Key words
preterm labour - progesterone - 17-α-hydroxyprogesterone caproate - tocolysis - maintenance
treatment/tocolysis
Introduction
The work of A. Csapo in 1956, which indicated that progesterone inhibits the activity
of the myometrium while prostaglandins promote it, was groundbreaking for the clinical
use of progesterone [1]. In 1960, Fuchs and Stakemann [2] used high doses of progesterone applied intramuscularly in comparison to placebo
for the treatment of preterm labour. They did not find any significant differences
between the two investigation groups with regard to a prolongation of pregnancy with,
however, an inadequate statistical power of the study.
With the development of effective tocolytics (e.g. beta sympathomimetics), the focus
of interest shifted away from progesterone for the inhibition of preterm labour, and
it was not until 1986 that Erny et al. [3] once again used oral progesterone for the treatment of preterm labour within the
scope of a placebo-controlled study (see below).
In the past 20 years, experimental and clinical studies have greatly expanded our
knowledge on the mode of action of progesterone on myometrium, placenta, membranes
and cervix (overviews in [4], [5]).
In the foreground of these investigations was the inhibition of myometrial contractions,
among others, by a progesterone-mediated expression of connexin 43 resulting in reduced
formation of gap junctions (intramyometrial cellular bridges which promote the propagation
of contractions in the uterus), the modulation of the activity of calcium channels
with direct inhibition of the contractile activity, as well as the decrease of oxytocin
receptors in the myometrium. Progesterone binds to progesterone receptors and modulates
the expression of specific target genes. Coactivators of the progesterone receptors
(the cAMP-dependent protein kinase binding protein, among others) and the histone
acetylation of myometrial cells are changed by progesterone and thus the contractility
of the myometrium and the expression of proinflammatory cytokines are affected. Progesterone
leads to a reduction in proinflammatory cytokines (such as TNFα, interleukin-2) through
the production of PIBF (progesterone induced blocking factor), among others, and inhibits
the synthesis of contraction-inducing and cervix-ripening prostaglandins.
In membranes, progesterone reduces apoptosis through the decreased production of proinflammatory
cytokines and thus counteracts premature rupture of membranes.
In animal models, it was able to be shown that progesterone inhibits metalloproteinase-mediated
collagen breakdown by inhibiting the synthesis of proinflammatory cytokines and thus
prevents premature ripening of the cervix.
In vitro and animal experimental studies have shown that progesterone is able to increase
the myometrial efficiency of nifedipine and indomethacin in comparison to the use
of these tocolytics alone [6] and to sensitise the myometrium for beta sympathomimetics [7]. Using uterine electromyography, it was able to be demonstrated recently in a placebo-controlled
study (n = 30) that the vaginal administration of 400 mg progesterone 48 hours after
acute tocolysis significantly decreases the speed of propagation of electrical signals
within the myometrium over 2 hours post-application in comparison to placebo and inhibits
the myometrial activity [8].
These experimental and clinical investigations were the basis for using progesterone
and 17-α-hydroxyprogesterone caproate (17-OHPC) within the scope of tocolysis as well,
following promising results on the primary and secondary prevention of preterm birth
[9], [10]. This involved use for primary tocolysis (initially and exclusively in the case
of preterm labour), for adjunctive tocolysis (in combination with an established tocolytic)
and as maintenance tocolysis/maintenance treatment following successful primary tocolysis.
Progesterone for Primary Tocolysis
Progesterone for Primary Tocolysis
After the first randomised placebo-controlled study by Fuchs and Stakemann in 1960
[2], the efficacy of treatment with 400 mg oral progesterone in addition to bed rest
was investigated in a prospective, placebo-controlled study on pregnant women with
preterm labour (n = 58). This yielded a significant reduction in contractions (tocographically
measured decrease in contractions within 1 h after start of treatment) after progesterone
in 80% of cases versus 42% in the placebo group [3]. Points of criticism regarding this study were the overall inadequate number of
pregnant women, a lack of data on the prolongation of the pregnancy and neonatal outcome,
as well as the inclusion of pregnant women with premature rupture of membranes.
In another randomised study by Chawanpaiboon et al. in 2010 [11], the tocolytic efficacy of nifedipine (20 mg orally initially, after 30 and 60 min,
followed by 20 mg nifedipine retard every 12 h), 17-OHPC 250 mg intramuscularly/week
or bed rest for the treatment of preterm labour between the 28th–35th week of gestation
with a cervical length of < 30 mm was comparatively investigated in 50 pregnant women
in each case. The greatest tocolytic efficacy (stopping contractions within 12 h)
was demonstrated by nifedipine with a rate of 80%, followed by 17-OHPC with 66% and
bed rest with 64%; this was also the case for the most rapid onset of action (nifedipine
2.9 ± 2.1 h, 17-OHPC 4.6 ± 3.2 h, bed rest 6.2 ± 3.8 h); no significant differences
were seen with regard to the mean gestational age at birth and the average birth weight.
However, the statistical power of this study was inadequate. According to current
findings, bed rest is no longer a suitable method for the treatment of pregnant women
with threatened preterm birth.
