Fat-Soluble Nutrients and Omega-3 Fatty Acids as Modifiable Factors Influencing Preterm Birth Risk

Abstract

Preterm birth is a leading cause of child morbidity and mortality, so strategies to reduce early birth must remain a priority. One key approach to enhancing birth outcomes is improving maternal dietary intake. Therefore, the purpose of this review is to discuss mechanisms on perinatal status of fat-soluble nutrients (carotenoids, retinol, tocopherols) and omega-3 fatty acids and how they impact risk for preterm birth. Literature review demonstrates that maternal dietary intake and biological (blood and placental tissue) levels of fat-soluble nutrients during pregnancy may provide antioxidative, anti-inflammatory, and immunomodulatory health benefits. Omega-3 fatty acids also promote increased production of specialized pro-resolving mediators, subsequently mediating inflammation resolution. Combined effects of these nutrients support appropriate placental organogenesis and function. Consequently, fat-soluble nutrients and omega-3 fatty acids serve as strong influencers for preterm birth risk. As dietary intake remains a modifiable factor, future intervention would benefit from a focus on optimizing perinatal status of these specific nutrients.

Introduction:

Preterm birth (defined as birth <37 weeks gestation) is a global health problem, with prevalence rates ranging between 5–18% worldwide [1]. It also remains a leading cause of death for children under 5 years of age [2]. While certain demographics are known contributors to preterm birth, there is often no identified cause [1]. One often overlooked, yet vital approach to enhance birth outcomes is adequate nutrient provision. Adequate maternal nutrition during pregnancy is associated with appropriate fetal growth and a decreased risk of maternal disease development, such as preeclampsia [3]. A review of the consequences attained from insufficient or superfluous nutrient provision during fetal development reveals worsened cardiometabolic health and alters overall life course in offspring [4]. While this highlights the importance of appropriate perinatal nutrition, defined mechanisms of how it may influence preterm birth risk is complex.

Adequate maternal intake of varying singular nutrients have been associated with decreased risk of preterm birth, such as vitamin D [5]. In addition, a 2019 Cochrane meta-analysis concluded that multiple micronutrient supplementation to pregnant women (19/20 studies were in low/middle income countries) likely reduces incidence of preterm birth [6]. Additional literature is contrasting, as results of the United States Pregnancy Risk Assessment Monitoring System reported multivitamin supplement use during one month preconception and in the final three months of pregnancy to have no association with preterm birth in a majority of the population [7]. While it may be anticipated that most benefit will be attained from a nutrient-rich, comprehensive maternal diet, most optimal food sources and dietary patterns have not been entirely well-defined. In example, a meta-analysis (n=167,507) found that a “healthy” maternal diet (high intake of fruits, vegetables, whole grains, low-fat dairy, lean proteins) reduced risk of preterm birth (top vs. bottom tertile, OR 0.79; 95% CI 0.68–0.91) compared to an “unhealthy” diet (high intake of refined grains, processed meats, foods high in sugar or saturated fat) [8]. Additional studies also support intake of less processed foods, as a 2019 systematic review reported that higher dietary intakes of certain sources (including vegetables, fruits, nuts, seeds, and fish), may be protective against early birth [9]. Though current evidence may be conflicting or incomplete, many of the above-reported food groups are notably rich in fat-soluble nutrients or omega (n)-3 fatty acids [10]. Therefore, the purpose of this review is to discuss mechanisms of how perinatal status of fat-soluble nutrients and n-3 fatty acids impact risk for preterm birth.

Review of the Literature:

Maternal factors (related to fat-soluble nutrients and n-3 fatty acids) identified as significant in association with preterm birth risk are summarized in Table 1. References are listed as they appear in the text.

