Transcript Document

Inflammatory
Bowel Disease:
Overview
IBD: Overview


1CCFA
Prevalence: ~250 cases per
100,0001
– More than 1 million cases
estimated in United States1
– Ulcerative colitis (UC): 50%1
– Crohn’s disease (CD): 50%1
Incidence: 15 cases per
100,0001
– Onset: 30% between 10
and 19 years of age2
– Young children: <2%2
– Peak age of onset: 20s &
30s, again in 60s3
– Slightly greater risk for
women and elderly4
100
80
60
East
40
West
20
North
0
1st
Qtr
2nd
Qtr
3rd
Qtr
4th
Qtr
Library: Basic Facts. Available at: http://www.ccfa.org. 2Grand RJ, et al. Clin Invest Med. 1996;19:373-380.
3Hanauer SB. Cecil Textbook of Medicine. 20th ed. Philadelphia, Pa: WB Saunders Co; 1996:707. 4Lashner BA.
In: Stein SH, Rood RP, eds. Inflammatory Bowel Disease: A Guide for Patients and Their Families. 2nd ed.
Philadelphia, Pa: Lippincott-Raven Publishers; 1999:23-29.
IBD: Overview (cont’d)

Scope of disorder (United States)
– 700,000 physician visits per year
– 100,000 hospitalizations per year
– CD accounts for two thirds

Long-term outlook
– Chronic, lifelong disease
– Acute flare-ups alternating with remission
– Complications and increased mortality
– Surgery for 50% to 80% of CD patients
Calkins BM. Digestive Diseases in the United States: Epidemiology and Impact. Bethesda, Md: National Institutes
of Health; 1994.
Risk for Developing CD
Empiric Risk for Developing
Crohn's Disease (%)
60
50
50.0
40
37.0
30
20
16.8
10
0
7.5
Offspr Both
Parents
MZ Twin
Sib Ashk
Jew
7.4
7.0
Offspr
Ashk Jew
Parent
4.6
<4.0
Sib
Non-Jew
DZ Twin
<0.2
0.1
Heterozygote
NOD2
Homozygote
NOD2
General
Population
IBD: Systemic Complications
Eye
inflammation*
Lower
bone density*
Liver and
bile duct
inflammation
Gallstones
Skin lesions
*Higher incidence in women.
Growth failure
in children
Kidney
stones
Subfertility*
Ovaries
Uterus
Arthritis and
joint pains
Influence of Gender on
Illness-Related Concerns
in IBD

Study of 343 men and women
– Women report higher levels of
symptom severity (P=.04)
– Higher levels of rating of IBD patient
concerns (P<.001)
Maunder R, et al. Can J Gastroenterol. 1999;13:728-732.
Patients’ Concerns in IBD

Greater in Women Than
in Men
– Feelings about body
– Attractiveness
– Feeling alone
– Having children
– Intimacy (CD)
– Sexual performance (CD)
Maunder R, et al. Can J Gastroenterol. 1999;13:728-732.

Independent of Gender
– Energy level
– Medication effects
– Uncertain nature of IBD
– Having surgery
– Having ostomy bag
– Reaching full potential
– Being a burden
Gender-Related
Considerations in IBD
Women
Reproductive
issues
 fertility after IPAA or
proctocolectomy
 risk of relapse if
disease active at
time of conception
Disease-related
concerns
Sexuality
 concern re:
body stigma,
loss of bowel control
Men
fertility
with
sulfasalazine
Sperm
count with
methotrexate
—
 sexual activity
 libido and sexual
because of dyspareunia,
satisfaction after
abdominal pain, etc
proctocolectomy
The Effect of Smoking on
Crohn’s Disease in Women

There are now two studies that have specifically addressed the
gender effect of tobacco

Women smokers undergoing surgery are 5 times more likely to
have a recurrence than a non-smoker, and recur more quickly1

Women smokers hastened onset of disease and increased the
need for immunomodulators2
1Kane
SV, Gastroenterol 2002; 124(5):A1169 2 Cosnes J Clin Gastro and
Hepatol 2004;2:41-48.
Special
Considerations for
Women With IBD
Special Considerations for
Women With IBD

Cervical Dysplasia

Menstruation/contraception

Body image/sexuality

Conception/pregnancy/breast-feeding

Menopause/hormone replacement therapy

Risk of osteoporosis

Adherence
– Physician-patient partnership

Overlapping IBS
Incidence of Abnormal Pap
Smears in IBD

Abnormal Pap smears associated with both infection and
progression to cancer

Incidence study of women with IBD and a history of
abnormal Pap smears

Adjusted for smoking, OCP use and parity

Women with IBD were more likely to have an abnormal
Pap

Use of azathioprine increased risk 3 fold
Kane SV Am J Gastro 2008;103(3):631-6.
IBD:
Issues With Menstruation
and Contraception
Menstrual Cycle and
Bowel-Pattern Fluctuations

Bowel-pattern fluctuation is common
during the menstrual cycle

IBD symptoms may increase during the
menstrual cycle

Suppression of menses via hormonal
contraceptive methods may be considered
in presence of debilitating symptoms
Potential IBD-Related
Menstrual Symptoms

Most frequently reported symptoms
– Pelvic pain
52%
– Lower back pain
36%
– Diarrhea
26%
– Irritability
23%
– Headache
20%

Incidence of any menstrual symptoms
significantly higher for IBD patients than
for healthy controls (P.01)
Kane SV, et al. Am J Gastroenterol. 1998;93:1867-1872.
IBD:
Issues With Menstruation

There is a trend for patients with CD to be affected
by IBD symptoms during menstruation to a greater
extent than are patients with UC

CD patients experienced diarrhea significantly more
often than did controls (P=.004)
Kane SV, et al. Am J Gastroenterol. 1998;93:1867-1872.
OCs and IBD Risk

Controversial data

Increased incidence of CD with use of OCs?

