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American Journal of Clinical Nutrition, Vol. 87, No. 4, 887-895, April 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Maternal n–3, n–6, and trans fatty acid profile early in pregnancy and term birth weight: a prospective cohort study1,2,3

Manon van Eijsden1, Gerard Hornstra1, Marcel F van der Wal1, Tanja GM Vrijkotte1 and Gouke J Bonsel1

1 From the Department of Epidemiology, Documentation, and Health Promotion, Municipal Health Service, Amsterdam, The Netherlands (ME and MFW); the Department of Social Medicine, Public Health Epidemiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands (ME, TGMV, and GJB); the Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands (GH); and the Institute Health Policy and Management, Erasmus Medical Centre, Rotterdam, The Netherlands (GJB)

2 Supported by grants from the Netherlands Organisation for Health Research and Development (ZonMw) in The Hague, the Municipal Health Service and Municipal Council of Amsterdam, the Academic Medical Centre, and Nutricia Research BV in Zoetermeer for the Amsterdam Born Children and their Development cohort study.

3 Reprints not available. Address correspondence to M van Eijsden, Municipal Health Service (GGD)/Cluster EDG, PO Box 2200, 1000 CE Amsterdam, The Netherlands. E-mail: mveijsden{at}ggd.amsterdam.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Maternal n–3, n–6, and trans fatty acids are claimed to affect fetal growth, yet evidence is limited.

Objective: We investigated the association between maternal n–3, n–6, and trans fatty acids measured early in pregnancy and fetal growth.

Design: Amsterdam pregnant women (n = 12 373) were invited to complete a questionnaire (response 67%) and donate blood around the 12th pregnancy week for nutrient analysis. For 4336 women, fatty acid concentrations were measured in plasma phospholipids (gas-liquid chromatography). Associations of these concentrations with birth weight and small-for-gestational-age (SGA) risk were analyzed (liveborn singleton term deliveries, n = 3704).

Results: Low concentrations of individual n–3 fatty acids and 20:3n–6, the precursor of arachidonic acid (20:4n–6), but high concentrations of the other n–6 fatty acids and the main dietary trans fatty acid (18:1n–9t) were associated with lower birth weight (estimated difference in univariate analysis –52 to –172 g for extreme quintile compared with middle quintile). In general, SGA risk increased accordingly. After adjustment for physiologic, lifestyle-related and sociodemographic factors, low concentrations of most n–3 fatty acids and 20:3n–6 and high concentrations of 20:4n–6 remained associated with lower birth weight (–52 to –57 g), higher SGA risk, or both (odds ratios: 1.38–1.50). Infants of the 7% of women with the most adverse fatty acid profile were on average 125 g lighter and twice as likely to be small for gestational age.

Conclusion: An adverse maternal fatty acid profile early in pregnancy is associated with reduced fetal growth, which, if confirmed, gives perspective for the dietary prevention of lower birth weight.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The pregnancy outcomes low birth weight (<2500 g) and small for gestational age (SGA; <10th percentile of reference population) that are due to intrauterine growth restriction are important determinants of children's future health and development. At the short term, infants born with low birth weight or SGA are at increased risk of infant mortality and morbidity (1), whereas at the long term, they have higher risks of metabolic and cardiovascular diseases (2, 3).

Although adequate maternal nutrition has since long been accepted as vital to fetal growth, it is still largely unclear to what extent which (combinations of) nutrients matter (4, 5). Consequently, no evidence-based nutritional preventive strategies exist at this stage. Among the nutrients with potential clinical relevance, the essential fatty acids {alpha}-linolenic acid (18:3n–3) and linoleic acid (18:2n–6), and more particular their longer-chain, more-unsaturated derivatives (commonly referred to as long-chain polyunsaturated fatty acids, LC-PUFAs) have increasingly gained interest. LC-PUFAs are key components of virtually all cellular membranes and, besides, exert a wide array of biological functions (6, 7). Although LC-PUFAs are considered essential for fetal growth, evidence of their growth-promoting effect is limited. Results of the few small-sized observational studies that directly measured n–3 and n–6 fatty acid concentrations, either maternal (8), neonatal (9), or both (10–12), are inconclusive. Evidence from existing randomized clinical trials is restricted to maternal n–3 LC-PUFA intake only; although positive associations are reported, these are commonly interpreted as the consequence of a prolonged gestation rather than a direct effect on fetal growth (13, 14).

