Hypertension

REVIEW

Developmental and Early Life Origins of

Cardiometabolic Risk Factors
Novel Findings and Implications
Empar Lurbe, Julie Ingelfinger

ABSTRACT: The intent of this review is to critically consider the data that support the concept of programming and its
implications. Birth weight and growth trajectories during childhood are associated with cardiometabolic disease in adult life.
Both extremes, low and high birth weight coupled with postnatal growth increase the early presence of cardiometabolic risk
factors and vascular imprinting, crucial elements of this framework. Data coming from epigenetics, proteomics, metabolomics,
and microbiota added relevant information and contribute to better understanding of mechanisms as well as development of
biomarkers helping to move forward to take actions. Research has reached a stage in which sufficiently robust data calls for
new initiatives focused on early life. Prevention starting early in life is likely to have a very large impact on reducing disease
incidence and its associated effects at the personal, economic, and social levels.

Key Words:  cardiovascular disease ◼ coronavirus ◼ birth weight ◼ proteomics ◼ traction

RELEVANCE-WHY IS THE TOPIC EARLY ORIGINS OF CARDIOMETABOLIC

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IMPORTANT RISK FACTORS

Before the present pandemic of the severe acute respi-
ratory syndrome coronavirus 2, noncommunicable dis-
eases caused more deaths than infectious diseases
worldwide; once the pandemic recedes, that is likely to
be the case again. Over the past several decades, the
concept that perinatal conditions, both intrauterine and
immediately after birth, increase the risk of many dis-
eases later in life, has gained traction, based both on epi-
demiological studies and experimental studies in animal
models. Strong epidemiological data suggest that low
birth weight (LBW) and prematurity, surrogates for intra-
uterine conditions, are associated with adverse health
conditions later in life, and even transgenerationally.
The intent of this review is to critically consider the
data that support the concept of programming and its
implications. Why is this important? Obviously, if adverse
perinatal conditions can be avoided or ameliorated,
then perhaps the implied legacy of higher risk can be
diminished.
The concept of the developmental origins of health and
disease (DOHaD) and the knowledge contributing to it
amassed during the latter part of the 20th century has
consistently attracted intense interest.1,2 There is grow-
ing evidence from observational studies indicating an
association between early life and later cardiometabolic
risk factors. While initial studies emphasized intrauterine
conditions as the main factor, further research has pos-
tulated that postnatal growth patterns have an important
additional impact on cardiovascular disease (CVD).3–6
Currently, the concept that a life course perspective may
be the optimal way to understand adult health and dis-
ease is recognized.
Although in childhood it is extremely rare to suffer the
adverse CV events experienced by adults, cardiovascu-
lar and metabolic disease risk factors may already be
present and related to the development of future adult
CVD.7 The challenge is to elucidate the main risk factors,
know when and how to assess these factors and discern

 
Correspondence to: Empar Lurbe, Department of Pediatrics, Consorcio Hospital General, University of Valencia, Avda. Tres Cruces s/n, 46014 Valencia, Spain. Email
empar.lurbe@uv.es
For Sources of Funding and Disclosures, see page 315.
© 2020 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp

308   February 2021 Hypertension. 2021;77:308–318. DOI: 10.1161/HYPERTENSIONAHA.120.14592

 Lurbe and Ingelfinger
Nonstandard Abbreviation and Acronyms
ACE-1 angiotensin-converting enzyme 1
AGA appropriate for gestational age
AT1b angiotensin type 1b receptor
AT2 angiotensin type 2 receptor
BMI body mass index
CVD cardiovascular disease
DOHaD developmental origins of health and
disease
HBW high birth weight
IMT intima-media thickness
LBW low birth weight
miRNA microRNA
SGA small for gestational age
how to manage them in children and adolescents. Birth
weight, growth trajectories during childhood, and the
cardiometabolic risk factors themselves are crucial ele-
ments of this framework.
