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Keywords:

  • neonatal outcome;
  • preterm birth;
  • progesterone

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information

Objective

To quantify the effect on perinatal outcome in women treated with progesterone for the prevention of preterm birth.

Methods

MEDLINE and SCOPUS searches, including references of the retrieved articles and additional automated search using the ‘search for related articles’ PubMed function, were used. Randomized controlled trials assigning women at risk for preterm birth to progesterone or placebo were included (both singleton and multiple pregnancies). Outcomes were neonatal and perinatal death, respiratory distress syndrome (RDS), retinopathy, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) Grade 3–4, sepsis, admission to the neonatal intensive care unit (NICU) and composite adverse outcome.

Results

Sixteen studies (singletons, n = 7; twins, n = 7; triplets, n = 2) were included in the meta-analysis. For singleton pregnancies, progesterone reduced the rates of neonatal death (risk ratio (RR) 0.487 (95% CI, 0.290–0.818)), RDS (RR 0.677 (95% CI, 0.490–0.935)), NICU admission (RR 0.410 (95% CI, 0.204–0.823)) and composite adverse outcome (RR 0.576 (95% CI, 0.373–0.891)). No favorable effect was observed in twins; in fact, progesterone was associated with increased rates of perinatal death (RR 1.551 (95% CI, 1.014–2.372)), RDS (RR 1.218 (95% CI, 1.038–1.428)) and composite adverse outcome (RR 1.211 (95% CI, 1.029–1.425)). No significant effect was observed in triplet pregnancies.

Conclusion

Progesterone administration in singleton pregnancies at risk for preterm birth improves perinatal outcomes, but may actually have adverse effects in multiple pregnancies. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information

Accumulating evidence over the last 15 years has shown that screening of pregnant women for preterm birth, based mainly on obstetric history and measurement of the length of the uterine cervix, can identify more than 50% of those who will deliver before 34 weeks' gestation1. At almost the same time, two large randomized studies2, 3, soon followed by more, showed that administration of progesterone in women with a singleton pregnancy at risk can significantly reduce the rates of preterm birth both in cases of previous history and in cases with a short cervix.

Therefore, having both a reliable screening tool and a treatment option for women identified as being at highest risk, it may be that ‘doing nothing is no longer an option’ in singleton pregnancies4. Progesterone has been used for decades in reproductive medicine without any documented effect on the risk for congenital abnormalities5, and the allegedly increased risk for fetal hypospadias does not appear to be confirmed in currently used progestogens6; the United States Food and Drug Administration has recently approved the use of hydroxyprogesterone caproate for the prevention of prematurity in women with a previous history of preterm birth7.

However, although progesterone prophylaxis clearly reduces the risk of preterm birth in women at risk, its effects on the actual perinatal and long-term consequences of prematurity are more difficult to assess. This is because these events are relatively uncommon even in preterm births, with the exception of extremely preterm births, and therefore individual studies are usually underpowered for these outcomes because of small sample size. As a result, existing randomized controlled trials (RCTs), and to some extent systematic reviews as well, have so far focused mainly on the primary outcome of reduction of preterm birth rates.

The aim of this meta-analysis was to systematically review published evidence and pool data on the perinatal outcome in women treated with progesterone for the prevention of preterm birth.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information

We searched the literature (last update December 2011) for clinical trials in which progesterone was given for the prevention of preterm birth in pregnant women at risk compared to placebo. MEDLINE and SCOPUS searches used combinations of the terms ‘progesterone’ AND ‘preterm’. These searches were complemented by perusal of the references of the retrieved articles and additional automated search using PubMed's ‘search for related articles’ function. All studies were carefully compared to ensure avoidance of duplicate or overlapping samples. In case of overlap, the study with the largest number of cases was included.

