Active placental nutrient transport - hopkinsmedicine.org · lower perceptional performance motor disability poor cognition poor concentration deficient short-term memory poorer school

1 1

Neurodevelopment & placental dysfunction

Ahmet A. Baschat, MD Professor, Director of Maternal-Fetal

Medicine and Section of Fetal Therapy

University of Maryland School of Medicine

Important outcomes in FGR Hypoxemia

Stillbirth

Acidemia for the obstetrician

for parents A normal child

for the neonatologist

Prematurity

Neonatal death Morbidity

Nutrient partitioning in the fetus

Umbilical vein

PLACENTA

GLUCOSE

GLUCOSE

AMINO ACIDS

AMINO ACIDS

FATTY ACIDS

FATTY ACIDS

O2 O2 O2 O2 O2

O2 O2 O2 O2 O2 O2

O2 O2

Active placental nutrient transport

Fetal circulation

Fetal circulation – nutrient streaming

Ductus arteriosus

Ductus venosus

60-70%

Foramen ovale

UV

Glucose

Insulin / IGF axis Glycogen

Foramen ovale

aortic isthmus

Umbilical arteries

Ductus venosus

Natural disease progression:

The 3 phases of FGR

Preclinical : Venous redistribution & evolving growth delay

Clinical : Growth delay and arterial redistribution

Deterioration : fetal decompensation

2 2

Maternal compartment

Fetal compartment

ET - 1

ET - 1

ET - 1 ET - 1

ET - 1 TX A2

TX A2

TX A2

NO

NO NO

P-cyclin

P-cyclin

VENOUS REDISTRIBUTION

UV

Ductus venosus

↓ UV Volume flow maternal Diet behavioral State

Rigano et al., 2006, Haugen et al., 2006, Bellotti et al., 2008

Insulin / IGF axis Glycogen Liver size

maternal Compartment

fetal Compartment

notching

↑ PI

↑ PI

AEDV

REDV

Uterine artery

■  Abnormal Trophoblast Invasion: ◆  40-70% Pre-eclampsia ◆  15-30% fetal growth restriction (FGR)

Umbilical artery

■  abnormal villous tree ◆  40 – 100% FGR

30 %

50 %

70 %

■  Adverse Outcomes ◆  Hypoxemia / Acidemia ◆  Stillbirth ◆  Preterm birth ◆  neonatal complications ◆  poor neurodevelopment

Middle cerebral artery ■  Branch of the circle of Willis

◆  Use parietal bone window ◆  Parallel to wings of sphenoid ◆  Distal portion recommended ◆  Insonate at 0 degrees

■  Two parameters of importance ■  Increased peak systolic velocity (0º)

◆  Fetal anemia ◆  Increased paCO2

■  Decreased pulsatility index in ◆  Fetal hypoxemia ◆  Fetal hypertension ◆  indistinguishable by waveform.

Cerebroplacental Doppler ratio (CPR)

“centralization” =

middle cerebral artery Pulsatility

index

umbilical artery Pulsatility index

“ A cerebral-umbilical Doppler ratio below 1.08 can be considered as evidence of centralization of cardiac output towards the fetal brain. “

Gramellini et al., Obstet Gynecol, 1992; 79: 416-20.

Vessel Diameter 0º PW Doppler

AAO

MPA

RV. Output

LV. Output

MCA PI

Umbilical PI

Gramellini et al., Obstet Gynecol, 1992; 79: 416-20.

Bonnin et al., Circulation, 1993; 88: 216-22.

Al Ghazali et al., BJOG 1989; 96: 697-704.

Makikallio et al., UOG, 2002; 19: 147-52.

3 3

AFTERLOAD

LV FO

Isthmus

RV

PRELOAD

LV RV

ARTERIAL REDISTRIBUTION

Umbilical vein

Ductus venosus

■  Increased venous pressure ■  Ductus venosus dilatation ■  High placental afterload ■  Fetal Acidemia ■  Cardiac dysfunction

Baschat 2010

DV

cCTG

DV

BPP

“early changes”

“late changes”

Hecher et al., UOG 2001

>32. weeks A. umbilikalis

D. venosus

cCTG

MCA

AFI

UA

Ductus

MCA

<34

>34

<34

>34

<34

>34

<34

>34

-4

-2

0

2

4

6

8

10

12

14

-1 -5 -9

Examinations prior to stillbirth Baschat et al., Am J Obstet Gynecol 2009

Two Types of FGR (n=1024)

0

50

100%

-1 -5 -9

reactive CTG

Tone / Movement

Oligohydramnios

<34

>34

>34

<34

>34

<34 > 34 SSW – Brain Sparing

declining AFI Nonreactive FHR

Loss of breathing

FHR variation loss late decelerations

declining amniotic fluid volume Loss of breathing

Loss of movement Loss of tone

Elevated Doppler index Normal umbilical artery

Elevated Doppler index Absent / reversed a wave Normal ductus venosus

Elevated Doppler index Absent / reversed end-diastolic velocity Normal umbilical artery

Normal middle cerebral artery

“Brain sparing”

Normal middle cerebral artery

“Brain sparing”

