Correlation of umbilical cord blood haematopoietic stem and progenitor cell levels with birth weight: implications for a prenatal influence on cancer risk

ABSTRACT We examined the relation with birth weight and umbilical cord blood concentrations of haematopoietic stem and progenitor populations in 288 singleton infants. Across the whole range

of birth weight, there was a positive relation between birth weight and CD34+CD38− cells, with each 500 g increase in birth weight being associated with a 15.5% higher (95% confidence

interval: 1.6–31.3%) cell concentration. CD34+ and CD34+c-_kit_+ cells had J-shaped relations and CFU-GM cells had a U-shaped relation with birth weight. Among newborns with ⩾3000 g birth

weights, concentrations of these cells increased with birth weight, while those below 3000 g had higher stem cell concentrations than the reference category of 3000–3499 g. Adjustment for

cord blood plasma insulin-like growth factor-1 levels weakened the stem and progenitor cell–birth weight associations. The positive associations between birth weight and stem cell

measurements for term newborns with a normal-to-high birth weight support the stem cell burden hypothesis of cancer risk. SIMILAR CONTENT BEING VIEWED BY OTHERS BLOOD AND IMMUNE DEVELOPMENT

IN HUMAN FETAL BONE MARROW AND DOWN SYNDROME Article 29 September 2021 NUCLEATED RED BLOOD CELLS EXPLAIN MOST OF THE ASSOCIATION BETWEEN DNA METHYLATION AND GESTATIONAL AGE Article Open

access 27 February 2023 MUTATION ACCUMULATION AND DEVELOPMENTAL LINEAGES IN NORMAL AND DOWN SYNDROME HUMAN FETAL HAEMATOPOIESIS Article Open access 31 July 2020 MAIN The _in utero_

environment and perinatal factors may influence cancer risk of the offspring later in life (Trichopoulos, 1990). One parameter that reflects _in utero_/perinatal influences, that is birth

weight, has been positively correlated with subsequent risk of childhood cancer (Schüz and Forman, 2007) and, in adults, breast (Michels and Xue, 2006), prostate (Eriksson et al, 2007) and

colorectal cancers (Nilsen et al, 2005) and, indeed, overall cancer risk (Ahlgren et al, 2007). Mechanistically, a ‘stem cell burden’ theory (Adami et al, 1995) has been proposed to account

for the positive relationship between birth weight and the risk of certain cancers, especially that of the breast. By this hypothesis, the levels of _in utero_/perinatal mitogens and other

factors determine the size of the stem cell pools in the developing fetus; elevated tissue stem cell numbers drive the formation of larger organs and hence might be associated with larger

birth weights. The greater the stem cell pool size, however, the greater the chance that one of the stem cells will be mutated by a carcinogen, or undergo a DNA replicative error, initiating

oncogenic transformation. Hence, individuals with high birth weights might be at greater lifetime cancer risk (Trichopoulos et al, 2005). The stem cell burden theory predicts (1) that the

_in utero_ levels of particular mitogens should correlate positively with stem cell population levels and (2) that the stem cell levels should correlate positively with birth weight. In a

previous study, we demonstrated that the umbilical cord blood concentrations of various haematopoietic stem and progenitor populations correlated with cord blood plasma levels of particular

mitogens, especially insulin-like growth factor-1 (IGF-1) (Savarese et al, 2007). Here, we determine whether or not these measurable haematopoietic stem cell/progenitor values, serving as

surrogates of overall stem cell potential, are positively associated with birth weight. MATERIALS AND METHODS The umbilical cord blood study protocol was approved by the institutional review

boards of the American Red Cross, the University of Massachusetts Medical School, the University of Massachusetts/Memorial Health Care System, St. Vincent's Hospital and Tufts-New

England Medical Center (T-NEMC). Consenting study subjects were recruited from one of two sources: (1) participants in the Worcester, MA-based American Red Cross cord blood program (ACBP),

in which a haematopoietic stem cells from umbilical cord blood were collected for possible transplantation, from August 2002 to June 2003, and (2) pregnant women delivering at T-NEMC from

