Crohn's Disease, Ulcerative Colitis and Pregnancy

Crohn’s Disease,Ulcerative Colitisand Pregnancy

The informed patient

084679_Falk_S82e_Umschlag.qxp:Dr_Falk_S82e_Umschlag 30.12.2008 15:56 Uhr Seite 1

Author’s address

Prof. Dr. Axel DignassMedical Director, Medical Clinic IGastroenterology, Hepatology,Metabolic Disorders and Oncology

Markus-KrankenhausFrankfurter Diakonie-KlinikenWilhelm-Epstein-Str. 2D-60431 Frankfurt am MainGermany

Tel.: +49 (0)69/95 33-22 01Fax: +49 (0)69/95 33-22 91E-Mail: [email protected]

12th edition 2009© 2009 Falk Foundation e.V.All rights reserved.

Publisher

Leinenweberstr. 579108 FreiburgGermany

FALK FOUNDATION e.V.

www.falkfoundation.com

F

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Crohn’s Disease,Ulcerative Colitisand Pregnancy

Author: A. Dignass, Frankfurt am Main, Germany

The informed patient

084679_Falk_S82e.qxp:Dr_Falk_S82e_UK_Inhalt 08.01.2009 9:01 Uhr Seite 1

Contents

Page

Introduction 4

Can women and men with inflammatorybowel diseases become parents? 6

How do inflammatory bowel diseases affectfemale and male fertility and chances forsuccessful pregnancy? 8

How do inflammatory bowel diseasesaffect the course of pregnancy and thebaby’s health? 12

Which medical examinations are importantprior to a planned pregnancy? 16

How does bowel surgery for treatmentof inflammatory bowel disease affect apregnancy? 18

Does pregnancy have an impact on thenatural course of inflammatory boweldisease? 20

Can inflammatory bowel disease first appearduring pregnancy? 24

Can drugs for the treatment of inflammatorybowel diseases be taken during pregnancy? 26

Does the standard drug treatment of inflam-matory bowel diseases harm the baby? 28

Can the immunomodulating drugs azathio-prine or 6-mercaptopurine be taken beforeor during pregnancy? 32

Can immunomodulatory agents such asmethotrexate (MTX), tacrolimus orcyclosporine A be used during pregnancy? 36


Contents

Page

Can infliximab or the newer TNF- � inhibitorsbe used before or during pregnancy? 38

Is the use of cortisone safe during latepregnancy and nursing? 40

Should 5-ASA therapy be interrupted priorto delivery? 42

Can oral contraceptives cause or aggravateinflammatory bowel diseases? 44

Are there medical reasons requiring termi-nation of pregnancy in women with inflam-matory bowel diseases? 46

Which diagnostic methods are consideredto be safe during pregnancy? 48

What special considerations are necessaryduring delivery? 50

Is a special diet during pregnancy benefi-cial in women with inflammatory boweldiseases? 52

How high is the risk of later developing aninflammatory bowel disease in childrenwhose parent(s) suffer from Crohn’s diseaseor ulcerative colitis? 54

Should women with inflammatory boweldiseases nurse? 56


Inflammatory bowel diseases (IBD), such asCrohn’s disease and ulcerative colitis, frequentlyoccur in younger patients who are concernedabout planning a family and related questions.Women and men suffering from IBD – as wellas their partners – are often unsure of theeffects of diagnostic and therapeutic measureson the outcome of their pregnancy. They mayhave questions about such issues as endoscopicexaminations of the gastrointestinal tract, radio-logic examinations, not to mention the possibleneed for surgery and/or the use of various drugs.

Patients may also have questions on how preg-nancy may affect the course of their boweldisease and whether any special precautions(such as the method of delivery) have to be con-sidered. Does pregnancy lead to a worseningof pre-existing inflammatory bowel diseases orcause an acute episode?

Patients are frequently unsure whether their fer-tility is reduced by inflammatory bowel diseasesand whether pregnancy may be even possible.Patients and their families may also have ques-tions relating to the probable hereditary predis-position involved in the development of inflam-matory bowel diseases.

It is important for patients affected with inflam-matory bowel diseases together with theirspouses and families to be adequately counseledbefore, during and after pregnancy. This will helpto reduce unreasonable fears regarding pregnan-cy and to recognize as soon as possible anydangers or complications for mother or baby.

4

Introduction


The purpose of this brochure is to offer answersto commonly asked questions. Current know-ledge is explained on the basis of the latestscientific studies.

At the same time, we remind our readers thatthis brochure does not provide the only validanswer to the many controversial questionsinvolved in the context of pregnancy and inflam-matory bowel diseases. It also cannot replacethe trust you place in your personal physicianand the value of personal discussions relating toyour care. Finally, no brochure can address allof the many individual situations that can affectboth your pregnancy and your inflammatorybowel disease.

It must also be emphasized that, as a result ofadvances in our understanding of these issues,our recommendations with respect to medicalcare and general measures may change. Thisapplies to both diagnostic methods and especiallyto the use of medications, not only becauseof continued advances in the form of newmethods and drugs, but also because increasingexperience with existing methods and drugsprovides improved understanding of their advan-tages and disadvantages. For this reason, youshould always discuss these questions with yourtreating physicians.

