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PERSPECTIVES

The Role Of Progestogens In Threatened And

Idiopathic Recurrent Miscarriage
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Hisham Arab 1 Abstract: It is well known that progesterone plays a major role in the maintenance of
Ahmed Jaber Alharbi 2 pregnancy, particularly during the early stages, as it is responsible for preparing the endo-
Ayman Oraif 3 metrium for implantation and maintenance of the gestational sac. The management of
Emad Sagr 4 pregnant women at risk of a threatened or idiopathic recurrent miscarriage is complex and
critical. Therefore, a group of obstetricians and gynecologists practicing in Saudi Arabia
Hana Al Madani 5
gathered to update the 2014 Saudi guidelines for threatened and recurrent miscarriage
Hassan Abduljabbar 3
For personal use only.

management. In preparation, a literature review was conducted to explore the role of oral,
Osama Sadeak Bajouh 3
vaginal, and injectable progestogens: this was used as a basis to develop position statements
Yaser Faden 6 to guide and standardize practice across Saudi Arabia.
Yasser Sabr 7 Keywords: idiopathic recurrent miscarriage, progesterone, progestin, progestogen, Saudi
1
Obstetrics and Gynecology Arabia, threatened miscarriage
Department, Dr. Arab Medical Center,
Jeddah, Saudi Arabia; 2Obstetrics and
Gynecology Department, Ibinsina Medical
Private College, Jeddah, Saudi Arabia; Introduction
3
Department of Obstetrics and It is estimated that about 70% of conceptions are lost prior to live birth: 30% due to
Gynecology, King Abdulaziz University,
Jeddah, Saudi Arabia; 4Obstetrics and implantation failure, 30% following implantation but before a missed period, and
Gynecology Department, The about 10% as clinical miscarriage.1 Despite considerable advances in science and
International Medical Center, Jeddah,
Saudi Arabia; 5Obstetrics and technology, preventing and managing patients at risk of clinical miscarriage in early
Gynecology Department, Maternity pregnancy continues to be a distressing problem.2 The possible causes of miscar-
Hospital – King Saud Medical City,
Riyadh, Saudi Arabia; 6Department of riage, which can be broadly divided into two categories, are listed in Table 1.2–4
Obstetrics and Gynecology, King Saud bin
Abdulaziz University for Health Sciences –
Ministry of National Guard Health Affairs, The Role Of Hormones In Pregnancy
Jeddah, Saudi Arabia; 7Maternal Fetal Pregnancy is a hormone-mediated physiological state that involves a decrease in
Medicine Division, Department of
Obstetrics and Gynecology, College of uterine vascular tone and an increase in uterine blood flow.5 Progesterone and
Medicine, King Saud University, King Khalid estrogen are two key hormones that remain elevated during pregnancy and play
University Hospital, Riyadh, Saudi Arabia
significant roles in causing anatomical adjustments within the uterus to create an
environment conducive to fetal growth.5
Progesterone, rightly called the “pregnancy hormone”, is crucial in the main-
tenance of pregnancy as it is involved in modulation of the maternal immune
response, suppression of inflammatory response, reduction of uterine contractility,
improvement of utero-placental circulation, and luteal-phase support.6 Particularly
in early pregnancy, progesterone is responsible for preparing the endometrium for
implantation and maintenance of the gestational sac in the uterus.7
Correspondence: Hisham Arab
Obstetrics and Gynecology Department,
Dr. Arab Medical Center, P.O. Box 17440, Mechanisms Involved In Miscarriage
Jeddah 21484, Saudi Arabia
Tel +966 12 2832111
Considerable progress has been made in the fields of cytogenetics and immunoge-
Email [email protected] netics, which has in turn contributed to a better understanding of the mechanisms