In the present large cohort study, we explore the potential role of the maternal n–3 and n–6 fatty acid profile in fetal growth by investigating in detail the association between maternal concentrations of these fatty acids during early pregnancy and infant birth weight at term. We also explore the role of elaidic acid (18:1n–9t), the main industrial trans fatty acid in the diet, which can inhibit the conversion of {alpha}-linolenic acid and linoleic acid to their respective LC-PUFAs and was suggested to inhibit fetal growth (15). The simultaneous measurement of a predefined set of cofactors relevant to fetal growth enables us to investigate the independent association of these maternal diet-derived fatty acids with infant birth weight. If the early pregnancy fatty acid profile proves to be relevant, this may open new avenues for optimizing infant development and disease prevention by adaptation of the maternal fatty acid status.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population and design
This study is part of the Amsterdam Born Children and their Development (ABCD) study, a prospective community-based cohort study that examines the relation between maternal lifestyle and psychosocial conditions during pregnancy and the child's health at birth as well as in later life. Essentials of the study design were described previously (16). In short, between January 2003 and March 2004, all pregnant women living in Amsterdam were invited to enroll in the ABCD study at their first prenatal visit to the obstetric care provider (around the 12th week of gestation) and were requested to complete a questionnaire, covering sociodemographic data, obstetric history, lifestyle, dietary habits, and psychosocial factors. The questionnaire was available in Dutch and in English, Turkish, or Arabic for immigrant women. In addition, women were invited to participate in the ABCD biomarker study. For this, an additional blood sample was taken during routine blood collection for screening purposes after the first prenatal checkup.

Of the invited 12 373 pregnant women, 8266 returned the pregnancy questionnaire (response rate 67%). Of those respondents, 53% (n = 4389) participated in the biomarker study. Approval of the study was obtained from the Medical Ethical Committees of participating hospitals and the Registration Committee of Amsterdam. Written informed consent was obtained from all participants.

Measurements
Primary outcome variables for this study were birth weight (in g) and SGA (yes, no) at term, with SGA defined as a birth weight below the 10th percentile for gestational age on the basis of sex- and parity-specific standards from the Netherlands Perinatal Registry (data available from the authors on request). Date of birth, birth weight, infant sex, and gestational age [ultrasound-based or, if unavailable (<10%), based on time of last menstrual period], as recorded by the obstetric care providers, were obtained through the Youth Health Department at the Municipal Health Service in Amsterdam. Gestational age at blood sampling was calculated with the available information on gestational age at birth, date of birth, and date of blood sampling. Information on maternal physiologic, lifestyle, and sociodemographic characteristics was obtained from the questionnaire.

The sociodemographic covariables included cohabitant status (living together with partner, not living together, single), educational attainment after primary school (≤5, 6–10, ≥11 y), and ethnicity. Ethnicity was defined by country of birth and included the following categories, based on the Dutch main ethnic populations: the Netherlands, Surinam, Turkey, Morocco, other non-Western country, and other Western country.

Lifestyle factors included self-reported alcohol consumption (last week's consumption, recoded into yes, no), self-reported smoking (last week's behavior, recoded into yes, no), pregravid body mass index (in kg/m2) based on self-reported height and weight, and psychosocial stress (presence of 0, 1, or ≥2 stressors). A random imputation procedure with the use of linear regression analysis was used to complete missing data on height (3.8% missing) or weight (9.9% missing) (17). Psychosocial stressors were measured by validated Dutch versions of internationally accepted questionnaires and included depression (18), general anxiety (19), pregnancy-related anxiety (20), parenting stress (21), and work stress (22). For all scales, thresholds for nonnormal scores were, in the absence of internationally agreed cutoff points for pregnant women, chosen at the 90th percentile. Self-reported maternal physiologic characteristics were parity (0, ≥1), age (≤24, 25–34, and ≥ 35 y), and height.

