Selinger CP, Leong RW, Lal S. Pregnancy related issues in inflammatory bowel disease: Evidence base and patients' perspective. World J Gastroenterol 2012; 18(21): 2600-2608
Corresponding Author of This Article
Dr. Christian P Selinger, Department of Gastroenterology, Salford Royal Hospital, Stott Lane, Salford M6 8HD, United Kingdom. firstname.lastname@example.org
Article-Type of This Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Pregnancy related issues in inflammatory bowel disease: Evidence base and patients' perspective
Christian P Selinger, Rupert WL Leong, Simon Lal
Christian P Selinger, Simon Lal, Department of Gastroenterology, Salford Royal Hospital, Salford M6 8HD, United Kingdom
Christian P Selinger, Rupert WL Leong, Gastroenterology and Liver Services, Sydney Local Health Network, Concord Hospital, NSW 2139 Sydney, Australia
Rupert WL Leong, Faculty of Medicine, The University of New South Wales, NSW 2052 Sydney, Australia
ORCID number: $[AuthorORCIDs]
Author contributions: All authors made substantial contributions to conception and design, drafting the article and revising it critically for important intellectual content.
Correspondence to: Dr. Christian P Selinger, Department of Gastroenterology, Salford Royal Hospital, Stott Lane, Salford M6 8HD, United Kingdom. email@example.com
Telephone: +44-161-7897373 Fax: +44-161-2061048
Received: July 8, 2011 Revised: September 9, 2011 Accepted: September 16, 2011 Published online: June 7, 2012
Inflammatory bowel disease (IBD) affects women of childbearing age and can influence fertility, pregnancy and decisions regarding breastfeeding. Women with IBD need to consider the possible course of disease during pregnancy, the benefits and risks associated with medications required for disease management during pregnancy and breastfeeding and the effects of mode of delivery on their disease. When indicated, aminosalicylates and thiopurines can be safely used during pregnancy. Infliximab and Adalimumab are considered probably safe during the first two trimesters. During the third trimester the placenta can be crossed and caution should be applied. Methotrexate is associated with severe teratogenicity due to its folate antagonism and is strictly contraindicated. Women with IBD tend to deliver earlier than healthy women, but can have a vaginal delivery in most cases. Caesarean sections are generally recommended for women with active perianal disease or after ileo-anal pouch surgery.While the impact of disease activity and medication has been addressed in several studies, there are minimal studies evaluating patients’ perspective on these issues. Women’s attitudes may influence their decision to have children and can positively or negatively influence the chance of conceiving, and their beliefs regarding therapies may impact on the course of their disease during pregnancy and/or breastfeeding. This review article outlines the impact of IBD and its treatment on pregnancy, and examines the available data on patients’ views on this subject.
Citation: Selinger CP, Leong RW, Lal S. Pregnancy related issues in inflammatory bowel disease: Evidence base and patients' perspective. World J Gastroenterol 2012; 18(21): 2600-2608
Inflammatory bowel disease (IBD) predominantly affects the younger-aged population and therefore is prominent in women of child-bearing age. It often requires medication for maintenance of remission. Literature on pregnancy in IBD has mainly utilized tertiary hospital cohorts and focused on pregnancy outcomes. Current guidelines emphasize the importance of inducing and maintaining disease remission prior to conception and during pregnancy[1,2]. Studies of patients’ perspective of the influence of IBD on fertility, pregnancy and breastfeeding are highly relevant and beginning to emerge. This review article summarizes this evidence and examines the currently available data describing the patients’ views.
A literature search was conducted using Pubmed from 1980 to 2010 with the search terms “IBD”, “Crohn’s disease (CD)”, “ulcerative colitis (UC)”, “pregnancy”, “breast feeding” and “nursing”. Further relevant articles were identified from the reference lists of identified articles.
Fertility and fecundity
Factors determining fecundity and fertility in IBD include disease systemic effects (e.g., fatigue and anaemia) as well as libido and sexual inactivity, which, in turn, may be influenced by body image issues and dyspareunia. Furthermore, concerns over the influence of disease activity or medications on a successful pregnancy may also influence fecundability. In UC, overall fertility is comparable to that of the healthy population[3-5], but women with ileo-anal pouches (IPAA) have reduced fecundity[6,7]. Fertility in CD in remission is equivalent to that of healthy women[4,8,9] but may be reduced in patients with active disease[9-12]. As in UC, women with CD also have reduced fecundity following extensive surgery involving the pelvis[5-7,13-18].
Disease behaviour during and after pregnancy
Disease activity during pregnancy is similar to that in non-pregnant women as reported by two Danish cohort studies. In 97 women with UC, flare rates were 34% per year during pregnancy and 32% per year outside pregnancy, while in 68 women with CD there was also no increased risk of a flare during pregnancy. The vast majority of women have quiescent disease during pregnancy as shown in a population based cohort of 461 women from the Northern California Kaiser Permanente population.
Women with IBD might experience a more benign course of disease in the post-partum period. A significantly reduced number of flares in comparison to pre-pregnancy in a small cohort of 18 CD and 19 UC patients was reported by Castiglione et al. A larger pan-European study of 93 women with CD and 173 women with UC confirmed this finding. The reason for this phenomenon is unknown, but it has been proposed that disparity between maternal and foetal human leukocyte antigen class II antigens leads to a state of immuno-tolerance or suppression that in turn leads to a more benign course of IBD.
