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Early life determinants of arterial stiffness in neonates, infants, children and adolescents: A systematic review and meta-analysis

      Highlights

      • This is the first review to investigate pulse wave velocity in youth and exposure to early life risks.
      • Limited evidence supports increased pulse wave velocity when exposed to maternal diabetes or born small for gestational age.
      • These changes in pulse wave velocity appear to manifest in childhood and adolescence.
      • Further research is required to better understand the observed associations.

      Abstract

      Background and aims

      Certain exposures and risk factors during the first 1,000 days of life are known to influence future cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a measure of arterial stiffness and a recognised surrogate marker of CVD. We performed a systematic review and meta-analyses to investigate whether early life exposures were associated with increased PWV compared with controls in youth.

      Methods

      Databases AMED, MEDLINE, EMBASE, CINAHL and Scopus were searched from inception until February 2022. Eligibility criteria: observational controlled studies in youth aged <20 years with risk factors/exposure during the first 1,000 days and PWV measurement. This review is registered with PROSPERO (CRD42019137559). Outcome data were pooled using random-effects meta-analysis. Meta-regression was used to investigate potential confounders.

      Results

      We identified 24 eligible studies. Age of participants ranged from 1-day to 19-years at time of PWV assessment. Exposures included pre-term birth, small for gestational age (SGA), maternal diabetes and assisted reproductive technologies, none of which were significantly associated with PWV in meta-analysis. Sub-group analysis by age demonstrated increased PWV in childhood and adolescence in those exposed to maternal diabetes or born SGA. In meta-regression of pre-term studies, higher prevalence of SGA was associated with increased PWV compared with controls (p = 0.034, R2 = 1).

      Conclusions

      We found limited evidence that youth exposed to maternal diabetes or born SGA have increased PWV, consistent with increased future CVD risk. These changes in PWV appear to manifest in later childhood and adolescence. Further research is required to better understand the observed relationships.

      Graphical abstract

      Keywords

      Abbreviations:

      PWV (Pulse wave velocity), aIMT (Aortic intima-media thickness), cIMT (Carotid intima-media thickness), CVD (Cardiovascular disease), SGA (Small for gestational age), ART (Assisted reproductive technologies)