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 Arab et al Dovepress

Table 1 Causes Of Miscarriage Terminology

Categories Features At present, there is no consensus on the number of miscar-
Abnormal embryo Structural anomalies incompatible with life
riages needed to fulfill the criteria for recurrent miscarriage;
however, this group of experts from Saudi Arabia agreed to
Chromosomal abnormalities: trisomy,
follow the guidelines proposed by the European Society of
polyploidy, monosomy X, structural
abnormalities of individual chromosomes
Human Reproduction and Embryology (ESHRE), which
define recurrent miscarriage as “the loss of two or more
Hostile maternal Uterine abnormalities: congenital anomalies,
pregnancies”.10 A “biochemical loss” is defined as a miscar-
environment adhesions, leiomyoma
riage that occurs (usually before 6 weeks of gestation) fol-
Infection: bacterial vaginosis, toxoplasmosis, lowing a positive urinary human chorionic gonadotropin
listeriosis, chlamydia, gonorrhea, rubella
(hCG) or a raised serum β-hCG, but prior to ultrasound or
Chronic maternal disease: poorly controlled histological verification.2 The term clinical miscarriage is
diabetes, celiac disease used when ultrasound examination or histological evidence
Immune dysfunction: antiphospholipid has confirmed that an intrauterine pregnancy has existed.2
antibody syndrome and thyroid autoimmunity Clinical miscarriages may be subdivided into early (before
Endocrine: absence of proper progesterone gestational week 12) and late (gestational weeks 12 to 21).2
concentration, thyroid hormone levels As per the expert panel, patients with a biochemical
Note: Data from Larsen et al2, Griebel et al3 and Zhang et al.4 and ultrasound confirmation of pregnancy depicting the
clinical signs of threatened miscarriage should be thor-
oughly investigated prior to prescribing treatment.
involved in miscarriage.2 The main mechanisms involved
in early miscarriage include chromosomal abnormalities or
Materials And Methods
aberrations, immunological and immunogenetic causes,
A group of nine obstetricians and/or gynecologists, each
thrombophilias, endocrinological disorders, sperm DNA
with over 10 years of clinical practice experience in Saudi
fragmentation, failure of embryo selection, uterine malfor-
Arabia, met on November 15, 2018, and January 31, 2019,
mations, hCG gene polymorphisms and epigenetic causes,
in Jeddah, Saudi Arabia, with the objective of updating the
and lifestyle factors.2 Fetal malformations were found to
current Saudi guidelines for threatened and recurrent mis-
be responsible for 85% of early clinical miscarriages, with carriage management,11 which were published in 2014.
chromosomal abnormalities found in one partner of 3–6% During the first meeting, the initial guidelines were
of couples experiencing a recurrent miscarriage, which is reviewed, recent updates in clinical practice identified,
ten times higher than the rate in the general population.2 and gaps in practice enumerated. Based on this evaluation,
Cytokine-mediated immunological reactions are estimated the expert panel took 2 months to conduct a literature
to be responsible for 40–60% of all cases of idiopathic review on the role of oral, vaginal, and injectable proges-
recurrent spontaneous miscarriages.8 togens in early pregnancy and in the prevention and treat-
In recent years, it has become increasingly clear that ment of threatened and idiopathic recurrent miscarriage.
maternal immune tolerance of the fetus is key to promoting The experts also collated information on progestogens
fetal survival.9 It has been suggested that successful preg- currently approved by the Saudi Food and Drug
nancy is associated with downregulation of Th1-type activity Administration (SFDA) for the treatment of threatened
and enhancement of Th2-type activity.8 Studies have and idiopathic recurrent miscarriage. A literature review
reported that women with spontaneous recurrent miscar- was conducted using PubMed. Articles were short-listed
riages have elevated levels of the Th1 cytokines interleukin based on title and then abstracts were reviewed for rele-
(IL)-2 and interferon-γ and decreased levels of the Th2 vancy. Only articles published in English were reviewed.
cytokine IL-10, as assessed by antigen- and mitogen-induced The expert panel presented all collated information during
activation of peripheral blood mononuclear cells.8 the second meeting and used it as a basis for the position
Progesterone favors the development of human T-cells pro- statements presented within this paper.
ducing Th2 cytokines and blocks the production of Th1 This paper will outline recommendations for using pro-
cytokines, indicative of its role in pregnancy maintenance.8 gestogens in threatened and idiopathic recurrent miscarriage,

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in Saudi Arabia. This document is intended as a reference for women on dydrogesterone versus 24% in the control
local general physicians, obstetricians/gynecologists, and group (odds ratio [OR] 0.47, 95% confidence interval
fertility specialists for the management of the aforemen- [CI] 0.31–0.7, 11% absolute reduction in miscarriage
tioned patients. However, physicians are required to manage rate).16 Carp et al concluded that the 47% reduction in
patients based on the best available evidence and using their the odds of miscarriage observed with dydrogesterone
clinical judgment and should also take factors such as patient compared with standard of care was indicative of real
characteristics, drug profile, and available resources into treatment effect.16 A more recent study by Lee et al that
consideration. collated data from nine randomized trials including 913
patients (322 on dydrogesterone, 213 vaginal progester-
Review Summary one, and 378 control) reported that the incidence of mis-
What Progestogens Are Currently carriage was significantly lower in the oral dydrogesterone
group than in the control group (11.7% vs 22.6%; OR
Available For The Treatment Of
0.43; 95% CI 0.26–0.71; P = 0.001; I2 0%).17 Similar
Threatened And Idiopathic Recurrent findings were reported by Wahabi et al: oral progestogens
Miscarriage? (dydrogesterone and micronized progesterone) were found
At present, the SFDA has registered only two of the four to reduce the rate of miscarriage compared with no treat-
products listed in Table 2 for the treatment of threatened ment (risk ratio [RR] 0.57; 95% CI 0.38–0.85; three trials;
and idiopathic recurrent miscarriage, both are progesto- 408 patients).19 Wang et al pooled data from eight rando-
gens. It is important that hormonal treatment prescriptions mized controlled trials, including 845 women with threa-
are limited to those indicated for the treatment of threa- tened miscarriage, and reported that women receiving
tened or recurrent miscarriage by the SFDA. dydrogesterone were at a lower risk of miscarriage (RR
0.49, 95% CI 0.33–0.75) than women on natural proges-
What Is The Role Of Oral Progestogens terone (RR 0.69, 95% CI 0.40–1.19).18 Furthermore,
In The Prevention And Treatment Of women treated with oral progestogens demonstrated a
Threatened And Idiopathic Recurrent lower risk of miscarriage (RR 0.55, 95% CI 0.38–0.79)
than those on vaginal progestogens (RR 0.58, 95% CI
Miscarriage?
0.28–1.21).18
Oral Micronized Progesterone
Four recent clinical trials have reported beneficial
Available data suggest that oral micronized progesterone
effects with dydrogesterone in threatened miscarriage.20–23
may have a role in preterm labor12–15 but not in threatened
In a study by El-Zibdeh and Yousef, 146 women presenting
or recurrent miscarriage.
with mild-to-moderate vaginal bleeding during the first
Dydrogesterone (Oral Progestogen) trimester were randomized to 10 mg oral dydrogesterone
Threatened Miscarriage twice daily (n = 86) or no treatment (n = 60).20 The inci-
Based on data from recent systematic reviews and meta- dence of miscarriage was found to be 17.5% with dydro-
analyses, oral dydrogesterone effectively prevents miscar- gesterone versus 25% with no treatment (P < 0.05).20
riage in pregnant women experiencing threatened Another open-label study reported that both dydrogesterone
miscarriage.16–18 The meta-analysis by Carp et al, which (n = 59) and micronized progesterone (n = 59) effectively
collated data from five randomized trials including 660 reduced the extent of bleeding within 4–10 days, with
patients, reported that the miscarriage rate was 13% in comparable miscarriages rates.21 Furthermore, it was

Table 2 Progestogens Currently Available For The Treatment Of Threatened (TM) And Idiopathic Recurrent Miscarriage (RM) In
Saudi Arabia
Generic Name Trade Name Unit Strength Route Of Administration Indicated For TM And RM

Hydroxyprogesterone caproate Proluton Depot 250/500 mg/mL Intramuscular injection Yes

Dydrogesterone Duphaston 10 mg Oral tablet Yes
Progesterone Cyclogest 200/400 mg Vaginal pessaries No
Progesterone Endometrin 100 mg Vaginal tablet No

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found that patients with low progesterone (<35 nmol/L) There are few reports of side effects in mothers taking
were 23 times more likely to experience a miscarriage dydrogesterone. Some studies have reported drowsiness,
than women with high progesterone (≥35 nmol/L) (OR nausea and vomiting, although such symptoms might be
23.8; 95% CI 6.5–86.6; P < 0.0001).21 Overall both treat- associated with the pregnancy itself.16
ments were tolerated well, although drowsiness was experi- Recommendation 1: Oral progestogens, namely dydro-
enced by a greater number of patients on micronized gesterone, are well tolerated and effectively reduce mis-
progesterone compared with dydrogesterone (P = carriages in women at risk of threatened or idiopathic
0.003).21 Pandian reported that the rate of continuing preg- recurrent miscarriages.
nancy beyond 20 weeks was statistically higher with dydro-
gesterone (87.5%) versus conservative management
What Is The Role Of Vaginal
(71.6%) (P < 0.05).23 The rate of miscarriage was also
lower with dydrogesterone versus control (12.5% vs
Progestogens In The Prevention And
28.4%; P < 0.05), with no differences in rates of cesarean Treatment Of Threatened And Idiopathic
section, placenta previa, antepartum hemorrhage, preterm Recurrent Miscarriage?
labor, pregnancy-induced hypertension, or low birth weight Data on the efficacy and safety of vaginal progestogens are
(<2500 g) babies.23 In a similar study by Omar et al, the rate limited. A single-blind study by Yassaee et al that included
of continuing pregnancy beyond 20 weeks was significantly 60 pregnant women with threatened miscarriage reported
higher with dydrogesterone versus conservative treatment that progesterone suppositories (400 mg) reduced the num-
(95.9% vs 86.3%; OR 3.773; 95% CI 1.009–14.108; P = ber of miscarriages compared with control (6 vs 10 cases);
0.037).22 In terms of safety, no intrauterine deaths, conge- however, this difference was not statistically significant.28
nital abnormalities, or pregnancy-related complications In a single-center, randomized, double-blind study includ-
were reported with dydrogesterone.20,23 ing 50 women with a previous diagnosis of inadequate
luteal phase and threatened miscarriage, vaginal progester-
Idiopathic Recurrent Miscarriage one gel (Crinone 8%) was found to help reduce pain and
Data from two recent systematic reviews and meta-analyses the frequency of uterine contractions within 5 days of
showed that dydrogesterone could be effectively used to administration (P < 0.005), with a reduction in the rate
prevent miscarriage in women with a history of idiopathic of miscarriage after 60 days (P < 0.05), compared with
recurrent miscarriage.24,25 Carp collated data from three stu- placebo.29 More recently, a large randomized trial found
dies, including 509 patients, and reported that the rate of that micronized vaginal progesterone was no better than
miscarriage with dydrogesterone was lower than with control placebo for the treatment of threatened miscarriage.30
(10.5% vs 23.5%; OR 0.29; 95% CI 0.13–0.65; 13% absolute However, the authors cautioned that other formulations
reduction in miscarriage).24 Saccone et al collated data from of progestational agents have different molecular struc-
10 trials, 1586 patients, and reported that women randomized tures and therefore potentially different mechanisms of
to receive progestogens in the first trimester and before 16 actions and pharmacologic features.
weeks of gestation had a lower risk of recurrent miscarriage The multicenter, randomized, double-blind, placebo-
(RR 0.72, 95% CI 0.53–0.97) and higher rate of live birth controlled PROMISE study exploring the effect of micro-
(RR 1.07, 95% CI 1.02–1.15) versus control/placebo.25 nized vaginal progesterone (400 mg capsules) in women
Looking at clinical trial data, Kumar et al reported that with a history of unexplained recurrent miscarriage (n =
the risk of miscarriage after three miscarriages was 2.4 836; 404 progesterone, 432 placebo) did not find any
times higher with placebo than dydrogesterone (RR 2.4; benefit of vaginal progesterone in improving rates of live
95% CI 1.3–5.9).26 Both mean gestational age at delivery birth, clinical pregnancy between 6 and 8 weeks of gesta-
and birth weight were higher with dydrogesterone com- tion, ongoing pregnancy at 12 weeks of gestation, miscar-
pared with placebo.26 In another study, dydrogesterone riage, ectopic pregnancy, stillbirth, neonatal survival, or
was found to significantly reduce the rate of miscarriage neonatal congenital anomalies.31 In contrast, in a similar
versus no treatment (13% vs 29%; P = 0.028) with no study, Ismail et al reported that vaginal progesterone (400
reports of pregnancy complications or congenital abnorm- mg pessaries) significantly reduced the rate of miscarriage
alities when given to women with history of idiopathic compared with placebo (12.4% vs 23.3%; P = 0.001) in
recurrent miscarriages.27 addition to an improvement in live birth rate (91.6 vs

