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Obstetrics & Gynecology 2004;104:372-376
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Nucleated Red Blood Cells in Uncomplicated Prolonged Pregnancy

Tamar Perri, MD*, Asaf Ferber, MD{dagger}, Ayala Digli, MD*, Esther Rabizadeh, PhD*, Alina Weissmann-Brenner, MD* and Michael Y. Divon, MD{dagger}

From the Departments of Obstetrics and Gynecology, *Rabin Medical Center, Petah-Tikva, Israel, and {dagger}Lenox Hill Hospital, New York, New York.

Address reprint requests to: Michael Y. Divon, MD, Department of Obstetrics and Gynecology, Lenox Hill Hospital, 100 East 77th Street, New York, NY 10021; e-mail: mdivon{at}lenoxhill.net.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: Elevated counts of nucleated red blood cells (NRBCs), as well as prolongation of pregnancy, have been suggested as predictors of adverse perinatal outcome. However, the association between these 2 variables has received only minimal attention. We sought to evaluate fetal NRBCs in prolonged pregnancies.

METHODS: Umbilical cord blood was prospectively collected at delivery from 75 prolonged (at or beyond 287 days) pregnancies. One hundred and fifty term deliveries (260–286 days) served as controls. All pregnancies were accurately dated with the use of first-trimester sonography. Fetal biophysical profile testing was initiated at 40 weeks of gestation. Patients were delivered if they were in spontaneous labor or the biophysical profile was nonreassuring or by 42 weeks of gestation. Nucleated red blood cell counts were expressed per 100 white blood cells (WBC). Umbilical artery pH studies, as well as other demographic and clinical variables, were obtained.

RESULTS: Prolonged pregnancy was associated with a significantly increased incidence of induction of labor and a greater birth weight. There were no other differences between the study group and controls. The median NRBCs per 100 WBCs in prolonged pregnancy was not significantly elevated over the term values (median 3, range 0–35 versus median 3, range 0–34, respectively; P = .25). Neonatal outcome was also comparable between groups. The univariate regression analysis demonstrated a significant association between elevated NRBC counts and low arterial cord blood pH (P < .008, R = 0.175), elevated base excess (P = .02, R = 0.149), low platelet counts (P = .046, R = 0.134), and male gender (P = .028). Stepwise regression analysis revealed that low arterial cord blood pH and male gender were the only independent variables predicting elevated NRBC counts at birth.

CONCLUSION: The findings of this study suggest that elevated NRBC counts are associated with specific pregnancy complications rather than uncomplicated prolonged pregnancies in general.

LEVEL OF EVIDENCE: II-2

Prolonged pregnancies have long been associated with an increased risk for adverse perinatal outcome, including higher fetal mortality and morbidity rates. Recently, large studies of well-dated pregnancies have concluded that there is a significant increase in fetal mortality from 41 weeks of gestation onward.1 Furthermore, prolonged pregnancies were shown to be associated with an increased frequency of neonatal convulsions, meconium aspiration syndrome, and Apgar scores of less than 4 at 5 minutes.1,2

Recent publications have described a significant association between nucleated red blood cell (NRBC) counts and adverse perinatal outcome. Nucleated red blood cells are immature erythrocytes found in the peripheral blood of newborn infants. It has been suggested that elevated umbilical cord NRBC counts are associated with either acute or chronic hypoxic fetal environment.3–6 Elevated NRBC counts have also been suggested as a possible predictor of adverse perinatal outcome, such as low Apgar scores and pH values, fetal growth restriction, perinatal brain damage, early-onset neonatal seizures, and cerebral palsy.7–11

Hence, both elevated NRBC counts and prolonged pregnancies are associated with adverse perinatal outcome. However, the association between these variables has received limited attention. Jazayeri et al12 studied a small cohort of pregnancies delivering at or beyond 41 weeks of gestation. Cord plasma erythropoietin levels were significantly increased compared with pregnancies delivered at 37–40 weeks of gestation. Decreased Po2 is a known stimulator of erythropoietin production, which in turn increases erythroid production and results in an increased NRBC count in the fetal peripheral circulation. Therefore, it is reasonable to assume that if prolonged pregnancy is associated with fetal hypoxia, the fetal NRBC count would also be elevated. This hypothesis has been studied by Axt et al,13 who concluded that fetal NRBC counts are elevated in prolonged pregnancies. However, a detailed analysis of their results showed that it was an increased incidence of fetal acidosis, rather than prolongation of pregnancy, that resulted in an increased NRBC count. Therefore, the purpose of our study was to evaluate the role of fetal NRBCs in prolonged pregnancies.