Prof. Dr. Axel Dignass

5

Introduction


”Can women and men with

inflammatory bowel diseases

become parents

Can women and men with


become parents?

6

?


s

7

In general, the answer to this question is “yes”.There are, however, a number of fundamentalissues that must be addressed when planning apregnancy. As we will discuss in more detailbelow, it is particularly important to plan a preg-nancy during a period when your disease isinactive. At such times, your fertility, with fewexceptions, is not diminished and your pregnancywill not differ significantly from that in healthywomen and men.

In some cases, inactive disease may be due tothe use of drugs, which may be harmful duringpregnancy. In these cases, it is very important todiscuss your desire for pregnancy with the phy-sicians involved in your care as early as possible.


”How do inflammatory bowel

diseases affect female and

male fertility and chances for

successful pregnancy

� Fertility in women with inflammatorybowel diseases

Women with ulcerative colitis are usually as fer-tile as healthy women. Exceptions are encoun-tered more frequently after extensive surgeries.Just a few years ago, the general consensus wasthat reduction in fertility following extensive sur-gery was only temporary, more recent researchhas provided evidence that a total colectomy with

8

How do inflammatory bowel

diseases affect female and

male fertility and chances for

successful pregnancy?

?


r

9

subsequent creation of a small bowel reservoir orpouch and attachment of the small bowel to therectum (ileoanal pouch) may lead to a permanentreduction in fertility in a not inconsiderable num-ber of women. Studies from Scandinavia and theUnited States have found that even five yearsafter such surgeries only about 40% of women ofreproductive age with a desire to start a preg-nancy conceive naturally. By comparison, amongwomen with an inflammatory bowel disease whohave not undergone surgery, who are of childbear-ing age and desire to start a pregnancy, about90% conceive naturally – a rate similar to thatobserved in healthy women. If, however, as aresult of assisted reproductive techniques, apregnancy is initiated, these women are able tosustain a normal pregnancy and give birth naturally.Hence, women who have undergone surgery andhave unsuccessfully attempted to conceiveshould consider assisted reproductive techniquesand be referred for evaluation by appropriate spe-cialists.

In cases of less extensive surgical procedures,such as the partial removal of the bowel or crea-tion of an artifical bowel outlet (ileostomy), reduc-tion in fertility is more often temporary in nature.Thus, normal fertility returns within a period ofweeks to months, although the overall fertility inwomen undergoing these types of operations ispresumably reduced to some degree.

The question of female fertility is not so clear-cutin Crohn’s disease. While it appears that fertilityis not affected during periods of quiescent dis-ease, a temporary reduction in fertility duringacute disease phases and following extensive

?


surgery can be frequently observed. This mayresult in a missed menstrual period (amenorrhea,i.e. absence of menstruation), a symptom fre-quently observed following significant weightloss caused by active disease.

Reduced fertility during phases of increasedinflammatory activity would also seem to makesense biologically: Pregnancy is postponed untilthe best possible conditions for its successfuloutcome can be assured, while, at the sametime, additional stresses are avoided for the pa-tient.

Following complete surgical wound healing andstabilization of disease activity, female fertilitydoes not appear to be significantly affected,though studies do suggest a slight reduction in

10


fertility in surgically treated patients. It should beremembered that the failure of pregnancy tooccur cannot always be blamed on inflammatorybowel diseases: Even in healthy women expe-riencing regular, unprotected intercourse, onlyabout 90% become pregnant.

� Fertility in men with inflammatorybowel diseases

Male fertility is usually not affected in inflamma-tory bowel diseases. Abscesses and fistulas inthe pelvis and anal region may, however, causedisturbances in erection and ejaculation. Similardisturbances can also occur in patients who haveundergone extensive surgery, particularly fol-lowing ileo-anal pouch operation. They are, how-ever, very rare.

A particular situation may arise in connection withthe use of salazosulfapyridine or sulfasalazine.These drugs can cause temporary infertility inmen, which normalizes about two months afterdiscontinuing the drugs or switching to puremesalazine or 5-aminosalicylic acid (5-ASA) pre-parations.

The reasons for this temporary infertility include adecreased sperm count, a reduced amount ofseminal fluid and abnormalities in the structureand motility of the sperm cells. These changesoccur in about 80% of men treated with thesedrugs.

11


”12


diseases affect the course

of pregnancy and the baby’s

health


diseases affect the course

of pregnancy and the baby’s

health?

?


13

Numerous studies have investigated the effect ofthe inflammatory bowel diseases Crohn’s diseaseand ulcerative colitis on the outcome of pregnan-cy and the health of the child. Results of thesestudies have generally shown that about 85% ofwomen with Crohn’s disease or ulcerative colitisexperience normal, uncomplicated pregnancies.Congenital malformations in infants born towomen with Crohn’s disease or ulcerative colitisoccur in only about 1%. The risk of miscarriagealso does not, in general, appear to be increased.These rates correspond to those observed inhealthy women. Here again, one should not for-get that pregnancies, even in healthy women, donot progress normally in all cases: In fact, prob-lems or complications relating to the pregnancyor affecting the baby’s health occur in about 15%of cases.

