PSC and IBD Women’s Health Issues Alina Allen, MD Laura Raffals, MD, MS

Gynecologic issues and family planning Effect of pregnancy on IBD and PSC Effect of IBD and PSC on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Meet Heather. . . 17 yo female recently diagnosed with extensive ulcerative colitis and PSC She is started on prednisone and mesalamine Difficulty tapering off of prednisone so started on azathioprine and responds well She is not sexually active She has questions about birth control

Contraception is safe in IBD/PSC The choices for contraception are generally the same as those for the general population Hormonal or non-hormonal intrauterine device or contraceptive implants are safest/most effective Non-estrogen containing contraception is preferred due to increased risk of venous thromboembolism Low-dose estrogen OCP is okay if no other risk factors for thromboembolism Active small bowel disease or extensive small bowel resection can affect absorption and efficacy of oral contraceptives Cirrhosis: no restriction, except in severe decompensated cirrhosis (lack of data)

Heather. . . 1 year later develops severe flare and hospitalized Unresponsive to iv steroids and started on infliximab Responds well and continues on azathioprine and mesalamine as well

Heather. . . 2 years later she is having recurrent symptoms Planning on getting married next year to Steve Wants to have children in the future Worries about future surgery if symptoms persist as her sister underwent IPAA for medical refractory UC and had trouble conceiving after

Fertility in IBD and PSC Fertility: achieving pregnancy within 1 year of intercourse without contraception Background rate – 1 in 7 couples (14%) Majority of women with IBD or PSC have normal fertility Potential impact on infertility Disease activity in IBD Decompensated PSC cirrhosis (no menstrual cycles) Medication (sulfasalazine in men) Voluntary Surgery Patient choice I have seen several pts who were told not to have kids.. General population infertility rate = 10%

Heather. . . Medications adjusted and she has been in remission for 2 years Actively trying to conceive Wonders about the risk of her baby developing IBD

Heritability of IBD and PSC Inheritance is major concern expressed by patients considering having children IBD: family history is most important risk factor to predict lifetime risk CD is more often familial than UC Children of CD parent have 5-10% lifetime risk of IBD (2% with UC) 2 parents affected (1 with CD) have 35% lifetime risk PSC: genetic risk variants identified, but familial disease is rare

Heather & Steve… She is now 2 months pregnant and has an appointment with MFM She wonders how her disease will affect her baby and likewise how being pregnant could affect her colitis and PSC

Gynecologic issues and family planning Effect of pregnancy on IBD and PSC Effect of IBD and PSC on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Effect of pregnancy on IBD

Effect of Pregnancy on CD: Disease Activity at Conception 73% 33% 27% 32% 34% Inactive Active No Relapse Relapse Worsened Activity Continued Activity Decreased Activity n=186 n=93 Effect of pg on ibd depends mainly on activity of the disease at conception. Patients in remission are likely to stay in remission during pregnancy. Active dz to start rule of thirds Inactive dz 1/3 relapse most don’t similar rate of relapse for nonpg uc patients in a 9 month period****** Is some data to suggest higher rates of relapse post partum and with breastfeeding. Also some thought that ibd should theoretically get better during pregnancy secondary to the somewhat immunosuppressed state of pregnancy. Don’t want to harm baby so less immunogenicity all around. Post-partum: some thought that ibd can flare at this time due to revived immune system. ALSO every pg is different. No guarentee. 2nd square similar to uc, rule of 1/3rds 1st square if in remission at conception likely to stay in remission What about perianal disease or fistulizing dz Always been thought that vaginal delivery could worsen perianal cd Some studies say it doesn’t but majority of patients with perianal dz have elective c-sections (for that matter most patients with ibd ) Could get fistulae at episiotomy site. Miller JP. J R Soc Med. 1986;79:221-5.