Effects of IBD and IBD disease activity on pregnancy
Active disease during pregnancy has been linked to adverse pregnancy outcomes of low birth weight, pre-term birth and foetal loss[19,25-27]. Population-based studies have, however, reported conflicting results. In 461 women (300 with UC) of the Kaiser Permanente population in North America, no correlation between adverse pregnancy outcomes and disease activity was found, while a study of 157 Danish women with CD revealed that active disease increased the risk of pre-term birth. The higher proportion of patients with active disease in the Danish study (45% vs 20% in the Kaiser Permanente population) may explain this difference.
Some studies, including a meta-analysis by Cornish et al, reported an increase in pre-term births in IBD patients. Other studies, however, that differentiated UC from CD found an increase in pre-term birth rates for patients with CD only[30,31]. CD women also delivered lower birth weight babies than healthy controls and UC women[30,31]. It is important to recognise that all studies examining pregnancy outcomes in IBD used healthy women controls rather than those with other chronic diseases.
Congenital abnormalities in offspring of mothers with IBD
Congenital abnormalities of variable severities occur in 3%-7% of babies of healthy mothers. Studies of congenital malformations in the offspring of mothers with IBD have reported conflicting results. In a population based cohort of 262 women from Washington state, North America, an increased risk of congenital malformations was found in the offspring of UC patients (7.9% vs 1.7% in healthy controls; P < 0.001) but not in those of CD patients (3.4%; P = NS). The study did not control for medication use. In contrast, the Hungarian Case Control Surveillance of Congenital Anomalies (HCCSCA) (1980-1996) found no increase in the risk for “any” malformation [odd ratio (OR): 1.2, 95% (confidence interval) CI: 0.9-1.8] in the offspring of 79 UC mothers compared to 95 control mothers after adjusting for parity, age and medication use. Specific malformations of the limb (OR: 6.2, 95% CI: 2.9-13.1), urinary tract (OR: 3.3, 95% CI: 1.1-9.5) and multiple malformations (OR: 2.6, 95% CI: 1.3-5.4), however, were significantly increased.
An Italian case-control study reported a significantly increased risk of congenital anomalies in the offspring of 90 women with IBD (5.5% vs 0% in 240 healthy controls) and that CD and UC had equivalent risks. The reported 0% incidence of congenital abnormality rate in healthy controls, however, was unusually low given this rate can approach 7%.
The risk of congenital malformations in the offspring of 461 women with IBD from the Northern California Kaiser Permanente population was not increased in comparison to 493 healthy controls. Cornish et al found in a meta-analysis of four studies an increased risk (OR: 2.37, 95% CI: 1.47-3.82) of reporting congenital abnormalities for UC, while for CD the risk increase was not statistically significant (OR: 2.14, 95% CI: 0.97-4.74; P = 0.06).
Data on congenital malformations may be contradictory due to differences in study design, the inclusion of cohort vs population subjects, and sample sizes. The majority of studies, however, report an increased risk for malformations in UC, but not in CD. Further prospective studies adjusting for disease activity, medication and age of the mother are needed.
Medication during pregnancy
The risks and benefits of medication need to be considered on an individual patient level, since active disease poses a risk to the pregnancy[26-28]. The European Crohn’s and Colitis Organisation (ECCO) guidelines state the risk of adverse pregnancy outcomes from active disease to be higher than the risk of using most IBD medications. The United States Food and Drug Administration issued a categorisation of drugs safety in pregnancy (Table 1).
Table 1 Food and Drug Administration categories of drug safety during pregnancy.
Controlled studies in animals and women have shown no risk in the first trimester, and possible foetal harm is remote
Either animal studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester
No controlled studies in humans have been performed, and animal studies have shown adverse events, or studies in humans and animals not available; give if potential benefit outweighs the risk
Positive evidence of foetal risk is available, but the benefits may outweigh the risk if life-threatening or serious disease
Studies in animals or humans show foetal abnormalities; drug contraindicated
FDA: Food and Drug Administration.
Aminosalicylates: Sulfasalazine, mesalazine and balsalazide are category B medications, while olsalazine is category C. Initial case reports[35-37] suggesting sulphasalazine teratogenicity was refuted by a Danish cohort study demonstrating no adverse outcomes in 17 pregnant CD patients exposed to sulfasalazine. Another study of 181 pregnant patients with IBD exposed to sulfasalazine reported lower rates of adverse outcomes than those expected in the general population. Sulfasalazine impairs folate absorption, which is vital for neural tube development. Therefore folate supplementation is mandated.
Several studies have demonstrated the safety of mesalazine[39-41]. Robust data from a Danish population-based cohort and a prospective controlled trial of 165 pregnant women with mesalazine exposure reported no increased risk of congenital abnormalities[42,43]. It is unclear whether an excess of stillbirth and preterm birth in 88 pregnancies of women with CD on mesalazine reported in the population based study, occured as a result of IBD itself rather than the medication since this study incorporated 19 418 pregnancies of healthy women without any chronic illnesses and medication exposure as the control group. Thus, sulfasalazine and mesalazine are considered safe in pregnancy.
