Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis

Abstract

Objectives: To compare the efficacy of bed rest, cervical cerclage (McDonald, Shirodkar, or unspecified type of cerclage), cervical pessary, fish oils or omega fatty acids, nutritional supplements (zinc), progesterone (intramuscular, oral, or vaginal), prophylactic antibiotics, prophylactic tocolytics, combinations of interventions, placebo or no treatment (control) to prevent spontaneous preterm birth in women with a singleton pregnancy and a history of spontaneous preterm birth or short cervical length.

Design: Systematic review with bayesian network meta-analysis.

Data sources: The Cochrane Pregnancy and Childbirth Group's Database of Trials, the Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials.

Eligibility criteria for selecting studies: Randomised controlled trials of pregnant women who are at high risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. No language or date restrictions were applied.

Outcomes: Seven maternal outcomes and 11 fetal outcomes were analysed in line with published core outcomes for preterm birth research. Relative treatment effects (odds ratios and 95% credible intervals) and certainty of evidence are presented for outcomes of preterm birth <34 weeks and perinatal death.

Results: Sixty one trials (17 273 pregnant women) contributed data for the analysis of at least one outcome. For preterm birth <34 weeks (40 trials, 13 310 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was associated with fewer women with preterm birth <34 weeks (odds ratio 0.50, 95% credible interval 0.34 to 0.70, high certainty of evidence). Shirodkar cerclage showed the largest effect size (0.06, 0.00 to 0.84), but the certainty of evidence was low. 17OHPC (17α-hydroxyprogesterone caproate; 0.68, 0.43 to 1.02, moderate certainty), vaginal pessary (0.65, 0.39 to 1.08, moderate certainty), and fish oil or omega 3 (0.30, 0.06 to 1.23, moderate certainty) might also reduce preterm birth <34 weeks compared with placebo or no treatment. For the fetal outcome of perinatal death (30 trials, 12 119 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was the only treatment that showed clear evidence of benefit for this outcome (0.66, 0.44 to 0.97, moderate certainty). 17OHPC (0.78, 0.50 to 1.21, moderate certainty), McDonald cerclage (0.59, 0.33 to 1.03, moderate certainty), and unspecified cerclage (0.77, 0.53 to 1.11, moderate certainty) might reduce perinatal death rates, but credible intervals could not exclude the possibility of harm. Only progesterone treatments are associated with reduction in neonatal respiratory distress syndrome, neonatal sepsis, necrotising enterocolitis, and admission to neonatal intensive care unit compared with controls.

Conclusion: Vaginal progesterone should be considered the preventative treatment of choice for women with singleton pregnancy identified to be at risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. Future randomised controlled trials should use vaginal progesterone as a comparator to identify better treatments or combination treatments.

Systematic review registration: PROSPERO CRD42020169006.

Fig 1

PRISMA (preferred reporting items for systematic reviews and meta-analyses) study flow diagram. *No duplicates because only Cochrane Pregnancy and Childbirth’s Trial Register (containing over 25 000 reports of controlled trials in the field of pregnancy and childbirth, and identified from regular searches of Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials) was searched. †Thirty nine studies of pregnant women with risk factors for preterm birth linked directly to vaginal infection will be included in a separate network meta-analysis as part of a larger project examining a series of network meta-analyses within different populations of pregnant women

Fig 2

Network meta-analysis results for preterm birth <34 weeks and perinatal death. 17OHPC=17α-hydroxyprogesterone caproate. CrI=credible interval

Fig 3

Impact on preterm birth <34 weeks of various preventative treatments for pregnant women at risk of spontaneous preterm birth using placebo or no treatment as comparator. Solid lines represent direct comparison. Network meta-analysis estimates reported as odds ratios and 95% credible intervals instead of confidence intervals because bayesian analysis was conducted (credible interval is interpreted as interval where there is 95% probability that values of odds ratio will lie). Anticipated absolute effect compares two risks by calculating difference between risk of intervention group with risk of control group. GRADE (grading of recommendations assessment, development, and evaluation) working group grades of evidence (or certainty of evidence): high quality—very confident true effect lies close to that of estimate of effect; moderate quality—moderately confident in effect estimate; true effect is likely to be close to estimate of effect, but there is a possibility that it is substantially different; low quality—confidence in effect estimate is limited; true effect may be substantially different from estimate of effect; very low quality: very little confidence in effect estimate; true effect is likely to be substantially different from estimate of effect. *Based on an assumed control risk of spontaneous preterm birth <34 weeks of 19.1% (corresponding to a pooled 19.1% rate of spontaneous preterm birth <34 weeks in women receiving placebo or no treatment in included trials). †Serious imprecision because odds ratio <1 (suggesting greater likelihood of benefit than harm) but wide 95% credible interval (relative risk >1.25), suggesting appreciable harm. ‡Imprecision because 95% credible interval crosses 1, suggesting uncertainty in estimate. §Serious imprecision because odds ratio >1 (suggesting greater likelihood of harm than benefit) but wide 95% credible interval (relative risk <0.75); unable to rule out reasonable chance of benefit. ¶Serious imprecision because wide 95% credible interval, suggesting uncertainty in estimate probably due to single trial and low numbers of events contributing to network meta-analysis (n=34 Shirodkar cerclage arm, 1 preterm birth <34 weeks). **Serious imprecision because extremely wide 95% credible interval crossing 1. 17OHPC=17α-hydroxyprogesterone caproate; Amox=amoxicillin; CrI=credible interval; Met=metronidazole; RCT=randomised controlled trial

