Factors Affecting Human Umbilical Cord Blood Quality Before Cryopreservation: The Importance of Birth Weight and Gestational Age

Abstract

Background:

Umbilical cord blood (UCB) is a rich source of hematopoietic stem cells and is useful for the treatment of blood diseases. The cost of UCB storage is high; thus, it is necessary to evaluate the quality of UCB before collection and cryopreservation.

Aim:

This study aimed to determine the maternal and neonatal factors that influence UCB before selection for cryopreservation.

Materials and Methods:

The analysis included 403 processed UCB units. The effects of maternal characteristics including maternal age and delivery method and neonatal factors such as birth weight, gestation duration, and sex on UCB quality were determined based on the collected blood volume, total nucleated cell (TNC) count, and CD34⁺ cell count.

Results:

The neonatal birth weight influenced the collected blood volume, TNC count, and CD34⁺ cell count. Neonates with higher birth weights produced better quality UCB units because of increased collected blood volumes, TNC counts, and CD34⁺ cell counts. However, an increase in the gestational age from 35 to 41 weeks led to decreases in the collected blood volume and CD34⁺ cell count.

Conclusion:

These data may be useful for determining the optimal cord blood units for collection and cryopreservation and for advising pregnant women using private banking services.

Introduction

Umbilical cord blood (UCB) stem cell transplantation has proven to be effective in the treatment of a variety of hematologic disorders and metabolic storage diseases.¹ Rapid growth in the field has been recorded since the first blood stem cell transplant reported by Dr. E. Donnall Thomas in 1957.^2,3 In 2006, there were 50,417 hematopoietic stem cell (HSC) transplants reported worldwide, and by December 2012, the number reached one million, according to the Worldwide Network for Blood and Marrow Transplantation (WBMT).³

The first cord blood transplantation was performed in France for a child with Fanconi anemia in 1988.⁴ In 2013, this patient was reported as healthy, 25 years after transplantation.⁵ The sources of HSCs for transplantation are usually bone marrow, peripheral blood, or UCB.^6,7 Transplantations may be autologous, allogeneic, or syngeneic (from an identical twin) for patients with certain diseases of the blood or bone marrow.⁷

Currently, UCB is a popular source of HSCs, with the benefit of being a noninvasive method to collect cells. UCB is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSCs than is normally found in adult blood. Comparatively, UCB HSCs have an extensive proliferative capacity that exceeds that of bone marrow HSCs; in addition, UCB can be left for days at room temperature without a significant loss of functional HSCs.^4,5,8–10 Moreover, these cells can be cryopreserved for over 20 years and later thawed with efficient recovery of HSCs,¹¹ leading to the realization that there are many more HSCs present in a single collection of UCB than previously known. However, the small quantity of HSCs obtained from an umbilical cord makes this method more suitable for transplantation into small children than into adults. The limited number of cells remains a problematic element restricting the usage of UCB, especially for adults who require the transplantation of a higher number of cells. Thus, newer techniques using the ex vivo expansion of stem cells allow cord blood to be transplanted into adults.

The collection and banking of UCB-derived cells has become a popular option worldwide. Improving the quality of harvested cord blood is important in addition to examining the quality of cord blood units at the time of cryopreservation.¹² Other studies have revealed factors that may impact the quality of UCB, for example, maternal and neonatal factors.^13,14 Additionally, temporal dimensions have been reported to influence the UCB volume and total nucleated cell (TNC) and CD34⁺ cell number in the UCB units collected from Tuscany and Apulia Cord Blood Banks in Italy.¹⁵

Our study aimed to analyze the factors influencing the quality of cord blood units before cryopreservation in a private cord blood bank in Vietnam. We hypothesized that maternal and neonatal characteristics will affect UCB volume and cell components in the UCB, which are responsible for good quality of a UCB unit. The knowledge gained from this study will ultimately allow us to understand the donor effects on the quality of cord blood units, enabling us to provide this information for potential recipients.

Materials and Methods

Materials

This study was conducted with 403 UCB samples that met the requirements for cryopreservation at the private cord blood bank at Vinmec International Hospital in Vietnam from January to December 2017. Extensive medical and family histories were self-reported by the mothers. Transmissible diseases were tested before blood collection. To be eligible, the blood had to be negative for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and syphilis. After delivery, data regarding the neonate's weight, sex, gestational age, delivery method, and blood type were collected.