Early onset FGR Evolution over 4-6 weeks

Late onset FGR Evolution over 6-9 weeks

Pre-clinical phase

Growth

Circulation

Metabolism

Deterioration Clinical phase

10. centile

5. centile 3. centile

AC HC

Venous redistribution

Arterial redistribution

Decompensation

Altered nutrient partitioning & endocrine axis Cerebral switching of nutrient

utilization

Metabolic deterioration

Hypoxemia

4 4

Proposed origins of damage

Hypoxemia

Acidemia

neurologic

Damage

Stillbirth James al. al, Soothill et al., Arduini et al., Senat et al., Harrington et al., Bilardo et al., Hecher et al,, Ribbert et al., Ferrazzi et al., Baschat et al., Cosmi et al., Divon et al.

abnormal Umbilical Brain sparing

abnormal venous Doppler

abnormal cCTG

abnormal biophysical

Delivery !

If this were true… ■  FGR fetuses should be normal before deterioration

■  Deterioration should be associated with worse neurodevelopmental outcome

■  Early intervention should make a difference

Am J Obstet Gynecol 2011

Fetal neurodevelopment

1st trimester 2nd trimester 3rd trimester

Individual movement coupling Rest / activity

Behavioral states

Dynamic fetal variables

Breathing

Movement & Tone

Accelerations

7.5 – 9 wks

12-14 wks

18 – 20 wks

cerebral cortex

RAS

ANS

VMC

Blood pressure

peripheral resistance Heart rate

modified by O2

Fetal heart rate control

CARDIAC OUTPUT IS ADJUSTED TO BODY NEEDS

Basic control High baseline Little variability

Reactive control lower baseline Higher variability Accelerations with activity

Behavioral control lower baseline Higher variability Changes with behavioral state

5 5

1st trimester 2nd trimester 3rd trimester

Individual movement coupling Rest / activity

Behavioral states

REM

FHR

Movement Incidental Periodic Absent Present

Absent Present Present Present

1F Quiet sleep

2F Active sleep

3F Quiet awake

4F Active awake

Time to complete BPS

26 min 3 min 14 min 2 min

•  Established by 34 wks

•  In 2 hours characteristic: •  Concurrence •  Organized transition

Behavioral states Evidence of abnormal fetal neurodevelopment in FGR ■ Abnormal organization of fetal behavior

■  Decreased percentage of coincidence ■  Abnormal state transition ■  Abnormal state organization ■  Delayed achievement of stable behavioral states

Arduini al., JPM 1988, Nijhuis et al., Dev Psychobiol 1999, Visser et al., Early Hum Dev 1990

Henson et al., BJOG 1984, Smith et al., BJOG 1987, Yum et al., EJOGRB 2001

■ Abnormal central integration of FHR control ■  Decreased accelerations – 80% nonreactive at 32 weeks ■  Increased baseline ■  Decreased variability and variation

Conclusions

■  Fetal neurodevelopment is abnormal when FGR is diagnosed

Fetal growth and neurodevelopment

Perc

entile

Gestational age 20 40

Perc

entile

Perc

entile

Asymmetrically small Symmetrically small

Symmetrically small

Symmetrically small

Harvey et al., Pediatrics 1982 •  HC delay <26 weeks stronger impact on motor & cognitive development at age 5 than overall growth percentile

Roth et al., 1994 & 1999 •  Slowing of 3rd trimester AC growth had no independent impact on 1 year developmental outcomes

•  6% hemiplegia or spastic diplegia •  30% mild motor disability

•  Despite identical cognitive scores ~50% required education aid at age 8

Van Batenburg-Edes et al., Pediatr Res •  large sample size n=2965 •  1 SD deviation in cephalization index (HC/EFW)

•  10-13% increased risk for suboptimal neurodevelopment

Conclusions

■  Fetal neurodevelopment is abnormal when FGR is diagnosed

■  Lagging head growth is the physical characteristic with the greatest impact on neurodevelopment with gestational age as an independent cofactor

■  Lagging head growth is associated with: lower perceptional performance motor disability poor cognition poor concentration deficient short-term memory poorer school achievement

i.e all brain areas are affected

6 6

Umbilical Doppler & neurodevelopment

Gestational week 26 28 30 32 34 36 38 40

Neonatal period

Infancy

Childhood

Adolescence

Figueras et al. SGA normal UA Doppler

NBAS

Vossbeck et al. AREDV –AGA control

2-5 year Bayley / K-ABC

Brodszki et al. AREDV –AGA controls

2 year CP rates

Padilla et al. AREDV –AGA control

1 year Bayley

Shand et al. FGR stratified by UA EDV

18-22 month outcomes

Figueras et al. SGA – AGA controls

2 year ASQ

McCowan et al. SGA – perinatal variables

2 year Bayley

Wienerroither et al. AREDV – AGA controls

6 year K-ABC

Shreuder et al. IUGR stratified by UA EDV

16 year motor / sensory / intelligence

Morsing et al. IUGR / AGA matched

5-8 year Wechsler scale

Brodszki et al., UOG 2000 •  40 AREDV & 40 gestational age matched controls delivered < 30 weeks •  Identical rate of cerebral palsy in cases and controls (14 vs 11%)