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 Dovepress Arab et al

77.4%) and continuation of pregnancy beyond 20 weeks sensitive organ that responds to the presence of estrogen
(87.6 vs 76.7%), both of which were statistically signifi- and progesterone, each binding to their cognate receptors
cant (P < 0.05).32 However, a recent Cochrane review, (ESR1 and PGR, respectively) and working in concert to
which included data from the Ismail study, demonstrated establish and maintain pregnancy.44 Disruption to this bal-
no difference between the incidences of recurrent miscar- ance may increase the likelihood of miscarriage by lowering
riage in patients receiving placebo (n=763) and patients the number of available progesterone receptors and/or estro-
receiving vaginal progestogen (n = 738), with a RR of 0.73 gen receptors within the endometrium45 or by the dysregula-
(95% CI 0.40–1.31).33 tion of gene transcription and uterine biology.46
Guidelines published by ESHRE,10 European Progestin Recommendation 4: There is no evidence to support
Club (EPC),34 the German Society of Gynecology and the use of combination progestogens in the prevention and
Obstetrics (DGGG), Austrian Society of Gynecology treatment of threatened and idiopathic recurrent miscar-
and Obstetrics (ÖGGG), and Swiss Society of Gynecology riage. Progestogen monotherapy administered in the
and Obstetrics (SGGG)35 confirm that vaginal progesterone appropriate dose is recommended.
has no beneficial effect in early pregnancy and does not
improve live birth rates in women with unexplained recurrent
miscarriage and therefore cannot be recommended for routine Are The Available Progestogens Safe In
use in the treatment of threatened or recurrent miscarriage. Early Pregnancy?
Recommendation 2: Available evidence is insufficient Clinical studies of oral and vaginal routes of administra-
to recommend the use of vaginal progestogens (capsule, tion are associated with acceptable and minimal side
suppository, micronized, or gel) for the treatment of threa- effects,6,17,31,36,47,48 with fatigue, fluid retention, lipid
tened or recurrent miscarriage. level alterations, dysphoria, hypercoagulant states, and
increased androgenicity reported most commonly.49
What Is The Role Of Injectable Natural progestogens are reported to have milder side
Progestogens In The Prevention And effects, with oral micronized natural progestogens having
fewer side effects than natural progesterones.49 However,
Treatment Of Threatened And Idiopathic
given the poor bioavailability of oral micronized proges-
Recurrent Miscarriage? terone, high doses may be required, which may result in
Many studies refer to the benefit of intramuscular progestogens
drowsiness20 and liver toxicity.20,26
for luteal-phase support and for treating preterm birth,36–42 but
Dydrogesterone, a progestogen that is highly selective for
not to prevent/treat threatened or recurrent miscarriage. Only
the progesterone receptor, lacks estrogenic, androgenic, ana-
one randomized controlled study, by Beigi et al, reported that
bolic, and corticoid properties;26,50 most studies report no
the risk of preterm labor in pregnant women with threatened
significant side effects16,24 including no masculinization of
miscarriage at <34 weeks’ gestation was similar in intramus-
cular (8.6%) and vaginal (6.52%) progesterone groups [RR the female fetus27 or congenital abnormalities.20,23 In com-
1.31; 95% CI 0.47–3.66; P = 0.59].43 parison with micronized progesterone, dydrogesterone was
Recommendation 3: There is insufficient evidence to found to cause significantly fewer cases of drowsiness (P =
support the use of injectable progestogens in miscarriage 0.003), with no differences in nausea, vomiting, giddiness,
prevention and treatment. bloating, diarrhea, or headache.21 Astoundingly, although 38
million women were treated with dydrogesterone between
1977 and 2005, with >10 million fetuses exposed in utero,
What Is The Role Of Combination
only 28 cases of potential links between its use and congeni-
Treatment (Oral And/Or Vaginal And/Or tal birth defects were reported.51 Thus, dydrogesterone is
Injectable) In The Prevention And very unlikely to be teratogenic.51,52 Furthermore, dydroges-
Treatment Of Threatened And Idiopathic terone has been used for a variety of indications worldwide in
Recurrent Miscarriage? an estimated 113 million women since 1960, with approxi-
There are no published articles assessing the efficacy and mately 20 million fetuses being exposed in utero, which
safety of progestogens in combination administered through demonstrates its continued favorable safety and tolerability
different routes. Furthermore, the uterus is a hormone- profile during pregnancy.50

