Hypertension in Children and Adolescents: New Perspectives

This book is devoted to hypertension in children and adolescents, a clinical issue that – thanks to the strides made in several areas of pathophysiological and clinical research – has received growing interest in cardiovascular medicine over the last several years.

Given the increasing prevalence of hypertension in children and adolescents, this book represents an important and useful tool to address what has become a significant public health issue. It covers a diverse range of topics, from advances in the definition of hypertension and the identification of new risk factors, to current treatment strategies.

The book also presents an overview of the latest findings, including the clinical significance of isolated systolic hypertension (ISH) in youth, the importance of out-of-office and central blood pressure measurement, new methods for assessing vascular phenotypes, and clustering of CV risk factors.

Gathering contributions by international experts and pursuing a practice-oriented approach, the book offers a valuable tool for cardiologists, pediatricians and nephrologists, as well as general practitioners.

• Language: English
• Publisher: Springer
• Release date: Jul 29, 2019
• ISBN: 9783030181673

Book preview

© Springer Nature Switzerland AG 2019

Empar Lurbe and Elke Wühl (eds.)Hypertension in Children and AdolescentsUpdates in Hypertension and Cardiovascular Protectionhttps://doi.org/10.1007/978-3-030-18167-3_1

1. From Pregnancy to Childhood and Adulthood: The Trajectory of Hypertension

Manish D. Sinha¹, ²  

(1)

Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guys & St Thomas’ NHS Foundation Trust, London, UK

(2)

Kings College London, London, UK

Manish D. Sinha

Email: [e-mail]

Keywords

MalnutritionBirth weightBlood pressureChildLife course

1.1 Undernutrition and Cardiovascular Disease

There is no doubt that events occurring before birth and during infancy influence risks of developing cardiovascular disease in the future. Over three decades ago, following the seminal observations by Barker and colleagues, it was first suggested that foetal events may influence risk of adult cardiovascular disease [1–3]. Barker’s observations highlighted that adverse events that impair foetal development can result in foetal programming of adult diseases including those affecting the cardiovascular, renal, respiratory and metabolic system [4, 5]. Several studies in different populations have confirmed the association of low birth weight (LBW) or reduced foetal growth with coronary heart disease (CHD), stroke and cardiovascular disease [6]. The concept of "programming" has been described as a process whereby a stimulus or insult at a critical period of development has lasting or lifelong significance [7]. The Barker hypothesis and the resultant foetal programming concept were expanded to the Developmental origins of health and disease (DOHaD) approach to recognise the broader scope of the developmental cues from conception to the infant and beyond and the concept that the early life environment has widespread consequences for later health [8–10].

Following Barker’s early observations of small size at birth and cardiovascular morbidity and mortality in a famine cohort in Hertfordshire, UK, similar observations were made by the Dutch famine study investigators who reported adverse cardiovascular outcomes in populations who had a period of poor nutrition during their early development [11–13]. These investigators highlighted differing outcomes following undernutrition during different exposure periods during pregnancy. Those affected during the early gestation period were observed to have higher rates of CHD compared to those not exposed at all or exposed to undernutrition during mid or late gestation [13]. Significant periods of undernutrition beyond foetal life are also important. Data from the Prospect-EPIC investigators examined risks of CHD and stroke in adults who experienced the Dutch famine during different ages as children (age categories 0–9, 10–17, 18–21 years) [14]. These investigators reported that greater exposure to famine resulted in the highest risk of CHD as adults, with risk being most evident in women who were adolescent girls at the time of the famine when compared with those who had no exposure to famine [14]. The Prospect-EPIC investigators thus proposed that beyond foetal life, poor nutrition during the period of adolescence may additionally result in an increase in the risk of adult-onset cardiovascular disease. An editorial by Jamshidi et al. highlighted evidence in the literature from other famine cohorts that confirm these observations of adverse nutritional status during childhood significantly associating with chronic disease processes in later life [15].

