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Keywords:

  • inflammatory bowel disease;
  • azathioprine;
  • mercaptopurine;
  • methotrexate;
  • infliximab;
  • adalimumab;
  • pregnancy;
  • breast-feeding

Abstract

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

The aim of this article is to critically review available data regarding the safety of immunomodulators and biological therapies during pregnancy and breast-feeding in women with inflammatory bowel disease. Methotrexate and thalidomide can cause congenital anomalies and are contraindicated during pregnancy (and breast-feeding). Although thiopurines have a Food and Drug Administration (FDA) rating D, available data suggest that these drugs are safe and well tolerated during pregnancy. Although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe in this scenario. Treatment with cyclosporine for steroid-refractory ulcerative colitis (UC) during pregnancy can be considered safe and effective, and the use of this drug should be considered in cases of severe UC as a means of avoiding urgent surgery. Breast-feeding is contraindicated for patients receiving cyclosporine. Biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Therefore, the limited clinical results available suggest that the benefits of infliximab and adalimumab in attaining response and maintaining remission in pregnant patients might outweigh the theoretical risks of drug exposure to the fetus. Stopping therapy in the third trimester may be considered, as it seems that transplacental transfer of infliximab is low prior to this. Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an antitumor necrosis factor alpha monoclonal antibody, and therefore it may not be necessary to stop certolizumab in the third trimester. The use of infliximab is probably compatible with breast-feeding. (Inflamm Bowel Dis 2009;)

The majority of patients with inflammatory bowel disease (IBD) are affected during their peak reproductive years.1–20 Consequently, many female patients affected by Crohn's disease (CD) and ulcerative colitis (UC) are interested in bearing children.1–20 One of the most frequently asked questions during consultation with those affected by IBD is what are its effects on pregnancy, and how will the treatment impact conception and pregnancy outcomes. Discussion and education about pregnancy is an essential component of the management of young women with IBD. This should allow informed decisions to be made before conception.1–20

In any woman with quiescent IBD at the time of conception, the likelihood of a flare-up of IBD during pregnancy or the puerperium is, in general, no greater than in any other year of her life.1–10 Although a diagnosis of either UC or CD does not by itself pose a risk to pregnancy, it has been shown that active disease or disease flare is associated with poor obstetrical outcomes, such as preterm delivery and low birth weight.1–20 Therefore, women with IBD can expect to have, in most cases, a normal pregnancy outcome provided they have inactive disease.1–14, 21 They may have, perhaps, an increased risk of having a small or premature baby, but this is a small risk.5, 6, 8, 22

As a result, effective control of disease activity is vitally important during pregnancy.1–20 In fact, it has been shown that the most important factor in the success of a pregnancy in patients with IBD is the state of disease activity. A flare of disease during pregnancy may be more deleterious to neonatal outcome than any potential risk from the medication.14 Therefore, the goal prior to and during pregnancy is to best optimize control of the disease through medical therapy.1–20

While initial concerns focus on attaining a durable remission and avoiding the side effects of medications, once in remission the focus often shifts to the effect of disease and the medications used to treat it on fertility and the ability to conceive a healthy child.23 The use of medications during the conception period and pregnancy is a cause of great concern for patients and the physicians caring for them.23 Most women's initial reaction is that they would not want to contemplate taking any sort of medication if they were planning conception or became pregnant. Therefore, an informed pre-pregnancy discussion, with the patient (and her partner if appropriate), facilitates a decision made in partnership with clinicians and the formulation of a management plan.5–8

Overall, the majority of medications used for the treatment of IBD are not associated with significant adverse effects. The United States Food and Drug Administration (FDA) classification of drugs offers a guide to the use of medications during pregnancy (Table 1).24 Table 2 summarizes the safety of IBD medications for pregnancy.

Table 1. Food and Drug Administration (FDA) Categories for the Use of Medications in Pregnancy24
FDA Pregnancy CategoryInterpretation
AControlled studies in animals and women have shown no risk in the first trimester, and possible fetal harm is remote
BEither 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
CNo controlled studies in humans have been performed, and animal studies have shown adverse events, or studies in humans and animals are not available; give if potential benefit outweighs the risk
DPositive evidence of fetal risk is available, but the benefits may outweigh the risk if lifethreatening or serious disease
XStudies in animals or humans show fetal abnormalities; drug contraindicated
Table 2. Medications Used in the Treatment of Inflammatory Bowel Disease (IBD)
DrugFDA Pregnancy CategoryRecommendations for Pregnancy
AdalimumabBLimited human data: low risk
Azathioprine/MercaptopurineDData in IBD, transplant literature suggest low risk
BalsalazideBLow risk
CorticosteroidsCLow risk; possible increased risk: cleft palate, adrenal insufficiency, premature rupture of membranes
CyclosporineCLow risk
InfliximabBLow risk
MesalamineBLow risk
MethotrexateXContraindicated: teratogenic
OlsalazineCLow risk
SulfasalazineBConsidered low risk; give folate 2 mg daily
TacrolimusCUse if mother's health mandates
ThalidomideXContraindicated: teratogenic

On the other hand, breast-feeding is not associated with an increased risk of disease flare and may even provide a protective effect against disease flare in the postpartum year.25 Breast-feeding is known to provide significant health benefits to infants, including the transmission of protective antibodies through breast milk.26

The commonly used drugs, in particular the aminosalicylates, appear to be safe and well tolerated in pregnancy.1–19 No evidence of teratogenicity has been demonstrated and the outcome of pregnancy has been shown to be similar to that in healthy women.1–20 Thus, all aminosalicylates (sulfasalazine, mesalamine, balsalazide) are pregnancy category B except olsalazine (which is pregnancy category C).14 Steroids are also probably safe and should be used for exacerbations of active disease.1–20 There has been no convincing evidence of teratogenesis despite reports of cleft lip and palate in the past.1–20 This small risk is often outweighed by the benefit of controlling the mother's IBD and, therefore, corticosteroids are considered pregnancy category C drugs.14

However, the use of other agents for treating IBD during pregnancy is more controversial. In particular, the recommendation on the use of immunomodulators (mainly azathioprine or mercaptopurine) has been controversial and, although thiopurine drugs have FDA rating D, available data suggest that they may be safe and well tolerated during pregnancy. The safety of biological therapies (mainly infliximab and adalimumab) has been scarcely studied and, although they are considered pregnancy category B by the FDA, this classification and their presumed safety is based on limited data.

