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Higher n-3 polyunsaturated fatty acid status during early pregnancy is associated with lower risk for depression at 12 months postpartum: The NuPED study
Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, SwitzerlandCentre of Excellence for Nutrition, North-West University, Potchefstroom, South AfricaDepartment of Nutritional Sciences, King’s College London, London, United Kingdom
Higher red blood cell (RBC) DHA and n-3 index were associated with lower odds for depression at 12 months postpartum.
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Higher n-6/n-3 PUFA and AA/EPA ratios at early pregnancy were associated with higher odds for depression at 12 months postpartum.
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Women with higher RBC n-3 PUFA status during early pregnancy may be at lower risk for depression at 12 months postpartum.
Abstract
Perinatal depression can negatively affect the health of the mother and her offspring. N-3 polyunsaturated fatty acids (PUFA) may play a role in the aetiology of depression. Therefore, we investigated the association of n-3 PUFA status during early pregnancy with perinatal depression among women living in urban Johannesburg, South Africa. For this prospective analysis, we analysed red blood cell (RBC) total phospholipid fatty acid (FA) composition (% of total FA) of 242 pregnant women at 18 weeks’ gestation. We used the Edinburgh Postnatal Depression Scale (EPDS) to identify women at risk for depression (EPDS score 9) at 18, 22 and 36 weeks’ gestation, and at 6 and 12 months postpartum. RBC EPA status was negatively (=-0.22, ), and the AA/EPA ratio positively (=0.24, ) associated with EPDS scores at 12 months postpartum. Higher RBC DHA and n-3 index were further associated with lower odds (OR=0.56 [95% CI: 0.32-0.91]; OR=0.63 [95% CI: 0.39-0.94]), while higher n-6/n-3 PUFA and AA/EPA ratios early in pregnancy were associated with higher odds for depression at 12 months postpartum ((OR=2.34 [95% CI: 1.12-4.97]; OR=1.02 [95% CI: 1.00-1.05]). Our results suggest that women with a higher RBC n-3 PUFA status during early pregnancy may be at lower risk for depression at 12 months postpartum.
]. Perinatal depression may result in women finding it difficult to perform everyday tasks, failure to seek perinatal care, poor dietary intake, and self-harm or suicide [
]. Furthermore, perinatal depression has been associated with poorer childhood outcomes such as behavioural problems, attentional deficits and impaired cognitive function [
]. Thus, perinatal depression can have serious health implications for both the mother and her child.
Even though the aetiology of depressive disorders remains unclear, it is likely multifactorial. There is a growing body of research indicating a link between depressive symptoms and modifiable nutritional risk factors, especially poor n-3 polyunsaturated fatty acid (PUFA) status [
]. Some of the putative mechanisms underlying the observed associations between n-3 PUFA status and mental health involve their role in neurogenesis and neuroplasticity, the tryptophan-kynurenine metabolism and the gut-microbiota-brain axis [
]. The n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are precursors for the production of anti-inflammatory and inflammation-resolving mediators [
]. A low n-3 PUFA status might be particularly detrimental during the perinatal period when women are at increased risk of depression relapse or newly diagnosed depression. However, data on the associations between maternal n-3 PUFA status and perinatal depression are limited and inconsistent [
The n-3 PUFA status of an individual can be assessed by measuring the fatty acid (FA) composition of red blood cell (RBC) membranes and expressed either as individual n-3 PUFA (in percentage of total FA) or as the sum of EPA + DHA (also called the "omega (n)-3 index"). Globally, low and very low levels of n-3 PUFA status (n-3 index 6% and 4%, respectively) have been observed in many high-income populations, while data from LMIC are still scarce [
]. Low conversion rates of the essential n-3 PUFA precursor alpha-linolenic acid (ALA) to EPA and DHA contribute to a low n-3 PUFA status in populations with a low intake of preformed EPA and DHA, e.g. from fish or supplements. Conversion rates can be further affected by variations in genes coding for desaturase and elongase enzymes. During pregnancy and lactation, requirements of n-3 PUFA are increased because the supply to the foetus mainly depends on the mother’s intake [
]. The nutritional status of pregnant women in South Africa is poorly described. However, a previous South African study in women of reproductive age indicated that the intake of n-3 PUFA is below recommendations in both rural and urban areas [
]. Therefore, the aim of this study was to investigate the association of n-3 PUFA status during early pregnancy with perinatal depression among women living in urban Johannesburg, South Africa. Thereby, we described the n-3 PUFA status as single RBC n-3 PUFA, the n-3 index, and the n-6/n-3 PUFA ratio. We further determined RBC FA patterns by Principal Component Analysis (PCA) to overcome the limitations of other n-3 PUFA status indicators not considering the mutual dependence of FA and the influence of change in proportion of one FA on the rest of the FA in RBC membranes.