Study selection

Inclusion criteria. Type of studies: RCTs; intervention: progesterone vs placebo for the prevention of preterm birth in women at risk; type of participants: women with singleton pregnancy at risk for preterm birth owing to previous history or short cervix during the second trimester or multiple pregnancies; language: no language restrictions. Exclusion criteria. Studies were excluded if there was no adequate randomization or no placebo group, the administration of progesterone was done in women with symptoms of preterm labor, bleeding or rupture of membranes, or if they did not provide data on neonatal outcomes. Cases with fetal structural defects responsible for perinatal complications in the studies included in the meta-analysis were identified when possible, and were excluded from the analysis.

Data extraction and study quality assessment were independently performed by two authors (S.P. and A.S.); in case of disagreement a consensus was reached after discussion between the two authors or after evaluation by the third author (G.M.).

Quality assessment of the included studies

The CONSORT statement was used for addressing the reporting quality of the RCTs included in our meta-analyses8. The risk of bias in the randomized trials was assessed with the ‘Risk-of-bias’ tool from the Cochrane Collaboration9. This is an assessment of the internal validity of each study and is based on six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and ‘other sources of bias’.

Both methods of quality control were assessed independently by two reviewers (S.P. and A.S.) and any discrepancies were resolved by discussion between the two and if this was not possible, after evaluation by G.M.

Quantitative data synthesis

The primary outcome was the rate of neonatal mortality, meaning the number of deaths from birth to under the age of 28 days, and perinatal mortality. Perinatal deaths refer to fetal deaths and live births with only brief survival (days or weeks) and are grouped on the assumption that similar factors are associated with these losses. There are three definitions of perinatal death in use: infant deaths that occur at less than 7 days of age and fetal deaths following a stated or presumed period of gestation of 28 weeks or more; infant deaths that occur at less than 28 days of age and fetal deaths following a stated or presumed period of gestation of 20 weeks or more; and infant deaths that occur at less than 7 days of age and fetal deaths following a stated or presumed gestation of 20 weeks or more. Although there is no consensus regarding the use and interpretation of these definitions, the second is more inclusive and, hence, more appropriate for monitoring perinatal deaths throughout gestation, because most fetal deaths occur before 28 weeks of gestation10. The rates of perinatal complications (respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) Grade 3–4, sepsis, necrotizing enterocolitis (NEC), sepsis and retinopathy), admission to the neonatal intensive care unit (NICU) and composite adverse outcome were assessed as secondary outcomes. In general, composite adverse outcome was defined as the presence of any perinatal morbidity or mortality. The definitions of composite adverse outcome across studies are presented in Appendix S1 (online).

Descriptive statistics are given as proportions, together with their 95% CIs. Comparisons were made using the risk ratio (RR), which is the probability that a member of an exposed group will develop a disease relative to the probability that a member of an unexposed group will develop that same disease. We also calculated the number needed to treat, which is defined by the inverse of the absolute value of the risk difference, and shows the number of patients who need to be treated with one intervention rather than its comparator to have one more event of interest. The equivalent indicator in case of harmful effect of the treatment is the number needed to harm.

We used random effects models (DerSimonian and Laird) for data synthesis. Fixed effects models assume that differences in the results of studies are due to sampling error alone. Random effects allow for between-study differences, and incorporate an estimate of the between-study variance in the calculations. In the absence of between-study heterogeneity, the two approaches coincide; otherwise random effects usually give wider confidence intervals. Unless stated otherwise, random effects estimates are presented in the text. Between-studies heterogeneity was assessed using the I2 statistic, which is the ratio of between-study variance over the sum of the within- and between-study variances and describes the percentage of variation that is due to heterogeneity rather than chance (range, 0–100%). A simplistic grouping would tentatively assign descriptions of low, moderate and high heterogeneity to I2 values of 25, 50 and 75%11.

