The relationship between gestational age, systolic blood pressure and ...

Journal of Human Hypertension (2008) 22, 352–357 & 2008 Nature Publishing Group All rights reserved 0950-9240/08 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

The relationship between gestational age, systolic blood pressure and pulse pressure in children CL Relton1, MS Pearce1 and JJ O’Sullivan2 1

Institute of Health and Society, School of Clinical Medical Sciences (Child Health), University of Newcastle upon Tyne, Newcastle upon Tyne, UK and 2Department of Paediatric Cardiology, Freeman Hospital, Newcastle upon Tyne, UK

This cross-sectional study investigates the relationship between gestational age and systolic blood pressure and pulse pressure in childhood. Blood pressure was measured in 483 schoolchildren, free from cardiovascular disease, aged between 6 and 16 years. Pulse pressure was estimated as the difference between the 24-h mean systolic and diastolic blood pressure values. Linear regression showed an inverse relationship between gestational age and mean 24-h systolic blood pressure (adjusted regression coefficient mm Hg per week gestation 0.631, 95% confidence interval (CI) 1.21 to 0.04, P ¼ 0.036). Further, linear regression showed a significant negative association between gestational age and log-transformed pulse pressure (adjusted antilog regression coefficient mm Hg per week of gestation 1.39, 95% CI 2.96 to 0.3, P ¼ 0.013),

which after gender-specific analyses was found to be restricted to the girls in the study. The results of the present study suggest that low gestational age is associated with elevated systolic blood pressure and pulse pressure in childhood, the latter particularly in girls. This observation provides some support for the developmental origins of adult disease hypothesis—that adverse events in early life may have long-term consequences for cardiovascular health. However, as gestational age itself is unlikely to be the causal event in determining blood pressure control, further investigation is required, particularly with regard to the nutritional, physiological and molecular mechanisms that explain such epidemiological observations. Journal of Human Hypertension (2008) 22, 352–357; doi:10.1038/sj.jhh.1002319; published online 3 January 2008

Keywords: blood pressure; pulse pressure; gestational age; preterm birth; developmental origins of adult disease

Introduction It is well established that preterm birth is associated with elevated risk of perinatal mortality and morbidity, including neurological impairment and disability.1 However, less is known about the longerterm effects of preterm birth on health, especially with regard to chronic disease in later life. It has been proposed that the risk of adverse health in middle age, including hypertension, cardiovascular disease and diabetes, is ‘programmed’ by impaired foetal development or adverse exposures during early life.2 In particular, a number of epidemiological studies have demonstrated a negative correlation between birth weight and blood pressure in adulthood.3–6 It has been estimated that a 1 kg higher birth weight is typically associated with a 2–4 mm Hg Correspondence: Dr CL Relton, Institute of Health and Society, School of Clinical Medical Sciences (Child Health), University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. E-mail: [email protected] Received 1 August 2007; revised 2 November 2007; accepted 2 November 2007; published online 3 January 2008

lower systolic blood pressure.7 Evidence also exists for such a relationship in childhood,8–11 but it has been suggested to vary with age and gender.12 Fewer studies have addressed the contribution of length of gestation at birth in determining risk of adverse health in later life. Dalziel et al.13 recently reported that adults born moderately preterm had increased blood pressure at 30 years of age. Low gestation at birth was the key feature of this association, whereas birth weight, adjusted for gestational age was not. Other studies support this observation, linking earlier gestation and/or preterm birth with higher blood pressure in adults.14–18 In a large family-based study of gestational age, intrauterine growth and blood pressure, Lawlor et al.19 provide evidence for an inverse association of gestational age with systolic blood pressure at age 17–19 years in both siblings and nonsiblings. Gestation length has also been linked to raised blood pressure in children.20–22 Blood pressure in adulthood is unequivocally positively associated with coronary heart disease and stroke risk and recent research has suggested that increased pulse pressure, defined as the difference

