Restriccion del crecimiento Fetal: Manejo basado en estadios

Dr. Jorge Avalos

Restricción de crecimiento Fetal

•manejo •consecuencias en la programación fetal

www.medicinafetalbarcelona.org/

Neuroimage*2012 PLoS*One*2012


Neuroimage*2012 PLoS*One*2012

medicina maternofetal

HNDAC

Lagercrantz 1997 - The Lancet

“Better born too soon than too small”


HNDAC

Antenatal identification of SGA and outcome 261

**

**

*

*

Normalgroup

20thpercentile

10thpercentile

ModerateSGA

SevereSGA

ExtremeSGA

32

16

8

4

2

1

Grade of weight deviation

Risk

of se

rious

fetal

comp

licati

on (o

dds r

atio ±

95%

Cl)

§ §§

Figure 1 Risk of adverse fetal outcome and antepartum recognitionof small-for-gestational age (SGA), showing fetuses recognized (°)and those not recognized (ž) antepartum. Weight deviation =(birth weight − expected birth weight)/expected birth weightexpressed as a percentage. Classification of birth-weight deviation:normal group < + 22% to ≥−11%; 20th percentile <−11% to≥−16.5%; 10th percentile <−16.5% to >−22%; moderate SGA≤−22% to >−27%; severe SGA ≤−27% to >−33%; extreme SGA≤−33%. Difference between identified and unidentified SGA cases:*P = 0.01, **P = 0.02, ***P < 0.001. Difference between thenormal group and the 10th percentile and extreme SGA subgroups:§P < 0.001 and §§P = 0.04, respectively.

model. The data were analyzed using SPSS software 11.5(Statistical Package Social Sciences (SPSS) Inc., Chicago,IL, USA). P-values < 0.05 were considered statisticallysignificant.

Power estimation

We assumed the rate of serious complication to be 10%among SGA pregnancies. A two-sided χ2 test with a 0.05significance level applied to two equal groups of 600pregnancies would yield a power of 87% to detect ahalved incidence of serious complications in the groupwith antepartum recognition of SGA.

RESULTS

The number and risk of serious fetal complicationsamong those with SGA and AGA are given in Table 1.Compared with AGA fetuses, SGA fetuses were at afour-fold increased risk (OR, 4.1; 95% CI, 3.2–5.0) forserious fetal complications, and about 8% of SGA fetusessuffered adverse fetal outcome. However, SGA fetuseswere at an approximately seven-fold increased risk fordeath (either intrauterine or infant death). Compared withAGA fetuses, fetuses with moderate SGA, severe SGA,and extreme SGA were at a 4.2- (95% CI, 2.9–6.2), 7.0-(95% CI, 4.2–11.6), and 35.8- (95% CI, 20.4–62.8) foldincreased risk of serious fetal complications, respectively.Similarly, compared with women delivering at term, thosedelivering extremely preterm, preterm and post-term wereat a 24.7- (95% CI, 18.1–33.6), 2.9- (95% CI, 2.2–3.8),and 1.4- (95% CI, 1.0–1.9) fold increased risk of seriousfetal complications (adjusted for SGA ‘yes/no’).

Table 2 presents adverse fetal outcome among SGAfetuses, divided into those either ‘identified’ or ‘notidentified’ before delivery. The risk is presented bothas a bivariate OR and an adjusted OR for adverse fetaloutcome. SGA fetuses not identified before delivery, whencompared with those identified, were characterized bya four-fold increased risk of serious complications (OR,4.1; 95% CI, 2.5–6.8). Fifty-four percent of all SGApregnancies were identified as SGA in advance of delivery.Pregnancies with moderate SGA were identified in 44%(297/683) of all cases, and the proportions of severe

Table 1 Fetal outcome for pregnancies with small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) fetuses

SGA(n = 1291) (n (%))

AGA(n = 24 585) (n (%))

BivariateOR (95% CI)

Adverse outcome* 101 (7.8) 508 (2.1) 4.1 (3.2–5.0)Cerebral damage 17 (1.3) 81 (0.3) 4.0 (2.4–6.8)

HIE 2–3 3 (0.2) 29 (0.1) 2.0 (0.6–6.5)Intracranial hemorrhage 6 (0.5) 23 (0.1) 5.0 (2.0–12.3)Cerebral palsy 4 (0.3) 16 (0.1) 4.8 (1.6–14.3)Mental retardation 5 (0.4) 18 (0.1) 5.3 (2.0–14.3)

Severe fetal distress 46 (3.6) 364 (1.5) 2.5 (1.8–3.4)Apgar score < 4 at 5 min 15 (1.2) 92 (0.4) 3.1 (1.8–5.4)Neonatal convulsions 6 (0.5) 75 (0.3) 1.5 (0.7–3.5)Umbilical pH < 7.0 28 (2.2) 236 (1.0) 2.3 (1.5–9.8)

Fetal or infant death 49 (3.8) 137 (0.6) 7.0 (5.1–9.8)Stillborn† 26 (2.0) 50 (0.2) 10.1 (6.3–16.3)Intrapartum death 0 (0.0) 3 (0.0) NAInfant death 23 (1.8) 84 (0.3) 5.3 (3.3–8.4)

Adverse outcome was defined as at least one of the presented variables. *The same infant might appear in more than one subgroup. †pH andAPGAR at 5 min were not recorded for those stillborn. HIE 2-3, hypoxic ischemic encephalopathy grade 2 or 3; NA, not applicable.

Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2005; 25: 258–264.

OR: 4.1; 95% CI, 2.5–6.8


HNDAC

Adaptacion fetal a la insuficiencia placentaria


Programación fetal!Evidencias actuales y papel de la “nutrición” fetal!

!Eduard Gratacos!

BCNatal – Centre de Medicina Maternofetal i Neonatologia de Barcelona!Hospital Sant Joan de Déu i Hospital Clínic, Universitat de Barcelona!

www.medicinafetalbarcelona.org

Gestación de 14 sem


Normal and abnormal placental implantation

Saturday, April 20, 13


HNDAC


Programación fetal!

Evidencias actuales y papel de la “nutrición” fetal!

!Eduard Gratacos!

