Management of inflammatory bowel disease in pregnancy

Abstract

The management of inflammatory bowel disease (IBD) in women who are pregnant or contemplating pregnancy requires special considerations. Although many of the medications in IBD treatment are generally low risk, this is not the case for all agents, and substitution of medications or adjustments in dosage or dose timing may be needed. Furthermore, while women with IBD who have not had prior pelvic surgery are as likely to conceive as non-IBD counterparts, there is evidence to suggest that pregnancy outcomes may be worse in women with IBD, particularly if they have active disease during conception or pregnancy. Therefore, a thoughtful discussion between the patient and her healthcare team is critical to ensure awareness of the possible risks of pregnancy to the mother and her infant and how these risks can be minimized with a coordinated effort in counseling, monitoring and medication adherence.

Keywords::

• biologics
• corticosteroids
• Crohn’s disease
• disease flare
• heritability
• inflammatory bowel disease
• infliximab
• pregnancy
• thiopurines
• ulcerative colitis

Medscape: Continuing Medical Education Online

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertimmunology; (4) view/print certificate.

Release date: 6 February 2013; Expiration date: 6 February 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the effect of inflammatory bowel disease on fertility

• • Distinguish negative pregnancy outcomes associated with inflammatory bowel disease

• • Identify medications used to treat inflammatory bowel disease which should be avoided during pregnancy

• • Evaluate the use of other medications to treat inflammatory bowel disease during pregnancy and breast feeding

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Associate Professor and Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Uma Mahadevan, MD

Associate Professor of Medicine; Co-Medical Director of Clinical Research, UCSF Center for Colitis and Crohn’s Disease, University of California,

San Francisco, CA, USA.

Disclosure: Uma Mahadevan has disclosed the following relevant financial relationships: served as a consultant for Abbott, UCB, Janssen, Elan and Shire, and received research support from Prometheus.

Susie W Ng, MD

Department of Gastroenterology, University of California, San Francisco, CA, USA.

Disclosure: Susie W Ng, MD, has disclosed no relevant financial relationships.

Inflammatory bowel disease (IBD) is a condition that can affect women during their reproductive years. Therefore, understanding the nuances of IBD management in women who are considering pregnancy, attempting to conceive or already pregnant is an important task for physicians who treat IBD. In particular, patients may have questions around heritability, fertility, safety of medications during pregnancy, the effect of IBD on the course of pregnancy and the health of the child and the effect of pregnancy on disease activity. This article will review each of these topics and pay special attention to updates in IBD management in pregnancy since the last Expert Reviews publication in 2010 [1].

Heritability

Children born to parents with Crohn’s disease (CD) or ulcerative colitis (UC) are genetically predisposed to developing IBD themselves. Children with one parent affected by IBD have a two- to 13-fold higher risk of developing IBD in their lifetime compared with the general population [2], which translates to a 5.2 and 1.6% chance of IBD in the offspring of an individual with CD and UC, respectively [3]. Children with both parents affected with IBD have a 33–36% likelihood of developing IBD [4,5].

There is new data emerging on whether mode of delivery may influence risk of IBD in the child. In a Swedish case-controlled study of 1536 pediatric CD patients, birth by cesarean (C-) section was associated with an increased risk of CD among boys (odds ratio [OR]: 1.25; 95% CI: 1.01–1.54) but not girls [6]. A Danish population-based study showed similar findings, with increased IBD risk among children aged 0–14 years (incidence rate ratio: 1.26; 95% CI: 1.11–1.49) in those born via C-section, which was irrespective of parental IBD. The trend was greater among boys and with incidence of UC greater than CD in subgroup analysis [7]. The reasons for these associations are not clear, but possible explanations include perturbation of the normal bacterial colonization of the newborn’s intestine during C-section. Further studies are warranted to confirm these findings.

Fertility

Fertility (defined as achieving pregnancy within 1 year of regular intercourse without contraception) is reduced in active IBD [8,9]. Reasons for this are likely multifactorial and may be related to fever, pain, diarrhea and malnutrition frequently seen in IBD flares, as well as dyspareunia, decreased libido and depression [10–12]. There may also be an immunologic basis involving T-cell dysfunction given young infertile women without IBD but with Th1/Th2 cytokine elevation have improved in vitro fertilization rates using adalimumab, which as a TNF-α inhibitor has been proposed to cause a shift in the Th1/Th2 balance [13].

Among women with inactive disease, the major IBD-associated factor affecting their fertility is prior pelvic surgery. For women who have not had previous pelvic surgery, their fertility is similar to age-matched peers in the general population [14]. Women who have undergone pelvic surgery have increased rates of infertility, particularly those who have had proctocolectomy with ileal pouch anal anastomosis (IPAA) [14–16]. A recent meta-analysis by Rajaratnam et al. looking at female fertility in familial adenomatous polyposis patients post-IPAA found a 3.91-fold increased risk of infertility (95% CI: 2.06–7.44) [17]. It is suspected that the major reason for this is pelvic scarring and adhesions from surgery resulting in tubal infertility. Indeed, interventions that produce relatively fewer abdominal and pelvic adhesions, such as ileorectal anastomoses (IRA) and laparoscopic surgery, are associated with higher fertility rates. Two studies looking at IRA – one with familial adenomatous polyposis patients, another with UC patients – found pregnancy rates after IRA were similar to controls and greater than rates after IPAA [14,18]. Building off of a recent study showing fewer adhesions with laparoscopic IPAA technique [19], a recent cross-sectional study by Bartels et al. suggests pregnancy rates are significantly higher among women who have undergone laparoscopic IPAA versus open IPAA [20]. While more studies in this area are needed, for women requiring surgery and interested in conceiving in the future, IRA or laparoscopic IPAA should be considered as they may result in greater maintenance of fertility compared with open IPAA.

