Issue 25, November 2008 Early Health and Neonatal Care

Preterm birth predisposes to cardiovascular disease in adulthood

Correspondence: Stefan Johansson, MD, Division of Neonatology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. (E-mail and other contact info can be obtained from CWWJ’s Editor-in-Chief).

Key Words: early health, preterm birth, cardiovascular disease, newborn, neonatal intensive care, early life programming effects.
Running title: Preterm birth predisposes to cardiovascular disease.

Clinical Window Web Journal #25: Preterm birth predisposes to cardiovascular disease in adulthood (November 2008). ISSN 1795-6269.

Introduction

The decreased mortality rates among preterm infants due to improvements in neonatal intensive care over the last decades has led to a new and growing generation of young adults – the survivors of preterm births. However, the life-long health effects after preterm birth are virtually unknown and late morbidity may be an increasing problem.

In the late 1980s, it was observed that low birth weight was associated with an increased risk of ischemic heart disease. Although the mechanisms are not fully understood, low birth weight is now an established risk factor for cardiovascular disease in adulthood.

When discussing birth weight and its effects on future health, one needs to consider that low birth weight can have two principally different explanations. Most of the earlier work in this research field focused on low birth weight at term, supposedly due to poor intrauterine conditions resulting in foetal growth restriction. However, more recent observations indicate that low birth weight due to preterm birth is also an indicator for increased risk of cardiovascular disease later in life. In fact, the most common cause of low birth weight in most countries today is preterm birth.

This article will give insights into the expanding research field concerned with so-called programming effects in early life, emphasizing that preterm birth may predispose to cardiovascular disease in adulthood.

The foetal origin of cardiovascular disease in adulthood

In a classic British study published in 1989, professor David Barker and co-workers reported in the Lancet that birth weight was inversely related to mortality risk by coronary heart disease [1]. An extended study including almost 16,000 British men and women born between 1911 and 1930, repeated this finding a few years later [2]. Men and women who weighed less than 2.5 kg at birth, faced a two-fold risk of cardiovascular mortality compared to those whose birth weights had been between 4.0 and 4.3 kg. Professor Barker and other front-line researchers developed a hypothesis about “foetal origins of adult disease”, often referred to as the “Barker hypothesis”, which proposed that foetal and/or maternal malnutrition may lead to permanent metabolic and endocrine changes in the foetus; changes that “program” the foetus to become predisposed to cardiovascular disease later in life [3].

This pioneering research was criticized for some important methodological issues, which needed to be addressed. Most importantly, the association between birth weight and risk of cardiovascular disease could have been confounded by socioeconomic factors. Low birth weight is more common in families with low socioeconomic status, in which lifestyle factors such as smoking, alcohol and inactivity are overrepresented. However, socioeconomic confounding does not seem explain the association between low birth weight and cardiovascular disease. For example, birth weight was also inversely related to mortality of ischemic heart disease in a large Swedish study, when the statistical analyses were adjusted for several potential socioeconomic confounders, such as occupation, education, marital status, and paternal occupation [4].

Preterm birth and high blood pressure later in life

Another methodological problem in the early studies is related to the fact that birth weight is a function of gestational age. Many infants with a low birth weight (below 2500 grams) have not suffered from foetal growth restriction, but are born preterm with a normal birth weight for gestational age. Consequently, individuals with low birth weights in the early studies likely represented a heterogeneous group, including term born individuals small for gestational age as well as individuals born preterm. To disentangle the independent contributions of foetal growth restriction and preterm birth to the risk of future cardiovascular disease, information on both birth weight and gestational age is needed. When designing studies of perinatal effects on health in adulthood today, this is an essential methodological issue. Thanks to the development of neonatal care, preterm birth is now the most common cause of low birth weight in industrialized countries.

A large-scale Swedish study, performed by our own group, characterised the independent effects of low birth weight due to preterm birth and being small for gestational age on cardiovascular morbidity [5]. This study was based on individually linked information from the Medical Birth Register, the Military Conscript Register and sociodemographic data registers. Almost 330,000 young men were included, born 1973 to 1981 and conscripted for military service 1993 to 2001 (Table 1).

