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134 G. Colucci, G.G. Delaini, F. Nifosì
must be carefully examined in regard to physical
problems, difficulties relating to their sex life and the
possibility of pregnancy [11]. Women with UC usual-
ly do not present a higher incidence of gynaecologi-
cal diseases, except those who have undergone ileal
pouch anal anastomosis (IPAA) and presenting a
higher incidence of dyspareunia. In women with CD,
approximately 25% develop organic and functional
gynaecological complications such as menstrual
irregularity, amenorrhoea, inflammatory pelvic
masses, abscesses and fistulae that, in the case of fail-
ure of medical therapy, require surgery, which is psy-
chologically invalidating and greatly affect their
quality of life and sexuality, especially if associated
with laparotomies and creation of stomas.
Heredity
Another problem that often affects the reproductive
and affective environment of patients with IBD is the
fear that their children may inherit the same disease
[12]. There is a 10.5% risk that the children of a par-
ent with IBD may develop the disease, and 10% of
patients have a first-degree relative with the disease,
attesting to the role of heredity and genetic suscepti-
bility to these morbid conditions in which multifac-
torial pathogenesis requires triggering factors of an
environmental origin.
The modality of transmission of the genes that may
cause the development of IBD is complex and cannot
be explained with a mere Mendelian pattern. Studies
on twins revealed that, in the case of MC, consistency
is 44–50% in monozygotic twins and 0–3% in zygotic
twins whereas in the case of UC, consistency is lower,
at 6–14% in monozygotic twins and 0-5% in heterozy-
gotic twins [12]. Some studies revealed that there is a
stronger familial tendency in CD, attesting to the
importance of the genetic arrangement in determining
the tendency to develop the disease [12]. Recent
researches [13] began to detect the chromosome
regions that are probably involved in order to deter-
mine susceptibility to the disease. Some of these
regions seem to be specific in CD and UC whereas oth-
ers have a lower specificity. These discoveries are rele-
vant in light of the possibility, from studying the geno-
type of a certain patient, of anticipating phenotypical
features of the disease, distinguishing – for example, in
the case of CD – types with a higher risk of fistulisation
from those with a predominant tendency to form
stenosis. Knowledge of a patient’s genetic arrangement
could help in the evaluation of risk of extraintestinal
manifestations and the probability of response to med-
ical and surgical therapy. For example, a gene was
detected, called CARD 15, situated on chromosome 16,
which codifies for a protein involved in the primary
immune response to infections through the activation
of the NF-kB. In patients with MC, mutations of this
gene seem to be associated with a tendency to ileal
localisation, an earlier age of onset and a higher ten-
dency to stenosis. In the light of these considerations,
it is reasonable to think that, in a more or less remote
future, physicians may be able to anticipate features of
the evolutive course of the disease in each patient by
targeted genetic studies, optimising management by
individualising medical–surgical therapy [13].
Effect of IBD on Pregnancy
As for the progress of pregnancy during IBD, many
studies show that pregnant patients may have an
ordinary gestational course during the stages of dis-
ease quiescence even if there still is, for reasons not
yet explained, a risk that is about twice as high com-
pared with healthy women to have complications
such as delay of foetal intrauterine growth, prematu-
rity and low birth weight. Therefore, strict obstetrical
follow-up, particularly during the third trimester, is
necessary [14, 15].
There is much evidence that any relapse of the dis-
ease, especially CD, increases considerably the risk of
adverse events such as foetal malformations, prema-
ture delivery and miscarriage, emphasising the
importance of planning for conception during the
quiescence stage and the use of all diagnostic and
therapeutical tools available to prevent or intensively
treat any relapse of the activity stage during the
entire course of pregnancy [16].
As for UC, any activity stage during pregnancy
often determines a state of weakness for the expectant
mother that frequently affects foetal growth negative-
ly, causing low birth weight and premature delivery.
This fact emphasises the importance of thorough and
early nutritional therapy and intensive support of the
overall conditions of the expectant mother. A recent
study revealed the likely association between UC
relapse during pregnancy and an increased tendency
of foetal malformations [17]. The percentage of mis-
carriage–premature delivery associated with CU in
the active non-fulminating stage is 18–40%, with val-
ues up to 60% in the case of fulminating relapses.
