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Nucleated Red Blood Cells in Healthy Infants of Women With Gestational Diabetes

From the Department of Neonatology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and Magella Medical Associates, Dallas, Texas.

Address reprint requests to: Shaul Dollberg, MD, Department of Neonatology, Tel Aviv-Sourasky Medical Center, Lis Maternity Hospital, 6 Weizman Street, Tel Aviv 64239, Israel, E-mail: dolberg{at}post.tau.ac.il

	Abstract

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Objective: To evaluate whether absolute nucleated red blood cell (RBC) counts are elevated in large-for-gestational-age (LGA) infants of women with gestational diabetes compared with appropriate-for-gestational-age (AGA) infants of women with or without gestational diabetes.

Methods: We compared absolute nucleated RBC counts during the first 12 hours of life in three groups of term, vaginally delivered infants, LGA infants of women with gestational diabetes (n = 20), AGA infants of women with gestational diabetes (n = 20), and AGA infants of nondiabetic women (n = 30). We excluded infants of women with hypertension, smoking, alcohol or drug abuse, and those with fetal heart rate abnormalities in labor, low Apgar scores, hemolysis, blood loss, or chromosomal anomalies.

Results: There were no significant differences among groups in gestational age, gravidity, parity, maternal analgesia, 1- and 5-minute Apgar scores, and lymphocyte counts. Corrected white blood cell counts and hematocrit were significantly higher in LGA infants of women with gestational diabetes than in the other groups. The median nucleated RBC count was significantly higher in LGA infants of women with gestational diabetes (0.56 x 10⁹/L, range 0–1.8 x 10⁹/L) than AGA infants of women with gestational diabetes (0.13 x 10⁹/L, range 0–0.65 x 10⁹/L) and controls (0.0005 x 10⁹/L, range 0–0.6 x 10⁹/L) (P < .001). Multiple regression analysis showed that absolute nucleated RBC count was significantly correlated with birth weight (or macrosomia) and maternal diabetic status (r² = .25, P < .001 for the multiple regression, contribution of birth weight r² = .19, and diabetes r² = .06).

Conclusion: At birth, term LGA infants born to women with gestational diabetes had higher absolute nucleated RBC counts compared with AGA infants born to women with gestational diabetes and controls.

Infants of insulin-dependent diabetic women are at increased risk of intrauterine hypoxia, shown by an increased incidence of abnormal fetal heart rate patterns in labor,¹ low neonatal Apgar scores,¹ and in extreme cases fetal death.² One of the consequences of chronic intrauterine hypoxia in infants of insulin-dependent diabetic women is increased erythropoiesis resulting from erythropoietin stimulation. Those infants at birth have increased circulating erythropoietin concentrations,³ increased hematocrit,^4,5 and increased circulating nucleated red blood cells (RBC).⁶ Their neonatal hematocrit level correlates with maternal glycohemoglobin, an index of glycemic control in pregnancy.⁴

There is little information about the hematologic status of infants of women with gestational diabetes. The purpose of this study was to test the hypothesis that, in infants of women with gestational diabetes, the absolute number of nucleated RBC at birth is higher than that of controls and that the increase in absolute nucleated RBC is more marked in large-for-gestational-age (LGA) infants.

	Materials and Methods

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We prospectively studied three groups of consecutive term infants (38–41 weeks’ gestation by last menstrual period, confirmed by early [before 20 weeks] ultrasonographic assessment), who were born vaginally at the Lis Maternity Hospital, Tel Aviv Sourasky Medical Center between May and December 31, 1998. The first group consisted of 20 infants with appropriate weight for gestational age (AGA) born to women with gestational diabetes, the second group consisted of 20 infants who were born large for gestational age (LGA) to women with gestational diabetes, and the third group consisted of 30 AGA infants of healthy nondiabetic women. Appropriateness for gestational age was determined by intrauterine growth curves of Lubchenco et al.⁷ Gestational diabetes was diagnosed by abnormal glucose challenge screens at 24–28 weeks’ gestation,⁸ and confirmed by abnormal results of 3-hour oral glucose challenge tests.^9,10 Glucose challenge screens were normal in the mothers of control infants. To eliminate confounding variables known to affect the number of absolute nucleated RBC at birth, we excluded infants born to women with pregnancy-induced hypertension¹¹; placental abruption or previa¹¹; maternal heart, kidney, lung, or other chronic conditions; maternal smoking,¹¹ drug, or alcohol abuse; and perinatal infection (eg, fever, leukocytosis, or signs of chorioamnionitis). We also excluded infants with abnormal results of intrapartum electronic monitoring or low Apgar scores (less than 8 at 1 and 5 minutes); with perinatal blood loss; hemolysis (ABO or other blood group incompatibility with positive Coombs test)¹¹; and with chromosomal anomalies.

Venous blood samples for complete blood counts were collected from infants within 12 hours of birth and analyzed according to laboratory routine using an STK-S counter (Coulter Counter Corporation, Hialeah, FL). Differential cell counts were done manually, and absolute nucleated RBC counts were expressed per 100 white blood cells (WBC). We expressed the number of nucleated RBC as an absolute number rather than per 100 WBC, and WBC counts were expressed as corrected for the presence of nucleated RBC. We showed previously that WBC counts and absolute nucleated RBC counts were not independent; thus, traditional expression of nucleated RBC as their number per 100 WBC might introduce a significant error.⁶ The study was approved by our local institutional review board. All infants are screened routinely for polycythemia with complete blood counts at the age of 0–12 hours, so the requirement for informed consent was waived.

