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Gynecol Endocrinol, 2015; 31(6): 447–449

! 2015 Informa UK Ltd. DOI: 10.3109/09513590.2015.1017459

PROGESTOGENS IN MISCARRIAGE

European Progestin Club Guidelines for prevention and treatment of

threatened or recurrent (habitual) miscarriage with progestogens
Adolf E. Schindler1, Howard Carp2, René Druckmann3, Andrea R. Genazzani4, Johannes Huber5, Jorge Pasqualini6,
Karl W. Schweppe7, and Julia Szekeres-Bartho8
1
Institute for Medical Research and Education, University Clinic, Essen, Germany, 2Department of Obstetrics & Gynecology, Sheba Medical Center,
Tel Hashomer, Israel, 3Department of Gynecology, ANEMO – Menopausecenter, Nice, France, 4Department of Obstetrics and Gynecology, University
of Pisa, Pisa, Italy, 5Department of Obstetrics and Gynecology, Division of Gynecologic Endocrinology and Reproductive Medicine, University of
Vienna, Vienna, Austria, 6Hormones and Cancer Research Unit, Paris, France, 7Endometriosis Center Ammerland, Westerstede, Germany, and
8
Department of Medical Microbiology and Immunology, Medical School Pecs University, Pecs, Hungary

Abstract Keywords
This guideline has been developed based on studied and clinical investigations. Therefore, it Miscarriage, prevention, progestogens
appears to be appropriate to use all the available evidence, which are very encouraging, in a
summarized form to propose guidelines by a group of European experts in order to give the History
gynecologists, obstetricians and reproductive medicine specialists have direction with regard to
the prevention or treatment of miscarriage for the benefit of the endangered pregnancies. Received 23 December 2014
There are a number of statements, opinions and guidelines already published for this topic, Accepted 6 February 2015
which are not entirely in agreement. Published online 15 May 2015

Introduction These publications are the following:

The European Progestin Club (EPC) was founded in 1996. Since
then, a total of 21 symposia of the EPC were held mostly in
connection with congresses such as the World Congress of the
International Society of Gynecological Endocrinology, World
Congress of the International Menopause Society, European
Congresses by EMAS and ESG among others.
Besides the seven founding members (Schindler, Campagnoli,
Druckmann, Huber, Pasqualini, Schweppe, Thijssen), many guests
have been involved (Bouchard, Genazzani, Gompel, Mueck,
Sitruk-Ware, Skouby, Soederquist, Stanczyk, Zaimul).
Until now, 134 peer-reviewed papers have been published,
mostly in International journals such as Gynecological
Endocrinology, Journal Steroid Biochemistry and Molecular
Biology, Maturitas, Hormone Molecular Biology and Clinical
Investigation.
This guideline has been developed based on studies and
clinical investigations. Therefore, it appears to be appropriate to
use all the available evidence, which are very encouraging, in a
summarized form to propose guidelines by a group of European
experts in order to have the gynecologists, obstetricians and
reproductive medicine specialists have direction with regard to
the prevention or treatment of miscarriage for the benefit of the
endangered pregnancies. There are a number of statements,
opinions and guidelines already published for this topic, which are
not entirely in agreement.
(1) Royal College of Obstetricians and Gynecologists
Guidelines, 2011 [1] (RCOG)
(2) Indonesian Obstetric and Gynecologic Society 2011 [2].
(3) Statement of the Australian and New Zeeland Royal College
of Obstetricians and Gynecologists last reviewed March 2013
(RANZCOG)
(4) Practice Committee of the ASRM 2013 [4].
(5) NICE Guidelines 2012, [5] Clinical guidelines.
(6) NICE Guidelines 2013, [6] Miscarriage – NICE CKS.
(7) Saudi Society of Obstetrics and Gynecology Guidelines,
2014 [7].
Terms and definitions
This guideline addresses two types of miscarriages:
(1) Threatened miscarriage
(2) Recurrent (habitual) miscarriage
(1) Threatened miscarriage is the diagnosis for the pregnant
patient of less than 20 weeks gestation, who presents with
vaginal bleeding and no cervical dilation or effacement.
These patients may present with spotting to severe vaginal
bleeding of several hours to days in duration [8]. The time
span is up to 24 weeks of gestation [6].
(2) Recurrent (habitual) miscarriage can be based on obstetrical
history with two or more spontaneous consecutive miscar-
riages (RCOG, [3]) or defined as three consecutive spontan-
eous recurrent pregnancy losses or more [3].