Gestation, blood pressure and pulse pressure CL Relton et al 353

between systolic and diastolic blood pressure, may also be an important component of increased risk of cardiovascular disease, particularly when observed in conjunction with raised systolic blood pressure.23,24 It is generally accepted that the importance of pulse pressure in adulthood is in relation to the wellestablished association between increased pulse pressure and arterial stiffness. A small number of studies have focused on early life determinants of pulse pressure variation in children; a recent study by Lurbe et al.25 suggested an association between birth weight and ambulatory pulse pressure in a group of 300 healthy adolescents. Cheung et al.20 found some evidence of increased arterial stiffness, measured by pulse wave velocity, rather than using pulse pressure as a surrogate, in babies born small for gestational age. In summary, previous studies have reported an inverse association between gestational age and adult systolic blood pressure, with an increasing body of evidence to support a similar relationship between gestational age and systolic blood pressure in children. Pulse pressure has been investigated as a biomarker of cardiovascular health and it shows an inverse relationship with birth weight in adults, with a similar pattern inferred in children. The aim of the present study was to explore the relationship between gestational age and systolic blood pressure and pulse pressure in a cross-sectional study of children. Previous studies using the same data have shown a negative association between birth weight and mean 24-h systolic blood pressure, and similarly between birth weight and pulse pressure although the significant associations were shown in girls, but not boys.26,27

Materials and methods A total of 26 schools in Newcastle upon Tyne agreed to participate in this study.12,26,28 The average participation rate of the target classes was 43%. Parents were requested to complete a questionnaire for information on birth weight and gestation of the child. Gestational age was estimated from the last menstrual period and corroborated by ultrasound scan routinely conducted at 19 weeks gestation. The reported data on birth weight and gestational age were confirmed for over 600 cases by retrieving the original hospital birth records.29 Recalled and recorded data were highly correlated (r ¼ 0.95). Children who reported any history of renal or cardiac problems on the questionnaire were not enrolled into the study. A total of 1129 children were recruited, although 8 children were excluded due to either fainting during the validation procedure thus not wearing the monitor (n ¼ 5) or because they did not produce sufficient valid systolic readings (n ¼ 3). Only those children with a complete set of data on mean 24-h systolic blood pressure, pulse pressure, gestational age and birth weight were

included in this study. Pubertal stage was not assessed. The study used a TM-2421 device (A and D, Japan) giving Korotkoff readings to measure 24-h blood pressure. As it is very difficult to validate ambulatory readings of systolic and diastolic pressures, the recommendations of the British Hypertension Society were followed, dictating that devices should be validated at rest. Due to the potential problems of measuring systolic and diastolic blood pressure when active, children were asked to remain still while the reading was taken. Oscillometric readings were also available, but were excluded due to the poor British Hypertension Society grades obtained. Measurements were taken every 30 min during the day and every 60 min between 2200 and 0700 hours. The protocol has been described in detail elsewhere.12 All readings were accepted unless the recorded systolic blood pressure was p50 or X200 mm Hg; the diastolic blood pressure was p30 or X100 mm Hg and the heart rate X200 or p30 beats per min. If more than 25% of the recordings for an individual were erroneous all data from that individual were excluded. Pulse pressure was estimated as the difference between the mean 24-h systolic and diastolic blood pressure measurements, and was log-transformed to normality. Linear regression was used to model the relationship first between gestational age and mean 24-h systolic blood pressure and second between gestational age and log-transformed pulse pressure. Results were adjusted for birth weight standard deviation (z) scores and the current weight of the participants at enrolment. Potential interactions between sex and gestational age were assessed for each outcome variable using the F test. Analyses were performed using the statistical software package Stata, version 8.0 (StataCorp, College Station, TX, USA). Ethical approval for this study was given by the Joint Research Ethics Committee of Newcastle and North Tyneside Local Health Authority. Informed consent was obtained from the parent or guardian of each child prior to enrolment in the study.

Results A total of 483 children (274 girls) had mean 24-h systolic blood pressure, pulse pressure or gestational age data available and were included in this study. Table 1 details the blood and pulse pressure values and other descriptive data by gender. A total of 9.5% of the study participants were born o37 weeks and 0.6% were born o32 weeks. Mean systolic blood pressure was positively correlated with log-transformed mean pulse pressure (r ¼ 0.87). Gestational age was shown to be negatively associated with 24-h systolic blood pressure in all children, but with only borderline significance (r ¼ 0.51 mm Hg per week of gestation, 95% Journal of Human Hypertension


