A Severe Neonatal Lymphopenia Associated With Administration of Azathioprine to the Mother in a Context of Crohn’s Disease

Abstract

Azathioprine is commonly used in Crohn's disease. It has been administered to many pregnant women over many years without significant side effects. However, pancytopenia and severe combined immune deficiency-like disease have been reported in infants whose mothers received azathioprine throughout pregnancy. Moreover, myelotoxicity has been described in patients being treated with azathioprine and having a low or absent thiopurine S-methyl transferase [TPMT] activity.Here, we describe the case of a newborn girl found to be highly lymphopenic [< 300 CD3+ T cells] after a positive newborn screening for severe combined immuno deficiency. The clinical examination was normal. The mother was treated with azathioprine throughout her pregnancy, without any reduction of the dose. It was shown that the mother was heterozygous for the 3A [TPMT] activity mutation and that the baby was homozygous for the same mutation; 6-thioguanine nucleotides were high (744 pmol/8.108 red blood cells [RBC]) in the mother and detectable in the infant [177 pmol/8.108 RBC].Although rare, this case illustrates the potential grave consequences of unsuspected TPMT homozygosity in a newborn of a mother receiving thiopurines during pregnancy. Because of the severity of the risk for the newborn, consideration should be given to performing maternal genetic testing and newborn routine blood count in cases of thiopurine treatment during pregnancy.

Neonatal Screening for SCID: The French Experience

“…Among the remaining 140 infants recalled, 62 suffered from lymphopenia [14] due to SCID (3 cases) or secondary causes (Figure 3), as has previously been described [21,22]. In one of the two cases of maternal medication with azathioprine, the infant had a homozygous TPMT mutation, undetectable TRECs, and <300 CD3 + lymphocytes per mi- In one of the two cases of maternal medication with azathioprine, the infant had a homozygous TPMT mutation, undetectable TRECs, and <300 CD3 + lymphocytes per microliter, with levels returning to normal in 3 months [23]. This case has previously been discussed in the literature [21,22].…”

“…In one of the two cases of maternal medication with azathioprine, the infant had a homozygous TPMT mutation, undetectable TRECs, and <300 CD3 + lymphocytes per microliter, with levels returning to normal in 3 months [ 23 ]. This case has previously been discussed in the literature [ 21 , 22 ].…”

Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates

“…We did, however, detect a small number (n = 3) of cases of mild transient neutropenia or lymphopenia in infants from 6 weeks (Table S1), which appeared unrelated to thiopurine metabolite levels and may have been as a result of an intercurrent infant viral illness. Severe neonatal neutropenia has been previously reported in the setting of supra‐therapeutic maternal 6‐TGN levels and reduced TPMT activity detected post‐partum 14 . Severe neutropenia was not detected in any infants in our cohort.…”

Neuromyelitis optica spectrum disorders and pregnancy: relapse-preventive measures and personalized treatment strategies

“…However, the latter could also be caused by the individual underlying disease or other drugs administered as part of the treatment plan. Case reports describe bone marrow suppression with anemia and severe lympho-and pancytopenia in infants after maternal AZA exposure [92][93][94]. Because rare side effects cannot be ruled out, the risk of relapse by stopping or reducing AZA treatment should be carefully weighed against the possible risk to the child by continuing the treatment.…”