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Keywords:

  • Crohn's disease;
  • ulcerative colitis;
  • inflammatory bowel disease;
  • fertility;
  • pregnancy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background: Smaller family size and voluntary childlessness has been reported in IBD; however, the disease-related reasons for this from a patient viewpoint are not described. The aims were to 1) determine whether IBD patients' perceptions of the issues surrounding IBD, pregnancy, and childbearing influence their reproductive behavior, and 2) describe these specific perceptions and concerns related to fertility and pregnancy.

Methods: All contactable subjects between 18–50 years of age from a hospital-based IBD database were surveyed by postal questionnaire. Data were obtained regarding age, gender, IBD diagnosis and treatment, body image and sexual relationships, as well as both objective and subjective data regarding fertility and pregnancy. Comparisons were made to community norms where data were available. Contingency tables with Fisher's exact test were used.

Results: Of 365 subjects, 255 responded (70%). The mean age was 35.5 years overall, 34.7 years for women. In all, 34% of participants were male, 127 had Crohn's disease (CD), 85 ulcerative colitis (UC), and 5 indeterminate colitis (IC). The average fertility rate was no different between women with CD and UC (1.0 and 1.2 births/woman, respectively; P = 0.553), compared with 1.81 for all Australian women. Although 42.7% of IBD patients reported a fear of infertility, patients only sought medical fertility advice at the same rate as the general population. Fear of infertility was most evident in women, those with CD, and those reporting previous surgery. Specific patient concerns, which appear to have decreased patients' family size, included IBD heritability, the risk of congenital abnormalities, and medication teratogenicity.

Conclusions: The unusually high response rate indicates the centrality of reproductive issues to IBD patients. “Voluntary” childlessness in this group appears to result from concerns about adverse reproductive outcomes that may not be justified. Patients require accurate counseling addressing fertility and pregnancy outcomes in IBD to assist in their decision making.

(Inflamm Bowel Dis 2008)

Inflammatory bowel disease (IBD) commonly affects patients during their reproductive years, making the interaction between fertility, pregnancy, and IBD an important issue for both genders. Despite the postulated interaction between a diagnosis of IBD and family planning decisions, there is a paucity of data in this area, particularly from the patients' perspective. The published literature predominantly addresses pregnancy outcomes or is limited to population-based estimates of fertility and congenital abnormalities.1

Studies in male and female IBD patients have not demonstrated great differences in fertility (the capacity to conceive or induce conception) when compared with the general population,2–5 with the exception of notable subgroups. Active bowel inflammation appears to have a small detrimental effect on male6 and female fertility,7 as do some surgical procedures such as rectal excision and pouch formation, although the literature is conflicting.8, 9 Previous data suggest that high disease activity at conception increases infant risk of prematurity and low birth weight4, 10; this may be minimized by planning conception during IBD remission.

IBD medications have not been shown to affect fertility in women11 but reversible male infertility with sulfasalazine7, 12–14 and methotrexate15 is documented. These agents are easily avoided in modern IBD management, and should not necessarily influence reproductive opportunities.

To date, studies on reproductive decisions and family size have been observational16 and thus do not inform us of patient perceptions or intentions with regard to the interaction between IBD and family planning.

“Voluntary childlessness” has been described in IBD.17 However, whether this was due to IBD itself or to particular characteristics of the cohort (predominantly Caucasian, higher educational achievement) is uncertain. Despite this report, and Mayberry et al's observation about male IBD patients' family size, specific IBD-related reasons for having fewer children have not been specifically explored from a patient perspective. Given the fact that fertility appears to be reduced in only a small subset of IBD patients, it may be that “voluntary childlessness” is the main cause of the reduced fertility rate (number of live births per woman) reported in the IBD literature. We therefore sought to examine individual patient's perceptions of the interaction between their diagnosis of IBD and fertility and pregnancy issues, and how these perceptions affected their behavior with regard to reproductive choices.