Adjunctive Tocolysis
The prospective, placebo-controlled study by Noblot et al. in 1991 [12] investigated the efficacy of treatment – as a supplement to ridodrine – with oral
progesterone (400 mg every 6 h in the first 24 h, 400 mg every 8 h in the next 24 h,
followed by 300 mg every 8 h as maintenance dose) or placebo in 44 pregnant women
with regular contractions (every 10 min) after 1 h bed rest, persistent contractions
or contractions affecting the cervix between the 30th–33rd week of gestation. This
did not reveal any significant differences between progesterone in comparison to placebo
with regard to the rate of preterm birth < 37 weeks of gestation (27.2 vs. 36.4%),
however in the progesterone group, a significantly lower overall dose of the beta
mimetic was necessary (245 vs. 875 mg, p < 0.01). Moreover, the length of hospitalisation
of the pregnant patients was significantly shorter after progesterone (13.6 vs. 17.8
days, p < 0.05). However, the small number of pregnant patients and the inclusion
of patients with multiple pregnancies and premature rupture of membranes limit the
value of this study.
In another prospective randomised study which recruited 83 pregnant women between
the 24th–34th week of gestation with regular preterm labour (> 6 contractions/30 min)
and digitally verified cervical shortening, 200 mg progesterone/day vaginally until
delivery or the 36 + 6 week of gestation was administered adjunctively to standard
tocolysis with ritodrine intravenously (dose adjustment every 20 min until maximum
dose of 0.35 mg/min until cessation of contractions or the appearance of serious maternal
side effects with the need to discontinue treatment) [13]. A significant prolongation of the latency period until delivery (32.1 ± 17.8 vs.
21.2 ± 16.3 days) and a significant increase in birth weight (2983 ± 698 vs. 2585 ± 747 g)
was able to be achieved by the additional administration of progesterone, however
no significant reduction in the rate of preterm birth < 37 weeks of gestation (50
vs. 65%). The small number of cases (n = 40 vs. 43), the lack of a placebo group and
the late randomisation in week 32 of pregnancy on average were limiting factors in
this study.
In a randomised, placebo-controlled study on a total of 112 pregnant women with preterm
labour between the 22nd–35th week of gestation, Tan et al. [14] compared the treatment with nifedipine (initially 10 mg orally every 15 min up to
5 administrations, followed by 20 mg of a slow-release nifedipine preparation orally
every 8 h up to 48 h) + placebo (NaCl) with the same nifedipine regimen combined with
the single intramuscular application of 250 mg 17-OHPC. The primary outcome criterion
of this study was prolongation of pregnancy by 48 h and 7 days. There were no significant
differences between the two treatment groups with regard to the prolongation of pregnancy
by 48 h (20.4 vs. 26.8%, p = 0.50) and 7 days (25.0 vs. 35.2%, p = 0.29). Likewise
there were no significant differences with regard to the rate of preterm deliveries
< 34th and < 37th week of gestation (44.2 vs. 46.3%) as well as the neonatal outcome.
Here as well, the small number of cases resulting from early termination of the study
due to insufficient recruitment of pregnant women as well as the lack of detailed
information on the frequency of contractions and cervical status during randomisation
limit the value of this study.
The objective of a randomised, placebo-controlled, double-blind study on 84 pregnant
women between the 24th–34th week of gestation was to evaluate the additional oral
administration of dydrogesterone 20 mg/day until delivery or until the 37th week of
gestation in combination with nifedipine tocolysis (10 – 20 mg orally every 6 h) in
comparison to placebo [15]. The primary outcome criterion of this investigation was the recurrence of regular
contractions after 48 h. No significant differences with regard to the recurrence
of contractions (87.5 vs. 91.7%) were seen; likewise there were no significant differences
in the latency period until birth (32.7 ± 20.2 vs. 38.2 ± 24.2 days) or in the rate
of preterm birth < 34 (16.7 vs. 12.5%) and < 37 weeks of gestation (33.3 vs. 37.5%)
and the neonatal outcome. However, this study had an overly low statistical power
with regard to the prolongation of pregnancy, the rate of preterm birth < 34th/< 37th
week of gestation, as well as the neonatal outcome.
The largest randomised, placebo-controlled, double-blind study so far on adjunctive
tocolysis was published in 2014 by Martinez de Tejada et al. [16]. This multicentre study included 379 pregnant women between weeks 240 – 7 and 336/7 of pregnancy with preterm labour (at least 2 painful contractions in 10 min over
30 min) in conjunction with cervical shortening demonstrated on ultrasound (cervical
length ≤ 30 mm up to the 31st week of gestation or ≤ 25 mm as of the 32nd week of
gestation) or a cervical length of ≤ 10 mm confirmed on vaginal examination or a Bishop
score ≥ 6, progressive cervical shortening of ≥ 5 mm during two consecutive examinations
or a positive qualitative fibronectin test, if available. The randomisation was performed
within 48 h after the start of tocolysis. Depending on the centre, this was performed
with beta sympathomimetics, oxytocin receptor antagonists or calcium channel blockers.
In addition, either 200 mg progesterone vaginally/day or placebo was administered
on an outpatient basis (self-medication) until delivery, premature rupture of membranes,
or until 36 + 6 weeks of gestation.
The primary outcome criterion of the study was the rate of preterm birth < 37 weeks
of gestation. There were no significant differences between the two treatment groups
with regard to gestational age at birth (36.1 vs. 36.6 weeks of gestation), the frequency
of preterm birth < 37 weeks of gestation (55.0 vs. 35.4%, RR 1.20; 95% CI 0.92 – 1.55),
preterm deliveries < 34 weeks of gestation (20.3 vs. 12.4%; RR 1.65; 95% CI 1.01 – 2.67),
in the readmission rate with preterm labour (6.7 vs. 10.3%; RR 0.65; 95% CI 0.33 – 1.28),
in the latency period until delivery (median 45 vs. 52 days) and in the neonatal results
and the rate of maternal adverse effects (5.7 vs. 6.5%). The problem in this study,
which was conducted in Switzerland and Argentina, was the inadequate compliance in
25% of the pregnant women.
