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Fertility and Pregnancy
Uma MahadevanMahadevan-Velayos MD
Associate Professor of Medicine
UCSF Center for Colitis and Crohn’s
Disease
Fertility
n
With both UC and CD, the risk of fertility
prior to surgery appears to be similar to the
general population
– Infertility in NE Scotland population based study
n
n
15% UC (n= 138) vs. 14% general population
14% CD (n= 177) vs., 14% general population
– Surgical therapy:20% Medical therapy: 8%
n
Olsen: 290 women with UC with IPAA
– After diagnosis of UC: FR = 1.01
– After surgery IPAA: FR*= 0 .20
Olsen KØ, et al. Gastroenterology. 2002;122:15-19
Hudson, Int J Gynaecol Obstet 1997;58:229-37.
1
IPAA: Cumulative Incidence of
Pregnancy Within 5 Years
1.0
Cumulative Incidence
of Pregnancy
0.8
Before diagnosis
Reference
Before surgery
After surgery
0.6
0.4
0.2
0.0
0
12
24
36
60
48
Time to Pregnancy (months)
Reprinted from Olsen KØ, et al. Gastroenterology. 2002;122:15-19 with permission from American
Gastroenterological Association.
Pregnancy Outcomes:
Population Based Studies
Preterm Birth
LBW
IBD
UC
CD
X
X
X
XX
XX
SGA
X
Congenital
Malformation
Caesarean Section
1.
2.
3.
4.
X
X
Kornfeld: Am J Obstet Gynecol 1997 (n=756 IBD)
Fonager: Am J Gastroenterol 1998 (n=510 CD)
Norgard:Am J Gastroenterol 2000 (n=1531 UC)
Dominitz: Am J Gastroenterol 2002 (n=107 UC, 155 CD)
2
Pregnancy Outcomes
n
n
n
n
Retrospective cohort study of all pregnant women
in Northern California Kaiser Permanente: 199519952002
All pregnancies in women with IBD (n=461) were
frequency--matched for age and hospital to women
frequency
without IBD (n=493) and were assessed for
differences in conception and pregnancy outcomes,
pregnancy complications and newborn outcomes
CD (n=154), UC (n=300), and indeterminate colitis
(n=7)
Medication exposure during conception or
pregnancy included aminosalicylates (51%),
corticosteroids (21%), immunosuppressants (4%)
Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112.
Results
Adverse
Outcomes
Conception
OR*
95% CI
1.65
1.09--2.48
1.09
Pregnancy
Outcomes
Pregnancy
Complications
1.54
1.00--2.38
1.00
1.78
1.13--2.81
1.13
Newborn
Outcomes
1.89
0.98--3.69
0.98
*Controlled for maternal age, current ETOH, current tobacco,
Caucasian ethnicity, number of prenatal visits (except conception)
3
Disease activity during
pregnancy in women with IBD
Percentage of patients
n
Exposure: IBD disease activity during conception, each trimester
and the postpartum period (1 month)
– Inactive, mild, moderate, severe
100
80
60
40
20
0
100
Disease activity in Crohn’s disease
Inactive
Mild
Disease activity in ulcerative colitis
Moderate
80
60
40
20
0
Severe
Concept
T1
T2
T3
PP
Trimester
Mahadevan U, et al. Gastroenterol. 2007;133:1106-1112
MEDICAL THERAPY
4
Pregnancy Category
n
n
n
Category A: Controlled studies show no risk
Category B: No evidence of risk in humans
Category C:
– Animal reproduction studies show adverse effect
– No adequate studies in humans
– Drug’s benefits in pregnant women may be
acceptable despite its potential risk
n
n
Category D
D:: Positive Evidence of Risk
Category X:
X: Contraindicated in Pregnancy
Fish Oil
n
Essential Fatty acids (EFA) and
Docosahexaenoic acid (DHA)
– Potential antithrombotic effect
– Prolong gestation
– No evidence of prevention of proteinuric
pregnancy
n
Mild benefit in Crohn’s disease
Belluzzi N Engl J Med. 1996 Jun 13;334(24):1557-60
5
Aminosalicylates (B,C)
n
Meta--analysis 7 studies: 642 5ASA, 1158 no med
Meta
–
–
–
–
–
n
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
n
n
n
Placental and Breast Transfer Occurs
n
n
n
Folic acid: neural tube defects, CV, GU, cleft palate
Case reports of congenital malformation
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
Corticosteroids (C)
n
Case--control study in 1st T
Case
– Increased risk of oral clefts
– Overall risk of malformations low
– In transplant setting:
n
n
n
n
Adrenal suppression in newborn
Premature rupture of membranes
Compatible with breast feeding
Budesonide
– Orally inhaled budesonide not associated with
increase risk of fetal abnormalities
– 8 CD patients treated with oral budesonide