The specific aims of this study were to 1) understand whether, and to what extent, IBD patients' perceptions of risk influence their reproductive behavior, and 2) describe IBD patients' specific concerns related to fertility and pregnancy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects and Recruitment

All patients age 18–50 years from a tertiary hospital-based IBD database were surveyed by postal questionnaire. Each questionnaire was mailed with an invitation letter and “opt out” slip. After 4 weeks an IBD Project Officer not involved in direct patient care (R.P.) made 2 attempts to contact each nonresponding patient by phone to establish receipt of the questionnaire, and encourage its completion or return of the opt out slip. The total data collection period was 13 months.

Survey Content

The questionnaire sent to subjects was entitled “Quality of Life, Body Image, Sexual Function and Pregnancy in Inflammatory Bowel Disease: A survey of patients in their reproductive years.” It consisted of 94 questions divided into 4 sections; Parts A and B addressed body image and sexual function, Part C fertility, and Part D pregnancy outcomes. Data pertaining to patient age, gender, disease type and duration, and previous surgery were also obtained. Many questions required free text qualification and subsection answers. As a result, a large amount of data was gathered and this article reports only section C results. Data regarding body image and sexual function18 and also pregnancy19 are presented elsewhere.

The fertility section of the questionnaire comprised both objective and subjective components, with multiple-choice “check-box” and free text response fields. As this is a relatively unexplored area within IBD, there are no validated assessment tools available to apply, and as such no formal pilot validity testing was performed. Questions arose from concerns and ideas expressed by IBD patients and physicians over many years of collective clinical experience. Male and female subjects were asked to report how many children they had (live births), how many they wished to have, whether conception had been difficult, whether they feared infertility and the reasons for this, and whether they had received medical consultation about fertility and IBD. Patients were asked about previous IBD surgery, termination of pregnancy, and the reasons for termination. Where available, population data were obtained from the Australian Bureau of Statistics20 for comparison. Data obtained in Part A such as gender, age, disease type, and relationship status were recorded. Subjects were given an opportunity to offer free text responses describing their thoughts about the interaction between IBD and fertility and pregnancy.

Descriptive data are presented, and comparisons made using contingency tables with Fisher's exact test, except for mean fertility rate data which were compared using a 2-tailed t-test. In all analyses a P-value < 0.05 was considered significant.

Ethics approval for the questionnaire was obtained via the Flinders Medical Centre Ethics Committee, with receipt of a completed questionnaire taken as signifying individual patient consent. Each patient had given prior consent to be enrolled in the clinical/research IBD database.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographic and Disease Data

In all, 365 subjects (146 male [M]; 219 female [F]) fell within the prespecified age range (18–50 years) and had a current mailing address. Of these, 217 participated and 38 returned the “opt out” slip. A total of 110 did not return the questionnaire despite 3 contact attempts (1 postal and 2 phone attempts). Our final response rate was therefore 70% (255/365) with a questionnaire completion rate of 59% (217/365). There were 127 respondents with Crohn's disease (CD), 85 with ulcerative colitis (UC), and 5 with indeterminate colitis (IC). Overall, 34% were male, with a mean age of 35.5 years. The mean age of female respondents was 34.7 years. As expected, a significantly higher proportion of those with CD as compared to UC reported previous IBD surgery (56.7% versus 15.3%, P = 0.0001) (Table 1). Respondents were no different from nonrespondents with regard to disease type, gender, and age.

Table 1. Demographics
 Crohn's Disease N (%)Ulcerative Colitis N (%)
  • *

    P = 0.0001.

Male39 (31%)33 (39%)
Mean age (years)35.135.9
Mean duration of disease (years)12.911.2
Previous IBD surgery72 (56.7%)*13 (15.3%)
Current relationship96/127 (76%)67/85 (79%)

In all, 71% of participants returned their questionnaire without need for telephone follow-up. The average time taken for questionnaires to be completed and returned was 6 weeks.

