INTRODUCTION

Docosahexaenoic acid (DHA or 22:6n-3) is an omega n-3 polyunsaturated fatty acid (PUFA). Chemically, it is a carboxylic acid like all fatty acids (FAs). DHA is considered as the most important long-chain PUFA of the n-3 family. Physiologically, the human body is able to metabolize DHA through conversion in the organism of alpha linolenic acid (ALA), another n-3 PUFA. This conversion takes place principally in the liver and it is transported as a phospholipid by plasma albumin, almost exclusively, to the brain and retina. In cases of pregnancy, adipose tissue also acts as a temporary reserve, but the degree of conversion is reduced, making it difficult to meet recommended levels of DHA, considered to be an essential prenatal nutrient (¹). For this reason, the European Food Safety Authority (EFSA) (²) recommendation ranges from 100 to 200 mg/day.

Factors that can influence low DHA intake in pregnant females include level of education, older age, smoking and insufficient fish and seafood consumption, especially in the second and third trimesters (³). DHA is found in fish oil and some algae. In turn, most DHA in fish and other complex organisms comes from their access to photosynthetic heterotrophic microalgae. Foods that contain it include cold-water fish (like salmon, herring or anchovy), tuna and codfish oil (¹). As it can be difficult to reach the recommended amounts through dietary intake, the consumption of DHA supplements with or without other FAs is advised. It should also be noted that omega-3 fatty acid supplements are well tolerated by pregnant and lactating women (⁴).

In this group of women, this n-3 PUFA participates in different functions (⁵,⁶). In terms of mental health, significantly lower levels of DHA, EPA and total n-3 PUFAs have been found in adult patients with depression, suggesting that n-3 PUFAs play a role in the pathogenesis of this illness (⁷), participating in neurobiological processes including control of serotonergic and dopaminergic function, modulation of brain-derived neurotrophic factor in the hippocampus, regulation of the hypothalamic-pituitary-adrenal axis, and with effects on neuroinflammation (⁸). In this regard, Lin et al. (⁷) argued the need for studies examining the specific functions of DHA in different population groups with depressive symptoms. In this context, the present study focuses on maternal mental health.

One possible solution to mental health issues in such situations is the application of prescription drugs. However, because of their potential toxic, teratogenic or even lethal effects on the fetus, the use of many of them is not recommended during pregnancy. In addition, the physiological changes inherent to pregnancy and lactation condition the absorption, transfer, excretion and metabolism of antipsychotics (⁹). For this reason, nutrition-based treatments have been proposed as an aid to alleviate and/or prevent prenatal anxiety and depression (¹⁰). There is therefore an evident need to know the real effect of DHA on mental health during pregnancy and the postpartum period.

Nonetheless, despite the findings of the referenced studies, the relationship between DHA and its effect on mental health in the prenatal stage is not fully clear (⁷). It can be speculated that different actions can occur simultaneously. On one hand, by maintaining and increasing the brain structures and preserving their function by interacting with phospholipid metabolism and, hence, the modulation of signal transduction. On the other hand, preventing or decreasing the inflammatory status occurring during depression (¹¹). The aim of this scoping review is therefore to evaluate the effect of DHA during pregnancy and the postpartum period on maternal mental health in terms of depressive symptoms and anxiety.

MATERIAL AND METHODS

The scoping review framework adopted was based on the methodological model of Arksey and O’Malley (¹²), with contributions from the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) (¹³). Following the model, the methodological process was divided into five stages.

STUDY SELECTION

Study selection was carried out as described above and following PRISMA (¹⁴). First, the search results were imported into Mendeley (https://www.mendeley.com) to perform the duplication check, thus eliminating 563 articles. Of the remaining 964 studies which were subsequently analyzed according to title and abstract, 883 were discarded based on the inclusion and exclusion criteria, while 81 were found to be potentially eligible articles. Subsequently, the relevance of each of the abstracts was analyzed, eliminating 46 in this process. Finally, the full text of the remaining 35 articles was examined and 14 were chosen for final analysis (Fig. 1). The entire process was recorded using an Excel Information Manager spreadsheet (¹⁵).

