Relationship between birthweight and blood lipid concentrations in later life: evidence from the existing literature

Liisa Laurén1, Marjo-Riitta Järvelin2, Paul Elliott2 the EURO-BLCS Study Group, Ulla Sovio2, Anne Spellman2, Mark McCarthy3, Pauline Emmett4, Imogen Rogers4, Anna-Liisa Hartikainen5, Anneli Pouta5, Rebecca Hardy6, Michael Wadsworth6, Gunnhild Helmsdal7, Sjurdur Olsen7, Chryssa Bakoula8, Vasso Lekea8 and Iona Millwood2,9

1 Department of Epidemiology and Public Health, Imperial College London, Faculty of Medicine, Norfolk Place, London W2 1PG, UK. E-mail: l.lauren{at}imperial.ac.uk
2 Department of Epidemiology and Public Health, Imperial College London, UK.
3 MRC Clinical Science Centre, Imperial College London, UK.
4 Unit of Paediatric and Perinatal Epidemiology, University of Bristol, UK.
5 Department of Public Health Science and General Practice, University of Oulu, Finland.
6 MRC National Survey of Health Division, Department of Epidemiology, University College London, UK.
7 Danish Epidemiology Science Centre, Copenhagen, Denmark.
8 1st Department of Paediatrics Medical School, Athens University Children’s Hospital, Athens, Greece.
9 Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.


    Abstract
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 Abstract
 Methods
 Results
 Discussion
 References
 
Background It has been suggested that there is a link between fetal growth and chronic diseases later in life. Several studies have shown a negative association between birthweight and cardiovascular diseases, as well as cardiovascular disease risk factors, such as blood pressure and type 2 diabetes. Far fewer studies have focused on the association between size at birth and blood lipid concentrations. We have conducted a qualitative assessment of the direction and consistency of the relationship between size at birth and blood lipid concentrations to see whether the suggested relationship between intrauterine growth and cardiovascular diseases is mediated by lipid metabolism.

Methods A literature search covering the period January 1966 to January 2003 was performed using Medline, Embase, and Web of Science. All papers written in English and reporting the relationship between size at birth and lipid levels in humans were assessed. Bibliographies were searched for further publications.

Results From an initial screen of 1198 references, 39 papers were included involving 28 578 individuals. There was no consistent relationship between size at birth and blood lipid levels; the one exception being triglyceride concentration, which showed statistically significant negative or U-shaped, but not positive, relationships with birthweight.

Conclusion This review does not strongly support a link between birthweight and blood lipid levels in later life. However, the research in this area is limited and in order to make any definitive conclusions, longitudinal studies with sufficient power, data, and prospective follow-up are needed.


Keywords Birthweight, birth length, fetal growth, total cholesterol, HDL, LDL, triglyceride, lipid, hyperlipidaemia, cardiovascular diseases

Accepted 2 April 2003

The influence of early life exposures on risk of cardiovascular diseases (CVD) was first suggested by Forsdahl, who demonstrated a geographical association between past living conditions and current rates of coronary heart disease mortality1 and cholesterol values2 in Norway. Subsequently, the link between fetal growth and chronic diseases in later life has been investigated in numerous studies, and a negative association has been demonstrated between birthweight and risk of CVD,3–6 blood pressure,7–11 and type 2 diabetes.8,12,13 It has been proposed that adverse conditions in utero, such as fetal under-nutrition, can result in metabolic and physiological ‘programming’ of functions of the body with lifelong effects on disease risk.14 This has been known as the fetal origins, or ‘Barker’, hypothesis.

The first study on the association between fetal growth and lipids after Forsdahl’s observation was published in 1993,15 and it has been suggested that the link between fetal growth and CVD may operate via altered lipid metabolism.16–18 We have conducted a qualitative assessment of the direction and consistency of the relationship between birthweight and blood lipid concentrations in childhood, adolescence, and adulthood, based on a review of existing literature.


