Heart morphology differences induced by intrauterine growth restriction and premature birth measured on the ECG in pre-adolescents

Pre-adolescents who had suffered from intrauterine growth restriction (IUGR) during their mothers'' pregnancy usually present more spherical hearts (smaller relation between base to apex measure and basal diameter), measured using echocardiograms, which has been associated with long-term cardiac disfunction. The present work aims to analyse these heart morphology changes by means of the surface ECG so as to have an early diagnostic tool of this pathology. The dataset is conformed by 148 pre-adolescents with either preterm or term births, and with or without IUGR. Once QRS and T-wave loops were obtained from the vectorcardiogram, the angles between the dominant vector of the QRS loop and -XY or -YZ planes(FR-XY, FR-YZ) and the difference between FR-XY and the angle between the dominant vector of T-wave loop (FT-XY) and the XY-plane showed different values for pre-adolescents who suffered from premature birth and IUGR than for control subjects (p < 0.05). These characteristics can open the door for a much easier diagnosis and follow-up of candidates for these disfunctions

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 kidneyvolumes, 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 andkidney 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

Placental function, body composition and cardiovascular autonomic function

Hypertension is an important modifiable risk factor for cardiovascular disease. An important recent advancement in hypertension research is an understanding that hypertension often may have a developmental origin. Birthweight is associated with hypertension across the lifespan and adult cardiovascular disease, such that those at both ends of the spectrum are at increased risk. Nonetheless, birthweight is a crude surrogate of fetal growth and it may be that quantification of body composition, may more accurately identify the “at risk” individual. A causative mechanism linking birthweight and cardiovascular risk is yet to be identified but may involve changes to the structure and function of organs including the placenta which may impair development and predispose individuals to later cardiovascular disease. The aims of this thesis were to investigate the associations between placental function, body composition and cardiovascular autonomic function. Studies outlines in this thesis indicate different mechanism control fat mass and fat free mass in the newborn and that placental weight partly mediates the association of maternal factors with newborn body composition. While low birthweight has previously been shown to be associated altered autonomic function in the infant our studies suggests that body fatness may provide information beyond that obtained from birthweight assessment alone. Previous studies have shown altered blood pressure control in those born preterm, our studies found altered cardiovascular outcomes even in the late preterm newborn. Assessment of body composition in children and adolescents at rest and in response to an exercise test suggests worsening of autonomic control due to adiposity and may develop over time during childhood and adolescence. Collectively, these results emphasise the implications of altered in-utero and early life exposures on cardiovascular outcomes

Cardiovascular Programming During and After Diabetic Pregnancy: Role of Placental Dysfunction and IUGR

Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero genemodification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included

Management of hypertension in pregnancy — prevention, diagnosis, treatment and long-term prognosis. A position statement of the Polish Society of Hypertension, Polish Cardiac Society and Polish Society of Gynaecologists and Obstetricians

ADDITIONAL INFORMATION This article has been co‑published in Kardiologia Polska (doi:10.33963/KP.14904), Arterial Hypertension (doi:10.5603/AH.a2019.0011), and Ginekologia Polska (doi:10.5603/GP.2019.0074). The articles in Kardiologia Polska, Arterial Hypertension, and Ginekologia Polska are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Any citation can be used when citing this article

Early indicators for adverse development of cardiovascular, renal and metabolic function in children born with low birth weight