1.2 Overnutrition, Catch Up Growth and Cardiovascular Disease

It is well recognised that although foetal undernutrition remains very relevant for large parts of the world, in significant parts of the developed and developing world, overnutrition, as evidenced by increasing prevalence of obesity in the general population, is now more relevant [16]. Overnutrition of the population in general [17] has resulted in increasing prevalence of maternal obesity [18] and is associated with adverse maternal outcomes both during and following pregnancy [19, 20]. Maternal obesity during pregnancy is though not limited in its adverse consequences to the mother alone and has been associated with increased all-cause mortality and cardiovascular morbidity in offspring as adults [21, 22]. Maternal obesity has also been associated with increased rate of structural congenital anomalies [23] and mortality in term infants although this is largely unrelated to underlying cardiovascular disease [24], and both maternal obesity and excessive weight gain during pregnancy (gestational weight gain, GWG) have been sighted as risk factors for adverse offspring outcomes including those relating to the metabolic and cardiovascular system [25].

There are data associating worse outcomes for adult cardiovascular risk [26] and hypertension [27] in those with LBW and those who are obese subsequently as adults. In those experiencing foetal undernutrition, as represented by LBW, availability of excess calories through early childhood and later as young adults resulted in maladaptive responses leading to higher risk of chronic diseases in later life [5, 28]. Thus, Barker and colleagues showed that the risk of coronary artery disease is increased in adults and is independently associated, following adjustment for measures of socio-economic status in adulthood, with small size at birth, low body mass index (BMI) at 2 years of age and high BMI at 11 years of age [28]. Thus, beyond the foetal environment, the subsequent environment is also important during childhood and adult life.

These concepts and supporting data are essential to our understanding of early life environment and subsequent development of irreversible consequences such as cardiovascular disease, particularly when considering the evolution of hypertension, which is the focus of this chapter. As discussed in an authoritative review by Whincup [29], it remains important to examine the interplay of foetal factors and later influences. Thus, size at birth, usually reported as birth weight and representing the contribution of the intrauterine environment, and size through childhood reported as adiposity and representing one of the main later influences need further discussion. Both birth weight and subsequent childhood obesity are important as they have been shown to have a consistent relationship with blood pressure (BP).

We next discuss birth size and blood pressure and discuss risk factors and the association of birth weight and subsequent catch up growth with blood pressure, focusing on infants with LBW.

1.3 Birth Size, Birth Weight and Blood Pressure

Several publications highlight the relationship between foetal growth restriction, LBW and elevated blood pressure [30, 31]. The inverse relationship of systolic blood pressure with birth weight has been shown across different populations. The magnitude of the effect following adjustment for current weight or BMI was 2–3 mmHg decrease in systolic BP in children and adolescents and 3–4 mmHg decrease in systolic BP in adults for every 1 kg increase in birth weight [31]. A subsequent meta-analysis of the results highlighted likely publication bias that attenuated the strength of the association but continued support for the inverse relationship [32]. In neonates, there is a positive association of systolic BP with birth weight, and in adolescents, there is a continued but an attenuated negative association of systolic BP with birth weight [31]. The only other measure of birth size to have a consistent association with BP is head circumference, and effect size shown to be ~0.5 mmHg reduction in systolic BP per 1 cm increase in head circumference. Data regarding association of other birth measures with systolic BP are not consistent, including ponderal index (weight/length³) and gestational age [31].

The association of systolic BP with placental weight, placental/birth weight ratio and placental area has not been observed consistently [31], although a recent study by Wen et al. provides some convincing data in support of the association with BP [33]. The authors examined associations between placental morphology measures (size and vascular lesions) and systolic BP measured at 4 months and age 7 years [33]. Their comprehensive placental analysis showed convincingly that placental weight and placenta/birth weight ratio are positively associated with systolic BP at 7 years but not at 4 months, while placental volume was negatively associated with 4 months and positively with 7-year BP. The authors concluded that placental inefficiency, reflected by disproportionately large weight and size, predicts long-term blood pressure, whereas vascular resistance and lesions may only influence short-term blood pressure [33].

