This randomized controlled study evaluated the efficacy of vaginal progesterone in preterm labor treated with tocolysis and corticosteroids. This study showed that the latency period was prolonged in the vaginal progesterone group more so than in the no-progesterone group. GA at delivery in the vaginal progesterone group was also more than in the no-progesterone group. Further, there were significant reduction rates in preterm delivery less than 34 weeks, LBW, and rate of neonatal respiratory distress syndrome. Similar results between groups were found in terms of the rate of preterm delivery less than 37 weeks, obstetric outcomes, other neonatal outcomes, maternal compliance with medication use, and side effects.
In this study, the latency period was prolonged more so in the vaginal progesterone group than in the no-progesterone group (32.8 days vs. 25.8 days, p = 0.045). This finding was consistent with those of prior studies that assessed vaginal micronized progestogen in women with threatened preterm labor [5, 10, 13, 14]. In their treatment efforts, one study used 400 mg of vaginal progesterone [5] while some studies employed 200 mg of vaginal progesterone [13]. This present finding was in contrast with Noblot et al’ study (1991)[15]. These authors assessed the maintenance of tocolysis with oral micronized progesterone 400 mg in cases of preterm labor and found no difference in the latency period [15]. Of note, differences between this prior research and our study may be from the different route of medication used.
The results of this study were also different from those of our previous study that assessed oral dydrogesterone 20 mg in the adjunctive management of preterm labor. There, latency periods were not different between the groups [4]. The difference between the studies may be due to the difference in type of progesterone and the route of drug administration used.
Vaginal micronized progesterone was chosen for use in the present study because the vaginal route enhanced the bioavailability and the absence of undesirable side-effects such as sleepiness, fatigue, or headache [5, 16]. Micronized progesterone 400 mg was used in this study, similar to in a previous study [5].
In the present study, the rate of preterm delivery less than 34 weeks was significantly reduced in the vaginal progesterone group. This finding was consistent with that in a previous study [17], where the authors reviewed the use of vaginal progesterone 200 mg in threatened preterm labor after tocolysis. They found that vaginal progesterone reduced preterm delivery before 34 weeks when compared with no medication [17]. However, this finding was in contrast with other results in previous studies [11-13], where the authors found that the rates of preterm delivery less than 34 and 37 weeks were not significantly reduced when compared with placebo [11]. The difference in results between these studies could be attributed to the variations in the study population, dose of vaginal progesterone, and time of starting progesterone.
A recent systemic review and meta-analysis compared vaginal progesterone, oral progesterone, 17 α-hydroxyprogesterone caproate, cerclage, and pessary for preventing preterm birth in at-risk singleton pregnancies. The study notably found that vaginal progesterone was the only intervention with a consistent level of effectiveness for preventing preterm birth in singleton at-risk pregnancies overall and in those with a previous preterm birth [18].
Neonatal outcomes including birth weight were higher, and LBW, RDS, and NICU admission were reduced in the vaginal progesterone group than in the no-progesterone group. This may be explained by the higher GA at delivery and the reduced rate of preterm delivery less than 34 weeks in the vaginal progesterone group.
The mechanisms of progesterone for prolonging pregnancy are not clearly understood, but progesterone inhibits myometrial activity by way of several mechanisms. Specifically, progesterone suppresses genes that regulate uterine contractions (i.e., genes for calcium channels, oxytocin receptors, and the gap junction protein connexin), upregulates relaxation mechanisms (i.e., the generation and action of cyclic adenosine monophosphate, and cyclic guanosine monophosphate), and acts by opposing estrogen, which increases myometrial contractility [19]. In a human study from Lucovnik et al, it was found that maintenance tocolysis with 400 mg of vaginal micronized progesterone reduced the propagation velocity of electrical signals within the myometrium [20].
A strength of this study was that it was a randomized controlled study conducted to assess the efficacy of vaginal micronized progesterone for both tocolytic and the maintenance treatment of preterm labor. Vaginal micronized progesterone was chosen in the present study because the vaginal route enhances bioavailability and had no undesirable known side-effects such as sleepiness, fatigue, and headache [5, 16]. Micronized progesterone 400 mg was used in this study like in a previous study [5]. A limitation of this study was that it was not a placebo-controlled trial and a limitation of sample size in the vaginal progesterone group. Future randomized, placebo-controlled studies with larger sample sizes should be performed to evaluate the value of vaginal micronized progesterone as a secondary prevention method in preterm labor.