UCB collection

UCB was collected from the umbilical vein after the umbilical cord was detached from the infant but while the placenta was still in utero; the UCB was placed into a collection bag containing 35 mL of citrate phosphate dextrose adenine (CPDA-1) anticoagulant (Teruflex; Terumo BCT, UK). The UCB was then stored at 15°C–25°C for a maximum of 48 hours before processing.

Sample processing

The UCB was transferred from the collection bag to the processing bag set (code 8-5101-1, Thermogenesis). To collect the HSCs, the UCB underwent two centrifugation steps. The first heavy spin was processed at 1400 × g for 20 minutes, and the second light spin was processed at 80 × g for 10 minutes. Approximately 20–22 mL of the final UCB was collected by the AutoXpress system (CESCA Therapeutics; Thermogenesis). A volume of 0.5–1 mL of the final UCB was withdrawn for cell viability testing and cell counting. Finally, 10% dimethyl sulfoxide (Protide Pharmaceutical) and 1% Dextran T40 (Protide Pharmaceutical) were added to the cord blood unit before cryopreservation in liquid nitrogen in the BioArchive System (Cesca Therapeutics; Thermogenesis).

Pre- and postprocessing blood samples (0.5–1 mL) were withdrawn for bacterial examination and the analysis of whole blood cells.

Cell count and viability

Pre- and postprocessed cord blood samples were analyzed for mononuclear cells (MNCs) and TNCs using a Celltac Es MEK-7300K automated machine (Nihon Kohden).

Postprocessed cord blood samples were analyzed for cell viability and CD34⁺ cell counts using the Stem Kit Reagent (IM3630; Beckman Coulter). Briefly, 100 μL of UCB was mixed with 20 μL of CD45-FITC/CD34-PE reagent and 20 μL of 7-AAD Viability Dye. The mix was incubated at room temperature for 20 minutes in the dark. After incubation, 2 mL of 1 × NH₄Cl lysing solution was added, and the mixture was incubated for 15 minutes in the dark before the addition of 100 μL of Stem-Count Fluorospheres. The cell populations and viability were analyzed by the Navios flow cytometry system (Beckman Coulter). Manual gating and protocol analysis were performed according to the manufacturer's instructions. Viable cells are negative for 7-AAD, and CD34⁺ cells are positive for CD45-FITC/CD34-PE.

Statistics

Descriptive statistics were performed for the maternal and neonatal factors. Univariate analyses were conducted using Spearman's rank correlation and Kruskal–Wallis test. In multivariate analysis, the effects of the maternal and neonatal factors (independent variables) on the log-transformed laboratory parameters (dependent variables) were analyzed using multivariate linear regression models. The estimated proportion difference in laboratory results affiliated with each dependent variable was calculated by exponenciating the fitted coefficients from the regression analyses. Differences were considered statistically significant if p-value <0.05 (two-sided).

Results

Maternal and neonate characteristics

The general maternal and neonate characteristics including maternal age, delivery method, neonate blood type, gestation duration, birth weight, and neonate gender are reported in Table 1. The mean maternal age was 30.36 years, ranging from 18.52 to 43.54 years. More mothers chose cesarean section (C-section) (71.5%) than vaginal delivery (28.5%). With regard to the neonate blood type, 45.7% of the neonates were type O, 27.3% were type B, 20.3% were type A, and only 6% were type AB. The mean gestation duration was 38.65 weeks, with a median of 39 weeks and a range from 35 to 41 weeks.

Table 1.

Maternal and Neonate Characteristics

Variable	Unit/category	n (%)	Mean ± SD	Median	Range
Donor age	Year	403	30.36 ± 4.86	29.62	18.52–43.54
Delivery method	Vaginal delivery	115 (28.5)
Delivery method	C-section	288 (71.5)
Neonate blood type	A	82 (20.3)
	B	110 (27.3)
	AB	24 (6.0)
	O	184 (45.7)
Gestation duration	Weeks	403	38.65 ± 1.07	39.0	35.0–41.0
Birth weight of the neonate	kg		3.17 ± 0.40	3.19	1.80–4.42
Sex of neonate	Male	225 (55.8)
Sex of neonate	Female	178 (44.2)

SD, standard deviation.