BCNatal – Centre de Medicina Maternofetal i Neonatologia de Barcelona!

Hospital Sant Joan de Déu i Hospital Clínic, Universitat de Barcelona!


resistencia placentariaarteria umbilical arteria uterina

<30% de función





HNDAC




!Eduard Gratacos!




resistencia placentariaarteria umbilical

<30% de función

disminución flujo vena umbilical

crecimiento fetal

restringido




!Eduard Gratacos!



www.medicinafetalbarcelona.orgwww.medicinafetalbarcelona.org/




HNDAC

resistencia placentaria

arteria umbilical

disminución flujo vena umbilical

crecimiento fetal

restringidoredistribucion de flujo

arteria cerebral media

arteria umbilicalarteria cerebral mediaICP




!Eduard Gratacos!








HNDAC


arteria umbilical

disminución flujo vena umbilicalremodelacion cardiaca


sistole

diastole




!Eduard Gratacos!








HNDAC


arteria umbilical

disminución flujo vena umbilicaldisfuncion cardiaca


sistole

diastoleHTA fetal disfuncion diastolica

Doppler pre-cordial


HNDAC

Manejo enfocado en estadios y severidad


Programación fetal!Evidencias actuales y papel de la “nutrición” fetal!

!Eduard Gratacos!

BCNatal – Centre de Medicina Maternofetal i Neonatologia de Barcelona!Hospital Sant Joan de Déu i Hospital Clínic, Universitat de Barcelona!


Secuencia de deterioro fetal

Enfermedad placentaria > impedancia

Hipoxia Centralización

Hipoxia avanzada Acidosis

Injuria severa Muerte fetal

Marcadores crónicos Marcadores agudos

IP AUt >p95

ICP<p5

IP AU>p95

IP ACM<p5 IP IAo >p95

DV >p95

cCTG <3ms

PBF <4

CTG dips

DV DRv

AU DAu AU DRv


www.fetalmedicinebarcelona.org/Savchev 2013

IPUA=p80

Cerebroplacental ratio is more sensitive than UA or MCA alone

CPR <p5

IPMCA=p20

=+

deliver when risks are:

www.fetalmedicinebarcelona.org/

IVIIIIIIStage fetal deterioration

HIGHMILDMINIMALRisks of prematurity


<26 26-28 >28

Baschat'2003Hecher'2003'Grivell'2010Cruz6Lemini'2012

DVa'(rev)

Yes No

cCTG%STV<3*ms

Pathological'CGT

BPPIUFD 23% in BPP=6 and 11% in BPP=8

Poor correlation with DVa(rev)Cochrane: poor contribution to prediction

Baschat'2007,'Kafur'2008,'Lalor'2010,'Crispi'2009



Fetal I+D Protocol early-onset IUGR Sequence Doppler (and CTG) changes

CPR<p5

Ut A >p95

MCA<p5

DV (a rev)

CGT decelerations of reduced short-term

variability

REDV DV >p95 UVpuls

I Doppler normal but EFW<p3

II Increased resistance Initial redistribution

III Severely increased resistance and/or redistribution

IV Severe hemodynamic alteration

V High risk of death

AEDV AoI >p95







IP AUt >p95

ICP<p5

IP AU>p95


DV >p95

cCTG <3ms

PBF <4

CTG dips

DV DRv

AU DAu AU DRv



IPUA=p80


CPR <p5

IPMCA=p20

=+






<26 26-28 >28


DVa'(rev)

Yes No

cCTG%STV<3*ms

Pathological'CGT







CPR<p5

Ut A >p95

MCA<p5

DV (a rev)


variability

REDV DV >p95 UVpuls






AEDV AoI >p95







IP AUt >p95

ICP<p5

IP AU>p95


DV >p95

cCTG <3ms

PBF <4

CTG dips

DV DRv

AU DAu AU DRv



IPUA=p80


CPR <p5

IPMCA=p20

=+






<26 26-28 >28


DVa'(rev)

Yes No

cCTG%STV<3*ms

Pathological'CGT







CPR<p5

Ut A >p95

MCA<p5

DV (a rev)


variability

REDV DV >p95 UVpuls






AEDV AoI >p95


LEVE ALTOMEDIO

RIESGO DE PREMATURIDAD

Prematuridad Intra-utero

Prematuridad

Intra-utero

•Mortalidad •Daño neurologico •Madurez fetal •Ingreso a UCIN




!Eduard Gratacos!




RCIU

mortalidad

daño neurologico

madurez fetal

ingreso UCI-NPrematuridad

daño por insuficiencia placentaria

Edad gestacional




!Eduard Gratacos!




RCIU

*TRUFFLE 2013

Edad gestacional26ss 28ss

2% por cada dia

mortalidad

>90% <10%*20 - 40%*

Bashat 2007

30%*superviviencia intacta >50%

Bashat 2007

mortality was determined by gestational age at delivery,birth weight, low 5-minute Apgar score, cord artery pHless than 7.20, and ductus venosus velocity, forward orabsent/reversed (P!.001, r2"0.42). Intact survival todischarge was determined by gestational age at delivery,birth weight, low 5-minute Apgar score, umbilical arteryabsent or reversed end-diastolic umbilical artery flow

velocity, and ductus venosus velocity, forward or ab-sent/reversed (all P!.001, r2"0.41).

Thresholds for the impact of gestational age weredifferent for neonatal mortality and neonatal morbid-ity. In the logistic regression analysis, gestational agewas the most significant determinant of neonatalsurvival until 266/7 weeks and a significant contributor

Fig. 1. Neonatal survival and in-tact survival rates per gestationalweek. This figure shows the in-crease in survival (black dia-monds) and intact survival ratesuntil discharge (black bars) ingrowth-restricted neonates withadvancing gestational week.Baschat. Neonatal Outcome inFetal Growth Restriction. ObstetGynecol 2007.

