41 Fertility and pregnancy in inflammatory bowel disease

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41 Fertility and pregnancy in inflammatory bowel disease

WILLIAM CONNELL

Introduction

Most patients with inflammatory bowel disease (IBD) experience concerns regarding fertility and pregnancy at some point of their reproductive life.

These may relate to uncertainties concerning the future ability to have children, the wisdom and timing of pregnancy in IBD, the impact of disease on fetal development and delivery, and the safety of drug usage during this time. Anxiety regarding such issues is not always expressed, especially when the prospect of pregnancy is not a matter of immediate relevance. Nevertheless, many pregnancies are unex- pected, and it is important for the clinician to prepare patients for such a possibility by introducing a general discussion of the topic soon after disease diagnosis. More specific details can then be provided to those who are actually pregnant or planning parenthood in the near future.

In the past, attention has focused on the relevance of these issues among women with IBD. However, there is an increasing recognition that the disorder and its treatment may also impact on male fertility and the wellbeing of babies born to men with the condition.

Genetic counseling

Although no prenatal test for IBD is currently available, genetic counseling is still appropriate for couples contemplating pregnancy in which one or both partners have IBD. Generally, this involves a discussion of the estimated risk to an off^spring developing IBD as well as providing a perspective of the risk by highlighting background rates of mal- formation, miscarriage and perinatal death that apply in all pregnancies. Several studies have shown IBD tends to run in families, and a positive family history is reported to occur in 8-25% [1]. A higher

frequency of IBD occurs among relatives of patients with Crohn's disease (CD) rather than ulcerative colitis (UC), and among relatives of patients who are Jewish [2]. Where one parent has CD the empiric risk of a child developing CD or IBD is estimated to be 7.4%, and 10.5% respectively [1]. There is pre- liminary evidence suggesting the transmission of susceptibility to CD in off*spring may be higher if the affected parent with IBD is the mother [3]. If both parents have IBD the lifetime risk to children is quite high [4].

Because of a reluctance to use any medication during pregnancy, the indications for therapy and potential impact on fetal development are best dis- cussed prior to conception. The effects of medication include those related to their use during pregnancy and lactation, as well as those exerted on men and women receiving therapy prior to, and at the time of, conception. Women with active disease who are unwilling to accept any possible risk of medical treatment may be best advised to consider surgical therapeutic alternatives or, in special circumstances, arrange egg storage. The need for folic acid supple- ments, which are routinely recommended before conception to reduce the risk of neural tube defects, should be emphasized to women using sulfasalazine.

Fertility

Although experience from the 1950s and 1960s suggested fertility rates were lower among women with UC [5], contemporary evidence shows this is not the case, at least in those with an intact colon [6-8].

Two large uncontrolled studies from the UK showed that 70-81% of women with UC under the age of 45 conceived normally, depending on the rate of volun- tary birth control [7, 8]. The consistent finding in both studies was a 7-9% involuntary infertility rate, a figure that compares favorably with that occurring in

Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 16?>-11\.

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the general population. In contrast, fecundity (the biological ability to conceive) appears to be substan- tially reduced in women with UC who have under- gone restorative proctocolectomy, probably due to the development of pelvic adhesions [6].

Evidence shows fertility rates are decreased in females with CD. Early series suggested 32-53% of women with CD were infertile, especially those with Crohn's colitis [9, 10]. More recent surveys from Oxford and northeast Scotland recorded an involun- tary infertility rate of 12-14% [8, 11]. An extensive case-controlled study from five different European countries showed a significant reduction in the proportion of women with CD who became pregnant and a reduced number of offspring in this group [12].

There are several factors which may explain why women with CD have fewer pregnancies. Among these, the most important appears to be a personal preference to avoid pregnancy [13]. In some cases women are discouraged from becoming pregnant by clinicians who focus excessively on the possible negative effects of drug therapy during this time [14]. Reduced sexual activity is more common among women with CD, especially in those with perianal inflammation, because of dyspareunia, abdominal pain, diarrhea and fear of incontinence [15].

It is well recognized that suffasalazine may cause reversible infertility in men by reducing sperm motility and function [16]. This effect is usually transient, and not encountered with other 5-amino- salicylic agents. It has been presumed that this therapy accounts for the reduction in fertility observed among men with IBD. However, a study from the United Kingdom found that males with CD (but not UC) had fewer children, an effect that was independent of sulfasalazine usage [17]. The possible reasons for this finding are not explained, but a previous report has highlighted that long-term effects of disease activity or malnutrition may lead to oligospermia in some males with CD [18].