The mean neonate weight was 3.17 kg, and the median was 3.19 kg. The neonate weights ranged from 1.80 to 4.42 kg. In total, 55.8% of the neonates were male, and 44.2% were female.

Characteristics of collected blood volume and cord blood cell populations

The characteristics of blood cell populations were statistically analyzed and are reported in Table 2. The analysis of the factors associated with the collected blood volume and the blood cell type showed that the mean collected blood volume was 122.6 mL (median 119.8 mL), including 35 mL of anticoagulant, with a range from 60 to 211 mL. Regarding the cell components, the mean TNC count was 11.58 × 10⁸ (range from 2.78 to 32.57 × 10⁸), mean total MNC count was 4.45 × 10⁸ (range from 0.5 to 12.14 × 10⁸), and mean total CD34⁺ cell count was 3.66 × 10⁶ (range from 0.5 to 17.13 × 10⁶). Additionally, the percentage of viable cells was 95.83%, with a range from 75.53% to 99.57%.

Table 2.

Summary Statistics of Cell Population and Blood Volume Data

Variable	N	Mean ± SD	Median	Range
Volume (mL)	403	122.46 ± 25.96	119.8	60–211
TNC ( × 10⁸)	403	11.58 ± 4.4	11.04	2.78–32.57
MNC ( × 10⁸)	403	4.45 ± 1.84	4.29	0.5–12.14
CD34⁺ ( × 10⁶)	403	3.66 ± 2.37	3.24	0.5–17.13
Viability (%)	403	95.83 ± 3.31	96.81	75.53–99.57

MNC, mononuclear cell; TNC, total nucleated cell.

The correlation between UCB volume and cord blood cells is described in Table 3. There was a positive correlation between the volume of collected blood and the cell counts of different cell populations, including TNCs, MNCs, and CD34⁺ cells. In addition, a positive correlation was observed between the collected blood volume and the percentage of viable cells. These data indicate that the higher the volume of cord blood collected, the higher the number of cord blood cells.

Table 3.

Relationship Between Blood Volume and Blood Cell Populations

Cell population	r	p
TNC ( × 10⁸)	0.424	<2.2e-16
MNC ( × 10⁸)	0.441	<2.2e-16
CD34⁺ ( × 10⁶)	0.305	<2.2e-16
Viability (%)	0.087	0.009

Association of maternal and neonatal predictors with blood volume, TNCs, and CD34⁺ cells

To reveal the associations between blood volume and maternal and neonatal factors, we calculated Spearman's correlation coefficient for the association between the collected blood volume and maternal factors, such as maternal age, delivery method, and gestation duration, and neonatal factors, including the neonate birth weight and sex (Table 4). The results showed that there were no correlations between the collected UCB volume and donor age or gestation duration. Additionally, there was no difference in the collected UCB volume between male and female neonates. However, the blood volume collected from neonates delivered by C-section was higher than that collected from neonates delivered vaginally.

Table 4.

Distribution of Volume (mL) According to Maternal and Neonatal Predictors

Maternal and neonatal predictors	Volume (mL)
	n	Spearman's correlation (r)	Mean ± SD	Percentile					p
	n	Spearman's correlation (r)	Mean ± SD	Min	25%	Median	75%	Max	p
Donor age^a	403	0.044							0.375
Delivery method^b
Vaginal delivery	115		114.8 ± 24.05	60.0	96.73	111	129.00	184.0	<0.001
C-section	288		125.5 ± 26.1	70.0	108.0	122.7	140.0	211	<0.001
Gestation duration^a	403	−0.039							0.432
Birth weight of the neonate^a	403	0.306							<0.001
Sex of neonate^b
Male	225		124.2 ± 25.88	75	107.0	120.3	138.0	211	0.1716
Female	178		120.3 ± 25.98	60	103.0	117.8	135.0	203	0.1716

Spearman rank correlation coefficients (r) for continuous variables.

Nonparametric Kruskal–Wallis test for categorical variables.