Relationship Status

Seventy-seven percent of all IBD subjects reported being in a current relationship, with 5.5% having never been partnered. This is similar to rates observed in the Australian population. Additionally, rates of sexual intercourse reported by our study population in Section B appeared adequate to allow conception at normal rates, although no local population data are available for comparison addressing intercourse frequency.

Fertility Data

The average fertility rate among female IBD patients did not differ among those with CD and UC (CD, 1.0 live births per woman versus UC, 1.2; P = 0.553). In the same time period, however, the average Australian women's “Total Fertility Rate” (the number of babies a woman would bear during her life if she experienced current age-specific fertility rates at each age of her reproductive life) was 1.81 (Fig. 1).20

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Figure 1. Fertility rates in Australian IBD versus non-IBD women. **Government of Australia, Australian Bureau of Statistics, Adelaide 2007. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Overall, 42.7% of IBD respondents reported a fear of infertility, with this being greater in patients with CD compared to UC (CD 47.2% versus UC 25.8%) P = 0.0032 (Fig. 2). Fear of infertility was significantly higher among female patients compared to males (F 47/87 [54%] versus M 13/40 [32.5%]; P = 0.035) (Fig. 2). Interestingly, this gender-based difference was not seen in UC patients (F 15/52 [28.8%] versus M 7/33 [21.2%]; P = 0.61). A history of prior surgery appeared to contribute to this fear, as 43/83 patients (52%) who reported a fear of infertility had a history of previous IBD surgery, compared to only 29/111 (26%) patients without a fear of infertility (P = 0.0003) (Fig. 3).

thumbnail image

Figure 2. IBD-related fear of infertility by disease type and by gender. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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thumbnail image

Figure 3. The interaction between surgery and fear of infertility. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Despite the highly prevalent reported fear of infertility, only 19.4% of patients reported consulting a doctor for fertility problems, and this did not differ significantly between CD and UC patients (21.3% versus 15.3%, P = 0.27), despite the greater prevalence of this fear in those with CD (as reported above); nor did it differ from the currently estimated rates of fertility consultation for the non-IBD population21, 22 (Table 2).

Table 2. Fertility Data
 Crohn's DiseaseUlcerative ColitisNon-IBD Population
  • *

    Population data not available.

Never had children62/127 (49%)27/85 (32%)24%20
Medical fertility opinion27 (21.3%)13 (15.3%)20-26.4%21 22
Difficulty conceiving27 (21.6%)18 (20.8%)20-26.4%21
Fearing lack of fertility60 (47.2%)22 (25.8%)N/A*
Fewer children than desired31 (24.5%)20 (23.5%)N/A*
Termination of pregnancy21 (16.5%)13 (15.3%)27%23
ToP attributable to IBD4 (3%)2 (2.4%)

Childlessness, Choices, Intentions

Forty-two percent of IBD respondents reported being childless; 14% of childless IBD patients reported making this decision as a direct result of IBD. When considering only respondents with children, approximately one-quarter reported having fewer children than desired or planned, with no difference between those with CD and UC (CD 24.5% versus UC 23.5%; P = 0.9; Table 2). Directly comparable data are not available for the non-IBD Australian population, although in the developed world there is an acknowledged gap between the number of children women plan to have and the number they eventually have.

Termination of pregnancy was reported in females with IBD or female partners of male IBD patients in 21 CD and 13 UC respondents (CD 16.5% versus UC 15.3%; P = 0.61), compared with 27% in Australian women without IBD23 (Table 2). The decision to terminate a pregnancy was directly attributed to IBD in only 6 of the 34 respondents who reported a termination (17.7%). The IBD-related reasons for this decision fall into the areas listed in Table 3.