Although pregnancies in women with inflamma-tory bowel diseases usually progress in a mannercomparable to healthy women, various studieshave shown that, in both Crohn’s disease andulcerative colitis, increased inflammatory activityat the time of conception may unfavorably affectthe pregnancy and is associated with a signifi-cantly higher rate of complications (table 1).


Table 1

Course of pregnancy in healthy women and in patientswith inflammatory bowel diseases in relation to diseaseactivity (%).(Mean percentages from European and American studies)

Normal Malfor- Premature Abor-mations births tions

General population 83 2 6 9

Crohn’s disease in remission 82 1 7 10

Crohn’s disease inactive phase 54 1 25 20

Ulcerative colitis in remission 84 1 6 9

Ulcerative colitis inactive phase 65 2 12 21

14

These findings indicate that pregnancies con-ceived during inactive disease or during a phaseof mild inflammatory activity progress normallyand without an increased risk of complications.Therefore, pregnancies should, if possible, beplanned during phases of inactive disease or mildinflammatory activity. If conception occurs in aperiod of increased disease activity, the rate ofabortions, premature births and other pregnancycomplications increases significantly. If possible,active disease should be treated and the necessityof therapeutic intervention should be clarifiedprior to beginning a pregnancy. For example, if itis known that surgery will be necessary in thenear future (for example, to treat stenoses causedby scarring), the operation should occur prior to aplanned pregnancy.


15

Ultrasound profile of the face of ahealthy female fetus in the 25thweek of pregnancy.


”Which medical examinations

are important prior to a

planned pregnancy

16

Which medical examinations

are important prior to a

planned pregnancy?

?


17

No general plan can be offered here. This is amatter to be discussed individually with your doc-tor. Invasive procedures such as endoscopies orradiologic examinations are not required in allcases.

A detailed discussion with your doctor regardingyour medical history and actual condition andlaboratory tests to determine the activity of thedisease and to exclude any dietary deficienciesseem advisable prior to a planned pregnancy. Anultrasound examination of the abdomen and theintestine performed by an experienced examinercan also provide valuable information.

Individual patients may require more extensiveexaminations including endoscopic and radiologicstudies of the bowel. Results of these tests mayindicate the need for anti-inflammatory therapy oradditional supplementation of certain vitaminsand minerals (e.g., vitamin B12, folic acid, iron). Inparticular, dietary supplementation with folic acidis recommended in the period leading up to aplanned pregnancy, since it helps to prevent theoccurrence of rare neural tube defects in thedeveloping fetus. It is possible that the absorptionand metabolism of folic acid is further reducedduring treatment with sulfasalazine or sulfapyridine.Thus, these women should either receive prophy-lactic administration of folic acid or considerswitching from this group of medications to other5-ASA-containing agents.


”How does bowel surgery

for treatment of inflammatory

bowel disease affect

a pregnancy

Past abdominal operations for treatment of in-flammatory bowel diseases do not in general ap-pear to have a negative impact on the course ofpregnancy. Pregnancies without complicationsare seen even after extensive intestinal surgeryincluding colectomy or creation of an ileostomy.Here, it is important that a sufficient interval pass-es between the operation and the time of con-ception, so that surgical wounds have healed andthere is no significant disease activity.

18

How does bowel surgery

for treatment of inflammatory

bowel disease affect

a pregnancy?

?


ry

19

As described above on pages 8 and 9, the totalremoval of the bowel (proctocolectomy) withsubsequent creation of a small bowel reservoirand connection of the small bowel to the rectum(ileoanal pouch) is more frequently associatedwith permanent reduction in fertility. Women inthis situation desiring to start a pregnancy shouldbe referred promptly for consultation with a fer-tility specialist to discuss the option of assistedreproductive techniques.

Following a surgical procedure, it is usually advis-able to wait 6–12 months before becomingpregnant. This is true regardless of whether anartificial intestinal orifice has been created or thepatient has undergone continence-preservingsurgery. Occasionally, complications relating tothe ileostomy (e.g., prolapse, occlusion) mayoccur during pregnancy. It has been suggestedthat the rate of premature births may alsoincrease following total colectomy and ileostomy.In certain cases, surgical intervention may be-come necessary during an existing pregnancy.This may in a few, generally rare cases resultin premature birth or in spontaneous abortion(miscarriage). On the other hand, normal pregnan-cies free of complications are possible even incases in which extensive surgery, such as totalcolectomy, was required during the pregnancydue to severe ulcerative colitis flares that didnot respond to pharmaceutical treatment.


”Does pregnancy have an

impact on the natural course

of inflammatory bowel

disease

Does pregnancy have an

impact on the natural course


disease?

20

?