TNCs are one of the most important factors used to determine whether cord blood units are stored. Therefore, we analyzed the associations between the TNC count and the maternal and neonatal predictors (Table 5). The data showed that there were no correlations between TNC count and maternal age or gestation duration. However, there was a positive correlation between the birth weight of the neonate and the TNC count. Moreover, a higher TNC count was observed in neonates delivered vaginally (12.531 × 10⁸) in comparison with neonates delivered by C-section (11.198 × 10⁸). Additionally, female neonates had a significantly higher TNC count (12.121 × 10⁸) than male neonates (11.150 × 10⁸).

Table 5.

Distribution of Total Nucleated Cell Count According to Maternal and Neonatal Predictors

Maternal and neonatal predictors	TNC ( × 10⁸)
	n	Spearman's correlation (r)	Mean ± SD	Percentile					p
	n	Spearman's correlation (r)	Mean ± SD	Min	25%	Median	75%	Max	p
Donor age^a	403	−0.039							0.424
Delivery method^b
Vaginal delivery	115		12.531 ± 4.62	3.6	9.408	12.191	4.940	32.568	0.002
C-section	288		11.198 ± 4.263	2.781	8.246	10.486	13.257	31.604	0.002
Gestation duration^a	403	0.041							0.411
Birth weight of the neonate^a	403	0.365							<0.001
Sex of neonate^b
Male	225		11.150 ± 4.192	2.781	8.428	10.583	13.189	31.604	0.042
Female	178		12.121 ± 4.612	3.526	8.559	11.299	14.922	32.568	0.042

Spearman rank correlation coefficients (r) for continuous variables.

Nonparametric Kruskal–Wallis test for categorical variables.

We also sought to determine whether there was any relation between CD34⁺ cells, which are a key indicator of the quality of a cord blood unit, and maternal and neonatal factors. To this end, we performed an analysis of the correlations between the CD34⁺ cell count and maternal and neonatal factors (Table 6). The results showed that there were no correlations between the CD34⁺ cell count and maternal age or gestation duration. However, a positive correlation was observed between the CD34⁺ cell count and the birth weight of the neonate. There was no difference in CD34⁺ cell count according to the sex of the neonate. However, more CD34⁺ cells were counted in the UCB units originating from vaginally delivered neonates (4.016 × 10⁶) than in those from neonates delivered by C-section (3.515 × 10⁶).

Table 6.

Distribution of CD34⁺ Cells According to Maternal and Neonatal Predictors

Maternal and neonatal predictors	CD34⁺ ( × 10⁶)
	n	Spearman's correlation (r)	Mean ± SD	Percentile					p
	n	Spearman's correlation (r)	Mean ± SD	Min	25%	Median	75%	Max	p
Donor age^a	403	−0.008							0.858
Delivery method^b
Vaginal delivery	115		4.016 ± 2.440	0.612	2.246	3.810	5.339	17.134	0.017
C-section	288		3.515 ± 2.328	0.499	1.799	3.000	4.518	13.101	0.017
Gestation duration^a	403	0.005							0.912
Birth weight of the neonate^a	403	0.271							<0.001
Sex of neonate^b
Male	225		3.673 ± 2.313	0.499	1.996	3.248	4.752	13.101	0.706
Female	178		3.639 ± 2.443	0.612	1.814	3.132	4.834	17.134	0.706

Spearman rank correlation coefficients (r) for continuous variables.

Nonparametric Kruskal–Wallis test for categorical variable.

To reveal the effects of maternal and neonatal factors, a multivariate analysis was performed. Donor age, gestation duration, birth weight, and sex of the neonate had significant effects on the UCB cell type and blood volume. Specifically, each additional 1 week of gestation (ranging from 35 to 41 weeks) contributed to a 3% decrease in the collected blood volume. Each additional 500 g of neonate weight contributed to an 11.1% increase in the blood volume collected, a 21.25% increase in the TNC count, and a 35.43% increase in the CD34⁺ cell number. Additionally, the gestation duration influenced the CD34⁺ cell count, with a decrease in CD34⁺ cells of 7.90% for each additional week of gestation. The TNC count was 11.1% higher in female neonates than in male neonates (Table 7).

Table 7.

