For more than 30 years, observational studies have linked early life programming and low birth weight to blood pressure elevation and established hypertension. It all started in 1988 with studies from Sweden by Gensser [1] and the UK by Barker et al.[2], and later on, this relationship has been confirmed in the majority of studies, based on cohorts [3,4] or register linkages [5]. Low birth weight, prematurity and impaired foetal growth with small-for-gestational age babies, some of them experiencing rapid postnatal catch-up growth, are phenotypes all linked to blood pressure elevation, as well as a number of other cardiovascular risk factors and even increased risk for cardiovascular events [6–8]. However, also, U-shaped relationships have been documented for the association between both low and high birth weight with risk of type 2 diabetes [9]. A still unsettled questions is to what degree these associations reflect nature or nurture, that is the influence of genes or the environment. In favour of genetic explanations are reports that state that genes regulating maternal hypertension could also influence blood pressure elevation in the offspring when low birth weight is just a side phenomenon [10], and that genes associated with low birth weight also increase the risk of coronary artery disease and other disease conditions [11]. However, on the contrary, we know that environmental manipulations of maternal diet and living conditions during pregnancy in laboratory animals could influence offspring haemodynamics and blood pressure [12]. This corresponds to historical events with periods of war [13–15], famine [16] or stress caused by civil unrest [17] that could influence birth weight, as well as blood pressure elevation and cardiovascular risk in surviving children during long-term follow-up. This means that it is likely that environmental influences could interact with epigenetic mechanisms to programme organ development and function, including the cardiovascular system [18].

In this issue of the Journal, a group of authors report on findings from the STANISLAS cohort covering two generations of related individuals (n = 1028) in north-eastern France [19]. This study includes information on self-reported birth weight and screening in adult life for blood pressure, renal function, pulse wave velocity (PWV) and measures of target organ function (TOD) related to the heart and carotid artery.

The finding in general was an inverse association between birth weight and blood pressure elevation, or hypertension in adult life, but less strong evidence for associations between birth weight and TOD, only found in some subgroups. No association was found with renal function using the CKD-EPI algorithm based on creatinine. The authors suggest that hypertension comes first, which in turn promotes vascular damage (increased atherosclerosis and arterial stiffness).

Even if self-report of birth weight is highly correlated with register-based information on birth weight (r = 0.9) according to a systematic review and meta-analysis [20], the lack of information on pregnancy duration (i.e. gestational age) in the STANISLAS study is a shortcoming. In subgroups, self-report of prematurity and breastfeeding was available, but not for all, as is often the case in population-based studies when people are asked for such information based on recollection. The standard definition of low birth weight (LBW; <2500 g) and prematurity (<37 weeks of gestational age) in western populations is one way to use categories, standards in clinical medicine, but in epidemiology, one should more focus on continuous variables over a wider range. The problem is that some of these relationships are not linear, in itself a rare phenomenon in biology, but rather curvilinear or even nonlinear, for example the U-shaped association of birth weight with adult obesity and risk of type 2 diabetes [9].

No association was found between birth weight and PWV [19], a marker of arterial stiffness and vascular ageing [6]. In other studies, such an association was found, as in one study examining adolescents from Austria [21], but neither in 6-year-old children in Finland [22] nor in very premature children from the UK during follow-up [23]. This means that such associations with PWV are either lacking in most cases, or depending on age range and phenotype at birth. On the contrary, increased Augmentation Index (Aix) has repeatedly been shown to be inversely associated with birth weight and prematurity [24]. Aix is a far more complex variable than PWV, as it is influenced by a number of contributing factors, not only aortic stiffness, but also total peripheral resistance TPR, blood pressure, the aortic reflex wave and cardiac function [25]. In a study of very premature babies followed until age of 18 years, there was an association between all these three variables: prematurity, Aix and TPR [23].

In the STANISLAS study, no association was found between birth weight and renal function. However, other studies have found such an association if using other algorithms for renal function or different populations. For example, a study from Sweden used cystatin-C instead of creatinine for estimating renal function and could show an association [26]. It is also known that LBW is associated with a reduced number of nephrons, first proposed by the nephrologist Brenner [27]. If so, in early stages of renal dysfunction, there could well be compensatory hyperfiltration and thus a normal, or even supernormal estimated renal function, but later on replaced by impaired renal function. Another measure is albuminuria or the albumin/creatinine ratio, but no association was found in the French study.

