Nicolaou 2 Screening for preeclampsia - SASUOGsasuog.org.za/subsiteTeachings/Presentations/2010 Congress/10... · Screening for Pre-Eclampsia K Spencer at al Ultrasound ObstetGynecol2007;

Screening for PreScreening for Pre--eclampsiaeclampsia

SASUOG 2010SASUOG 2010

Ermos Nicolaou

Maternal & Fetal Medicine Unit

University of the Witwatersrand

Pre-eclampsia

“Hypertensive disease of pregnancy" remains a leading cause of direct

maternal mortality and morbidity worldwide

•Hypertension and/or proteinuria is the leading single identifiable risk factor in

pregnancy associated with stillbirth (one in five stillbirths in otherwise viable

babies) babies)

•Pre-eclampsia is strongly associated with fetal growth restriction, low birth

weight, preterm delivery, respiratory distress syndrome, and admission to

neonatal intensive care

Fiona Milne at al,

BMJ 2005;330:576 580 doi:10.1136/bmj.330.7491.576

Pre-eclampsia

•Worldwide, each year, more than four million women will develop pre-

eclampsia

•Approximately 100 000 women will have eclamptic convulsions,

•Over 90% occur in developing countries.

•2% of women with pre-eclampsia will develop eclampsia•2% of women with pre-eclampsia will develop eclampsia

RCOG: Pre-eclampsia - study group consensus statement

•By conservative estimates, these disorders are responsible for 76,000

maternal and 500,000 infant deaths each year.

Preeclampsia Foundation

Pre-eclampsia

Pre-eclampsia is a multisystemic syndrome usually recognised by

1. new onset hypertension and proteinuria appearing in the second half of

pregnancy.

2. Clinicians should be aware that pre-eclampsia may occasionally occur

with hypertension in the absence of proteinuria (and proteinuria without

hypertension)

3. but with other features such as eclampsia, renal impairment, 3. but with other features such as eclampsia, renal impairment,

thrombocytopenia, liver dysfunction or fetal compromise.

RCOG: Pre-eclampsia - study group consensus statement

EPICure Study: Outcome at 30 months

Wood N et al. N Engl J Med 2000;343:378-384

EPICure Study: Outcome at 6 years

40

50

60

70

Percentage of Survivors

Severe disability Mild to Moderate No impairment

0

10

20

30

22 wks 23 wks 24 wks 25 wks

Percentage of Survivors

Gestational Age

Marlow N, et al. NEJM 2005

Improved Survival: 80’s to 90’s :500-999

1982-1989 1990-1998

Gestational Age (wks) 25.8 25.5

Birth Weight (grams) 761 756

Antenatal Steroids (%) 0 42

Caesarian Section (%) 32 45

Assisted Ventilation (%) 81 89

Surfactant (%) 1 68

Survival at 20 months (%) 49 67

Wilson-Costello D, et al. Pediatrics 2005

Improved Survival: 80’s to 90’s

30

40

50

60

70

801982-89 1990-98

0

10

20

30

Survived 500-999

Survived Normal 500-

999

Survived Impaired 500-999

Survived Impaired 500-749

For every 100 infants born weighing 500-999, there were 18 additional

survivors- 7 normal and 11 impaired. (Pediatrics 2005)

Definition

• Abdominal circumference < 5th

centile for gestation (US)

• 80% of such fetuses are

constitutionally small, with no

increased perinatal death or

15% 5%

The Small Fetus

increased perinatal death or

morbidity

• 15% are growth restricted due

to reduced placental perfusion

and "utero-placental

insufficiency“

• 5% are growth restricted due to

low growth potential

(abnormal small)

80 %

IUGR or AGA?

When both the anomaly scan and umbilical artery waveforms are

normal, the small fetus should be classified as a “normal small fetus”.

When the anomaly scan is abnormal and the waveforms are normal,

the fetus is an “abnormal small fetus”.

When the anomaly scan is normal and Doppler waveforms are

abnormal, there is IUGR.