While the focus of this review is the female patient, some medications affecting male fertility deserve mention. Sulfasalazine causes well-documented infertility through oligospermia, abnormal sperm morphology and reduced sperm motility [21–24]. These findings are dose related and do not improve with supplemental folate [24]. Semen quality returned to normal 2–3 months after discontinuing sulfasalazine [25]. Therefore, it is advised that men with IBD on sulfasalazine considering conception should be switched to another oral mesalamine agent. A recent study with azathioprine did not demonstrate clear detrimental effects on semen quality or, by extension, male fertility [26]. Limited data reviewed by French et al. looking at male fertility and methotrexate monotherapy described conflicting reports on whether methotrexate affects semen quality, but any adverse effects that have been reported appear to be reversible when methotrexate is discontinued [27].

Effect of pregnancy on disease activity

Pregnancy has not been shown to increase likelihood of disease flare. Large population-based studies conducted in the 1970s in Europe by Nielsen et al. established that in both UC and CD patients, rates of disease flare are similar between pregnant and nonpregnant women [9]. Specifically, Nielsen reported UC flare rates of 34 versus 32% in pregnant and nonpregnant women, respectively. A similar finding was seen among CD patients [28]. A large northern California population-based cohort study of 461 pregnant IBD patients showed the majority of patients with UC and CD had inactive or mild disease throughout pregnancy (65–80% based on the pregnancy stage) [29].

Whether or not a woman experiences a flare during her pregnancy is influenced greatly by her disease activity at the time of conception. Prior literature suggests only a third of UC and CD patients with quiescent disease at conception will relapse during pregnancy, while two-thirds of patients with active disease at conception will continue to have active disease during pregnancy [30–33]. An older review by Miller found that, among UC patients with active disease at conception, 45% will experience worsening flare during pregnancy, 24% will continue to have active but stable disease and only a quarter of patients will have flare resolution; among women with active CD at conception, a third will have worsening disease, a third will have stable but active symptoms during their pregnancy and a third will achieve remission [34]. Similarly, a recent study by Ujihara et al. examining 90 pregnancies in 63 pregnant women with UC found that 48.3% of pregnant women with active disease at conception developed moderate or severe disease activity during pregnancy, compared with only 14% of women with quiescent disease at pregnancy onset who later developed significant active symptoms [35]. These studies emphasize the importance of attaining disease remission in women before pregnancy when possible.

There is conflicting data on when a flare is most likely to occur during pregnancy. Flares had previously been thought to occur most often in the first trimester and in the postpartum period, but this may have been confounded by women discontinuing their medications early in pregnancy and resuming smoking postpartum. The northern California cohort study demonstrated that the rate of flares was low and similar throughout pregnancy and the postpartum period [29].

Management of IBD flares during pregnancy

Should a pregnant IBD patient develop symptoms suggestive of an IBD flare, the ensuing workup should be similar to that typically initiated for nonpregnant patients. Stool studies should be sent to rule out an infectious etiology, particularly as Clostridium difficile infection is increased in the peripartum period [36]. If imaging is needed, ultrasound is preferable to computed tomography to avoid radiation exposure to the fetus. If more detailed imaging is needed, MRI can be considered, but gadolinium should be avoided in the first trimester given the risk of teratogenicity. Sedation should be avoided if possible; thus, unsedated flexible sigmoidoscopy is favored if endoscopic evaluation is needed.

A more detailed discussion of each drug class can be found later in this review, but in general, most medications used to treat IBD flares are compatible with pregnancy. The major exception is methotrexate, which has been shown to cause multiple congenital anomalies, induce spontaneous abortion and affect cellular metabolism. Overall, azathioprine (AZA) and 6-mercaptopurine (MP) are low risk; however, AZA/6MP should not be started for the first time during pregnancy given the risk of bone marrow suppression and pancreatitis. Cyclosporine can be used successfully in pregnancy, although it can cause premature labor and small-for-gestational-age (SGA) infants. In general, studies suggest that use of currently available medications to treat flares during pregnancy will lead to successful remission in greater than 80% of cases [37].

Mode of delivery in IBD

Large population-based studies have repeatedly shown increased risk of cesarean delivery up to 1.5-times that of the general population among women with CD but not UC [38,39]. This probably reflects the concern of patients and providers for complications around anal sphincter damage, development or worsening of perianal disease and pouch dysfunction in patients with IPAA prior to pregnancy. More recently, a 2010 Scandinavian population-based study noted that women with UC also had an increased rate of C-section (OR: 2.01; 95% CI: 1.84–2.19) compared with the general, non-IBD population [40], although the reasons for this are unclear.

The concern for precipitating or exacerbating perianal disease in CD is grounded on findings from an older retrospective questionnaire-based study that suggested women with CD without a history of perianal disease had an 18% chance of developing perianal disease after vaginal delivery, especially after episiotomy [41]. Larger studies, however, have shown vaginal delivery with inactive perianal disease does not lead to or worsen perianal disease [42,43]. At this time, current guidelines recommend C-section in the setting of active perianal disease, but vaginal delivery can be considered in women with no history of or inactive perianal disease.