      1. Introduction

      Atherosclerosis is a progressive disease that begins in-utero [
      • Shin P.S.
      • KIm D.S.
      Histochemical studies of fetal arteries of Koreans with special reference to atherogenesis in adults.
      ] with the formation of fatty steaks or lesions in the arterial walls [
      • McGill Jr., H.C.
      • McMahan C.A.
      • Herderick E.E.
      • Malcom G.T.
      • Tracy R.E.
      • Strong J.P.
      Origin of atherosclerosis in childhood and adolescence.
      ] and is a major pathophysiological process that underlies many cardiovascular disease events. Early arterial injury can be evaluated in children and adolescents using non-invasive techniques, including measurement of carotid (CIMT) or aortic intima-media thickness (aIMT), coronary artery calcification and flow-mediated dilation [
      • Urbina E.M.
      • Williams R.V.
      • Alpert B.S.
      • et al.
      Noninvasive assessment of subclinical atherosclerosis in children and adolescents.
      ]. Arteriosclerosis or arterial stiffness is another important pathophysiological process that reflects the age related degenerative changes of large arteries [
      • Vasan R.S.
      • Pan S.
      • Larson M.G.
      • Mitchell G.F.
      • Xanthakis V.
      Arteriosclerosis, atherosclerosis, and cardiovascular health: joint relations to the incidence of cardiovascular disease.
      ]. Arterial stiffness can be evaluated with different modalities including augmentation index and pulse wave analysis, however pulse wave velocity (PWV) is generally regarded as the gold-standard for non-invasive estimate assessment of arterial stiffness [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ]. PWV reflects the mechanical and elastic properties of the arteries and predicts future cardiovascular disease and cardiovascular events [
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 Subjects.
      ].
      The first 1,000 days of life describes the period from conception until 24 months of age and is a critical time period for shaping health in later life [
      • Hoffman D.J.
      • Reynolds R.M.
      • Hardy D.B.
      Developmental origins of health and disease: current knowledge and potential mechanisms.
      ]. Early exposures, particularly pre-term birth and low birth weight, including small for gestational age (SGA) and intra-uterine growth restriction, increase the risk for adult cardiovascular disease [
      • Belbasis L.
      • Savvidou M.D.
      • Kanu C.
      • Evangelou E.
      • Tzoulaki I.
      Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses.
      ,
      • Markopoulou P.
      • Papanikolaou E.
      • Analytis A.
      • Zoumakis E.
      • Siahanidou T.
      Preterm birth as a risk factor for metabolic syndrome and cardiovascular disease in adult life: a systematic review and meta-analysis.
      ]. Assessing early arterial injury in youth may help to identify individuals with an early life exposure who are at greatest later risk of cardiovascular disease. The utility of measuring aIMT and cIMT in early life to assess arterial injury in high-risk populations compared with controls has been described in recent systematic reviews [
      • Epure A.M.
      • Rios-Leyvraz M.
      • Anker D.
      • et al.
      Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: a systematic review with meta-analyses.
      ,
      • Varley B.J.
      • Nasir R.F.
      • Skilton M.R.
      • Craig M.E.
      • Gow M.L.
      Early Life Determinants of Vascular Structure in Fetuses, Infants, Children and Adolescents: A Systematic Review and Meta-Analysis.
      ]. However, less is known about how early life exposures influence arterial stiffness, despite the extensive published reference ranges for children and adolescents [
      • Hidvégi E.V.
      • Jakab A.E.
      • Lenkey Z.
      • Bereczki C.
      • Cziráki A.
      • Illyés M.
      Updated and revised normal values of aortic pulse wave velocity in children and adolescents aged 3–18 years.
      ] and evolving techniques to enhance assessment efficiency [
      • Pereira T.
      • Correia C.
      • Cardoso J.
      Novel methods for pulse wave velocity measurement.
      ]. A greater understanding of how PWV is impacted by early life exposures might offer an alternative method to assess future CVD risk in high-risk individuals from early life.
      Therefore, the aim of this systematic review and meta-analysis was to examine early life determinants during the first 1,000 days of life and their association with PWV in childhood and adolescence. We also investigated potential moderators of these associations.

      2. Materials and methods

      This systematic review and meta-analysis was performed in accordance with the Meta-analysis of Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols guidelines and registered with PROSPERO (CRD42019137559).

      2.1 Search strategy

      Electronic databases AMED, MEDLINE, EMBASE, CINAHL and Scopus were searched from earliest record until February 2022. Studies were not restricted by date of publication and the search strategy was modified to suit each database (Supplementary Table 1). Reference lists of retrieved articles were also searched for potentially relevant articles.

      2.2 Eligibility criteria

      Eligible studies reported PWV as an outcome measure in an exposure and control group in participants aged <20 years at time of PWV assessment. Exposures were limited to the first 1,000 days of life i.e., conception to 2 years of age. Transmissible diseases or natural events were not considered exposures and studies were excluded if participants in the exposure group had any congenital or genetic conditions. Study designs eligible for review included observational/longitudinal/cohort, case-control or cross-sectional studies.

      2.3 Selection of studies

      Identified studies were imported and managed by Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). Duplicate studies were removed, and two reviewers (BJV and RFN) screened studies by title and abstract and then by full text against the selection criteria, recording reasons for exclusion. When any discrepancies arose in study eligibility, reviewers met to discuss and consulted a third reviewer where necessary.

      2.4 Data extraction

      Data extracted from eligible full-texts included study characteristics (design, setting, duration of exposure/follow-up), study population (age, sample size, gender distribution, birth weight, gestational age, BMI), exposures (type and definition), outcome measurements (PWV mean and standard deviation), method of PWV assessment (type of device, measurement segment and distance calculation) and potential modifiers or confounding factors. Exposures assessed were SGA, defined as birth weight <10th percentile, maternal diabetes including gestational and pre-gestational, pre-term birth and assisted reproductive technologies. All data were extracted by one reviewer and validated by a second reviewer (BJV and RFN). Data were extracted and managed using a purpose-built REDCAP electronic database hosted by the University of Sydney [
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.
      ]. Authors of studies were contacted via email where information was missing or clarification was required (BJV).
      When multiple studies reported data from the same cohort, the study with the largest sample size was included as the primary study and missing information was pooled [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ], with others excluded from the review [
      • Bolton C.E.
      • Stocks J.
      • Hennessy E.
      • et al.
      The EPICure study: association between hemodynamics and lung function at 11 years after extremely preterm birth.
      ,
      • Kowalski R.R.
      • Beare R.
      • Mynard J.P.
      • et al.
      Increased aortic wave reflection contributes to higher systolic blood pressure in adolescents born preterm.
      ,
      • Do V.
      • Eckersley L.
      • Lin L.
      • et al.
      Persistent aortic stiffness and left ventricular hypertrophy in children of diabetic mothers.
      ]. When studies included multiple PWV segments [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ], carotid-femoral was chosen as the preferential segment as it is considered the gold standard for PWV measurement [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ]. When studies reported multiple timepoints, only the earliest timepoint was used to minimise the impact of potential confounders [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ].

