Original Article
317
Increased Nucleated Red Blood Cells Counts in Prolonged Rupture of Membranes is not Erythropoietin Driven
1 Departments of Obstetrics and Gynecology, The Lis Maternity
Hospital and the Dana Duek Children’s Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 2 Departments of Pediatrics, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 3 Departments of Hematology, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 4 Departments of Neonatology, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 5 The Sackler School of Medicine, Tel Aviv, Israel
Neta Cohen, MD4,5
Address for correspondence Ronella Marom, MD, Department of Neonatology, Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel (e-mail: [email protected]).
Am J Perinatol 2015;32:317–320.
Abstract
Keywords
► nucleated red blood cells ► erythropoietin ► prolonged rupture of membranes ► cord blood
Objective The aim of this study is to examine the hypothesis that prolonged rupture of membranes (PROM) is associated with increased cord blood erythropoietin (EPO) concentrations, proportional to the duration of ruptured membranes. Study Design This study is a prospective, cross-sectional, observational (noninterventional) cohort study of mother–infant pairs. Criteria for inclusion were as follows: active labor with or without ruptured membranes and vaginally delivered neonates. Excluded were infants with major factors known to be associated with a potential increase in fetal erythropoiesis. Results A total of 40 mother–infant pairs were recruited. EPO was not influenced by duration of ruptured membranes and significantly correlated only with maternal body mass index. Conclusion Cord blood concentrations of EPO do not appear to be significantly affected by the duration of ruptured membranes. We speculate that erythropoiesis is upregulated in PROM by mechanisms that involve the production of cytokines and are not EPO driven.
Chorioamnionitis has been described as one of the risk factors for elevation of nucleated red blood cells (NRBC) at birth. In a study published in 2005, we showed that prolonged rupture of membranes (PROM) per se, without clinical signs of chorioamnionitis, was associated with elevated neonatal absolute NRBC (ANRBC) counts.1 However, the mechanism by which PROM is associated with increased circulating
neonatal ANRBC counts is unknown, and we speculated that this increase is erythropoietin (EPO) driven, due to relative fetal hypoxia, as a consequence of fetal cord compression.1,2 Indeed, in situations typically associated with intrauterine hypoxia, there is an elevation of ANRBC at birth; these situations include, for instance, intrauterine growth restriction,3 maternal pregnancy-induced hypertension,4
received January 29, 2014 accepted after revision June 5, 2014 published online July 31, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384643. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sarit Barak, MD1,5 Francis B. Mimouni, MD2,5 Ruth Stern, BA3 Dana Barbing Goldstein, MD1,5 Ronella Marom, MD4,5
Increased NRBC Counts in Prolonged Rupture of Membranes maternal diabetes5,6 active or passive smoking,7,8 alcohol abuse,9 chorioamnionitis,10 infants with low Apgar scores (below 8 at 1 or 5 minutes),11 abnormality in electronic intrapartum monitoring,12 perinatal blood loss,13 and chromosomal anomalies.5 We therefore conducted the following study to test the hypothesis that PROM is associated with increased cord blood EPO concentrations, proportional to the duration of ruptured membranes.
Patients and Methods Patients The study was designed as a prospective, cross-sectional, observational (noninterventional) cohort study of mother– infant pairs delivered at the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center from 2011 until 2013 and who were admitted in labor. The study was approved by our local institutional review board and a written consent form was obtained from all the mothers recruited into the study. Patients were consecutively selected during night duties of two of the investigators (S.B. and D.B.). Criteria for inclusion were that patients were admitted in active labor with or without ruptured membranes and who delivered vaginally. As described in our previous study, we attempted to control for the various variables known to affect ANRBC counts by excluding from the study infants born to women with gestational or insulin-dependent diabetes; pregnancy-induced hypertension; placental abruption or placenta previa; any maternal heart, kidney, lung, or other chronic condition; drug, tobacco, or alcohol abuse; perinatal infections (e.g., fever, leukocytosis, clinical signs of chorioamnionitis); any abnormality in electronic intrapartum monitoring; or infants with low Apgar scores (below 8 at 1 or 5 minutes). We also excluded infants with perinatal blood loss, hemolysis (blood group incompatibility with positive Coombs test or hematocrit below 45%) or chromosomal anomalies.
Hematologic Methods At birth, venous cord blood was collected from a doubleclamped segment of cord. Plasma was obtained after centri-
Barak et al.
fugation and frozen until EPO analysis. EPO was measured by using the Quantikine In Vitro Diagnostic EPO ELISA (R&D Systems, Minneapolis, MN) (normal adult range, 3–16 mIU/mL; intra-assay coefficient of variation, 2.3% at 42 IU/L and 2.4 at 13 IU/L; interassay coefficient of variation, 5.2 and 3.4%, respectively).
Statistical Analysis The study was designed as a pilot one that would enable to calculate the sample size necessary for a larger, definitive study. We therefore elected to recruit 30 to 40 consecutive children. Data are reported as mean standard deviation, n (%), or for nonnormally distributed variables (such as nucleated RBC’s or Apgar scores) as median (range). For the purpose of analyses, we used the 2011 ACOG definition of prolonged rupture of membranes (PROM) as a duration of ruptured membranes of > 18 hours.16 Statistical analysis included two-tailed paired t-test for normally distributed variables and paired Wilcoxon test for ANRBC or Apgar scores and chi-square test or Fisher exact test for discrete demographic and clinical variables. Backward stepwise regression analysis was used to assess the effect of gestational age, 1- or 5-minute Apgar scores and the PROM status as independent variables on the absolute nucleated RBC count as the dependent variable. A p value < 0.05 was considered significant.
Results A total of 40 mother–infant pairs were recruited that met the inclusion criteria. ►Table 1 depicts some major demographic and clinical characteristics of the patients recruited. The cord serum EPO concentrations are shown in ►Fig. 1. There was no significant correlation between EPO concentrations and time of ruptured membranes. We then conducted a backward stepwise regression analysis to assess whether EPO (dependent variable) could be influenced by the duration of ruptured membranes while taking into account possible confounding variables such as gestational age, 1- or 5-minute Apgar scores, or maternal body mass index (BMI).14 In this analysis again, EPO was not influenced by duration of ruptured membranes and only maternal BMI was weakly, but
Table 1 Demographic and perinatal characteristics of the study participants. Mean SD
Variable
Median (range)
Percentage
Maternal age (y)
32 5
32 (23–42)
NA
Maternal BMI (kg/m2)
23.2 3.4
22.0 (17.0–35.5)
NA
Parity
2.3 1.7
2 (1–9)
NA
Gestational age (wk)
38.5 1.7
39 (34–42)
NA
Birth weight (g)
3,217 432
3,300 (2,060–4,000)
NA
Apgar score 1 min
8.7 0.8
9 (7–9)
NA
Apgar score 5 min
9.8 0.4
10 (8–10)
NA
Gender (% males)
NA
NA
52
Length of ruptured membranes (min)
1,409 2,397
760 (0–1,1458)
NA
Abbreviations: BMI, body mass index; SD, standard deviation. Note: Data are expressed as mean SD, median and range, or n (%). American Journal of Perinatology
Vol. 32
No. 4/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
318
Fig. 1 Cord blood erythropoietin concentration (mIU/mL) (y-axis) versus duration of ruptured membranes (hours) (x-axis). EPO, erythropoietin.
Fig. 2 Cord blood EPO concentration (mIU/mL) (y-axis) versus body mass index (BMI) (kg/m2) (x-axis). In this analysis, EPO was significantly correlated with BMI (R2 ¼ 0.12, p ¼ 0.04). BMI, body mass index; EPO, erythropoietin.
volving the production of cytokines during PROM. Indeed, many inflammatory cytokines are elevated in maternal and cord serum of infants delivered after PROM17,18 and it is known that cytokines such as interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor receptors share a common β chain. Both cytokines enhance EPO-dependent in vitro erythropoiesis by primary hematopoietic progenitors and factor-dependent cells because of functional and physical interaction of the β chain with the EPO receptor.19 Both IL-3 and GM-CSF have burst promoting activity and bind to specific receptors on erythroid progenitor cells.19 Thus, it is theoretically possible that inflammatory molecules that have a synergistic effect on EPO, rather than elevation of EPO itself, are responsible for the increased erythropoiesis that we reported in PROM. This hypothesis is currently under investigation in our laboratory. The strength of our study is that we excluded important confounding variables that may affect fetal oxygenation were excluded, as mentioned in the Patients and Methods section. A limitation is the relatively small sample size, which leaves room for a large type 2 error. Nevertheless, there appears to be no trend whatsoever between duration of ruptured membranes and cord blood concentrations of EPO. In summary, we showed that duration of ruptured membranes does not appear to affect cord serum EPO concentrations. More studies are needed to investigate whether or not inflammatory cytokines are involved in the mechanism of increased fetal erythropoiesis in PROM.
References 1 Mandel D, Oron T, Mimouni GS, Littner Y, Dollberg S, Mimouni FB.
significantly correlated with EPO (R2 ¼ 0.12, p ¼ 0.04) (►Fig. 2).
2
Discussion
3
Contrary to our hypothesis, we found that in neonates, cord blood EPO concentrations do not appear to be significantly affected by the duration of ruptured membranes. In a previous study, we showed that infants born after PROM have increased ANRBC counts compared with suitable controls.1 The earlier mentioned study was the basis for the current one, which aimed to verify the speculation that increased ANRBC counts in PROM is driven by relative fetal hypoxemia (maybe due to cord compression2 and subsequent EPO driven erythropoiesis). This study, although a pilot one, does not allow in any fashion to confirm this hypothesis. If increased erythropoiesis in PROM is not EPO driven, one must speculate that it might be driven by other mechanism (s). A theoretical one that remains to be proven, is that erythropoiesis is upregulated in PROM by mechanisms in-
Barak et al.
4
5 6
7
8
9
The effect of prolonged rupture of membranes on circulating neonatal nucleated red blood cells. J Perinatol 2005;25(11): 690–693 Nageotte MP, Bertucci L, Towers CV, Lagrew DL, Modanlou H. Prophylactic amnioinfusion in pregnancies complicated by oligohydramnios: a prospective study. Obstet Gynecol 1991;77(5): 677–680 Shuper A, Mimouni F, Merlob P, Zaizov R, Reisner SH. Thrombocytopenia in small-for-gestational-age infants. Acta Paediatr Scand 1983;72(1):139–140 Sinha HB, Mukherjee AK, Bala D. Cord blood haemoglobin (including foetal haemoglobin), and nucleated red cells in normal and toxaemic pregnancies. Indian Pediatr 1972;9(9): 540–543 Oski FA, Naiman JL. Hematologic Problems in the Newborn. 2nd ed Philadelphia, PA: W. B. Saunders Co.; 1972:15–17 Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet Gynecol 1986;68(3):370–372 Yeruchimovich M, Dollberg S, Green DW, Mimouni FB. Nucleated red blood cells in infants of smoking mothers. Obstet Gynecol 1999;93(3):403–406 Dollberg S, Fainaru O, Mimouni FB, Shenhav M, Lessing JB, Kupferminc M. Effect of passive smoking in pregnancy on neonatal nucleated red blood cells. Pediatrics 2000;106(3):E34 Halmesmäki E, Teramo KA, Widness JA, Clemons GK, Ylikorkala O. Maternal alcohol abuse is associated with elevated fetal erythropoietin levels. Obstet Gynecol 1990;76(2):219–222 American Journal of Perinatology
Vol. 32
No. 4/2015
319
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Increased NRBC Counts in Prolonged Rupture of Membranes