Women who are post-IPAA should consider C-section due to the risk of pouch dysfunction and sphincter damage leading to increased incontinence. However, there are studies showing vaginal delivery is safe for those with a pouch in disease remission, with possible altered sphincter dysfunction during late pregnancy and postpartum usually returning to normal within 3 months of delivery without increased risk of fissure or anal sphincter injury [44,45]. In general, mode of delivery should be made on an individual basis with risks and benefits clearly discussed with the patient and providers involved.

Effect of IBD on pregnancy course & pregnancy outcomes

There has been a large volume of literature to suggest that women with IBD are at increased risk of pregnancy complications compared with age-matched non-IBD peers [29,38,41,46–48]. In concordance with these prior findings are two recent Scandinavian population-based studies conducted by Stephansson et al. in 2011 and 2010 on UC and CD, respectively [40,49]. Among 2637 women with UC compared with 868,942 controls, there was an increased risk of moderately preterm birth (defined as 32–36 weeks gestation; OR: 1.77; 95% CI: 1.54–2.05), very preterm birth (defined as before 32 weeks; OR: 1.41; 95% CI: 1.02–1.96), SGA birth (OR: 1.27; 95% CI: 1.05–1.54), C-section (OR: 2.01; 95% CI: 1.84–2.19) and neonatal death (OR: 1.93; 95% CI: 1.04–3.60) [40]. Among 2377 cases of maternal CD within the same Danish and Swedish population, this group reported increased risk of moderate preterm birth (OR: 1.76; 95% CI: 1.51–2.05), very preterm birth (OR: 1.86; 95% CI: 1.38–2.52), C-section (OR: 1.93; 95% CI: 1.76–2.12) and SGA birth (OR: 1.43; 95% CI: 1.09–1.89) [49]. Secondary analysis looking at outcomes compared with duration of CD from time of formal diagnosis did not reveal a significant trend. A similar analysis was not performed in the UC population. A 2010 European multicenter comparative case-controlled study by Molnár et al. looking at pregnancies of UC and CD patients before and after IBD diagnosis (70 and 97 pregnancies, respectively) also concluded that preterm birth (p = 0.008) and low birthweight (p = 0.048) were more common after the diagnosis of IBD [50]. However, when CD and UC was analyzed separately, only preterm birth in UC remained statistically significant (p = 0.047), which could be due to decreased power of subgroup analyses. There was reportedly no difference in pregnancy outcomes depending on location or extension of disease, perianal complications, surgery or type of delivery. Additionally, a 2007 northern California cohort study found increased rates of spontaneous abortion and pregnancy complications such as eclampsia/preeclampsia, abruption placenta, fetal distress, placenta previa and prolonged/premature rupture of membranes [29].

In contrast to these findings is a 2011 prospective study by the European Crohn–Colitis Organization, which looked at 332 pregnant women with IBD (145 CD and 187 UC) and found no statistically significant difference in the frequency of preterm deliveries, C-sections, birthweight or abortions between babies of IBD women and matched non-IBD controls [51]. A majority of patients (86.9%), however, were in remission at conception and maintained quiescent disease throughout pregnancy (85.8%) while 73.7% of those with active disease at conception achieved remission later in pregnancy. Secondary analysis within UC found older age and active disease was associated with low birthweight; while older age and combination therapy were risk factors for preterm delivery. Similar analyses of CD patients revealed older age was associated with congenital abnormalities and preterm delivery, and smoking increased the risk of preterm delivery.

The question of increased risk of congenital abnormalities in the fetus is of particular concern for many IBD patients. A 2002 population study by Dominitz et al. comparing computerized birth records of infants born to women with and without IBD diagnosis in Washington state (USA) found an increased risk of congenital abnormalities among children born to mothers with UC but not CD [48]. However, this study failed to take disease activity or medication use into consideration. A 2007 meta-analysis by Cornish et al. suggested a 2.37-fold increased risk of congenital abnormalities among children born to women with IBD, but this finding was influenced solely by the Dominitz study [38]. Other studies analyzed by the Cornish meta-analysis found no increased risk of congenital abnormalities, and this has also not been replicated in large population and registry-based studies, including the recent Stephansson studies discussed above [29,40,49,51].

Disease activity during pregnancy has traditionally been thought to lead to worse pregnancy outcomes. Earlier studies showed active disease at conception was associated with a higher rate of fetal loss [52] and preterm birth [9,28]. Disease activity during pregnancy has also previously been associated with preterm birth and low birthweight [37,46,53,54]. Secondary analysis conducted by Stephansson et al. attempted to correlate pregnancy outcomes with disease activity, specifically looking at women who had ever been hospitalized for UC compared with those with outpatient management only [40]. They found that women with UC hospitalizations and therefore possibly more active disease were associated with higher risk of moderately preterm birth, SGA birth and C-section compared with women receiving only ambulatory care. Stephansson et al. conducted a similar secondary analysis with CD patients, but no statistically significant trends were noted [49].

Studies suggesting a weaker impact of disease activity on pregnancy outcomes do exist. The northern California study by Mahadevan et al. looking at 154 women with CD and 300 women with UC showed that disease activity did not predict adverse pregnancy outcomes, albeit the majority of patients in this study had inactive disease [29]. A 2007 cohort study by Nørgård et al. of women with CD found that disease activity during pregnancy was associated with increased risk of preterm birth but not low birthweight or congenital anomalies [55]. Additionally, in the recent Molnár study, disease activity did not predispose to abnormal birth outcome (preterm delivery, low birthweight, congenital abnormalities) compared with inactive disease. However, average 9.5-year follow-up in the IBD group and 26.2 years in the control cohort suggested childhood disease occurred more frequently in children of mothers with active UC during pregnancy (p = 0.001). No similar finding was noted in CD patients, although the majority of CD mothers had inactive disease [50].