It should be noted that only the studies by Noblot et al. [12] and Tan et al. [14] involved exclusively adjunctive tocolysis. In the 3 other investigations, the administration
of progesterone was continued in terms of maintenance treatment ([Table 1]).
Table 1 Randomised studies: Adjunctive tocolysis with and without maintenance treatment.
|
Author/year
|
n
P vs. C
|
P/17-OHPC
|
Dose/
Interval (mg)
|
Controls
|
Tocolytics
|
Preterm birth < 37 weeks of gestation (%) [S]
|
Average latency period until delivery (days) [S]
|
Comments
|
|
n = Number of patients, P = Progesterone, 17-OHPC = 17-α-hydroxyprogesterone caproate,
C = Controls, S = Significant (p < 0.05), NS = Not significant
|
|
Noblot et al. 1991
|
44
22 vs. 22
|
P oral
|
300 mg/8 h
|
Placebo
|
Ritodrine
|
27.2 vs. 36.4 [NS]
|
19 vs. 21 [NS]
|
Only adjunctive through P ritodrine dose ↓
|
|
Arikan et al. 2011
|
83
43 vs. 40
|
P vaginal
|
200/day
|
No treatment
|
Ritodrine
|
50 vs. 65 [NS]
|
32 vs. 21 [S]
|
Tocolysis until delivery/36 + 6 weeks of gestation
|
|
Tan et al. 2012
|
112
56 vs. 56
|
17-P i. m.
|
250/1 ×
|
Placebo
|
Nifedipine
|
44 vs. 46 [NS]
|
35 vs. 24 [NS]
|
Single application of 17-P
|
|
Areeruk 2016
|
84
24 vs. 24
|
Dihydro-P oral
|
200/day
|
Placebo
|
Nifedipine
|
33 vs. 37.5 [NS]
|
32 vs. 38 [NS]
|
Tocolysis until delivery/37th week of gestation
Recurrence of contractions: 87.5 vs. 92%
|
|
Martinez de Tejada 2015
|
379
193 vs. 186
|
P vaginal
|
200/day
|
Placebo
|
Atosiban/Nifedipine
|
55 vs. 35 [NS]
|
45 vs. 52 [median, NS]
|
Tocolysis until delivery/36 + 6 weeks of gestation
|
In a retrospective observational study from Poland [17], 96 pregnant women between the 24th and 34th weeks of gestation and following successful
tocolysis with fenoterol were administered either 100 mg progesterone vaginally twice
daily until the 34th week of gestation (time period 2009 – 2010) or no treatment (observation
period 2007 – 2008). There were no significant differences with regard to the mean
gestational age at delivery (35 vs. 34 weeks of gestation) and in the rate of preterm
birth < 34 weeks of gestation (23 vs. 34%), but instead in the prolongation of pregnancy
by an average of 7.6 vs. 6.3 weeks.
The retrospective study design, the lack of definition of preterm labour as well as
the low number of cases considerably limit the value of this study.
Maintenance Tocolysis/Treatment
Maintenance Tocolysis/Treatment
To date there has been no uniform and authoritative definition of “maintenance tocolysis/treatment”.
It is mostly understood to mean the continuation of drug-based tocolysis beyond 48
hours. Contractions still persist in 20 – 30% of pregnant women after initial tocolysis
and up to 60% experience the recurrence of contractions at various intervals after
initial tocolysis [9]. Maintenance tocolysis/treatment is not an evidence-based measure for reducing neonatal
morbidity and mortality and is therefore not recommended in the current guidelines
[18], [19], [20], however it is repeatedly discussed in clinical practice as an option for prolongation
of pregnancy and is the subject of current clinical-scientific investigations.
Due to the loss of efficacy through tachyphylaxis, beta sympathomimetics are not suitable
and ineffective for use beyond 48 h. Oxytocin receptor antagonists are not approved
for maintenance tocolysis and the data in this regard are wholly inadequate (only
one randomised, placebo-controlled, double-blind study); with regard to the use of
prostaglandin synthetase inhibitors, there are no randomised, controlled studies on
maintenance treatment tocolysis available, and magnesium sulphate, in view of the
inadequate data beyond 48 h, is not associated with a decrease in the rate of preterm
birth (overview in [21]). According to a 2016 meta-analysis [22] which included 6 randomised, controlled studies with 787 pregnant women, oral nifedipine
used beyond 48 h is not more effective for prolonging pregnancy in comparison to placebo
and does not lead to any reduction in perinatal and neonatal morbidity.
New investigations therefore focus on the use of progesterone and 17-OHPC for maintenance
treatment after arrested preterm labour.
A 2014 Cochrane analysis [23] included 7 randomised, controlled studies with 538 pregnant women. It evaluated
investigations between 1960 and 2012 with the use of progesterone and synthetic progesterone
derivatives for primary tocolysis or for adjunctive and/or maintenance tocolysis with/after
ritodrine [12], [13], nifedipine [14] or atosiban [24]. Given the significant heterogeneity and inadequate statistical power of the individual
studies, the Cochrane analysis concluded that the evidence for the use of progesterone/17-OHPC
in pregnant women with preterm labour is insufficient. A summary overview of these
studies including the randomised, controlled study by Martinez de Tejada et al. [16] is also found in Navathe and Berghella 2016 [25].