We ran separate analyses for singleton and multiple pregnancies. When the proportion of twin pregnancies in a study was < 20% and separate data were not provided, the study was grouped together with the singleton-pregnancy studies. Planned subgroup analyses were carried out according to the indication (short cervix vs history) for and route (local (vaginal) vs systemic (intramuscular or oral)) of progesterone administration, in order to explore whether these factors affected the perinatal outcome.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information

Study selection

Of the 628 items retrieved from our electronic search, 458 were excluded based on the title and/or abstract. The remaining 170 articles were retrieved for screening in full text. A flow chart of the selection procedure is shown in Figure 1. In total, 17 RCTs on progesterone in asymptomatic women in order to prevent preterm birth, which provided data on perinatal mortality and/or morbidity, were eligible for inclusion in our meta-analysis2, 3, 12–26. One of them (Cetingoz et al.13), including both singleton and twin pregnancies, was finally excluded because it was not possible to split the results accordingly, although we contacted the authors for clarification. Therefore, 16 studies were included in our meta-analysis (Figure 1). One study16 is a subset of a larger study17; the smaller study was used only in subgroup analysis for which the larger study was not eligible.

thumbnail image

Figure 1. Flowchart of included studies.

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Descriptive characteristics of the included studies are shown in Supplementary Table S1 online.

Quality assessment

Overall reporting of the studies included in the meta-analysis was good. Only a study that was conducted in 1980 and provided data on twin pregnancies did not follow the guidelines of reporting as expected24. The risk-of-bias tool from the Cochrane Collaboration did not reveal significant sources of bias in most of the studies (Table 1), so we present our results in a single meta-analysis and not separate analyses stratified according to the risk of bias.

Table 1. Summary of bias risk in the 16 papers included in the study
 Risk of bias
 Selection bias     
StudyRandom sequence generationAllocation concealmentPerformance bias*Detection biasAttrition biasReporting bias§Other bias
  • *

    Participants and personnel blinded.

  • Blinding to outcome assessment.

  • Incomplete outcome data.

  • §

    Selective reporting.

Briery et al. 200921LowLowLowUnclearLowLowNone
Caritis et al. 200926LowLowLowLowLowLowNone
Combs et al. 201025LowLowLowLowLowLowNone
Combs et al. 201118LowLowLowLowLowLowNone
Fonseca et al. 20073LowLowLowLowLowLowNone
DeFranco et al. 200716LowLowLowLowLowLowNone
Hartikainen-Sorri et al. 198024HighUnclearUnclearUnclearLowLowNone
Hassan et al. 201112LowLowLowLowLowLowNone
Ibrahim et al. 201014UnclearLowHighHighLowLowNone
Lim et al. 201119LowLowLowLowLowLowNone
Meis et al. 20032LowLowLowLowLowLowNone
Norman et al. 200922LowLowLowLowLowLowNone
O'Brien et al. 200717LowLowLowLowLowLowNone
Rai et al. 200915LowLowLowLowLowLowNone
Rode et al. 201120LowLowLowLowLowLowNone
Rouse et al. 200723LowLowLowLowLowLowNone

Singleton pregnancies

Seven studies provided data on the impact of progesterone on perinatal mortality and morbidity2, 3, 12, 14–17. Pooling all studies that provide such data (Table 2), we found that progesterone administration in women at risk for preterm birth (either because of a short cervix or obstetric history) significantly decreased the risk for composite adverse outcome (RR 0.576 (95% CI, 0.373–0.891)) (Figure 2a), neonatal death (RR 0.487 (95% CI, 0.290–0.818)) (Figure 2b), RDS (RR 0.677 (95% CI, 0.490–0.935)) (Figure 2c) and admission to the NICU (RR 0.410 (95% CI, 0.204–0.823)). No significant difference was found in the rates of perinatal death, Grade 3–4 IVH, NEC, retinopathy or sepsis.

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Figure 2. Forest plot for composite adverse outcome (a), neonatal death (b) and respiratory distress syndrome (c) in singleton pregnancies (all indications, all progestogens). In (a), both studies used local progesterone for women with a short cervix. Only the first author of each study is given.

