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Progestational agents reduce the risk of preterm birth and low birth weight in women at increased risk - meta-analysis. Progesterone reduces the risk of preterm birth and low birth weight, and may prevent perinatal death - meta-analysis
ARTICLE IN PRESS OBSTETRICS
Progestational agents reduce the risk of preterm birth and low birth weight in women at increased risk ç meta-analysis Sanchez-Ramos L, Kaunitz AM, Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstet Gynecol 2005; 105: 273^9.
OBJECTIVE To evaluate the e⁄cacy of progestational agents in preventing preterm birth in women at increased risk. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE, EMBASE, and the Cochrane Library (1966 to January 2004), handsearches of conference abstracts and the reference lists of textbooks and relevant articles, and consultation with investigators. STUDY SELECTION Randomized controlled trials, published in any language or unpublished, that compared a progestational agent with placebo for prevention of preterm birth in asymptomatic women at increased risk, mainly because of a history of preterm birth or multiple miscarriages. Studies were assessed for methodological quality blindly and independently by two reviewers.
preterm labour, birth weight o2500 g, respiratory distress syndrome. MAIN RESULTS Ten trials, published between 1964 and 2003 and involving a total of 1290 subjects, were included in the meta-analysis. The results of the meta-analysis are shown in Table 1. The results were similar when only the 8 trials using ahydroxyprogesterone caproate were included in the meta-analysis. CONCLUSION Progestational agents reduce the risk of preterm birth and low birth weight in women at increased risk of preterm birth. The meta-analysis did not have su⁄cient power to demonstrate a signi¢cant reduction in perinatal mortality.
Overall study quality (out of 10)
DATA EXTRACTION Data were extracted into 2 2 tables independently by two reviewers. MAIN OUTCOME MEASURES Preterm birth (o37 weeks gestation), perinatal mortality, threatened
Topic importance Methodological quality Practical relevance
10 9 10
Table 1 Results of the meta-analysis of progestational agents vs placebo to prevent preterm birth Outcome Preterm birth Perinatal mortality Threatened preterm labour Birth weight o2500 g Respiratory distress syndrome
No. trials (subjects) 8 (983) 8 (1223) 5 (902) 6 (872) 3
Progestational agent 26% 3.2% 15% 20% 10%
Placebo
Odds ratio (95% CI)
NNT (95% CI)
36% 4.2% 19% 28% 12%
0.45 (0.25^0.80)
10 (6^24) ç ç 12 (7^43) ç
0.69 (0.38^1.26) 0.68 (0.35^1.34) 0.50 (0.36^0.71) 0.83 (0.25^2.76)
NNT=number needed to treat to avoid one adverse outcome
Signi¢cant statistical heterogeneity present, random e¡ects model used
174
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176 doi:10.1016/j.ebobgyn.2005.09.014
0021-9290/$ - see front matter r 2005 Elsevier Ltd. Allrights reserved.
ARTICLE IN PRESS
Progesterone reduces the risk of preterm birth and low birth weight, and may prevent perinatal death ç meta-analysis Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2005; 84: 526 ^33.
OBJECTIVE To evaluate the e⁄cacy of progesterone in preventing preterm birth in women at increased risk. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE (1966 to January 2005) and the Cochrane Pregnancy and Childbirth Group’s specialized register of controlled trials, and handsearches of the reference lists of relevant articles. STUDY SELECTION Published, randomized (including quasi-randomized) controlled trials, that compared progesterone, administered by either the intramuscular or vaginal route, with placebo or no treatment for prevention of singleton preterm birth. Studies were assessed for methodological quality.
placebo-controlled. The results of the meta-analysis are shown in Table 2. The results were similar when only the 6 trials using a-hydroxyprogesterone caproate, the 6 trials involving women at increased risk, the 5 trials with truly randomized design, and the 3 trials with adequate allocation concealment were included in the meta-analysis. The exception was, in two trials (n ¼ 503) with adequate allocation concealment, there was a signi¢cant reduction with progesterone treatment for the outcome perinatal death (relative risk 0.48, 95% CI 0.23^0.98). CONCLUSION Progesterone supplementation reduces the risk of preterm birth and low birth weight in women at increased risk of preterm birth. From the highest quality studies, there was also a signi¢cant reduction in perinatal mortality.