    Methods
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 Abstract
 Methods
 Results
 Discussion
 References
 
A literature search covering the period January 1966 to January 2003 was performed using Medline, Embase, and Web of Science. The following keywords were used; birth weight, birthweight, birth length, ponderal index, intrauterine growth retardation, fetal growth retardation, and abdominal circumference combined with cholesterol, triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), lipid, lipoprotein, hyperlipidemia, hyperlipidaemia, dyslipidemia, or dyslipidaemia. Traditional measures of size at birth were used, since there were no studies with information on ultrasound measures in pregnancy. The literature search yielded 1198 references. All papers written in English and reporting the relationship between size at birth and lipid levels in humans were assessed by reviewing the abstracts. Bibliographies of the included papers were searched for further publications. Papers were excluded if they reported solely on subjects with a pathological condition such as maternal hypertension during pregnancy or premature birth, or if lipid status was only studied neonatally. All forms of quantitative and qualitative analyses were included. Meta-analysis was not performed due to the paucity of studies, lack of quantitative information, and inconsistencies in methodology.


    Results
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The main features of the studies are presented in Tables 1–4GoGoGoGo. Table 1Go includes the number of studies on each lipid in children, adolescents, and adults. Table 2Go summarizes the adjustments in the studies, and Table 4Go presents the reported regression estimates. The main characteristics of the studies are presented in Table 3Go, including information on the study type, source of study subjects, source of birthweight, birth year, age at the time of lipid measurements, sample size, birthweight, confounding factors, outcomes considered, the direction of association with birthweight for the significant findings at the 5% level, and correlation coefficients.


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Table 1 Number of studies describing the association between birthweight and lipid values
 

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Table 2 Factors adjusted for in the analyses
 

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Table 3 Summary of the literature on the association between birthweight and blood lipid concentrations in the reviewed studies (by first author, country, and publishing year). (See footnote for abbreviations; superscript numbers refer to table footnotes, not to references)
 

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Table 4 Reported regression estimates (ß, mmol/l if not otherwise stated) for each 1-kg higher birthweight and 95% CI or standard error (SE) in children (<=12 years), adolescents (13–17 years), and adults (>=18 years). Statistically significant findings in italics; superscript numbers refer to table footnotes, not to references
 
A total of 39 papers were published between January 1966 and January 2003 describing, but not necessarily focusing on, the relationship between birthweight and lipid concentrations in later life including total cholesterol (TC), HDL, LDL, and TG. A majority of the studies included both males and females with the subjects’ age ranging between 31 months19 and 84 years,17 and with year of birth ranging from 1900 to 1992. In total, the studies involved 28 578 individuals. Ten papers reported results in children aged 31 months–12 years, 4 in adolescents aged 13–17 years, and 25 in adults (>=18 years) (Table 1Go). Altogether 33 papers described the relationship between birthweight and TC, 29 papers the relationship between birthweight and HDL, 21 papers the relationship between birthweight and LDL, and 31 papers the relationship between birthweight and TG. The total number of study subjects ranged from 3220 to 7206,21 but only six studies included more than 1000 participants.21–26 A majority of the studies used a longitudinal study design with retrospective information on birth data; only nine19,20,23,27–32 of the studies had a prospective follow-up from birth. Adjustments for potential confounding factors varied (Tables 2 and 3GoGo), and only a few papers provided regression estimates (Table 4Go).

Adjusting for current size has been noted to affect the association between birthweight and blood pressure,33 and for this reason the following results are presented separating unadjusted analyses and analyses adjusted for current size. Table 5Go presents the number and proportion of the reviewed studies supporting the fetal origins hypothesis when unadjusted and adjusted for current size.


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Table 5 Number and proportion of the reviewed studies supporting the fetal origins hypothesis when unadjusted and adjusted for current size
 
Total cholesterol
Unadjusted analyses
Nine papers21,25,34–40 described the relationship between birthweight and TC as a quantitative difference in mean TC between birthweight categories. Two of these reported a statistically significant negative association in adults.21,35 Other unadjusted analyses15,19,20,23,26,27,30,39,41–44 (e.g. those reporting regression or correlation coefficients) showed a statistically significant negative41,44 and positive41 relationship in adults, and a negative relationship in adolescents.42

Analyses adjusted for current size
Altogether 18 papers described the relationship between birthweight and TC adjusting for current size; either weight,26,28,37,45 body mass index (BMI),16,18,19,21,29,40,41,44,46–49 skinfold thickness,25 or waist circumference.34 Three of these reported a statistically significant negative association in adults,26,40,44 while one study reported a positive association.46 Both statistically significant positive19 and negative37 relationships were also reported in children.