Effect of Pregnancy on IBD Course
Many studies have been conducted on the effect of
pregnancy on the course of intestinal inflammatory
diseases [18–20]. From available meta-analytical
data, we found that the probability of relapse of dis-
ease activity stages did not increase considerably
during pregnancy or during puerperium. A study of
IBD and Pregnancy 135
over 500 pregnancies in patients suffering from UC
in a quiescent stage revealed that the percentage of
patient at risk for relapse of the active stage is 34%,
similar to the rate of recrudescence of patients suf-
fering from UC who are not pregnant [20]. Most
relapses take place during the first trimester, partly
because of the high frequency of therapy interruption
during the pregnancy period.
In the abcence of therapy, UC in the active stage at
the moment of conception shows a further worsening
during pregnancy in 45% of patients; in 26%, it
remains unchanged. In a small percentage of women,
pregnancy causes improvement or remission during
the disease activity stage, mostly during the first
trimester. If conception occurs during the active
stage, it is likely that the latter does not change dur-
ing the entire course of pregnancy in about two
thirds of patients. It may happen that the first acute
onset of UC coincides with the beginning of pregnan-
cy; in this case, its disease course tends to be particu-
larly aggressive. Moreover, in some patients, the dis-
ease stays subclinical in the extra-pregnancy periods
and becomes symptomatic only during pregnancy.
The course of CD during pregnancy is similar to
UC. The patient with quiescent disease at the time of
conception usually does not present a higher risk of a
relapse during pregnancy whereas the patient con-
ceiving during the activity stage presents a further
worsening in one third of cases, and in one third they
show no change at all [21]. There are no definitive
data regarding desirable optimal duration of remis-
sion prior conception in order to assure a high prob-
ability of a favourable pregnancy course for both the
expectant mother and the foetus; however, the longer
the quiescence stage, the better the outcome.
In addition to disease activity state at the time of
conception, according to two recent studies [22], a
previous pregnancy might affect the overall course of
IBD. In particular, in patients with UC, it seems that
the more the parity increases, the lower the need for
surgery. Moreover, patients with a history of multiple
pregnancies would present, in comparison with non-
parous patients, a need for a lower number of intes-
tinal resections and a higher interval among the var-
ious surgeries besides a reduction of the rate of dis-
ease. These remarks should partly be explained by
the effect of pregnancy on the immune system [22].
Diagnostic Tools Usable During Pregnancy in
Patients Suffering from IBD
Laboratory
Regarding possible diagnostic means to monitor the
disease and for early recognition of recrudescences,
the role of laboratory parameters is limited, as they
are undermined by poor reliability of values during
pregnancy. Constant physiological modification,
connected with hemodilution, is necessary for some
parameters that do not present suitable specificity to
monitor pregnant women with IBD. These physio-
logical changes include reduction of haemoglobin of
about 1 g/dl, reduction of blood iron level, a two- to
three-fold increase in erythrocyte sedimentation rate
(ESR), reduction of about 1 g/dl of blood albumin
and an increase of alkaline phosphatase of about
1.5% . As these parameters may be analogously mod-
ified even during the early stages of IBD relapse, they
should not be used as diagnostic tools during preg-
nancy to avoid false positivities, or at least they
should always be set in a wider clinical evaluation.
For example, if a pregnant patient with CD shows
good health conditions but her hematocrit decreased
and her ESR increased, she probably is in a quiescent
stage of the disease and does not need further exam-
ination. On the contrary, a pregnant patient showing
ingravescent diarrhoea, abdominal pain and highly
altered laboratory parameters does require further
diagnostic examination, possibly including an endo-
scopic evaluation.
Radiology
During pregnancy, it would be best to avoid whenev-
er possible the use of ionising radiation and all exam-
inations emitting them, such as abdominal-X-ray,
barium meal, barium follow-through or computed
tomography, given their likely teratogenic, genotoxic
and carcinogenic effect [19], particularly during the
first trimester. According to the American Radiology
Society, exposition to a radiation dose lower than
5 rads does not considerably increase the risk of
foetal damage. For this reason, if a certain radiologic
procedure is highly suggested, it should be per-
formed after a careful discussion with the patient
regarding cost/benefit ratios and after exclusion of
any additional diagnostic procedures that are safer
but equally effective.