Table 2

Effect of pregnancy on disease activity in Crohn’sdisease following conception during remission

Remission maintained ~85%

Beginning of an acute episode: ~15%

• during the first trimester ~13%

• during the second trimester <1%

• during the third trimester <1%

• during puerperium (childbed) ~2%

21

In the large majority of cases pregnancy has noeffect on the activity or maintenance of remissionof inflammatory bowel diseases. In individualcases, however, a dramatic improvement orworsening of symptoms of inflammatory boweldiseases can be observed (tables 2 and 3).

Table 3

Effect of pregnancy on disease activity in Crohn’sdisease following conception in a phase of acute disease

Achieving remission 15%

Improved 20%

No change in disease activity 30%

Worsening during pregnancy 25%

Worsening during puerperium (childbed) 10%


22

Only about 15% of women with Crohn’s diseasewho conceived during a remission phase experi-ence an acute disease episode during their preg-nancy. This rate approximates the normal clinicalcourse of Crohn’s disease. If an increased dis-ease activity is already present at the beginningof pregnancy, this increased activity remainsmore or less constant throughout pregnancy inabout one-third of patients (table 3). Episodes ofacute disease occur more frequently during pa-tients’ first trimester of pregnancy and during thepuerperium (childbed).

Pregnancy also does not seem to exert a majoreffect on disease activity in patients with ulcera-tive colitis. About one-third of women with ulcer-ative colitis who conceived during a phase of re-mission experience an episode of acute diseaseduring pregnancy (table 4). This corresponds tothe normal course of the disease in women whoare not pregnant.

Table 4

Effect of pregnancy on disease activity of ulcerativecolitis following conception during remission

Remission maintained ~70%

Beginning of an acute episode: ~30%

• during the first trimester ~20%

• during the second trimester ~7%

• during the third trimester <1%

• during puerperium (childbed) ~3%


Table 5

Effect of pregnancy on disease activity in ulcerativecolitis following conception in a phase of acute disease

Achieving remission 19%

Improved 18%

No change in disease activity 32%

Worsening of disease activity 31%

23

Episodes of acute disease occur more frequentlyduring the first six months of pregnancy andduring the puerperium (childbed). As in Crohn’sdisease, the majority of women who conceiveduring an active disease phase usually continueto have active disease throughout pregnancy(table 5).

Generally, the natural course of inflammatorybowel diseases can be improved by drug therapyeven during pregnancy. Drugs may induce remis-sion or decreased disease activity, which canthen be maintained for the remainder of the preg-nancy. In addition, worsening of symptoms ininflammatory bowel diseases during one preg-nancy does not automatically implicate that thismay occur in subsequent pregnancies.


”Can inflammatory bowel

disease first appear during

pregnancy

Can inflammatory bowel

disease first appear during

pregnancy?

24

?


25

Both Crohn’s disease and ulcerative colitis canshow their first symptoms during pregnancy. Ingeneral, the course of inflammatory bowel dis-eases in these patients is not more unfavourablethan in patients who are not pregnant.

A significant problem that may delay the definitediagnosis is the understandable fear of under-going diagnostic procedures, such as endoscopyor radiologic examinations, at this time (see alsopage 48).


” ?

26

Everyone knows the importance of avoidingmedications during and even prior to a plannedpregnancy in order to protect the unborn childfrom unnecessary risks. The use of drugs in treat-ing inflammatory bowel diseases represents aspecial problem. It is only natural that patientsand their families may be unsure and have manyquestions relating to this issue. These concernsare reinforced by the package inserts of a greatmajority of medications, which advise patients touse them during pregnancy only on the advice ofa doctor and for a strictly defined indication. Thedecision to treat a pregnant woman with any drug

Can drugs for the treatment


diseases be taken during

pregnancy

Can drugs for the treatment


diseases be taken during

pregnancy?


27

must be made for each patient individually, ifnecessary after consultation of the proper specia-lists. This advice is based on the requirement forthe highest possible degree of safety. Even in thecase of drugs for which no adverse effects havebeen reported to date for either mother or baby,there is always a remaining risk, which, though itmay be ever so slight, cannot be totally excluded.

Therefore, the general rule during pregnancy is totake only those medications that are absolutelynecessary. However, we should not forget thatmany diseases, if inadequately treated, also posea serious threat to the well-being of the motherand her child.

In this context, it is important to repeat, what wesaid above: Even in healthy women, only about85% of pregnancies develop without any compli-cations.

Overall, the treatment of inflammatory boweldiseases in pregnant women is, in most of itscomponents, based on the same general princi-ples as are applied to patients who are not preg-nant. Optimal care, however, depends on closeand regular interaction between the gastroenter-ologist and the gynecologist and should considersome important differences and exceptions withregard to determining the individual medical treat-ment of a single patient.


” ?

28

Does the standard drug

treatment of inflammatory

bowel diseases harm

the baby

Does the standard drug

treatment of inflammatory

bowel diseases harm

the baby?


