Mohamed El Sherbiny

foulgirlsUrban and Civil

Nov 15, 2013 (3 years and 7 months ago)

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Magnesium
Sulphate

(MgSO
4
)

For Fetal Neuroprotection In
Preterm Delivery

"An Evidence Based View"


Dr. Mohamed El Sherbiny

MD Ob.& Gyn. Senior Consultant

Damietta
, Egypt


ERC RCOG Second Annual International Meeting

March,
3
rd

-
4
th

,
2012

Sources of Evidence


PubMed

(RCT , Meta analysis & Reviews)
3
-
2012



Cochrane Library till
3
-
2012
.


Australian National Clinical P. Guidelines
2010


ACOG ,

Committee Opinion
2010



SOGC Clinical Practice Guideline
2011


UpToDate

19.3
, January
2012


Preterm Birth And CNS Injuries

Pathologically :
2
CNS injuries :

(1)
Intraventricular

Hemorrhage (IVH)

Usually diagnosed by ultrasound (U/S)

(2)
White Matter Injury.

Usually diagnosed by MRI


SOGC Clinical Practice Guideline No.
258
, May
2011

MIR left lateral I.V. Hemorrhage T
1
&T
2

Tran cranial U/S

I.V. Hemorrhage

MRI T
2
White Matter Injury

Preterm Birth And CNS Injuries

Clinically:
The most frequent adverse

CNS outcomes are

1
-
Cerebral palsy
(CP)

2
-
Cognitive impairment

3
-
Blindness,deafness & developmental
delay.

SOGC Clinical Practice Guideline No.
258
, May
2011

The Etiology Of CP

It is multi factorial

Prematurity :
42
*
-
78
%

Intrauterine growth restriction:
34
%

Intrauterine infection :
28
%

Antepartum

hemorrhage :
27
%

Severe placental pathology :
21
%

Multiple pregnancy :
20
%


Strijbis

et al. ,
Obstet

Gynecol.
2006
;
107
(
6
):
1357
.

*
(Australian Cerebral Palsy Register Group
2009
)

Clinical Types of CP

There are
4
main types of CP:

1
. Spastic (increased muscle tone)

2
.
Dyskinetic

(slow, uncontrolled movements)

3
. Ataxic (problems with balance and depth
perception)

4
. Mixed

The most common pattern is spasticity plus

dyskinetic

movements.

CP can be reliably diagnosed by the age of
2
years.

Center for Disease Control and Prevention (CDC).. Accessed March
3
,
2011
.

Ataxic CP

Spastic CP

Spastic CP

Cerebral Palsy (CP)

The Magnitude Of The Problem

CP is the most common cause of severe motor

disability in childhood

CP increases inversely according to G. age:

All live births :
0.25
%

Compared with infants at

term
the CP risk is:


At
34
-
36
weeks :
3
fold


At
30
-
33
weeks :
8
-

14
fold


At
28
-
30
weeks :
46
fold


At <
28
weeks :
80
Fold




SOGC Clinical Practice Guideline No.
258
, May
2011

Cerebral Palsy (CP)

The Magnitude Of The Problem

The Economic Burden:
Health care,
productivity, and social costs

USA:

Lifetime for a person :
US$
1
billion

The community cost (year
2000
) :
$
11.5
billion


Australia :

The person cost/annum :
AUD$
115
,
000

The community / annum. :
AUD$
4
billion



(Access Economics
2008
).

US CDC,
2003
. MMWR
Morb

Mortal Wkly Rep
2004
;
53
:
57

9
.

Australian National Clinical Practice Guidelines. Adelaide
2010

Cerebral Palsy (CP)

The Magnitude Of The Problem

To date, there is no known :

Cure for CP.

Effective antenatal preventive
measures



SOGC Clinical Practice Guideline No.
258
, May
2011

MgSO
4
Use in Obstetrics


Eclampsia
: Prophylaxis & management
*


Tocolysis

:No longer recommended
**


Fetal neuroprotection
in preterm delivery
: A new evidence &validation

*
Altman et
al,Lancet
,
90
-
10877
(
9321
)
359
;
2002
Duley


et al ,. Lancet
1995
;
345
(
8963
):
1455

63
.

*
Magee et
al.,SOGC

Clinical Practice Guideline no.
206
, March
2008

**
Doyle et al Cochrane Database
Syst

Rev
2009
;(
1
):CD
004661

Evidence Of The Neuroprotective
Effects Of MgSO
4

Observational studies


Randomized controlled trials


Meta
-
analyses.

