INFLAMMATORY BOWEL DISEASE AND PREGNANCY

PREGNANCY AND GASTROINTESTINAL DISORDERS

0889-8553/98 $8.00

+ .OO

INFLAMMATORY BOWEL DISEASE AND PREGNANCY Burton I. Korelitz, MD

When it is considered that the peak age ranges for pregnancy and inflammatory bowel disease (IBD) coincide, it is inevitable that the gastroenterologist and the obstetrician will see an increasing number of pregnant women with either ulcerative colitis or Crohn’s disease. Nevertheless, meaningful data on the course and management of IBD have been limited by the following circumstances: First, the classic studies of pregnancy in patients with Crohn’s diseasez3 and ulcerative colitis’, lo, z2 were reported in the 1950s. Although these studies provided meaningful information on the natural course, they preceded the modern era of drug therapy. Furthermore, patients treated with corticosteroids during that period were not clearly separated from those who were not, and the drug therapy of pregnant patients was inconsistent. Second, in the early and even later studies, there was no patient stratification. In Crohn’s disease, no meaningful distinction was made among ileitis, ileocolitis, and colitis or among unoperated, operated with no recurrence, and operated with recurrence. Furthermore, little mention was made of the complications of strictures, abscesses, fistulas, and previous intestinal obstruction. In ulcerative colitis, little distinction was made among proctitis, proctosigmoiditis, left-sided colitis, and universal colitis. Third, subsequent advances in drug therapy and understanding of the pathophysiology of IBD have led to a large number of permutations of disease types, anatomic distributions, disease complications, and administered drugs; this heterogenicity of clinical presentation and therapy further decreases the clinical usefulness of the classic studies. There also were no controlled trials of drug therapy during pregnancy. Because of these problems, even the largest studies of IBD and pregnancy included a variety of case material, so that conclusions can be made only tentatively. Despite these limitations, some conclusions have been reached and have been confirmed by numerous investigators. The following generalities may be considered as reasonable premises that have been repeatedly substantiated. From the Section of Gastroenterology Department of Medicine, Lenox Hill Hospital, New York, New York

GASTROENTEROLOGY CLINICS OF NORTH AMERICA ~

VOLUME 27 * NUMBER 1 * MARCH 1998

213

214

KORELITZ

FERTILITY

Women with ulcerative colitis are believed to be relatively less fertile than the general p o p u l a t i ~ nWhen . ~ ~ adjusted for patient age and desire for pregnancy, however, their fertility rate is probably normal.69Contrariwise, fertility is reduced in Crohn’s disease in proportion to disease activity and can be restored when appropriate drug therapy results in disease remission? The ovaries and fallopian tubes are occasionally affected by the inflammatory process of Crohn’s disease, especially on the ride side, because of proximity to the terminal ileum; this could theoretically cause reduced fertilityz7One study concluded that fertility is lower with Crohn’s colitis than with ileitis. Perhaps this phenomenon is related to the higher prevalence with colitis of perirectal, perineal, and rectovaginal abscesses and fistulas that results in dyspareunia and decreased libido in either the patient or the sexual partner. The overall toxicity of Crohn‘s disease, from fever, abdominal pain, diarrhea, and suboptimal nutrition, has also been implicated in the decreased fertility8,*l Although difficult to quantify, fear of pregnancy is probably also a major factor reducing fertility among young women with Crohn’s disease. This fear is often introduced by an obstetrician or gastroenterologist who emphasizes the potential fetal toxicity of drug therapy. Baird and colleagues9compared 177 women with Crohn’s disease, 84 with ulcerative colitis, and 216 control subjects. Women with IBD whose first pregnancy occurred after disease onset had fewer pregnancies per patient than controls, whereas women whose first pregnancies occurred before the onset of symptoms had the same average number of pregnancies per patient as controls. These authors suggested that reduced fertility was due to the patient’s choice and not to disease-related impairment. Infertility in men owing to sulfasalazine therapy is well documented.12 Within 2 months of therapy initiation, sperm counts may decrease, and abnormal sperm morphology and motility may be observed.63Some or all of these abnormalities appear in 64% of men treated with sulfasalazine. Beginning 2 months after drug withdrawal, however, semen quantity and quality improve to a level satisfactory for impregnation. If fertility becomes a priority for a male patient, withdrawal of sulfasalazine, which has confirmed value in maintaining a remission in ulcerative colitis, can lead to disease exacerbation. The problem of infertility is reduced by use of oral 5-aminosalicylic acid (5-ASA) preparations; these preparations contain the therapeutically effective split product of sulfasalazine, which does not damage sperm. Narendranathan and concluded that the overall reproductive capacity of men with IBD was not markedly diminished. INHERITANCE AND INFLAMMATORY BOWEL DISEASE

