Question 2: What medications are safe to use for maintenance of remission, or for induction of remission?
Most of the medications used to treat IBD are safe during gestation, except for Methotrexate and Thalidomide. The US FDA classification of drugs should be used to guide the use of medications during pregnancy. The FDA categories are listed in Table 1.
Table 1. Food and drug administration (FDA) classes in pregnancy
|A||Controlled studies in women fail to demonstrate a risk to the foetus in the first trimester (and there is no evidence of risk in later trimesters) and the possibility of foetal harm appears remote|
|B||Either animal reproduction studies have not demonstrated a foetal risk, but there are NO controlled studies in pregnant women OR animal reproduction studies have shown an adverse effect (other than decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of risk in later trimesters)|
|C||Either studies in animals have repeated adverse effects on the foetus (teratogenic, embryonic or other) and there are NO controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus|
|D||There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective)|
|X||Studies in animals or human beings have demonstrated foetal abnormalities OR there is evidence of foetal risk based on human experience OR both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.|
The medications used to treat IBD include aminosalicylates (e.g. mesalamine), immunomodulators (azathioprine and methotrexate), corticosteroids and biologics (infliximab, adalimumab). In an attempt to determine the effect of medications on pregnancy in IBD, Moskovitz et al. (2004) assessed the effect of 5-ASA drugs, metronidazole, ciprofloxacin, prednisone, mercaptopurine (MP), azathioprine and ciclosporin (CsA) on pregnancy outcomes in 113 IBD patients with 207 documented conceptions. They looked at spontaneous abortion, therapeutic abortion, maternal or foetal illness resulting in abortion, premature birth, healthy full-term birth, multiple births, ectopic pregnancy and congenital defects. They analysed the effect of medication use during the first trimester and at any time during pregnancy on the pregnancy outcome, and found no significant differences among groups.
5-Aminosalicylates: sulfasalazine/mesalamine (FDA B)/olsalazine (FDA C)
Sulfasalazine was one of the earliest therapeutics used in IBD, and has been assigned to pregnancy category B by the FDA. It is metabolized by intestinal bacterial flora to sulfapyridine and 5-ASA. Sulfapyridine crosses the placenta to reach the foetus. It may lead to deficiency of dihydrofolate and tetrahydrofolate by acting as a competitive inhibitor of the enzyme dihydropteroate synthase in the folate metabolism. Patients receiving sulfasalazine should receive folic acid supplementations to prevent the development of foetal neural tube defect.[50, 51] In men, sulfasalzine can cause oligospermia and infertility, which are reversible when sulfasalzine has been discontinued.
In a review of studies including 1155 pregnancies in women with UC being treated with sulfasalazine during pregnancy, the pregnancy outcome was similar to that expected in the general population with no significant increase in prevalence of selected congenital abnormalities.
At the 2006 Digestive Disease Week in Los Angeles, USA, Mahadevan and Corley reported that the use of 5-ASA and sulfasalazine during pregnancy was associated with an increased risk of congenital malformations when sulfasalazine was used during conception and the first trimester, but not with 5-ASA use. The use of 5-ASA was not associated with an increase in adverse outcomes; an increased risk of adverse outcomes was seen in women not taking 5-ASA during the second and third trimesters, suggesting a protective effect of the medication.
However, a meta-analysis of seven studies prior to 2007, with a total of 2200 pregnant women with IBD, 642 on 5-ASA drugs and 1158 on no medication, reported an 1.16-fold increase in congenital malformations, an 2.38-fold increase in stillbirth, an 1.14-fold increase in spontaneous abortion, an 1.35-fold increase in preterm delivery and an 0.93-fold increase in low birth weight in infants of the pregnant women exposed to 5-ASA drugs.
Asacol is a mesalamine covered with a special enteric coating that prevents the medication from degrading before it reaches the small intestine. This coating, dibutyl phthalate (DBP), was associated with external and skeletal malformations and adverse effects on the male reproductive rodents system. Patients who are using Asacol have 50 times higher mean urinary concentration of the main DBP metabolite, monobutyl phthalate, than nonusers (2257 μg/L vs. 46 μg/L; P < 0.0001). These results raise concern about potential human health risks for pregnant women and children. Although this has not been shown in any human study, Asacol should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. At the present time, physicians should caution their patients regarding this effect and consider switching patients to non-DBP containing meslamine.
Immunomodulators: azathioprine/mercaptopurine (FDA D).