The strength of the association
Regression estimates for TC (mmol/l for each 1-kg higher birthweight), both negative26,37,40,41,44 and positive,19,46 were reported in seven of the reviewed studies (Table 4Go). The statistically significant negative estimates in males varied between –0.1644 and -0.25,40 and there was 5.3% lower TC for every 1-kg higher birthweight in children (boys and girls analysed together).37 Only one study26 reported a statistically significant negative estimate (-0.09) in women. Statistically significant positive estimates were also reported, in boys (0.25)19 and girls (0.30),19 and in men (0.95).46

High density lipoprotein
Unadjusted analyses
Seven papers21,34,35,37–39,50 described the relationship between birthweight and HDL as a quantitative difference in mean HDL between birthweight categories, and both statistically significant negative39 and positive50 associations were reported in children. Of the other unadjusted analyses19,22,23,30,39,41–43 one showed a statistically significant negative relationship between birthweight and HDL in boys.19

Analyses adjusted for current size
Altogether 14 papers described the relationship between birthweight and HDL adjusting for current size; either weight,28,37,43 BMI16–19,22,29,47–49,51 or waist circumference.17,34 A statistically significant negative association was reported in children.19 Four studies16–18,51 reported a statistically significant positive relationship in adults.

The strength of the association
Regression estimates for HDL (mmol/l for each 1-kg higher birthweight), both negative and positive, were reported by one of the reviewed studies19 (Table 4Go). Statistically significant associations were all negative, and were found in 43-month-old boys, so that there was 0.079 mmol/l lower HDL for each 1-kg higher birthweight adjusting for height and BMI, and 0.093 mmol/l lower HDL adjusting for height, BMI, waist circumference:arm circumference, and breastfeeding history. Furthermore, the risk of an unfavourable HDL (<=1.4 mmol/l) level in women who were in the lowest birthweight tertile was 1.96 compared with those in the highest tertile adjusting for BMI, and 2.29 adjusting for waist circumference.17

Low density lipoprotein
Unadjusted analyses
Five papers34,35,37–39 described the relationship between birthweight and LDL as a quantitative difference in mean LDL between birthweight categories. One of these reported a statistically significant negative association in children,37 while one showed a statistically significant positive association in adolescents.38

Analyses adjusted for current size
Nine papers described the relationship between birthweight and LDL adjusting for current size; either weight,28,37 BMI,16,18,19,29,48,49 or waist circumference.34 A statistically significant negative association in children was reported by one paper.37

The strength of the association
Regression estimates for LDL (mmol/l for each 1-kg higher birthweight), both negative19 and positive,46 were reported in two of the reviewed studies (Table 4Go). A statistically significant positive association was shown in men, with 0.86 mmol/l higher LDL for every 1-kg higher birthweight (converted from pounds) adjusting for weight at 1 year of age.

Triglycerides
Unadjusted analyses
Eight papers21,23,34,36–39,50 described the relationship between birthweight and TG as a quantitative difference in mean TG between birthweight categories. Two of these reported a statistically significant negative association, in adolescents39 and adults,21 and one showed a U-shaped association in children.23 Of the other unadjusted analyses,19–22,30,39,41,43,44,52 one reported a statistically significant negative association in adolescents,39 and one in adults.44

Analyses adjusted for current size
Altogether 17 papers described the relationship between birthweight and TG adjusting for current size; either weight,28,37,39 BMI,16–19,22,23,29,44,47–49,51 waist circumference,17,34 or total body fat %.31 A statistically significant negative association was reported in children,23 adolescents,39 and adults.18,22,34,44,48

Strength of the association
Regression estimates for TG, either positive19,23 or negative,19,23,34,37,39,44 were reported in six of the reviewed studies (Table 4Go). All the statistically significant associations were negative. One of them34 showed 10% lower TG for every 1-kg higher birthweight. The two other studies reported 0.15 mmol/l44 and 0.12 mmol/l39 lower TG in males, and 0.10 mmol/l lower TG in females39 for every 1-kg higher birthweight. Furthermore, the risk of an unfavourable TG level (>=2.3 mmol/l) in women who were in the lowest birthweight tertile was 2.04 compared with those in the highest tertile adjusting for BMI, and 2.37 adjusting for waist circumference.17