Gastrointestinal Endoscopy
Many studies have found that flexible colonoscopy
frequently necessary to examine pregnant patients
with IBD is relative safe, with no considerable risk of
complications for the expectant mother or the foetus
[19]. The main indications for endoscopy during
pregnancy and IBD are the need to confirm clinical
suspicion of disease relapse and for management of
complications such as gastrointestinal bleeding and
136 G. Colucci, G.G. Delaini, F. Nifosì
biliary obstructions. Indications for flexible colo-
noscopy include haematochezia, chronic diarrhoea
and abdominal and rectal pain. Moreover, this pro-
cedure is necessary in patients in the active disease
stage who do not respond to medical therapy. Also, it
may help those with atypical symptoms. As to
colonoscopy during pregnancy, few data are avail-
able because of the limited casuistics although gener-
ally it should be reserved exclusively for patients
where the diagnostic benefit is higher than the risk.
Endoscopic examination of the superior intestinal
tract is usually used less frequently than other proce-
dures even although many studies emphasise good
tolerability both for the expectant mother and the
foetus as well as its high diagnostic value in the case
of gastrointestinal bleeding.
Pharmacological Therapeutical Management of
IBDs During Pregnancy
As for therapeutic management of IBD during preg-
nancy, recent studies have shown that pregnant
patients should continue pharmacological therapy
for the duration of the pregnancy, with the primary
aim being to prevent disease relapse given the high
risk of negative effects on the foetus. It is necessary
that the physician perform a careful preliminary
evaluation of the risk/benefit ratio associated with
therapy during pregnancy, comparing any harmful
effect on the foetus and the expectant mother caused
by drugs on one hand and by disease relapse in the
absence of pharmacological treatment on the other
hand. The results of many studies [23] suggest that it
would be best to continue therapy during the disease
quiescent stage, treating intensively any recrudes-
cences given the higher danger of the latter in com-
parison with most available drugs [24].
For patients with IBD, the 5-aminosalicylate (5-
ASA) group (mesalamine, sulfasalazine, balsalazide),
which have become the mainstay of pharmacological
therapy of intestinal inflammatory diseases, may be
used on pregnant patients to induce and maintain
remission, as there is significant evidence regarding
their safety during pregnancy. Many patients may be
treated with aminosalicylates only [25–27].
However, for nonresponsive patients or for those
allergic to 5-ASA and/or suffering from a more
extended disease, corticosteroids are frequently pre-
scribed [28]. Corticosteroids are particularly indicat-
ed during the stages of moderate–serious activity
analogous to cases of the disease outside the preg-
nancy period. Many study attest to sufficient tolera-
bility of these drugs and their poor effect on the risk
of foetal malformations; despite their ability to cross
the placental barrier, they are rapidly transformed by
placental 11-hydroxigenasis in less active metabolites
with a consequent reduction of their levels in placen-
tal blood, especially in the case of some types of
steroids, such as prednisone. For this reason, sup-
pression of the hypothalamus-hypophysis-
suprarenal axis of the foetus is rare. Among the latest
steroidal compounds, Budesonide – a synthetic glu-
cocorticoid selectively released in the small bowel
and therefore particularly indicated in the case of
ileal localisation of CD – falls into classification cate-
gory C of drugs that may be used during pregnancy,
as a teratogenic effect was found in animals but not
in humans.
Another likely therapeutic option in non-respon-
sive patients or in patients allergic to first-choice
drugs is represented by immunosuppressant drugs
[30]. Rationale for their use is based on the recog-
nised immunomediated pathogenesis of IBDs,
including azathioprine, 6-mercaptopurine,
cyclosporine, methotrexate and infliximab. Azathio-
prine and 6-mercaptopurine [29], taken in the usual
doses, showed no negative effect on gametogenesis
or evidence of a likely teratogen effect. However,
given the poor number of studies investigating their
use in pregnant patients with IBD, it would be best
not to begin therapy with these agents during preg-
nancy.
Cyclosporine is not associated with an increased
risk of teratogenesis [29], but given the high inci-
dence of hepatic and kidney toxicity in the expectant
mother, it must be exclusively used in pregnant
women suffering from fulminating colitis who are
non-responsive to steroids in order to avoid an
urgent proctocolectomy, which is associated with a
high risk of losing the foetus.
Methotrexate [31] is an antimetabolite drug and
antagonist of folic acid. It is a teratogen and mutagen
and therefore is contraindicated during pregnancy in
those planning a pregnancy. Guinea pigs in utero
exposed to methotrexate develop craniofacial and
cardiovascular malformations and flaws of the neural
tube caused by this drug’s antagonism of folic acid.
For these reasons, patients with IBD beginning ther-
apy with methotrexate should use effective contra-
ceptive methodologies. If conception takes place and
interruption of pregnancy is not considered, high
doses of folic acid should be administered during the
entire course of pregnancy.