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We prospectively studied consecutive low-risk patients with prolonged pregnancy who delivered at Rabin Medical Center between May and September of 2002 and agreed to participate in the study. Prolonged pregnancy was defined as a pregnancy in which delivery occurred at or beyond 41 weeks of gestation (ie, at or beyond 287 days). The control group was comprised of pregnant women whose gestational age at delivery was 37–40.9 weeks (260–286 days). All study patients and controls gave their informed consent for participation in the study. Gestational age was defined by first-trimester sonography in all patients. Exclusion criteria included multiple gestation, rupture of the membranes at admission, known pregnancy complications that might elevate NRBC counts, such as gestational or pregestational diabetes, hypertension, preeclampsia, intrauterine fetal growth restriction, maternal isoimmunization, maternal infection, and congenital or chromosomal abnormalities. Demographic and obstetric variables were recorded. Biophysical profile testing was initiated at 40 weeks of gestation and repeated at 3-day intervals. Patients were delivered before 42 weeks of gestation if oligohydramnios was diagnosed (ie, amniotic fluid index [AFI] < 5 cm), the fetal heart rate was nonreassuring, or the biophysical profile score was less than or equal to 6. All undelivered patients were delivered at 42 weeks of gestation. The AFI was obtained at admission to labor and delivery, and the intrapartum course was documented prospectively. Umbilical cord blood was collected immediately after delivery. These AFIs were not made available to the clinicians managing the course of labor. Umbilical venous samples were collected into ethylenediaminetetraacetic acid (EDTA) k3 tubes and analyzed with an automated hematology cell-counting machine (Bayer, Tarrytown, NY). Blood smears were stained with Wright Stain using Hematek 2000 (Bayer) in duplicates. Two experienced laboratory technicians using a light microscope manually counted nucleated red blood cells. These technicians were blinded to the clinical course and to each other's results. The average count was expressed as NRBCs per 100 white blood cells (WBCs). Previous studies have shown that this methodology is associated with a low interobserver variability.14 Umbilical artery blood was used for acid-base balance studies.

The Institutional Review Board of Rabin Medical Center approved the study. All women gave an informed consent to participate in the study.

A power analysis performed before the initiation of the study indicated that 75 study patients and 150 controls would be required to demonstrate a 40% difference in NRBC counts between groups (with power of 0.8, {alpha} < 0.05, mean NRBC per 100 WBC of 9.2, and variance of 18.17). Results were analyzed with Statview 5.0 (SAS Institute Inc, Cary, NC). Statistical analysis included the Student t test, {chi}2 test, Spearman correlation, analysis of variance, and simple and stepwise regression. P < .05 was considered statistically significant.


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The study group comprised 75 patients. The median gestational age at delivery was 41.6 weeks, with a range of 41–42 weeks. The control group consisted of 150 pregnant women. The median gestational age at delivery was 39.8 weeks, with a range of 37–40.9 weeks. There were no significant demographic differences between these groups (Table 1). Likewise, there were no differences in NRBC counts between groups (Table 2). As expected, birth weights were greater in the prolonged pregnancy group (median 3,506 g, range 2,665–4,370 g versus 3,303 g, range 2,152–4,770 g, respectively; P < .002). There were more inductions of labor in the prolonged pregnancy group (19/75 versus 16/150, respectively, P < .005). Neonatal outcome was comparable between groups (Table 3). Cord blood data are shown in Table 2. No difference was detected between pH values of the prolonged pregnancies and the controls (median pH = 7.26 ± 0.06 versus 7.25 ± 0.07, respectively, P = .9). Likewise, there was no difference in the incidence of fetal acidosis between groups.


