Can fetal vascular morphology at 30 weeks of gestation have impact on cardiovascular outcomes in childhood?

Many studies demonstrate an association between low birth weight and intrauterine growth retardation, cardiovascular abnormalities, and an increase in blood pressure later in life ^[1]. Although the initial hypothesis that intrauterine development is a dominant determinant of later blood pressure development and metabolic disorders has been slightly modified ^[2,3], the developmental origin of adult diseases is a continuing area of research. The question of whether there might be a particular period during fetal development when growth disturbances are of special importance for later cardiovascular outcome has not been thoroughly investigated. The study of fetal hemodynamics in normal-weight, uncomplicated pregnancies and its association with later cardiovascular outcome in childhood is important and might give us additional clues into the origins of the human cardiovascular disease hypothesis. Although reduced umbilical artery resistance has been associated with SBP and left-ventricular mass, low birth weight alone had little effect on childhood blood pressure ^[4]. In this issue of Journal of Hypertension, Kooijman et al.^[5] investigated fetal haemodynamics in fetuses from 917 pregnant women at gestational week 30 and related these findings to the cardiovascular outcomes of offspring at 6 years of age. They examined fetal growth, arterial hemodynamics, and cardiac hemodynamics in developing fetuses by echocardiography. At 6 years, blood pressure measurement, carotid-femoral pulse wave velocity, and an echocardiogram were performed investigating left cardiac structures and function. The only robust correlation was observed between aorta ascendens diameter during fetal development and aortic root diameter measurements at 6 years of age (P < 0.01). In addition, fetal cardiac output correlated with childhood aortic root diameter and fetal left-ventricular filling patterns correlated with aortic root diameter. No consistent associations were observed between fetal vascular resistance variables and cardiovascular function at follow-up. Thus, their study shows only weak associations between fetal cardiac dynamics in normally grown fetuses at approximately 30 gestational weeks (range 28.8–32.3 gestational weeks) with cardiac structural findings at 6 years of age. Neither do fetal vascular resistance variables during the same period correlate with, or have an influence on, blood pressure or arterial stiffness at 6 years of age.

The direct correlation between the fetal diameter of aorta ascendens and cardiac output with childhood aortic root size might be due to both hemodynamic and anatomical reasons. The inverse relationship between fetal diastolic filling patterns and later aortic root diameter is more difficult to explain. The diastolic filling pattern, that is the ratio of the early (E) maximum diastolic filling velocity divided by the late atrial (A) generated velocity (E/A ratio), depends on several factors, such as compliance, also reflecting left-ventricular mass, as well as the strength of atrial contraction. Previous studies of diastolic filling patterns in normal fetuses have suggested that maturational changes in ventricular properties accelerate after 25 gestational weeks and might be even more profound at 32–39 gestational weeks ^[6,7]. At birth, important changes occur in the transition from fetal to newborn heart: there is a fall in pulmonary vascular resistance, and blood flow through the foramen ovale ceases, causing the closure of the foramen ovale, ductus arteriosus, and ductus venosus. It has been suggested that the heart is stiffer and less elastic early in development, but the present and earlier studies indicate that ventricular stiffness decreases during the course of fetal development as ventricular elasticity increases. This shift constitutes a maturation process that appears to be at its peak towards the end of gestation ^[8], even extending beyond gestation and continuing during the first months after birth. The exact mechanism(s) responsible for these changes remain to be elucidated. In this large study by Kooijman et al.^[5], fetuses were examined using ultrasound and Doppler measurements at approximately 30 gestational weeks; thus, no evaluations were made during the later part of the third trimester.

Demonstrable cardiovascular differences between the sexes during fetal development in this study were small; fetal pulse and umbilical artery pulsatility index, reflecting umbilical artery resistance, were lower (P < 0.01 for each), and aortic diameter was increased (P = 0.01) in male fetuses compared with female fetuses. The differences between girls and boys were greater at 6 years of age than during fetal development; left atrial diameter, aortic root diameter, and left-ventricular mass were all greater in boys than in girls. The differences presented at 6 years of age might reflect sex-based differences found in later life, and the differences observed are likely to be of small clinical importance or clinically insignificant. Left atrial diameter might partly be influenced by an increased cardiac output in the males, although we do not have this information. The sex differences in blood pressure level are small. However, slightly lower SBP and DBP were observed in the males.

The incidence of hypertension in the cohort was only 0.8% in relation to 5% in the reference material ^[9]. Thus, it appears that fewer children in this cohort meet the criteria for hypertension compared with the reference material.

Former preterm patients have been shown to exhibit differences in cardiac structures such as an increased left-ventricular mass in adulthood ^[10]. Furthermore, among preterm patients, male infants appear to be most at risk for later increased blood pressure and hypertension, as recently shown when Roberts et al.^[11] performed 24-h ambulatory blood pressure measurements during late adolescence. This might relate to early reports in which male newborns appear to be most at risk of developing adverse morbidities after preterm birth. Results from preterm infants demonstrate a certain modulation of growth factors in neonates, with blood pressure outcome at 4 years of age ^[12]. Among preterm infants, the modulation of later DBP outcome by insulin-like growth factor (IGF)-I/IGF binding protein (BP)-1 levels appears to be most profound during a period corresponding to a postmenstrual gestational age of 32.5–34.5 weeks ^[12]; male infants are most at risk for low early neonatal IGF-I levels ^[13].