Table 2. Doppler and Outcome Individual Characteristics by Gestational WeekGestational Week

P24 25 26 27 28 29 30 31 32

Infants delivered (n) 16 21 40 78 78 93 109 93 76Umbilical artery EDV

Positive 6 (37.5) 6 (28.6) 5 (12.5) 14 (17.9) 27 (34.6) 38 (40.9) 45 (41.3) 45 (48.4) 56 (73.7)Absent 4 (25) 9 (42.9) 10 (25) 12 (15.4) 22 (28.2) 25 (26.9) 34 (31.2) 10 (10.8) 7 (9.2) !.001Reversed 6 (37.5) 6 (28.6) 25 (62.5) 52 (66.7) 29 (37.2) 30 (32.3) 30 (26.5) 38 (40.9) 13 (17.1)

Brain sparing 11 (68.8) 16 (76.2) 33 (82.5) 61 (78.2) 56 (71.8) 62 (66.7) 80 (72.4) 64 (68.8) 41 (54.0) .039Elevated DV index 11 (68.8) 8 (38.1) 27 (67.5) 52 (66.7) 37 (47.4) 42 (45.2) 42 (38.5) 45 (48.4) 19 (25) !.001DV-RAV 0 (0) 5 (23.8) 12 (30) 32 (41) 19 (24.4) 18 (19.4) 13 (11.9) 20 (21.5) 9 (11.8) !.001Cord pH less than 7.20 5 (31.3) 9 (42.9) 17 (42.5) 37 (47.4) 31 (39.7) 39 (41.9) 36 (33.0) 28 (30.1) 21 (27.6) .146pH less than 7.00 and/orBE less than –12 1 (6.3) 4 (19.0) 0 (0) 11 (14.1) 1 (1.3) 3 (3.2) 5 (4.6) 1 (1.1) 4 (5.3) .063*5-minute Apgar less than 7 8 (50) 8 (38.1) 13 (32.5) 30 (38.5) 27 (34.6) 31 (33.3) 25 (22.9) 19 (20.4) 8 (10.5) !.001*BPD 4 (28.6) 9 (42.9) 19 (47.5) 37 (47.4) 20 (25.6) 25 (26.9) 13 (11.9) 11 (11.8) 2 (2.6) !.001*Grade III/IV IVH 9 (57.1) 6 (28.6) 9 (22.2) 21 (26.9) 14 (18) 12 (12.9) 11 (10.1) 9 (9.7) 1 (1.3) !.001*NEC 2 (14.3) 1 (4.8) 6 (15) 17 (21.8) 13 (16.7) 13 (14) 11 (10.1) 7 (7.5) 5 (6.6) .085*Early NND 8 (50.0) 9 (42.9) 8 (20) 10 (12.8) 3 (3.8) 0 (0) 5 (4.6) 1 (1.1) 0 (0) !.001*Late NND 4 (25) 3 (14.3) 8 (20) 15 (19.2) 14 (18) 13 (14) 12 (11.0) 7 (7.5) 1 (1.3) !.001*Infant death 2 (12.5) 0 (0) 1 (2.5) 2 (2.6) 1 (1.3) 1 (1.1) 1 (1) 0 (0) 1 (1.3) .107*

EDV, end-diastolic velocity; DV, ductus venosus; DV-RAV, ductus venosus absence or reversal of atrial velocities; BE, base excess; BPD,bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NND, neonatal death.

Data are presented as n (%).* Indicates analysis by Fisher exact test; all other analyses by !2 test. P indicates overall distribution of all degrees of abnormality.

VOL. 109, NO. 2, PART 1, FEBRUARY 2007 Baschat et al Neonatal Outcome in Fetal Growth Restriction 257

analysis, neither center of origin nor country of origininfluenced the relationship between gestational age,birth weight, and Doppler parameters and neonatalmorbidity (Nagelkerke r2!0.05, P!.796), neonataldeath (Nagelkerke r2!0.09, P!.534) and intact sur-vival (Nagelkerke r2!0.06, P!.206).

DISCUSSIONFetal growth restriction is a prominent contributor toperinatal mortality and morbidities extending all theway into adulthood.1–3,17 In otherwise normal fetuses,the adverse sequelae of growth-restricted follow the

interactions of deteriorating fetal status, poor transi-tion to extrauterine life, and prematurity.3,4,8,11,12,18

The at-risk growth-restricted fetus is now reliablyidentified by high resolution ultrasound evaluation ofanatomy and size, combined with Doppler ultra-sonography for umbilical artery flow dynamics.10

Fetal cardiovascular responses to placental dysfunc-tion and risks of deterioration are further assessedwith arterial and precordial venous Doppler.4,5,11,12,19

Using these ultrasound tools, we can precisely depictthe fetal effects of placental failure. But because thereis no effective therapy for the failing placenta, we are

Fig. 2. Neonatal mortality andintact survival related to the duc-tus venosus a-wave. The figuresshow neonatal mortality rates forfetuses with forward flow duringatrial systole in the ductus veno-sus (open triangles indicate for-ward flow in atrial systole) andthose with absent, or reversedflow (solid triangles indicate ab-sent or reversed flow in atrial sys-tole). A. Intact survival. B. Neona-tal mortality. Significant !2

comparisons for fetuses with pos-itive and absent or reversed duc-tus venosus a-wave within eachgestational week are indicated.* P".05; ** P".005.Baschat. Neonatal Outcome inFetal Growth Restriction. ObstetGynecol 2007.

VOL. 109, NO. 2, PART 1, FEBRUARY 2007 Baschat et al Neonatal Outcome in Fetal Growth Restriction 259


<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT





mortalidad

DV : ausente o reverso: buena correlación con academia mortalidad perinatal : 40 -100%

Hecher 1995-2003 Schwarze 2005


<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT




variabilidad a corto plazo STV <3ms

marcador agudo de muerte fetalHecher 2001




!Eduard Gratacos!




RCIU

*TRUFFLE 2013


2% por cada dia

mortalidad

>90% <10%*20 - 40%*

Bashat 2007

30%*superviviencia intacta >50%

Solo indicación materna


<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT





<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT




DV ar STV<3ms




!Eduard Gratacos!




RCIU

mortalidad

daño neurologico

madurez fetal



Edad gestacional


<29 29-32 >32.0

Fouron'2004Del'Rio'2008Cruz6MarQnez'2012

0

15

30

45

60

(%)

ControlsIUGR antegrade AoIIUGR retrograde AoI

ControlsIUGR DV<5 z-scoreIUGR DV>5 z-score

**

Brain US anomalies in 30w IUGR




!Eduard Gratacos!