In 2015 two meta-analyses on the use of vaginal progesterone [26] and intramuscular 17-OHPC [27] for maintenance tocolysis were published. The meta-analysis of Suhag et al. [26] included 5 randomised, controlled studies (441 singleton pregnancies) with vaginal
progesterone versus placebo/no treatment [13], [28], [29], [30], [31]. The daily vaginal progesterone dose in 3 studies was 200 mg and in 2 studies, it
was 400 mg. Primary tocolysis was performed using magnesium sulphate (3 studies),
ritodrine (1 study) and atosiban (1 study). Preterm labour was defined as at least
6 contractions/30 min or 4 contractions/20 min in combination with cervical shortening
confirmed digitally or on ultrasound. Progesterone led to a significant decrease in
the rate of preterm birth < 37th week of gestation (42 vs. 58%, RR 0.71; 95% CI 0.57 – 0.90)
in 3 studies, a significant prolongation of the latency period until birth (mean difference
13.8 days) in 4 studies, a greater gestational age at birth (mean difference 1.3 weeks)
in 4 studies, a significantly lower frequency of the recurrence of contractions (24
vs. 46%; RR 0.51; 95% CI 0.31 – 0.84) as well as a lower rate of neonatal sepsis (2
vs. 7%, RR 0.34; 95% CI 0.12 – 0.98) in 4 studies. Despite promising results in individual
studies, the meta-analysis concluded that, based on the considerable heterogeneity
between the studies, their low quality (no double-blind studies, selection bias, among
others) and the inadequate statistical power, no recommendation for the use of vaginal
progesterone as maintenance tocolysis can be made.
The meta-analysis of Saccone et al. [27] evaluated 5 randomised, controlled studies with 426 pregnant women who, after arrested
labour (atosiban, nifedipine, magnesium sulphate), received 250 mg 17-OHPC (3 studies)
weekly or 341 or 500 mg 17-OHPC twice per week intramuscularly vs. no treatment or
placebo (1 study) [24], [31], [32], [33], [34]. It revealed no significant differences with regard to the rate of preterm birth
< 37 weeks of gestation (42 vs. 51%; RR 0.78; 95% CI 0.50 – 1.22) and < 34 weeks of
gestation (25 vs. 34%; RR 0.60; 95% CI 0.28 – 1.12), the frequency of the recurrence
of contractions as well as the rate of neonatal complications and transfers to the
neonatal intensive care unit in comparison to the control groups. However, after intramuscular
17-OHPC, there was a significantly longer latency period until birth (mean difference
8.4 days) and a significantly higher birth weight (mean difference 224 g). The value
of this meta-analysis is limited by the lack of data on risk factors for preterm birth
in the studies, the different dosages and application intervals for 17-OHPC, the different
primary outcome criteria of the investigations, as well as the low numbers of cases
with inadequate statistical power.
According to the authors, the intramuscular application of 17-OHPC is indeed promising,
however it cannot be recommended for routine clinical practice due to the insufficient
data.
Three additional meta-analyses from 2016 also addressed the use of progesterone/17-OHPC
for maintenance tocolysis, however the selection of the randomised, controlled trials
(RCT) was entirely different.
Eke et al. [35] thus analysed four of the RCTs already cited with 362 pregnant women [12], [24], [28], [32] in which vaginal/oral progesterone and 17-OHPC were compared with placebo/no treatment.
Here, the search strategies/criteria are unclear in view of the large number of studies
published by then and not taken into account in this meta-analysis. The outcome criteria
of this meta-analysis were the latency period from randomisation until delivery and
the rate of preterm birth < 37 and < 34 weeks of gestation. With regard to these criteria,
there were no significant differences between the treatment groups and the mean birth
weight was 203 g higher on average following progesterone/17-OHPC than in comparative
groups.
A meta-analysis by Ding et al. [36] investigated 10 RCTs, 5 of which had oral nifedipine and 5 had oral/vaginal progesterone
in comparison to placebo/no treatment for maintenance tocolysis between the 24th–34th
week of gestation in the period from 1980 – 2014 [13], [28], [30], [37], [38]. Not included were studies with intramuscular 17-OHPC; the progesterone dosages
were 200 and 400 mg/day, primary tocolysis was performed with nifedipine, magnesium
sulphate, ritodrine or atosiban.
In comparison to placebo/no treatment, a significant prolongation of pregnancy (on
average by 1.6 weeks), a reduction in the rate of preterm birth < 37 weeks of gestation
(RR 0.63; 95% CI 0.47 – 0.83) and a significant increase in the birth weight (by 318 g
on average) was able to be achieved with progesterone. The treatment had no effect
on the neonatal outcome. By contrast, maintenance tocolysis with nifedipine, compared
to placebo/no treatment, did not result in any significant prolongation of pregnancy.
A randomised study [37] included in this meta-analysis compared 20 mg oral nifedipine every 8 h directly
with the administration of 400 mg vaginal progesterone: 10% of the pregnant women
in the nifedipine group and 61% of the pregnant women in the progesterone group reached
term (p: 0.000). The mean prolongation of pregnancy was 16.6 vs. 40.1 days, the adverse
effects following nifedipine were significantly higher than after vaginal progesterone
(e.g. hypotension 15.7 vs. 0%).
The authors conclude from their results that, in contrast to nifedipine, progesterone
is beneficial for maintenance treatment after arrested labour.
It is unclear why other RCTs published during the observation period were not included
in this meta-analysis (among others [13], [29], [31], [39]), which limits its value.