Neonatal outcome

According to the cumulative experience derived from several uncontrolled studies evaluating neona- tal outcome in pregnant women with UC and CD, the chances of delivering a normal, full-term, live infant appear to be generally good [5-11, 19-25].

However, two case-controlled surveys have observed higher rates of neonatal complications among

women with IBD [26, 27]. A population-based study of women who had single births in Sweden during a 12-month period showed an increased rate of Cesar- ian section, prematurity and low-birthweight infants among IBD patients compared to healthy controls [26]. Details regarding underlying disease diagnosis and degree of disease activity were not reported in this study.

There is no evidence from either uncontrolled or case-controlled studies that neonatal complications are increased in UC [5-7, 19-24, 28]. In contrast, less favorable neonatal outcomes have been observed in CD [12-13, 28,29]. A report from Denmark during a

10-year period showed a higher risk of prematurity and low-birthweight babies among women with CD compared to controls [29]. These findings support the findings of two earlier case-controlled studies in which an increased risk of prematurity was observed among patients with CD [12, 13].

There is considerable evidence linking disease activity, especially at the time of conception, to a higher frequency of fetal complications in IBD. In UC, women with quiescent disease at conception have higher rates of normal live births, and reduced rates of prematurity and spontaneous abortion compared to those with active disease at conception [22]. An increased rate of malformations has been described among medically treated women with active, but not inactive, UC [7].

In CD 80% of patients with quiescent disease at conception had a normal, uncomplicated live birth, compared to 50% of those with active disease [30].

Prematurity and spontaneous abortion are signifi- cantly increased in women with active disease at conception [25]. In women with active CD at conception, neonatal outcome is more favorable when inflammation improves during the remainder of pregnancy compared to when it is persistent [30].

Disease progress in pregnancy

In general the course of UC during pregnancy

depends on the degree of intestinal inflammation at

conception. According to the results of several

uncontrolled studies evaluating pregnant patients

with quiescent colitis at conception, approximately

two-thirds remain in remission and one-third

relapse. This proportion is similar to expected rates

in the non-pregnant UC population. However, if

colitis is active at conception, one-third improve,

one-third remain persistently active and another

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third deteriorate. In other words, if UC is active at conception, two-thirds continue to have ongoing, persistent inflammation throughout pregnancy [5-7,

19-20, 22]. These symptoms can be particularly troublesome to control, thereby requiring vigorous medical therapy. Data from Israel raised the possibi- lity t h a t relapses were m o r e c o m m o n when pregnancy was unplanned [23].

Disease activity at conception also determines the course of CD during pregnancy. Uncontrolled studies of patients with quiescent CD at conception indicate that 75% remain in remission. In contrast, disease that is active at conception is likely to remain in this state, or actually deteriorate during pregnancy [9-11, 25]. Furthermore, the more severe the disease at conception, the more likely it is to remain active during pregnancy [30].

Whereas early studies suggested that post-partum flare-ups in CD were common [9, 10], recent data suggest this is not the case [8, 11, 25]. The reason for such a discrepancy is not known, but possibly relates to the past practice of elective withdrawal of sulfa- salazine late in pregnancy due to concerns regarding the risk of neonatal kernicterus developing from sulfur-containing drugs [31]. In the light of further evidence showing this actual risk to be negligible, nowadays the drug is continued throughout this time [32].

The onset of UC in pregnancy or the puerperal period is not uncommon. In a study of 147 women with UC from Oxford, 8% experienced its onset during pregnancy and 4% post natally. Most cases were mild to moderate, and generally brought under control. Neonatal outcome was no different than if the disease preceded pregnancy [7]. The onset of CD appears relatively rare in pregnancy, possibly because of a natural reluctance to investigate pregnant women with pain and diarrhea. In the past the prognosis of such an event was thought to be poor [33], but data collected subsequently are more encouraging [8, 11, 25, 30].

Mode of delivery

For patients with quiescent colitis the risk of perineal sepsis following childbirth is low, and the mode of delivery is governed by obstetric indications [28]. It is unknown if patients with more active colitis are at higher risk of perineal complications. To avoid sphincter damage, Caeserian section has been advised for women with active, relapsing or fulmi-

nant disease, where the future prospect of ileoanal pelvic pouch surgery is high [34].

