BACKGROUND

Omega-3/Omega-6

Fatty acids are aliphatic monocarboxylic acids derived from or contained in esterified form in a vegetable or animal fat, oil, or wax, and are divided into short-chain (SCFA), medium-chain (MCFA), long-chain (LCFA), or very long chain (VLCFA), depending on the number of carbon atoms present.¹ α-linoleic acid (ALA), cervonic or docosahexaenoic acid (DHA), and thymnodonic or eicosapentaenoic acid (EPA) are among the major fatty acids of the omega-3 group, which, together with arachidonic acid (AA) of the omega-6 group, are generally considered to be potent anti-inflammatory antioxidants and immunomodulators, which are especially important for brain development, cognitive performance, and the immune system^2-3 and if deficient during pregnancy or lactation can have adverse effects on the unborn child.^4-5 Specifically, several sources of information suggest that humans evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFAs) of ~ 1, whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids and have excessive amounts of omega-6 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFAs) and a very high omega-6/omega-3 ratio, as found in current Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, while increased levels of omega-3 PUFAs (a low omega-6/omega-3 ratio) cause suppressive effects.²

Fatty acids belonging to the omega-3 group (such as ALA and AA)⁶ and omega-9 group (such as OLA)⁷ should also be juxtaposed with the omega-3 group, again for their antioxidant and anti-inflammatory properties. Introductory sources can be both animal (animal oils and fats, fish oil, especially cod liver, herring and oily fish, salmon, and in lesser amounts in cod, trout, and human milk)⁸ and plant sources (corn seed oil, sunflower oil, nuts, transgenic Camelina sativa seed oil (CSOs),^9-10 blueberries,¹¹ and microalgae,¹² both in natural and synthetic forms. In particular, n-3 PUFAs of marine and plant origin have different effects on erythrocyte fatty acid composition and regulation of glycolipid metabolism.¹³ 

However, the exact dose to be administered has not been determined, although there are studies that emphasize both personalization of therapy (as is the case with individuals with obesity, who may be affected by different assimilation/absorption due to their clinical condition)¹⁴ and use at night, in that in the absence of dietary intake of EPA and DHA, circulating levels of these fatty acids decrease during the nighttime period and reach their lowest point in the morning, and therefore, overnight consumption of n-3 PUFAs, which counteracts this pattern, may have functional significance.¹⁵ One study went on to focus on the assumption that omega-3 (n-3) fatty acid (FA) supplements increase blood concentrations of EPA and DHA and that most supplements on the market are esterified to triglycerides (TG) or ethyl esters (EE), which limits their absorption and may cause gastrointestinal side effects. Specifically, the 24-hour plasma EPA values were ~2-fold and ~1-fold higher after esterification than the EE and TG forms of n-3 FA, respectively (P ≤ 0.0027). The effects of the EE and TG treatments did not differ. The 3 supplements had similar side effects of belching, dysgeusia, abdominal discomfort, nausea, and bloating. With this in mind, and intending to compare the 24-hour plasma concentrations of EPA, DHA, and EPA+DHA when provided esterified in monoglycerides (MAG), this study showed that the plasma concentration of n-3 FA in adults is higher after acute supplementation with n-3 FA esterified in MAG than in EE or TG, suggesting that with a lower dose of n-3 FA MAG, the plasma concentrations of n-3 FA achieved are similar to those achieved after higher doses of n-3 FA esterified in EE or TG.¹⁶

Omega-3/omega-6 and pregnancy 

In the literature, supplementation of these fatty acids is so often linked to increased weight gain (of the gestating mother) and a better fetal growth/duration of gestation ratio,^17-20 although there is no lack of contrary studies.²¹ Discordance there is, on the other hand, concerning the risk of preterm birth in case of their deficiency: some studies affirm the lack of correlation,^20,22 while others confirm both the risk of preterm birth and placental damage.²³ However, it was also found that: preterm birth < 37 weeks and early delivery < 34 weeks were reduced in women receiving omega-3 LCPUFAs compared with those not receiving omega-3 LCPUFAs; the risk of perinatal death and admission to neonatal care was probably reduced; the risk of low birth weight (LBW) infants was reduced; the risk of large for gestational age (LGA) infants was slightly increased with omega-3 LCPUFA supplementation. Thus, it was shown that omega-3 LCPUFA supplementation during pregnancy is an effective strategy to reduce the incidence of preterm births, although it probably increases the incidence of post-term pregnancies.²⁴