OCs related to flare of CD activity?

Newer OCs with lower estrogen content associated
with decreasing incidence of CD in women?
CD Flare and OCs
Patients With Flare (%)
60
50
40
OC use
No OC use
30
20
10
0
0
100
200
300
400
Days After Inclusion
Adapted from Cosnes J, et al. Gut. 1999;45:218-222 with permission from BMJ Publishing Group.
500
OCs and IBD Risk
F:M Incidence Ratio
2.5
2.0
Baltimore
F:M incidence
for 20-29-year
age group
1.5
Olmstead
F:M incidence
for 20-29-year
age group
1.0
US OC use
(5 million)
0.5
0.0
1960
1965
1970
1975
1980
1985
1990
Adapted from Alic M. Gut. 2000;46:140 with permission from BMJ Publishing Group.
Contraindications for OCs

History of thromboembolic disease

Active obstructive liver disease with
elevated liver enzymes

Breast cancer

Smokers over the age of 35

Pregnancy
IBD and Contraception:
Conclusions

OCs should have lower estrogen content (eg, 35 µg)

Avoid for women with known hypercoagulability

Avoid for women with IBD-associated liver disease

Avoid for women with IBD who smoke
IBD:
Issues With Body Image
and Sexuality
IBD and Sexuality:
Physical Impact

Impact of disease
– Perianal complications
– Draining cutaneous
fistulae
– Skin lesions
– Arthritic deformities
– Pain
– Fatigue

Impact of treatment
– Surgical scars
– Stoma
– Medication
side effects
IBD and Sexuality:
Psychological Impact

Affected aspects
– Behavior patterns
– Communication
– Sexual drive
– Sensations connected
with sexual activity

Negative effects
– Feeling dirty, unsexy,
unattractive
– Reduced self-esteem
– Loss of former identity
– Anxiety over disclosure
Maintaining Femininity
Following IBD Surgery

Body image

Sexuality

Communication

Fertility

Pregnancy
Sexual Function
Following IPAA

Usually improved because of improved
general well-being

Some problems may continue
– Dyspareunia
– Vaginal drying

Sexual function improved 16%-25%1,2

Frequency of intercourse increased 35%2
IPAA = ileal pouch-anal anastomosis.
1Farouk
R, et al. Ann Surg. 2000;231:919-926. 2Damgaard B, et al. Dis Colon Rectum. 1995;38:286-289.
Women With Restorative
Proctocolectomies:
Satisfaction With Sexual
Relationships

22% improved

51% unchanged

26% less satisfactory

Overall 86% moderately
to extremely satisfied
Bambrick M, et al. Dis Colon Rectum. 1996;39:610-614.
Gynecologic Function
Before and After IPAA
Results of Questionnaire (n=110)1
Before
After
Dyspareunia*
5%
15%
Fecal incontinence
during intercourse
3%
7%
Menstrual problems
23%
31%
*Rates range from 0% to 26%.2-5
1Counihan
TC, et al. Dis Colon Rectum. 1994;37:1126-1129. 2Tiainen J, et al. Scand J Gastroenterol. 1999;34:185188.
B, Peppen B. Acta Obstet Gynecol Scand. 1995;74:51-55. 4Damgaard B, et al. Dis Colon Rectum.
1995;38:286-289. 5Bambrick M, et al. Dis Colon Rectum. 1996;39:610-614.
3Sjogren
Women With Ileostomies:
Sexual Function
% Patients

No change
47%

Adversely affected
– Mild (22%)
– Severe (14%)
– Moderate (11%)
47%

Improved
Awad RW, et al. Br J Surg. 1993;80:252-253.
7%
Women With Ileostomies:
Sexual Concerns
(n=50)

Sexual attractiveness decreased 52%
– Appliance
72%
– Stoma
16%
– Odor
4%

More women (60%) than men (52%)
felt less desirable

Sexual intercourse is more difficult
– Psychologically
46%
– Physically
32%
Rolstad BS, et al. Dis Colon Rectum. 1983;26:170-171.
Conception and Fertility
in Women With IBD
Effects of IBD on Fertility

Women
– UC: normal fertility rate overall (92.2%)1,2
• IPAA reduces fertility
– CD: normal fertility, but pelvic inflammation may
block fallopian tubes3
– Voluntary childlessness higher for IBD patients4