      2.5 Quality assessment

      Two reviewers independently assessed the methodological quality of included papers using the Joanna Briggs Institute appraisal tools [
      • Moola S.
      • Munn Z.
      • Tufanaru C.
      • et al.
      Chapter 7: systematic reviews of etiology and risk Australia.
      ]. Any discrepancies were resolved by discussion or by a third reviewer. Studies were judged as i) low risk of bias if they scored ‘yes’ for at least 70% of items, ii) moderate risk of bias if they scored 50–69% ‘yes’ and iii) high risk of bias if they scored less than 50% ‘yes’ [
      • Melo G.
      • Dutra K.L.
      • Rodrigues Filho R.
      • et al.
      Association between psychotropic medications and presence of sleep bruxism: a systematic review.
      ]. Publication bias was assessed by visual inspection of funnel plots.

      2.6 Data synthesis

      Descriptive analysis and a narrative synthesis of the major findings were performed. Meta-analysis of pooled exposures including sub-group by age (i.e. neonate, infant, childhood and adolescent) was performed using a random-effects model and was conducted with Comprehensive Meta-analysis (Version 3, Biostat, Englewood, NJ). Statistical heterogeneity was tested with the I2 statistic providing the percentage of variance of the summary effect attributable to heterogeneity between studies. Heterogeneity was considered to be low if I2 is ≤ 40% and considerable heterogeneity if I2 is ≥ 75% [
      • Deeks J.J.
      • Higgins J.P.
      • Altman D.G.
      Chapter 10: analysing data and undertaking meta-analyses.
      ]. Forest plots were generated with RevMan (Version 5.4.1, Copenhagen). When mean and standard deviation were not available, they were estimated from the median and interquartile range [
      • Wan X.
      • Wang W.
      • Liu J.
      • Tong T.
      Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
      ]. Moderator analysis was used to analyse how various measurement methods (type of device and measurement segment) were associated with PWV, and meta regression was used to examine potential confounding variables and explore sources of heterogeneity using Comprehensive Meta-analysis.

      3. Results

      3.1 Included studies

      The search identified 8943 articles, of which 24 were included (Fig. 1). Participant and study characteristics are shown in Supplementary Table 2 and Supplementary Table 3. Included study designs were cross-sectional (n = 21) [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ,
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ,
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ,
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ,
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ,
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ,
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ], case control (n = 1) [
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ] and cohort (n = 2) [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ]. Studies were conducted in UK/Ireland [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ,
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ,
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ,
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ], Sweden [
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ], Canada [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ], Australia [
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ], Pakistan [
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ], Netherlands [
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ,
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ], China [
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ], Spain [
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ], France [
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ], Austria/Italy [
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ], Belgium [
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ], Finland [
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ], Hong Kong [
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ], Switzerland [
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ] and USA [
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ]. The age of participants at the time of assessment ranged from 1 day to 19 years. PWV was measured in neonates [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ], infants [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ], children [
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ,
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ,
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ,
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ] and adolescents [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ,
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ,
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ]. Studies were conducted in a hospital setting (n = 15) [
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ,
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ,
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ,
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ,
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ,
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ], school setting (n = 1) [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ], child assessment clinic (n = 1) [
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ] or were not explicitly stated [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ,
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ]. Control participants were described as age and/or gender matched (n = 4) [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ] or described some level of matching (n = 3) [
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ,
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ]. The remaining studies described no level of matching [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ,
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ,
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ,
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ,
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ,
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ,
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ].
      Exposures identified and pooled in meta-analysis for their association with PWV included pre-term birth (n = 7) [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ], SGA (n = 6) [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ,
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ], maternal diabetes (n = 4) [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ,
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ], and assisted reproductive technologies (ART, n = 2) [
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ]. Exposures identified from single studies and described in narrative synthesis were in-utero maternal BP [
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ], in-utero maternal vitamin D [
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ], poor feto-placental circulation [
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ], breastfeeding [
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ], in-utero maternal smoking [
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ], peeclampsia [
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ], in-utero maternal iron [
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ] and large for gestational age [
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ].

