SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

The management of inflammatory bowel disease during pregnancy is a particular challenge because adequate disease control before and during gestation is essential for both maternal and foetal health. As a practical problem this situation arises frequently, because a quarter of patients conceive after the diagnosis of their disease.

Many of the clinical, biochemical, radiological and endoscopic investigations that are used to monitor and assess disease activity are difficult to use and interpret during pregnancy. Furthermore, patients and clinicians often have concerns about the safety of medical and surgical treatments for the foetus.

This review is designed for the practising clinician, to guide the management of patients with inflammatory bowel disease before and during pregnancy. The literature is at times conflicting and data on some issues are scanty, therefore recommendations are based on the balance of evidence including, if necessary, extrapolation from other conditions.


WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Sulphasalazine is well recognized as a reversible cause of male infertility, requiring a 2–3 month recovery period.1 Beyond this it is speculated that inflammatory bowel disease itself may be a cause of subfertility. Studies have used a variety of methodologies including case-control design, comparison of fecundity before and after diagnosis,2, 3 and comparison of infertility rates to those in the general population. The definition of infertility has differed between studies and this may account for the variable rates of fertility described ( Table 1). Overall the picture that emerges is that fertility is nearly normal in ulcerative colitis, but is slightly reduced in Crohn’s disease, especially Crohn’s colitis. The cause of this infertility or subfertility is not known. Direct extension of the inflammatory process to include the fallopian tubes can occur,4 although less direct effects, such as poor nutrition and systemic inflammation, are probably more important.5 Decreased libido in either the patient or their partner, due to illness or specific complications such as perianal disease and rectovaginal fistulae, may also partially explain the subfertility. There is evidence to support this, in that there is reduced fecundity but not fertility in some studies, implying patient’s choice.2

Table 1.  . Studies of fertility rates in female inflammatory bowel disease patients Thumbnail image of

Overall the contribution of inflammatory bowel disease against the background rate of infertility of 10% in the general population is usually small.

WHAT ARE THE RISKS OF INHERITING THE DISEASE?

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

The fact that inflammatory bowel disease is at least partially genetically determined has been demonstrated by twin studies6, 7 and, more recently, by molecular genetic studies.8 From these studies it appears that the genetic component is more important in Crohn’s disease than in ulcerative colitis. The question that a prospective parent wants answered is ‘What is the risk that my child will develop this disease?’. Although many studies have assessed the prevalence of inflammatory bowel disease in relatives of probands, rather fewer have assessed the lifetime risk. Furthermore, the risk in Jewish families appears to be higher than in non-Jewish families. Studies show a lifetime risk of 11% with a parent with ulcerative colitis, and 0–7.4% with a parent with Crohn’s disease, if non-Jewish.9, 10 For Jewish families the comparable rates are 2.9–7.4% and 7.4–15.8%.9, 11 The wide variation in the results of the studies probably reflects different study groups (i.e. population-based vs. tertiary referral centre patients). In discussion with parents, lifetime risks of the disease of 5–10% for developing inflammatory bowel disease can be quoted. For Jewish families the figures are probably a few per cent higher. The risk to the offspring if both parents have inflammatory bowel disease is much higher, with prevalence rates of up to 36%,12 and presumably lifetime risk is even higher.

THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Many studies have described the pattern of both ulcerative colitis and Crohn’s disease in pregnancy. The belief, based on early reports, that inflammatory bowel disease is likely to run a severe course,13 has been replaced by an understanding that in most patients the pregnancy has remarkably little effect on disease activity.14[15][16]–17 This has most convincingly been demonstrated by studies comparing relapse rates in the period before conception with those during pregnancy and puerperium.15, 16 There is remarkably little difference between these time periods, with relapse rates of 38% vs. 44% per year (pregnancy and puerperium vs. before conception) in Crohn’s disease and 34% vs. 32% in ulcerative colitis. Because patients with active disease are less likely to conceive, conception is likely to occur during periods of remission. This would result in a tendency to underestimate the average risk of relapse in the non-pregnant state. Therefore the course of both diseases is, if anything, likely to improve during pregnancy. Indeed studies that have followed patients for up to 4 years post-partum show a reduced relapse rate as compared to preconception.18 Overall, however, about one-third of patients will still have a coincidence of disease relapse with pregnancy.

If a relapse does occur, predilection for the first trimester14, 15, 19[20]–21 and for puerperium4, 21, 22 have been observed. This increased risk in the puerperium has been disputed by other studies.15, 16, 19 Patients who developed the disease during their pregnancy were also thought to run a more severe course, but this too has been refuted by more recent reports.14

In summary, the frequency of relapses while pregnant is no greater than in the non-pregnant state. If relapses do occur, they tend to be in the first trimester.

THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Variation in study methodology has led to difficulty in comparing data from some of the largest studies. Studies should aim to record all gestations within a defined population, without bias to the eventual outcome of the pregnancy. Mogadam et al.23 identified 531 pregnancies in a national survey. However, the spontaneous abortion rate in the ‘no treatment’ group was 0.8%, 10 times lower than in the general population, and indicates a probable substantial recruitment bias. Kornfeld et al. used a case-linkage methodology to identify all pregnancies in women with inflammatory bowel disease booked for antenatal care, during a 2-year period in Sweden.24 This avoided incomplete ascertainment, but only late pregnancies (after booking for antenatal care) were studied, thus excluding pregnancies that resulted in early foetal loss. Ulcerative colitis was not differentiated from Crohn’s disease in this study. Seven hundred and seventy-three pregnancies were identified and compared with the 239 000 single pregnancies in non-inflammatory bowel disease patients during this period. Adjusted odds ratios for a variety of conditions were calculated, showing a significant risk for low birth weight babies (< 1.5 kg) odds ratio 2.2, prematurity (< 32 weeks) 1.9, and small for gestational age 1.4, in the inflammatory bowel disease patients. Reassuringly, the risk for late foetal/infant death was no greater than for the non-inflammatory bowel disease population.