Men
– Reversible sperm abnormalities with sulfasalazine5
– Azathioprine: Semen analysis normal with
immunomodulators6
– Methotrexate caused temporary low sperm count
in animals7
1Willoughby
CP, Truelove SC. Gut. 1980;21:469-474. 2Kane SV. In Kirsner JB, Shorter RG, eds. Inflammatory Bowel
Disease. 4th ed. 1995. 3Järnerot G. Scand J Gastroenterol. 1982;17:1-4. 4Baird DD, et al. Gastroenterology.
1990;99:987-994. 5Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:204-211. 6Rajapakse RO, et al. Am J
Gastroenterol. 2000;95:684-688. 7Johnson FE, et al. J Surg Oncol. 1994;55:175-178.
Effects of CD on Female
Fertility: Conflicting Findings
1Fielding

In 5 studies, inability of patients to conceive
because of CD ranged from 12% to 67%1-5

Risk of inability to conceive was higher in
patients with large-bowel disease than in
those with small-bowel disease1-4
– Difference sometimes significant1
– No difference5

Chances of conceiving increased after
surgery for CD2
JF, Cooke WT. Br Med J. 1970;2:76-77. 2De Dombal FT, et al. Br Med J. 1972;3:550-553. 3Homan WP,
Thorbjarnarson B. Arch Surg. 1976;111:545-547. 4Khosla R, et al. Gut. 1984;25:52-56. 5Mayberry JF, Weterman IT.
Gut. 1986;27:821-825.
Female Fertility After IPAA
(n=343)
Fecundability
Ratio
Reference
population
Patients before
diagnosis
Patients before
colectomy
Patients after
IPAA
P Value
1
Number of Menstrual
Periods Observed
(time to pregnancy)
914
1.46
98
.002
1.01
84
.92
0.20
149
<.0001
—
Adapted from Gastroenterology, Vol 122, Olsen KØ, Juul S, Berndtsson I, Öresland T, Laurberg S, Ulcerative Colitis:
Female Fecundity Before Diagnosis, During Disease, and After Surgery Compared with a Population Sample,
pages 15-19, Copyright 2002 with permission from Elsevier.
Cumulative Incidence of
Pregnancy Within 5 Years
Cumulative Incidence
of Pregnancy
1.0
0.8
Before diagnosis
Reference
Before surgery
After surgery
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Time to Pregnancy (months)
Adapted from Gastroenterology, Vol 122, Olsen KØ, Juul S, Berndtsson I, Öresland T, Laurberg S, Ulcerative Colitis:
Female Fecundity Before Diagnosis, During Disease, and After Surgery Compared with a Population Sample,
pages 15-19, Copyright 2002 with permission from Elsevier.
Surgical Approaches to
Minimize Infertility

Possibly delay pelvic surgery

Minimize septic complications

Decrease adhesion formation
– Ferric hyaluronate adhesion-prevention gel
– “Pexing” ovaries

Laparoscopic procedures
IBD and Conception:
Summary

Close to normal fertility with UC, decreased after IPAA

Conflicting findings regarding influence of CD on
ability to conceive

Conflicting findings regarding influence of surgery for
CD on ability to conceive

Some IBD treatments may cause sperm abnormalities
in men
Pregnancy and
Pregnancy Outcomes
in Women With IBD
Effects of IBD on
Pregnancy Outcomes

Preterm birth
–  risk in both UC and CD1,2,5

4 of 5 studies: no major impact on risk of congenital
abnormalities1-5

Significant  in risk of low birth weight2-5

1Baird
 risk of maternal/delivery complications5
DD, et al. Gastroenterology. 1990;99:987-994. 2Dominitz JA, et al. Am J Gastroenterol. 2002;97:641-648.
RJ, Stirrat GM. Br J Obstet Gynaecol. 1986;93:1124-1131. 4Fonager K, et al. Am J Gastroenterol.
1998;93:2426-2430.4Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112
3Porter
Meta-analysis

12 studies
– N= 3907 (CD 1952, UC 1113) vs. 320, 531

Prematurity OR = 1.87 (1.52-2.31) p<0.001

LBW OR = 2.10 (1.38-3.19) , p<0.001

C-section OR = 1.50 (1.26-1.79) p <0.001

Congen Abnorm. = 2.37 (1.47-3.82) p <0.001
– 4 studies reported on the incidence IBD vs. controls, no difference
– UC vs. controls in two studies (Larzilliere 1998, Dominitz)
Cornish Gut 2006;0:1-8.
Effect of Pregnancy on UC:
Disease Activity at
Conception
80
70
n=528
66
n=227
Percent
60
50
45
40
34
30
24
27
20
10
0
No
Relapse
Relapse
Inactive
Miller JP. J R Soc Med. 1986;79:221-225.
Worsened Continued Decreased
Activity
Activity
Activity
Active
Effect of Pregnancy on CD:
Disease Activity at
Conception
80
73
n=186
70
n=93
Percent
60
50
40
27
30
33
32
34
20
10
0
No
Relapse
Relapse
Inactive
Miller JP. J R Soc Med. 1986;79:221-225.
Worsened Continued Decreased
Activity
Activity
Activity
Active
Disease activity during pregnancy in
women with IBD
Percentage of patients

Majority of patients have inactive to mild disease during pregnancy
100
80
60
40
20
0
Disease activity in Crohn’s disease
Inactive
Mild
100
80
60
40
20
0
Disease activity in ulcerative colitis
Moderate
Severe
Concept
T1
T2
Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112
T3
PP
Trimester
Effect of Pregnancy on IBD:
Maternal-Fetal HLA Disparity

Prepartum disease activity significantly predicts
disease activity during pregnancy (P=.008)

In single-locus disparity, no significant difference
between DR and DQ prepartum, during trimesters 1-3,
or postpartum

Disparity at both DR and DQ loci significantly predicts
disease activity during pregnancy (P=.001)

Maternal immune response to paternal HLA antigens
may play role in pregnancy-induced remission of IBD
Kane S, et al. Gastroenterology. 1998;114:A1006. Abstract G4121.
Concerns Regarding
Pregnancy and Delivery

What is the effect of pregnancy on pouch
function before and after delivery?