Increased NRBC Counts in Prolonged Rupture of Membranes 10 Leikin E, Garry D, Visintainer P, Verma U, Tejani N. Correlation of
11
12
13
14
15
neonatal nucleated red blood cell counts in preterm infants with histologic chorioamnionitis. Am J Obstet Gynecol 1997;177(1): 27–30 Hanlon-Lundberg KM, Kirby RS. Nucleated red blood cells as a marker of acidemia in term neonates. Am J Obstet Gynecol 1999; 181(1):196–201 Korst LM, Phelan JP, Ahn MO, Martin GI. Nucleated red blood cells: an update on the marker for fetal asphyxia. Am J Obstet Gynecol 1996;175(4 Pt 1):843–846 Thomas RM, Canning CE, Cotes PM, et al. Erythropoietin and cord blood haemoglobin in the regulation of human fetal erythropoiesis. Br J Obstet Gynaecol 1983;90(9):795–800 Sheffer-Mimouni G, Mimouni FB, Dollberg S, Mandel D, Deutsch V, Littner Y. Neonatal nucleated red blood cells in infants of overweight and obese mothers. J Am Coll Nutr 2007;26(3):259–263 Satar M, Turhan E, Yapicioglu H, Narli N, Ozgunen FT, Cetiner S. Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship
American Journal of Perinatology
Vol. 32
No. 4/2015
16
17
18
19
Barak et al. with morbidity and mortality. Eur Cytokine Netw 2008;19(1): 37–41 Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R. Histologic chorioamnionitis and umbilical serum levels of proinflammatory cytokines and cytokine inhibitors. BJOG 2002; 109(5):534–539 Satar M, Turhan E, Yapicioglu H, Narli N, Ozgunen FT, Cetiner S. Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship with morbidity and mortality. Eur Cytokine Netw 2008;19(1): 37–41 Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R. Histologic chorioamnionitis and umbilical serum levels of proinflammatory cytokines and cytokine inhibitors. BJOG 2002; 109(5):534–539 Sieff CA, Schrier SL, Landaw SA, Regulation of erythropoiesis, in upto-date reviews, retrieved on May 4, 2014, at: http://www.uptodate.com/contents/regulation-of-erythropoiesis/contributors? utdPopup=true
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
320
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
317
Increased Nucleated Red Blood Cells Counts in Prolonged Rupture of Membranes is not Erythropoietin Driven
1 Departments of Obstetrics and Gynecology, The Lis Maternity
Hospital and the Dana Duek Children’s Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 2 Departments of Pediatrics, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 3 Departments of Hematology, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 4 Departments of Neonatology, The Lis Maternity Hospital and the Dana Duek Childrens Hospital, The Tel Aviv Medical Center, Tel Aviv, Israel 5 The Sackler School of Medicine, Tel Aviv, Israel
Neta Cohen, MD4,5
Address for correspondence Ronella Marom, MD, Department of Neonatology, Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel (e-mail: [email protected]).
Am J Perinatol 2015;32:317–320.
Abstract
Keywords
► nucleated red blood cells ► erythropoietin ► prolonged rupture of membranes ► cord blood
Objective The aim of this study is to examine the hypothesis that prolonged rupture of membranes (PROM) is associated with increased cord blood erythropoietin (EPO) concentrations, proportional to the duration of ruptured membranes. Study Design This study is a prospective, cross-sectional, observational (noninterventional) cohort study of mother–infant pairs. Criteria for inclusion were as follows: active labor with or without ruptured membranes and vaginally delivered neonates. Excluded were infants with major factors known to be associated with a potential increase in fetal erythropoiesis. Results A total of 40 mother–infant pairs were recruited. EPO was not influenced by duration of ruptured membranes and significantly correlated only with maternal body mass index. Conclusion Cord blood concentrations of EPO do not appear to be significantly affected by the duration of ruptured membranes. We speculate that erythropoiesis is upregulated in PROM by mechanisms that involve the production of cytokines and are not EPO driven.