Fig 4

Impact on perinatal death of various preventative treatments for pregnant women at risk of spontaneous preterm birth using placebo or no treatment as comparator.Solid lines represent direct comparison. Network meta-analysis estimates reported as odds ratios and 95% credible intervals instead of confidence intervals because bayesian analysis was conducted (credible interval is interpreted as interval where there is 95% probability that values of odds ratio will lie). Anticipated absolute effect compares two risks by calculating difference between risk of intervention group with risk of control group. GRADE (grading of recommendations assessment, development, and evaluation) working group grades of evidence (or certainty of evidence): high quality—very confident true effect lies close to that of estimate of effect; moderate quality—moderately confident in effect estimate; true effect is likely to be close to estimate of effect, but there is a possibility that it is substantially different; low quality—confidence in effect estimate is limited; true effect may be substantially different from estimate of effect; very low quality: very little confidence in effect estimate; true effect is likely to be substantially different from estimate of effect. *Based on assumed control risk of perinatal death of 4.7% (corresponding to a pooled 4.7% rate of perinatal death in women receiving placebo or no treatment in included trials). †Imprecision because although 95% credible interval does not cross 1, total number of events is low. ‡Imprecision because 95% credible interval wide and crosses 1. §Serious imprecision because odds ratio <1 (suggesting greater likelihood of benefit than harm) but wide 95% credible interval (relative risk >1.25), suggesting appreciable harm. ¶Serious imprecision because odds ratio >1 (suggesting greater likelihood of harm than benefit) but wide 95% credible interval (relative risk < 0.75); unable to rule out reasonable chance of benefit. **Serious imprecision because extremely wide 95% credible interval crossing 1. ††Very serious imprecision because 95% credible interval crosses unity with very wide 95% credible interval, suggesting uncertainty in estimate likely due to single trials or very low numbers of events (<5) contributing to network meta-analysis. 17OHPC=17α-hydroxyprogesterone caproate; Amox=amoxicillin; CrI=credible interval; Met=metronidazole; RCT=randomised controlled trial

Fig 5

Impact on preterm birth <34 weeks of various preventative treatments for pregnant women at risk of spontaneous preterm birth using vaginal progesterone as comparator. Solid lines represent direct comparison. Network meta-analysis estimates reported as odds ratios and 95% credible intervals instead of confidence intervals because bayesian analysis was conducted (credible interval is interpreted as interval where there is 95% probability that values of odds ratio will lie). Anticipated absolute effect compares two risks by calculating difference between risk of intervention group with risk of control group. GRADE (grading of recommendations assessment, development, and evaluation) working group grades of evidence (or certainty of evidence): high quality—very confident true effect lies close to that of estimate of effect; moderate quality—moderately confident in effect estimate; true effect is likely to be close to estimate of effect, but there is a possibility that it is substantially different; low quality—confidence in effect estimate is limited; true effect may be substantially different from estimate of effect; very low quality: very little confidence in effect estimate; true effect is likely to be substantially different from estimate of effect. *Based on assumed control risk of spontaneous preterm birth <34 weeks of 13.6% (corresponding to a pooled 13.6% rate of preterm birth <34 weeks in women receiving vaginal progesterone in included trials). †Serious imprecision because odds ratio <1 (suggesting greater likelihood of benefit than harm) but wide 95% credible interval and includes appreciable harm (odds ratio >1.25). ‡Serious imprecision because odds ratio >1 (suggesting greater likelihood of harm than benefit) but wide 95% credible interval and includes appreciable benefit (odds ratio <0.75). §Serious imprecision because 95% credible interval extremely wide, but does not cross 1, suggesting greater likelihood of harm than benefit. ¶Imprecision because 95% credible interval crosses 1, suggesting uncertainty in estimate. **Extreme imprecision because 95% credible interval crosses 1 and extremely wide, suggesting gross uncertainty in estimate. 17OHPC=17α-hydroxyprogesterone caproate; Amox=amoxicillin; CrI=credible interval; Met=metronidazole; RCT=randomised controlled trial

Fig 6

Impact on perinatal death of various preventative treatments for pregnant women at risk of spontaneous preterm birth using vaginal progesterone as a comparator. Solid lines represent direct comparison. Network meta-analysis estimates reported as odds ratios and 95% credible intervals instead of confidence intervals because bayesian analysis was conducted (credible interval is interpreted as interval where there is 95% probability that values of odds ratio will lie). Anticipated absolute effect compares two risks by calculating difference between risk of intervention group with risk of control group. GRADE (grading of recommendations assessment, development, and evaluation) working group grades of evidence (or certainty of evidence): high quality—very confident true effect lies close to that of estimate of effect; moderate quality—moderately confident in effect estimate; true effect is likely to be close to estimate of effect, but there is a possibility that it is substantially different; low quality—confidence in effect estimate is limited; true effect may be substantially different from estimate of effect; very low quality: very little confidence in effect estimate; true effect is likely to be substantially different from estimate of effect. *Based on assumed control risk of perinatal death of 2.3% (corresponding to a pooled 2.3% rate of perinatal death in women receiving vaginal progesterone in included trials). †Serious imprecision because odds ratio >1 (suggesting greater likelihood of harm than benefit) but wide 95% credible interval and includes appreciable benefit (odds ratio <0.75). ‡Serious imprecision because odds ratio <1 (suggesting greater likelihood of benefit than harm) but wide 95% credible interval and includes appreciable harm (odds ratio >1.25). §Very serious imprecision because 95% credible interval crosses 1 with wide credible intervals suggesting uncertainty in the estimate likely due to single trials and low numbers of events contributing to network meta-analysis, with additional high possibility of harm. 17OHPC=17α-hydroxyprogesterone caproate; Amox=amoxicillin; CrI=credible interval; Met=metronidazole; RCT=randomised controlled trial