Information concerning the perianal conse- quences of vaginal delivery and episiotomy in patients with CD are conflicting. A highly selected survey of 117 female members of the Crohn's and Colitis Foundation of America who were free of perianal disease prior to pregnancy found 18%

reported the development of complications in this region following vaginal delivery, most of which occurred within the first 2 months [35]. In contrast, a larger population study from Canada showed vaginal delivery rarely initiated the development of perianal disease in women without a previous history of this problem, and did not evoke a deterioration of symptoms in those with pre-existing inactive perianal disease. However, one-quarter of patients with active perianal disease at birth experienced an aggravation of their condition after vaginal delivery [36]. Accordingly, Ceserian section seems justified for women with active perianal CD, but not when perianal disease is absent or inactive prior to birth. It is important for obstetricians to exercise excellent care of the perineum if vaginal delivery is to be undertaken, and when episiotomy is required a mediolateral incision is preferable to reduce the risk of rectal tear [35].

Patients who have previously undergone total colectomy and iloestomy have an increased risk of stomal complications during pregnancy. Chnically, this may result in stomal dysfunction, prolapse, skin irritation, leakage, and sometimes intestinal obstruc- tion [37]. Vaginal delivery may be undertaken in most of these patients without compromising maternal or neonatal outcome.

Patients who have previously undergone ileoanal pelvic pouch surgery for UC may experience an aggravation of stool frequency and incontinence during pregnancy. These effects are usually transient, and return to normal after delivery. Cesarian section is often recommended, though this practice is neces- sary only in patients with a scarred, non-compliant perineum, unless other obstetric reasons apply. For the majority of women with pelvic pouches, vaginal delivery and episotomy is well tolerated and rarely associated with the development of a rectal tear [38].

Investigations

Generally, investigations should be minimized

during pregnancy and undertaken only when there

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is a very good clinical reason to do so. Provided it is done with exquisite care, flexible sigmoidoscopy and biopsy may be performed during pregnancy. In contrast, more extensive evaluation by colonoscopy should be reserved only for exceptional cases where its u n d e r t a k i n g will influence m a n a g e m e n t decisions; in which case fetal monitoring should be performed [39]. Investigations containing ionizing radiation should be avoided. Where necessary, ultra- sound or magnetic resonance image scanning may be used to provide information regarding abscess formation or to assess bowel wall thickness. If obstruction or incipient toxic dilation is suspected, it is reasonable to perform a single plain abdominal X-ray. The risk of fetal toxicity from this investiga- tion is extremely small, and outweighed by the consequences of these potentially serious maternal complications [40].

Surgery

The indications for surgery in IBD during pregnancy are similar to those in the non-pregnant state, namely severe hemorrhage, perforation, obstruction or severe disease unresponsive to medical therapy. The risks to mother and baby increase when surgical intervention is unduly delayed. Fetal morbidity is probably related more to the effects of underlying disease rather than the operation itself, since bowel surgery in pregnancy for reasons other than IBD has a relatively low risk to fetus. Although maternal mortality from emergency surgery for fulminant UC during pregnancy is declining, the risk of fetal death and social morbidity among parents thereafter is high [41].

Drug therapy

In view of the evidence associating a more favorable neonatal outcome with inactive maternal IBD, pharmacotherapy is often required to control disease activity before conception and to maintain remission or treat flare-ups during pregnancy. Although drugs may be associated with side-effects, the risk to the fetus is greater from uncontrolled disease inflamma- tion [24]. The choice of agents depends on the severity of the disease, potential for side-effects, and the preference of the individual patient.

Clinical studies evaluating drug treatment in pregnant women with IBD are largely limited to 5- aminosalicylic acid drugs and corticosteroids.

Published data among IBD patients using other treatments in pregnancy are limited. Information regarding the safety of these drugs is mainly derived from the results of animal studies or clinical experi- ence among patients with other conditions, such as organ transplantation or connective tissue disorders.

A summary of the effects of commonly used drugs for IBD during pregnancy and lacation is shown in Table I.

5-Aminosaliylic acid

Sulfasalazine and other 5-aminosalicylic formula- tions appear to be safe in pregnancy when used in recommended doses [42, 43]. The rates of sponta- neous abortion, premature delivery, or congenital malformations for women with either UC or CD taking sulfasalazine are not increased [7, 11, 21, 22, 24]. A recent study showed that men with IBD who fathered a congenitally abnormal child were more likely to have used sulfasalazine [17]. Clinical series have demonstrated the overall safety in pregnancy of other 5-aminosalicylic formulations when used in low to moderate doses [43, 44]. A single case of renal insufficiency was reported in a newborn exposed to 4 g/day Pentasa during the mid-trimester [45]. Both sulfasalazine 5-aminosalicylic agents may be used during breast feeding, though isolated cases of tran- sient acute diarrhea in the newborn have been reported [46, 47]. Concentrations of sulfasalazine and sulfapyridine in breast milk are insufficient to cause kernicterus [32].