The Importance of Birth Weight
Birth weight is a sentinel marker of fetal health, reflect-
ing both intrauterine growth and length of gestation. The
World Health Organization defines LBW as <2.5 kg, with
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the prevalence ranging from 2% to 12%. Low BW has
been rising due to the increment in the number of mul-
tiple births, partly as a result of the increase in fertility
treatments, to the increasing age of mothers at child-
birth and to the rise in smoking among young mothers.8
Despite the birth of more newborns with LBW, medical
care has been successful in reducing infant mortality,
raising the number of persons at risk.
Not only does LBW merit consideration but so does
high BW (HBW) as a consequence of intrauterine over-
nutrition, since that occurrence also has been related to
cardiometabolic risk factors. One of the main causes of
fetal overnutrition is maternal obesity, with its inherent
increased risk of complications in pregnancy, among
them, gestational diabetes. Newborns of obese moth-
ers are generally heavier, with more body fat9 and higher
body mass index (BMI) in childhood compared with
children of nonobese mothers.10,11 As mothers become
heavier, which is occurring in almost all populations, the
incidence of diabetes during pregnancy is increasing,12
which is likely to exacerbate the burden of obesity and
diabetes in the succeeding generation.
Following original observations by Barker et al,1
epidemiological studies demonstrated an association
between LBW and adverse cardiometabolic risk fac-
tors. Meta-analyses and systematic reviews with a large
number of studies supported an inverse association
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Early Life Origins of Cardiometabolic Risk Factors
between LBW with systolic blood pressure13,14 and type
2 diabetes risk.15–17 Aside from analyses of the impact of
LBW, the impact of different BW categories on cardio-
metabolic risk patterns in both children and adults has
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become recognized.
Data in children from the National Health and Nutri-
tion Examination Survey from 1999 through 2014, which
included 28 153 subjects from birth to 15 years, were
divided into 5 BW categories (<2.5, 2.5–3.0, 3.0–3.5, 3.5–
4.2, and ≥4.2 kg), with <2.5 kg as the LBW group (8.2%)
and ≥4.2 kg as the HBW group (10.4%).18 Over the entire
population, with an increasing BW, the results showed a
significant rising trend for the risk of general and central
obesity. In contrast, BW was significantly and inversely
associated with high systolic blood pressure, high glycated
hemoglobin, and low high-density lipoprotein cholesterol,
independent of current body size. The relation between
BW and childhood cardiometabolic risk factors showed
different patterns, depending on ethnic background.18
While reports consistently note that upon reaching
adult life there is an association between BW and type
2 diabetes,15–17 the link with CVD has been inconsis-
tent.19–23 Both of these issues were evaluated in a meta-
analysis of almost 8 million participants from 135 studies
stratified into 6 BW groups from <2.5 kg to >4.5 kg.24
The findings suggested that BW is associated with the
risk of type 2 diabetes and CV disease in a J-shaped
trend with increments of risk at both extremes. In con-
trast, the risk of hypertension was inversely associated
with BW—the lower the BW the higher the risk. Further-
more, among those at the higher end of the BW distribu-
tion (>4.5 kg), BW associated more strongly with type 2
diabetes and CVD in females than in males. Considering
these data and given that the prevalence of both low and
HBW is increasing, these findings are highly relevant to
population health and risk estimates for chronic disease.
Moreover, sex may act as an effect modifier rather than
as a confounder at the upper tail of the BW distribution.24
The Case of Prematurity
Studies concerning DOHaD have predominantly been
performed in full-term births, even when prematurity has
become a relatively common reason for LBW in devel-
oped countries. Of concern, however, adults who were
born prematurely have an increased prevalence of car-
diometabolic risk factors in comparison with persons who
were born after a full-term pregnancy.25,26 Epidemiologi-
cal data have focused mainly on prematurity per se, often
without accounting for BW contingent on gestational
age, with a paucity of knowledge concerning whether all
persons born prematurely have a tendency for higher risk
in adult life or whether the risk is increased only in the
presence of fetal growth restriction.