Delineation of which characteristics of the disease (type, disease activity, treatment) affect pregnancy have been best studied by single centres, using interviews with the patients as well as hospital records. Tables 2 and 3 list the major studies of ulcerative colitis and Crohn’s disease and from these certain general conclusions can be drawn. The spontaneous abortion or stillbirth rate in both diseases is related to disease activity during the pregnancy.14[15]–16, 19, 25 In patients who remain in remission or have only mildly active disease, the spontaneous abortion rate is similar to the general population at approximately 10%. With increased disease activity the foetal death rate rises, with a combined abortion/stillbirth rate of 60% in severe Crohn’s disease,15 18–40% in active but non-fulminant ulcerative colitis16, 19 and 60% in fulminant ulcerative colitis requiring surgery.26 This effect appears not to be related to drug therapy, although this is inferred by showing that the drugs have no deleterious effects in quiescent disease.25 In addition no relationship of outcome to site of disease in Crohn’s disease or extent of disease in ulcerative colitis has been observed.15

Table 2.  . Studies of outcome of pregnancy in ulcerative colitics Thumbnail image of
Table 3.  .  Studies of outcome of pregnancy in Crohn’s disease Thumbnail image of

An increased rate of prematurity (before 37 weeks of gestation) is seen, and again appears to be related to the activity of the disease.2, 16 This has implications for the obstetric management of such patients. An increased frequency of low birth weight babies14, 19, 27, 28 is found in most, although not all, studies.16 There is a trend to lower birth weight in patients with more active disease, as expected.

Concern that either the disease itself or its treatment may result in congenital abnormalities has been addressed by a variety of studies. Although in one abstract 4/54 live births had uncharacterized ‘malformations’,28 in none of the larger studies was an increased risk of congenital malformations detected.14[15]–16, 21[22]–23, 25, 29, 30 [30] Patients can be reassured that there is no evidence of an increased risk of congenital abnormalities in inflammatory bowel disease.

Perianal Crohn’s disease

The added consideration in these patients is whether vaginal delivery with or without an episiotomy is contraindicated. Obviously, a Caesarian section may be preferred in the presence of active disease, as a vaginal tear or episiotomy may be slow to heal. Recently the issue of whether vaginal delivery and episiotomy may lead to the development or worsening of perianal Crohn’s disease has been raised.31 The evidence is scanty and with inactive disease there is no absolute contraindication to vaginal delivery.

Previous surgery

Patients with ileostomies have been shown to be capable of normal pregnancies.20, 21, 32 In a study by Porter & Stirrat, patients with ileostomies were shown to have lower haemoglobin during pregnancy,27 but apparently without ill-effect. Stomal problems of displacement or prolapse are not uncommon, but remit post-partum. The most serious complication described is intestinal obstruction, which may occur in up to 8% of ileostomies, and should be considered as a differential of any unusual abdominal pain.33 Vaginal delivery is possible, but a generous episiotomy may be necessary because of perineal scarring. Patients with ileal pouch anal anastomosis (IPAA) often have a deterioration in pouch function during pregnancy, with increased incontinence, pad usage and stool frequency, but this returns to normal post-partum.34, 35 Vaginal delivery irrespective of neonatal weight, length of labour or multiple births does not appear to lead to any long-term sequelae on pouch function. In Crohn’s patients, previous resections appear to increase the risk of prematurity, but have no effect on foetal loss.15 Indeed there are many reports of the use of parenteral nutrition for short bowel syndrome throughout pregnancy, with successful outcomes.36[37][38][39]–40

WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Most pregnant patients are concerned about the risk from medication to the developing foetus. Fortunately there is an extensive body of work on this subject, and guidelines and reassurance can be given ( Table 4).

Table 4.  . Drugs in pregnancy Thumbnail image of

Sulphasalazine

Sulphasalazine competitively inhibits the brush border enzyme folate conjugase, and can lead to folate deficiency. This is of particular relevance given the benefit of periconception folate supplementation in the prevention of neural tube defects.41 Inflammatory bowel disease patients will require a larger folate dose than the 0.4 mg/day recommended for women generally. Red cell folate levels may be used to assess the effectiveness of larger doses.

Sulphasalazine and its metabolite sulphapyridine have been shown to cross the placenta resulting in equivalent maternal and foetal serum levels.42 In addition it can be found in breast milk in significant amounts.42 This has raised two concerns: firstly, is there any effect on the growing foetus; secondly, can it lead to kernicterus in the neonate?

This drug has been studied in over 300 pregnancies. Although there have been occasional case reports of congenital abnormalities,43, 44 no harmful effects on the foetus or pregnancy have been observed in the larger studies.15[16]–17, 19, 23, 42, 45 The one exception was a study of the effects on fertility and offspring of inflammatory bowel disease and drug therapy in 1400 patients: around 60% of men took sulphasalazine and the rate of congenital malformations in their offspring was significantly greater than in non-users.46 However, the observed ‘high’ rate of congenital abnormalities of 2% was virtually identical to that of the reference general population (1.8%).

Initial concerns about sulphasalazine in the neonatal setting were raised because a related sulphonamide (sulphisoxozole) could cause kernicterus in neonates47 via its bilirubin displacing effect on albumin.48 Several studies have shown that there is no increased incidence of neonatal jaundice16, 19, 23, 45, 49 and it is accepted that sulphasalazine is safe unless the neonate suffers from pre-existing haemolysis. Only if a rhesus incompatibility between foetus and mother is suspected should sulphasalazine be avoided. Similar considerations apply to breast-feeding of an icteric neonate.

Newer 5-aminosalicylic acid preparations

5-ASA (mesalazine) crosses the placenta and is also found in breast milk in a similar fashion to sulphasalazine.50 The effects on male fertility seen with sulphasalazine are not apparent with 5-ASA preparations.51 The literature regarding the clinical use of 5-ASA in pregnancy is slowly increasing. Three short series detail 11, 19 and 19 pregnancies, respectively,52[53]–54 and an abstract based on pharmacovigilance by Ferring Laboratory (which incorporates some of these series) describes the outcome of 76 pregnancies.55 In this later series three congenital malformations were reported (cataract, thumb, cardiac), but the only worrying case involved a child with renal insufficiency. The woman involved took 4 g/day (Pentasa) for 5 weeks in her second trimester. The foetus developed bilateral renal hyperechogenicity between the 17th and 21st weeks of gestation. Subsequently the neonate had renal impairment that improved over the following 6 months, and a renal biopsy that revealed an interstitial fibrosis and tubular atrophy.56

A controlled cohort study by Diav-Citrin et al.57 compared the outcome of 165 women exposed to 5-ASA during pregnancy with a matched control group. One hundred and forty-six had taken 5-ASA during the first trimester, and 20% had taken greater than 3.2 g/day. There was an increase in pre-term deliveries (13% vs. 5%), a decrease in mean maternal weight gain (13.1 kg vs. 15.6 kg) and a decrease in mean birth weight (3.3 kg vs. 3.5 kg). However, there was no difference in the rates of congenital abnormalities, abortions, live births or foetal distress.57

5-ASA should be considered safe in pregnancy, with the proviso that higher doses (i.e. ≥ 3 g/day) carry a potential risk of foetal nephrotoxicity. In scenarios where higher doses are considered it may be more appropriate to use corticosteroids.

