Women`s health issues in IBD

Report
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 10.1007/s00535-012-0700-2


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 States1
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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 2008:103:1989-1997
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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 patients1
Selby Inflamm Bowel Dis. 2008:14:253-258

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

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Health
Maintenance
Immunosuppressants
OR (95%
CI)
Yes
No
Pap Smear
102/151
(67%)
65/82
(79%)
0.54
(0.29-1.03)
Influenza
Vaccine
172/242
(71%)
81/122
(66%)
1.24
(0.78-1.99)
Pneumococcal
Vaccine
64/242
(26%)
22/122
(18%)
1.63
(0.95-2.81)
Hepatitis B
Vaccine
125/242
(52%)
61/122
(50%)
1.07
(0.69-1.65)
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 (1.26-7.89)
Decreased trend towards pap smear utilization in immunosuppressed patients
Sheibani S, et al. Presented at DDW; May 20, 2013. Abstract 563.
5

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 (1.5-12.3)
 Bhatia: 116 IBD18% vs. 5% controls abnormal pap
(p=0.004)
 Venkatesan: 518 IBD: INF  risk of abnl pap (OR
5.0, 2.11-11.85)
 Lees (Scotland) 362 IBD women;1644 controls: no
difference

2 Population based studies
 Singh - >10 OCP, CS + AZA increased risk OR
1.41, CI 1.09-1.81
 Hutfless - no increased risk cervical cancer (OR
1.45 CI 0.74-2.84)
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All women <age 26 with IBD should get HPV
vaccination

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HPV: 0, 2, 6 mos. for females 9-26 yrs.
Recommended age at 11-12 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
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Fecundity:
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Fertility:

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the ability to have children
fecundation - aka fertilization (natural or IVF)
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

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Men

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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

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Colectomy with ileorectal
anastomosis preserves female fertility
Higgins P. Gut 2006; 7:1-6. Mortier PE. Gastroenterol Clin Biol. 2006;30(4):594-7.
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21 women undergoing loop takedown after
laparoscopic IPAA
American Fertility Society Adhesion Score
used
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15 (71%) no adnexal adhesions
5 filmy enclosing <1/3 one adnexa
1 filmy enclosing 1/3 - 2/3rd 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.
IBD
UC
CD
Preterm Birth**
X
X
XX
LBW
X
SGA
** with active disease)
1.
2.
3.
4.
Kornfeld et al. Am J Obstet Gynecol. 1997 (n=756 IBD)
Fonager et al. Am J Gastroenterol. 1998 (n=510 CD)
Norgard et al. Am J Gastroenterol. 2000 (n=1531 UC)
Dominitz et al. Am J Gastroenterol. 2002 (n=107 UC, 155 CD) – Knight, no c
XX
X
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Medication choices are similar
Avoid new aza/6mp in pregnancy
 Avoid mnzl, CS in T1

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Laboratory/Stool Tests

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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!
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Endoscopy: Unsedated flexible sigmoidoscopy
Surgery: Indications similar to non-pregnant patient ;
T2 best time