Unfortunately, it is impossible to give a generallyvalid answer to this question. The care of eachindividual patient should be one of cooperationbetween the gynecologist and the specialist ininternal medicine or gastroenterology. The variouscortisone (prednisone, prednisolone, hydrocorti-sone) and mesalazine or 5-ASA preparations inthe customary doses generally prescribed forthe treatment of inflammatory bowel diseasesdo not appear to represent an increased risk tothe unborn fetus based on current evidence.Nevertheless, the package inserts for all ofthese drugs do urge caution and strict determina-tion of indication during the first trimester ofpregnancy. Patients who depend on 5-ASA- orcorticosteroid- (cortisone) preparations for main-taining remission, should continue this therapyeven after pregnancy is confirmed: An increasein the inflammatory activity of the disease is amuch greater risk for the fetus. If an acute epi-sode of an inflammatory bowel disease shouldoccur during pregnancy, these drugs should betaken in adequate dosages in order to controldisease activity as quickly as possible. Inadequa-tely treated, inflammatory bowel diseases harmboth the baby and its mother more than the drugtherapy.

The conventional therapy of inflammatory boweldiseases with pure 5-ASA- or corticosteroid-pre-parations in fathers does not have any adverseeffects on the outcome of a pregnancy based onour current knowledge. Only the above describedtemporary reduction in fertility (see page 11) causedby salazosulfapyridine or sulfasalazine shouldlead to substitution of pure 5-ASA- or mesalazine-preparations in males who wish to start a family.

29


30

With regard to therapy with budesonide, it is notyet possible to give any general recommenda-tions since we do not yet possess the extensiveclinical experience that characterizes our know-ledge of the classic cortisone preparations. Ourown experience and that reported by colleagues,however, has provided no evidence of danger foreither the mother or child, though a comprehen-sive evaluation of the pregnant patient shouldalways be done prior to and during a contemplat-ed treatment with budesonide. In recent years, alarge number of pregnancies that were normaland free of complications have been reported inpatients treated with budesonide, either orally orin the form of enemas. Based on our currentexperience, there is no evidence for any harmfuleffect of this agent during pregnancy. Becauseour experience with the classic cortisone prepara-tions is much more extensive, in cases of doubtit is probably safer to choose one of these inpreference to budesonide. There is no indicationfor pregnancy termination in cases in whichconception has occurred while a patient is beingtreated with budesonide.

The use of other medications, such as antibiotics,or of immunomodulatory substances such as aza-thioprine or 6-mercaptopurine (6-MP), methotrexate(MTX), cyclosporine, tacrolimus or of TNF-� inhi-bitors requires critical evaluation and should onlyoccur following comprehensive consultation withan experienced and appropriately trained specia-list (see also page 32 ff. of this booklet).

The use of antibiotics, such as metronidazole orciprofloxacin, which are used especially in pa-tients with Crohn’s disease who develop fistulae,


31

requires careful evaluation in pregnancy. As a rule,long-term therapy with these antibiotics is contra-indicated. Because these are second-line drugswith generally lower efficacy, in cases of medicalnecessity, a comprehensive discussion with thetreating physician should focus on other, possiblymore effective therapy options.

Various other drugs used for symptomatic relief ininflammatory bowel diseases can, according toour current state of knowledge, be continuedwithout risk to the unborn child. For example, theanti-diarrheal agent loperamide can be used safe-ly in cases of very severe diarrhea. Patients withdiarrhea may also benefit from the use of psylliumseed shells (Plantago ovata). To date, no negativeeffects of psyllium have been reported, as wouldbe expected in an agent of herbal derivation.According to our current state of knowledge, pro-biotics, such as E. coli Nissle and lactobacilli, canbe used without increased risk for the newborn.


”?

32

Can the immunomodulating

drugs azathioprine or

6-mercaptopurine be taken

before or during pregnancy?

Can the immunomodulating

drugs azathioprine or

6-mercaptopurine be taken



There have been, in recent years, significantchanges in the risk assessment for use of theimmunomodulatory drugs azathioprine and 6-mer-captopurine (6-MP). While it was believed onlya few years ago that use of these drugs before aplanned pregnancy or during the pregnancy itselfwas associated with a relatively high risk of sideeffects (miscarriage, premature birth, birth defects),current data and the increased use of azathioprineand 6-MP in other disorders (e.g. organ trans-plantation, rheumatoid arthritis) have shown thatuse of these drugs before or during pregnancy isnot associated with an increased risk of compli-cations during pregnancy or with birth defectsin the child. There have also been a number ofcase reports that suggest that patients withinflammatory bowel diseases do not experiencean increased risk due to use of azathioprine or6-MP. Naturally, there can be no 100% guaranteethat a given drug will not adversely affect thecourse of pregnancy. A careful review of the lite-rature also reveals case reports which show aslightly increased rate of pregnancy complicationsand miscarriages in association with the use ofazathioprine or 6-MP. Upon closer examination,however, it becomes rapidly clear that, becauseof the small number of cases, no statistical con-clusions can be made; in addition, other factors,such as an increased disease activity, may beresponsible for the negative effects in thesepatients. Thus, a consensus has formed in Europeand the United States that azathioprine and 6-MPcan be used during pregnancy if medically neces-sary and, in fact, should be used if other measuresfail to control inflammatory activity. The decisionon whether azathioprine should be stoppedin women planning a pregnancy or whether con-

?

