disease at conception (same as non-pregnant controls at 12 months) – ½ to 2/3 flare if active disease at conception – Significantly higher rate of disease activity in pregnant patients with UC compared to pregnant patients with Crohn’s Disease • Risk of flare of Crohn’s Disease during pregnancy – 1/5 flare if no active disease at conception – 1/3 flare if active disease at conception Pedersen N, et al. Aliment Pharmacol Ther 2013 Preconception Management of IBD Toronto Consensus Statements for the management of IBD in pregnancy. Gastroenterology 2016 Old FDA pregnancy labeling Category Description A B C No increased risk of fetal abnormalities demonstrated in wellcontrolled studies in pregnant women D Risk to the fetus demonstrated in well-controlled or observational studies in pregnant women, but benefits of the therapy may outweigh potential risk X Positive evidence of fetal abnormalities demonstrated in wellcontrolled or observational studies in pregnant women or in animals so use of the product is contraindicated in women who are or may become pregnant No well-controlled studies in pregnant women, but animal studies have not shown fetal harm No well-controlled studies in pregnant women, but an adverse effect has been shown in animal studies -ORWell-controlled studies in pregnant women have NOT shown a risk to the fetus, but adverse effects seen in animal studies Pregnancy and Lactation Labeling Rule Pregnancy subsection *Information for a pregnancy exposure registry if available *Risk summary *Clinical considerations *Data Lactation subsection Females and Males of Reproductive Potential *Information about using drug while breast-feeding (amount of drug in breast milk and potential effects on breast-fed infant) *Need for pregnancy testing *Contraception recommendations *Information about infertility related to the drug 5-ASAs Medication Pregnancy Placental transfer Male/female fertility Sulfasalazine *Low risk *Folic acid antagonist *Need high-dose (2mg/day) folic acid replacement to reduce risk of fetal neural tube defects YES *Can decrease sperm counts and motility (reversible) *Higher doses may cause infant interstitial nephritis *Asacol contains dibutyl phthalate coating which is associated with congenital abnormalities in animals *Mesalamine enemas are also safe YES *Low risk YES Category B Mesalamine Category B (Asacol is category C) Balsalazide Category B Mahadevan U, et al. Gastroenterology 2017 Corticosteroids Medication Pregnancy Placental transfer Male/female fertility Prednisone *May increase risk of orofacial clefts if administered in 1st trimester *Increased risk preterm birth, low birth weight, and gestational diabetes, with non-significant increase risk of infant infections in first 4 months (PIANO registry) *Closely monitor blood glucose levels YES but rapidly converted to less active metabolites causing low fetal blood concentrations Low risk Appears to be low-risk YES Low risk Category C Budesonide Category C Mahadevan U, et al. Gastroenterology 2017 Antibiotics Medication Pregnancy Placental transfer Metronidazole *Likely low risk but avoid in 1st trimester (case-control study showed cleft defects but recent MAs show no increased risks of congenital anomalies) YES Category B Ciprofloxacin Category C Amoxicillinclavulanic acid *MA showed no increased risk in 1st trimester YES but animal data show fetus musculoskeletal abnormalities so consider avoiding in 1st trimester *Low risk but limited data *Preferred antibiotic for pregnancy YES *AVOID in pregnancy (animal studies of supratherapeutic doses show teratogenicity but no good studies in humans) Unknown Male/female fertility Decreased sperm motility and viability in males Category B Rifaximin Category C Mahadevan U, et al. Gastroenterology 2017 Immunomodulators Medication Pregnancy Placental transfer Male/female fertility Thiopurines (6MP, Azathioprine/ Imuran) *Low risk *Avoid starting during pregnancy--risk of pancreatitis and bone marrow suppression, as well as slow-onset response *Increased risk of infant infections in combination therapy with anti-TNF (PIANO) YES (active metabolite 6TGN crosses placenta) *Low risk Category D** Infant anemia? Cyclosporine Category C *Limited data--Renal transplant literature suggests increased risk of preterm delivery, small for gestational age, gestational diabetes, maternal HTN, pre-eclampsia YES Limited data does not show negative impact on male fertility Mahadevan U, et al. Gastroenterology 2017 Immunomodulators Medication Pregnancy Placental transfer Male/female fertility Methotrexate *Contraindicated—TERATOGENIC *Causes congenital limb and craniofacial anomalies *Stop 6 months prior to conception bc of long half-life YES *May reversibly affect semen quality Category X Tofacitinib *Limited human data but