IUGR AND LONG TERM CV FUNCTION

IUGR AND LONG TERM CV FUNCTION Eduard Gratacós www.fetalmedicinebarcelona.org www.fetalmedicinebarcelona.org/

1. Fetal growth and cardiovascular function 2. IUGR and cardiac programming 3. Clinical implications www.fetalmedicinebarcelona.org/

GROWTH RESTRICTION AND THE FETAL HEART Adaptive response Progressive failure Permanent Epigenetic changes CLINICAL MONITORING CARDIAC PROGRAMMING

GROWTH RESTRICTION AND THE FETAL HEART IUGR target organ in hypoxic centralization Adaptive response Progressive failure Permanent Epigenetic changes CLINICAL MONITORING CARDIAC PROGRAMMING

Cardiac function Myocardial Performance Index Cord blood BNP Mod-MPI (z-scores) 4 3 2 1 * * * BNP (pg/ml) 400 350 300 250 200 150 100 * * * 0 term AGA IUGR-s1 s2 s3 50 0 term AGA preterm AGA IUGR-s1 s2 s3 Data are mean(sem). *P<0.01 compared to AGA. Doppler parameters in Z-scores Cardiac dysfunction: early event & progression www.fetalmedicinebarcelona.org/ Girsen et al UOG 2007 Crispi et al. AJOG 2008

CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR 3,5 DV AoI TEI 3,0 2,5 2,0 1,5 Z-scores 1,0 0,5-30 -25-20 -15-10 -5 0 Days before delivery 0 www.fetalmedicinebarcelona.org/

CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR 3,5 DV AoI TEI 3,0 2,5 2,0 1,5 Z-scores 1,0 0,5-30 -25-20 -15-10 -5 0 Days before delivery 0 Cruz- Mar(nez, 2010 www.fetalmedicinebarcelona.org/

CARDIOVASCULAR DYSFUNCTION IN LATE-ONSET IUGR 50 30 Controls * Frequency of abnormality (%) 25 20 15 10 5 0 SGA DV AoI MPI * Tissue Doppler E > 90th centile (%) 40 30 20 10 0 CONTROL SGA * LEFT RIGHT www.fetalmedicinebarcelona.org/

1. Fetal growth and cardiovascular function 2. IUGR and cardiac programming 3. Clinical implications www.fetalmedicinebarcelona.org/

1986 Barker (MRC Unit, Southampton, UK): Coronary heart disease mortality rates Cardiovascular risk factors

Cardiovascular risk factors FETAL GROWTH RESTRICTION: 6-7% NEWBORNS Low birth weight cardiovascular mortality coronary heart disease hypertension stroke type 2 diabetes obesity Barker Lancet 1989, Barker BMJ 1993, Osmond BMJ 1993, Barker BMJ 1995, Fall BMJ 1995, Stein Lancet 1996, Leon BMJ 1998, Forsen BMJ 1999, Eriksson BMJ 2001, Osmond Stroke 2007

The Barker hypothesis Fetal programming: Coronary heart disease originates through responses to under nutrition during fetal life, which permanently change the body's structure, physiology and metabolism www.fetalmedicinebarcelona.org/

CLASSIC HYPOTHESIS Fetal growth restriction Epigenetic changes in metabolic regulation Normalization of diet (or overnutrition) Insulin resistance Obesity/Diabetes/ Hypertension Cardiovascular disease ALTERNATIVE/ COMPLEMENTARY HYPOTHESIS Fetal growth restriction Epigenetic changes in cardiac regulation Persistence of abnormal cardiac function Lack of ability to further adaptation Cardiovascular disease

Animal data: restriction of oxygen leads to dilated and lessefficient hearts Chicken embryo model Effects of hypoxia on the embryonic heart Tintu et al. Plos One 2009

Evidence of the impact of IUGR in postnatal cardiac function Maria Height 106 cm (normal) Weight 21 kg (normal) Carlota Height 104 cm (p3) Weight 16 kg (p9)

Maria (N) E/A mitral E = 91 cm/s 76 ms Tissue Doppler: E/E = 6 Myocardial velocities (septal annulusl) S = 10 cm/s E = 15 cm/s Normal cardiac function

Maria (N) Normal heart

Maria (N) Carlota (IUGR) Normal heart Globular heart

Cardiac remodelling in IUGR Systolic function Cardiac shape Diastolic function www.fetalmedicinebarcelona.org/ Crispi et al. Circulation 2010

Impact of prenatal severity on cardiovascular programming in late-iugr control IUGR Crispi 2010

Impact of prenatal severity on cardiovascular programming in late-iugr control IUGR Fetuses EFW<p10 evaluated at 5 years Classified by CPR, p3 and UtA Doppler: All normal: SGA Any abnormal: late-iugr Crispi 2010

1. Fetal growth and cardiovascular function 2. IUGR and cardiac programming 3. Clinical implications www.fetalmedicinebarcelona.org/

Effect of dietary interventions on CV disease ADULTHOOD PREDIMED NEJM 2013

Effect of dietary interventions on CV disease CHILDHOOD Childhood Asthma Prevention Study www.fetalmedicinebarcelona.org/ CAPS Pediatrics 2012

direct effect To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA Factors associated to cimt Characteristics Adjusted coef. (n=88) Coef. (95%CI) P value IUGR 0.0264(0.0170; 0.0358) <0.001 Gestational age at delivery -0.0024(-0.0036;-0.0011) <0.001 Female sex -0.0003(-0.0096;0.0090) 0.95 Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02 BMI at follow up 0.0035(0.0013;0.0057) 0.01 www.fetalmedicinebarcelona.org/

direct effect To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA Factors associated to cimt Characteristics Adjusted coef. (n=88) Coef. (95%CI) P value IUGR 0.0264(0.0170; 0.0358) <0.001 Gestational age at delivery -0.0024(-0.0036;-0.0011) <0.001 cimt Female sex -0.0003(-0.0096;0.0090) 0.95 Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02 SGA/IUGR BMI at follow up 0.0035(0.0013;0.0057) 0.01 AGA % polyunsaturated fats www.fetalmedicinebarcelona.org/

Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR ABNORMAL CV OUTCOME: DBP >95th centile Aortic IMT >95th centile

Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR IUGR n=100 Conventional Doppler Fetal Echocardiography ABNORMAL CV OUTCOME: DBP >95th centile Aortic IMT >95th centile IUGR: EFW / birthweight <p10.

CV Risk in IUGR children at 6 months DBP >95th centile + aimt>95th centile YES 26% n=100 NO 74%

Prediction of hypertension and increased vascular thickness at 6 months of age in fetuses with IUGR CV score: DR 90% - FPR 25% (PPV 38%, NPV 98%) Cruz, 2013

Conclusions www.fetalmedicinebarcelona.org/

Conclusions Cardiac dysfunction/adaptation is a constitutional feature of IUGR Cardiac dysfunction in fetal life induces permanent CV programming and remodelling resulting in child conditions demonstrated to increase susceptibility to cardiovascular disease later in life This opens new public health opportunities for the prevention of cardiovascular disease from early life, and new research lines exploring early intervention. www.fetalmedicinebarcelona.org/