Thiopurines during pregnancy in inflammatory bowel disease: is there a risk for the (unborn) child?

Keywords::

• azathioprine
• inflammatory bowel disease
• intrauterine exposure
• mercaptopurine
• pregnancy
• teratology
• thiopurine

Conventional thiopurines, being azathioprine (AZA) and mercaptopurine (MP) are considered the cornerstone of immunosuppressive maintenance therapy in patients with inflammatory bowel disease (IBD) [1]. Since the majority of (female) patients are in the fertile phase of their life when IBD is diagnosed, treating physicians and their patients frequently face the dilemma whether thiopurines could be prescribed or maintained safely before and throughout pregnancy. In animal studies, although difficult to extrapolate to the human setting, the possibility of teratogenicity due to thiopurine administration has been reported. Data in humans suggested that thiopurine use during pregnancy may be associated with an increased risk of preterm birth and low birth weight [2]. In addition, serious neonatal complications of maternal thiopurine therapy have been described in several case studies, including myelotoxicity, neonatal infections, severe combined immune deficiency and hypogammaglobulinemia [3,4]. The US FDA labeled AZA and MP as category D medications, indicating that its use may be of benefit for pregnant women, although fetal risk may exist.

Nonetheless, international and national IBD guidelines and consensus papers advise to continue thiopurines throughout pregnancy [5]. This recommendation is partly based on the increased risk of low birth weight and premature birth, in case the underlying IBD remains or becomes active during pregnancy, combined with the reassuring data from several patient series showing no clear association between thiopurine use during pregnancy in IBD patients and teratogenic effects [6,7]. Consequently, guidelines pragmatically conclude that the beneficial effect of thiopurines outweighs potential fetal risk. A worldwide survey showed that almost nine out of 10 gastroenterologists with a specific (scientific) interest in IBD currently treat their pregnant IBD patients according to these guidelines and continue thiopurines [8].

Indeed, there is mounting evidence from many large observational studies that thiopurine therapy itself is most likely not associated with unfavorable pregnancy outcome. In the landmark study by Francella and colleagues it was concluded that MP administration during pregnancy appears to be safe. The authors subsequently stated that discontinuation of this thiopurine before or during pregnancy is not indicated or advisable [9]. Another study from France describing 86 pregnant IBD patients, underlined the general notion that thiopurine use during pregnancy is not associated with congenital abnormalities [10]. More recently, a prospective study in 30 female IBD patients giving birth to 31 infants during steadystate thiopurine therapy confirmed the general opinion that AZA and MP could be prescribed safely to pregnant women with IBD [11].

The majority of the published series on safety of thiopurine use throughout pregnancy specifically focuses on the presence of potential congenital abnormalities by thorough physical examination of the newborn. The nature of these (generally retrospective) studies and their designs do not allow for answering another important question whether or not the neonate may have developed systemic complications, like bone marrow toxicity. A recent pharmacological study in thiopurine using pregnant females with IBD confirmed that the unborn child is exposed in utero to the pharmacologically active thiopurine metabolites 6-thioguanine nucleotides (6-TGNs). More importantly, almost two out of three neonates was born with (mild) anemia and in two newborns a thrombocytopenia was detected directly after birth [11], however not leading to apparent clinical problems. Leukopenia and anemia may occur as adverse events during AZA or MP use in non-pregnant IBD patients [12], this may be largely explained by elevated 6-TGNs levels. From a pharmacodynamic point of view, it is sensible that signs of bone marrow toxicity are present in newborns when 6-TGNs are detectable. Despite the reassuring data on long-term (immune) development of these children [13], the observation that maternal thiopurine use may cause anemia and thrombocytopenia in newborns raises the question whether this group of neonates should be checked for signs of possible myelotoxicity directly after birth. However, the current available data do not warrant an advice to perform laboratory investigation to check for bone marrow suppression as a routine in all newborns intrauterine exposed to thiopurines. In all described cases, the anemia and thrombocytopenia were only mild and presumably of minor or no clinical interest. This is underlined by daily clinical experience and the lack of additional scientific data on the occurrence of clinically significant problems in this group of infants exposed to 6-TGN throughout pregnancy [14]. A pragmatic recommendation is therefore to check for bone marrow suppression only in those newborns with clinical signs of anemia, like pale skin color, tachycardia or tachypnea, reflected by a lower APGAR score. In case infections or an unexplained bleeding tendency would occur in the neonatal period, physicians should also be alerted and assess possible thiopurine therapy induced myelosuppression.

Notwithstanding, the increasing evidence that thiopurine therapy can be safely continued during pregnancy in IBD patients, conclusive and definite studies are lacking, mainly due to ethical reasons. Hence women with IBD, their partners and family must be well informed and educated. The treatment should be individualized and balanced, based on available literature and preferences of the patient. The complex care for pregnant IBD patients, especially while taking immunosuppressive therapies, is challenging and all these patients should, as a consequence, be monitored and treated by a dedicated team of (experienced) physicians.

We conclude that the risk for the unborn child due to maternal thiopurine use is minimal (however not insignificant), but is outweighed by the beneficial effect on pregnancy outcome most likely due to sustained remission of disease. As a general rule, there is no need to discontinue thiopurine therapy when a female IBD patient is (planning to get) pregnant.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.