Validation:
Guidelines&

Committee Opinion


Australian National Clinical P. Guidelines
2010


ACOG ,

Committee Opinion
2010



SOGC Clinical Practice Guideline May
2011

1
-
Observational Studies


Preterm infants born to women with preeclampsia


had a lower incidence of adverse CNS outcomes

than those without preeclampsia.


Levitonetal

.
Obstet

Gynecol

1988
;
72
:
571

6
.
Van de B

et al . J
Perinat

Med
1987
;
15
:
333

9
.

There was an association between antenatal
MgSO
4
administration and reduction of of CP
among infants born <
1500
g.


Nelson &
Grether

,Pediatrics
1995
;
95
:
263

9
. (California Cerebral Palsy project)

Randomized Controlled Trials (RCT)

From
2002
to
2008
:
5
RCTs (
6145
babies)

1
-

Mittendorf

et al., Am J
Obstet

Gynecol

2002
;
186
:
1111

8
.
(+
tocolytic

arm)

2
-
Altman , et al, Lancet
2002
;
359
(
9321
)
:
1877

90
.
(+ preeclampsia arm)

1
&
2
have a
neuroprotective

and other arm




Randomized Controlled Trials (RCT)

From
2002
to
2008
:
5
RCTs (
6145
babies):

3
,
4
,&
5
were specifically for
neuroprotective

effect

3
-
ACTOMgSO
4
:
The Australasian Collaborative

Trial of MgSO
4
Group:
1062
women


4
-
BEAM

:


Beneficial Effects of Antenatal MgSO
4
:
Multicenter
2241
women


5
-

PREMAG

:
573
women Multicenter(
15
)
Reregistered as International RCT










Crowther

et al , JAMA.
2003
;
290
(
20
):
1062
. Australia

Rouse et al , N
Engl

J Med.
2008
;
359
(
9
):
895
USA

Marett

et al.,
Gynecol

Obstet

Fertil
.
2008
;
36
(
3
):
278
(France)

The
3
large, well
-
done RCTs (Placebo)

Significant
reduction

of
CP

Dose of
MgSO
4

Inclusion

Trial & No.


Moderate to
severe CP

(
3.4
% Vs
6.6
%

)

4
g Loading

then
1
g/h

<
30
Ws

ACTOMgSO
4

Crowther

et al (
2003
)

n.:
1062
Australia

Moderate to
severe CP

(
1.9
% Vs
3.5
%)

6
g loading
then
2
g/h

24
-
31
Ws

cost $
25
million and
took
10
years

BEAM

Rouse et al , N
Engl

J
Med.
2008
;
359
(
9
):
895

n.
2241
USA

Death & gross
motor dysfunction
(
0.6
% Vs
0.4
%)

Single
4
g
loading

<
33
Ws

PREMAG

Marett

et al.,
Gy
. Ob.
Fertil
.
2008
;
36
(
3
):
278

n.
573
France.


MgSO
4
significantly ↓risk of CP in early preterm birth


The Mechanism Of Neuroprotective Effect

The mechanism is not well understood


potential neuroprotective actions include:



Antioxidant effects



Reduction in pro
-
inflammatory cytokines



Inhibition of calcium influx into cells


Stabilization of membranes



Increased cerebral blood flow


Prevention of large blood pressure fluctuations

Marret

et al .,
Semin Fetal Neonatal Med.
2007
;
12
(
4
):
311
.

Gathwala

,. Neuronal protection with magnesium. Indian J
Pediatr

2001
;
68
:
417

9

Hyagriv

& Katherine .,
UpToDate

19.3
: January
2012

Meta
-
analyses


In
2009
, a milestone was reached with

the publication of
3
meta
-

analyses, all

of which included the same
5
RCTs and

concluded that :

MgSO
4
for fetal neuroprotection

decreases the risk of childhood CP

Doyle et al.
Cochrane

Database
Syst

Rev.
2009

Costantine

et al.
Obstet

Gynecol.
2009
;
114
(
2
Pt
1
):
354
.

Conde
-
Agudelo

et al. Am J
Obstet

Gynecol

.
609
-
200
:
595
,
200

The Cochrane Review :Result


I
-
MgSO
4
significantly reduced

the risk of :


Cerebral palsy


Substantial gross motor dysfunction

(inability to walk without assistance ) at
2

years of age

II
-

MgSO
4
had

No significant
effect of on

pediatric
(fetal, neonatal and later)
mortality.

