Published online before print October 9, 2006, doi: 10.1161/CIRCULATIONAHA.106.625848
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;114:1687-1692.)
© 2006 American Heart Association, Inc.
Epidemiology |
Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth
From the Center for Cardiovascular Research/Institute of Pharmacology (T.P., M.G., B.H.), Department of Nephrology (T.P., T.S.), Department of Obstetrics and Gynecology (H.H.), and Institute of Laboratory Medicine (F.P.), Charité, Berlin, Germany.
Correspondence to Professor Dr Berthold Hocher, Center for Cardiovascular Research/Institute of Pharmacology, Charité Mitte, Hessische Straße 3-4, 10115 Berlin, Germany. E-mail berthold.hocher{at}charite.de
Received March 8, 2006; revision received August 15, 2006; accepted August 17, 2006.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— It remains unclear whether the association between low birth weight and insulin resistance in adulthood has its origin in utero or whether it develops later in life depending on predisposition and exogenous factors.
Methods and Results— Total glycosylated hemoglobin (TGH) was quantified at delivery in 1295 mother/child pairs serving as a surrogate of maternal and fetal glycemia. Multivariable regression analysis considering gestational age at delivery, the child’s sex, maternal body mass index, and smoking during pregnancy revealed that an increase in TGH by 1% in the child was significantly associated with a mean birth weight reduction of 135 g (P<0.0001), whereas the same increase in the mother was associated with a mean birth weight increase of 88 g (P<0.0001). The ratio of fetal/maternal TGH suggests that lighter newborns have a higher percentage of TGH than would be expected from maternal TGH.
Conclusions— The study demonstrates for the first time in a large population that there is an inverse association between TGH of a newborn and its birth weight. This might be due to increased insulin resistance in newborns with lower birth weight. Our data suggest that the pathophysiological mechanisms linking prenatal growth and postnatal sensitivity to insulin are present as early as before birth.
Key Words: birth weight • cardiovascular diseases • diabetes mellitus • hemoglobin • insulin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Several epidemiological studies have confirmed the intriguing finding that low birth weight is an independent risk factor for glucose intolerance and type 2 diabetes mellitus, as well as other cardiovascular diseases, in later life.1–7 Potential mechanisms of this association are still controversial.8,9 Insulin resistance probably plays an important role, because it is one of the major underlying causes of glucose intolerance, and its multifaceted consequences include dyslipidemia, hypertension, hypercoagulation, and impaired fibrinolysis.8,10
Clinical Perspective p 1692
Attenuated responses to insulin in small groups of hyperglycemic low–birth weight infants have been reported.11,12 It remains unclear, however, whether the association between birth weight and traits such as glucose intolerance and insulin resistance is already present in utero and thus detectable at birth or whether it develops later in life depending on predisposition and exogenous factors such as lifestyle. The present study was aimed at answering this question. Because measurement of glucose tolerance and insulin sensitivity is practically difficult and ethically not viable in a large cohort of healthy newborns, we instead quantified total glycosylated hemoglobin (TGH) as a surrogate of glycemia during the last weeks of pregnancy.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A total of 1372 white women with singleton pregnancies delivering consecutively at the Charité obstetrics department in Berlin, Germany were invited to participate. Women with preterm birth (<37 weeks) were excluded. The local ethics committee approved the study. A total of 5.6% of the women refused to participate, which resulted in 1295 remaining mother/child pairs. After written consent was obtained, a structured medical history was taken. German guidelines for medical follow-up in pregnancy compose the so-called "Mutterpass" (pregnancy health document), which contains essential data about the pregnancy. The following data were extracted into our database: age, body height, weight before and during pregnancy, gravidity, parity, gestational age at delivery, urine dipstick results, evaluation of edema, and blood pressure. Weight before pregnancy was self-reported. Weighing during pregnancy, urine dipstick tests, evaluation of edema, and blood pressure readings were performed at all follow-up visits (minimum of 6 and maximum of 23 visits). For all individuals, mean weight and mean blood pressure were calculated for each half of pregnancy from all available readings. Biometric data of the newborns were routinely measured immediately after delivery. Fetal blood was collected from the umbilical cord. Midwives collected maternal blood from a cubital vein in the delivery room or on the ward.