teratogenic at high Likely doses in animal studies Unknown Category C *RA/psoriasis data showed risk of spontaneous abortion and possible congenital anomaly *Data confounded by concomitant methotrexate use Mahadevan U, et al. Gastroenterology 2017 Biologics in pregnancy Medication Pregnancy Placental transfer Male/female fertility Natalizumab *Low risk *Last dose 4-6 weeks before delivery Yes Limited data Category C Vedolizumab IgG4 *Low risk—limited data *Last dose 8-10 weeks before delivery Category B Ustekinumab Category B YES Limited data IgG1 *Low risk—limited data *Last dose 8-10 weeks before delivery YES Limited data IgG1 Mahadevan U, et al. Gastroenterology 2017 Biologics Medication Pregnancy Placental transfer Male/female fertility Infliximab (IFX) Category B *Low risk *Last dose 8-10 weeks before delivery *Can give dose 24H after vaginal delivery or 48H after C-section Yes Low risk Adalimumab (ADA) Category B *Low risk *Last dose 3-4 weeks before delivery YES Certolizumab pegol *Low risk *Continue throughout pregnancy Category B Low risk IgG1 Fc+ Minimal Low risk Peglyated Fab fragment of humanized monoclonal Ab (no Fc) Category B Golimumab IgG1 Fc+ *Low risk *Last dose 4-6 weeks before delivery Yes IgG1 Fc+ Low risk IgG placental active transport Malek A, et al. Am J Reprod Immunol 1996 Infant drug levels Julsgaard M, et al *Prospective study of 80 pregnant IBD pts in Denmark/Australia/New Gastroenterology Zealand 2016 *Inverse correlation between time from last exposure to anti-TNF agent and umbilical cord drug concentration *Higher infant drug level compared to maternal level *Mean time to drug clearance in infants was 4 months and 7 months for ADA and IFX, respectively *Drugs were not detected in infants after 12 months of age *Higher risk of infection with combination therapy Mahadevan U, et al CGH 2013 PIANO registry *31 pregnant IBD pts *Baseline maternal, cord, and infant drug levels followed by monthly assessment of infant drug levels *Median IFX and ADA levels in the cord was 160% and 153% of maternal levels, respectively *IFX and ADA could be detected in the infants up to 6 months *No congenital anomalies or serious complications were reported Early cessation of biologics? De Lima A, et al *Prospectively followed two pregnant IBD groups: sustained remission Gastroenterology “stop” group (stopped anti-TNF at median time of 22 weeks--51 pts) vs 2016 remaining “continue” group who continued beyond week 30 (32 pts) *No significant difference in relapse rate between groups *Median biologic cord blood level significantly lower in stop group and all infants had <3 micrograms/mL at 3 months in “stop” group *Growth, infection rate (even with combo therapy), eczema, adverse reactions to vaccines comparable in both groups and to non-IBD women’s children at 1 year *In “stop” group, 5 pts relapsed, 2 developed allergic reaction to anti-TNF post-partum, and 1 developed loss of response Zelinkova Z, et al CGH 2013 *18 pts IFX—12 discontinued before 30 weeks gestation *13 pts ADA—all discontinued before 30 weeks gestation *2 ADA and 0 IFX patients relapsed *Significantly less drug in cord blood samples if drug discontinued prior to 30 weeks Infant biologic exposure Mahadevan U, et al Gastroenterology 2014 PIANO registry *117 infants exposed to biologic agents *Detectable biologic agent in maternal/placental/infant serum at birth NOT associated with increase risk of infections, NICU stay, or reduced achievement of developmental milestones *Elevated birth sera drug levels in maternal/placental sera associated with increased risk of preterm birth Early cessation of biologics • Can consider stopping biologic agent at 22-24 weeks • Can consider stopping immunomodulator in patients on combination therapy – Sustained symptomatic remission for 12 months prior to conception – No active disease on endoscopy/imaging during preconception period – No prior secondary loss of response to anti-TNF therapy/dose escalation – Demonstrated therapeutic levels of anti-TNF – No prior intestinal resections – No hospitalizations in the past 36 months Toronto Consensus Statements for the management of IBD in pregnancy. Gastroenterology 2016 Early cessation of biologics • Consider risk of disease relapse and development of immunogenicity • Consider therapeutic drug monitoring to guide dosing as pregnancy can alter pharmacokinetics in 2nd and 3rd trimester Infant vaccines Centers for Disease Control and Prevention CDC.gov Disease flare during pregnancy • Usually respond well to medical management • Similar evaluation to non-pregnant IBD patients – Low albumin, low hemoglobin, and elevated ESR common in pregnancy and may not reflect inflammation • Stool studies to exclude infection (esp Clostridium difficile, which is more prevalent during