Mercaptopurine and its prodrug azathioprine (AZA) are purine analogues that interfere with the synthesis of adenine and guanine ribonucleosides, precursors of DNA and RNA. They are classified as pregnancy FDA category D drugs. When taken orally, 47% of AZA is available to the systemic circulation, whereas only 16% of MP is available. These have been proven to be effective in the treatment of steroid-dependent or resistant IBD. These drugs are also used as immunosuppressive therapies in autoimmune diseases, transplant patients and in leukaemia.
The safety of azathioprine in pregnancy has been shown in studies in transplantation and rheumatology patients. The foetus lacks the enzyme inosinate phosphorylase that is necessary to convert AZA and MP to active metabolites, and therefore is protected from potential teratogenic effects of AZA and MP. Small doses of these medications do not appear to have adverse effects on human reproduction.[59, 60] In a retrospective study of patients who had received MP for IBD before or during conception compared with controls, there was no statistical difference in conception failure, abortion due to birth defect, major congenital malformations, neoplasia or increased infections (RR = 0.85 (0.47–1.55), P = 0.59).
In a recent prospective, controlled, multicenter study conducted by the Tel Aviv University (Israel), there was no increase in congenital malformation, but there was more prematurity (21% vs. 5%, P < 0.001) and low birth weight (23% vs. 6%, P < 0.001) in the AZA treated women.
A large Danish nationwide cohort study on women who were exposed to azathioprine or MP during pregnancy reported an overall increased risk of preterm birth, low birth weight at term babies and congenital anomalies among newborns of AZA or MP exposed women, but when the comparison was limited to women with same types of underlying disease, only the risk of induced preterm birth remained elevated (RR 4.0, 95% CI: 1.5–10.8). The conclusion of the authors was that the adverse effects may have been caused by the underlying disease rather than being drug induced.
However, in a study on 900 children born to women with CD between 1996 and 2004, the risk of preterm birth and congenital abnormalities in thiopurine exposed women were 4.2 (95% CI 1.4–12.5) and 2.9 (95% CI 0.9–8.9) respectively; these risks remained elevated even after adjusting for confounders. However, some challenged the findings of this study based on issues with confidence interval difference, lack of primary endpoint and bias of confounding by indication of drug therapy for disease activity.
A retrospective Swedish registry study that reviewed patients receiving azathioprine (AZA) during pregnancy (for IBD, autoimmune disorders, malignancy, organ transplantation) reported the rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98–2.04). Infants exposed to AZA were more likely to be preterm, weight <2500 gm, small for gestational age and had increased risk of congenital malformations (adjusted OR: 1.42; 95% CI: 0.93–2.18). Early pregnancy AZA exposure was associated with ventricular/atrial septal defects (adjusted OR: 3.18; 95% CI: 1.45–6.04). The authors make note that there may be an association between severity of disease and drug use which may influence the results.
Recently, in a study of 19 births exposed to AZA/MP and 74 controls, the use of AZA/MP was not associated with an increased risk of preterm birth, LBW at term, neonatal adverse outcomes or congenital anomalies. Also reporting similar findings, the results from 215 pregnancies in 204 women who were a cohort of the CESAME study in France was published. Three groups of women were compared – women exposed to thiopurines, women receiving other drugs and women not receiving any medication. The study showed that thiopurine use during pregnancy was not associated with increased risks of adverse outcomes (prematurity, birth weight, congenital abnormalities, death).
Based on most of the literature and all-observational studies, it appears that thiopurines are safe during pregnancy and should not be discontinued. The most recent ECCO consensus guidelines consider AZA to be safe and well tolerated in pregnant women. Although there are some cases of negative outcomes reported with the use of these medications, the majority of case series or cohort studies have not reported an increase in congenital anomalies. The American Gastroenterology Association recommends the continuation of AZA treatment during pregnancy. Stopping medication use during pregnancy may precipitate a flare resulting in adverse neonatal outcome. However, the risks and benefits of treatment must be carefully balanced by the patient in consultation with her doctor and partner.