6
Antibiotics
n
Metronidazole (B) /Ciprofloxacin (C)
– Low risk of teratogenicity
n
Metronidazole: prospective controlled study, 2 metameta-analysis
– However, 2nd, 3rd T use, 1st T cleft lip, palate
n
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 useuse-avoid
n
Rifaximin: Pregnancy C
– teratogenicity in animal studies
– Safety in humans in pregnancy/breastfeeding unknown
6MP/AZA (D)
n
Teratogenic in animals (mice, rabbits, rats)
– Given IV/IP at supratherapeutic doses. (low oral
bioavailability: 47% AZA, 16% 6MP)
– Increased cleft palate, ocular, skeletal,urogenital
anomalies, hydrocephalus
– Poor oral bioavailability may produce levels too
low to have substantial teratogenic effect
n
Fetal liver in early pregnancy lacks inosinate
pyrophosphorylase to convert AZA to active
metabolites
–Polifka and Friedman (Teratology 65:240-261. 2002)
7
Danish Cohort Study
Danish cohort study of 900
children born to CD women
(1996--2004)based on the
(1996
National Registry of
Patients, the Birth Registry,
and nationwide prescription
database.
n
– Pregnancies were classified
according to receipt of
prescriptions for CD
medication: no drugs
(reference group), 55ASA/sulfasalazine, steroids,
and azathioprine (AZA)/6(AZA)/6mercaptopurine (6(6-MP).
– Proxy measure for disease
activity.
Control
PTB
(6.5%)
AZA
Steroid
25%
12.3%
RR =4.2 RR = 1.4
[1.4,12.5] [0.6,3.3]
15.4%
CA
(5.7%) RR = 2.9
(0.9, 8.9)
Norgard AJG 2007 July 102 (7)
Azathioprine and
Teratogenicity
n
n
189 pregnant women on AZA who contacted one of
seven teratogen information services were compared
to a cohort of 230 pregnant women who took nonnonteratogenic 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).
n
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]
n
The AZA group had more prematurity
– 21.4% vs. 5.2% [p < .001]
n
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
8
Azathioprine/6MP
n
Swedish Medical Birth Register
– 476 women used AZA in early pregnancy
– Most common indication was IBD (>300)
– Rate of CA 6.2% AZA vs. 4.7% other
n
OR 1.41, 95% CI: 0.98-2.04
– Increased rate of VSD/ASD
n
OR 3.18, 95% CI: 1.45-6.04
– Increased rate of preterm, LBW, SGA
n
Likely disease effect
Cleary. Birth Defects Research 85:647-654, 2009
Breastfeeding on
AZA/6MP
n
8 lactating women received Aza 7575-200 QD
– Milk and plasma at 30, 60 min and every hour x
5
n
n
n
Variation in bioavailability reflected in wide
range in milk an plasma first 3 hours
Major excretion in breast milk within 4 hours
of drug intake
Worst case scenario: max concentration
0.0075 mg/kg. In most cases, will be
<10% of maximum concentration
Christensen APT 2008:28, 1209-1213
9
Cyclosporine/ Tacrolimus
(C)
n
Cyclosporine
– MetaMeta-analysis of 15 studies (14 pts) OR malformations
3.83 (0.75(0.75-19.6)
– 8 pts: IV steroids 7 d then Csa. 7/8 effective, no
colectomy. 7 term pregnancies, 2 PTB, 1 in utero death
due to mother with absence of S protein. [Branche 2009
IBD J]
– In fulminant colitis, better than emergent colectomy
– Breast feeding not advised: Csa secreted in breast milk
n
Tacrolimus
–
–
–
–
Benefit over CSA, lower hypertension, hyperlipidemia
Higher incidence of diabetes in newborn, prematurity
5.6% malformation rate in newborns, no specific pattern
IBD: 31F, remission on tacrolimus, continued drug
throughout pregnancy. Healthy infant. [Baumgart Gut 2005]
– Breastfeeding not recommended
Use with Caution
n
n
n
Diphenoxylate (C): Teratogenic in animals
Loperamide (B): Ý CV defects in one study
Bisphosphonates (C): Half life 10 years
– animal studies: alendronate crosses placenta
causes anatomic changes in fetal bone
– 24 pregnancies, no increased teratogenic risk1
n
Methotrexate (X)
– Known abortifacient
– Teratogenic (skeletal defects, cleft palate)
n
Thalidomide (X)
– Birth defects
1. Ornoy. Reproductive Toxicology 22 (2006:578)
10
BIOLOGICS
Three Molecules of AntiAnti-TNF
Infliximab
Adalimumab
Fab′
Certolizumab
pegol
Fab
PEG
IgG1
Fc
Chimeric
Human
Monoclonal
antibody
PEGylated
humanized
Fab′ fragment
2 × 20 kDa
PEG
Adapted from: Hanauer SB. Rev Gastroenterol Disord. 2004;4(Suppl. 3):S18-S24.