2. Methods and materials
2.1 Study design and participants
This study formed part of the Nutrition during Pregnancy and Early Development (NuPED) study, a prospective cohort study conducted in Johannesburg, South Africa. The NuPED protocol has been published previously [
]. The NuPED study was approved by the Health Research Ethics Committee (HREC) of the North-West University (NWU), South Africa (NWU-00186-15-A1 and NWU-00049-16-A1) as well as the University of Witwatersrand, Johannesburg (M150968 and M161045). In brief, generally healthy pregnant women were recruited from primary healthcare clinics in Johannesburg between March 2016 and November 2017. The women were followed throughout pregnancy to birth and up to 12 months postpartum at Rahima Moosa Mother and Child Hospital (RMMCH) in Johannesburg, South Africa until June 2018. Data were collected at early pregnancy (18 weeks of gestation), mid-pregnancy (22 weeks), late pregnancy (36 weeks), and at 6 weeks, 6 months, and 12 months postpartum.
Women were eligible for inclusion if they were aged 18-39 years, 18 weeks of gestation with singleton pregnancies, proficient in local languages, born in South Africa or neighbouring countries, and if they have been residing in Johannesburg for at least 12 months. Women were excluded if they reported using illicit drugs, were smoking, or had been diagnosed with a non-communicable disease such as diabetes, renal disease, high cholesterol, and hypertension; an infectious disease such as tuberculosis and hepatitis; or a serious illness such as cancer, lupus or psychosis. Due to South Africa’s high prevalence of HIV infection (36%) [
South African National HIV Prevalence, Incidence and Behaviour Survey, 2012.
Technical Report. 2014
], women living with HIV were included in the study to be a better representation of the general South African population.
2.2 Outcome measurements
The primary outcome measure was perinatal depression at six time points: early pregnancy (18 weeks of gestation), mid-pregnancy (22 weeks), late pregnancy (36 weeks), and at 6 weeks, 6 months, and 12 months postpartum. Depression was assessed using the interviewer-administered Edinburgh Postnatal Depression Scale (EPDS). The EPDS is a 10-item scale assessing depressive symptoms experienced in the past 7 days [
]. To classify women as being at risk of depression, we used an EPDS cut-off score of 9 (out of a maximum score of 30), which was shown to have a high sensitivity for detecting perinatal depression in African contexts [
The primary exposure measure was maternal n-3 PUFA status assessed at 18 weeks of gestation by analysing the FA composition of RBC total phospholipids and expressed as single FA (ALA, DHA and EPA), the n-6/n-3 PUFA ratio, and the n-3 index. Further exposure variables were RBC FA patterns derived by conducting principal component analysis (PCA).
Maternal venous blood for the analysis of RBC FA composition was drawn into EDTA-coated evacuated tubes (Vacuette®, Greiner Bio-One) and was processed within 1 h. During processing, RBC were separated from plasma by centrifugation at 2000 g for 10 min and were washed twice with normal saline solution. Aliquots were stored on site at -20C for a maximum of 14 days until transportation for final storage at -80C until analysis.