UA Doppler & early onset FGR

Padilla et al., Acta Paediatr 2010 •  AREDV & gestational age matched controls delivered at 30 weeks •  Identical 1 year testing in cases and controls

•  FGR had smaller HC & trend to lower PDI •  Birthweight & gestational age correlated with motor development index

•  HC & cephalization index correlated with psychomotor development

Shand et al., Austr N Z J Obstet Gynaecol 2009 •  Early onset FGR (n=87) retrospectively stratified by UA EDV •  Mild & moderate 2 year disability in 18% of AREDV vs 3% PEDV •  Gestational age was main determinant of outcome

UA Doppler & early onset FGR

Morsing et al., Pediatrics 2011 •  AREDV had lower verbal and global IQ compared to controls •  Boys at greater risk for developmental delay

Vossbek et al., Eur J Pediatr 2000 •  40 AREDV & 40 gestational age matched controls delivered at 27 weeks •  16 completed Bayley or Kaufman ABC

AREDV Control P MDI Bayley 76 98 0.03 Delay/retardation 14 6 0.033 MPC Kaufman 57 89 0.03 Severe motor impairment 6 3 0.07

UA Doppler & Childhood development Wienerroither et al., Obstet Gynecol 2001 •  35 AREDV vs gestational age matched controls delivered 33 weeks •  6 year Kaufmann ABC – no single determinant identified

ResultsIn the 23 study group fetuses, 17 (74%) had absent andsix (26%) had reversed end-diastolic flow in the umbil-ical artery. The cesarean delivery rate was 91% in thestudy group compared with 52% in the control group(P ! .004). Birth weight was significantly lower in thestudy group according to the inclusion criteria. Perina-tal demographics were not significantly different, ex-cept for base deficit. Neonatal intensive care was signif-icantly longer in the study group, and there was atendency toward more days on ventilation (Table 1).

Results of the tests at preschool and school age foundsignificant deficits in the study group in all four subsetsof the Kaufman-Assessment Battery for Children (Fig-ures 1 and 2). The intelligence level of this group wasbelow average, whereas the control group had results

that corresponded to published average levels repre-senting 50% of the normal population. There were nostatistically significant differences between the twogroups on the Man-Drawing Test and the Child Behav-ior Checklist. The study group had significantly lowerresults in 20% of details (especially fine motor items) onthe Zurich Neuromotor Test. The rest of the test’ssubsets showed the same tendency. Similarly, neurope-diatric testing showed significant deficits in 22% ofsubsets in the study group (Table 2).

For the study group, correlations between the Kauf-man-Assessment Battery for Children variables andmother’s age, gestational age, placental weight, umbil-ical artery pH, and umbilical artery base deficit werecalculated. Furthermore, multiple regression modelswere checked for each of the four Kaufman-AssessmentBattery for Children variables separately and as amultivariable general linear model for the four compo-nents simultaneously. The only variable with predictivevalue was birth weight with respect to the Achievement

Figure 1. Intellectual outcomes according to mean values of thesubgroups. SEPS " Sequential Processing Scale; SIPS " SimultaneousProcessing Scale; MPC " Mental Processing Composite; AS "Achievement Scale of the Kaufman-Assessment Battery for Children;SD " standard deviation.

Figure 2. Comparison of matched pairs of children. Intellectual out-comes is the mean value of all subgroups of the Kaufman-AssessmentBattery for Children.

Table 1. Maternal and Fetal Demographics

Variable

Study group Control group

PMax Min Median Mean SD Max Min Median Mean SD

Maternal age (y) 39 17 26 26.1 5.4 38 21 31 29.5 4.7 NSGravidity 3 1 1 1.3 0.6 7 1 2 2.1 1.5 NSGestational age (wk) 40 28 33 34.1 3.5 40 28 33 34.3 3.3 NSBirthweight (g) 2270 600 1200 1258 482.9 3350 920 2120 2148 703.7 !.001Placenta weight (g) 730 110 260 296 148.6 1050 240 490 489 170.4 !.001Apgar score

1 min 9 1 5.5 2.3 9 2 7 2.1 NS5 min 10 5 7.9 1.5 10 7 8.8 0.9 NS10 min 10 6 8.7 1.1 10 7 9.5 0.8 .002

UA-pH 7.32 6.86 7.19 0.13 7.50 7.22 7.30 0.06 .001UA-BD (mval/L) 1.8 #18.1 #3.25 5.7 1.2 #8.1 #1.2 2.4 NSNeonatal hospitalization (days) 217 14 66.4 48.6 101 0 42.4 27.3 NSVentilation treatment (days) 59 0 7.4 12.8 21 0 5.4 7.6 NS

Max " maximum; Min " minimum; SD " standard deviation; NS " not significant; UA-pH " umbilical artery pH; UA-BD " umbilical arterybase deficit.

