Professor Soo Downe presenting at the Doctoral Midwifery Research Society Alcohol & Medication in Pregnancy Conferene about 'Which horse for which courses? The EBM Problem in studies of pharmacological substances in maternity care'.

1. ‘Which
horses
for
which
courses?
The
EBM
Problem
in
studies
of
pharmacological
substances
in
maternity
care
Soo
Downe
University
of
Belfast
September
10th
2015
Alcohol
&
Medica-ons
in
Pregnancy:
Sharing
Research
Evidence
on
Recrea-onal
and
Prescribed
Substances.
Penthouse
Suite,
Europa
Hotel
Belfast.
With
thanks
to
all
who
gave
permission
for
their
images
to
be
used

2. CreaGng
formal
acceptable
knowledge

3. • Theory-­‐pracGce
gap
• ‘Ivory
towers’
and
real
life…

4. On
the
high
ground,
manageable
problems
lend
themselves
to
soluGon
through
the
applicaGon
of
research
method
and
theory…

5. ‘In
the
swampy
lowland,
messy
confusing
problems
defy
technical
soluGon..
[these
are]…
the
problems
of
greatest
human
concern’
Schon
1983
The
Reflec1ve
Prac11oner:
How
professionals
think
in
ac1on.
London:
Temple
Smith, p14

6. Impact
of
medicaGons
during
pregnancy
on
the
fetus
…A
2011
study
of
medica1ons
approved
by
the
Food
and
Drug
Administra1on
(FDA)
from
1980
through
2010
found
that
91%
of
the
medica1ons
approved
for
use
in
adults
lacked
sufficient
data
to
determine
the
risk
of
birth
defects
due
to
use
of
[those]
medica1ons
during
pregnancy….

7. Why
this
maSers…
DiethylsGlbestrol
(DES)
• Oestrogen
mimic
• Used
from
the
1940s
to
the
1970s
to
prevent
miscarriage.
Impact
on
1st
genera1on
• Increased
risk
of
breast
cancer
(approximately
doubled
in
exposed
women).

8.
US
NaGonal
Cancer
InsGtute
DES
follow-­‐up
study:
1992
onwards
(Hoover
et
al
2011)

9. How
did
we
know
this?
“Our
study…documents
elevated
risk
for
DES-­‐exposed
daughters
for
a
host
of
medical
problems—many
of
them
also
quite
common
in
the
general
populaGon…
Without
the
senGnel
finding
of
a
very
rare
cancer
in
young
women,
and
without
the
sustained
follow-­‐up
of
those
who
were
exposed,
we
would
not
know
the
full
extent
of
harm
caused
by
DES
exposure
in
the
womb.”
Robert
N.
Hoover,
M.D.,
director
of
the
Epidemiology
and
Biosta1s1cs
Program
in
NCI’s
Division
of
Cancer
Epidemiology
and
Gene1cs.

10. Impact
on
future
generaGons…
?
EpigeneGc
influence?
Impact
on
3rd
genera1on
• QuesGonnaire
to
793
women
whose
mothers
had
documented
in-­‐
utero
DES
exposure.
• Mean
age
of
menstruaGon
the
same
• Daughters
of
exposed
women
regularized
menstruaGon
later
(mean
16.2
years
vs.
15.8
years;
p
=
0.05),
• More
likely
to
report
irregular
menstrual
periods
(
OR
=
1.54
(95%
CI
1.02-­‐2.32))
• Daughters
of
exposed
women
had
fewer
live
births
(1.6)
than
the
unexposed
(1.9)
(P
=
0.005).

11. The
current
situaGon
in
terms
of
drugs
and
pregnancy
(USA)
(Adam
et
al
2011)
• Majority
of
women:
at
least
one
medicaGon
during
pregnancy
• Review
of
safety
of
172
drugs
approved
by
FDA
from
2000
to
2010,
and
468
drugs
approved
1980-­‐2000
• TERIS
risk
raGng
system
• Teratogenic
risk
in
human
pregnancy
"undetermined"
for
168
(97.7%)
of
drug
treatments
approved
between
2000
and
2010.
• No
data
regarding
safety
available
for
126
(73.3%)
of
these
drugs.