Data are reported as mean ± standard deviation [SD] or median and range. Statistical analysis (using Minitab Inc., State College, PA) included Kruskal-Wallis test due to non-normal distribution of absolute nucleated RBC and Apgar scores (normality was tested by the Ryan Joiner test for normality), analysis of variance for comparisons of means followed by Tukey test for pairwise corrections, and backward stepwise regression analysis. P < .05 was considered statistically significant.

	Results

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There were no significant differences between groups in gestational age, gender, maternal gravidity or parity, analgesia during labor, and 1- and 5-minute Apgar scores, but nondiabetic women were younger than diabetic women (Table 1). The LGA group differed significantly from the two AGA groups in weight; however, there were no significant birth weight differences between controls and AGA infants of diabetic women. Absolute nucleated RBC counts were statistically significantly higher in LGA infants of diabetic women compared with controls and AGA infants of diabetic women. There were no significant differences between the two latter groups. In stepwise regression, the difference persisted after introduction of maternal age as a potential confounder. Hematocrit and WBC counts were higher in LGA infants of diabetic mothers compared with the other groups. There were no significant differences in platelets counts, RBC counts, or lymphocyte counts among the groups.

	Discussion

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This study showed that macrosomic infants of women with gestational diabetes had higher absolute nucleated RBC counts than infants of nondiabetic women or AGA infants of diabetic women. A similar increase was documented in infants of insulin-dependent diabetic women, in whom it is believed to show a compensatory increase in erythropoiesis from chronic intrauterine hypoxia resulting from poor glycemic control.⁴ In humans and some animals, poor maternal glycemic control was associated with maternal hyperglycemia and subsequent fetal hyperglycemia, and hyperinsulinism,¹² and maternal hyperketonemia with subsequent fetal hyperketonemia.¹² Those findings have been shown in several animal models to cause, independently and in various combinations, fetal hypoxemia, most likely because of increased placental oxygen consumption and decreased oxygen delivery to the fetus.¹²

Within hours, fetal hypoxia stimulates fetal erythropoietin production.¹³ If hypoxia is prolonged, continued increased RBC production might lead to neonatal polycythemia. Besides elevated absolute nucleated RBC counts at birth,⁶ infants of insulin-dependent diabetic women had higher rate of neonatal polycythemia,⁵ and their hematocrit at birth correlated with maternal glycohemoglobin A1 at delivery, an index of glycemic control during the last trimester of pregnancy.⁴ Only macrosomic infants of women with gestational diabetes had higher absolute nucleated RBC counts and hematocrit in our study, supporting the theory that poor glycemic control was the cause of that increase. Fetal macrosomia in gestational diabetes is believed to be a consequence of fetal hyperglycemia and hyperinsulinism, and it relates to maternal glycohemoglobin A1 levels at delivery.⁴

In this study, although there were no truly polycythemic infants, the mean hematocrit was significantly higher in LGA infants of diabetic women than in the other groups. White blood cell counts of macrosomic infants of diabetic women were higher than in the other groups, confirming the findings of our previous study.¹⁴ The cause of leukocytosis in those infants was not known but might be related to leukocyte demargination secondary to increased cortisol secretion.¹⁴

	Footnotes

 
PII S0029-7844(99)00511-6

Received April 26, 1999. Received in revised form July 8, 1999. Accepted July 29, 1999.

	References

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1. Mimouni F, Miodovnik M, Siddiqi TA, Khoury J, Tsang RC. Perinatal asphyxia in infants of insulin-dependent diabetic mothers. J Pediatr 1988;113:345–53.[Medline]

2. White P. Pregnancy complicating diabetes. Am J Med 1949;7:609–16.[Medline]

3. Widness JA, Teramo KA, Clemons GK, Voutilainen P, Stenman UH, McKinlay SM, et al. Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy. Diabetologia 1990;33:378–83.[Medline]

4. Green DW, Khoury J, Mimouni F. Neonatal hematocrit and maternal glycemic control in insulin-dependent diabetes. J Pediatr 1992;120:302–5.[Medline]

5. Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet Gynecol 1986;68:370–2.[Abstract]

6. Green DW, Mimouni F. Nucleated erythrocytes in healthy infants and in infants of diabetic mothers. J Pediatr 1990;116:129–31.[Medline]

7. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from live-born birth weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793–9.[Abstract/Free Full Text]

8. Lavin J, Barden TP, Miodovnik M. Clinical experience with a screening program for gestational diabetes. Am J Obstet Gynecol 1981;141:491–4.[Medline]

9. American College of Obstetricians and Gynecologists. Management of diabetes in pregnancy. ACOG technical bulletin no. 92, Washington DC: American College of Obstetricians and Gynecologists, 1986.

10. American Diabetes Association. Position statement: Gestational diabetes mellitus. Diabetes Care 1986;9:430.[Medline]

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

12. Clark KF, Miodovnik M, Skillman CA, Mimouni F. Review of fetal cardiovascular and metabolic responses to diabetic insults in the pregnant ewe. Am J Perinatol 1988;5:312–8.[Medline]

13. Widness JA, Terramo KA, Clemons GK, Garcia JF, Cavalieri RL, Piasecki GJ, et al. Temporal response of immunoreactive erythropoietin to acute hypoxemia in fetal sheep. Pediatr Res 1986;20:15–9.[Medline]

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