Should the woman deliver vaginally or have
cesarean section?

Are there unique concerns if cesarean section
is performed?
Delivery Mode and
Perineal Injury

Study indicates that more women with IBD have
cesarean sections1

Vaginal delivery is usually safe for women with inactive
perianal symptoms1
1Ilnyckyji
A, et al. Am J Gastroenterol. 1999;94:3274-3278.
Pouch Function During and
After Pregnancy

10 vaginal deliveries, 6 cesarean sections
– No pouch complications

8.1 bowel movements/day during pregnancy
vs 6.5/day postpartum

3 women had incontinence during pregnancy,
1 frequent and 2 mild

1 woman had nighttime incontinence
postpartum
Scott HJ, et al. Int J Colorectal Dis. 1996;11:84-87.
Pregnancy, Delivery,
and Pouch Function
After IPAA in UC

Questionnaires sent to women with IPAA for UC

Results
– 49 deliveries for 29 women (25 vaginal, 24 c-sections)
– 6 pouch-related complications (2 during pregnancy;
4 postpartum)
–  stool frequency and incontinence during pregnancy
– 83% regained prepregnancy function; 17% had some
permanent pouch function deterioration not related to
delivery method
– Delivery method did not affect incontinence,
stool frequency

Conclusion: Pregnancy is safe for women with IPAA
Ravid A, et al. Dis Colon Rectum. 2002;45:1283-1288.
IBD in Pregnancy:
Summary

Pregnancy outcomes best if patient in remission at time of
conception, though even patients in remission can have higher
rates of adverse outcomes compared to the general
population

IBD increases the risk of preterm birth and low birth weight and
maternal complications

No significant increase in risk of congenital abnormalities

Women with IBD have a higher rate of cesarean sections

Pregnancy may not increase the risk of relapse or significantly
increase disease activit
Management of IBD
in Pregnancy
Assessment of
Disease Activity in
Pregnant IBD Patients

Laboratory studies (ESR, Hgb, albumin, CRP)

Ultrasound – low risk

Low-dose X-rays pose minimal fetal risk1

Endoscopy – low risk if used for appropriate indications2

Flexible sigmoidoscopy – low risk2

Colonoscopy – should only be used for life-threatening
colonic disease or when only alternative is laparotomy2
ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein.
1Hufton
AP. Br J Radiol. 1979;52:735-740. 2Cappell MS, et al. Dig Dis Sci. 1996;41:2353-2361.
Drugs in Pregnancy

Pharmaceutical companies almost never test
products in pregnant women

PDR® disclaimer: use in pregnancy is not
recommended unless benefits justify risk to fetus

FDA classifications (A, B, C, D, X)
– Ambiguous
– Difficult to interpret and use in counseling
PDR® = Physicians’ Desk Reference®; FDA = Food and Drug Administration.
Koren G, et al. N Engl J Med. 1998;338:1128-1137.
Pregnancy-Risk Categories

A: Controlled human studies do not show risk to fetus;
chance of risk remote

B: No evidence of risk to fetus in human studies; chance
of risk remote but possible

C: Inadequate studies in humans; risk cannot be ruled
out, but benefits may outweigh risks

D: Positive evidence of fetal risk; benefits might outweigh
risks in life-threatening situations when safer drugs are
ineffective

X: Contraindicated in pregnancy
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
Summary: Safety of IBD
Medications During Pregnancy
Category B
Category C
Category D
Category X
Loperamide
Ciprofloxacin
Azathioprine†
Methotrexate
Mesalamine
Cyclosporine
6-Mercaptopurine†
Thalidomide
Balsalazide
Diphenoxylate
Corticosteroids
Olsalazine
Sulfasalazine
Tacrolimus
Anti-TNF agents
Natalizumab
Metronidazole*
*Safe for use after first trimester. †Increasing use in pregnancy.
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.
Sulfasalazine in Pregnancy
1Stein

Most side effects linked to sulfapyridine moiety1

No increase in fetal malformations

Readily crosses placenta, but only minimal amounts
in breast milk2

Interferes with folic acid metabolism
– Folate important for neural tube development3
– Folic acid supplements (1 mg BID) advised prior
to conception and throughout pregnancy
RB, Hanauer SB. Gastroenterol Clin North Am. 1999;28:297-321. 2Miller JP. J R Soc Med. 1986;79:221-225.
3Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835.
Aminosalicylates (B,C)

