JACN
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sheffer-Mimouni, G.
Right arrow Articles by Littner, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sheffer-Mimouni, G.
Right arrow Articles by Littner, Y.
Journal of the American College of Nutrition, Vol. 26, No. 3, 259-263 (2007)
Published by the American College of Nutrition

Neonatal Nucleated Red Blood Cells in Infants of Overweight and Obese Mothers

Galit Sheffer-Mimouni, MD, Francis B. Mimouni, MD, FACN, Shaul Dollberg, MD, FACN, Dror Mandel, MD, Varda Deutsch, PhD and Yoav Littner, MD

Departments of Obstetrics and Gynecology, the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, and the Sackler School of Medicine, Tel Aviv, ISRAEL
Departments of Neonatology, the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, and the Sackler School of Medicine, Tel Aviv, ISRAEL
Departments of Hematology, the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, and the Sackler School of Medicine, Tel Aviv, ISRAEL

Address reprint requests to: Shaul Dollberg, MD, Department of Neonatology, Lis Maternity Hospital, Tel Aviv, Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, ISRAEL. E-mail: dollberg{at}tasmc.health.gov.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: The perinatal outcome of the infant of obese mother is adversely affected and in theory, may involve fetal hypoxia. We hypothesized that an index of fetal hypoxia, the neonatal nucleated red blood cell (NRBC) count, is elevated in infants of overweight and obese mothers.

Study Design: Absolute NRBC counts taken during the first 12 hours of life in 41 infants of overweight and obese mothers were compared to 28 controls.

Results: Maternal body mass index and infant birthweight were significantly higher in the overweight and obese group (P < 0.01). Hematocrit, corrected white blood cell and lymphocyte counts did not differ between groups. The absolute NRBC count was higher (P = 0.01), and the platelet count lower (P = 0.05) in infants of overweight and obese mothers than in controls. In stepwise regression analysis, the absolute NRBC count in infants of overweight and obese mothers remained significantly higher even after taking into account birthweight or gestational age and Apgar scores (P < 0.02).

Conclusion: Infants of overweight and obese mothers have increased nucleated red blood cells at birth compared with controls. We speculate that even apparently healthy fetuses of overweight and obese mothers are exposed to a subtle hypoxemic environment.

Key words: fetal hypoxemia, obesity, nucleated red blood cells, term infants

Abbreviations: BMI = body mass index • NRBC = nucleated red blood cells • WBC = white blood cells


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The incidence of obesity has significantly increased over the past 20 years [1, 2]. The perinatal outcome of infants of obese mothers is significantly worse than that of infants born to control mothers in terms of both perinatal and neonatal morbidity and mortality, and in particular in terms of increased rates of intrauterine fetal death [2–4]. The mechanism by which the perinatal outcome of the infant of an obese mother is affected is not clear, but might involve fetal hypoxia.

We hypothesized that a recognized marker of prolonged fetal hypoxia, the absolute number of circulating nucleated red blood cells (NRBC) [5–7], measured at birth, is increased in infants of overweight and obese mothers, compared to singleton controls.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We prospectively studied two groups of singleton term infants (38–41 weeks gestation by last menstrual period, confirmed by early ultrasound), delivered at the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center between January 1, 2000 and September 30, 2003. In each group, infants underwent a spontaneous vaginal delivery, or an elective cesarean delivery by patient request for repeat cesarean delivery. We have shown in a previous study that the mode of delivery per se, or the presence or absence or duration of physiologic labor does not affect the NRBC count [8]. Appropriateness for gestational age was determined using the Lubchenco intrauterine growth charts [9], which have been shown to be similar to locally established curves developed in Beer Sheva, Israel (unpublished data); infants were recruited consecutively whenever one of the authors (GSM) was on call. Group 1 consisted of 41 infants of mothers with excess weight and group 2, of 28 singleton control infants. The excess weight group was composed of 21 overweight women (pre-pregnancy with body mass index (BMI = weight (kg)/height2 (m2)) of 25 kg/m2 or greater, but lower than 30 kg/m2) and of 20 obese women (pre-pregnancy BMI of 30 kg/m2 and greater). Control mothers had a pre-pregnancy BMI ranging from >20 to <25 kg/m2. All infants were Caucasians of Jewish origin. In both groups we excluded infants with other factors associated with a potential increase in absolute NRBC counts, as described by us and others, such as small for gestational age infants [10], pregnancy-induced hypertension [11]; placental abruption or placenta previa; any maternal heart, kidney, other lung, or other chronic condition; maternal asthma [12]; maternal drug, active [13] or passive [14] tobacco exposure or alcohol abuse [6, 15]; perinatal infections (e.g. fever, leukocytosis, signs of chorioamnionitis) [16]; abnormal electronic intrapartum monitoring [17, 18]; or infants with low Apgar scores (below 7 at 1 or 5 minutes). We also excluded infants with perinatal blood loss, meconium stained amniotic fluid [19], hemolysis (blood group incompatibility with positive Coombs test) [20] or chromosomal anomalies [21]. In both groups, a glucose challenge test was performed at 24–28 weeks of gestation, and infants born to women with gestational or insulin-dependent diabetes were excluded as well [22, 23]. Cord blood gases were not routinely obtained in all these apparently low risk, uncomplicated deliveries.