12. We
are
doing
beSer
now…?
(Adam
et
al
2011
cont)
Drugs
approved
between
1980
and
2000:
only
23
(5%)
changed
a
full
risk
category
or
more
in
the
past
10
years.
Revised
risks
were
derived
from:
exposure
cohort
studies/record
linkage
studies,
teratogen
informaGon
services,
large
populaGon-­‐based
case-­‐control
studies
pregnancy
registries
(animal
studies?)
The
mean
Gme
for
a
treatment
to
move
from
an
"undetermined"
risk
to
be
assigned
a
more
precise
risk
was
27
years
(95%
confidence
interval
26-­‐28
years)

13. Unknown
unknowns…

14. Pregnant
women
who
need
medicaGon..
Women
with
epilepsy
(+/-­‐
anG-­‐epilepGcs)
vs
no
epilepsy
.
outcome
OR
95%
CI
for
OR
miscarriage
1.54
1·∙02-­‐2·∙32
APH
1.49
1·∙01-­‐2·∙20
PPH
1.29
1·∙13-­‐1·∙49
Hypertension
1.37
1·∙21-­‐1·∙55
InducGon
1.67
1·∙31-­‐2·∙11
CS
1.40
1·∙23-­‐1·∙58
Preterm
birth
1.16
1·∙01-­‐1·∙34
Fetal
growth
restricGon
1.26
1·∙20-­‐1·∙33

16. RouGne
use
of
medicaGon
for
all/most:
and
what
about
labour?
• Short
term
benefits/long
term
risks?
• Why
are
drugs
our
default
posiGon?
• AlternaGves
with
less
risks?
– InducGon
of
labour
to
reduce
CS
in
healthy
women
and
babies
(:
OR
– RelaGonship
based
conGnuity
of
care/out
of
hospital
birth
(added
benefits
for
preterm
birth)

17. ‘AlternaGve’
sesngs
(Cochrane
review)
Hodnett ED, Downe S, Walsh D, Weston J 2010"
• for
the
care
of
pregnant
women
who
prefer
and
require
liSle
or
no
medical
intervenGon.
•
The
sesngs
may
offer
care
throughout
pregnancy
and
birth,
or
only
during
labour;
• they
may
be
part
of
hospitals
or
freestanding
enGGes.

18. AlternaGve
sesngs:
findings
10 trials; n = 11795
-­‐ reduced
likelihood
of
medical
intervenGons
-­‐ increased
likelihood
of
:
-­‐ spontaneous
vaginal
birth,
-­‐ maternal
saGsfacGon
-­‐ conGnued
breasueeding
at
1-­‐2
months
postpartum
-­‐
no
risks
to
mother
or
baby.

19. Birthplace
UK
• Birth
is
generally
very
safe
(4.3/1000
adverse
events).
• MLU’s
(alongside
or
freestanding:
safe
for
the
baby,
benefits
for
the
mother
• significantly
fewer
intervenGons,
(fewer
intrapartum
caesarean
secGons,
and
more
‘normal
births’)
than
planned
birth
in
an
obstetric
unit.
• Mul-parous
women:
home
births
and
midwifery
unit
births
safe
for
the
baby,
benefits
for
the
mother

20. Midwife
led
care:
evidence
Sandall
et
al
2013
• 13
trials
involving
16,242
women
• Women
who
had
midwife-­‐led
conGnuity
models
of
care
were
less
likely
to
experience:
– regional
analgesia
(RR
0.83,
95%
CI
0.76
to
0.90)
– episiotomy
(
RR
0.84,
95%
CI
0.76
to
0.92),
– instrumental
birth
(RR
0.88,
95%
CI
0.81
to
0.96)
– preterm
birth
(
RR
0.77,
95%
CI
0.62
to
0.94)
– fetal
loss
before
24
weeks'
gestaGon
RR
0.81,
95%
CI
0.66
to
0.99),

21. Sweden
oxytocin
outcomes:
neonate
Effects
of
induc1on
and
augmenta1on
• Oxytocin
use
and
Apgar
score
<
7
at
5
min
– OR
2.3;
95%
CI
1.8-­‐2.9
• Need
for
neonatal
intensive
care
– OR
1.6;
95%
CI
1.5-­‐1.7)
• OperaGve
birth
– OR
4.0;
95%
CI
3.7-­‐4.2).

22. Longer
term
risks
of
the
use
of
oxytocin?
Induced
foals
up
to
10
days
postnatal
(Holdstock
et
al
2012)
• Differences
in
pancreaGc
endocrine
cell
funcGon
with
delivery
method
were
associated
with
2-­‐3
fold
higher
corGsol
levels
in
the
induced
foals
and
with
differences
in
the
absolute
and
age-­‐related
changes
in
basal
concentraGons
of
glucose,
alpha-­‐amino
nitrogen
and
insulin.
• Induced
delivery
leads
to
changes
in
pancreaGc
beta
cell
sensiGvity
to
glucose
and/or
Gssue
insulin
resistance
in
associaGon
with
persistent
neonatal
hypercorGsolaemia.