Patients with IBD wish to know the probability of their child developing IBD. For decades, it has been recognized that genetic factors play a role in the cause of the various forms of IBD.62The IBDs are fundamentally genetic diseases with complex nonmendelian patterns of inheritan~e.5~ The most firmly established and quantitatively largest risk factor for ulcerative colitis and Crohn’s disease is a positive family history.” Many studies have shown a greater risk of Crohn’s disease when a first-degree relative has Crohn’s disease as compared to the risk of ulcerative colitis when a relative has that disease.65Extending these observations, Yang and colleague^^^^ 71 observed a significantly different empiric risk of IBD between Jews and gentiles. For the first-degree relatives of gentile

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

215

probands, the lifetime risk of IBD was 5.2% when probands had Crohn’s disease and 1.6% when probands had ulcerative colitis. These rates were consistently and significantly lower than the corresponding risks for relatives of Jewish probands of 7.8% when probands had Crohn’s disease and 4.5% when probands had ulcerative colitis. One study analyzed the risk of IBD in offspring when both parents had IBD.” The risk was as high as 36%, which was substantially greater than double the empiric risk for offspring of couples in which one partner has IBD. When the children were divided into three groups according to whether both parents, one parent, or neither parent had yet developed symptoms of IBD at the time of the children’s conception, the risk of IBD was similar among the three groups. In addition, the concordance rate for type of IBD (ulcerative colitis versus Crohn’s disease) between parent and child in couples who both had onset of IBD after marriage was not greater than in couples of whom both or one was affected before marriage. The data indicate that genetic, as opposed to acquired, factors are essential in the development of IBD and in determining the type of IBD. Current genetic research is pointing to a strong hereditary influence on disease location and disease manifestations as well. INFLUENCE OF ULCERATIVE COLITIS ON FETAL OUTCOME Reports including many more than 100 pregnant patients with ulcerative colitis show normal, healthy offspring in 76% to 97%, congenital abnormalities in 0% to 3%’ spontaneous abortions in 1%to 13%, and stillbirths in 0% to 3%.33 These figures approximate those for the normal population. In the author’s study with Baiocco: 83% of the mothers with ulcerative colitis delivered normal healthy infants; premature delivery occurred in 2% to 5% and spontaneous abortion in 12%; and there were no stillbirths or congenital abnormalities. The presence of ulcerative colitis did not influence the mode of delivery (vaginal versus cesarean section) or the incidence of preeclampsia/eclampsia during gestation. INFLUENCE OF CROHN’S DISEASE ON FETAL OUTCOME Somewhat fewer pregnancy outcomes for pregnant women with Crohn’s disease have been analyzed compared with pregnant women with ulcerative colitis. Studies involving more than 100 pregnant women with Crohn’s disease report normal offspring in 70% to 93%, congenital abnormalities in 0% to 1%, stillbirths in 1%to 4%, and spontaneous abortion in 3% to 9%; these figures also approximate the incidence in the population without IBD.33In the author’s study with Baiocco; however, when developmental defects, stillbirths, or spontaneous abortion did occur, active Crohn‘s disease was present in 62%. Most of these patients were taking one or more medications for Crohn’s disease, but case analysis revealed that disease activity and not specific drugs was responsible for the increased complication rate. If a severe exacerbation occurs during pregnancy that requires surgery, the fetal mortality is high. Nevertheless, Hill and c o - ~ o r k e r sreported ~~ six cases with intraperitoneal sepsis, three with onset of Crohn‘s disease during pregnancy, who required surgery. All six women recovered, of whom five delivered healthy infants, and one had a miscarriage. The overall incidence of cesarean section has been the same in Crohn’s

216

KORELITZ

disease patients as in healthy women, so that a normal vaginal delivery can be anticipated in the majority. Nevertheless, cesarean section may be the preferred route of delivery for patients with anorectal and perirectal abscesses and fistulas to reduce the likelihood of fistulas developing or extending to the episiotomy scar.