Other measures of size at birth
Some studies considered other measures of size at birth than birthweight, such as birth length and ponderal index (birthweight/length3), a measure of thinness. The association between birth length and blood lipids was described in five studies,15,29,40,43,45 one of which reported a statistically significant negative association with TC in men, with and without adjusting for age, BMI, smoking, and alcohol.40 A negative association was also reported between birth length and HDL in boys, but this disappeared after adjusting for current weight and height.43 In addition, TC and LDL were noted to be higher in adults who were short at birth, but the trend was not significant in a simultaneous analysis with abdominal circumference.15 The association between ponderal index and lipids was described in eight studies,22,27–29,34,40,48,52 one of which reported a positive association with TC and HDL in adults, with and without adjusting for BMI.48 Another study reported a negative association with TC and LDL, and a positive association with HDL in children adjusting for BMI.29


    Discussion
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 Abstract
 Methods
 Results
 Discussion
 References
 
This overview, based on the limited data so far published does not provide strong evidence of a consistent relationship between birthweight, or any other measure of size at birth, and blood lipid concentrations. One possible exception is TG, which showed statistically significant negative or U-shaped, but not a positive association with birthweight. A majority of the published studies were based on only a small number of study subjects. However, the largest studies in terms of statistical power,22,24–26 or studies with representative data,18,19,21,37 do not give strong support to the hypothesis either. Overall, the existing literature showed no pattern in the results in terms of age, sex, generation, or any other aspect in the study subjects, possibly due to the sparse and varying information available.

The inconsistencies in the results between the studies may be due to several reasons, such as varying power or differences in the study populations in terms of age, sex, and ethnic or genetic background. The association between birthweight and blood pressure has been noted to amplify with age,53 which may also be the case with lipids, although this was not apparent among the studies reviewed. In addition, lipid levels change with age, remaining relatively stable until the onset of puberty, but increasing after puberty,54 which may obscure the results in adolescents. It is also possible that the associations are stronger in older generations, although again this was not apparent in the studies reviewed. The different findings in males and females19,40,43 may be due to the difference in the relationship between current body weight and lipids, as has been suggested.42 The differences noted in the reviewed studies between races23,55 may be due to an interaction between genes/ethnicity and birthweight, as has been suggested56 and recently reported in terms of insulin metabolism.50,57

Furthermore, adjustment for possible confounding factors varied to a great extent and was often incomplete (Tables 2 and 3GoGo), and this may have affected the results. Socioeconomic status, both in early and adult life, is associated with CVD risk,58 but was controlled for in three studies16,21,37 only, although it was otherwise taken into account (e.g. in the study design) in 11 studies.16–19,32,35,38,39,42,45,46 Although the noted associations16,37 were reported to be independent of social status, it remains unclear whether the associations are confounded in other populations, or in subjects of different age, sex, or generation. In addition, gestational age, which is known to be positively correlated with birthweight,59,60 was adjusted for15,18,26,32 or otherwise taken into account20,47,51 in only a few studies. Reported associations between birthweight and TC26 and TG18 were independent of gestational age, but the magni-tude of the reported association between birthweight and HDL decreased when adjusted for gestational age18 and there is no information about LDL.

Adjustment for current size was done in most of the studies. However, current size may act as an intermediate rather than a confounding factor, which makes interpretation of the results complex. In studies on the relationship between birthweight and blood pressure, adjustment for current size has been noted to lead to twice as large a negative association as without adjustment.33 An increase in the magnitude of the association when adjusted for current size was noted in five of the reviewed studies,23,26,34,37,40 and in general the studies adjusting for current size tended to give relatively more support for the hypothesis compared with the unadjusted studies (Table 5Go). In addition, an interaction between the effects of birthweight and current size is possible, but not confirmed in any of the studies which examined this.22,37,39 A few studies have reported that those who were small at birth, but who belong to the upper end of the bodyweight distribution in later life, possibly owing to an affluent lifestyle, are more prone to unfavourable lipid levels23,37 and cardiovascular risk factor profile11,16,17,32,37 than those who were small at birth, but not overweight in later life, thus agreeing with Forsdahl’s hypothesis. This also corresponds with the findings of accelerated catch-up growth and its relation to increased risk of high blood pressure,11 diabetes,61 and death from CVD.62 So far, there is little information about the influence of catch-up growth on lipids, but it has been reported that mean heights for age from birth to 10 years in adolescents in the upper quartile of LDL values are lower compared with those in lower LDL quartiles,43 contradicting the findings related to other CVD risk factors.