Table 3. Patient-reported Reasons for Voluntary Infertility in IBD
Area of Patient ConcernN (% of 48 Subjects)
Fear of IBD-related congenital abnormalities9 (18%)
Concern about genetic risk of IBD in child7 (15%)
Concern about medication teratogenicity (methotrexate and non-methotrexate)14 (30%)
Medical advice that conception not possible/ inadvisable with IBD17 (35%)
IBD-related fatigue prohibitive1 (2%)

Forty-eight subjects took the opportunity offered in the questionnaire to make subjective “free text” comments on their perceived interaction between fertility/pregnancy/family planning and their disease. IBD-related patient concerns that negatively influenced reproductive decisions could be divided into 5 themes (Table 3). Of particular note, in these 48 patients, 17 (35%) reported their doctor advised against pregnancy “because of IBD or IBD surgery”; 14 (30%) described “concern about medication side effects”; 9 (19%) reported fear of congenital abnormalities; 7 (15%) were worried about “the genetic risk of my child having IBD”; 1 male on sulfasalazine reported attempting conception for 15 years before being informed of the reversible infertility associated with this agent, and 1 female reported severe IBD-related fatigue which she felt would prohibit the care of a child. Other subjects gave adverse social circumstances or other medical problems as the reason for fewer children than desired.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This is the first large study to examine this important issue from a patient-centered perspective. Moreover, the high response rate (70%) not only strengthens our data, but also indicates the centrality of these concerns to our patients.

Despite little evidence for decreased fertility (ability to conceive) in the IBD literature,5 our respondents have a lower observed or actual fertility rate (fewer children) than the non-IBD population.20 Our IBD patients demonstrated a much higher rate of concern regarding infertility than the Australian female population (>40% versus 9%22). Interestingly, despite lower observed rates of fertility, medical fertility advice was only sought with similar frequency between IBD and non-IBD women,21 suggesting this reduction in fertility may be at least in part “voluntary.” This fear of infertility was most evident in those diagnosed with CD, females, and those reporting previous surgery. Of interest, while Mahadevan et al24 reported an increase in adverse conception outcomes in IBD patients with previous surgery compared with non-IBD patients (odds ratio [OR] 2.26 (1.12-4.55)), there was no difference in conception outcome between operated and nonoperated IBD subjects. While there are other data supporting adverse effects of any IBD surgery on fertility, the rate of fear affecting decision-making in our surgical patient population appeared disproportionately high.

These findings offer new and more generalizable insights into reproductive decision-making in patients with IBD due to the very high response rate to our questionnaire (70% compared with ≈20% in previous similar studies.17 Additionally, our questionnaire's subjective, open-ended nature, which allowed patients to report their own responses without categorical limitation, has added a greater depth of understanding in this area. Although “voluntary childlessness” in IBD patients has been previously reported,17 it was attributed to non-IBD (demographic) factors. Our data offer an open exploration of the IBD-related concerns patients feel negatively influence or constrain their reproductive choices.

Interestingly, IBD-related reproductive risk appeared to be overestimated by our respondents, and this misperception seemingly altered their subsequent reproductive behavior. To address respondents' specific concerns, the current literature suggests no overall fertility reduction and only a slight increase in the risk of adverse pregnancy outcomes in most IBD subgroups.7 As physicians, we need to more accurately communicate this message to our patients.

A recent population-based meta-analysis suggests a 1.87-fold increase in prematurity in all IBD patients, a 2-fold increase in low birth weight (LBW), and a 1.5-fold increased risk of cesarean section in CD patients.1 Importantly, however, population-based, case-control studies suggest no increase in more serious adverse outcomes including still birth, neonatal death, and spontaneous abortion.25, 26 While most published data do not associate IBD with a risk of congenital abnormalities,27, 28 2 studies suggested a slight increase in congenital abnormalities in patients with UC but not CD29, 30; however, this risk, if present, is very low, and certainly not of a magnitude to justify a medical recommendation to avoid reproducing.