INFLUENCEOFPREGNANCYONTHECOURSEOF ULCERATIVE COLITIS On the basis of old reports and accumulated experience, it may be fairly concluded that the course of ulcerative colitis during pregnancy is correlated with disease activity at the time of conception. Several studies have shown that two thirds of those in whom ulcerative colitis was inactive at conception continue to have inactive disease throughout pregnancy,4s.69 and most with active disease at conception usually continue to have active disease during pregnancy. Active ulcerative colitis at conception is at risk of worsening during unless drug therapy is initiated or used more vigorously.*Despite this exacerbation of active disease, many women, even some women with multiple pregnancies, state that their ulcerative colitis was best controlled during pregnancy. It is not a unique experience, however, to see onset of ulcerative colitis during pregnancy and even quiescence between pregnancies with exacerbations during subsequent pregnan~ies.~’ Onset during pregnancy used to carry a poor prognosis,22but this is no longer the case when drug therapy is introduced and used vigorously. Most changes in the status of the colitis, whether improvement or exacerbation, occur during the first trimester.s1 Severe ulcerative colitis infrequently requires surgical intervention during pregnan~y.~, 67 Most gastroenterologists with experience in managing ulcerative colitis during pregnancy agree that the anticipated course is the same as when the patient is not pregnant and that remission throughout pregnancy can be maintained by appropriate drug therapy. Occasionally, psychological factors strongly influence the symptoms from colitis during pregnancy; in these cases, the pregnant patient who desires the pregnancy does better than the patient with an unwanted pregnancy.

INFLUENCEOFPREGNANCYONTHECOURSEOF CROHN’S DISEASE

The course of Crohn’s disease during pregnancy is similar to that of ulcerative colitis in that quiescence of disease before conception is likely to be followed by quiescence during pregnancy, whereas active disease at conception is likely to remain active or exacerbate during pregnancyjl Historically, exacerbations were commonly reported postpartum. As in ulcerative colitis, the course of Crohn’s disease, whether quiescent or active at conception, proceeds similarly to that in the nonpregnant patient and is influenced by maintenance drug therapy after the disease has been brought into remission. The onset of Crohn’s disease during pregnancy, similar to that for ulcerative colitis, used to carry a poor prognosis, but the prognosis has improved with the advent of effective drug therapy.

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

217

EPISIOTOMY IN INFLAMMATORY BOWEL DISEASE Crohn‘s disease affects the decision about whether to perform an episiotomy at delivery.61Crohn’s disease promotes the development of fistulas arising from the rectum and draining to perirectal tissues, including the perineum and vagina. Trauma of diseased tissue predisposes to aggravation, recurrence, and even creation of fistulas. Brandt and c01leagues~~ determined by questionnaire that 18%developed de novo perineal involvement after vaginal delivery, most commonly with episiotomy. This finding should warrant cesarean section in patients with active or inactive perirectal, rectovaginal, or perianal fistulas and possibly even in patients with Crohn’s disease without perineal abscess or fistula, particularly when colitis is present. Episiotomy is generally not contraindicated in patients with ulcerative colitis. If the patient is severely ill at the time of delivery, however, cesarean section is preferred over vaginal delivery. INFLUENCE OF DRUG THERAPY ON THE PREGNANT WOMAN AND THE FETUS The safety of drug therapy is the foremost consideration in pregnant women with IBD. Even though it has been recognized that pregnancy should be postponed when either Crohn’s disease or ulcerative colitis is active, patients may become pregnant despite active disease, or patients with quiescent disease may require maintenance drug therapy during pregnancy. This area has caused considerable conflict between obstetricians, who often recommend stopping all drug therapy during pregnancy, and gastroenterologists, who have evidence that most drugs used for IBD are safe and necessary to induce or maintain remission. The evidence for safety has been determined for most drugs commonly used for IBD. Sulfasalazine, the first proven effective agent, is a diazo-linkage of 5-ASA and sulfapyridine. 5-ASA is the active therapeutic agent, released in the colon by bacterial action on the diazo-linkage, whereas the sulfapyridine serves merely as a carrier to reach that d e s t i n a t i ~ nMost . ~ ~ sulfasalazine toxicity is caused by the sulfapyridine moiety. Toxicity includes fever, rash, headaches, and rarely drug-induced hepatitis, Stevens-Johnson disease, interstitial pneumonitis, nephritis, and agranulocytosis. Kernicterus has been mentioned as a possible complication of sulfasalazine, but neonatal jaundice is rare, probably because sulfasalazine is poorly absorbed from the small bowel and has a low affinity for protein Long-term sulfasalazine therapy is not associated with prematurity, low birth weight, or spontaneous abortion17 but does interfere with folate absorption. Because folate is important during ~regnancy,5~ folate supplementation is necessary when administering sulfasalzine. No adverse effects have been reported from sulfasalazinein nursing infants despite an approximately 50%level of sulfapyridine in the breast milk as compared to the maternal serum level. Sulfasalazine has been used during pregnancy for many years, and many studies have shown no detrimental effects on the pregnancy or fetal development?,39, Four reports involving six infants described congenital malformations after sulfasalazine exposure,2’,37, 42, 53 however; these anecdotal reports do not prove an association because the observed effects may have been due to disease severity or coincidence. 5-Aminosalicylic Acid (Mesalamine, Olsalazine)

