a combination treatment of prednisone aspirin folate and progesterone in women with idiopathic...

A Combination Treatment of Prednisone, Aspirin, Folate, and

Progesterone in Women with Idiopathic Recurrent

MiscarriageA 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

IntroductionRecurrrent 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)


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%


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



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

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


Supplementation of progesterone in the 1st 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

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


Objective

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


prednisone

progesterone

aspirin

folate

IRM

Materials & MethodsPatients

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


Treatment All women with IRM were asked to participate in

a prospective mathced-pair study to evaluate a combination treatment consisting of :

All treatment was given orallyFertility and Sterility® Vol. 86, No.1, July 2006

Prednisone (20 mg/d) Folate (5 mg/d)

Progesterone (20 mg/d) Aspirin (100 mg/d)

IRMFirst 12w

38 w

Every second day


Flow Charts80 women

Gave informed consent

210 Consecutive womenWith recurrent miscarriages

52 womenBecame pregnant

1 ectopic pregnancy1 was terminated due to fetal

chromosome abberation

130 womenDid not participate

67 womenBecome pregnant

52 womenUsed as controlls

18 live birth

33 first trimester miscarriages1 second trimester miscarriage

10 first trimester miscarriages0 second trimester miscarriage

40 live birth

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


Results



No significant difference in pregnancy rates (p=1.0)

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

210 consecutive womenWith recuurent miscarriage

80 womenGave informed consent


130 womenDid not participate

67 womenBecome pregnant

52 womenUsed as controls


Miscarriage :1st trimester : 19% & 63% (p=.09)2nd trimester : 0% & 2% (p=1.0)

Overall live birth rates of the treatment & control groups were 77% & 18% (p=.04)



52 womenUsed as controls

40 live birth

10 first trimester miscarriage0 second trimester miscarriage

1 ectopic pregnancy1 was terminated due to fetal

Chromosome abberation

16 live birth

33 first trimester miscarriages1 second trimester


Premature birth among the treatment & controll groups, 2 (4%) & 3 (6%)

• Occurred in 27th & 24th weeks• Due to severe preeclampsia

& cervical insufficiency

Cushing’s disease & IUGR were not observed

Discussion


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

Prednisone (20 mg/d) Folate (5 mg/d)

Progesterone (20 mg/d) Aspirin (100 mg/d)

IRM

42% higher live birth rate

Preterm birth or IUGR were not increased

First 12w

38 w

Every second day


High-dose treatment cover-ing the 1st trimester might deliver antiinflammatory protection during the most sensitive period

Folate neuroprotection might severely limit the pro-tective effect of cortico-steroids

duration

dosage

Conclusion


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

Design of study is a matched-pair case-control study

The strength of this study1. All participant managed in equal manner2. The treatment scheme was covering the full

length of early pregnancy3. There is an appropriate group of control


Several limitations1. The number of participants included in this study is low

• Does not allow for ruling out small differences in unwanted side effects

• Thus, the safety of this treatment cannot be established2. Participants were compared in a matched-pair design

• Possible selection bias3. 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


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


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


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



Are the results of this study valid? The aim of this study are clearly stated. There is appropriate qualitative methodology. The study’s sampling strategy is appropriate to adress the aims. The study’s 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

a combination treatment of prednisone aspirin folate and progesterone in women with idiopathic...

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