Late-Onset Neutropenia in Very Low Birth Weight Infants

Background. Neutropenia, defined as absolute neutrophil count (ANC) <1500/mm3, affects 6% to 58% of premature infants in the first week of life. This early-onset neutropenia in premature infants has previously been correlated with sepsis, maternal hypertension, severe asphyxia, and periventricular hemorrhage. Late-onset neutropenia, defined as ANC <1500/mm3 at a postnatal age of >3 weeks, has not been previously reported. Objectives. The purposes of this study were to determine the prevalence of late-onset neutropenia in very low birth weight (VLBW) infants and to examine the factors that may be associated with this phenomenon. Methods. A weekly complete blood cell count (CBC) was performed routinely in all premature infants with birth weight <1500 g (n 5 225) admitted to the neonatal intensive care in a 3-year period who survived until discharge. CBC and differentials were recorded at day 1, day 3, and then weekly until discharge. The clinical data of the study infants were collected by reviewing the medical records retrospectively. Results. Late-onset neutropenia was detected in 51 infants (22%). In both neutropenic (n 5 51) and nonneutropenic infants (n 5 174), ANC increased postnatally, remained above 5000/mm3 for the first 3 weeks of life, and had a marked decrease at ;4 weeks of age. Thereafter, ANC decreased to a level of ;1400/mm3 in the neutropenic infants and 4000/mm3 in the nonneutropenic infants. The neutropenic infants had a significantly lower nadir ANC, lower hemoglobin, and higher reticulocyte count than did the nonneutropenic infants with similar platelet counts. None of the study infants received erythropoietin during their hospitalization. This late-onset neutropenia occurred at postnatal age of 6 6 2 weeks (range: 3–10 weeks). The duration of neutropenia was 1.7 6 .7 weeks (range: 1–3 weeks). All of the neutropenic infants had anemia of prematurity with high reticulocyte count and normal platelet count. The neutropenic infants were stable, growing on full oral feedings, and had no signs or symptoms of sepsis. No adverse effects of late-onset neutropenia were apparent in these infants. Conclusion. Late-onset neutropenia is a common incidental finding in stable, growing VLBW infants that has not been previously reported. Late-onset neutropenia is a phenomenon that occurs in anemic premature infants who have marked reticulocytosis. Normal regulation of hematopoiesis is accompanied by a balance between colony-stimulating factors, such as erythropoietin and granulocyte colony-stimulating factor, which regulate erythropoiesis and granulopoiesis. We speculate that imbalance of these factors with increased reticulocytopoiesis in response to anemia of prematurity may explain this phenomenon. We recommend avoiding institution of aggressive, potentially harmful therapy for this phenomenon in healthy, growing VLBW infants. Pediatrics 2000;106(4). URL: http://www.pediatrics.org/cgi/content/ full/106/4/e55; neutropenia, absolute neutrophil count, very low birth weight, infants, sepsis. ABBREVIATIONS. CBC, complete blood cell count; ANC, absolute neutrophil count; VLBW, very low birth weight; SGA, small for gestational age; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; WBC, white blood cell count; SEM, standard error of the mean; G-CSF, granulocyte colony-stimulating factor. The complete blood cell count (CBC) with differential is the most common screening test performed in the evaluation of infants admitted to the neonatal intensive care unit. Recognition of significantly abnormal CBC and differential values requires adequate normative data to be available for comparison. The use of absolute neutrophil count (ANC) has improved early recognition and sensitivity in screening for neonatal bacterial sepsis.1–4 Several investigators have suggested reference values for neutrophil cell counts in premature infants during the first 28 days of life.1–9 This published data may be inadequate when dealing with stable, growing premature infants .28 days of age. Neutrophils are important as a host defense against bacterial infection.10 When the neutrophil supply is inadequate, neutropenia can develop and the possibility of surviving an infection decreases.2,11,12 Neutropenia, defined as ANC ,1500/mm3, affects 6% to 58% of premature infants in the first week of life.13–15 This early-onset neutropenia has been reported to occur within the first week of life, with one half of the total episodes starting on the first day of life and approximately two thirds of all episodes lasting ,1 week.13 Christensen, Manroe, and others1,16–20 had proposed several explanations for this early-onset neutropenia. Premature infants may have a decreased neutrophil storage pool and may exhaust their reserve of neutrophils quickly.20 Neutropenia can be a sign of inadequate neutrophil production or increased consumption.16,17 In addition, neutropenia can occur even in the presence of normal neutrophil supply, as during margination of circulating neutrophils.21 Thus, the detection of neutropenia does not signify From the *Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan; and the ‡Division of Neonatology, Sparrow Regional Children’s Medical Center, Lansing, Michigan. This work was presented in part at the Society for Pediatric Research Meeting; May 1–4, 1999; San Francisco, CA. Received for publication Feb 14, 2000; accepted Apr 25, 2000. Reprint requests to (S.A.O.) Division of Neonatology, Sparrow Health System, 1215 E Michigan Ave, Lansing, MI 48912. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad-