The purpose of this study was to evaluate the efficacy of omega-3 supplementation for the prevention of recurrent preterm birth (PTB) in asymptomatic singleton gestations with previous PTB. We searched fish oil , long chain polyunsaturated fatty acids , pregnancy , and omega-3 in MEDLINE, OVID, Scopus, ClinicalTrials.gov , the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, and the Cochrane Central Register of Controlled Trials from inception of each database to December 2014 with no limit for language. In addition the reference lists of all identified articles were examined to identify studies that were not captured by electronic searches. We performed a metaanalysis of randomized controlled trials of asymptomatic singleton gestations with previous PTB who were assigned randomly to prophylactic omega-3 supplementation vs control (either placebo or no treatment). The primary outcome was predefined as PTB at <37 weeks of gestation. The pooled results were reported as relative risk (RR) with 95% confidence interval (95% CI). The protocol of this review was registered with PROSPERO (registration number: CRD42015016371). Two randomized controlled trials that included 1080 women were analyzed. The mean gestational age at randomization was approximately 134 days in both groups (mean difference, 0.01 days; 95% CI, –0.13 to 0.14). Women who received omega-3 had similar rates of PTB at <37 weeks of gestation (34.5% vs 39.8%; RR, 0.81; 95% CI, 0.59–1.12) and PTB at <34 weeks of gestation (12.0% vs 15.4%; RR, 0.62; 95% CI, 0.26–1.46) compared with control subjects. The omega-3 groups had a statistically significantly longer latency (mean difference, 2.10 days; 95% CI, 1.98–2.22) and higher birthweight (mean difference, 102.52 g; 95% CI, 20.09–184.95) compared with control subjects; the other secondary outcomes (which included gestational age at delivery, spontaneous PTB at <37 and 34 weeks of gestation, admission to the intensive care unit, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and perinatal death) were similar. Omega-3 supplementation during pregnancy does not prevent recurrent PTB in asymptomatic singleton gestations with previous PTB. The benefits in longer latency and higher birth weight may deserve further study.
Preterm birth (PTB) remains the number 1 cause of perinatal death in many countries, including the United States. Women with previous PTB are considered to be at high risk for recurrent PTB in a subsequent pregnancy.
The exact mechanisms for the onset of term or preterm labor are not known exactly, but several biochemical changes have been reported. Prostaglandin concentrations are elevated in the maternal circulation before the beginning of spontaneous labor, and exogenous administration of prostaglandins induces cervical dilation and uterine contractions. Omega-3 fatty acids depress the synthesis of prostaglandins, but the role of omega-3 supplementation in the prevention of PTB is not yet clear.
Randomized controlled trials (RCTs) performed to assess whether supplementation during pregnancy with polyunsaturated fatty acids (such as eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) may prevent recurrence of PTB have shown contradictory results.
The aim of this metaanalysis was to evaluate the efficacy of omega-3 supplementation during pregnancy in the reduction of recurrence of PTB in asymptomatic singleton gestations with previous PTB.
Methods
Search strategy
We searched fish oil , long chain polyunsaturated fatty acids , pregnancy , and omega-3 in MEDLINE, OVID, Scopus, ClinicalTrials.gov , the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, Sciencedirect, and the Cochrane Central Register of Controlled Trials from inception of each database to December 2014 with no limit for language. In addition, the reference lists of all identified articles were examined to identify studies that were not captured by electronic searches. The electronic search and the eligibility of the studies were assessed independently by the authors. Differences were resolved by discussion.
Study selection, data extraction, and assessment of risk of bias
We included all RCTs of asymptomatic singleton gestations with previous PTB who were assigned randomly to prophylactic treatment with either omega-3 or control (either placebo or no treatment). All published RCTs on omega-3 during pregnancy 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), trials in women with multiple gestations, and trials in women with intrauterine growth restriction or gestational hypertension/preeclampsia at the time of random assignment.
The primary outcome was PTB at <37 weeks of gestation. Secondary outcomes included gestational age at delivery, interval from random assignment to delivery (ie, latency), PTB at <34 weeks of gestation, spontaneous PTB (sPTB) at <37 and <34 weeks’ gestation, and neonatal outcome that included birthweight, admission to neonatal intensive care unit, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, and perinatal death. All analyses were done with an intention-to-treat approach. All authors of the included trials were contacted for missing data.