Further studies are needed to clarify the impact of disease severity on pregnancy outcomes. Other potential predictors of an adverse outcome warranting further investigation include ileal CD, previous bowel resection and strong family history of IBD (i.e., first-degree relative of the expectant parent with IBD [29,56,57]).

IBD can also complicate a pregnancy course by placing the expectant mother at increased risk of thromboembolism and malnutrition. Venous thromboembolism develops at a higher rate among pregnant women with CD and UC (adjusted OR: 6.12 and 8.44, respectively) compared with non-IBD controls [32]. Similarly, protein–calorie malnutrition occurs more frequently among women with IBD. Thus, care should be taken to ensure appropriate deep venous thromboembolism prophylaxis when patients are hospitalized, and dietary intake and weight should be monitored carefully.

Postpartum period & breastfeeding in IBD

The postpartum period does not appear to constitute a time of risk for disease flare compared with the general IBD population unless the patient has had active disease prior to and during pregnancy or is smoking. An earlier study of 122 women with IBD who were followed after delivery found 43% of women experienced a postpartum flare, of which 64% had a history of breastfeeding for at least 1 month prior to flare onset, with the trend persisting among CD patients (OR: 2.1; 95% CI: 1.1–8.5) but not for UC (OR: 0.9; 95% CI: 0.34–2.5) when stratified [58]. However, after adjusting for the high proportion of women who stopped medications prior to delivery and breastfeeding, there was no statistically significant increase in disease exacerbation with breastfeeding. Moffatt et al. found in a Canadian population-based study that breastfeeding was associated with a nonsignificant decrease in flares, suggesting that breastfeeding may actually be protective against flares in the postpartum period [59]. Additionally, while some earlier studies have suggested no reduced risk of IBD with breastfeeding [60,61], Barclay et al. concluded in their 2009 systematic review that breastfeeding among non-IBD women exerted a protective effect (OR: 0.69; 95% CI: 0.51–0.94) against developing early-onset IBD [62].

Despite this, Kane et al. showed that a lower percentage of women with IBD breastfeed their infants, with only 44% of total study participants doing so compared with a historical average of 60% among the general population [52]. In recent data from the PIANO registry, 75% of mothers with IBD breastfed, but there was a significantly lower percentage of women on immunomodulators and biologics who were likely to do so compared with women not on these medications [63]. Reasons quoted for not breastfeeding include concern of drugs being transferred through the breast milk and physician recommendation. However, given many studies suggest that breastfeeding is safe in the setting of most IBD medications (see discussion under ‘Medications’ for more information) and given the well-established benefits of breastfeeding in the neonate, women should not be discouraged from breastfeeding by their physicians.

Medications

In general, most medications used for management of IBD – with the exception of Category X drugs methotrexate and thalidomide – are considered relatively low risk to the fetus and infant and can be continued during pregnancy and breastfeeding (Tables 1 & 2). Long-term safety data for the child have historically been lacking, although the PIANO registry will provide 4-year follow-up data. Moreover, additional studies are needed to establish safety of administration and dosing of IBD medications during conception and pregnancy.

Aminosalicylates

Asacol^® (mesalamine) (Procter & Gamble Pharmaceuticals, OH, USA)and Asacol HD^® (Procter & Gamble Pharmaceuticals, OH, USA) were recently moved from pregnancy category B to category C. This recent change is due to dibutyl phthalate in the medication coating. Animal studies employing doses greater than 190-times those used in IBD patients showed external and skeletal malformations and adverse effects on the male reproductive system [64]. Case reports of dibutyl phthalate use ten-times greater than that generally found in maximum recommended IBD dosing suggest possible precocious puberty may result [65]. To date, however, there have been no clinical studies linking an increase in birth defects to the use of Asacol.

All other formulations of mesalamine (e.g., Pentasa, Lialda^® [Shire US Manufacturing Inc., MD, USA]), as well as other aminosalicylates sulfasalazine and balsalazide, are pregnancy category B. A folate deficiency can result from sulfasalazine’s inhibitory effect on the enzyme dihydrofolate reductase, so this medication should be taken with supplemental folic acid 1 mg twice daily in women who are attempting to conceive or are pregnant. As mentioned earlier, men on sulfasalazine should be switched to an alternate mesalamine preparation 3–4 months prior to attempting conception given sulfasalazine’s detrimental effect on sperm. Olsalazine is pregnancy category C although a higher level of harm has not been demonstrated.

A meta-analysis of seven studies of 5-ASA drugs in pregnant patients with IBD showed no statistically significant increase in congenital abnormalities (OR: 1.16; 95% CI: 0.76–1.77), stillbirth (OR: 2.38; 95% CI: 0.65–8.72), spontaneous abortion (OR: 1.14; 95% CI: 0.65–2.01), preterm delivery (OR: 1.35; 95% CI: 0.85–2.13) or low birthweight (OR: 0.93; 95% CI: 0.46–1.85) [66]. Some providers advocate a maximum of 2 g a day of mesalamine during pregnancy, which may be based on a 1994 case report of oral mesalamine being associated with neonatal renal insufficiency [67]. However, this finding has not been replicated in several large-scale studies [29,41,46,48].