Corticosteroids

Corticosteroids cross the placenta but the maternal:foetal ratio of serum concentrations varies depending on the actual steroid used. Dexamethasone and betamethasone are less efficiently metabolized by the placenta than prednisolone,58 whose foetal levels are only 10–12% of those in the maternal serum.55 Animal studies in rodents have shown that corticosteroids during pregnancy can lead to an increased frequency of cleft palate in the offspring.59

Given the range of indications for corticosteroids, it is unsurprising that there is considerable experience of their use during human pregnancy. Individual series of their use in rheumatoid arthritis,60 SLE61 and antiphospholipid syndrome62 have not revealed an increased risk of foetal malformations. A review of 468 pregnancies in the literature revealed a greater than expected frequency of cleft palates (2 vs. 0.2 expected).63 Whether this represents a real increase could not be determined, but given animal models showing an increase in cleft palates,59 it warrants further surveillance. The largest series in inflammatory bowel disease comes from Mogadam et al., in which 168 mothers received corticosteroids for a significant period of their pregnancy with no increased risk of congenital malformations,23 but this study may have been subject to recruitment bias. The observation of the increased risk of spontaneous abortion, stillbirth and pre-term labour in women taking corticosteroids19 is almost certainly secondary to the disease process and not the drug.1

There is a theoretical risk of adrenal suppression in the mother and foetus after long-term use of corticosteroids. In common with the perioperative practice of giving an increased dose of corticosteroids, mothers should receive supplemental doses during labour. Several studies have assessed adrenal function in neonates of mothers using long-term corticosteroids without showing any evidence of adrenal suppression.64 It would be advisable to use a corticosteroid that results in low foetal levels, such as prednisolone, to continue to avoid this potential complication.

Corticosteroids are transferred into breast milk, but in low concentrations. A 4 h delay after oral dosing and before nursing will reduce neonatal exposure.65

Metronidazole

Extensive animal studies have not revealed any teratogenicity or increased foetal loss with metronidazole.66 Although there have been case reports of congenital abnormality,67 in larger unbiased series there have been no reported problems arising from its use in pregnant women.68 While almost certainly safe, alternatives treatments are at least as efficacious in inflammatory bowel disease, and its use would not be recommended.

Ciprofloxacin

Animal studies have revealed no evidence of teratogenicity with ciprofloxacin; however, it can cause arthropathy in immature animals.69 In one study using a prescription-event monitoring system, the use of quinolones was recorded in 307 pregnancies, including 55 women in the first trimester: no congenital abnormalities were recorded.70 A more detailed analysis of 38 pregnancies associated with quinolone use revealed an increased Caesarian section rate but no foetal abnormalities.71 While probably safe, alternative treatments are at least as efficacious in inflammatory bowel disease, and so the use of ciprofloxacin would not be recommended.

Azathioprine/6-mercaptopurine

Azathioprine crosses the placenta but usually in its inactive form. In animal studies at suprapharmacological daily doses (20 mg/kg), azathioprine can cause foetal loss. However, at lower doses (2–4 mg/kg), normal foetal development can occur.65 It has been shown to be teratogenic in mice and rabbits but not in rats. This variability in species sensitivity may be due to different metabolism of the drug, and reinforces the need to study the evidence in humans.72

Most of the literature derives from the experience in female kidney transplant recipients. In a detailed report of 238 such pregnancies, 93% were maintained on azathioprine, usually in addition to steroids. Seven per cent of pregnancies resulted in a spontaneous abortion, and 3% in a stillbirth, while 52% of births were premature. Neonatal complications were recorded in 30%, although this included apnoea and jaundice, as well as some congenital abnormalities (although a breakdown was not included). There was a 2.4% neonatal death rate.73 Obviously the post-transplant setting has considerable differences in immunology and in polypharmacy to that of inflammatory bowel disease, and the evidence suggests that this worrying picture may not translate to a different setting.

The evidence in the inflammatory bowel disease setting is considerably less extensive. Alstead et al.72 reported 16 pregnancies in 14 women, with the concurrent use of azathioprine (seven continued medication throughout gestation). There were two elective terminations and two premature births delivering healthy infants. All the other pregnancies were normal.72 Francella et al.74 report on 72 pregnancies in patients taking 6-mercatopurine or azathioprine (only eight continued medication throughout gestation). There was an 18% spontaneous abortion rate, 4% significant congenital abnormality rate and in one case a Wilm’s tumour developed in the child. These rates were nearly identical to those in pregnancies in patients either before or after the use of these immunosuppressants. The authors conclude that this supports the safety of these drugs; however, further follow-up is required.74

A neonatal side-effect of the maternal use of these drugs can be myelosuppression. In monitoring the maternal dose one should be aware of the different haematological normal ranges during pregnancy. Maternal leucopenia can predict subsequent neonatal myelosuppression.

There are few alternatives to azathioprine/6-mercaptopurine in controlling steroid dependent or resistant inflammatory bowel disease.75 Because failure to control active disease may lead to foetal loss rates of up to 60%, these drugs should be continued if the indications are clear. Sometimes a patient has been maintained in remission for several years, and in these circumstances withdrawal of the drug before conception can be considered.

Methotrexate

Methotrexate is a folic acid antagonist, and is used as an alternative to azathioprine in the treatment of steroid dependent or resistant Crohn’s disease.76 In animal studies it has been shown to be both teratogenic and embryotoxic.65 Indeed methotrexate at higher doses is used therapeutically to abort tubal pregnancies.77 Against this background it is not surprising that there are few data regarding its use in human pregnancy. Folic acid supplementation protects against the development of neural tube defects. Therefore it is no surprise that in a review of 14 pregnancies in patients on methotrexate, two infants were born with spina bifida.78 Equally the high spontaneous abortion rates reported, ranging from 37 to 44%, are expected from methotrexate’s embryotoxicity.78, 79

The evidence clearly contraindicates the use of methotrexate during pregnancy, especially as azathioprine/6-mercaptopurine provides a safer alternative for the vast majority of patients. Less clear is the advice that should be given to mothers who unexpectedly conceive while on the drug. While 40% of the pregnancies will end in spontaneous abortions, some will lead to congenital malformations. The neural tube defects can be screened for by obstetric ultrasound, maternal serum and amniotic fluid α-foetoprotein. However, other abnormalities, such as stenosis of the tubular long bones and abnormal facial features,80 are not detectable by such screening. Not all the infants will be affected79 and the difficult question of a therapeutic abortion without definite evidence of an abnormality will need to be discussed with the parents.

