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Inflammatory bowel disease in women of reproductive age Expert Rev. Gastroenterol. Hepatol. 8(4), 417–425 (2014)
Kara M De Felice and Sunanda V Kane* Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA *Author for correspondence: Tel.: +1 507 284 0959 Fax: +1 507 284 0538
[email protected] Management of inflammatory bowel disease in women of reproductive age requires special attention. Even though fertility in women without previous pelvis surgery is similar to the general population, active disease at conception and during pregnancy can lead to unfavorable pregnancy and fetal outcomes. In general, most medications needed to treat inflammatory bowel disease are low risk during pregnancy and breastfeeding. Achieving and maintaining disease remission, patient education, and a multidisciplinary team approach is the key to a successful pregnancy. KEYWORDS: aminosalicylates • antibiotics • biologic • breastfeeding • Crohn’s disease • fertility • immunomodulators • inflammatory bowel disease • pregnancy • ulcerative colitis
Inflammatory bowel disease (IBD) is a chronic condition that affects women in their reproductive years. Historically, there has been great concern regarding pregnancy in women with IBD. The fear of infertility, disease activity during pregnancy, medication use during pregnancy, teratogenicity, adverse pregnancy and fetal outcomes are all concerns voiced by patients. With a better understanding of the safety of medical therapy and the importance of controlling disease activity before conception and during pregnancy, a favorable pregnancy outcome is now realistic. Achieving and maintaining disease remission, educating the patient and a multidisciplinary team approach are the keys to a successful pregnancy. This review covers topics about heritability, fertility, effects of IBD on pregnancy, effects of pregnancy on IBD, mode of delivery, and specifically, an overview of medications used in the treatment of IBD during pregnancy. Heritability
Children born of parents with IBD have an increased risk of developing IBD. The risk is higher for Crohn’s disease (CD) (2–3%) than for ulcerative colitis (UC) (0.5–1%). The highest risk appears to be in children whose both parents have IBD [1]. C-sections have been associated with an increased risk of IBD developing in children.
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A Swedish case–control study of 1536 CD children showed that delivery by C-section increased the risk of CD among boys (odds ratio [OR]: 1.25; 95% CI: 1.01–1.54) but not girls [2]. Similarly, a Danish population-based study showed an increased risk of IBD at age 0–14 years in those born via C-section (incidence rate ratio: 1.29; 95% CI: 1.11–1.49) [3]. Fertility
Fertility is a concern for both men and women with IBD [4]. Fertility in women with IBD is similar to the general population, the exceptions are the patients who have undergone pelvic surgery and those with active CD [5]. Pelvic surgery results in adhesions that can block tubal patency. Those patients who have had colectomy with ileal pouch anal anastomosis (IPAA) are at higher risk for infertility than those who had ileorectal anastomosis or laparoscopic surgery, presumably because of the need for manipulation within the deep pelvis resulting in scar tissue [6]. A recent study showed higher rates of fertility among those women who had undergone laparoscopic IPAA versus open IPAA [7]. Male fertility can be affected by medications such as sulfasalazine,which cause oligospermia, decreased sperm motility and abnormal sperm morphology. These effects are not dose-dependent, but are reversible (within 2–3 months) when stopped, and switching to mesalamine is
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recommended if a male encounters difficulty conceiving [8]. There are some reports that methotrexate causes reversible oligospermia; however, data are conflicting. In light of the theoretical risk of sperm mutation, men are advised to discontinue methotrexate 3 months prior to conception [9]. There has been concern that infliximab therapy in men decreases sperm motility. A recent case–control study showed no significant difference of sperm quality between healthy controls and anti-TNF (infliximab, adalimumab and etanercept)-treated patients [10]. Pelvic surgery may lead to impotence or ejaculatory problems in men; however, the effect on fertility has not been studied [11]. Effect of IBD on pregnancy
Patients with IBD, compared with the general population, have been found to have higher rates of pregnancy complications, specifically small-for-gestational-age newborns, premature birth, low birthweight and increased rates of C-sections [12]. Adverse pregnancy outcomes are more frequent in women with CD compared with UC. While studies regarding disease activity and pregnancy have been conflicting, it is believed that it is disease activity prior to and during pregnancy, and not medication use, that drives the risk for unfavorable outcomes [13]. An older prospective study of 145 CD and 187 UC pregnant patients found no statistical difference in frequency of abortions, C-sections, premature delivery, congenital abnormalities or birthweight when compared with matched healthy controls. However, 87% of the CD and 79% of the UC patients were in remission at conception. Of