VOL. 97, NO. 3, MARCH 2001 Wienerroither et al Postnatal Long-Term Outcome 451

ResultsIn the 23 study group fetuses, 17 (74%) had absent andsix (26%) had reversed end-diastolic flow in the umbil-ical artery. The cesarean delivery rate was 91% in thestudy group compared with 52% in the control group(P ! .004). Birth weight was significantly lower in thestudy group according to the inclusion criteria. Perina-tal demographics were not significantly different, ex-cept for base deficit. Neonatal intensive care was signif-icantly longer in the study group, and there was atendency toward more days on ventilation (Table 1).

Results of the tests at preschool and school age foundsignificant deficits in the study group in all four subsetsof the Kaufman-Assessment Battery for Children (Fig-ures 1 and 2). The intelligence level of this group wasbelow average, whereas the control group had results

that corresponded to published average levels repre-senting 50% of the normal population. There were nostatistically significant differences between the twogroups on the Man-Drawing Test and the Child Behav-ior Checklist. The study group had significantly lowerresults in 20% of details (especially fine motor items) onthe Zurich Neuromotor Test. The rest of the test’ssubsets showed the same tendency. Similarly, neurope-diatric testing showed significant deficits in 22% ofsubsets in the study group (Table 2).

For the study group, correlations between the Kauf-man-Assessment Battery for Children variables andmother’s age, gestational age, placental weight, umbil-ical artery pH, and umbilical artery base deficit werecalculated. Furthermore, multiple regression modelswere checked for each of the four Kaufman-AssessmentBattery for Children variables separately and as amultivariable general linear model for the four compo-nents simultaneously. The only variable with predictivevalue was birth weight with respect to the Achievement

Figure 1. Intellectual outcomes according to mean values of thesubgroups. SEPS " Sequential Processing Scale; SIPS " SimultaneousProcessing Scale; MPC " Mental Processing Composite; AS "Achievement Scale of the Kaufman-Assessment Battery for Children;SD " standard deviation.

Figure 2. Comparison of matched pairs of children. Intellectual out-comes is the mean value of all subgroups of the Kaufman-AssessmentBattery for Children.

Table 1. Maternal and Fetal Demographics

Variable

Study group Control group

PMax Min Median Mean SD Max Min Median Mean SD

Maternal age (y) 39 17 26 26.1 5.4 38 21 31 29.5 4.7 NSGravidity 3 1 1 1.3 0.6 7 1 2 2.1 1.5 NSGestational age (wk) 40 28 33 34.1 3.5 40 28 33 34.3 3.3 NSBirthweight (g) 2270 600 1200 1258 482.9 3350 920 2120 2148 703.7 !.001Placenta weight (g) 730 110 260 296 148.6 1050 240 490 489 170.4 !.001Apgar score

1 min 9 1 5.5 2.3 9 2 7 2.1 NS5 min 10 5 7.9 1.5 10 7 8.8 0.9 NS10 min 10 6 8.7 1.1 10 7 9.5 0.8 .002

UA-pH 7.32 6.86 7.19 0.13 7.50 7.22 7.30 0.06 .001UA-BD (mval/L) 1.8 #18.1 #3.25 5.7 1.2 #8.1 #1.2 2.4 NSNeonatal hospitalization (days) 217 14 66.4 48.6 101 0 42.4 27.3 NSVentilation treatment (days) 59 0 7.4 12.8 21 0 5.4 7.6 NS

Max " maximum; Min " minimum; SD " standard deviation; NS " not significant; UA-pH " umbilical artery pH; UA-BD " umbilical arterybase deficit.

VOL. 97, NO. 3, MARCH 2001 Wienerroither et al Postnatal Long-Term Outcome 451

UA Doppler & Adolescent development Schreuder et al., Arch Dis Child 2002 •  Cohort of 76 FGR adolescents stratified by UA EDV •  Average GA at delivery 32 weeks •  Intelligence, neurological, cognitive & school performance testing

•  Poor performance with REDV persisted after correction for GA

( 1 4%) , a n d < 7 0 ( < −2 SD ) i n fi ve ( 7 %) . Th e r e wa s n o di f f e r -e n c e i n GCA b e t we e n t h e i n f a n t s t h a t h a d A R E D F V a n dF E D F V. Ho we ve r, me a n GCA wa s lo we r f o r t h e R E D F V g r o upwh e n c o mp a r e d t o t h e F E D F V g r o up a n d a ls o wh e n c o mp a r e dw i t h t h e A E D F V g r o up ( t a b le 3 ) . O n t h e c lus t e r o f vi s uo s p a t i a lo r p i c t o r i a l a b i li t y , t h o s e w i t h R E D F V s c o r e d wo r s e t h a n t h o s ew i t h F E D F V a n d wo r s e t h a n t h o s e w i t h A E D F V ( t a b le 3 ) .

Neurological screeningIn t h e wh o le g r o up , we f o un d a me a n t o t a l r i s k s c o r e o n Q N S To f 2 3 . 5. Th e r e wa s n o di f f e r e n c e i n me a n t o t a l r i s k s c o r eb e t we e n t h e g r o up w i t h A R E D F V a n d t h e g r o up w i t h f o r wa r dfl o w. Ho we ve r, t h e s ub g r o up w i t h R E D F V h a d s i g n i fi c a n t lywo r s e me a n s c o r e s t h a n F E D F V o r A E D F V s ub g r o up s ( t a b le4) .