Another study claims that maternal DHA supplementation in pregnancy can reduce placental inflammation and differentially modulate nutrient transport capacity in the placenta, mitigating the adverse effects of maternal obesity on placental function,²⁵ while another study states that DHA supplementation has no significant impact on the neurological development of offspring at 12 months of age,²⁶ unless there is combined DHA/Choline supplementation and this affects the neurological development of the hippocampus²⁷ (however, this statement refers only to the «rat» animal model and thus may be considered for possible future studies in human models). 

Omega-3/omega-6 and preterm

Concerning neurological and cognitive development, one study found that AA and DHA supplementation, at low doses, results in no improvement [21], while high doses of DHA/EPA can cause serious damage, inducing preterm delivery, prolonged gestation, and hemorrhagic episodes.²⁸ 

Preterm infants who miss the peak period of DHA accretion in the brain during the last trimester of pregnancy (being an important component of neural lipids that accumulate in brain tissue during development),²⁹ precisely because of their clinical condition also exhibit altered gut microbial composition, partly compensated by omega-3 supplementation, which prompted in the next two weeks by dietary supplementation result in the increase of short-chain fatty acid-producing bacteria (SCFA), such as Bacteroides, Enterobacteriaceae, Veillonella, Streptococcus, and Clostridium.³⁰ 

Recent studies, again in the premature, have then shown that supplementation of DHA, and also in some cases AA, in a combined DHA/AA ratio,³¹ significantly improves infant psychomotor and visual development (but without significant effects on global IQ assessed in later years of life.³² It also improves the cognitive function of attention³³ but not concerning language.³⁴ 

Also, in premature, fatty acid administration can limit retinopathic damage³⁵ and prevent necrotizing enterocolitis,³⁶ but does not seem to improve already manifested allergic symptoms³⁷ despite having a direct correlation with the onset of allergic disease, with protective effects.³ 

The same argument also applies to the hypothesis of bronchopulmonary dysplasia at 36 weeks postmenstrual age,³⁸ although one study states the opposite, i.e., that due to the reduction of interleukins 1-beta and 6 in serum, the intake provides benefits on symptoms, provided the preterm is very premature.³⁹

This paper aims to verify the state of the art on the utilization of omega-3/omega-6 type fatty acids, either through diet or supplementation by supplementation, in the preterm maternal and neonatal population to assess the impact on the health of pregnant women and outcomes on the growth and neurodevelopment of the preterm infant.

MATERIALS AND METHODS

We searched in PubMed until March 30, 2023, for meta-analyses, clinical trials and randomized controlled trials, using the keywords “omega-3/omega-6 fatty acids”, “DHA/EPA/ALA/AA”, “pregnancy”, the fetus” and “preterm”, content on the abstract and title have been selected 10,675 useful results, of which 44 original articles were used for the present review as they focused on the topics of growth and neurodevelopment. A single reference (book) related to the analyzed topic from sources outside PubMed was added in the first note. Simple reviews, opinion contributions, or publications in popular volumes were excluded because they were irrelevant or redundant for this paper, and publications that did not present results or statistical samples but only research protocols and proposals, those that did not specifically address the topic of investigation, those with contradictory data, unreliable data, or otherwise with a deficient research design.  The search was not limited to English-language articles. No limit was placed on the year of publication, covering the time window from January 1979 until March 2023. Figure 1⁴⁰