23. …pregnancy
and
birth
intervenGons
and
non-­‐
communicable
disease…?
• ?Feedback
loops
between
the
hormonal/
physiological
effects
of
pregnancy
and
birth
and
outcomes
for
the
baby
in
later
life:
• Type
1
diabetes
• Eczema
• Asthma
• MulGple
sclerosis
• Some
cancers
(esp
acute
lymphoblasGc
leukemia)
• Obesity
• Etc….
• …changes
in
white
blood
cell
DNA-­‐methylaGon
in
cord
blood

24. Complex
interplay
between
genes,
epigeneGcs,
life
experiences,
and
our
‘Old
Friends’?

25. What
the
World
Health
OrganisaGon
says:
• ….Generally,
between
70
and
80%
of
all
pregnant
women
may
be
considered
as
low-­‐risk
at
the
start
of
labour.
• ….The
uncriGcal
adopGon
of
a
range
of
unhelpful,
unGmely,
inappropriate
and/or
unnecessary
intervenGons,
all
too
frequently
poorly
evaluated,
is
a
risk
run
by
many
who
try
to
improve
the
maternity
services…..
WHO
hSp://www.who.int/reproducGvehealth/publicaGons/MSM_96_24/
MSM_96_24_Chapter1.en.html

26. Taking
account
of
the
mother
baby
dyad:
InverGng
the
evidence
hierarchy
for
pharmacological
research…?
• Cohort
studies
• Case-­‐control
studies
• PragmaGc
RCT’s…
• (mulGmethod)
systemaGc
reviews..

27. SystemaGc
reviews
with
individual
level
data

28. N
of
one
(?two?)
studies

30. Personalised
medicine

31. Taking
account
of
placebo…
Studies
of
doctors
and
diabeGc
paGents
Hojat
et
al
2013
• Study
one:
29
family
physicians.
891
paGents
(USA)
– physicians’
higher
scores
on
the
Jefferson
Scale
of
Empathy
significantly
associated
with
indicators
of
diabeGc
control
• Study
two:
242
general
pracGGoners,
20
961
paGents
(Italy)
– associaGon
between
higher
physician
empathy
and
lower
incidence
of
acute
metabolic
complicaGons
that
required
hospitalisaGon

32. The
real
effect
of
placebo
even
in
randomised
trials
(issues
of
generalisibility
of
size
of
effect?)
• Pain
relief
scores.
• 5
placebo-­‐controlled
single-­‐dose
parallel-­‐group
RCTs
in
acute
postoperaGve
pain
• 130/525
had
a
placebo.
• Scores
varied
from
0
to
100%
maximum
possible
pain
relief.
• >
50%
maximum
possible
pain
relief
across
trials:
– 7%
to
37%
with
placebo
– 5
to
63%
with
acGve
drugs

33. Untangling
to
Gordian
knot:
Finding
out
what
works…beyond
RCT’s
• Full
range
of
standard
quanGtaGve
methods
• QualitaGve
research
• Realist
research
• Mixed
methods…
• Views
of
stakeholders,
including
service
users

34.
Gesng
the
balance
right..

35. From
knowledge
hierarchies
to
a
knowledge
matrix
Pescrew
M
Roberts
H
2003
Evidence,
hierarchies,
and
typologies:
horses
for
courses
J
Epidemiol
Community
Health
2003;57:527-­‐529

36. Horses
for
courses:
squaring
the
circle

37. Adam
MP1,
Poli~a
JE,
Friedman
JM.
Evolving
knowledge
of
the
teratogenicity
of
medicaGons
in
human
pregnancy.
Am
J
Med
Genet
C
Semin
Med
Genet.
2011
Aug
15;157C(3):175-­‐82.
doi:
10.1002/ajmg.c.30313.
Epub
2011
Jul
15.
Hojat
M,
Louis
DZ,
Maio
V,
Gonnella
JS.
Empathy
and
health
care
quality.
Am
J
Med
Qual.
2013
(1):6-­‐7.
doi:
10.1177/1062860612464731.
Holdstock
NB,
Allen
VL,
Fowden
AL.
PancreaGc
endocrine
funcGon
in
newborn
pony
foals
a€er
induced
or
spontaneous
delivery
at
term.
Equine
Vet
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Suppl.
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Feb;(41):30-­‐7.
Hoover
RN,
Hyer
M,
Pfeiffer
RM,
Adam
E,
Bond
B,
Cheville
AL,
Colton
T,
Hartge
P,
et
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Adverse
Health
Outcomes
in
Women
Exposed
In
Utero
to
DiethylsGbestrol.
NEJM.
Oct.
6,
2011.
6,500
women
(4,600
exposed
and
1,900
unexposed),
Lillie
EO1,
Patay
B,
Diamant
J,
Issell
B,
Topol
EJ,
Schork
NJ
The
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clinical
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the
ulGmate
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for
individualizing
medicine?
Per
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161-­‐173.
McQuay
H
Carroll
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Moore
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VariaGon
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in
randomised
controlled
trials
of
analgesics:
all
is
as
blind
as
it
seems
Pain
64
(
2)
331–335

38.
Oscarsson
ME,
Amer-­‐Wåhlin
I,
Rydhstroem
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Källén
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TJ,
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M
EpigeneGc
modulaGon
at
birth
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white
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a€er
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PracGGoner:
How
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think
in
acGon.
London:
Temple
Smith,
p14
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Troisi
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Hatch
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