October 2004 to April 2006. All the cord blood samples were from full-term (gestational age ⩾37 weeks) singleton infants. The processing of samples, which includes the determination of cord

blood volumes, the determination of initial levels of total nucleated cells (TNC) and mononuclear cells (MNC) before centrifugations or manipulation, the quantitation of haematopoietic

stem/progenitor cell populations and the determination of cord blood plasma hormone levels, have been described (Savarese et al, 2007). The haematopoietic stem and progenitor populations

that were quantitated (1) CD34+ cells, a heterogeneous population of early multipotent stem and progenitor cells, committed progenitors and differentiating cells (Xiao and Dooley, 2000); (2)

CD34+CD38− cells, which represent more primitive stem cells depleted of lineage-committed precursors (Xiao and Dooley, 2000); (3) CD34+c-_kit_+ cells, which also represent a more primitive

stem cell population that has relatively high cloning efficiencies in semisolid culture (Sharkey et al, 1994; Mayani and Lansdorp, 1998); and (4) granulocyte–macrophage colony forming units

(CFU-GM), a functional measure of the number of proliferative granulocyte/macrophage-committed haematopoietic precursor cells (Abboud et al, 1992; Hoffbrand et al, 2001). Birth weight was

first studied as a categorical variable (<3000, 3000–3499, 3500–3999 and ⩾4000 g). Geometric means for the stem cell measurements were estimated within the indicated categories of birth

weight. Multivariate linear regression was used to examine the association between natural log-transformed measures of stem cell potential (dependent variable) and birth weight (independent

variable, using 3000–3499 g as the reference), adjusting for maternal and neonatal characteristics (mother's age, race of parents, number of live births, gestation duration, baby's

gender, delivery time and study site). To assess whether there was an underlying linear trend, birth weight was next analyzed as a continuous variable across the whole range of birth weight

values with the effect estimates expressed for each 500 g increase in birth weight. The fitted coefficients from the regression analyses were exponentiated to obtain the estimated

proportional change in birth weight associated with each independent variable. Statistical significance was set at 0.05 (two-sided). Levels of IGF-1, which had the strongest association with

levels of stem cells among the hormones and growth factors examined in a previous analysis (Savarese et al, 2007), were further adjusted to explore its influence on the association between

birth weight and stem cell measurements. RESULTS The characteristics of the study subjects are shown in Table 1. Subjects from the ACBP and T-NEMC patient groups had similar age and

gestation duration. Parental ethnicity was more varied in the T-NEMC samples, while the ACBP subjects had higher parities, more male newborns and lower birth weights. The associations were

analysed in multivariate analysis adjusting for maternal age, parental race, parity, gestation duration, gender, delivery time and study site (Table 2, upper panel). There was a J-shaped

association between birth weight categories and concentrations of TNC (lymphocytes, monocytes and granulocytes), as well as a J-shaped relation with MNC (lymphocytes and monocytes), both

including more differentiated cells. Among the stem cell populations, there was a positive association with CD34+CD38− cells across the whole range of birth weight categories, with each 500 

g increase being associated with 15.5% higher levels of this cell population (95% confidence interval: 1.6, 31.3%). A J-shaped relation was observed for the CD34+ and CD34+c-_kit_+ cells:

for birth weights of 3000 g or greater, stem cell concentrations increased with birth weight, while the lowest category of <3000 g had higher levels than the category of 3000–3499 g. For