Table 1:

Maternal Factors That May Alter Risk of Preterm Birth

Factors that Lower Risk	Ref	Factors that Increase Risk	Ref
Increase α-carotene (blood level)	15	Maternal obesity	14
Increase β-carotene (blood level, dietary intake)	15, 16	Maternal hypertension	14
Increased lycopene (blood level)	15	Smoking	19
Increased lutein and zeaxanthin (blood level)	15	Retinol deficiency (blood level)	25
Vitamin C and vitamin E among smokers (dietary supplementation)	30	High gamma-tocopherol (dietary intake)	15
Omega (n)-3 fatty acids (dietary supplementation)	36–38	Endotoxemia	42

Role of Preconception Nutrition

Currently, little is known about the relationship between diet before conception (i.e. in adolescence) and risk of preterm birth. In the Lancet series on Preconception Health, Stephenson et al. conducted a review of published evidence on the relationship between preconception health, particularly nutritional status, and neonatal outcomes [11]. Only three studies were identified investigating the association between preconception diet and preterm birth. A United States-based study of adolescent mothers where measures of diet and offspring neonatal outcomes were close together in time (i.e., on average 2.5 years), found no associations between self-reported food intake (i.e., frequency of milk, fruit, vegetables, grains, and sweets) and vitamin use, and preterm delivery of offspring [12]. Gresham et al. showed that lower diet quality (low vegetable and whole grain intakes) 10–15 months before pregnancy in an Australian cohort of reproductive women was not significantly associated with preterm delivery [13]. A small Australian retrospective cross-sectional study (n=309) found that a dietary pattern 12 months prior to conception that included protein-rich foods, fruit, and whole grains was associated with reduced likelihood for preterm delivery, while a dietary pattern that included energy-dense foods was associated with increased likelihood for preterm delivery and shorter birth length [14]. Due to varying evidence, further research is needed in this area. However, these final findings open questions as to how preconception diet impacts chronic disease development in women before pregnancy (obesity, hypertension, etc.), which has additional implications for risk of preterm birth.

Role of Fat-soluble Nutrients

Carotenoids

Fat-soluble nutrients, specifically carotenoids, have received special attention secondary to their antioxidative, anti-inflammatory, immunomodulatory, and overall synergistic effects on health. Altered provision of such nutrients during pregnancy may impact these health benefits, ultimately contributing to risk of preterm birth. For example, increased blood levels of certain maternal carotenoids at mid-pregnancy have been identified to lower risk of spontaneous preterm birth, including α-carotene (crude OR 0.7; 95% CI 0.5–0.9), β-carotene (OR 0.7; 0.5–0.9), and lycopene (OR 0.7; 0.5–0.9), but not β-cryptoxanthin (OR 0.8; 0.5–1.1) or lutein (OR 0.9; 0.6–1.2) [15]. Comparatively, pregnant women (n=5,738) eating the lowest quartiles (vs. middle two quartiles) of β-carotene had an increased odds of delivering preterm at <32 weeks gestation (OR 1.9; 95% CI 1.1–3.5), though there was no difference in the highest quartiles of intake (OR 0.9; 0.4–1.8) [16]. Maternal intake of lutein and α-carotene had no effect on preterm birth risk in this study [16]. Carotenoid levels also have placental implications, as Palan et al. reported lower levels of placental lycopene (330.0 vs. 198.2 ng/g; p=0.009) and β-carotene (77.6 vs. 52.9 ng/g; p=0.032) in cases of mothers with diagnosed preeclampsia in the third trimester compared to healthy controls [17]. Placental levels of α-carotene showed no significant difference between groups (14.5 vs. 4.8 ng/g; p=0.096) [17]. Furthermore, carotenoids lutein + zeaxanthin have been identified as the two most prevalent of analyzed carotenoids in placental tissue (49.1%), theorized to enhance placental functioning via antioxidative action, membrane structure support, and enhanced selective placental permeability [18]. Similarly, a case-control study reported maternal plasma lutein levels above the cohort median at 24–26 weeks gestation to be independently associated with lower odds for decidual vasculopathy (crude OR 0.5; 95% CI 0.3–0.9) [15]. Therefore, the continuing hypothesis is that increasing levels of lutein and zeaxanthin will enhance placental function and ultimately the intrauterine growth environment. However, limitations to this theory are that placental carotenoid levels have not been well-analyzed to date or compared with birth outcomes.