Placental and breast milk transfer does occur with these medications, but they are approved by the American Academy of Pediatrics for use with lactation if necessary. Of note, the sulfapyridine moiety contained in aminosalicylates is less likely to displace bilirubin from its albumin binding sites than other sulfonamides, and the amount transferred in breast milk is negligible. Therefore, increased rates of kernicterus have not been described [68]. There is a single case report of an infant developing severe, reversible watery diarrhea after being breastfed by a mother who had used rectal 5-ASA [69], so stool patterns should be monitored if a mother is on mesalamine.

Corticosteroids

Prednisone is pregnancy category C and is appropriate for use in the setting of disease flares. An earlier case–control study of 1092 children born with various congenital anomalies found that women who were exposed to steroids in the month before conception and during the first trimester had a greater prevalence of infants born with orofacial clefts [70]. This was confirmed in a meta-analysis reporting a summary OR of 3.35 (95% CI: 1.97–5.69) for cleft palates, but the overall risk of major malformations was low (OR: 1.45; 95% CI: 0.80–2.60) [71]. Observations from transplant literature suggest steroid use may lead to premature rupture of membranes and adrenal suppression in the mother and, much more rarely, in the newborn. Budesonide (Entocort^®, AstraZeneca, Turkey), which is usually used in the setting of mild to moderate CD involving the ileum, was studied in a small case series by Beaulieu et al., which did not show increased rates of adverse outcomes or congenital abnormalities [72]. In general, steroids should be avoided if possible during the first trimester due to the possible risk of cleft palate, and the lowest possible dose should be used for the shortest period of time necessary.

Corticosteroids, including budesonide, are considered compatible with breastfeeding by the American Academy of Pediatrics. A six-subject study by Ost et al. looking at dose-dependent excretion of prednisolone into breast milk recommended delaying breastfeeding for at least 4 h after maternal ingestion of 40 mg or greater [73]. However, the same study showed prednisolone doses up to 80 mg led to only 0.1% of drug secreted into breast milk, which corresponds to less than 10% of the infant’s endogenous cortisol production. Other studies have demonstrated small amounts of prednisolone are secreted in breast milk, and these amounts are likely to be clinically insignificant [74,75]. At this time, there are no formal recommendations in timing breastfeeding around steroids.

Antibiotics

The two main antibiotics used in IBD management, metronidazole and ciprofloxacin, are pregnancy category B and C, respectively. Previous studies have demonstrated low risk of teratogenicity in the second and third trimesters [76–79]. However, a 1998 case–control study of 17,300 women exposed to metronidazole showed that drug exposure during the second and third months of pregnancy was associated with a slightly increased rate of cleft lip and palate in the neonate [80], and this, along with animal studies showing teratogenicity, has given rise to the recommendation that metronidazole should be avoided in the first trimester. Breastfeeding is not advised with metronidazole because it is excreted in breast milk and can lead to potential toxicity.

Ciprofloxacin, as part of the fluoroquinolone family, has an affinity for bones and can cause arthropathy in children, but a prospective controlled study of 200 women exposed to fluoroquinolones showed low risk of clinically significant major musculoskeletal dysfunction or other birth defects [81]. Still, it is not recommended in pregnancy. It is excreted in breast milk but, given the usually short duration of treatment, is felt compatible with breastfeeding by the American Academy of Pediatrics.

Rifaximin has demonstrated teratogenicity in animal studies and is pregnancy class C. Its safety in humans in pregnancy and breastfeeding are unknown. Amoxicillin/clavulanic acid is pregnancy class B and is a good option for patients with pouchitis during pregnancy.

Azathioprine/6-MP

The safety of AZA and 6-MP during pregnancy is incompletely understood. Animal studies have suggested there may be risk of teratogenicity [82]. Therefore, 6-MP and its prodrug AZA are classified as pregnancy category D and recommended against use during conception and pregnancy. However, multiple studies in IBD have not noted a similar increase in congenital anomalies and suggest it may be low risk during pregnancy if other alternative therapy is lacking.

A number of studies have reported worse pregnancy outcomes associated with AZA/6-MP [83,84]. The largest and most recent is by Cleary et al., which included 476 women on AZA in early pregnancy, the majority of whom had IBD [85]. This group demonstrated a trend toward increased congenital anomalies (OR: 1.41; 95% CI: 0.98–2.04), with ventricular and atrial septal defects in particular showing a threefold higher rate (OR: 3.18; 95% CI: 1.45–6.04). Preterm delivery, low birthweight and SGA were also more common in women on AZA, although these latter findings are probably due to disease effect.

Conversely, Goldstein et al. looked at 189 women on AZA for various treatment indications who contacted a teratogen information service after AZA exposure during pregnancy and compared them with 230 pregnant women on nonteratogenic treatments who contacted the same service [84]. This group found no statistically significant difference in the rate of major malformations (3.5 vs 3%; OR: 1.17; 95% CI: 0.37–3.69), but exposed infants did have a statistically significant increase in premature birth and low birthweight. A more recent French study of 204 pregnant women with IBD found no association between AZA use and risk of adverse pregnancy outcomes, such as interrupted pregnancies (due to spontaneous or elective abortion), congenital abnormalities, preterm deliveries or low birthweight [86].

The PIANO registry is a large national prospective cohort of pregnant women with IBD who have been identified at various sites around the USA and who have agreed to be longitudinally followed through each pregnancy trimester, at delivery and for the first 4 years of the child’s life. The mother’s medication exposure, IBD history and disease activity and complications during pregnancy and postpartum are recorded. Interval data analysis is currently available for 896 women, of whom 279 were exposed to azathioprine/6-MP during pregnancy. There was no observed increase in the risk of congenital malformations or other complications compared with unexposed infants [55].

A recent prospective study of 115 pregnancies among men exposed to AZA or 6-MP during conception showed no statistically significant increase in major malformations (3 vs 2.2%). However, there was a higher rate of elective terminations in the exposed group, and a nonsignificant increase of spontaneous abortions (cumulative 19 vs 13%) [87].

AZA/6-MP is likely to be compatible with breastfeeding. Several small studies have shown very low levels of drug excretion in breast milk that do not amount to clinically significant concentrations in the healthy breastfeeding infant [88–90]. Caution should be used in infants with compromised immune systems.

Methotrexate

Methotrexate is a folate acid antagonist and has demonstrated multiple congenital anomalies when used during organogenesis (6–8 weeks postconception). Methotrexate is consequently classified as pregnancy category X and is absolutely contraindicated in pregnancy [91]. Women of childbearing years taking methotrexate should be on one to two forms of contraception with counseling about the teratogenic effects of methotrexate. Because methotrexate can remain in tissues for weeks, it is recommended that women considering pregnancy wait at least 6 months from discontinuation of the drug before attempting conception.

For men on methotrexate, a recent study looking at 42 pregnancy outcomes involving paternal exposure to methotrexate at the time of conception or up to 3 months before conception concluded that there was no increased risk of congenital birth defects [92]. However, given the limited data available to date, some providers still recommend that men wait at least 3 months after discontinuing methotrexate before trying to conceive [201]. Methotrexate is excreted in breast milk and may accumulate in neonatal tissues with the possibility of interfering with cellular metabolism [93]. Methotrexate is therefore contraindicated in breastfeeding.

Cyclosporine/tacrolimus

Both cyclosporine and tacrolimus are pregnancy class C. The majority of experience in pregnancy with these medications is from transplant literature. Registries of transplant recipients have shown that cyclosporine and tacrolimus do not increase the rate of congenital abnormalities in the newborn [94]. An older multicenter survey of 100 pregnancies from 84 mothers on tacrolimus primarily in the setting of solid-organ transplant found that 71 pregnancies progressed to delivery (68 live births, two neonatal deaths, one stillbirth), 24 were terminated (12 spontaneous, 12 induced) and five had unavailable data. Of infants with available information on gestational age and size for gestational age, 59% of neonates had preterm delivery and 5% had low (<10th percentile) birthweight. Four neonates had malformations without any consistent pattern [95]. A more recent single-center retrospective study of maternal complications and pregnancy outcomes among kidney transplant patients on various immunosuppressants including tacrolimus and cyclosporine showed increased rates of maternal and perinatal complications, but no congenital abnormalities were noted in the tacrolimus or cyclosporine patients [96]. There is a published case report of a normal pregnancy and delivery of a healthy infant with the mother on tacrolimus for refractory UC [97].

Both medications are contraindicated in breastfeeding due to high concentrations excreted in milk. Cyclosporine in the young infant can potentially cause neutropenia and immunosuppression. Tacrolimus ingestion via breast milk may lead to toxicity in the neonate.

Biologics

This class of drugs is relatively new, and short- and long-term effects are still being elucidated. However, given clinical experience to date, these medications are generally compatible with use during pregnancy. Furthermore, given the importance of maintaining control over disease activity, biologics should be continued during pregnancy. Infliximab (INF), adalimumab (ADA) and certolizumab (CZP) are all pregnancy class B. Natalizumab (NAT) is pregnancy class C. INF and ADA have been shown to cross the placenta efficiently during the third trimester [98], probably via the FcRn receptor, and are present in the newborn in high levels. To date, however, aside from reported cases of infections following administration of live vaccines [99], there have been no reported adverse events associated with elevated drug levels in newborns when controlled for preterm birth. Still, the issue of stopping INF and ADA early to minimize placental transfer remains a controversial topic, and further research is needed.

In the PIANO registry, among the 291 patients exposed to biologics alone and 75 patients who received a combination of biologics and immunomodulators, there was no increase in the rate of congenital anomalies, infections or developmental delay based on medication exposure [63]. However, there was an increase in infections in the combination therapy group when CZP (which has minimal placental transfer) excluded from the biologic groups, suggesting the presence of placentally transferred INF/ADA may play a role in infectious risk. For INF and ADA, dose adjustment needs to be balanced with maternal disease control, as the biggest risk to the pregnancy remains disease activity with its attendant risk of preterm birth and associated sequelae. Switching biologics during pregnancy in a patient in remission is also not advocated since this may result in disease flare, which again would be harmful to the pregnancy. Timing of drug dosage can be manipulated during pregnancy to limit the amount of drug transfer to the neonate and yet keep the mother in remission. Our current practice is to time the last dose of INF to 32 weeks gestation and to continue CZP on schedule throughout pregnancy. ADA is more difficult given the need for biweekly dosing and the risk of flares when stopped too early. The authors generally give the last dose at around week 36 of gestation. However, these recommendations will evolve as further data are accumulated.

Infliximab

INF is an IgG1 antibody used in the induction and maintenance of remission in CD and UC. The two earliest studies looking at INF safety in pregnancy come from the TREAT Registry and the INF Safety Database. In TREAT, a prospective registry of Crohn’s patients, 117 of a total 168 pregnancies had prior INF exposure. The rate of miscarriage (10 vs 6.7%) and neonatal complications (6.9 vs 10%) were not significantly different between the two groups [100]. There were no reports of fetal malformation in any of the pregnancies. The INF Safety Database retrospectively analyzed outcome data for 96 women who were exposed to INF during their pregnancy and found similar rates of spontaneous abortions. Most of the women in the study stopped INF upon learning of their pregnancy, so exposure was primarily during conception and the first trimester [101]. Other smaller studies have been mixed, with one reporting all ten pregnancies studied ending in live births without congenital anomalies [102], while another study of 22 patients exposed to INF during the first trimester reported three spontaneous abortions, one missed abortion, one stillbirth at 36 weeks (from umbilical strangulation), two preterm births, three low-birthweight infants and no congenital malformations [103].

Schnitzler et al. compared outcomes of 42 pregnancies with direct exposure to anti-TNF treatment (INF n = 35; ADA n = 7) to 23 pregnancies in women later diagnosed with IBD and did not find a higher incidence of adverse pregnancy outcomes [104]. However, the small study size may have prevented adequate statistical strength as there were reports of seven premature deliveries, six low birthweight, one stillbirth and one premature birth from necrotizing enterocolitis. In addition, Carter et al. conducted a review of the FDA database and found 61 congenital abnormalities in 41 newborns after exposure to anti-TNF therapy in pregnant women with rheumatic disease [105]. Nineteen of the mothers were on INF. Whether this represents a higher incidence of specific birth anomalies is unclear, but further information is certainly needed.

Previous data showed that while INF is detectable in newborns, drug levels progressively dropped after birth [106], suggesting drug transfer occurs through the placenta with minimal to no transfer via breast milk. More recent studies suggest INF is minimally present in breast milk, but the small amounts ingested by the infant are felt unlikely to result in systemic immunosuppression [107]. Caution is recommended for any live vaccines given to the infant during the first 6 months, particularly in the setting where IFN or ADA levels may be present and effecting some degree of immunosuppression. There has been a case report of fatal disseminated BCG infection in an infant born to a mother taking INF for CD who received a BCG vaccine at age 3 months [99].

Adalimumab

ADA, like INF, is an IgG1 antibody used in CD for induction and maintenance of remission. In a summary of published case reports and registry data available on ADA experience with pregnancy, Jürgens et al. reviewed 132 pregnancies with ADA exposure and found no reports of fetal abnormalities [108]. The PIANO study includes a cohort of 126 women exposed to ADA during pregnancy with no increased risk of adverse events in congenital anomalies, infant growth status, infection rates or developmental progress yet observed [55]. ADA appears to be excreted in very small amounts in breast milk [109] and is therefore likely compatible with breastfeeding.

ertolizumab Pegol

CZP is a pegylated Fab fragment of a humanized anti-TNF-α monoclonal antibody, currently approved for use in CD. As it does not have an Fc portion, it should not be actively transported across the placenta like INF and AZA, and animal studies suggest there may be significantly lower levels of drug in infants and breast milk with only the Fab’ fragment compared with the full antibody [110]. Clinical studies are needed to further understand the safety of CZP use in pregnancy. The ongoing PIANO study includes 47 women with exposure to CZP during their pregnancy with no increased risk of adverse events in congenital anomalies, infant growth status and rates of infection reported to date [55]. One case report measuring breast milk levels of CZP at 4 h, 3 days and 6 days after the first postpartum dose showed CZP was undetectable in all samples [111], suggesting CZP is compatible with breastfeeding.

Natalizumab

NAT is pregnancy category C. There have been no adequate and well-controlled studies in pregnant women. A prospective study of women with multiple sclerosis who accidentally became pregnant on natalizumab resulted in 28 healthy children, one child with hexadactyly, five early miscarriages and one elective termination [112]. An earlier review through May 2008 of the natalizumab global safety database (which includes patients from clinical trials, the natalizumab pregnancy exposure registry and postmarketing surveillance) reported 164 pregnancies with natalizumab exposure with no increase in birth defects [113]. The ongoing multicenter PIANO study includes a cohort of six women to date who have had NAT exposure during pregnancy with no observed increased rates of adverse events in congenital anomalies nor infant growth or developmental progression [55].

Summary

Most women with IBD can have healthy pregnancies with stable disease management. The key to successful symptom management and optimized pregnancy outcomes in IBD depends on an interdisciplinary approach involving the patient, her partner, primary care provider, gastroenterologist and obstetrician with close monitoring and ample counseling throughout. The intersection of pregnancy and IBD continues to be an area of significant research interest. The advances in disease management through increasing clinical experience and ongoing clinical studies will give more women the opportunity to have a successful pregnancy.

Expert commentary

Management of IBD in pregnancy poses special challenges to the healthcare provider. One must balance the risks of medication to the fetus with the risks of stopping therapy and the impact of subsequent disease activity to both mother and the fetus. This summary provides updated safety data on thiopurines, biologics and the impact of disease activity on pregnancy outcome. Data suggest that inflammatory bowel disease in the mother is associated with increased risk of adverse pregnancy outcomes, more so in patients with active disease during gestation. Ideally, women should only attempt conception when in remission, and this remission should be maintained throughout pregnancy. While this may not always be possible, medical therapy should be used to help achieve and maintain quiescent disease. Most IBD medications are compatible with use during conception, pregnancy and lactation as discussed in this review. Overall, the large majority of women with IBD will be able to have successful pregnancies if monitored closely and medicated appropriately.