CFU-GM, an approximate U-shaped relation was observed, with the lowest birth weight category having the highest levels of this cell population (Table 2, upper panel). Adjusting for cord

blood plasma levels of IGF-1 in the multivariate analysis weakens the association (Table 2, lower panel). The association with CD34+CD38− remained positive but was no longer statistically

significant: each 500 g increase in birth weight was associated with a 7.9% increase in this cell sub-population (95% confidence interval: −6.2, 24.0%). The lowest weight category continued

to have the highest CFU-GM cells after adjusting for IGF-1 levels. We conducted further analyses adjusting for other hormones and in samples from different ethnic groups. Adjusting for

estriol or insulin-like growth factor binding protein-3, which had statistically significant but weaker associations with cord blood levels of stem cells (Savarese et al, 2007), in place of

IGF-1, had much less effect on the association with birth weight (data not shown). A linear relation between stem cell measurements and birth weight was observed for newborns whose parents

were Caucasian, but did not have a consistent shape among samples in the mixed non-Caucasian group (Table 3). DISCUSSION The stem cell burden hypothesis has been invoked as an explanation

for the positive link between birth weight and risk for both childhood and adult cancers (Adami et al, 1995). This hypothesis proposes that _in utero_ environments that promote expansion of

stem cell pools result in infants with high birth weights; the larger the stem cell pool, the greater the risk that one of these stem cells will undergo malignant transformation. In support

of the first tenet of this hypothesis, we have demonstrated that the concentrations of stem and progenitor cell populations in umbilical cord blood, serving as surrogates for overall stem

cell potential, correlate with cord blood plasma levels of certain mitogens, notably IGF-1 (Savarese et al, 2007). The hypothesis also predicts that newborns with high birth weights should

have elevated stem cell populations. Our findings indicate that there is a positive association between birth weight and haematopoietic stem cell measurements in the cord blood samples among

newborns with normal-to-high (⩾3000 g) birth weights. This association is strongest with CD34+CD38− cells, a relatively primitive haematopoietic stem cell population. These data are in line

with previous studies, which showed a positive relationship between cord blood CD34+ or CFU-GM levels and birth weight (Shlebak et al, 1998; Ballen et al, 2001; Aroviita et al, 2004).

However, in our study, newborns in the lowest birth weight category (<3000 g) can have higher levels of stem/progenitor cell measurements than those with 3000–3499 g birth weight

resulting in a J- or U-shaped relation between stem cell levels and birth weight. This finding is intriguing, as J- or U-shaped relationships have often been observed in childhood cancers

(Schüz and Forman, 2007) and neurological (Schüz et al, 2001; Von Behren and Reynolds, 2003), prostate (Eriksson et al, 2007), colorectal (Nilsen et al, 2005) and early-onset breast cancers

(Sanderson et al, 1996; Innes et al, 2000; Mellemkjaer et al, 2003). The possible elevated levels of stem cells at low birth weight warrant further investigations. Using birth weight to

define small-for-gestation for full-term healthy infants, a majority (>86%) of such infants undergo accelerated growth during the first 6–12 months after birth and attain normal height

later in life (Karlberg and Albertsson-Wikland, 1995). Premature infants (i.e., those born before the 33rd gestational week, generally with low birth weights) have been shown to have

elevated foetal and cord blood CD34+ and CD34+CD38− levels relative to full-term infants (most with a normal birth weight) (Shields and Andrews, 1998; Wyrsch et al, 1999). Relevant to this

phenomenon, it has been reported that premature female newborns have an increased risk for breast cancer later in life (Ekbom et al, 2000). It is not known whether premature or small

newborns harbour elevated stem/progenitor cell populations, because these populations have not had enough developmental time to undergo a normal course of differentiation, or if such infants

build up a stem cell reserve for growth compensation during the postnatal period. In any case, our J-shaped relation observed between birth weight and stem cell measurements requires

further confirmation as ethnicity-specific results showed a linear relation in the considerably larger group of Caucasian cord blood samples. Finally, we examined cord blood plasma IGF-1

levels in relation to stem cell levels and birth weight. Insulin-like growth factor-1 had a positive association with stem cell measurements in our samples (Savarese et al, 2007) and was

strongly associated with birth weight (geometric means were 41.18, 57.86, 78.45 and 102.77 ng ml−1, respectively, for the four categories of birth weight in Table 2 and in the literature

