Immature granulocytes in pregnancy: A story of Virchow, anxious fathers, and expectant mothers

Abstract

A 20-year-old woman (G2P1) was followed for an uncomplicated second pregnancy. She was not taking any medications besides a daily oral multivitamin and iron supplement. At 23 weeks and 5 days, she was feeling well, and vital signs, physical exam, and urinalysis were normal. A complete peripheral venous blood count using a Sysmex XT-1800i instrument showed a white cell count of 15.6 × 103 μl−1, red cell count of 3.6 × 106 μl−1, hemoglobin concentration of 10.5 g/dl, hematocrit of 30.8%, mean corpuscular volume of 86.0 fl, mean corpuscular hemoglobin of 29.3 pg, and a platelet count of 351 × 103 μl−1. An automated differential count (Image 1A, left panel; SSC, side scatter; SFL, side fluorescence) revealed 59.3% neutrophils (population colored in cyan/teal), 15.3% lymphocytes (magenta), 9.0% monocytes (green), 2.9% eosinophils (red), 1.2% basophils (cyan/teal; overlapping with neutrophils in this projection), and 12.3% (1,920 μl−1) immature granulocytes (i.e., promyelocytes, myelocytes, and/or metamyelocytes [1, 2]; dark blue, yellow arrows). Manual review of a blood smear confirmed these results and showed that the immature granulocytes were composed of 5.0% myelocytes and 7.3% metamyelocytes (Image 1A, middle and right panels). No promyelocytes, myeloblasts, or dysplastic features were seen. Not surprisingly, the marked increase of immature myeloid cells caused significant anxiety in this young patient and her family. At 39 weeks, the woman delivered a healthy daughter by Cesarean section without complications. 2 weeks post partum, a complete blood count showed a white cell count of 7.3 × 103 μl−1, red cell count of 5.0 × 106 μl−1, hemoglobin concentration of 14.3 g/dl, hematocrit of 42.7%, mean corpuscular volume of 85.1 fl, mean corpuscular hemoglobin of 28.5 pg, and a platelet count of 304 × 103 μl−1. An automated differential count (Image 1B, left panel) revealed 38.1% neutrophils, 42.5% lymphocytes, 8.4% monocytes, 10.3% eosinophils, 0.6% basophils, and 0.1% (10 μl−1) immature granulocytes (note the virtual absence of a dark blue population above the cyan/teal neutrophils/basophils). Manual review of a blood smear confirmed these results (Image 1B, middle and right panels). This case highlights two interesting issues in pregnancy-related hematology, namely physiologic leukocytosis and marked left shift in the myeloid-neutrophilic lineage. Described early on by Rudolf Virchow [3], physiologic leukocytosis of pregnancy has been very well documented and studied quantitatively [4-10]. By contrast, the question of, indeed, how many circulating immature granulocytes in peripheral blood is “normal” during uncomplicated pregnancy remains surprisingly little studied. Normal peripheral blood shows very few circulating immature granulocytes, typically <0.2% of all white cells [1, 2, 11-13]. While much of the medical literature states qualitatively that circulating promyelocytes, myelocytes, or metamyelocytes may “increase” in pregnant women (whether or not concomitant leukocytosis of pregnancy is also present), the expected numerical increase is virtually never quantified [4-6, 9, 10]. In fact, we are aware of only one older study where an observed upper limit of 3% immature granulocytes is given [14]. It is indeed instructive to look at the deeper motivation for this study published in the New England Journal of Medicine in 1962 [14]: “[…] Peripheral white-cell counts in the wives of two physicians during the course of their pregnancies revealed the presence of immature granulocytes that persisted until delivery. The anxiety produced in the prospective fathers, because of the paucity of quantitative information regarding the differential neutrophil leukocyte count during pregnancy, prompted this investigation. […]” Traditionally, such marked increase in immature granulocytes has been thought to occur mostly in association with hematologic malignancies (e.g., CML) or secondary to drug treatment (e.g., chemotherapy or glucocorticoids) or growth factors (e.g., G-CSF) [4, 10]. Over a period of 3 months, we have now seen another otherwise healthy pregnant woman with significantly elevated immature granulocyte counts (4.2%/670 μl−1) that normalized readily after delivery. We show here that even relative counts >12%, i.e., more than 4-fold greater than previously appreciated, may hold no pathological significance, greatly reassuring anxious prospective fathers, expectant mothers, and their doctors alike [14].