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Original Article The Effect of Prolonged Rupture of Membranes on Circulating Neonatal Nucleated Red Cells

Dror Mandel, MD, MHA INTRODUCTION Tal Oron, MD Prolonged rupture of membranes (PROM) is usually defined as Galit Sheffer Mimouni, MD rupture of membranes more than 24 hours prior to delivery.1 A Yoav Littner, MD major concern for exposed to PROM is maternal–fetal Shaul Dollberg, MD infection,2 but other risks include placental abruption,3 fetal lung Francis B. Mimouni, MD, FAAP hypoplasia,4 fetal distress due to cord compression and/or cord prolapse,1 and fetal deformation syndrome.1,5 A recent review of the significance of elevated neonatal nucleated red blood cells (NRBC) in the and the neonate included as a OBJECTIVES: ‘‘known’’ risk factor of elevation;6 this article suggests that ‘‘acute To test the hypothesis that absolute nucleated red blood cells (ANRBC) chorioamnionitis’’ may lead to increased levels of , counts are higher at birth in infants who were born after prolonged and increased newborn NRBC, but does not relate the finding of rupture of membranes (PROM, >24 hours). elevated NRBC counts with the occurrence or not of PROM. As mentioned earlier, PROM may lead to cord compression1 and STUDY DESIGN: subsequently to fetal ;1,7 a well-described consequence of Retrospective study of 31 infants admitted to the neonatal intensive care is increased compensatory due 8–10 unit who were born after PROM, and pair matched for gestational age to increased erythropoietin secretion. In situations associated and Apgar scores with 31 no PROM controls. Venous ANRBC counts were with intrauterine hypoxia, such as intrauterine growth restriction, obtained within 1 hour of life. maternal pregnancy-induced , or maternal diabetes or smoking, there is an elevation of the NRBC at birth, presumably RESULTS: due to increased compensatory erythropoiesis.9 Groups did not differ in birthweight, gestational age, Apgar scores, and The aim of this study was to examine circulating NRBC in counts. The ANRBC counts and were significantly infants born after PROM compared to suitable controls. We higher in infants who were born after PROM than in controls. hypothesized that higher neonatal absolute NRBC (ANRBC) counts CONCLUSIONS: would be found in infants born after PROM, compared to control infants. Infants born after PROM have higher ANRBC counts at birth than control infants. We suggest that increased fetal erythropoiesis exists in infants who are delivered after PROM. If correct, our interpretation supports the theory that fetal hypoxia and/or ischemia may result from PROM. MATERIAL AND METHODS Journal of Perinatology (2005) 25, 690–693. doi:10.1038/sj.jp.7211389; Patients published online 13 October 2005 We retrospectively analyzed the charts of all infants born at the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center from January 1, 2003 to February 29, 2004, who were admitted to our neonatal intensive care unit, and were delivered after prolonged (at least 24 hours prior to delivery) rupture of membranes. Each infant born after PROM was pair matched with the infant without PROM admitted immediately after it, with the same gestational age (±1 week), and 1- and 5-minute Apgar scores (±1 point). In an Department of Neonatology (D.M., T.O., Y.L., S.D., F.B.M.), Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel; Department of Pediatrics (T.O.), Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel; attempt to control for the various variables known to affect NRBC Department of Obstetrics and Gynecology (G.S.M.), Tel Aviv Sourasky Medical Center, Tel Aviv, counts, we excluded from the study infants born to women with Israel; and Sackler Faculty of Medicine (D.M., Y.L., S.D., F.B.M.), Tel Aviv University, Tel Aviv, 11 Israel. gestational or insulin-dependent diabetes; pregnancy-induced hypertension;12 placental abruption or placenta previa;13 any Address correspondence and reprint requests to Dror Mandel, MD, MHA, Department of Neonatology, Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, 6 Weizman Street, Tel Aviv maternal heart, kidney, lung, or other chronic condition; drug, 14 64239, Israel. tobacco (active and passive) or alcohol abuse; perinatal

Journal of Perinatology 2005; 25:690–693 r 2005 Nature Publishing Group All rights reserved. 0743-8346/05 $30 690 www.nature.com/jp Premature Rupture of Membrane and Nucleated Red Blood Cells Mandel et al.