Corticosteroids (FDA C)
Corticosteroids, including prednisone, prednisolone, dexamethasone and budesonide, are FDA class C drugs. They are often used to induce remission in CD and UC patients. They are given as oral or topical formulations and in severe cases via parenteral solution. Corticosteroids are not effective in maintenance therapy and are associated with side effects in almost 100% of patients who use them long term. The placenta contains the enzyme 11 beta hydroxysteroid dehydrogenase type 2 (11 beta – HSD2), which metabolizes cortisol and corticosterone to inert 11-keto forms (cortisone, 11-dehydrocorticosterone). This inactivates the maternal cortisol, so that the majority of cortisol in the foetal circulation is foetal adrenal cortisol.[72-75] However, dexamethasone is not inactivated by this placental enzyme, and as it passes the placenta freely, it should be avoided during conception and pregnancy. In a prospective study of 287 IBD pregnancies using corticosteroids and/or sulfasalazine vs. 244 pregnant IBD patients on no treatment, there were no increased incidences of prematurity, spontaneous abortion, stillbirth or developmental defects in pregnancies with corticosteroid use. Corticosteroids have been associated with oral cleft palate when used in the first trimester.[30, 77, 78] Recently, in a systematic review covering 17 studies in which pregnant women were treated with dexamethasone or betamethasone, nine of the 17 studies reported a reduction in birth weight (range 12–332 g), five of nine, a reduction of head circumference (range 0.31–1.02 cm) and two of four, a reduction in birth length (0.8 cm). The authors concluded that there is an association between in utero exposure to synthetic glucocorticoids and reduced birth size. A large Danish health registry data study did not find this association.
Budesonide has a pH and time-dependent coating that times its release into the ileum and ascending colon. It has extensive first-pass hepatic metabolism, and therefore acts locally with minimal systemic side effects. It has been shown to be effective for induction of remission and treatment of mild to moderate CD. A small study of eight patients with CD using 6–9 mg budesonide daily did not find any evidence of foetal abnormality.
Ciclosporin (FDA C)
Ciclosporin is a selective immunosuppressant that inhibits the activation of T cells, thus preventing formation of IL-2. It is often used in solid organ transplant (liver, kidney, heart). In IBD, it is sometimes used to induce remission in acute UC that is nonresponsive to conventional therapy and intravenous corticosteroids,[82, 83] and to delay surgery as well.
A meta-analysis of 15 studies of pregnancy in 410 transplant patients receiving CsA reported that the incidence of congenital malformations was 4.1%, which was similar to the general population. Pregnant transplant patients who are clinically stable on CsA have good pregnancy and foetal outcome.
Biologics: infliximab, adalimumab, etanercept, certolizumab (FDA B)
TNF-alpha is important in embryonic implantation, foetal development and labour.
TNF-alpha induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts, thus increasing the synthesis of prostaglandins (PGE2 and PGF2alpha), which promotes blastocyst implantation, endometrial vascular permeability and uterine deciduation. TNF-alpha may promote blastocyst implantation in early pregnancy, but it may also mediate recurrent spontaneous abortion at a later stage of gestation. Levels of TNF-alpha and TNFR-1 were found to be higher in women who had spontaneous early abortions. TNF-alpha production is low in the first trimester, and increases to reach a peak at the onset of labour. TNF-alpha appears to have a dual role in embryogenesis. Researchers have hypothesised that it may prevent the birth of offspring with structural anomalies by boosting death signalling if the foetus has been exposed to detrimental damages that will lead to structural anomalies, but trigger protective mechanisms if these damages can be repaired to prevent anomalies.
Crohn's disease and UC appear to be mediated by different aspects of the immune system. CD seems to be related to the over expression of T cell helper (Th) 1 cytokines, such as TNF-alpha, which stimulate cell-mediated immunity and result in transmural inflammation of the gut. On the other hand, UC is thought to be a result of dysregulation of intestinal immunity involving the Th2 cytokine response, although increased expression of TNF-alpha has been observed in patients with UC.
Anti-TNF agents have improved the management of IBD refractory to conventional treatment. It can be used for steroid-sparing therapy, in perianal disease, and maintenance of remission. In addition, it has been shown to result in mucosal healing, an important foundation of IBD treatment. Anti-TNF agents are classified as FDA B drugs because although animal studies have not shown risk to the foetus, there are no adequate and well-controlled studies of pregnant women.