Capillary blood samples for complete blood cell counts were collected from the infant within 12 hours of birth and analyzed according to laboratory routine using a GEN-S counter (Beckman-Coulter Inc. Switzerland). Differential cell counts were performed manually and absolute NRBC counts were counted per 100 white blood cells (WBC). We showed previously that leukocyte counts and absolute NRBC numbers are not independent [5]; thus, traditional expression of NRBC as their number per 100 white blood cells might introduce a significant bias [5]. Therefore, we expressed the number of NRBC as an absolute number rather than per 100 leukocytes, and both WBC and lymphocyte counts were expressed as corrected for the presence of NRBC [24].

Our local Institutional Review Board approved the study. Since all newborn infants in our hospital are screened routinely for polycythemia with complete blood count by 12 hours of life, the requirement for informed consent was waived.

We aimed for a sample size of approximately 30 infants in each group because when n > 30, the mean of a given variable in samples obtained from a given population approximates the normal distribution [25]. Statistical analysis included Kruskal-Wallis test for non-normally distributed variables, and Student t-tests for normally distributed variables. Backward stepwise regression analysis was used to determine the influence of potential confounders such as birthweight, gestational age, or Apgar scores upon the absolute NRBC counts. Data are reported as mean ± standard deviation SD or median (range). A P value <0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Table 1 depicts the demographic and hematologic characteristics of our patient population. There were no differences between groups in maternal age, gravidity, parity, but, as expected, the pre-pregnancy BMI was significantly higher in the overweight and obese mothers (P = 0.001). Infant birthweight was significantly higher in the overweight and obese mothers group (P < 0.001), while there were no significant differences between groups in terms of gestational age, sex, and 1- and 5-minute Apgar scores. The hematocrit level, the absolute leukocyte count and the absolute lymphocyte count did not differ significantly between groups, while the absolute NRBC count was significantly higher (P = 0.01) and the platelet count, lower (P = 0.05), in the overweight and obese group than in controls, although BMI and absolute NRBC were not linearly correlated. In backward stepwise multiple regression using the absolute NRBC count as the dependent variable, and the overweight-obese status (yes/no), maternal age, parity, gestational age or birthweight or birthweight z score and Apgar scores (1- or 5-minute) as independent variables, overweight-obese status remained the only variable significantly affecting the absolute NRBC count (R2 = 0.09, p < 0.02). When we used the platelet count as the dependent variable, and overweight-obese status (yes/no), maternal age, parity, gestational age or birthweight or birthweight z score and Apgar scores (1- or 5-minute) as independent variables, gestational age and overweight-obese status remained the only variables significantly affecting the platelet count.