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  		Table 1. Demographic and Delivery Variables

 

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  		Table 2. Cord Blood Data

 

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  		Table 3. Newborn Outcome

 

Univariate regression analysis (performed on all 225 patients) demonstrated a significant association between elevated NRBC counts and low arterial cord blood pH (P < .008, R = 0.175), elevated base excess (P = .02, R = 0.149), low platelet counts (P = .046, R = 0.134), and male gender (P = .028).

No significant correlation was detected between NRBC counts and maternal weight or body mass index, maternal tobacco use, gravidity, parity, AFI at presentation, induction of labor, type or duration of anesthesia, meconium staining of the amniotic fluid, mode of delivery, newborn weight, Apgar score at 1 or 5 minutes, neonatal intensive care unit admission, and newborn hemoglobin or hematocrit.

A stepwise regression analysis was used to identify independent variables that were associated with elevated NRBC counts. Low pH values and male gender were identified as the only variables independently predicting elevated NRBC counts at birth (P = .009, R = 0.17 and P = .001, R = 0.24, respectively).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results indicate that NRBC counts are not elevated in uncomplicated prolonged pregnancies. These results do not support the conclusion reached by Axt et al,13 who have recently studied 43 postterm patients and 261 controls and reported a significant increase in NRBC counts in postterm deliveries (median 6.5, range 0–24 versus median 3.7, range 0–14; P < .05). The difference between their results and the results of the present study may be explained by the fact that their study population had an increased incidence of postterm pregnancies resulting in fetal acidemia. There is a growing body of evidence describing the role of NRBC counts in the identification of fetal hypoxia and the prediction of adverse perinatal outcome.3–11 A possible explanation for the lack of increased NRBCs in our study group relates to the fact that all complicated pregnancies were a priori excluded from the study and that all other ongoing pregnancies were closely monitored from 40 weeks of gestation onward by semiweekly biophysical profile testing. This also explains the absence of differences between study patients and controls in terms of AFI, rate of meconium staining, Apgar scores, umbilical cord pH, or neonatal intensive care unit admissions.

In the present study, there was an inverse relationship between NRBCs and umbilical artery pH values. Thus, our results support previous studies that showed a correlation between fetal acidemia and elevated NRBC counts.3,7,13

We observed a statistically significant correlation between lower platelet counts and elevated NRBC counts at birth. This finding was previously reported by Bernstein et al,15 who hypothesized that enhanced bone marrow erythroid production results in thrombocytopenia. An increased consumption of platelets, associated with placental thrombotic events, provides an alternative hypothesis explaining both fetal hypoxia and thrombocytopenia. These thrombotic events may result in red blood cell destruction, which would provide an explanation of the fact that elevated NRBC counts were not accompanied by a concomitant increase in hematocrit or hemoglobin in our study. In fact, a similar conflict was reported by Bernstein et al,15 who showed that NRBC counts were elevated in small-for-gestational-age fetuses whose umbilical artery Doppler studies were abnormal, but there was no association between elevated NRBC counts and fetal hemoglobin.

Our data indicate that male gender is an independent predictor of elevated NRBC counts. There are studies suggesting that fetal response to hypoxia is gender-specific. Loidl et al16 in their study on rats, have found that female rats had a higher survival rate than male rats after perinatal asphyxia. Likewise, male gender was an independent risk factor for perinatal asphyxia in a recent human study by Sutton at al.17

No significant correlation was found between NRBC counts and the admission AFI. Lack of correlation between AFI and fetal hypoxia, as reflected by elevated NRBC counts, supports previous studies which concluded that isolated oligohydramnios is probably not a marker of fetal compromise in term or postterm pregnancies.18,19

In conclusion, our results indicate that prolongation of pregnancy is not an independent predictor of elevated NRBC counts in low-risk pregnancies.


   Footnotes
 
Received January 7, 2004. Received in revised form May 9, 2004. Accepted May 12, 2004.

