Marla Dubinsky, MD Director Pediatric IBD Center Claire and Abe Levine Chair in Pediatric IBD Los Angeles, CA

Marin L et al J Gastroenterol DOI /s

 Rates of depression in IBD are 15-35%  A comparison of lifetime prevalence suggests higher rates of panic, generalized anxiety, and obsessive-compulsive disorders and major depression and lower rates of social anxiety and bipolar disorders in the IBD sample than in national samples in the United States 1  Twice the rate of depression as in controls  Depression reduces health-related quality of life and increases self-perceived functional disability irrespective of symptom severity 1. Walker Am J Gastroenterol 2008:103:

 Many patients with IBD are young and do not have co-morbid illnesses  The gastroenterologist will often serve as their only physician  Patients with IBD receive less preventive health services than general primary care patients 1 Selby Inflamm Bowel Dis. 2008:14:

 364 patients from the PIANO registry  Utilization obtained via questionnaires at 1 year post-delivery  Immunosuppressant exposure:  Azathioprine/6-MP or biologics during pregnancy  or year follow-up  Utilization rates within the 12 months  Pap smear: 72% within the year  Vaccines: Influenza: 70% within the year, Pneumococcal: 24% (ever), Hepatitis B: 51% (ever)  Bone density in steroid exposed patients; 35% (ever)  Predictors of utilization:  Influenza: Caucasian vs non-Caucasian OR 3.15, 95% CI ( )  Decreased trend towards pap smear utilization in immunosuppressed patients 5 Health Maintenance Immunosuppressants OR (95% CI) YesNo Pap Smear 102/151 (67%) 65/82 (79%) 0.54 ( ) Influenza Vaccine 172/242 (71%) 81/122 (66%) 1.24 ( ) Pneumococcal Vaccine 64/242 (26%) 22/122 (18%) 1.63 ( ) Hepatitis B Vaccine 125/242 (52%) 61/122 (50%) 1.07 ( ) Sheibani S, et al. Presented at DDW; May 20, Abstract 563.

 Higher incidence of abnormal Pap smears in women with IBD  4 tertiary care center studies  Kane: 40 pts with 134 paps vs. 120 controls: on IMM: OR = 4.5 ( )  Bhatia: 116 IBD18% vs. 5% controls abnormal pap (p=0.004)  Venkatesan: 518 IBD: INF  risk of abnl pap (OR 5.0, )  Lees (Scotland) 362 IBD women;1644 controls: no difference  2 Population based studies  Singh - >10 OCP, CS + AZA increased risk OR 1.41, CI  Hutfless - no increased risk cervical cancer (OR 1.45 CI )

 All women <age 26 with IBD should get HPV vaccination  HPV: 0, 2, 6 mos. for females 9-26 yrs.  Recommended age at years  Should men be vaccinated as well?  The 3 dose series of HPV4 may be administered to males 9 through 26 years of age to reduce their likelihood of acquiring genital warts  Increased anal dysplasia with perianal CD  High Risk behavior

 Fecundity:  the ability to have children  fecundation - aka fertilization (natural or IVF)  Fertility:  the ability to conceive & become pregnant through normal sexual activity  Infertility:  failure to conceive s/p 1 yr of intercourse  background rate – 1 in 7 couples (14%)

 Women  In UC, normal fertility overall  Voluntary childlessness higher in IBD patients  Women with active Crohn’s disease may be at risk  Post-surgical patients with pouches at increased risk for infertility  Men  Sulfasalazine causes reversible sperm abnormalities in 60%, not dose related  Erectile dysfunction secondary to depression

 Meta analysis regarding risk of infertility  Eight studies included in analysis  RR of infertility for medically treated UC was 15%, and 48% after IPAA  There were no procedural factors identified that consistently affected risk  Colectomy with ileorectal anastomosis preserves female fertility Higgins P. Gut 2006; 7:1-6. Mortier PE. Gastroenterol Clin Biol. 2006;30(4):594-7.

