Very preterm birth and fetal growth restriction in adolescence - Cardiovascular and renal aspects

This thesis applied magnetic resonance imaging (MRI) to investigate to what extent very preterm birth due to early onset fetal growth restriction (FGR) impacts the cardiovascular system and kidneys in adolescence. The thesis further investigated whether FGR exacerbates the organ-specific effects of very preterm birth.

Study I validated a widely available non-contrast enhanced MRI method for quantification of renal cortical and medullary parenchymal volumes and showed that kidney volumes can be quantified with high accuracy and precision.

Study II validated an MRI method for pulse wave velocity (PWV) acquisition in neonates and adolescents and showed how the acquired PWV was influenced by commonly used MRI methods. The study proposed the use of 3D angiography images and the time-to-foot method for accurate and precise PWV acquisition.

Study III implemented the proposed PWV method from Study II and 24-hour ambulatory blood pressure measurements and showed that very preterm birth due to early onset FGR was associated with higher, yet normal, blood pressure in adolescent boys while very preterm birth was associated with higher arterial stiffness in girls.

Study IV showed that very preterm birth was associated with smaller ventricular volumes without alterations in left or right longitudinal and radial pumping. Early onset FGR did not exacerbate the effects of very preterm birth.

Study V implemented the newly validated non-contrast enhanced MRI method from Study I together with biomarkers of kidney function. Very preterm birth due to FGR was associated with smaller total kidney and medullary kidney volumes, but not with markers of kidney dysfunction or renin-angiontensin-aldosterone system activation in adolescence.

This thesis concludes that adolescents born very preterm with and without preceding fetal growth restriction show alterations in cardiovascular and renal morphology. Changes were more pronounced in girls. Cardiovascular and kidney function were however normal, possibly indicating a decreased long-term effect of very preterm birth and fetal growth restriction on these organ systems compared to earlier studies, where clear signs of increased risk were observed already in childhood and adolescence. As indicated by increases in blood pressure, male sex and fetal growth restriction might increase cardiovascular risk in those born preterm. Morphological changes in the heart and in the kidneys may still precede functional decline in this population, and the alterations observed could potentially be used as prognostic markers in the future.

Improved obstetric and neonatal care have increased the number of fetuses in high risk pregnancies that can be identified, surveilled, and who eventually survive. Early onset fetal growth restriction is a clinical syndrome in which the fetus risks intrauterine death due to dysfunctional fetal placental circulation. At Skåne University Hospital in Lund, Sweden, it has been the clinical practice to actively deliver fetuses, due to early onset fetal growth restriction, even in very early gestation, when organ maturation has not yet been completed. The long-term effects of this management are not known. There is, however, a strong association between both preterm birth and fetal growth restriction with an increased risk of cardiovascular disease (CVD) and kidney disease later in life. Whether the heart, the vasculature or the kidneys drives this increased risk is not known. It is further not known whether early onset fetal growth restriction adds to the effects of very preterm birth. This thesis included a cohort of adolescents born very preterm due to early onset fetal growth restriction at Skåne University Hospital between the years 1998-2004. Two sex-matched control groups with appropriate birth weight were included, one in similar gestational and one born at term after a healthy pregnancy. To diagnose and quantify organ specific alterations, magnetic resonance imaging (MRI) was used. This method is the reference method for quantification of cardiovascular structure and function and is central in assessing kidney structure. 24-hour ambulatory blood pressure measurements were performed and biochemical markers in blood and urine for the assessment of cardiovascular risk, kidney function and inflammatory activity were sampled. This thesis includes five studies. Two are validation studies in which methods for the quantification of kidney volumes and pulse wave velocity in the aorta, a measure of arterial stiffness, respectively, are developed and assessed. These methods are then applied to assess differences between groups in the primary cohort. The overall aim of this thesis was to investigate to what extent very preterm birth due to fetal growth restriction effects the heart, the vasculature, and the kidneys in adolescence. The aim was also to investigate whether the organ specific alterations induced by very preterm birth was exacerbated by fetal growth restriction.

Study I. Validated renal cortical and medullary volume assessment with a readily available non-contrast-enhanced MRI method. For comparison, renal cortical and medullary volumes were quantified with Archimedes’ principle, after dissection of extracted kidneys. The MRI method agreed with ex-vivo measurements and the intra-and interobserver variability was low.

Study II. Validated a method for pulse wave velocity acquisition with MRI in neonates and in adolescents. A computer phantom was created to determine the temporal resolution needed for reliable quantification of pulse wave velocity in the respective cohort, with the actual physical parameters as input. The study showed what method for pulse wave velocity that should be used and determine the temporal resolution needed for reliable assessment of pulse eave velocity in the respective group.

Study III. Investigated blood pressure variability and aortic stiffness in the three groups, born very preterm with and without preceding fetal growth restriction and born at term. 24-hour ambulatory blood pressure measurements and the validated method for pulse wave velocity measurements were used. The study showed that blood pressure is higher in boys born very preterm and that fetal growth restriction exacerbates this increase. The study further showed, in contrast to earlier studies of adolescents born very preterm with and without fetal growth restriction, that arterial stiffness was similar between groups.

Study IV. Cardiac structure and function were assessed with common clinical and new MRI methods. The study showed that very preterm birth was associated with smaller cardiac volumes but also that cardiac function was unaffected after very preterm birth and fetal growth restriction in adolescence.

Study V. Cortical and medullary kidney volume were assessed with the validated method from Study I. The study showed that very preterm birth due to fetal growth restriction was associated with smaller kidney volumes. This volume change was mostly driven by smaller medullary volumes. Kidney function was not affected.

In summary, this thesis has taken a comprehensive approach to assess the effects of very preterm birth and fetal growth restriction on the cardiovascular system and the kidneys in adolescence. Potential prognostic biomarkers of future cardiovascular and renal disease have been assessed using new validated MRI methods together with standard clinical methods. Overall, this thesis indicates lessened long-term effects and degree of cardiovascular impact of very preterm birth with and without preceding fetal growth restriction.