RCIU


>90% <10%*30 - 40%*

daño neurologico

AUdr después de las 30s los riesgos de obito superan a los de la prematuridad

Fouron’2004

Del'Rio'2008

Cruz Martinez'2012




!Eduard Gratacos!




RCIU


>90% <10%*30 - 40%

daño neurologico


<29 29-32 >32.0


0

15

30

45

60

(%)



**





!Eduard Gratacos!




RCIU

mortalidad

daño neurologico

madurez fetal



Edad gestacional




!Eduard Gratacos!




RCIU

Sotiriadis - Bashat ACOG junio 2015


corticoterapia

madurez fetal

el neurodesarrollo mejora con la administración de corticoides

Fig. 2. Relative risks (RRs) for the neurodevelopmental outcomes (any steroid compared with no treatment). Ev/Trt, event/treatment; Ev/Ctrl, event/control; CI, confidence interval.Sotiriadis. Antenatal Steroids and Neurodevelopment. Obstet Gynecol 2015.

VOL. 125, NO. 6, JUNE 2015 Sotiriadis et al Antenatal Steroids and Neurodevelopment 1391

Copyright ª by The American College of Obstetriciansand Gynecologists. Published by Wolters Kluwer Health, Inc.

Unauthorized reproduction of this article is prohibited.

Fig. 2. Relative risks (RRs) for the neurodevelopmental outcomes (any steroid compared with no treatment). Ev/Trt, event/treatment; Ev/Ctrl, event/control; CI, confidence interval.Sotiriadis. Antenatal Steroids and Neurodevelopment. Obstet Gynecol 2015.

VOL. 125, NO. 6, JUNE 2015 Sotiriadis et al Antenatal Steroids and Neurodevelopment 1391

Copyright ª by The American College of Obstetriciansand Gynecologists. Published by Wolters Kluwer Health, Inc.

Unauthorized reproduction of this article is prohibited.

Paralisis Cerebral Disfuncion severa

AU diastole ausente

precede el deterioro fetal en 1 semana

Ferrazi 2002





Doppler sequence in IUGR Ferrazzi et al.

142 Ultrasound in Obstetrics and Gynecology

are reported. Continuous variables were tested for normality(Shapiro-Wilks test) and then analyzed with Student’s t-test.Categorical variables were analyzed with Fisher’s exact test.P < 0.05 was considered significant. The duration of inten-sive fetal monitoring from admission in the fetal intensivecare unit to delivery was expressed as number of days priorto delivery. In each patient, we calculated the number of daysprior to delivery when a persistently abnormal velocimetricmeasurement (i.e. for two consecutive examinations) wasidentified for the first time.

Longitudinal cumulative onset time curves were calculatedfor each Doppler measurement to describe the proportionof cases with abnormal Doppler measurements during theobservation time. To allow for a statistical analysis, umbilicalchanges from absent to reverse end-diastolic flow (AEDF toREDF) and ductus venosus changes from abnormal wave-form (DV S/a) to reverse a-wave (DV RF) were consideredindependently, as two different marks of adaptation of pro-gressive severity. Linear regression analysis was used toapproximate this biological phenomenon described by thelongitudinal cumulative curves. The α-coefficient and theintercept value were calculated and anova and Student’st-test were carried out to test the differences between the dif-ferent curves. Univariate logistic regression was used to iden-tify which one of the independent variables (fetal weight,gestational age at birth or Doppler changes) was a significantpredictor of the dependent variable (perinatal outcome).Additionally, in a subset of nine cases that entered the studywith Doppler abnormalities in the UA and middle cerebralartery (MCA) (‘early’ changes), the average incidence rate ofsubsequent abnormal Doppler findings in other vessels wasestimated by the Kaplan-Meier approach (Software from StataCorp. 1999, College Station, TX, USA).

RESULTS

Seventy-five singleton pregnancies with a diagnosis of IUGRand abnormal umbilical Doppler velocimetry were admittedto the Department of Maternal–Fetal Medicine of DMCOSan Paolo between 1 January 1996 and 31 May 1999. Of these,26 IUGR fetuses met the study inclusion criteria and com-pleted the longitudinal study from admission until delivery.

Figure 1 depicts longitudinal cumulative onset time curvesof Doppler abnormalities calculated for each vessel. Theseobservations show that abnormalities in Doppler indices ofdifferent vessels occur in a time-dependent fashion. Basedupon the days from delivery (i.e. days from a non-reactiveFHR tracing), the Doppler abnormalities can be categorizedinto ‘early’ stage and ‘late’ stage changes. In addition to theentry criteria of an abnormal Doppler index in the UA anduterine artery, which by the inclusion criteria were necessar-ily the first Doppler changes noted, the subsequent earliestsequential Doppler abnormalities identified were the abnor-mal MCA PI and then the UA AEDF. These were categorizedas early stage Doppler abnormalities. Fifty percent of fetusesshowed early stage changes by –16 and –15 days from deliv-ery. Following the early stage changes, subsequent temporalDoppler changes appeared and included (in order of appear-ance) increased DV S/a ratio, UA reverse flow (RF), decreased

pulmonary artery PV, DV RF and, lastly, decreased aorticPV. Since these indices began to appear by –6 days fromdelivery and well after the early changes, they were categor-ized as late stage changes. The first late stage circulatorychange to occur was an abnormal ductus venosus S/a ratio.Thirty-five percent of fetuses had this abnormality by –5days. The last velocimetric abnormalities were abnormal pul-monary artery peak velocity (PV), ductus venosus RF andabnormal peak velocities in the outflow-tract of the aorta.Fifty percent of fetuses showed these changes from –4 and–3 days. We did not find significant differences in the preva-lence of cases with an amniotic fluid index < 5 cm at the timeof admission (4/11 and 10/15) and at the time of delivery (5/11 and 11/15), respectively, in fetuses with early and latechanges.