DATA EXTRACTION Data were extracted into 2 2 tables. MAIN OUTCOME MEASURES Preterm birth (o37 weeks gestation), perinatal mortality, birth weight o2500 g, respiratory distress syndrome. MAIN RESULTS Seven trials, published between 1964 and 2003 and involving a total of 1020 subjects, were included in the meta-analysis. All trials were
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
10 9 10
Table 2 Results of the meta-analysis of progesterone vs placebo to prevent preterm birth Outcome
No. trials (subjects)
Relative risk (95% CI)
Preterm birth Perinatal mortality Birth weight o2500 g Respiratory distress syndrome
7 (1020) 6 (876) 6 (872) 2 (536)
0.58 (0.48^0.70) 0.60 (0.32^1.12) 0.62 (0.49^0.78) 0.63 (0.38^1.05)
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176
175
ARTICLE IN PRESS Commentary These two systematic reviews are not the f|rst to be published on the topic of the effectiveness of progestational agents to prevent preterm birth. Mark Keirse discussed two earlier meta-analyses in 1990, adding to them his own meta-analysis, restricted to the prophylactic use of17 alpha-hydroxyprogesterone acetate in women perceived to be at high risk of miscarriage or preterm birth, outcomes that were often combined at that time. His review provided no support for miscarriage prevention, but did show that the available evidence supported the view that progestogen reduced the recurrence of preterm birth, although with no statistically signif|cant reduction in perinatal mortality or morbidity.1 This limited history is relevant to some of the key issues in the current reviews: the use of preterm birth as a single outcome rather than including earlier pregnancy loss, combining the various clinical paths to preterm birth (ruptured membranes, uterine contractions) rather than treating them separately, and the need for attention to substantive maternal and fetal outcomes as well as the prolongation of pregnancy. The context for the new reviews is the lack of any improvement in preterm birth prevalence in last decade, despite substantial biomedical and clinical research.Thus, the publication of two randomised trials in 2003, almost 20 years after the last published trial, with one of them substantially larger than any earlier trial, prompted further meta-analyses to see whether the additional data would resolve the inconsistencies in earlier pooled analyses. The strengths of these two new reviews are very clear. Both gave a careful and thorough description of their search strategy, inclusion criteria, and assessment of trial quality, in addition to reasons for specif|c exclusions, and both met the criteria for reporting meta-analyses. Both reviews were rightly given high scores for the importance of the topic and its practical relevance, with a marginally lower score for methodological quality. Although it was disconcerting, at f|rst, to f|nd that one review included three more trials than the other, the rationale was clear and explicit in the framing of the research question, i.e. the Dodd review was restricted to singleton births and excluded trials that used agents other than intramuscular 17a-hydroxyprogesterone caproate or vaginal progesterone, while the Sanchez-Ramos review was less restrictive. Both meta-analyses identif|ed signif|cant reductions in the risks of preterm birth (o37 weeks) and low birth weight (o2,500 g), and both found a substantial reduction in the risk of perinatal mortality, which did not reach statistical signif|cance. The two papers took different approaches to the use of sensitivity analyses, the Sanchez-Ramos review focusing on whether any single trial might have exerted a disproportionate effect on the f|ndings, and the Dodd review analysing subgroups with a history of prior preterm birth or considered to be at risk of preterm birth, and also looking at the effect of excluding trials that used quasi-randomisation procedures or did not have adequate concealment of allocation. The limitations of these meta-analyses reflect the limitations of the trials themselves. Most obvious is the virtual absence of
176
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176