those in remission, 86% CD and 74% UC patients remained in remission during pregnancy [14]. In contrast, a Northern California study with 461 pregnant IBD patients were found to have a statistically significant increase in adverse conception, pregnancy complication and adverse pregnancy outcomes compared with healthy controls. However, adverse newborn outcomes were not statistically significant. Independent predictors of an adverse outcome included diagnosis of IBD, history of surgery for IBD and non-Caucasian ethnicity. Disease activity and medical treatments were not associated with an adverse outcome [15]. Two Scandinavian population-based cohorts included 2637 pregnant women with UC and 2377 women with CD. In the UC cohort, there was an increase in C-sections, premature birth, small-for-gestational-age newborns and neonatal death. In the CD cohort, there was an increase in C-sections, premature birth and small-for-gestational-age newborns. Secondary analysis found that disease severity in UC was associated with a higher risk of C-sections, premature birth and small-forgestational-age newborns. However, disease severity in the secondary analysis in the CD cohort was not statistically significantly associated with adverse outcomes [16,17]. Another European case–control study examining pregnancy outcomes before and after diagnosis of IBD found that preterm birth and low birth weight were more common after onset of IBD. Disease activity in CD and UC during pregnancy did not predispose to abnormal birth outcome compared with inactive disease [18]. 418
Effect of pregnancy on IBD
Historically, the rate of disease flare (~30%) during pregnancy was similar for CD and UC. However, a recent prospective cohort study comparing pregnant IBD women with nonpregnant IBD controls found an increased risk of relapse in UC, both during pregnancy (relative risk: 2.19; 95% CI: 1.25–3.97) and postpartum period (relative risk: 6.22; 95% CI: 2.05–79.3). If conception occurs when the disease activity is quiescent, 67–80% will remain in remission throughout the pregnancy and postpartum period [19]. About two-thirds of patients who have active disease at conception will have persistence or worsening of active disease during pregnancy. Disease flares are often related to discontinuation of medical therapy and to smoking. Historically, it was thought that disease activity worsens in the postpartum period. Active disease during pregnancy, smoking and discontinuation of medications during pregnancy are risk factors for postpartum disease flares [20,21]. The management of an IBD flare during pregnancy should be similar to a non-pregnant IBD patient. Most medications are low risk for use for an IBD flare, with the notable exception of methotrexate. Ultrasound is the preferred imaging modality during pregnancy. High-resolution ultrasound at experienced centers can be used to assess small bowel pathology. MRI can be used to rule out intra-abdominal pathology, but gadolinium should be withheld in the first trimester due to its possible teratogenicity. However, one prospective study showed that MRI with gadolinium is safe during the first trimester [22]. Unsedated flexible sigmoidoscopy either unprepped or with tap water enemas is the preferred endoscopic procedure for colon assessment, as full colonoscopy is rarely needed for management decision-making [23]. The need for surgery during pregnancy is similar to the non-pregnant IBD patient. Surgery increases fetal and maternal morbidity and should be delayed until the second or third trimester if possible. Mode of delivery
Multiple studies have shown that women with CD and UC have an increased rate of C-sections when compared with the general population. Vaginal delivery is not recommended for those patients with active perianal fistulizing disease given the increased risk for perineal trauma. One small study has suggested that vaginal delivery during quiescent perianal disease is not associated with a higher risk of complications [24]. Vaginal delivery is not absolutely contraindicated in patients with an IPAA, although mode of delivery should be discussed with both the surgeon and obstetrician for each individual patient [25]. Breastfeeding
Breastfeeding is not an independent risk factor for worsening disease activity in the postpartum period [26]. Breastfeeding has well-established important benefits to the newborn and should be encouraged in the postpartum IBD patient. Most IBD medications are considered safe during lactation with the exception of methotrexate, metronidazole and cyclosporine [27,28]. Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)
IBD in women of reproductive age
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Medications
Most medications used to treat IBD are low risk during pregnancy except for the US FDA pregnancy category X drugs (methotrexate and thalidomide). Medication adherence and adequate disease control during pregnancy is of utmost importance to minimize adverse pregnancy and fetal outcomes. Despite this, medication adherence is low and premature discontinuation of medications is common. Adherence can be improved by education and counseling [29]. Antibiotics/probiotics
Antibiotics are frequently used for the treatment of pouchitis, perianal fistulizing CD and intra-abdominal abscesses related to penetrating CD. Most antibiotics themselves can cause diarrhea. In general, antibiotic use increases the risk for Clostridium difficile infection and should be used sparingly. Metronidazole