Doyle et al.,
Cochrane

Database
Syst

Rev.
2009

Cochrane review
2009
MgSO
4
Vs no MgSO
4
,
Outcome
6
Substantial gross motor dysfunction.

Doyle et al . Cochrane Database
Syst

Rev
2009
;(
1
):CD
004661
.

The Cochrane Systematic Review concluded
that :

MgSO
4
reduced the risk of cerebral palsy by
32
%


(from
5.4
% to
3.7
% with absolute risk reduction


of
1.7
%
.)
*


The number needed to treat(NNT) to benefit one

baby was
63
women. These compare
favourably


with the
70
women with preeclampsia to prevent

one
eclamptic

fit.
**

Doyle et al Cochrane Database
Syst

Rev.
2009
*

Sibai

,
Obstet

Gynecol.
2005
;
105
(
2
):
402
**

The Cochrane Systematic Review concluded
that :

There were no significant differences observed for
the major maternal outcomes of:



Death (RR=
1.25
;
95
%ci=
0.51
-
3.07
)



Cardiac arrest (RR=
0.34
;
95
%ci=
0.04
-
3.26
)


Respiratory arrest (
rr
=
1.02
;
95
%ci=
0.06
-
16.25
).

Doyle et al Cochrane Database
Syst

Rev.
2009

The Cochrane Systematic Review concluded
that :

Regarding secondary maternal outcomes,MgSO
4
therapy was associated with
significantly more
:


Hypotension (RR=
1.51
;
95
%ci=
1.09
-
2.09
)


Tachycardia (
rr
=
1.53
,
95
%ci=
1.03
-
2.29
).

There were
no differences
seen in rates of :


Maternal respiratory depression


Postpartum
haemorrhage



Caesarean delivery

Doyle et al Cochrane Database
Syst

Rev.
2009

Despite these
favourable

results, strong

Evidence is lacking with respect to
4
clinical


issues:.

1
-
The gestational age below which this
therapy should be offered.

2
. The optimal loading and maintenance
doses.

Doyle et al Cochrane Database
Syst

Rev.
2009

Costantine

et al
Obstet

Gynecol.
2009
;
114
(
2
Pt
1
):
354
.

Doyle
Obstet

Gynecol.
2009
;
113
(
6
):
1327
.

The
3
Meta
-
analyses
Conclusion :



Strong Evidence is lacking with (cont).


3
-

MgSO
4
has not been associated with ↓ in :

CNS pathology


Intraventricular

hemorrhage



White matter injury

Other adverse developmental outcomes


Developmental delay& neurological impairment.


Blindness


Deafness

The
3
Meta
-
analyses
Conclusion :



Doyle et al Cochrane Database
Syst

Rev.
2009

Costantine

et al
Obstet

Gynecol.
2009
;
114
(
2
Pt
1
):
354
.

Doyle
Obstet

Gynecol.
2009
;
113
(
6
):
1327
.

Strong Evidence is lacking with(cont.)


4
:There is no information on the effect of


MgSO
4
on outcomes beyond
2
years :


Age on learning disabilities



School difficulties & disabilities

The
3
Meta
-
analyses
Conclusion :



Doyle et al Cochrane Database
Syst

Rev.
2009

Costantine

et al
Obstet

Gynecol.
2009
;
114
(
2
Pt
1
):
354
.

Doyle
Obstet

Gynecol.
2009
;
113
(
6
):
1327
.

Validations : Clinical Practice Guidelines

And Committee Opinion

1
-

The
Australian
National Clinical Practice
Guidelines
March
2010
by the Antenatal
MgSO
4
for Neuroprotection Guideline
Development Panel.

2
-

The
ACOG

Committee Opinion on MgSO
4
for


Fetal Neuroprotection
March
2010
.

3
-

SOGC

Clinical Practice Guideline No.
258
,
May
2011

1
-

The Australian National Clinical
Practice Guidelines March
2010
.

In women at risk of early preterm imminent

Birth(expected within
24
Hs), use MaGS
4
for

neuroprotection of the fetus, infant and child:


The gestational age :
<
30
weeks

Dosage:
4
g IV loading dose, over
30
minutes.

followed by a
1
g/hr , maintenance infusion until


birth.

The Antenatal Magnesium
Sulphate

for Neuroprotection Guideline Development Panel. :
National Clinical Practice Guidelines. The Australian Research Centre for Health of Women
and Babies, The University of Adelaide;
2010
.