View this table:
[in this window]
[in a new window]

  		Table 1. Demographic and Hematologic Characteristics*

 

   DISCUSSION
 
To the best of our knowledge, and from a Medline search including the words nucleated red blood cells, newborn, fetus, maternal obesity and maternal overweight, our study is the first to find that maternal overweight and obesity are associated with an increase in NRBC count, and a decrease in platelet count in term infants. In our study we excluded SGA infants, an important confounding variable. We also excluded infants with other factors associated with potential increase in absolute NRBC counts, including preterm labor with histological placental signs of chorioamnionitis [13], maternal smoking [6], meconium stained amniotic fluid [16], hemolysis, chromosomal anomalies [18], maternal diabetes [5, 20], and potential neurological insults [14, 26].

In our patient population, there was an expected higher birthweight in infants of overweight and obese mothers than in controls. Since in a previous study we showed that large for dates infants of non-diabetic mothers may have increased NRBC counts, we conducted a multiple regression analysis which confirmed that the absolute NRBC count was higher in infants of overweight and obese mothers even after taking into account birthweight. Thus, our study supports the hypothesis that maternal excessive weight is an independent risk factor for an increased newborn absolute NRBC counts.

The mechanism by which maternal excessive weight increases circulating neonatal absolute NRBC counts is unknown. A likely explanation is fetal hypoxia. In our study, this hypoxia was apparently of insufficient duration and/or intensity to cause an increase in hematocrit. However, the platelet count was at the limit of statistical significance (p = 0.05) for being lower in infants of overweight and obese mothers, which is in support of the theory of an erythropoietin-induced shift of the multipotent stem-cell in favor of erythropoiesis, and at the expense of thrombopoiesis [10, 27]. However, other theories are possible, and may include decreased platelet life span, increased apoptosis and others. In the present study, the corrected lymphocyte counts were very similar in infants of overweight and obese mothers as compared to controls. We and others have reported on the elevation of neonatal lymphocyte counts in hypoxic fetuses [7, 27, 28], but elevated lymphocyte counts may be a marker of a more acute, rather than chronic hypoxia [27, 28]; nevertheless, to date, there is no known mechanism explaining this elevation.

Our speculation of fetal hypoxia in infants of overweight and obese mothers is supported by the previously described higher incidence of intrauterine fetal death [3, 4, 29] in pregnancies complicated by maternal obesity. These studies did not try to determine the relative influence of obesity, and that of the frequently associated gestational diabetes [4]. In our study, we carefully excluded all women diagnosed with gestational diabetes by glucose challenge test confirmed or by a 100 g- oral glucose-tolerance test. However it is possible that some of our patients were born to mothers with under-diagnosed maternal diabetes due to failure of the glucose challenge test to recognize all women with gestational diabetes [30]. Another potential explanation is that fetal hypoxia was related to some metabolic imbalance associated with overweight and obesity, such as an increase in circulating intermediary metabolite concentrations e.g. ketones [31]. Indeed, in several animal models, increased maternal or fetal ketonemia has been shown to induce fetal hypoxemia [32, 33]. Another potential explanation might be linked to sleep-apnea induced hypoxia in overweight and obese pregnant women [34]. In our study, cord blood gases were not obtained in all these apparently low risk, uncomplicated deliveries. Cord blood gases do not reflect the "chronic" metabolic milieu of the fetus, but are rather influenced by acute (intrapartum) changes in fetal oxygenation, and therefore we chose to study absolute NRBC.

It may appear as paradoxical that infants in the study group, if relatively hypoxic, did not have decreased fetal growth. Indeed, if present, decreased fetal growth rate would indeed be an excellent additional index of decreased oxygenation. However, infants such as infants of diabetic mothers also suffer from enhanced growth, together with being at risk for decreased fetal oxygenation [22, 23]. By design, we excluded from both control and study groups small for gestational age infants, who are known to have increased NRBC counts [10]. Thus, we did not expect to find infants with decreased fetal growth in this study. Nevertheless we conclude that maternal excessive weight, even when leading to apparently "healthy" infants, affects in a subtle manner the erythropoiesis of the fetus. The clinical significance of our observation cannot be determined from our study where, by design we excluded poor outcomes such as low Apgar scores, meconium-stained amniotic fluid, abnormal fetal monitoring, etc. ... Thus our study cannot evaluate the epidemiologic risks of maternal overweight and obesity upon perinatal outcome. Moreover, while NRBC are recognized indices of fetal hypoxia, they do not necessarily indicate brain damage [35]. However, from a pathophysiological and medico-legal standpoint, it allows us to conclude that maternal overweight and obesity must be added to the list of maternal conditions that elevate the absolute nucleated RBC count and decrease the platelet count.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Dr Emilia Klebanov, hematology laboratory, for assistance in the performance of blood smear analysis for this study.