Although long-term safety data are not yet available for the biologic agents, accumulating evidence suggests a moderately favorable safety profile for most IBD medications.7 Pooled analysis suggests no significant increase in the risk of still births, ectopic pregnancies, spontaneous abortions, or LBW infants for 5-ASA agents, corticosteroids, azathioprine, anti-TNF agents, and cyclosporine.31 A small increase in congenital abnormalities was noted for 5-ASA, anti-TNF agents and azathioprine,31 as well as a slightly increased risk of cleft palate with the use of systemic steroids in pregnancy. Most antibiotics are considered safe for brief periods in pregnancy, except for tetracycline, ciprofloxacin, and sulfonamides. Breast feeding should be encouraged in most IBD patients,7 with exceptions for patients on thiopurines, methotrexate, and cyclosporine.32

Regarding patients' fear of IBD inheritance, current data suggest that IBD does have a partial genetic component, with disease concordance higher in monozygotic than dizygotic twins.33 One parent with IBD confers a 2–13-fold higher risk of disease compared with the general population.34, 35 Looking at this from the converse, it should be emphasized that the risk of a child not having IBD is always far greater than the risk of a child developing IBD (>91% for 1 affected parent and >60% even if 2 parents are affected). It is important to emphasize to patients that a family history is neither necessary nor sufficient to predict IBD in their offspring, the absolute risk of UC and CD remaining low, at 1.6% and 5.2%, respectively, being slightly higher in Jewish populations.17

Somewhat disappointingly, several subjects attributed their negative reproductive decisions to medical advice. Unfortunately, 1 male patient reported unawareness of sulfasalazine-induced infertility while trying to conceive for 15 years. A surprising number of other subjects reported receiving generic medical advice indicating that IBD or IBD surgery rendered them infertile. The proportion of patients receiving such advice far exceeded the expected proportion of medically infertile patients in our sample. This tendency has been noted previously, in 1986, when more than 50% of IBD patients were counseled against having children by their physicians, and a similar proportion reported advice to terminate pregnancies for IBD-related reasons.36 More recent data published in 2007 suggest that 68% of IBD patients discuss reproductive issues with their IBD physician at some stage,17 providing an ideal opportunity for accurate education and correction of misperceptions.

Despite the fact that our study subjects were known to a tertiary hospital IBD Service, with access to specialist gastroenterology care and a full-time IBD nurse, the level of misinformation was high. Patients whose IBD care is entirely community-based may have even lower levels of IBD knowledge, and thus an even higher rate of misperception regarding their reproductive risk. Physicians should instigate discussion about reproductive issues as part of routine IBD care in the under-50s, especially when treating women, those with CD, and those with previous IBD surgery.

