INTRAUTERINE GROWTH RESTRICTION AND ITS IMPACT ON CARDIAC FUNCTION AND ARTERIAL COMPLIANCE IN THE YOUNG CHILD

Transcription

1 INTRAUTERINE GROWTH RESTRICTION AND ITS IMPACT ON CARDIAC FUNCTION AND ARTERIAL COMPLIANCE IN THE YOUNG CHILD Edgar Jaeggi, MD, FRCPC Associate Scientist, RI Fetal Cardiac Program, The Hospital for Sick Children University of Toronto Toronto, Canada

2 BACKGROUND

3 Birth Weight and BP In national samples of year olds and 3259 adults in Britain, systolic BP was inversely related to birth weight, independent of GA. 10-year olds living in areas with high cardiovascular mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter and had higher diastolic BP. Fetal origin of adult disease hypothesis : This suggests that the intrauterine environment associated with reduced fetal growth influences BP during adult life. Barker DJ et al, BMJ 1989;298:564-7

4 Blood Pressure and Arterial Stiffness BP is the pressure (force per unit area) exerted by circulating blood on the walls of blood vessels MAP = (CO x Systemic VR) + CVP Stiffness or compliance of arterial walls is determined by age, wall thickness and smooth muscle tone: Stiffer central arterial walls: systolic and diastolic pressure pulse pressure Stronger pulsatile flow in smaller arteries cardiac work load left ventricular hypertrophy

5 Interrelation of arterial stiffness and increased WT

6 Birth Weight, Age & Vascular Property in Children Cheung YF et al, Arch Dis Child 2004

7 Increased brachioradial PWV in 8 year old children born preterm and small for GA * P < versus group 1 Preterm IUGR Preterm AGA Term AGA

8 Increased mean blood pressure in 8 year old children born preterm and small for GA

9 Martin H et al, Circulation 2000 Premature carotid artery stiffening in 8 year old children born SGA (open circles) vs. normal weight P < 0.01

10 Brodszki J et al, Circulation 2005 Smaller end-diastolic diastolic diameters of abdominal aorta and popliteal artery in 18 year old born IUGR

11 Intrauterine Growth Restriction Condition in which a fetus is unable to achieve its genetically determined potential size Birth weight < 10 th percentile adjusted for gestational age and gender (Kramer, 2001) Mainly result of placental failure

12 Reversed end-diastolic UA flow (RED)

13 Parallel Arrangement of Fetal Circulation

14 Potential Fetal Impact of Placental Failure transfer of O2/nutrients to & toxic wastes from the fetus Vascular effects: oxygen radical stress NO availability ET-1 1 and other vasoconstrictors hypertrophy Hemodynamic effects: Blood flow redistribution abnormal vascular growth? Abnormal ventricular vascular coupling cardiac workload

15 Elastin & Collagen Deposition in Central Arteries Martyn CN, Greenwald SE, Lancet 1997

16 IUGR: possible vascular modifications

17 Study Hypothesis Chronic placental failure leads to a cascade of harmful events which profoundly alters the development and function of fetal and postnatal vasculature, the degree of which is related to the onset and severity of IUGR pathology.

18 Objectives To create a data base for normal vascular properties in young children and to determine the impact of IUGR on fetal and postnatal myocardial mass and performance; the degree of vascular stiffness in early neonatal period; the evolution of brachio-radial radial stiffness during infancy; and the degree of correlation between placental stem arterial vascular changes, UA wall thickness/diameter, PWV, and to assess their role as early predictor of increased cardio-vascular risk

19 METHODS

20 Design/Subjects Prospective longitudinal 3-year 3 pilot study 38 growth restricted (IUGR) cases associated with placental insifficiency 53 appropriately grown (AGA) cases

21 Exclusion Criteria Prematurity < 26 weeks of gestation Subjects with major congenital anomalies Conditions affecting CV function (hypoxia, large PDA, inflammation, vasoactive drugs, etc)