Biochemical analyses
For each participant of the biomarker study, one blood sample was taken in a 10-mL EDTA(K2) evacuated tube (Vacutainer; Becton Dickinson BV, Alphen aan de Rijn, The Netherlands) and sent to the Regional Laboratory of Amsterdam for processing. Transport was by courier or by overnight mail in special envelopes, enabling processing within 28 h of sampling. A previous study of our group showed that this delay did not compromise the validity of measured biomarkers (23). At the laboratory, plasma was prepared by centrifugation (1600 x g for 10 min at room temperature) and stored as 1-mL aliquots at –80 °C until analysis.

Fatty acid analysis was performed at the Analytic Biochemical Laboratory (ABL, Assen, the Netherlands), as previously described (24, 25). In short, after the addition of an internal standard (1,2-dinonadecanoyl-sn-glycero-3-phosphocholine) and 10-heptadecenoic acid (17:1) to check for carryover of free fatty acids during the isolation procedure, plasma lipid extracts were prepared by a modified Folch extraction method (26) after which phospholipids were isolated by solid-phase extraction on aminopropyl-silica columns (500 mg/3 mL; Varian, Palo Alto, CA) (27). Phospholipids were then hydrolyzed, and the resulting fatty acids were methylated with boron trifluoride-methanol (28). Finally, the fatty acid methyl esters were separated and quantified by capillary gas chromatography with flame ionization detection (HP5890 series II; Hewlett-Packard, Palo Alto, CA) with the use of a polar and a nonpolar column (BPx70 and BP1, respectively; SGE Analytical Science Pty. Ltd, Ringwood, Victoria, Australia). The oven temperature was programmed to begin at 160 °C for 4 min and then to increase to 200 °C by 6.0 °C/min. After 3 min, the temperature was further increased to 260 °C at a rate of 7 °C/min and kept constant for 2.34 min. The injector temperature was kept at 250 °C and the detector temperature at 300 °C.

Absolute amounts of fatty acids (in mg/L plasma) were quantified on the basis of recovery from the internal standard and calculated in relative values (percentage of total fatty acids). For the present study, the following fatty acids were relevant and will be presented: the trans fatty acid elaidic acid (18:1n–9t), the essential fatty acids {alpha}-linolenic acid (18:3n–3) and linoleic acid (18:2n–6), and their respective LC-PUFAs eicosatetraenoic acid (20:4n–3), eicosapentaenoic acid (EPA; 20:5n–3), docosapentaenoic acid (DPA; 22:5n–3), docosahexaenoic acid (DHA; 22:6n–3), dihomo-{gamma}-linolenic acid (DGLA; 20:3n–6), arachidonic acid (AA; 20:4n–6), adrenic acid (22:4n–6), and Osbond acid (22:5n–6). Interassay CVs for these fatty acids varied from ≤22% (for 20:4n–3, the fatty acid with the lowest concentration) to ≤2% (for 18:2n–6, the fatty acid with the highest concentration). The essential fatty acid derivatives{gamma}-linolenic acid (18:3n–6) and stearidonic acid (18:4n–3) were not included, because their concentrations were <0.1% of total fatty acids. Other measured, nonessential fatty acids were not considered because they were outside the scope of our study.

Statistical analysis
Fatty acid results were available for 4336 of the 4389 participants. From this group, 4112 women gave birth to a liveborn singleton infant for whom information on birth weight and gestational age was available. We excluded all respondents with known diabetes (n = 21) or hypertension (n = 127) at the time of blood sampling, respondents who delivered preterm (n = 213), and respondents with missing values on ≥1 of the above-mentioned covariables (n = 55). The final sample available for analysis was 3704.