Methotrexate is found at low levels in breast milk; however, it is unlikely that the mother will be commenced on methotrexate in the puerperium. If she is, breast-feeding should be contraindicated.81

Cyclosporin

Cyclosporin has recently found a role in the treatment of severe ulcerative colitis.82 Its use delays surgery in many patients, and in up to half avoids it altogether.83 Therefore it is of particular interest for severe attacks in the second trimester of pregnancy, where delaying surgery for a few weeks may be of profound importance for the viability of the foetus. Unlike other immunosuppressive agents, cyclosporin does not affect cell proliferation, but interferes with IL-2 signalling in T lymphocytes. Theoretically this makes it a safer drug for a growing foetus to be exposed to. This is supported by animal studies showing no effect on organogenesis.84 A well recognized side-effect of cyclosporin in adults is renal impairment, and there is evidence from animal studies of renal proximal tubular damage in foetuses, although at higher than therapeutic doses.85 Other concerns raised have been the effect on foetal T cell subsets and the development of autoimmunity.86

Most of the experience in human pregnancy is again derived from transplant patients, with their obvious differences to inflammatory bowel disease patients. Armenti et al. reported a series of 154 pregnancies in 115 women, but interpretation is further complicated in that 70% were also on azathioprine.73 The comparison group in this study were transplant patients on a non-cyclosporin based immunosuppresion regimen (92% azathioprine-based). The addition of cyclosporin increased maternal hypertension, serum creatitine levels, foetal loss (19%) and rates of prematurity (56%). There was evidence that the cyclosporin-treated patients had greater co-morbidity before pregnancy. Despite this, there were less neonatal complications (21%), only one neonatal death, and no pattern of congenital malformation emerged. This is in agreement with a Norwegian series which also revealed increased miscarriage and prematurity rates.87 The issue of foetal nephrotoxicity was addressed by a follow-up study of 22 neonates, whose mothers used cyclosporin during the pregnancy. None had evidence of renal impairment.88 There is only a single case report of cyclosporin use in pregnancy for ulcerative colitis. In this case the patient was treated for steroid resistant toxic megacolon in her 29th week of gestation. The exacerbation was controlled, and she delivered, by Caesarian section, a healthy boy at 36 weeks.89

Cyclosporin’s safety profile in pregnancy is at least as good as that of azathioprine. Cyclosporin can be used to delay surgery when this is necessary to allow for foetus maturation. The length of delay in surgery needed to significantly improve the neonate’s chance of survival should be included in any consideration about using the drug. For instance, at 36 weeks of gestation a neonate’s chance of survival is high, while at 24 weeks a 1-month delay might prove invaluable.

Cyclosporin passes into breast milk, and so breast-feeding is contraindicated to avoid neonatal immunosuppression.

Total parenteral nutrition

There are many case reports of the use of total parenteral nutrition to sustain pregnancy in inflammatory bowel disease36[37][38][39]–40, 90[91]–92 or other conditions.93 There have been concerns raised about possible placental fat embolization leading to placental insufficiency. However, in most of the case reports, fat emulsions were used and the placenta appeared to be unaffected.39 Obviously nutritional requirements are significantly different during pregnancy and more intensive monitoring is warranted.38

Surgery

Decisions about the timing and appropriateness of surgery are often challenging. In situations with an absolute indication for surgery, such as intestinal perforation in Crohn’s disease or toxic megacolon in ulcerative colitis, decision making is easier. Unfortunately a more common scenario is a severe exacerbation that has only poorly responded to medical therapy.94 In this case there is a natural reluctance to proceed to surgery, either in the belief that the patient may respond eventually, or that surgery will be harmful to the foetus. There are few reports of surgery for inflammatory bowel disease in pregnancy on which to base recommendations.

From 1951 to 1987 there were only 35 cases in the literature of fulminating ulcerative colitis requiring surgery, with a 29% maternal and 53% foetal mortality.26 There are even fewer reports of surgery for Crohn’s disease.15, 95, 96 The perception arose that surgery in pregnancy resulted in a high maternal and foetal mortality. This contrasts with the extensive experience from non-obstetric, non-inflammatory bowel disease surgery in pregnancy. Planned procedures in the second trimester resulted in no significant increase in perinatal mortality in two major studies.97, 98 Surgery for uncomplicated appendicitis results in a 1.5% foetal loss rate. Similarly, for cholecystectomy, if uncomplicated, the foetal loss is about 5%. However, if there is peritonitis the foetal losses can increase to 40%.99 The foetal loss does not result from the anaesthestic or uncomplicated surgery, but as a result of the severity of the underlying maternal pathology. In addition, as Kammerer states, ‘the procrastination and confusion often associated with such cases may lead to more complex surgery and intraoperative and post-operative problems’99 which may explain the high mortality from surgery in inflammatory bowel disease. Other studies confirm that delays occur in the diagnosis of an acute abdomen during pregnancy.100 It is conceivable that in our patients the natural reluctance to proceed to major surgery leads to a worse outcome for both mother and neonate. Anderson et al. described four women who relapsed between the 28th and 37th weeks of gestation. Three made sufficient response to medical treatment that they were allowed to proceed to labour an average of 4 weeks later. This resulted in two stillbirths and one living neonate. All three women required colectomy in the following days or weeks. The fourth case also relapsed at 28 weeks of gestation but because of a toxic megacolon had surgery at 31 weeks and delivered 2 weeks later.26 Surgery in this case seems to have resulted in a better outcome than continuing medical treatment.

Definitive evidence that surgical management of severe inflammatory bowel disease is better than continuing medical treatment does not exist, but from the available data it seems likely. The role of surgery in the management of toxic megacolon is clear, but severe disease, unresponsive to medical treatment, should be no less clear an indication. Indeed, perhaps the threshold for surgery should if anything be lower in pregnant women, in view of the high foetal losses.

A variety of operations for inflammatory bowel disease have been performed during pregnancy, including panprotocolectomy,26 subtotal colectomy with ileostomy and mucous fistula101 or rectal stump,26, 102, 103 right hemicolectomy95, 96 with primary anastomosis or defunctioning ileostomy,95 combined subtotal colectomy and Caesarian section,104 sigmoid colectomy and primary anastomosis.95 Some conclusions can be drawn from these varied reports. First, primary anastomosis following whichever operation carries an increased risk of dehiscence and a covering defunctioning stoma is preferred.105 Second, if the foetus is sufficiently mature, combining a Caesarian section with the intestinal surgery is probably the optimal procedure.

HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Biochemistry and haematology

An accurate assessment of disease activity is often difficult clinically, and information from biochemical and haemotological parameters are incorporated into disease activity scoring systems. However, there are normal physiological changes in these laboratory parameters during pregnancy that should not be attributed to pathological processes ( Table 5).106[107][108][109][110][111]–112 The most significant changes are in the serum albumin and ESR. Both are incorporated into many scoring systems,113, 114 as well as being used on their own as a guide to disease activity. A serum albumin of 30 g/L, an ESR of 40 mm/h and a haemogloblin of 11 g/dL in a woman in her third trimester may reflect perfect health. As a result modest changes in these tests must be interpreted cautiously.