In summary, the STANISLAS study is of interest, as it could show an (expected) inverse association with blood pressure (even 24-h ABPM) and hypertension, but also some degree of heritability of birth weight (42–44%) across two generations. Associations with measures of TOD were either lacking (eGFR, PWV, diastolic dysfunction) or present only in subgroups, for example a higher left ventricular mass index (LVMI) in participants with a birth weight higher than 3 kg. The lack of information on Aix is regretful, as it could have shed more light on the association between birth weight and arterial function. We now have a wealth of data from observational, epidemiological studies, but more information is needed about mediating mechanisms between early life factors and adult outcomes (traits, events) within the so-called Developmental Origin of Health and Disease (DOHaD) concept [28]. Finally, also, intervention studies are needed to prove the importance of preventive maternal and child healthcare for these measures and outcomes. This was recently shown in a randomized study from India when such preventive efforts during preconception and pregnancy improved not only birth outcomes but also maternal health [29]. Thus, cardiovascular prevention should start early in life, even before birth. The health and lifestyle of pregnant women is of great importance, not only for the women themselves but also for their children, thereby linking reproductive health with family health and forming a basis for normal development of blood pressure and vascular function in offspring [30]. It is a truism that we all have been children and that we all undergo ageing, including vascular ageing, but this simple fact of life should inspire for more focus on early life programming of adult health, prevention and research [31], especially on mechanistic links – targets of interventions.

ACKNOWLEDGEMENTS

This editorial was supported by a grant from the Swedish Research Council (2013-2756).

Conflicts of interest

There are no conflicts of interest.

REFERENCES 1. Gennser G, Rymark P, Isberg PE. Low birth weight and risk of high blood pressure in adulthood. Br Med J (Clin Res Ed) 1988; 296:1498–1500. 2. Barker DJ, Osmond C. Low birth weight and hypertension. BMJ 1988; 297:134–135. 3. Mu M, Wang SF, Sheng J, Zhao Y, Li HZ, Hu CL, Tao FB. Birth weight and subsequent blood pressure: a meta-analysis. Arch Cardiovasc Dis 2012; 105:99–113. 4. Knop MR, Geng TT, Gorny AW, Ding R, Li C, Ley SH, Huang T. Birth weight and risk of Type 2 diabetes mellitus, cardiovascular disease, and hypertension in adults: a meta-analysis of 7 646 267 participants from 135 studies. J Am Heart Assoc 2018; 7:e008870. 5. Nilsson PM, Ostergren PO, Nyberg P, Söderström M, Allebeck P. Low birth weight is associated with elevated systolic blood pressure in adolescence: a prospective study of a birth cohort of 149378 Swedish boys. J Hypertens 1997; 15 (12 Pt 2):1627–1631. 6. Nilsson PM, Lurbe E, Laurent S. The early life origins of vascular ageing and cardiovascular risk: the EVA syndrome. J Hypertens 2008; 26:1049–1057. 7. 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; 359:61–73. 8. Arima Y, Fukuoka H. Developmental origins of health and disease theory in cardiology. J Cardiol 2020; 76:14–17. 9. Pettitt DJ, Jovanovic L. Birth weight as a predictor of type 2 diabetes mellitus: the U-shaped curve. Curr Diab Rep 2001; 1:78–81. 10. Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, et al. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet 2019; 51:804–814. 11. Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, et al. Genome-wide associations for birth weight and correlations with adult disease. Nature 2016; 538:248–252. 12. Sellayah D, Cagampang FR. The divergent effect of maternal protein restriction during pregnancy and postweaning high-fat diet feeding on blood pressure and adiposity in adult mouse offspring. Nutrients 2018; 10:1832. 13. Kyle UG, Pichard C. The Dutch Famine of 1944-1945: a pathophysiological model of long-term consequences of wasting disease. Curr Opin Clin Nutr Metab Care 2006; 9:388–394. 14. Hult M, Tornhammar P, Ueda P, Chima C, Bonamy AK, Ozumba B, Norman M. Hypertension, diabetes and overweight: looming legacies of the Biafran famine. PLoS One 2010; 5:e13582. 15. Rotar O, Moguchaia E, Boyarinova M, Kolesova E, Khromova N, Freylikhman O, et al. Seventy years after the siege of Leningrad: does early life famine still affect cardiovascular risk and aging? J Hypertens 2015; 33:1772–1779. 16. Chen C, Nie Z, Wang J, Ou Y, Cai A, Huang Y, et al. Prenatal exposure to the Chinese famine of 1959-62 and risk of cardiovascular diseases in adulthood: findings from the China PEACE million persons project. Eur J Prev Cardiol 2022; 29:2111–2119. 17. Dybjer E, Linvik J, Nilsson PM. Civil unrest linked to intrauterine growth restriction in western Kenya. J Dev Orig Health Dis 2014; 5:370–373. 18. Cutfield WS, Hofman PL, Mitchell M, Morison IM. Could epigenetics play a role in the developmental origins of health and disease? Pediatr Res 2007; 61:68R–75R. 19. Lopez-Sublet M, Merkling T, Wagner S, Xhaard C, Flahault A, Bozec E, et al. Birth weight and subclinical cardiovascular and renal damage in a population-based study (The STANISLAS Cohort Study). J Hypertens 2023; 41:1040–1050. 20. Shenkin SD, Zhang MG, Der G, Mathur S, Mina TH, Reynolds RM. Validity of recalled v. recorded birth weight: a systematic review and meta-analysis. J Dev Orig Health Dis 2017; 8:137–148. 21. Stock K, Schmid A, Griesmaier E, Gande N, Hochmayr C, Knoflach M, Kiechl-Kohlendorfer U. Early Vascular Aging (EVA) Study Group. The impact of being born preterm or small for gestational age on early vascular aging in adolescents. J Pediatr 2018; 201:49–54. 22. Olander RFW, Sundholm JKM, Suonsyrjä S, Sarkola T. Arterial health during early childhood following abnormal fetal growth. BMC Pediatr 2022; 22:40. 23. Hurst JR, Beckmann J, Ni Y, Bolton CE, McEniery CM, Cockcroft JR, Marlow N. Respiratory and cardiovascular outcomes in survivors of extremely preterm birth at 19 years. Am J Respir Crit Care Med 2020; 202:422–432. 24. Sperling J, Nilsson PM. Does early life programming influence arterial stiffness and central hemodynamics in adulthood? J Hypertens 2020; 38:481–488. 25. Santos LMD, Gomes IC, Pinho JF, Neves-Alves CM, Magalhães GS, Campagnole-Santos MJ, da Glória Rodrigues-Machado M. Predictors and reference equations for augmentation index, an arterial stiffness marker, in healthy children and adolescents. Clinics (Sao Paulo) 2021; 76:e2350. 26. Laucyte-Cibulskiene A, Sharma S, Christensson A, Nilsson PM. Early life factors in relation to albuminuria and estimated glomerular filtration rate based on cystatin C and creatinine in adults from a Swedish population-based cohort study. J Nephrol 2022; 35:889–900. 27. Luyckx VA, Perico N, Somaschini M, Manfellotto D, Valensise H, Cetin I, et al. writing group of the Low Birth Weight and Nephron Number Working Group. A developmental approach to the prevention of hypertension and kidney disease: a report from the Low Birth Weight and Nephron Number Working Group. Lancet 2017; 390:424–428. 28. Hanson MA, Gluckman PD. Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 2014; 94:1027–1076. 29. Taneja S, Chowdhury R, Dhabhai N, Upadhyay RP, Mazumder S, Sharma S, et al. WINGS Study Group. Impact of a package of health, nutrition, psychosocial support, and WaSH interventions delivered during preconception, pregnancy, and early childhood periods on birth outcomes and on linear growth at 24 months of age: factorial, individually randomised controlled trial. BMJ 2022; 379:e072046. 30. Okoth K, Chandan JS, Marshall T, Thangaratinam S, Thomas GN, Nirantharakumar K, Adderley NJ. Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review. BMJ 2020; 371:m3502. 31. Lurbe E, Ingelfinger J. Developmental and early life origins of cardiometabolic risk factors: novel findings and implications. Hypertension 2021; 77:308–318.