5-ASA, the effective component of sulfasalazine, is available in various oral forms to prevent drug absorption in the stomach and small bowel.29These forms

218

KORELITZ

include olsalazine (Dipenturn), which is a diazo-linkage of two 5-ASA molecules that are split apart by bacterial action once the drug reaches the colon; mesalamine (Asacol), which is protected by a eudragit coating and released in an alkaline or neutral pH environment as it travels distally into the small bowel; and mesalamine (Pentasa), which is composed of multiple ethylcellulose beads that are released progressively in the stomach and small bowel by mechanical agitation.30Mesalamine is also available in enemas and suppositories for use in ulcerative colitis limited to the rectum and distal colon. Compared with the parent drug sulfasalazine, 5-ASA rarely causes toxicity.60 Nevertheless, there have been reported rare cases of fever (akin to the allergic response to aspirin), interstitial pneumonitis, myocarditis, interstitial nephritis, pancreatitis, skin eruptions, elevated serum levels of hepatic enzymes, thrombocytopenia, neutropenia, and even diarrhea, particularly with olsalazine. These rare complications are no more common than in nonpregnant patients with IBD and are almost entirely reversible, as in nonpregnant patients with IBD. Habal and colleagues3zreported 18 full-term deliveries by mothers with IBD taking oral mesalamine, with all 18 children well and with normal growth and development at ages 1 to 6.5 years. Marteau and D e ~ a u reported x~~ that extremely high doses of mesalamine cause toxicity to rats and rabbits and therefore suggested that high doses should be used with caution. Jonville-Bern and colleagues40 reported that 9 of 10 mothers taking oral mesalamine during pregnancy delivered healthy infants; one infant had multiple congenital malformations. There has been one case of renal insufficiency and one case of anencephaly reported in the newborns of mothers taking mesalamine during pregnancy. Traillori and c o - w ~ r k e r sreported ~~ no adverse fetal effects in 19 pregnant mothers administered oral 5-ASA. Topical 5-ASA has been demonstrated to be safe during pregnancy.31

Corticosteroids In studies performed on laboratory animals, corticosteroids were associated with a high rate of spontaneous abortion, small litter size, and cleft ~ a l a t e . 2In~ the series of Mogadam and Co-workers,48among 287 pregnancies in IBD patients treated with corticosteroids, the frequency of fetal complications was actually lower than in the general population. Crohn‘s disease patients treated with corticosteroids experienced a slightly higher rate of fetal complications in comparison with a study control group not requiring steroids. This effect was attributed to the activity of Crohn’s disease and not to the corticosteroids.8In the Collaborative Perinatal Project, no relation was found between first-trimester exposure and congenital defects in 34 p r e g n a n ~ i e sThe . ~ ~ use of corticosteroids is indicated for patients with moderate to severe disease activity during pregnancy because the threat to the fetus from severely active maternal IBD is greater than the risk of medication teratogenicity. In humans, cortisol crosses the placenta, but cortisol is rapidly converted to the less active cortisone, and fetal circulation concentration is only 10% of the maternal serum level. Prednisone and prednisolone poorly cross into the fetal circulation, and pituitary adrenal axis suppression is, therefore, rare. As regards nursing, the amount of steroids received by the newborn infant in breast milk is minimal. Steroids are therefore generally safe during pregnancy. The small potential fetal risk from temporary use of large doses must be weighed against the greater fetal risk from severe Crohn’s disease activity and from the alternative of surgical intervention.