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Table 2. Perinatal outcomes in singleton pregnancies in the study set (all indications—all progestogens)
OutcomeStudiesSubjects (n)Controls (n)I2 (%)Risk ratio (95% CI)NNT
  1. IVH, intraventricular hemorrhage; N/A, not applicable; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; NNT, number needed to treat; RDS, respiratory distress syndrome.

Neonatal deathMeis et al.223/108539/9150.00.487 (0.290–0.818)57 (32–1000)
 Fonseca et al.3     
 Hassan et al.12     
 Ibrahim et al.14     
 Rai et al.15     
 O'Brien et al.17     
Perinatal deathMeis et al.225/67730/5140.00.602 (0.354–1.023)N/A
 Fonseca et al.3     
 Hassan et al.12     
RDSMeis et al.281/98595/81518.40.677 (0.490–0.935)26 (15–83)
 Fonseca et al.3     
 Hassan et al.12     
 O'Brien et al.17     
IVH Grade 3–4Meis et al.23/9852/8160.00.965 (0.200–4.666)N/A
 Fonseca et al.3     
 Hassan et al.12     
 O'Brien et al.17     
NECMeis et al.28/98514/81519.50.569 (0.202–1.606)N/A
 Fonseca et al.3     
 Hassan et al.12     
 O'Brien et al.17     
RetinopathyMeis et al.27/4415/29048.41.034 (0.125–8.549)N/A
 Fonseca et al.3     
SepsisMeis et al.220/69523/54125.90.735 (0.339–1.162)N/A
 Fonseca et al.3     
 Hassan et al.12     
 DeFranco et al.16     
NICU admissionFonseca et al.349/254103/26472.00.410 (0.204–0.823)4 (2–15)
 Ibrahim et al.14     
 Rai et al.15     
 DeFranco et al.16     
Composite adverse outcomeFonseca et al.329/37149/3610.00.576 (0.373–0.891)17 (10–77)
 Hassan et al.12     
Birth < 34 weeksFonseca et al.346/19980/1990.00.577 (0.427–0.779)6 (4–13)
 Rai et al.15     
Birth < 32 weeksMeis et al.286/68982/52942.90.814 (0.563–1.117)N/A
 Rai et al.15     
 O'Brien et al.17     
Birth < 28 weeksHassan et al.1222/61835/59931.40.633 (0.307–1.304)N/A
 Rai et al.15     
 O'Brien et al.17     

Three studies tested vaginal progesterone in women with a short cervix during the second trimester3, 12, 16. Pooling the relevant data, local progesterone in asymptomatic women with a short cervix appeared to significantly decrease the rate of composite adverse outcome (RR 0.576 (95% CI, 0.373–0.891)) and RDS (RR 0.464 (95% CI, 0.275–0.786)), but failed to reach statistical significance regarding the rates of neonatal death, perinatal death, Grade 3–4 IVH, NEC, sepsis or admission to the NICU (Table S2).

Three studies2, 14, 15 tested systemic progesterone (Rai et al.15 used oral administration) in women with a singleton pregnancy and a history of preterm birth. Pooling relevant data, progesterone was found to significantly decrease the rates of neonatal death (RR 0.412 (95% CI, 0.201–0.842)) and NICU admission (RR 0.277 (95% CI, 0.160–0.479)) (Table S3).

Twin pregnancies

Seven RCTs reported on the effect of progesterone administration in women with twin pregnancies18–24. The pooled results showed that progesterone administration did not significantly affect the rates of neonatal death, Grade 3–4 IVH, NEC, retinopathy, sepsis or NICU admission. In fact it was found to significantly increase the rates of composite adverse outcome (RR 1.211 (95% CI, 1.029–1.425)) (Figure 3a), perinatal death (RR 1.551 (95% CI, 1.014–2.372)) (Figure 3b) and RDS (RR 1.218 (95% CI, 1.038–1.428)) (Figure 3c; Table 3).