Table 5.  . The effect of pregnancy on haematological and biochemical tests Thumbnail image of

C-reactive protein (CRP) levels are not substantially altered by pregnancy, and remain valuable in monitoring disease activity.

Endoscopy

Rigid sigmoidoscopy and rectal biopsy are part of the routine assessment of disease activity in ulcerative colitis patients, and can be performed safely during pregnancy without risk to the foetus.5, 32, 115 More extensive evaluation of the colon is required if the results might significantly affect the management of the patient. Indications include delineating the extent of disease in ulcerative colitis (changing from topical to oral steroids) and assessing possible colonic or anastomotic stricture formation in Crohn’s disease (avoiding laparotomy for a presumed stricture). In these scenarios both flexible sigmoidoscopy and colonoscopy can be performed safely,116 although with additional monitoring of the foetal heart rate. The most experienced endoscopist and the least extensive procedure possible should be used.

Ultrasound

This is used extensively in obstetric practice and is the safest form of radiological imaging. Traditionally used in inflammatory bowel disease management to assess abscess formation, additional information on bowel wall thickness (as evidence of active inflammation) can be obtained.

Abdominal X-ray

There is a natural reluctance to expose mother and foetus to X-rays, although the actual risks vary considerably during the pregnancy. These risks have been extensively reviewed by Mole117 and more recently by Brent.118Table 6 summarizes their conclusions. Risk estimates are given for foetal exposure doses of 1 and 5 rads, because it may not be possible to detect any increased risk at the lower dose. The mean foetal radiation dose from an abdominal X-ray is 0.1 rad119 (posterior–anterior < anterior–posterior). In mothers not exposed to X-rays there will be 350 cases of congenital malformation, mental retardation or childhood leukaemia resulting from every 10 000 pregnancies. Extrapolating from Table 6, 10 abdominal X-rays (1 rad) in the first 4 months of pregnancy would result in an increase of between 0 and 3 cases in every 10 000 pregnancies of these conditions. Therefore, in the management of toxic megacolon, the risks to the foetus of an abdominal X-ray (1 in 30 000) compared to the condition being poorly managed (60% foetal mortality rate) indicate that the patient should be imaged as would a non-pregnant patient.

Table 6.  The effects of ionizing radiation during pregnancy on the foetus and neonate Thumbnail image of

Magnetic resonance imaging

As a non-ionizing radiation imaging system, MRI can be used safely during pregnancy. Indeed it is now being introduced into regular obstetric practice.120 There is a case report of its use in diagnosing terminal ileal Crohn’s disease in two women during pregnancy.121

Summary of disease assessment

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Flexible sigmoidoscopy and rectal biopsy are the optimal investigations in the diagnosis and management of ulcerative colitis during pregnancy. In terminal ileal Crohn’s disease, ultrasound or MRI provide the safest radiological confirmation but plain radiography may be used. Monitoring of disease activity is made more difficult by the changing normal ranges for haemogloblin, ESR and serum albumin, although CRP levels remain unchanged. Colonoscopy can be performed with suitable foetal monitoring but is rarely indicated. In fulminant colitis the risk to the foetus of an X-ray (1 in 30 000) is insignificant compared to that of the disease (20–60% foetal mortality).

MANAGEMENT STRATEGY

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References

Discussions on fertility and pregnancy should be incorporated into the general education of a patient, because a quarter of patients conceive after the diagnosis of their disease.30 A patient should expect to be able to conceive, carry a foetus to full term and deliver a healthy baby, as for the general population, if the disease is inactive. This will allay unspoken fears in many cases, and also allow preconception planning of medical treatment (i.e. folate supplementation, stopping certain immunosuppressants). Discussions on the risks of inheritance should probably be initiated by the patient. At the beginning of a pregnancy more detailed reassurance should be given about the safety of the drugs and the importance of maintaining good control of disease activity.

Most of the drug armentarium for inflammatory bowel disease can be used safely during pregnancy, but as with any prescription in pregnancy the benefit must be clear. Relapses of disease should be treated aggressively, because the danger to the foetus results from the active disease and not the drug regimens. Non-urgent endoscopy should be deferred but, again if the indication is clear, it can be conducted safely. In severe and life-threatening disease the best interest of the foetus is the appropriate management of the mother’s inflammatory bowel disease. In these circumstances the indications for imaging are unaltered by the pregnancy, and surgery should be delayed only if aggressive medical treatment might allow critical maturation of the foetus.