10.1097/01.AOG.0000133483.94020.04


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Divon MY, Haglund B, Nisell H, Otterblad PO, Westgren M. Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 1998;178:726–31.[Medline]

2. Clausson B, Cnattingius S, Axelsson O. Outcomes of post-term births: the role of fetal growth restriction and malformations. Obstet Gynecol 1999;94:758–62.[Abstract/Free Full Text]

3. Lim FT, Scherjon SA, van Beckhoven JM, Brand A, Kanhai HH, Hermans JM, et al. Association of stress during delivery with increased numbers of nucleated cells and hematopoietic progenitor cells in umbilical cord blood. Am J Obstet Gynecol 2000;183:1144–52.[Medline]

4. Ferber A, Grassi A, Akyol D, O'Reilly-Green C, Divon MY. The association of fetal heart rate patterns with nucleated red blood cell counts at birth. Am J Obstet Gynecol 2003;188:1228–30.[Medline]

5. Yeruchimovich M, Mimouni FB, Green DW, Dollberg S. Nucleated red blood cells in healthy infants of women with gestational diabetes. Obstet Gynecol 2000;95:84–6.[Abstract/Free Full Text]

6. Yeruchimovich M, Dollberg S, Green DW, Mimouni FB. Nucleated red blood cells in infants of smoking mothers. Obstet Gynecol 1999;93:403–6.[Abstract/Free Full Text]

7. Hanlon-Lundberg KM, Kirby RS. Nucleated red blood cells as a marker of acidemia in term neonates. Am J Obstet Gynecol 1999;181:196–201.[Medline]

8. Axt-Fliedner R, Hendrik HJ, Schmidt W. Nucleated red blood cell counts in growth-restricted neonates with absent or reversed-end-diastolic umbilical artery velocity. Clin Exp Obstet Gynecol 2002;29:242–6.[Medline]

9. Buonocore G, Perrone S, Gioia D, Gatti MG, Massafra C, Agosta R, et al. Nucleated red blood cell count at birth as an index of perinatal brain damage. Am J Obstet Gynecol 1999;181:1500–5.[Medline]

10. Blackwell SC, Refuerzo JS, Wolfe HW, Hassah SS, Berry SM, Sokol RJ, et al. The relationship between nucleated red blood cell count and early onset neonatal seizures. Am J Obstet Gynecol 2000;182:1452–7.[Medline]

11. 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;175:843–6.[Medline]

12. Jazayeri A, Tsibris JC, Spellacy WN. Elevated umbilical cord plasma erythropoietin levels in prolonged pregnancies. Obstet Gynecol 1998;92:61–3.[Abstract]

13. Axt R, Ertan K, Hendrik J, Wrobel M, Mink D, Schmidt W. Nucleated red blood cells in cord blood of singleton term and post-term neonates. J Perinat Med 1999;27:376–81.[Medline]

14. Ferber A, Akyol D, Kane LA, Grassi A, Divon MY. Nucleated red blood cells in human fetal scalp capillary blood samples: a feasibility study. J Matern Fetal Neonatal Med 2002;11:26–9.[Medline]

15. Bernstein PS, Minior VK, Divon MY. Neonatal nucleated red blood cell counts in small-for-gestational age fetuses with abnormal umbilical artery Doppler studies. Am J Obstet Gynecol 1997;177:1079–84.[Medline]

16. Loidl CF, Gavilanes AW, Van Dijk EH, Vreuls W, Blokland A, Vles JS, et al. Effects of hypothermia and gender on survival and behavior after perinatal asphyxia in rats. Physiol Behav 2000;68:263–9.[Medline]

17. Sutton L, Sayer GP, Bajuk B, Richardson V, Berry G, Henderson-Smart DJ. Do very sick neonates born at term have antenatal risks? 1. Infants ventilated primarily for problems of adaptation to extra-uterine life. Acta Obstet Gynecol Scand 2001;80:905–16.[Medline]

18. Conway DL, Adkins WB, Schroeder B, Langer O. Isolated oligohydramnios in the term pregnancy: is it a clinical entity? J Matern Fetal Med 1998;7:197–200.[Medline]

19. Kreiser D, el-Sayed YY, Sorem KA, Chitkara U, Holbrook RH Jr, Druzin ML. Decreased amniotic fluid index in low-risk pregnancy. J Reprod Med 2001;46:743–6.[Medline]





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