Maternal smoking during pregnancy is also a risk factor for preterm birth, estimated to increase the odds of preterm birth by 1.27 (95% CI 1.21–1.33) [19]. One possible rationale for this association may be that smoking also decreases carotenoid levels, with an estimated decrease in circulating lutein + zeaxanthin levels by 14%, lycopene by 5%, and α-carotene, β-carotene, and cryptoxanthin by 25% [20]. It could be theorized that if carotenoids are consumed in an antioxidant capacity to combat smoking-induced oxidative damage, concentrations of these nutrients are then less available to provide antioxidant benefits to the developing fetus, which may exacerbate or contribute to smoking-related prematurity risk. Smoking also reduces placental vascular function [21], so continuing theory is that fewer carotenoids are able to be transported to the placenta and fetus.

Carotenoids β-cryptoxanthin, α-carotene, and β-carotene are known for their pre-vitamin A activity (measured in retinol activity equivalents, or RAE), and are able to be converted to retinol (vitamin A) in the body [22]. Carmichael et al. reported that maternal dietary RAE (micrograms) in the lowest and highest quartiles (compared to middle two quartiles) had no association with risk of preterm delivery <32 weeks gestational age, (OR 1.8; 95% CI 0.9–3.3 lowest quartile; OR 1.0; 0.5–2.1 highest quartile) [16]. A 2015 Cochrane analysis also reported that maternal dietary vitamin A supplementation in pregnant women does not reduce risk of preterm birth (RR 0.98; 95% CI 0.94–1.01) [23]. However, Hanson et al. identified retinol deficiency during pregnancy to be associated with maternal anemia (p=0.04) [24], an identified risk factor for preterm birth [25]. Deficiencies in retinol and its metabolic derivatives (i.e. retinoic acid) have further potential to increase risk for preterm birth given their crucial role in organogenesis, including the placenta [26]. Retinol deficiency is also associated with increased risk of systematic inflammation and infection [27], both recognized contributors to preterm birth [1]. Though not yet analyzed, placental retinol deficiency may have significant impact on placental function, including tissue inflammation and poor structural development. This abnormal placental development has theoretic implications for risk of early delivery, as inability to provide appropriate oxygenation or nutrient delivery cannot support appropriate fetal growth.

Tocopherol

Another nutrient that may have important perinatal biological roles is vitamin E in its major isoforms: alpha- and gamma-tocopherol. Although its potent antioxidant capacity is well known, its role during pregnancy is poorly understood. Multiple studies have investigated what impacts vitamin E supplementation may have on the rate of preterm birth, with mixed results. One randomized controlled trial by Hauth et al. provided either 1,000 milligrams vitamin C + 400 international units of vitamin E or a matched placebo to over 10,000 women participating in the trial. Although overall rates of preterm birth were not different between the two trial arms, recipients of the vitamin combination were less likely to be born before 32 weeks gestation (0.3% vs 0.6%, adjusted odds ratio 0.3–0.9) [28]. In contrast, Kramer et al. reported pregnant women (n=5,337) eating the highest quartile (compared to the middle two quartiles) of gamma tocopherol at mid-pregnancy had increased odds of preterm birth <32 weeks gestation (crude OR 1.8; 95% CI 1.3–2.6) [15]. A 2015 Cochrane Review of vitamin E supplementation trials concluded that vitamin E had no impact on risk of preterm birth across 11 trials with 20,565 participants (average RR 0.98; 95% CI 0.88–1.09) [29] – indicating with a fair degree of rigor that vitamin E may play no direct role in rates of prematurity. However, numerous studies have highlighted the impact of vitamin E isoforms on outcomes related to prematurity such as fetal growth, as well as possible roles in ameliorating the impact of smoking. A secondary analysis of the same vitamin C + vitamin E supplementation trial found that while supplementation had no effect on prematurity risk in non-smokers, supplementation did reduce risk of preterm birth among smokers (RR 0.76, 95% CI 0.58–0.99) [30] – suggesting that targeting dietary interventions to groups particularly susceptible to inflammatory insult may be impactful.