Meta-analysis 7 studies: 642 5ASA, 1158 no med
–
–
–
–
–

Congenital anomalies: OR 1.16 (0.76, 1.77)
Stillbirth OR 2.38 (0.65, 8.72)
SAB OR 1.14 (0.65, 2.01)
Preterm delivery 1.35 (0.85, 2.13)
LBW OR 0.93 (0.46, 1.85)
Sulfasalazine given w/ folic acid 1 mg BID
• Folic acid: neural tube defects, CV, GU, cleft palate
• Case reports of congenital malformation

Placental and Breast Transfer Occurs
• Potential allergic reaction newborn: watery diarrhea
• SAS not associated with kernicterus or displacement of
bilirubin from albumin

Olsalazine: Pregnancy category C. All others, B
Rahimi Reprod Toxicol 2008
Safety of Mesalamine
in Pregnancy
Study
Marteau et al1
Diav-Citrin et al2
n
123*
165
Mean
Mesalamine
Dosage
2.1 ± 0.8 g/d
2.0 ± 1.6 g/d
Incidence of Fetal
Malformations (%)
Patients
3.1
0.8
Controls
1.7-3.4†
3.8
*96 taking mesalamine during first trimester. †General population in France.
1Marteau
P, et al. Aliment Pharmacol Ther. 1998;12:1101-1108. 2Diav-Citrin O, et al. Gastroenterology.
1998;114:23-28.
Topical 5-ASA in Pregnancy

Study of 19 pregnancies
– Maintenance 5-ASA topical therapy at time
of conception and throughout pregnancy
– Successful full-term pregnancies for all patients,
with no fetal abnormalities

Minimal excretion of 5-ASA and metabolites in
breast milk

Many years of safe use
Bell CM, Habal FM. Am J Gastroenterol. 1997;92:2201-2202.
Antibiotics

Metronidazole (B) /Ciprofloxacin (C)
– Low risk of teratogenicity
• Metronidazole: prospective controlled study, 2 metaanalysis
– However, 2nd, 3rd T use, 1st T cleft lip, palate
• Ciprofloxacin: prospective controlled study low risk of
defects
– Affinity for bones, arthropathy in children
– Breast feeding not advised on MNZL, probably compatible
with ciprofloxacin
– Minimal benefit in CD and UC with longer use-avoid

Rifaximin: Pregnancy C
– teratogenicity in animal studies
– Safety in humans in pregnancy/breastfeeding unknown
Corticosteroids in Pregnancy

Increased spontaneous abortions, cleft palate,
stillbirths in mice; rare teratogenicity in humans (cleft
palate)

High doses associated with retardation of fetal growth

No fetal adrenocortical insufficiency

Safety uncertain with long-term use of high doses while
breast-feeding

Active-disease risks greater than drug risks to fetus, so use
if needed
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
AZA/6-MP in Pregnancy

Several studies in transplant recipients have reported safe
use during pregnancy1

Study of IBD patients showed no  in prematurity, spontaneous
abortion, congenital abnormalities, or childhood neoplasia2
– Study population included fathers treated with
AZA/6-MP

In another study, AZA/6-MP did not reduce fertility in men3

Risk of birth defects similar to that in general population4
1Briggs
GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
A, et al. Gastroenterology. 2003;124:9-17. 3Dejaco C, et al. Gastroenterology. 2001;121:1048-1053.
4Library: IBD & Your Family. Available at www.ccfa.org/medcentral/library/family/drugpreg.htm. Accessed March
6, 2003.
2Francella
Azathioprine and Teratogenicity

Largest Study to date

189 pregnant women on AZA who contacted one of seven
teratogen information services were compared to a cohort of 230
pregnant women who took non-teratogenic treatments

Rate of major malformations did not differ with six neonates each:
– AZA (3.5%) vs control ( 3.0%) (p = .775; OR 1.17; CI: 0.37, 3.69).

Mean birth weight and gestational age were lower in AZA group:
– 2,995g vs. 3,252g [p = .001]
– 37.8 weeks vs. 39.1 weeks [p = .001]

The AZA group had more prematurity
– 21.4% vs. 5.2% [p < .001]

The AZA group had more low birth weight
– 23% vs. 6.0% [p < .001]
Goldstein Birth Defects Res A Clin Mol Teratol. 2007 Sep 10;79(10):696-701
Thiopurines and Nursing

2 infants breast fed with mothers on 6MP
– 6MP levels by HPLC < 0.09% maternal dose1

4 mother-infant pairs 3 months post-partum were tested
for 6MP metabolites
– All infants were nursing
– Maternal levels within therapeutic range
– No metabolites found in offspring2
Moretti M. Ann Pharmacother 2006; Dec (40); Gardiner S. Br J Clin Pharmacol 2006; 62:453-56.
Cyclosporine in Pregnancy

Registry data on transplant recipients1
– No specific congenital abnormalities or birth defects
– Prematurity: 56%
– Low birth weight: 49.5%

Study in 5 women with IBD2
– 4 live births, 1 missed abortion
– No congenital abnormalities

Should be given at experienced IBD centers3
1Armenti
VT, et al. Transplantation. 1994;57;502-506. 2Marion JF, et al. Am J Gastroenterol. 1996;91:1975.
3Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:204-211.
Infliximab (B) Safety Database in Pregnancy:
Outcomes of Women Exposed to Infliximab During Pregnancy
Proportion of Patients (%)
80
70
67
67
66
67
60
Live births
50
Miscarriages
40
Therapeutic
termination
30
20
17 16
20
19
17
15
13
All infliximab
patients
(N=96)
Infliximab
patients with
CD (N=82)
11
10
0
General
population
Crohn’s
disease
Katz JA, et al. Am J Gastroenterol. 2004;99:2385-2392.
Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59
Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.
Medications: Biologics