A s t h e c h i ldr e n i n t h e R E D F V g r o up we r e a s s e s s e d a t a s i g -n i fi c a n t ly y o un g e r a g e t h a n t h e F E D F V c h i ldr e n , t h e Q N S Ts c o r e s we r e a djus t e d f o r a g e a t a s s e s s me n t .

A f t e r a djus t me n t , t h e me a n Q N S Ts c o r e f o r t h e R E D F Vg r o up wa s 3 0 . 3 . Th i s wa s s i g n i fi c a n t ly h i g h e r t h a n t h e me a ns c o r e f o r t h e F E D F V g r o up , wh i c h wa s 2 1 . 9 . Th e di f f e r e n c eb e t we e n me a n s c o r e s f o r t h e R E D F V a n d t h e F E D F V wa s 8 . 4( p = 0 . 0 3 3 ) .

VisionF o r t y t h r e e p e r c e n t o f i n f a n t s ( 3 2 /7 4) h a d o n e o r mo r e vi s ua la b n o r ma li t i e s . F i f t e e n o f t h e s e ( 47 %) h a d m i n o r a c ui t y p r o b -le ms , 1 5 ( 47 %) h a d s e ve r e a c ui t y p r o b le ms , a n d t wo h a d n ode p t h p e r c e p t i o n w i t h n o r ma l a c ui t y . Th e r e wa s n o s i g n i fi c a n tdi f f e r e n c e b e t we e n t h e A R E D F V a n d F E D F V g r o up s w i t hr e s p e c t t o t h e p r o p o r t i o n o f c h i ldr e n w i t h a n y vi s ua la b n o r ma li t y ( 42 % ( 1 5/3 6) ve r s us 45% ( 1 7 /3 8 ) ) , o r i n t h e p r o -p o r t i o n t h a t wo r e g la s s e s /le n s e s ( 1 7 % ( 6/3 6) ve r s us 1 8 %( 7 /3 8 ) ) . Th e r e we r e mo r e c h i ldr e n w i t h s e ve r e a c ui t y lo s s i nt h e R E D F V g r o up ( 5/9 , 56%) t h a n i n t h e A E D F V g r o up ( 3 /2 7 ,1 1 %; p = 0 . 0 1 4) o r t h e F E D F V g r o up ( 7 /3 7 , 1 9 %; p = 0 . 0 47 ) .

HearingD a t a o n h e a r i n g t h r e s h o ld we r e o n ly a va i la b le f o r 48 c h i ldr e n .M e a n h e a r i n g t h r e s h o ld wa s a lmo s t i de n t i c a l, b e t we e n 1 7 a n d1 8 de c i b e ls , f o r a ll g r o up s . Th e r e we r e t h r e e c h i ldr e n ( 6%) w i t ha s i g n i fi c a n t h e a r i n g lo s s , 0 /6 i n t h e R E D F V g r o up , 1 /1 6 i n t h eA E D F V g r o up , a n d 2 /2 6 i n t h e F E D F V g r o up .

GrowthO f t h e t o t a l g r o up , 63 % h a d a h e i g h t b e lo w t h e 50 t h c e n t i lea n d 1 9 % h a d a h e i g h t le s s t h a n t h e 1 0 t h c e n t i le a c c o un t i n g f o r

Table 3 Results of mental development testing using the British Ability Scales (BAS-II)

Umbilical artery EDFV pattern

Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)

General conceptual abilityMean score 101 101.1 87.7*(95% CI of mean) (97–105) (95–107) (71–105)

Distribution of GCA scores<70 2 1 270–84 2 3 185–115 31 18 6115+ 4 5

Verbal abilityMean score 102.5 103.8 90.2(95% CI of mean) (98–107) (97–111) (70–111)

Non-verbal reasoningMean score 104.4 104.2 92.6(95% CI of mean) (99–110) (97–111) (75–110)

Spatial/pictorial abilityMean score 96.3 96.2 80.7†(95% CI of mean) (91–102) (90–102) (64–97)

*p=0.049, reversed versus forward; p=0.048, reversed versus absent.†p=0.023, reversed versus forward; p=0.025, reversed versus absent.

Table 4 Findings on Quick Neurological Screening Test (QNST-II )


Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)

QNST raw total risk scoreMean 21.5 23.2 32.8*(95% CI of mean) (18.1–24.9) (18.3–28.1) (24.9–40.6)

QNST moderate or severe discrepancy; score>25

No. 17 12 7(%) (44) (44) (78)

QNST total risk score after correction for age atassessment

Mean 21.9 23.4 30.3(95% CI of mean) (18.7–25.2) (19.5–27.3) (23.4–37.2)

*p=0.006, reversed versus forward; p=0.045, reversed versus absent.