The randomised, placebo-controlled, double-blind study by Palacio et al. published
in 2016 (PROMISE-Trial [40], EL1) was not taken into account in the meta-analyses previously cited. This investigation
included 248 pregnant women with randomisation between 24 + 0 to 30 + 6 weeks of gestation
and 31 + 0 to 33 + 6 weeks of gestation. Preterm labour was defined as 2 painful contractions/10 min
in conjunction with shortening/opening of the cervix. After successful primary tocolysis
(atosiban, nifedipine), the pregnant women were discharged from the hospital with
a cervical length of < 25 mm: 126 pregnant women received 200 mg vaginal progesterone/day
and 132 placebo until delivery or until 36 + 6 weeks of gestation. It was planned
to recruit a total of 350 pregnant women; however this study was discontinued early
due to financial problems.
There were no significant differences with regard to the rate of preterm deliveries
< 34 weeks of gestation (7.1 vs. 7.6%) and < 37 weeks of gestation (28.6 vs. 22%),
nor when the stratification of the investigational groups was considered as a function
of gestational age. The differences in gestational age at birth were also non-significant
(38.0 vs. 38.2 weeks of gestation).
It is debatable whether the study would have achieved different results if the entire
planned number of pregnant women had been recruited than in the case of the 75.7%
achieved upon premature termination of the study.
Palacio et al. included their study in their own subsequent meta-analysis with 16
RCTs and 1917 pregnant women (reporting period 1991 to June 2015) [41]. Primary tocolysis was performed in most cases with magnesium sulphate (7 studies);
in 11 RCTs, progesterone was administered vaginally or orally at dosages of 200 – 400 mg/day
for maintenance treatment either in addition to acute tocolysis or after arrested
preterm labour, in 5 RCTs, 17-OHPC was administered intramuscularly at dosages between
250 – 500 mg once to twice per week. Randomisation was performed between 24 + 0 – 34 + 6/7
weeks of gestation. Pregnant women with a previous preterm birth were also included.
The definitions of preterm labour differed: in most cases, ≥ 6 contractions/30 min
or 4 contractions/20 min associated with cervical shortening confirmed digitally or
on ultrasound. The number of pregnant women recruited was between 40 [42] and 379 [16]. In comparison to placebo/no treatment, a significant decrease in the rate of preterm
birth < 37th week of gestation from 44.3 to 38.2% (RR 0.79; 95% CI 0.65 – 0.97) was
achieved overall through the use of progesterone/17-OHPC. The prolongation of pregnancy
after progesterone/17-OHPC was 8.1 days on average (95% CI 3.8 – 12.4 days). No significant
differences were seen in the rate of preterm birth < 34th week of gestation (15.6
vs. 18.3%, RR 0.77; 95% CI 0.53 – 1.12). In the sensitivity analysis which included
5 “high-quality” studies, no significant differences were seen with regard to the
rate of preterm birth < 37 weeks of gestation in comparison to placebo/no treatment
(37.2 vs. 36.9%; RR 0.91; 95% CI 0.67 – 1.21) nor in the latency period between randomisation
and delivery (mean difference 0.6 days; 95% CI − 3.7 – 4.9).
In comparison to the meta-analyses of Suhag et al. [26] and Saccone et al. [27], the meta-analysis of Palacio et al. [41] evaluated 6 additional RCTs between 2009 and 2016, primarily from India, Egypt and
Iran [38], [39], [42], [43], and studies with adjunctive tocolysis with and without the continuation of the
progesterone treatment as maintenance treatment were also included (see [Table 2]).
Table 2 Meta-analyses: Progesterone/17-OHPC vs. placebo/no treatment as maintenance tocolysis*
after arrested preterm labour.
|
Author/year
|
Suhag 2015
|
Saccone 2015
|
Palacio 2016
|
Eke 2016
|
Wood 2017
|
|
* = Maintenance treatment until delivery or 35th – < 37th week of gestation, + = Significant results (p < 0.05), # = No percent values, N/I = No information, P = Progesterone, 17-OHPC = 17-α-hydroxyprogesterone
caproate, RR = Relative risk, OR = Odds ratio
|
|
Number of studies included
|
5
|
5
|
16
|
4
|
15
|
|
Total number of pregnant women
|
441
|
426
|
1917
|
362
|
1742
|
|
P/17-OHPC (number of studies)
|
vag. P
|
17-OHPC i. m.
|
P (12)
17-OHPC (4)
|
P (2)
17-OHPC (2)
|
P (11)
17-OHPC (4)
|
|
Preterm birth < 37th week of gestation (%)
RR (95% CI)
|
42 vs. 58+
0.71 (0.57 – 0.9)
|
42 vs. 51
0.78 (0.5 – 1.2)
|
38.2 vs. 44.3+
0.79 (0.65 – 0.97)
|
RR 0.8# (0.58 – 1.1)
|
OR 0.77+# (0.62 – 0.96)
|
|
Preterm birth < 34th week of gestation (%)
RR (95% CI)
|
N/I
|
25 vs. 34
0.60 (0.28 – 1.12)
|
15.6 vs. 18.3
0.77 (0.53 – 1.12)
|
RR 0.69# (0.4 – 1.2)
|
OR 0.80 (0.60 – 1.08)
|
|
Latency period until delivery (days, mean difference range)
|
13.8+ (4.0 – 23.6)
|
8.4+ (3.2 – 13.5)
|
8.1+ (3.8 – 12.4)
|
2.4 (− 1.5 – 6.3)
|
9.1+ (3.7 – 14.5)
|
Taking the Cochrane risk of bias tool [44] into account revealed significant heterogeneity between the studies, especially
with regard to the rate of preterm birth < 37, < 34 weeks of gestation and the latency
period until delivery. In 10 out of 16 studies, a selection bias can be assumed (no
double-blind studies, inadequate randomisation, different inclusion criteria).