References

  1. Top of page
  2. Abstract
  3. WHAT IS THE EFFECT OF INFLAMMATORY BOWEL DISEASE AND ITS TREATMENT ON FERTILITY?
  4. WHAT ARE THE RISKS OF INHERITING THE DISEASE?
  5. THE EFFECTS OF PREGNANCY ON INFLAMMATORY BOWEL DISEASE
  6. THE EFFECT OF INFLAMMATORY BOWEL DISEASE ON PREGNANCY
  7. WHAT TREATMENT IS APPROPRIATE DURING PREGNANCY AND BREAST-FEEDING?
  8. HOW CAN DISEASE ACTIVITY BE ASSESSED DURING PREGNANCY?
  9. Summary of disease assessment
  10. MANAGEMENT STRATEGY
  11. References
  • 1
    O’morain C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984; 25: 1078 84.
  • 2
    Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease. Gastroenterology 1990; 99: 987 94.
  • 3
    Mayberry JF & Weterman IT. European survey of fertility and pregnancy in women with Crohn’s disease: a case control study by European collaborative group. Gut 1986; 27: 821 5.
  • 4
    Fielding JF & Cooke WT. Pregnancy and Crohn’s disease. Br Med J 1970; 2: 76 7.
  • 5
    Korelitz BI. Inflammatory bowel disease in pregnancy. Gastroenterol Clin North Am 1992; 21: 827 34.
  • 6
    Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability influence of smoking. Gut 1988; 29: 990 6.
  • 7
    Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. Br Med J 1996; 100: 350 8.
  • 8
    Satsangi J, Parkes M, Louis E, et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 1996; 14: 199 202.
  • 9
    Yang H, McElree C, Roth M-P, Shanahan F, Targan SR, Rotter JI. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993; 34: 517 24.
  • 10
    Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn’s disease: Increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology 1996; 111: 597 603.
  • 11
    Roth M-P, Petersen GM, McElree C, Vadheim CM, Panish JF, Rotter JI. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology 1989; 96: 1016 20.
  • 12
    Bennett RA, Rubin PH, Present D. Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease. Gastroenterology 1991; 100: 1638 43.
  • 13
    Banks BM, Korelitz BI, Zetzel L. The course of nonspecific ulcerative colitis: review of twenty years’ experience and late results. Gastroenterology 1957; 32: 983 1012.
  • 14
    Khosla R, Willoughby CP, Jewell DP. Crohn’s disease and pregnancy. Gut 1984; 25: 52 6.
  • 15
    Nielsen OH, Andreasson B, Bondesen S, Jacobsen O, Jarnum S. Pregnancy in Crohn’s disease. Scand J Gastroenterol 1984; 19: 724 32.
  • 16
    Nielsen OH, Andreasson B, Bondesen S, Jarnum S. Pregnancy in ulcerative colitis. Scand J Gastroenterol 1983; 18: 735 42.
  • 17
    Levy N, Roisman I, Teodor I. Ulcerative colitis in pregnancy in Israel. Dis Colon Rectum 1981; 24: 351 4.
  • 18
    Castiglione F, Pignata S, Morace F, et al. Effect of pregnancy on the clinical course of a cohort of women with inflammatory bowel disease. Ital J Gastroenterol 1996; 28: 199 204.
  • 19
    Willoughby CP & Truelove SC. Ulcerative colitis and pregnancy. Gut 1980; 21: 469 74.
  • 20
    McEwan HP. Ulcerative colitis in pregnancy. Proc R Soc Med 1972; 65: 279 81.
  • 21
    De Dombal FT, Watts JM, Watkinson G, Goligher JC. Ulcerative colitis and pregnancy. Lancet 1965; 2: 599 602.
  • 22
    De Dombal FT, Burton IL, Goligher JC. Crohn’s disease and pregnancy. Br Med J 1972; 3: 550 3.
  • 23
    Mogadam M, Dobbins WO, Korelitz BI, Ahmed SW. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981; 80: 72 6.
  • 24
    Kornfeld D, Cnattingius S, Ekbom A. Pregnancy outcomes in women with inflammatory bowel disease—A population-based cohort study. Am J Obstet Gynecol 1997; 177: 942 6.
  • 25
    Woolfson K, Cohen Z, McLeod RS. Crohn’s disease and pregnancy. Dis Colon Rectum 1990; 33: 869 73.
  • 26
    Anderson JB, Turner GM, Williamson RC. Fulminant ulcerative colitis in late pregnancy and the puerperium. J R Soc Med 1987; 80: 492 4.
  • 27
    Porter RJ & Stirrat GM. The effects of inflammatory bowel disease on pregnancy: a case-controlled retrospective analysis. Br J Obstet Gynaecol 1986; 93: 1124 31.
  • 28
    Bortoli A, Tatarella M, Prada A, et al. Pregancy and inflammatory bowel diseases. Ital J Gastroenterol Hepatol 1997; 29(Suppl. 2): A13.
  • 29
    MacDougall I. Ulcerative colitis and pregnency. Lancet 1956; 2: 641 3.
  • 30
    Baiocco PJ & Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 1984; 6: 211 16.
  • 31
    Brandt LJ, Estabrook SG, Reinus JF. Results of a survey to evaluate whether vaginal delivery and episiotomy lead to perineal involvement in women with Crohn’s disease. Am J Gastroenterol 1995; 90: 1918 22.
  • 32
    Webb MJ & Sedlack RE. Ulcerative colitis in pregnancy. Med Clin North Am 1974; 58: 823 7.
  • 33
    Hudson CN. Ileostomy in pregnancy. Proc R Soc Med 1972; 65: 281 3.
  • 34
    Juhasz ES, Fozard B, Dozois RR, Ilstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. An extended evaluation. Dis Colon Rectum 1995; 38: 159 65.
  • 35
    Metcalf A, Dozois RR, Beart RW Jr, Wolff BG. Pregnancy following ileal pouch-anal anastomosis. Dis Colon Rectum 1985; 28: 859 61.
  • 36
    Abboud P, Messing B, Quereux C, Napoleone C, Zeitoun P, Wahl P. Crohn’s disease and pregnancy. Two case reports. [French]. J Gynecol Obstet Biol Reprod 1996; 25: 608 11.
  • 37
    Gatenby SJ. Maintenance of pregnancy in Crohn’s disease by parenteral nutrition: a case study. Human Nutr Appl Nutr 1987; 41: 345 9.
  • 38
    Nagamatsu Y, Tatsuta E, Yagita M, Miura Y, Taoka Y. A pregnant woman with active ulcerative colitis maintained on total parenteral nutrition. [Japanese]. Sangyo Ika Daigaku Zasshi 1987; 9: 193 9.
  • 39
    Nugent FW, Rajala M, O’shea RA, et al. Total parenteral nutrition in pregnancy: conception to delivery. J Parent Ent Nutr 1987; 11: 424 7.
  • 40
    Robin P, Fignon A, Metman E, Tariel D, Durouchet E, Vandooren M. Parenteral nutrition for Crohn disease in the third trimester of pregnancy. Apropos of a case. [French]. J Gynecol Obstet Biol Reprod 1987; 16: 379 82.
  • 41
    Czeizel EA & Dudas I. Prevention of the first occurrence of neural-tube defects with folic acid supplementation. New Engl J Med 1992; 327: 1832 5.
  • 42
    Esbjorner E, Jarnerot G, Wranne L. Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatr Scand 1987; 76: 137 42.
  • 43