The aim of the present article is to critically review available data regarding the safety of immunomodulators and biological therapies during pregnancy and breast-feeding in women with IBD.

SEARCH STRATEGY

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Bibliographical searches were performed in the MedLine electronic database up to August 2009 looking for the following words (all fields): (“inflammatory bowel disease” OR “Crohn's disease” OR “ulcerative colitis”) AND (pregnancy OR pregnant OR breastfeeding OR breast-feeding OR “congenital abnormality” OR “congenital anomaly”). Articles published in any language were included. Reference lists from the trials selected by electronic searching were handsearched to identify further relevant trials. Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria (that is, providing data regarding the safety of immunomodulators and biological therapies during pregnancy in women with IBD) were recorded. References of reviews on the treatment of IBD in pregnant women, and from the articles selected for the study, were also examined for articles meeting inclusion criteria. Where information regarding the use of a drug in IBD was limited, articles referring to its use for other indications were reviewed.

AZATHIOPRINE/MERCAPTOPURINE

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Mercaptopurine and its prodrug azathioprine are widely used to maintain remission in IBD, particularly in patients who are steroid-dependent.27, 28 Animal studies involving parenteral therapy with azathioprine or mercaptopurine have shown various teratogenic effects, including cleft lip, skeletal, urogenital, and central nervous system anomalies.29 However, in animal studies evaluating doses similar to those recommended in humans (2.5 mg/kg for azathioprine and 1.5 mg/kg for mercaptopurine), the only adverse outcomes reported were decreased fertility rates and low birth weights.30–33 On the other hand, thiopurine drugs have been shown to be teratogenic in mice and rabbits but not in rats. This variability in species sensitivity may be due to different metabolism of the drug, and reinforces the need to study the evidence in humans.34

Azathioprine crosses the placenta, but the immature fetal liver lacks the enzyme inosinate pyrophosphorylase needed to convert azathioprine to its active metabolite, mercaptopurine.2, 35 This feature may protect the fetus from toxic drug exposure during the crucial period of organogenesis.14, 23 Accordingly, human studies have not shown any consistent pattern of malformation.29 Furthermore, there has never been any clear demonstration of teratogenicity of these agents in humans, but because of a paucity of clinical data, many patients have been advised to discontinue azathioprine before pregnancy.5, 6 However, azathioprine withdrawal is associated with a high risk of relapse, whatever the duration of remission under this treatment.36, 37

First, studies where the safety of azathioprine or mercaptopurine during pregnancy in women without IBD has been evaluated will be briefly commented on. The largest evidence on safety comes from transplantation studies, where no evidence of recurrent patterns of congenital anomalies emerged.29 Data on drug use and births have also been obtained from Danish population registries.38 A nationwide cohort study examined the risk of adverse birth outcome among newborns in 76 pregnancies exposed to azathioprine or mercaptopurine in 69 women. Azathioprine- or mercaptopurine-exposed women had a higher risk of adverse birth outcomes than unexposed controls. However, when the comparison was limited to newborns of women with the same types of underlying disease, relative risks for spontaneous and induced preterm birth, low birth weight at term, and congenital abnormalities were 1.1 (95% confidence interval [CI], 0.5–2.4), 4.0 (95% CI, 1.5–10.8), 1.7 (95% CI, 0.3–8.7), and 1.1 (95% CI, 0.5–2.9), respectively. Therefore, it may be concluded that adverse birth outcomes may be caused by the underlying disease rather than by use of azathioprine or mercaptopurine. Goldstein et al39 reported on 189 women taking azathioprine compared with women from a control group. No difference in major malformations was observed, although the mean birth weight was lower and more cases of prematurity were observed in the azathioprine group. Unfortunately, disease activity was not reported and adequate disease-matched controls were not selected in this analysis.

Sporadic congenital anomalies have been observed in newborns of mothers who had taken thiopurines, but not in any characteristic pattern.2 The frequency of malformations in early series of renal transplant recipients requiring azathioprine during pregnancy was up to 9%,40 but the effects of high therapeutic doses, small sample size, other medical treatment, hypertension and renal dysfunction may have contributed. In contrast, several other transplant and nontransplant series have shown the frequency of malformations following exposure to azathioprine in pregnancy to be similar to the reported rate of 3.9% in the general population.2

Although only isolated cases of neonatal myelotoxicity and immunosuppression are reported,2 they are potentially serious. Lethal pancytopenia and severe combined immune deficiency, nonfatal lymphopenia, hypogammaglobulinemia, thymic hypoplasia, neonatal infections, and reversible neonatal immunosuppression have all been described.41–44

Studies where the safety of azathioprine or mercaptopurine during pregnancy in women with IBD has been evaluated will now be commented on in detail. They will be presented following their chronological order of publication.

Present et al,45 in 1989, reported on 13 children born to women with IBD who had been taking mercaptopurine, although only 3 of the patients had taken this drug at the time of conception. None of the children had congenital anomalies.

One year later, Alstead et al34 reported 16 pregnancies in 14 women, with the concurrent use of azathioprine (7 continued medication throughout gestation). There were 2 elective terminations and 2 premature births delivering healthy infants. All the other pregnancies were normal (there were no congenital abnormalities or subsequent health problems in the children).

One of the largest studies was performed by Francella et al,46 who compared 155 women with IBD who received mercaptopurine at conception or during the first trimester of pregnancy to a similar group of women with IBD who had conceived but not been exposed to this drug during the course of pregnancy. The authors did not find a significant increase of spontaneous abortions and major malformations (relative risk 0.85; 95% CI, 0.5–1.5). However, O'Connell47 noted in a comment letter that, in this retrospective study, only 15 female patients took mercaptopurine throughout the entire pregnancy (at doses ranging from 25 mg every other day to 175 mg daily), with 4 preterm deliveries and 1 spontaneous abortion. In the 10 full-term pregnancies, 2 children had major infections, 1 had a major congenital abnormality, and 1 had a minor abnormality. He therefore commented that the author's conclusion that “it is safe to stay on mercaptopurine throughout the entire pregnancy” is premature because of the wide variation in mercaptopurine administration and the extremely small sample size of the relevant subgroup.47 Updated data from this series noted a prematurity rate of 3% and congenital malformation rate of 5% in women who conceived while they were receiving mercaptopurine.48

Norgard et al49 reported 9 pregnancies (5 with CD, 1 with UC) exposed to azathioprine or mercaptopurine 30 days before conception or during the first trimester compared with 19,418 controls. Two cases of malformation were observed: 1 aphakia (azathioprine, mother with CD), and 1 case of multiple malformations (mercaptopurine, mother with autoimmune hepatitis). This indicates an increased risk of malformation in offspring of women using azathioprine or mercaptopurine (2/9 [22%] versus 711/19,418 [3.7%]). More women were smokers in the azathioprine than the control group (44 versus 26%) but, unfortunately, other potential confounding factors such as disease activity and concurrent use of other drugs could not be analyzed. The adjusted odds ratio for congenital malformations was 6.7 (95% CI, 1.4–32). However, when a single severely ill patient with autoimmune hepatitis and multiple other medications was removed from the cohort, the statistical significance was lost (odds ratio was then 3.4; 95% CI, 0.4–27).

Moskovitz et al50 conducted chart reviews of pregnancies from the Mount Sinai IBD database to investigate the effect of different drugs, including 101 patients treated with azathioprine/mercaptopurine, and none of the drugs used to treat IBD was associated with poor pregnancy outcome.

Norgard et al51 examined the risk of adverse birth outcomes in a nationwide Danish cohort of newborns of mothers with CD, according to type of drugs prescribed during pregnancy, and concluded that the risk of preterm birth and congenital abnormalities was greater when azathioprine/mercaptopurine was prescribed. Preterm births were more prevalent among thiopurine-exposed women (25%) compared to the reference group (6.5%). Congenital abnormalities were also more prevalent among azathioprine/mercaptopurine-exposed women (15.4 versus 5.7%, adjusted relative risk, 2.9; 95% CI, 0.9–8.9). Among thiopurine-exposed women, the risk of preterm birth was also increased to 4.2 (95% CI, 1.4–12.5) compared to the control group. However, several relevant limitations of this study should be taken into account. After careful review of the article, it has been suggested that the data do not appear to support their conclusions.52 First, in the abstract the authors reported differences in the prevalence of congenital abnormalities and prematurity between fetuses exposed to thiopurines compared with those who were not. Only after examining the 95% CIs was it apparent that the difference seen in congenital abnormalities was not statistically significant.52 Second, the article by Norgard et al may suffer from the bias of confounding by indication.52 Thus, as previously mentioned, it is known that greater disease activity is associated with a risk of premature delivery. As thiopurines are more likely to be prescribed for patients with more severe disease, the use of these medications could be expected to be a proxy for disease activity. Therefore, as has been pointed out, even if no true medication effect existed, one might expect to see an increased rate of prematurity in the treated patients.52 In this respect, the measures of disease activity used in this study were not very precise due to the nature of these databases (the authors defined active disease as a hospital admission of ≥2 days' duration; as has been suggested, it would indeed have been better and more precisely measured by review of outpatient charts).16 Only a prospective pregnancy IBD cohort will definitively differentiate between the effects of disease activity and medication use on adverse pregnancy outcome.

In a very recent publication, the Swedish Medical Birth Register was used to identify 476 women who reported the use of azathioprine in early pregnancy.53 The most common indication for azathioprine use was IBD (300 patients, being the largest published study of pregnancy outcomes after azathioprine exposure). The rate of congenital malformations was 6.2% in the azathioprine group and 4.7% among all infants born (adjusted odds ratio: 1.41; 95% CI, 0.98–2.04). Specifically, an association between azathioprine exposure and ventricular/atrial septal defects was found. Exposed infants were also more likely to be preterm, to weigh <2500 g, and to be small for gestational age. However, as the authors point out, these associations may be confounded by the severity of maternal illness.

With respect to breast-feeding, it is not recommended by the manufacturers of azathioprine or mercaptopurine. Traditionally, women receiving azathioprine have been discouraged from breast-feeding because of theoretical potential risks of neonatal bone marrow suppression, susceptibility to infection, and pancreatitis.14, 23, 54

A case series of 4 mothers who remained on azathioprine throughout lactation was recently published.55 The investigators analyzed the mother's breast milk on several occasions and found undetectable levels of mercaptopurine in all samples. They also noted no adverse events in the infants, and therefore concluded that azathioprine likely poses no threat to the suckling infant.55

Some authors have determined infant exposure to 6-thioguanine and 6-methylmercaptopurine nucleotides during maternal use of azathioprine in breast-feeding in 4 women (all had the wildtype TPMT genotype).56 Neither 6-thioguanine nor 6-methylmercaptopurine was detected in any of the infants. These data suggest that azathioprine may be safe during breast-feeding, at least in patients with the wildtype TPMT genotype (which is the case of ≈90% of Caucasian patients).

Some authors have measured the concentration of mercaptopurine in breast milk of 10 mothers receiving azathioprine and in the blood of their babies, and have investigated any immunosuppressive effects on the babies.57 Very low concentrations of mercaptopurine (compared with therapeutic immunosuppressant level achieved in serum) were detected in 2 breast milk samples obtained from 1 woman, while mercaptopurine was not detected in any of the other 29 samples. Mercaptopurine and 6-thioguanine nucleotides were undetectable in the neonatal blood. Furthermore, there were no clinical or hematological signs of immunosuppression in any of the 10 neonates. Therefore, the authors concluded that breast-feeding should not be withheld in infants of mothers receiving azathioprine.

Finally, 8 lactating women—all of them with IBD—receiving maintenance therapy with azathioprine were studied.58 The authors showed that the major part of mercaptopurine was excreted in breast milk within the first 4 hours after drug intake and the estimated maximum exposure of drug to the infant was <0.008 mg mercaptopurine/kg/day, representing <1% of the maternal dose. These findings indicate that breast-feeding during treatment with azathioprine generally seems safe and led the authors to conclude that breast-feeding should be recommended considering the otherwise beneficial effects (in fact, it seems quite plausible that breast-feeding would have a protective effect on the development of IBD59–61).