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

219

lmmunosuppressives

Immunosuppressive therapy with either azathioprine or 6-mercaptopurine (6-MP) has an established role in treating refractory Crohn’s disease and ulcerative colitis.2,54, 55 These agents have the therapeutic advantage of eliminating the needs for steroids and of maintaining remission in both diseases. Their safety in pregnancy, however, is questionable. Animal models have shown that these immunosuppressives result in low birth weight, congenital abnormalities, and small litter size. Nevertheless, these drugs were used with relative safety in more than 500 renal transplant patients who were pregnant.6When birth anomalies occurred, a higher dose of azathioprine (2.3 mg/kg) was used to prevent renal allograft rejection than is usually used for IDB. A retrospective study by Alstead and colleagues4on azathioprine therapy during the course of 16 pregnancies in women with IBD demonstrated no resultant congenital abnormalities. Seven women continued the drug throughout pregnancy without complications. All the offspring have been well with a follow-up of 6 months to 16 years after birth. Francella and colleaguesz8contacted 450 patients who had received 6-MP, of whom 155 had conceived at least once. The percentage of congenital anomalies was 4% in patients who stopped 6-MP before pregnancy, 2% in patients who conceived before the use of 6-MP, and 2% in those taking 6-MP at the time of conception. Despite these data suggesting minimal or no drug risk, the use of azathioprine or 6-MP during pregnancy cannot be recommended until the safety is further established. Exacerbation of IBD infrequently follows immediately after drug cessation, which permits time to stop the 6-MP while attempting conception. During this period, maintenance therapy with 5-ASA products should be continued or substituted. If the IBD reactivates, the 6-MP can be reintroduced with or without a brief course of corticosteroids. If conception occurs and the IBD does not reactivate, the medication should not be reintroduced until after delivery. Recommendations regarding therapeutic abortion when accidental conception occurs while a patient is taking 6-MP are controversial; this should remain the patient’s decision after appropriate counseling. The effect of immunosuppressives during nursing is unknown. Cyclosporine

Cyclosporine is an immunosuppressive that is beneficial in severe ulcerative colitis that is poorly responsive to corti~osteroids~~ but may not be used during pregnancy because of nephrotoxicity, hypertension, and hepatotoxicity. Cyclosporine also promotes closing of complex fistulas of Crohn‘s disease.” It is not useful when used orally to maintain remission.58Experience with pregnant transplant patients on cyclosporine has shown a high incidence of prematurity and low birth weight but also a high survival rate? There are no data on congenital malformations, but children exposed to cyclosporine in utero have not developed immune deficiency or long-term autoimmunity.’6 Marion and reported successful completion of pregnancy in four of five women with severe IBD treated with intravenous cyclosporine without development of renal toxicity, congenital malformations, or developmental defects. Methotrexate

Methotrexate is effective in some patients with Crohn’s disease. It is used mostly in those who failed 6-MP therapy or developed hypersensitivity reactions

220

KORELITZ

to it. The drug is contraindicated during pregnancy because of a high incidence of mutagenicity and teratogenicity? Methokexate is also contraindicated during nursing. Antibiotics

Metronidazole is an effective agent for perirectal abscesses and fistulas from Crohn's disease.% Its major toxicity is a peripheral neuritis, usually reversible when the drug is stopped.30In animals, metronidazole crosses the placenta and is teratogenic and tumorigenic in high doses. It also passes into breast milk. It is a known carcinogen in rodents, causing pulmonary, hepatic, and mammary tumors. This toxicity has raised concern about use in humans during pregnancy, despite an absence of well-controlled therapeutic trials. Long-term studies of pregnant women treated with metronidazole for trichimonal vaginitis have not revealed fetal A study of 206 pregnant women treated during the first trimester revealed no association with congenital malformations or spontaneous abortions.% Controlled trials have not confirmed the efficacy of other antibiotics for Crohn's disease or ulcerative colitis. Nevertheless, antibiotics appear to have therapeutic and maintenance value in some cases of Crohn's disease. Data on toxicity during pregnancy of antibiotics used in IBD are limited, but reports on the brief use of ampicillin, cephalosporin, or ciprofloxacin suggest that they are not terat~genic.'~ SMOKING

Epidemiologic studies have shown a positive correlation between smoking and Crohn's disease, and smoking is, therefore, contraindicated.a This recommendation is particularly true for pregnant women with active Crohn's disease because smoking can exacerbate Crohn's disease and thereby increase fetal risk. EFFECT OF SURGERY FOR INFLAMMATORY BOWEL DISEASEONTHECOURSEOFSUBSEQUENT PREGNANCIES

Patients with ileostomies tolerate pregnancy well. Mechanical problems, including prolapse, and skin irritation may occur during the gestational period. however, reported a 10% incidence of intestinal obstruction in patients 20 pregnant patients with with ileostomies. Nelson and ~ o - w o r k e r sexamined ~~ the ileal-pouch anal anastomosis for ulcerative colitis and concluded that pregnancy and delivery were safe for these patients. The type of delivery, whether vaginal or by cesarean section, did not affect the pouch. MANAGEMENT OF INFLAMMATORY BOWEL DISEASE DURING PREGNANCY

There is no contraindication to flexible sigmoidoscopy, gastroscopy, or endoscopic biopsies if indicated, for proper management during the course of pregnancy.18,20 There are limited data on the safety of colonoscopy during pregnancy;

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

221

however, the procedure should be avoided unless the information to be gained is essential for clinical management.I9 This topic is discussed further in the article on safety of endoscopy in pregnancy in this issue. Radiologic examinations should be avoided during pregnancy because of radiation teratogenicity except for plain films to confirm the diagnosis of toxic megacolon or gastrointestinal obstruction. Studies have demonstrated that exposures to 24 rads or less in the prenatal period have not been associated with birth defects or cancer in the first years after birth.15 Diagnostic x-ray procedures are probably safer during the third trimester than during the first or second trimester. Computed tomography, which exposes the fetus to less radiation than traditional barium x-ray studies, may be used, when absolutely necessary, to aid in the diagnosis or recognition of complications of Crohn’s disease. Surgical intervention for ulcerative colitis during pregnancy is appropriate for unequivocal indications, including severe hemorrhage, perforation, and megacolon refractory to intensive medical therapy with tube decompression. Total colectomy and ileostomy, however, with attendant intraoperative manipulation of the uterus, carries a 60% risk of postoperative spontaneous abortion. This is why an attempt at treatment with intravenous cyclosporine is favored over surgery in some cases. The clinician should attempt aggressive medical management to induce remission of IBD as early as possible if a patient is contemplating pregnancy or is already pregnant. When surgery is required for Crohn’s disease, fetal mortality has also been high. This is particularly true when the diagnosis is recognized late and when drug therapy and surgical intervention are delayed. Maternal mortality has also been high for these reasons.

References 1. Abrahamson D, Jankelson IR, Milner LR: Pregnancy and colitis. Am J Obstet Gynecol 61~121-129, 1951 2. Adler DJ, Korelitz BI The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol85717-722, 1990 3. Al-Khader AA, Absy M, Al-Hasani MK, et a1 Successful pregnancy in renal transplant recipients treated with cyclosporine. Transplantation 45:987-988, 1988 4. Alstead EM, Ritchie JR, Lennard-Jones JE, et al: Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 99:443-446, 1990 5. Anderson JB, Turner GM, Williamson RCN: Fulminant ulcerative colitis in late pregnancy and the puerperium. J R SOCMed 80:492494, 1987 6. Annenti VT: The National Transplantation Program Registry: An analysis of 504 pregnancies. Presented at the Eighteenth Annual Meeting of the American Society of Transplant Surgeons, 1992 7. Azad Khan AK, Truelove SC Placental and mammary transfer of sulfasalazine. Br Med J 23553-1555, 1979 8. Baiocco PJ, Korelitz BI: The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 6211-216, 1984 9. Baird DD, Narendranathan M, Sandler RS: Increased risk of preterm births for women with inflammatory bowel disease. Gastroenterology 99:987-994,1990 10. Banks BM, Korelitz BI, Zetzel L: The course of nonspecific ulcerative colitis: A review of twenty years experience and late results. Gastroenterology 32:983-1012, 1957 11. Bennett RA, Rubin PH, Present D H Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease. Gastroenterology 1001638-1643,1991 12. Bimic GG, McLeod TF, Watkinson G: Incidence of sulfasalazine induced male infertility. Gut 22452455, 1981