confidence interval (CI) 1.03 to 0.027, P ¼ 0.063; Table 2). When adjusted for birth weight z-score, this reached statistical significance (r ¼ 0.63 mm Hg per week of gestation, 95% CI 1.21 to 0.04, P ¼ 0.036) and equates to an increase of 6.2 mm Hg for every preterm week of gestation. This association remained statistically significant when adjusted for current age and/or body mass index (BMI) at enrolment in the study. Gestational age was not significantly associated with 24-h diastolic blood pressure (P ¼ 0.356). There was a significant negative unadjusted association between gestational age and log-transformed pulse pressure (antilog r ¼ 1.29 mm Hg per week of gestation, 95% CI 2.33 to 0.10, P ¼ 0.013; Table 3), which remained unchanged when adjusted for birth weight z-score or current age and BMI. This equates to an increase of 5.75 mm Hg for every preterm week of gestation. However, this was restricted to the girls in the study (antilog r ¼ 1.69 log mm Hg per week of gestation, 95% CI 2.96 to 0.40, P ¼ 0.011), with no association being seen among the boys. There was no evidence of an interaction between sex and gestational age on either mean 24-h systolic blood pressure or pulse pressure (P40.4). No evidence of non-linearity in the relationship between

gestational age and either mean 24-h systolic blood pressure or pulse pressure was found.

Discussion This study reports an association between reduced gestation length and elevated 24-h systolic blood pressure in children, which supports several recent studies linking reduced gestational age to elevated blood pressure in adults13–19 and children.20–22 Furthermore, evidence is presented linking reduced gestation length with elevated pulse pressure in children, suggesting that early arterial stiffness may be involved in the causal pathway culminating in hypertension in adulthood. Several possible mechanisms may contribute to the observed association between reduced gestation length and elevated blood pressure. Doyle et al.8 demonstrated that blood pressure was higher in preterm children of very low birth weight when compared to those of normal birth weight. However, this relationship did not appear to be attributable to growth restriction in utero. Prematurity per se and/ or the immediate post-natal environment may be contributing factors. Thus, rather than growth restriction in utero being the critical event in

Table 1 Descriptive statistics, by gender, for the study population Boys (n ¼ 209) Median (IQR) Age (years) Birth weight (kg) Gestational age (weeks) Current weight (kg) 24-h SBP (mm Hg) 24-h DBP (mm Hg) 24-h pulse pressure (mm Hg)

11.2 3.5 40 37.5 112.1 61.7 49.6

Girls (n ¼ 274) Range

(8.7–13.5) (2.1–4.7) (39–40) (30.0–50.0) (104.8–117.9) (58.5–64.8) (43.9–56.8)

7.1–15.6 1.8–5.0 32–43 19.5–94 76.8–147.2 50.2–73.0 30.4–82.3

Median (IQR) 10.5 3.3 40 38.3 109.1 62.4 46.5

Range

(8.9–13.8) (3.0–3.6) (39–40) (29.0–53.0) (104.7–115.1) (59.3–65.1) (41.7–52.8)

7.0–16.1 1.7–4.8 31–43 20.5–82.0 88.8–154.6 49.4–73.0 22.4–69.4

Abbreviations: DBP, diastolic blood pressure; IQR, interquartile range; SBP, systolic blood pressure.

Table 2 Relationship between gestational age and systolic blood

Table 3 Relationship between gestational age and pulse pressure

pressure Regression coefficient a Unadjusted All children Girls only Boys only Adjusted b All children Girls only Boys only a

0.51 0.665 0.318 0.631 0.700 0.604

95% CI

1.03 to 0.027 1.35 to 0.022 1.14 to 0.516 1.21 to 0.04 1.45 to 0.53 1.54 to 0.334

0.063 0.058 0.447 0.036 0.068 0.206

Regression coefficient 24-h systolic blood pressure (mm Hg) per week of gestation. b Adjusted for birth weight z-score. Journal of Human Hypertension

Regression coefficient a

95% CI

P

Unadjusted All children Girls only Boys only

1.29 1.69 0.80

2.33 to 0.10 2.96 to 0.40 1.98 to 0.70

0.013 0.011 0.288

Adjusted b All children Girls only Boys only

1.39 1.69 1.29

2.96 to 0.30 2.96 to 0.30 2.96 to 0.60

0.013 0.019 0.173

P

a Regression coefficient log pulse pressure (mm Hg) per week of gestation. Antilogs have been calculated to indicate the percentage change in pulse pressure for 1 week of gestation. b Adjusted for birth weight z-score.