Prematurity affects more than 10% of infants worldwide and is the main reason for neonatal mortality. Improvements in neonatal care have led to higher survival rates into adulthood. Adverse events during organogenesis and development, intra-or extrauterine, can increase the risk for chronic disease later in life. Developmental origins of health and disease is the epidemiologic research field linking early life events to related clinical phenotypes. In this thesis, we present 4 studies designed to follow up consequences of prematurity or low birth weight at term compared to term controls with normal birth weight in two different cohorts. The first cohort of children, studied at a mean age of 9.7 and again at 12.6 years (studies I-III), were born either very preterm (<32 weeks gestational age) or at term but small for gestational age. We studied kidney volume and function, the autonomous nervous system using heart rate variability and identified markers for insulin resistance. The second cohort of children, studied at a mean age of 7.7 years (study IV), were born extremely preterm (<28 weeks gestational age). We measured kidney volume and function and divided the group into those who developed and those who did not developed nephrocalcinosis during the neonatal period. We also studied blood pressure at the time of their visit, including 24-h ambulatory blood pressure measurements. Kidney volume or function was not significantly different between the three groups in study I. In study IV we found that children born extremely premature had smaller kidneys then children born at term, in particular the right sided kidney volume was significantly smaller compared to controls. Preterm born girls had smaller kidneys than full-term born girls (controls) but preterm born boys were not different to controls. Among preterm born children without nephrocalcinosis girls, had smaller kidney volumes than boys. Kidney function was normal and not affected by kidney volume. Paper II showed signs for insulin resistance in very preterm born children and children born small for gestational age. Preterm born children presented signs for hepatic insulin resistance while small for gestational age born children had a decreased peripheral insulin sensitivity. Both, very preterm and full-term small for gestational age born children had a generalized depression of heart rate variability compared to controls indicating an impaired function of the autonomous nervous system (study III). Office blood pressure as well as 24-hour ambulatory blood pressure were in the normal range for children born very or extremely preterm as well as for children born small for gestational age at term. Circadian blood pressure regulation was adversely affected in 50% of children born extremely preterm illustrated by the absence of normal day-to-night dipping in 24-hour ambulatory blood pressure measurements (study IV). In conclusion, children born preterm or full-term but small for gestational age showed several morphological or functional changes at early school age. The detected changes are indicating a possible development towards impaired kidney function, hypertension and the metabolic syndrome

Cardiovascular Programming During and After Diabetic Pregnancy: Role of Placental Dysfunction and IUGR

Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero gene modification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included

Maternal diabetes during pregnancy – obstetrical considerations and long term effects

Maternal diabetes mellitus (DM) during pregnancy has detrimental health impacts on both the mother and fetus, and include increased risks of cardiac malformations, cesarean section (CS), and asphyxia. The aim of the thesis was to investigate short and long term cardiac effects after fetal exposure to DM, investigate the ability of a 5 minute Apgar score as a marker for obstetrical care, investigate the association between mode of delivery in diabetic pregnancies and a low 5 minute Apgar score, and to investigate the association between offspring birth weight and maternal risk of future DM. Paper 1: Fetuses to mothers with either type 1 DM (p = 0.0015) and gestational diabetes mellitus (GDM) (p = 0.006) showed increased pulsatility index in the ductus venosus (PI-DV) in relation to gestational age. After the exclusion of SGA fetuses and those with blood flow changes, the PI-DV was still increased in type 1 DM (p = 0.02) and GDM pregnancies (p = 0.035), presumably reflecting short term cardiac impact. Paper 2: Fetuses exposed to type 1 DM showed an increased risk of future cardiovascular disease, as measured by consumption of drugs for cardiovascular disease, OR 1.46 (95% CI 1.16-1.83), this increased risk was however no longer present when data was adjusted for offspring with insulin dependent DM, OR 1.22 (95% CI 0.97-1.54). As previous studies have showed, an increased risk of future cardiovascular disease was found when born SGA, OR 1.29 (95% CI 1.24-1.35). No increased risk was found after being born LGA. Paper 3: The Apgar score is a resourceful marker of obstetrical care, as a substantial risk increase of needing education in special schools, OR =1.93(95% CI 1.75-2.14) low, or no grades when graduating from compulsory school, in nearly all school subjects, was found after being born with a 5 minute Apgar score under 7. One of 44 children born with an Apgar-score <7 at 5 minutes after birth will need education in a special school due to the factors leading to the low Apgar score. Paper 4: A 50% decreased risk of an Apgar score<7 at 5 minutes was found in DM+GDM pregnancies after a planned CS in gestational week 38 as compared to planned vaginal birth (from gestational week 39 and beyond), (p= 0.021), but no decreased risk was found in the DM group (p=0.08), GDM group (p=0.12) or LGA group alone (p=0.06). Paper 5: Offspring birth weight is a direct mirror of the maternal metabolic status, as a profound risk increase of developing both type 1 OR=3.46 (95% CI 3.12-3.83) or type 2 DM OR= 2.90 (95% CI 2.80-3.01) was found subsequent to giving birth to a LGA or macrosomic fetus