Numerous studies have linked vitamin E to improved fetal growth, including birthweight, length, and head circumference. For instance, Gadhok et al. described significantly lower maternal serum levels of vitamin E in pregnancies with intrauterine growth restriction compared to healthy controls [31], although the number of control subjects in this study is low. Additional work has highlighted the potential benefit vitamin E may provide to the developing fetus. After adjusting for confounders, Hanson et al. found that maternal levels of vitamin E isoforms had positive associations with numerous measures of infant growth [32]. Interestingly, the relationship reverses when assessing infant cord blood levels of vitamin E, as higher umbilical cord levels were inversely associated with growth outcomes. A potential hypothesis could be that vitamin E plays a critical role in infant development during gestation, and that higher serum levels in the infant may suggest inefficient tissue uptake of vitamin E isoforms in the perinatal period, although this has not been studied. In addition, the role of the placenta may be of key importance, as our theory is that the placenta may be a key site of activity for these potent antioxidant compounds and high umbilical cord serum levels may imply dysfunction in this unknown placental pathway.

Role of Omega-3 Fatty Acids and Specialized Pro-resolving Mediators

Omega-3 Polyunsaturated Fatty Acid Supplementation

Preterm birth is a significant contributor to perinatal morbidity and mortality to infants in the newborn intensive care unit [33]. The association of preterm birth with inflammation and infection are evident from both clinical data and preterm animal models of infection-induced inflammation [34,35]. The levels of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL1β) were shown to be elevated in maternal circulation at preterm birth compared to the term-delivered control population. Further, trophoblast isolated from term placenta exposed to inflammatory stimulus like bacterial lipopolysaccharide (LPS) or TNFα were shown to induce inflammation and inflammasome activation [34]. Supplementation of omega (n)-3 polyunsaturated fatty acids (PUFA) prevents LPS and TNFα -induced placental trophoblast inflammation activation, proinflammatory cytokines and cell death [34] suggesting that n-3 PUFA supplementation could be protective against placental inflammation in preterm mothers. Indeed, review of evidence consistently demonstrates decreasing preterm birth with increasing intakes of n-3 fatty acids. In example, a 2018 Cochrane analysis reported decreased risk for preterm birth in mothers receiving n-3 long chain PUFA supplementation vs. no supplementation (11.9% vs. 13.4%; RR 0.89, 95% CI 0.81–0.97; n=10,304). Findings were similar when comparing risk for early birth, defined as birth <34 weeks gestation (2.7% vs. 4.6%; RR 0.58, 95% CI 0.44–0.77; n=5,204) [36]. Of particular interest, a cross-sectional study of 184 countries found an inverse relationship with increased population dietary intakes of n-3 fatty acids and number of preterm births, but only up to a dietary threshold of 600 mg/day [37]. Supplementation of n-3 PUFA in a recent clinical trial, docosahexaenoic acid (DHA) prevents premature rupture of membranes in both term and preterm mother. Moreover, DHA supplementation also correlated with a longer duration of pregnancy implicating their protective role against preterm labor [38].

