Transcript Pregnancy and Inflammatory Bowel Disease

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