In a longitudinal study among participants of the pro-
spective Cardiovascular Risk in Young Finns Study for
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 Lurbe and Ingelfinger
whom there was information on BW and gestational age,
together with longitudinal data on cardiovascular risk
markers from age 3 to 18 years in 1980 to age 34 to 49
years in 2011, the authors observed increased BP lev-
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els among those participants born prematurely and who
were also small for gestational age (SGA). In contrast,
preterm appropriate for gestational age (AGA) did not
have elevated BP levels when compared with those born
at term. The difference between those born at term and
those born preterm but at normal weights (AGA) only
became evident when they reached the mean age of 41
years, not earlier.27 For other cardiovascular risk factors,
no significant differences have been observed based on
birth characteristics.27 A recent systematic review and
meta-analysis has pointed out that while only the preterm
AGA population was included, instead of the total pre-
term population, the significant preterm versus term dif-
ferences of outcomes assessed remained significant.28
Overall, multiple confounders make it difficult to
reach firm conclusions, and it remains controversial as to
whether prematurity constitutes an independent risk fac-
tor for the subsequent development of CVD. A marked
racial disparity is also persistent, even though the rates
of adverse birth outcomes have declined for all groups
over the last century. Adjusting for maternal characteris-
tics, income, race, and race plus income concentrations
remained negatively associated with preterm birth.29
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The Role of Postnatal Growth
Early childhood growth trajectories and rapid catch-up
growth have also been shown to independently influence
the development of risk factors and the incidence of
chronic disease. In a study of the Helsinki Birth Cohort by
Barker et al,3 adults with a coronary event were noted to
be relatively small at birth and thin at 2 years of age and
thereafter gained weight rapidly. This pattern of growth
during childhood was associated with insulin resistance
in later life. Furthermore, the risk of coronary events was
more related to the pace of childhood BMI gain than to
the BMI achieved at any particular age.3
The impact of BW and postnatal growth on the pres-
ence of overweight or obesity, BP values, metabolic
parameters, and diseases such as hypertension and type
2 diabetes, was the topic of a systematic review that
included children, adolescents, and adults.30 While some
studies reviewed had a significant association with BW
and postnatal growth, in others no association was found.
The most frequent association was seen with BP values
and fasting insulin. Furthermore, the greatest adverse
levels of cardiometabolic risk factors in children were
consistently present in those who started life as LBW
newborns but then became relatively heavy.30 It is worth
noting that the use of obesity criteria to detect children at
risk of future cardiometabolic risk will miss many at risk
persons. An upward crossing of BMI percentiles during
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Early Life Origins of Cardiometabolic Risk Factors
childhood, that does not necessarily connote childhood
obesity, also increases the risk, which underscores the
importance of regular growth monitoring.
Identifying Cardiometabolic Risk Factors
The interest in assessing the presence of cardiometabolic
risk factors during childhood is based on identifying peo-
ple at increased risk of developing adult CVD, to estab-
lish timely strategies for CVD prevention. Examination of
the conventional risk factors obesity, hypertension, insu-
lin resistance, and dyslipidemia31 show heterogeneous
results due to age at which they have been analyzed, the
variables used and the design of the studies. The dis-
crepancies, according to age and conditions under which
the variables are examined, derive from changes in body
proportions in growing children and the absence of the
stability of risk factors across different ages. Addition-
ally, physiological changes over time imply variations in
the classification of relevant parameters. Fluctuations in
cardiometabolic risk factor levels during puberty are well
known.32 Moreover, considering all of these factors, along
with the fact that most studies are cross-sectional and
retrospective, the disparate results are understandable.
To better comprehend the effect of fetal life and post-
natal growth on cardiometabolic risk factors, longitudinal
studies may add relevant information, even though the
length of follow-up and the focus on different outcomes
have been limitations up to now. The major focus of
longitudinal studies has been the association with later
obesity. New findings on the predictors of obesity from
the Family Life Project, assessing longitudinal patterns of
obesity, were that by age 6 stable obesity was associated
with both LBW and HBW.33 Repeating BMI measure-
ments, from childhood into adolescence, the UK Mille-
nium Cohort Study showed that rapid weight gain in early
life was associated with higher BMI at 5 years and more
rapid BMI gain subsequently from 5 to 14 years, espe-
cially in those large for gestational age at birth.34 Further
follow-up of these cohorts will be needed to examine if
the increased risk of obesity associated with HBW and
LBW is accompanied by obesity-related markers of dis-
ease such as insulin resistance or high BP.
