Posted 3/19/2018 1:42 PM (GMT -6)
Azathioprine and 6-mercaptopurine/Purinethol (FDA Class D): Although thiopurines are classified as FDA Class D drugs, because of teratogenicities in animal studies, the use of azathioprine/6-MP during pregnancy in IBD is not associated with increased risk of preterm birth, low birth weight, neonatal adverse outcomes, or congenital abnormalities[33,49,56-60]. Disease activity rather than medication use can lead to neonatal adverse outcomes.
5.2. Medical treatment of IBD and adverse pregnancy outcomes
ECCO Statement 5B Most drugs used for the treatment of IBD are considered to be of low risk during pregnancy [EL3]. However, methotrexate and thalidomide, are contraindicated [EL3]
ECCO Statement 5C In cases of relapse, depending on the disease phenotype and activity, 5-ASA or corticosteroids are the preferred therapies [EL5]. Anti-TNF agents can be considered to treat flares in appropriate situations [EL5]
ECCO Statement 5D Infliximab and adalimumab cross the placenta and their use beyond the second trimester results in neonatal levels exceeding maternal levels [EL3]. This exposure can be limited by stopping the treatment around gestational week 24–26 when considered appropriate by the clinician and the patient [EL3]
Table 1. ECCO overview on drug risk during pregnancy and lacatation.
Drug ……..…….During pregnancy……During lactation
Mesalazine….. Low risk………………….. Low risk
Sulfasalazine…Low risk ……………..……Low risk
Corticosteroids Low risk ………………..Low risk, 4h delay before breastfeeding is advised
Thiopurines Low risk,……………….. limited data on 6-TG Low risk
Anti-TNF agents Low risk, …………..consider stopping around week 24 in patients with sustained remission. See text Probably low risk, limited data
Methotrexate Contraindicated Contraindicated
Thalidomide Contraindicated Contraindicated Metronidazole Avoid first trimester Avoid Ciprofloxacin Avoid first trimester Avoid
5.2.3. Azathioprine (AZA) and 6-mercaptopurine (6-MP)
AZA and its metabolite 6-MP are purine analogues which interfere with the synthesis of adenine and guanine ribonucleotides. AZA crosses the placenta and its metabolites have been determined in fetal red blood cells.153 In a recent study evaluating prospectively the pharmacokinetics of thiopurines during 30 pregnancies, a metabolic shift towards higher 6-methylmercaptopurine (6-MMP) production was shown in mothers but without clinically relevant toxicity. In cord blood, thiopurines’ active metabolites (6-TG) were detected in levels reaching on average 50% of maternal levels.104 In this study, 60% of infants had anemia and, therefore, immediate postnatal blood count assessment of children exposed to thiopurines in utero might be considered. Fetal exposure to AZA and 6-MP has been reported in several hundreds of cases.99,100,136,154 The adverse pregnancy outcomes described in these studies were an increased rate of spontaneous miscarriage, preterm delivery and low birthweight,99,155 which could have been caused by the underlying disease rather than by the use of thiopurines.156 More recent controlled studies102,103,106,111 and a metaanalysis157 reported no increased risk for adverse pregnancy outcome in IBD patients treated during pregnancy with thiopurines, compared with pregnancy outcomes of IBD patients without this treatment. An association with preterm birth, but no congenital malformations, and low birthweight was shown in one recent meta-analysis.98 A few cases of immunologic and hematologic abnormalities and chromosomal aberrations in newborns and infants, probably caused by immunosuppression, have been described.100 However, a prospective study following 30 children exposed to thiopurines in utero revealed neither developmental nor immunologic abnormalities in these children during a median follow-up of 3.8 years.107 It has been reported that 6-T6 passes through the placenta,158 and in the absence of further safety data it should not be used during pregnancy.