Catherine S Bobrow, Peter W Soothill

THE LANCET • Vol 353 • May 1, 1999

Screening for pre-eclampsia

•The underlying mechanism for PE is thought to be impaired placentation,

documented by the findings of

1. abnormal blood flow in the uterine arteries and

2. reduced maternal serum levels of placental products

Screening for Pre-eclampsia

80

90

100

Detection rate (%)

Screen +ve

5%Age (yrs) <20

20-35

>35

Maternal history LR

0.7

1.0

1.5

NHSNHSNational InstituteNational Institute

for Clinical Excellencfor Clinical Excellencee

The patient-specific risk of

developing PE can be

predicted by a combination of

factors in the

0

10

20

30

40

50

60

70

Detection rate (%)

33%

Cigarette smoking

Obstetric history

Nullipara

no PET

PET

1.6

0.5

4.0

Body Mass Index <20

20-30

>30

0.7

1.0

1.5

Ethnicity White

Black

1.0

1.5

0.6

•Maternal history

•Race

•High body mass index

•Prior or family history of PE

K..and the following measurements taken at

11-13 weeks:

•maternal blood pressure

•uterine artery pulsatility index (PI)

•maternal serum level of PAPP-A

•maternal serum level of PLGF

Screening for pre-eclampsia

•Screening by this combined approach could

identify about 90% of patients developing early-

PE at a FPR of 5%

K Nicolaides

Screening in pregnancy

FMF 2009

Vascular dysfunction in pre-eclampsia

In preeclampsia, excess placental soluble Flt-1 (VEGFR-1) binds circulating VEGF and PlGF and prevents

their interaction with endothelial cell-surface receptorsPreeclampsia: A renal perspective

S ANANTH, Kidney International

Pre-eclampsiaFetal growth restriction

Fetal death

Good

diastolic

flow

Impaired placentation

Poor

diastolic

flow

Early

diastolic

notch

Preeclampsia: A renal perspective

S ANANTH, Kidney International

The placenta is a two compartment nutrient, fluid and gas exchange organ:

The maternal compartment is assessed by uterine artery Doppler

The fetal compartment is assessed by umbilical artery Doppler

Vascular dysfunction in pre-eclampsia

A Baschat,

Doppler Ultrasound,

FMF 2010

Umbilical Arteries

Abnormal villous vascular perfusion results in abnormal waveform in the

umbilical arteries;

Depending on the degree of impaired vasculature:

30% impairment results in high pulsatility index

50% impairment results in absent end-diastolic velocity 50% impairment results in absent end-diastolic velocity

70% impairment results in reversed end-diastolic velocity

The risk for hypoxemia / acidemia is proportional to the decrease in

umbilical end-diastolic flow

A Baschat,

Doppler Ultrasound,

FMF 2010

Arterial BP (m

mHg) 105

95

Ute

rine

artery

PI 3.5

3.0

2.5

2.0

1.5

1.0

0.5 Normal PET

Screening for pre-eclampsia at 11-13+6 wks

Mate

rnal se

rum PAPP

-A (MoM

)

4.0

3.5

3.0

2.5

2.0

1.5

90%

Arterial BP (m

mHg)

95

85

75

65

55

Normal PET

Card

iac ou

tput (L/m

in)

8

7

6

5

4

3

2 Normal PET

PET

Mate

rnal se

rum

1.0

0.5

0.0

Normal

J. E. A. K. BAMFO, et al

Maternal cardiac function in fetal growth-restricted

and non-growth-restricted small-for-gestational

age pregnanciesUltrasound Obstet Gynecol 2007; 29: 51–57

K Spencer at al

First-trimester maternal serum PP-13, PAPP-A

and second-trimester uterine artery Doppler

pulsatility index as markers of pre-eclampsia

Ultrasound Obstet Gynecol 2007; 29: 128–134

Maternal history, uterine artery Doppler & serum biochemistry

70

80

90

100

De

tectio

n r

ate

(%

)

90%

80%

Screen +ve 5%

Screening for Pre-Eclampsia

0

10

20

30

40

50

60

De

tectio

n r

ate

(%

)

PET <33w

33%

0

10

20

30

40

50

60

70

80

90

0.5 1 1.5 2 2.5 3

Mean uterine artery PI

Risk (%)

Yu et al 2004 + Biochemistry

+ Uterine PI

His

tory

K Nicolaides

Editorial: Some thoughts on the true value of ultrasound


PAPP-A as a predictor of IUGR

Spencer, Nicolaides et al, 2006 – outcome of 55,000 pregnancies

PAPP-A as a predictor of PET

The value of Biochemical Screening in the 1st and 2nd Trimester

K Spenser, SASUOG, 2006

PAPP-A as a predictor of poor outcome

• Our series of 1236 patients (WITS) April 2008- April 2009

• 152 patients with low PAPP-A (normal karyotype)