Recently, monoclonal antibodies (infliximab)
against tumour necrosis factor (TNF) [32] were
introduced as therapy for CD. In guinea pigs, these
molecules, belonging to the class of biologic drugs,
were not associated with a high risk of toxicity,
embryotoxicity or teratogenic effect, and from data
presently available, there is no definite evidence on
the outcome of a woman’s pregnancy. As rare cases
IBD and Pregnancy 137
of foetal death secondary to cerebral and/or pul-
monary haemorrhage were found, as well as cardiac
malformations such as Fallot’s tetralogy and prema-
ture delivery, and given the small amount of studies
regarding the effect of these drugs during pregnancy,
their use is contraindicated in pregnant patients with
CD and those planning to become pregnant.
In patients with IBD, some antibiotics, such as
metronidazole and the fluoroquinolones, are some-
times used [33] not only to treat intervening infec-
tions but as primary therapy to treat CD. However,
little data exists regarding the safety of antibiotics
during pregnancy. In particular, metronidazole is the
teratogen, foetotoxin and carcinogen in the mouse
but these effects were not found in humans. For this
reason short cycles of therapy with metronidazole
may be used relatively safely to treat vaginal candi-
dosis during pregnancy.
Regarding fluoroquinolones such as ciprofloxacin,
there is no evidence of possible harmful effect on the
foetus although available data are still limited.
In addition to the above-mentioned drugs, many
studies show that the quality of life of pregnant
patients may be incredibly improved by aspecific
symptomatic drugs active on more frequently report-
ed symptoms, such as abdominal pain, nausea and
diarrhoea [34]. Among these drugs, metoclopramide
(Plasil) may be used as an antiemetic without risk of
foetal damage. On the contrary, given the small
quantity of available data, loperamide, an antihemor-
rhoidal drug frequently used by patients with IBD,
must be taken cautiously and exclusively by patients
where probable benefits are higher than the risks. An
alternative to loperamide, kaolin with pectin or
cholestyramine may be used, the latter being sug-
gested especially in ileal localisation of CD or in
patients with gravidic cholestasis.
Musculoskeletal and some other forms of abdom-
inal pain may be treated safely with acetaminophen
whereas non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin, are contraindicated
because of the risk of premature delivery, extended
labour and extended postpartum haemorrhage [35].
How to Approach Delivery in Patients with IBD
On the basis of data given in the literature, patients
with RCU may expect ordinary labour and a trans-
vaginal delivery unless there are contraindications
connected with concomitant morbid conditions. This
consideration is generally valid also for patients who
underwent IPAA, as transvaginal delivery does not
seem to considerably compromise the integrity of
anastomosis [36]. However, as will be discussed later,
there is still no consensus regarding this subject.
Differently from pregnant women with UC, most
patients with CD, especially those with active per-
ineal involvement, should have a caesarean deliver. If
transvaginal delivery cannot be avoided, episiotomy
should be avoided [37]. If unavoidable, a mediolater-
al episiotomy is preferable in order to avoid anal
sphincter damage. According to recent studies,
development of new perineal complications after
transvaginal delivery, usually associated with epi-
siotomy, in patients without previous perineal dis-
ease is 17.9%. Moreover, while planning how to per-
form the delivery, the obstetrician should take into
account the specific features of each patient.
Restorative Proctocolectomy with Ileal Pouch
Anal Anastomosis and Women’s Health
The restorative proctocolectomy with IPAA (RP-
IPAA) is now a standard operation proposed for the
treatment of UC. It is a complex operation requiring
an expert surgical team. Despite the fact that it is gen-
erally performed in third-level centres only, compli-
cation rate is extremely high, varying in the studies
reported in the literature between 13% and 64%
[37–39]. Indications for this procedure are different
in emergency or elective surgery: toxic megacolon,
perforation or massive bleeding (in emergency sur-
gery] or failure of medical therapy and rectal dyspha-
sia/cancer (in elective surgery]. The operation great-
ly modifies the anatomy of the pelvic space because,
after resection of the entire colon and rectum, an ileal
reservoir (pouch] is engaged in the top of the anal
canal. Since 1978, the year of the first formal descrip-
tion of the operation, many women of child-bearing
age have undergone this operation. In the last 20
years, many studies have been published attempting
to analyse two aspects: how this operation may influ-
ence female reproductive health and whether preg-
nancy affects functionality of the ileal pouch.