Figure 1. PRISMA chart. DHA: docosahexaenoic acid; n-3 PUFA: omega-3 polyunsaturated fatty acids. 

RESULTS

The results are set out in three different sections: characteristics of the included studies, studies which show the effectiveness of DHA in terms of maternal mental health, and studies which show no such effectiveness.

CHARACTERISTICS OF INCLUDED STUDIES

The 14 papers came from a total of 11 countries: two from Brazil, United States and Japan; and one each from Australia, The Netherlands, Iran, Kenya, Mexico, Norway, United Kingdom and Taiwan. Exactly half of the papers were published between 2016 and 2018 (n = 7). As for the type of study, six were RCT, four were prospective cohorts, three were cross-sectional studies and one, a longitudinal case-control study. These and other characteristics of the studies are shown in table I.

Table I. Overview of included studies. 

DSM-IV: Diagnostic and Statistical Manual, 4th edition; IG: intervention group; CG: control group; WG: gestation week; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; STAI: State-Trait Anxiety Inventory (Spanish version); EPDS: Edinburgh Postpartum Depression Scale; FA: fatty acids; ALA: alpha-linolenic acid; BDHQ: self-administered diet history questionnaire; CES-D: Center for Epidemiologic Studies Depression Scale; PDSS: Postpartum Depression Screening Scale; HIV: human immunodeficiency virus; n-3: omega-3; SFA: saturated fatty acids; MUFA: monounsaturated fatty acids; PUFA: polyunsaturated fatty acids; sFFQ: semi-quantitative food frequency questionnaire; n-3 PUFA: omega-3 polyunsaturated fatty acids.

DISCUSSION

The results were classified according to whether the studies showed beneficial effects or otherwise of the intake of DHA during pregnancy on maternal mental health in terms of depressive symptoms and anxiety. The observational ones almost all show that the DHA has an important effect in relation to maternal mental health (6 yes, 2 no). On the other hand, the experimental ones do not show that effect so clear (3 yes, 3 no). This lower effect in the experimental ones may be due to various causes (i.e., the different doses, the sample size and even the different countries in which the studies have been performed, since it is known that there are clear differences in diets [³¹].

According to the analysis of the papers that has been undertaken, dose is one of the conditioning factors that may affect the effectiveness of DHA. Different doses were administered in the RCTs (²²-²⁴) (Table I). These doses meet the recommended daily DHA intake of the EFSA (²) (a range from 100 to 200 mg/day). It should also be noted that the effectiveness of DHA reported in these studies may be affected by the exclusion criteria of a prior history of depression, anxiety or certain other illnesses.

In other RCTs with higher doses of DHA, no beneficial effect on mental health was reported, though this may be due to how the studies were developed. In the case of Dos Santos Vaz et al. (³⁰), the inclusion criteria were a prior history or risk of depression. Likewise, in the study of HIV-positive pregnant women (²⁹), the illness itself could imply a bias in the results given the different physiological and psychological conditioning factors of this group of women. Finally, it should be noted that in the study by Makrides et al. (²⁸), a dietary DHA supplement of 800 mg/day was found to be ineffective in the prevention or reduction of depressive symptoms. However, as limitations to their study, the authors reported that they did not verify the clinical diagnosis of depression before the start of the RCT. In addition, they associated the lower than expected rate of depressive symptoms in the CG to the so-called Hawthorne effect (³³), according to which the mere fact of participation in a trial with a high degree of contact with researchers helps to prevent such symptoms. Finally, in relation to the non-effectiveness of DHA in pregnant women with an established diagnosis of prenatal depression, a recent study by Mezquida et al. (³⁴) reported the association of a specific pattern of obstetric complications with a more severe clinical symptomology like depression. All of this may be influential in terms of the results of the non-effectiveness of DHA in this population with a history of mental illness.

