Prospective follow up of the natural history of Inflammatory Bowel Disease during pregnancy

Crohn*s disease and ulcerative colitis, collectively referred to as
inflammatory bowel disease (IBD), are chronic, relapsing diseases. The exact
etiology remains unknown, however, it is currently believed to be a complex
interaction between genetic susceptibility, gut microbiota, the host immune
response and environmental factors(1). IBD typically arises at a young, fertile
age, as 50% of patients will be younger than 35 years old when the diagnosis is
established(2). Therefore, reproductive issues are of important concern for
both the IBD patients and their treating physicians. Preconception counseling
in these patients remains challenging, as many complex questions can only be
answered with limited, mainly retrospective and sometimes conflicting data. In
addition, most of the (registry based) cohorts are outdated(3-10), not
including the most recent therapies for IBD like anti-TNF, which have become a
mainstay in IBD treatment over the last decade(11). Obviously, the need for an
up-to-date, properly conducted, prospective cohort is long overdue. We
therefore propose to conduct a prospective cohort study in IBD females with a
pregnancy wish and pregnant IBD females, to gather data on IBD characteristics
during pregnancy and the effect of pregnancy on IBD. Furthermore, as a recent
study has shown pregnancy to influence gut microbiota in non IBD patients(12),
we also propose to investigate whether the gut microbiome in IBD patients
changes during pregnancy and whether these changes have any clinical
implications. Studies have described an altered bacterial diversity in the gut
of women with IBD as compared to healthy controls.(13, 14) Infants born to
mothers with IBD have shown to have lower diversity and altered gut microbiome
at least until age 3 months. (13) This might be important since prenatal and
early life microbiome is thought to influence the development of the immune
system.(13) Whether this altered gut microbiome remains in women after
pregnancy and in infants beyond age 3 months is unclear. We will perform follow
up on the gut microbiome of women who previously in the study participated and
their children beyond 3 months of age.

- to analyze the changes in the gut microbiome of IBD patients during pregnancy
and try to find an association with disease activity
- to analyze whether changes in the gut microbiome remain after post partum
period of 3 months
-to analyze gut microbiome of children born to mothers with IBD and to analyze
whether lower diversity remains beyond age 3 months

A cohort study will be performed at the Erasmus Medical Center, Rotterdam, the
Netherlands. Since 2008, as part of standard clinical care this tertiary
referral center has set up a specialized preconception outpatient clinic (POC)
for IBD patients (both male and female). This study will focus on the women
exclusively.
All women between 18 and 43 years of age, with a confirmed diagnosis of IBD
(CD, UC or IBD unclassified (IBDU) who visited this special outpatient clinic
from January 2008 to July 2013 will be included for the retrospective part of
this study, and from the approval of this protocol until 2018 (approximately 5
years) eligible IBD females visiting the POC will be included for prospective
follow up.
At the POC, IBD women receive counseling on fertility, heredity of IBD,
pregnancy, IBD medication use during pregnancy, mode of delivery, lactation and
other life style factors. The POC is meant as an addition to routine
obstetric-gynecologic visits and has been part of standard clinical care since
2008. After a first preconception visit, the women will be prospectively
followed every three months. If a pregnancy occurs, she will return to this
clinic every two months during the entire pregnancy. Follow up ends three
months after delivery.
Since 2008, all data from the pre-conception outpatient clinic has been
collected. For the retrospective part of this study, we propose to conduct a
chart review and questionnaire-based study in all patients who have visited the
pre-conception outpatient clinic, to gather information on patient
characteristics, life style factors, medication use, disease course during
pregnancy and pregnancy outcomes.
For the prospective part of this study, all eligible women will be asked to
sign an informed consent to be followed up during pregnancy every two months
and to donate fecal and blood samples before pregnancy, at each trimester
during pregnancy and 3 months after delivery. Clinical disease activity scores
(Harvey Bradshaw Index (HBI) for CD and Simplified Clinical Colitis Activity
Index (SCCAI) for UC) will be obtained every two months during pregnancy and
every three months before pregnancy and three months after delivery.
For the follow up part of the study, concerning the gut microbiome, women who
previously visited the POC and participated in the original cohort study will
be contacted and asked to donate a fecal sample of themselves and their
children and fill out a questionnaire concerning the diet, medication and
lifestyle of themselves and their child.

Participants will experience no direct benefit from participating in this study.
The burden associated with participation is the donation of fecal samples (4 x
combined with routine visits), donating extra vials of blood (4x 20 ml with
routine bloodwork) and filling out a food and lifestyle questionnaire (2 x 15
minutes).
Extra blood will be collected at routine blood control visits during pregnancy
(each trimester). No adverse events from drawing extra blood (20 ml) is to be
expected.
For the follow up part of the study women will be asked to donate a fecal
sample of themselves and their child once and to fill out a food and lifestyle
questionnaire for themselves and their child (2 x 15 minutes). A control group
of healthy women with healthy children at the same age will be asked to donate
a faecal sample of themselves and their child and fill out the same
questionnaire as the IBD women. No extra blood will have to be drawn for the
follow up part of the study.