      3.2 Risk of bias

      All cross-sectional studies were judged as low risk of bias, except for three studies judged as moderate (Supplementary Table 4A) [
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ,
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ]. The case control study was judged as low risk (Supplementary Table 4B). Of cohort studies, one study was judged low risk and the other as moderate (Supplementary Table 4C) [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ].

      3.3 Pre-term

      Seven studies investigated the association between PWV and pre-term birth: One measured PWV in childhood [
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ] and six in adolescence [
      • McEniery C.M.
      • Bolton C.E.
      • Fawke J.
      • et al.
      Cardiovascular consequences of extreme prematurity: the EPICure study.
      ,
      • Kowalski R.R.
      • Beare R.
      • Doyle L.W.
      • Smolich J.J.
      • Cheung M.M.H.
      Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm.
      ,
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ,
      • Wei F.F.
      • Raaijmakers A.
      • Melgarejo J.D.
      • et al.
      Retinal and renal microvasculature in relation to central hemodynamics in 11-year-old children born preterm or at term.
      ]. PWV was significantly greater in one [
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ] of seven studies. In meta-analysis of seven studies (pre-term n = 444 vs control n = 1169), PWV was not significantly different between pre-term and control groups (mean difference 0.02 m/s, 95% CI -0.17, 0.20, p = 0.853, I2 = 63%) (Fig. 2). Funnel plots were symmetrical therefore publication bias is unlikely.
      Fig. 2
      Fig. 2Meta analysis of pre-term studies with pulse wave velocity.

      3.3.1 SGA

      Six studies investigated the association between PWV and SGA: two measured in childhood [
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ] and three in adolescence [
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Rossi P.
      • Tauzin L.
      • Marchand E.
      • Boussuges A.
      • Gaudart J.
      • Frances Y.
      Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ]. One study longitudinally measured PWV in neonates and infants [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ], however only the earliest timepoint was included in meta-analysis. One study included participants with evidence of fetal growth restriction (i.e., birth weight <10th percentile and/or umbilical artery pulsatility index >2 SD) [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ]. PWV was significantly greater in three [
      • Muñiz Fontán M.
      • Oulego Erroz I.
      • Revilla Orias D.
      • Muñoz Lozón A.
      • Rodriguez Núñez A.
      • Lurbe I.
      • Ferrer E.
      Thoracic aortic intima-media thickness in preschool children born small for gestational age.
      ,
      • Bradley T.J.
      • Potts J.E.
      • Lee S.K.
      • Potts M.T.
      • De Souza A.M.
      • Sandor G.G.
      Early changes in the biophysical properties of the aorta in pre-adolescent children born small for gestational age.
      ,
      • Stock K.
      • Schmid A.
      • Griesmaier E.
      • et al.
      The impact of being born preterm or small for gestational age on early vascular aging in adolescents.
      ] and lesser in one [
      • Makikallio K.
      • Shah J.
      • Slorach C.
      • et al.
      Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.
      ] of five studies. In meta-analysis of five studies (SGA n = 346, control n = 1056), PWV was not significantly different in the SGA group compared with controls (mean difference 0.07 m/s, 95% CI -0.19, 0.32, p = 0.604, I2 = 76.4%) (Fig. 3). There was significant heterogeneity (p=0.012, I2 = 77.5%) and when analysed by age sub-groups, PWV assessed in neonates (single study) was lesser in the SGA group compared with controls (mean difference −0.80 m/s, 95% CI -1.45, −0.15, p=0.015) with no difference in PWV observed between groups in childhood and adolescent sub-groups. Funnel plots were symmetrical therefore publication bias is unlikely.
      Fig. 3
      Fig. 3Meta analysis of small for gestational age studies with pulse wave velocity and sub-group by age at measurement.