33


34

ception should be planned during ongoing aza-thioprine therapy requires careful consideration ofthe advantages and disadvantages and compre-hensive counseling of the parents. This decisionrequires a high degree of responsibility andshould include a joint interview between theparents, the treating gynecologist and/or familyphysician, as well as a gastroenterologist with thecorresponding experience. There is no indicationfor pregnancy termination in women who becomepregnant while being treated with azathioprine or6-MP.

Also controversial is the use of azathioprine or6-MP by the male partner in couples planning apregnancy. Here, too, extensive experience fromtransplantation medicine and in patients withrheumatic disorders and inflammatory boweldiseases who were treated with azathioprine or6-MP prior to or during the period of conceptiondoes not reveal any increased risk for pregnancycomplications or birth defects. As with women,however, there are also individual case reports inthe scientific literature that suggest possiblenegative effects on pregnancy secondary toazathioprine or 6-MP. Here, too, data is based ona very small number of cases, which precludesstatistical evaluation. European and Americanpharmaceutical regulatory agencies do not cur-rently recommend that males being treated withazathioprine or 6-MP should discontinue therapyprior to a planned conception. Patients desiringmaximum safety, however, can be advised to dis-continue azathioprine three months prior to aplanned conception. In the intervening period,males will produce sperm whose genetic materialis not damaged by azathioprine. Over the past


35

years, we have followed a large number ofwomen and men who have been treated withazathioprine before and during conception andpregnancy. There have been no reportedinstances of birth defects or pregnancy complica-tions that could be associated with this therapy.


”36

Can immunomodulatory

agents such as methotrexate

(MTX), tacrolimus or

cyclosporine A be used during

pregnancy?

Can immunomodulatory

agents such as methotrexate

(MTX), tacrolimus or

cyclosporine A be used during

pregnancy?

?


g

The use of immunomodulatory agents other thanazathioprine or 6-mercaptopurine must be carefullyconsidered in each individual case.

Methotrexate (MTX) should never be used in pa-tients actively planning to become pregnant.Based on data from animal experiments, there isa high risk of chromosomal damage, increasedoccurrence of birth defects and pregnancy com-plications (miscarriage, premature birth). In fact,MTX, at high doses, can be used to induce abor-tion. For this reason, we recommend discontin-uing therapy with MTX in both men and womenthree to six months prior to planned conception.If therapy with MTX is absolutely necessary, pa-tients must use a reliable method of contraception.

With respect to the use of cyclosporine A andtacrolimus, there are a series of case reports inpatients undergoing organ transplantation andwith inflammatory bowel diseases that describenormal pregnancies free of complications and noincreased rate of birth defects during use of thesedrugs. The existing data, however, are by nomeans adequate to support a general recommen-dation for starting or continuing these medica-tions during pregnancy. Use of these agents mustbe carefully considered in conjunction with bothparents and an experienced specialist based onthe patient’s prior disease course and the latestscientific knowledge.

37


”Can infliximab or the newer

TNF-α inhibitors be usedbefore or during pregnancy?

Can infliximab or the newer

TNF-α inhibitors be used


?

38


Our current state of knowledge would suggestthat the administration of infliximab is not asso-ciated with an increased rate of either birth de-fects or pregnancy complications. Data from animalexperiments do not show any negative effects ofthe course of pregnancy or an increase in birthdefects. To date, more than 100 pregnancieshave been described in patients treated with infli-ximab for rheumatoid disorders and inflammatorybowel diseases. Statistically, the available datado not show any increase in pregnancy com-plications or birth defects in cases in which priorto or during pregnancy either the male or thefemale parent was treated with infliximab. In arecent study in patients planning a pregnancy,therapy with infliximab was continued unchangedthrough the entire pregnancy without any adverseeffects on either the course of the pregnancy orthe rate of birth defects.

At present, corresponding statements cannot bemade for the newer TNF- � inhibitors, such asadalimumab and certolizumab pegol, since signifi-cantly fewer patients have been treated withthese agents and there is still inadequate experi-ence with these agents. Experimental data,however, does not point to an increased risk. Forone TNF- � inhibitor, certolizumab, there existexperimental data that show only low transferinto the child’s system, which may represent afactor that enhances safety. As the use of thesedrugs is expected to increased in coming years,further scientific data will certainly be forth-coming. There is no indication for pregnancytermination should a patient using one of thethree currently available TNF-� inhibitors experi-ence an unplanned pregnancy.

39


”Is the use of cortisone safe

during late pregnancy and

nursing

It is generally accepted that the dosages of corti-costeroid preparations (e.g. prednisone, predniso-lone, hydrocortisone) usually prescribed for thetreatment of inflammatory bowel diseases arenot associated with an increased risk of miscar-riage or fetal malformations. It is theoreticallypossible that very high doses of corticosteroidstaken during the final phases of pregnancy mightcause reduced corticosteroid production in thenewborn’s adrenal gland resulting in low levels ofcirculating cortisone after birth, together withapathy and reduced activity. Therefore, infantsborn to mothers taking high corticosteroid doses

?