RP-IPAA and Menses
In the literature, four major works analyse this aspect
[40–43]. These studies found that most patients
noted no change in menses or that initial cycle irreg-
ularity eventually disappeared.
IPAA and Pelvic Anatomy
As we will soon see, most studies show a reduction in
fertility after RP-IPAA. One hypothesis to explain
this phenomenon is the presence of postoperative
adhesions. Oresland [41] observed that, even if 20/21
138 G. Colucci, G.G. Delaini, F. Nifosì
women who underwent RP-IPAA had a normal phys-
ical examination, a hysterosalpingography showed
some anomalies in 67% of subjects (14/21). Finding
such as tubes adhered to the pelvis (48%) or bilateral
tubal occlusion (10%) may certainly explain the
decreased fertility, as recently emphasised by Dia-
mond [44]. An important bias in this work, however,
is the lack of performance of an examination before
surgery, making the comparison between the pre-
and postoperative situation impossible. Also, a study
by Sjogren [45] showed an altered endopelvic status
with reduced uterine mobility in 47% of women after
RP-IPAA or the presence of adnexal tenderness in
13%.
Female Sexual Function After RP-IPAA
Many studies examined sexual function after RP-
IPAA and particularly sexual satisfaction, desire,
ability to experience orgasm and coital frequency
[40, 43, 45, 46]. Results were satisfactory, as most of
these aspects are influenced very little by surgery.
However, a percentage of patients, ranging from 3%
to 18%, were afraid of having stool leaks during
intercourse. In contrast, especially in those with
postoperatively unchanged or increased coital fre-
quency from 82% to 100%, the appearance of dys-
pareunia was a rather frequent complication. Inci-
dence varied considerably, from 0% to 38% [41, 42],
stabilising in most works at 25%. Moreover, Farouk
found that the incidence of this complication after
surgery seems to increase over time [47].
RP-IPAA and Fertility
The desire to have a child is one of the primary
instincts of the woman. This may explain why many
women, despite the sequelae of such a serious sur-
gery, decide to have a child. As already seen, UC in
itself does not seem to influence fertility [6]. Almost
all studies present in the literature agree on ascribing
the serious negative effect of RP-IPAA on fertility
[40, 41, 43, 45]. However, these works contained
important methodologic bias or included a small
number of participants. Three recent publications
stand out, being points of reference on this topic.
Johnson et al. [48] compared 153 patients who
underwent RP-IPAA with 60 patients with UC but
treated with medical therapy. In this study, we come
to two essential conclusions:
1. Women who underwent surgery had an infertility
rate significantly higher in comparison with
women who did not undergo surgery (28.1% vs
13.3%).
2. Surgery is the key element to explaining this dif-
ference. If the infertility rate in women before sur-
gery matched that of patients treated with medical
therapy only (odds ratio 0.68, P=0.23), reduction
of the fertility rate in the same study group of
women evaluated before and after surgery is very
high (odd ratio 0.021, P<0,0001).
Moreover, through univariate data analysis, the
authors attempted to identify which variables might
influence the reduction in fertility. Surprisingly, only
the increase of age seemed to have a statistically
higher influence on fertility while the history of
small-intestinal obstruction, the number of abdomi-
nal operations and postoperative pelvic sepsis (three
events predisposing the development of adhesions)
did not seem to have any influence.
The other two important studies come from the
same Scandinavian group. In the first, the fertility
rate of a cohort of patients who underwent RP-IPAA
was compared with the expected number of births in
the general population [49]. Also in this study, the
fertility of patients with UC seemed to be slightly
reduced in the preoperative stage but is halved after
surgery. This reduction reaches the 35% if operated
patients who underwent in vitro fertilisation are not
included. In the second study, the fecundity rate of
290 women with UC who underwent surgery was
compared with 661 healthy women, showing in this
case also a reduction of fertility of 80%.
The implications of these studies are very impor-
tant for preoperative counselling, which must
explore the desire for maternity of women waiting to
undergo RP-IPAA and, if the clinical situation allows,
advise postponement of surgery until after pregnancy.
Ileal Pouch Function, Pregnancy and Delivery
There are at least two theoretical premises regarding
a negative effect of pregnancy on pouch function.
The first concerns the volumetric increase of the
uterus, with a consequent increase of endoabdominal
pressure (besides a direct compression effect on the
reservoir). The second concerns the worsening of
sphincterial function (it may already have been com-
promised after surgery) after vaginal delivery [50].
Surprisingly, most authors emphasise that pregnancy
influences pouch functionality in a small way [47,
51–53], limited to a few cases of slight worsening and
temporary incontinence, which generally disappears
after delivery.