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Figure 3. Forest plot for composite adverse outcome (a), perinatal mortality (b) and respiratory distress syndrome (c) in twin pregnancies (all progestogens). In (a), all three studies used systematic (injectable) progestogen (17 alpha-hydroxyprogesterone caproate). Only the first author of each study is given.

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Table 3. Perinatal outcomes in twin pregnancies in the study set (all progestogens)
OutcomeStudiesSubjects (n)Controls (n)I2 (%)Risk ratio (95% CI)NNH
  1. IVH, intraventricular hemorrhage; N/A, not applicable; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; NNH, number needed to harm; RDS, respiratory distress syndrome.

Neonatal deathCombs et al.1847/283243/267824.41.117 (0.662–1.884)N/A
 Lim et al.19     
 Rode et al.20     
 Briery et al.21     
 Norman et al.22     
 Rouse et al.23     
Perinatal deathNorman et al.2252/120434/12180.01.551 (1.014–2.372)71 (36–1000)
 Rouse et al.23     
 Hartikainen-Sorri et al.24     
RDSCombs et al.18312/2397237/22500.01.218 (1.038–1.428)39 (23–125)
 Lim et al.19     
 Rode et al.20     
 Briery et al.21     
 Rouse et al.23     
 Hartikainen-Sorri et al.24     
IVH Grade 3–4Combs et al.1814/16298/14740.01.497 (0.625–3.583)N/A
 Lim et al.19     
 Rouse et al.23     
NECCombs et al.1812/231911/21760.01.124 (0.509–2.481)N/A
 Lim et al.19     
 Rode et al.20     
 Briery et al.21     
 Hartikainen-Sorri et al.24     
RetinopathyCombs et al.186/16044/14670.01.165 (0.352–3.857)N/A
 Rode et al.20     
 Rouse et al.23     
SepsisCombs et al.1870/229156/21511.11.228 (0.861–1.749)N/A
 Lim et al.19     
 Rode et al.20     
 Rouse et al.23     
NICU admissionLim et al.19627/1834628/184281.21.053(0.846–1.312)N/A
 Rode et al.20     
 Norman et al.22     
Composite adverse outcomeCombs et al.18284/1633216/14770.01.211 (1.029–1.425)31 (17–167)
 Lim et al.19     
 Rouse et al.23     
Birth < 34 weeksCombs et al.18143/741123/67657.41.101 (0.766–1.582)N/A
 Rode et al.20     
 Norman et al.22     
Birth < 32 weeksCombs et al.18142/1155117/108117.31.160 (0.890–1.513)N/A
 Rode et al.20     
 Rouse et al.23     
Birth < 28 weeksCombs et al.1857/115546/11670.01.244 (0.850–1.817)N/A
 Lim et al.19     
 Rode et al.20     
 Rouse et al.23     

Subgroup analysis was carried out for women treated with vaginal (Table S4) and systemic (Table S5) progesterone, but there were too few studies to obtain data on most of the outcomes.

Triplet pregnancies

Two recent RCTs examined the administration of progesterone in asymptomatic women with triplets25, 26. The pooled data did not show significant differences in the rates of composite adverse outcome, neonatal death, RDS, Grade 3–4 IVH, NEC or sepsis (Table 4).

Table 4. Perinatal outcomes in triplet pregnancies in the study set
OutcomeStudiesSubjects (n)Controls (n)I2 (%)Risk ratio (95% CI)NNT
  1. No studies on triplet pregnancies reported outcomes of perinatal death, retinopathy, admission to neonatal intensive care unit or birth < 34 weeks. IVH, intraventricular hemorrhage; N/A, not applicable; NEC, necrotizing enterocolitis; NNT, number needed to treat; RDS, respiratory distress syndrome.