After a descriptive analysis of fatty acid concentrations, outcome variables, and maternal and infant characteristics, the univariate (ie, unadjusted) associations between individual maternal fatty acid concentrations and infant birth weight were explored by linear regression analyses. For each fatty acid, 2 separate models were explored: 1) a continuous model, which included the SD score as continuous measure of fatty acid concentrations, and 2) a categorical model, which included quintiles as categorical measure of fatty acid concentrations. The categorical model was chosen to explore the potential nonlinearity of the association; with the use of the middle quintile as reference, this analysis allowed us to examine whether associations were apparent over the full exposure distribution or at the extremes only, as observed before for the n–3 LC-PUFAs (29). Subsequently, multivariate analyses with the use of a stepwise hierarchical approach were performed to assess the adjusted contributions of the individual fatty acids. In the first step (model 1) we included maternal physiologic characteristics (see "Measurements"), infant sex, gestational age at birth, and gestational age at blood sampling. The latter covariate was included to standardize for changes in fatty acid concentration that normally occur during pregnancy (24). In the second step (model 2) we subsequently added all lifestyle and sociodemographic factors. Finally, to assess the association between the overall maternal fatty acid profile and birth weight, thereby taking into account their metabolic interrelations (6, 30), we calculated a cumulative exposure score. For each fatty acid a dichotomous (0, 1) classification of exposure was determined on the basis of its univariate association with birth weight. For each fatty acid positively associated with birth weight (ie, for 6 fatty acids, see "Results") the lowest quintile was scored as 1 (exposure); for each fatty acid negatively associated with birth weight (5 fatty acids), the highest quintile was scored as 1. After summation of the scores for each of the 11 fatty acids (the so-called cumulative exposure score), multivariate linear regression analysis was performed to explore the association between this cumulative exposure score and birth weight. To allow for sufficiently sized groups for comparison, scores were combined into 4 categories: 0–1, 2–3, 4–5, and ≥ 6, with the latter category defined as the most adverse profile.

All regression analyses were repeated with the use of logistic regression to explore the associations between maternal fatty acid status and SGA. Associations were considered significant at P < 0.05. All analyses were conducted with SPSS version 14.0 (SPSS Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the included mother-infant pairs (n = 3704) are presented in Table 1Go; maternal fatty acid concentrations with quintile distributions are shown in Table 2Go. Blood samples were taken at a mean (±SD) gestational duration of 13.5 ± 3.3 wk. Compared with the infants born to mothers who did not provide a blood sample (n = 3564; data not shown), the infants included in the present study were more often of the female sex, less often born SGA, and had higher birth weights. The included mothers were older, taller, and higher educated; had a lower body mass index; experienced less stress; and were more likely to consume alcohol. They were also more often nulliparous and of Dutch origin and were less often living alone.


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  		TABLE 1 Infant and maternal characteristics in the study population (n = 3704)

 

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  		TABLE 2 Concentrations of selected fatty acids by quintile (Q) in maternal plasma phospholipids at early pregnancy (n = 3704)1

 
Univariate regression results showed that birth weight was positively related to all n–3 fatty acids as well as the n–6 LC-PUFA DGLA (20:3n–6) but negatively related to all other n–6 fatty acids and elaidic acid (18:1n–9t) (Table 3Go). The categorical model showed these associations to be present at the extremes of the exposure scale only. Compared with infants born to women with intermediate concentrations, infants born to women in the lowest quintile of {alpha}-linolenic acid (18:3n–3), eicosatetraenoic acid (20:4n–3), EPA (20:5n–3), DPA (22:5n–3), DHA (22:6n–3), or DGLA (20:3n–6) had birth weights 56–172 g lower; infants of women in the highest quintile of linoleic acid (18:2n–6), AA (20:4n–6), adrenic acid (22:4n–6), Osbond acid (22:5n–6), or elaidic acid (18:1n–9t) had birth weights 52–90 g lower.


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  		TABLE 3 Association between maternal fatty acid concentrations in plasma phospholipids [SD scores and quintiles (Q)] and birth weight1

 
Given the nonlinearity of the univariate results, multivariate analyses were restricted to the categorical model. Overall, adjustment did not change directions of the associations. Adjustment for physiologic factors (model 1) however largely attenuated the estimates, whereas additional adjustment for lifestyle and sociodemographic factors (model 2) showed less effect. After full adjustment, the n–3 LC-PUFA EPA and the n–6 LC-PUFAs DGLA and AA were still significantly associated with birth weight (estimated difference compared with reference: –55 and –57 g for lowest quintiles of EPA and DGLA, respectively, and –52 g for the highest quintile of AA).