Effect of Pregnancy on UC: Disease Activity at Conception 66% 45% 34% 24% 27% Inactive Active No Relapse Relapse Worsened Activity Continued Activity Decreased Activity n=227 n=528 Effect of pg on ibd depends mainly on activity of the disease at conception. Patients in remission are likely to stay in remission during pregnancy. Active dz to start rule of thirds Inactive dz 1/3 relapse most don’t similar rate of relapse for nonpg uc patients in a 9 month period****** Is some data to suggest higher rates of relapse post partum and with breastfeeding. Also some thought that ibd should theoretically get better during pregnancy secondary to the somewhat immunosuppressed state of pregnancy. Don’t want to harm baby so less immunogenicity all around. Post-partum: some thought that ibd can flare at this time due to revived immune system. ALSO every pg is different. No guarentee. Miller JP. J R Soc Med. 1986;79:221-5.

Effect of pregnancy on PSC

Pregnancy does not worsen PSC progression, but can complicate cirrhosis NO CIRRHOSIS Portal hypertension No portal hypertension EGD to screen for esophageal varices prior to conception and 2nd trimester Treat varices to prevent bleeding Ultrasound to screen for splenic artery aneurysm Risk of complications: ascites (10%), variceal bleeding (7%), encephalopathy (1%) Itching may occur -consider UDCA Complications in 30-50% of patients Pregnancy can be completed safely under close medical supervision

Gynecologic issues and family planning Effect of pregnancy on IBD and PSC Effect of IBD and PSC on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Guiding Principle in Pregnant Patients With Active IBD “The greatest risk to pregnancy is active disease—not active medicine.” Goals Establish remission before conception Maintain remission during pregnancy Basic science studies suggest that active inflammation bad for any pregnancy, not just in IBD Sachar D. Gut. 1998;43:316.

Effect of IBD on Pregnancy Outcomes Case-controlled studies and population based studies suggest: Increased risk of adverse pregnancy outcomes Spontaneous abortion Low birth weight Preterm delivery Complications of L&D (pre-eclampsia, liver, and platelet disorders) C-section rate No major impact congenital abnormalities Likely influenced by disease activity Many different studies, mostly retrospective Population based from Sweden 1991-2 Norwegian study May2010 Conflicting data sometimes, congenital abnormalities Population based study of 756 females with ibd. Are the results due to disease activity? Yes may be more in crohns Definitions: LBW <2500g (5.5#) Very LBW 401-1500g (1-3.3#) Very PT <32 weeks PT <37 weeks Data may be confounded by frequent and inappropriate discontinuation of maintenance medications, increasing risk of flare

Impact of PSC cirrhosis on pregnancy Maternal risk: - correlates with liver disease severity. MELD ≥10 has worse outcomes Fetal risk: higher rate of prematurity and early fetal loss (20% vs 3-6% in general population) Lower live birth rate (58%)

Gynecologic issues and family planning Effect of pregnancy on IBD Effect of IBD on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Safety of IBD Medications During Pregnancy Safe to Use Limited Data When Indicated Available Contraindicated Oral mesalamine Cyclosporine Methotrexate Topical mesalamine Natalizumab Thalidomide Sulfasalazine Vedolizumab Rifaximin Metronidazole/Cipro? Ustekinumab Anti-TNF agents Tofacitinib (likely contraindicated) Azathioprine/6-MP Corticosteroids Likely safe and we use them steroids, AZA/6mp, Remicaide ?humira I wouldn’t use cipro

Placental transfer of biologics Infliximab and adalimumab do not cross the placenta in the 1st TM 1st TM important for organ/neural development Cross efficiently in the 3rd TM Infliximab is detected in infant blood up to 6 months from birth Certolizumab is pegylated Fab portion of Ab Minimal placental transfer by passive diffusion Humira doesn’t have commercially avail levels Can check infliximab level in the newborns and if neg can vaccinate Rotavirus only live vaccine given at early age MMR and varicella which are live are not given until 12+months, should be ok May need to check titres to killed vaccines in baby

Newer biologics Vedolizumab Ustekinumab Tofacitinib Low risk; limited data Ustekinumab Tofacitinib Limited data, teratogenic in animal studies Not recommended in pregnancy Mahadevan et al. Gastroenterology 2017 Moens et al. J Crohns Colitis 2019

Heather. . . 28 weeks pregnant, on bedrest for pre-term labor No colitis symptoms Wonders about infliximab dosing She is due for dose in 2 weeks Ob feels she will likely deliver early 36wks? When should she get her last infliximab dose?