In addition to the incomplete control for possible confounding variables, the existing study populations are generally fairly small and possibly biased due to the nature of this kind of study where it is not only difficult, but sometimes impossible, to collect fully representative data. Most of the early life information on birth variables in the studies reviewed were retrospective and thus prone to selection and recall bias, although a minority of the birthweights in the studies were recalled.17,24,25,63 Maternally recalled birthweights are reasonably accurate compared with recorded birthweights,64 but self-recorded birthweights are noted to be inaccurate,64 especially in older people.65 The problem with prospective studies (follow-up from birth) on the other hand, is the length of the follow-up, which in the studies reviewed was generally short and therefore the associations may not yet be apparent. The two reviewed prospective studies lasting nearly 30 years28,32 were based on small study populations with insufficent data to throw light on the hypothesis. Varying statistical power of the studies may also have lead to inconsistencies between the results, since at least among those populations where the associations are weak, a high power would be needed to detect them. In the studies reviewed the reported regression estimates (Table 4Go) were all small.

As regards biological explanations, the possible underlying mechanisms linking size at birth to subsequent lipid levels in humans are so far unclear, although there is a vast amount of evidence from animal studies.66 Barker originally noted that smaller abdominal circumference at birth is associated with higher lipid levels. Based on this observation he suggested that, since abdominal circumference at birth is thought to reflect liver size, and cholesterol metabolism is regulated by the liver, impaired liver growth in uterus re-sets cholesterol concentration towards a more atherogenic profile.15 This view is supported by one other study that shows a negative association between abdominal circumference and TG in growth-retarded human fetuses.67 There is also evidence that uteroplacental insufficiency in rats can lead to lower birthweight and altered hepatic fatty acid metabolism,68 and that levels of apolipoprotein B, that can predict atherosclerosis, have been elevated in growth-retarded human fetuses.69 However, more research is needed to show whether the association between abdominal circumference and lipids exists in other populations, and how accurately measurement of abdominal circumference reflects the size of the liver in a new-born baby. The concordance between the size of the liver and abdominal circumference in humans is so far weak.70 It has also been suggested that in addition to size at birth, infant feeding may affect lipid metabolism,46 but the results are contradictory.19,43,63,71,72 The relationship between size at birth and lipid levels could also be considered as one feature of a more extensive metabolic disorder involving insulin resistance. This view is in line with the fact that TG, which is positively correlated with insulin,73–75was the only lipid showing a somewhat consistent relationship with birthweight. However, this has been contradicted by some earlier studies22,34,52 and more research is needed. In addition, the noted associations may also be explained by gene-mediated mechanisms, although there is not much support for this in the published literature so far.76–78

In conclusion, the evidence from the literature reviewed found no consistent relationship between size at birth and subsequent blood lipid concentrations, with the possible exception of a negative association between birthweight and TG. However, the research in this area is limited and most of the studies published so far may have lacked the power to detect apparently weak associations. There is some evidence in humans that the associations are biologically plausible, and this gives good reason for further research. However, longitudinal studies with high quality data, sufficient power, and prospective follow-up are needed.


KEY MESSAGES

  • The literature on the association between birthweight and lipids in later life is limited.
  • The existing studies show no consistent relationship between fetal growth and blood lipids in later life, with the possible exception of triglyceride.
  • There are plenty of inconsistencies between the studies, which may be due to several reasons, such as varying power and genetic/ethnic background.
  • Studies adjusting for current size tended to give relatively more support to the fetal origins hypothesis compared with studies not adjusting for current size.

 


    Acknowledgments
 
This study was financially supported by the European Commission, Quality of Life and Management of Living Resources Programme, contract number QLG1-CT-2000–01643. It forms part of a PhD thesis supported by the UK Medical Research Council being submitted by the first author to the University of London.


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