Chorioamnionitis has been described as one of the risk factors for elevation of nucleated red blood cells (NRBC) at birth. In a study published in 2005, we showed that prolonged rupture of membranes (PROM) per se, without clinical signs of chorioamnionitis, was associated with elevated neonatal absolute NRBC (ANRBC) counts.1 However, the mechanism by which PROM is associated with increased circulating
neonatal ANRBC counts is unknown, and we speculated that this increase is erythropoietin (EPO) driven, due to relative fetal hypoxia, as a consequence of fetal cord compression.1,2 Indeed, in situations typically associated with intrauterine hypoxia, there is an elevation of ANRBC at birth; these situations include, for instance, intrauterine growth restriction,3 maternal pregnancy-induced hypertension,4
received January 29, 2014 accepted after revision June 5, 2014 published online July 31, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384643. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sarit Barak, MD1,5 Francis B. Mimouni, MD2,5 Ruth Stern, BA3 Dana Barbing Goldstein, MD1,5 Ronella Marom, MD4,5
Increased NRBC Counts in Prolonged Rupture of Membranes maternal diabetes5,6 active or passive smoking,7,8 alcohol abuse,9 chorioamnionitis,10 infants with low Apgar scores (below 8 at 1 or 5 minutes),11 abnormality in electronic intrapartum monitoring,12 perinatal blood loss,13 and chromosomal anomalies.5 We therefore conducted the following study to test the hypothesis that PROM is associated with increased cord blood EPO concentrations, proportional to the duration of ruptured membranes.
Patients and Methods Patients The study was designed as a prospective, cross-sectional, observational (noninterventional) cohort study of mother– infant pairs delivered at the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center from 2011 until 2013 and who were admitted in labor. The study was approved by our local institutional review board and a written consent form was obtained from all the mothers recruited into the study. Patients were consecutively selected during night duties of two of the investigators (S.B. and D.B.). Criteria for inclusion were that patients were admitted in active labor with or without ruptured membranes and who delivered vaginally. As described in our previous study, we attempted to control for the various variables known to affect ANRBC counts by excluding from the study infants born to women with gestational or insulin-dependent diabetes; pregnancy-induced hypertension; placental abruption or placenta previa; any maternal heart, kidney, lung, or other chronic condition; drug, tobacco, or alcohol abuse; perinatal infections (e.g., fever, leukocytosis, clinical signs of chorioamnionitis); any abnormality in electronic intrapartum monitoring; or infants with low Apgar scores (below 8 at 1 or 5 minutes). We also excluded infants with perinatal blood loss, hemolysis (blood group incompatibility with positive Coombs test or hematocrit below 45%) or chromosomal anomalies.
Hematologic Methods At birth, venous cord blood was collected from a doubleclamped segment of cord. Plasma was obtained after centri-
Barak et al.
fugation and frozen until EPO analysis. EPO was measured by using the Quantikine In Vitro Diagnostic EPO ELISA (R&D Systems, Minneapolis, MN) (normal adult range, 3–16 mIU/mL; intra-assay coefficient of variation, 2.3% at 42 IU/L and 2.4 at 13 IU/L; interassay coefficient of variation, 5.2 and 3.4%, respectively).
Statistical Analysis The study was designed as a pilot one that would enable to calculate the sample size necessary for a larger, definitive study. We therefore elected to recruit 30 to 40 consecutive children. Data are reported as mean standard deviation, n (%), or for nonnormally distributed variables (such as nucleated RBC’s or Apgar scores) as median (range). For the purpose of analyses, we used the 2011 ACOG definition of prolonged rupture of membranes (PROM) as a duration of ruptured membranes of > 18 hours.16 Statistical analysis included two-tailed paired t-test for normally distributed variables and paired Wilcoxon test for ANRBC or Apgar scores and chi-square test or Fisher exact test for discrete demographic and clinical variables. Backward stepwise regression analysis was used to assess the effect of gestational age, 1- or 5-minute Apgar scores and the PROM status as independent variables on the absolute nucleated RBC count as the dependent variable. A p value < 0.05 was considered significant.