Five-year view

In the next 5 years, the authors anticipate that the results of the PIANO registry, discussed in this review, and other such studies will provide an unprecedented amount of prospective data on the impact of IBD medications on pregnancy and newborn outcomes, including birth defects, infections and developmental milestones. While this will certainly allow us to provide a more informed response to concerned mothers-to-be, it will be balanced by the likely release of at least three new medications for IBD without significant pregnancy safety data. The existence of ongoing, independently funded registry vehicles will be critical in providing ongoing safety data.

Table 1. US FDA categories for the use of medications in pregnancy.

FDA category	Definition
A	Controlled studies in animals and women have shown no risk in the first trimester, and possible fetal harm is remote
B	Either animal studies have not demonstrated a fetal 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
C	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
D	Positive evidence of fetal risk is available but the benefits may outweigh the risk if life-threatening or serious disease
X	Studies in animals or humans show fetal abnormalities; drug contraindicated

Table 2. Medications for inflammatory bowel disease management.

Medication	US FDA category	Recommendations for pregnancy	Recommendations for breastfeeding
Adalimumab	B	Low risk: possible increased risk of newborn infection when given with AZA; time last dose to approximately 36 weeks gestation	Limited human data; probably compatible
Amoxicillin/clavulanate	B	Low risk; consider in treatment of pouchitis and perianal disease	Enters breast milk; caution advised
AZA/6- mercaptopurine	D	Low risk: compatible with use in pregnancy as monotherapy	Low transfer to infant. Ideally ‘pump and dump’ milk 4 h after ingestion
Balsalazide	B	Low risk	Enters breast milk but probably compatible
Budesonide	C	Limited human data but probably low risk	Probably compatible
Certolizumab	B	Low risk: no dose adjustment needed	Limited human data: likely to be compatible
Ciprofloxacin	C	Not recommended: possible musculoskeletal dysfunction	Compatible
Cyclosporine	C	No increase in congenital anomalies in transplant literature	Contraindicated
Infliximab	B	Low risk: possible increased risk of newborn infection when given with AZA; time last dose to approximately 32 weeks gestation	Limited human data; probably compatible
Mesalamine	B	Low risk	Enters breast milk but probably compatible
Mesalamine (Asacol^®, Asacol HD^®)	C	Teratogenicity in animal models with DBP coating of Asacol formulation	Enters breast milk but probably compatible
Methotrexate	X	Contraindicated: teratogenic	Contraindicated
Metronidazole	B	Avoid in first trimester as possible increased risk of cleft lip/palate	Enters breast milk and may cause toxicity
Natalizumab	C	Low risk. Limited human data	Limited human data; probably compatible
Olsalazine	C	Low risk. Limited human data	Enters breast milk but probably compatible
Prednisone	C	Risk of adrenal insufficiency, premature rupture of membranes. Avoid during first trimester as possible small risk of cleft palate	Enters breast milk but probably compatible
Rifaximin	C	Animal teratogen. No human data	Safety unknown
Sulfasalazine	B	Low risk when administered with 2 mg folic acid	Enters breast milk but probably compatible; no increased risk of kernicterus
Tacrolimus	C	No increase in congenital anomalies in transplant literature	Contraindicated
Thalidomide	X	Contraindicated: teratogenic	No human data: potential toxicity
AZA: Azathioprine; DBP: Dibutyl phthalate.

Key issues

• • Women with inflammatory bowel disease (IBD) are able to conceive at rates similar to age-matched, non-IBD peers; an exception to this is women who have had pelvic surgery, whose fertility is significantly lower than women without such surgical history.

• • There is data to suggest that women with IBD are at increased risk of fetal loss, preterm delivery, low birthweight and other adverse pregnancy outcomes, particularly if they have active disease at conception or during pregnancy.

• • Many of the medications available for IBD treatment are considered low risk to use in pregnancy and lactation; however, adjustments to dosage or dose timing may be needed.

• • Further studies are needed to elucidate the full safety profile of IBD medication use during pregnancy and breastfeeding and impact on childhood development.

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Management of inflammatory bowel disease in pregnancy

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1. You are seeing a 33- year-old woman with a history of Crohn disease (CD) who wants to become pregnant. Her disease has been inactive for 2 years. What can you tell her as part of pre-conception counseling?

• □ A The presence of CD alone reduces her fertility by approximately 60%

• □ B Pregnancy will increase the risk of a disease flare

• □ C CD activity prior to conception affects the risk of disease flare during pregnancy

• □ D Cesarean section is the preferred mode of delivery for all women with CD in order to reduce the risk of perianal disease

2. Of the options below, what can you tell this patient is the most important complication of pregnancy associated with the presence of CD?

• □ A Preeclampsia

• □ B Failure to progress during labor

• □ C Postpartum hemorrhage

• □ D Preterm birth

3. Which of the following medications for CD should be AVOIDED during pregnancy?

• □ A Methotrexate

• □ B Azathioprine

• □ C Prednisone

• □ D Mesalamine

4. What else should you consider regarding medical treatment of CD during and after pregnancy?

• □ A Corticosteroids may increase the risk of cleft palate

• □ B Metronidazole may be safely used during pregnancy and breast feeding

• □ C Azathioprine and 6-mercaptopurine were recently changed to pregnancy category B

• □ D Biologic agents need to be discontinued during pregnancy