(Bennett et al, 1983; Fant et al, 1993; Reece et al, 1994)). The growth hormone/IGF-1 axis has been suggested to serve as a master developmental regulator, coordinating stem cells in

multiple organs (Ginestier and Wicha, 2007). When we controlled for cord plasma IGF-1 levels, the associations were considerably weakened. This would be expected if IGF-1 regulates stem cell

potential and this is, in turn, a determinant of birth weight. To determine whether birth weight is an accurate reflection of stem cell potential, the focus should be on the results without

adjusting for IGF-1. We conclude that there is a J- or U-shaped positive association between birth weight and stem cell measurements, linear among term newborns with normal-to-high birth

weight and stronger with the more primitive stem cell sub-population. The nonlinear relationship, however, suggests that birth weight is not an unequivocal indicator of stem cell potential

in the context of a prenatal origin of cancer risk. Quantitation of stem cell pools might prove to be a more accurate predictor of cancer risk than birth weight _per se_, in accordance with

the stem cell burden hypothesis. CHANGE HISTORY * _ 16 NOVEMBER 2011 This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at

publication _ REFERENCES * Abboud M, Xu F, LaVia M, Laver J (1992) Study of early hematopoietic precursors in human cord blood. _Exp Hematol_ 20: 1043–1047 CAS  PubMed  Google Scholar  *

Adami H-O, Persson I, Ekbom A, Wolk A, Ponten J, Trichopoulos D (1995) The aetiology and pathogenesis of human breast cancer. _Mutat Res_ 333: 29–35 Article  CAS  Google Scholar  * Ahlgren

M, Wohlfahrt J, Olsen LW, Sørensen TIA, Melbye M (2007) Birth weight and risk of cancer. _Cancer_ 110: 412–419 Article  Google Scholar  * Aroviita P, Teramo K, Hiilesmaa V, Westman P,

Kekomaki R (2004) Birthweight of full-term infants is associated with cord blood CD34+ cell concentration. _Acta Paediatr_ 93: 1323–1329 Article  CAS  Google Scholar  * Ballen KK, Wilson M,

Wuu J, Ceredona AM, Hsieh C, Stewart FM, Popovsky MA, Quesenberry PJ (2001) Bigger is better: maternal and neonatal predictors of hematopoietic potential of umbilical cord blood units. _Bone

Marrow Transplant_ 27: 7–14 Article  CAS  Google Scholar  * Bennett A, Wilson DM, Liu F, Nagashima R, Rosenfeld RG, Hintz RL (1983) Levels of insulin-like growth factors I and II in human

cord blood. _J Clin Endocrinol Metab_ 57: 609–612 Article  CAS  Google Scholar  * Ekbom A, Erlandsson G, Hsieh CC, Trichopoulos D, Adami H-O, Cnattingius S (2000) Risk of breast cancer in

prematurely born women. _J Natl Cancer Inst_ 92: 840–841 Article  CAS  Google Scholar  * Eriksson M, Wedel H, Wallander M-A, Krakau I, Hugosson J, Carlsson S, Svärdsudd K (2007) The impact

of birth weight on prostate cancer incidence and mortality in a population-based study of men born in 1913 and followed up from 50 to 85 years of age. _The Prostate_ 67: 1247–1254 Article 

Google Scholar  * Fant M, Salafia C, Baxter RC, Schwander J, Vogel C, Pezzullo J, Moya F (1993) Circulating levels of IGFs and IGF binding proteins in human cord serum: relationships to

intrauterine growth. _Regul Pept_ 48: 29–39 Article  CAS  Google Scholar  * Ginestier C, Wicha MS (2007) Mammary stem cell number as a determinate of breast cancer risk. _Breast Cancer Res_