Corticosteroids

Controlled and uncontrolled studies in patients with

IBD, asthma and connective tissue disorders have

shown no overall increase in the rate of any mal-

formations nor fetal morbidity among babies

exposed to steroids during pregnancy [21, 42, 48,

49]. Animal studies indicate an increased risk of oral

cleft among offspring exposed to high doses of

corticosteroids [50], and a report from the 1950s

suggested this complication may also occur in

humans [51]. A controlled study of 468 pregnant

women treated with corticosteroids during preg-

nancy observed two cases of cleft palate in newborns,

compared to 0.2 expected - numbers that were too

small to be meaningful [52]. It can be presumed that

any possible risk of cleft lip or palate from steroids is

likely to be small, and one that must be weighed up

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Table 1. Effects of drugs used for IBD jn pregnancy and lacation

Drug Pregnancy Breast feeding

Sulfasalazine

5-Aminosalicylic acid

Risk of miscarriage, prematurity or malformations not increased. Folate supplements recommended

Probably safe in doses < 3 g/day; higher doses may be nephrotoxic

Safe - reduce dose if neonatal jaundice is present

Safe - occasional reports of reversible neonatal diarrhea

Corticosteroids

Azathioprine

6-Mercaptopurine

Methotrexate

Cyclosporine

Metronidazole

Ciprofloxacin

Probably safe - conflicting evidence regarding risk of oral cleft

Malformations do not appear to be increased, but possible.

Small risk of prematurity, low birthweight, fetal myelotoxicity, immunosuppression, transient chromosomal aberrations.

Potential toxicity must be discussed with parents in advance and used only when clinically necessary

Teratogenic in animals at high doses. Human data sparse, but so far reassuring. Risks probably similar to azathioprine

Contraindicated due to risk of congenital abnormalities and abortion

Possibly associated with prematurity and low birthweight

Safe in short courses ( < 10 days) but not recommended in high doses for prolonged periods

Defects in developing cartilage in animals.

Short courses in human probably safe but not recommended for prolonged periods

Safe

Not recommended due to risk of neonatal myelotoxicity or immunosuppression

Contraindicated

Not recommended

against the drug's known beneficial effects in appro- priate clinical circumstances. Women requiring pre- dnisolone should not be discouraged from lactation [53]. There are no pubhshed data regarding the use of controlled-release budesonide preparations during pregnancy.

Azathioprine/6-mercaptopurine

Of all the various drug options to treat IBD, the safety of azathioprine and 6-mercaptopurine during pregnancy is the most controversial. Historically, pregnant women were cautioned against using these agents, due to early concerns about teratogenesis [54]. However, further data during the past two decades from patients with organ transplantation or connective tissue diseases have shown azathioprine

to be generally well tolerated [55-58]. Occasional malformations have been reported, but the overall frequency is no different compared to observed rates in the general population, and no characteristic pattern of abnormality is evident [57, 58]. It is possible that the fetal immune system is transiently compromised from azathioprine exposure during the second and third trimesters, and this may result in growth retardation [59]. Cases of prematurity, neonatal myelotoxicity, thymic atrophy and transient chromosomal abnormalities have also been reported with azathioprine usage in pregnancy [58, 60].

Importantly, long-term follow-up effects among

children who were exposed to the drug antenatally

are lacking. One study in IBD observed no

congenital abnormalities or subsequent health

problems in 16 children born to mothers treated with

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azathioprine during pregnancy [61]. Provided the d r u g is used in r e c o m m e n d e d doses d u r i n g pregnancy, the risks associated with azathioprine appear to be small. Because potential complications may be serious, its use should be reserved for refractory maternal disease only.

Little clinical information exists concerning 6- mercaptopurine usage in pregnancy, leading to uncertainty about its safety [49, 62]. In animals, 6- mercaptopurine is teratogenic and long-term effects have been described on germ cells of exposed off- spring [63]. A study among patients with IBD observed rates of prematurity and significant congenital malformation to be 3% and 5% respec- tively [62]. Until more data are available the use of this drug in pregnancy will remain controversial.