Only 5 studies met the Jadad criteria (validated scale for assessing the methodological
study quality [45]); in the sensitivity analysis, they did not demonstrate any significant differences
with regard to the outcome criteria.
In the authorsʼ opinion, based on the lack of qualified studies and the significant
heterogeneity between the studies, the data are insufficient for using progesterone
as maintenance treatment after arrested preterm labour with the goal of decreasing
the preterm birth rate and prolonging pregnancy.
A randomised, controlled, multicentre study from Italy published in 2017 with 254
pregnant women between 220/7 – 316/7 weeks of gestation and a cervical length ≤ 25 mm compared the application of 200 mg
progesterone vaginally/day vs. 341 mg 17-OHPC/week intramuscularly vs. no treatment
until the end of the 36th week of gestation after arrested labour with atosiban, nifedipine
or indomethacin [46]. The recruitment of 160 pregnant women/study arm was planned. The primary outcome
criterion was indicated as the rate of preterm birth < 37 weeks of gestation. Following
an interim analysis of more than 50% of the pregnant women included up to that point,
the study was discontinued prematurely by an independent monitoring committee, since
even after the originally planned number of pregnant women was reached, no statistically
significant advantages with regard to the primary outcome criterion through the use
of progesterone/17-OHPC could be expected. The initial hypothesis was that the risk
of a preterm birth < 37 weeks of gestation can be reduced by 50% when using progesterone.
Taking the evaluated cases into account, the rate of preterm birth < 37 weeks of gestation
was 39% after vaginal progesterone, 23% after 17-OHPC and 22% in the control group,
thus without statistically significant differences. Likewise there were no significant
differences between the treatment groups with regard to the rate of preterm birth
< 35 and < 32 weeks of gestation.
The conclusion of the study is that progesterone/17-OHPC as maintenance tocolysis
does not decrease the rate of preterm births.
In the same year (2017) Wood et al. [47] conducted another randomised, placebo-controlled study and an update of previous
meta-analyses. Included were pregnant women between 23 + 0 – 32 + 6 weeks of gestation
with cessation of contractions at least 12 h after initial tocolysis or after spontaneous
cessation of contractions and positive fibronectin test, who received either 200 mg
vaginal progesterone/day or placebo until the 35th week of gestation. The recruitment
of 60 pregnant women in each treatment arm was planned. Because of the inadequate
recruitment and the fact that the study medication ran out, the investigation was
discontinued prematurely after the inclusion of 41 pregnant women (19 with progesterone,
22 with placebo); added to this was the lack of compliance by the pregnant women.
The meta-analyses incorporated 15 RCTs (n = 1742) including the results from their
own study. In contrast to the meta-analysis by Palacio et al. [41], 3 RCTs which are in part not listed in PubMed [42], [43], are not taken into account, but the randomised, controlled study of Kamat et al.
was, however [37]; 4 randomised, controlled studies related to the use of 17-OHPC, 2 to the use of
oral progesterone and 8 to the use of vaginal progesterone; 5 studies were assessed
as “high-quality” and 10 as “low-quality”. The 5 “high-quality” studies included,
in addition to their own study, the 4 which also have this quality feature in the
meta-analysis of Palacio et al. The results of this meta-analysis can be summarised
as follows: overall, the use of progesterone/17-OHPC decreased the rate of preterm
birth < 37th week of gestation significantly (OR 0.77; 95% CI 0.62 – 0.96), however
significances for vaginal/oral progesterone and 17-OHPC alone could not be identified.
Not significant for both was also the rate of preterm birth < 34 weeks of gestation
(OR 0.80; 95% CI 0.60 – 1.08). In comparison to the control groups (placebo/no treatment),
the latency period overall until delivery was able to be prolonged through progesterone
by an average of 9.1 days (95% CI 3.7 – 14.5 days). Comparable with the meta-analysis
of Palacio et al. [41], this meta-analysis also revealed in the “low-quality” studies a significant decrease
in the rate of preterm birth < 37 weeks of gestation (OR 0.47; 95% CI 0.34 – 0.64),
< 34 weeks of gestation (OR 0.55; 95% CI 0.35 – 0.86) and the mean latency period
until delivery (16 days; 95% CI 14.1 – 17.8 days), however not in the “high-quality”
studies (rate of preterm birth < 37 weeks of gestation: OR 1.23; 95% CI 0.91 – 1.67,
< 34 weeks of gestation: OR 1.22; 95% CI 0.74 – 1.69 and latency period until delivery:
− 0.95 days; 95% CI − 5.5 – 3.6 days).
In the “low-quality” studies, the progesterone treatment was associated with a significant
reduction in perinatal mortality (OR 0.39; 95% CI 0.12 – 0.87), however not in the
“high-quality” studies (OR 0.52; 95% CI 0.14 – 1.95).
The authors conclude that, at present, neither vaginal/oral progesterone nor 17-OHPC
as maintenance treatment is suitable for clinical practice and the results of further
randomised, controlled (double-blind) studies should be awaited.