The risk of bias in each included study was assessed by the use of the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Review authors’ judgments were categorized as “low risk,” “high risk,” or “unclear risk” of bias.
Data synthesis
The data analysis was completed independently by the authors who used Review Manager (version 5.3, 2014; The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Discrepancies were resolved by discussion. Heterogeneity across studies was assessed with the use of the Higgins I 2 test. In case of statistically significant heterogeneity, the random effects model of DerSimonian and Laird was used, otherwise a fixed effect model was managed. The pooled results were reported as relative risk (RR) or as mean difference with 95% confidence interval (95% CI).
The protocol of this review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration no. CRD42015016371). The metaanalysis was performed according to the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) statement.
Results
Study selection, study characteristics, and risk of bias of included studies
We identified 29 trials on omega-3 supplementation during pregnancy. No similar systematic reviews were found during the search process. Two trials that met inclusion criteria for this metaanalysis were analyzed. The flow of study identification is shown in Figure 1 . From one of the studies, we obtained additional and unpublished data about PTB at <34 weeks of gestation, sPTB at <34 weeks of gestation, and birthweight. The quality of RCTs that were included in our metaanalysis and assessed by the Cochrane Collaboration’s tool revealed that both studies had a low risk of bias ( Figure 2 ). Risk of publication bias was assessed by visual inspection of the funnel plot, and the symmetric plot suggested no publication bias ( Figure 3 ).


The characteristics of the included trials are summarized in Table 1 . A total of 1080 singleton gestations with at least 1 previous PTB were included. Both studies used daily oral docosahexaenoic and eicosapentaenoic acids supplementation as treatment and placebo as control. In one of the included studies, all participants (both intervention and control group) received weekly intramuscular 17-alpha-hydroxyprogesterone caproate 250 mg. Of the 1080 singleton gestations included in the 2 trials, 544 gestations (50.4%) were assigned randomly to the omega-3 group and 540 gestations (49.6%) were assigned randomly to the control group. The mean of GA at randomization was approximately 134 days in both groups (mean difference, 0.01 days; 95% CI, –0.13 to 0.14).
Variable | Olsen et al 2000 | Harper et al 2010 |
---|---|---|
Study location | Northern Europe | United States |
Patients, n (n/N) a | 228 (108/120) | 852 (434/418) |
Intervention daily | Docosahexaenoic acid 900 mg and eicosapentaenoic acid 1300 mg | Docosahexaenoic acid 800 mg and eicosapentaenoic acid 1200 mg |
Control | Placebo | Placebo |
Follow up, % | 98 | 100 |
Gestational age at random assignment, d | 131.8 vs 130.5 | 137.2 vs 137.2 |
Mean age, y | 29 vs 30 | 28 vs 27 |
Smoking, n/N a | 50/110 vs 50/122 | 64/434 vs 72/418 |
Previous preterm birth, n/N a | ||
1 | 110/110 vs 122/122 | 274/434 vs 282/418 |
>1 | 0/100 vs 0/122 | 160/434 vs 136/418 |
Race, n/N | ||
African American | N/A | 148/434 vs 145/418 |
White | N/A | 245/434 vs 240/418 |
Other | N/A | 41/434 vs 33/418 |
Primary outcome: preterm birth, wk | <37 | <37 |
a Data are presented as the number of intervention vs the number of control subjects or as total number (intervention/control).
Results
Study selection, study characteristics, and risk of bias of included studies
We identified 29 trials on omega-3 supplementation during pregnancy. No similar systematic reviews were found during the search process. Two trials that met inclusion criteria for this metaanalysis were analyzed. The flow of study identification is shown in Figure 1 . From one of the studies, we obtained additional and unpublished data about PTB at <34 weeks of gestation, sPTB at <34 weeks of gestation, and birthweight. The quality of RCTs that were included in our metaanalysis and assessed by the Cochrane Collaboration’s tool revealed that both studies had a low risk of bias ( Figure 2 ). Risk of publication bias was assessed by visual inspection of the funnel plot, and the symmetric plot suggested no publication bias ( Figure 3 ).

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