Antibiotics: Antibiotics play an important role in the management of perianal CD. Metronidazole is a category B medication. In a population based case-control study using HCCSCA data (1980-1991), metronidazole exposure during the second or third trimester was associated with cleft defects. Other studies including two meta-analyses and a prospective controlled study, however, found no increased risk of congenital abnormalities relating to metronidazole use[45,46]. Quinolones can induce congenital abnormalities in animals due to their accumulation in bone and cartilage. In 2 human studies totalling over 250 patients without IBD, no increased risk of adverse pregnancy outcomes or foetal malformations was found[48,49].
Short-term antibiotic use in pregnancy appears safe in largely non-IBD cohorts. In IBD, however, exposure to antibiotics can be prolonged and the associated risks may therefore be higher. A small series of IBD patients found no adverse pregnancy outcomes in 27 patients exposed to metronidazole and 18 to ciprofloxacin.
Tetracyclines (retardation of foetal skeletal development) and sulphonamides (interferes with folic acid metabolism) should both be avoided in pregnancy.
Corticosteroids: Prednisone and budesonide have category C ratings. Corticosteroids cross the placenta and some adverse data exist in humans. A meta-analysis of ten cohort and case-control studies totalling 50 845 patients without IBD found no increase in overall risk of major congenital abnormalities, but there was a significant risk of oral clefts. In contrast a prospective study of 262 women found that neither the overall risk for malformations nor the risk for clefts was increased. No human data exist on orally administered budesonide, but studies looking at women exposed to inhaled or intra-nasal budesonide have found it to be safe during pregnancy[53,54]. Due to oral budesonide’s high first pass hepatic metabolism, significant foetal exposure is less likely.
Thiopurines: Mercaptopurine and its pro-drug azathioprine are category D due to previous links with spontaneous abortions[55,56]. Animal studies, using doses of 1.5-2.5 mg/kg, have not reported any adverse outcomes apart from low birth weights[57,58]. Transplant and rheumatology cohorts demonstrated the safety of thiopurines[59-61]. Most studies in pregnant IBD patients report no adverse outcomes[62,63], but a Danish study reported a increased pre-term birth, low birth weight and foetal abnormalities in a cohort of only 10 patients. That study compared pregnancy outcomes in thiopurine exposed patients to those of the general population rather than non-exposed IBD patients. It is therefore unclear whether the increased risk detected in the study was due to medication or IBD itself. In contrast, a prospective Austrian abstract of 33 women and a French study on 86 women show no increase in adverse outcomes. Paternal thiopurine exposure within 3 mo prior to conception led to a higher rate of pregnancy related complications in one study, but another study reported no increased risk of adverse outcomes.
Thus, studies comparing outcomes of thiopurine exposed and unexposed IBD patients demonstrate no association with adverse outcomes. The single study showing a possibly increased risk is small and compares exposed patients to the general population. Based on the overall evidence and despite the category D classification, the ECCO guidelines therefore consider thiopurines safe and well tolerated in pregnancy.
Methotrexate: Methotrexate is rated category X as it is clearly teratogenic and an abortifacient due its biological action as a folate antagonist. It is associated with numerous foetal abnormalities and high risk of foetal mortality and absolutely contraindicated for women attempting pregnancy[69,70].
Other immunosuppressants: Data on cyclosporine and tacrolimus mainly stems from the transplant and rheumatology literature and both are rated category C.
Biological agents: Infliximab has been classed as category B. It does not cross the placenta during the first trimester and hence there is no exposure in this critical phase of development. Infliximab crosses the placenta in later stages of pregnancy and may be present in the newborn for several weeks. Safety data for infliximab are provided by three large scale studies. The Crohn’s Therapy Resource, Evaluation and Assessment Tool registry-a prospective, North American observational multi-centre study-enrolled infliximab-exposed and unexposed CD patients from 1999 to 2004. No differences in miscarriages and neonatal complications were found between infliximab-exposed (117 pregnancies) and unexposed (49 pregnancies) women. The retrospective Infliximab Safety Database (maintained by Centocor) found no differences in adverse outcomes between 96 pregnancies in women with infliximab exposure compared to the general population. The Leuven group in Belgium treated 29 women treated with infliximab during 35 pregnancies and six women with adalimumab during seven pregnancies. In comparison to IBD patients without infliximab or adalimumab exposure, no increased risk of adverse events was found.
Adalimumab is also classed as a category B drug and expected to have the same placental transfer as infliximab. Apart from the Leuven experience there are few reports on IBD patients exposed to adalimumab during pregnancy[75,76]. The organisation for teratology specialists’ registry of women with rheumatoid arthritis compared 34 adalimumab-exposed pregnancies to 52 pregnancies of healthy women and found no increased risk of adverse pregnancy outcomes. Certolizumab and natalizumab are category B and C drugs respectively, but there is currently little data on their effects in pregnancy.
Infliximab use in pregnancy resulted in the death of a 3 mo old child with disseminated Bacillus Calmette-Guérin (BCG) after receiving the live BCG vaccination. Live vaccinations are contra-indicated for immuno-compromised patients. Newborns to mothers exposed to infliximab and adalimumab mothers should have their vaccination postponed.
Mode of delivery
Patients with IBD (especially CD) were more likely to have a caesarean section in Cornish’s meta-analysis of six studies (OR: 1.5, 95% CI: 1.26-1.79; P < 0.001) compared to the general population, but there was no difference in caesarean rates between UC and controls. Concerns regarding the preservation of the anal sphincter function and the development of perianal disease after traumatic injuries occurring during vaginal delivery may partially explain this phenomenon. However, the chance of developing perianal disease in women with CD without prior perianal involvement is low; in a population based cohort study from Mannitoba, Canada only one of 27 women without prior perianal disease developed perianal disease after vaginal delivery and episiotomy. Conversely, in a self-report survey of 179 women without perianal disease, 18% reported perianal involvement after delivery, but it is possible that selection bias, that is, more women with than without perianal disease may have responded, and recall bias may have occurred.
