Key words
chronic inflammatory bowel disease - Crohnʼs disease - ulcerative colitis - pregnancy
Forms of Chronic Inflammatory Bowel Disease
Forms of Chronic Inflammatory Bowel Disease
AGG Statement
The two most important forms of chronic inflammatory bowel diseases in pregnancy are
Crohnʼs disease and ulcerative colitis.
Chronic inflammatory bowel disease (chronic IBD) is the term used to describe immune-mediated
chronic inflammation of the bowel. The two most important forms of chronic IBD are
Crohnʼs disease and ulcerative colitis.
Crohnʼs disease is typically a non-continuous inflammation extending from the terminal
ileum to a segmental colitis, which often spares the rectum. Many patients do develop
perianal changes with fistula formation. Affected persons suffer from abdominal pain;
abdominal resistance develops and stenosis of the small intestine is common. The incidence
of disease is approximately 6.6/100 000; the mean age at onset of disease is 33 years.
The definitive diagnosis is obtained using sonographic imaging and an ileocolonoscopy
to provide evidence of discontinuous inflammation together with histological confirmation
of granulomas [1].
Ulcerative colitis typically is a continuous inflammation emanating from the rectum.
Affected persons may pass blood or mucus in their stools, although pain only occurs
intermittently. Stenosis or fistula formation does not occur. The incidence is approximately
3 – 3.9/100 000. The highest age-specific incidence occurs between the ages of 16
and 25 years. The diagnosis of ulcerative colitis is based on the patientʼs history,
ultrasound examinations, and endoscopic findings [2].
There are some transitional forms between the two types of chronic IBD. The following
recommendations were agreed by the AGG. The recommendations are based on a search
of the literature, and they aim to provide assistance to treating physicians during
preconception counseling and when caring for affected patients.
Methods
A literature search of the PubMed database for the period from 1995 to January 2021
was carried out, using the search terms “chronic inflammatory bowel disease and pregnancy”.
Randomized clinical studies on this issue are lacking. Almost 200 publications were
found during the literature search. The articles considered to be most relevant for
the care of pregnant patients with chronic IBD were reviewed. They were taken as the
basis for recommendations on the treatment of women with chronic inflammatory bowel
disease in pregnancy, and voted on by the “Maternal Diseases” section of the Obstetrics
and Prenatal Medicine Working Group of the DGGG (AGG).
Preconception Counseling
AGG Recommendation
Women with chronic inflammatory bowel disease should be offered preconception counseling.
AGG Recommendation
Clinical remission of disease should be aimed for prior to conception, as disease
activity at the time of conception is correlated with an increased risk of premature
birth and placental insufficiency.
AGG Recommendation
With the exception of methotrexate, medication to maintain remission or deal with
a flare-up should, where indicated, be continued even if the woman wishes to have
a child.
The fertility of women with Crohnʼs disease is not or only slightly lower [3]. Reduced fertility has only been reported for patients with active ulcerative colitis
or who have undergone placement of an ileoanal pouch (IAP) [4]. Nevertheless, the percentage of affected persons who have children is lower than
in the overall population. This voluntary childlessness has been reported for both
women and men with chronic IBD [4]. Reported causes include fear of heritability, the risk of fetal malformations,
and worries about the teratogenicity of the medication [5].
Although women with chronic IBD often receive long-term medical care, there appears
to be a lot of uncertainty around family planning. These women are in urgent need
of counseling and would particularly benefit from preconception counseling [6].
Discussions during counseling should include the discussion on how chronic IBD can
affect the course of pregnancy and the impact pregnancy may have on chronic IBD.
Stable disease with the disease in remission does not affect the course of pregnancy,
and pregnancy has no negative impact on disease activity. A European cohort study
showed that the flare-up rate among women who were stable prior to conception is comparable
with the rate reported for non-pregnant women. However, if conception occurs during
an active disease phase, then ⅔ of women had increased flare-ups during the subsequent
course of pregnancy and an higher risk of worsening disease after pregnancy [7].
Active disease during conception was also found to be correlated with an increased
risk of miscarriage, premature birth, and a higher incidence of growth-restricted
fetuses [8], [9].
A recent meta-analysis [10] showed a 2.42 times higher risk of premature birth (95% CI: 1.81 – 8.02), a 1.48
times higher risk of SGA (95% CI: 1.19 – 1.85), a 1.87 times higher risk of miscarriage
(95% CI: 1.17 – 3.0), and a 2.27 times higher risk of intrauterine fetal death (95%
CI: 1.03 – 5.04) in women who had active disease at the time of conception compared
to women with inactive disease at conception.
The majority of women with chronic IBD take long-term medication which needs to be
reviewed before becoming pregnant.
According to the recommendations of the European Crohnʼs and Colitis Organisation
(ECCO) and the AWMF guideline on Crohnʼs disease [1], [11], women can continue to take their usual medication with the exception of methotrexate.
According to information from Embryotox, 5-ASA drugs, particularly mesalazine and
sulfasalazine, have been investigated in detail and are considered to be generally
very well tolerated. Glucocorticoids are permissible at all stages of pregnancy. Possible
effects on the fetus depend on the glucocorticoid, the dosage, the duration of treatment,
and the period of pregnancy. As local applications such as budenoside are not absorbed
very well, they are considered harmless. If treatment consists of systemic application
of a drug, it is important to bear in mind that fluorinated corticosteroids such as
dexamethasone and betamethasone cross the placental barrier, while non-fluorinated
preparations such as prednisone and prednisolone are largely enzymatically inactivated
in the placenta. Systemic long-term medication with corticoids should be avoided where
possible. In the rare cases requiring higher dose treatment over many weeks, fetal
growth should be monitored by ultrasound. If
treatment is continued up until the birth, it is important to be aware of the
possibility of adrenal insufficiency in the neonate and to treat the infant accordingly.
The mother may also develop relative adrenal insufficiency when giving birth, and
steroid treatment should be adjusted peripartum if necessary. When planning the birth,
it is important to already consider how to adjust the steroid dosages in stress situations
for any pregnant woman receiving long-term steroid therapy and to set up a substitution
plan.
Azathioprine, followed by cyclosporine, is the most studied immunomodulator. TNF-α
inhibitors are also acceptable if their use is imperative. However, the administration
of TNF-α inhibitors in the second half of pregnancy should be limited to selected
cases and must be justified. The antibiotic drugs metronidazole and ciprofloxacin
can be used in pregnancy [12].
[Table 1] lists the most common drugs used to treat chronic IBD and their safety levels in
pregnancy (modified from [13]).
Table 1 Overview of the most common medications used to treat chronic IBD and their safety
during pregnancy.
|
Safe
|
Probably safe
|
Contraindicated
|
|
Oral 5-aminosalicylates
|
Infliximab
|
Methotrexate
|
|
Topical 5-aminosalicylates
|
Adalimumab
|
Thalidomide
|
|
Sulfasalazine/mesalazine
|
Certolizumab
|
6-Thioguanine (no data)
|
|
Azathioprine
|
Cyclosporine
|
|
|
6-Mercaptopurine
|
Tacrolimus
|
|
|
|
Budenoside
|
|
|
|
Metronidazole
|
|
|
|
Ciprofloxacin
|
|
Data on the monoclonal IgG1 antibodies vedolizumab and ustekinumab in pregnancy is
limited. Both drugs should therefore only be used during pregnancy after carefully
weighing up the benefits and disadvantages in each individual case and after other
treatment options have failed [12], [14].
Care During Pregnancy
AGG Recommendation
Pregnant women with chronic inflammatory bowel disease should be cared for by a gastroenterologist
who is supported an interdisciplinary team.
AGG Recommendation
With the exception of methotrexate, treatment to maintain disease remission should
not be discontinued in pregnancy.
AGG Recommendation
The diagnostic work-up should consist of carefully differentiated, sonography-based
detailed examinations in accordance with DEGUM II criteria.
AGG Recommendation
Regular sonographic controls should be carried out (at least every 4 weeks) to confirm
fetal growth.
AGG Recommendation
Flare-ups of chronic inflammatory bowel disease in pregnancy must be treated.
AGG Recommendation
From week 40 + 0 of gestation, the pregnant woman should be informed about the option
of inducing labor.
The overall data on pregnancy risks is inconsistent. Some studies have reported a
higher risk of premature birth in women with chronic IBD, particularly women who had
active disease during pregnancy [15], [16]. In a meta-analysis carried out in 2007, the risk of premature birth for women with
chronic IBD was 1.87 times higher (95% CI: 1.52 – 2.31, p < 0.001) [16]. A more recent meta-analysis came to a similar conclusion, reporting a 1.85 times
higher risk of premature birth [18]. As the causes of premature birth (e.g., preterm labor, premature rupture of membranes
or iatrogenic cause due to fetal growth restriction) were not differentiated in the
studies, is it not possible to make any generalized statements on the etiology of
these premature births.
The meta-analysis by OʼToole et al. found a 1.36 times higher risk of SGA (small for
gestational age) fetuses (95% CI: 1.16 – 1.60), while the meta-analysis by Cornish
even reported a 2 times higher risk of giving birth to an infant with a birth weight
of < 2500 g. The analysis did not differentiate between fetal growth restriction (e.g.,
due to placental insufficiency) and constitutionally small fetuses with no pathological
causes. The reason for the increased rate of smaller infants can therefore not be
conclusively determined. In addition to the risk of placental insufficiency, the effects
of anti-inflammatory drugs and the parentʼs constitution must also be weighed up.
The above-mentioned meta-analyses found an increased risk of malformations. The risk
was calculated to be 1.3 and 2.3 times higher, although no serious malformations were
reported. The meta-analysis by Cornish et al. only reported an increased risk of malformations
for patients with ulcerative colitis. No increased risk was found for patients with
Crohnʼs disease. The risk of intrauterine fetal death was marginally higher by a factor
of 1.57 in the meta-analysis by Cornish et al.; this was not confirmed in the meta-analysis
by OʼToole. However, both meta-analyses almost exclusively used only retrospective
case series, meaning that the results must be interpreted with caution.
A prospective European study of 332 pregnant women with chronic IBD investigated the
course of pregnancy in patients with chronic IBD compared to a matched control group
[19]. According to this study, there was no difference in the rates of live births, miscarriages,
intrauterine fetal deaths, premature births, SGA fetuses, and cesarean sections. A
maternal age of > 35 and smoking were risk factors for premature birth and associated
with a higher rate of fetal malformations.
Patients should also be monitored for the development of gestational diabetes, as
the incidence of gestational diabetes is higher in women with chronic IBD [20].
In summary, it is not possible to make a reliable statement about the course of pregnancy
in women with chronic IBD, which is why any flare-ups in pregnancy must be treated.
Pregnancies of women with chronic IBD are considered high-risk pregnancies. These
women should be monitored by an interdisciplinary team who can advise the treating
gastroenterologist. Organ screening in accordance with DEGUM II criteria should be
carried out in every case, and particular attention should be paid over the course
of the pregnancy to the possible development of fetal growth restriction. As the data
on the risk of intrauterine fetal death is not clear, the pregnant woman should be
informed about the option of having her labor induced at her calculated due date.
Mode of Delivery
AGG Recommendation
Pregnant women with ulcerative colitis and an ileoanal pouch should be advised to
have a cesarean section.
AGG Recommendation
Pregnant women with active perianal Crohnʼs disease should be advised to have a cesarean
section.
AGG Recommendation
Prophylactic episiotomy should not be carried out.
