Role of Omega-3 Unsaturated Fatty Acids in the Postpartum Depression : Systematic Review and Narrative Synthesis

Background: Postpartum depression (PPD) is a complex mental health disorder that affects women during their childbearing years. It is a serious medical condition that occurs in approximately 15% of women after birth and has an adverse effect on both the mother and the infant. Hypotheses exist relating dietary deficiencies in a pregnant or postnatal woman’s diet may cause postnatal depression. It is unclear whether Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are effective for treating or preventing PPD. Objectives: To assess the best available evidence to date regarding the effect of n-3 PUFAs on the etiology, prevention and treatment of postnatal depression. Methods: A systematic review and narrative synthesis was conducted in order to address the gaps in knowledge. For the systematic review, a broad search of electronic databases of published quantitative literature was conducted. The narrative synthesis consists of four elements: 1) developing a theory; 2) developing a preliminary synthesis; 3) exploring relationships in the data; 4) assessing the robustness of the synthesis. Published experimental and observational studies were accepted involving women who were pregnant or who had given birth in the previous six weeks. N-3 PUFAs was the intervention of interest and PPD was the outcome. Results: Out of 181 potential articles, a total of 17 studies met the inclusion criteria. The overwhelming majority of the studies found that n-3 PUFAs had no inverse association with PPD evaluations. Significant heterogeneity was observed among included studies. Conclusions: Overall, This systematic review and narrative synthesis failed to find a significant positive association between n-3 PUFAs intake and PPD.


Introduction
Depression is a major cause of disability for all ages and both genders (World Health Organization [WHO], 2008).Women are at the highest risk of depression during their childbearing years; and the birth of a child may precipitate a depressive episode in vulnerable women (Stewart, Robertson, Dennis, Grace, & Wallington, 2003).Postpartum depression (PPD) can affect up to 15% of new mothers during the first year after delivery (Stewart et al., 2003).
N-3 PUFAs are necessary for a healthy brain function and structure; they prevent or decrease the inflammatory status occurring during depression and may be important for maintaining healthy mood and controlling mental distress (Bourre et al., 1991;Maes & Smith, 1998;Suarez et al., 2003).
Several experimental and observational studies evaluated the effectiveness of the n-3 PUFAs on PPD, but there was no current systematic review that has examined all quantitative designs that have been conducted to assess the efficacy n-3 for PPD.There were, however, some brief, non-systematic literature and article reviews which dealt with a broad range of issues related to our topic rather than addressing the n-3 PUFAs and PPD in particular in depth (Borja-Hart & Marino, 2010;Freeman, 2006;Levant, 2010;Jans, Giltay, & Willem Van der Does, 2010;Ramakrishnan, 2011;Wojcicki & Heyman, 2011).
Research indicated that systematic reviews are more transparent than literature and article reviews with a goal of decreasing bias by identifying, appraising, and synthesizing all relevant studies on a specific topic (Uman, 2001).
As no systematic review was conducted on the role of n-3 PUFAs for PPD, the aim of this study was to fill this gap of knowledge and update the current information about the overall published evidence concerning whether n-3 PUFAs exposure in the perinatal and postpartum period are beneficial for treating depression, up to 12 months post-partum.

Methods
We employed a systematic review of published evidence, with a narrative synthesis in lieu of statistical meta-analysis (Cochrane Collaboration, 2008;Popay et al., 2006).

Searching the Literature
With the assistance of a librarian, research papers published in English between 1990 and 2014 were identified via searches of the following databases: Ovid, CINHAL (Cumulative Index of Nursing and Allied Health Literature), Embase, Chochrane, and Google Scholar, using the following keywords, their derivatives and conjugated terms: "fish oils", OR "omega fatty acids", OR "omega-3", OR "fatty acids", OR "α linolenic acid", OR "docosahexaenoic acids", OR "eicosapentaenoic acid" AND "Postpartum depression", OR "postnatal depression".
Abstracts, animal studies, and individual case reports were excluded, as were studies that failed to clearly describe the intervention and outcome measures.

Quality Appraisal
The Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project (EPHPP) was used to assess methodological quality (EPHPP, 2009;Thomas, Ciliska, Dobbins, & Micucci, 2004).This quality assessment tool allows quantitative studies (randomized and nonrandomized trials) to be rated on six components: selection bias, study design, confounders, blinding, data collection methods, withdrawals and dropouts.Each study was rated as "strong," "moderate," or "weak" on each of these components.An overall global rating was then given to each study with studies classified as "strong" (at least four strong ratings without any weak ratings), "moderate" (less than four strong ratings and one weak rating), or "weak" (two or more weak ratings).
Concerning the data collection methods, the validity and reliability of the methods were rated in relation to PPD outcome measures only.