Results for SGA were largely similar. The univariate categorical models showed increased risks of SGA at lower concentrations of most n–3 fatty acids (exception: {alpha}-linolenic acid and DHA) and the n–6 fatty acid DGLA and at higher concentrations of most other n–6 fatty acids (exception: Osbond acid) (Table 4Go). Again, adjustment did not change directions of the associations but attenuated the univariate estimates. After full adjustment (model 2), significantly increased risks of delivering an infant that was SGA were still observed for women with the lowest concentrations of n–3 eicosatetraenoic acid [odds ratio (OR): 1.50; 95% CI: 1.07, 2.11] and DPA (OR: 1.49; 95% CI: 1.06, 2.10). For DGLA, the largest increase in risk was observed for women in the 2 lowest quintiles; however, the increase was only significant for women in the second quintile (OR: 1.38; 95% CI: 1.00, 1.91).


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  		TABLE 4 Association between maternal fatty acid concentrations in plasma phospholipids [SD scores and quintiles (Q)] and small-for-gestational-age (SGA) birth1

 
The multivariate exposure score analysis showed that the largest decreases in birth weight and increases in risk of SGA were observed for the {approx}20% women with scores ≥ 4. Infants born to these mothers were on average 72 g lighter and 1.5 times (95% CI: 1.14, 2.06 times) more likely to be SGA than were infants born to mothers with the lowest score. Infants born to the 7% mothers with the most adverse fatty acid profile (score ≥ 6) were 125 g lighter and twice as likely to be SGA (95% CI: 1.44, 3.13) (Table 5Go).


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  		TABLE 5 Multivariate association between maternal fatty acid profile as represented by the cumulative exposure score and birth weight and small-for-gestational-age (SGA) birth, respectively1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this large, community-based cohort study suggest that the maternal n–3 and n–6 fatty acid status early in pregnancy affects fetal growth. After adjustment for relevant covariables, both low maternal plasma concentrations of n–3 eicosatetraenoic acid, EPA, and DPA, and of the n–6 LC-PUFA DGLA, and high concentrations of the n–6 LC-PUFA AA were associated with reduced fetal growth, with an estimated 50–60-g decrease in birth weight and 40–50% increase in risk of SGA. The observed negative association between the maternal elaidic acid concentration, the major dietary trans fatty acid, and fetal growth disappeared after adjustment. To overcome potential interpretation problems resulting from metabolic interrelations between n–3, n–6, and trans fatty acids (6, 30), we developed a measure to define an adverse fatty acid profile. Results showed, for infants of the 7% mothers with the most adverse profile, a growth difference comparable to the estimated effect of smoking (31), with a 125-g lower birth weight and 100% higher risk of SGA. A lower threshold of adversity, defining just >20% of the women to have an adverse profile, still corresponded with a 72-g decrease in birth weight and a 50% increase in risk of SGA. Even if we recognize the independent importance of other physiologic factors, these results, if confirmed, offer perspectives for the dietary prevention of lower birth weight.