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24 Antenatal Assessment MSH: Obstetrical US & Patient Recruitment SickKids: Fetal Echo 1) Questionnaire (risk factors, antenatal treatment) 2) Fetal biometry (FL; BPD) 3) Hemodynamic: UA (PI), MCA (RI; peak flows), DV 4) LV/RV function: LV SF, myocardial performance index (MPI), IVRT, E/A ratio, AV inflow durations; peak E.AE.A and S S tissue velocities from RV and LV freewalls 5) Cardiovascular dimensions: wall; ventricles, valves

25 Expected IUGR-related Fetal Cardiovascular Effects Small fetus with reduced CV dimensions and outputs Blood flow redistribution ( brain( sparing ) placental resistance RV afterload RCO Hypoxia cerebral vasodilation ( MCA RI) LV afterload LCO Impaired cardiovascular function (hypoxia, cardiac mass, abnormal systolic and diastolic function)

26 At Delivery 1) Gestational age, biometry (weight, height, HC) 2) Umbilical cord: hemoglobin and BGA 3) Placenta: weight; samples of villous tissue using stereology tools focusing on arterial structure (Imperial College London) 4) Cord plasma frozen and stored 5) Umbilical artery: elastin/collagen content, stressstrain curves, wall thickness

27 UA Load-Extension & Load-Failure UC Histology

28 At 7 (5-10) days and 6 (5-7) months of age Echolab or Neonatology: unsedated 1) Weight, height, head circumference 2) Resting BP 3) Complete echocardiogram 4) Non-invasive vascular studies

29 Ascending and descending aorta Distensibility = Dd-Ds/Ds Stiffness index = ln(bps/bpd)/distensibility

30 Sandor G et al, JASE 2003 Aortic arch Central PWV = distance/transit time

31 Right brachio-radial radial artery (PPG) PWV = distance/transit time

32 Expected IUGR-related Postnatal Cardiovascular Effects, when Compared to Age-matched AGA Cases Smaller biometry, cardio-vascular dimensions and output Increase in BP, PWV, ventricular WT and mass if adjusted for birth weight and age Greater changes in body weight, BP and PWV in early infancy Persistently smaller central arteries (adjusted for BSA and sex)

33 Statistics Descriptive statistics: Fisher exact or Chi-square test Normally distributed continuous variables: t-testt test Non-normally normally distributed variables: univariable linear regression Differences between 1 st and 2 nd exam between IUGR and AGA: multivariable linear regression model adjusted for repeated measures

34 RESULTS

35 Maternal Characteristics

36 Late Pregnancy Characteristics

37 Differences in Age (GA), Femur Length (FL) and Biparietal Diameter (BPD) at Fetal Echocardiography AGA (n=53) vs. IUGR (n=38) 40 GA FL BPD 35 Weeks p < p < p <

38 Fetal Middle Cerebral Arterial (MCA) Perfusion AGA (n=53) vs. IUGR (n=38) MCA velocity (cm/s) P = 0.03 P < systolic systolic diastolic diastolic MCA RI (z-score) P < Peak flow velocities Resistance index z-score

39 Fetal Left Heart N.S.: LV MPI, MV inflow duration, IVRT, LV TD velocities, LV SF, heart rate

40 Fetal Right Heart N.S.: RV MPI, TV inflow duration, RV TD velocities, RV SF, heart rate

41 Fetal Right/Left Ventricular Output and Dimensions 3 P = NS P = 0.03 RV/LV Ratio CO CO EDD EDD AGA (n=53) vs. IUGR (n=38)

42 Conclusions I: IUGR vs. AGA Blood flow redistribution ( brain( sparing ): systolic and diastolic MCA flow velocities and RI Increase in placental resistance does no result in RV dysfunction and a R-L R L shift in cardiac output: The RV adapts with a relative increase in RV dimensions to maintain a normal RCO Largely preserved systolic and diastolic function of both ventricles at the stage of the fetal exams

43 Neonatal Characteristics

44 Distribution of Gestational Ages and Birth Weights Birth Weight (kg) AGA (n=53) IUGR (n=38) P < Gestational Age (weeks)

