Objective
We sought to evaluate the efficacy of maintenance tocolysis with vaginal progesterone compared to control (placebo or no treatment) in singleton gestations with arrested preterm labor (PTL) in a metaanalysis of randomized controlled trials.
Study Design
Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov , and the Cochrane Central Register of Controlled Trials with the use of a combination of key words and text words related to “progesterone,” “tocolysis,” and “preterm labor” from 1966 through November 2014. We included all randomized trials of singleton gestations that had arrested PTL and then were randomized to maintenance tocolysis treatment with either vaginal progesterone or control (either placebo or no treatment). All published randomized studies on progesterone tocolysis were carefully reviewed. Exclusion criteria included maintenance tocolysis in women with preterm premature rupture of membrane, maintenance tocolysis with 17-alpha-hydroxyprogesterone caproate, and maintenance tocolysis with oral progesterone. The summary measures were reported as relative risks (RRs) with 95% confidence interval (CI). The primary outcome was preterm birth (PTB) <37 weeks.
Results
Five randomized trials, including 441 singleton gestations, were analyzed. Women who received vaginal progesterone maintenance tocolysis for arrested PTL had a significantly lower rate of PTB <37 weeks (42% vs 58%; RR, 0.71; 95% CI, 0.57–0.90; 3 trials, 298 women). Women who received vaginal progesterone had significantly longer latency (mean difference 13.80 days; 95% CI, 3.97–23.63; 4 trials, 368 women), later gestational age at delivery (mean difference 1.29 weeks; 95% CI, 0.43–2.15; 4 trials, 368 women), lower rate of recurrent PTL (24% vs 46%; RR, 0.51; 95% CI, 0.31–0.84; 2 trials, 122 women), and lower rate of neonatal sepsis (2% vs 7%; RR, 0.34; 95% CI, 0.12–0.98; 4 trials, 368 women).
Conclusion
Maintenance tocolysis with vaginal progesterone is associated with prevention of PTB, significant prolongation of pregnancy, and lower neonatal sepsis. However, given the frequent lack of blinding and the generally poor quality of the trials, we do not currently suggest a change in clinical care of women with arrested PTL. We suggest instead well-designed placebo-controlled randomized trials to confirm the findings of our metaanalysis.
Preterm birth (PTB), defined as birth between 20 and 36 6/7 weeks, is responsible for the majority of the neonatal morbidity and mortality in the United States, and 35% of all US health care spending on infants. Globally, about 28% of the 4 million annual neonatal deaths are directly attributable to PTB.
Preterm labor (PTL) is the final pathway for about 50% of all PTB. Tocolytic agents are drugs that can slow or stop labor contractions in the attempt to delay births preceded by PTL. Primary tocolysis is defined as tocolysis given on initial presentation of women with PTL. In most of these women, PTL stops, but as their risk of PTB remains high, some have advocated use of maintenance tocolysis, ie, tocolysis after arrested PTL. So far, no maintenance tocolytic agent has been shown to be beneficial in preventing PTB. Recently, progesterone has been used successfully for prevention of PTB, in particular in asymptomatic singleton gestations with either short cervical length or with prior spontaneous PTB. The efficacy of vaginal progesterone in preventing PTB in women with arrested PTL is not clear.
The aim of this study was to evaluate the efficacy of maintenance tocolysis with vaginal progesterone compared to control (placebo or no treatment) in singleton gestations with arrested PTL in a metaanalysis of randomized trials.
Materials and methods
Study design
The research protocol was designed a priori, defining methods for searching the literature, including and examining articles, and extracting and analyzing data. Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov , and the Cochrane Central Register of Controlled Trials with the use of a combination of key words and text words “progesterone,” “tocolysis,” and “preterm labor” from 1966 through November 2014. To locate additional publications, we reviewed proceedings of international society meetings on PTB and tocolysis and bibliographies of identified studies and reviews articles. No restrictions for language or geographic location were applied.
We included randomized trials of singleton gestations that had arrested PTL and then were randomized to maintenance tocolysis treatment with either vaginal progesterone or control (either placebo or no treatment). All published randomized studies on progesterone tocolysis were carefully reviewed. Exclusion criteria included quasirandomized trials (ie, trials in which allocation was done on the basis of a pseudorandom sequence, eg, odd/even hospital number or date of birth, alternation), maintenance tocolysis in women with preterm premature rupture of membrane (PPROM), maintenance tocolysis with 17-alpha-hydroxyprogesterone caproate (17P), and maintenance tocolysis with oral progesterone.
Before data extraction, the protocol was registered with PROSPERO (registration number: CRD42014013706; http://www.crd.york.ac.uk/PROSPERO/ ). The metaanalysis was reported following the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) statement.
Data abstraction was completed by 3 independent investigators (G.S., A.S., V.B.). Each investigator independently abstracted data from each study and analyzed data separately. Differences were reviewed, and further resolved by common review of the entire data. All authors were contacted for missing data.
