Impact of (early and late) IUGR on neurodevelopment

Transcription

1 Impact of (early and late) IUGR on neurodevelopment Eduard Gratacos Maternal-Fetal Medicine Department and Research Center Hospitals Clinic and Sant Joan de Deu - University of Barcelona

2 Impact of (early and late) IUGR on neurodevelopment Eduard Gratacos Maternal-Fetal Medicine Department and Research Center Hospitals Clinic and Sant Joan de Deu - University of Barcelona

3 Impact of (early and late) IUGR on neurodevelopment Eduard Gratacos Maternal-Fetal Medicine Department and Research Center Hospitals Clinic and Sant Joan de Deu - University of Barcelona

4 1. IUGR vs. SGA - Early vs. Late 2. Early-onset IUGR and neurodevelopment 3. Late-onset IUGR and neurodevelopment

5 1. IUGR vs. SGA - Early vs. Late 2. Early-onset IUGR and neurodevelopment 3. Late-onset IUGR and neurodevelopment

6 Savchev

7 The discovery of UA and hemodynamics of IUGR Savchev

8 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect IUGR = abnormal UA Doppler Savchev

9 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler Savchev

10 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler Savchev

11 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler N cases 0 N cases Savchev

12 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler N cases 0 N cases Savchev

13 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler N cases UA Doppler + (EARLY-ONSET) 0 N cases Savchev

14 The discovery of UA and hemodynamics of IUGR Constitutionally small Placental insufficiency Extrinsic cause Primary fetal defect SGA IUGR IUGR = abnormal UA Doppler N cases UA Doppler + (EARLY-ONSET) 0 UA Doppler N (LATE-ONSET) N cases Savchev

15 Distribution of cases when IUGR = abnormal UA Doppler Savchev 2013

16 Distribution of cases when IUGR = abnormal CPR or UtA or EFW<p3 Savchev 2013

17 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR

18 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR

19 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%)

20 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%) PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS

21 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%) PROBLEM: MANAGEMENT Placental disease: high (UA+, PE high) PROBLEM: DIAGNOSIS Placental disease: low (UA-, PE low)

22 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%) PROBLEM: MANAGEMENT Placental disease: high (UA+, PE high) Hypoxia ++: systemic CV adaptation PROBLEM: DIAGNOSIS Placental disease: low (UA-, PE low) Hypoxia +/-: central CV adaptation

23 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%) PROBLEM: MANAGEMENT Placental disease: high (UA+, PE high) Hypoxia ++: systemic CV adaptation Tolerance to hypoxia. Natural history PROBLEM: DIAGNOSIS Placental disease: low (UA-, PE low) Hypoxia +/-: central CV adaptation Low tolerance: no natural history

24 IUGR= low CPR or high UtA or EFW<p3 or low PlGF 6 % SGA? 3 IUGR EARLY IUGR (1%) LATE IUGR (5-7%) PROBLEM: MANAGEMENT Placental disease: high (UA+, PE high) Hypoxia ++: systemic CV adaptation Tolerance to hypoxia. Natural history High mortality and morbidity PROBLEM: DIAGNOSIS Placental disease: low (UA-, PE low) Hypoxia +/-: central CV adaptation Low tolerance: no natural history Low mortality but poor long outcome.

25 1. IUGR vs. SGA - Early vs. Late 2. Early-onset IUGR and neurodevelopment 3. Late-onset IUGR and neurodevelopment

26 early-iugr is associated with higher frequency of ultrasound brain lesions and abnormal neonatal neurobehaviour Controls IUGR Controls IUGR 30,0 22,5 * * * 30,0 22,5 15,0 (%) 15,0 % 7,5 7,5 0 BGL PVL IVH Brain abn. 0 Abnormal neurobehavior * p<0.05 IUGR Controls p n (fetuses) GA at birth (wks) 31.2 (2.4) 31.1 (2.4) 0.73 Birthweight (g) <0.001 Cruz et al

27 early-iugr is associated with higher frequency of ultrasound brain lesions and abnormal neonatal neurobehaviour Controls IUGR Controls IUGR 30,0 22,5 * * * 30,0 22,5 * 15,0 * (%) 15,0 % 7,5 7,5 0 BGL PVL IVH Brain abn. 0 Abnormal neurobehavior * p<0.05 IUGR Controls p n (fetuses) GA at birth (wks) 31.2 (2.4) 31.1 (2.4) 0.73 Birthweight (g) <0.001 Cruz et al

28 Early-onset IUGR PREDICTION OF SERIOUS NEUROLOGICAL MORBIDITY < >32.0 Perinatal >90% 30-40% <10% Mortality Fouron 2004 Del Rio 2008 Cruz- Mar5nez 2012

