ASMA KHALIL

(1)

The Fetal Medicine Foundation

Asma Khalil

Consultant/Reader in Fetal Medicine

St George’s Hospital London - UK

Cerebroplacental Ratio: When and How?

(2)

Early FGR (<32 weeks)

• AC <3^rd centile

• EFW <3^rd centile

• AEDF umbilical artery

• AC or EFW <10th centile combined with umbilical artery or uterine artery PI >95th centile

Late FGR (>32 weeks)

• AC <3^rd centile

• EFW <3^rd centile

• AC or EFW <10th centile or crossing centiles of >2 quartiles and CPR <5th centile

Consensus definition of placental FGR (2016)

Gordijn et al UOG 2016

Failure to Reach Growth Potential

(3)

Normal

Hypoxia

Fetal Doppler in FGR: Umbilical and Middle cerebral artery

Reversed

Brain Sparing in SGA/FGR

Normal

Hypoxia

Acidosis

(4)

Cerebroplacental Ratio

Brain Sparing in SGA/FGR

CPR is an earlier predictor of adverse pregnancy outcome at term than:

• MCA PI

• UA PI alone

• Biophysical profile

Cerebroplacental Ratio (CPR)

MCA PI

UA PI

=

DeVore AJOG 2015

(5)

Abnormal CPR: 3 scenarios

↑UA PI

↓MCA PI CPR <5th

Normal UA PI MCA PI <5^th CPR <5th

UA PI >90^th MCA PI <5^th CPR <5th

(6)

Cerebroplacental Ratio: when is it abnormal?

Brain Sparing in SGA/FGR

• < 1

• < 1.08

• < 0.05MoM

• < 5^th centile

• < 2.5^th centile

(7)

Nassr et al, J prinat med 2016

CS for fetal distress: OR 7.4 (95% CI 2.5-21.5)

5-min APGAR scores: OR 6.9 (95% CI 0.96-49.1)

Brain Sparing in SGA/FGR

(8)

NICU admission: OR 13.0 (95% CI 6.03-27.9)

Neonatal complications: OR 20.4 (95% CI 8.7-47.6)

Brain Sparing in SGA/FGR

(9)

Brain Sparing in SGA/FGR

Early-onset (<34 wk) SGA + low CPR

• ↓ GA at delivery

• ↓ Birthweight centile

• ↑ CS for fetal distress

• ↑ Apgar score at 5min <7

• ↑ neonatal acidosis

• ↑ NNU admission

• ↑ Neonatal morbidity

• ↑ Perinatal death

(10)

Morphologically normal singleton stillbirth and fetal size

301 stillbirth cases

0 5 10 15 20 25

25 27 29 31 33 35 37 39 41 Gestational age (weeks)

All Morphologically normal Singleton Stillbirth (%)

%

0 5 10 15 20 25 30 35 40

<10 10-20 20-50 50-70 70-90 >90 Birthweight centiles

Morphologically normal Singleton Stillbirth born ≥34 wk (n=155)

%

0 5 10 15 20 25 30 35 40 45

<5 5 - 10 10 - 20 20 - 50 50 - 70 70 - 90 >90 Birthweight centiles

%

53% of SB have BW ≥10^th centile 52% of SB ≥34wk and 38% ≥37wk 64% of SB have BW ≥10^th centile

Most studies investigating CPR focused on SGA (BW <10^th centile) pregnancies

Birthweight and

Stillbirth

(11)

The Fetal Medicine

Foundation

Birthweight and

Stillbirth

2·6 (1·5 - 4·6) Previous stillbirth

2·7 (1·6 - 4·7) Assisted reproduction

3.1 (1.4 - 7.0) Chronic hypertension

2·9 (2·1 - 4·1) Diabetes mellitus

1·9 (1·0 - 3.1) Smoking

1·7 (1·2 - 2.5) Black race

OR (95% CI)

DV reversed a-wave 2.2 (1.1 - 4.4)

2-stage screening (12 and 32 wks)

24 26 28 30 32 34 36 38 40 42 44 Gestational age (wks)

Birth weight (g)

0 1000 2000 3000 4000 5000

90^th 50^th 10^th

SGA 35%

SGA 70%

(12)

Model 1

0 10 20 30 40 50 60 70 80 90 100 0.0

0.5 1.0 1.5 2.0 2.5 3.0

SGA

BW p10th

BW centiles

CPR MoM

Model 2

0 10 20 30 40 50 60 70 80 90 100 0

5e-001 1 2 2 3 3

FRGP

0.6765 MoM

BW centiles

CPR MoM

FRGP Model

Birthweight centile

CPR and Birthweight

CPR and Late FGR

11,576 pregnancies scanned at term within 2 weeks of birth

0 5 10 15 20

<10 10-25 25-50 50-75 75-90 >90 p=0.241 p=0.083 p=0.002 p<0.001 p<0.001

Birthweight centile Fetuses with FRGP (low CPR <5th centile) (%)