      3.4 Maternal diabetes

      Four studies investigated the association between PWV and maternal diabetes: two studies measured PWV in childhood [
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ] and one in adolescence [
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ]. One study longitudinally measured PWV in early infancy and late infancy [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ], however only the earlier timepoint was included in meta-analysis. PWV was not significantly different compared to controls in three of four studies [
      • Hoodbhoy Z.
      • Mohammed N.
      • Aslam N.
      • et al.
      Is the child at risk? Cardiovascular remodelling in children born to diabetic mothers.
      ,
      • Sundholm J.K.M.
      • Litwin L.
      • Rono K.
      • Koivusalo S.B.
      • Eriksson J.G.
      • Sarkola T.
      Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood - RADIEL study six-year follow-up.
      ,
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ]. In the longitudinal study, PWV measured in late infancy was significantly greater compared to controls [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ]. In meta-analysis of four studies (maternal diabetes n = 242, control n = 293), PWV was not significantly different in the maternal diabetes group compared with controls (mean difference 0.04 m/s, 95% CI -0.13, 0.20, p=0.680, I2 = 66.6%) (Fig. 4). There was significant heterogeneity (p=0.012, I2 = 88.8%) and when analysed by age sub-groups, PWV assessed in adolescence (single study) was greater in the maternal diabetes group compared with controls (mean difference 0.17 m/s, 95% CI 0.14, 0.20, p < 0.001) but not different in other age sub-groups. Funnel plots were not symmetrical, therefore publication bias is possible.
      Fig. 4
      Fig. 4Meta analysis of maternal diabetes studies with pulse wave velocity and sub-group by age at measurement.

      3.5 Assisted reproductive technologies

      Two studies investigated the association between PWV and ART. One measured PWV in childhood [
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ] and one in adolescence [
      • Zhang W.Y.
      • Selamet Tierney E.
      • Chen A.
      • Fleischmann R.
      • Baker V.
      Vascular health of children conceived via in vitro fertilization.
      ]. PWV was significantly greater in the ART exposure group compared with controls in the childhood study [
      • Scherrer U.
      • Rimoldi S.F.
      • Rexhaj E.
      • et al.
      Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.
      ]. In meta-analysis (ART n = 82 vs control n = 87), ART was not significantly different in the ART exposed participants compared with controls (mean difference 0.66 m/s, 95% CI -0.53, 1.84, p=.277, I2 = 90.1%) (Fig. 5). There were insufficient studies to assess publication bias.
      Fig. 5
      Fig. 5Meta analysis of assisted reproductive technologies studies with pulse wave velocity.

      3.6 Single exposures

      Of exposures identified in a single study, greater PWV was associated with preeclampsia [
      • Hoodbhoy Z.
      • Aslam N.
      • Mohsin S.
      • et al.
      Cardiovascular dysfunction in children exposed to preeclampsia during fetal life.
      ] compared with controls assessed in childhood, whereas lower PWV was associated with higher in-utero maternal BP (≥108 mmHg vs < 108 mmHg) when assessed in neonates. [
      • Koudsi A.
      • Oldroyd J.
      • McElduff P.
      • Banerjee M.
      • Vyas A.
      • Cruickshank J.K.
      Maternal and neonatal influences on, and reproducibility of, neonatal aortic pulse wave velocity.
      ] In-utero vitamin D [
      • Gale C.R.
      • Robinson S.M.
      • Harvey N.C.
      • et al.
      Maternal vitamin D status during pregnancy and child outcomes.
      ], poor feto-placental circulation [
      • Mone F.
      • Thompson A.
      • Stewart M.C.
      • Ong S.
      • Shields M.D.
      Fetal umbilical artery Doppler pulsatility index as a predictor of cardiovascular risk factors in children--a long-term follow up study.
      ], breastfeeding [
      • de Jonge L.L.
      • Langhout M.A.
      • Taal H.R.
      • et al.
      Infant feeding patterns are associated with cardiovascular structures and function in childhood.
      ], maternal smoking in-utero [
      • Taal H.R.
      • de Jonge L.L.
      • van Osch-Gevers L.
      • et al.
      Parental smoking during pregnancy and cardiovascular structures and function in childhood: the Generation R Study.
      ], in-utero maternal iron [
      • Alwan N.A.
      • Cade J.E.
      • Greenwood D.C.
      • Deanfield J.
      • Lawlor D.A.
      Associations of maternal iron intake and hemoglobin in pregnancy with offspring vascular phenotypes and adiposity at age 10: findings from the Avon Longitudinal Study of Parents and Children.
      ] and large for gestational age [
      • Olander R.F.W.
      • Sundholm J.K.M.
      • Suonsyrjä S.
      • Sarkola T.
      Arterial health during early childhood following abnormal fetal growth.
      ] were not associated with differences in PWV compared with controls.