Increasing attention has been drawn to the possi- ble effects of azathioprine or 6-mercaptopurine on spermatogenesis. Among 13 children born to fathers receiving 6-mercaptopurine for IBD at conception, the rate of congenital malformations and sponta- neous abortions was higher than in a control group of men who did not receive the drug [64]. In contrast, 58 of 60 babies born to male transplant recipients treated with azathioprine at conception were normal [65]. A recent study showed that semen quality was not affected by azathioprine, and in a small number of children born to fathers treated with azathioprine at conception, fetal outcome and post natal develop- ment were normal [66]. At present, there is insuffi- cient evidence to discourage the use of either azathioprine or 6-mercaptopurine in men contem- plating fatherhood.

Azathioprine is transferred to breast milk in small quantities, and lactating babies may be at slight risk of immunosuppression and myelotoxicity [67]. Its use is not generally recommended during breast- feeding, but a decision regarding this should take into account the benefits of breast milk, as well as the personal preference of the mother [58].

Cyclosporine

Occasionally, cyclosporine may be justified in pregnancy for patients with severe UC who would otherwise require emergency surgery. Two large ser- ies of transplant recipients receiving cyclosporine during pregnancy observed rates of congenital malformations that were similar to that expected in the general population [55, 68]. However, the drug has been associated with growth retardation and prematurity in patients with organ transplants [58].

Fetal and maternal outcomes were satisfactory according to a single case report when cyclosporine was administered during the second trimester for severe UC [69]. Due to concerns regarding possible nephrotoxicity or immunosuppression, cyclosporine has not been recommended during lactation. How- ever, a recent report showed concentrations of the drug in breast milk to be low, and breast-fed babies did not develop any adverse effects [70].

Methotrexate

The elective use of methotrexate is contraindicated in pregnancy because of its embyrotoxic and terato- genic effect [49]. The critical period of exposure is between 6 and 8 weeks of gestation, and the harmful effects on the fetus may be dose-related [71 ]. Its use in pregnancy can also be associated with fetal growth retardation, neonatal bone marrow suppression and possible chromosomal aberration [72]. Methotrexate may temporarily impair male fertility, and its effects can persist for several months after drug withdrawal.

Accordingly, men and women are advised to discon- tinue methotrexate for several months before attempting conception [49]. Methotrexate is excreted into breast milk in small amounts, and is contra- indicated during breast-feeding.

Antibiotics

Metronidazole and ciprofloxacin are increasingly

used as primary therapy for CD. According to two

large meta-analyses, treatment with metronidazole

for less than 10 days during the first trimester was not

associated with an increased risk of malformations

[73, 74]. Moreover, this therapy does not seem to be

associated with an increased frequency of stillbirths,

growth retardation or prematurity [75]. Ciproflaxa-

cin has been associated with the development of

arthropathy in the offspring of animals exposed to

the drug antenatally [76]. However, a prospective

study in humans demonstrated no increased risk of

malformations or musculoskeletal problems in 38

women receiving either ciprofloxacin or norfloxacin

during the first trimester for urinary tract infection

[77]. Nonetheless, there are no published data

concerning the safety of either drug in IBD, espe-

cially when given at high doses for a prolonged

period. Because the effects on breast-fed babies are

uncertain, their use in lactation is not recommended.

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Infliximab

There is little published information regarding the safety of infliximab on the developing fetus or breast- fed infant. Mutagenesis was not observed in preclini- cal studies with infliximab, and successful live births have occurred following its use in pregnancy [78].

However, the drug should not be used electively during pregnancy or lactation until more data are available.

Does pregnancy alter the natural history of IBD?

The future outcome of pregnancy in IBD cannot be predicted on the basis of what happened in a previous pregnancy [7]. However, it is possible that parity may improve the long-term outcome of IBD. A study of patients with CD showed the mean number of resections was lower and the interval between resections was longer in parous women than non- parous individuals [79]. A small study from Italy found rates of relapse from IBD to be reduced 3-4 years after delivery compared to the corresponding period prior to pregnancy [80].

Summary

Most women with IBD can expect an uneventful pregnancy. Evidence compiled over many years indicates the importance of controlling disease activ- ity at the time of conception and during pregnancy to optimize the outcome for mother and baby. For this reason drug therapy is often required to treat flare- ups and maintain remission during this time. Where possible, women with IBD should plan a pregnancy to coincide with times when the disease is quiescent, and drug treatment minimal. In practice, however, many pregnancies are unexpected or occur in women with active disease that requires intensive medical therapy. Provided adequate information has been supplied in advance of conception, much of the apprehension that accompanies these events can be substantially reduced. Ongoing supervision by the clinician during pregnancy and the puerperium pro- vides invaluable support, and enables maternal dis- ease flare-ups to be identified and treated as expedi- ently as possible.

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