RBC total phospholipids FA analysis was carried out at the North-West University Centre of Excellence for Nutrition using Gas Chromatography-Mass Spectrometry (GC-MS) as described previously [
Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa.
]. Lipid extracts were concentrated using nitrogen gas, and thin-layer chromatography (silica gel 60 plates without fluorescent indicator, 10 x 20 cm; Merck) was used to separate neutral lipids from the phospholipids. Phospholipids were eluted using petroleum ether: diethyl ether (peroxide free): acetic acid (90:30:1, vol:vol:vol) and a pinch of UV fluorescent indicator 2.5-Bis(5-tert-butyl-benzoxazol-2-yl) thiophene. The lipid fraction containing the phospholipids was visualized under long-wave UV light, removed from the thin-layer chromatography plate and trans-methylated with methanol: sulphuric acid (95:5, vol:vol) at 70C for 2 h. This led to the formation of fatty acid methyl esters (FAME). The FAME were extracted using hexane and water. The organic layer was aspirated, evaporated, redissolved in hexane, and analysed by gas chromatography-electron ionisation mass spectrometry. All solvents used during the extraction procedure contained 0.01% butylated hydroxytoluene. Samples were analysed on an Agilent Technologies 7000 GC/MS Triple quad system comprising an Agilent 7890A gas chromatograph equipped with an Agilent G7001B triple quad mass spectrometer (Agilent Technologies). The gas chromatography separation of FAME was carried out on an HP-88 capillary column (100m x 0.25 mm x 0.20 m; Agilent Technologies) by using helium as the carrier gas at a flow rate of 2.2 mL/min. Initial inlet temperature was held at 70C for 0.02 min, after which it was ramped to 270C at 500C/min. The mass spectrometer source was maintained at a temperature of 230C. A sample volume of 1 L was injected and a split ratio of 80:1 for RBC samples was used. The oven temperature was maintained at 50C for 1 min, then ramped to 170C at 30C/min, then from 170C to 215C at 2C/min, after which it was ramped to 230C at 4C/min. The temperature was then held isothermally at 230C for 7 min. The total analysis time was 38.25 min. Mass spectrometry with 70 eV electron-ionisation was carried out in multiple-reaction monitoring mode, with at least two transitions per compound. The FAME were quantified using MassHunter Quantitative Analysis software (Version B.05.02, Agilent Technologies). FAME peaks were identified and calibrated against a standard reference mixture of 33 FAME (Nu-Check-Prep) and two single FAME standards (Larodan Fine Chemicals AB). Relative percentages of FAs were calculated by expressing the concentration of a given FAME as a percentage of the total concentration of all FAME identified in the sample [
Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa.
All the covariates were assessed at the first visit (18 weeks gestation).
Maternal socio-economic and -demographic data were collected during a structured interview, and included date and country of birth, marital status, ethnicity, educational level, and living standards measure (LSM) scores. The LSM score was developed by the South African Audience Reference Foundation (SAARF) and is widely used in South Africa to describe the socio-economic status of the population [
Anthropometric measurements, such as height and weight, were obtained using standardised methods from the International Society for the Advancement of Kinanthropometry [
]. All measurements were conducted twice and recorded to the nearest 0.05 kg of weight and 0.1 cm for height.
Medical files were inspected to obtain data on maternal HIV status and sex of the baby. During analyses, women were considered HIV positive irrespective of date of HIV contraction (prior to or during pregnancy).
2.5 Statistical methods
Data were tested for outliers and normality by means of Q-Q plots, histograms and Shapiro-Wilk test. Outliers were inspected and checked for unrealistic values, typing errors, and quantitation errors. Normally distributed data and non-normally distributed data were expressed as mean (SD) and as medians (interquartile range (IQR)), respectively. We used multivariate linear regression analysis to assess associations of different FA status indicators with EPDS scores as continuous outcome variable, and logistic regression analysis to assess associations of FA status indicators with perinatal depression defined as EPDS score 9 (dichotomous variable). Thereby we applied two models: In the basic model 1, age of the mother and gestational age were included as covariates; in model 2, age of the mother, gestational age, BMI, HIV status, and the LSM score were included as covariates. All statistical tests were two tailed and type-I error rate was set at =0.05. Raw data were captured in Microsoft Access (Microsoft Corporation, Washington, USA) and 20% of all captured data were randomly checked for correctness. Data processing and statistical analysis of data were performed using R Version 3.6.0 [
]. R packages used for PCA were: ‘corpcor’, ‘GPA rotation’, ‘psych’.