The enthusiasm shown by IBD patients in returning the questionnaire highlights the importance of reproductive issues in this group, and the pressing need to incorporate realistic discussion and education into the IBD consultation. Patients should be encouraged to seek reproductive advice to address fears, and physicians should liaise with obstetric colleagues to provide individualized and specific counseling regarding fertility and pregnancy planning.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Cornish J, Tan E, Teare J, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut. 2007; 56: 830837.
  • 2
    Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut. 1980; 21: 469474.
  • 3
    Kroser J, Srinivasan R. Drug therapy of inflammatory bowel disease in fertile women. Am J Gastroenterol. 2006; 101(12 Suppl ): S633639.
    Direct Link:
  • 4
    Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease. Gastroenterology. 1990; 99: 987994.
  • 5
    Hudson M, Flett G, Sinclair TS, et al. Fertility and pregnancy in inflammatory bowel disease. Int J Gynaecol Obstet. 1997; 58: 229237.
  • 6
    Karbach U, Ewe K, Schramm P. [Quality of semen in patients with Crohn's Disease]. Z Gastroenterol. 1982; 20: 314320.
  • 7
    Heetun ZS, Byrnes C, Neary P, et al. Review article: reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther. 2007; 26: 513533.
  • 8
    Johnson P, Richard C, Ravid A, et al. Female infertility after ileal pouch-anal anastomosis. Dis Colon Rectum. 2004; 47: 11191126.
  • 9
    Caprilli R, Gassull M, Escher J. European Crohn's and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn's disease: special situations. Gut. 2006; 55: 3658.
  • 10
    Nielsen OH. Pregnancy in ulcerative colitis. Scand J Gastroenterol. 1983; 18: 735742.
  • 11
    Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanised antiTNF alpha monoclonal antibody. Hum Exp Toxicol. 2000; 19: 226228.
  • 12
    O'Morain C, Smethurst P, Dore CJ, et al. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut. 1984; 25: 10781084.
  • 13
    Cosentino MJ, Chey WY, Takihara H, et al. The effects of sulfasalazine on human male fertility potential and seminal prostaglandins. J Urol. 1984; 132: 682686.
  • 14
    Toovey S, Hudson E, Hendry WF, et al. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut. 1981; 22: 445451.
  • 15
    Hinkes E, Plotkin D. Reversible drug induced sterility in a patient with acute leukemia. JAMA. 1973; 223: 14901491.
  • 16
    Burnell D, Mayberry J, Calcraft BJ, et al. Male fertility in Crohn's disease. Postgrad Med J. 1986; 62: 269272.
  • 17
    Marri SR, Ahn C, Buchman AL, et al. Voluntary childlessness is increased in women with inflammatory bowel disease. Inflamm Bowel Dis. 2007; 13: 591599.
  • 18
    Body Image, Sexual Function and IBD. San Diego: Digestive Diseases Week; 2008. Abstract 944.
  • 19
    Pregnancy, disease activity and IBD medication: this two edged sword from a patient perspective. Brisbane, Australia: Australian Gastroenterology Week; 2008. Abstract 1417.
  • 20
    Government of Australia. Australian Bureau of Statistics. Adelaide, 2007.
  • 21
    Schmidt L. Infertility and assisted reproduction in Denmark: epidemiology and psychosocial consequences. Dan Med Bull. 2006; 53: 390417.
  • 22
    Fertility. Society of Australia. Fertility Study: Attitudes, Experiences and Beliefs of Australia's General Public. Sydney, Australia, 2006.
  • 23
    Department of Health and Family Services. Medicare Statistics; Australian Institute of Health and Welfare, National Hospital Morbidity Database. Canberra: Australian Institute of Health and Welfare, 2008.
  • 24
    Mahadevan U, Sandborn WJ, Li DK, et al. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007; 133: 11061112.
  • 25
    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: 942946.
  • 26
    Norgard B, Fonager K, Pedersen L, et al. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study. Gut. 2003; 52: 243247.
  • 27
    Elbaz G, Fich A, Levy A, et al. Inflammatory bowel disease and preterm delivery. Int J Gynaecol Obstet. 2005; 90: 193197.
  • 28
    Fedorkow DM, Persaud D, Nimrod CA. Inflammatory bowel disease: a controlled study of late pregnancy outcome. Am J Obstet Gynecol. 1989; 160: 9981001.
  • 29
    Larzilliere I, Beau P. [ Chronic inflammatory bowel disease and pregnancy. Case control study.] Gastroenterol Clin Biol. 1998; 22: 10561060.
  • 30
    Dominitz JA, Young JC, Boyko EJ. Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study. Am J Gastroenterol. 2002; 97: 641648.
    Direct Link:
  • 31
    Katz J. Outcome of pregnancy in women receiving Infliximab for the treatment of Crohn's disease and rheumatoid arthritis. Am J Gastroenterol. 2004; 99: 23852392.
    Direct Link:
  • 32
    Reddy S, Burakoff R. Inflammatory bowel disease in African Americans. Inflamm Bowel Dis. 2003; 9: 380385.
  • 33
    Binder V. Genetic epidemiology in inflammatory bowel disease. Dig Dis. 1998; 16: 351355.
  • 34
    Orholm M, Munkholm P, Langholz E. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991; 324: 8488.
  • 35
    Orholm M, Fonager K, Sorenson H. Risk of ulcerative colitis and Crohn's disease among offspring of patients with chronic inflammatory bowel disease. Am J Gastroenterol. 1999; 94: 32363238.
    Direct Link:
  • 36
    Mayberry J, Weterman I. European survey of fertility and pregnancy in women with Crohn's disease: a case control study by European Collaborative Group. Gut. 1986; 27: 821825.