Fetal and maternal blood was analyzed with the high-performance liquid chromatography–based Variant Total Glycated Hemoglobin Testing System (Bio-Rad, Hercules, Calif). It works independently of the hemoglobin type and is thus able to quantify glycosylation of fetal hemoglobin and adult hemoglobin. Briefly, the system separates glycosylated from nonglycosylated hemoglobin by boronate-affinity chromatography. The separated hemoglobins pass through a filter photometer, where changes of absorbance are measured at 415 nm. A secondary filter at 690 nm corrects for matrix effects caused by mixing buffers of different ionic strength, and a calibrator is analyzed with each run. No interference with labile glycosylated hemoglobins, lipemia, bilirubin, temperature fluctuations, or age-related degradation is observed. The system has been certified by the US National Glycohemoglobin Standardization Program.
Data were analyzed with SPSS version 11.5 (SPSS, Inc, Chicago, Ill). Normal distribution of birth weight was checked and confirmed descriptively (Figure 1). Bivariate correlation was assessed by correlation analysis, and a correlation matrix for birth weight and other relevant variables was generated. Pearson’s correlation coefficient was used. A forward stepwise multivariable regression model was used to identify and confirm relevant confounding variables that independently influence birth weight. Multivariable regression analysis was used to adjust for confounding variables known to independently influence birth weight. Normality, linearity, and homoscedasticity of residuals was tested and confirmed graphically with residual plots as described by Altman.13 Probability values <0.05 were considered significant.
|
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Detailed descriptive data of the study population are shown in Table 1. A birth weight histogram is shown in Figure 1. Biometric data of the newborns and TGH are shown in Table 2.
|
|
Fetal TGH was found to be negatively correlated with birth weight (Figure 2A and 2D), whereas there was a positive correlation between maternal TGH and birth weight (Figure 2B and 2E). We calculated an individual ratio of maternal and fetal TGH for every mother/child pair to evaluate a possible correlation with birth weight. As depicted in Figure 2C and 2F, there was an even stronger, highly significant negative correlation between this ratio and birth weight, which indicates that correlations between TGH and fetal growth are opposed to each other in mothers and their newborns, ie, lighter newborns have a higher percentage of TGH than would be expected from maternal TGH.
|
200 cases per group) were formed for TGH of child, mother, and its ratio with low to high values (1–6) from left to right. Data are given as mean±SEM. Correlation coefficients and probability values are given.
A forward stepwise multivariable regression model that included all relevant variables from Tables 1 and 2
confirmed previous reports14–16 that gestational age at delivery, the child’s sex, maternal body mass index, and smoking during pregnancy are the most important variables independently associated with birth weight (model A in Table 3). Models B and C in Table 3 demonstrate that maternal and fetal TGH are significantly associated with birth weight when added to the model separately. R2 was largest when both maternal and fetal TGH were included in the model, as shown in model D in Table 3. An increase in TGH by 1% in the child was significantly associated with a mean birth weight reduction of 135 g, whereas the same increase in the mother was associated with a mean birth weight increase of 88 g. It is worth noting that a percentage point of fetal TGH spans a slightly wider range of the distribution than a percentage point of maternal TGH.
|
A correlation matrix (Table 4) presents bivariate correlation coefficients for all individual variables. Corresponding to the multivariable regression model, birth weight was significantly correlated with all other variables. There was also a significant correlation between maternal and fetal TGH. However, as stated above, its ratio (child/mother) was significantly higher in children with lower birth weight. Most other variables were not correlated with each other. As an exception, maternal body mass index was positively correlated with maternal TGH, which fits into the concept of the metabolic syndrome.