A factor analysis based on PCA of the correlation matrix with orthogonal rotation (varimax) was conducted on the 29 phospholipid FA to explore maternal FA patterns. To correct for skewness, we applied a Blom transformation on the data [
]), and all KMO values for individual variables were 0.3. An initial analysis was run to obtain eigenvalues for each component in the data. Four components had eigenvalues over Kaiser’s criterion of 1 and in combination explained 46.9% of the variance. The scree plot was slightly ambiguous and showed inflexions that would justify retaining both four and five components. Given the convergence of the scree plot and Kaiser’s criterion on four components, four components were retained in the final analysis. Factor loadings describing the strength of individual FA contributing to each FA pattern are presented in Table 3. On the basis of high factor loadings (|0.40|) for the respective fatty acids (Table 3), we named these patterns: 1) ‘high saturated FA’ pattern; 2) ‘Low DHA and n-6 PUFA, and high trans FA’ pattern; 3) ‘high ALA, EPA, n-3 DPA and n-6 DGLA’; and 4) ‘high n-3 PUFA’ pattern. Each pregnant woman had an individual score on each of the four components, so called FA patterns. These individual scores were used in the logistic and linear regression models (as continuous variables).
3. Results
3.1 Participant characteristics
A flow-chart of the pregnant women included and followed-up in the NuPED study and the availability of data for analysis in this study is shown in Fig. 1. A total of 250 women were enrolled into the NuPED study, but FA data were available for 242 women only and therefore included in the analysis. Of these, EPDS data were available from 238, 224, 191, 50, 84, and 89 women at enrolment, mid-pregnancy (22 weeks), late pregnancy (36 weeks), and at 6 weeks, 6 months, and 12 months postpartum, respectively.
Fig. 1Flow-chart of pregnant women included in the NuPED study and in the prospective analysis of this study (boxes in bold). EPDS: Edinburgh Postnatal Depression Scale; IUFD: Intrauterine foetal death; RMMCH: Rahima Moosa Mother and Child Hospital.
Baseline characteristics of study participants are presented in Table 1. We found a median age of 28 years and a median (IQR) BMI of 26.5 (12.1, 16.1) kg/m. Most study participants lived in medium living standards according to the LSM. Finally, around one quarter of study participants were HIV positive.
Table 1Characteristics of the pregnant women at enrolment (18 weeks of gestation).