RESULTS

In the literature, the use of omega-3/omega-6 for supplementation purposes for pregnant women appears encouraging, in terms of fetal growth, maternal weight, and term gestation; in particular, the results show that balanced supplementation based on the patient’s medical history, in addition to prescribed drug therapies, improves expected fetal growth outcomes, increasing maternal weight by 5% to 20%, as well as promoting full-term gestation with lower risk of preterm or at-risk births, although there are studies with outcomes to the contrary or otherwise claiming limited benefits in these terms. Differently, however, is the case with preterm infants (with a better health impact if the infant has a gestational age of less than 28 weeks), which although there is encouraging data regarding improvement in certain clinical conditions, such as nonchronic retinopathy damage, bronchopulmonary dysplasia allergic diseases, and necrotizing enterocolitis, due to the reduction of serum interleukin 1-beta and 6, do not appear to be significantly impacting the neurodevelopment of the infant at 2, 4, and 6 years of age, except with interesting results on the improvement of psychomotor, visual, and cognitive-attentive areas. Further studies then concern the hypothesis of nighttime intake of fatty acids (to the detriment of daytime schedules), the use of alternative sources to animal fats (thus plant-based), and interactions with the gut microbiota/microbiome, which open the door to interesting future scenarios that are certainly encouraging and exciting. Table 1

DISCUSSION AND LIMITATIONS 

In the literature, the use of omega-3/omega-6 for supplementation purposes for pregnant women and preterm infants is encouraged by the positive outcomes found and the growing interest in intervening in an impactful manner on fetal growth, maternal weight, and full-term gestation, and for preterm infants to boost the chances of recovery of specific and severe clinical hypotheses. However, these exciting findings must be tempered, by several critical issues that have emerged and been noted during this analysis. In fact, most of the published studies suffer from several shortcomings, both structural and functional, which emerge precisely from their research design and implementation; specifically: a) major structural deficiencies, such as frequent small sample sizes for each category evaluated; b) questionable quality of the included studies or possible conflicts of interest, for commercial reasons; c) technical errors (as in the case of the study adding curcumin to omega-3 supplementation but not taking into account the fact that it requires piperine to be activated or the lack of knowledge of the exact doses to be administered or the interaction between fatty acids, foods, and pharmacological products); d) the difficulty of reliably measuring cognitive performance in childhood patients; and e) the non-comparability of blood levels of omega-3 long-chain polyunsaturated fatty acids; f) the possible influence of environmental and genetic factors (such as in the case of the presence of the APOEɛ4 -APOE4- allele that accelerates the oxidation of omega-3 polyunsaturated fatty acids -PUFAs- or in the hypothesis of the minor allele rs3834458 in FADS2 that results in lower delta-6 desaturase activity resulting in increased ALA and decreased EPA, DPA, and DHA in the blood); g) the absence of recognized and agreed international guidelines about the exact maximum administration and dosage (effectively leaving wide discretion to the clinician or investigator); h) the pharmacological profiles that interact in the therapeutic plan with fatty acid administration; i) the quality of the fatty acids selected and administered.^41-46 These limitations, therefore, can significantly affect the often-agreed conclusion that studies do not show a statistically significant association between DHA/EPA supplementation and assessed cognitive parameters or birth weight, as well as may undermine the reliability of the results obtained to an alleged advantage in administering.

In the Table 2 showed the clinical message, as the final result of the literature search. 

CONCLUSION 

Significant critical issues emerge concerning published studies, despite encouraging evidence regarding the usefulness of omega-3/omega-6 used during pregnancy, lactation, in states of malnutrition and inflammatory-based processes, while data regarding effective use in fetal, neonatal, and pediatric patients are conflicting. The noted structural and functional shortcomings of the samples studied lead to the inference that such correctives could ensure a better perception of the phenomenon, also taking into account that the hypothetical assumption of almost all studies is that fatty acid supplementation can have a curative effect on already active diseases, whereas in reality such prescriptions should be considered as adjuvant therapies to prevent or promote symptomatic regression, precisely because of their anti-inflammatory, antioxidant and immunomodulatory virtues. Future research is expected to solve some critical questions with better approaches to answer how omega-3/omega-6 fatty acid supplementation can contribute to better human growth and nutrition in the clinical practice of Gynecology and Pediatrics.

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