40

Is the use of cortisone safe

during late pregnancy and

nursing?


in late pregnancy should be closely monitored byan experienced neonatologist. If necessary, thebaby can receive cortisone substitution until theadrenal glands are able to produce sufficient cor-tisone.

Since cortisone can pass through breast milk intothe baby, it is conceivable that an infant’s corti-sone intake during nursing could result in a sim-ilar depression of cortisone production in thebaby’s adrenal glands. Again, careful follow-up byan experienced pediatrician is important.

In both instances, however, no permanent harmto the infant is to be expected. Once cortisonetherapy is discontinued, the function of theinfant’s adrenal gland normalizes with adequateproduction of cortisone.

Regarding the use of budesonide during pregnan-cy and lactation, it is still too early to give general-ly valid statements, since experience with thisdrug during pregnancy is quite limited. In theory,the rapid metabolism of budesonide in themother’s liver leads to relatively low circulatinglevels of the drug and thus only a slight transmis-sion to the baby through the milk. Our own expe-rience with budesonide during pregnancy andnursing has been positive and no adverse effectshave been observed in the infants. The use ofbudesonide sprays for the treatment of asthmaduring pregnancy also does not seem to be asso-ciated with an increased risk of fetal malforma-tions. Because of the limited experience with thedrug, however, the use of budesonide duringpregnancy and nursing should include compre-hensive counseling of the mother.

41


”Should 5-ASA therapy

be interrupted prior to

delivery

Should 5-ASA therapy

be interrupted prior to

delivery?

?

42


Unlike acetylsalicylic acid (aspirin), 5-aminosalicy-lic acid (5-ASA, mesalazine) at therapeutic dos-ages does not affect coagulation of the blood orinhibit the aggregation of the platelets, which isimportant for the control of bleeding.

Therefore, interruption of 5-ASA therapy prior todelivery is not generally required, particularlysince blood levels of 5-ASA are very low.

43


” ?Can oral contraceptives cause

or aggravate inflammatory

bowel diseases

Can oral contraceptives cause

or aggravate inflammatory

bowel diseases?

44


?e

45

In the past, several investigators have presentedevidence suggesting that women taking oral con-traceptives have a slightly higher incidence ofCrohn’s disease and suffer from acute episodesof the diseases more frequently. Other investiga-tors, however, have been unable to confirm thesefindings. To date, no evidence has suggested anunfavorable connection between oral contracep-tives and ulcerative colitis.

In general, our experience has shown that the riskof developing inflammatory bowel diseases or ofa worsening of symptoms due to the use of oralcontraceptives is quite low. Thus, we see no con-traindication for the use of oral contraceptives inwomen with inflammatory bowel diseases.

It is important to remember, however, that thesevere diarrhea accompanying inflammatorybowel diseases in individual cases may disturbuptake of the contraceptive hormones in thebowel and thus compromise the efficacy of themethod. Patients using contraceptive medicationwith low amounts of hormone (such as the so-called “minipills”) should be particularly awareof this possible reduction in contraceptive pro-tection. Discussion of this issue with your gyne-cologist is advisable.


”Are there medical reasons

requiring termination

of pregnancy in women

with inflammatory bowel

diseases

Are there medical reasons

requiring termination

of pregnancy in women

with inflammatory bowel

diseases?

?

46


47

Termination of pregnancy is very rarely or evennever necessary because of inflammatory boweldiseases in the mother. Instead, there should beadequate therapy of the woman’s inflammatorybowel disease together with comprehensive careby her doctors.

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”Which diagnostic methods are

considered to be safe during

pregnancy

Which diagnostic methods are

considered to be safe during

pregnancy?

?

48


Ultrasound examinations of the abdomen andbowel can be performed without danger to themother or child; these diagnostic examinationsprovide important evidence regarding diseaseactivity and the extent of the inflammation. In thehands of an experienced examiner, even gastros-copy or endoscopy of the lower gastrointestinaltract (rectoscopy, sigmoidoscopy and ileocolonos-copy) are not associated with increased risk orwith the increased frequency of premature birth.

These invasive methods, however, should only beused when absolutely necessary to determinethe most appropriate type of therapy. Magneticresonance imaging (MRI), which is probably alsonot harmful, may be useful in certain cases. Dia-gnostic procedures involving radiation exposureshould be postponed until after delivery and re-served to emergency situations.

Capsule endoscopy or double balloon endoscopywill not, as a rule, be medically necessary duringpregnancy. Especially double balloon endoscopy,because of its invasive character and increasedrisk of premature labor, should not be used.

re

49


”What special considerations

are necessary during

delivery

What special considerations

are necessary during

delivery?

?

50


Vaginal delivery is generally preferred even inwomen with inflammatory bowel diseases. Gen-erally, vaginal delivery is possible in women whohave undergone ileostomy, although the increasedintra-abdominal pressure due to contractions maycause prolapse of the intestinal orifice. In suchcases, many obstetricians prefer delivery bycesarean section. The method of delivery in pa-tients with ileostomy, therefore, should be dis-cussed in advance with the patient’s obstetrician.