Received October 11, 2004. Accepted July 11, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Grantmakers in Health, Washington, DC: Weighing in on obesity: America's growing health epidemic.Issue Brief (Grantmakers Health).111 :1 –32,2001 .
  2. Ehrenberg HM, Dierker L, Milluzzi C, Mercer BM: Prevalence of maternal obesity in an urban center.Am J Obstet Gynecol187 :1189 –1193,2000 .
  3. Froen JF, Arnestad M, Vege A, Irgens LM, Rognum TO, Saugstad OD, Stray-Pedersen B: Comparative epidemiology of sudden infant death syndrome and sudden intrauterine unexplained death.Arch Dis Child Fetal Neonatal Ed87 :F118 –F121,2002 .[Abstract/Free Full Text]
  4. Castro LC, Avina RL: Maternal obesity and pregnancy outcomes.Curr Opin Ostet Gynecol14 :601 –606,2002 .
  5. Green DW, Mimouni F: Nucleated erythrocytes in healthy infants and in infants of diabetic mothers.J Pediatr116 :129 –131,1990 .[Medline]
  6. Yeruchimovich M, Dollberg S, Green DW, Mimouni FB: Nucleated red blood cells in infants of smoking mothers.Obstet Gynecol93 :403 –406,1999 .[Medline]
  7. Naeye RL, Localio R: Determining the time before birth when ischemia and hypoxemia initiated cerebral palsy.Obstet Gynecol86 :713 –719,1995 .[Medline]
  8. Sheffer-Mimouni G, Mimouni FB, Lubetzky R, Kupferminc M, Deutsch V, Dollberg S: Labor does not affect the neonatal absolute nucleated red blood cell count.Am J Perinatol20 :367 –371,2003 .[Medline]
  9. Lubchenco LO, Hansman C, Dressler M, Boyd E: Intrauterine growth as estimated from live-born birthweight data at 24 to 42 weeks gestation.Pediatrics32 :793 –799,1963 .[Abstract/Free Full Text]
  10. Shuper A, Mimouni F, Merlob P, Zaizov R, Reisner SH: Thrombocytopenia in small for gestational age infants.Acta Paediatr Scand72 :139 –140,1983 .[Medline]
  11. Sinha HB, Mukherjee AK, Bala D: Cord blood haemoglobin (including foetal haemoglobin), and nucleated red cells in normal and toxaemic pregnancies.Ind Pediatr9 :5490 –5493,1972 .
  12. Littner Y, Mandel D, Sheffer-Mimouni G, Mimouni FB, Deutsch V, Dollberg S: Nucleated red blood cells in infants of mothers with asthma.Am J Obstet Gynecol188 :409 –412,2003 .[Medline]
  13. Yeruchimovich M, Dollberg S, Green DW, Mimouni FB: Nucleated red blood cells in infants of smoking mothers.Obstet Gynecol93 :403 –406,1999 .[Medline]
  14. Dollberg S, Fainaru O, Mimouni FB, Shenhav M, Lessing JB, Kupferminc M: Effect of passive smoking in pregnancy on neonatal nucleated red blood cells.Pediatrics106 :E34 ,2000 .[Medline]
  15. Halmesmaki E, Teramo KA, Widness JA, Clemons GK, Ylikorkala O: Maternal alcohol abuse is associated with elevated fetal erythropoietin levels.Obstet Gynecol76 :219 –222,1990 .[Medline]
  16. Leikin E, Garry D, Visintainer P, Verma U, Tejani N: Correlation of neonatal nucleated red blood cell counts in preterm infants with histologic chorioamnionitis.Am J Obstet Gynecol177 :27 –30,1997 .[Medline]
  17. Korst LM, Phelan JP, Ahn MO, Martin GI: Nucleated red blood cells: an update on the marker for fetal asphyxia.Am J Obstet Gynecol175 :843 –846,1996 .[Medline]
  18. Hanlon-Lundberg KM, Kirby RS: Nucleated red blood cells as a marker of acidemia in term neonates.Am J Obstet Gynecol181 :196 –201,1999 .[Medline]