Even though this topic has been discussed for a
long time, vaginal delivery is considered safe by most
authors. Two large, retrospective, controlled series
compare pouch function after vaginal delivery with
pouch function in nulliparous [47] or after caesarean
IBD and Pregnancy 139
delivery [52], showing no differences. All authors
emphasise, moreover, that episiotomy, especially
medial episiotomy, must be avoided. We should con-
clude, therefore, considering the risks connected
with caesarean delivery, it must be reserved for cases
in which there is obstetrical indication.
In 2005, the authoritative group of Fazio [54] pub-
lished a work that seems to refute what has been so
far written. Recognising that the effects of delivery on
sphincterial function in the short term are reduced, it
emphasises a high incidence of sphincter injuries
that can be detected with endorectal ultrasonogra-
phy. Using the words from the title of this work, “a
word of caution” is essential because, in the long run,
functional response to this sphincter damage will
need to be assessed. The authors suggested the oppo-
site of what thus far appears in the literature, as they
advise a planned caesarean delivery. In light of this
work, it is necessary to carefully evaluate each patient
in an attempt to assess the risk/benefit ratio between
the two delivery modalities.
Conclusion
UC and CD are inflammatory diseases of the intes-
tine, with a multifactor pathogenesis and the tenden-
cy to especially afflict young women of reproductive
age, affecting their quality of life as well as their inter-
personal relationships. In reference to this aspect, it
is important to emphasise the psychological effect of
the disease on patients’ sexual life, which can under-
mine the opportunity of having children despite the
fact that IBD itself does not considerably affect fertil-
ity. Moreover, even if pregnant women suffering
from IBD require strict monitoring, particularly con-
cerning the nutritional aspect and the need for
aggressive treatment of any disease relapses, risk to
the foetus or the expectant mother are moderate in
suitably controlled disease, and many concerns
about pregnancy and its possible consequences are
not justified.
Risks increase in insufficiently treated disease, as
in this case, relapses are frequent and invariably
influence foetal growth negatively, resulting in low
birth weight, premature delivery and miscarriage.
For this reason, it is necessary when treating young
women with IBD to apply a multidisciplinary
approach involving careful evaluation of patients’
psychosocial status and including discussion about
medical, psychological and sexual problems, inform-
ing and educating them about the peculiar aspects of
pregnancy and its management during IBD.
On the basis of the present trend, a patient with
IBD that is kept in a quiescent stage thanks to
increasingly effective medical therapies, most of
which are well tolerated during pregnancy, may
expect pregnancy course and outcome not too differ-
ent from those expected in young healthy women.
Acknowledgment
The authors thank Dr. Isabella Pichiri for her pre-
cious help and assistance.
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Introduction
Urogenital involvement is not rare in patients with
inflammatory bowel disease (IBD), but its real inci-
dence has not been defined yet, as demonstrated by
the wide range (4–27%) of percentages reported in
literature [1–6]. In 1943, Hyams et al. [7] described a
ureteral obstruction secondary to chronic enteritis.
According to them, that was the first case of urinary
disorder of the earliest 1 000 patients suffering from
Crohn’s disease (CD). In contrast, 40 years later, Kyle
stated that as many as 27% of patients with CD will
experience urinary disturbances during their life [2].
This apparent discrepancy simply reflects the fact
that urinary diseases in IBD patients were (and still
are!) often missed or misunderstood. This happens
mainly because symptoms are frequently absent or
modest and easily obscured by the more severe intes-
tinal problems. However, since minor urinary
involvement can result in serious illness (i.e. chronic
renal failure), it is important for surgeons and physi-
cians who deal with IBD patients, to be aware of these
frequent complications in order to know how to pre-
vent them, to be able to identify high-risk patients,
and to chose the most appropriate treatment when
these problems occur.
People with inflammatory bowel disease can also
experience sexual difficulties. The exact incidence of
this phenomenon is not known, as patients may feel
embarrassed in discussing it with the doctor. Howev-
er, it seems to be a common finding which is directly
related to the duration and extent of the disease [8].
This is obviously an important problem, especially
considering that IBD often affect young adults for a
long period of their life.
In 1992, a prospective case-control study among
50 women with CD which had been not surgically
treated, showed that although 45 of them had a stable
relationship, 24% had no intercourse, compared to
4% of the control group, and the reason for this was
mainly the frequent presence of abdominal pain and
diarrhoea or the fear of faecal incontinence [9].