information on maternal clinical outcomes, such as use of tocolytic agents or concurrent chorioamnionitis. Similarly, the reporting of fetal and neonatal mortality and morbidity rarely separated stillbirths and neonatal deaths. Only the largest trial included information on severe and disabling conditions affecting the infant, such as the need for neonatal ventilatory support or the occurrence of intraventricular haemorrhage, necrotizing enterocolitis, or retinopathy of prematurity. The reviews do differ, to some extent, in their summary conclusions. Sanchez-Ramos and colleagues stated: ‘‘The use of progestational agents and 17a-hydroxyprogesterone acetate reduced the incidence of preterm birth and low birth weight newborns.’’ However, the f|nal paragraphs of their paper provide more nuanced advice, drawing attention to the lack of statistically and clinically important evidence on key outcome variables, such as perinatal mortality, and to their pooling of data from women exposed to different progestational agents. They stopped short of an explicit recommendation for more randomized trials prior to implementation. Dodd and colleagues also qualif|ed their conclusion, describing their f|ndings as promising. They did recommend further large trials, to assess the benef|ts and risks to mothers and babies more fully, before widespread clinical use. It would be ideal if these future large trials involving hormone administration also planned for long-term follow-up of the participants.2,3 The implications of these meta-analyses for clinical practice are consistent. Both sets of authors agreed that the f|ndings are promising, and we have all been waiting a long time for promising results in this area.Both groups, in the f|ne print, draw our attention to the very substantial uncertainties, which remain problematic at present. Neither research group recommended immediate implementation of progesterone supplementation to prevent preterm birth. Although this conclusion is disappointing for practitioners and researchers alike, it provides the opportunity for research groups to collaborate in a truly large trial, which could give reliable answers relatively quickly. Judith Lumley, MBBS, PhD LaTrobe University, Carlton,Victoria, Australia
Literature cited 1. Keirse MJ. Progesterone administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol 1990; 97: 149^54. 2. Wilcox AJ, Maxey J, Herbst AL. Prenatal diethylstilbestrol exposure and performance on college entrance examinations. Horm Behav 1992; 26: 433^9. 3. Venn A, Bruinsma F, Werther G, et al.The use of oestrogen treatment to reduce the adult height of tall girls: long term effects on fertility. Lancet 2004; 364: 1513^ 8.
Progestational agents reduce the risk of preterm birth and low birth weight in women at increased risk ç meta-analysis Sanchez-Ramos L, Kaunitz AM, Delke I. Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstet Gynecol 2005; 105: 273^9.
OBJECTIVE To evaluate the e⁄cacy of progestational agents in preventing preterm birth in women at increased risk. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE, EMBASE, and the Cochrane Library (1966 to January 2004), handsearches of conference abstracts and the reference lists of textbooks and relevant articles, and consultation with investigators. STUDY SELECTION Randomized controlled trials, published in any language or unpublished, that compared a progestational agent with placebo for prevention of preterm birth in asymptomatic women at increased risk, mainly because of a history of preterm birth or multiple miscarriages. Studies were assessed for methodological quality blindly and independently by two reviewers.
preterm labour, birth weight o2500 g, respiratory distress syndrome. MAIN RESULTS Ten trials, published between 1964 and 2003 and involving a total of 1290 subjects, were included in the meta-analysis. The results of the meta-analysis are shown in Table 1. The results were similar when only the 8 trials using ahydroxyprogesterone caproate were included in the meta-analysis. CONCLUSION Progestational agents reduce the risk of preterm birth and low birth weight in women at increased risk of preterm birth. The meta-analysis did not have su⁄cient power to demonstrate a signi¢cant reduction in perinatal mortality.