Men born preterm had increased blood pressure; systolic blood pressure increased with decreasing gestational age (0.31 mm Hg per week). In logistic regression analyses, men born extremely preterm (at 24-28 weeks) showed a doubled risk of high systolic blood pressure (defined as =140 mm Hg) compared to men born at term (at 37-41 weeks). Men born with “low birth weight”, in the sense that they were smaller than expected at birth (small for gestational age, birth weight less than -2 standard deviations from the mean birth weight at a particular gestational age), also had increased systolic blood pressure, but the effect of preterm birth was greater than the effect of “smallness”.

Naturally, one may argue that our endpoint, increased blood pressure at 18 to 20 years of age, is less reliable than more definite cardiovascular endpoints such as morbidity and mortality due to myocardial infarction. However, manifest cardiovascular disease may be viewed as the end-stage phase of a progressive development over a lifetime. It is likely that an increased systolic risk of blood pressure in young adulthood will translate into an increased risk of hypertension, coronary disease and cardiovascular mortality.

Our epidemiological findings are supported by a number of recent clinical observations that also indicate what biological mechanisms in preterm infants could be predisposing them to cardiovascular disease in adulthood. Abnormal growth and development of the vascular tree may lead to higher vascular resistance, as demonstrated by abnormal retinal vascularization and lower peripheral blood flow in school-aged girls and young women born preterm [6-7]. Very preterm infants commonly suffer from metabolic problems such as transient hyperglycaemia, in spite of high levels of insulin. Increased levels of insulin may cause persisting changes in glucose and lipid metabolism, predisposing to increased blood pressure later in life [8]. Very preterm infants are also exposed to pain, inflammation and other stressful stimuli while undergoing neonatal intensive care. This perinatal stress may induce lasting changes in the sympathoadrenal activity, as indicated by our own study in which young children born preterm were found to have higher heart rate and to excrete more chatecolamines than did term born peers [9].

Public health implications and future challenges

The strong effect of preterm birth on later blood pressure, provided it is causal, may have important public health implications. In Sweden, approximately 6% of pregnancies end preterm and the corresponding figure in the US is reported to be as high as 12%. Hence, a similarly large proportion of offspring could be at risk of increased blood pressure later in life. A proposed strategy to diagnose blood pressure elevation in early life includes measurement of blood pressure any time a preterm born child presents in health care [10]. It may also be appropriate to suggest routine follow-up of preterm born infants with regard to blood pressure, and to advise children and adults born preterm to retain to an active and healthy lifestyle, avoiding other known risk factors for cardiovascular disease, such as smoking and obesity.

More knowledge is also needed on the biological mechanisms behind this phenomenon, in order to develop strategies that can reduce the impact of preterm birth on future cardiovascular health. In contrast to the situation today, efforts to lower the incidence of preterm birth needs to become successful. It is also likely that stressful exposures and nutritional status during neonatal care also have a role in modulating the risk of elevated blood pressure later in life.

References

1. 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.

2. Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ. Early growth and death from cardiovascular disease in women. Bmj 1993;307(6918):1519-24.

3. Barker DJ. The developmental origins of adult disease. Eur J Epidemiol 2003;18(8):733-6.

4. Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29. Bmj 1998;317(7153):241-5.

5. Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S. Risk of high blood pressure among young men increases with the degree of immaturity at birth. Circulation 2005;112(22):3430-6.

6. Kistner A, Jacobson L, Jacobson SH, Svensson E, Hellstrom A. Low gestational age associated with abnormal retinal vascularization and increased blood pressure in adult women. Pediatr Res 2002;51(6):675-80.

7. Bonamy AK, Bendito A, Martin H, Andolf E, Sedin G, Norman M. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls. Pediatr Res 2005;58(5):845-9.

8. Plagemann A, Harder T, Rake A, et al. Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res 1999;836(1-2):146-55.

9. Johansson S, Norman M, Legnevall L, Dalmaz Y, Lagercrantz H, Vanpee M. Increased catecholamines and heart rate in children with low birth weight: perinatal contributions to sympathoadrenal overactivity. J Intern Med 2007;261(5):480-7.

10. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114(2 Suppl 4th Report):555-76.

Clinical Window Web Journal #25: Preterm birth predisposes to cardiovascular disease in adulthood (November 2008). ISSN 1795-6269.

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Last updated: 30 November 2008
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