Absent or reversed end diastolic flow velocity in the umbilical artery F111

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Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)









Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)



No. 17 12 7(%) (44) (44) (78)


Mean 21.9 23.4 30.3(95% CI of mean) (18.7–25.2) (19.5–27.3) (23.4–37.2)





m i d-p a r e n t a l h e i g h t . 2 5 Th e r e we r e n o di f f e r e n c e s b e t we e n t h ef o r wa r d, a b s e n t , o r r e ve r s e d E D F V g r o up s i n t h e p r o p o r t i o n o fc h i ldr e n w i t h we i g h t , h e i g h t , h e i g h t c o r r e c t e d f o r m i d-p a r e n t a l h e i g h t ,2 5 o r m i d up p e r a r m c i r c u mf e r e n c e 2 6 b e lo w t h e1 0 t h c e n t i le f o r a g e a n d s e x.

O f t h e 1 0 c h i ldr e n wh o h a d a h e a d c i r c u mf e r e n c e b e lo w t h e1 0 t h c e n t i le f o r a g e a n d s e x , e i g h t ( 2 4%) we r e i n t h e g r o upw i t h A R E D F V a n d t wo ( 5%) i n t h e f o r wa r d fl o w g r o up( p = 0 . 0 41 ) .

Blood pressureB lo o d p r e s s ur e ( B P ) wa s w i t h i n n o r ma l li m i t s f o r a g e i n a llc h i ldr e n t h a t we r e a s s e s s e d. 2 9 M e a n s y s t o li c B P wa s 9 9 m m Hg( r a n g e 9 3 –1 0 5) a n d me a n di a s t o li c B P wa s 54 m m Hg ( r a n g e49 –62 ) . Th e r e we r e n o s i g n i fi c a n t di f f e r e n c e s i n B P b e t we e ns ub g r o up s .

BehaviourQ ue s t i o n n a i r e s we r e r e t ur n e d b y 66/7 6 p a r e n t s a n d 55/7 4t e a c h e r s . Th e p a r e n t s o f t wo c h i ldr e n di d n o t a g r e e t o us c o n -t a c t i n g t h e s c h o o l. F o r t h e wh o le g r o up , t h e me a n s o f t h e t o t a lb e h a vi o ur a l de vi a n c e s c o r e s r a t e d b y p a r e n t s a n d t e a c h e r swe r e 1 1 . 6 a n d 8 . 7 r e s p e c t i ve ly . O ve r a ll, 1 4 o f 66 c h i ldr e n ( 2 1 %)h a d a n a b n o r ma lly h i g h t o t a l b e h a vi o ur a l de vi a n c e s c o r e a sr a t e d b y p a r e n t s , a n d n i n e o f 55 ( 1 6%) a s r a t e d b y t e a c h e r s( t a b le 5) . Th e g r o up w i t h R E D F V s c o r e d h i g h e r o n t h es ub s c a le s i n di c a t i n g h y p e r a c t i vi t y ( me di a n 5. 5 ( r a n g e 4. 4–8 . 3 )ve r s us 3 . 0 ( 1 . 0 –5. 0 ) , p = 0 . 0 1 5) a n d p e e r p r o b le ms ( me di a n4. 5 ( 2 . 2 –6. 0 ) ve r s us 2 . 0 ( 1 . 4–2 . 8 ) , p = 0 . 0 2 8 ) wh e n c o mp a r e dw i t h t h e g r o up w i t h f o r wa r d fl o w.

EducationIn t o t a l, 2 0 /55 c h i ldr e n ( 3 6%) r e qui r e d a ddi t i o n a l e duc a t i o n a lh e lp o r we r e i n a c la s s lo we r t h a n e xp e c t e d f o r t h e i r a g e . F i f -t e e n c h i ldr e n we r e r e c e i vi n g n o n -t e a c h i n g h e lp ( t h r e e i n t h eR E D F V, fi ve i n t h e A E D F V, a n d s e ve n i n t h e F E D F V g r o up s ) .O n e c h i ld i n t h e F E D F V a n d o n e i n t h e R E D F V g r o up we r e i na c la s s lo we r t h a n a p p r o p r i a t e f o r t h e i r a g e . Th r e e c h i ldr e nwe r e i n ma i n s t r e a m e duc a t i o n b ut h a d r e qui r e d s t a t e me n t s o fs p e c i a l e duc a t i o n a l n e e ds , t wo we r e i n t h e g r o up w i t h R E D F V,a n d o n e wa s i n t h e g r o up w i t h A E D F V. F o ur we r e n o t i nma i n s t r e a m e duc a t i o n ( o n e i n t h e R E D F V a n d t h r e e i n t h eA E D F V g r o up s ) . So me c h i ldr e n r e c e i ve a c o mb i n a t i o n o fdi f f e r e n t t y p e s o f e xt r a h e lp .

