Maternal neutrophil apoptosis in normal pregnancy, preeclampsia, and normotensive intrauterine growth restriction

OBJECTIVE: In normal pregnancy there is both a neutrophilia and a mild neut rophil activation. In preeclampsia both direct and indirect evidence suppor ts further marked neutrophil activation. In the pathogenesis of preeclampsi a peripheral blood neutrophils may play a vital role in communicating betwe en the preeclamptic placenta and the maternal vascular endothelium and cont ribute to the endothelial cell dysfunction that char acterizes the maternal syndrome of preeclampsia. Preeclampsia shares many elements with the syste mic inflammatory response syndrome. Neutrophils, key effecters of the syste mic inflammatory response syndrome, are associated with hepatic necrosis an d adult respiratory distress syndrome, both of which most commonly kill wom en with preeclampsia. We hypothesized that delayed neutrophil apoptosis cou ld explain (I) the neutrophilia of normal pregnancy and (2) the differentia l maternal responses to the shared placental abnormality of preeclampsia an d normotensive intrauterine growth restriction. STUDY DESIGN: Neutrophils were isolated (dextran 500, Ficoll [Amersham Phar macia Biotech AB, Uppsala, Sweden], and erythrocyte lysis) from (1) case pa tients with preeclampsia at less than or equal to 34 weeks' gestation, (2) healthy pregnant control subjects, (3) case patients with normotensive intr auterine growth restriction at less than or equal to 34 weeks' gestation, a nd (4) nonpregnant female control subjects. Apoptosis was determined after 18 hours of incubation (with or without endotoxin or anti-fas monoclonal an tibody) by deoxyribonucleic acid profile (propidium iodide study), annexin V binding, and CD16 expression. RESULTS: Compared with propidium iodide profile values in nonpregnant women (median, 25%; range, 14%-40%) neutrophil apoptosis was significantly delay ed in normal pregnancy (median, 9.5%; range, 7.6%-15%) and normotensive pre gnancy with intrauterine growth restriction (median, 11%; range. 9.3%-19%)a nd was further delayed in preeclampsia (median, 6.9%; range, 4.1%-8.2%; P l ess than or equal to.005 vs normal pregnancy and normotensive intrauterine growth restriction). All neutrophils remained sensitive to endotoxin inhibi tion but were resistant to anti-fas induction of apoptosis. Spontaneous neu trophil apoptosis decreased as gestational age increased (r(2) = 0.48). CONCLUSIONS: Impaired neutrophil apoptosis may explain the neutrophilia ass ociated with normal pregnancy. In women with preeclampsia activated neutrop hils remain in the circulation, perhaps contributing to the persistence of preeclampsia after delivery. Neutrophils appear to modulate the Variation i n maternal response between preeclampsia and normotensive intrauterine grow th restriction.