programming blood pressure, it is the change in size between birth and the point of measurement of the outcome which is most significant. Rapid catch-up growth has been implicated in the developmental origins of adult disease,30,31 and more specifically high blood pressure32–34 and feeding regimen for infants born with low gestational age are intentionally energy dense with the aim of promoting weight gain. Investigation of the effect of early nutrition has shown that a nutrient-enriched diet increases later blood pressure and breastmilk consumption reduces it.35,36 However, it is unlikely that the influence of reduced gestation length on systolic blood pressure and pulse pressure can be attributed wholly to nutrition in the early post-natal period. Perturbation of the hypothalamic–pituitary–adrenal axis (HPAA) may also be an important mechanism mediating the association between reduced gestation length and elevated blood pressure. Increased HPAA activity during pregnancy is associated with regulation of parturition.37 Diet-induced HPAA hyperactivity in pregnancy has been associated with a modest elevation in HPAA, and in turn transient hypertension, in offspring.38 Factors originating in the foetus, such as genetic make-up, may influence length of gestation as well as later blood pressure. Family studies have demonstrated that factors that vary between pregnancies in the same woman (including foetal genotype) can influence later blood pressure in the offspring.39 It is plausible that variants such as those reported in the angiotensin-converting enzyme or methylenetetrahydrofolate reductase gene, which have been linked to preterm delivery, may influence both placental function and cardiovascular health in later life40,41 and may be a common feature explaining the association between low gestation length and elevated 24-h systolic blood pressure and pulse pressure seen here. Indeed, gestational hypertension or pre-eclampsia is a major contributor to preterm delivery and reduced gestational age in a proportion of this cohort is likely to be due to this. A positive association exists between gestational hypertension and offspring blood pressure measured in childhood, which is possibly due to the transmission of genetic risk from parent to child.42 However, the relationship between gestational hypertension, gestation length and childhood blood pressure could not be addressed within this study. Although blood pressure has long been recognized as a risk factor for cardiovascular events,43 the relative effect of pulse pressure has only more recently been investigated. The evidence so far suggests that while having a lesser effect than systolic blood pressure,44 pulse pressure, in middle and old age, may be an independent predictor in determining cardiovascular risk,23,24 possibly by altering haemostasis or endothelial function.45 In the current study, the relationship between gestational age and pulse pressure remained after adjustment for mean 24-h systolic blood pressure,

although as pulse pressure is estimated as the difference between systolic and diastolic blood pressure, it will be ‘mathematically coupled’ to both blood pressure variables.46 Such adjustments may in turn lead to misleading inferences regarding the adjusted associations between outcomes and explanatory variables.47 This is particularly likely to be the reason for the reduced (non-significant) regression coefficient for the relationship between gestational age and pulse pressure after adjustment for mean 24-h systolic blood pressure, which was highly correlated with pulse pressure (r ¼ 0.87). This raises the possibility that pulse pressure may be acting as a surrogate for 24-h systolic blood pressure, particularly as there is no significant change in diastolic blood pressure with gestation, which would serve to distort the ratio determining pulse pressure. As little work has been published relating to the determinants of pulse pressure, more data are required to clarify the importance of this biomarker in cardiovascular health. While the results of this investigation should not be interpreted as a causal association, if the association between gestational age and pulse pressure is a true relationship, further research is required into the mechanism or mechanisms responsible. The reasons for the gender differences in our study are not known and were not formally addressed. While the possibility that the gender difference is a chance finding cannot be ruled out, the implication of such an observation is that gender differences in risk factors for disease should be investigated and, if true gender differences are involved, that they may be used to inform studies of the mechanisms of such differential effects. Blood pressure in childhood rises progressively with age and more rapidly in puberty, with girls reaching puberty earlier than boys.48 Hence, the gender effect observed here may in part be attributable to variation in the age of onset of puberty. Pubertal stage was

What is known about topic K Early life exposures are believed to influence long-term cardiovascular health. K Evidence exists for an inverse relationship between birth weight and blood pressure, both in adults3–6 and in children.8–11 K Less is known regarding the potential link between being born early, independent of birth size, and subsequent blood pressure. What this study adds K This study reports a significant negative association between gestational age and mean 24-h systolic blood pressure in children and a further significant association between gestational age and pulse pressure, although the latter association was restricted to the girls in the study. K The results suggest that preterm birth may influence both mean 24-h systolic blood pressure and pulse pressure in childhood. The specific exposures for which preterm birth acts as a proxy require further research.

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not measured the cohort investigated here and is a limitation of the study. Blood pressure, and hence pulse pressure, measurement is prone to errors, particularly in children,49 but is unlikely to have introduced a systematic bias to this investigation. In summary, the data presented here suggest that an inverse and significant relationship exists between gestation length and 24-h systolic blood pressure and pulse pressure in childhood. This may have implications for the cardiovascular health of the increasing number of infants born preterm and now reaching adulthood.

13 14

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Acknowledgements This study was supported by a grant from the National Heart Research Fund and by the Ann Coleman legacy.

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