Ta b le 6 s h o ws t h a t 2 6/55 ( 47 %) o f t h e wh o le g r o up s c o r e d“p o o r ly o r ve r y p o o r ly ” o n t wo o r mo r e s ub je c t s a c c o r di n g t ot h e i r t e a c h e r s . P o o r o r ve r y p o o r p e r f o r ma n c e wa s r e p o r t e d i n2 2 % f o r s p e a k i n g /li s t e n i n g , 3 5% f o r wr i t i n g ( c o mp o s i t i o n ) ,2 7 % f o r wr i t i n g ( fi n e mo t o r s k i lls ) , 3 1 % f o r a r i t h me t i c /ma t h e ma t i c s , 2 2 % f o r r e a di n g , a n d 2 5% f o r P E /g a me s . We di dn o t fi n d s i g n i fi c a n t di f f e r e n c e s b e t we e n R E D F V, A E D F V, a n dF E D F V g r o up s w i t h r e s p e c t t o t h e me a n o f t h e t e a c h e r s ’r a t i n g s o n a n y o f t h e s e s c a le s .

Perinatal risk factorsIn t h i s s e le c t e d h i g h r i s k p o p ula t i o n we di d n o t fi n d a s t a t i s t i -c a lly s i g n i fi c a n t di f f e r e n c e i n me a n B A S s c o r e n o r i n t o t a lQ N S Ts c o r e b e t we e n t h e c h i ldr e n b o r n b e lo w t h e 3 r d c e n t i lef o r b i r t h we i g h t o r t h o s e b o r n b e t we e n t h e 3 r d a n d 1 0 t h c e n -t i le , o r t h o s e wh o h a d a b i r t h we i g h t a p p r o p r i a t e f o rg e s t a t i o n a l a g e . Th e R E D F V g r o up h a d s i g n i fi c a n t ly lo we r

Table 5 Behaviour from parent and from teacher completed questionnaires(Strengths and Difficulties Questionnaire)

SDQ

Umbilical artery EDFV pattern*

Forward

(n=36)

Absent

(n=22)

Reversed

(n=8)

Parent’s total scoreMean 10.5 11.8 15.4(95% CI) (7.9–13.6) (9.2–14.4) (10.7–20.6)

Parent’s total score; high >17No. 5 5 4(%) (14) (23) (50)

Forward

(n=28)

Absent

(n=19)

Reversed

(n=8)

Teacher’s total scoreMean 9.5 6† 12.6(95% CI) (6.9–12.1) (3.8–8.1) (5.4–19.9)

Teacher’s total score; high >16No. 5 0 4‡(%) (18) (50)

*A total of 66 questionnaires were returned by parents and 55 by teachers.†p=0.035, absent versus forward; ‡p=0.008, reversed versus absent.

Table 6 School performance as reported by teachers: number (%)

School performance*


Forward

(n=28)

Absent

(n=19)

Reversed

(n=8)

All six subjects average or above 14 (50) 8 (42) 3 (38)Below average in two or more subjects 14 (50) 7 (37) 5 (62)Any extra educational provision 8 (29) 8 (42) 4 (50)Not in mainstream education 3 (16) 1 (13)

A total of 55 questionnaires returned by teachers.*Subjects may appear in one or more columns.

F112 Schreuder, McDonnell, Gaffney, et al












Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)









Forward

(n=39)

Absent

(n=27)

Reversed

(n=9)



No. 17 12 7(%) (44) (44) (78)


Mean 21.9 23.4 30.3(95% CI of mean) (18.7–25.2) (19.5–27.3) (23.4–37.2)





7 7

McCowan et al., Am J Obstet Gynecol 2002 •  220 SGA infants with 2 year Bayley, stratified by UA Doppler

•  Average gestational age at delivery 36 weeks •  MDI of 96 lower than reference population, 20% abnormal MDI, 14%

abnormal PDI •  Delivery for maternal hypertension protected motor development •  PDI related to HC, NICU stay and breastfeeding

UA Doppler & late onset FGR

Figueras et al., EJOG 2008, Pediatrics 2009 •  Term SGA with normal UA Doppler

•  Abnormal NBAS for attention, habituation, social and state regulation. •  Term SGA with normal UA Doppler matched with AGA

•  2 year ASQ – lower scores for problem solving and social domains. •  Abnormalities relate to frontal lobe function

Conclusion – UA Doppler

■  In early onset FGR Gestational age overrides effects of UA Doppler until early third trimester Compared to PEDV – AREDV have worse motor development at age 2 Childhood intelligence, psychomotor, speech development worse with AREDV In adolescence and worst intelligence, and motor development with REDV

■  In late onset FGR Even with normal UA Doppler neonatal state organization is abnormal Among SGA psychomotor development primarily related to HC

Compared to AGA controls worse frontal lobe function with abnormal UA

Cerebral Doppler & neurodevelopment

Early onset FGR Kutchera et al., EJOBG 2002 •  16 ARED matched with abnormal CPR & Controls delivered at 32 weeks •  3-6 year Kaufman ABC

ARED & abnormal CPR are associated with similar degree of impaired neurodevelopment

Del < 33 wks)

<0.005 SGA 7% 30% At birth

VEP 148 ms 122 ms <0.05 6-12 months

Scherjon et al., 1996, 1998, 2000, 2010 117 singleton monitored pregnancies

abnormal CPR normal CPR

<0.005 Steroids 1 % 98%

IVH 4% 1% <0.05 Abnormal Hempel score 8% 0% <0.05

HC 50 cm 48 cm <0.05 3 years

IQ 96 87 <0.02

IQ < 85 20% 54% 0.003 5 years

TRF 20 21.4 CBCL 22.8 23.3

11 years

Late onset FGR Oros et al., UOG 2010, Cruz-Martinez et al., AJOG 2009 •  Term FGR with MCA and ACA Doppler and NBAS (28 days of life)