infections (e.g., fever, leukocytosis, clinical signs of Table 1 depicts demographic and clinical characteristics of infants chorioamnionitis);15 any significant abnormality in electronic with PROM and controls. There were no significant differences intrapartum monitoring, such as decreased variability, fetal between groups for all clinical or demographic parameters tachycardia, variable decelerations or fetal bradycardia;13 or infants considered. By design, infants with PROM did not differ from controls with low Apgar scores (below 7 at 1 or 5 minutes).16 We also in terms of gestational age, birthweight and Apgar scores. excluded infants with perinatal blood loss, hemolysis (blood group Table 2 depicts the hematologic data obtained for both groups. incompatibility with positive Coombs test or hematocrit below There were no differences between the two groups in terms of 45%)17 or chromosomal anomalies.6 lymphocyte counts and counts. ANRBC count at birth and hematocrit were significantly higher in infants with PROM than in Hematologic Methods control infants. In our institution, all admitted infants undergo a routine complete In backward stepwise regression analysis, taking into account blood count, with differential count and NRBC count within the gestational age (GA), the 1- or 5-minute Apgar scores, mode of first hour of life. Venous blood samples for complete delivery and the PROM status as independent variables and the counts were analyzed according to laboratory routine using a ANRBC count as the dependent variable, only PROM (p<0.001) GEN-S counter (Beckman-Coulter Inc., Switzerland). Differential and gestational age (p<0.01) were predictors of increased ANRBC cell counts were performed manually and NRBC counts were counts. We conducted an additional backward stepwise regression counted per 100 white blood cells (WBC). We showed previously analysis taking into account GA, 1- or 5-minute Apgar scores, 18 that leukocyte counts correlate inversely with ANRBC numbers. mode of delivery, and the duration of ruptured membranes as Thus, the traditional expression of NRBC as their number per 100 independent variables, and the NRBC counts as the dependent WBC might introduce a significant bias. Therefore, we expressed variables. In this analysis, only the rupture of membrane duration the number of NRBCs as an absolute number (ANRBC) rather than predicted significantly the NRBC counts (Figure 1) (R2 ¼ 0.24, per 100 leukocytes, and the WBC count was expressed as corrected p<0.001). for the presence of NRBC.

Statistical Analysis SIGNIFICANCE Data are reported as mean±standard deviation (SD), n (%), or, for non-normally distributed variables (such as NRBCs or Apgar We found that infants born after PROM have increased ANRBC scores) as median and range. Statistical analysis included two- counts compared with suitable controls. In our study, we excluded 19 tailed paired t-test for normally distributed variables and paired SGA infants, an important confounding variable. We excluded Wilcoxon test for ANRBC or Apgar scores and w2 test or Fisher’s exact test for discrete demographic and clinical variables. Backward stepwise regression analysis was used to assess the effect of Table 1 Demographic and Perinatal Characteristics of Infants with gestational age, 1- or 5-minute Apgar scores and the PROM status PROM and Matched Controls as independent variables, with the ANRBC count as the dependent PROM* Controls* variable. A p-value <0.05 was considered significant. (n ¼ 31) (n ¼ 31) Our local Institutional Review Board approved the study. Since all infants in our institution receive a routine Administration of prenatal betamethasone 10 (32.3) 9 (29.0) including NRBC count after birth, the requirement for informed Birthweight (g) 2347±707 2444±650 consent was waived. Gestational age (weeks) 34.0±2.9 34.2±2.7 1-minute Apgar score 8 (7–9) 8 (7–9) 5-minute Apgar score 9 (9–10) 9 (8–10) RESULTS Presence of UVC 5 (16.1) 5 (16.1) Duration of UVC (days) 1±1.5 1±1.6 A total of 58 infants were eligible for the study in the PROM group. Presence of UAC 6 (20.1) 5 (16.1) In all, 27 of them were excluded because of at least one of the Duration of UAC (days) 2±1.8 1.7±1.6 exclusion criteria described in the Methods section. The 31 Infants requiring mechanical ventilation 8 (25.8) 7 (22.8) remaining infants were matched with 31 appropriate controls. Duration of ventilation (days) 3±2 3±2 Whenever an eligible control was found to meet one of the Number diagnosed with patent ductus arteriosus 6 (20) 5 (16.7) exclusion criteria, it was replaced by the next eligible control *Data are expressed as mean±SD, or n (%) except for Apgar scores, which are without exclusion criteria. A total of 13 control infants were expressed as median (range). The two groups did not differ significantly for any of the replaced in manner such that six of the infants in each group were variables considered. UVC ¼ 3D umbilical vein catheter; UAC ¼ 3D umbilical artery catheter. born at term and 25 were preterm.