Grade A

Grade C

Grade A

2
-

The ACOG Committee Opinion on
MgSO
4
for March
2010
.

The available evidence suggests that
MgSO
4
given

before anticipated early preterm birth
reduces the

risk of cerebral palsy

in surviving infants.

No official opinion
was given on a gestational age


cut
-
off.

It was recommended that physicians develop

guidelines

around the issues of inclusion criteria,

dosage, concurrent tocolysis, and monitoring .

larger trials.

American College of Obstetricians and Gynecologists ACOG Committee on Obstetric
Practice; Society for Maternal
-
Fetal Medicine. Committee Opinion
19
. No.
455
:


Obstet

Gynecol.
2010
;
115
(
3
):
669
-
71
.

3
-

SOGC Clinical Practice Guideline
No.
258
, May
2011


Mgso
4
for Fetal Neuroprotection

Magee et al . SOGC Clinical Practice Guideline. Magnesium
sulphate

for fetal
neuroprotection. J
Obstet

14
.
Gynaecol

Can.
2011
;
33
(
5
):
516
-
29
.

Canadian Task Force on Preventive Health Care Recommendations

SOGC Clinical Practice Guideline

Canadian Task Force on Preventive Health Care Recommendations

SOGC Clinical Practice Guideline

For women with imminent preterm

birth (<
32
weeks), antenatal
MgSO
4


administration should be considered

for fetal neuroprotection. (I
-
A)

SOGC Clinical Practice Guideline No.
258
, May
2011

SOGC Guideline Recommendations

For women with imminent preterm birth (<
32

weeks), antenatal
MgSO
4

administration should

be considered for fetal neuroprotection. (I
-
A)

SOGC Clinical Practice Guideline No.
258
, May
2011

SOGC Guideline Recommendations

What is the Imminent Preterm Birth

One or both of the following conditions (II
-
2
):

1
-
Active
labour

with ≥
4
cm of cervical dilation,

with or without PPROM.

2
-
Planned preterm birth for fetal or maternal

indications.

What is the Imminent Preterm Birth

Imminent preterm birth” is defined as a high

likelihood of birth due to one or both of the

following conditions (II
-
2
):

1
-
Active
labour

with ≥
4
cm of cervical dilation,

with or without PPROM.

2
-
Planned preterm birth for fetal or maternal

indications.

SOGC Clinical Practice Guideline No.
258
, May
2011

What Is The Cut
-
off Gestational Age For
MgSO
4
?

Although there is controversy about upper


G. age ,antenatal MgSO
4
should be considered
from
viability to <
32
weeks
. (II
-
1
B)

SOGC Clinical Practice Guideline No.
258
, May
2011

If antenatal MgSO
4

has been started,
tocolysis

should be discontinued. (III
-
A)

Should MgSO
4
Course Be Repeated ?

There is insufficient evidence that a repeat

course of antenatal MgSO
4
should be
administered. (III
-
L)

SOGC Clinical Practice Guideline No.
258
, May
2011


Delivery should not be delayed if there are
maternal and/or fetal indications for
emergency delivery. (III
-
E)

Should Delivery Be Delayed To Give
MgSO
4
Course?

What Is The Recommended Dose ?

4
g Mg

SO
4

IV loading dose, over
30

minutes, followed by a maintenance

infusion of
1
g/ hours until birth or for
24

hours, whichever comes first.

.(II
-
2
B)

Mg SO
4
should be started, ideally within
4
hours before birth

.(II
-
2
B)

SOGC Clinical Practice Guideline No.
258
, May
2011

What Is The Recommended Dose ?

Although strong evidence supports the

use of antenatal MgSO
4
for
neuro
-


protection prior to very preterm birth,

no trials comparing different treatment
regimens have been completed.

Bain et al.
Cochrane

Database
SystRev
.
2012
Feb
15
;
2
:CD
009302

What Is The Recommended Dose ?

Research should be directed towards

comparisons of different dosages and

other variations in regimens, evaluating
both maternal and infant outcomes.

Bain et al.
Cochrane

Database
SystRev
.
2012
Feb
15
;
2
:CD
009302

Conclusions



MgSO
4
should be considered from viability to

31
+
6
weeks with imminent preterm birth.




The best available

evidence

recommended

dose is
4
g IV loading dose, over
30
minutes,

followed by a maintenance infusion of
1
g/ hours


until birth or for
24
hours, whichever comes first.

Thank You