•  MCA brain sparing : abnormal motor function & state organization •  ACA brain sparing : poor state organization •  Decreased frontal lobe flow : abnormal social interactive, state organization

and attention scores

Roza et al., Am J Epidemiol 2008 •  935 term FGR with ACA & MCA Doppler with CBCL at age 18 months

•  MCA PI change : somatic complaint scores •  ACA PI change : emotional reactive, attention and somatic complaint scores

Eixarch et al., UOG 2008 •  128 term FGR & AGA controls stratified by MCA Doppler – ASQ at 2 years

•  Brain sparing : 53-57% communication delay : 39-47% abnormal problem solving

8 8

Conclusions – Cerebral Doppler

■  In early onset FGR Studies stratifying appropriately by MCA Doppler are lacking

■  In late onset FGR Abnormal MCA Doppler is associated with worse neurodevelopment Regional alterations in brain blood flow impedance have differential effects

Aorta, Isthmus & neurodevelopment

Ley, 1996, Tideman 2006 FGR & GA matched controls

abnormal DAO -BFC

Normal DAO - BFC

7 years

18 years

Normal 53% 29%

MND -1 33% 36%

MND -2 13.3% 36%

Determined by degree of FGR HC BFC (III)

Verbal IQ 103 95

Verbal IQ <85 9.5% 18.9%

Global IQ 102 96

Global IQ <85 8.8% 22%

Determined by BFC (III) & SE status

WAIS Performance 108 98

WAIS Total 104 96

School grade 2.5 3.1

•  44 FGR delivered at 33 weeks gestation – Griffiths DQ & neurologic exam •  Net antegrade flow : 49% suboptimal development •  Net retrograde : 100% suboptimal development

•  Isthmic flow index <0.7 predicts suboptimal development with 55% sensitivity & 85% specificity

•  Prediction independent of UA Doppler

•  85 FGR delivered at 32 weeks gestation – 2 year Bayley •  AREDV, abnl CPR & abnormal aorta associated with cognitive delay •  Isthmus blood flow non-contributory •  Main determinant of cognitive outcome was cerebral volume

•  Declining cardiac output & abnormal venous Doppler main factors. •  Isthmus non-contributory

Venous Doppler, BPS & development

9 9

Neurosensory delay (52%)

●  UA REDV ●  Birthweight ●  Gestational age

r2 = 0.31, p=0.006

Global delay (23.6%)

Cerebral palsy (8.3%) ●  Gestational age ●  Birthweight ●  neonatal morbidity ●  UA REDV

r2 = 0.52, p<0.0001

●  Birthweight r2 = 0.54, p<0.0001

<27 SSW.

92 % Sensitivity 82 % Specificity AUC = 0.903 P=0.001

<640 gr. 85 % Sensitivity 83 % Specificity AUC = 0.866 P=0.003

Baschat 2010

Conclusion – Central hemodynamics

■  Even when central hemodynamics are considered Head size, overall growth delay

Gestational age at delivery

Placental Doppler parameters

Are primary determinants of neurodevelopment

■  Fetal deterioration and abnormal venous Doppler parameters play a small contributory role

Management & neurodevelopment

GRIT Studies, 2003, 2004, 2010

Lancet 2004 “2 year Follow-up: Griffith DQ, CP, Mortality”

547 singleton / Twins - 24-36 GA

Unsure about delivery timing

Immediate delivery

Deliver when no longer in doubt

<0.05 C-section 91% 76% BJOG 2003

+4.9 days (*6.9 > 31 SSW)

FDIU 2 9 <0.05 neonatal Death 27 18 0.06 Perinatal Mortality 29 27 n.s.

AJOG 2010 “6-13 year Follow-up: Kaufmann ABC, Cognitive Outcome”

Identical Long-term outcomes

8 17 Prematurity-related <0.05 <30 weeks

Cerebral palsy 0 8 <0.01 5 14 Dev. delay <0.05

<30 weeks

Summary

■  Germinal matrix / IVH Primary effects are motor Primarily related to prematurity Apparent by 2 years

■  Regional perfusion State organization Mental processing Apparent at 2 years

■  Global impact of growth delay Cognition Speech / communication Apparent in childhood

10 10

Conclusions

■  Fetal neurodevelopment is abnormal when FGR is clinically apparent

■  Lagging head growth is the physical characteristic with the greatest impact on neurodevelopment

■  Gestational age overrides effects of UA Doppler until early third trimester

■  Independent contribution of MCA Doppler is more apparent in the vulnerable term brain

■  Abnormalities in central hemodynamics appear to play a small contributory role.

■  Motor delay is related to prematurity. Cognitive delay becomes apparent later and is more related to fetal status

Documents

Active placental nutrient transport - hopkinsmedicine.org · lower perceptional performance motor disability poor cognition poor concentration deficient short-term memory poorer school