Biologics
– Category B: Infliximab, adalimumab, certolizumab
– Category C: Natalizumab

Infliximab: 102 pregnancies, 54 outcomes1
– “Rescue” infliximab successful2
– Infliximab not detected in breast milk (n=5)
– Demonstrated to cross the placenta and detectable in cord
blood for up to 6 months from birth5

Adalimumab: 2 IBD pregnancies in published literature3,4
– 47 reported in OTIS registry

Certolizumab: no published data in humans

Natalizumab: IgG4, placental transfer in 1st trimester
1Katz
J. Am J Gastroenterol 2004; 99(12):2385-92. 2Mahadevan U. APT 2005; 21(6):733-8. 3Vesga L. Gut 2005;
54(6):890.4Mishkin DS. IBD 2006; 12(8):827-8.5 Mahadevan Gastroenterology 2007;132:A-144
Methotrexate in Pregnancy

Contraindicated during pregnancy
– Chromosomal damage, teratogenic
– Abortifacient

Oligospermia noted during treatment of men
– Returns to baseline posttreatment
– Long-term effects unknown
Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
Conclusions:
IBD Drugs in Pregnancy

5-ASAs and corticosteroids low risk for use during
pregnancy and breast-feeding

Immunosuppressants
– AZA/6-MP appear low risk during pregnancy
– Methotrexate contraindicated

Antibiotics
– Ampicillin and cephalosporins are low risk
– Ciprofloxacin and metronidazole should be avoided
for longterm use

Biologics:
– Anti-TNF agents low risk. Infliximab and likely
adalimumab cross placenta in third trimester
Safety of IBD Medications in
Breast-Feeding
Low risk to Use When
Warranted
Oral mesalamine
Topical mesalamine
Sulfasalazine
Limited Data
Available
Azathioprine
6-Mercaptopurine
Infliximab
Contraindicated
Methotrexate
Cyclosporine
Metronidazole
Corticosteroids
Tacrolimus
Ciprofloxacin
Infliximab
Natalizumab
Adalimumab
Certolizumab
Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.
Management of IBD in
Pregnancy: Summary

Pregnancy outcomes best if patient in remission at
time of conception

Many IBD-specific therapies appear to be low risk in
pregnancy

Monitoring of fetal growth particularly important

May need additional nutritional therapy because
of malabsorption
Menopause
in Women With IBD
Menopause

Natural menopause results from gradual decline
in number of estradiol-producing ovarian follicles

Surgical menopause may occur at any age as
a result of oophorectomy

Estradiol decreases; estrone becomes primary
circulating hormone

Testosterone declines at varying rate

No data on effect of menopause on IBD
Carr BR, Bradshaw KD. In: Braunwald E, et al, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York,
NY: McGraw-Hill; 2002.
Menopausal Symptoms

Bone loss—may be accelerated in CD and by
corticosteroid use

Vasomotor symptoms—“hot flashes” (50%–85%)

Increases in total and LDL cholesterol

Urogenital symptoms (45%)
– Dyspareunia
– Dysuria
– Incontinence
– Urinary tract infections
U.S. Preventive Services Task Force. Guide to Clinical Preventive Services, 2nd ed. 1996. Available at:
http/www.ahcpr.gov/clinic/cpsix.htm. Accessed January 28, 2003.
Postmenopausal HRT

Replaces estrogen in postmenopausal women

Goal: manage symptoms caused by loss of estrogen

Unopposed estrogen: only for women who have
had hysterectomies

Combined estrogen/progestin: recently found to
increase risks for breast cancer, heart attacks, stroke
HRT Protective Against
Disease Activity After
Menopause

Cohort of post-menopausal women

Disease activity pre and post menopause

Those taking HRT less likely to have a disease flare in 2
years post menopause

Dose response for length of use

Form of menopause did not matter
Kane SV Am J Gastro 2008; 103(5):1193-96.
Potential Benefits vs Risks
of HRT
Potential Benefits
Potential Risks

Decrease in
vasomotor symptoms

Increase in invasive breast
cancer

Slower changes in
body morphology


Fewer osteoporotic
fractures
Side effects: bloating,
irritability, weight gain,
depression, vaginal bleeding

Increased risk of
thromboembolic events
(blood clots, stroke)

Increase in CVD

Improvement in lipid
balance

Reduce IBD flare
Clements D, et al. Gut. 1993;34:1543-1546. Stampfer MJ, et al. N Engl J Med. 1991;325:756-762. Women's Health
Initiative. JAMA. 2002;288:321-333.
HRT Guidelines for
IBD Patients

As with all therapeutic choices, therapy for menopausal
symptoms should be individualized

For women with severe osteopenia or osteoporosis, HRT
benefits may outweigh risks if alternatives are not feasible

For women at increased risk for breast cancer, HRT risks
may outweigh benefits

CVD risk vs benefit is controversial, but risk may outweigh
benefit
Osteoporosis
in IBD
General Risk Factors
for Osteoporosis