Minimizing Placental Transfer Adjustment of dosing schedule Resume biologic: 24 hours after vaginal delivery 48 hours after c-section Biologic Timing of Last Dose Infliximab Week 30-32 Adalimumab Week 36-37 Certolizumab pegol No adjustment Golimumab Week 34-36 Natalizumab Vedolizumab Ustekinumab

Pregnancy after liver transplant (LT) Impact of LT on fetus Early conception within 12 months after LT is a risk factor for stillbirth  WAIT 1 year after LT. Live birth: 69-77% of pregnancies. Higher rate of complications: preeclampsia (22%), cesarean section (45-50%), and premature delivery (31- 39%). Antirejection medications can lead to congenital malformations and miscarriage  DISCONTINUE: mycophenolate mofetil sirolimus

Pregnancy after liver transplant (LT) Impact of pregnancy on the liver allograft Pregnancy increases the risk of rejection The risk is higher with early pregnancy vs 1 year after LT: 46% compared with 11% Avoid unplanned pregnancy in the first year after LT!

Gynecologic issues and family planning Effect of pregnancy on IBD Effect of IBD on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Mode of Delivery Women with IBD or cirrhosis have 1.5-2-fold greater risk of C- section Women with UC and perianal CD have increased risk of C- section Delivery method should be at discretion of the OB/Mom Most women with IBD can have vaginal delivery Exceptions: those who need C-section: Active (or quite recent) perianal disease History of rectovaginal fistula UC patients with J pouch (?) Women with large esophageal varices Burke (and Cheifetz) did a 10-year retrospective cohort study on nulliparous women who delivered a singleton infant. Overall incidence of c section in women with CD was similar to that among women without IBD. Women with active and inactive perianal disease did have increased risk. Women with UC had a 1.8 fold increased risk of c section, with highest incidence in women with IPAA Burke KE et al. Inflamm Bowel Dis 2017 Manosa et al. Scand J Gastroenterol 2013

Gynecologic issues and family planning Effect of pregnancy on IBD Effect of IBD on pregnancy Treatment in pregnancy Delivery Breastfeeding Vaccines

Breastfeeding: IBD Medications LactMed US National Library of Medicine free online database Most IBD medications are safe for breastfeeding

Summary: IBD Meds & Breastfeeding Medication Recommendation Potential concerns Aminosalicylates Compatible Rare diarrhea in infant Metronidazole Contraindicated Ciprofloxacin Probably compatible Delay feeding 4 hours Amoxicillin-clavulanic acid Rifaximin Avoid No human data Corticosteroids Methotrexate Thiopurines Biologics Low or undetectable levels (Vedo unknown) Tofacitinib Unknown Ustekinumab – low or undetectable levels – Vedo – unknown Tofacitinib - unknown

Post-liver transplant meds & Breastfeeding Compatible: tacrolimus, cyclosporine, prednisone, UDCA. Limited data: sirolimus, MMF.

Take Home Points Majority of women with IBD and non-cirrhotic PSC have normal fertility Contraception is safe in IBD/PSC The greatest risk to pregnancy is active disease— not active medicine Pregnancy is contraindicated in cirrhosis with MELD>10 or portal hypertension (varices, ascites) Pregnancy after transplant has good outcomes if conception occurs >1 year after LT Most medications can be continued during pregnancy and lactation Interdisciplinary approach is essential

Questions & Discussion