222

KORELITZ

13. Bomford JAL, Ledjer JC, OKeefe BJ, et al: Ciprofloxacin used during pregnancy. Drugs 45:461462, 1993 14. Brandt L, Estabrook SG, Reinus JF: Results of a survey to evaluate whether vaginal delivery and episiotomy lead to perirectal involvement in women with Crohn’s disease. Am J Gastroenterol901915-1922, 1995 15. Brent RL: Irradiation in pregnancy. In Gerbie AB, Sciarra JJ (eds): Gynecology and Obstetrics. New York, Harper & Row, 1979, pp 1-23 16. Briggs GG, Freeman RK, Yaffe SJ: Cyclosporine. In Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, ed 4. Baltimore, Williams & Wilkins, 1994, pp 241-243 17. Briggs GG, Freeman RK, Yaffe SJ: Sulfasalazine. In Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, ed 4. Baltimore, Williams & Wilkins, 1994, pp 793-795 18. Cappell MS, Sidhom 0 A multicenter, multiyear study on safety and efficacy of flexible sigmoidoscopy during pregnancy in 24 females with follow-up of fetal outcome. Dig Dis Sci 40472-479, 1995 19. Cappell MS, Sidhom 0, Colon V 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 41:2353-2360, 1996 20. Cappell MS, Sidhom 0, Colon V: A study of eight medical centers of the safety and clinical efficacy of esophagogastroduodenoscopyin 83 pregnancies with follow-up of fetal outcome. Am J Gastroenterol91:34&354, 1996 21. Craxi A, Pagliarello F Possible embryotoxicity of sulfasalazine [letter]. Arch Intern Med 140:1674, 1980 22. Crohn BB, Yarmis H, Crohn EB, et al: Ulcerative colitis and pregnancy. Gastroenterology 30:391-403,1956 23. Crohn BB, Yarmis H, Korelitz BI Regional ileitis and pregnancy. Gastroenterology 31:615-628, 1956 24. DeCosta EJ, Abelman MA: Cortisone and pregnancy: An experimental and clinical study of the effects of cortisone on gestation. Am J Obstet Gynecol M746-767, 1952 25. DeDombal FT, Watts JM, Watkinson G, et al: Ulcerative colitis and pregnancy. Lancet 2:599-602, 1965 26. Esbjorner E, Jamerot G, Wranne L Sulfasalazine and sulfapyridine levels in children bom to mothers treated with sulfasalazine during pregnancy and lactation. Acta Paediatr Scand 76:137-142,1987 27. Fielding JF, Cooke WT: Pregnancy and Crohn’s disease. Br Med J 2:76-77, 1970 28. Francella A, Dayan A, Rubin P, et a 1 6-Mercaptopurine (6-MP) is safe therapy for child bearing patients with inflammatory bowel disease (IBD): A case controlled study [abstr]. Gastroenterology 110(suppl):909, 1996 29. Greenfield SM, Funchard NA, Terre JP, et al: The mode of action of the aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther 7369-383, 1993 30. Griffin MG, Miner PB Jr: Conventional drug therapy in inflammatory bowel disease. Gastroenterol Clin North Am 24:509-521, 1995 31. Habal FM, Hamat H. Safety of topical 5-aminosalicylic acid in pregnancy [abstr]. Gastroenterology 106(suppl):A9, 1994 32. Habal FM, Hiu G, Greenberg G R Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: Safety and clinical course. Gastroenterology 1051057-1060,1993 33. Hanan M, Kirsner J B Inflammatory bowel disease in pregnant women. Clin Perinatol 12682499,1985 34. Hanauer SB, Shulman M I New therapeutic approaches. Gastroenterol Clin North Am 24523-540,1995 35. Heinonen OP, Slone D, Shapiro S Birth Defects and Drugs in Pregnancy. Littleton, MA, Publishing Sciences Group, 1977, pp 389-391 36. Hill J, Clark A, Scott NA. Surgical treatment of acute manifestations of colonic disease during pregnancy. J R SOCMed 90:64-68,1997 37. Hoo JJ, Hadro TA, von Behren P: Possible teratogenicity of sulfasalazine [letter]. N Engl J Med 318:1128, 1988

