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A Combination Treatment of
Prednisone, Aspirin, Folate, and
Progesterone in Women with
Idiopathic Recurrent
Miscarriage
A Matched-Pair
Study
Clement B. Tempfer, M.D., Christine Kurz, M.D., Eva-Katrin Bentz,
M.D., Gertrud Unfried, M.D.,
Katharina Walch, M.D., Ullrike Czizek, and Johannes C. Huber, M.D.,
Ph.D.

Fertility and Sterility Vol. 86, No.1, July 2006

Introduction
Recurrrent miscarriage :
3 consecutive pregnancy losses with the same partner
before 20weeks gestation
A standar diagnostic workup including :
Hysteroscopy
paternal & maternal karyotype
cervical culture for chlamydia, ureaplasma, & mycoplasma
A comprehensive hormonal status
Evaluation APS with IgM & IgG anticardiolipin antibody
assessment & lupus anticoagulant testing
40 60% are found to have none of these pathologies
Idiopathic Recurrent Miscarriage (IRM)
Fertility and Sterility Vol. 86, No.1, July 2006

Treatment strategies for IRM

Among corticosteroids, aspirin, heparin, &
leucocyte immunization
A series of uncontrolled prospective &
retrospective studies : live birth rates of up
to 75% after therapy cortisone with/without
aspirin
Reznikoff-Etievant : high-dose prednisone
(20mg/d) + aspirin (100mg/d) for the 1st
weeks of gestation in 277 IRM live birth
rate 90%
Fertility and Sterility Vol. 86, No.1, July 2006

contrary

Laskin compared
prednisone (0.5-0.8
mg/kg) + aspirin
(100 mg/d)
placebo
in 202 women no
difference in live
birth rates

contrary

In addition, a
systematic review of
5 controlled studies
on prednisone and
aspirin in women
with IRM found no
decrease in
miscarriage rates

Fertility and Sterility Vol. 86, No.1, July 2006

 A prospective randomized controlled trial :

Efficacy in women with IRM + concomitant
antiphospolipid syndrome :
Aspirin
low-molecular-weight heparin
a combination of both
a combination of both is superior

Fertility and Sterility Vol. 86, No.1, July 2006

 Up to 20% of women with IRM display

elevated serum levels of homocysteine.
In addition, polymorphisms associated with
an impaired folate metabolism are
overpresented among women with IRM.
therapeutic doses of folate is a biologic
rationale

Fertility and Sterility Vol. 86, No.1, July 2006

 Supplementation of progesterone in the 1 st

trimester of pregnancy has been used to
improve pregnancy outcome in IRM
Goldstein & Daya found that
progesterone significantly
improved pregnancy outcome
in women with recurrent
miscarriages

Fertility and Sterility Vol. 86, No.1, July 2006

 All these data demonstrate that prednisone,

aspirin, & progesterone have at least in some
trials efficacy in treating women with IRM
In case-control study, author compared clinical
outcomes & side effects in women treated with
prednisone + aspirin + folate + progesterone
and in women without treatment
They hypothesized that women with the
combination treatment would have a higher live
birth rate
Fertility and Sterility Vol. 86, No.1, July 2006

Objective
This study was undertaken to compare a
combination treatment of prednisone,
aspirin, folate, & progesterone with no
treatment in women with IRM
folate

prednisone

IRM

progesterone
aspirin
Fertility and Sterility Vol. 86, No.1, July 2006

Materials & Methods

Patients
A diagnosis of IRM was consistent with the
ACOG definition
A total of 210 consecutive women
March 2000 February 2005
A standard diagnostic workup
Approval from the Institutional Review
Board at the Medical University of Vienna
Fertility and Sterility Vol. 86, No.1, July 2006

 Treatment
All women with IRM were asked to participate
in a prospective mathced-pair study to evaluate
a combination treatment consisting of :
Progesterone (20 mg/d)

First 12w

Prednisone (20 mg/d)

Aspirin (100 mg/d)

IRM

Folate (5 mg/d)

All treatment was given orally

Fertility and Sterility Vol. 86, No.1, July 2006

210
210 Consecutive
Consecutive women
women
With
With recurrent
recurrent miscarriages
miscarriages

Flow Charts

80
80 women
women
Gave
informed
Gave informed consent
consent

130
130 women
women
Did
not
participate
Did not participate

52
52 women
women
Became
Became pregnant
pregnant

67
67 women
women
Become
Become pregnant
pregnant

52
52 women
women
Used
Used as
as controlls
controlls

40
40 live
live birth
birth

10
10 first
first trimester
trimester miscarriages
miscarriages
00 second
trimester
second trimester miscarriage
miscarriage

18
18 live
live birth
birth

11 ectopic
ectopic pregnancy
pregnancy
11 was
terminated
was terminated due
due to
to fetal
fetal
chromosome
chromosome abberation
abberation

33
33 first
first trimester
trimester miscarriages
miscarriages
11 second
trimester
second trimester miscarriage
miscarriage

Fertility and Sterility Vol. 86, No.1, July 2006

 Statistical Analysis
Variables of interest were described by
median, range, mean, & standard deviation in
case of skewed & normal distributions,
respectively
Differences between categorical variables
were compared by X2 test
Differences between paired continuous
variables were assessed by paired t-test after
checking for deviations of normality of
distribution according to Shapiro & Wilk
Fertility and Sterility Vol. 86, No.1, July 2006

Results

Fertility and Sterility Vol. 86, No.1, July 2006

210 consecutive women

With recuurent miscarriage

80 women
Gave informed consent

130 women
Did not participate

52 women
Became pregnant

67 women
Become pregnant

52 women
Used as controls

No significant difference in pregnancy rates (p=1.0)

Assigned to the control group after matching for age &
number of miscarriage

Fertility and Sterility Vol. 86, No.1, July 2006

52 women
Became pregnant

67 women
Became pregnant

52 women
Used as controls

40 live birth

10 first trimester miscarriage

0 second trimester miscarriage

16 live birth

1 ectopic pregnancy
1 was terminated due to fetal
Chromosome abberation

Overall live birth rates of the

treatment & control groups
were 77% & 18% (p=.04)

33 first trimester miscarriages

1 second trimester

Miscarriage :
1st trimester : 19% & 63% (p=.09)
2nd trimester : 0% & 2% (p=1.0)
Fertility and Sterility Vol. 86, No.1, July 2006

 Premature birth among the treatment &

controll groups, 2 (4%) & 3 (6%)
Occurred in 27th & 24th weeks
Due to severe preeclampsia
& cervical insufficiency

Cushings disease & IUGR were

not observed

Fertility and Sterility Vol. 86, No.1, July 2006

Discussion
Progesterone (20 mg/d)

First 12w

Prednisone (20 mg/d)

Aspirin (100 mg/d)

38

IRM
Eve

ry s
e

Folate (5 mg/d)
con

d da

Preterm birth or IUGR

were not increased

42% higher live birth rate

In accordance with data by Reznikoff-Etievant suggesting that prednisone treatment limited to the
1st trimester may be effective , while not being associated with an increased rate of side effect
Fertility and Sterility Vol. 86, No.1, July 2006

dosage

duration

High-dose treatment covering the 1st trimester might

deliver antiinflammatory
protection during the most
sensitive period
Folate neuroprotection
might severely limit the protective effect of corticosteroids
Fertility and Sterility Vol. 86, No.1, July 2006

Conclusion
This study indicate that combinatiion
treatment consisting of high-dose, lowduratiion
prednisone
&
aspirin,
progesterone, and folate might be
effective treatment for women with IRM

Fertility and Sterility Vol. 86, No.1, July 2006

Critical Appraisal

 Design of study is a matched-pair

case-control study
The strength of this study
1. All participant managed in equal manner
2. The treatment scheme was covering the full
length of early pregnancy
3. There is an appropriate group of control

Fertility and Sterility Vol. 86, No.1, July 2006

 Several limitations
1. The number of participants included in this study is low

2.

Does not allow for ruling out small differences in unwanted

side effects
Thus, the safety of this treatment cannot be established

Participants were compared in a matched-pair design

3.

Possible selection bias

The investigator have not karyotyped the aborted

pregnancy tissued, therefore, are not able to differentiate
between euploid & aneuploid miscarriages

It could be speculated that the efficacy of the treatment would

be greater if women with aneuploid miscarriages are excluded

Fertility and Sterility Vol. 86, No.1, July 2006

 How were the cases obtained?

Women who visited investigator outpatient clinic for
recurrent miscarriage eligible based on a documented
history of IRM, underwent a standard diagnostic
procedures, then, asked to participate in this study
Is the control group appropriate?
Yes, the number of women in control group is equal with
treatment group
Were data collected the same way for cases
and controls?
Yes, there were. The data collected retrospectively and
prospective by observe all women from the beginning the
treatment, throughout prenancy period, until termination or
delivery
Fertility and Sterility Vol. 86, No.1, July 2006

 Are the aims clearly stated?

Yes, the aim of this study was undertaken to
compare a combination treatment of
prednisone, aspirin, folate, & progesterone
with no treatment in women with IRM
Is the method appropriate to the
aims?
Yes, although this is a case-control study,
there were a prospective observation of
intervention
Fertility and Sterility Vol. 86, No.1, July 2006

 Where are the biases?

There possible selection bias because participants were

compared in a matched-pair design
Could there be confounding?

All women underwent a standard diagnostic procedures to rule

out any causes of recurrent miscarriages.

Only one small counfounder, investigator have not karyotyped

the aborted pregnancy tissued, therefore, are not able to
differentiate between euploid & aneuploid miscarriages
Was there data-dredging?

No, the study just collect some important & accordant data for
statistical analysis to objective of study
Fertility and Sterility Vol. 86, No.1, July 2006

Are the results of this study valid?

The aim of this study are clearly stated.

There is appropriate qualitative methodology.
The studys sampling strategy is appropriate to adress the aims.
The studys findings are clear & easy to understand.

Are the results of this study important?

Yes, the study results are important because there
were are significantly
different between treatment and no treatment group

Can I apply these valid, important findings

to my patient ?

Yes, I can apply the study findings for managing women with IRM
Fertility and Sterility Vol. 86, No.1, July 2006

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