9: 109 Article  Google Scholar  * Hoffbrand AV, Pettit JE, Moss P (2001) _Essential Haematology_ 4th edn, pp 1–11. Malden, MA: Blackwell Science Google Scholar  * Innes K, Byers T, Schymura

M (2000) Birth characteristics and subsequent risk for breast cancer in very young women. _Am J Epidemiol_ 152: 1121–1128 Article  CAS  Google Scholar  * Karlberg J, Albertsson-Wikland K

(1995) Growth in full-term small-for-gestational-age infants: from birth to final height. _Pediatr Res_ 38: 733–739 Article  CAS  Google Scholar  * Mayani H, Lansdorp PM (1998) Biology of

human umbilical cord blood-derived hematopoietic stem/progenitor cells. _Stem Cells_ 16: 153–165 Article  CAS  Google Scholar  * Mellemkjaer L, Olsen ML, Sorensen HT, Thulstrup AAM, Olsen J,

Olson JH (2003) Birth weight and risk of early-onset breast cancer (Denmark). _Cancer Causes Control_ 14: 61–64 Article  Google Scholar  * Michels KB, Xue F (2006) Role of birth weight in

the etiology of breast cancer. _Int J Cancer_ 119: 2007–2025 Article  CAS  Google Scholar  * Nilsen TIL, Romundstad PR, Troisi R, Potischman N, Vatten LJ (2005) Birth size and colorectal

cancer risk: a prospective population based study. _Gut_ 54: 1728–1732 Article  CAS  Google Scholar  * Reece EA, Wiznitzer A, Le E, Homko CJ, Behrman H, Spencer EM (1994) The relation

between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins and receptors. _Obstet Gynecol_ 84: 88–95 CAS  PubMed  Google Scholar  *

Sanderson M, Williams MA, Malone KE, Stanford JL, Emanuel I, White E, Daling JR (1996) Perinatal factors and risk of breast cancer. _Epidemiology_ 7: 34–37 Article  CAS  Google Scholar  *

Savarese TM, Strohsnitter WC, Low HP, Liu Q, Baik I, Okulicz W, Chelmow DP, Lagiou P, Quesenberry PJ, Noller KL, Hsieh CC (2007) Correlation of umbilical cord blood hormones and growth

factors with stem cell potential: implications for the prenatal origin of breast cancer hypothesis. _Breast Cancer Res_ 9: R29 Article  Google Scholar  * Schüz J, Forman MR (2007)

Birthweight by gestational age and childhood cancer. _Cancer Causes Control_ 18: 655–663 Article  Google Scholar  * Schüz J, Kaletsch U, Meinert R, Kaatsch P, Spix C, Michaelis J (2001) Risk

factors for neuroblastoma at different stages of disease Results from a population-based case–control study in Germany. _J Clin Epidemiol_ 54: 702–709 Article  Google Scholar  * Sharkey AM,

Jokhi PP, King A, Loke YW, Brown KD, Smith SK (1994) Expression of c-kit and kit ligand at the human maternofetal interface. _Cytokine_ 6: 195–205 Article  CAS  Google Scholar  * Shields

LE, Andrews RG (1998) Gestational age changes in circulating CD34+ hematopoietic stem/progenitor cells in fetal cord blood. _Am J Obstet Gynecol_ 178: 931–937 Article  CAS  Google Scholar  *

Shlebak AA, Roberts IAG, Stevens TA, Syzdlo RM, Goldman JM, Gordon MY (1998) The impact of antenatal and perinatal variables on cord blood haemopoietic stem/progenitor cell yield available

for transplantation. _Br J Haematol_ 103: 1167–1171 Article  CAS  Google Scholar  * Trichopoulos D (1990) Does breast cancer originate _in utero_? _Lancet_ 335: 939–940 Article  CAS  Google

Scholar  * Trichopoulos D, Lagiou P, Adami HO (2005) Towards an integrated model for breast cancer etiology: the crucial role of the number of mammary tissue-specific stem cells. _Breast