Multivariate Analysis

Variable^a	Unit or baseline group	% difference
Variable^a	Unit or baseline group	Volume	p	TNC	p	CD34⁺	p
Donor age	5 years	1.32	0.196	0.73	0.681	3.02	0.358
Gestation duration	1 week	−3.0	0.002	2.34	0.189	−7.90	0.010
Birth weight of the neonate	500 g	11.1	0.000	21.25	0.000	35.43	0.000
Sex of neonate	Male	−1.67	0.396	10.94	0.003	3.84	0.553

All variables mutually adjusted in the model.

Discussion

UCB is emerging as a source of stem cells that are used for the treatment of blood diseases because it is enriched with HSCs that can be reconstituted after storage.¹ Patients who require HSC transplantation need preserved stem cells as a ready-to-use transplantation material. For this reason, UCB has been cryopreserved in both public and private banks. Therefore, it is necessary to determine the optimal conditions for blood collection and assess the quality of the UCB before cryopreservation. This study reported data from 403 UBC units stored at the Vinmec International Hospital private bank in 2017. The general maternal and neonatal characteristics, which are partly associated with race (Vietnamese), have been described. Additionally, the collected blood volume, cell viability, and cell populations, such as TNCs, MNCs, and CD34⁺ cells, which are parameters for determining the quality of UCB before cryopreservation, have been shown. Some of these parameters, such as volume and cell viability, are similar to the data reported by Ballen et al. and Nunes and Zandavalli.^14,16

The cord blood volume is clearly associated with the delivery method and birth weight of the neonate. A larger volume of blood was collected from neonates delivered by C-section than from those delivered vaginally. This finding is in line with data reported by Nunes and Zandavalli.¹⁴ Additionally, a larger blood volume was collected from neonates with higher birth weights than from those with lower birth weights, which is similar to results reported previously.^13,14,16 The results of the univariate analyses show no significant effect of gestational age or donor age on the collected blood volume. However, when adjusting for these neonatal and maternal factors in the multivariate analysis, a significant effect of gestation duration on the collected UCB volume was found. Specifically, for each additional week of pregnancy, there was a 3% decrease in UCB volume. This decrease in collected blood volume has also been reported in a previous observation.^16,17 It is noteworthy that the blood volume is crucial, as this factor affects the TNC and CD34⁺ cell counts.

In this study, the TNC count (mean 11.58 × 10⁸ ± 4.4) was higher than that (mean 93.8 × 10⁷ ± 44.7) reported by Ballen et al..¹⁶ The TNC count is one of the important indicators used to select blood units for transplantation. The standard accepted for infusion is 2.5 × 10⁷ TNC/kg at collection, which is equivalent to 2.0 × 10⁷ TNC/kg after thawing.¹ This means that the cord blood cryopreserved in our bank is appropriate for infusing a recipient with a 10 kg or greater body weight. The distribution of TNC was related to the delivery method and baby gender. Higher TNC counts were found in blood units collected from neonates born vaginally (n = 115) and were female (n = 178). Similar results have been reported in several previous studies.^17–19 However, other authors have reported the opposite result, with the higher TNC count associated with C-section.^13,20–22 This finding could be due to the time point of the UCB collection, which differs across studies, for example, at 1 minute after delivery.¹⁵ In this study, the UCB was collected during the 2 minutes after the umbilical cord was cut, while the placenta was still in the uterus. Moreover, compared with the UCB from male neonates, the UCB from female neonates contained a higher number of TNCs (11.1%). These data are in line with the data reported in a previous study.¹⁷ Furthermore, the birth weight of babies influenced the number of TNCs in the collected blood, with a higher cell number observed in UCB from larger babies. For each additional 500 g of birth weight, there was a 21.25% increase in the TNC number.