A recent retrospective study of 124 patients with chronic IBD found increased cesarean
section rates, with 63.1% of women with ulcerative colitis and 40.7% of women with
Crohnʼs disease having a cesarean section [21]. The highest cesarean section rates for women with Crohnʼs disease were found in
women with active or inactive perianal disease. In the group of women with ulcerative
colitis, the highest cesarean section rate was found in the group of women with an
ileoanal pouch (IAP). The cesarean section rate in the meta-analysis by Cornish was
1.5 times higher for women with chronic IBD compared to the control group [17]. The differentiated analysis showed that the cesarean section rate was only significantly
increased in the group of women with Crohnʼs disease, while the increase in women
with ulcerative colitis was not significant. However, in the prospective study by
Bortoli et al., the cesarean section
rate was not higher in women with chronic IBD [19].
As large prospective studies are lacking, the question inevitably arises about the
criteria that should be used by the physician when considering the planned mode of
delivery and discussing it with the expectant mother. In addition to the wishes of
the mother, who typically will have a long history of disease, a number of different
aspects need to be considered when determining the mode of delivery. Considerations
which must be incorporated in the decision in every case include the type of disease,
the disease activity, any prior abdominal surgery and the patientʼs obstetric history.
Typically, patients are very worried about potential perianal injuries, wound healing
disorders, fistula formation, pelvic floor injuries and possible subsequent incontinence
[22].
The ECCO [18] recommends vaginal delivery in women with inactive or mild forms of disease and
cesarean section for women with active perianal or rectal disease. In a systematic
review, Foulon et al. were able to show that the overall cesarean section rate was
higher for women with chronic IBD [24]. One of the reasons for this could be the fear of developing perianal disease and
possibly incontinence after vaginal delivery.
However, it appears that worries about developing perianal manifestation of disease
after vaginal delivery could be unfounded [24]. Even an episiotomy, vaginal-surgical delivery and birth injuries did not lead to
a higher incidence of perianal manifestation in this group of patients. More episiotomies
were carried out to prevent 3rd or 4th degree perineal tears. However, the benefit
of carrying out a prophylactic episiotomy to avoid 3rd or 4th degree perineal tears
is extremely dubious and prophylactic episiotomies should not be carried out [24]. As expected, the rate of cesarean sections in women with perianal manifestation
of disease prepartum was significantly higher. In the group of women who aimed for
vaginal delivery despite active perianal disease, there was a tendency for disease
to get worse after vaginal delivery. The risk for women with healed perianal lesions
should be carefully considered. Risks
include parity, estimated fetal birth weight, perineal distance and consistency
of the perineum.
Women with ulcerative colitis and an ileoanal pouch (IAP) represent a special group
of women with IBD. One study reported an increased rate of sphincter defects with
impairment of the pouch function, and these patients should be advised to have a cesarean
section [26].
[Fig. 1] shows a potential algorithm which can be used to determine the appropriate mode
of delivery for patients with no ileoanal pouch [22], [24].
Fig. 1 Algorithm to determine the mode of delivery for patients with chronic IBD and a prior
history of ileoanal anastomosis (PCD = perianal Crohnʼs disease) [22].
Postpartum Care
AGG Recommendation
The medication prescribed to treat chronic inflammatory bowel disease should be continued
during lactation.
AGG Recommendation
Use of mesalazine and corticosteroids can be continued during the period of lactation
after carefully weighing up the indications.
The benefits of breastfeeding for mother and child are undisputed. Maternal worries
about the safety of medication during lactation means that women often stop regularly
taking their medication. According to some reports, 60% of women with Crohnʼs disease
decide to stop taking their medication because of concerns that the drugs could harm
their child if the infant is being breastfed [27].
Most medications are compatible with breastfeeding. Less than 1% of the maternal plasma
dosage of corticoids, thiopurines or anti-TNF preparations is transferred and these
medications should therefore be classed as harmless [28]. In every case, the issue should be discussed by interdisciplinary team.