The risk of bias in each included study was assessed by using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Seven domains related to risk of bias were assessed in each included trial since there is evidence that these issues are associated with biased estimates of treatment effect: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. Review authors’ judgments were categorized as low risk, high risk, or unclear risk of bias. Risk of bias was assessed by 2 investigators (A.S., G.S.). Disagreements were resolved by consensus with a third reviewer (V.B.).
The primary outcome was PTB <37 weeks. Secondary outcomes included PTB <34 weeks, gestational age at delivery, latency, birthweight, neonatal death, admission to neonatal intensive care unit, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal sepsis. We performed a subgroup analysis by examining only those trials that included a placebo, and examined the trials by the dose of progesterone.
Data analysis
The data analysis was completed independently by authors (G.S., A.S., V.B.) using Review Manager 5.3 (The Nordic Cochrane Center, Cochrane Collaboration, 2014, Copenhagen, Denmark). The completed analyses were then compared, and any difference was resolved with review of the entire data and independent analysis. Statistical heterogeneity between studies was assessed using the Cochrane Q statistic and I 2 statistics of Higgins et al. In case of statistical significant heterogeneity ( P value of the Cochrane Q statistic < .1) the random effects model of DerSimonian and Laird was used to obtain the pooled relative risks (RRs) estimate, otherwise a fixed effect models was planned. The summary measures were reported as RRs, with 95% confidence interval (CI). P value < .05 was considered statistically significant.
Results
Study selection and study characteristics
Figure 1 shows the flow diagram of information through the different phases of the review. In all, 21 trials on progesterone as tocolytic were identified. Eleven trials were identified that evaluated the effect of progesterone for maintenance tocolysis after PTL. Six of them were excluded: 4 were excluded because 17P was evaluated ; 1 was excluded because women with PPROM were evaluated ; and 1 was excluded because oral progesterone was evaluated. Five trials that met inclusion criteria for this metaanalysis were analyzed.
Descriptive data for each trial are presented in Table 1 . A total of 441 singleton gestations with arrested PTL were included. Most studies used 200 mg of vaginal progesterone daily. Three of 5 used no treatment as control. Three studies defined PTL as the presence of at least 6 contractions in 30 minutes accompanied by cervical changes ; 1 defined it as the presence of at least 4 contractions per 20 minutes, accompanied by 2-cm dilatation ; and 1 defined it as uterine contractions at least 4 per 20 minutes accompanied by cervical length <25 mm.
| Variable | Borna and Sahabi, 2008 | Sharami et al, 2010 | Arikan et al, 2011 | Lotfalizadeh et al, 2013 | Areia et al, 2013 | Total |
|---|---|---|---|---|---|---|
| Study location | Iran | Iran | Turkey | Iran | Portugal | – |
| No. of patients–progesterone vs control | 70 (37 vs 33) | 163 (80 vs 83) | 83 (43 vs 40) | 73 (37 vs 36) | 52 (26 vs 26) | 441 (223 vs 218) |
| Daily dose, mg | 400 | 200 | 200 | 400 | 200 | – |
| Control | No treatment | Placebo | No treatment | No treatment | Placebo | – |
| Primary tocolytic agent | Magnesium sulfate | Magnesium sulfate | Ritodrine | Magnesium sulfate or nifedipine | Atosiban | – |
| GA at randomization, wk a | 24 0 –34 6 | 28 0 –36 6 | 24 0 –34 6 | 26 0 –36 6 | 24 0 –34 6 | – |
| Mean GA at randomization, wk | 31/32 | 33/34 | 32/32 | 34/33 | 28/29 | Mean difference –0.37 d (95% CI, –1.17 to 0.44) |
| Definition of PTL | At least 6 contractions in 30 min accompanied by cervical changes | At least 6 contractions in 30 min accompanied by cervical changes | At least 6 contractions in 30 min accompanied by cervical changes | At least 4 contractions per 20 min accompanied by 2-cm dilatation | At least 4 contractions per 20 min accompanied by cervical length <25 mm | |
| Prior PTB–progesterone vs control, n/N (%) | 5/37 (13.5%) vs 4/33 (12.1%) | 1/80 (1.3%) vs 3/83 (3.6%) | 4/43 (9.3%) vs 3/40 (7.5%) | N/R | 9/26 (34.6%) vs 9/26 (34.6%) | 28/186 (15.0%) vs 19/182 (10.4%) P = .19 |
| Study primary outcomes | Latency period, recurrent PTL | Latency period, PTB <37 wk, PTB <34 wk | Latency period, GA at delivery, PTB <37 wk | Rate of recurrent PTL | Latency period | – |
The quality of randomized controlled trials (RCTs) included in our metaanalysis was assessed by the Cochrane Collaboration’s tool ( Figure 2 ). All studies but one had adequate random sequence generation and allocation concealment. One study was double blind. Figure 3 shows the funnel plot for assessing publication bias for PTB <37 weeks. Potential publication bias was assessed by visual inspection of the funnel plot, and the symmetric plot suggested no publication bias.