  19. Dollberg S, Livny S, Mordecheyev N, Mimouni FB: Nucleated red blood cells in meconium aspiration syndrome.Obstet Gynecol97 :593 –596,2001 .[Medline]
  20. Thomas RM, Canning CE, Cotes PM, Linch DC, Rodeck CH, Rossiter CE, Huehns ER: Erythropoietin and cord blood haemoglobin in the regulation of human fetal erythropoiesis.Br J Obstet Gynaecol90 :795 –800,1983 .[Medline]
  21. Oski FA, Naiman JL: "Hematologic Problems in the Newborn," 2nd ed. Philadelphia: W.B. Saunders Co., pp15 –17,1972 .
  22. Creasey RK, Resnik R (eds): "Maternal-Fetal Medicine: Principles and Practice," 2nd ed. Philadelphia: W.B. Saunders Co., pp1162 –1163,1989 .
  23. Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC: Neonatal polycythemia in infants of insulin-dependent diabetic mothers.Obstet Gynecol68 :370 –372,1986 .[Medline]
  24. Green DW, Hendon B, Mimouni F: Nucleated erythrocytes and intraventricular hemorrhage in preterm neonates.Pediatrics96 :475 –478,1995 .[Abstract/Free Full Text]
  25. Schwartz D: "Méthodes Statistiques à l'Usage des Médicins et des Biologists," 3rd ed. Paris: Flammarion Médicine-Sciences, p151 ,1975 .
  26. Phelan JP, Korst LM, Ahn MO, Martin GI: Neonatal nucleated red blood cell and lymphocyte counts in fetal brain injury.Obstet Gynecol91 :485 –489,1998 .[Medline]
  27. Saade GR, Moise KJ Jr, Copel JA, Belfort MA, Carpenter RJ Jr: Fetal platelet counts correlate with the severity of the anemia in red-cell alloimmunization.Obstet Gynecol82 :987 –991,1993 .[Medline]
  28. Dollberg S, Marom R, Mimouni FB, Yeruchimovich M: Normoblasts in large for gestational age infants.Arch Dis Child Fetal Neonatal Ed83 :F148 –F149,2000 .[Abstract/Free Full Text]
  29. Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, Regan L, Robinson S: Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London.Int J Obes Relat Metab Disord25 :1175 –1182,2001 .[Medline]
  30. Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R: Relation of glucose tolerance to complications of pregnancy in nondiabetic women.N Engl J Med315 :989 –992,1986 .[Abstract]
  31. Robertson DA, Singh BM, Nattrass M: Effect of obesity on circulating intermediary metabolite concentrations in the absence of impaired glucose tolerance.Int J Obes15 :635 –645,1991 .[Medline]
  32. Miodovnik M, Mimouni F, Berk M, Clark KE: Alloxan-induced diabetes mellitus in the pregnant ewe: metabolic and cardiovascular effects on the mother and her fetus.Am J Obstet Gynecol160 :1239 –1244,1989 .[Medline]
  33. Clark KE, Miodovnik M, Skillman CA, Mimouni F: Review of fetal cardiovascular and metabolic responses to diabetic insults in the pregnant ewe.Am J Perinatol5 :312 –318,1988 .[Medline]
  34. Maasilta P, Bachour A, Teramo K, Polo O, Laitinen LA: Sleep-related disordered breathing during pregnancy in obese women.Chest120 :1448 –1454,2001 .[Medline]
  35. Hamrick SE, Miller SP, Newton NR, Parer JT, Ferriero DM, Barkovich AJ, Partridge JC: Nucleated red blood cell counts: not associated with brain injury or outcome.Pediatr Neurol29 :278 –283,2003 .[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sheffer-Mimouni, G.
Right arrow Articles by Littner, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sheffer-Mimouni, G.
Right arrow Articles by Littner, Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS