Medication

FDA category

Summarized data

Recommendation

5-ASA derivative

Dibutyl phthalate (DBP)-coated mesalamine (e.g., Asacol HD^®)

C

•  Cleft palate, skeletal defects, and adverse effects related to androgen-dependent development of the male reproductive organs were seen in rats [1]

•  Urine concentrations of DBP metabolite is 200× higher in women [2]

•  No human studies with increased birth defects exist

•  Likely low risk, may consider alternative 5-ASA

Non-DBP coated 5-ASAs and balsalazide (e.g., Pentasa^®, Delzicol^®, Lialda^®, Apriso^®) (e.g., Giazo^®, Colazal^®)

B

•  Meta-analysis of seven studies (2,200 pregnant women with IBD); 642 received 5-ASA drugs and 1,158 received no medications → no significant difference between groups [3]

•  Increased risk of adverse outcomes in women with ulcerative colitis who were not on 5-ASA in the 2nd/3rd trimesters [4]

•  Case report of interstitial nephritis and renal insufficiency in infant with prenatal exposure linked to drug [5]

•  Low risk, continue medication

Olsalazine (Dipentum^®)

C

•  Reduced fetal weight, retarded ossification, and immaturity of the fetal visceral organs in rats

•  No human data

•  Likely low risk, may consider alternative 5-ASA

Sulfasalazine (e.g., Azulfidine^®, Sulfazine^®)

B

•  No increased risk of fetal congenital malformations in multiple studies [6, 7]

•  One study shows a trend toward increased congenital malformation risk with exposure during conception and first trimester [4]

•  Initial concerns about kernicterus have not been validated in later studies

•  Low risk, consider stopping 3 months prior to conception (for men and women) and during first trimester; or consider switching to alternate 5-ASA

•  Must supplement with folic acid (1 mg BID)

Enema and suppository preparations of 5-ASAs (e.g., Canasa^®, Rowasa^®)

B

•  Drug FDA rating is based on mesalamine component only

•  Low risk; no data to suggest increased risk of preterm labor or miscarriage, however general obstetric concerns about rectal stimulation causing uterine contractions may outweigh benefits, especially in third trimester or in select cases

Thiopurines

Azathioprine (AZA) and 6-mercaptopurine (6MP) (e.g., Azasan^®, Imuran^®) (e.g., Purinethol^®, Purixan^®)

D

•  Increased teratogenicity with cleft lip, skeletal, and urogenital anomalies in animal models [8]

•  Some guidelines suggest AZA/6MP to be safe and well tolerated in pregnancy [9]

•  No increased risk of congenital malformation, spontaneous abortion, neoplasia, or risk of infection in pregnant IBD patients or with paternal exposure during conception in IBD or in pregnant renal transplant recipients in several studies [8, 10–17]

•  Increased risk of preterm labor and increased risk of low birth weight in some studies [10, 11, 18]

•  Increased risk of ventricular/atrial septal defects in one study [11]; however confounding factor of IBD activity

•  Nonsignificant increased risk of spontaneous abortions; higher rate of elective terminations of pregnancy in the exposed group with paternal exposure during conception [17]

•  Anemia in some infants born to mothers on purine analogues reported in a small study [19]

•  Probably low-risk; likely safe to continue medication if patient has been stable on drug

•  Possible adverse effects of bone marrow suppression and pancreatitis need to be considered when initiating medication during pregnancy

•  May consider checking infant for anemia after birth

Corticosteroids

Prednisone, prednisolone, dexamethasone

C*

•  Increased risk of oral cleft in newborns, with nonsignificant risk of other major malformations in some studies [20–22]

•  No increased risk of oral cleft in one study [23]

•  Increased risk of premature rupture of membranes; increased risk adrenal insufficiency in pregnant organ transplant recipients and rarely in newborn [24]

•  Reduced head circumference, birth length or birth weight in a systemic review of studies in which pregnant women received dexamethasone or betamethasone [25]

•  Dexamethasone and betamethasone (i.e., fluorinated steroids) pass through the placenta without inactivation; risk of increased exposure [26]

•  Non-fluorinated steroids (such as prednisone, prednisolone, methylprednisolone, and hydrocortisone) are better suited to treat IBD as they are metabolized by the placenta and have less effects on the fetus until 36 weeks, when the fetal liver can resynthesize the original steroid from the placental metabolites

•  Probably avoid in the first trimester due to increased but small risk of orofacial clefts

•  Lower risk in second and third trimesters and may be used to acutely control IBD flare

•  Monitor for hypoadrenalism; rare but may occur in infants

Oral budesonide (e.g., Entocort^®, Uceris^®)

C

•  Teratogenic and embryocidal in rabbits and rats with increases in fetal loss, low weight in fetus, and skeletal abnormalities

•  No maternal side effects or fetal congenital abnormalities in eight pregnant women with Crohn’s disease on budesonide for 1–8 months [27]

•  Likely low risk, may consider alternate medication

Calcineurin inhibitors

Cyclosporine (CS) and tacrolimus (e.g., Neoral^®, Gengraf^®, Sandimmune^®) (e.g., Prograf^®)

C

•  Embryo- and fetotoxic in animals exposed to 2–5 times the human dose. Reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency in rabbits, and increased ventricular septal defects in rats with CS

•  Unclear how much of drug crosses the placenta

•  Case report of tacrolimus used successfully as maintenance therapy for ulcerative colitis in pregnancy [28]

•  Case report of cyclosporine used successfully to treat a 27-week pregnant woman with fulminant, steroid-refractory ulcerative colitis [29]

•  No increase in risk of congenital malformations or prematurity in a meta-analysis of 15 studies of pregnant women taking CS for transplant/autoimmune disease [30]

•  Out of 116 patients on CS and other drugs for transplant → 16 fetal losses; 47 % premature deliveries with 85 % of patients with pregnancy complications, 27 % with neonatal complications, and seven congenital anomalies; results confounded with concomitant meds [31]

•  Congenital anomalies in transplant recipients receiving tacrolimus are comparable to the general population, but high rate of prematurity (57 %) and maternal and neonatal complications [32]

•  May be suitable for use in acute colitis unresponsive to other therapies

Biologic agents

Infliximab (IFX) (Remicade^®)

B

•  IFX (an IgG1 subclass molecule) and other biologics with an Fc portion can concentrate in the fetus by crossing the placenta at a high rate [33]; IgG transfer starts early as 13 weeks and increases linearly with the most transferred after 32 weeks and especially in the third trimester [34]; levels are high in newborn if drug is given in the last few weeks; drug is detectable in newborns up to 6 months after birth [33]

•  Pregnancy outcomes with IFX in women with rheumatoid arthritis and Crohn’s disease are similar to the general population with regard to live births, miscarriages, and therapeutic terminations [35]

•  TREAT registry → no difference in congenital malformations, miscarriage, or neonatal complications in 36 women with Crohn’s disease [36]

•  PIANO registry → no increase in risk of birth defects with exposure to biologic agents or in combination with AZA/6MP in IBD [16]

•  No increase in infection or developmental milestones in infants [16], but possible increased risk of newborn infection when given with AZA

•  Fatal case reported of disseminated BCG infection after vaccination of infant with in utero exposure to IFX [37]

•  Low risk; continue drug

•  Consider holding IFX at about 30 weeks of gestation and restarting immediately after delivery if risk of flare is low, weighed against risk of infection in the newborn by continuing drug throughout pregnancy

•  Live vaccinations (e.g., BCG vaccines) are not recommended for the first 6 months of life to newborns whose mothers have received IFX throughout the pregnancy

Adalimumab (ADA) (Humira^®)

B

•  Animal models with ADA show no increased obstetric risks and no teratogenic effects [38]

•  Actively transported across placenta; detectable in newborns up to 6 months after birth [33]

•  No reports of congenital abnormalities in 155 pregnancies [39, 40] and in IBD pregnancies in the PIANO registry

•  No changes in growth status or rate of infection in IBD pregnancies [41]

•  No increased risks of miscarriage or congenital anomalies in rheumatoid arthritis patients exposed in the first trimester and beyond [42]

•  Low risk; recommendations are the same as IFX

Certolizumab (CZ) (Cimzia^®)

B

•  Minimal placental transfer; minimal blood levels in newborns and cord blood [33] and drug levels are less compared to IFX and ADA

•  No increased risk of congenital abnormalities, growth status changes or increased rate of infection in 47 pregnancies in the PIANO IBD registry [16]

•  Low risk; continue drug

•  Probably can continue throughout pregnancy

•  No change needs to be made to newborn immunization schedule, although data is limited

Golimumab (Simponi^®)

B

•  Adverse events not observed in animal reproductive studies; the drug was noted to cross the placenta reaching 50 % of the maternal levels in the fetus

•  No human data available

•  Consider limiting exposure after 30 weeks of gestation

•  Live vaccinations are not recommended to newborns whose mothers have received the drug throughout the pregnancy

Natalizumab (Tysabri^®)

C

•  In monkeys, the drug at 2.3 times human dose causes anemia, low platelets, lower weight of spleen, liver, and thymus in the fetus

•  Thought to actively across the placenta

•  No increase in birth defect risk in exposed multiple sclerosis patients [43]; or in the natalizumab global safety database with 164 pregnancies [44]

•  In one observational study of 13 pregnancies with multiple sclerosis exposed during third trimester → mild to moderate hematologic abnormalities in 10 of 13 infants [45]

•  In another observational study of 35 pregnancies with multiple sclerosis exposed to drug → 28 healthy births, 1 with hexadactyly; 5 with early miscarriage; 1 with elective abortion [46]

•  Likely low risk

•  Live vaccinations are not recommended for newborns whose mothers have received the drug throughout the pregnancy

Vedolizumab (Entyvio^®)

B

•  No adverse effects reported in animal models given 20 times the recommended human dose

•  Transported across placenta in a linear fashion as pregnancy progresses, mostly transferred during the third trimester, with adverse effects probably greater during second and third trimester

•  No human data available, however a registry of pregnancy outcomes has been established

•  Consider limiting exposure after 30 weeks of gestation

•  Live vaccinations are not recommended for newborns whose mothers have received the drug throughout the pregnancy

Other

Methotrexate (MTX) (e.g., Otrexup^®, Rheumatrex^®, Trexall^®)

X

•  Causes fetal death/congenital abnormalities

•  British registry showed higher rate of spontaneous abortion among patients exposed to anti-TNF with MTX/leflunomide at the time of conception [47]

•  Small study reviewed paternal exposure to MTX at time of conception or up to 3 months before conception → no major adverse effect to baby [48]

•  Contraindicated during pregnancy

•  Should be stopped in women 6 months prior to conception and in men 3 months prior to conception, based on limited data

Ciprofloxacin (Cipro^®)

C

•  Causes arthropathy in children

•  Study of 200 pregnant women exposed to ciprofloxacin showed low risk of birth defects and clinically significant musculoskeletal dysfunction [49]