11
Transfer Across Placenta
n
n
Fetal immunity is acquired by transfer of Ab
as IgG from maternal to fetal circulation
IgG is actively transported across the
placenta
– Smooth linear rise in fetal IgG as early as 13
weeks (earliest examined), after 32 weeks,
significant increase in ratio
n
Preferential transport:
– IgG1>IgG4>IgG3>IgG2
n
Certolizumab is a Fab’ fragment
– Likely passive diffusion
Kane AJG Jan 2009;104:228-233
Placental Transfer of IgG Ab
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
n
n
n
20
B: Fetal
r2=0.87, p<0.04
IgG (g/L)
15
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
12
Infliximab (B) Safety Database
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
17 16
20
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.
Infliximab in Pregnancy
10 Crohn’s disease patients
intentionally exposed to
infliximab during pregnancy
8 women received
maintenance infusions
2 women received
initial infusions
10 Live Births
Congenital
malformations
(N=0)
IUGR
(N=0)
SGA
(N=0)
Preterm
(N=3)
LBW
(N=1)
8 Caesarean sections: 2 active luminal, 3 perianal disease, 1 preterm
Mahadevan U, et al. Aliment Pharmacol Ther. 2005;21:733-738.
13
Infliximab Levels in Infants
Born to Women with IBD
n
n
Eight women completed pregnancy.
Six had Crohn's disease and 2 had UC
– 2 were on concomitant azathioprine
– Mean maternal age was 36 years (range 3030-40)
– Pts were on 5 mg/kg of infliximab
n
n
Mean infusion interval: 8 wks (4(4-12)
Mean time b/w birth and last INF infusion:
– 66 days (2(2-120)
n
All patients were in remission at birth.
– 3 flared within 5 months postpost-partum
Mahadevan, DDW 2007
Pt #
*
Breastfed
Infliximab in Cord Blood
1
2
3*
4*
5*
6
7*
Last Dose
30
3
14 90 120 55
46
(days)
Mother
INF
15.1 1.4 19.2 3.8 4.8 14.5 16.5
(mcg/ml)
Cord
Blood
--
2.0 26.5 3.3 8.8 20.5 26.5
Newborn 25.3 2.9
23.6 4.2
W:2*
INF
undetected
6
2
7
2
8*
9
10
35
70
74
2.2
4.1 5.1
8.4
13. 20.
6
4
8.4
8.7 28.2 27.5 10.6 4.7
2m*
1m*
3
5
5
4
>3
4
14
Response to Vaccines
n
Nine infants participated in the study
Mean Age of mother
Diagnosis
32 years (22(22-38)
8 Crohn’s disease
1 Ulcerative colitis
Disease Duration
6.6 years (1(1-17)
Biologic Therapy
8 Infliximab
1 Adalimumab
Concomitant
Medications
8 T1
9 T2T2-T3
4 Aza/6MP
3 Steroids/Budesonide
Mean Age of infant
12.8 mos (7(7-28)
Trimesters (T)
Biologic Used
Results
Mean
Levels
Range
(normal
range)
# Response
IgG (mg/dl)
416
297--510
297
(217--904)
(217
0
IgA (mg/dl)
26
12--46
12
(11--90)
(11
0
IgM (mg/dl)
46
17--129
17
(34--126)
(34
4/7*
HiB (mcg/ml)
1.09
0.36--9
0.36
( > 1.0 )
1/9*
Tetanus
Toxoid
4.91
0.33--3.2
0.33
( > 0.15 )
0
Inadequate
(IU/ml)
*Only 7/9 patients had Ig levels assessed
15
Adalimumab (B)
n
OTIS (Organization for Teratology
Information Specialists) reports 27 women
enrolled in a prospective study of
adalimumab in pregnancy and an additional
47 adalimumab exposed pregnant women in
a registry
– The rate of spontaneous abortion and stillbirth
was similar to the diseased comparison and the
general population. The rates of congenital
malformation and preterm delivery are also within
the expected range.