To further confirm the temporal sequence of Dopplervelocimetric changes, the ratio between the α-coefficient andintercept of each cumulative curve was calculated (Table 2).In order to estimate the risk of occurrence of any of the latevascular changes, we identified a subset of nine fetuses thatentered our study with evidence of only abnormal earlychanges (abnormal MCA PI and UA AEDF). The Kaplan-Meier incidence estimates and the incidence rates of each late

0

10

20

30

40

50

60

70

80

90

100

–16 –14 –12 –10 –8 –6 –4 –2 0

Days prior to delivery

Abno

rmal

Dopp

ler fi

ndin

gs (%

)

262521191411975Observed fetuses (n)

Figure 1 Cumulative onset time curves of Doppler abnormalities for each fetal vessel examined. Time ‘0’ refers to the date of delivery. !, MCA PI; ", UA AEDF; #, DV S/a; $, UA RF; , PA PV; %, DV RF;

, AO PV. Abbreviations are given in Table 1.

Table 2 Statistical analysis between α-coefficient/ intercept ratios of cumulative curves

t d.f. P*

MCA — UA AEDF 18 24 < 0.0001UA AEDF — DV S/a 12 24 < 0.0001DV S/a — PA 5.3 24 < 0.0001PA — UA RF 2.2 24 < 0.03UA RF — DV RF 1.0 24 NSDV RF — AO 0.04 24 NS

*Student’s t-test. d.f., degrees of freedom. Abbreviations are given in Table 1.


<29 29-32 >32.0


0

15

30

45

60

(%)



**



<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT




precede en 1 semana a la alteracion del DV

Cruz-Martinez 2011 Figueras 2009




!Eduard Gratacos!




RCIU


corticoterapia

madurez fetal






<29 29-32 >32.0


0

15

30

45

60

(%)



**





!Eduard Gratacos!




RCIU

mortalidad

daño neurologico

madurez fetal



Edad gestacional




!Eduard Gratacos!




RCIU

DIGITAT 2011

Edad gestacional34ss 37-38ss

Ingreso UCI-N

ausencia de descompensacion fetal

www.medicinafetalbarcelona.org/docencia

650 SGA >37 weeks

Induction

GA at delivery 38w

(96% indution)

Fetal distress

18%

Acidosis

12%

NICU admission

3%

Expectantmanagement

GA at delivery 39.4w

(50% induction)

Fetal distress

20%

Acidosis

13%

NICU admission

4%

Induction versus expectant monitoring for intrauterine growth restriction at term:randomised equivalence trial (DIGITAT). BMJ 2011




!Eduard Gratacos!




RCIU

(NEURO)DEVELOMENTAL DIGITAT 2011


Ingreso UCI-N

ausencia de descompensacion fetal


292 24-months SGA >37 weeks

Induction

GA at delivery 38w

Abnormal

neurodevelopment*

25%

Abnormal

neurobehavior

14%

Expectantmanagement

GA at delivery 39.4w

Abnormal

neurodevelopment

29%

Abnormal

neurobehavior

11%

Effects on (neuro)developmental and behavioral outcome at 2 years of age of inducedlabor compared with expectant management in intrauterine growth-restricted infants:long-term outcomes of the DIGITAT trial. AJOG 2012

SevereIUGR

AdmissionNeonatal

Unit




!Eduard Gratacos!




RCIU


Ingreso UCI-N

ausencia de descompensacion fetal Termino electivo


Late-onsetIUGR

c

Late-onset IUGR: follow-up

Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA

* (UtA)1st visit +UA+MCA** (UtA) 1st visit +UA+MCA+DV


Late-onsetIUGR

c


Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA



Late-onsetIUGR

c


Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA





!Eduard Gratacos!




RCIU

Edad gestacional

34ss 37ss

Manejo basado en estadios


Late-onsetIUGR

c


Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA



Late-onsetIUGR

c


Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA



Late-onsetIUGR

c


Doppler* /2 weeks

Doppler* /1 week

Doppler* /1 week

Doppler** /3-4d

ConstitutionalSGA


30ss26ss 28ss


<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT





<26 26-28 >28


DVa'(rev)

Yes No

cCTG6STV<3'ms

Pathological'CGT





<29 29-32 >32.0


0

15

30

45

60

(%)



**







<29 29-32 >32.0


0

15

30

45

60

(%)



**

Brain US anomalies in 30w IUGRmarcadores agudos: muerte fetal / daño neurológico diagnostico

Alta sospecha acidemia baja sospecha acidemia Insf. placentaria sev. Inf. plac. leve

Parto por cesarea induccion

diario 1-2 dias 2v semanal semanal

IIIIIIIV


HNDAC




!Eduard Gratacos!




RCIU: consecuencias en la programación fetal


HNDAC




!Eduard Gratacos!




Reorganizacion cerebral

Remodelacion cardiovascular


HNDAC

Remodelacion cardiovascular1986 Barker (MRC Unit, Southampton, UK):!Coronary heart disease mortality rates


HNDAC

Redistribuir FlujoRCIU

cambios adaptativos cambios epigeneticos

Programacion cardiaca

alteracion doppler


HNDAC

RCIU

postnatal persistance of cardiovascular

remodeling

Barker&BMJ&1986,&Barker&BMJ&1995&,&Hecher&Circula6on&1995,&Crispi&AJOG&2008,&Crispi&Circula6on&2010,&Cruz&FDT&2011,&Crispi&AJOG&2012&

fetal cardiac dysfunction

cardiovascular disease in adulthood

INTRAUTERINE GROWTH

RESTRICTION hypertension coronary disease!

stroke!obesity!

diabetes

FETAL CARDIOVASCULAR PROGRAMMING

disfuncion cardiaca

remodelacion cardiaca

persiste infancia

Enfermedad cardiaca en el adulto

HTA enfermedad coronaria

obesidad ACV

diabetes


HNDAC

RCIU

Skilton&Lancet&2007,&Crispi&Circula6on&2010,&Crispi&AJOG&2012

Cardiovascular,remodeling

control IUGR

TA)90/65

cIMT = 0.386 mm

TA)115/80

cIMT = 0.434 mm

postnatal cardiovascular remodelling

globular)heart!↓longitudinal)mo;on!

↓stroke)volume!↑heart)rate!

