Prenatal depression significantly increases the risk of preterm birth (PTB), a highly prevalent and consequential condition. While antidepressant medications are used, their efficacy in reducing PTB risk is questionable and may even increase adverse pregnancy outcomes. Worldwide, prenatal depression affects 7-25% of pregnancies, and preterm delivery occurs in 5-18% of livebirths, leading to long-term health problems in offspring. Long Chain Omega-3 Polyunsaturated Fatty Acids (LC Omega-3 PUFA) supplementation has shown promise in reducing Major Depressive Disorder (MDD) and PTB risk, but research findings have been inconsistent. Inconsistencies stem from complexities in LC omega-3 PUFA research, including the need to consider baseline intakes, sufficiency thresholds, and endogenous conversion of ingested precursors. Clinical trials, while showing an average reduction in depressive symptoms and PTB risk with omega-3 supplementation, lack consistent results due to the failure of most trials to account for baseline intakes, sufficiency thresholds, and precursor conversion. This underscores the need to examine the relationship between omega-3 intake and MDD/PTB beyond randomized controlled trials (RCTs). Observational studies and re-evaluations of RCTs suggest a link between high habitual omega-3 intake and reduced risk of depression, perinatal depression, and preterm birth. Furthermore, molecular evidence suggests a biological plausibility, showing that low omega-3 levels can alter neurotransmitter function, increase neuroinflammation, and impair neurogenesis (for MDD), and increase labor-inducing prostaglandins, promote placental cell death, and have deleterious inflammatory effects (for PTB). This study hypothesizes that communities with low omega-3 PUFA intakes will have high rates of both depression and preterm birth, testing this hypothesis using available country-level data from 2010.

Existing literature reveals a complex relationship between omega-3 fatty acids, depression, and preterm birth. While studies show a correlation between low levels of LC omega-3 PUFAs and an increased risk of both depression and preterm birth, the results from clinical trials are mixed. Inconsistencies arise from factors like baseline omega-3 intake, the existence of sufficiency thresholds, and the body's ability to convert plant-based omega-3s (ALA) into long-chain omega-3s (EPA and DHA). Some studies show that omega-3 supplementation can reduce depressive symptoms and the risk of preterm birth, while others show no effect or even negative effects. The lack of consistency across studies highlights the need to consider these complexities, which is often overlooked in clinical trials. However, observational studies and re-analyses of existing data suggest that high habitual omega-3 intake is associated with a lower risk of depression and preterm birth. Molecular evidence supports a biological mechanism for this association, suggesting that low omega-3 levels can disrupt various biological processes leading to both depression and preterm birth.

This study used country-level data from 2010 for 184 countries with complete information on major depressive disorder (MDD) prevalence, omega-3 intake, preterm birth (PTB) rate, and country income level. MDD prevalence data was derived from the 2010 Global Burden of Diseases study, using a Bayesian meta-regression approach to harmonize prevalence estimates. Omega-3 intake data, estimated by the Nutrition and Chronic Diseases Expert Group (NutriCoDE), utilized a Bayesian hierarchical imputation model to account for data heterogeneity. PTB rates were similarly harmonized from various datasets using regression models. Country income data was obtained as a four-category ordinal ranking based on per capita Gross National Income. A composite omega-3 metric was calculated for each country, combining seafood-based and plant-based omega-3 intakes, adjusting for the endogenous conversion of ALA to EPA (assuming a 15% conversion rate). Penalized splines were used to evaluate the relationship between LC omega-3 PUFA levels and MDD/PTB rates, identifying potential non-linearity and thresholds. Separate linear regression models were constructed above and below these thresholds, adjusting for country income and PTB rate (for MDD analysis) or MDD prevalence and country income (for PTB analysis). Supplementary analyses explored different ALA to EPA conversion rates and analyzed seafood and plant-based omega-3 intakes separately. Statistical analyses were performed using R and SAS.

The analysis included 184 countries. The mean prevalence of MDD was 5.3 cases per 100 people (SD: 1.8), the mean LC omega-3 PUFA was 343 mg/day (SD: 380), and the mean PTB rate was 10.2 PTBs per 100 live births (SD: 3.0). Penalized spline analyses revealed a non-linear relationship between LC omega-3 PUFA intake and both MDD and PTB rates. For MDD, a threshold was observed around 1000 mg/day of LC omega-3 PUFA. Below this threshold, a one standard deviation increase in LC omega-3 PUFA (380 mg/day) was associated with a 0.50 decrease in MDD prevalence per 100 people (95% CI 0.13, 0.88) after adjusting for country income and PTB rate. Above the threshold, no significant association was found. For PTB, a threshold was found around 550 mg/day. Below this threshold, a one standard deviation increase in LC omega-3 PUFA was associated with a 1.5 decrease in PTB rate per 100 live births (95% CI 0.2, 2.9) after adjusting for country income and MDD prevalence. Above the threshold, no significant association was observed. Geographic patterns showed countries with low omega-3 intake primarily in Africa, South-Central Asia, and Central America, while higher intakes were found in Southeast Asia and along the North Atlantic coast of Europe. Six countries were above the MDD threshold and 26 above the PTB threshold; 158 countries were below both thresholds. When seafood and plant-based omega-3s were analyzed separately, the thresholds varied, indicating potential differences in their effects. Variations in the assumed ALA to EPA conversion rate resulted in minor shifts in threshold locations but did not alter the overall findings. MDD and PTB rates were positively correlated at the country-level.

This study's findings support the association between low omega-3 intake and higher rates of MDD and PTB at the country level. The observed threshold effects for both MDD and PTB, aligning with individual-level findings, suggest the existence of sufficiency levels for omega-3 intake. The consistency of these findings after adjusting for confounding factors like country income strengthens the results. The positive correlation between MDD and PTB prevalence at the country level aligns with individual-level studies. The study's findings are in line with previous meta-analyses and observational studies, demonstrating the importance of considering baseline intakes, sufficiency thresholds, and ALA conversion when studying omega-3s and health outcomes. The study complements the existing literature by providing a country-level perspective, highlighting the potential impact of dietary patterns on national health outcomes.

This study provides compelling evidence of an association between low omega-3 intake and elevated rates of MDD and PTB across countries. The identification of sufficiency thresholds reinforces the need to consider these factors in future research. While this study does not definitively prove causation, the convergence of country-level data with individual-level findings supports the notion that increasing omega-3 intake could significantly reduce MDD and PTB rates globally. Further research should focus on developing safe and effective strategies for increasing omega-3 intake in populations with low levels, considering cultural and economic factors, as well as the investigation of individual-level variations in omega-3 metabolism and response.

The cross-sectional nature of the study limits the ability to establish causality. The reliance on country-level data may lead to ecological fallacy, where associations observed at the country level may not hold true for individuals. Limited covariate information restricts the ability to fully account for potential confounding factors beyond country income and PTB rates (for MDD) or MDD prevalence and country income (for PTB). Furthermore, the study does not address potential reverse causation or evaluate distinct subtypes of LC-omega-3 PUFAs (EPA vs. DHA) at the country level. Also, the study's focus on intake data, rather than direct measurement of circulating omega-3 levels, may introduce some uncertainty. Finally, the study only assesses one of the multiple factors influencing depression and preterm birth.