Maternal characteristics
n
Age (years)
242
28.0 (24.0, 32.0)
Gestational age (weeks)
242
14.3 (12.1, 16.1)
BMI (km/m)
241
26.5 (23.2, 30.7)
Underweight (18.5 km/m)
8 (3)
Normal weight (18.5-24.9 km/m)
82 (34)
Overweight (25-29.9 km/m)
81 (34)
Obese (30 km/m)
70 (29)
Ethnicity
241
Black African
211 (87)
Mixed ancestry
28 (12)
Indian
1 (0.4)
White
1 (0.4)
Country of birth
233
South Africa
169 (70)
Zimbabwe
57 (24)
Lesotho
4 (2)
Swaziland
3 (1)
Living Standards Measure (LSM)
242
7.0 (6.0, 8.0)
Low (LSM 1-4)
17 (7)
Medium (LSM 5-7)
141 (58)
High (LSM 8-10)
84 (35)
Maritial Status
241
Unmarried / single
96 (40)
Married
67 (30)
Living together
55 (23)
Traditional marriage
21 (9)
Divorced/Separated
2 (1)
Highest level of education
241
Primary school or less
7 (3)
Grade 8-10
37 (15)
Grade 11-12
140 (58)
Tertiary post school education
57 (24)
Parity
242
Nulliparous
69 (29)
Primiparous
86 (36)
Biparous
67 (28)
Multiparous
20 (8)
HIV status
242
Negative
179 (74)
Positive
63 (26)
EPDS score
238
5(2, 8)
EPDS score 9
179 (74)
EPDS score 9
59 (24)
Inflammatory status
242
No inflammation (CRP 5mg/L; AGP 1g/L)
92 (38)
Inflammation (CRP 5mg/L and/or AGP 1g/L)
150 (62)
Values are displayed as median (interquartile range) for continuous variables and n (%) for categorical variables. AGP: alpha-1 glycoprotein; BMI: body mass index; CRP: C-reactive protein; EPDS: Edinburgh Postnatal Depression Scale
Fig. 2 shows the prevalence of having an EPDS score indicative for perinatal depression (cut-off 9) in the women at the pre- and postnatal follow-ups. The prevalence rates ranged from 17% to 26%, with the highest prevalence at 6 months postpartum (26%) and the lowest prevalence at 36 weeks of gestation (17%). The median (IQR) EPDS scores were 5 (2, 8) at 18 weeks gestation, 3 (1, 6) at 22 weeks gestation, 3 (0, 6) at 36 weeks gestation, 4.5 (0.25, 7.75) at 6 weeks postpartum, 5 (2, 9) at 6 months postpartum, and 4 (1, 8) at 12 months postpartum. We did not find a significant difference in the medians between the pre- and post-delivery visits. Only 4% (n = 9) of the women who showed symptoms of depression (cut-off 9) at 18 weeks gestation were also depressed at 12 months postpartum. When considering all antenatal timepoints, 5% (n = 12) of women experienced depression both antenatally and at 12 months postpartum. As for postpartum depression, 3% (n = 8) of women experiencing depression at 6 months postpartum also experienced depression at 12 months postpartum.
Fig. 2Prevalence of women with EPDS score indicative for perinatal depression along the study course. 18 weeks of gestation; 22 weeks; 36 weeks; 6 weeks postpartum; 6 months postpartum; 12 months postpartum.
3.3 Maternal red blood cell fatty acid composition and patterns
Table 2 shows the RBC phospholipid FA composition of the pregnant women at 18 weeks of gestation. Mean RBC phospholipid EPA and DHA was 0.29 0.15% and 5.28 1.15%, respectively. The mean n-3 index (sum of EPA + DHA) was 5.92 1.39%, and 55% and 5% of women had an n-3 index indicative of a low (6%) and very low (4%) n-3 PUFA status, respectively. The mean n-6/n-3 PUFA ratio was 4.53 0.94.
Table 2Red blood cell total phospholipid fatty acid composition of 242 pregnant women at study enrolment (18 weeks gestation).
With the four retained components from PCA, we identified four major RBC FA patterns shown in Table 3: high saturated FA (Pattern 1); low DHA and n-6 PUFA, and high trans FA (Pattern 2); high ALA, EPA, n-3 DPA and n-6 GLA (Pattern 3); and high n-3 PUFA (Pattern 4).
Table 3Summary of Principal Component Analysis (PCA) factor loadings for four maternal fatty acid patterns after conduction of a PCA on 29 red blood cell phospholipid fatty acids with orthogonal rotation (varimax).
Factor loadings |0.40| appear in bold. KMO = 0.62 and Bartlett’s test of sphericity (406) = 3’653, p 0.001, indicate sufficiently large correlations for PCA.
a Pattern 1: High saturated FA
b Pattern 2: Low DHA and n-6 PUFA, and high trans FA
3.4 Associations of indices of n-3 PUFA status and FA patterns with perinatal depression
Table 4 shows a summary of results from the conducted multivariate linear regression models on the associations of different FA status indicators at 18 weeks gestation with EPDS scores at 12 months postpartum. In the fully adjusted model 2, RBC EPA at 18 weeks gestation was negatively associated with EPDS scores at 12 months postpartum (=-0.22; ). Furthermore, RBC FA pattern 4 (high n-3 PUFA) at 18 weeks gestation was negatively associated with EPDS scores at 12 months postpartum (=-0.23; ). We found a positive association of the AA/EPA ratio at 18 weeks gestation with EPDS scores at 12 months postpartum (=0.24; ).