Delivery should be at the discretion of the
obstetrician

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Most women with IBD can have an uncomplicated
vaginal delivery
Exceptions:
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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.
2.
Ilnyckyji A, Am J Gastroenterol 1999;94:3274-8
Juhasz ES, Dis Colon Rectum 1995;38:159-65.
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Spontaneous vaginal birth vs. C section
(n=1011)
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Operative vaginal birth significantly
increased the odds for all pelvic floor
disorders, especially prolapse
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Stress incontinence (OR 2.9, 1.5-5.5)
Prolapse to or beyond the hymen (OR 5.6, 95% CI
2.2-14.7)
(OR 7.5, 95% CI 2.7-20.9).
Forceps deliveries and perineal lacerations,
but not episiotomies, were associated with
pelvic floor disorders 5-10 years after a first
delivery.
Handa Obstet Gynecol. 2011 Oct;118(4):777-84
Handa Obstet Gynecol. 2012 Jan 5.
Medication
FDA
Category
5ASA
Asacol, olsalazine
B
C
Corticosteroids
Budesonide
C
C
Azathioprine/6MP
D
Methotrexate
X
Anti-TNF
B
Odd ratio
(fixed
effect)
Confidence
interval
P-value
Status of
heterogeneity
(homogenous
Congenital
abnormalities
1.16
0.76–1.77
0.5734
P = 0.9697
Stillbirth
2.38
0.65–8.72
0.3231
P = 0.9594
Spontaneous
abortion
1.14
0.65–2.01
0.7384
P = 0.2151
Preterm delivery
1.35
0.85–2.13
0.2621
P = 0.0768
Low birth weight
0.93
0.46–1.85
0.9636
P = 0.7057
Type of pregnancy
outcome
Rahimi R et al Reproductive Toxicology 25 (2008) 271–275
DBP
ASACOL
400 mg
ASACOL
HD
800 mg
DELZICOL
400mg
Pentasa
Apriso
Lialda
YES
YES
NO
NO
NO
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: 198-203
• 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 preeclampsia)
• 60% had anemia at birth: Median Hb 9.25 [9.259.60].
• 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)
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Three studies on breastfeeding:
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Sau: 31 samples/10 women (AZA 75-150
mg)
 1 patient had low levels in breast milk
 6mp and 6tgn undetectable in neonatal blood
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Gardiner: 4 women aza 1.2-2.1 mg/kg/d
 6TGN and 6MMPn not found in infant
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Moretti: 4 women aza
 Levels of 6mp undetectable by HPLC
Sau: BJOG 2007; Moretti: Ann Pharmacol 2006:40:2269-72; Gardiner: Br J Clin Pharmacol 62:4 (453-6)
References
Medication
N
Congenital Anomalies
Katz 2004
Infliximab
96
1 Tetralogy Fallot; 1 intes Malrotation
Lichtenstein 2006
Infliximab
117
1 VSD, 1 anencephaly
Mahadevan 2005
Infliximab
10
None
Schnitzler 2007, 2011
IFX/ADA
35/7
--/1 trisomy 8
Zelinkova 2011
Infliximab
4
1 polydactyly
Verstappen 2011
Infliximab
Etanercept
Adalimumab
9
48
14
All: 1 pyloric stenosis, 1 congen hip
dysplasia, 1 trisomy 21, 1 megacolon
Roux 2007
Adalimumab
1
1 VSD, 1 hemangioma
Weberschoendorfer/Hultz 2011
IFX/ADA
25/28
1 renal agenesis/ 1 WPW, 1
neurofibromatosis
Casanova 2012
Infliximab
Adalimumab
Certozlizumab
49
16
1
-1 Cardiac malformations
--
Seirafi (Getaid) 2012
Infliximab
Adalimuamb
Certolizumab
89
42
5
1 missing finger
Johnson 2013 (OTIS)
ADA/CZP
589/18
No Pattern seen
Cimiza Database
Certolizumab
152
Adapted from Chambers Birth Defects Research 2012
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INF and ADA are IgG1 antibodies
Fc portion of IgG actively transported across placenta by specific neonatal
FcR
Highly efficient transfer in 3rd T leads to elevated levels of drug in newborn
20
B: Fetal
r2=0.87, p<0.04
15
IgG (g/L)

10
5
0
0
10
20
30
40
50
Gestational age (weeks)
Wiley-Blackwell Publishing Ltd. Malek A, Evolution of maternofetal transport of immunoglobulins
During human pregnancy. Am J Reprod Immunol 1996; 36(5):248-55.
Image Courtesy of Sundana Kane MD
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Infliximab:
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Adalimumab
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Study of 10 mothers on IFX
In all cases, infant and cord IFX level were greater than
mother. 6 months to clear
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
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
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. 2013 Mar
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Infliximab
 Breastmilk 1/200th 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 1/200th 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 2010 3. Friitzsche J Clin Gastro 2012
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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 36-38
 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. 2011 Feb;106(2):214-23
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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
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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


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