Chambers CD The OTIS Autoimmune Diseases in Pregnancy Project. Personal
communication. July 13, 2007 .
n
Certolizumab: data on file
– 16 pregnancies:
n
4 healthy infants, 8 IAB, 1 SAB, 1 preterm, 2 unknown
– Reduced placental transfer
n
Natalizumab (C):
– IgG4, placental transfer in third trimester
– 143 pregnant patients exposed to tysabri
– No birth defects reported
Mahadevan ACG 2008
16
Certolizumab Placental
Transfer
Interval:
Maternal
Last dose to Level DOB
delivery
(µg/ml)
(weeks)
Cord Blood
Level DOB
(µg/ml)
Newborn
level DOB
(µg/ml)
Pt 1
2
18.83
1.65
--
Pt 2
<1
59.57
0.94
1.02
Pt 3
4
4.87
1.19
1.22
Pt 4
2
20.13
0.57
0.44
LOQ 0.41 µg/ml
Infant #2
n
n
The mother received CTZ every 4 weeks postpartum
At one month of age, plasma levels were:
– Mother 22.93 µg/ml
– Infant 0.84 µg/ml
n
Breast milk was collected at the following time points:
– CZP last dose given 1 week prior to delivery
n
n
1 week post delivery
2 weeks post delivery
– First postpost-partum injection of CZP
n
n
n
n
4 hours post injection
3 days post injection
6 days post injection
All samples were below the limit of quantification for the
assay (<0.41µ
(<0.41µg/ml)
17
FDA Database: AntiAnti-TNF’s
n
61 reported CA’s/ 41 offspring (12/2005):
–
–
–
–
22 etanercept, 19 INF
15 (37%) > 1 CA
Most common is cardiac defect
1 VACTERL (ETN) Separate VACTERL in ADA
n
n
n
24/41 (59%) had some component of VACTERL (11
INF)
24/41 cases (59%) mother on no other meds
Vertebral, anal atresia, cardiac defect (VSD),
tracheosphageal fistula with esoph atresia, renal, limb
abnormality (radial dysplasia)
– Associated with DM: Inhibition of cholesterolcholesteroldependent sonicsonic-hedgehog morphogenetic
pathway
Carter J J Rheumaol 2009;36:3
PIANO
Pregnancy in Inflammatory Bowel
Disease And Neonatal Outcomes:
A National Prospective Registry
Uma MahadevanMahadevan-Velayos, Christopher Martin,
Robert Sandler, Sunanda Kane, Marla
Dubinsky, James Lewis, Sylvia DegliDegli-Espositi,
William Sandborn, Bruce Sands
& CCFA Clinical Alliance
18
AIM
n
Population based studies, single referral center
studies, and case series are limited by small
numbers of patients on drugs of interest and
limitations in data collection
n
AIM: Determine whether the rates of adverse
AIM:
events in a prospective national sample of women
from the US with IBD exposed to azathioprine/6MP
or antianti-TNF therapy are greater than the rate of
adverse events among IBDIBD-affected women not
exposed to these medications
– Adverse events: congenital malformations, spontaneous
abortion, preterm birth and low birth weight infants
n
Patients were divided into 3 groups:
– Group 1: no immunomodulators/biologics
n
(mesalamine, steroids, antibiotics allowed)
– Group 2: AZA/6MP
+/- Group 1 medications
+/n 2b: MTX, CSA, Tacrolimus
n
– Group 3: INF, ADA, CZP
+/- Group 1,2 medications
+/n 3b: Natalizumab
n
19
RESULTS
n
404 enrolled eligible women (5/29/2009)
n
237 pregnancies ended
– Group 1: n = 106
n
12 no medications
– Group 2: n = 56
n
1 CSA
– Group 3: n = 75
n
n
n
n
45 INF (1 MTX + INF)
18 ADA
2 INF + ADA
3 CZP + ADA
Results
n
No increase in rate of:
– Any complication
– Spontaneous abortion
– Preterm Birth
– Low Birth Weight
– IUGR
– Cesarean Section
– NICU
20
Summary
n
n
Yes: 5ASA, Steroids, 6MP/AZA
Yes: Infliximab
Infliximab,, adalimumab
adalimumab,, certolizumab
– Consider stopping dose 10 weeks (INF) or 44-6
weeks (ADA) prior to EDC
– Certolizumab can be maintained throughout
pregnancy
n
n
No: MTX, Thalidomide, Diphenoxylate
Recommendations:
– Control disease prior to conception
– Continue most medications
– High Risk Obstetrician
21