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Intramuscular progestogen is commonly associated Recurrent Miscarriage

with injection-site reactions, including soreness, swelling, 1. Thorough investigations are warranted to rule out
itching, and bruising,53 with daily injections associated other causes of miscarriage. Once ruled out, a diag-
with pain at injection site and local abscess formation.50 nosis of idiopathic recurrent miscarriage is confirmed.
Carmichael et al reported that intake of progestogens 2. For women presenting with a clinical diagnosis of
during pregnancy was associated with an increased risk of idiopathic recurrent miscarriage (having experi-
hypospadias, with an OR of 3.7 (95% CI 2.3–6.0).54 Looking enced two or more), there is a reduction in the rate
at data published before 1990, two studies report no conge- of miscarriage with the use of dydrogesterone.
nital abnormalities with use of progestogens (vaginal and 3. Dydrogesterone should be administered as early as
intramuscular) during pregnancy.55,56 In 2008, the Practice possible, at the diagnosis of pregnancy or during the
Committee of the American Society for Reproductive luteal phase, in stimulated cycles.
Medicine stated that there is no evidence to indicate that 4. Oral dydrogesterone should be offered. Manufacturer
supplementation with progestogens during early pregnancy dosage: 10–20 mg daily, until the 20th week of preg-
poses any significant risk of hypospadias or other types of nancy. Treatment should preferably start before con-
birth defect.57 For treatment during pregnancy, progestogens ception. If symptoms of threatened miscarriage occur
with the least androgenic or with anti-androgenic properties during treatment, continue treatment as stated for that
are particularly sought because they are expected to cause the indication.
least alterations in the sexual development of a fetus.58
Clinical studies in which a limited number of women were Acknowledgments
treated with dydrogesterone early in pregnancy have not The authors would like to thank Abbott for providing
shown any increase in the risk of hypospadias. The funding for medical writing assistance. Medical writing
Cochrane Reviews on the role of progestogen treatment support in the development of this manuscript was pro-
during pregnancy19,59 and the meta-analysis by Carp16 con- vided by Leris D’Costa of OPEN Health Dubai, funded by
cluded that no safety issues were suspected when comparing Abbott, Saudi Arabia. Abbott played no role in the collec-
newborns of mothers who had received progestogens with tion, analysis, and interpretation of data or in the prepara-
those who did not, including no increased risk of congenital tion of this manuscript. The consensus meetings held on
abnormalities. November 15, 2018, and January 31, 2019, in Jeddah,
Recommendation 5: Progestogens are generally well Saudi Arabia, were sponsored by Abbott, Saudi Arabia.
tolerated, with minimal side effects. Although progestogen Sponsorship included travel expenses and an honorarium
administration during the first trimester was linked to for participating authors.
hypospadias risk, recent and more thorough reports have
not shown an increase in the rate of hypospadias. Author Contributions
Hisham Arab was involved in the conception and execu-
tion of the project and helped outline and draft the manu-
Position Statements script. All authors were involved in the acquisition and
Threatened Miscarriage interpretation of the data, provided critical comments and
1. For women presenting with a clinical diagnosis of concepts during the consensus meeting that were incorpo-
threatened miscarriage, dydrogesterone may reduce rated into the manuscript. All authors conducted literature
the rate of miscarriage. reviews in support of the recommendations; participated in
2. Oral dydrogesterone should be offered. Manufacturer the consensus meeting for generating recommendations;
dosage: 40 mg loading, then 30 mg once daily until and contributed to the development, drafting or revising,
symptoms (bleeding) remit. If symptoms persist/ and finalization of the manuscript. All authors approved
recur, increase dose by 10 mg three times a day. the final submitted version of the manuscript. All authors
Maintain effective dose for 1 week after symptoms agree to be accountable for all aspects of the work in
have ceased and then gradually reduce dose. ensuring that questions related to the accuracy or integrity
Immediately resume treatment at effective dose, if of any part of the work are appropriately investigated and
symptoms recur. resolved.