Advancing age

Smoking

Female gender

Physical inactivity

Family history

Low calcium intake

Alcohol use


White/Asian race
Small and thin body
habitus
Valentine JF, Sninsky CA. Am J Gastroenterol. 1999;94:878-883. Christchilles EA, et al. Arch Intern Med.
1991;151:2026-2032.
Risk of Osteoporosis in IBD

Low bone mass in 31% to 59% of IBD patients1-3

IBD-related risk factors4
– Onset of IBD before reaching age of peak bone mass
– Inflammatory cytokines
– Calcium malabsorption
– Vitamin D deficiency (CD patients)
– Drugs (corticosteroids, methotrexate, cyclosporine)
1Compston
JE. Aliment Pharmacol Ther. 1995;9:237-250. 2Roux C, et al. Osteoporos Int. 1995;5:185-190.
H, et al. Scand J Gastroenterol. 1997;32:1247-1255. 4Valentine JF, Sninsky CA. Am J Gastroenterol.
1999;94:878-883.
3Andreassen
Prevention and Treatment of
Osteoporosis in IBD

Prevention
– Baseline and follow-up measurements of bone density
(DEXA)
– Lifestyle and nutritional measures (eg, weight-bearing
exercise, smoking cessation, calcium supplementation)
– Possible HRT for high-risk postmenopausal women

Treatment
– Calcitonin
– Bisphosphonates
– PTH
– IV therapies
Valentine JF, Sninsky CA. Am J Gastroenterol. 1999;94:878-883.
Corticosteroid-Induced
Bone Loss

Bone loss occurs early (weeks to months after
initiation of therapy)

Cumulative dose, dosage, and duration of
corticosteroids may play a role

Calcium and small doses of vitamin D may
confer limited prophylactic benefit
Valentine JF, Sninsky CA. Am J Gastroenterol. 1999;94:878-883. Van Staa TP, et al. J Bone Mineral Res.
2000;15:993-1000.
Corticosteroid-Induced Loss
of Bone Mass

Enhanced bone resorption
– Reduced intestinal calcium absorption and calcitonin
synthesis
– Increased renal calcium excretion, osteoclastic activity,
and parathyroid hormone secretion
– Enhanced binding of macrophages to bone

Reduced bone formation
– Reduced synthesis of osteoblasts and proliferation of
osteoblasts
– Impaired gonadal hormone production
– Prednisone associated with increased rate of bone loss
– Conflicting data regarding budesonide
Reducing the Risk of
Osteoporosis
History and physical lab (25-hydroxy vitamin D, albumin, calcium, PTH)
Bone density (DEXA)
Minimize corticosteroids
Normal T Score
Monitor regularly
Low BMD:
T Score <–1 SD
Osteoporosis:
T Score <–2.5 SD
Hormone
(if appropriate)
Hormone
(if appropriate)
Raloxifene
(if appropriate)
Raloxifene
(if appropriate)
Calcium
Calcium
Vitamin D
Vitamin D
General guidelines
Bisphosphonates
Repeat DEXA
General guidelines
Repeat DEXA
Bisphosphonates in the Prevention
and Treatment of Osteoporosis
Lumbar Spine BMD
12 month diff. = 3.8%
12 month diff. = 2.7%
% Change from Baseline
2
4
*†
1
†
†
†P<.05
0
control
-1
0
3
*
†
*†
Placebo
*
-3
vs
3
2
*
-2
-4
*P<.05 vs
baseline
6
*
9
12
Ris
5.0 mg
*
1
0
0
6
Months
Months
Prevention Study
Treatment Study
Cohen S, Levy RM, Keller M, Boling E, et al. Risedronate therapy
prevents corticosteroid-induced bone loss: a twelve-month,
multicenter, randomized, double-blind, placebo-controlled,
parallel-group study. Arthritis Rheum. 1999;42:2309-2318.
Copyright© American College of Rheumatology. Reproduced
with permission of John Wiley & Sons, Inc.
12
Reproduced from J Bone Miner Res. 2000:15;1006-1013 with
permission of the American Society for Bone and Mineral
Research.
Infliximab in Patients
With CD and Osteoporosis

Prospective, 4-week trial with patients taking
corticosteroids

Significant decrease in CDAI with infliximab
(P=.0001)

Increase in surrogate markers for bone turnover

Conclusion: increased bone synthesis with
no increase in bone resorption
CDAI = Crohn’s disease activity index.
Abreu MT, et al. Am J Gastroenterol. 2002;97:S269. Abstract 819.
Summary:
Osteoporosis and IBD

Bone density is unusually low in patients with
active IBD who are taking steroids

IBD causes other risk factors, eg, poor calcium
absorption and disease-related inflammatory
processes, that increase risk of bone loss

Monitoring BMD is important

Selection of treatment should be considered
Clinical Management
and Adherence Issues
in IBD
Illness-Related Factors
Affecting Adherence in IBD

Severity, extent, duration of disease

Frequency, duration, intensity of flare-ups

Type and severity of complications

Patients with well-controlled disease and
few flares are most likely to discontinue
maintenance therapy
Treatment-Related Factors
Affecting Adherence in IBD

Convenience
– Dosage/dosing
regimen
– Formulation
– Method of
administration
– Pill size