Table 4Multivariate linear regression models assessing associations of different fatty acid status indicators at 18 weeks gestation with Edinburgh Postnatal Depression Scale scores at 12 month postpartum.
Table 5 displays a summary of results from the conducted logistic regression models on the associations of different FA status indicators at 18 weeks gestation with depression (EPDS score 9) at 12 months postpartum. In the fully adjusted model 2, higher RBC DHA and n-3 index levels at 18 weeks’ gestation were associated with lower odds for depression at 12 months postpartum (OR=0.56 [95% CI: 0.32-0.91]; ). Likewise, we found that women with higher scores for the RBC FA pattern 3 (high ALA, EPA, n-3 DPA and n-6 GLA) at 18 weeks gestation had lower odds for depression (EPDS 9) at 12 months postpartum (OR=0.47 [95% CI: 0.22-0.92]; ). On the contrary, higher n-6/n-3 PUFA and AA/EPA ratios at 18 weeks’ gestation were associated with higher odds for depression at 12 months postpartum (OR=2.34 [95% CI: 1.12-4.97]; ; and OR=1.02 [95% CI: 1.00-1.05]; , respectively).
Table 5Multivariate logistic regression models assessing associations of different fatty acid status indicators at 18 weeks gestation with Edinburgh Postnatal Depression Scale scores with cut-off 9 at12 month postpartum.
None of the indices of n-3 PUFA status and FA patterns at early pregnancy were associated with depression at the prenatal visits or at 5 weeks and 6 months postpartum (results not shown).
4. Discussion
This prospective cohort study conducted in Johannesburg, South Africa, followed 242 pregnant women throughout pregnancy up to 12 months postpartum. We found various associations of different FA status indicators early in pregnancy (18 weeks of gestation) with perinatal depression at 12 months postpartum. In the multivariate linear regression models, RBC EPA levels were negatively, and the RBC AA/EPA ratio positively associated with EPDS scores at 12 months postpartum. In the multivariate logistic regression models, higher RBC DHA and n-3 index were associated with lower odds for depression, while higher n-6/n-3 PUFA and AA/EPA ratios early in pregnancy were associated with higher odds for depression at 12 months postpartum. We further identified four major RBC FA patterns by conducting a PCA: high saturated FA (Pattern 1); low DHA and n-6 PUFA, and high trans FA (Pattern 2); high ALA, EPA, n-3 DPA and n-6 GLA (Pattern 3); and high n-3 PUFA (Pattern 4). Consistently with the associations observed for the single RBC n-3 PUFA and ratios, higher scores for pattern 4 and pattern 3 were associated with lower EPDS scores and lower odds for depression, respectively. However, we found no significant associations between the various FA status indicators and depression at any of the prenatal or other postnatal time points.
In our cohort of generally healthy pregnant women, we observed relatively high and constant prevalence rates of depression of around 22% during the pre- and postnatal period (ranging from 17 to 26%). These rates are comparable to the estimated prevalence of perinatal depression in LMIC from recent reviews [
]. The high prevalence of depression in women from LMIC has been attributed to low socio-economic status, lack of social support, low maternal educational attainment, and sexual abuse [
]. However, to our knowledge, this is the first study to investigate whether there is a link between maternal n-3 PUFA status and perinatal depression in a LMIC.