A prospective study went a step further, reaching
the end of the first decade of life and analyzing car-
diometabolic risk factors.35,36 Healthy, full-term infants
of uncomplicated pregnancies were stratified as SGA,
AGA, or large for gestational age. At age 5 years, fast-
ing insulin levels were higher in all children who had
become heavy by that time, and the levels were high-
est among the SGA group. Even the SGA infants who
remained small at 5 years of age had measures of insulin
resistance comparable to those who became heavy at
5 years, suggesting metabolic programming in the SGA
group.35 Among participants reexamined at 10 years of
age, children with fasting insulin levels >15 U/L had a
 Lurbe and Ingelfinger
clustering of cardiometabolic risk factors: higher office
systolic blood pressure, higher plasma triglyceride and
uric acid levels, and lower high-density lipoprotein cho-
lesterol.36 Such findings are especially relevant, consid-
ering that insulin resistance does not resolve in youth
who are entering puberty, which may result in increased
cardiometabolic risk. Notably, puberty is associated with
a marked decrease in insulin sensitivity. Little is known
about the underlying pathophysiology of insulin resis-
tance in puberty, and how it might contribute to increased
disease risk (eg, type 2 diabetes).37
Vascular Imprinting
Using the life course perspective concept of the con-
tinuum of aging, new elements need to be considered.
There is a constant debate over whether the assess-
ment of arterial wall function and structure can add
relevant information for further lowering the cardio-
vascular risk beyond that from assessing conventional
risk factors. Though there are an increasing number
of methods currently available to evaluate arterial wall
function and structure, those used the most in pedi-
atrics are arterial stiffness, intima-media thickness
(IMT), and endothelial function. However, information
that links early life programming to arterial function and
structure is still scarce.
Arterial stiffness is a dynamic parameter that depends
on the arterial wall, its function and concomitant BP val-
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ues. An increment in arterial stiffness may be an early
marker of higher cardiovascular risk. Considered as a
core component in the concept of early vascular aging,
it has been associated with early life factors, BW, and
postnatal growth patterns.38,39
Arterial IMT is an acknowledged marker of subclini-
cal vascular damage in both adults and children. Even
though carotid IMT has been the most frequently ana-
lyzed as a target, previous studies have suggested that
aortic IMT may be a more discriminating measure in
childhood.40,41 Aortic wall thickening is increased in SGA
neonates compared with that of healthy newborns.40,41
A recent study found increased IMT both at the carotid
and thoracic aorta in 6- to -8-year-old children born SGA
as compared to that for those born AGA, somewhat not
explained by differences in body size.42
A few studies that have tested the impact of BW on
endothelial function, measured by flow-mediated vaso-
dilation induced by ischemia, indicated that children with
a history of LBW show impaired endothelial function.43
More recently, LBW has been associated with a decrease
in the circulating/functional capacity of endothelial pro-
genitor cells among healthy children 7 to 11 years of age,
independent of traditional cardiovascular risk factors.44
There are still many unanswered questions regarding the
effect of BW on endothelial function. Indeed, because
of the time requirements and the absence of reliable
Hypertension. 2021;77:308–318. DOI: 10.1161/HYPERTENSIONAHA.120.14592
Early Life Origins of Cardiometabolic Risk Factors
pediatric normative data, this method remains a research
tool rather than a predictor in pediatrics.
Review
MOLECULAR TECHNIQUES AND THEIR
CONTRIBUTION TO UNDERSTANDING OF
PROGRAMMING
The molecular era brought the capacity to perform rapid
nucleic acid sequencing and microarray studies, as well
as other molecular techniques and has provided the
potential for far more understanding of DOHaD. Molec-
ular and proteomic techniques have made it feasible to
investigate the mechanisms underlying both epidemio-
logical data and experimental studies that have been
heretofore phenomenological. Ultimately, such studies
may be able to define causality for developmental ori-
gins. For example, one of the most logical explanations
for programming presently lies in the many observa-
tions that epigenetic mechanisms play an important role
in DOHaD.45
An early molecular approach involved seeking variants
(mutations) induced by perinatal stressors. Indeed, some
toxins may lead to mutations. However, finding germ-
line mutations or somatic mutations in promoter regions
of genes, or in coding or noncoding areas and relating
these to DOHaD has not resulted in cogent explanations.