Hormonal and biochemical background

Address for correspondence: Prof. Dr. Adolf E. Schindler, Institute for
Medical Research and Education, University Clinic, Hufelandstrasse 55, Progesterone is the dominant hormone throughout pregnancy in
D-45122 Essen, Germany. Tel: +49-201-7991833. Fax: +49-201- the human. It is not only essential for conception and implant-
7499533. E-mail: adolf.schindler@uni-due.de ation, but also throughout pregnancy until term [9,10]. The first
448 A. E. Schindler et al.
trimester of pregnancy is characterized by the activity of the
corpus luteum up to 8 weeks of gestation and thereafter
progesterone production and secretion starts to be taken over by
the placenta, creating the so-called luteoplacental shift between 8
and12 weeks of gestation. During this time there can be a plateau
of circulating endogenous progesterone or even a decrease [9,10].
This is the time, where most of the clinical symptoms of
threatened or recurrent (habitual) miscarriages occur. Biologically
spoken: this is a time period that is weak in respect to endogenous
progesterone, particularly when there is a disturbance of the
luteal-placental shift, which can be due to either a limited corpus
luteum function or a delay and/or a deficiency of placental
progesterone production and secretion [9,10]. Also in cases with
ovulation induction where mostly progesterone at the beginning
can be quiet high, a rapid decrease of progesterone occurs
inducing a progesterone withdrawal bleed as the basis of the
clinical signs of threatened miscarriage [10]. Overall, during
the first trimester, spontaneous miscarriage can occur in up to
10–20% [11,12]. In women with various risk factors (such as
corpus luteum insufficiency, all women undergoing ART proced-
ures like IVF and ICSI), women with a history of recurrent
(habitual) miscarriage and also pregnant women under definite
stress suffer from a decrease of endogenous progesterone [13].
Treatment approach for pregnant women with the
diagnosis of threatened miscarriage
The Wahabi et al. [14] and then updated Wahabi et al. [15]
Cochrane review on progestogen for treating threatened miscar-
riage were reviewed. Wahabi [14] Cochrane review of progester-
one in threatened miscarriage included only two studies (84
participants) of vaginal progesterone. The first study was Gerhard
et al. [16] This study compared vaginal progesterone supposi-
tories 25 mg twice daily with placebo, which were both given
until the women miscarried or 14 days after bleeding stopped.
Only 34 out of 56 women had fetal viability confirmed by
ultrasound and were therefore included in the meta-analysis. The
progesterone used followed galenic process from 1976. The
second study compared vaginal micronized progesterone gel
90 mg once daily with placebo, which were both given for five
days [17]. All participants met the inclusion criteria for the meta-
analysis. The final conclusion was that there was no evidence of
effectiveness with the use of vaginal progesterone compared to
placebo in reducing the risk of miscarriage (relative risk 0.47;
95% confidence interval [CI] 0.17–1.30). Thus, there was no
evidence to support the routine use of vaginal progesterone for the
treatment of threatened miscarriage. The author concluded based
on scarce data from two methodologically poor trials, there is no
evidence to support the routine use of progestogens for the
treatment of threatened miscarriage.
Wahabi updated the Cochrane review in 2011 and included
two additional trials with dydrogesterone that had been recently
published [18] and, [19] increasing the number of participants
from 84 to 421.There was evidence of a reduction in the rate of
spontaneous miscarriage with the use of progestogens compared
to placebo or no treatment (risk ratio [RR] 0.53; 95% confidence
interval [CI] 0.35–0.79). It was concluded that the use of
progestogens is effective in the treatment of threatened miscar-
riage with no evidence of increased rates of pregnancy-induced
hypertension, antepartum hemorrhage or congenital abnormalities
in the newborn. However, the power of the meta-analysis was
limited by the studies.
The third systematic review by Carp [20] included the largest
number of participants (n ¼ 660 from five dydrogesterone trials)
and offered more robust conclusions than those provided by the
previous two systematic reviews [14,15]. The results showed a
Gynecol Endocrinol, 2015; 31(6): 447–449