Another group of patients in whom cesarean sec-tion is preferred and may be useful are thosewomen suffering from extensive formation offistulas in the perianal area and pelvis. This issue,however, must also be decided in consensus be-tween the patient and her obstetrician.

Whether an episiotomy (incision in the perineum)contributes to an increased risk of perianal fistulaformation remains controversial. Most data pub-lished to date do not support an increased risk ofperianal fistula formation following episiotomy.

51


”Is a special diet during

pregnancy beneficial in

women with inflammatory

bowel diseases

Is a special diet during

pregnancy beneficial in

women with inflammatory

bowel diseases?

?

52

Patients with inflammatory bowel diseases gener-ally do not require a special diet. Patients should,of course, follow the general recommendationsfor a balanced diet with adequate intake of calo-ries, vitamins and minerals during pregnancy. Spe-cial dietary recommendation must, however, beconsidered if, due to the underlying disease orsome associated disorder the patient developslactose intolerance, bile acid loss syndrome or


stenosis (narrowing) of some segment of thegastrointestinal tract. Patients with lactose intol-erance benefit from reduction or elimination ofdietary lactose. Because this often means areduction in dietary calcium intake, patients mayneed calcium supplementation in the form of oraltablets. Patients with existing bile acid loss syn-drome often experience positive effects fromfoods rich in mid-chain triglycerides. Patients withconfirmed stenoses in the gastrointestinal tractoften benefit from a diet low in dietary fiber, whichshould also be continued during pregnancy.

53


”How high is the risk of later

developing an inflammatory

bowel disease in children

whose parent(s) suffer from

Crohn’s disease or ulcerative

colitis

How high is the risk of later

developing an inflammatory

bowel disease in children

whose parent(s) suffer from

Crohn’s disease or ulcerative

colitis?

?

54

The risk for the children of parents with inflamma-tory bowel diseases to develop Crohn’s disease orulcerative colitis themselves is relatively small.Inflammatory bowel diseases are not hereditarydiseases in the strict sense. What is passed on toone’s children is a genetic predisposition to devel-op these diseases under certain circumstances. Inindividual cases, there may be an increased pre-valence of inflammatory bowel diseases in certainfamilies.


Table 6

Estimated relative risk of developing an inflammatorybowel disease

Risk for children with one affected parent 1–7%

Risk for children with both parents affected up to 36%

Risk for other siblings, when one child is affected 2–6%

Risk for the parents, when one child is affected 1–5%

A person’s individual risk to develop an inflamma-tory bowel disease when another family memberis affected cannot be precisely predicted and canbe estimated only on the basis of empirical ob-servations. Thus, the relative risk of developing aninflammatory bowel disease ranges from zero to36% depending on how closely related the per-son is to the already affected family member(table 6).

Despite a generally increased risk that children ofparents with IBDwill also develop IBD, this shouldnot be considered a reason not to have children.If diagnosed early, inflammatory bowel diseasesare relatively well treated by improved medicaltherapy. Indeed, the life expectancy of patientswith inflammatory bowel diseases does not differsignificantly from that of normal, healthy subjects.

55


”Should women with


nurse

Should women with


nurse?

?

56

The use of cortisone or 5-ASA preparations by themother is not a problem during nursing since onlynegligible amounts of these drugs enter thechild’s organism through the milk and no perma-nent harmful effects on the baby are known. Theuse of cortisone preparations should, however,be reduced as quickly as possible, both in preg-nant and non-pregnant patients. If a high-dosecortisone therapy has been necessary, the infantshould be carefully monitored by the pediatrician.If there is interruption of lactation during a periodof high-dose cortisone therapy in the mother,


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there is the risk of temporary adrenocortical insuf-ficiency in the infant. The pediatrician will deter-mine the infant’s need for a possible temporarycortisone replacement therapy. The use of bude-sonide during lactation has been addressed in thisbrochure on page 41.

If the use of immunomodulatory agents such asazathioprine, 6-mercaptopurine, methotrexate(MTX), cyclosporine, tacrolimus or infliximab isnecessary, the newborn should not be breast-fedsince the long-term effects and possible harm tothe baby cannot yet be predicted. Because thechild’s liver is still immature and has not de-veloped a full detoxification capacity, it cannot bepreducted to what extent the above-describedmedications may remain in the child’s system.Thus, acute and long-term adverse effects cannotbe fully excluded at this time.

s

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Further information for patients withinflammatory bowel diseases:

– Ulcerative colitis and Crohn’s diseaseAn overview of the diseases and their treatment68 pages (S80e)

– Diet and Nutrition in Crohn’s Disease andUlcerative Colitis20 Questions – 20 Answers60 pages (S84e)

– Crohn’s disease and its associated disorders40 pages (S85e)

– Corticosteroid therapy in inflammatory boweldiseases32 pages (Bu80e)

These brochures can be orderedfree of charge from Falk Foundation e.V.or the local Falk partner.



www.falkfoundation.com

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Documents

Crohn's Disease, Ulcerative Colitis and Pregnancy