Metronidazole is used in perianal fistulizing CD and pouchitis, and in the prevention of postoperative recurrence of CD [30,31]. Short-term use of metronidazole is safe in pregnancy (FDA pregnancy category B); however because its use is usually for longer than 5–7 days, it is not the treatment of choice for the above clinical situations [32]. It is excreted in breast milk and is therefore generally not recommended during breastfeeding. It should only be used during lactation if the potential benefit of therapy to the mother justifies the potential risk to the infant. Ciprofloxacin
Ciprofloxacin causes arthropathies in children due to its high affinity for bone and cartilage. Studies in humans have not associated ciprofloxacin use during pregnancy with an increased rate of congenital abnormalities. However, due to the possible risk, it is a FDA pregnancy category C drug and not recommended during pregnancy. Ciprofloxacin is excreted in breast milk but it is deemed safe by the American Academy of Pediatrics for use during lactation [33,34], although still considered relatively contraindicated in the European countries. Rifaximin
Rifaximin is commonly used to treat pouchitis [35], as well as for induction of mild CD [36]. Rifaximin is FDA pregnancy category C, but its use in IBD is not well studied and thus not recommended for routine use during pregnancy. Amoxicillin/clavulanic acid
Amoxicillin/Clavulanic acid can also be used in the treatment of pouchitis and is safe in pregnancy and lactation (FDA pregnancy category B). Probiotics
Probiotics are commonly used by IBD patients and some data suggest that it prevents acute flares in chronic pouchitis or maintains pouch health [30]. One meta-analysis, several randomized controlled trials and observational studies did not show informahealthcare.com
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any adverse maternal or fetal outcomes when using probiotics during pregnancy [37–40]. Probiotic use during lactation has not been associated with adverse outcomes [41]. Aminosalicylates
Mesalamine preparations Delzicol, Lialda and Pentasa are FDA pregnancy category B and are safe for use during pregnancy [42]. Mesalamine preparations Asacol HD and Apriso are FDA pregnancy category C, the former covered with an enteric coating of dibutyl phthalate (DBP). Animal studies have demonstrated DBP, at very high doses, has been associated with malformations of the urogenital reproductive system of male offspring. However, there have been no clinical cases in humans showing an increase in birth defects with DBP use [43]. Apriso was recently FDA approved, and with the lack of compelling safety data, it has been designated category C. Sulfasalazine and balsalazide are both FDA pregnancy category B. Sulfasalazine is known to inhibit folate synthesis. [44]. Therefore, women who are taking sulfasalazine should take folic acid (2 mg daily) 3 months prior to conception, during pregnancy and while lactating [45]. Sulfasalazine causes reversible infertility in men only. It induces oligospermia that is reversible once the medications are discontinued and switching to mesalamine products is recommended. No adverse fetal outcomes have been reported by pregnancies fathered by IBD patients on sulfasalazine [8]. Olsalazine is FDA pregnancy category C, mainly because of the lack of documented pregnancy outcomes with exposure. In a meta-analysis, neither mesalamine nor sulfasalazine drugs have been associated with a statistical significant increase in congenital malformations (OR: 1.16; 95% CI: 0.76–1.77), premature birth (OR: 1.35; 95% CI: 0.85–2.13), spontaneous abortions (OR: 1.14; 95% CI: 0.65–2.01) or low birth weight (OR: 0.93; 95% CI: 0.46–1.85) [46]. Drug transfer into breast milk does occur with both preparations, but the amounts are considered so miniscule that they are clinically irrelevant [47]. Corticosteroids
Corticosteroids are commonly used to treat active IBD. It is a FDA pregnancy category C drug. There has been conflicting evidence that corticosteroid use during pregnancy is associated with orofacial clefts. An older case–control study followed by a meta-analysis demonstrate an increased risk of orofacial clefts (OR: 3.35; 95%CI: 1.79–5.69) [48,49]. However, subsequent case–control studies and a large Danish population study did not show an increased risk (OR: 1.05; 95% CI: 0.8–1.38) [50,51]. While early studies reported that lower birthweights, premature delivery, fetal adrenal suppression and an increase in intrauterine infection are associated with steroid use during pregnancy [49,52,53], larger population-based studies found no association between corticosteroid use and congenital abnormalities or low birth weights [54]. Budesonide, a steroid preparation with a large first-pass metabolism, is FDA-approved to treat mild-to-moderate CD, but published experience during pregnancy is limited. A single 419
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case series of eight pregnant CD patients did not report any adverse fetal outcomes [55]. Corticosteroid use during lactation should be considered on an individual basis, as there is minimal excretion in the breast milk with maternal health weighed against risk to infant [56].
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Thiopurines
Azathioprine and its metabolite mercaptopurine cross the placenta and can be detected in the fetal blood reaching levels of 1–5% of their prospective maternal levels [57]. Animal models have suggested teratogenic effects of azathioprine when administered intraperitoneally, and therefore, FDA pregnancy category D [58]. There have been conflicting studies in humans, with some studies showing an increased risk of congenital anomalies (especially cardiac), perinatal mortality, preterm delivery, low birthweight and small-for-gestational-age newborns [59,60], while more recent studies have found that thiopurine exposure during pregnancy is not associated with an increased risk of these outcomes, and its use likely a marker for more aggressive disease [61–63]. A recent retrospective study of 187 pregnant IBD patients exposed to thiopurines compared with 318 non-exposed pregnant IBD patients found that thiopurines had a protective effect on pregnancy outcomes in IBD patients with no adverse fetal outcomes [64]. The pregnancy in IBD and neonatal outcomes (PIANO) registry, which is an ongoing national prospective cohort of pregnant women with IBD, has not found an increase in adverse fetal outcomes on interim analysis [65]. Overall, thiopurines are considered low risk during pregnancy, with the emphasis on disease control; adverse outcomes such as low birth weight and preterm delivery are most likely due to disease activity rather than drug adverse effects [66]. There are concerns that men who are taking thiopurines at the time of conception increase the risk of congenital abnormalities. However, two recent case–control studies do not show a statistical significant difference in spontaneous abortions, ectopic pregnancies, fetal death, preterm birth, low birth weight or congenital abnormalities [67,68]. In light of these larger, more recent studies, there is no need for an across-the-board recommendation to stop therapy in males wishing to start families. Thiopurines are detected in breast milk, with concentrations detectable only 4 h after maternal ingestion [69]. Studies have shown that infants are not at an increased risk of infections when breastfed by mothers exposed to thiopurines [70]. Overall, thiopurines are considered compatible with breastfeeding, although the long-term outcome of infants exposed to minute amounts during lactation are not known. The advantages of nursing may outweigh this risk and should be discussed with each patient. Methotrexate
Methotrexate is a FDA pregnancy category X drug and should not be used in IBD pregnant women or those contemplating pregnancy. It is highly teratogenic and is used as an abortifacient [71]. It is recommended that women who were on methotrexate therapy wait 3–6 months prior to conceiving in light of 420
the long half-life and distribution in other tissues. Prior methotrexate use does not affect female fertility [72]. Paternal exposure to methotrexate 3 months prior to or at conception has not been associated with adverse fetal outcomes. However, limited data are available, and therefore, it is recommended that men discontinue therapy 3 months prior to conception [9]. Methotrexate is excreted in the breast milk and therefore is contraindicated in breastfeeding [28]. Cyclosporine/tacrolimus
Cyclosporine is used in severe refractory UC [73]. Cyclosporine is FDA pregnancy category C. A meta-analysis in the transplant literature showed no statistical difference in malformations, prematurity and low birth weight [74]. In a retrospective case series of 8 pregnant patients with severe UC treated with cyclosporine, treatment was effective in 7. Seven pregnancies were carried to term, with a single in utero death occurring due to maternal absence of S protein. Two newborns were premature, including one case of hypotrophy. No malformations were observed [75]. Cyclosporine reaches high levels in breast milk and should be avoided during breastfeeding [27]. Tacrolimus is used in the treatment of fistulizing CD [76]. It is a FDA pregnancy category C drug. Tacrolimus pharmacogenetics is altered during pregnancy and requires close follow-up and frequent dose adjustments [77]. In a study of 100 pregnancies in 84 mothers who had undergone transplant and were exposed to tacrolimus during pregnancy, 59% neonates were born premature. Four had congenital malformations [78]. A 13-year follow-up study of 49 infants to 37 liver transplant mothers showed no increase in congenital malformations, but an increase in premature birth [79]. A case report of one pregnant patient with UC treated with tacrolimus had a successful pregnancy without any maternal or fetal complications [80]. Tacrolimus are detectable in breast milk at low levels. Data suggest that breastfeeding while on tacrolimus therapy is safe [81]. Biologics TNF-a inhibitors
Infliximab, adalimumab, certolizumab pegol and golimumab are FDA pregnancy category B. Infliximab is a chimeric mouse/human IgG1 antibody, adalimumab and golimumab are fully human IgG1 antibodies against TNF-a. Certolizumab is a humanized monoclonal antibody Fab fragment linked to polyethylene glycol with activity against TNF-a. In pregnancy, IgG is actively transported across the placenta mediated by fetal Fc receptors. Placental transport of IgG increases with gestational age and starts at week 20, with the highest transfer occurring in the third trimester (>30 weeks). Therefore, infliximab, adalimumab and golimumab cross the placenta if administered after week 20 and can remain in an infant’s blood up to 6 months after birth. Certolizumab does not contain the Fc portion, and therefore, does not cross the placenta [82]. There is a concern that infliximab, adalimumab and golimumab will affect the maturation of the infant’s immune system Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)
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Table 1. Medications used to treat inflammatory bowel disease. Drug
US FDA category
Fertility
Pregnancy
Breastfeeding
Comments
Metronidazole
B
ü
ü
X
Ciprofloxacin
C
ü
X
ü
Amoxicillin/clavulanate
B
ü
ü
ü
Rifaximin
C
ü
(ü)
(ü)
Probiotics
N/A
ü
ü
ü
B
ü
ü
ü
Mesalamine (Asacol, Asacol HD )
C
ü
(ü)
(ü)
Teratogenic in animal studies
Sulfasalazine
B
ü
ü
ü
Give with folic acid 2 mg daily. Affects fertility in men
Olsalazine
C
ü
X
ü
Limited data available
Prednisone
C
ü
ü
ü
Budesonide
C
ü
ü
ü
Azathioprine/6-Mercaptopurine
D
ü
ü
ü
Methotrexate
X
X
X
X
Cyclosporine
C
ü
ü
X
Tacrolimus
C
ü
ü
ü
Infliximab
B
ü
ü
ü
Adalimumab
B
ü
ü
ü
Certolizumab
B
ü
ü
ü
Golimumab
B
ü
(ü)
(ü)
Limited data available
Natalizumab
C
ü
(ü)
(ü)
Limited data available
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Antibiotics
Limited data available
Aminosalicylates Mesalamine
Corticosteroids
Immunomodulators
Teratogenic
Biologics
(ü): Limited data, caution; ü: Safe to use; X: Do not use; N/A: Not applicable.
and lead to malformations and increase in infection [83]. In animal studies, anti-TNF exposure throughout the entire pregnancy and lactation did not alter the immune system [84]. In the observational Crohn’s therapy, resource, evaluation and assessment tool registry, 117 out of 168 pregnancies had exposure to infliximab during pregnancy. There was no statistical difference in neonatal complications, rate of miscarriage or any fetal malformations [85]. In a review of case reports filed with the FDA, 132 pregnancies with exposure to adalimumab did not show any fetal abnormalities [86]. Preliminary reports from the PIANO registry describe 126 women exposed to adalimumab and 47 women exposed to certolizumab during pregnancy have not been associated with an increase in congenital anomalies, infection rates, infant growth status or informahealthcare.com
developmental progress. However, combination therapy with infliximab/adalimumab with azathioprine/6-mercaptopurine showed an increases risk in infection compared with those on monotherapy [65]. In a retrospective multicenter study comparing pregnancies in IBD patients among three groups (nonexposed, thiopurines and anti-TNF), there was no difference in pregnancy complications and a decrease in neonatal complications in the thiopurine and anti-TNF groups. This highlights the importance of control of disease activity during pregnancy [64]. Because infliximab, adalimumab and golimumab cross the placenta and can remain in the infant up to 6 months of age, live virus vaccines should be avoided in the first 6 months of life, if there has been in utero exposure after week 20 [87]. 421
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There continues to be controversy on whether to discontinue infliximab, adalimumab or golimumab after the second trimester to prevent placental transfer. There is general agreement that this is a reasonable strategy in those women in remission, but that there is a risk for disease flare in those who stop if not in remission [88]. The most important factor is maintaining adequate control of disease activity. Anti-TNF drugs are either detected in small amounts or undetectable in breast milk. Therefore, they are safe for use during breastfeeding [89–91]. Current recommendations suggest that the advantages of nursing outweigh any potential risks of the possible effect of exposure given the proteinaceous nature of these molecules and the ability of infant gastric acid to breakdown antibody. Natalizumab
Natalizumab is a humanized monoclonal IgG4 antibody against a-4 integrin. It is FDA pregnancy category C. Women with multiple sclerosis treated with natalizumab resulted in 28 healthy children, 1 with hexadactyly and 5 early miscarriages [92]. Preliminary results from the PIANO registry show healthy children from six women with CD exposed to natalizumab [65]. Limited information is available on lactation and therefore it is not recommended at this time. Conclusion
Most patients with IBD have successful and healthy pregnancies. It takes careful planning, education and a multidisciplinary approach. Of utmost importance is achieving and maintaining disease remission, as active disease at conception and during pregnancy is associated with adverse pregnancy and fetal outcomes. Most medications are safe to use at conception, during pregnancy and during breastfeeding (TABLE 1). The risk–benefit ratio between maintaining disease remission and possible medication side effects should be discussed on a case-by-case situation. In most cases, the benefit of achieving and maintaining disease remission outweighs the risk of medication side effects. Expert commentary
The thought of fertility and pregnancy are daunting to both patient and care provider. Previously, it was thought that a diagnosis of IBD was a contraindication to pregnancy given the
suboptimal treatment of the inflammation and its complications. With the understanding of the need for controlling inflammation and the introduction of therapies that can modify disease by healing the mucosa, these fears are no longer valid. Unfortunately, knowledge and its dissemination takes years and there is still the problem of inadequate education of obstetricians with regard to the importance of maintaining maternal health in the face of using therapies with seemingly high-risk profiles. Take for example the thiopurines. When introduced in the mid-1950s, the doses used to treat leukemia and the animal studies performed certainly made the category D rating justified for its time. Subsequent to that, however, have been the population-based studies to show that for a myriad of nonmalignant conditions the use during pregnancy is protective against a poor outcome, as its use has sustained maternal health. As the incidence of IBD continues to rise around the world, the need for proper communication between internist, gastroenterologist, obstetrician and pediatrician will continue to be paramount. Patients should continue to be counseled that disease activity and other health habits, such as smoking and excessive alcohol use, are more detrimental to a pregnancy outcome than medications. Five-year view
The PIANO registry will continue to provide invaluable information in a prospective manner with regard to the health of children born to mothers using biologics and immunomodulators during pregnancy. Early data have been encouraging but only with data out 4–7 years will we understand the impact of therapy on childhood development. Another future trend is the advancing age of first-time mothers and the increasing use of fertility drugs to enhance the likelihood of conception. What impact these factors will have on the mother and the disease course is yet to be seen. Financial & competing interests disclosure
SV Kane serves as a consultant to AbbVie, Amgen, UCB and Takeda and has received research funding from UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Fertility in inflammatory bowel disease (IBD) women without previous pelvic surgery is similar to the general population. • Patients should achieve and maintain remission at conception and during pregnancy to have favorable pregnancy outcomes. • Active disease during pregnancy, smoking and discontinuation of medications during pregnancy are risk factors for IBD flares. • Most IBD medications are safe during lactation with the exception of methotrexate, metronidazole and cyclosporine. • Most medications used to treat IBD are low risk during pregnancy except for US FDA pregnancy category X drugs (methotrexate and thalidomide). • The risk–benefit ratio between maintaining disease remission and possible mediation side effects should be discussed on a case-by-case situation.
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References 1.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/19/15 For personal use only.
2.
3.
4.
5.
6.
7.
8.
Laharie D, Debeugny S, Peeters M, et al. Inflammatory bowel disease in spouses and their offspring. Gastroenterology 2001;120: 816-19 Malmborg P, Bahmanyar S, Grahnquist L, et al. Cesarean section and the risk of pediatric Crohn’s disease. Inflamm Bowel Dis 2012;18:703-8 Bager P, Simonsen J, Nielsen NM, Frisch M. Cesarean section and offspring’s risk of inflammatory bowel disease: a national cohort study. Inflamm Bowel Dis 2012;18:857-62 Mountifield R, Bampton P, Prosser R, et al. Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions. Inflamm Bowel Dis 2009;15:720-5 Ording Olsen K, Juul S, Berndtsson I, et al. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterology 2002;122:15-19 Olsen KO, Joelsson M, Laurberg S, Oresland T. Fertility after ileal pouch-anal anastomosis in women with ulcerative colitis. Br J Surg 1999;86:493-5 Bartels SA, D’Hoore A, Cuesta MA, et al. Significantly increased pregnancy rates after laparoscopic restorative proctocolectomy: a cross-sectional study. Ann Surg 2012;256: 1045-8 O’Morain C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984;25:1078-84
9.
French AE, Koren G. Effect of methotrexate on male fertility. Can Fam Physician 2003;49:577-8
10.
Villiger PM, Caliezi G, Cottin V, et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis 2010;69: 1842-4
11.
Tiainen J, Matikainen M, Hiltunen KM. Ileal J-pouch – anal anastomosis, sexual dysfunction, and fertility. Scand J Gastroenterol 1999;34:185-8
12.
Cornish J, Tan E, Teare J, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 2007;56:830-7
13.
14.
Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 1984;6: 211-16
informahealthcare.com
15.
16.
Bortoli A, Pedersen N, Duricova D, et al. Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006. Aliment Pharmacol Ther 2011;34:724-34 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: 1106-12 Stephansson O, Larsson H, Pedersen L, et al. Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden. Inflamm Bowel Dis 2011;17: 795-801
17.
Stephansson O, Larsson H, Pedersen L, et al. Crohn’s disease is a risk factor for preterm birth. Clin Gastroenterol Hepatol 2010;8:509-15
18.
Molna´r T, Farkas K, Nagy F, et al. Pregnancy outcome in patients with inflammatory bowel disease according to the activity of the disease and the medical treatment: a case-control study. Scand J Gastroenterol 2010;45:1302-6
19.
Pedersen N, Bortoli A, Duricova D, et al. The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women. Aliment Pharmacol Ther 2013;38:501-12
20.
Kane S, Lemieux N. The role of breastfeeding in postpartum disease activity in women with inflammatory bowel disease. Am J Gastroenterol 2005;100:102-5
21.
Mogadam M, Korelitz BI, Ahmed SW, et al. The course of inflammatory bowel disease during pregnancy and postpartum. Am J Gastroenterol 1981;75:265-9
22.
De Santis M, Straface G, Cavaliere AF, et al. Gadolinium periconceptional exposure: pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 2007;86:99-101
23.
Cappell MS, Colon VJ, Sidhom O. A. A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups. Dig Dis Sci 1996;41:2353-61
24.