A population based cohort study from Mannitoba of 11 patients with inactive perianal disease and two single case reports from France and United States, revealed that inactive perianal disease may tolerate a vaginal delivery with episiotomy if needed without risking a flare[79,81,82]. However, women with active perianal disease should be advised to have a caesarean section as a high risk of deterioration is anticipated. Delivery trauma can lead to poor-healing in the perineum. ECCO guidelines advise that elective caesarean section is indicated for all women with perianal involvement even though there is little evidence suggesting harm from a vaginal delivery in cases of inactive disease.
ECCO guidelines recommend mandatory caesarean sections after IPAA. Changes in anal sphincter function are temporary and long-term disturbances seem to be independent of the mode of delivery in patients with IPAA[14,16,83]. The largest study of 232 females with pregnancies after IPAA found no difference in pouch-related complications between women undergoing vaginal delivery or caesarean section. In another survey, functional pouch outcomes of 85 women with vaginal deliveries after IPAA were no different to those of 343 age matched women who did not have children after IPAA. A Finish survey study of 39 women with IPAA found no differences in pouch function after 19 vaginal deliveries in comparison to 21 caesarean sections and the rate of 5 tears after vaginal delivery was similar to a healthy control group. In a cohort of women investigated four years after IPAA at the Cleveland clinic, United States no clinical differences were demonstrated between 20 women with at least one vaginal delivery compared to 62 women who only had caesarean sections. Subclinical differences in anorectal physiology were however demonstrated as women with vaginal deliveries had significantly lower squeeze pressure on anorectal manometry and significantly more anal sphincter defects detected by anorectal sonography than those women with caesarean sections.
The ECCO guidelines state that women are at borderline incontinence after IPAA surgery and that any further disruption by a vaginal delivery might compromise this. This theoretical concern is supported by sonographic and manometric evidence of sphincter dysfunction, but this does not translate to clinical differences in pouch function or quality of life. Precautionary caesarean sections are however recommended.
Thus, mandatory recommendation for caesarean sections in IBD is only for very specific indications and decisions should be made on a case by case basis.
Breast milk provides ideal nutrition and has positive effects for the immune system of the newborn. Data on the protective effect of breastfeeding against the development of IBD report are conflicting. Study design, recall bias, definition of breast feeding (especially duration) and the design bias often inherent in retrospective case-control studies may explain some of the differences. A meta-analysis of 17 studies found reduced ORs of 0.67 (95% CI: 0.52-0.86) for CD and 0.77 (95% CI: 0.61-0.96) for UC. The relevance of a French case-control study reporting an increased risk (OR: 2.1, 95% CI: 1.3-3.4) of developing CD remains unclear, in light of previous studies showing no effect or a protective effect[89,91].
Fewer patients with IBD breastfeed compared to the general population, and this may relate to fears about adverse effects of maternal medication. Most maternal medications can be detected in breast milk, but this does not always lead to biological effects in the infant.
Based on two case reports of bloody diarrhoea in newborns breastfed by mothers taking sulfasalazine and 5-aminosalicylates respectively, the American Academy of Pediatrics advises against breastfeeding by mothers taking these medications[93-95]. In contrast, several studies demonstrate the safety of sulfasalazine and 5-aminosalicylates while breastfeeding by detecting low levels of drug in breast milk or the infant’s serum[39,96,97]. Based on above evidence mothers on sulfasalazine and 5-aminosalicylates should not be discouraged from breastfeeding unless the infant develops diarrhoea.
Since corticosteroids are found in human breast milk in low concentrations, women are advised to avoid feeding within 4 h of taking an oral dose to reduce exposure[2,98]. Thiopurine and associated metabolite levels are either at undetectable, or extremely low levels, in human breast milk[99-101], while infants’ levels were undetectable[102,103]. Infliximab can not be detected in infants of breastfeeding mothers, but adalimumab has been found in miniscule concentrations in breast milk in a single case. Methotrexate should be avoided as it is found in breast milk. Sulfasalazine, 5-aminosalicylates, steroids and thiopurines are all considered advisable during breast feeding (Table 2).
Table 2 Medication recommendation for pregnancy and breast feeding.
Detection in breast milk
Sulfasalazine, balsalazide, mesalazine
Safe to use (folate supplementation for sulfasalazine)
Low levels detectable
Safe to use
Safe to use
Limited data; probably safe
Safe to use
Safe to use
Very low levels detectable
Probably safe (avoid during 3rd trimester)
Probably safe (avoid during 3rd trimester)
Very low levels detectable
FDA: Food and Drug Administration.
Women’s beliefs and attitudes
Few studies have evaluated the perspectives of patients with IBD on fertility, pregnancy, breast feeding and pregnancy outcomes. Women with IBD may have fewer children as more stay “voluntarily childless”. A survey of Crohn’s and Colitis Foundation of America members reported that 18% of females with CD and 14% of females with UC decided to stay childless compared to 6% of the general population (P = 0.001 for CD, P = 0.08 for UC). Notably, the decision to stay childless amongst IBD patients contrasts to the much lower “involuntary” childlessness rates (inability to conceive) (5% in CD, 1.7% in UC and 2.5% in the general population, P = NS). Concerns about the effect of pregnancy on their disease, about passing on IBD to their children and about their ability to look after children were given as the main reasons for voluntarily childlessness. IBD patients have expressed a high interest in genetic testing to determine their future health or that of their family members, but there are no data whether women with IBD would base decisions to have children on the results of genetic testing should a reliable test become available.