Term LBW infants have been shown to have significantly higher blood pressure by age 6 years than normal birth weight babies [34]. Lurbe et al. showed that initial BP was significantly lower, and heart rate significantly higher, in the LBW (<2500 g) babies compared with those with birth weight ≥2500 g. During the first month of life, those with LBW showed a significantly faster rise in BP, and through the remainder of the first year they maintained BP at the same levels as the bigger babies, thereby sustaining a higher BP per kg body weight [35]. In a series of related studies, Lurbe et al. have further demonstrated that LBW infants not only have the highest BP value but also the highest BP variability at 1 year of age [36], which is inversely related to pulse pressure measured using ambulatory BP monitoring in adolescents [37]. Finally, the results of a meta-analysis show that those who were preterm at birth (<32 weeks) or had very low birth weight (<1500 g) have higher systolic BP of about 2.5 mmHg than term infants when measured during late adolescence [38].

Finally, to assess the impact of birth weight and postnatal weight gain on BP and metabolic profile during the first 5 years of life, Lurbe et al. reported a cohort of 139 term infants with measurements performed at day 2, 6 months, 2 years and 5 years [39]. Blood pressure at birth was related to birth weight but with increasing age, current weight had a stronger association than birth weight; BP was increasingly dependent on current weight and total weight gain during the study, while the impact of birth weight disappeared. Birth weight additionally was associated with adverse cardiometabolic markers, leading to the conclusion that the acceleration of early infant weight gain may aggravate the effects of low birth weight [39]. Further, data support the finding that weight changes during childhood impact subsequent BP levels [40–42] and that more recent changes may be more relevant to the current BP value [43].

As childhood adiposity is one of the main modifiers of BP, we next discuss risk factors during pregnancy and early life that have been associated with childhood obesity with a focus on those with shared relevance with BP.

1.4 Size During Childhood—Risk Factors from Conception to Early Life for Obesity

In keeping with the foetal overnutrition hypothesis [44], there is a consistent association of large mothers including those with excessive GWG having ≥2× increased risk of large for gestational age babies and increased birth weight [45, 46]; these findings appear to be independent of genetic factors when examined across several pregnancies in the same mother [47]. Conversely, the pre-pregnancy underweight status increased the risk of small for gestational age (SGA) [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.76–1.87]. Investigating the role of maternal obesity versus increased GWG, the Generation-R investigators observed a stronger association of maternal obesity when compared with increased GWG for having large for gestational age offspring [19]. Beyond the foetal period and infancy, results of a meta-analysis including several studies suggest large mothers [45] and those with increased GWG [48] have an increased risk of childhood excess weight [OR, 3.06; 95% CI, 2.68–3.49; and OR 1.21; 95% CI 1.05–1.40, respectively], when compared with offspring of mothers with normal weight. Pre-pregnancy obesity has also been shown to have a significant association in adolescence and young adulthood [49, 50]. GWG has also been shown to be associated with increased BMI in adults aged 42, with adult BMI only partly associated with childhood BMI [51].

In a recent systematic review conducted by Baidal and colleagues [52], modifiable risk factors associated with childhood obesity from conception to 2 years were investigated. The authors reported that higher maternal pre-pregnancy BMI (mppBMI), prenatal tobacco exposure, maternal excess gestational weight gain, high infant birth weight and accelerated infant weight gain were most commonly implicated, with lesser evidence for gestational diabetes and indicators suggesting lower socio-economic status [52]. In addition to the above, early introduction of solid foods has also been observed as an additional risk factor for childhood overweight during the first year of life [53]. The association of childhood overweight with maternal cigarette smoking, another modifiable risk factor, in children ≥2 years appears strong and contributes about 50% increased risk of overweight when compared with children whose mothers did not smoke during pregnancy [54]. The authors highlight that analysis of the included studies suggests that socio-demographic and behavioural differences between smokers and non-smokers do not explain the observed association [54].