      3.7 Equipment methodologies

      Methodologies of PWV varied widely (Supplementary Table 5). The most common PWV measurement type was using tonometry with either SphygmoCor or Complior device, and measured directly between the carotid and femoral arteries.

      3.8 PWV moderators

      When comparing different device types for non-invasive estimation of PWV in pre-term studies, greater PWV was associated with photoplethysmography method (n = 2), compared with tonometry (n = 2) and pressure transducer (n = 2, p=0.001, Supplementary Table 6). Comparing the PWV measurement segment, greater PWV was associated with brachial-radial segment (n = 2) compared with carotid-femoral (n = 4) and carotid-radial (n = 2, p=0.005, Supplementary Table 6). No other moderators were associated with differences in PWV between exposure and control groups.

      3.9 Meta-regression

      In preterm studies, higher prevalence of SGA was associated with greater difference in PWV compared with controls (p=0.034, R2 = 1, Supplementary Table 7). In SGA studies, gestational age at birth (p=0.003), birth weight (p=0.017), age at measurement (p=0.007) and BMI (p=0.016) were associated with greater differences in PWV compared with controls. No other variables were associated with differences in PWV between exposure and control groups.

      4. Discussion

      We have investigated associations between early life determinants with PWV for the first time. Early life factors including pre-term birth, SGA, maternal diabetes, and ART, were not significantly associated with greater PWV. Overall, risk of study bias was low, supporting confidence in our findings.
      Overall, SGA birth was not associated with changes in PWV compared with controls. However, three of five childhood and adolescent studies reported significantly greater PWV in the SGA exposed group compared with controls. This finding supports age-related functional changes of the vasculature that may not manifest until adolescence when assessed by PWV. The relationship between growth restriction and arterial stiffness is not fully understood, however it is well established that low birth weight increases cardiovascular risk in later life [
      • Belbasis L.
      • Savvidou M.D.
      • Kanu C.
      • Evangelou E.
      • Tzoulaki I.
      Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses.
      ]. Mechanistically, it has been proposed that the rate of elastin and collagen synthesis in the arterial wall is altered when fetal growth is impaired. These changes can result in permanent structural modifications including increased arterial stiffness and may predispose to increased risk of cardiovascular disease in later life [
      • Martyn C.N.
      • Greenwald S.E.
      Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension.
      ].
      Reviews of early life determinants on arterial injury are scarce, however a recent systematic review of the impact of exposures during the first 1,000 days of life on cIMT only identified associations between increased cIMT and SGA [
      • Epure A.M.
      • Rios-Leyvraz M.
      • Anker D.
      • et al.
      Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: a systematic review with meta-analyses.
      ]. In sub-group analysis by age at measurement, cIMT was greater when measured between 0 and 1 years of age compared with older children (0–16 years). However, fatty streaks or lesions are prone to forming in the intima of the abdominal aorta earlier than the carotid arteries [
      • McGill Jr., H.C.
      • McMahan C.A.
      • Herderick E.E.
      • Malcom G.T.
      • Tracy R.E.
      • Strong J.P.
      Origin of atherosclerosis in childhood and adolescence.
      ]. We recently reviewed the impact of risk factors and exposures during the first 1,000 days of life on aIMT and found increased aIMT was associated with SGA, intra-uterine growth restriction, preeclampsia and large for gestational age (under review) [
      • Varley B.J.
      • Nasir R.F.
      • Skilton M.R.
      • Craig M.E.
      • Gow M.L.
      Early Life Determinants of Vascular Structure in Fetuses, Infants, Children and Adolescents: A Systematic Review and Meta-Analysis.
      ]. In SGA studies, the magnitude of difference compared to controls was greater in aIMT (SMD 1.52; 95% CI: 0.98–2.06) than previously reported for cIMT (SMD 0.40; 95% CI: 0.15–0.64) [
      • Epure A.M.
      • Rios-Leyvraz M.
      • Anker D.
      • et al.
      Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: a systematic review with meta-analyses.
      ]. This suggests aIMT may be a more sensitive marker for arterial injury in SGA born infants and children, compared to cIMT [
      • Skilton R.M.
      • Celermajer S.D.
      • Cosmi E.
      • et al.