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Disclosure 17. Lee HJ, Park TC, Kim JH, Norwitz E, Lee B. The influence of oral
dydrogesterone and vaginal progesterone on threatened abortion: a sys-
Hisham Arab has received speaker honoraria from Bayer, tematic review and meta-analysis. Biomed Res Int. 2017;2017:3616875.
Abbott, and MSD, and advisor honoraria from Vifor and doi:10.1155/2017/3616875
Sanofi. The authors report no other conflicts of interest in 18. Wang XX, Luo Q, Bai WP. Efficacy of progesterone on threatened
miscarriage: difference in drug types. J Obstet Gynaecol Res.
this work. 2019;45(4):794–802. doi:10.1111/jog.13909
19. Wahabi HA, Fayed AA, Esmaeil SA, Bahkali KH. Progestogen for
treating threatened miscarriage. Cochrane Database Syst Rev. 2018;8:
References CD005943.
20. El-Zibdeh MY, Yousef LT. Dydrogesterone support in threatened
1. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing preg- miscarriage. Maturitas. 2009;65 Suppl 1:S43–S46. doi:10.1016/j.
nancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update. maturitas.2009.11.013
2002;8(4):333–343. doi:10.1093/humupd/8.4.333 21. Siew JYS, Allen JC, Hui CYY, et al. The randomised controlled trial
2. Larsen EC, Christiansen OB, Kolte AM, Macklon N. New insights of micronised progesterone and dydrogesterone (TRoMaD) for threa-
into mechanisms behind miscarriage. BMC Med. 2013;11:154. tened miscarriage. Eur J Obstet Gynecol Reprod Biol. 2018;228:319–
doi:10.1186/1741-7015-11-154 324. doi:10.1016/j.ejogrb.2018.07.028
3. Griebel CP, Halvorsen J, Golemon TB, Day AA. Management of 22. Omar MH, Mashita MK, Lim PS, Jamil MA. Dydrogesterone in
spontaneous abortion. Am Fam Physician. 2005;72(7):1243–1250. threatened abortion: pregnancy outcome. J Steroid Biochem Mol
4. Zhang HX, Qin YZ, Liu WH, Hao R. Hypothyroidism and first- Biol. 2005;97(5):421–425. doi:10.1016/j.jsbmb.2005.08.013
trimester spontaneous miscarriages. Clin Exp Obstet Gynecol. 23. Pandian RU. Dydrogesterone in threatened miscarriage: a Malaysian
2014;41(2):182–185. experience. Maturitas. 2009;65(Suppl 1):S47–S50. doi:10.1016/j.
5. Chang K, Lubo Z. Review article: steroid hormones and uterine maturitas.2009.11.016
vascular adaptation to pregnancy. Reprod Sci. 2008;15(4):336–348. 24. Carp H. A systematic review of dydrogesterone for the treatment of
doi:10.1177/1933719108317975 recurrent miscarriage. Gynecol Endocrinol. 2015;31(6):422–430.
6. Di Renzo GC, Giardina I, Clerici G, Brillo E, Gerli S. Progesterone doi:10.3109/09513590.2015.1006618
in normal and pathological pregnancy. Horm Mol Biol Clin Investig. 25. Saccone G, Schoen C, Franasiak JM, Scott RT Jr., Berghella V.
2016;27(1):35–48. doi:10.1515/hmbci-2016-0038 Supplementation with progestogens in the first trimester of pregnancy
7. Czyzyk A, Podfigurna A, Genazzani AR, Meczekalski B. The role of to prevent miscarriage in women with unexplained recurrent miscar-
progesterone therapy in early pregnancy: from physiological role to riage: a systematic review and meta-analysis of randomized, con-
therapeutic utility. Gynecol Endocrinol. 2017;33(6):421–424. doi:10.
trolled trials. Fertil Steril. 2017;107(2):430–438 e433. doi:10.1016/j.
1080/09513590.2017.1291615
fertnstert.2016.10.031
8. Raghupathy R, Al Mutawa E, Makhseed M, Azizieh F, Szekeres-
26. Kumar A, Begum N, Prasad S, Aggarwal S, Sharma S. Oral dydroges-
Bartho J. Modulation of cytokine production by dydrogesterone in
terone treatment during early pregnancy to prevent recurrent pregnancy
lymphocytes from women with recurrent miscarriage. BJOG.