Cost/reimbursement

Choice of medication
– Sulfasalazine, corticosteroids
• Need to balance efficacy
vs safety
• Start with low doses, titrate
slowly upward
– Mesalamine
• Dose-related efficacy but
not toxicity
• Initiate and maintain
treatment with high doses
• Induction dose =
maintenance dose
Patient-Related Factors
Affecting Adherence
1Martin

Inadequate education1; inadequate skills/knowledge
to follow regimen2

Patients’ main concerns
– Uncertain nature of IBD
– Effects of medications3

Patients’ belief systems (treatment will not help,
side effects outweigh benefits)2

Psychiatric disorders4

Male, unmarried, younger age5,6

Patterns of nonadherence7
A, et al. Ital J Gastroenterol. 1992;24:477-480. 2Levy RL, Field AD. Am J Gastroenterol. 1999;94:1733-1742.
3Drossman DA, et al. Psychosom Med. 1991;53:701-712. 4Nigro G, et al. J Clin Gastroenterol. 2001;32:66-68.
5Kane S. Am J Gastroenterol. 2001;96:2929-2932. 6Kane S. Am J Gastroenterol. 2001;96(suppl):S296. 7Kane S. In:
Bayless TM, Hanauer SB, eds. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: BC Decker,
2001:9-11.
Prevalence of Nonadherence
to IBD Maintenance Therapy
1Blackwell

Failure to take medication by patients with
other illnesses: 25%–50%1

41% of patients on maintenance sulfasalazine
do not take prescribed dosages2

Clinical research protocols overestimate
drug adherence
B. Clin Pharmacol Ther. 1972;13:841-848. 2van Hees PAM, van Tongeren JHM. J Clin Gastroenterol.
1982;4:333-336.
Impact of Nonadherence
on Outcomes in IBD
% of Patients With
Quiescent UC Remaining
in Remission
100
90
Adherent to
5-ASA therapy
(Asacol®)
80
70
60
Nonadherent to
5-ASA therapy*
(Asacol®)
50
40
30
20
10
0
0
5
10
15
20
25
30
Time (months)
*P=.001.
Adapted with permission from Am J Med., Vol 114, Kane S, Huo D, Aikens J, Hanauer S. Medication
nonadherence and the outcomes of patients with quiescent ulcerative colitis, pages 39-43, Copyright 2003 with
permission from Excerpta Medica.
Strategies for Optimizing
Patient Adherence

IBD is a chronic, lifelong illness

Induce then maintain remission

Reciprocal patient:clinician relationship

Educate patient and family

Individualize therapy/simplify regimen

Promote emotional/psychological support

Obtain patient’s commitment to
therapeutic objectives
Guided Self-Management
in UC
Intervention Group
n=101

Personalized, guided
self-management regimen

Single 15-30-minute session
– Relapse recognition
– Treatment protocols

Patients given written protocols

Copy to primary MDs
Robinson A, et al. Lancet. 2001;358:976-981.
Control Group
n=102

Routine treatment
and follow-up
Relapses Are Treated Earlier
in Self-Managed Patients
Proportion Untreated (%)
100
90
80
70
60
Control
group
50
40
30
20
Intervention
group
10
0
0
2
4
6
Time (days)
Reprinted with permission from Elsevier (The Lancet. 2001;358:976-981).
8
10
12
Patient Self-Management

Trends in self-management group (vs controls)
– Fewer relapses (1.53 vs 1.93; P=NS)
– Shorter duration of relapse if treated in first
24 h (17.7±17.1 d vs 25.5±37.4 d; P=.16)
– 82% preferred self-management
– 95% of controls said they were adopting
self-management
Robinson A, et al. Lancet. 2001;358:976-981.
General Conclusions:
Special Considerations for
Women With IBD

Women have more severe symptoms, more disease
concerns than men

Menstrual symptoms may be more severe

OCs may be related to disease-activity flares

IPAA improvement may be accompanied by feelings
of decreased attractiveness

Most women experience postoperative improvement
in sexual activity
General Conclusions:
Special Considerations for
Women With IBD (cont’d)

Fertility
– Normal or near normal
in UC
– May be affected in CD
– IPAA reduces fertility
– Voluntary childlessness
makes data difficult to
interpret

Pregnancy
– IBD has minimal effect on
pregnancy outcomes
– Conception during
remission preferable
– Some IBD drugs safe in
pregnancy and breastfeeding
– Disease activity is greater
threat to pregnancy than
treatment
General Conclusions:
Special Considerations for
Women With IBD (cont’d)

Menopause
– Bone loss, especially in
CD, is greatest risk,
leads to osteoporosis
– Cardiovascular risk
increases, equal to risk
in men by age 75
– Benefits of HRT are
increasingly questioned
as risks are observed

Osteoporosis
– Common in
postmenopausal women,
aggravated by CD and
steroid therapy
– Active plan to prevent bone
loss and osteoporosis is vital
– Nonsteroidal IBD drugs
– Treatment options to
preserve bone mass
General Conclusions:
Special Considerations for
Women With IBD (cont’d)

Adherence improves outcomes; nonadherence
leads to relapse

Patient must understand nature of disease, goals
of treatment

Treatment plan tailored to patient’s life and needs

Adherence improved by good physician-patient
communication