The CD34⁺ cell infusion dose is also important to improve engraftment.^1,23,24 The mean CD34⁺ cell number in the UCB units in this study was 3.66 × 10⁶ cells, ranging from 0.5 to 17.3 × 10⁶ cells. Previous studies have shown that the number of CD34⁺ cells infused is ∼1 × 10⁵/kg.^1,23 This finding indicates that the cord blood units reported in this study could be used for children or adults depending on the precise number of CD34⁺ cells in each unit. For allogeneic transplantation, a higher number of CD34⁺ cells has been associated with a better survival of patients with myeloablation.²³ Therefore, the use of the blood units stored in our bank also depends on whether they are intended for autologous or allogeneic grafts. In this analysis, the CD34⁺ cell number was affected by the delivery method and birth weight of the neonate. Neonates born vaginally had a higher number of CD34⁺ cells than those born via C-section. Moreover, there was a positive correlation between the birth weight of the neonates and the CD34⁺ cell number, with a higher number of CD34⁺ cells found in larger neonates. In contrast, there was a negative correlation between CD34⁺ cell count and gestational age, with the number of CD34⁺ cells decreasing with each additional gestational week. This finding agreed with the results of the study reported by Ballen et al., which revealed that CD34⁺ cells decreased with increasing gestational age.¹⁶ These data showed that maternal and neonatal factors can be used to predict the quality of cord blood units.

The birth weight of neonates has an important impact on all precryopreservation indicators used to determine the quality of a unit of UCB. Neonates with higher birth weights produced a greater volume of UCB and higher counts of TNCs and CD34⁺ cells. This may be because neonates with higher birth weights have experienced better nutrient conditions, which also result in larger placental volumes, leading to larger volumes of UCB.²⁵ A small placental volume is related to low fetal body weight and is associated with abnormal fetal growth.²⁶ In contrast, a decrease in the CD34⁺ cell count was influenced by increasing gestational age. The multivariate analysis showed that each additional week of gestation contributed to a 3% decrease in collected blood volume and a 7.9% decrease in the CD34⁺ cell count. These data were similar to those reported previously.^16,17 This finding is important for the estimation of an appropriate gestational age for cord blood collection. In our study, the relationship between volume and gestation duration was not so strong and was not statistically significant (r = −0.039, p = 0.432). Larger sample sizes may detect the significance in the future studies. In sum, the multivariate analysis showed a cross-relation between birth weight, blood volume, and cell number. All maternal and neonatal factors must be favorable to result in a suitable UCB unit.

In this study, other factors that are considered important and that might impact the quality of the collected blood units such as alcohol intake and smoking during pregnancy were not studied because this information did not exist in the patient records. Additionally, in Vietnamese culture, the majority of women do not smoke or use alcohol, especially during pregnancy. Therefore, alcohol consumption and smoking habits were not analyzed or reported.

Conclusion

Maternal and neonatal factors are important as they affect the quality of the cord blood unit before cryopreservation. These maternal and neonatal factors impacted the collected blood volume and influenced the TNC and CD34⁺ cell counts. The neonatal weight at birth and gestational age have important impacts on almost all indicators of the quality of blood units, such as volume, TNC count, and CD34⁺ cell count. Neonates with higher birth weights produce higher quality UCB, while those with longer gestational periods produce lower quality UCB. This information can be used for prenatal consultation and early assessment of the quality of UCB units being chosen for storage.

Footnotes

Acknowledgments

The authors acknowledge all participants and the Vinmec Research Institute of Stem Cell and Gene Technology who helped in conducting this research.

Authors' Contributions

All authors contributed to and made critical revisions related to the important intellectual content of the article. The first (P.H.N.), second (V.T.N.), and last authors (L.T.N.) as well as U.T.T.T. contributed to the experimental design. P.H.N., V.T.N., U.T.T.T., T.T.C., L.H.T., T.T.H.D., T.N.D., and A.V.B. contributed to the collection and analysis of the data and drafted the article. P.H.N., V.T.N., L.T.N., and U.T.T.T. revised the article. All authors contributed to the final version of the article.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

There was no funding for this study.

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Factors Affecting Human Umbilical Cord Blood Quality Before Cryopreservation: The Importance of Birth Weight and Gestational Age

Abstract

Background:

Aim:

Materials and Methods:

Results:

Conclusion:

Introduction

Materials and Methods

Materials

UCB collection

Sample processing

Cell count and viability

Statistics

Results

Maternal and neonate characteristics

Characteristics of collected blood volume and cord blood cell populations

Association of maternal and neonatal predictors with blood volume, TNCs, and CD34+ cells

Discussion

Conclusion

Footnotes

Acknowledgments

Authors' Contributions

Author Disclosure Statement

Funding Information

References

Association of maternal and neonatal predictors with blood volume, TNCs, and CD34⁺ cells