Neonatal deathCombs et al.2511/3674/2580.01.759 (0.567–5.458)N/A
 Caritis et al.26     
RDSCombs et al.25109/36778/25857.80.940 (0.643–1.374)N/A
 Caritis et al.26     
IVH Grade 3–4Combs et al.256/3677/2580.00.552 (0.182–1.674)N/A
 Caritis et al.26     
NECCombs et al.2510/3668/25835.70.736 (0.204–2.661)N/A
 Caritis et al.26     
SepsisCombs et al.2524/36617/25840.70.964 (0.385–2.411)N/A
 Caritis et al.26     
Composite adverse outcomeCombs et al.25141/38096/2580.00.984 (0.801–1.210)N/A
 Caritis et al.26     
Birth < 32 weeksCombs et al.2548/12732/8875.80.949 (0.464–1.992)N/A
 Caritis et al.26     
Birth < 28 weeksCombs et al.2516/1279/880.01.149 (0.506–2.608)N/A
 Caritis et al.26     

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information

Preterm birth has always been a major cause of perinatal mortality and morbidity with long-term consequences27–31. However, it is only in the last decade that progesterone has been successfully shown to prevent preterm birth in singleton (but not in multiple) pregnancies at risk, either because of a short cervix32 or previous history of preterm birth2.

As the impact of progesterone treatment in the reduction of prematurity rates has been extensively quantified (level-1 evidence), in this meta-analysis we focused on the effects of progesterone on the actual perinatal outcomes of treated pregnancies. We found that prophylactic progesterone administration in singleton pregnancies at risk reduces rates of neonatal mortality, RDS, admission to the NICU and composite adverse outcome. In contrast, current data fail to support the presence of a beneficial effect of progesterone in multiple pregnancies and, in fact, the rates of perinatal death, RDS and composite adverse outcome may even be increased in twins.

In singleton pregnancies, we found that progesterone decreased the risk for neonatal mortality and common morbidity, when all data were pooled. We furthermore planned to run subgroup analyses based on the indication for progesterone treatment and the type of progestogen used. The design of available studies allowed for only two groupings, i.e. local (natural) progesterone for women with a short cervix and systemic (essentially 17 alpha-hydroxyprogesterone caproate (17-OHPC)) progestogen for women with previous preterm birth. For the latter pair, data could be pooled only for neonatal mortality and NICU admission; progesterone prevented one death per 24 women treated and one NICU admission per three women treated. For local progesterone in women with a short cervix, 17 women needed to be treated in order to prevent one perinatal death or complication. However, statistical significance was not reached for most of the other outcomes, although the direction of effect was usually in favor of progesterone. For the outcome of neonatal mortality, 829 infants per arm would be needed based on our pooled results, in order for the effect to reach significance. In addition, we were not able to reach any conclusions about the most clinically relevant question, i.e. whether local or systemic progesterone is better for women with a short cervix.

Studies and systematic reviews on twins have shown that progesterone fails to reduce the rate of preterm birth33. Two commonly cited hypotheses for this are (1) that the doses used in singleton pregnancies may be insufficient in twin pregnancies and (2) that the mechanisms underlying spontaneous preterm delivery in twins are different from those in singletons18, 21, 33. It is difficult to prove or discard these hypotheses but, at least for the first hypothesis, maternal body mass did not have significant impact on the effectiveness of 17-OHPC in a study of singletons34, and its half-life and plasma levels were not found to be affected by parity and the number of fetuses35. Therefore, a threshold effect for 17-OHPC has not been proposed so far, and we would expect it to have some effect on preterm labor rather than none. As for the second hypothesis, accepting that infection would be the main cause for preterm birth in singletons vs uterine stretch in twins, the effectiveness of progesterone would depend on its ability to reduce uterine excitability. Many36, 37, but not all38, studies indicate that progesterone may indeed induce uterine quiescence through a multitude of mechanisms, from alteration of the electrical activity of the uterine muscle to alteration of gene expression and peripheral leukocyte activation.