In this study, we observed that women with a higher n-3 PUFA status during early pregnancy have a lower risk for postnatal depression at 12 months postpartum. This is in agreement with a recent prospective cohort study in 72 Belgian women, which reported a low n-3 PUFA status and high n-6/n-3 PUFA ratio during early pregnancy to be associated with an increased risk for postnatal depression at 12 months postpartum [
]. A recent longitudinal case-control study including 54 Swiss pregnant women with diagnosed anxiety disorder, major depressive disorder, or a mixed anxiety-depression disorder, and 40 healthy controls found lower n-3 PUFA levels and higher n-6/n-3 PUFA ratios to be associated with prenatal and postnatal depression [
]. In the current study, the associations between the n-3 PUFA indices and depression at 12 months postpartum remained significant when adjusting for prenatal depression (data not shown). A prospective cohort study (=2’663) in the South West of England showed no robust association of EPA or DHA with postnatal depression at 8 weeks postpartum [
]. In contrast, in a community-based prospective cohort study in Norway (=43), a low n-3 index in late pregnancy was associated with higher depression scores at 3 months postpartum [
]. Overall, the time point of assessing postpartum depression in these studies differed, ranging from 1 week up to 3 months. Few studies have assessed depression up to 12 months postpartum. Still, symptoms of postnatal depression can occur at any time within the first 21 months postpartum [
]. We only found associations of FA status with depression at 12 months postpartum but no other time points. Furthermore, only 3% of women experiencing depression at 6 months postpartum also experienced depression at 12 months postpartum. This finding may indicate a different aetiology of depression at 12 months than at 6 months postpartum.
There are various mechanisms that may explain the protective role of n-3 PUFA in the aetiology of depression. The most widely researched one is related to EPA and DHA being pre-cursors for the synthesis of anti-inflammatory and inflammation-resolving lipid mediators, while molecules derived from n-6 PUFA mainly exhibit pro-inflammatory properties [
]. Evidence from animal models demonstrates that an imbalance in the n-6/n-3 PUFA ratio in phospholipid membranes in favour of n-6 PUFA can lead to an exaggerated immune response to an inflammatory stimulus, such as stress, and compromise the resolution of inflammation [
]. Thus, higher n-6/n-3 PUFA and AA/EPA ratios in RBC membranes have been associated with higher levels of inflammation, as well as postpartum depression [
]. The prevalence of inflammation in our study was high, with 60% of women having elevated C-reactive protein (CRP) or alpha-1 glycoprotein (AGP) concentrations at 18 weeks of gestation (CRP 5 mg/L or AGP 1 g/L). This high prevalence may be related to the high prevalence of overweight and obesity, and infectious disease, such as HIV, in the study population. Thus, our results support the hypothesis of n-3 PUFA and the balance of n-3 to n-6 PUFA playing a role in the aetiology of depression via their immune-modulatory properties [
In this study, we used various indicators to reflect the n-3 PUFA status of pregnant women. There are limited data on blood levels of PUFA in African women. However, the mean n-3 index in pregnant women participating in the NuPED study is comparable to previously reported n-3 index levels in 101 male and female South African fisher people, where the n-3 index in erythrocyte equivalents was found to be between 4-6% [
]. In contrast to the n-3 index target range for cardiometabolic health of 8-11%, there is no established n-3 index target range for pregnant and lactating women. However, increasing evidence suggests that achieving an n-3 index 8% during pregnancy might reduce the risk of premature birth and is therefore desirable also during pregnancy [
In addition to the single n-3 PUFA, the n-3 index and the PUFA ratios, we identified four major RBC FA patterns by conducting a PCA. PCA is used to reduce the data set to a more manageable size while retaining as much of the original information as possible [
]. In this study, we used this technique to identify groups of women with similar RBC FA compositions, so called patterns. These patterns, in comparison to single FA status indicators, do consider the interdependencies of FA and therefore can give insight into FA metabolism. The patterns derived in our sample of pregnant women are similar to the FA patterns detected in a sample of Dutch pregnant women from the Generation R Study at early pregnancy [
], specifically the high saturated FA (Pattern 1) and high n-3 PUFA (Pattern 4) pattern. However, the Dutch study did not determine associations between these patterns and perinatal depression, instead they suggest that FA patterns during pregnancy may affect the offspring’s body composition and cardiometabolic health [
]. To our knowledge, this is the first study to show that women with higher scores for a RBC FA pattern characterised by high levels of n-3 PUFA at early pregnancy have a lower risk for developing depression at 12 months postpartum.