    Koyama N, Komori S, Bessho T, Koyama K, Hiraumi Y, Maeda Y. Holoprosencephaly in a fetus with maternal medication of sulfasalazine in early gestation. A case report. Clin Exp Obstet Gynecol 1996; 23: 136 40.
  • 44
    Zwi LJ & Becroft DM. Intrauterine aplastic anemia and fetal hydrops: a case report. Pediatr Pathol 1986; 5: 199 205.
  • 45
    Jarnerot G, Andersen S, Esbjorner E, Sandstrom B, Brodersen R. Albumin reserve for binding of bilirubin in maternal and cord serum under treatment with sulphasalazine. Scand J Gastroenterol 1981; 16: 1049 55.
  • 46
    Moody GA, Probert C, Jayanthi V, Mayberry JF. The effects of chronic ill health and treatment with sulphasalazine on fertility amongst men and women with inflammatory bowel disease in Leicestershire. Int J Colorectal Dis 1997; 12: 220 4.
  • 47
    Silverman WA, Andersen DH, Blanc WA, Crozier DN. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956; 18: 614 24.
  • 48
    Odell GB. The dissociation of bilirubin from albumin and its clinical implications. J Pediatr 1959; 55: 268 79.
  • 49
    Jarnerot G, Into-Malmberg MB, Esbjorner E. Placental transfer of sulphasalazine and sulphapyridine and some of its metabolites. Scand J Gastroenterol 1981; 16: 693 7.
  • 50
    Christensen LA, Rasmussen SN, Hansen SH. Disposition of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in fetal and maternal body fluids during treatment with different 5-aminosalicylic acid preparations. Acta Obstet Gynecol Scand 1994; 73: 399 402.
  • 51
    Chatzinoff M, Guarino JM, Corson SL, Batzer FR, Friedman LS. Sulfasalazine-induced abnormal sperm penetration assay reversed on changing to 5-aminosalicylic acid enemas. Dig Dis Sci 1988; 33: 108 10.
  • 52
    Jonville-Bera AP, Soyez C, Fignon A, Moraine C, Berger C, Autret E. Pentasa (mesalazine) and pregnancy. [French]. Therapie 1994; 49: 443 5.
  • 53
    Trallori G, D’albasio G, Bardazzi G, et al. 5-Aminosalicylic acid in pregnancy: clinical report. Ital J Gastroenterol 1994; 26: 75 8.
  • 54
    Habal FM, Hui G, Greenberg GR. Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course. Gastroenterology 1993; 105: 1057 60.
  • 55
    Beitens IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr 1972; 81: 936 45.
  • 56
    Colombel JF, Brabant G, Gubler MC, et al. Renal insufficiency in infant: side-effect of prenatal exposure to mesalazine? Lancet 1994; 344: 620 1.
  • 57
    Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998; 114: 23 8.
  • 58
    Blanford AT & Murphy BEP. In vitro metabolism of prednisolone, dexamethasone, betamethasone and cortisol by the human placenta. Am J Obstet Gynecol 1977; 127: 264 7.
  • 59
    Pinsky L & DiGeorge AM. Cleft palate in the mouse: a teratogenic index of glucocorticoid potency. Science 1965; 147: 402 3.
  • 60
    Bulmash JM. Rheumatoid arthritis and pregnancy. Obstet Gynecol Annu 1979; 8: 223 76.
  • 61
    Bulmash JM. Systemic Lupus erythematosus and pregnancy. Obstet Gynecol Annu 1978; 7: 153 94.
  • 62
    Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166: 1318 23.
  • 63
    Fraser FC & Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51: 45 6.
  • 64
    Kenny FM, Preeyasombat C, Spaulding JS, Migeon CJ. Cortisol production rate. Infants born of steroid-treated mothers and of diabetic mothers, infants with trisomy syndrome and with anencephaly. Pediatrics 1966; 37: 960 6.
  • 65
    Bermas BL & Hill JA. Effects of immunosuppressive drugs during pregnancy. Arthritis Rheum 1995; 38: 1722 32.
  • 66
    Roe FJ. Toxicologic evaluation of metronidazole with particular reference to carcinogenic, mutagenic, and teratogenic potential. Surgery 1983; 93: 158 64.
  • 67
    Cantu JM & Garcia-Cruz D. Midline facial defect as teratogenic effect of metronidazole. Birth Defects: Original Article Series 1982; 18: 85 8.
  • 68
    Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993; 82: 348 52.
  • 69
    Linseman DA, Hampton LA, Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin. Fundam Appl Toxicol 1995; 28: 59 64.
  • 70
    Wilton LV, Pearce GL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol 1996; 41: 277 84.
  • 71
    Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol 1994; 84: 535 8.
  • 72
    Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990; 99: 443 6.
  • 73
    Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. National transplantation pregnancy registry – outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994; 57: 502 6.
  • 74
    Francella A, Dayan A, Rubin P, et al. 6-mercaptopurine (6-MP) is safe therapy for child bearing patients with inflammatory bowel disease (IBD): a case controlled study. Gastroenterology 1996; 110: A909.
  • 75
    Kirk AP & Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J 1982; 284: 1291 2.
  • 76
    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. New Engl J Med 1995; 332: 292 7.
  • 77
    Goldenberg M, Bider D, Admon D, Mashiach S, Oelsner G. Methotrexate therapy of tubal pregnancy. Human Reprod 1993; 8: 660 6.
  • 78
    Donnenfield AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G. Methotrexate exposure prior to and during pregnancy. Teratology 1994; 49: 79 81.
  • 79
    Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS, Segal AM. Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990; 88: 589 92.
  • 80
    Mulinsky A, Graef JW, Gaynor MF. Methotrexate induced congenital abnormalities. Acta Endocrinol 1956; 28: 37 45.
  • 81
    Committee on Drugs American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics 1989; 84: 924 36.
  • 82
    Lichtiger S, Present D, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. New Engl J Med 1994; 330: 1841 5.
  • 83
    Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996; 91: 2498 9.
  • 84
    Schmid BP. Monitoring of organ formation in rat embryos after in vitro exposure to azathioprine, mercaptopurine, methotrexate or cyclosporin A. Toxicology 1984; 31: 9 21.
  • 85
    Mason RJ, Thomson AW, Whiting PH, et al. Cyclosporine-induced fetotoxicity in the rat. Transplantation 1985; 39: 9 12.
  • 86
    Classen JB & Shevach EM. Evidence that cyclosporine treatment during pregnancy predisposes offspring to develop autoantibodies. Transplantation 1991; 51: 1052 7.
  • 87