      Natural history of atherosclerosis and abdominal aortic intima-media thickness: rationale, evidence, and best practice for detection of atherosclerosis in the young.
      ] or PWV.
      Studies of maternal diabetes also suggest functional changes manifest in later life i.e, childhood and adolescence. Although no differences were found in meta-analysis, differences in PWV were found in sub-group analysis by age, whereby PWV assessed in adolescence was greater compared with controls (single study) [
      • Tam W.H.
      • Ma R.C.W.
      • Yip G.W.K.
      • et al.
      The association between in utero hyperinsulinemia and adolescent arterial stiffness.
      ], whereas infant and childhood sub-groups were not significantly different compared with controls. Furthermore, in the longitudinal study by Do et al., 2019 [
      • Do V.
      • Al-Hashmi H.
      • Ojala T.
      • et al.
      Cardiovascular health of offspring of diabetic mothers from the fetal through late-infancy stages.
      ], PWV did not differ between controls when measured in neonates, but was significantly greater when measured in infants, although the latter time point was not included in meta-analysis to minimise the effect of confounders. When the same cohort was followed up in childhood, PWV was still greater compared to controls [
      • Do V.
      • Eckersley L.
      • Lin L.
      • et al.
      Persistent aortic stiffness and left ventricular hypertrophy in children of diabetic mothers.
      ]. Exposure to maternal diabetes in-utero is known to influence cardiovascular health of offspring [
      • West N.A.
      • Crume T.L.
      • Maligie M.A.
      • Dabelea D.
      Cardiovascular risk factors in children exposed to maternal diabetes in utero.
      ] and this persistent elevated PWV may be the result of epigenetic alternation or increased inflammation, which contribute to vascular remodelling in-utero [
      • Do V.
      • Eckersley L.
      • Lin L.
      • et al.
      Persistent aortic stiffness and left ventricular hypertrophy in children of diabetic mothers.
      ] although not fully understood.
      Pre-term birth increases cardiovascular risk in later life [
      • Belbasis L.
      • Savvidou M.D.
      • Kanu C.
      • Evangelou E.
      • Tzoulaki I.
      Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses.
      ,
      • Markopoulou P.
      • Papanikolaou E.
      • Analytis A.
      • Zoumakis E.
      • Siahanidou T.
      Preterm birth as a risk factor for metabolic syndrome and cardiovascular disease in adult life: a systematic review and meta-analysis.
      ], however PWV was not different compared to controls with six of seven studies assessing PWV in adolescence. As there was heterogeneity in meta-analysis of pre-term studies, meta-regression was used to explore potential confounders and identified SGA was significantly associated with increased PWV within these pre-term studies. The rate of SGA was <1.8% except for a single study [
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ] which reported 26.5%. This suggests over representation of SGA in pre-term births and likely explain the heterogeneity. Further research is needed to explore measures of arterial stiffness in those born pre-term.
      We also performed moderator analysis of PWV methods to investigate potential confounders and explore potential sources of heterogeneity. When comparing different segments of non-invasive PWV estimate, greater PWV was associated with measurement of the brachial-radial segment (n = 2) compared with carotid-femoral (n = 4) and carotid-radial (n = 2) segments in pre-term studies. Although measurement of PWV is possible on any segment of human circulation, the carotid-femoral segment is considered the gold standard for measurement of arterial stiffness and has the largest amount of epidemiological evidence demonstrating its predictive value for cardiovascular events [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ,
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 Subjects.
      ]. Other segments such as ankle-brachial, or single point estimates of PWV are not recommended as the prediction of cardiovascular outcomes do not generalise globally or they lack predictive evidence [
      • Townsend R.R.
      • Wilkinson I.B.
      • Schiffrin E.L.
      • et al.
      Recommendations for improving and standardizing vascular research on arterial stiffness.
      ].
      When comparing different techniques for non-invasive estimation of PWV, greater PWV was associated with using photoplethysmography (n = 2), compared with tonometry (n = 2) and pressure transducer (n = 2) in pre-term studies. Pressure transducer and applanation tonometry are typically measured at carotid-femoral segment and their PWV estimates are well correlated [
      • Salvi P.
      • Magnani E.