Specialized Pro-resolving Mediators

While intake of n-3 fatty acids have been shown to reduce the rate of preterm birth [36]; the mechanism by which n-3 fatty acids function to provide this protective effect is not well understood. Recently, n-3 fatty acids have been found to serve as substrates for the biosynthesis of specialized pro-resolving mediators (SPMs), which are bioactive lipid metabolites that regulate inflammation resolution and play a role in maternal-fetal health outcomes [39]. SPMs are primarily derived from the n-3 fatty acids DHA, EPA, and docosapentaenoic acid which produce D-, E-, T-series resolvins (Rv), protectins, and maresins [40]. In an analysis of SPM and clinical outcomes in maternal-infant pairs, SPM levels of DHA-derived RvD1 and RvD2 were significantly elevated in maternal plasma in the setting of preterm delivery (defined as delivery before 36 weeks infant gestational age) compared to mothers delivering at term (36 weeks or greater gestational age). Cord blood levels also demonstrated a significantly higher level of RvD2 in preterm deliveries [41]. Interestingly, a recent Taiwanese report has identified that the levels of SPM RvD1 is reduced in the maternal circulation at preterm compared to term birth [34]. In contrast, Nordgren et al. reported that maternal RvD1 and RvD2 were increased in cases when infants were admitted to the newborn intensive care unit compared to non-admitted infants, including increased maternal RvD1 and RvD2 and cord RvD2 in births at <36 weeks gestation versus >36 week [41]. These varying findings implicate a role for SPM in preterm birth and suggest that increased SPM levels may provide a mechanism behind the benefits of n-3 fatty acids by increasing the available substrate for the production of SPM during high-risk pregnancies. Preclinical findings are in support of this hypothesis; LPS-induced preterm birth in fat-1 mice (a transgenic mouse model that converts n-6 FA into n-3 FA) with eicosapentaenoic acid (EPA) supplementation dramatically decreased the incidence of preterm and SPM, resolvin(Rv)E3 is elevated in EPA-supplemented fat-1 mice and administration of RvE3 also protects against LPS-induced preterm birth [42].

In support of the role of SPM in protecting against preterm birth, new roles for SPM have been identified in the regulation of placental functioning [41,43]. The SPM RvD2 activates a distinct G-protein–coupled receptor denoted GPR18 (also termed D-resolvin receptor 2), which among innate immune cells, is expressed on human leukocytes, monocytes, and macrophages [44]. Immune cells, such as macrophages and natural killer cells, are present at the placental maternal-fetal interface to facilitate innate immune responses [45]. In addition to these immune cells, previous studies demonstrated that trophoblasts are able to respond to pathogen-associated molecular patterns such as LPS or peptidoglycan. This finding strongly supports that trophoblasts can recognize pathogens and initiate an immune response [45]. Initial studies indicate that SPM receptors, including GPR18, are located on the placental/umbilical vascular smooth muscle cells and invading/extravillous trophoblasts (as demonstrated in Figure 1) from term and preterm births, suggesting placental sites of action for maternal-derived circulating SPM [43]. The expression of GPR18 on the vascular smooth muscle cell is of physiological significance, because appropriate vascular functioning is critical to maintain maternal-fetal health and prevent negative perinatal outcomes. Inflammatory stimuli have been shown to reduce invasive capacities of extravillous trophoblasts, while inducing their release of proinflammatory cytokines [43]. These findings suggest a mechanism by which an inflammatory placental environment may lead to placental vascular dysfunction leading to negative pregnancy outcomes [43]. Therefore, placental GPR18 expression may play a protective role controlling inflammation and vascular injury in pregnancy and preterm birth.

Figure 1:

GPR18 Immunostain cytoplasmic Expression on Placental Vascular Smooth Muscle (stem villus blood vessel) (A) and Extravillous Trophoblast (B). Scale bars represent 50 μm.

Conclusion:

In summary, fat-soluble nutrients and n-3 fatty acids have potential to profoundly influence risk of preterm birth due to their antioxidative, anti-inflammatory, and immunomodulatory health benefits. These nutrients may also support appropriate placental function, further supporting appropriate pregnancy duration. However as current literature may demonstrate varying evidence, further research is needed to identify exact mechanisms of how these nutrients impact birth outcomes. As dietary intake remains a modifiable factor, future intervention must also focus on optimizing perinatal status of these specific nutrients.