Discussion
In view of a preterm birth rate in Europe between 5 – 18% (in Germany 2017: 8.6%),
tocolysis is among the most frequent obstetric measures. In pregnant women with preterm
labour, common tocolytics are able to prolong the pregnancy by 48 h in 75 – 93% of
cases and by 7 days in 61 – 78% of patients [48]. The increase in the tocolytic efficacy with a simultaneous reduction in maternal
adverse effects through additional measures is a worthwhile pursuit of clinical research
for practical application. Another objective following acute tocolysis is to develop
new therapeutic methods which effectively prolong pregnancy until near term and are
able to significantly reduce the rate of preterm deliveries and associated neonatal
morbidity.
As shown in experimental and clinical studies, progesterone inhibits the contractility
of the myometrium through a number of various mechanisms [6], [7], [8], [49].
According to in-vitro studies [6], progesterone has synergistic effects in combination with nifedipine, indomethacin
and beta sympathomimetics. According to clinical investigations, the tocolytic efficacy,
particularly of beta sympathomimetics, can be increased by progesterone and the dosage
of the tocolytic can be significantly reduced [3], [10], [12], [13]. However, the randomised placebo-controlled study of Martinez de Tejada et al. [16] arrived at contrary results in this regard.
There are only 3 studies from 1960, 1986 and 2011 on primary tocolysis with progesterone/17-OHPC
with small numbers of cases, different study design and different primary outcome
criteria. In two studies, 17-OHPC (n = 276) was used, in one study (n = 57) oral progesterone
was used and in no study was vaginal progesterone used. While an inhibition of uterine contractions
through progesterone/17-OHPC was unanimously confirmed, no details were given regarding
a decrease in the rate of preterm birth and the interval between the start of treatment
and delivery.
Because of these insufficient data, it is unclear whether or not progesterone/17-OHPC
is suitable for primary tocolysis. In this connection, the question arises as to the
optimal mode of application, the effective, contraction-inhibiting dosage and the
suitable application intervals of the substances. Of note is the fact that, since
2011, no study on primary tocolysis with progesterone/17-OHPC has been published and
thus here as well, there is evidently considered to be no need for research.
The data on adjunctive tocolysis are also completely inadequate, especially as oral
progesterone and 17-OHPC were used concomitantly/in addition to conventional tocolytics
in only 2 out of 5 studies [12], [14]. A limiting factor in the placebo-controlled study by Noblot et al. [12] is the small number of cases (n = 44), in the study of Tan et al. [14], it is its premature termination with 112 out of 254 planned pregnant women who
actually should have been included in the study in view of an adequate statistical
power. The randomised, placebo-controlled, double-blind study of Martinez de Tejada
et al. [16], which is the largest to date and which has precise inclusion criteria, clear information
on the randomisation and defined outcome criteria (evidence level I), is of great
clinical significance. In this study, vaginal progesterone was applied within 48 h
additively to tocolysis and then as maintenance treatment until delivery or up to
36 + 6 weeks of gestation. During an interim analysis (n = 302), the power analysis
revealed that even if the planned number of patients is reached, the probability of
an advantage of progesterone in comparison to placebo with regard to the primary outcome
criterion (rate of preterm birth < 37 weeks of gestation) would be 0%. Independent
of this, the authors conclude that the daily administration of 200 mg vaginal progesterone
does not decrease the rate of preterm birth or improve the neonatal outcome.
One problem of this and other studies [47] which is difficult to overcome is the self-medication of progesterone by the pregnant
woman after discharge from the hospital which leads to an incalculable influence on
the results. The repeated weekly i. m. administration of 17-OHPC may demonstrate even
lower compliance [47].
Whether exclusively adjunctive tocolysis with progesterone is effective can only be
clarified in randomised, placebo-controlled studies with an adequate number of cases
without additional maintenance treatment. In light of this, the extent to which this
approach decreases the rate of preterm birth without further maintenance treatment
is questionable.
The objective of maintenance tocolysis (treatment) is the prolongation of the latency
period until delivery and thus a reduction in the rate of preterm birth < 37 [34] weeks of gestation, as well as a decrease in neonatal morbidity and mortality. This
objective could not be achieved for various reasons with the use of beta sympathomimetics,
calcium channel blockers, cyclooxygenase inhibitors, magnesium sulphate and the selective
oxytocin receptor antagonist atosiban in comparison to placebo [26]. Particularly in regard to a reduction of serious neonatal complications/neonatal
mortality, their low prevalence calls for high numbers of cases which are not reached
in previous randomised, controlled studies, however. Whether this objective can be
achieved with progesterone/17-OHPC was and is the subject of clinical research in
the past 10 years to date. Overall, the results of this research are contradictory.
Notwithstanding the considerable heterogeneity between the studies, the meta-analysis
of Suhag et al. [26] revealed a significant prolongation of the latency period until delivery and a significant
decrease in the rate of preterm birth < 37 weeks of gestation following vaginal progesterone.
The contemporaneous meta-analysis of Saccone et al. [27] achieved opposite results after the use of intramuscular 17-OHPC as maintenance
treatment. In both meta-analyses, no subgroup analysis with regard to the quality
of RCTs evaluated was performed.
Two other meta-analyses from 2016 [35], [36] which included 4 and 5 RCTs also yielded contradictory statements. While Eke et
al. [35] included RCTs with oral/vaginal progesterone and 17-OHPC in their analysis and found no significant reduction in the rate of preterm
birth < 37/<34 weeks of gestation, Ding et al. [36] evaluated only RCTs with oral/vaginal progesterone as maintenance treatment. In
comparison to oral nifedipine, a significant prolongation of pregnancy and a significant
decrease in the rate of preterm birth < 37 weeks of gestation were able to be achieved
with progesterone. For both meta-analyses, there is evidence of a publication bias
[41], since other RCTs published during the period covered by these meta-analyses were
not taken into account. Moreover, the low number of cases (n = 362 and n = 410) in
both meta-analyses limits their value.