On the other hand, Makrides et al. (²⁸) only analyzed the effect of DHA in the postpartum period, while the effectiveness of DHA was only found to be statistically significant in other studies during pregnancy (¹⁶-²⁴). In this regard, a total of five studies (²⁴,²⁶-²⁹) found, after analyzing the effect of DHA in the postpartum period, no positive effect in terms of the prevention or reduction of depressive or anxiety symptoms. This may be because the dietary supplements were administered during pregnancy and, therefore, the concentrations of DHA would have lowered considerably in the postpartum period. However, the importance of DHA for maternal mental health in the third trimester has been shown. This appears to be a critical period to ensure adequate levels of maternal DHA to facilitate optimal cognitive development at the end of infancy (³⁵). In this regard, the potential effects of DHA during infancy and adulthood are becoming more widely recognized, suggesting at the same time that DHA levels can play a role in cognitive decline and in relation to the main psychiatric disorders (³⁶). The effect may be related to the intake of DHA supplements increasing the concentrations of 17-hydroxy-docosahexaenoic acid in maternal and umbilical cord blood (p = 0.02) (³⁷).

Finally, another conditioning factor that may have affected the results is the way depressive symptoms were measured. One of the scales used, in the study by Judge et al. (²³), was the Center for Epidemiologic Studies Depression scale (CES-D) (³⁸). In the study, a Cronbach's α coefficient of 0.89 in the IG and 0.90 in the CG was reported. A noteworthy result if compared with the original coefficients of 0.85 and 0.9, respectively (³⁸). For this reason, Judge et al. (²³) concluded that the maternal CES-D score during pregnancy was a significant predictor of postpartum depressive symptoms. This finding also supports previous research that identified psychological disturbance during the prenatal period as a significant predictor of postpartum depression (³⁹,⁴⁰). However, this scale was not used in the other studies, where the most commonly used scale was the EPDS (²⁵) (n = 11). This scale measures depression and the emotional feelings of mothers in the last weeks of gestation. The prevalence of depression ranged between 5.9 % and 50 % (¹⁶-²²,²⁴,²⁶-²⁸,³⁰). The EPDS has been used with different cut-off values (≥ 12 points, ≥ 11, ≥ 10, ≥ 9 and > 8) or simply the mean values. Although a high EPDS score (²⁵) cannot confirm a diagnosis of depression, it is considered that a score higher than 12 may indicate a probable depressive disorder (²⁸). A score of 10 to 12 represents a crossover point and a score of 0 to 9, the absence of postpartum depression (⁴¹). In contrast, Markhus et al. (²¹) argue that the cut-off value should be ≥ 10, as this is the value commonly used in Primary Care settings.

CONCLUSIONS

This scoping review focuses on identifying the effectiveness of DHA with respect to maternal mental health. In most of the studies analyzed (n = 9), higher serum concentrations of this n-3 PUFA, whether due to a high natural intake or dietary supplements, were shown to influence reducing the prevalence of depressive and anxiety symptoms. Although more research is needed, these exploratory results therefore seem to indicate that DHA plays an important role in the prevention of the pathogenesis of these two mental illnesses during the gestation period. However, it appears to lose effectiveness in the postpartum period, since no studies analyzed in this review had shown an effect of DHA on depressive or anxiety symptoms. The findings lend support to the hypothesis of the implication of phospholipids in depression. However, further research in this area is required. Future investigations should aim to replicate findings in larger data sets and clarify possible pathophysiological mechanisms. Another research line would be to investigate what happens with multiple pregnancies given that all the studies made to date have concentrated on singleton pregnancies. It should also be noted that very few of the papers have considered only the use of DHA, with most studying DHA in combination with other PUFAs like EPA. Further research is therefore required to know the individual effect of DHA on maternal mental health.

Finally, different scales were used to detect depressive symptoms, with the EPDS being the most frequently employed. However, there appears to be no consensus on the cut-off value. Clarifying this question is key in terms of the healthcare implications for the systematic detection of depression during pregnancy and the postnatal period and, in this way, ensuring early intervention and the correct tackling of the disorder.