 21 women undergoing loop takedown after laparoscopic IPAA  American Fertility Society Adhesion Score used  15 (71%) no adnexal adhesions  5 filmy enclosing <1/3 one adnexa  1 filmy enclosing 1/3 - 2/3 rd of one adnexa  0 adhesions to both adnexae  Lap IPAA led to fewer adhesions to abdominal wall or adnexa than open operations with or without Seprafilm Indar AA. Surg Endosc 2009; 23(1):174-7.

IBDUCCD Preterm Birth** XX X XX XX XX X LBWX X XX XX XX X SGA X 1.Kornfeld et al. Am J Obstet Gynecol (n=756 IBD) 2.Fonager et al. Am J Gastroenterol (n=510 CD) 3.Norgard et al. Am J Gastroenterol (n=1531 UC) 4.Dominitz et al. Am J Gastroenterol (n=107 UC, 155 CD) – Knight, no c ** with active disease)

 Medication choices are similar  Avoid new aza/6mp in pregnancy  Avoid mnzl, CS in T1  Laboratory/Stool Tests  LFT’s (Alk Phos), ESR may be elevated  Albumin may be low; mild anemia normal  C. dificile  Imaging  MRI preferred to CT, though no gadolinium in T1  Ultrasound!  Endoscopy: Unsedated flexible sigmoidoscopy  Surgery: Indications similar to non-pregnant patient ; T2 best time

 Delivery should be at the discretion of the obstetrician  Most women with IBD can have an uncomplicated vaginal delivery  Exceptions:  Women with active perianal disease should have a cesarean section. Women with inactive perianal disease may deliver vaginally without increased complications (1)  Women with an ileoanal J pouch should consider cesarean section, though vaginal delivery is possible (2)  Preserve sphincter function and continence later in life 1.Ilnyckyji A, Am J Gastroenterol 1999;94: Juhasz ES, Dis Colon Rectum 1995;38:

 Spontaneous vaginal birth vs. C section (n=1011)  Stress incontinence (OR 2.9, )  Prolapse to or beyond the hymen (OR 5.6, 95% CI )  Operative vaginal birth significantly increased the odds for all pelvic floor disorders, especially prolapse  (OR 7.5, 95% CI ).  Forceps deliveries and perineal lacerations, but not episiotomies, were associated with pelvic floor disorders 5-10 years after a first delivery. Handa Obstet Gynecol Oct;118(4): Handa Obstet Gynecol Jan 5.

Medication FDA Category 5ASA Asacol, olsalazine BC CorticosteroidsBudesonideCC Azathioprine/6MPD MethotrexateX Anti-TNFB

Rahimi R et al Reproductive Toxicology 25 (2008) 271–275 Type of pregnancy outcome Odd ratio (fixed effect) Confidence interval P -value Status of heterogeneity (homogenous Congenital abnormalities – P = Stillbirth – P = Spontaneous abortion – P = Preterm delivery – P = Low birth weight – P =

ASACOL 400 mg ASACOL HD 800 mg DELZICOL 400mg PentasaAprisoLialda DBPYES NO Has NOT been reformulated

CD Pregnancies With Use of Steroid Outcome/Total (%) CD Pregnancies in the reference group Outcome/Total (%) Adjusted RR Low Birth Weight 5/73 (6.9)31/628 (4.9)1.1 (0.2–5.7) Pre Term Birth 9/73 (12.3)41/628 (6.5)1.4 (0.6–3.3) Low birth weight at term 1/73 (1.4)9/628 (1.4)0.9 (0.1–7.1) Congenital abnormalities 2/48 (4.2)36/628 (5.7)0.7 (0.2–3.2) Nørgard et al, Am J Gastroenterol 2007;102:1406–1413)

Coehho J et al Gut 2011; 60:

Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except 1 with pancytopenia and high alk phos (severe pre- eclampsia) 60% had anemia at birth: Median Hb 9.25 [ ]. 6-TGN 230 vs. 90 in infants with anemia No major congenital abnormalities were observed. Jharap B et al Gut 2013 Feb 19. [Epub ahead of print)