Model 1

0 10 20 30 40 50 60 70 80 90 100

0.0 0.5 1.0 1.5 2.0 2.5 3.0

SGA

BW p10th

BW centiles

CPR MoM

Model 2

0 10 20 30 40 50 60 70 80 90 100

0 5e-001 1 2 2 3 3

FRGP

0.6765 MoM

BW centiles

CPR MoM

SGA Model

The lower the BW, the higher the proportion of fetuses showing redistribution

(13)

CPR at term and Delivery for presumed fetal compromise

0 5 10 15 20 25

SGA low CPR

(n=303)

SGA normal CPR

(n=966)

AGA low CPR

(n=534)

AGA normal CPR

(n=6579)

Delivery for presumed fetal compromise (%)

p<0.01 p<0.01

p<0.01

Factors OR

Age (yr) 1.04

Multiparous 0.39

CPR MoM 0.68 BW centile 0.996

Epidural 4.03

GA at delivery 1.21

Induction 1.24

Race 1.08

IP pyrexia 2.67 IP hemorrhage 3.12 Meconium 2/3 2.87

0.1 1 10

Meconium Oxytocin IP hemorrhage IP pyrexia Epidural Induction BW centile GA

CPR MoM Alcohol Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2) Age (yr)

Adjusted odds ratio

AGA only (n=6786)

22.8 17.3 22.3 16.5

n= 8,382 singleton pregnancies at term (≥37wk)

Khalil et al AJOG 2015

(14)

Foundation CPR and Late FGR

CPR and intrapartum fetal compromise

(15)

(16)

(17)

AGA fetuses at term: 10% abnormal CPR

CPR

Abnormal Normal

CS for intrapartum fetal distress 36%

10%

CPR >95^th centile: No CS for fetal distress

Late-onset SGA fetuses: 39% abnormal CPR

CPR

Abnormal Normal

CS for intrapartum fetal distress 79%

11%

(18)

Admission to the neontal unit (%)

CPR at term and NNU admission

n= 9,198 singleton pregnancies at term (≥37wk) SGA

low CPR (n=341)

(n=1065)

AGA low CPR (n=567)

(n=7225) p<0.01

p<0.01

0 1 2 3 4 5 6 7 8 9 10

0.01 0.1 1 10 100

Meconium 2/3 Oxytocin GA

IP hemorrhage IP pyrexia Epidural Induction CPR MoM BW centile Alcohol Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2) Age

Adjusted odds ratio

9.1 4.4 3.5 3.6

(19)

CPR at term and NNU admission

(20)

CPR at term and Neonatal Morbidity

0.1 1 10 100

IP hemorrhage IP pyrexia Epidural CPR MoM BW centile Alcohol Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2) Age

Odds ratio

n= 9,145 singleton pregnancies at term (≥37wk)

The outcome was a composite consisting of one or more of the following:

• NND

• RDS

• Culture-proven sepsis

• Stage 2 or 3 NEC

• Bronchopulmonray dysplasia

• Grade 3 or 4 IVH

• Periventricular leukomalacia

The incidence of neonatal morbidity was 1.2%

(21)

CPR and uterine artery Doppler >26wk

0 1 2 3 4

p<0.001 p<0.001

p<0.001 p=0.535

SGA low CPR

n=110

n=128

AGA low CPR

n=123

n=2451

Uterine mean pulsatility index MoM

Factors OR

BW centile 0.96 CPR MoM 0.004 Uterine PI MoM 4.19

Stillbirth (n=10)

P value OR*

0.001 0.98

<0.001 0.02

<0.001 1.09

P value

0.092 0.014 0.87

BW centile 0.96 CPR MoM 0.003 Uterine PI MoM 3.36

Perinatal death (n=18)

<0.001 0.98

<0.001 0.004

<0.001 0.63

0.080

<0.001 0.300

n= 2,812 singleton pregnancies

* adjusted

0 0.4 0.8 1.2 1.6 2.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Uterine artery mean pulsatility index MoM

Cerebroplacental ratio MoM

Figure 1a

n= 8382

CPR MoM

Uterine mean PI MoM

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

0 10 20 30 40 50 60 70 80 90 100

Birthweight centile

Cerebroplacental ratio MoM

Birthweight centile

Uterine mean PI MoM

(22)

CPR and uterine artery Doppler >26wk

n= 2,812 singleton pregnancies 0

25 50 75 100

Detection rate (%)

0 25 50 75 100

False positive rate (%)

Stillbirth

Perinatal loss

0.86

0.85 8.89

5.42 + LR

78%

70%

DR

0.33

0.26 - LR AUC

14%

8%

FPR

Stillbirth

Perinatal death

CPR + EFW + uterine mean PI

Khalil et al UOG 2016

(23)

Foundation CPR and Growth velocity

EFW <10th centile + AC velocity in the lowest decile:

RR of SGA with neonatal morbidity 17·6 (95% CI 9·2-34·0, p<0·0001)

(24)

0 2 4 6 8 10 12 14 16

1-1.5 1.5-3 3-5 ≥5

<1

Abdominal circumference ratio

Low CPR MoM (%)

n=6,793

P<0.001

AGA pregnancies only

0 5 10 15 20 25 30

1-1.5 1.5-3 3-5 ≥5

<1

Abdominal circumference ratio

Low CPR MoM (%)

n=7,944

P<0.001

AC ratio and CPR at term

(25)

0 1 2 3 4

Abdominal circumference ratio

AGA low CPR

AGA normal CPR P=0.003

0 5 10 15 20 25 30 35 40

SGA low CPR

AGA low CPR

Abdominal circumference ratio

P<0.001

P=0.003 P<0.001

P<0.001 P<0.001

P<0.001

(26)

0.1 1 10

Meconium grade 2/3 Oxytocin

IP hemorrhage IP pyrexia Epidural Induction AC ratio BW centile GA

CPR MoM Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2)

age AGA only

Odds ratio

0.1 1 10

Meconium grade 2/3 Oxytocin

IP hemorrhage IP pyrexia Epidural Induction AC ratio BW centile GA

CPR MoM Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2) age

Odds ratio

Delivery for fetal compromise: AC ratio and CPR

(27)

0.01 0.1 1 10 100

IP hemorrhage IP pyrexia Epidural Induction CPR MoM BW centile AC ratio Drug abuse Smoking Ethnicity Multiparous BMI (Kg/m2) Age

Odds ratio

NNU admission: CPR at term and AC ratio

(28)

(29)

CPR and Short term variation (STV)

0 2 4 6 8 10 12 14 16

Normal Respiratory acidosis

Metabolic acidosis

STV (ms)

P<0.001

0 5 10 15 20 25 30

IUD (%)

STV (ms)

<2.6 2.6-3.0

>3.0

P<0.001 24%

4%

0%

0 2 4 6 8 10 12

Metabolic acidaemia (%)

STV (ms)

>3.0 2.6-3.0 <2.6 P<0.001

10%

4%

2.7%

Low STV is strongly linked to:

•Metabolic acidosis

•Impending intrauterine death

0 2 4 6 8 10 12 14 16 18 20 22 24

2 3 4 5 6 7 8 9 10 11 12

+LR

STV threshold (ms) Metabolic acidosis

Serra et al BJOG 2008

(30)

Foundation

CPR and STV

0 2 4 6 8 10 12 14

SGA low CPR

AGA low CPR

Low STV (%)

P<0.001 12.1%

8.4%

10%

5.9%

0 2 4 6 8 10 12 14 16 18

AGA

Low STV (%)

P=0.005

SGA 6.2%

15.4%

0 2 4 6 8 10 12

Normal CPR

Low STV (%)

P=0.002

low CPR 6.2%

11%

0 10 20 30 40 50 60 70

SGA AGA 38.2%

61.8%

Population (n=3,745 singleton pregnancies) (n=1961 within 72 h of delivery)

(31)

Brain Sparing in SGA/FGR

Late-onset (>34 wk) SGA or AGA + low CPR

• ↑ CS for fetal distress

• ↓ Umbilical cord pH

• ↑ NNU admission

(32)

When to measure the Cerebroplacental Ratio?

Brain Sparing in SGA/FGR

Third trimester US irrespective of:

• UA Doppler

• MCA Doppler

• EFW

DeVore AJOG 2015

(33)

Management Scenarios at term

EFW centile CPR

<10^th Low

>10^th Low

<10^th Normal

Management Delivery

Delivery Delivery Growth velocity

Normal or reduced

reduced reduced

<10^th Normal normal Delivery ??

>10^th Low normal Delivery ??

(34)

Conclusions

Thank you

• AGA fetuses with impaired growth velocity

• AGA fetuses subject to placental insufficiency

• Low Short term variation

• Need for operative delivery for fetal compromise at term

• NNU admission at term

• An independent predictor of stillbirth

Assessment of CPR could be more informative

than standard fetal biometry in detecting late FGR

(35)

Thank you

(36)

Brain Sparing in SGA/FGR

NICU admission 5 min APGAR score CS for fetal distress

Neonatal complications

Sensitivity

Specificity

Sensitivity (%)

Specificity (%)

ASMA KHALIL

Asma Khalil

Cerebroplacental Ratio: When and How?

Brain Sparing in SGA/FGR

Brain Sparing in SGA/FGR

Abnormal CPR: 3 scenarios

Cerebroplacental Ratio: when is it abnormal?

Brain Sparing in SGA/FGR

Brain Sparing in SGA/FGR

Brain Sparing in SGA/FGR

Brain Sparing in SGA/FGR

Early-onset (<34 wk) SGA + low CPR

Birthweight and

Stillbirth

Birthweight and

Stillbirth

CPR and Short term variation (STV)

CPR and STV

Brain Sparing in SGA/FGR

Late-onset (>34 wk) SGA or AGA + low CPR

When to measure the Cerebroplacental Ratio?

Brain Sparing in SGA/FGR

Brain Sparing in SGA/FGR

44-70 56-93

50-80 54-80

40-81 53-96

39-86 53-97