|
We compared TGH of women with a history of diabetes mellitus during pregnancy to those without diabetes using an unpaired t test. Normal values of TGH are known to be higher than HbA1c.17 As expected, TGH was significantly elevated in women with diabetes mellitus (6.6±1.1% versus 6.3±0.7%, P<0.01). The small absolute difference most likely reflects tight therapeutic control of diabetes mellitus during pregnancy. The same result applied for TGH of newborns whose mothers had diabetes mellitus during pregnancy (4.8±0.7% versus 4.6±0.5%, P<0.05). The results of the multivariable models were consistent when mothers with diabetes mellitus and their children were excluded from the analyses.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study demonstrates for the first time in a large study population of 1295 mother/child pairs that there is an inverse association between TGH of a newborn and its birth weight, ie, lighter newborns have a higher percentage of glycosylated hemoglobin. TGH was quantified as a surrogate of fetal glycemia, which possibly reflects insulin resistance. Insulin resistance as a cause for hyperglycemia in low–birth weight neonates has been described previously.11 Similar to the monitoring of glycosylated hemoglobin in diabetic adults, our approach assumes that increased insulin resistance in utero elevates fetal blood glucose concentrations and consequently the percentage of TGH. Glycosylated hemoglobins are hemoglobin components formed through a 2-step nonenzymatic reaction between hemoglobin and blood glucose. In healthy adults, glycosylated HbA1c is the major fraction of TGH. The first step consists of the formation of a reversible aldimine form of hemoglobin to glucose linkage. In the second step, the labile aldimine form is converted slowly to the stable and irreversible ketoamine form through an Amadori rearrangement. The level of glycosylated hemoglobin (eg, fetal hemoglobin) is directly related to average blood glucose levels over the lifespan of the hemoglobin in the circulation.
The finding of an association between maternal TGH and birth weight corresponds to the well-known phenomenon of macrosomic children born to women with diabetes mellitus in pregnancy. Glycosylated hemoglobin is known to be associated with birth weight in diabetic women,18 but even in normoglycemic pregnancies, there is a correlation between maternal blood glucose and birth weight.19 Multivariable regression analysis demonstrates that the association between the newborn’s TGH and its birth weight is the opposite of (and, when one considers confounding factors, even stronger than) the association between maternal TGH and birth weight (–135 g versus 88 g per percent increase of TGH). The finding that the ratio of child/mother TGH is strongly associated with birth weight suggests that the fetal response to glucose is associated with fetal growth. When exposed to a similar maternal glucose load (reflected by maternal TGH), lighter fetuses appear unable to lower their blood glucose concentrations (reflected by the newborn’s TGH), as do heavier fetuses. Fetal blood glucose concentrations are usually regarded as a passive reflection of maternal glucose levels; however, the present data demonstrate that the fetal response to similar maternal glucose levels is not as uniform as previously thought. We hypothesize that this might be due to reduced fetal insulin secretion and/or insulin sensitivity in utero. Insulin resistance might play an important role, as reported in neonates and prepubertal children with low birth weight.11,12,20 It is a limitation of the study methodology that insulin sensitivity was not measured directly; however, standard methods have not been validated in newborns, because most methods are highly invasive and thus not viable in large cohorts of healthy newborns.21 A single measurement of glucose and insulin in cord blood gives little information because it reflects acute metabolic modifications induced by parturition. Decreased blood glucose concentrations in small-for-date babies at birth reflect the reduced ability to cope with stress during delivery.22
The results of the present study support the hypothesis that the association between birth weight and modifications of glucose metabolism develops in utero and is already detectable at birth. Our findings are in line with 4 smaller studies that reported reduced glucose tolerance or increased insulin resistance in 7-, 4-, and even 1-year-old children with low birth weight.20,23–25 The mechanisms of the association are controversial. Barker and Bagby’s developmental origins hypothesis9 postulates that tissues are permanently influenced by the intrauterine environment ("developmental plasticity"), whereas Hattersley and Tooke8 proposed that low birth weight, measures of insulin resistance in life, and ultimately glucose intolerance and diabetes mellitus might all be phenotypes of the same insulin-resistant genotype.