Several mechanisms beyond the foetal overnutrition theory have been suggested to explain the association of mppBMI and GWG with childhood adiposity. Details of these are outside the scope of this chapter and include tracking of body size, shared genetics and environmental factors and the emerging recognition of epigenetic pathways triggered perhaps in the obesogenic intrauterine environment [9, 10, 44, 55]. Results of a meta-analysis showed a variable influence of maternal BMI over paternal BMI, thus suggesting only limited evidence to support the foetal overnutrition hypothesis [56]. The Cardiovascular Risk in Young Finns Study investigators observed maternal BMI was significantly more strongly associated with offspring birth weight than paternal BMI, although at later ages of 3–39 years there were no such differences in parent-offspring associations for BMI [57]. Further, the Young Finns investigators observed adult BMI of the offspring was 1.21 units higher than the BMI of their parents at the same age, indicating an increase in obesity levels across generations (P < 0.0001), and leading to the conclusion that environmental influences are more significant than shared genetics with parents [57]. An interesting study by Jääskeläinen et al. [58] showed that children whose both parents were overweight or obese both before pregnancy and after a 16-year follow-up had a strikingly high risk of overweight at age 16 [boys OR, 5.66; 95% CI, 3.12, 10.27; girls OR, 14.84; 95% CI, 7.41, 29.73], concluding that persistent parental overweight status over 16 years (both pre-pregnancy and after 16 years) conveys the highest risk of childhood obesity at age 16 [58].

Although an understanding of risk factors of obesity and its trajectory through childhood are important and have been the focus of several studies in this area, unfortunately, data relating to BP in these studies have historically often not been measured/reported. In addition to obesity and its own predictors briefly discussed above, other risk factors during pregnancy that have been associated with the risk of hypertension in the offspring include gestational hypertensive disorders [59], maternal smoking [60] and gestational diabetes mellitus [61].

Over the last 10–15 years, several large prospective studies have been reported and include analyses of several risk factors including those relating to the mother, events during pregnancy, measures of socio-economic status, birth and childhood characteristics. In the next section, we discuss the results of the main prospective parent-offspring birth cohort studies with a focus on the association of maternal pre-pregnancy BMI and GWG with offspring blood pressure. Table 1.1 summarises the main findings relating to BP from these studies.

Table 1.1

Parent-offspring birth cohort studies investigating the associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with blood pressure

BP blood pressure, SBP systolic blood pressure, BMI body mass index, mppBMI maternal pre-pregnancy BMI, WC waist circumference, DXA DEXA bone density measurement

1.5 Parent-Offspring Birth Cohort Studies—Associations of Maternal Pre-pregnancy BMI and Gestational Weight Gain with Blood Pressure

The "Mater-University study of pregnancy and its outcomes (MUSP)" from Australia showed that maternal age, BMI and smoking were all independently and positively associated with offspring BP aged 5 years [62]. They observed an increase of ~1 mmHg for every +1 standard deviation score (SDS) change in the risk factor. The association of offspring systolic BP with paternal BMI was lesser. The investigators concluded that interventions aimed at early risk factors such as quitting smoking during pregnancy, breast feeding and prevention of obesity in all family members may be helpful in reducing childhood BP levels [62]. The "Viva Project" investigators from USA reported on GWG and its association with childhood adiposity and BP [63]. They observed a positive association with child BMI and systolic BP in children aged 3 years; for BP, the magnitude of the association was nearly halved when adjusted for current child BMI. In a report using data from the "MUSP Australian birth cohort", Mamun et al. examined the association of GWG with offspring BMI and BP aged 21 years [64]. They reported that greater GWG was significantly associated with higher adult BMI with significant differences by gender for the association of GWG with BMI and BP. The relationship of GWG with BP though was not significant in this study [64].

