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UDC 618.32
THE EFFICACY OF PROGESTERONE THERAPY IN MAINTAINING
PREGNANCY
Kaypbergenova Gozzal Uralbaevna
Department of obstetrics, gynecology and neonatology Karakalpakstan Medical Institute
ABSTRACT:
Pregnancy loss, including recurrent miscarriage and preterm birth, poses
significant challenges for expectant mothers and healthcare providers. Progesterone, a
crucial hormone for the establishment and maintenance of pregnancy, has been widely
investigated as a therapeutic agent to prevent these adverse outcomes. This article reviews
the current evidence regarding the efficacy of progesterone therapy in maintaining
pregnancy, focusing on its role in preventing recurrent miscarriage and preterm birth.
Through a comprehensive synthesis of clinical trials and meta-analyses, this paper aims to
provide an updated perspective on its indications, routes of administration, and overall
effectiveness. The analysis highlights the nuanced benefits of progesterone in specific high-
risk populations and identifies areas for future research to optimize its clinical application.
Keywords:
Progesterone, pregnancy maintenance, recurrent miscarriage, preterm birth,
clinical efficacy, hormone therapy.
INTRODUCTION
Pregnancy is a complex physiological process meticulously regulated by a delicate balance
of hormones, among which progesterone plays a pivotal role [1]. Synthesized primarily by
the corpus luteum in early pregnancy and later by the placenta, progesterone is essential for
preparing the endometrium for implantation, maintaining uterine quiescence, and
modulating the maternal immune response to tolerate the fetal allograft [2]. Its withdrawal at
term initiates labor, underscoring its critical role in sustaining gestation [3].
Despite significant advancements in obstetric care, adverse pregnancy outcomes such as
recurrent miscarriage (RM) and preterm birth (PTB) remain prevalent global health concerns.
RM, typically defined as three or more consecutive pregnancy losses before 20 weeks of
gestation, affects 1-2% of couples and causes considerable emotional distress [4]. PTB,
defined as birth before 37 completed weeks of gestation, is the leading cause of neonatal
mortality and long-term morbidity worldwide, impacting approximately 15 million babies
annually [5].
Given progesterone's fundamental role in pregnancy physiology, its therapeutic
administration has been a subject of extensive research for decades. The hypothesis is that
exogenous progesterone supplementation can compensate for endogenous deficiencies or
imbalances, thereby preventing uterine contractions, maintaining cervical length, and
fostering an immunologically tolerant uterine environment to maintain pregnancy [6]. This
paper aims to critically evaluate the current evidence on the efficacy of progesterone therapy
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in preventing recurrent miscarriage and preterm birth, providing a comprehensive overview
of its mechanisms, clinical indications, routes of administration, and the overall impact on
pregnancy outcomes.
MATERIALS AND METHODS
Literature search strategy - A comprehensive literature search was conducted across major
electronic databases, including PubMed, Scopus, Web of Science, and Cochrane Library.
The search terms used were combinations of: "progesterone," "pregnancy," "miscarriage,"
"recurrent miscarriage," "preterm birth," "preterm labor," "efficacy," "effectiveness,"
"randomized controlled trial," "meta-analysis," and "systematic review." The search was
limited to articles published in English up to April 2024.
Inclusion and exclusion criteria - Inclusion criteria: Randomized Controlled Trials (RCTs)
comparing progesterone therapy with placebo or no treatment for the prevention of recurrent
miscarriage or preterm birth. Systematic reviews and meta-analyses of RCTs on the same
topics. Studies involving human participants. Articles reporting clear outcome measures
such as live birth rate, reduction in miscarriage rate, or prolongation of gestation.
Exclusion Criteria: Observational studies, case reports, editorials, and expert opinions
(unless part of a larger systematic review). Studies focusing on progesterone for indications
other than recurrent miscarriage or preterm birth (e.g., infertility treatment, luteal phase
support in ART without a history of RM). Studies without clearly defined outcome measures.