The most comprehensive and qualitatively best meta-analysis to date, which included
16 RCTs with 1917 pregnant women, was published in 2016 by Palacio et al. [41]. A detailed analysis of the RCTs regarding heterogeneity and an assessment of their
quality was performed using the Cochrane risk of bias tool and the Jadad criteria.
In “low-quality” studies, there was a significant decrease in the rate of preterm
birth < 37 weeks of gestation and a significant prolongation of pregnancy following
progesterone/17-OHPC; this could not be demonstrated in 5 “high-quality” studies.
Comparable results were also found in the meta-analysis of Wood et al. 2017 (15 RCTs
with 1742 pregnant women) which was not able to demonstrate any significant differences
in the 5 “high-quality” studies with regard to the primary outcome criteria [47]. In doing so, in both meta-analyses, the same RCTs were classified as “high quality”
4 times in each case [12], [16], [34], [40]; in the meta-analysis of Palacio et al. [41] additionally the RCT of Choudhary et al. [38], in that of Wood et al. [47] their own RCT which was, however, prematurely terminated after recruiting 41 pregnant
women. According to the conclusion from both meta-analyses, there is no sufficient
evidence to date that maintenance treatment with progesterone/17-OHPC, in comparison
to placebo/no treatment, significantly decreases the rate of preterm deliveries and
is thus suitable for clinical use.
Two other recently published RCTs [40], [46] also support this statement. The randomised, placebo-controlled, double-blind study
by Palacio et al. [40] was discontinued prematurely after recruiting 258 pregnant women (350 planned) after
no significant differences were seen between maintenance treatment with 200 mg vaginal
progesterone/day vs. placebo with regard to the rate of preterm birth < 37 and < 34
weeks of gestation. A randomised, controlled, multicentre study from Italy [46] was also terminated prematurely after the interim analysis which revealed no significant
differences with regard to the primary outcome criterion (rate of preterm birth < 37
weeks of gestation) following maintenance treatment with vaginal progesterone and
intramuscular 17-OHPC versus no treatment.
As is evident from the different clinical results of the meta-analyses of Suhag et
al. [26] and Saccone et al. [27], differences in effect with regard to the tocolytic potency between natural progesterone
and synthetic progesterone derivates which affect the metabolisation and receptor
affinity, among others (discussion in [4]), can be assumed. In-vitro investigations have shown that not 17-OHPC but rather
natural progesterone inhibits myometrium contractions dose-dependently [49], [50]. In comparison to natural progesterone, 17-OHPC has a lower relative binding affinity
of 26 – 30% to the progesterone receptors [51]. In animal models, birth processes could be fully inhibited only by the substitution
of progesterone and not by 17-OHPC, however [52]. Moreover, the mode of application and the solvent used (castor oil in the case
of 17-OHPC, stimulating effect on the uterus) in particular play a further role [52]. The direct transport of the substance from the vagina to the uterus (first uterine
pass effect [53]) is considered to be an advantage of vaginally applied progesterone as compared
to systemically administered 17-OHPC.
Natural progesterone is commercially available in Germany, however 17-OHPC is only
available via the international pharmacy.
Problems become clear from the critical analysis of published data which apply not
only for the evaluation of RCTs and resultant meta-analyses on progesterone/17-OHPC,
but rather clearly for other treatment studies as well. The high degree of heterogeneity
between the studies limits the validity of pooled data in meta-analyses. Crucial problems
in this connection which make the interpretation and comparability of studies difficult
are especially different inclusion criteria with the risk of a selection bias (differences
in the definition of preterm labour, gestational age and cervical status at randomisation,
in the assessment of the cervix using palpation or ultrasound, in the exclusion or
inclusion of risk factors for preterm birth such as a prior preterm birth or ethnic
affiliation, among others). Added to this are the considerable methodological differences
between the studies (e.g. nature and quality of the randomisation, double-blind study
vs. no blinding, placebo-controlled study vs. no treatment, selection of primary outcome
criteria) as well as in the approach (e.g. local vs. systemic application, dosages,
application frequency). Another problem is the insufficient number of cases in studies
with inadequate statistical power. Studies with low numbers of cases often arrive
at different results with regard to the primary outcome criteria in comparison to
studies with high numbers of cases. Thus, in comparison to studies with small numbers
of cases (n < 100, e.g. [28], [30], [33], [37], [38]) in the largest RCT to date of Rozenberg et al. (n = 184 [32]) with 17-OHPC and in that of Martinez de Tejada et al. (n = 385 [16]) with vaginal progesterone, no significant differences in the latency period until
delivery and in the rate of preterm birth could be demonstrated.
Not to be underestimated with regard to the results is also the lack of compliance
during self-medication of progesterone after discharge from the hospital [16], [47] and during repeat outpatient application of 17-OHPC [14]. The controversial data on progesterone in meta-analyses is the subject of current
discussions [54].
Conclusion
Based on current knowledge, progesterone/17-OHPC is not suitable either for primary
or adjunctive tocolysis. In line with the forthcoming AWMF guideline “Prävention und
Therapie der Frühgeburt” [Prevention and treatment of preterm birth], maintenance
treatment with progesterone, after arrested preterm labour, is also not a suitable
measure for the prevention of preterm birth.