The "Avon Longitudinal Study of Parents and Children (ALSPAC)" investigators in UK presented a detailed analysis of the association of GWG with childhood cardiometabolic outcomes, including adiposity and blood pressure [65]. Pre-pregnancy weight and excessive absolute GWG over the entire pregnancy was associated with markers of adiposity (BMI, WC and fat mass by DEXA) [65]. With regard to blood pressure, mppBMI was associated with BP but excessive absolute GWG was associated with systolic but not diastolic BP. The association of GWG with blood pressure by time of exposure was non-linear and variable. Importantly, inclusion of both birth weight and pre-pregnancy BMI did not alter the associations of GWG with outcomes [65]. As part of the "Collaborative Perinatal Project" from the USA, Wen et al. [66] attempted to determine the association of five modifiable risk factors for intrauterine growth retardation (IUGR) with blood pressure aged 7. Several risk factors (including maternal heavy smoking, pre-pregnancy overweight, chronic hypertension and preeclampsia/eclampsia) were significantly associated with IUGR and BP. Both child’s current weight and weight trajectory attenuated all associations with BP to non-significance. GWG was not associated with systolic BP. Thus, childhood weight and BMI trajectory, as opposed to IUGR, mediate childhood BP levels [66]. Similar findings were reported by the "Jerusalem Perinatal Family Follow up study (JPS)" investigators who examined the association of mppBMI and GWG with a range of offspring cardiometabolic risk factors in subjects aged 32 years [67]. Both pre-pregnancy BMI and GWG associated with offspring adiposity and BP (mppBMI systolic > diastolic and systolic BP only with GWG), although all associations attenuated to non-significance following adjustment for current adiposity. Other studies including the "IDEFICS project (Identification and prevention of Dietary- and lifestyle induced health EFfects In Children and infantS)", a multicentre European study including 12775 mother-child dyads [68] in children aged 6.1 years, the "Project Viva" [69] in children aged 7.7 years, and the "Rhea study" [70] in aged 4 years showed no significant association of mppBMI and or GWG with BP once this was adjusted for current adiposity. These differences between study cohorts may in part relate to the study size, differences in study population and age at evaluation.

Further evidence regarding the importance of the foetal and familial environment is seen in the Amsterdam Born Children and their Development (ABCD) study results [71]. They showed in young children mppBMI was associated with systolic and diastolic BP; adjustment for birth weight had no significant effect on this association but child’s current BMI reduced the strength of the association by ~50%, although it remained significant [71]. The strongest association was of child BMI with current BP which also significantly modified the association of pre-pregnancy weight with current BP. Thus, for every unit increase in BMI, the systolic BP increased by 1.3 mmHg. LBW was an independent predictor of higher childhood BP. The authors were unable to find any evidence that mppBMI programmed the autonomic nervous system of the offspring at rest toward an increased sympathetic drive or reduced parasympathetic drive [71]. In a subsequent follow-up study, the ABCD investigators showed that in addition to the mppBMI, growth during the early neonatal period between 1 and 3 months is associated with adverse cardiometabolic outcomes, including blood pressure in children with a mean age of 5.6 years [72]. The combination of a heavier mum and accelerated growth in this early period would amplify these effects in later life, and interventions could, therefore, be considered at one of two or both periods to ameliorate outcomes [72].

Direct intrauterine mechanisms were implicated for offspring cardiovascular health by the "Generation R" investigators from Rotterdam, the Netherlands, in 4871 trios examined the association of both mppBMI and paternal BMI with cardiometabolic outcomes aged 6 [73]. Higher systolic BP was associated with children of obese mothers, and paternal excess weight had an independent adverse association but smaller effect size. Once confounders were accounted for, only maternal BMI (and not paternal BMI) had a positive association with systolic BP [73]. Gaillard et al., in another study from the "Generation-R cohort", reported the associations of GWG during different periods of pregnancy with childhood cardiometabolic outcomes measured aged 6 (n = 5908 mother-child dyads) [74]. Higher early pregnancy weight gain was significantly associated with higher childhood systolic BP (reported as part of a metabolic cluster), following adjustment for current childhood BMI and independent of mppBMI [74]. In contrast, in a smaller study, as part of the West Australian Raine cohort, Gaillard et al. [75] reported associations of mppBMI and GWG with systolic BP, but reported attenuation to non-significance for mppBMI following adjustment for current adolescent BMI; and no significant association of GWG with BP.

"Trajectory" has been defined as an established sequence of transitions from one state or phenotype to another describing its evolution over time [76, 77]. Trajectory modelling in children has previously been used primarily to identify BMI trajectories [78, 79], but recently the relationship of blood pressure with BMI trajectories has also been reported [80, 81]. Longitudinal studies have also identified subgroups with differential BP trajectories among older adults [82] and recently in children and young adults aged 7–38 years [83]. In this final section, we highlight recent data describing the trajectory of hypertension through childhood.