Anti-TNF agents include infliximab, a chimeric monoclonal immunoglobulin G1 (IgG1) anti-TNF antibody, adalimumab, a human monoclonal IgG1 anti-TNF antibody and etanercept, a soluble TNF receptor fusion protein linked to the Fc portion of a human IgG1 antibody. These agents cross the placenta by the late second trimester and the third trimester. Certolizumab another anti-TNFα antibody, is a PEGylated Fab’ fragment of humanized anti-TNF-alpha monoclonal antibody rather than a whole human IgG1 antibody. A recent abstract on Certolizumab found low levels of the antibody in cord blood confirming placental transfer.[91, 92]
Although there are few studies regarding anti-TNF agents in pregnant IBD patients, these medications are used in autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and ankylosing spondylitis. Many studies on anti-TNF-alpha agents in pregnancy are on rheumatoid arthritis patients. These studies are retrospective, registry studies or case reports. In 2007, Roux et al. presented their experience with three rheumatoid arthritis patients who became pregnant while using anti-TNF-alpha therapy. One patient terminated her pregnancy although there was no known pregnancy or foetal complications, and the other two delivered healthy infants. Recently, the British Society for Rheumatology Biologics Register (BSRBR) reported a higher rate of spontaneous abortion among patients exposed to anti-TNF agents at the time of conception (with methotrexate/leflunamide 33% and without 24%) compared with 17% spontaneous abortions in those with prior exposure to anti-TNF agents, and 10% spontaneous abortions in the control group. They suggested that these drugs be avoided at the time on conception although no firm conclusions can be drawn about the safety of anti-TNF agents during pregnancy.
In the first large series of infliximab (IFX) use in 96 women with RA and CD, Katz et al. queried the infliximab safety database and found that results of pregnancy outcomes in women exposed directly to infliximab were similar to the general US population in terms of live births, miscarriages and therapeutic termination. In a series of intentional infliximab use during pregnancy in 10 CD patients, Mahadevan et al. showed good outcomes, with no congenital malformations, intrauterine growth retardation or small for gestational age infants. However, three infants were premature, and one had low birth weight. Other smaller case reports and case series of IFX use in pregnancy in IBD patients have also reported no congenital malformations, although infants were preterm or small for gestational age.[97-101]
A recent observational study assessed pregnancy outcomes in 212 women with IBD treated with anti-TNF treatments- 42 pregnancies in women who received anti-TNF (35 IFX, 7 ADA), 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX and 56 matched pregnancies in healthy women. They found that pregnancy outcomes after exposure to anti-TNF treatments were no different than before anti-TNF treatment, but were worse than before IBD diagnosis.
Both the recent review by the mother risk programme in Canada and the London position statement at the World Congress of Gastroenterology consensus guideline[102, 103] consider infliximab to have a low foetal risk and to be compatible with the use during conception in at least first and second trimester. Studies have not shown an increased risk of embryo toxicity, teratogenicity or adverse pregnancy outcome in patients treated with anti-TNF therapy.
However, the use of IFX up to week 30 of gestation results in foetal intra-uterine exposure to high IFX levels (up to three fold higher than in the maternal peripheral blood), which raises concern regarding long-term effects of IFX on the children of women with IBD on IFX. The authors recommended that such therapy be avoided after 30 weeks gestation when possible.
Particularly, caution should be taken when considering vaccination for the infants who were exposed to IFX. There is a case report of an infant who was exposed to IFX during gestation and then vaccinated with BCG vaccine at 3 months. This infant died of disseminated BCG.
Bisphosphonates (FDA C)
Bisphosphonates are used to treat and prevent osteoporosis due to corticosteroid use. Almost 50% of the bisphosphate binds to the skeleton and the remainder is excreted by the kidneys. The half-life of alendronate, one of the commonly used bisphosphonates, is >10 years, and the long-term effects on human bone development remain unknown. The drug may be slowly released from the maternal bone, and may cross the placenta, incorporating itself into the foetal bone during gestation. In animal studies, bisphosphonates cross the placenta, accumulate in the foetal skeleton, decrease foetal weight, decrease bone growth and resulted in protracted deliveries and neonatal deaths. In 2006, Ornoy et al. published a short report of the pregnancy outcome of 24 women on alendronate, 1–6 months before pregnancy (eight women) or before and during the first 3–8 weeks of pregnancy (15 women). They found significantly lower weight and gestational age at birth in these pregnancies compared with a control group. They also found a higher rate of spontaneous abortions (20.8%), but they reported no major anomalies in the children of the treated women, whereas 2.8% of the control children had major anomalies.
There have been multiple other small studies and case reports on the effect of bisphosphonate use prior to conception, and the literature shows that preconceptional bisphosphonate therapy does not seem to induce substantial foetal or maternal risks or serious adverse effects.
A recent multi-centre, prospective cohort study of 21 women exposed to Bisphosphonate (alendronate, etidronate, risedronate, pamidronate) during or <3 months before pregnancy and 21 matched-comparison group women without exposure to known teratogens, also did not find any statistically significant difference in spontaneous or therapeutic abortion, mean gestational age, mean birth weight or congenital anomalies. The risks and benefits of using bisphosphonates in women of childbearing age must be considered, and discussed with the patient and her partner.