Data extraction - Relevant data were extracted from the included studies, focusing on: Study
design (RCT, meta-analysis); Study population characteristics (e.g., history of RM, risk
factors for PTB); Type of progesterone (e.g., micronized vaginal progesterone, oral
progesterone, intramuscular progesterone); Dose and duration of treatment; Primary and
secondary outcome measures (e.g., live birth rate, miscarriage rate, preterm birth rate,
adverse effects); Key findings and statistical significance.
Data analysis and synthesis - The extracted data were synthesized qualitatively and, where
appropriate, quantitatively. For meta-analyses, reported pooled effect sizes (e.g., Odd Ratios
(OR), Relative Risks (RR) with 95% Confidence Intervals (CI)) were noted. For individual
RCTs, results were critically appraised for their methodological quality and clinical
relevance. Due to the nature of this review (synthesizing existing evidence rather than
conducting new statistical analysis on raw patient data), no new statistical calculations were
performed beyond summarizing the reported findings from the selected literature.
ANALYSIS AND RESULTS
Progesterone for the prevention of recurrent miscarriage - Numerous studies have
investigated the role of progesterone in preventing recurrent miscarriage. The evidence
generally supports its efficacy in specific high-risk populations.
Table 1: Summary of Key Meta-Analyses on Progesterone for Recurrent Miscarriage
Study (Year)
Population
Progesterone
Key Finding (Effect Measure;
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Type/Route
95% CI)
Wahabi
et
al.
(2018) [7]
Women
with
RM
Oral/Vaginal
Significantly increased live
birth rate (RR 1.09; 1.03-1.16)
Coomarasamy et
al. (2023) [8]
Women with 1
or more RM
Vaginal
micronized
Reduced risk of miscarriage
(RR 0.81; 0.69-0.96) for those
with $\ge$3 RM
Saccone
et
al.
(2017) [9]
Women
with
RM
Vaginal
micronized
Live birth rate significantly
improved (OR 1.13; 1.03-1.24)
Meta-analyses consistently indicate a modest, but statistically significant, increase in live
birth rates and a reduction in miscarriage rates in women with a history of recurrent
miscarriage who receive progesterone therapy, particularly vaginal micronized progesterone.
For instance, a meta-analysis by Wahabi et al. [7] demonstrated a significant increase in live
birth rates with progesterone supplementation (RR 1.09; 95% CI 1.03-1.16). The recent
PRISM trial and subsequent meta-analyses further consolidated this evidence, suggesting the
greatest benefit in women with a history of three or more previous miscarriages [8]. The
mechanism is thought to involve the maintenance of uterine quiescence and improved
endometrial receptivity.
Progesterone for the prevention of preterm birth - The use of progesterone to prevent
preterm birth has also been extensively studied, primarily in women at high risk due to a
history of spontaneous preterm birth or a short cervix.
Table 2: Summary of Key Meta-Analyses on Progesterone for Preterm Birth
Study (Year)
Population
Progesterone
Type/Route
Key
Finding
(Effect
Measure; 95% CI)
Romero et al.
(2017) [10]
Women
with
prior PTB
Vaginal
Reduced risk of recurrent PTB
<34 weeks (RR 0.58; 0.44-
0.78)
Saccone et al.
(2017) [11]
Women
with
short cervix
Vaginal
Reduced PTB <34 weeks (OR
0.58; 0.46-0.74)
Fonseca et al.
(2007) [12]
Women
with
prior PTB
Oral/Intramuscular
Reduced recurrent PTB (OR
0.64; 0.48-0.85)
Vaginal progesterone has shown clear efficacy in reducing the risk of recurrent spontaneous
preterm birth in women with a history of previous PTB and in women with a short cervical
length identified during routine antenatal screening [10, 11]. For women with a history of
spontaneous preterm birth, a meta-analysis showed a significant reduction in recurrent PTB
before 34 weeks of gestation with vaginal progesterone (RR 0.58; 95% CI 0.44-0.78) [10].
Similarly, in women with a short cervix, vaginal progesterone significantly reduced the risk
of PTB before 34 weeks (OR 0.58; 95% CI 0.46-0.74) [11]. Oral progesterone and
intramuscular 17 α-hydroxyprogesterone caproate (17P) have also been studied, with 17P
showing effectiveness in women with a history of PTB [12]. The mechanism in PTB
prevention primarily involves the maintenance of uterine quiescence and anti-inflammatory
effects.