According to the developmental origins hypothesis, either maternal undernutrition or abnormal uteroplacental function reduces nutrient delivery to the fetus and may produce secondary adaptations in metabolism and gene expression that may be beneficial during intrauterine life but may contribute to disease risk in later life. Tissue resistance to the effects of insulin is viewed as a fetal response by which in a situation of malnutrition, blood glucose concentrations are maintained, eg, for the benefit of the brain but at the expense of glucose transport into the muscles and insulin-mediated growth.9,26 This response might cause higher plasma glucose levels even as early as the end of pregnancy in children with low birth weight and thus explain the present findings. The alternative approach that genetically determined insulin resistance results in low insulin-mediated fetal growth and elevated blood glucose in utero8 would also fit with the data presented in the present study. This hypothesis might explain the reduced ability of the lighter fetus to react to maternal glucose, resulting in a slight increase in fetal blood glucose, which nonenzymatically increases fetal TGH. In summary, our data suggest that the pathophysiological mechanisms that link prenatal growth and postnatal sensitivity to insulin are present as early as before birth.
|
Acknowledgments |
|---|
We thank Tania Schinck for valuable statistical advice.
Sources of Funding
This study was supported in part by the Deutsche Forschungsgemeinschaft (grant No. Ho1665/5-2 to Dr Hocher).
Disclosures
None.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991; 303: 1019–1022.[Medline]
[Order article via Infotrieve]
- Leon DA, Koupil I, Mann V, Tuvemo T, Lindmark G, Mohsen R, Byberg L, Lithell H. Fetal, developmental, and parental influences on childhood systolic blood pressure in 600 sib pairs: the Uppsala Family study. Circulation. 2005; 112: 3478–3485.
[Abstract/Free Full Text] - Clausen JO, Borch-Johnsen K, Pedersen O. Relation between birth weight and the insulin sensitivity index in a population sample of 331 young, healthy Caucasians. Am J Epidemiol. 1997; 146: 23–31.
[Abstract/Free Full Text] - Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM. Fetal growth and impaired glucose tolerance in men and women. Diabetologia. 1993; 36: 225–228.[CrossRef][Medline]
[Order article via Infotrieve]
- Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, Gillman MW, Hennekens CH, Speizer FE, Manson JE. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med. 1999; 130: 278–284.
[Abstract/Free Full Text] - Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ. 1996; 312: 406–410.
[Abstract/Free Full Text] - Mi J, Law C, Zhang KL, Osmond C, Stein C, Barker D. Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med. 2000; 132: 253–260.
[Abstract/Free Full Text] - Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet. 1999; 353: 1789–1792.[CrossRef][Medline]
[Order article via Infotrieve]
- Barker DJ, Bagby SP. Developmental antecedents of cardiovascular disease: a historical perspective. J Am Soc Nephrol. 2005; 16: 2537–2544.
[Abstract/Free Full Text] - Reusch JE. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol. 2002; 90: 19G–26G.[Medline]
[Order article via Infotrieve]
- Goldman SL, Hirata T. Attenuated response to insulin in very low birthweight infants. Pediatr Res. 1980; 14: 50–53.[Medline]
[Order article via Infotrieve]
- Pollak A, Cowett RM, Schwartz R, Oh W. Glucose disposal in low-birth-weight infants during steady-state hyperglycemia: effects of exogenous insulin administration. Pediatrics. 1978; 61: 546–549.
[Abstract/Free Full Text] - Altman DG. Practical Statistics for Medical Research. London, UK: Chapman & Hall; 1991.
- Catalano PM, Kirwan JP. Maternal factors that determine neonatal size and body fat. Curr Diab Rep. 2001; 1: 71–77.[Medline]
[Order article via Infotrieve]
- Abell TD, Baker LC, Ramsey CN Jr. The effects of maternal smoking on infant birth weight. Fam Med. 1991; 23: 103–107.[Medline]
[Order article via Infotrieve]
- Miller HC, Hassanein K. Maternal smoking and fetal growth of full term infants. Pediatr Res. 1974; 8: 960–963.[Medline]
[Order article via Infotrieve]
- Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. St Louis, Mo: Elsevier Saunders; 2006.
- Gold AE, Reilly R, Little J, Walker JD. The effect of glycemic control in the pre-conception period and early pregnancy on birth weight in women with IDDM. Diabetes Care. 1998; 21: 535–538.[Abstract]
- Wellik SR, de Veciana M, Morgan MA, Berkowitz KM, Arquilla ER. Naturally occurring insulin autoantibodies in neonates of normal pregnancies and their relationship to insulinemia and birth weight. Am J Obstet Gynecol. 1995; 173: 1878–1884.[CrossRef][Medline]
[Order article via Infotrieve]
- Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD. Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab. 1997; 82: 402–406.