Much of the data that suggest that other changes,
termed epigenetic changes, which do not alter DNA
sequence, but, rather, accessibility to genes, in con-
trast, may play a substantial role in both maternal and
paternal influences on the fetus. Such alterations may
persist and exert not only effects on offspring but on
future generations.
Epigenetics as a concept (and term) was coined by
Waddington nearly 80 years ago (1942) and was envi-
sioned broadly.45–48 It has evolved as a field with mul-
tiple dimensions with potential application to the area
of DOHaD.46–48 The known manner in which epigenetic
changes occur include DNA methylation, histone modifi-
cations, and changes through noncoding RNAs such as
microRNAs (miRNAs), IncRNAs, and piRNAs—which are
small, noncoding RNAs that contribute greatly to tissue-
specific phenotype and function. Beyond that, other phe-
nomena are considered epigenetic as well.
Within the cell (and there are over 200 cell types in
mammals), chromatin stores the DNA—packaged either
as heterochromatin, which is closed and tightly wound,
and euchromatin, which is relatively open. Studies in
the 1970s showed that DNA lies within nucleosomes,
where it is wrapped around dimers of histone (classified
as H2A, H2B, H3, and H4; histone H1 does not form
dimers).49 The structure of chromatin changes substan-
tially both during development and cell differentiation.
Further, processes such as acetylation (which is the
most extensively studied), methylation, ubiquitylation, as
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 Lurbe and Ingelfinger
well as by ribosylation, phosphorylation, citrullination, and
sumoylation all modify histone.45–48
Both maternal and paternal epigenetic changes
impact the fetus—the mother, through changes from
Review
the inception of fertilization to birth (and beyond in
breast fed infants) and via epigenetic changes in sperm
that fertilize the egg. The exposures in the environ-
ment reported to affect male germ cells include stress,
heavy metals, bisphenols, and endocrine disruptors, as
well as some foods, and more, shown directly in animal
models (Figure 1).
There is now a growing literature concerning the
role of epigenetics in DOHaD, the majority of which has
been performed in experimental models, particularly in
rodents.50,51 There are, however, some epidemiological
data, as well as epigenome-wide association studies.
Taken together, such investigation is presently consid-
ered highly relevant to the observational data amassed
over the past decades.52
Methylation (and demethylation) of cytosine nucleo-
tides within the promoter region in a gene alters gene
expression. The most commonly methylated cytosines are
adjacent to guanosine and the event impacts hydrophilic
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Figure 1. Epigenetic changes and developmental origins of health and disease.
Fetal DNA sequences are not altered by epigenetic changes, yet these profoundly influence DNA configuration. The processes of DNA
methylation, post-translational histone modification, RNA modulation are involved and can affect gene availability and activation over the lifespan.
312   February 2021
Early Life Origins of Cardiometabolic Risk Factors
and hydrophobic properties of DNA. Methylation gener-
ally impacts gene expression—hypermethylation lowers
expression, while hypomethylation increases it. Within
the body of a gene, methylation generally increases tran-
scription by changing how compact chromatin is through
attracting proteins that complex with the methyl group
and, then, the DNA, silencing or enhancing transcription
factors.53 Further, modifications of histones can alter the
N-terminal region of histones, which affects the conden-
sation of chromatin.
The genome’s methylation profile undergoes changes
early in embryogenesis with demethylation in the pater-
nal genome (except for paternally imprinted genes), and
remethylation occurs.54–56 Most animal studies of epi-
genetics have focused on changes in maternal protein-
calorie intake during gestation.