Overall study quality (out of 10)
DATA EXTRACTION Data were extracted into 2 2 tables independently by two reviewers. MAIN OUTCOME MEASURES Preterm birth (o37 weeks gestation), perinatal mortality, threatened
Topic importance Methodological quality Practical relevance
10 9 10
Table 1 Results of the meta-analysis of progestational agents vs placebo to prevent preterm birth Outcome Preterm birth Perinatal mortality Threatened preterm labour Birth weight o2500 g Respiratory distress syndrome
No. trials (subjects) 8 (983) 8 (1223) 5 (902) 6 (872) 3
Progestational agent 26% 3.2% 15% 20% 10%
Placebo
Odds ratio (95% CI)
NNT (95% CI)
36% 4.2% 19% 28% 12%
0.45 (0.25^0.80)
10 (6^24) ç ç 12 (7^43) ç
0.69 (0.38^1.26) 0.68 (0.35^1.34) 0.50 (0.36^0.71) 0.83 (0.25^2.76)
NNT=number needed to treat to avoid one adverse outcome
Signi¢cant statistical heterogeneity present, random e¡ects model used
174
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176 doi:10.1016/j.ebobgyn.2005.09.014
0021-9290/$ - see front matter r 2005 Elsevier Ltd. Allrights reserved.
ARTICLE IN PRESS
Progesterone reduces the risk of preterm birth and low birth weight, and may prevent perinatal death ç meta-analysis Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2005; 84: 526 ^33.
OBJECTIVE To evaluate the e⁄cacy of progesterone in preventing preterm birth in women at increased risk. DESIGN Meta-analysis of randomized, controlled trials. DATA SOURCES Computerized searches of MEDLINE (1966 to January 2005) and the Cochrane Pregnancy and Childbirth Group’s specialized register of controlled trials, and handsearches of the reference lists of relevant articles. STUDY SELECTION Published, randomized (including quasi-randomized) controlled trials, that compared progesterone, administered by either the intramuscular or vaginal route, with placebo or no treatment for prevention of singleton preterm birth. Studies were assessed for methodological quality.
placebo-controlled. The results of the meta-analysis are shown in Table 2. The results were similar when only the 6 trials using a-hydroxyprogesterone caproate, the 6 trials involving women at increased risk, the 5 trials with truly randomized design, and the 3 trials with adequate allocation concealment were included in the meta-analysis. The exception was, in two trials (n ¼ 503) with adequate allocation concealment, there was a signi¢cant reduction with progesterone treatment for the outcome perinatal death (relative risk 0.48, 95% CI 0.23^0.98). CONCLUSION Progesterone supplementation reduces the risk of preterm birth and low birth weight in women at increased risk of preterm birth. From the highest quality studies, there was also a signi¢cant reduction in perinatal mortality.
DATA EXTRACTION Data were extracted into 2 2 tables. MAIN OUTCOME MEASURES Preterm birth (o37 weeks gestation), perinatal mortality, birth weight o2500 g, respiratory distress syndrome. MAIN RESULTS Seven trials, published between 1964 and 2003 and involving a total of 1020 subjects, were included in the meta-analysis. All trials were
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
10 9 10
Table 2 Results of the meta-analysis of progesterone vs placebo to prevent preterm birth Outcome
No. trials (subjects)
Relative risk (95% CI)
Preterm birth Perinatal mortality Birth weight o2500 g Respiratory distress syndrome
7 (1020) 6 (876) 6 (872) 2 (536)
0.58 (0.48^0.70) 0.60 (0.32^1.12) 0.62 (0.49^0.78) 0.63 (0.38^1.05)
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176
175
ARTICLE IN PRESS Commentary These two systematic reviews are not the f|rst to be published on the topic of the effectiveness of progestational agents to prevent preterm birth. Mark Keirse discussed two earlier meta-analyses in 1990, adding to them his own meta-analysis, restricted to the prophylactic use of17 alpha-hydroxyprogesterone acetate in women perceived to be at high risk of miscarriage or preterm birth, outcomes that were often combined at that time. His review provided no support for miscarriage prevention, but did show that the available evidence supported the view that progestogen reduced the recurrence of preterm birth, although with no statistically signif|cant reduction in perinatal mortality or morbidity.1 This limited history is relevant to some of the key issues in the current reviews: the use of preterm birth as a single outcome rather than including earlier pregnancy loss, combining the various clinical paths to preterm birth (ruptured membranes, uterine contractions) rather than treating them separately, and the need for attention to substantive maternal and fetal outcomes as well as the prolongation of pregnancy. The context for the new reviews is the lack of any improvement in preterm birth prevalence in last decade, despite substantial