=)cardiac)output

hypertension!preCarteriosclerosis

IMPACT,OF,LATE,IUGR/SGA

near)term)SGA)fetuses)without)signs)of)poor)

prognosis)also)presented)CV)remodeling)



control IUGR

TA)90/65

cIMT = 0.386 mm

TA)115/80

cIMT = 0.434 mm




=)cardiac)output





control ART

ValenzuelaIAlcaraz&Circula6on&2013&

decreased)systolic)mo;on impaired)relaxa;on

8

7

6

4

3

0

Rig

ht lo

ngitu

dina

l sys

tolic

mot

ion!

Ann

ular

pea

k ve

loci

ty (S

’, cm

/s)!

Dis

plac

emen

t (TA

PS

E, m

m)

*

5

1

2

right S’

*

TAPSE

80

70

60

40

30

0

Dia

stol

ic fu

nctio

n!Le

ft is

olum

etric

rela

xatio

n tim

e (IR

T, m

s)!

Rig

ht E

del

ecel

erat

ion

time

(Ede

c, m

s)

*

50

10

20

E dec

*

IRT

Data)are)median+SEM.)*P<0.05)adjusted)by)GA,)birthweight)cen;le)and)preeclampsia)

CONTROL ART

Remodelacion Cardiovascular Posnatal

Control corazon globular hipertrofia

menor movimiento menor volumen eyección

incremento FC

control ART

ValenzuelaIAlcaraz&Circula6on&2013&

decreased)systolic)mo;on impaired)relaxa;on

8

7

6

4

3

0

Righ

t lon

gitu

dina

l sys

tolic

mot

ion!

Annu

lar pe

ak ve

locity

(S’, c

m/s)!

Disp

lacem

ent (T

APSE

, mm)

*

5

1

2

right S’

*

TAPSE

80

70

60

40

30

0

Dias

tolic

func

tion!

Left i

solum

etric

relax

ation

time (

IRT,

ms)!

Righ

t E de

lecele

ration

time (

Edec

, ms)

*

50

10

20

E dec

*

IRT

Data)are)median+SEM.)*P<0.05)adjusted)by)GA,)birthweight)cen;le)and)preeclampsia)

CONTROL ART



control IUGR

TA)90/65

cIMT = 0.386 mm

TA)115/80

cIMT = 0.434 mm




=)cardiac)output







control IUGR

TA)90/65

cIMT = 0.386 mm

TA)115/80

cIMT = 0.434 mm




=)cardiac)output





Hipertension pre-ateroesclerosis


HNDAC

RCIU


remodeling




INTRAUTERINE GROWTH


stroke!obesity!

diabetes


Predecir?????

Prediccion Prevencion

Personalizada Participatoria

4P medicina


HNDAC

RCIUpostnatal persistance

of cardiovascular remodeling




INTRAUTERINE GROWTH


stroke!obesity!

diabetes


Predecir?????

Score Cardiovascular

Cruz-Lemini 2014


HNDAC

A fetal cardiovascular score to predict infant hypertension and arterial remodeling in intrauterine growth restriction

Cruz-Lemini, Crispi, Gratacos AJOG 2014

P < .001) demonstrated the strongestassociations.

To assess the potential interactionamong the different parameters, a

multivariate analysis was performed thatincluded TAPSE (the parameter thatshowed the strongest association withhypertension and arterial remodeling in

the univariate analysis) with other sig-nificant predictors of risk (Appendix;Supplemental Material). Most parame-ters continued to show independentpredictive values for the combined car-diovascular endpoint; cerebroplacentalratio (OR, 2.2; 95% CI, 1.5e3.1; P <.001), right sphericity index (OR, 2.8;95% CI, 1.4e10.9; P < .015), andIVRT (OR, 2.2; 95% CI, 1.4e3.5; P <.001) had the highest ORs. Finally, acomposite score that was based on thebest perinatal and fetal echocardio-graphic predictors was generated by thecombination of these variables in aregression analysis. This fetal cardiovas-cular score was comprised of TAPSE (z-score), cerebroplacental ratio (z-score),right sphericity index (crude value), andIVRT (z-score) (Figure 2) and yieldedthe following equation:

1:907 þ ðTAPSE # $0:589Þþ ðcerebroplacental ratio # $ 0:286Þþ ðright sphericity index # $1:938Þþ ðIVRT # 0:342Þ & 0:1253:

The equation resulted in 90% sensi-tivity, 77% specificity, 63% positivepredictive value, 95% negative predictivevalue, 3.9 positive likelihood ratio, and0.1 negative likelihood ratio to detectthose IUGR cases with infant hyperten-sion and arterial remodeling. Receiveroperating characteristic curve compari-son was performed to estimate area un-der the curve for isolated and combinedparameters with the highest ORs. Theaverage area under the curve for the fetalcardiovascular score was 0.87 (95% CI,0.79e0.93; P < .001), higher than fetal

TABLE 4Univariate analysis for the association between perinatal and fetal echocardiographic parameters withhypertension and arterial remodeling in IUGR infants (n [ 100) (continued)Variable Odds ratio 95% confidence interval P value

Tricuspid early-diastole peak velocity (z-score) 1.2 1.0e1.5 .096

Mitral lateral E wave/early-diastole peak velocity (z-score) 1.1 0.8e1.4 .642

Tricuspid E wave/early-diastole peak velocity (z-score) 0.8 0.6e1.0 .036

Isovolumic relaxation time (z-score) 2.4 1.4e3.9 < .001

Hypertension and arterial remodeling were defined as mean blood pressure at >95th percentile and aortic intima media at >75th percentile at 6 months of age (31%).

Cruz-Lemini. Fetal echocardiography to predict postnatal hypertension in IUGR. Am J Obstet Gynecol 2014.

FIGURE 1Univariate analysis for the association between perinatal and fetalechocardiographic parameters with hypertension and arterialremodeling in IUGR infants

Hypertension and arterial remodeling were defined as mean blood pressure of>95th percentile andaortic intima media of >75th percentile at 6 months of age. Fetal parameters included as z-scoreswhen available (Table 4). Odds ratio and 95% confidence intervals are shown.E/A, early/late transvalvular velocities; IVRT, isovolumic relaxation time; MAPSE, mitral annular plane systolic excursion; PI, pulsatilityindex; S’, systolic peak velocity; TAPSE, tricuspid annular plane systolic excursion.