Methylation and Perinatal Programming of
Hypertension
In a low protein model of induced programming Bogda-
rina et al,57 found that the angiotensin type 1b receptor
promoter was undermethylated in the adrenal, which they
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 Lurbe and Ingelfinger
took as a link between fetal insults and epigenetic modi-
fication. The investigators hypothesized that low protein
diet might decrease methyl donors, but, more plausibly,
that stress would influence glucocorticoid production
and release, affecting methylation. Goyal et al,58 using a
murine model, also found evidence that maternal protein
deprivation led to changes in the methylation in genes
of the renin-angiotensin system in the brain. They found
that CpG islands in the ACE-1 (angiotensin-converting
enzyme 1) promoter were hypomethylated, and, further
found that miRNAs that influence ACE-1 mRNA trans-
lation (mmu-mir-27a and -27b) were hypomethylated,
along with decreased levels of a miRNA that regulates
AT2 (angiotensin type 2 receptor) translation (miRNA
mmu-mir-330).
A number of studies that may be related to metabolic
syndrome are reviewed in Bianco-Miotto et al,59 none of
which related to directly to the programming of hyperten-
sion per se. The degree of adiposity in adult life has been
correlated with changes in methylation of DNA at birth or
early in life, suggesting that epigenetic markers might be
sought as a predictor.60–64
Payton et al65 studied miRNA in the placenta and
related that to BW using placental samples from the
Extremely Low Gestational Age Newborns cohort. They
observed that mRNA was upregulated for particular
pathways, especially glycoprotein VI, as well as hepa-
tocyte growth factor and human growth factors. Using
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networking approaches, they found that BW-associated
miRNAs in human placental tissues predicted which pro-
teins would be associated with individual BW.
In still other studies investigators found that intra-
uterine growth retardation led to methylation abnor-
malities in the offspring. Maternal diabetes has been
observed to result in growth restriction and epigen-
etic modulation of the Srebf2 gene in rat fetuses.66 In
the mouse, Radford reported that intrauterine growth
retardation changed the methylation of adult sperm,
affecting the metabolism in subsequent generations.67
Further, Broholm et al68 found that persons with LBW
had evidence of epigenetic changes (see recent review
by Arima and Fukuoka69). Recently, Felix and Cecil70
have suggested that DNA methylation may explain
much of the mechanism by which cardiovascular
changes take place through developmental program-
ming, and Chehade et al71 has summarized epigenetic
changes observed in premature birth.
The Microbiome and Programming
Much recent attention has focused on the microbiome
and its contribution to health and disease. Within the
intestine, microbes interact with signaling pathways—
in the neural system, endocrine system, and general
physiology.72 The food we eat and medications we take
alter the microbiome.73 It has been suggested that the
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Early Life Origins of Cardiometabolic Risk Factors
state of the microbiome influences BP and salt-sen-
sitive hypertension. Increasingly, the concept that the
microbiome may play a role in DOHaD with respect
to hypertension seems appealing.74 While a number
Review
of animal studies hint that the microbiome may play a
role in the development of hypertension, such data in
humans are lacking.
Proteomics and Perinatal Programming
The structure and function of the large number of pro-
teins within cells, organs, and whole beings is elucidated
by proteomics; in human beings there are over 100 000
known proteins, and presently, the use of high through-
put techniques makes it possible to examine differen-
tial expression of proteins, which are emblematic of
physiology, pathophysiology, and treatment. Proteomic
techniques are time intensive and difficult to perform in
large numbers of patients, rendering widespread clinical
applications difficult. These techniques involve 2-dimen-
sional gel electrophoresis, or 2-dimensional dimensional
difference gel electrophoresis, the use of Western blots,
and surface-enhanced laser desorption/ionization time-
of-flight mass spectrometry.75
While the promise of finding biomarkers or a mean-
ingful signature of protein changes that signify risk of
later disease in possibly at risk persons seems worthy,
there have not been many studies of proteomics with
respect to perinatal programming.