 Three studies on breastfeeding:  Sau: 31 samples/10 women (AZA mg)  1 patient had low levels in breast milk  6mp and 6tgn undetectable in neonatal blood  Gardiner: 4 women aza mg/kg/d  6TGN and 6MMPn not found in infant  Moretti: 4 women aza  Levels of 6mp undetectable by HPLC Sau: BJOG 2007; Moretti: Ann Pharmacol 2006:40: ; Gardiner: Br J Clin Pharmacol 62:4 (453-6)

ReferencesMedicationNCongenital Anomalies Katz 2004Infliximab961 Tetralogy Fallot; 1 intes Malrotation Lichtenstein 2006Infliximab1171 VSD, 1 anencephaly Mahadevan 2005Infliximab10None Schnitzler 2007, 2011 IFX/ADA35/7--/1 trisomy 8 Zelinkova 2011Infliximab41 polydactyly Verstappen 2011Infliximab Etanercept Adalimumab All: 1 pyloric stenosis, 1 congen hip dysplasia, 1 trisomy 21, 1 megacolon Roux 2007Adalimumab11 VSD, 1 hemangioma Weber- schoendorfer/Hultz 2011 IFX/ADA25/281 renal agenesis/ 1 WPW, 1 neurofibromatosis Casanova 2012Infliximab Adalimumab Certozlizumab Cardiac malformations -- Seirafi (Getaid) 2012Infliximab Adalimuamb Certolizumab missing finger Johnson 2013 (OTIS)ADA/CZP589/18No Pattern seen Cimiza DatabaseCertolizumab152 Adapted from Chambers Birth Defects Research 2012

INF and ADA are IgG1 antibodies INF and ADA are IgG1 antibodies Fc portion of IgG actively transported across placenta by specific neonatal FcR Fc portion of IgG actively transported across placenta by specific neonatal FcR Highly efficient transfer in 3 rd T leads to elevated levels of drug in newborn Highly efficient transfer in 3 rd T leads to elevated levels of drug in newborn Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins During human pregnancy. Am J Reprod Immunol 1996; 36(5): r 2 =0.87, p<0.04 B: Fetal Image Courtesy of Sundana Kane MD

 Infliximab:  Study of 10 mothers on IFX  In all cases, infant and cord IFX level were greater than mother. 6 months to clear  Adalimumab  Study of 10 mothers on ADA  In all cases, infant and cord ADA level was greater than mother. Up to 4 months to clear  ¾ pts who stopped ADA 35 days prior to delivery had a flare  Certolizumab  Study of 10 mothers  In all cases, infant and cord levels were less than 2 mcg/ml even if mom dosed the week of delivery Mahadevan Clin Gastroenterol Hepatol Mar

Infliximab  Breastmilk 1/200 th mother’s level (n=1) 1  Peak concentrations in BM 100 ng/ml  Induction therapy: (n=1) infant levels 1700 ng/ml (maternal level 78,300 ng/ml) 3 Adalimumab  Breastmilk 1/200 th mother’s level(n=1) 2  ADA undetectable in infant serum (n=1) 3 Certolizumab  Not detected in breastmilk (n=1) 1. Benhorin J Crohn’s Colitis 2011; Ben-Horin CGH Friitzsche J Clin Gastro 2012

 Debate: stop drug early or continue scheduled?  Last dose infliximab at week 32 weeks gestation  No real delay if patient gets next dose immediately after delivery (assume delivery around week 40 gestation)  Last dose adalimumab at week  Stopping earlier may lead to flares  If needed, can continue throughout on schedule  Continue certolizumab throughout pregnancy  If mom flares, treat her!  No live virus vaccine for first 6 months for infants exposed to IFX or ADA during pregnancy  Never switch drugs during pregnancy purely for placental transfer issues Mahadevan U. Am J Gastroenterol Feb;106(2):214-23

 Obstetrician:  Most IBD medications are low risk in pregnancy (exception methotrexate) and can be continued during pregnancy and lactation  Mode of delivery is per OB discretion except with active perianal disease at the time of delivery and perhaps J Pouch  Pediatrician  No live virus vaccines in the first 6 months if infant exposed to infliximab or adalimumab in utero  All other vaccines can be given on schedule  Monitor for infections