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

223

38. Hudson CN: Ileostomy in pregnancy. Proc R SOCMed 65:281-285, 1972 39. Jarnerot G, Malmberg MB: Sulfasalazine treatment during breast feeding. Scand J Gastroenterol 142369-871, 1979 40. Jonville-Bern AP, S u e z C, Fignon A, et a1 Pentasa (mesalamine) and pregnancy. Therapie 49:443-445, 1994 41. Khosla R, Willoughby CP, Jewell DP: Crohn’s disease and pregnancy. Gut 25:52-56, 1984 42. Koyarna N, Komori S, Bessho T, et a1 Holoprosencephaly in a fetus with maternal medication of sulfasalazine in early gestation: A case report. Clin Exp Obstet Gynecol 23:136-140, 1996 43. Lichitiger S, Present DH, Kornbluth A, et al: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330:1841-1845, 1994 44. Lindberg E, Jameret G, Huntfeldt 8: Smoking in Crohn’s disease: Effect on localization and clinical course. Gut 33779-782, 1992 45. MacDougall I: Ulcerative colitis and pregnancy. Lancet 2641443, 1956 46. Marion JF, Rubin PH, Lichtiger S, et a1 Cyclosporine is safe for severe colitis complicating pregnancy [abstr]. Am J Gastroenterol 91:1975, 1996 47. Marteau PH, Devaux CB: Mesalamine during pregnancy. Lancet 344:1708-1709, 1994 48. Mogadam DM, Dobbins WO 111, Korelitz BI, et al: Pregnancy in inflammatory bowel disease: Effect of sulfasalazine and corticosteroids on fetal outcomes. Gastroenterology 80~72-76, 1981 49. Mogadam DM, Korelitz BI, Ahmed SW, et a1 The course of inflammatory bowel disease during pregnancy and postpartum. Am J Gastroenterol 75:265-269, 1981 50. Narendranathan M, Sandler RS, Suchindran M, et a1 Male infertility in inflammatory bowel disease. J Clin Gastroenterol 11:403406, 1989 51. Nelson OH, Andreasson B, Bondesen S, et al: Pregnancy in ulcerative colitis. Scand J Gastroenterol 18:735-742, 1983 52. Nelson H, Dozois RR, Kelly KA, et al: The effect of pregnancy and delivery on the ileal pouch-anal anastomosis functions. Dis Colon Rectum 32384388, 1989 53. Newman NM, Correy JF: Possible teratogenicity of sulphasalazine. Med J Aust 1:522529, 1983 54. Present DH: 6-Mercaptopurine and other immunosuppressive agents in the treatment of Crohn’s disease and ulcerative colitis. Gastroenterol Clin North Am 18:57-71, 1989 55. Present DH, Korelitz BI, Wisch N, et al: Treatment of Crohn’s disease with 6-mercaptopurine. N Engl J Med 302:981-987,1980 56. Rosa EW, Baum C, Shaw M: Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol69:751-755, 1987 57. Rush D Periconceptional f ~ l a t e and neural tube defects. Am J Clin Nutr 59(~~ppl):511~-516~, 1994 58. Sartor RB: Cyclosporine therapy for inflammatory bowel disease. N Engl J Med 3301897-1898,1994 59, Satsangi J, Jewell DP, Rosenberg WMC, et a1 Genetics of inflammatory bowel disease. Gut 35:696-700, 1994 60. Singleton JW, Hanauer SB, Gitnick GL, et a1 Mesalamine capsules for the treatment of active Crohn’s disease: Results of a 16-week trial, Pentasa Crohn’s Disease Study Group. 104:1293-1301, 1993 61. Thacker SB, Banta HD: Benefits and risk of episiotomy: An interpretive review of the English language literature, 1860-1980. Obstet Gynecol Surg 36:322-338, 1983 62. Thompson NP, Driscoll R, Pounder RE, et al: Genetics versus environment in inflammatory bowel disease: Results of a British twin study. Br Med J 31295-96, 1996 63. Toovey S, Hudson E, Hendry WF, et al: Sulfasalazine and male infertility: Reversibility and possible mechanisms. Gut 22445451, 1981 64. Traillori G, d’Albasio G, Bardazzi G, et al: 5-Aminosalicylic acid in pregnancy: Clinical report. Ital J Gastroenterol 26:75-78, 1994 65. Tysk C, Lindberg E, Jarneret G, et a1 Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins: A study of heritability and the influence of smoking. Gut 29990-996, 1988

224

KORELITZ

66. Van Kruiningen HJ: On the use of antibiotics in Crohn's disease. J Clin Gastroenterol 20:310-316, 1995 67. Watson WJ, Gaines TE: Third trimester colectomy for severe ulcerative colitis: A case report. J Reprod Med 329369472, 1987 68. Weinstein GD: Methotrexate. Ann Intern Med 86199-204, 1977 69. Wiloughby CP, Truelove SC: Ulcerative colitis and pregnancy. Gut 21:469-474, 1980 70. Yang H, McElrece C, Roth MP, et a1 Familial empiric risks for inflammatory bowel disease: Differences between Jews and non-Jews [abstr]. Gastroenterology 102:A31, 1992 71. Yang H, Rotter J I The genetics of inflammatory bowel disease. In Targan SR, Shanahan F (eds): Inflammatory Bowel Disease: From Bench to Bedside. Baltimore, Williams & Wilkins, 1992, pp 3 2 4 4

Address reprint requests to Burton I. Korelitz, MD Department of Medicine Lenox Hill Hospital 100 East 77 Street New York, NY 10021