1.6 Birth Cohort Trajectory Studies

An interesting report from "the Isle of Wight birth cohort" presented data supporting the foetal overnutrition theory and showing its long-term consequences [80]. The authors examined the trajectory of excess weight during childhood and identified four distinct trajectories describing BMI changes in the first 18 years of life including early persistent obesity (3.9%), delayed overweight (11.5%) early transient overweight (13.1%), and the rest normal. Both maternal smoking and excess mppBMI were associated with increased risk of being in early persistent obesity and delayed overweight categories [80]. At age 18 years, systolic BP was reported to be higher in the persistent obesity and delayed overweight category (when compared with normal; with effect size shown as the adjusted mean difference between groups of 11.3 and 6.1 mmHg [80]).

Researchers from the "West Australian Raine study" have previously described seven distinct adiposity trajectories through childhood [79], and in this recent report they investigated the association of these trajectories with BP development [81]. They identified children who were in the three of seven accelerating adiposity trajectories, including stable high, rising to high and rising to moderate representing both maintenance of adiposity through childhood and accelerated infant weight gain from LBW trends [81]. Overall, they showed high risk for hypertension/pre-hypertension for adolescents aged 17 who belonged to these trajectories compared to normal BMI trajectory and represented 27% of the study population. One of the main findings was of higher BP level by 3 years of age in those with accelerated weight gain in infancy trajectories, thus allowing the opportunity to intervene appropriately [81].

Theodore et al. recently published different systolic BP trajectories from 7 to 38 years of age using data from "the Dunedin Multidisciplinary Health and Development Study, New Zealand" birth cohort study [83]. They identified four distinct trajectories identifiable from age 7 and up to 38 years. These included high-normal (43.3%), pre-hypertension (31.6%) and hypertension (4.2%), and the rest normal. Several risk factors were identifiable using trajectory modelling; increased BMI and smoking were significant modifiers and resulted in raised BP across all trajectories, and finally, hypertension trajectories were associated with worse cardiometabolic outcomes [83]. Thus, as argued by the authors, trajectories highlight that different individuals differ in the way their BP changes over lifetime and allow identification of early life risk factors even before any BP measurement has been made. Identification of modifiers of childhood BP and knowledge of the impact of modifiable risk factor on BP trajectories may help identify optimal time for intervention [81, 83].

1.7 Summary

Maternal malnutrition, both under and overnutrition, can adversely affect the developing foetus as a result of changes in the intrauterine milieu, but beyond foetal period, the shared genetic and familial environment are also important. Blood pressure is inversely related to birth weight, with accelerated infant weight gain in those with low birth weight associated with adverse BP characteristics. Childhood obesity is the main modifier of blood pressure with consistent results from the literature highlighting its adverse impact on BP level. A key message from this chapter is that the development of blood pressure through lifetime is complex with several risk factors and modifiers identifiable through pregnancy, infancy, childhood and later in life. Large life-course studies of parent-child pairs and longitudinal studies highlighting the differences in BP changes among individuals offer an opportunity to improve our understanding of the development of hypertension.

Acknowledgements

The author acknowledges financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre and Clinical Research Facilities awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

Conflicts of interest: None.

References

1.

Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1(8489):1077–81.PubMed

2.

Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2(8663):577–80.

3.

Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341(8850):938–41.PubMed

4.

Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990;301:1111.PubMedPubMedCentral

5.

Barker DJ. Mothers, babies, and health in later life. 2nd ed. Edinburgh: Churchill Livingstone; 1998.

6.

Nilsson PM, Lurbe E, Laurent S. The early life origins of vascular ageing and cardiovascular risk: the EVA syndrome. J Hypertens. 2008;26(6):1049–57.PubMed

7.

Lucas A. Programming by early nutrition in man. Ciba Found Symp. 1991;156:38–50. discussion 50-5.PubMed

8.