As shown in Table 1, some of the urologic and sex-
Urinary and Sexual Involvement in IBD
Luigi Zorcolo, Giuseppe Casula
Table 1. Classification of urinary and sexual manifestations
and complications
Urinary involvement
Related to the disease
• Indirectly related (secondary to metabolic
derangements):
Urinary tract calculi
Cystitis
Amyloidosis
Nephritis (glomerulonephritis, interstitial
nephritis)
• Directly related (secondary to the inflammatory
process):
Perirenal or perivesical abscesses
Entero-urinary fistulas
Ureteral obstruction
Related to medical treatment
• Nephrotoxicity from medical treatment
Related to surgical treatment
Urinary tract calculi
Urinary retention
Ureteral injury
Sexual involvement
Related to the disease
Psychological aspects
Loss of libido
Generalised debility
Presence of cutaneous/perianal disease
Dyspareunia secondary to pelvic/perineal
inflammation
Related to medical treatment
Loss of libido
Impotence
Infertility
Vaginal dryness and atrophy
Related to surgical treatment
Neurological damage (impotence, retrograde
ejaculation)
Vaginal dislocation (dyspareunia)
Presence of stoma
142 L. Zorcolo, G. Casula
ual manifestations are the consequence of the meta-
bolic derangement associated with IBD, while others
result from a direct involvement of the urinary tract
due to the intestinal inflammatory process. In addi-
tion, some of them can be caused or favoured by
medical or surgical treatment.
Urinary Manifestations Related to the Disease
Urinary Tract Calculi
The risk of developing urinary tract calculi is 10–100
times greater in patients with IBD than in the gener-
al population (Fig. 1) [3]. The reported incidence
ranges from 1 to 25%[1–3, 6, 10–12]. The metabolic
derangement leading to this complication can be
either related to the disease itself or a consequence of
its treatment. Patients with CD are much more affect-
ed than those with ulcerative colitis (UC)[10, 13], and
the risk is increased after surgery.
Calculi are primarily composed of calcium oxalate
or uric acid. In general, calcium oxalate stones are
more frequent in patients who have extensive ileal dis-
ease or an ileal resection but who also have a function-
ing colon [14, 15], while uric acid calculi are typical of
patients with chronic diarrhoea due to extensive coli-
tis or ileostomy diversion. Because of their different
pathogeneses they will be discussed separately.
Uric Acid Stones
Generally, uric acid renal stones are likely to form in
the following circumstances: (1) increased excretion
of uric acid in the urine, (2) persistently concentrat-
ed urine, (3) persistently low urinary pH. The last two
conditions are often present in IBD patients; in fact,
chronic diarrhoea secondary to UC or to an ileosto-
my generates a loss of water, sodium and bicarbonate
salt, which are able to concentrate the urine and
lower its pH.
Clarke et al. [16] noticed that people with ileosto-
my produced about 300 ml less urine in a day than
the control population; moreover the mean urinary
pH was 5.05. At these levels, the solubility of uric acid
(which has a pKa of 5.7) is almost 12 times lower [10],
and this predisposes to crystallization and formation
of uric stones, even in the absence of hyperuricemia
and hyperuricosuria [17]. Other circumstances like
urinary tract infection, chronic ureteral obstruction,
high urinary calcium and oxalate concentration,
steroid use (because they increase intestinal calcium
absorption), prolonged bed rest (which favours calci-
um mobilisation from the bones), all increase the
chance of stone formation.
Calcium Oxalate Stones
Calcium oxalate is the most common type of kidney
calculi not only in IBD patients but also in the gener-
al population. However, in the latter, urinary oxalate
concentration is often normal and the formation of
stones is mainly secondary to the abnormalities in its
solubility.
In contrast, the pathogenesis in IBD patients
appears to be related to hyperoxaluria combined
with fluid depletion. It has been shown that hyperox-
aluria is present in two thirds of patients with ileal
disease, or those that have had extensive ileal resec-
tion [18], and this condition renders these patients
more prone to develop calculi. Hyperoxaluria, as
demonstrated by Chadwick et al. [15] via the use of
C14-labelled oxalate, is the consequence of an
increased enteric absorption of dietary oxalate,
which is 5 times greater in people with ileal disease
compared to control population (30% vs. 6%). Since
excessive oxalate is mainly absorbed by colonic
mucosa, colectomy or ileostomy patients do not
manifest this phenomenon [15, 19
, 20]. Enteric
hyperoxaluria mainly depends on two mechanisms,
both of which are related to bile salt and the conse-
quent fat malabsorption.