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HNDAC

A fetal cardiovascular score to predict infant hypertension and arterial remodeling in intrauterine growth restriction

Cruz-Lemini, Crispi, Gratacos AJOG 2014

TAPSE alone (area under the curve,0.64; 95% CI, 0.56e0.73; P ¼ .030),fetal EF (area under the curve, 0.57;95% CI, 0.48e0.65; P ¼ .072), andperinatal factors (Figure 3).

COMMENT

This study shows that a fetal cardiovas-cular score is associated strongly with thepresence of postnatal hypertension andarterial remodeling at 6 months of agein IUGR infants. Echocardiographicparameters demonstrated a far betterperformance than perinatal factors andfetoplacental Doppler scans that wereused for establishing the severity of theIUGR.

Echocardiographic measurements infetuses were consistent with previousstudies that demonstrated significantdifferences in cardiac function underIUGR.1-3,5,11,12,32,37-40 Likewise, in-creased blood pressure and aIMT pre-viously had been reported in IUGRneonates and children.3,32,38,40-42 Thepresent study expands previous findings.Longitudinal follow-up evaluations dem-onstrated the relationship between pre-natal echocardiography and postnatalcardiovascular findings.

As expected, gestational age andbirthweight percentile showed no associ-ationwith the occurrence of hypertensionand arterial remodeling in childhood.Likewise, fetoplacental Doppler parame-ters that were used in fetal treatmentbecause of their associationwith perinataloutcome had only aweak associationwithpostnatal cardiovascular outcome. Theabsence of a direct relationship betweenthese factors, which are accepted severitycriteria and bear a strong association withperinatal and neurological outcome,43-45

suggests that cardiovascular program-ming may require the presence of pre-disposing factors. In line with thisnotion, fetal echocardiographic parame-ters showed a strong association withhypertension and arterial remodeling,which might indicate that, irrespective ofconventional perinatal criteria, there is afraction of subjects who display morepronounced adaptive cardiovascularchanges under IUGR and in whom thesechanges persist postnatally. The cardio-vascular score developed in this study

could identify this high-risk subgroupwith a sensitivity of 90%. We acknowl-edge that most of our population repre-sented late-onset IUGR infants who weredelivered near term; thus, our resultsmight not be generalized to early-onsetIUGR. However, because prematurityand prolonged neonatal intensive careunit stay are considered cardiovascularrisk factors by themselves,6 early IUGRwould be considered a high-risk sub-group by itself.Our proposed score logically com-

bines information for cardiovascularremodeling, namely the severity of theIUGR (cerebroplacental ratio), cardiacmorphologic condition (sphericity in-dex), systolic function (TAPSE), anddiastolic function (IVRT). All indicescomprised by the score can be obtainedwith any obstetric ultrasound device thatis equipped with M-mode, conventional

pulsed, and color Doppler and arereproducible in fetuses.16,27,28 TAPSEhas been used in fetuses to describecardiovascular dysfunction in IUGR,which reflects subclinical longitudinaldysfunction of the right ventricle.5

Postnatally, TAPSE has been reportedas a good predictor for death in Eisen-menger’s syndrome or to monitor post-operative function in resynchronizationtherapy.33,46 Changes in sphericity indexhad been described previously in IUGRchildren by our group3,11 and showsmore globular hearts probably becauseof cavity dilation because of hypoxia.In this study, we first report thatthese changes are already present inutero. IVRT is a known parameter forthe evaluation of diastolic dysfunctionbecause of poor myocardial relaxationand is used commonly in fetalechocardiography.24,28,35

FIGURE 2Components of the fetal cardiovascular score for the prediction ofhypertension and arterial remodeling

IVRT, isovolumic relaxation time; TAPSE, tricuspid annular-plane systolic excursion.


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MONTH 2014 American Journal of Obstetrics & Gynecology 1.e9


COMMENT















COMMENT















COMMENT














indice esfericidad ICP TAPSE TRI


HNDAC

A fetal cardiovascular score to predict infant hypertension and arterial remodeling in intrauterine growth restriction Cruz-Lemini, Crispi, Gratacos

AJOG 2014

Overall, our results show that fetalechocardiography can predict mid-termcardiovascular risk factors and supportthe concept of the inclusion of theselected IUGR population as a high-riskgroup for early screening in cardiovascu-lar guidelines.3 From a clinical perspec-tive, this study opens a line that may findnew applications for echocardiographyin fetal life. Considering that the diagnosisof IUGR is established in approximately5-10% of pregnancies, the findings ofthis study would affect thousands ofchildren per year who, at this moment,are not screened for hypertension at6 months. The parameters included inthe cardiovascular score are simple andeasy to measure, can be performed withconventional ultrasound equipment, andprovide information that would supporta request of a cardiovascular evaluationat 6 months of age in those children whoare classified as high-risk. In addition,recent prospective validation with long-term follow-up evaluation is required toconfirm the value of predictive scores thatare based on fetal echocardiography witha clear clinical application. If these ex-pectations are confirmed, the prediction

of hypertension and arterial remodelingfrom perinatal life would represent apublic health opportunity for interven-tion. It is recognized that mild cardio-vascular changes that remain subclinicalduring childhood may represent signifi-cant health issues if combined withadditional behaviors or stressors duringadulthood.47 Hypertension in the childhas been associated with substantial long-term health risks and are considered anindication for lifestyle modifications.6 Inaddition, aIMT measurement allows thedetection of increased cardiovascularrisk as an indicator of arterial remodelingin children.31,32,38 Interventions in thistarget group could include blood pressuremonitoring before 3 years of age, rec-ommendation of lack of exposure toother risk factors (secondary smoking,obesity), surveillance of catch-up growthor administration of hypotensors,7,9 andthe promotion of exercise and physicalactivity. Particularly, high intake of di-etary long-chain u-3 fatty acids is asso-ciated with lower blood pressure andmayprevent progression of subclinical ath-erosclerosis in childrenwho are bornwithlow birthweight.48 A recent randomized

trial in a large cohort of children suggeststhat the inverse association of fetal growthwith arterial wall thickness in childhoodcan be prevented by dietary u-3 fatty acidsupplementation over the first 5 years oflife.49

Among the strengths of this study wasthe longitudinal workup of structuraland functional echocardiographic find-ings from fetal life to infancy. Thisallowed us to examine prospectively theeffects of impaired fetal growth, whilecontrolling for postnatal confounders asmuch as possible. We acknowledge that,by including only cases with confirmedIUGR, external validity may be reduced,because our population does not includeall the spectrum of cases (prenatallysuspected IUGR). However, it is alsocertain that including nonconfirmedIUGR would affect internal validity, thatis, ascertaining the true relationshipbetween IUGR and our cardiovascularoutcome. Additionally, no adjustmentwas made for multiple comparisons ofechocardiographic parameters. Exami-nation at 6 months of age was chosenbecause it is a reasonable point in time toavoid the effects of neonatal cardiovas-cular transition to postnatal life andpotential interference with temporaryblood pressure changes. Although weacknowledge that longer term evaluationwould provide more robust data on thelong-term prediction value, this wouldentail the need for correction of poten-tial confounders that are associatedwith diet, exercise, or socioeconomicfactors. In addition, there is strong evi-dence on the longer term effects ofIUGR in children and adolescents.7,38,48

Notwithstanding these comments, weacknowledge that longer term follow-upevaluation is necessary to validate theclinical value of echocardiographic scoresto predict hypertension and other car-diovascular outcomes in childhood.Likewise, we acknowledge that there isno standard definition for increasedcardiovascular risk at 6 months of ageand that an ideal outcome for this typeof study would be information of car-diovascular disease or clinical events atadult age, such as myocardial infarction,heart failure, or death. Therefore, furtherlong-term follow-up evaluation of an

FIGURE 3Receiver operating characteristic curves illustrating the predictive valueof fetal CV score

Compared with A, tricuspid annular-plane systolic excursion (TAPSE ) and ejection fraction (EF ) andB, perinatal factors (gestational age [GA] at delivery, birthweight (BW ) percentile and umbilical arterypulsatility index [PI ]) for hypertension and arterial remodeling at 6 months of age.AUC, area under the curve; CPR, cerebroplacental ratio; CV, cardiovascular; IVRT, isovolumic relaxation time; RSI, right sphericity index.


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HNDAC

RCIU


remodeling




INTRAUTERINE GROWTH


stroke!obesity!

diabetes


S:90 - E: 85%

Score Cardiovascular

Remodelamiento vascular

Intervención

Estilo de vida Dieta: omega 3

ejercicio hipotensores

Williams 2009 Kavey 2006

Skilton 2012-2013


HNDAC




!Eduard Gratacos!





Remodelacion cardiovascular


HNDAC




!Eduard Gratacos!






Fetal&programming&

Brain&reorganiza0on&(+/4&injury)

exposure


Fetal&programming&

Brain&reorganiza0on&(+/4&injury)

exposure

Injuria


HNDAC




!Eduard Gratacos!





Normalacousticsignature

WMDacousticsignature

Normal WMD

WM

D S

core

Ultrasound texture analysis (feature extraction + machine

learning)

J Ultrasound Med 2011Fetal Diagn Ther 2012Am J Obstet Gynecol 2012

Normalacousticsignature

WMDacousticsignature

Normal WMD

WM

D S

core

Ultrasound texture analysis (feature extraction + machine

learning)

J Ultrasound Med 2011Fetal Diagn Ther 2012Am J Obstet Gynecol 2012

Cual es normal?


HNDAC




!Eduard Gratacos!




NEW THERAPIES

NEW IMAGING BIOMARKERS

IMPROVING NEURODEVELOPMENTAL DISORDERS OF FETAL ORIGIN

NOVEL RESEARCH LINES

IMPROVING DETECTION NEW THERAPIES




IMPROVING DETECTION

NEW THERAPIES




IMPROVING DETECTION

Mejorar Diagnostico

Nuevos Biomarcadores

nuevas terapias

Mejorando el estudio de los origenes fetales del neurodesarrollo


HNDAC




!Eduard Gratacos!




Microestructura

CONECTIVIDAD

Desarrollo cortical

Efectos de la desnutrición Fetal en el neurodesarrollo

MICROSTRUCTUREMETABOLISM

CONNECTIVITY

CORTICAL DEVELOPMENT


CONNECTIVITY



CONNECTIVITY



HNDAC

Microestructura

Analisis de Textura


CONNECTIVITY


TEXTURE ANALYSIS Sanz et al. Fet Diagn Ther 2013.

FETAL MRI

Texture analysis showed brain differences in SGA fetuses that increased in those that were VD

VD SGAs vs AGA SGAs vs AGA

LATE IUGR

TEXTURE ANALYSIS Sanz et al. Fet Diagn Ther 2013.

FETAL MRI

Texture analysis showed brain differences in SGA fetuses that increased in those that were VD

VD SGAs vs AGA SGAs vs AGA

LATE IUGR

J Ultrasound Med 2011

Fetal Diagn Ther 2012

Am J Obstet Gynecol 2012

Medicina Fetal Barcelona 2015


HNDAC




!Eduard Gratacos!




Infantes con RCIU muestran disminucion de la conectividad

Infants with IUGR show reduced connectivity

Background:-Children-with-aEenFonGdeficit-disorders-have-impaired-corFcoGstriatoGthalamic-connecFvity.--

Infants with IUGR show reduced connectivity

Background:-Children-with-aEenFonGdeficit-disorders-have-impaired-corFcoGstriatoGthalamic-connecFvity.--

normal RCIU

Medicina Fetal Barcelona 2012


HNDAC

Fetus Young OldChild Mature

IMPACT OF ENVIRONMENT

BIOLOGIC-PROGRAMMING-AND-AGE

OPPORTUNITY FOR CORRECTION


HNDAC

Gracias

Restriccion del crecimiento Fetal: Manejo basado en estadios

Health & Medicine

Transcript of Restriccion del crecimiento Fetal: Manejo basado en estadios