In summary, based on the large experience in transplantation patients, azathioprine and mercaptopurine are often continued during pregnancy. Furthermore, in IBD multiple case series or cohort studies have not demonstrated an increase in congenital anomalies. Thus, although thiopurines have FDA rating D (indicating “positive evidence of fetal risk is available, but the benefits may outweigh the risk if life-threatening or serious disease”), available data suggest that these drugs are safe and well tolerated during pregnancy. Therefore, in general, if a patient is established and well on azathioprine or mercaptopurine and it is felt to be essential to continue this drug to retain remission (which will be the case in most patients), after full discussion with the patient and her partner it is reasonable to decide to continue treatment during pregnancy.5, 6, 8 It should be remembered that there are few alternatives to azathioprine/mercaptopurine in controlling steroid-dependent or -resistant IBD. What remains for the patient, the gastroenterologist, and the obstetrician is to balance the importance of remaining in remission with the probably small risk of these drugs.62 For the pregnant IBD patient and her fetus, the known benefits of therapy with a thiopurine often outweigh the “hypothetical” risks. Moreover, patients should not stop their medication before conception. Indeed, a recent study suggests that the discontinuation of mercaptopurine before conception may actually increase the chance of fetal loss.63 It has been advised in the past to decrease the dose of azathioprine, with the hypothetical objective of reduce the probability of fetal adverse effects. However, a reduced incidence of complications due to this dose reduction has never been demonstrated. On the contrary, reduced azathioprine doses may be subtherapeutic,27 and the subsequent disease flare may be associated with poor obstetrical outcomes. However, in view of the complications which may arise at the start of treatment with these agents (such as pancreatitis or leukopenia), it is perhaps not advisable to commence treatment for the first time during pregnancy.5, 6, 8 Finally, although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe during breast-feeding.

METHOTREXATE

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Methotrexate is FDA category X, as it is clearly teratogenic, and therefore should not be used in women considering conception. Methotrexate is a folic acid antagonist and use during the critical period of organogenesis (6 to 8 weeks postconception) is associated with multiple congenital anomalies collectively called methotrexate embryopathy or the fetal aminopterin-methotrexate syndrome.14, 23 On the other hand, exposure in the second and third trimesters may be associated with fetal toxicity and mortality.14, 23 Consequently, as previously mentioned, methotrexate is absolutely contraindicated during pregnancy. It is imperative that women receiving methotrexate therapy for IBD be counseled on the importance of effective birth control with 1 or, better, 2 methods of contraception.15 Methotrexate may persist in tissues for long periods64 and it is suggested that patients wait at least 3–6 months from discontinuation of the drug prior to attempting conception.14, 23

Methotrexate is excreted in breast milk and may accumulate in neonatal tissues.65 Therefore, it is contraindicated in breast-feeding.54

CYCLOSPORINE

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Severe attacks of UC refractory to corticosteroids during pregnancy represent a clinical challenge. Cyclosporine is an alternative to colectomy in patients with severe UC.66, 67 In the setting of severe steroid-refractory UC, cyclosporine may be a better option than colectomy, which is associated with a high rate of fetal mortality.14, 68 Specifically, there is significant morbidity and mortality associated with colectomy during the third trimester of pregnancy.15

Cyclosporine is known to cross the placenta in high quantities but is rapidly cleared from the newborn and has not been shown to be teratogenic in animal models.69, 70 Cyclosporine is neither teratogenic, mutagenic, or myelotoxic in animals.40, 71

The data on the safety of cyclosporine during pregnancy in humans are primarily derived from transplant recipients. One large series evaluated 154 pregnancies in 115 renal transplant recipients treated with cyclosporine in addition to other immunosuppressive agents, and no malformations were seen.72 A 2005 update of the National Transplantation Pregnancy Registry has also failed to demonstrate any pattern of congenital abnormality associated with the use of cyclosporine.73 Finally, in a meta-analysis including 15 transplantation studies, 410 pregnancies were reported, and cyclosporine did not appear to increase the malformation frequency.74 Also, no increase in the rate of prematurity or of low birth weight was found. Accordingly, cyclosporine is pregnancy FDA category C.

The first case report of cyclosporine use in IBD included a refractory UC patient during the third trimester of pregnancy; 4 mg/kg for 10 days were administered, and a good obstetrical outcome with no malformations was reported.75 Successful fetal outcomes have been reported in 2 further cases using an intravenous dose of 2 mg/kg for 2 weeks76 and 3 weeks.77 Moskovitz et al50 conducted chart reviews of pregnancies from the Mount Sinai IBD database to investigate the effect of different drugs, including 2 patients treated with cyclosporine, and no congenital abnormalities were observed. More recently, cyclosporine treatment was prescribed for 2 cases of steroid-refractory UC during pregnancy78; remission was achieved, and the drug was considered safe when used at lower dosage, aiming for blood levels of 200 ng/mL. In another study, data regarding birth outcomes were available for 3 patients79; 2 had low birth weight infants, 1 of whom had a preterm birth at 26 weeks, and the remaining patient had a spontaneous abortion at 15 weeks.

Finally, in the largest series of patients with severe UC treated with cyclosporine during pregnancy, Branche et al80 identified 8 patients. Treatment was effective in 7 of them, no colectomy was performed during pregnancy, and 7 pregnancies were conducted to term; 2 newborns were premature, including 1 case of hypotrophy, and no malformations were observed. Furthermore, no maternal side effects due to cyclosporine therapy were observed in this study. Cyclosporine dose reduction from 4 to 2 mg/kg/day decreases the frequency of side effects,81 and as only 1 patient received the 4 mg/kg/day initial dose in these series, this can explain the absence of toxicity observed in that study.80

The characteristics of the 19 IBD patients treated up to now with cyclosporine during pregnancy are summarized in Table 3. As can be observed, this drug was highly effective to avoid colectomy, while no malformations were reported.

Table 3. Characteristics of IBD Patients Treated with Cyclosporine (CYA) During Pregnancy (Modified from Branche et al80)
AuthorAgeTerm of PregnancyIV CYA (Days)Oral CYAClinical ResponseTerm of Delivery (WG)Birth Weight (g)MalformationsColectomy
  • WG, weeks of gestation; C, cesarean section; V, vaginal delivery; NA, information not available.

  • a

    At week 15.

  • b

    Postdelivery.

  • c

    At week 22.

Bertschinger et al75232710YesYes34-C2070NoNo
Jayaprakash et al76361215YesYes32-C2070NoNo
Angelberger et al77211521YesYes29-C893NoYesb
Reindl et al7831NA7YesYes36-VNANoNo
341521YesYes29-CNANoNo
Reddy et al7929248NAYes261080NANA
25255NAYes391968NANA
30153NAYesAbortionaNo
27149NAYesNANANANA
2988NAYesNANANANA
Branche et al8038277YesYes32-V1820NoYesb
3265YesYes372600NoYesb
29155YesYes363000NoNo
28147NoYes33-V3340NoNo
30107YesYesFetal deathcNANoNo
251317NoNo35-C3160NoNo
31249YesYes37-V2710NoNo
32100YesYes37-V2920NoNo

Infliximab could constitute an alternative to cyclosporine in severe steroid-refractory attacks of UC. However, in the Jarnerot et al82 experience, infliximab appeared less effective in patients with “fulminant” UC than in moderately severe patients. In contrast to cyclosporine, no data are available regarding the use of infliximab in severe attacks of UC during pregnancy.

As hypertension is a common side effect of cyclosporine therapy and seizures have also been reported, the side effect profile of this drug would suggest that it should be used with extreme caution, especially if started in late pregnancy.5, 6, 8 Cyclosporine would therefore appear to be undesirable in most circumstances except the avoidance of urgent colectomy in a patient with fulminant UC.5, 6, 8

With respect to breast-feeding, although no untoward effect occurred within 2 years in an infant who was breast-fed for 14 months by a woman treated with cyclosporin,83 the drug is not advised in nursing mothers because high quantities of cyclosporine are excreted in the breast milk and the potential nephrotoxicity and immunosuppression.54, 84

In summary, treatment with cyclosporine for steroid-refractory UC during pregnancy can be considered safe and effective. Therefore, use of cyclosporine should be considered in cases of severe UC as a means of avoiding urgent surgery and reaching a gestational age when the fetus can be safely delivered. The length of delay in surgery needed to significantly improve the neonate's chance of survival should be included in any consideration about using the drug. For instance, at 36 weeks of gestation a neonate's chance of survival is high, while at 24 weeks a 1-month delay might prove invaluable.1 Finally, breast-feeding is essentially contraindicated for patients receiving cyclosporine.

TACROLIMUS

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Tacrolimus is a fungus-derived calcineurin inhibitor initially licensed for maintenance of organ transplants and, more recently, prescribed in some refractory cases with IBD.85 The transplant literature to date has been favorable for the use of tacrolimus during pregnancy, but has shown a tendency toward premature delivery, and a small increase in fetal malformations with no consistent pattern.86 Consequently, tacrolimus is pregnancy FDA category C. The largest series was published by Kainz et al,86 in which 100 pregnancies were reported in 84 mothers, and most of them resulted in favorable outcomes. One case report documents the use of tacrolimus in a steroid nonresponding UC patient who could not tolerate azathioprine. Tacrolimus was used as a single agent before, during, and after pregnancy with no ill-effects on the pregnancy, delivery, or newborn.87

Tacrolimus enters the breast milk and it is unknown what effects it might have on a suckling infant, thus it is currently noncompatible with breast-feeding.14, 15, 23, 84

THALIDOMIDE

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Thalidomide has some antitumor necrosis factor-α (TNF-α) effects and has been used successfully for the treatment of some patients with CD.88 Its teratogenicity has been extensively documented and includes limb defects, central nervous system effects, and abnormalities of the respiratory, cardiovascular, gastrointestinal, and genitourinary system.14, 23 Therefore, thalidomide is absolutely contraindicated during pregnancy and is considered pregnancy category X. Furthermore, women receiving thalidomide should be encouraged to use 2 different types of birth control.14, 15, 23 There are no human data on breast-feeding but it is not advised given the potential toxicity.14, 23

INFLIXIMAB

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Infliximab has proved to be effective for the management of CD89 and UC.90, 91 Other drugs that inhibit TNF-α have been linked to congenital anomalies, the most notable being thalidomide. However, embryo-fetal perinatal developmental toxicity studies performed in cynomolgus monkeys using doses several hundred times the recommended human dose of anti-TNF-α have revealed no evidence of teratogenic or other deleterious effect.92 Since infliximab does not crossreact with TNF-α in species other than humans and chimpanzees, animal reproduction studies have not been conducted with this drug. In spite of these obvious limitations, the 3 TNF-α antagonists are rated category B by the FDA (indicating that “animal studies have not demonstrated a fetal risk”), meaning they are presumed to be safe based on animal studies.

Early on in the history of anti-TNF-α therapy, several case reports appeared describing poor obstetrical outcomes, including a severely premature infant with intracerebral and intrapulmonary hemorrhage who died 3 days after birth.93 However, it should be taken into account that the mother receiving infliximab had active disease throughout, and was also on azathioprine, metronidazole, and mesalamine.93 However, thereafter larger longitudinal studies have not shown similar negative results, and a growing body of evidence suggests that infliximab is low risk in pregnancy.23

Interestingly, increased TNF-α has been associated with infertility, and TNF-α blockade is being investigated as a potential therapy for this condition. The idea that anti-TNF-α agents might be useful in pregnancy failure patients derived from basic science studies showing these drugs could have proreproductive effects, and a hypothesis was generated that TNF-α blockers should work in the subset of women with reproductive failure who have high Th1/Th2 cytokine ratios.94

First, studies where the safety of infliximab during pregnancy in women without IBD has been evaluated will be briefly commented on. The British Society for Rheumatology Biologics Register (BSRBR) is systematically collecting information on patients receiving anti-TNF-α therapies for rheumatic diseases.95 This register has collected data on 23 women exposed to anti-TNF-α therapy at the time of conception (etanercept in 17, infliximab in 3, and adalimumab in 3). All but 2 of these patients discontinued their therapy during the first trimester. There was a high spontaneous miscarriage rate, and 14 live births, the latter without any “major fetal abnormalities.”

A review of the FDA database of reported adverse events with etanercept, infliximab, and adalimumab from 1999 through 2005 was recently performed.96 The review of >120,000 adverse events revealed a total of 61 congenital anomalies in 41 children born to mothers taking an anti-TNF-α therapies. Of these mothers, 19 took infliximab. Fifty-nine percent of the children had 1 or more congenital anomalies that are part of vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limp abnormalities (VACTERL) association. Therefore, the authors concluded that a seemingly high number of congenital anomalies that are part of the VACTERL spectrum have been reported.

Studies where the safety of infliximab during pregnancy in women with IBD has been evaluated will now be commented on in detail. The characteristics of the 151 reported IBD patients treated with infliximab during pregnancy are summarized in Table 4. This table has been modified from O'Donnell and O'Morain, who in a recent review article evaluated the use of anti-TNF-α therapy in IBD during pregnancy and conception.97

Table 4. Characteristics of IBD Patients Treated with Infliximab During Pregnancy (Modified from O'Donnell and O'Morain97)
Author# PatientsDiseaseTrimesterLive BirthsComplicationsSpontaneous AbortionElective Abortion
  1. CD, Crohn's disease; UC, ulcerative colitis; RA, rheumatoid arthritis; C, within 3 months prior to conception; T1, first trimester; T2, second trimester; T3, third trimester.

Lichtenstein et al98 (TREAT Registry)36CDAny exposure8%11%
Katz et al99 (Infliximab Safety Database)9682 CD25-C681 preterm death, 4 fetal complications1418
1 UC28-C & T1
10 RA30-T1
7>3 months prior to conception
Mahadevan et al10010CD8-C, T1, T2, T3103 preterm0
1-C, T1
1-T3
Burt et al1021CDC, T11000
Srinivasan et al931CDC, T111 preterm 23 wk died at 3 days intracerebral bleed00
Stengel et al1011CDC, T1, T2, T31000
Tursi et al1121CDC, T1, T2, T31000
Vasiliauskas et al1041CDC, T1, T2, T31000
Kane et al1113CD2-C, T1, T2, T33000
1-T1, T2, T3
Angelucci et al1031CDT11000

The 2 largest studies in the IBD population are from the TREAT (Crohn's Therapy, Resource, Evaluation, and Assessment Tool) registry98 and the Infliximab Safety Database.99 The TREAT registry98 is a prospective registry of patients with CD. Of the 5807 patients enrolled, 66 pregnancies were reported, 36 of them with prior infliximab exposure. Fetal malformations did not occur in any of the pregnancies. Rates of miscarriage and neonatal complications were not significantly different between infliximab-treated and infliximab-naïve patients (11.1% versus 7.1%, and 8.3% versus 7.1%).

The Infliximab Safety Database99 is a retrospective data collection instrument set up by the manufacturers of infliximab (Centocor), of voluntary reports of adverse events associated with infliximab. Data were extracted from this infliximab postmarketing surveillance database regarding exposure to infliximab before or during pregnancy in women with rheumatoid arthritis or CD. Pregnancy outcome data are available for 96 women with direct exposure to infliximab. The 96 pregnancies resulted in 100 births. The expected versus observed outcomes among women exposed to infliximab were not different from those of the general population (and in patients with CD not on immunosuppressive agents).

In a series of 10 women with intentionally maintenance infliximab use throughout pregnancy, all pregnancies ended in live births, with no congenital malformations at mean follow-up of 6 months.100 There were 3 preterm infants and 2 neonatal illnesses, which were not felt to be secondary to the infliximab. This was the first study on the intentional use of infliximab during pregnancy for induction and maintenance of remission in CD, as all previous reports were on inadvertent exposure or rescue therapy in severely ill patients.97 This study suggests that the benefits of infliximab in achieving response and maintaining remission in mothers with CD may outweigh the risk to the fetus of exposure to the drug.

Stengel and Arnold101 reported a case of a pregnant patient with IBD who underwent treatment with infliximab during her pregnancy and while nursing her infant (the patient decided to attempt to begin breast-feeding and to continue treatment with infliximab), and no developmental abnormalities were noted in the child. Burt et al102 reported a successful pregnancy that had resulted from intercourse 3 days prior to infliximab infusion. Angelucci et al103 reported the case of a woman who inadvertently received infliximab for the treatment of CD within 3 months of conception. Three weeks after the second infliximab infusion, the patient was found to be pregnant in the sixth gestational week, and she decided to stop infliximab therapy. After 3 years of follow-up from the last infliximab infusion, CD was in clinical remission, and both mother and child had no medical problems.

Although large molecules like infliximab do not cross the placenta during the early stages of pregnancy, it has recently been shown that there are detectable levels present in fetal serum at birth, indicating that there may be diffusion across the placenta in the third trimester.104, 105 Thus, it is generally believed that the chimeric structure of the infliximab molecule containing a human immunoglobulin G1 (IgG1) constant region limits placental transfer during the first trimester.106 However, the safety of infliximab beyond the first trimester is unknown because IgG subclasses are readily passed into the fetus during the second and third trimesters.100 These findings suggest that pregnant patients should avoid therapeutic antibody treatments after 30 weeks' gestation, and if necessary the expectant mother can be bridged with steroids to control the disease activity until delivery.105, 107, 108 Anti-TNF-α can be safely restarted after delivery. Despite these recommendations, a French national survey on TNF-α antagonists use in IBD has been recently conducted and has demonstrated that, in case of pregnancy during anti-TNF-α treatment, only 35% of physicians discontinued therapy at the time of conception and did not administer anti-TNF-α therapy during pregnancy.109

A recent case report104 noted high infliximab levels in an infant born to a mother on infliximab therapy (at a dose of 10 mg/kg, higher than the usually recommended dose of 5 mg/kg) every 4 weeks. The mother continued to receive infliximab (the last infusion was 2 weeks before delivery) but the infant's infliximab level slowly dropped over 6 months. The effect of the high infliximab levels on the infant's developing immune system is not known, although at 7 months the infant had normal T and B cell development and appropriate response to vaccination. Therefore, infants might receive routine vaccinations, with the exception of those exposed to anti-TNF-α in utero, in whom live virus vaccines (rotavirus) should be avoided for the first 6 months unless infliximab levels have been documented to be absent.