The first mechanism regards oxalate solubility.
Under normal conditions, oxalate binds with dietary
calcium to form insoluble calcium-oxalate, which is
eliminated with the faeces. However, the affinity of
calcium is higher for fatty acids than for oxalate.
Thus, in the presence of malabsorption, calcium is
mainly bound by non-absorbed fatty acids and this
Fig. 1. Bilaterally dilated renal calices, renal and ureteral cal-
culi (white arrows) and calcifications (black arrow) in a
patient with longstanding CD
Urinary and Sexual Involvement in IBD 143
leads to an indirect augmentation of the soluble
oxalate which can be easily absorbed by the colonic
mucosa [19, 21]. It has been estimated that hyperox-
aluria occurs if steatorrhea exceeds 12–15 g/day [15].
The second mechanism is an increase in perme-
ability of colonic mucosa which is irritated by non-
absorbed fatty acid and bile salts [20, 22]. A third
described effect of bile salt malabsorption is the inhi-
bition of a bacterium (Oxalobacter formigenes) which
normally degrades oxalate in the colon [23–25].
Other factors such as excessive fluid loss, hypomag-
nesuria and hypocitruria due to hypokalemia [26],
metabolic acidosis, steroid use and prolonged bed
rest, predispose to stone formation.
Treatment
Treatment of urinary stones in IBD patients does not
differ from treatment in the general population:
extra-corporeal shock wave lithotripsy (ESWL) is the
gold standard. When it fails, endoscopic procedures
are an option, while open surgery is rarely required
[27]. In case of complete persistent obstruction, espe-
cially if associated with infection, an immediate
decompression with either a ureteral stent or
nephrostomy may be necessary.
Prevention
Whatever the nature of calculi, the mainstay of pre-
vention is maintaining a good hydration and min-
imising diarrhoea or ostomy output in order to have
a urine volume of 1 500–2 000 ml/day. Patients at risk
should regularly have urinary measurements of uric
acid, oxalate, calcium, citrate, phosphate and pH, to
keep them in the proper range.
In the presence of low pH, potassium/sodium cit-
rate (30–60 mEq/day) can be used to alkalinise the
urine [28]. Sodium bicarbonate (650 mg x 3/day) is
an alternative but this can increase the risk of form-
ing calcium stones [29]. If hyperuricosuria persists
despite fluid intake and correction of urinary pH, the
patient can start allopurinol (300 mg/day). However,
it should be kept in mind that this drug may interact
with azathioprine/6MP [30].
Prevention of hyperoxaluria is mainly obtained
with diet: avoiding food high in oxalate (see Table 2)
may be sufficient, but generally it is more effective to
assume a low-fat diet and to substitute fats with
medium-chain triglycerides in order to reduce fat
malabsorption.
Different cations may be added to bind excessive
oxalatum resistant to dietetic measures, but all of
them have side effects. In fact, extra calcium
(1–2 g/day), which is often necessary in patients with
malabsorption, may lead to formation of calcium-
phosphate calculi [31]; aluminium may interfere with
phosphate absorption, while magnesium can exacer-
bate diarrhoea, thus minimising its potential benefit.
A good oxalate binder is cholestyramine (4–10 g/day)
[14]. Still, it may also increase bile salt losses and
worsen steatorrhea. To date there is not a single
accepted strategy for enteric hyperoxaluria and treat-
ment needs to be personalised on the basis of haema-
tological and urinary parameters (see algorithm in
Table 3).
Table 2. Food with high concentration of oxalate
Spinach
Beets
Nuts
Wheat bran
Wild fruits
Chocolate
Tea
Cola
Table 3. Treatment of enteric hyperoxaluria as adapted from Pardi et al. [30]
Phase I Warning
Increase fluid intake for urine output of 3 L/day
Low-oxalate diet
Low-fat (50 g/day) diet
Calcium supplementation (1–2 g/day) Needs monitoring of urinary Ca; potential high risk
of Ca-phosphate stones
Cholestyramine (4 g × 4 day) May exacerbate steatorrhea
Phase II (if stones recur despite Phase I treatment)
Alkalinisation of urine and citrate supplementation
(K citrate or Na citrate 30 mEq × 4 day)
Mg supplementation May exacerbate diarrhoea
Allopurinol 300 mg/day (if stone contains uric acid) Interaction with azathioprine/6MP
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