Data Abstraction
The following data were abstracted: study designs, characteristics of the participants and interventions, intervention measurement, outcome measurement, findings and limitations.

Data Synthesis
A narrative synthesis of the findings about the association between n-3 PUFAs intake and PPD was carried out.This stepwise narrative methodology has been used previously in a wide range of study reviews (Arai et al., 2007;Dennison et al., 2009).
Narrative synthesis is an approach to synthesis findings that relies mainly on the use of words and text to summarize and explain findings.It is typically used when statistical meta-analysis is not suitable.Due to the significant clinical variability (variability in the participants, interventions and outcomes studied also variability in outcome measures) and methodological heterogeneity (variability in study design) between the selected studies of the papers in this study, statistical meta-analysis was contra-indicated, hence our reliance upon narrative methods.The four stages of the narrative synthesis were: (i) developing a theory; (ii) developing a preliminary synthesis; (iii) exploring relationships within and between studies; and (iv) assessing the robustness of the synthesis.

Element 1: Developing a Theory
This part is concerned with "how the intervention works, why, and for whom" (Popay et al., 2006, p.12).The purpose of this part is to develop an understanding of the theory behind the intervention in order to inform decisions about the review question and the types of studies to include.It is also important in "contributing to the interpretation of the review's findings and will be valuable in assessing how widely applicable those findings may be" (Popay et al., 2006, p.12).

Element 2: Developing a Preliminary Synthesis
The preliminary synthesis provides a description of the results of all included research studies in order to organize findings to provide an initial description of patterns across included studies (Popay et al., 2006).Studies were organized according to design and effects.For each included paper, the following data were extracted and tabulated: type of paper, study location, methodological approach, participant information and inclusion criteria, intervention and outcomes measurement, summary of main study findings, and limitation.

Element 3: Exploring Relationships Within and Between Studies
The purpose of this element is to consider relationship: first between study results and Key aspects for other studies and second the factors across included studies (Popay et al., 2006).The outcomes that emerged from the preliminary synthesis were subjected to further rigorous evaluation to identify any factors that may explain the differences within and across the included studies and to understand how and why n-3 PUFAs have or do not have an effect on PPD.

Element 4: Assessing the Robustness of the Synthesis
Assessing methodological quality is a way to ensure the robustness of the synthesis.The analysis of relationships within and between studies described previously helps in creating a thorough assessment of the strength of the evidence available for drawing conclusions on the basis of a narrative synthesis (Popay et al., 2006).
In terms of methodological quality assessment, our set indicated five strong, nine moderate, and three weak studies.Weak rating scores were given because of a poor study design, lack of controlling confounders, and/or high dropout rates.The most common reasons for a study not receiving a 'strong' rating were a low response rate from eligible participants and high withdrawal/dropout rate.Significant heterogeneity was observed among included studies, hence justifying our narrative synthesis approach.There are large differences among them in terms of study designs, sample size, population and time period of the study (depressed or healthy participants, pregnant and/or postpartum), characteristics of the intervention in terms of (type, dosage, duration), and choice of measures of predictors and outcomes.