Data from an Australian IBD cohort were recently described by Mountifield et al[109,110] in two studies. The first postal questionnaire study evaluated the experience and views regarding fertility in 255 women with IBD and found live birth rates of 1.0 for CD, 1.2 for UC, which are considerably lower than those of the general population of 1.8. This coincided with a fear of infertility in 42.7% of patients, which was particularly apparent in women with CD or previous surgery. Unfortunately, the study did not report whether women fearing infertility were indeed experiencing problems conceiving. Conversely, women sought fertility advice only as often as the general population. The study highlights a difference between the medical evidence and patients’ perception of infertility as patients overestimate their risk of infertility largely. The second study examined the experiences and views of 219 women after pregnancy. The patients’ main concern related to potential harm towards their pregnancy from IBD medication (84%) rather than the need to control active disease. “Free text” responses suggested that women would rather “put up with the disease than harm my baby with medications”. The main concerns regarding side effects of IBD medication related to congenital abnormalities rather than more common adverse outcomes of pregnancy such as pre-mature delivery or low birth weight. Of note, some patients considered steroid “rescue” therapy safer than continuation of IBD maintenance medication. The authors suggested their findings reflected a lack of patients’ knowledge in the field of IBD and pregnancy’. The study provides insight into patients’ views: many opinions were contrary to current medical evidence, and women may make decisions based on incorrect perceptions.
Two population based Danish studies have examined adherence to IBD medication prior and during pregnancy in 58 women with CD and 63 women with UC. Adherence, measured by retrospective self-reporting, was relatively high in both CD (72%) and UC (60%) as adherence in the non-pregnant IBD population ranges from 55%-70%. It is, however, difficult to interpret the study findings since there was no direct control group of non-pregnant patients included and selection bias (responders vs non-responders) and recall bias (the questionnaires were sent years after the pregnancies) may be likely. Furthermore, adherence was assessed using a simple question rather than a validated tool. Reasons for non-adherence were quiescent disease (59%) and a fear of negative effects on the unborn child (50%), while forgetfulness was uncommon (5%). These studies highlight that unwanted effects of medication play an important part in women’s views and influence decision making.
IBD affects women of childbearing age and may have an effect on their offspring. Fertility is reduced in active CD and after surgery. The risk of active disease during pregnancy carries a significant risk to baby and mother. The limited data available on patients’ beliefs and attitudes suggest that many women hold views contrary to medical evidence. Women with IBD are therefore at risk of making uninformed choices that could in turn lead to adverse outcomes. There is a need for further studies examining women’s views in more detail and to investigate whether these beliefs are driven by a lack of knowledge. In the meantime, women with IBD should receive advice and counselling by their physician prior and during pregnancy.
Peer reviewer: Masahiro Iizuka, MD, PhD, Director of Akita Health Care Center, Akita Red Cross Hospital, 3-4-23, Nakadori, Akita 010-0001, Japan
S- Editor Tian L L- Editor Cant MR E- Editor Xiong L
Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults.Gut. 2004;53 Suppl 5:V1-16.
Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, Guslandi M, Oldenburg B, Dotan I, Marteau P. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.J Crohns Colitis. 2010;4:63-101.
Dubinsky M, Abraham B, Mahadevan U. Management of the pregnant IBD patient.Inflamm Bowel Dis. 2008;14:1736-1750.
Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease.Gastroenterology. 1990;99:987-994.
Hudson M, Flett G, Sinclair TS, Brunt PW, Templeton A, Mowat NA. Fertility and pregnancy in inflammatory bowel disease.Int J Gynaecol Obstet. 1997;58:229-237.
Olsen KO, Joelsson M, Laurberg S, Oresland T. Fertility after ileal pouch-anal anastomosis in women with ulcerative colitis.Br J Surg. 1999;86:493-495.
Ørding Olsen K, Juul S, Berndtsson I, Oresland T, Laurberg S. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample.Gastroenterology. 2002;122:15-19.
Fonager K, Sørensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy outcome for women with Crohn's disease: a follow-up study based on linkage between national registries.Am J Gastroenterol. 1998;93:2426-2430.
Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome.J Clin Gastroenterol. 1984;6:211-216.
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;27:821-825.
Oresland T, Palmblad S, Ellström M, Berndtsson I, Crona N, Hultén L. Gynaecological and sexual function related to anatomical changes in the female pelvis after restorative proctocolectomy.Int J Colorectal Dis. 1994;9:77-81.
Ravid A, Richard CS, Spencer LM, O'Connor BI, Kennedy ED, MacRae HM, Cohen Z, McLeod RS. Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for ulcerative colitis.Dis Colon Rectum. 2002;45:1283-1288.
Tiainen J, Matikainen M, Hiltunen KM. Ileal J-pouch--anal anastomosis, sexual dysfunction, and fertility.Scand J Gastroenterol. 1999;34:185-188.
Juhasz ES, Fozard B, Dozois RR, Ilstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. An extended evaluation.Dis Colon Rectum. 1995;38:159-165.