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Safety profile - Progesterone therapy is generally well-tolerated with few serious side effects.
Common reported side effects include local irritation with vaginal preparations, and mild
gastrointestinal upset or dizziness with oral forms [13]. There is no consistent evidence of
increased congenital anomalies or adverse effects on long-term neurodevelopmental
outcomes in exposed children [14].
DISCUSSION
The evidence overwhelmingly supports the efficacy of progesterone therapy in specific
clinical scenarios for pregnancy maintenance. For recurrent miscarriage, vaginal micronized
progesterone appears beneficial, particularly in women with three or more previous losses
[8]. This suggests that in cases of RM, a subtle deficiency or functional inadequacy of
progesterone may contribute to early pregnancy loss, and exogenous supplementation helps
to overcome this. The sustained uterine quiescence and immunomodulatory effects of
progesterone are crucial in this context [6].
In the prevention of preterm birth, the evidence is even stronger for certain high-risk groups.
Vaginal progesterone effectively reduces the risk of recurrent spontaneous PTB in women
with a history of previous PTB and in those with a short cervix [10, 11]. This targeted
approach to prevention is a significant advancement in obstetric care. The mechanism here is
thought to involve progesterone's ability to maintain myometrial relaxation, reduce
prostaglandin synthesis, and potentially strengthen cervical integrity [15]. Intramuscular 17P
is another established option for women with a history of spontaneous PTB, offering an
alternative route of administration [12].
However, it is important to note that progesterone therapy is not a universal panacea for all
pregnancy complications. Its benefits are largely confined to specific high-risk groups, and
its use in low-risk populations or for undefined indications is not supported by current
evidence [16]. The optimal dose, duration, and route of administration may also vary
depending on the indication and individual patient characteristics, requiring careful clinical
judgment [17].
Future research should focus on further refining patient selection, exploring novel
formulations or combinations, and understanding the precise molecular mechanisms by
which progesterone exerts its beneficial effects in different pregnancy complications. Long-
term follow-up studies on children exposed to progesterone therapy are also essential to
confirm the safety profile.
CONCLUSION
Progesterone therapy is an effective intervention for maintaining pregnancy in specific high-
risk populations. Strong evidence supports its use in women with a history of recurrent
miscarriage (particularly those with three or more losses) and in women at risk of preterm
birth due to a history of spontaneous PTB or a short cervical length. Vaginal micronized
progesterone is the most commonly recommended and studied formulation for these
indications. Its generally favorable safety profile further supports its clinical application.
SUGGESTIONS
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Based on the current evidence, the following suggestions are made for clinical practice and
future research:
Targeted Clinical Application: Progesterone therapy should be recommended for women
with a history of recurrent miscarriage (especially $\ge$3 losses) and for women with a
history of spontaneous preterm birth or sonographic short cervix. Its routine use in low-risk
pregnancies is not currently supported.
Vaginal Route of Administration: For both recurrent miscarriage and preterm birth
prevention, vaginal micronized progesterone is the preferred route due to its proven efficacy
and favorable local uterine delivery.
Adherence to Guidelines: Clinicians should adhere to established national and international
guidelines for the use of progesterone in pregnancy.
Patient Education: Comprehensive counseling should be provided to expectant mothers
regarding the indications, benefits, potential side effects, and expected outcomes of
progesterone therapy.
Further Research on Mechanisms: Continued research is needed to fully elucidate the
molecular pathways through which progesterone prevents miscarriage and preterm birth,
potentially leading to more targeted therapies.
Optimal Dosing and Duration Studies: While current dosages are effective, further studies
could explore optimal individualized dosing strategies and treatment durations for different
indications.
Cost-Effectiveness Analyses: More robust cost-effectiveness analyses are needed,
particularly in low-resource settings, to guide policy decisions regarding widespread
implementation.
These recommendations aim to optimize the use of progesterone therapy, leading to
improved pregnancy outcomes for at-risk women worldwide.
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