Results A total of 40 mother–infant pairs were recruited that met the inclusion criteria. ►Table 1 depicts some major demographic and clinical characteristics of the patients recruited. The cord serum EPO concentrations are shown in ►Fig. 1. There was no significant correlation between EPO concentrations and time of ruptured membranes. We then conducted a backward stepwise regression analysis to assess whether EPO (dependent variable) could be influenced by the duration of ruptured membranes while taking into account possible confounding variables such as gestational age, 1- or 5-minute Apgar scores, or maternal body mass index (BMI).14 In this analysis again, EPO was not influenced by duration of ruptured membranes and only maternal BMI was weakly, but
Table 1 Demographic and perinatal characteristics of the study participants. Mean SD
Variable
Median (range)
Percentage
Maternal age (y)
32 5
32 (23–42)
NA
Maternal BMI (kg/m2)
23.2 3.4
22.0 (17.0–35.5)
NA
Parity
2.3 1.7
2 (1–9)
NA
Gestational age (wk)
38.5 1.7
39 (34–42)
NA
Birth weight (g)
3,217 432
3,300 (2,060–4,000)
NA
Apgar score 1 min
8.7 0.8
9 (7–9)
NA
Apgar score 5 min
9.8 0.4
10 (8–10)
NA
Gender (% males)
NA
NA
52
Length of ruptured membranes (min)
1,409 2,397
760 (0–1,1458)
NA
Abbreviations: BMI, body mass index; SD, standard deviation. Note: Data are expressed as mean SD, median and range, or n (%). American Journal of Perinatology
Vol. 32
No. 4/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
318
Fig. 1 Cord blood erythropoietin concentration (mIU/mL) (y-axis) versus duration of ruptured membranes (hours) (x-axis). EPO, erythropoietin.
Fig. 2 Cord blood EPO concentration (mIU/mL) (y-axis) versus body mass index (BMI) (kg/m2) (x-axis). In this analysis, EPO was significantly correlated with BMI (R2 ¼ 0.12, p ¼ 0.04). BMI, body mass index; EPO, erythropoietin.
volving the production of cytokines during PROM. Indeed, many inflammatory cytokines are elevated in maternal and cord serum of infants delivered after PROM17,18 and it is known that cytokines such as interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor receptors share a common β chain. Both cytokines enhance EPO-dependent in vitro erythropoiesis by primary hematopoietic progenitors and factor-dependent cells because of functional and physical interaction of the β chain with the EPO receptor.19 Both IL-3 and GM-CSF have burst promoting activity and bind to specific receptors on erythroid progenitor cells.19 Thus, it is theoretically possible that inflammatory molecules that have a synergistic effect on EPO, rather than elevation of EPO itself, are responsible for the increased erythropoiesis that we reported in PROM. This hypothesis is currently under investigation in our laboratory. The strength of our study is that we excluded important confounding variables that may affect fetal oxygenation were excluded, as mentioned in the Patients and Methods section. A limitation is the relatively small sample size, which leaves room for a large type 2 error. Nevertheless, there appears to be no trend whatsoever between duration of ruptured membranes and cord blood concentrations of EPO. In summary, we showed that duration of ruptured membranes does not appear to affect cord serum EPO concentrations. More studies are needed to investigate whether or not inflammatory cytokines are involved in the mechanism of increased fetal erythropoiesis in PROM.
References 1 Mandel D, Oron T, Mimouni GS, Littner Y, Dollberg S, Mimouni FB.
significantly correlated with EPO (R2 ¼ 0.12, p ¼ 0.04) (►Fig. 2).
2
Discussion
3
Contrary to our hypothesis, we found that in neonates, cord blood EPO concentrations do not appear to be significantly affected by the duration of ruptured membranes. In a previous study, we showed that infants born after PROM have increased ANRBC counts compared with suitable controls.1 The earlier mentioned study was the basis for the current one, which aimed to verify the speculation that increased ANRBC counts in PROM is driven by relative fetal hypoxemia (maybe due to cord compression2 and subsequent EPO driven erythropoiesis). This study, although a pilot one, does not allow in any fashion to confirm this hypothesis. If increased erythropoiesis in PROM is not EPO driven, one must speculate that it might be driven by other mechanism (s). A theoretical one that remains to be proven, is that erythropoiesis is upregulated in PROM by mechanisms in-
Barak et al.