Nicolaou E, Naidoo P, Bister S

PAPP-A as a predictor of poor pregnancy outcome

Mat & Fetal Med Unit, University of the Witwatersrand

2.0

2.5

3.0

3.5

4.0

4.5

5.0LR

of

PIH

0.0

0.5

1.0

1.5

0.4 0.45 0.5 0.55 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1

LR

of

PIH

PAPP-A MOM

Nicolaou E, Naidoo P, Bister S



40%

50%

60%

70%

80%

90%

100%

NORMAL

ICU

MB

ER

OF

PA

TIE

NT

S (

%)

0%

10%

20%

30%

ICU

NU

MB

ER

OF

PA

TIE

NT

S (

%)

PAPP-A MOM Nicolaou E, Naidoo P, Bister S



40%

50%

60%

70%

80%

90%

100%

ABRUPTIO

HYPERTENSION

UNEVENTFUL

NU

MB

ER

OF

PA

TIE

NT

S (

%)

0%

10%

20%

30%

40%

<0.45 0.46-0.65 >0.65

NU

MB

ER

OF

PA

TIE

NT

S (

%)

PAPP-A MOM Nicolaou E, Naidoo P, Bister S



Simon Glerup et al

Proteinase Inhibition by Proform of Eosinophil Major Basic Protein (pro-MBP)

Is a Multistep Process of Intra- and Intermolecular Disulfide Rearrangements*J. Biol. Chem., Vol. 280, Issue 11, 9823-9832, March 18, 2005


K Spencer at al


First-trimester maternal serum PP-13, PAPP-A

and second-trimester uterine artery Doppler

pulsatility index as markers of pre-eclampsia

PP13 is a protein expressed

only in the placenta. It is

involved in gluing the placenta

to the uterus, and in

remodelling the maternal

arteries to expand them


R Romero at al, Am J Obstet Gynecol, 2008, 199-(2); 122e1-122e11

First Trimester Maternal Serum PP13 in the Risk Assessment for Preeclampsia


Aspirin 150 mg / day

for abnormal Doppler at 23 wks

DRUG Aspirin Placebo

280 280

• Pre-eclampsia 18% 19%

• FGR <5th Centile 22% 24%

• Abruption 4% 2%

Yu et al 2003

Prevention of PET / FGR

Vitamin C 1000 mg / day &

Vitamin E 400 IU / day

DRUG Vitamins Placebo

935 942


• Antihypertensives 4.6%* 2.8%

• FGR (<10th centile) 8.7% 9.9%

Low-risk (nulliparous) women

Yu et al 2003

High-risk women

DRUG Vitamins Placebo

1199 1205


• Antihypertensives 7%* 3%

• FGR (BW<2.5Kg) 28%* 24%

• Baby deaths 4% 3%

Poston et al 2006

• FGR (<10 centile) 8.7% 9.9%

• Baby deaths 1.3% 1.8%

Rumbold et al 2006

Conclusion

Preeclampsia and its complications are as common today as they were

more than 30 years ago.

This is mainly because of our

•Failure to understand adequately the patho-physiology of the condition

•Failure (so-far) to develop adequate methods of screening to identify the

patients at high risk.

•Failure to develop effective strategies for their prevention, and

•Failure to develop adequate treatment strategies

Proposed screening for Preeclampsia

Universal 1st

trimester

Normal test: Review at 20weeks

Fetal anomaly scan,

Cx length, Dopplers

Increased NT, low PAPP-A

Consider karyotyping

If karyotype normal

Low dose Aspirin review at 20weeks trimester

screening

(NT, PAPP-A & free beta HCG,

UA-PI, BP)

low PAPP-A karyotyping review at 20weeks monitor BP,

Doppler

Normal NT

low PAPP-A,

UA PI

Low dose Aspirin, monitor BP,

Doppler

High BP, Hx of PET Low dose Aspirin,

monitor BP, Doppler

Documents

Nicolaou 2 Screening for preeclampsia - SASUOGsasuog.org.za/subsiteTeachings/Presentations/2010 Congress/10... · Screening for Pre-Eclampsia K Spencer at al Ultrasound ObstetGynecol2007;