Damgaard B, Wettergren A, Kirkegaard P. Social and sexual function following ileal pouch-anal anastomosis.Dis Colon Rectum. 1995;38:286-289.
Johnson E, Carlsen E, Nazir M, Nygaard K. Morbidity and functional outcome after restorative proctocolectomy for ulcerative colitis.Eur J Surg. 2001;167:40-45.
Nielsen OH, Andreasson B, Bondesen S, Jarnum S. Pregnancy in ulcerative colitis.Scand J Gastroenterol. 1983;18:735-742.
Nielsen OH, Andreasson B, Bondesen S, Jacobsen O, Jarnum S. Pregnancy in Crohn's disease.Scand J Gastroenterol. 1984;19:724-732.
Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California.Gastroenterology. 2007;133:1106-1112.
Castiglione F, Pignata S, Morace F, Sarubbi A, Baratta MA, D'Agostino L, D'Arienzo A, Mazzacca G. Effect of pregnancy on the clinical course of a cohort of women with inflammatory bowel disease.Ital J Gastroenterol. 1996;28:199-204.
Riis L, Vind I, Politi P, Wolters F, Vermeire S, Tsianos E, Freitas J, Mouzas I, Ruiz Ochoa V, O'Morain C. Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease.Am J Gastroenterol. 2006;101:1539-1545.
Kane S, Kisiel J, Shih L, Hanauer S. HLA disparity determines disease activity through pregnancy in women with inflammatory bowel disease.Am J Gastroenterol. 2004;99:1523-1526.
Morales M, Berney T, Jenny A, Morel P, Extermann P. Crohn's disease as a risk factor for the outcome of pregnancy.Hepatogastroenterology. 2000;47:1595-1598.
Bush MC, Patel S, Lapinski RH, Stone JL. Perinatal outcomes in inflammatory bowel disease.J Matern Fetal Neonatal Med. 2004;15:237-241.
Fedorkow DM, Persaud D, Nimrod CA. Inflammatory bowel disease: a controlled study of late pregnancy outcome.Am J Obstet Gynecol. 1989;160:998-1001.
Nørgård B, Hundborg HH, Jacobsen BA, Nielsen GL, Fonager K. Disease activity in pregnant women with Crohn's disease and birth outcomes: a regional Danish cohort study.Am J Gastroenterol. 2007;102:1947-1954.
Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, Tekkis PP. A meta-analysis on the influence of inflammatory bowel disease on pregnancy.Gut. 2007;56:830-837.
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;97:641-648.
Bortoli A, Saibeni S, Tatarella M, Prada A, Beretta L, Rivolta R, Politi P, Ravelli P, Imperiali G, Colombo E. Pregnancy before and after the diagnosis of inflammatory bowel diseases: retrospective case-control study.J Gastroenterol Hepatol. 2007;22:542-549.
Arbour LT, Beking K, Le ND, Ratner PA, Spinelli JJ, Teschke K, Gallagher RP, Abanto ZU, Dimich-Ward H. Rates of congenital anomalies and other adverse birth outcomes in an offspring cohort of registered nurses from British Columbia, Canada.Can J Public Health. 2010;101:230-234.
Nørgård B, Puho E, Pedersen L, Czeizel AE, Sørensen HT. Risk of congenital abnormalities in children born to women with ulcerative colitis: a population-based, case-control study.Am J Gastroenterol. 2003;98:2006-2010.
Craxi A, Pagliarello F. Possible embryotoxicity of sulfasalazine.Arch Intern Med. 1980;140:1674.
Hoo JJ, Hadro TA, Von Behren P. Possible teratogenicity of sulfasalazine.N Engl J Med. 1988;318:1128.
Newman NM, Correy JF. Possible teratogenicity of sulphasalazine.Med J Aust. 1983;1:528-529.
Mogadam M, Dobbins WO, Korelitz BI, Ahmed SW. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome.Gastroenterology. 1981;80:72-76.
Habal FM, Hui G, Greenberg GR. Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course.Gastroenterology. 1993;105:1057-1060.
Marteau P, Tennenbaum R, Elefant E, Lémann M, Cosnes J. Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules.Aliment Pharmacol Ther. 1998;12:1101-1108.
Trallori G, d'Albasio G, Bardazzi G, Bonanomi AG, Amorosi A, Del Carlo P, Palli D, Galli M, Pacini F. 5-Aminosalicylic acid in pregnancy: clinical report.Ital J Gastroenterol. 1994;26:75-78.
Diav-Citrin O, Park YH, Veerasuntharam G, Polachek H, Bologa M, Pastuszak A, Koren G. The safety of mesalamine in human pregnancy: a prospective controlled cohort study.Gastroenterology. 1998;114:23-28.
Nørgård B, Fonager K, Pedersen L, Jacobsen BA, Sørensen HT. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study.Gut. 2003;52:243-247.
Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy.Br J Obstet Gynaecol. 1998;105:322-327.
Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis.Am J Obstet Gynecol. 1995;172:525-529.
Caro-Patón T, Carvajal A, Martin de Diego I, Martin-Arias LH, Alvarez Requejo A, Rodríguez Pinilla E. Is metronidazole teratogenic? A meta-analysis.Br J Clin Pharmacol. 1997;44:179-182.
Niebyl JR. Antibiotics and other anti-infective agents in pregnancy and lactation.Am J Perinatol. 2003;20:405-414.
Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Moretti M, Lalkin A. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.Antimicrob Agents Chemother. 1998;42:1336-1339.
Larsen H, Nielsen GL, Schønheyder HC, Olesen C, Sørensen HT. Birth outcome following maternal use of fluoroquinolones.Int J Antimicrob Agents. 2001;18:259-262.
Moskovitz DN, Bodian C, Chapman ML, Marion JF, Rubin PH, Scherl E, Present DH. The effect on the fetus of medications used to treat pregnant inflammatory bowel-disease patients.Am J Gastroenterol. 2004;99:656-661.
Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, Friesen MH, Jacobson S, Kasapinovic S, Chang D. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.Teratology. 2000;62:385-392.
Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study.Reprod Toxicol. 2004;18:93-101.
Gluck PA, Gluck JC. A review of pregnancy outcomes after exposure to orally inhaled or intranasal budesonide.Curr Med Res Opin. 2005;21:1075-1084.
Norjavaara E, de Verdier MG. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide.J Allergy Clin Immunol. 2003;111:736-742.
Blatt J, Mulvihill JJ, Ziegler JL, Young RC, Poplack DG. Pregnancy outcome following cancer chemotherapy.Am J Med. 1980;69:828-832.
Nicholson HO. Cytotoxic drugs in pregnancy. Review of reported cases.J Obstet Gynaecol Br Commonw. 1968;75:307-312.
Platzek T, Bochert G. Dose-response relationship of teratogenicity and prenatal-toxic risk estimation of 6-mercaptopurine riboside in mice.Teratog Carcinog Mutagen. 1996;16:169-181.
Mosesso P, Palitti F. The genetic toxicology of 6-mercaptopurine.Mutat Res. 1993;296:279-294.
Bermas BL, Hill JA. Effects of immunosuppressive drugs during pregnancy.Arthritis Rheum. 1995;38:1722-1732.
Roubenoff R, Hoyt J, Petri M, Hochberg MC, Hellmann DB. Effects of antiinflammatory and immunosuppressive drugs on pregnancy and fertility.Semin Arthritis Rheum. 1988;18:88-110.
Willis FR, Findlay CA, Gorrie MJ, Watson MA, Wilkinson AG, Beattie TJ. Children of renal transplant recipient mothers.J Paediatr Child Health. 2000;36:230-235.
Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory bowel disease.Gastroenterology. 1990;99:443-446.
Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study.Gastroenterology. 2003;124:9-17.
Dejaco C, Angelberger S, Waldhoer T. Pregnancy and birth outcomes under thiopurine therapy for inflammatory bowel disease.Gastroenterology. 2005;128:A-12.
Coelho J, Beaugerie L, Colombel JF, Hébuterne X, Lerebours E, Lémann M, Baumer P, Cosnes J, Bourreille A, Gendre JP. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study.Gut. 2011;60:198-203.
Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease.Am J Gastroenterol. 2000;95:684-688.
Teruel C, López-San Román A, Bermejo F, Taxonera C, Pérez-Calle JL, Gisbert JP, Martín-Arranz M, Ponferrada A, Van Domselaar M, Algaba A. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines.Am J Gastroenterol. 2010;105:2003-2008.
Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation for PDA: A reference guide to fetal and neonatal risk. Philadelphia: Lippincott, Williams & Wilkins; 2005;.
Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome.Teratology. 1999;60:10-12.
Simister NE. Placental transport of immunoglobulin G.Vaccine. 2003;21:3365-3369.
Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, Pritchard ML, Sandborn WJ. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry.Clin Gastroenterol Hepatol. 2006;4:621-630.
Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn's disease and rheumatoid arthritis.Am J Gastroenterol. 2004;99:2385-2392.
Schnitzler F, Fidder H, Ferrante M, Ballet V, Noman M, Van Assche G, Spitz B, Hoffman I, Van Steen K, Vermeire S. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy.Inflamm Bowel Dis. 2011;17:1846-1854.
Coburn LA, Schwartz DA. The successful use of Adalimumab to treat active Crohn’s disease of an ioleanal pouch during pregnancy.Dig Dis Scis. 2005;51:2045-2047.
Mishkin DS, Van Deinse W, Becker JM, Farraye FA. Successful use of adalimumab (Humira) for Crohn's disease in pregnancy.Inflamm Bowel Dis. 2006;12:827-828.
Johnson DL, Jones KL, Chambers CD, Salas E. Pregnancy outcoms in women exposed to adalimumab: the OTIS autoimmune diseases in pregnancy project.Gastroenterology. 2009;136:A-27.
Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J. Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease.J Crohns Colitis. 2010;4:603-605.
Ilnyckyji A, Blanchard JF, Rawsthorne P, Bernstein CN. Perianal Crohn's disease and pregnancy: role of the mode of delivery.Am J Gastroenterol. 1999;94:3274-3278.
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;90:1918-1922.
Beniada A, Benoist G, Maurel J, Dreyfus M. [Inflammatory bowel disease and pregnancy: report of 76 cases and review of the literature].J Gynecol Obstet Biol Reprod (Paris). 2005;34:581-588.
Rogers RG, Katz VL. Course of Crohn's disease during pregnancy and its effect on pregnancy outcome: a retrospective review.Am J Perinatol. 1995;12:262-264.