Both umbilical artery pulsatility index and fetal E/A ratio were inversely related to left-ventricular mass at 6 years of age. At 2 years of age, umbilical artery pulsatility index was also inversely related to left-ventricular mass ^[4]. Whereas an abnormally high umbilical artery pulsatility index is associated with impaired fetal growth, a low umbilical pulsatility index has been associated with promoted fetal growth ^[14]. One may argue that during fetal development, several factors might affect left-ventricular mass, such as sex, age, and weight, including common growth factors (e.g. insulin, IGF-I and IGF-II). Hemodynamic relations also influence left-ventricular mass such as heart rate, blood pressure, cardiac output and physical activity ^[15–17]. Stress and hypoxia can also be of some importance ^[15]. A full explanation will likely require a complex model, and it therefore seems less likely that umbilical pulsatility index at 30 weeks alone would affect left-ventricular mass in a cohort of normal children.

Small for gestational age infants with catch-up during the early postnatal period seem to be most at risk of developing later cardiovascular abnormalities ^[18]. Intrauterine growth-restricted infants have been shown to exhibit smaller ascending aortic diameter in young adulthood ^[19]. In the study by Kooijman et al.^[5], girls were shorter at follow-up. The girls in the study also had lower birth weights, in accordance with the general population ^[20]; however, at follow-up, no difference in current weight is present between boys and girls. This finding indicates a slightly higher catch-up growth in the female group, with a greater weight compared with height increment. This proposed larger weight SD score (SDS)/height SDS ratio in the female group compared with males might correspond with the observed blood pressure differences, as girls in this cohort have slightly higher SBP and DBP compared with males; however, the timing of the growth spurt is unknown ^[21]. In the present study, information regarding birth weight SDS, birth length SDS, target height SDS or anthropometric data in SDS at follow-up is missing. This lack complicates the estimation of catch-up growth. Growth or weight gain during childhood ^[18] or during the first postnatal months appears to be of special importance for a negative metabolic profile and worse cardiovascular outcome in childhood or young adulthood ^[22]. Positive associations between peak BMI during infancy and body composition at 6 years of age have been presented; this association seems to be of particular importance in girls ^[23]. Physical activity might also be of importance, as we reflect upon how differences between girls and boys can contribute to obesity and blood pressure rise ^[24].

Blood pressure measurements at 6 years of age did not correlate with BMI at follow-up. BMI is commonly used to define obesity in adults, but has been considered a poor marker of adiposity during childhood and early puberty, partly because BMI does not fully adjust for height in children ^[25]. Might BMI SDS or percentage adipose tissue mass correlate better with the findings? Waist-to-length ratio or waist-to-hip ratio might also have been informative when comparing blood pressure and cardiac structure outcomes in childhood ^[26].

During fetal development, the most intense relative increase in growth and adipose tissue mass in the fetus occurs during the latter part of the third trimester. Factors associated with accretion of fetal adipose tissue in late gestation are not entirely clarified, but higher maternal fasting glucose at 28 weeks of gestation has been associated with greater off-spring adiposity at birth ^[27]. Estimated fetal weight at the time of investigation (at 30 gestational weeks) did not differ between boys and girls, although male newborns weighed more at birth. Thus, a prominent part of fetal growth had occurred during the final 7–8 weeks of gestation, and the boys exhibited a more intense growth accumulation during this period. This finding raises the question of whether an echocardiographic investigation at or just before birth would have provided more information with respect to childhood cardiac outcome. Furthermore, dividing the cohort into weight SDS or BMI SDS quintiles at follow-up in relation to birth weight SDS quartiles or quintiles might have revealed greater differences and associations in the cohort.

One of the major strengths of the study by Kooijman et al.^[5], apart from the large study population, is that it has been conducted systematically and methodically with little range or variation in the gestational ages of the fetuses investigated. This study will provide an important standard for future comparisons with studies of intrauterine growth-retarded fetuses and preterm infants, although echocardiography at the time of birth might be even more useful as a comparative material for these two groups.

One might propose critical windows of increased growth: during the end of the third trimester, after term birth (especially during the first 6 postnatal weeks to 3 postnatal months), and during puberty (11–14 years of age). These periods coincide with a rise in IGF-I levels, which might have a persistent impact on the developing cardiac structures, especially if preceded by a cessation of relative growth.

A continued follow-up of the present large cohort is indicated. Growth and adipose tissue mass constitute important information that will be needed to follow and study this cohort further in early adulthood, and to be able to study the influence of puberty, with an emphasis on cardiac structures and blood pressure outcome. Collecting such data would make it possible to correlate cardiac outcomes from 6 years of age to adulthood and from fetal development to adulthood.

The clinical relevance of these results might be of minor importance; however, the study does not exclude the possibility that fetal hemodynamic changes that occur during the later part of the third trimester might leave a permanent imprint on childhood cardiac function.

ACKNOWLEDGEMENTS

Conflicts of interest

The author has no conflicts of interest to declare.