Ilnyckyji A, Blanchard JF, Rawsthorne P, Bernstein CN. Perianal Crohn’s disease and pregnancy: role of the mode of delivery. Am J Gastroenterol 1999;94:3274-8
25.
Ravid A, Richard CS, Spencer LM, et al. Pregnancy, delivery, and pouch function after ileal pouch-anal anastomosis for
Review
ulcerative colitis. Dis Colon Rectum 2002;45:1283-8 26.
Moffatt DC, Ilnyckyj A, Bernstein CN. A population-based study of breastfeeding in inflammatory bowel disease: initiation, duration, and effect on disease in the postpartum period. Am J Gastroenterol 2009;104:2517-23
27.
Flechner SM, Katz AR, Rogers AJ, et al. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis 1985;5:60-3
28.
Johns DG, Rutherford LD, Leighton PC, Vogel CL. Secretion of methotrexate into human milk. Am J Obstet Gynecol 1972;112:978-80
29.
Julsgaard M, Norgaard M, Hvas CL, et al. Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis. Inflamm Bowel Dis 2011;17:1573-80
30.
Holubar SD, Cima RR, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev 2010(6):CD001176
31.
Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108: 1617-21
32.
Koss CA, Baras DC, Lane SD, et al. Investigation of metronidazole use during pregnancy and adverse birth outcomes. Antimicrob Agents Chemother 2012;56: 4800-5
33.
Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother 1998;42:1336-9
34.
Bar-Oz B, Moretti ME, Boskovic R, et al. The safety of quinolones – a meta-analysis of pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol 2009;143:75-8
35.
Isaacs KL, Sandler RS, Abreu M, et al. Rifaximin for the treatment of active pouchitis: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 2007;13:1250-5
36.
Prantera C, Lochs H, Grimaldi M, Retic Study Group (Rifaximin-Eir Treatment in Crohn’s Disease). Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology 2012;142:473-81. e474
37.
Allen SJ, Jordan S, Storey M, et al. Dietary supplementation with lactobacilli and
423
Review
De Felice & Kane
bifidobacteria is well tolerated and not associated with adverse events during late pregnancy and early infancy. J Nutr 2010;140:483-8
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/19/15 For personal use only.
38.
39.
40.
41.
42.
43.
44.
45.
46.
Dugoua JJ, Machado M, Zhu X, et al. Probiotic safety in pregnancy: a systematic review and meta-analysis of randomized controlled trials of Lactobacillus, Bifidobacterium, and Saccharomyces spp. J Obstet Gynaecol Can 2009;31:542-52 Huurre A, Laitinen K, Rautava S, et al. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebocontrolled study. Clin Exp Allergy 2008;38: 1342-8 Kukkonen K, Savilahti E, Haahtela T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebo-controlled trial. Pediatrics 2008;122:8-12 Abrahamsson TR, Sinkiewicz G, Jakobsson T, et al. Probiotic lactobacilli in breast milk and infant stool in relation to oral intake during the first year of life. J Pediatr Gastroenterol Nutr 2009;49:349-54 Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998;114:23-8 Hernandez-Diaz S, Mitchell AA, Kelley KE, et al. Medications as a potential source of exposure to phthalates in the U.S. population. Environ Health Perspect 2009;117:185-9 Baggott JE, Morgan SL, Ha T, et al. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J 1992;282(Pt 1):197-202 Mahadevan U, Kane S. American gastroenterological association institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006;131:283-311 Rahimi R, Nikfar S, Rezaie A, Abdollahi M . Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. Reprod Toxicol 2008;25: 271-5
47.
Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet 1993;342:618-19
48.
Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242-4
424
49.
50.
51.
inflammatory bowel disease. Inflamm Bowel Dis 2013;19:15-22
Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385-92
62.
Gur C, Diav-Citrin O, Shechtman S, et al. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18: 93-101
Hutson JR, Matlow JN, Moretti ME, Koren G. The fetal safety of thiopurines for the treatment of inflammatory bowel disease in pregnancy. J Obstet Gynaecol 2013;33: 1-8
63.
Coelho J, Beaugerie L, Colombel JF, et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut 2011;60:198-203
64.
Casanova MJ, Chaparro M, Dome`nech E, et al. Safety of thiopurines and antiTNF-alpha drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol 2013;108:433-40
Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 2011;183: 796-804
52.
Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382-90
53.
Tegethoff M, Pryce C, Meinlschmidt G. Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans: a systematic review. Endocr Rev 2009;30:753-89
65.
Mahadevan U, Martin CF, Sandler RS, et al. 865 PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology 2012;142:S-149
54.
Norgard BM. Birth outcome in women with ulcerative colitis and Crohn’s disease, and pharmacoepidemiological aspects of anti-inflammatory drug therapy. Dan Med Bull 2011;58:B4360
66.
55.