Romero et al76 studied 43 women with normal preg-
nancies that culminated in term deliveries at 3 to 6 time
points during the pregnancy and profiled the levels of
1125 proteins with the use of multiplex techniques and
then modeled protein abundance and correlated it with
gestational age. Ten percent of proteins changed signifi-
cantly between 8 weeks of gestation and term. Proteins
considered to be significantly changed were defined
as having the following45: >1.5-fold change between
8 and 40 weeks of gestation; and46 a false discovery
rate-adjusted value of P<0.1. Gene ontology enrich-
ment analysis was used to identify biological processes
overrepresented among the proteins that changed with
advancing gestation. Proteins that are recognized as
important in embryogenesis, growth, and angiogenesis,
as well as in immunoregulation and inflammation and
host defense response changed more than 5-fold (these
were glypican-3, sialic acid-binding immunoglobulin-type
lectin-6, placental growth factor, C-C motif-28, carbonic
anhydrase 6, prolactin, interleukin-1 receptor 4, dual-
specificity). The implications for the fetus are not known,
but one may speculate that such changes during preg-
nancy are important.
Wang et al77 found aberrant proteomic signals in an
intrauterine growth retardation study in pigs, suggesting
that maternal nutrition can influence the type and abun-
dance of proteins that regulate gut development.
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Again, examining protein-calorie malnutrition models
and growth-restricted kidneys Guo et al78 examined pro-
files of ion channel and transporter proteins. They looked
at 367 proteins that were differentially expressed and
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then used Ingenuity Pathway Analysis. These investiga-
tors found that in the kidneys of growth-restricted fetuses,
a number of carriers were differentially expressed, and,
they hypothesized, dysregulated. In analyzing the data,
they noted 22 differentially expressed proteins that are
known to be involved with transporters and ion channels.
They took the results to indicated that such dysregulation
may be involved with changes in kidney function in fetal
growth-restricted offspring.
Metabolomics and Programming
The examination of low molecular weight compounds in
a given biological sample to attain a picture of the com-
plete metabolites is called metabolomics.79 The involved
methodology, which requires high-resolution techniques
such as mass spectrometry, nuclear magnetic resonance
studies, and Fourier transform infrared spectrometry
are time and funding intensive.79 As the metabolome
changes quickly (within seconds to minutes), the choice
of sampling is crucial. With respect to DOHaD, metab-
olomic profiling has been performed in some animal
metabolome studies and on clinical samples from reposi-
tories.80 Such studies have the potential to contribute a
physiological signature to changes that may contribute to
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programming.81–84
Few perinatal programming studies have been pub-
lished to date. In an animal model of uterine ligation to
induce intrauterine growth retardation, Seferovic et al85
reported alterations in the metabolome that become
heritable, and that such changes occurred before the
onset of metabolic syndrome in adult life. They show
that in this model, dietary intervention may prevent
the metabolic syndrome. The investigators profiled the
serum metabolome in the F2 generation at weaning and
later, in adulthood to see whether metabolomic altera-
tions preceded development of metabolic syndrome.
Indeed, such changes occurred and were alterable to
dietary changes.
In a 2014 study Bassareo et al86 examined hematic
asymmetrical dimethylarginine levels in a small group
of former extremely LBW prematures (BW <1 kg)
and compared these to controls of term normal BW
young adults. They found that in the ex-premies the
asymmetrical dimethylarginine levels correlated with
their metabolic profiles, whereas this was not found
among the controls.86 Such pilot studies may indicate
the future feasibility of such an approach, but there is
not presently a signature that could be used clinically.
In another study of 226 mother: child pairs Lu et al87
examined cord blood lysophophatidylcholine levels and
found that these correlated with BW. The authors used
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Early Life Origins of Cardiometabolic Risk Factors
a metabolomic platform kit that quantified 163 metabo-
lites that included free carnitine, 40 acylcarnitines, 14
amino acids (13 proteinogenic+ornithine), hexoses
(sum of hexoses—about 90%–95% glucose), 92 glyc-
erophospholipids (15 lysophosphatidylcholines and 77
phosphatidylcholines), and 15 sphingolipids. In another
study, Horgan et al88 found that the metabolic profile
during pregnancy led to a potential phenotypic signa-
ture for fetuses who would become SGA neonates.