45 Age at Postnatal Exams

46 Patient Weights at 1 st and 2 nd Examinations 10 P < AGA IUGR 8 Weight (kg) P < Exam 1 Exam 1 Exam 2 Exam 2 Regression: greater weight gain in IUGR cases between exam 1 and 2 (p < 0.001)

47 Postnatal Echocardiographic Findings

48 Blood Pressure 120 p = 0.01 p = SBP (mmhg) DBP (mmhg) p < p = Exam 1 Exam 1 Exam 2 Exam 2 0 Exam 1 Exam 1 Exam 2 Exam 2 Pulse amplitude (mmhg) p = NS p = NS Exam 1 Exam 1 Exam 2 Exam 2

49 SBP (mmhg) Blood Pressure and Gestational Age at Birth Exam 1 Exam 2 IUGR AGA Gestational Age (weeks) SBP (mmhg) IUGR AGA Gestational Age (weeks) DBP (mmhg) IUGR AGA Gestational Age (weeks) DBP (mmhg) IUGR AGA Gestational Age (weeks)

50 IUGR versus AGA: Changes in BP between 1 st and 2 nd Exam

51 Postnatal Vascular Findings

52 Brachio-Radial Pulse Wave Velocity in Infants without IUGR PWV (cm/s) Y = 57.5*BW ; R 2 = 0.28; p = Exam Weight at Birth (kg) PWV (cm/s) 900 Y = -26.8*BW + 499; R2 = 0.03; p = NS Exam Weight at Birth (kg) PWV (cm/s) 600 Y = 12.3*GA ; R2 = 0.23; p = Gestational Age at Birth (weeks) PWV (cm/s) 900 Y = 3.2*GA ; R2 = 0.008; p = NS Gestational Age at Birth (weeks)

53 Brachio-Radial Pulse Wave Velocity at 1 st Exam and Age at Birth p = IUGR AGA PWV (cm/s) Gestational Age at Birth (weeks)

54 Brachio-Radial Pulse Wave Velocity Exam AGA: Y = 57.5*BW + 152; R 2 = 0.28; p = IUGR: Y = 62.5*BW + 163; R 2 = 0.25; p = AGA: Y = 12.3*GA ; R 2 = 0.23; p = IUGR: Y = 13.3*GA ; R 2 = 0.33; p = PWV (cm/s) PWV (cm/s) Birth Weight (kg) Gestational Age at Birth (weeks)

55 Brachio-Radial Pulse Wave Velocity Exam 2 PWV (cm/s) AGA: Y = 28.4*BW + 501; R 2 = 0.03; p = NS IUGR: Y = 20.7*BW + 347; R 2 = 0.01; p = NS Birth Weight (kg) PWV (cm/s) AGA: Y = 3.2*GA ; R 2 = 0.008; p = NS IUGR: Y = 4.1*GA ; R 2 = 0.02; p = NS Gestational Age at Birth (weeks)

56 IUGR versus AGA: Changes in PWV between 1 st and 2 nd Exam

57 Conclusions II: IUGR vs. AGA No evidence of congenital vasculopathy: Cardiovascular function and dimensions of young children to 6 months are not negatively affected by prematurity and growth restriction

58 Conclusions II: IUGR vs. AGA At birth: Comparable cardio-vascular function between IUGR and AGA neonates Younger age: lower PWV and lower SBP and DBP At 6 months: Similar PWV independent of GA Lower DBP Comparable changes in BP, PWV and LV mass/bsa in infancy despite more rapid weight gain in IUGR cases

59 Future Directions Extension of the current study: Larger study cohort Examination of the evolution of vascular function and arterial blood pressure at 5 years of age

60 Fetal Program Hong Qin and fellows Esther Delea Vascular Lab Tim Bradley Cameron Slorach Wei Hui Andrew Redington Research Institute Fred Keeley Esther Jaeggi Eva Sitarz The Parents Study Coordinators Jyotsna Shah Deepa Dalal Shilpa Saxena Thank You! Pregnancy Program John Kingdom Leslie Proctor Pathology Sarah Keating Neonatology Ed Kelly Bio Bank Imperial College. UK Tahera Ansari