Gillman MW, Barker D, Bier D, Cagampang F, Challis J, Fall C, Godfrey K, Gluckman P, Hanson M, Kuh D, Nathanielsz P, Nestel P, Thornburg KL. Meeting report on the 3rd international congress on developmental origins of health and disease (DOHaD). Pediatr Res. 2007;61(5 Pt 1):625–9.PubMed

9.

Wadhwa PD, Buss C, Entringer S, Swanson JM. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med. 2009;27(5):358–68.PubMedPubMedCentral

10.

Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61–73.PubMedPubMedCentral

11.

Roseboom TJ, Painter RC, van Abeelen AF, Veenendaal MV, de Rooij SR. Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas. 2011;70(2):141–5.PubMedPubMedCentral

12.

Stein AD, Zybert PA, Van dP-d BK, Lumey LH. Exposure to famine during gestation, size at birth, and blood pressure at age 59 y: evidence from the Dutch famine. Eur J Epidemiol. 2006;21(10):759–65.PubMedPubMedCentral

13.

Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart. 2000;84:595–8.PubMedPubMedCentral

14.

van Abeelen AFM, Elias S, Bossuyt P, Grobbee D, van der Schouw Y, Roseboom C, Uiterwaal C. Cardiovascular consequences of famine in the young. Eur Heart J. 2012;33:538–45.PubMed

15.

Jamshidi Y, Gibson P, Ray KK. Undernutrition in adolescence and risk of cardiovascular disease. Eur Heart J. 2012;33(4):433–5.PubMed

16.

Kett MM, Denton KM. Maternal obesity: bad for baby’s future. Hypertension. 2013;62(3):457–8.PubMed

17.

Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults 1999–2010. JAMA. 2012;307:491–7.PubMed

18.

Heslehurst N, Rankin J, Wilkinson JR, Summerbell CD. A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. Int J Obes. 2010;34(3):420–8.

19.

Gaillard R, Durmuş B, Hofman A, Mackenbach JP, Steegers EA, Jaddoe VW. Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy. Obesity. 2013;21(5):1046–55.PubMed

20.

Poston L, Harthoorn LF, Van Der Beek EM, Contributors to the ILSI Europe Workshop. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res. 2011;69(2):175–80.PubMed

21.

Reynolds RM, Allan KM, Raja EA, Bhattacharya S, McNeill G, Hannaford PC, Sarwar N, Lee AJ, Bhattacharya S, Norman JE. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ. 2013;347:f4539.PubMedPubMedCentral

22.

Fraser A, Tilling K, Macdonald-Wallis C, Sattar N, Brion MJ, Benfield L, Ness A, Deanfield J, Hingorani A, Nelson SM, Smith GD, Lawlor DA. Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood. Circulation. 2010;121(23):2557–64.PubMedPubMedCentral

23.

Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301(6):636–50.PubMedPubMedCentral

24.

Johansson S, Villamor E, Altman M, Bonamy AK, Granath F, Cnattingius S. Maternal overweight and obesity in early pregnancy and risk of infant mortality: a population based cohort study in Sweden. BMJ. 2014;349:g6572.PubMedPubMedCentral

25.

Gaillard R. Maternal obesity during pregnancy and cardiovascular development and disease in the offspring. Eur J Epidemiol. 2015;30(11):1141–52.PubMedPubMedCentral

26.

Frankel S, Elwood P, Sweetnam P, Yarnell J, Davey Smith G. Birthweight, body mass index in middle-age, and incident coronary heart disease. Lancet. 1996;348:1478–80.PubMed

27.

Leon DA, Koupilova I, Lithell HO, Berglund L, Mohsen R, Vagero D, Lithell U-B, McKeigue PM. Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50-year-old Swedish men. BMJ. 1996;312:401–6.PubMedPubMedCentral

28.

Barker DJP, Osmond C, Forsén TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med. 2005;353:1802–9.PubMed

29.

Whincup PH. Fetal origins of cardiovascular risk: evidence from studies in children. Proc Nutr Soc. 1998;57(1):123–7.PubMed

30.

Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens. 1996;14:935–41.PubMed

31.

Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000;18(7):815–31.PubMed

32.

