||Boxer LA, Bolyard AA, Marrero TM, Alter BP, Bonilla MA, Link D, Newburger PE, Rosenberg PS, Shimamura A, Dale DC
||There are currently no established guidelines for granulocyte colony stimulating factor (G-CSF) therapy during pregnancy for women with severe chronic neutropenia. To establish treatment recommendations, we reviewed records of women with the diagnoses of congenital, cyclic, idiopathic or autoimmune neutropenia and blood neutrophil counts chronically or recurrently <0.5 x 109/L who were enrolled in the North American branch of the Severe Chronic Neutropenia International Registry (SCNIR). We identified 88 women who had 183 pregnancies for this cross sectional study. We compared outcomes for women treated or not treated with G-CSF during their pregnancies.Fifty-five women [congenital neutropenia (CN) N=4, cyclic neutropenia (CyN) N=13, idiopathic neutropenia (IN) N=37, autoimmune neutropenia (AN) N=1] with 123 pregnancies while not on G-CSF therapy were compared with 41 women (CN =7, CyN=16, IN=15, AN=3) having 60 pregnancies while on G-CSF therapy.During pregnancy the patients not treated with G-CSF had the following complications: 6 premature labors, 1 premature rupture of membranes, 2 life-threatening infections, and 2 minor infections. The G-CSF treated group had no premature labors, no life threatening infections, 5 minor infections, and 1 patient developed severe thrombocytopenia. By diagnostic category the complications in the no G-CSF mothers occurred in 11 patients (IN=9, CyN=1, AN=1), compared with six in the G-CSF treated group (IN=3, CyN=2, CN=1). There were 32 spontaneous miscarriages in the women not on G-CSF (CN=1, CyN=8, and IN=23) compared with 3 in the women (CyN=3) on G-CSF.There were 82 live births from 123 pregnancies in the no G-CSF group. Thirteen of these infants had neonatal neutropenia. Other major neonatal complications in this group included 3 significant infections (1 meningitis, 2 septicemias), 1 minor infection (umbilical cord infection), 1 cerebral palsy, 1 respiratory distress syndrome, and 1 collapsed lung. In the G-CSF treated group there were 53 live births from 60 pregnancies. Twelve of these infants were neutropenic. Other complications in the G-CSF treated group included 1 umbilical cord infection (in a patient of mother with congenital neutropenia) and 1 tracheal esophageal fistula, 1 abruptio placenta associated with neonatal apnea, and 1 hydronephrosis (in infants with cyclic neutropenic mothers).The median G-CSF dose was 1.07 mcg/kg/day for all trimesters. Treatment was administered throughout the pregnancy in 62% (37/60) of the pregnancies. Seventeen percent (10/60) were treated only in the first trimester, 13% (8/60) were treated only in the last two trimesters, 3% (2/60) treated for the last trimester only, and 5% (3/60) treated in two of three trimesters (2 treated in 1st and 3rd trimesters, 1 treated in the 1st and 2nd trimesters). The two live births with congenital abnormalities occurred in G-CSF treated patients; one with tracheal esophageal fistula was exposed in the first trimester, one with hydronephrosis was exposed in all three trimesters.In summary, we found that G-CSF treatment was associated with a higher percentage of live births, 67% (82/123) without G-CSF compared with 88% (53/60) with G-CSF therapy (p=0.002, Fisher exact test). G-CSF therapy was associated with a lower number of spontaneous abortions, 26% (32/123) in the no G-CSF group versus 5% (3/60) in the G-CSF treated group (p=0.001). G-CSF therapy was associated with a lower rate of serious maternal complications. Two common congenital anomalies were observed in the offspring of the G-CSF treated mothers and no anomalies were observed in the offspring of the mothers not receiving G-CSF. Overall the newborns from the G-CSF treated mothers appeared to have fewer neonatal complications.Based on this analysis, we recommend that G-CSF therapy should be offered and continued during pregnancy in women with severe chronic neutropenia. The available data indicates that administration throughout pregnancy is well tolerated and protective of maternal health.