loss and its role in modulation of cytokine production: a double-blind,
2005;112(8):1096–1101. doi:10.1111/j.1471-0528.2005.00633.x
randomized, parallel, placebo-controlled trial. Fertil Steril. 2014;102
9. Mincheva-Nilsson L. Pregnancy and gamma/delta T cells: taking on
(5):1357–1363 e1353. doi:10.1016/j.fertnstert.2014.07.1251
the hard questions. Reprod Biol Endocrinol. 2003;1:120. doi:10.1186/
27. El-Zibdeh MY. Dydrogesterone in the reduction of recurrent sponta-
1477-7827-1-120
neous abortion. J Steroid Biochem Mol Biol. 2005;97(5):431–434.
10. ESHRE Early Pregnancy Guidline Development Group. Recurrent
doi:10.1016/j.jsbmb.2005.08.007
pregnancy loss. Guideline of the European Society of Human
28. Yassaee F, Shekarriz-Foumani R, Afsari S, Fallahian M. The effect of
Reproduction and Embryology. Available from: https://www.eshre.
progesterone suppositories on threatened abortion: a randomized
eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.aspx.
Accessed October, 15 2018. clinical trial. J Reprod Infertil. 2014;15(3):147–151.
11. Arab H, Alsofayan H, Alharbi A, Sendy S, Abduljabbar H; The Saudi 29. Palagiano A, Bulletti C, Pace MC, DEZ D, Cicinelli E, Izzo A.
Obstetrics and Gynecological Society (SOGS). National guidelines Effects of vaginal progesterone on pain and uterine contractility
for the prevention and treatment of miscarriage. Saudi J Obstet in patients with threatened abortion before twelve weeks of
Gynecol. 2014;15(1):40–63. pregnancy. Ann N Y Acad Sci. 2004;1034:200–210. doi:10.1196/
12. Pustotina O. Effectiveness of dydrogesterone, 17-OH progesterone and annals.1335.022
micronized progesterone in prevention of preterm birth in women with a 30. Coomarasamy A, Devall AJ, Cheed V, et al. A randomized trial of
short cervix. J Matern Fetal Neonatal Med. 2018;31(14):1830–1838. progesterone in women with bleeding in early pregnancy. N Engl J
doi:10.1080/14767058.2017.1330406 Med. 2019;380(19):1815–1824. doi:10.1056/NEJMoa1813730
13. Kececioglu M, Tokmak A, Kececioglu TS, Akselim B, Karakaya BK, 31. Coomarasamy A, Williams H, Truchanowicz E, et al. PROMISE:
Tasci Y. Does progesterone therapy increase nuchal translucency in first-trimester progesterone therapy in women with a history of unex-
women with threatened miscarriage? Ginekol Pol. 2016;87(5):390– plained recurrent miscarriages – a randomised, double-blind, pla-
394. doi:10.5603/GP.2016.0010 cebo-controlled, international multicentre trial and economic
14. Rai P, Rajaram S, Goel N, Ayalur Gopalakrishnan R, Agarwal R, Mehta evaluation. Health Technol Assess. 2016;20(41):1–92. doi:10.3310/
S. Oral micronized progesterone for prevention of preterm birth. Int J hta20410
Gynaecol Obstet. 2009;104(1):40–43. doi:10.1016/j.ijgo.2008.08.029 32. Ismail AM, Abbas AM, Ali MK, Amin AF. Peri-conceptional
15. Glover MM, McKenna DS, Downing CM, Smith DB, Croom CS, progesterone treatment in women with unexplained recurrent
Sonek JD. A randomized trial of micronized progesterone for the miscarriage: a randomized double-blind placebo-controlled trial.
prevention of recurrent preterm birth. Am J Perinatol. 2011;28 J Matern Fetal Neonatal Med. 2018;31(3):388–394. doi:10.1080/
(5):377–381. doi:10.1055/s-0031-1274509 14767058.2017.1286315
16. Carp H. A systematic review of dydrogesterone for the treatment of 33. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing
threatened miscarriage. Gynecol Endocrinol. 2012;28(12):983–990. miscarriage in women with recurrent miscarriage of unclear etiology.
doi:10.3109/09513590.2012.702875 Cochrane Database Syst Rev. 2018;10:CD003511.

submit your manuscript | www.dovepress.com

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 Arab et al Dovepress

34. Schindler AE, Carp H, Druckmann R, et al. European progestin club 46. DeMayo FJ, Zhao B, Takamoto N, Tsai SY. Mechanisms of action of
guidelines for prevention and treatment of threatened or recurrent estrogen and progesterone. Ann N Y Acad Sci. 2002;955:48–59.
(habitual) miscarriage with progestogens. Gynecol Endocrinol. doi:10.1111/j.1749-6632.2002.tb02765.x
2015;31(6):447–449. doi:10.3109/09513590.2015.1017459 47. Lucovnik M, Kuon RJ, Chambliss LR, et al. Progestin treatment for
35. Toth B, Wurfel W, Bohlmann M, et al. Recurrent miscarriage: diagnostic the prevention of preterm birth. Acta Obstet Gynecol Scand. 2011;90
and therapeutic procedures. Guideline of the DGGG, OEGGG and (10):1057–1069. doi:10.1111/j.1600-0412.2011.01178.x
SGGG (S2k-Level, AWMF Registry Number 015/050). Geburtshilfe 48. Rode L, Klein K, Nicolaides KH, Krampl-Bettelheim E, Tabor A,
Frauenheilkd. 2018;78(4):364–381. doi:10.1055/a-0586-4568 Group P. Prevention of preterm delivery in twin gestations
36. Saccone G, Khalifeh A, Elimian A, et al. Vaginal progesterone vs (PREDICT): a multicenter, randomized, placebo-controlled trial on
intramuscular 17alpha-hydroxyprogesterone caproate for prevention the effect of vaginal micronized progesterone. Ultrasound Obstet
of recurrent spontaneous preterm birth in singleton gestations: sys- Gynecol. 2011;38(3):272–280. doi:10.1002/uog.9093
tematic review and meta-analysis of randomized controlled trials. 49. Goletiani NV, Keith DR, Gorsky SJ. Progesterone: review of safety
Ultrasound Obstet Gynecol. 2017;49(3):315–321. doi:10.1002/ for clinical studies. Exp Clin Psychopharmacol. 2007;15(5):427–444.
uog.17245 doi:10.1037/1064-1297.15.5.427
37. Samson FD, Merriman AL, Tate DL, Apostolakis-Kyrus K, Gomez LM. 50. Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III
Adjuvant administration of 17-alpha-hydroxy-progesterone caproate in randomized controlled trial comparing the efficacy, safety and toler-
women with three or more second trimester pregnancy losses under- ability of oral dydrogesterone versus micronized vaginal progester-
going cervical cerclage is no more effective than cerclage alone. J one for luteal support in in vitro fertilization. Hum Reprod. 2017;32
Perinat Med. 2018;46(2):155–161. doi:10.1515/jpm-2017-0074 (5):1019–1027. doi:10.1093/humrep/dex023
38. Duan L, Yan D, Zeng W, Yang X, Wei Q. Effect of progesterone 51. Queisser-Luft A. Dydrogesterone use during pregnancy: overview of
treatment due to threatened abortion in early pregnancy for obstetric birth defects reported since 1977. Early Hum Dev. 2009;85(6):375–
and perinatal outcomes. Early Hum Dev. 2010;86(1):41–43.
377. doi:10.1016/j.earlhumdev.2008.12.016
doi:10.1016/j.earlhumdev.2009.12.007
52. Arab HA. An insight into early fetal loss. Obstet Gynecol. 2017;1
39. Haghighi L, Rashidi M, Najmi Z, et al. Comparison of intramuscular
(2):67–69.
progesterone with oral nifedipine for treating threatened preterm
53. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm
labor: a randomized controlled trial. Med J Islam Repub Iran.
delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med.
2017;31:56. doi:10.14196/mjiri.31.56
2003;348(24):2379–2385. doi:10.1056/NEJMoa035140
40. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV.
54. Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS,
Pharmacokinetics and endometrial tissue levels of progesterone after
Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch
administration by intramuscular and vaginal routes: a comparative
Pediatr Adolesc Med. 2005;159(10):957–962. doi:10.1001/archpedi.
study. Fertil Steril. 1994;62(3):485–490. doi:10.1016/s0015-0282(16)
159.10.957
56935-0
55. Check JH, Rankin A, Teichman M. The risk of fetal anomalies as a
41. Smitz J, Devroey P, Faguer B, Bourgain C, Camus M, Van Steirteghem
result of progesterone therapy during pregnancy. Fertil Steril.
AC. A prospective randomized comparison of intramuscular or intra-
vaginal natural progesterone as a luteal phase and early pregnancy 1986;45(4):575–577. doi:10.1016/s0015-0282(16)49292-7
supplement. Hum Reprod. 1992;7(2):168–175. doi:10.1093/oxford- 56. Rock JA, Wentz AC, Cole KA, et al. Fetal malformations following
journals.humrep.a137611 progesterone therapy during pregnancy: a preliminary report. Fertil
42. Sohn SH, Penzias AS, Emmi AM, et al. Administration of progester- Steril. 1985;44(1):17–19. doi:10.1016/s0015-0282(16)48670-x
one before oocyte retrieval negatively affects the implantation rate. 57. Practice Committee of the American Society for Reproductive M.
Fertil Steril. 1999;71(1):11–14. doi:10.1016/s0015-0282(98)00404-x Progesterone supplementation during the luteal phase and in early
43. Beigi A, Esmailzadeh A, Pirjani R. Comparison of risk of preterm pregnancy in the treatment of infertility: an educational bulletin.
labor between vaginal progesterone and 17-alpha-hydroxy-progester- Fertil Steril. 2008;89(4):789–792. doi:10.1016/j.fertnstert.2008.02.
one caproate in women with threatened abortion: a randomized 012
clinical trial. Int J Fertil Steril. 2016;10(2):162–168. 58. Rizner TL, Brozic P, Doucette C, et al. Selectivity and potency of the
44. Wetendorf M, DeMayo FJ. Progesterone receptor signaling in the retroprogesterone dydrogesterone in vitro. Steroids. 2011;76(6):607–
initiation of pregnancy and preservation of a healthy uterus. Int J Dev 615. doi:10.1016/j.steroids.2011.02.043
Biol. 2014;58(2–4):95–106. doi:10.1387/ijdb.140069mw 59. Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA. Progestogen for
45. Carranza-Lira S, Blanquet J, Tserotas K, Calzada L. Endometrial treating threatened miscarriage. Cochrane Database Syst Rev. 2011;
progesterone and estradiol receptors in patients with recurrent early (12):CD005943.
pregnancy loss of unknown etiology–preliminary report. Med Sci
Monit. 2000;6(4):759–762.

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