Schluchter MD. Publication bias and heterogeneity in the relationship between systolic blood pressure, birth weight, and catch-up growth--a meta analysis. J Hypertens. 2003;21(2):273–9.PubMed

33.

Wen X, Triche EW, Hogan JW, Shenassa ED, Buka SL. Association between placental morphology and childhood systolic blood pressure. Hypertension. 2011;57(1):48–55.PubMed

34.

Shankaran S, Das A, Bauer CR, Bada H, Lester B, Wright L, Higgins R, Poole K. Fetal origin of childhood disease—intrauterine growth restriction in term infants and risk for hypertension at 6 years of age. Arch Pediatr Adolesc Med. 2006;160:977–81.PubMed

35.

Lurbe E, Garcia-Vicent C, Torro I, Fayos JL, Aguilar F, de Lano JM, Fuertes G, Redon J. First-year blood pressure increase steepest in low birthweight newborns. J Hypertens. 2007;25:81–6.PubMed

36.

Lurbe E, Torro I, Rodríguez C, Alvarez V, Redón J. Birth weight influences blood pressure values and variability in children and adolescents. Hypertension. 2001;38(3):389–93.PubMed

37.

Lurbe E, Torró I, Alvarez V, Aguilar F, Redon J. The impact of birth weight on pulse pressure during adolescence. Blood Press Monit. 2004;9(4):187–92.PubMed

38.

de Jong F, Monuteaux MC, van Elburg RM, Gillman MW, Belfort MB. Systematic review and meta-analysis of preterm birth and later systolic blood pressure. Hypertension. 2012;59(2):226–34.PubMed

39.

Lurbe E, Garcia-Vicent C, Torro MI, Aguilar F, Redon J. Associations of birth weight and postnatal weight gain with cardiometabolic risk parameters at 5 years of age. Hypertension. 2014;63(6):1326–32.PubMed

40.

Sinaiko A, Donahue RP, Jacobs DR, Prineas RJ. Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin, and lipids in young adults. The Minneapolis Children’s blood pressure study. Circulation. 1999;99:1471–6.PubMed

41.

Srinivasan SR, Myers L, Berenson GS. Changes in metabolic syndrome variables since childhood in prehypertensive and hypertensive subjects the Bogalusa heart study. Hypertension. 2006;48:33–9.PubMed

42.

Horta BL, Barros FC, Victora CG, Cole TJ. Early and late growth and blood pressure in adolescence. J Epidemiol Community Health. 2003;57(3):226–30.PubMedPubMedCentral

43.

Chiolero A, Paradis G, Madeleine G, Hanley JA, Paccaud F, Bovet P. Birth weight, weight change, and blood pressure during childhood and adolescence: a school-based multiple cohort study. J Hypertens. 2011;29(10):1871–9.PubMed

44.

Poston L. Maternal obesity, gestational weight gain and diet as determinants of offspring long term health. Best Pract Res Clin Endocrinol Metab. 2012;26:627–39.PubMed

45.

Yu Z, Han S, Zhu J, Sun X, Ji C, Guo X. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PLoS One. 2013;8(4):e61627.PubMedPubMedCentral

46.

Gaudet L, Ferraro ZM, Wen SW, Walker M. Maternal obesity and occurrence of fetal macrosomia: a systematic review and meta-analysis. Biomed Res Int. 2014;2014:640291.PubMedPubMedCentral

47.

Ludwig DS, Currie J. The association between pregnancy weight gain and birthweight: a within-family comparison. Lancet. 2010;376(9745):984–90.PubMedPubMedCentral

48.

Tie HT, Xia YY, Zeng YS, et al. Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis. Arch Gynecol Obstet. 2014;289(2):247–57.PubMed

49.

Tequeanes AL, Gigante DP, Assuncao MC, Chica DA, Horta BL. Maternal anthropometry is associated with the body mass index and waist:height ratio of offspring at 23 years of age. J Nutr. 2009;139:750–4.PubMed

50.

Reynolds RM, Osmond C, Phillips DI, Godfrey KM. Maternal BMI, parity, and pregnancy weight gain: influences on offspring adiposity