4
5 6
7
8
9
The effect of prolonged rupture of membranes on circulating neonatal nucleated red blood cells. J Perinatol 2005;25(11): 690–693 Nageotte MP, Bertucci L, Towers CV, Lagrew DL, Modanlou H. Prophylactic amnioinfusion in pregnancies complicated by oligohydramnios: a prospective study. Obstet Gynecol 1991;77(5): 677–680 Shuper A, Mimouni F, Merlob P, Zaizov R, Reisner SH. Thrombocytopenia in small-for-gestational-age infants. Acta Paediatr Scand 1983;72(1):139–140 Sinha HB, Mukherjee AK, Bala D. Cord blood haemoglobin (including foetal haemoglobin), and nucleated red cells in normal and toxaemic pregnancies. Indian Pediatr 1972;9(9): 540–543 Oski FA, Naiman JL. Hematologic Problems in the Newborn. 2nd ed Philadelphia, PA: W. B. Saunders Co.; 1972:15–17 Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet Gynecol 1986;68(3):370–372 Yeruchimovich M, Dollberg S, Green DW, Mimouni FB. Nucleated red blood cells in infants of smoking mothers. Obstet Gynecol 1999;93(3):403–406 Dollberg S, Fainaru O, Mimouni FB, Shenhav M, Lessing JB, Kupferminc M. Effect of passive smoking in pregnancy on neonatal nucleated red blood cells. Pediatrics 2000;106(3):E34 Halmesmäki E, Teramo KA, Widness JA, Clemons GK, Ylikorkala O. Maternal alcohol abuse is associated with elevated fetal erythropoietin levels. Obstet Gynecol 1990;76(2):219–222 American Journal of Perinatology
Vol. 32
No. 4/2015
319
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Increased NRBC Counts in Prolonged Rupture of Membranes
Increased NRBC Counts in Prolonged Rupture of Membranes 10 Leikin E, Garry D, Visintainer P, Verma U, Tejani N. Correlation of
11
12
13
14
15
neonatal nucleated red blood cell counts in preterm infants with histologic chorioamnionitis. Am J Obstet Gynecol 1997;177(1): 27–30 Hanlon-Lundberg KM, Kirby RS. Nucleated red blood cells as a marker of acidemia in term neonates. Am J Obstet Gynecol 1999; 181(1):196–201 Korst LM, Phelan JP, Ahn MO, Martin GI. Nucleated red blood cells: an update on the marker for fetal asphyxia. Am J Obstet Gynecol 1996;175(4 Pt 1):843–846 Thomas RM, Canning CE, Cotes PM, et al. Erythropoietin and cord blood haemoglobin in the regulation of human fetal erythropoiesis. Br J Obstet Gynaecol 1983;90(9):795–800 Sheffer-Mimouni G, Mimouni FB, Dollberg S, Mandel D, Deutsch V, Littner Y. Neonatal nucleated red blood cells in infants of overweight and obese mothers. J Am Coll Nutr 2007;26(3):259–263 Satar M, Turhan E, Yapicioglu H, Narli N, Ozgunen FT, Cetiner S. Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship
American Journal of Perinatology
Vol. 32
No. 4/2015
16
17
18
19
Barak et al. with morbidity and mortality. Eur Cytokine Netw 2008;19(1): 37–41 Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R. Histologic chorioamnionitis and umbilical serum levels of proinflammatory cytokines and cytokine inhibitors. BJOG 2002; 109(5):534–539 Satar M, Turhan E, Yapicioglu H, Narli N, Ozgunen FT, Cetiner S. Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship with morbidity and mortality. Eur Cytokine Netw 2008;19(1): 37–41 Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R. Histologic chorioamnionitis and umbilical serum levels of proinflammatory cytokines and cytokine inhibitors. BJOG 2002; 109(5):534–539 Sieff CA, Schrier SL, Landaw SA, Regulation of erythropoiesis, in upto-date reviews, retrieved on May 4, 2014, at: http://www.uptodate.com/contents/regulation-of-erythropoiesis/contributors? utdPopup=true
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
320
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