Few studies have addressed the association between maternal fatty acid status as measured in blood samples (serum, plasma, or erythrocytes) and birth weight (8, 10–12). In none of the studies significant associations were however reported, possibly by lack of power (n for maternal samples ≤ 582). The remaining observational evidence on the role of trans, n–6, and n–3 fatty acids in fetal growth rests on studies addressing either maternal intake (29, 32–36) or neonatal status (9–12, 37). Two previous cross-sectional studies investigated the growth-restrictive potential of trans fatty acids in term infants (12, 37), with inconsistent results. Our results do not suggest an important influence of trans fatty acids on fetal growth, but, because trans concentrations in our population were relatively low (15), we cannot exclude a negative association at higher intakes. The single available cross-sectional study investigating n–6 status of term infants in detail (11) agrees with our findings for AA and DGLA. The apparent opposite effect of DGLA to AA is difficult to comprehend, but it may involve maternal insulin activity. DGLA as well as its n–3 counterpart eicosatetraenoic acid are elongation products of {gamma}-linolenic acid and stearidonic acid, respectively, which are formed in the human body by enzymatic conversion of the parent essential fatty acids linoleic acid (for {gamma}-linolenic acid) and {alpha}-linolenic acid (for stearidonic acid). The enzyme involved, {delta}-6 desaturase, is stimulated by insulin (38), a hormone also known to influence fetal growth (39). Alternatively, the AA-DGLA contrast may result from competitive inhibition between AA and DGLA, as suggested for the antiinflammatory effect of DGLA (40). Indeed, our effect estimates for DGLA resemble those of the n–3 LC-PUFA EPA, a well-established AA competitor. In comparison with the larger n–3 intake studies, our n–3 LC-PUFA results are in keeping with those of Olsen and Secher (29) and Rogers et al (36), who reported an {approx}80-g reduction in birth weight after adjustment for gestational age and an (unadjusted) 40–70% increase in intrauterine growth restriction at low n–3 intake.

At this stage, it is difficult to relate our findings to existing randomized clinical trials, even if results appear convergent. So far, no trial in a similar low-to-moderate risk population has commenced supplementation before the 15th week of pregnancy, whereas our results particularly support the possibility of an early effect. In addition, supplements have been restricted to n–3 fatty acids alone, and, finally, success or failure may have been influenced by the background fatty acid status (41). Nevertheless, the established effect of n–3 LC-PUFA supplementation in late gestation on pregnancy duration (13, 14), in combination with our results, marks the relevance of fatty acid supplementation as a preventive option at all phases of pregnancy.

Some limitations and strengths of our study should be addressed. Despite the large sample size, our results apply to a relatively healthy sample of pregnant women; our estimates may therefore be too conservative. We were able to measure the maternal fatty acid status in early pregnancy but, given the low-intrusive design, not thereafter. However, our results are not likely to be influenced by changes in fatty acid status in late gestation. Longitudinal studies have suggested that the early pregnancy profile well predicts the fatty acid profile later in pregnancy (24, 42). Moreover, our theoretical point of departure was based on existing evidence that the trajectory of fetal growth and development is set at this early stage (43). A strength of our study is the nonlinear statistical approach, which clearly showed the insufficiency of standard correlational analysis to describe associations. As can be expected from other biological relations (44), a linear relation between determinant and outcome is an exception rather than a rule in a normal population.

The implications of low birth weight for longer-term health and development of children is well established (1–3), and it has been suggested that, even within the normal range, reduced birth weight may influence a child's cognitive development (45). Our results, although observational and only indicative of causal relations, suggest that dietary adaptation of the maternal fatty acid profile may help prevent fetal growth restriction, thereby improving later health. Such adaptation may be obtained by supplying additional {gamma}-linolenic acid, EPA, or both, which has been shown to raise concentrations of DGLA and EPA, respectively, without increasing AA (46). Given the consequences of a lower birth weight for the child both at birth and at later age, a study investigating the feasibility and potential benefits of such intervention is worthwhile.


   ACKNOWLEDGMENTS
 
We thank all participating hospitals, obstetric clinics, and general practitioners for their assistance in the implementation of the ABCD study and thank all women who participated for their cooperation. We are indebted to the LinKID research team who provided national reference data on the birth weight distribution according to gestational age, sex, and parity.

The author's responsibilities were as follows—MFW and GJB: conceived and designed the ABCD study; GH: advised on the study design; ME and MFW: collected and processed the data; ME: conducted the statistical analysis, under the supervision of GJB; and GH, MFW, and TGMV: provided additional statistical advice. All authors contributed to the interpretation of the results and writing of the manuscript and have seen and approved the final version. None of the authors had a financial or personal conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 7, 2007. Accepted for publication November 8, 2007.




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A. R. Weseler, C. E. H. Dirix, M. J. Bruins, and G. Hornstra
Dietary Arachidonic Acid Dose-Dependently Increases the Arachidonic Acid Concentration in Human Milk
J. Nutr., November 1, 2008; 138(11): 2190 - 2197.
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