    Haugen G, Fauchald P, Sodal G, Leivestad T, Moe N. Pregnancy outcome in renal allograft receipients in Norway: the importance of immunosuppressive drug regimen and health status before pregnancy. Acta Obstet Gynecol Scand 1994; 73: 541 6.
  • 88
    Shaheen FAM, Al-Sulaiman MH, Al-Khader AA. Longterm nephrotoxicity after exposure to cyclosporine in utero. Transplantation 1993; 56: 224 5.
  • 89
    Bertschinger P, Himmelmann A, Risti B, Follath F. Cyclosporine treatment of severe ulcerative colitis during pregnancy. Am J Gastroenterol 1995; 90(2): 330.
  • 90
    Mathur S, Agarwal S, Lewis AAM, Pounder RE. Fulminant ulcerative colitis in late pregnancy. Eur J Gastroenterol Hepatol 1991; 99: 3281 3.
  • 91
    Jacobson LB & Clapp DH. Total parenteral nutrition in pregnancy complicated by Crohn’s disease. J Parent Ent Nutr 1987; 11(1): 93 6.
  • 92
    Hiki M, Kitano A, Obata A, et al. A case report of Crohn’s disease maintained on parenteral nutrition for almost the whole period of pregnancy. Nippon Shokakibyo Gakkai Zasshi – Jap J Gastroenterol 1986; 83(10): 2238 42.
  • 93
    Gineston JL, Capron JP, Delcenserie R, et al. Prolonged total parenteral nutrition in a pregnant woman with acute pancreatitis. J Clin Gastroenterol 1984; 6: 249 52.
  • 94
    Greenfield C, Pounder RE, Craft IL, Lewis AA. Severe ulcerative colitis during successful pregnancy. Postgrad Med J 1983; 59(693): 459 61.
  • 95
    Hill J, Clark A, Scott NA. Surgical treatment of acute manifestations of Crohn’s disease during pregnancy. J R Soc Med 1997; 90(2): 64 6.
  • 96
    Martimbeau PW, Welch JS, Weiland LH. Crohn’s disease and pregnancy. Am J Obstet Gynecol 1975; 122(6): 746 9.
  • 97
    Shnider SM & Webster GM. Maternal and fetal hazards of surgery during pregnancy. Am J Obstet Gynecol 1965; 92: 891 900.
  • 98
    Levine W & Diamond B. Surgical procedures during pregnancy. Am J Obstet Gynecol 1961; 81: 1046 52.
  • 99
    Kammerer WS. Non-obstetric surgery during pregnancy. Med Clin North Am 1979; 63: 1157 64.
  • 100
    Devore GR. Acute abdominal pain in the pregnant patient due to pancreatitis, acute appendicitis, cholecystitis or peptic ulcer disease. Clin Perinatol 1980; 7: 349 67.
  • 101
    Cooksey G, Gunn A, Wotherspoon WC. Surgery for acute ulcerative colitis and toxic megacolon during pregnancy. Br J Surg 1985; 72(7): 547.
  • 102
    Kelley MJ, Hunt TM, Wicks AC, Mayne CJ. Fulminant ulcerative colitis and parturition: a need to alter current management? Br J Obstet Gynaecol 1994; 101(2): 166 7.
  • 103
    Boulton R, Hamilton M, Lewis A, Walker P, Pounder R. Fulminant ulcerative colitis in pregnancy. Am J Gastroenterol 1994; 89(6): 931 3.
  • 104
    Bohe MG, Ekelund GR, Genell SN, et al. Surgery for fulminating colitis during pregnancy. Dis Colon Rectum 1983; 26(2): 119 22.
  • 105
    Winkler R. Ulcerative colitis and pregnancy. Surgical treatment of acute complications. Deutsche Med Wochenschrift 1976; 101(25): 963 5.
  • 106
    Ozanne P, Linderkamp O, Miller FC, Meiselman HJ. Erythrocyte aggregation during normal pregnancy. Am J Obstet Gynecol 1983; 147(5): 576 83.
  • 107
    Ashwood ER, Burtis CA, Ashwood EA (eds) Tietz Textbook of Clinical Chemistry, 2nd edn, Vol 39: Clinical Chemistry of Pregnancy. Philadelphia: W.B. Saunders Company, 1994: 2107 48.
  • 108
    Letsky EA & Swiet MD (eds). Medical Disorders in Obstetric Practice, 2nd edn, Vol. 2: Blood Volume, Haematinics, Anaemia. Oxford: Blackwell Scientific Publications, 1989: 48 103.
  • 109
    Fagan EA & Swiet MD (eds) Medical Disorders in Obstetric Practice, 2nd edn, Vol. 9: Disorders of the Liver, Biliary System and Pancreas. Oxford: Blackwell Scientific Publications, 1989: 426 520.
  • 110
    Girling JC, Dow E, Smith JH. Liver function tests in pre-eclampsia: importance of comparison with a reference range derived for normal pregnancy. Br J Obstet Gynaecol 1997; 104: 246 50.
  • 111
    Benzie RJ, Doran TA, Harkins JL, Jones Owen VM, Porter CJ. Composition of the amniotic fluid and maternal serum in pregnancy. Am J Obstet Gynecol 1974; 119: 798 810.
  • 112
    Allen JR & Ahlgren SA. A comparative study of the haematologic changes in pregnancy in the Macaca mulatta monkey and the human female. Am J Obstet Gynecol 1968; 100(7): 894 903.
  • 113
    Truelove SC & Witt LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. Br Med J 1955; 2: 1041 4.
  • 114
    Van Hees PAM, Van Lier HJJ, Van Elteren PH. Effect of sulphasalazine in patients with active Crohn’s disease: a controlled double-blind study. Gut 1981; 22: 404 9.
  • 115
    Hanan IM & Kirsner JB. Inflammatory bowel disease in the pregnant woman. Clin Perinatol 1985; 12(3): 669 82.
  • 116
    Cappell MS, Colon VJ, Sidhom OA. A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups. Dig Dis Sci 1996; 41(12): 2353 61.
  • 117
    Mole RH. Radiation effects on pre-natal development and their radiological significance. Br J Radiol 1979; 52: 89 101.
  • 118
    Brent RL. The effects of embryonic and fetal exposure to X-ray, microwave, and ultrasound: counseling the pregnant and nonpregnant patient about the risks. Semin Oncol 1989; 16(5): 347 68.
  • 119
    Hufton AP. Radiation dose to the fetus in obstetric radiography. Br J Radiol 1979; 52: 735 40.
  • 120
    Van Loon AJ, Montingh A, Serlieer EK, Kroon G, Moogaart EL, Huisjes HJ. Randomised controlled trial of Magnetic resonance pelvimetry in breech presentation at term. Lancet 1997; 350: 1799 804.
  • 121
    Shoenut JP, Semelka RC, Silverman R, Yaffe CS, Micflikier AB. MRI in the diagnosis of Crohn’s disease in two pregnant women. J Clin Gastroenterol 1993; 17(3): 244 7.
  • 122
    Crohn BB, Yarnis H, Crohn EB, Walter RI, Gabrilove LJ. Ulcerative Colitis and pregnancy. Gastroenterology 1956; 30: 391 403.
  • 123
    Schade RR, Van Thiel DH, Gavaler JS. Chronic idiopathic ulcerative colitis. Pregnancy and fetal outcome. Dig Dis Sci 1984; 29(7): 614 19.
  • 124
    Crohn BB, Yarnis H, Korelitz BI. Regional ileitis complicating pregnancy. Gastroenterology 1956; 31: 615 28.
  • 125
    Schofield PF, Turnbull RB, Hawk WA. Crohn’s disease and pregnancy. Br Med J 1970; 1(5705): 364.
  • 126
    Homan WP & Thorbjarnarson B. Crohn disease and pregnancy. Arch Surg 1976; 111(5): 545 7.
  • 127
    Rogers RG & Katz VL. Course of Crohn’s disease during pregnancy and its effect on pregnancy outcome: a retrospective review. Am J Perinatol 1995; 12(4): 262 4.