Kitayama T, Funayama Y, Fukushima K, Shibata C, Takahashi K, Ogawa H, Ueno T, Hashimoto A, Sasaki I. Anal function during pregnancy and postpartum after ileal pouch anal anastomosis for ulcerative colitis.Surg Today. 2005;35:211-215.
Hahnloser D, Pemberton JH, Wolff BG, Larson D, Harrington J, Farouk R, Dozois RR. Pregnancy and delivery before and after ileal pouch-anal anastomosis for inflammatory bowel disease: immediate and long-term consequences and outcomes.Dis Colon Rectum. 2004;47:1127-1135.
Farouk R, Pemberton JH, Wolff BG, Dozois RR, Browning S, Larson D. Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis.Ann Surg. 2000;231:919-926.
Lepistö A, Sarna S, Tiitinen A, Järvinen HJ. Female fertility and childbirth after ileal pouch-anal anastomosis for ulcerative colitis.Br J Surg. 2007;94:478-482.
Remzi FH, Gorgun E, Bast J, Schroeder T, Hammel J, Philipson E, Hull TL, Church JM, Fazio VW. Vaginal delivery after ileal pouch-anal anastomosis: a word of caution.Dis Colon Rectum. 2005;48:1691-1699.
Jackson KM, Nazar AM. Breastfeeding, the immune response, and long-term health.J Am Osteopath Assoc. 2006;106:203-207.
Klement E, Cohen RV, Boxman J, Joseph A, Reif S. Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis.Am J Clin Nutr. 2004;80:1342-1352.
Jantchou P, Turck D, Baldé M, Gower-Rousseau C. Breastfeeding and risk of inflammatory bowel disease: results of a pediatric, population-based, case-control study.Am J Clin Nutr. 2005;82:485-486.
Gearry RB, Richardson AK, Frampton CM, Dodgshun AJ, Barclay ML. Population-based cases control study of inflammatory bowel disease risk factors.J Gastroenterol Hepatol. 2010;25:325-333.
Kane S, Lemieux N. The role of breastfeeding in postpartum disease activity in women with inflammatory bowel disease.Am J Gastroenterol. 2005;100:102-105.
Branski D, Kerem E, Gross-Kieselstein E, Hurvitz H, Litt R, Abrahamov A. Bloody diarrhea--a possible complication of sulfasalazine transferred through human breast milk.J Pediatr Gastroenterol Nutr. 1986;5:316-317.
Nelis GF. Diarrhoea due to 5-aminosalicylic acid in breast milk.Lancet. 1989;1:383.
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk.Pediatrics. 2001;108:776-789.
Esbjörner E, Järnerot G, Wranne L. Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation.Acta Paediatr Scand. 1987;76:137-142.
Silverman DA, Ford J, Shaw I, Probert CS. Is mesalazine really safe for use in breastfeeding mothers?Gut. 2005;54:170-171.
Ost L, Wettrell G, Björkhem I, Rane A. Prednisolone excretion in human milk.J Pediatr. 1985;106:1008-1011.
Coulam CB, Moyer TP, Jiang NS, Zincke H. Breast-feeding after renal transplantation.Transplant Proc. 1982;14:605-609.
Christensen LA, Dahlerup JF, Nielsen MJ, Fallingborg JF, Schmiegelow K. Azathioprine treatment during lactation.Aliment Pharmacol Ther. 2008;28:1209-1213.
Moretti ME, Verjee Z, Ito S, Koren G. Breast-feeding during maternal use of azathioprine.Ann Pharmacother. 2006;40:2269-2272.
Gardiner SJ, Gearry RB, Roberts RL, Zhang M, Barclay ML, Begg EJ. Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs.Br J Clin Pharmacol. 2006;62:453-456.
Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine and breastfeeding: is it safe?BJOG. 2007;114:498-501.
Kane S, Ford J, Cohen R, Wagner C. Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn's disease before and after delivery.J Clin Gastroenterol. 2009;43:613-616.
Ben-Horin S, Yavzori M, Katz L, Picard O, Fudim E, Chowers Y, Lang A. Adalimumab level in breast milk of a nursing mother.Clin Gastroenterol Hepatol. 2010;8:475-476.
Johns DG, Rutherford LD, Leighton PC, Vogel CL. Secretion of methotrexate into human milk.Am J Obstet Gynecol. 1972;112:978-980.
Marri SR, Ahn C, Buchman AL. Voluntary childlessness is increased in women with inflammatory bowel disease.Inflamm Bowel Dis. 2007;13:591-599.
Mountifield R, Bampton P, Prosser R, Muller K, Andrews JM. Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions.Inflamm Bowel Dis. 2009;15:720-725.
Mountifield RE, Prosser R, Bampton P, Muller K, Andrews JM. Pregnancy and IBD treatment: this challenging interplay from a patients' perspective.J Crohns Colitis. 2010;4:176-182.
Nielsen MJ, Nørgaard M, Holland-Fisher P, Christensen LA. Self-reported antenatal adherence to medical treatment among pregnant women with Crohn's disease.Aliment Pharmacol Ther. 2010;32:49-58.
Julsgaard M, Nørgaard M, Hvas CL, Buck D, Christensen LA. Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis.Inflamm Bowel Dis. 2010;17:1573-1580.
Jackson CA, Clatworthy J, Robinson A, Horne R. Factors associated with non-adherence to oral medication for inflammatory bowel disease: a systematic review.Am J Gastroenterol. 2010;105:525-539.