PREGNANCY OUTCOME In GENETIC Subtypes of CONGENITAL Neutropenia

Abstract 4722

Severe congenital neutropenia (CN) comprises a heterogeneous group of disorders with a common hematological and clinical phenotype characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte / myelocyte stage with peripheral blood absolute neutrophil counts (ANC) below 0.5 ′ 10⁹/l and early onset of bacterial infections. Current data on the molecular causes have demonstrated that CN is a multigene disorder with more than 10 genes described to date. Genetic analyses in autosomal dominant and sporadic cases of CN indicate that the majority of these cases are attributable to mutations in the elastase 2 (ELANE) gene encoding neutrophil elastase. However, mutations in the ELANE gene do not discriminate between patients with CN and patients with cyclic neutropenia (CyN). Since 1987, recombinant human Granulocyte-Colony stimulating factor (G-CSF) is available for the treatment of CN. Independent of the genetic subtype, more than 90% of patients respond well to G-CSF with sustained increase of absolute neutrophil counts and prolonged life expectancy. Since our first patients have reached adulthood the desire for parenthood arises. To-date there is only limited data on the infectious risk for affected mothers and their children due to G-CSF treatment during pregnancy.

In this study we assessed the outcome of pregnancies reported to the SCNIR in Europe since 1994 with regard to:

1. The neutropenia status in newborns of mothers and fathers with different genetic CN subtypes as an indicator for inheritance.

2. The impact of G-CSF treatment on maternal and newborn complications in women of all neutropenia subtypes with or without G-CSF treatment during pregnancy.

Since 1994 the SCNIR has collected long-term follow-up data of 510 patients with severe chronic neutropenia subtypes. 3 patients are diagnosed with congenital (71 ELANE-CN, 31 HAX1, 9 GC6PC3, 47 SDS, 117 unknown, 45 other), 66 with cyclic and 82 with idiopathic neutropenia. Adulthood was reached by 144 out of 304 CN patients. These include 38 ELANE-CN patients (male:14, female:24) and 11 ELA-CyN patients (male: 5, female:6).

A total of 20 pregnancies in 12 mothers and 13 newborns by 7 fathers with different genetic subtypes of CN have been reported. Among them are pregnancies of 11 women with ELANE-CN, 8 with ELANE-CyN, 1 with SDS, 13 with an unknown genetic origin of CN (n=9) or CyN (n=4). No pregnancies were reported in patients with HAX1 or G6PC3 although 7 of these patients have reached adulthood.

Data on neutropenia status was documented in 24 out of 31 live births. Neutropenia in newborns was diagnosed in 16 out of 30 live births from parents with genetic subtypes of CN. In 8 of the 16 affected newborns neutropenia was related to ELANE mutations. One mother registered with SDS delivered a healthy child.

During pregnancy 17 women received G-CSF treatment (CN=11, CyN=4, IDN=2). Regardless of any cytokine treatment no major infectious complications were reported in our cohort. 24 of 31 reported pregnancies resulted in life births. 5 spontaneous terminations occurred in women with respectively without exposure to G-CSF. In addition, 2 still births were reported in women with idiopathic neutropenia, but G-CSF exposure remains unknown.