Nevertheless, if the only problem was lack of effectiveness, increasing the dose or selectively treating women with twin pregnancy and a short cervix might be a viable alternative; however we found that progesterone may actually increase the risk of adverse outcome in twin pregnancies. According to our pooled results, there may be one additional case of perinatal death per 71 fetuses, one additional case of RDS per 39 fetuses and one additional case of composite adverse outcome (perinatal death or complication) per 31 fetuses treated. It is not clear why this happens, but it appears to be independent of the rates of preterm birth, which did not differ between treated women and controls for the cut-off of 34 weeks (pooled rates)18, 20, 22, 32 weeks (pooled rates)18–20, 23 or 28 weeks (pooled rates)18–20, 23. The relatively small number of triplets prevented our achieving statistically significant results in this group; however one should still be cautious as the study of Combs et al.25 indicated an increased risk for fetal death in treated women.

A weakness of meta-analyses in general is that pooled studies cannot have identical inclusion criteria, as well as treatment and reporting protocols. This problem is addressed by subgroup and sensitivity analysis, at the cost of reducing the sample size. Indeed, when analyzing pre-defined groups, statistical significance was lost for many of the perinatal outcomes. However, in our case there was marked consistency in the results across studies for most outcomes, even before subgroup analysis. This was true even for the composite adverse outcome, despite its being defined differently in different studies. The lack of heterogeneity increases the strength of the results and may indicate that the number of fetuses is a more significant predictor of the effectiveness of progesterone treatment than the type of progesterone used (and the indication for treatment in singleton pregnancies). The outcome for which the highest variation was recorded was NICU admission, which may reflect the diversity in defining neonatal special care needs, together with different admission criteria across studies.

The next step after testing the effects of progesterone treatment on the rates of preterm birth and immediate perinatal complications is to examine its impact on the longer-term neurodevelopment of treated children. At the moment there has only been one study assessing neurodevelopment in twins up to 18 months of age; the authors report almost identical results in terms of Ages and Stages Questionnaire mean scores and rates of low scores20.

Based on current data, it appears that progesterone treatment in women with a singleton pregnancy at risk succeeds in reducing the rates of neonatal mortality, some of the common perinatal complications and composite adverse outcome (perinatal death or complications), in contrast to the case with twins, in which it may even exert an adverse effect.

Among ongoing studies, one will address the impact of cervical length screening and progesterone treatment for length ⩽ 30 mm on perinatal outcomes and cost39, an individual patient data meta-analysis in twin pregnancies will focus on the effect of progesterone treatment on perinatal mortality and morbidity40, while another prospective follow-up study will evaluate the differences in developmental outcomes of children aged 23–25 months, born to mothers who participated in a trial of the efficacy of 17-OHPC41.

SUPPORTING INFORMATION ON THE INTERNET

equation image Appendix S1 and Tables S1–S5 may be found in the online version of this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information
  • 1
    Celik E, To M, Gajewska K, Smith GC, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment. Ultrasound Obstet Gynecol 2008; 31: 549554.
  • 2
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  • 3
    Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357: 462469.
  • 4
    Campbell S. Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option. Ultrasound Obstet Gynecol 2011; 38: 19.
  • 5
    Norwitz ER, Caughey AB. Progesterone supplementation and the prevention of preterm birth. Rev Obstet Gynecol 2011; 4: 6072.
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    Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril 2008; 89: 15951602.
  • 7
    FDA. FDA statement on Makena. (http://www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm249025htm) 2011; Assessed 25/03/2012.
  • 8
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  8. Supporting Information
FilenameFormatSizeDescription
uog_11178_sm_supinfotabs1s5.doc413KSupporting Information: Tables S1–S5 may be found in the online version of this article.
uog_11178_sm_supinfoapps1.doc30KSupporting Information: Appendix S1 may be found in the online version of this article.
uog_11178_sm_suppinfo.doc43KSupporting Information: Legends to Table S1 to S5

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