      • Valbusa F.
      • et al.
      Comparative study of methodologies for pulse wave velocity estimation.
      ]. When compared to invasive measurement of carotid-femoral PWV using angiogram, pressure transducer and applanation tonometry were reliable estimates of aortic PWV [
      • Salvi P.
      • Scalise F.
      • Rovina M.
      • et al.
      Noninvasive estimation of aortic stiffness through different approaches.
      ]. However, comparison with photoplethysmography is difficult as PWV is commonly measured at different segments, including brachial-radial, as was the case of studies included in this review [
      • Bonamy A.K.E.
      • Bendito A.
      • Martin H.
      • Andolf E.
      • Sedin G.
      • Norman M.
      Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.
      ,
      • Cheung Y.F.
      • Wong K.Y.
      • Barbara C.C.
      • Lam B.C.C.
      • Tsoi N.S.
      Relation of arterial stiffness with gestational age and birth weight.
      ], fingertip [
      • Salvi P.
      • Magnani E.
      • Valbusa F.
      • et al.
      Comparative study of methodologies for pulse wave velocity estimation.
      ], or finger to toe [
      • Salvi P.
      • Scalise F.
      • Rovina M.
      • et al.
      Noninvasive estimation of aortic stiffness through different approaches.
      ], and therefore findings should be interpreted with caution.
      We used meta-regression and moderator analysis to explore heterogeneity between studies, however we were not able to check multiple comparisons in our meta-regression and we had limited capacity to perform sub-group analysis, therefore findings should be interpreted as exploratory. As there were a limited number of retrieved studies, more research is needed to explore the relationship between arterial stiffness and early life determinants. The majority of our meta-analyses were accompanied by substantial between-study heterogeneity (I2 >60%) and therefore should be interpreted with caution, particularly heterogeneity of SGA studies which are attributable to a single study. We acknowledge the small sample sizes for studies included in meta-analysis, particularly those participants exposed to the risk factors of interest. For example, in our meta-analysis of pre-term studies, 5 out of 7 studies had <68 participants in the exposed group. The measurement methodologies were highly variable between studies and may have influenced our findings. Although there is no standardised method for non-invasive estimate of arterial stiffness, carotid-femoral PWV is considered the gold standard [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ,
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 Subjects.
      ], which was used by <50% of our included studies. Best-practice methodologies need to be adopted to allow for appropriate comparison between studies. Guidance for arterial stiffness measurement are outlined in the European expert consensus [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ] and American Heart Association scientific statement [
      • Townsend R.R.
      • Wilkinson I.B.
      • Schiffrin E.L.
      • et al.
      Recommendations for improving and standardizing vascular research on arterial stiffness.
      ].
      We found limited evidence that youth exposed to maternal diabetes or born SGA have increased arterial stiffness compared with controls, consistent with increased cardiovascular risk in later life. Changes in PWV appear to manifest in later childhood and adolescence, suggesting that aIMT may be a better measure of arterial injury in high-risk children and adolescents due to its higher sensitivity in these younger age groups. More studies are needed to explore associations between arterial stiffness and early life determinants.

      Financial support

      BJV is funded by the Australian Government Research Training Program PhD scholarship. MLG is supported by a NHMRC Early Career Fellowships ( APP1158876 ), and MEC is supported by a NHMRC practitioner fellowship ( APP1136735 ).

      CRediT authorship contribution statement

      Benjamin J. Varley: Conceptualization, Methodology, Investigation, Validation, Data curation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization. Reeja F. Nasir: Validation, Writing – review & editing. Maria E. Craig: Conceptualization, Methodology, Investigation, Writing – review & editing, Supervision. Megan L. Gow: Conceptualization, Methodology, Validation, Investigation, Resources, Writing – review & editing, Supervision.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The authors acknowledge the technical assistance of Jim of the Sydney Informatics Hub, a Core Research Facility of the University of Sydney.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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