With respect to breast-feeding, the implications are unknown and it has been recommended that it is probably best avoided while receiving infliximab. However, theoretically, breast-feeding should be safe during infliximab therapy, as large protein molecules such as infliximab are broken down or inactivated by digestive enzymes in the gastrointestinal tract.15 Three case reports have shown that levels of infliximab in breast milk are consistently less than detectable limits.105, 110 Furthermore, case reports of women who breast-fed while on infliximab do not suggest toxicity,100, 104 and therefore the use of this drug is probably compatible with breast-feeding.23

The objective of a recent study was to determine whether infliximab is transferred in utero or through breast milk from nursing CD patients to their newborns.111 Three patients diagnosed with CD that had a history of infliximab use during and after pregnancy were followed prospectively. Patients received 5 mg/kg infliximab at regular intervals until approximately gestational week 30, and resumed infliximab treatment within 3 to 14 days after giving birth. Infliximab was detected in the mothers' sera, but not in the breast milk of nursing mothers or in the sera of the breast-fed newborns. Data from this small series of patients suggest that infliximab was not transferred from mother to child, either in utero or through breast milk. These data suggest that mothers receiving infliximab should not be discouraged from nursing their children (if abstained from infusions after week 32 of pregnancy).

In summary, there is a growing body of evidence that suggests that infliximab is low risk in pregnancy. Although it is difficult to prove absolute safety, the reviewed data suggest that women who inadvertently become pregnant while taking anti-TNF-α agents can be reassured that continuation of pregnancy does not appear to hold any increased risk to either themselves or their baby. The limited clinical results available suggest that the benefits of infliximab in attaining response and maintaining remission in pregnant IBD patients might outweigh the (theoretical) risks of drug exposure to the fetus.112 However, physicians should be aware that the fetus may be exposed to therapeutic monoclonal antibodies when administered to pregnant patients and the long-term implications on the child's developing immune system are unknown at this time. Therefore, use of infliximab during pregnancy should probably be limited to cases in which uncontrolled activity of intestinal disease could expose both mother and child to risks greater than those only potentially coming from the use of biologic therapies; if prescribed, stopping infliximab therapy in the third trimester should be considered to minimize placental transfer, unless the patient is having active disease. The use of infliximab is probably compatible with breast-feeding, although more experience is necessary.

ADALIMUMAB

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Adalimumab has proved to be effective for the management of CD.113 In animals, it appears that adalimumab does not increase obstetrical risk or have teratogenic effects.114 Accordingly, adalimumab is, like infliximab, pregnancy category B.

TNF-α has been hypothesized to be important in causing fetal loss.115 The use of adalimumab and intravenous immunoglobulin significantly improves in vitro fertilization outcome in young infertile women with Th1/Th2 cytokine elevation.116 Accordingly, in women with recurrent spontaneous abortion, addition of intravenous immunoglobulin plus adalimumab appears to improve live birth rates.117

There are existing data regarding anti-TNF-α agents and pregnancy in patients with other diseases different from IBD. OTIS is a collaborative research group prospectively following women exposed to TNF-α antagonists during pregnancy. To date, they have published data on 44 women exposed to etanercept or adalimumab during their first trimester, and there have been 6 congenital anomalies in 5 children.96 In the adalimumab registry, specifically, 21.6% of the women experienced spontaneous abortions versus 6.4% in the disease control group.96 In a group of 442 patients treated with anti-TNF-α, 1 woman with rheumatoid arthritis exposed to adalimumab unexpectedly became pregnant, and she delivered healthy infants.118 The objective of a very recent study was to report on the outcome of 15 cases of pregnancies in women treated with anti-TNF-α drugs during conception or pregnancy.119 French rheumatologists were asked to fill in a structured questionnaire reporting the outcome of pregnancy in women still treated by a TNF-α blocker at the time of conception. Three rheumatologic patients were treated with infliximab and 2 with adalimumab, and no developmental abnormalities were noted in the children.

Human data on adalimumab use during pregnancy in IBD patients are lacking, and only case reports exist in the IBD literature to date.15 A case report documented a successful pregnancy in a woman with longstanding CD who began adalimumab 1 month prior to conception and received a total of 38 doses every week during her pregnancy.120 There were no complications and the baby was well at 6-month follow-up. A second case is that of a 35-year-old woman with CD who had had a previous subtotal colectomy with ileorectal anastomosis and had lost response to infliximab.121 She had commenced adalimumab 80 mg as a loading dose and then received 40 mg every other week. Seven months later she became pregnant and she had a normal full-term vaginal delivery. The baby was well at 6-month follow-up. In a third case report, adalimumab was used to successfully treat active CD of an ileoanal pouch in a 34-year-old woman during pregnancy.122 She presented at 6 weeks gestation with an acute flare up. At 20 weeks gestation she was commenced on azathioprine and adalimumab. She responded well and the steroids were gradually tapered. She gave birth to a healthy baby at 38 weeks, and both were well at 1-year follow-up.

In contrast to infliximab, information on the diffusion of adalimumab across the placenta depending on the first, second, or third trimester is lacking. Furthermore, establishing recommendations about the time where adalimumab should be stopped during pregnancy is more difficult, given the shorter dosing interval and the fact that adalimumab levels cannot be commercially measured. Some authors have recommended to discontinue adalimumab 6–8 weeks before the estimated date of confinement,108 but this strategy has not been properly tested.

There is no information on the safety of adalimumab administration during breast-feeding, and therefore recommendations cannot be established.

In summary, reported pregnancies in patients exposed to adalimumab have resulted in healthy term deliveries with no malformations, which suggests that adalimumab, like infliximab, is low risk in pregnancy.

CERTOLIZUMAB

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Certolizumab has proved to be effective for the management of CD.123, 124 As certolizumab is a relatively new agent, there are no published data regarding its use in pregnancy. Oussalah et al125 reported (in abstract form) the case of a 22-year-old woman with a 4-year history of colonic CD who was successfully treated with certolizumab during the first and third trimesters, and she delivered a normal infant.

Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an anti-TNF-α monoclonal antibody rather than a whole human IgG1 antibody. Whole IgG antibodies cross the placenta via specific neonatal receptors (FcRns).106 Consistently, much higher drug levels were observed in fetal samples from pregnant rats with murinized IgG1 compared with PEGylated Fab versions of hamster antimurine TNF-α antibody.126 Accordingly, some authors have recommended limiting infliximab/adalimumab dosing in the third trimester, but continuing certolizumab on schedule through delivery.108 This could be an advantage to the use of certolizumab in pregnant woman over other biological therapies (such as infliximab or adalimumab) if this lack of placental transfer is also demonstrated in humans. Nevertheless, although active placental transport of certolizumab via Fc receptors should not occur, low levels of diffusion might theoretically occur via alternate mechanisms in all 3 trimesters.

LIMITATIONS OF STUDIES DURING PREGNANCY

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

Unfortunately, the conclusions of most aforementioned studies have to be considered with caution for several reasons:

  • 1)
    The lack of data in human trials. Although animal reproduction studies have been performed in some cases, animal studies are not always predictive of human response. In other words, safety in animal models does not ensure safety in humans because of species specificity. This variability in species sensitivity may be due to different metabolism of the drug, and reinforces the need to study the evidence in humans.
  • 2)
    The lack of data specifically in IBD patients. Most of the studies reporting the use of immunosuppressive drugs in pregnancy have been performed in the transplantation population. Obviously the posttransplant setting has considerable differences in immunology and in polypharmacy to that of IBD, and the evidence suggests that this worrying picture may not translate to a different setting.1
  • 3)
    The observational and retrospective nature of data collection. For ethical reasons, randomized trials cannot be designed to evaluate the safety of these drugs during pregnancy. Therefore, we have to base clinical decisions on evidence from observational studies that are often vulnerable to bias and confounding. As with any voluntary postmarketing adverse event reporting database, there is reporter bias: on the one hand, to better assess the risk associated with anti-TNF-α exposition during conception and pregnancies, all cases of new pregnancies occurring in women treated by anti-TNF-α drugs should be declared and/or reported; on the other hand, adverse events are likely to be reported, whereas pregnant women exposed to TNF-α antagonists without adverse events will probably not report this.
  • 4)
    The small sample size. There are few controlled trials that include pregnant patients and even fewer that are specifically designed to study this patient population. Almost all controlled trials with new agents excluded pregnancy. Therefore, in most cases the data must be obtained from postmarketing experience.
  • 5)
    The lack of a truly normal (nontreated) control group. For example, it should be remembered that congenital anomalies are present in 3%–5% of all live births in the general population. Furthermore, it has been estimated that in the general population 10%–12% of pregnancies terminate in clinically recognized spontaneous abortions during the first trimester.127
  • 6)
    The lack of information regarding disease activity, comorbidities, and concomitant medications. In some cases it is not clear whether the fetal effects are due to medication or the severity of the underlying illness. Furthermore, most studies looking at the effects of any 1 medication on pregnancy in IBD are confounded by the fact that most patients with comorbidities are on multiple medications.

CONCLUSION

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES

For patients with IBD, disease activity at the time of conception or during the course of pregnancy can be associated with a higher risk of low birth weight, premature infants, and spontaneous abortions. A key principle of management is that active disease, not therapy, poses the greatest risk to pregnancy.5, 6, 8–15, 18–20 Therefore, all women with IBD who become pregnant should be carefully monitored and aggressive control of disease activity prior to and during pregnancy is critical to optimize both maternal and fetal health. It is advisable that patients be in remission when considering pregnancy, and for the majority, this requires continuing their medications.14

The management of IBD in pregnancy is a partnership between patient and clinician and, as part of this, full discussion and planning before conception are required.5, 6 Very few drugs are licensed for use in pregnancy, and the continuance of maintenance treatment needs to be discussed in full with the patient and possibly her partner before conception.5, 6

For a drug to clearly be associated with congenital anomalies, the same defect must be seen repeatedly, a phenomenon not demonstrated with any IBD medication except methotrexate and thalidomide, both of which are contraindicated during pregnancy (and breast-feeding).23 Therefore, most medications used for the therapy of IBD are compatible with pregnancy. Nevertheless, it is most prudent to err on the side of caution when dealing with pregnancy and potentially teratogenic drugs.

Although thiopurines have FDA rating D, available data (mainly based on the large experience in transplantation patients) suggest that these drugs are safe and well tolerated during pregnancy. Although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe in this scenario.

Treatment with cyclosporine for steroid-refractory UC during pregnancy can be considered safe and effective, and the use of this drug should be considered in cases of severe UC as a means of avoiding urgent surgery. Breast-feeding is contraindicated for patients receiving cyclosporine.

The true short- and long-term implications of exposure to TNF-α blockers during the newborn period are as yet unknown. However, biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Therefore, the limited clinical results available suggest that the benefits of infliximab and adalimumab in attaining response and maintaining remission in pregnant IBD patients might outweigh the theoretical risks of drug exposure to the fetus. The decision to use anti-TNF-α therapy in pregnancy should be made on a case-by-case basis. In women with a complicated disease course, in whom biological therapies have been the only agents to induce and maintain remission, therapy should probably be continued during conception and pregnancy. On the other hand, stopping therapy in the third trimester may be considered, as we know that transplacental transfer of infliximab is low prior to this. This approach has the benefit of minimizing the break from treatment for the patient and therefore the risk of antibody development once treatment is recommenced postpartum.97 Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an anti-TNF-α monoclonal antibody, and therefore it may not be necessary to stop certolizumab in the third trimester, which could be an advantage over other biological therapies. In a patient on anti-TNF-α therapy in combination with azathioprine/mercaptopurine, it may be considered stopping these last drugs to minimize risks of immunosuppression and adverse events to the fetus, given the limited benefit of combination therapy versus when a patient is maintained on anti-TNF-α therapy alone.128 Finally, the use of infliximab is probably compatible with breast-feeding, although more experience is necessary.

REFERENCES

  1. Top of page
  2. Abstract
  3. SEARCH STRATEGY
  4. AZATHIOPRINE/MERCAPTOPURINE
  5. METHOTREXATE
  6. CYCLOSPORINE
  7. TACROLIMUS
  8. THALIDOMIDE
  9. INFLIXIMAB
  10. ADALIMUMAB
  11. CERTOLIZUMAB
  12. LIMITATIONS OF STUDIES DURING PREGNANCY
  13. CONCLUSION
  14. Acknowledgements
  15. REFERENCES