Cancer Res_ 7: 13–17 Article  Google Scholar  * Von Behren J, Reynolds P (2003) Birth characteristics and brain cancers in young children. _Int J Epidemiol_ 32: 248–256 Article  Google

Scholar  * Wyrsch A, dale Carbonare V, Jansen W, Chklovskaia E, Nissen C, Surbek D, Holzgreve W, Tichelli A, Wodnar-Filipowicz A (1999) Umbilical cord blood from preterm human fetuses is

rich in committed and primitive hematopoietic progenitors with high proliferative and self-renewal capacity. _Exp Hematol_ 27: 1338–1345 Article  CAS  Google Scholar  * Xiao M, Dooley DC

(2000) Cellular and molecular aspects of human CD34+CD38− precursors: analysis of a primitive hematopoietic population. _Leuk Lymphoma_ 38: 489–497 Article  CAS  Google Scholar  Download

references ACKNOWLEDGEMENTS We are grateful for the effort of the attending physicians and residents of the Department of Obstetrics and Gynecology and Family Practice and the staff on the

Labor and Delivery ward at the Tufts-New England Medical Center. This study was support by a Grant (R01CA90902) from the US National Institutes of Health. PL, HOA, DT and CCH were supported

in part by the W81XWH-05-1-0314 Innovator Award, USA. Department of Defense Breast Cancer Research Program, Office of the Congressionally Directed Medical Research Programs. AUTHOR

INFORMATION Author notes * T M Savarese: Deceased. AUTHORS AND AFFILIATIONS * Department of Obstetrics and Gynecology, Tufts-New England Medical Center, Boston, MA, USA W C Strohsnitter, D P

Chelmow & K L Noller * Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA T M Savarese, Q Liu, I Baik & C-C Hsieh *

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA H P Low * Department of Hygiene and Epidemiology, School of Medicine, Athens University, Athens,

Greece P Lagiou * Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden M Lambe, H-O Adami & C-C Hsieh * Division of Hematology/Oncology,

Department of Medicine, UMass Medical School and UMass Memorial Health Care, Worcester, MA, USA K Edmiston * Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA H-O

Adami, D Trichopoulos & C-C Hsieh Authors * W C Strohsnitter View author publications You can also search for this author inPubMed Google Scholar * T M Savarese View author publications

You can also search for this author inPubMed Google Scholar * H P Low View author publications You can also search for this author inPubMed Google Scholar * D P Chelmow View author

publications You can also search for this author inPubMed Google Scholar * P Lagiou View author publications You can also search for this author inPubMed Google Scholar * M Lambe View author

publications You can also search for this author inPubMed Google Scholar * K Edmiston View author publications You can also search for this author inPubMed Google Scholar * Q Liu View

author publications You can also search for this author inPubMed Google Scholar * I Baik View author publications You can also search for this author inPubMed Google Scholar * K L Noller

View author publications You can also search for this author inPubMed Google Scholar * H-O Adami View author publications You can also search for this author inPubMed Google Scholar * D

Trichopoulos View author publications You can also search for this author inPubMed Google Scholar * C-C Hsieh View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to C-C Hsieh. RIGHTS AND PERMISSIONS From twelve months after its original publication, this work is licensed under the Creative Commons

Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Strohsnitter, W., Savarese, T., Low, H. _et al._ Correlation of umbilical cord blood haematopoietic stem and progenitor cell levels with birth weight: implications

for a prenatal influence on cancer risk. _Br J Cancer_ 98, 660–663 (2008). https://doi.org/10.1038/sj.bjc.6604183 Download citation * Received: 29 October 2007 * Revised: 30 November 2007 *

Accepted: 07 December 2007 * Published: 05 February 2008 * Issue Date: 12 February 2008 * DOI: https://doi.org/10.1038/sj.bjc.6604183 SHARE THIS ARTICLE Anyone you share the following link

with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative KEYWORDS * birth weight * cancer risk * prenatal exposure * stem cell