biomedical and clinical research.Thus, the publication of two randomised trials in 2003, almost 20 years after the last published trial, with one of them substantially larger than any earlier trial, prompted further meta-analyses to see whether the additional data would resolve the inconsistencies in earlier pooled analyses. The strengths of these two new reviews are very clear. Both gave a careful and thorough description of their search strategy, inclusion criteria, and assessment of trial quality, in addition to reasons for specif|c exclusions, and both met the criteria for reporting meta-analyses. Both reviews were rightly given high scores for the importance of the topic and its practical relevance, with a marginally lower score for methodological quality. Although it was disconcerting, at f|rst, to f|nd that one review included three more trials than the other, the rationale was clear and explicit in the framing of the research question, i.e. the Dodd review was restricted to singleton births and excluded trials that used agents other than intramuscular 17a-hydroxyprogesterone caproate or vaginal progesterone, while the Sanchez-Ramos review was less restrictive. Both meta-analyses identif|ed signif|cant reductions in the risks of preterm birth (o37 weeks) and low birth weight (o2,500 g), and both found a substantial reduction in the risk of perinatal mortality, which did not reach statistical signif|cance. The two papers took different approaches to the use of sensitivity analyses, the Sanchez-Ramos review focusing on whether any single trial might have exerted a disproportionate effect on the f|ndings, and the Dodd review analysing subgroups with a history of prior preterm birth or considered to be at risk of preterm birth, and also looking at the effect of excluding trials that used quasi-randomisation procedures or did not have adequate concealment of allocation. The limitations of these meta-analyses reflect the limitations of the trials themselves. Most obvious is the virtual absence of
176
Evidence-based Obstetrics and Gynecology (2005) 7,174 ^176
information on maternal clinical outcomes, such as use of tocolytic agents or concurrent chorioamnionitis. Similarly, the reporting of fetal and neonatal mortality and morbidity rarely separated stillbirths and neonatal deaths. Only the largest trial included information on severe and disabling conditions affecting the infant, such as the need for neonatal ventilatory support or the occurrence of intraventricular haemorrhage, necrotizing enterocolitis, or retinopathy of prematurity. The reviews do differ, to some extent, in their summary conclusions. Sanchez-Ramos and colleagues stated: ‘‘The use of progestational agents and 17a-hydroxyprogesterone acetate reduced the incidence of preterm birth and low birth weight newborns.’’ However, the f|nal paragraphs of their paper provide more nuanced advice, drawing attention to the lack of statistically and clinically important evidence on key outcome variables, such as perinatal mortality, and to their pooling of data from women exposed to different progestational agents. They stopped short of an explicit recommendation for more randomized trials prior to implementation. Dodd and colleagues also qualif|ed their conclusion, describing their f|ndings as promising. They did recommend further large trials, to assess the benef|ts and risks to mothers and babies more fully, before widespread clinical use. It would be ideal if these future large trials involving hormone administration also planned for long-term follow-up of the participants.2,3 The implications of these meta-analyses for clinical practice are consistent. Both sets of authors agreed that the f|ndings are promising, and we have all been waiting a long time for promising results in this area.Both groups, in the f|ne print, draw our attention to the very substantial uncertainties, which remain problematic at present. Neither research group recommended immediate implementation of progesterone supplementation to prevent preterm birth. Although this conclusion is disappointing for practitioners and researchers alike, it provides the opportunity for research groups to collaborate in a truly large trial, which could give reliable answers relatively quickly. Judith Lumley, MBBS, PhD LaTrobe University, Carlton,Victoria, Australia
Literature cited 1. Keirse MJ. Progesterone administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol 1990; 97: 149^54. 2. Wilcox AJ, Maxey J, Herbst AL. Prenatal diethylstilbestrol exposure and performance on college entrance examinations. Horm Behav 1992; 26: 433^9. 3. Venn A, Bruinsma F, Werther G, et al.The use of oestrogen treatment to reduce the adult height of tall girls: long term effects on fertility. Lancet 2004; 364: 1513^ 8.