Of the 441 singleton gestations included in the 5 trials, 223 (50.5%) were randomized to vaginal progesterone, and 218 (49.5%) to control. Regarding important baseline characteristics of the populations in the original trials, 4 RCTs reported data about prior PTB ( Table 1 ), and 1 about cervical length. No differences in baseline characteristics were found between the progesterone and control groups in any study. The statistical heterogeneity between the studies was very low, with no inconsistency in the RR estimates (I 2 = 0%). However, given the clinical heterogeneity (eg, dose of progesterone, inclusion criteria), a random effect model was used to assessed the primary outcome.
Synthesis of results
Women with a singleton gestation who received vaginal progesterone maintenance tocolysis for arrested PTL had a significantly lower rate of PTB <37 weeks (42% vs 58%; RR, 0.71; 95% CI, 0.57–0.90; 3 trials, 298 women) ( Figure 4 ).
Women who received vaginal progesterone also had significantly longer latency (mean difference 13.80 days; 95% CI, 3.97–23.63; 4 trials, 368 women) ( Figure 5 ), later gestational age at delivery (mean difference 1.29 weeks; 95% CI, 0.43–2.15; 4 trials, 368 women) ( Figure 6 ), and lower rate of recurrent PTL (24% vs 46%; RR, 0.51; 95% CI, 0.31–0.84; 2 trials, 122 women). Regarding neonatal outcome we found no differences between progesterone and control group except for the rate of neonatal sepsis, which was lower in the progesterone group compared to control (2% vs 7%; RR, 0.34; 95% CI, 0.12–0.98; 4 trials, 368 women) ( Table 2 ). No data about bronchopulmonary dysplasia were reported in any of the trials.
| Variable | Borna and Sahabi, 2008 | Sharami et al, 2010 | Arikan et al, 2011 | Lotfalizadeh et al, 2013 | Areia et al, 2013 | Total | RR (95% CI) |
|---|---|---|---|---|---|---|---|
| No. of patients | 70 (37 vs 33) | 163 (80 vs 83) | 83 (43 vs 40) | 73 (37 vs 36) | 52 (26 vs 26) | 441 (223/218) | – |
| PTB <37 wk a | N/A | 33/80 (41%) vs 45/83 (54%) | 20/43 (47%) vs 28/40 (70%) | N/A | 9/26 (35%) vs 13/26 (50%) | 62/149 (42%) vs 86/149 (58%) | 0.71 (0.57–0.90) b |
| PTB <34 wk a | N/A | 8/80 (10%) vs 9/83 (11%) | N/A | N/A | 3/26 (12%) vs 6/26 (23%) | 11/106 (10%) vs 15/109 (14%) | 0.75 (0.36–1.57) |
| Recurrent PTL a | 13/37 (35%) vs 19/33 (58%) | N/A | N/A | N/A | 2/26 (8%) vs 8/26 (31%) | 15/63 (24%) vs 27/59 (46%) | 0.51 (0.31–0.84) b |
| Mean GA delivery, wk | 37 vs 35 | 37 vs 36 | 36 vs 35 | N/A | 38 vs 37 | – | Mean difference 1.29 wk (0.43–2.15) b |
| Mean latency, d | 36 vs 24 | 24 vs 17 | 32 vs 21 | N/A | 63 vs 39 | – | Mean difference 13.80 d (3.97–23.63) b |
| Mean birthweight, g | 3101 vs 2609 | 2997 vs 3025 | 2983 vs 2585 | N/A | 2547 vs 2628 | – | Mean difference 194 g (–100.01 to 488.32) |
| Neonatal death a | N/A | 1/80 (1%) vs 6/83 (7%) | 0/43 vs 1/40 (3%) | N/A | 2/26 (8%) vs 2/26 (8%) | 3/149 (2%) vs 9/149 (6%) | 0.43 (0.12–1.54) |
| Admission in NICU a | 9/37 (24%) vs 13/33 (39%) | 3/80 (4%) vs 2/83 (2%) | 3/43 (7%) vs 3/40 (8%) | 10/37 (27%) vs 14/36 (39%) | 5/26 (19%) vs 7/26 (27%) | 30/223 (13%) vs 39/218 (18%) | 0.72 (0.47–1.08) |
| RDS a | 4/37 (11%) vs 12/33 (36%) | 7/80 (9%) vs 10/83 (12%) | 1/43 (2%) vs 1/40 (3%) | N/A | 2/26 (8%) vs 2/26 (8%) | 14/186 (8%) vs 25/182 (14%) | 0.54 (0.30–1.00) |
| IVH a | 0/37 vs 0/33 | N/A | 0/43 vs 0/40 | N/A | 0/26 vs 0/26 | 0/106 (0%) vs 0/99 (0%) | N/E |
| NEC a | 0/37 vs 0/33 | N/A | 0/43 vs 0/40 | N/A | 0/26 vs 0/26 | 0/106 (0%) vs 0/99 (0%) | N/E |
| Sepsis a | 2/37 (5%) vs 6/33 (18%) | 0/80 vs 3/83 (4%) | 2/43 (5%) vs 2/40 (5%) | N/A | 0/26 vs 1/26 (4%) | 4/186 (2%) vs 11/156 (7%) | 0.34 (0.12–0.98) b |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