A major limitation of this study is the high loss to follow-up during the postnatal period resulting in a relatively small sample size and a potential bias. Participants experiencing a depressive episode might be more prone to drop out of extra-daily activities compared to non-depressed participants. However, the main reason for the high loss to follow-up is that many women in this urban setting moved back to their home towns after giving birth to get support by family members. Furthermore, we did not observe a significant decrease in the prevalence of depression during the course of the study. Therefore, the prevalence of depression observed at the postnatal visits may still be representative of the prevalence in the study population. Strengths of the current study include the prospective design and the long follow-up period until 12 months postpartum, as well as the analysis of n-3 PUFA status by measuring RBC total phospholipid FA composition and expressing it using various indices. Unfortunately, we did not measure RBC total phospholipid FA composition at 6 and 12 months postpartum. However, we assume that the n-3 PUFA status determined during early pregnancy is most representative for habitual dietary intake and is therefore strongly correlated with the n-3 PUFA status during the postpartum period. Major changes in dietary intake during pregnancy and lactation are not expected in this setting due to poor dietary counselling, limited financial means and neglectable seasonal impact on food intake in this urban setting [
To conclude, our results indicate that a higher RBC n-3 PUFA status during early pregnancy may lower the risk for perinatal depression at 12 months postpartum. This finding agrees with a previous study in Belgian women showing that a low n-3 PUFA status, alone and combined with a high n-6 status, during early pregnancy is associated with an increased risk for postnatal depression at 12 months postpartum [
]. However, evidence on the protective associations of n-3 PUFA status on perinatal depression is inconsistent and the time point of assessing postnatal depression varied from 1 week, a few months up to 12 months postpartum. Therefore, our results suggest a new perspective on postpartum depression, indicating that depression occurring at 12 months postpartum might be particularly sensitive to PUFA status in early pregnancy, which is likely to reflect habitual intake. Potential future studies should explore biochemical mechanisms underlying these associations.
Funding
The NuPED study was supported in part by the National Research Foundation of South Africa, Unique Grant 99374 (EAS) (https://www.nrf.ac.za/) and the South African Medical Research Council under a Self-Initiated Research Grant (CMS) (http://www.mrc.ac.za/). The NuPED work has further received financial support from the University of South Africa’s Research Department through the Academic Qualification Improvement Programme (EAS) (www.unisa.ac.za). EO received a PhD fellowship from the Ebnet Foundation, Teufen, Switzerland.
CRediT authorship contribution statement
Ester Osuna: Conceptualization, Methodology, Funding acquisition, Writing – original draft, Writing – review & editing. Elizabeth A Symington: Data curation, Methodology, Formal analysis, Funding acquisition, Writing – review & editing. Linda Malan: Data curation, Methodology, Writing – review & editing. Cristian Ricci: Conceptualization, Formal analysis, Writing – review & editing. Lizelle Zandberg: Data curation, Methodology, Writing – review & editing. Cornelius M Smuts: Data curation, Methodology, Funding acquisition, Writing – review & editing. Jeannine Baumgartner: Conceptualization, Data curation, Methodology, Supervision, Formal analysis, Writing – original draft, Writing – review & editing.
Declaration of Competing Interest
All authors declare that they have no conflict of interest.
Acknowledgements
We thank the following people for their contribution to the NuPED study: Prof A Coovadia, Dr A Wise, Prof H Lombaard, Dr E Loock, Dr R Adams, Dr R Strehlau, Prof M Faber, Dr O Sotunde, Dr M Rothman, Dr L Siziba, Mrs C Cooke, the sonographers and nurses of Rahima Moosa Mother and Child Hospital, the nurses at the primary healthcare clinics, the fieldworkers and the study participants.
Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa.
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