Beaulieu DB, Ananthakrishnan AN, Issa M, et al. Budesonide induction and maintenance therapy for Crohn’s disease during pregnancy. Inflamm Bowel Dis 2009;15:25-8
Langagergaard V, Pedersen L, Gislum M, et al. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy: a Danish nationwide cohort study. Aliment Pharmacol Ther 2007;25: 73-81
67.
Teruel C, Lo´pez-San Roma´n A, Bermejo F, et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines. Am J Gastroenterol 2010;105:2003-8
68.
Hoeltzenbein M, Weber-Schoendorfer C, Borisch C, et al. Pregnancy outcome after paternal exposure to azathioprine/ 6-mercaptopurine. Reprod Toxicol 2012;34: 364-9
69.
Christensen LA, Dahlerup JF, Nielsen MJ, et al. Azathioprine treatment during lactation. Aliment Pharmacol Ther 2008;28: 1209-13
70.
Angelberger S, Reinisch W, Messerschmidt A, et al. Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding. J Crohns Colitis 2011;5:95-100
71.
Lloyd ME, Carr M, McElhatton P, et al. The effects of methotrexate on pregnancy, fertility and lactation. QJM 1999;92:551-63
72.
Martinez Lopez JA, Loza E, Carmona L. Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding). Clin Exp Rheumatol 2009;27:678-84
73.
Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis
56.
57.
Beitins IZ, Bayard F, Ances IG, et al. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr 1972;81:936-45 Matalon ST, Ornoy A, Lishner M. Review of the potential effects of three commonly used antineoplastic and immunosuppressive drugs (cyclophosphamide, azathioprine, doxorubicin on the embryo and placenta). Reprod Toxicol 2004;18:219-30
58.
Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology 2002;65:240-61
59.
Cleary BJ, Kallen B. Early pregnancy azathioprine use and pregnancy outcomes. Birth Defects Res A Clin Mol Teratol 2009;85:647-54
60.
61.
Norgard B, Pedersen L, Fonager K, et al. Azathioprine, mercaptopurine and birth outcome: a population-based cohort study. Aliment Pharmacol Ther 2003;17:827-34 Akbari M, Shah S, Velayos FS, et al. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with
Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)
IBD in women of reproductive age
refractory to steroid therapy. N Engl J Med 1994;330:1841-5
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/19/15 For personal use only.
74.
Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001;71: 1051-5
75.
Branche J, Cortot A, Bourreille A, et al. Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy. Inflamm Bowel Dis 2009;15:1044-8
76.
Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380-8
77.
Zheng S, Easterling TR, Umans JG, et al. Pharmacokinetics of tacrolimus during pregnancy. Ther Drug Monit 2012;34: 660-70
78.
Kainz A, Harabacz I, Cowlrick IS, et al. Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus. Transpl Int 2000;13(Suppl 1):S299-300
79.
80.
Jain AB, Reyes J, Marcos A, et al. Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003;76:827-32 Baumgart DC, Sturm A, Wiedenmann B, Dignass AU. Uneventful pregnancy and neonatal outcome with tacrolimus in
informahealthcare.com
refractory ulcerative colitis. Gut 2005;54: 1822-3 81.
French AE, Soldin SJ, Soldin OP, Koren G. Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother 2003;37: 815-18
82.
Kane S. Anti-tumor necrosis factor agents and placental transfer: relevant clinical data for rational decision-making. Clin Gastroenterol Hepatol 2013;11:293-4
83.
Arsenescu R, Arsenescu V, de Villiers WJ. TNF-alpha and the development of the neonatal immune system: implications for inhibitor use in pregnancy. Am J Gastroenterol 2011;106:559-62
84.
Martin PL, Oneda S, Treacy G. Effects of an anti-TNF-alpha monoclonal antibody, administered throughout pregnancy and lactation, on the development of the macaque immune system. Am J Reprod Immunol 2007;58:138-49
85.
Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol 2012;107:1409-22
86.
Ju¨rgens M, Brand S, Filik L, et al. Safety of adalimumab in Crohn’s disease during pregnancy: case report and review of the literature. Inflamm Bowel Dis 2010;16: 1634-6
Review
87.
Cheent K, Nolan J, Shariq S, et al. 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;4:603-5
88.
Zelinkova Z, van der Ent C, Bruin KF, Dutch Delta IBD Group. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin Gastroenterol Hepatol 2013;11:318-21
89.
Ben-Horin S, Yavzori M, Katz L, et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol 2010;8:475-6
90.
Ben-Horin S, Yavzori M, Kopylov U, et al. Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease. J Crohns Colitis 2011;5:555-8
91.
Wakefield I, Stephens S, Foulkes R, et al. The use of surrogate antibodies to evaluate the developmental and reproductive toxicity potential of an anti-TNFalpha PEGylated Fab’ monoclonal antibody. Toxicol Sci 2011;122:170-6
92.
Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011;17: 958-63
425