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The mechanism by which PROM is associated with increased Table 2 Hematological Characteristics of Infants with PROM and Matched Controls circulating neonatal ANRBC counts is unknown. A likely explanation is relative fetal hypoxia or ischemia.6,11 In favor of PROM* Controls* p-Value a contribution of hypoxia/ischemia in the pathogenesis of PROM Hematocrit 0.55±0.07 0.50±0.04 0.03 is the fact that PROM is also associated with other indices of Absolute nucleated red 1856 (195–4580) 449 (0–1983) <0.0001 intrauterine hypoxia, such as nitric-oxide responsive pulmonary 25 26 blood cells ( Â 106/l) hypertension, necrotizing enterocolitis, fetal distress in labor, 27 28 Absolute lymphocyte 8.9±4.6 8.1±3.3 NSw fetal acidemia and low Apgar scores, and even cerebral palsy. In count ( Â 109/l) PROM, fetal hypoxia is believed to be due to fetal cord compression, w 27 Platelets ( Â 109/l) 277±104 292±56 NS which may be relieved during labor by amnio-infusion. In our *Data are expressed as mean±1 SD, except for the non-normally distributed absolute study, the presumed fetal hypoxia had been of sufficient duration nucleated RBC, which is expressed as median (range). to lead not only to an increase in ANRBC counts, but also to an wNS, not significant. increase in hematocrit. However, the lymphocyte count, also believed to be an indicator of fetal hypoxia,29 was not elevated, and 70 the platelet count, did not decrease, but these hematologic parameters might indicate acute, rather than chronic, hypoxia.11 60 An alternative theoretical explanation is that the elevation of 50 ANRBC in the PROM group would be mediated by inflammation. It has, indeed, recently demonstrated that placental inflammation 40 leads to an elevation of cord blood interleukin-6 (IL-6) 30 concentrations.30 IL-6 has been shown in vitro to lead to an

ANRBC rank 31 20 induction of erythroid progenitors, while an in vivo study showed that situations where fetal ‘‘non-reassuring status’’ is present are 10 associated with both an elevation of IL-6 and of ANRBC in cord 0 blood.32 In the present study, IL-6 concentration was not measured 0 100 200 and nor was placental histological examination routinely Rupture of membranes duration (hours) performed; thus, we can only speculate about this theory. Figure 1. Correlation between absolute nucleated In summary, we suggest that increased fetal erythropoiesis exists (ANRBC) counts, expressed by ascending rank, and the duration of in preterm infants who are delivered after PROM. If correct, our rupture of membranes. interpretation supports the theory that fetal hypoxia and/or ischemia may result from PROM. infants with other factors associated with potentially increased ANRBC counts, including hemolysis,20 chromosomal anomalies,6 11,12,21 22,23 maternal diabetes, and neurologic insults. The two References groups of our study (PROM and controls) were very similar in 1. Garite TJ. Premature rupture of the membranes. In: Creasy RK, Resnik R, birthweight, gestational age, Apgar scores, and major neonatal editors. Maternal–Fetal Medicine, 5th ed. Philadelphia: WB Saunders; 2004, complications. Thus, we believe that our study shows that as a pp. 723–39. group, infants born after PROM have increased ANRBC counts. 2. Mercer BM. Pretrem preamature rupture of the membranes. Obstet Gynecol Additionally, infants born after PROM also had increased 2003;101:178–93. hematocrit. 3. Ananth CV, Oyelese Y, Srinivas N, Yeo L, Vintzileos AM. Preterm premature These results contrast with those published in a recent study24 rupture of membranes, intrauterine infection, and oligohydramnios: risk on NRBC counts in three groups of infants born after vaginal factors for placental abruption. Obstet Gynecol 2004;104:71–7. delivery, by cesarean section after labor or by elective cesarean 4. Ernest JM. Neonatal consequences of preterm PROM. Clin Obstet Gynecol section. In that study, although NRBC counts differed significantly 1998;41:827–31. between the study groups, the duration of rupture of membranes 5. Thibeault DW, Beatty Jr EC, Hall RT, Bowen SK, O’Neill DH. Neonatal pulmonary hypoplasia with premature rupture of fetal membranes and was not found to be influential upon NRBC counts. Redzko’s24 oligohydramnios. J Pediatr 1985;107:273–7. study is significantly different from ours, in that the mean duration 6. Hermansen MC. Nucleated red blood cells in the fetus and newborn. Arch of rupture of membranes before delivery was of 301 minutes Dis Child Fetal Neonatal Ed 2001;84:F211–5. (approximately 5 hours), which probably prevented the authors of 7. Pajntar M, Verdenik I. Maternal and neonatal outcome related to delivery the study from determining the effect of prolonged rupture of time following premature rupture of membranes. Int J Gynaecol Obstet membrane upon NRBC counts. 1997;58:281–6.

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