statistically significant reduction with dydrogesterone in the odds
ratio for miscarriage compared to standard care of 0.47 (confi-
dence interval [CI] ¼ 0.31–0.7). It was noted that as two of the
trials included were published as early as 1967, bias could not be
assessed. However, omitting these two trials from the meta-
analysis still demonstrated a decreased rate of miscarriage in the
treatment group compared to standard care (odds ratio 0.42,
CI ¼ 0.25–0.69).
In conclusion, for women presenting with a clinical diagnosis
of threatened miscarriage, there is now data from meta-analyses
of several small studies which suggest that the progestogen,
namely dydrogesterone, is better than placebo or no therapy in
reducing the rate of spontaneous miscarriage. This would cover
the critical area of the luteo-placental progesterone shift.
Additional well-designed studies are recommended to confirm
these findings.
Recommendation 1
For women presenting with a clinical Consensus-based
diagnosis of threatened miscarriage, recommendation [15,20].
there is a reduction in the rate of
spontaneous miscarriage with the
use of dydrogesterone.
Prevention for women with a history of recurrent
(habitual) miscarriage
The Haas & Ramsey, [21] Cochrane systematic review analyzed
the use of progestogens for the prevention of miscarriage up to 20
weeks gestation compared with placebo or no treatment. No
restrictions were placed on past obstetric history, meaning this
review included those with threatened miscarriage as well as with
recurrent miscarriage. Randomized or quasi-randomized trials
were included and various treatment formulations. The main
results showed there was no evidence of reduction of miscarriage
by progestogen and there was no evidence of reduction by route of
administration (oral, vaginal, intramuscular) when threatened
miscarriage and recurrent miscarriage studies were evaluated
together.
In a subgroup analysis of four trials involving women who had
recurrent miscarriages (three or more consecutive miscarriages
[four trials, n ¼ 225], two dydrogesterone studies [22,23], one
medroxyprogesterone study and one study where progesterone
pellets were inserted within the gluteal muscle), progestogen
treatment showed a statistically significant decrease in miscar-
riage rate compared to placebo or no treatment (Peto odds ratio
[OR] 0.39; 95% confidence interval [CI] 0.21–0.72). However,
these four trials were of poorer methodological quality. There
were no significant differences in the rates of preterm birth,
neonatal death or fetal genital anomalies/virilization were found
between progestogen therapy versus placebo/control. No studies
reported adverse maternal effects.
Kumar et al. [24] recently published the results from a double-
blind, randomized, parallel group, placebo-controlled study on the
effect of dydrogesterone during early pregnancy on pregnancy
outcome and its correlation with Th1 and Th2 cytokine levels.
Treatment was given from confirmation of pregnancy to 20 weeks
of gestation. The study was run in one of the key public hospitals
for maternity services in India, and was solely funded by a
government grant. In addition to the 360 women with a history of
3first-trimester pregnancy losses, the Indian Council of Medical
Research requested that 180 healthy pregnant women with no
history of miscarriage and at least 1 live birth be recruited
as controls. All women with a live pregnancy were enrolled at
4–8 weeks of gestation and followed up until 20 weeks of
gestation. The study showed a lower miscarriage rate with
DOI: 10.3109/09513590.2015.1017459
dydrogesterone (6.9%) compared to placebo (16.8%; RR 2.4; 95%
CI 1.3–5.9). The mean gestational age at delivery was also higher
in the dydrogesterone group.
In conclusion, for women presenting with a history of three or
more recumbent miscarriages, there is now data from a meta-
analysis of several small studies and a large double-blind,
randomized, parallel group, placebo-controlled study which
suggest that the progestogens, namely dydrogesterone is better
than placebo in reducing the rate of miscarriage.
Recommendation 2
For women presenting with a clinical Consensus-based
diagnosis of recurrent miscarriage, recommendation [21,24].
3 or more, there is a reduction in
the rate of miscarriage with the use
of dydrogesterone.
Declaration of interest
The authors report no conflicts of interest.
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