the peri-partum period) • Imaging: Ultrasound or MRI preferred over CT to avoid exposing the developing fetus to radiation • Contrast agents, such as gadolinium, should be avoided in the first trimester as this has been shown to have teratogenic effects in animal studies – Usually can be used safely in 2nd and 3rd trimesters Induction therapy during pregnancy in antiTNF-naïve patients with ACTIVE DISEASE Toronto Consensus Statements for the management of IBD in pregnancy. Gastroenterology 2016 Endoscopy and pregnancy • Un-sedated flexible sigmoidoscopy is relatively safe during pregnancy and should be done if warranted to guide management during pregnancy • Colonoscopy can also be done, with consideration of risk of sedation • Preferably endoscopy is done in the 2nd trimester – However, recent systematic review, as well as prospective study of 42 IBD pregnant patients indicates lower GI endoscopy appears to be safe in all three trimesters De Lima A, et al. BMC Gastroenterol. 2015 De Lima A, et al. J Crohns Colitis. 2015 Endoscopy and pregnancy • Sedation – Lowest dose sedation or un-sedated – Propofol and Meperidine safest to use – Fentanyl appears safe in humans when given in low doses typical for endoscopy – Benzodiazepines do not seem to be associated with increased teratogenic risk per recent large MA, but casecontrolled studies suggested 2-fold increased risk of oral cleft • Midazolam preferred over other benzodiazepines but avoid use in first trimester • Position in left pelvic tilt or left lateral position to avoid vascular compression of IVC/aorta Shergill AK, et al. Gastrointest Endosc 2012 Enato E, et al. J Obstet Gynaecol Can 2011 Surgery and pregnancy • Surgery may be needed for refractory disease, severe bleeding, toxic dilatation of the colon, intestinal perforation, bowel obstruction, or perianal disease • Non-emergent operations should be performed during the second trimester, when spontaneous abortions (1st trimester) and preterm labor (3rd trimester) are less likely Killeen S, et al. Colorectal Dis. 2016 Mode of delivery • Recommendation for C-section delivery in patients with active perianal disease to preserve anal sphincter function – Perianal disease also appears to predict severe perianal laceration with vaginal delivery • Those with ileal pouch anal anastomosis should consider C-section delivery to try to preserve fecal continence but vaginal delivery may be safe Thromboprophylaxis • Many studies have shown that IBD (especially during disease flare) is a risk factor for development of venous thromboembolism • Anti-coagulant thromboprophylaxis with LMWH indicated – During hospitalization of pregnant IBD patient requiring C-section – For pregnant IBD patient hospitalized for active flare of IBD Toronto Consensus Statements for the management of IBD in pregnancy. Gastroenterology 2016 Breast-feeding and IBD • Not associated with increased risk of disease exacerbation, infant infection risk, or delayed developmental milestone achievement • May be protective against development of IBD in newborn Matro R, et al. Gastroenterology 2015 Breast-feeding and IBD Medication Recommendation 5-aminosalicylates Safe with minimal levels found in breast milk but may cause infant diarrhea (case reports) Corticosteroids and Thiopurines Safe—>pass into breast milk in small quantities usually in 1st 4 hours after drug ingestion so ideally wait 4 hours after dosing to breast-feed Anti-TNF alpha inhibitors (ADA, IFX, Golimumab, Certolizumab) Very low levels in breast-milk so low-risk Vedolizumab No human data Ustekinumab Limited human data, likely safe—low levels Natalizumab Limited human data, likely safe—low levels Methotrexate CONTRAINDICATED Tofacitinib Unknown if present in human milk Present in animal milk Mahadevan U, et al. Gastroenterology 2017 Breast-feeding and IBD Medication Recommendation Ciprofloxacin Likely safe Monitor for diarrhea and candidiasis as it enters breast milk Amoxicillin-clavulanic acid Likely safe Monitor for diarrhea and candidiasis as it enters breast milk—peak level 4-5 hours after dose Rifaximin Unlikely to reach breast milk but avoid given lack of human data Metronidazole AVOID—possible mutagen Mahadevan U, et al. Gastroenterology 2017 Summary • Disease control at conception improves pregnancy outcomes • Thiopurines and anti-TNF therapies seem to be safe during pregnancy • Most IBD medications can be continued during breastfeeding References • • • • • • • • • Abhyankar A, et al. 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. Ban L, et al. Limited risks of major congenital anomalies in children of mothers with IBD and effects of medications. Gastroenterology 2014; 146:76-84. Bortlik M, et al. Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children. Inflamm Bowel Dis 2014;20:495-5501. Broms G, et al. Birth Outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure. Inflamm Bowel Dis 2014;20:1091-8. Casanova MJ, et al. Safety of thiopurines and anti-TNF-alpha drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterology 2013;108:433-440. Cornish J, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 2007;56:830-837. De Lima A, et al. A prospective study of the safety of lower gastrointestinal endoscopy during pregnancy in patients with inflammatory bowel disease. J Crohn’s Colitis. 2015;9:519-524. De Lima A, et al. Does lower gastrointestinal endoscopy during pregnancy pose a risk for mother and child? A systematic review. BMC Gastroenterol 2015;15:15. De Lima, A, et al. Preconception counseling reduces relapse of inflammatory bowel disease during pregnancy. Clinical Gastroenterology and Hepatology, Volume 14, Issue 9, September 2016, Pages 1285-1292. References • • • • • • • De Lima A, et al. Tailored anti-TNF therapy during pregnancy in patients with IBD: Maternal and fetal safety. Gut 2016; 65: 1261-1268. Enato E, et al. The fetal safety of benzodiazepines: an updated meta-analysis. J Obstet Gynaecol Can 2011:33:46-48. Halme L, et al. Family and twin studies in inflammatory bowel disease. World J Gastroenterol. 2006 Jun 21; 12(23): 3668–3672. Jharap B, et al. Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease. Gut 2014;63:451-457. Julsgaard M, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology 2016; Jul;151(1):110-9. Khilleen S, et al. Surgical management of complicated and medically refractory inflammatory bowel disease during pregnancy. Colorectal Dis. 2016 Jun 18. Mahadevan U, et al. Exposure to anti-TNF alpha therapy in the third trimester of pregnancy is not associated with increased adverse outcomes: results from the PIANO registry [abstract]. Gastroenterology 2014: 146:S170. References • • • • • • • • • • • • Mahadevan U, et al. Drug Safety and Risk of Adverse Outcomes for Pregnant Patients with Inflammatory Bowel Disease. Gastroenterology 2017; 152: 451-462. Mahadevan U, et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy [abstract]. Gastroenterology 2012;142:S149. Mahadevan U, et al. Placental Transfer of Anti–Tumor Necrosis Factor Agents in Pregnant Patients With Inflammatory Bowel Disease. CGH 2013; 11(3): 286-292. Malek A, et al. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol 1996 Nov;36(5):248-55. Marri SR, et al. Voluntary childlessness is increased in women with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:591-599. Matro R, et al. Detection of biologic agents in breast milk and implication for infection, growth and development in infants born to women with inflammatory bowel disease: results from the PIANO registry [abstract]. Gastroenterology 2015;148:S141. McConnell R, et al. Pregnancy and the Patient with Inflammatory Bowel Disease: Fertility, Treatment, Delivery, and Complications. Gastroenterol Clin N Am 2016. 45: 285-301. McConnell R, et al. Use of Immunomodulators and Biologics before, during and after pregnancy. Inflamm Bowel Dis 2016; 22 (1): 213-223. Narula N, et al. Anti-TNF alpha therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2014;20:1862-1869. Nguyen GC, et al. The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. Gastroenterology 2016;150: 734-757. Oza S, et al. In Vitro Fertilization in Women With Inflammatory Bowel Disease Is as Successful as in Women From the General Infertility Population. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1641-6 References • • • • • • • • Pabby V, et al. In Vitro Fertilization Is Successful in Women With Ulcerative Colitis and Ileal Pouch Anal Anastomosis. Am J Gastroenterol. 2015 Jun;110(6):792-7. Pedersen N, et al. The course of inflammatory bowel disease during pregnancy and post-partum: a prospective European ECCO-EpiCom Study of 209 pregnant women. Aliment Pharmacol Ther 2013;38:501-512. Rajaratnam SG, et al. Impact of ileal pouch-anal anastomosis on female fertility: a meta-analysis and systematic review. Int J Colorectal Dis 2011:26:1365-1374. Shergill AK, et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc 2012; 76: 18-24. Selinger CP et al. Inflammatory Bowel Disease and pregnancy: lack of knowledge is associated with negative views. J Crohns Colitis 2013; 7:e206-13. Timmer A, et al. Determinants of female sexual function in inflammatory bowel disease: a survey based cross-sectional analysis. BMC Gastroenterol. 2008 Oct 3;8:45. Van der Woude CJ, et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. Journal of Crohn’s and Colitis 2015, 107-124. Zelinkova Z, et al. Effects of Discontinuing Anti–Tumor Necrosis Factor Therapy During Pregnancy on the Course of Inflammatory Bowel Disease and Neonatal Exposure. CGH. 2013. Volume 11, Issue 3Pages 318–321