[Abstract/Free Full Text] - Farrag HM, Nawrath LM, Healey JE, Dorcus EJ, Rapoza RE, Oh W, Cowett RM. Persistent glucose production and greater peripheral sensitivity to insulin in the neonate vs. the adult. Am J Physiol. 1997; 272: E86–E93.[Medline]
[Order article via Infotrieve]
- Hawdon JM, Ward Platt MP. Metabolic adaptation in small for gestational age infants. Arch Dis Child. 1993; 68: 262–268.[Abstract]
- Yajnik CS, Fall CH, Vaidya U, Pandit AN, Bavdekar A, Bhat DS, Osmond C, Hales CN, Barker DJ. Fetal growth and glucose and insulin metabolism in four-year-old Indian children. Diabet Med. 1995; 12: 330–336.[Medline]
[Order article via Infotrieve]
- Law CM, Gordon GS, Shiell AW, Barker DJ, Hales CN. Thinness at birth and glucose tolerance in seven-year-old children. Diabet Med. 1995; 12: 24–29.[Medline]
[Order article via Infotrieve]
- Soto N, Bazaes RA, Pena V, Salazar T, Avila A, Iniguez G, Ong KK, Dunger DB, Mericq MV. Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab. 2003; 88: 3645–3650.
[Abstract/Free Full Text] - Phillips DI. Insulin resistance as a programmed response to fetal undernutrition. Diabetologia. 1996; 39: 1119–1122.[Medline]
[Order article via Infotrieve]
CLINICAL PERSPECTIVE
Several epidemiological studies have confirmed the intriguing finding that low birth weight is an independent risk factor for glucose intolerance and type 2 diabetes mellitus, as well as other cardiovascular diseases, such as heart failure, in later life. Insulin resistance probably plays an important role, because it is one of the major underlying causes of glucose intolerance. Our study demonstrates, for the first time in a large population, that there is an inverse association between total glycosylated hemoglobin of a newborn and its birth weight. Glycosylated hemoglobins are hemoglobin components formed through a 2-step nonenzymatic reaction between hemoglobin and blood glucose. The level of glycosylated hemoglobin is directly related to the average blood glucose levels over the lifespan of the hemoglobin in the circulation and thus is a surrogate of insulin resistance. Our data suggest an increased insulin resistance in newborns with lower birth weight. These newborns are at risk for cardiovascular diseases in later life. Our data indicate that the pathophysiological mechanisms that link prenatal growth and postnatal sensitivity to insulin are present as early as before birth. The results of this study support the hypothesis that the association between birth weight and modifications of glucose metabolism develops in utero.Find additional patient-related information at:
This article has been cited by other articles:
 |
|
 |
|
  N. Brewer, C. S. Wright, N. Travier, C. W. Cunningham, J. Hornell, N. Pearce, and M. Jeffreys A New Zealand Linkage Study Examining the Associations Between A1C Concentration and Mortality Diabetes Care, June 1, 2008; 31(6): 1144 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-D. Nusken, J. Dotsch, M. Rauh, W. Rascher, and H. Schneider Uteroplacental Insufficiency after Bilateral Uterine Artery Ligation in the Rat: Impact on Postnatal Glucose and Lipid Metabolism and Evidence for Metabolic Programming of the Offspring by Sham Operation Endocrinology, March 1, 2008; 149(3): 1056 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Harder, J. W. Dudenhausen, and A. Plagemann Letter by Harder et al Regarding Article, "Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth" Circulation, May 15, 2007; 115(19): e462 - e462. [Full Text] [PDF]
|
|
|
|
|
|
T. Pfab, M. Godes, B. Hocher, T. Slowinski, H. Halle, and F. Priem Response to Letter Regarding Article, "Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth" Circulation, May 15, 2007; 115(19): e463 - e464. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hocher Fetal programming of cardiovascular diseases in later life - mechanisms beyond maternal undernutrition J. Physiol., March 1, 2007; 579(2): 287 - 288. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||