Such studies hint that there may be value in metabo-
lomic studies that could ultimately hone down the rea-
sons for programming of hypertension; however, these
presently constitute, at best, pilot data.
Overall, a variety of noncoding events impact the
future health of offspring. Some of the presently known
factors are epigenetics, proteomics, metabolomics, the
microbiome and other impactful events (Figure 2).
THE AT RISK CHILD AND A
PERSONALIZED MEDICINE APPROACH-
FEASIBILITY
Presently, the phenotype of LBW for gestational age
and prematurity (with either LBW for gestational age,
birth weight appropriate for age, or high for gestational
age) are easily determined. The data linking individual
children to future risk, however, are lacking.84 However,
a common-sense approach is feasible, as suggested
by Bassareo et al89 in which it was suggested that both
growth retardation and prematurity should be considered
in patient management. It would be useful to develop a
perinatal period of risk calculator, but the input data are
lacking. That being said, there are some simple mea-
sures to apply. It is reasonable to note a list of potential
historical risks: BW (if low for gestational age or high
for gestational age); gestational age at birth; perinatal
course; occurrence of severe illness or accident in child-
hood; the presence of obesity or overweight; the use of
medications that impact kidney function or perfusion, or
cardiac and vascular health. Then, current risks can be
assessed—current BP for age, weight for age, activity
level, and stress.
If the potential risks are multiple, then such a child
should be monitored carefully. It makes sense to fol-
low children and youth with increased numbers of red
flag factors more closely and to avoid nephrotoxins and
cardiotoxins.
On the contrary, there are not currently sufficient data
for an individualized approach, unless there are known
genetic and familial risk factors.90 In thinking about
hypertension and kidney disease, Barry Brenner has
promulgated90 that the single most important question to
ask a patient is, what was your birth weight? For now, that
question, followed by the assessment of additional (and
additive) risk factors would make sense.
 Lurbe and Ingelfinger
Downloaded from http://ahajournals.org by on January 15, 2023
Figure 2. OMICS and programming.
A variety of noncoding events impact the future health of offspring. Some of the presently known factors are epigenetics, proteomics,
metabolomics, the microbiome, and other impactful events.
FUTURE DIRECTIONS
Research into the developmental origins of cardiomet-
abolic risk factors and disease has reached a stage
in which sufficiently robust data call for new initiatives
focused on early life. New insights associated with a
life course perspective demand longitudinal rather than
cross-sectional studies. It is essential to design new
preconception and birth cohorts with precise pheno-
typic observations and long-term perspectives. After
that, it will be necessary to pair them with molecu-
lar studies. The identification of molecular changes,
together with later phenotypes, is critical to better
understanding the underlying mechanisms and to
delineating sensitive and specific biomarkers. This can
facilitate the detection of risk and monitor the efficacy
of preventive interventions to reduce the occurrence of
future disease.
The current epidemic of cardiometabolic disease
reveals that existing interventions are insufficient, and
a new approach to disease prevention with initiatives
emphasizing on early development is required. When we
Hypertension. 2021;77:308–318. DOI: 10.1161/HYPERTENSIONAHA.120.14592
Early Life Origins of Cardiometabolic Risk Factors
Review
see potential risk from that angle, we should resolve to
use the developmental perspective to devise interven-
tions in time to help the next generation. Prevention
starting early in life is likely to have a very large impact
on reducing disease incidence and its associated effects
at the personal, economic, and societal levels.
ARTICLE INFORMATION
Affiliations
From the Pediatric Department, Consorcio Hospital General, University of Va-
lencia (E.L.); CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto
de Salud Carlos III, Spain (E.L.); and Department of Pediatrics, Harvard Medi-
cal School, Mass General Hospital for Children, Massachusetts General Hospital,
Boston (J.I.).
Acknowledgments
We wish to thank Rob Flewell for editing the figures.
Sources of Funding
This work has been financially supported by: Ministerio de Ciencia, Innovación
y Universidades (Grant Number PI17/01517), Instituto de Salud Carlos III and
cofinanced by the European Regional Development Fund (to E. Lurbe).
Disclosures
None.
February 2021   315
 Lurbe and Ingelfinger
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