29 Early-onset IUGR PREDICTION OF SERIOUS NEUROLOGICAL MORBIDITY Brain US anomalies in 30w IUGR Controls IUGR antegrade AoI IUGR retrograde AoI Controls IUGR DV<5 z-score IUGR DV>5 z-score 60 * * 45 (%) < >32.0 Perinatal >90% 30-40% <10% Mortality Fouron 2004 Del Rio 2008 Cruz- Mar5nez

30 Early-onset IUGR: TARGETED NEUROSONOGRAPHY Abnormal findings = 16% (n=108) Eixarch 2013

31 SEVERE IUGR: TARGETED NEUROSONOGRAPHY

32 Early-onset IUGR has a strong association with poor short-term and long-term adverse neurological outcome Early-onset IUGR: Indication for neurosonography If NSG normal: strongest predictor is GA<30w Best predictor aside of GA: aortic isthmus (32-37w)

33 1. IUGR vs. SGA - Early vs. Late 2. Early-onset IUGR and neurodevelopment 3. Late-onset IUGR and neurodevelopment

34

35

36

37 exposure

38 exposure Fetal programming Brain reorganiza5on (+/- injury)

39 Batalle 2012 Eixarch 2012

40 Batalle 2012 Eixarch 2012

41

42

43 Dichorionic Twins. Born 34 weeks Twin 1: 1950 g (p45) Twin 2: 1200 g (p1). Normal Doppler

44 Dichorionic Twins. Born 34 weeks Twin 1: 1950 g (p45) Twin 2: 1200 g (p1). Normal Doppler * * * Bayley Score cognitive language motor socio-emot adaptive behavior Satchev, 2012 Figueras Baschat 2009, 2011 Vohr 2004 Geva Marsal Visser 01-11

45 Dichorionic Twins. Born 34 weeks Twin 1: 1950 g (p45) Twin 2: 1200 g (p1). Normal Doppler * * * Bayley Score cognitive language motor socio-emot adaptive behavior Lagercrantz H. Better born too soon than too small. Lancet 1997 Satchev, 2012 Figueras Baschat 2009, 2011 Vohr 2004 Geva Marsal Visser 01-11

46 Clinical implications: Does delivery at 37 weeks improve outcomes? Does SGA vs IUGR affect prognosis? Prediction with biomarkers

47 Effects on (neuro)developmental and behavioral outcome at 2 years of age Induced labor vs. expectant management in late SGA (EFW<10th cen5le) (DIGITAT trial) AJOG months SGA >37 weeks 13/21

48 Neurobehavioral performance of term SGA vs IUGR Bayley s scores at 2 years * * * 8 6 Bayley Score 4 2 cognitive language motor socio-emotional adaptive behavior

49 Neurobehavioral performance of term SGA vs IUGR Bayley s scores at 2 years * * * 8 6 No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler) Bayley Score 4 2 cognitive language motor socio-emotional adaptive behavior

50 Neurobehavioral performance of term SGA vs IUGR Bayley s scores at 2 years Cortical measures * * * 8 6 No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler) Bayley Score 4 2 cognitive language motor socio-emotional adaptive behavior Egaña 2013

51 Brain cortical development in patients with high risk of abnormal neurodevelopment (IUGR) Abnormal!! Normal A A Egaña 2013

52 Brain cortical development in patients with high risk of abnormal neurodevelopment (IUGR) Integrated algorithm with several brain CD measures Composite score= e-(y)/ (1 + e-(y)), where Y= [(LID/BPD * RID/BPD * ) + (LPOD/BPD * )]. Abnormal!! Normal A A Egaña 2013

53 BIOLOGIC PROGRAMMING AND AGE Early and Late-Onset IUGR IMPACT OF ENVIRONMENT Fetus Child Young Mature Old

54 BIOLOGIC PROGRAMMING AND AGE Early and Late-Onset IUGR IMPACT OF ENVIRONMENT OPPORTUNITY FOR CORRECTION Fetus Child Young Mature Old

55 BIRTH WINDOW OF OPPORTUNITY Fetus Child Brain organiza5on Problem evident

56 IDENTIFICATION OF RISK INDIVIDUAL BIOMARKERS INTERVENTION BIRTH WINDOW OF OPPORTUNITY Fetus Child Brain organiza5on Problem evident

57 Intelligence Fetal (Early) postnatal IDENTIFICATION OF RISK INDIVIDUAL BIOMARKERS Genes INTERVENTION BIRTH WINDOW OF OPPORTUNITY Fetus Child Brain organiza5on Problem evident

58 Being small for gestational age has a strong association with poor long-term adverse neurological outcome regardless of the cause Detection of smallness is an opportunity to improve long-term health outcomes and ageing Individualized prediction of risk will likely be possibly but not applicable as public health