Discussion (Narrative Synthesis: Element 3)
We demonstrated that the results of the use omega-3 PUFA as therapeutic and preventative agents for postpartum depression were varied.Many limitations complicated the interpretation of the findings, most prominently the small sample size, as only 17 studies met the inclusion criteria.
Furthermore, clinical and methodological heterogeneity were high.It was noticeable that the heterogeneity between studies may depend on clinical and methodological issues.Intervention trials were varied in terms of characteristics and number of participants, depression scales employed (EPDS, HAM-D, or BDI), baseline depression score, the nature of the intervention (e.g., formulation, dose, duration, timing, etc.), time period of study and supplementation (i.e., antenatal, postnatal or combined antenatal/postnatal), lack of control group, open label trials, low supplement dosages, under-reporting of fatty acid intake, short-term follow-up, unsuitable ratios of EPA:DHA.This considerable variability made the discussion of results more complex.
In addition, most studies measured depression using the EPDS without verification of high EPDS scores with a clinical diagnosis of depression, which can result in biased results since a high EPDS score can be due to anxiety as well as from depression (Stuart, Couser, Schilder, O'hara, & Gorman, 1998).
It has been hypothesized that n-3 PUFAs affects synaptic function by impacting membrane structure and through cytokine-immuno neuroendocrine interactions (Maes et al., 1998).Other studies stated that plasma levels of fatty acids are not a perfect measure of dietary intake nor a perfect predictor of fatty acid levels in brain tissue (Rapoport, Ramadan, & Basselin, 2011;Shapiro et al., 2012).While Erythrocytes are considered the gold standard to measure the long-term n-3PUFA status, However, several studies have indicated strong correlations between FA content of erythrocytes and plasma; consequently, we can consider the plasma as a valid biomarker to reflect n-3 status over the last month (Harris, 2008;Garneau et al., 2012;Paradis, Pérusse, Godin, & Vohl, 2008) Such theories could explain the lack of association found in some of the studies reviewed here between n-3 PUFAs supplementation and prevention of PPD.
Lastly, some important issues concerning the delivery of the intervention have been explored in recent meta-analyses, which showed that the positive effects of n-3 PUFAs on depressive symptoms appeared to depend more on EPA administration rather than DHA, severity of depression, and study quality (Bloch & Hannestad, 2012).However, some concerns regarding these findings still persist (Lin et al., 2012).The findings regarding the different efficacy of EPA compared to DHA and EPA-DHA combinations were confirmed by Grosso et al., (2014) in a meta-analysis in which the researchers grouped RCT's based on the type of n-3 PUFAs administered.Whether EPA is more effective than DHA, in improving depression, the different effects of the types of n-3 PUFAs is challenging for convincing explanation since DHA is a major structural constituent of neuronal membranes (Grosso et al., 2014).Thus, that increasing its dietery intake would be valuable on brain function, rather than EPA, which exists at lower levels (Arterburn, Hall, & Oken, 2006;Grosso et al., 2014).
Although heterogeneity among included studies makes it difficult to synthesize the findings, our narrative approach indicates a null benefit of n-3 PUFAs on depressive symptoms postpartum, as only one small pilot trial (Freeman et al., 2006), one weak ecological study (Hibbeln, 2002), and four small cohort and cross-sectional studies (da Rocha & Kac, 2012;De Vriese, Christophe, & Maes, 2003;Markhus et al., 2013;Otto, De Groot, & Hornstra, 2003) reported promising results, whilenone of the RCTs identified in this review showed an association of n-3 PUFAs with a decreased risk for maternal PPD.
In short, the only studies showing positive associations were of small sample size and comparatively weak designs.
Future research should focus on identifying the specific molecular mechanisms underlying the function of n-3 PUFAs in the brain.Moreover, factors related to the pathophysiological nature of the depression should be considered.
Research indicated that women during pregnancy and lactation are not getting enough n-3 PUFAs (Denomme, Stark, & Holub, 2005;Jia et al., 2015).In June, 2014, The Food and Drug Administration (FDA) issued an updated statement advising women to eat more fish during pregnancy and breastfeeding to aid in fetal growth and development.The FDA's recommendations are consume 8 to 12 ounces of a variety of fish each week from choices that are lower in mercury during pregnancy and breastfeeding (U. S. Food and Drug Administration, 2014).

Reflecting Critically on the Synthesis Process (Narrative Synthesis Element 4: Assessment of the Robustness of the Synthesis)
This is the first narrative synthesis systematic review on n-3 PUFAs and PPD literature.The use of defined eligibility criteria, the application of a rigorous search strategy, and the quality assessment of the studies and systematic analysis of the findings made this review transparent.However, there are some limitations to the approach taken in this systematic review and narrative synthesis.
First of all, the different designs of included studies increased heterogeneity.Also, the diversity of outcomes that result from different contexts and the heterogeneous research studies limited the extent to which clear conclusions could be drawn about the usefulness of n-3 PUFAs in PPD.One systematic review and synthesis cannot overcome these complexities alone, but can provide some clarity about the research evidence and its implications for practice and further research.
In addition, since the review yielded a small sample size, it is possible that the aim of the present research may not have been adequately addressed, particularly with relation to the ability to decide whether n-3 PUFAs components are effective for PPD.
The literature search required screening in the most potential databases using a robust search strategy and undertaking empirical checks on the inclusiveness of the search strategy results.However, only studies in the English language were included.It is unknown what other relevant materials in other languages was missed due to this limitation.
Overall, the narrative synthesis methodology used in this review facilitated the understanding and acknowledgement of the broader influences of theoretical and contextual variables when it was challenging to interpret multiple forms of heterogeneous studies.This method was suitable for integrating quantitative research findings and important as a mechanism for drawing messages from research in order to draw our own recommendations for future implication.

Conclusion
The majority of the studies found that PUFA had no association with PPD.The minority that reported a beneficial effect were of poor quality.In conclusion, n-3 PUFAs cannot be considered to be an empirically supported treatment or method for the prevention of PPD.However, since there are other benefits for n-3 PUFAs, then there is no harm in including them in prenatal/postnatal care.