Maternal nutritional interventions aim to address nutrient deficiencies in pregnancy, a leading cause of maternal and neonatal morbidity and mortality worldwide. How these interventions influence the placenta, which plays a vital role in fetal growth and nutrient supply, is not well understood. This leaves a major gap in understanding how such interventions could influence pregnancy outcomes and fetal health. We hypothesised that nutritional interventions influence placental phenotype, and that these placental changes relate to how successful an intervention is in improving pregnancy outcomes.

We searched PubMed, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform using pre-defined search terms for records published from January 2001 to September 2021 that reported on clinical trials in humans, which administered a maternal nutritional intervention during the periconceptional or pregnancy period and reported on placental phenotype (shape and form, function or placental disorders). These records were then screened by two reviewers for eligibility.

Fifty-three eligible articles reported on (multiple) micronutrient- (n = 33 studies), lipid- (n = 11), protein- (n = 2), and diet-/lifestyle-based (n = 8) interventions. Of the micronutrient-based interventions, 16 (48%) were associated with altered placental function, namely altered nutrient transport/metabolism (n = 9). Nine (82%) of the lipid-based interventions were associated with altered placental phenotype, including elevated placental fatty acid levels (n = 5), altered nutrient transport/metabolism gene expression (n = 4), and decreased inflammatory biomarkers (n = 2). Of the protein-based interventions, two (66%) were associated with altered placental phenotype, including increased placental efficiency (n = 1) and decreased preeclampsia risk (n = 1). Three (38%) of diet and lifestyle-based interventions were associated with placental changes, namely placental gene expression (n = 1) and disease (n = 2). In studies with data on maternal (n = 30) or offspring (n = 20) outcomes, interventions that influenced placental phenotype were more likely to have also been associated with improved maternal outcomes (n/N = 11/15, 73%) and offspring birth outcomes (n/N = 6/11, 54%) compared to interventions that did not associate with placental changes (n/N = 2/15 (13%) and n/N = 1/9 (11%) respectively).

Periconceptional and prenatal nutritional interventions to improve maternal/pregnancy health associate with altered placental development and function. These placental adaptations likely benefit the pregnancy and improve offspring outcomes. Understanding the placenta's role in the success of interventions to combat nutrient deficiencies is critical for improving interventions and reducing maternal and neonatal morbidity and mortality globally.

Intrauterine growth restriction (IUGR) arises when maternal stressors coincide with peak placental development, leading to placental insufficiency. When the expanding nutrient demands of the growing fetus subsequently exceed the capacity of the stunted placenta, fetal hypoxemia and hypoglycemia result. Poor fetal nutrient status stimulates greater release of inflammatory cytokines and catecholamines, which in turn lead to thrifty growth and metabolic programming that benefits fetal survival but is maladaptive after birth. Specifically, some IUGR fetal tissues develop enriched expression of inflammatory cytokine receptors and other signaling cascade components, which increases inflammatory sensitivity even when circulating inflammatory cytokines are no longer elevated after birth. Recent evidence indicates that greater inflammatory tone contributes to deficits in skeletal muscle growth and metabolism that are characteristic of IUGR offspring. These deficits underlie the metabolic dysfunction that markedly increases risk for metabolic diseases in IUGR-born individuals. The same programming mechanisms yield reduced metabolic efficiency, poor body composition, and inferior carcass quality in IUGR-born livestock. The ω-3 polyunsaturated fatty acids (PUFA) are diet-derived nutraceuticals with anti-inflammatory effects that have been used to improve conditions of chronic systemic inflammation, including intrauterine stress. In this review, we highlight the role of sustained systemic inflammation in the development of IUGR pathologies. We then discuss the potential for ω-3 PUFA supplementation to improve inflammation-mediated growth and metabolic deficits in IUGR offspring, along with potential barriers that must be considered when developing a supplementation strategy.

Decreased 5-hydroxymethylcytosine (5hmC) levels caused by mitochondrial dysfunction in the brain are closely associated with the development of neurodegenerative disease. It has been reported that n-3 polyunsaturated fatty acids (PUFAs) prevent cognitive dysfunction by improving mitochondrial function in the brain. However, whether n-3 PUFA prevents cognitive dysfunction by increasing the levels of 5hmC in the brain is undisclosed. Mice were randomly divided into six groups (n = 10), injected with D-galactose (200 mg kg-1 day-1) for the model group and given different oils [0.1 mL per 10 g body weight per day, fish oil (FO), peony seed oil (PSO), corn oil (CO) and olive oil (OO)] for the prevention groups, and injected with the same dose of saline for the normal control group (NC) for 10 weeks, respectively. Peony seed oil and fish oil have shown preventive effects on D-galactose-induced cognitive dysfunction in behavioral tests. The content of docosahexaenoic acid (C22:6n-3, DHA content) in the brain was significantly higher in FO and PSO groups than in the other groups. Brain oxidative stress and neuronal apoptosis were significantly lower in PSO and FO groups than in the other groups. RNA-seq results showed that the different genes between PSO and FO compared with the model group were involved in the DNA demethylation process and the 5-methylcytosine metabolic process. The brain levels of 5hmC and the ten-eleven translocation family of dioxygenases (TETs) were significantly higher in FO and PSO groups compared with the model group, as analyzed by dot-blot and western blot. In conclusion, peony seed oil and fish oil increased the C22:6n-3 content, which activated the TET activity, led to up-regulation of the 5hmc level, resulted in inhibition of neuronal apoptosis, and then improved the cognitive function in D-gal-induced mice.

Maternal obesity, affecting nearly 1 in 4 pregnancies, is associated with increased circulating saturated fatty acids, such as palmitate. These fatty acids are implicated in placental inflammation, which may in turn exacerbate both maternal-fetal tolerance and responses to pathogens, such as group B Streptococcus. In this review, we address the question, "How do obesity and associated fatty acids influence placental inflammation?"

In this narrative review, we searched PubMed and Google Scholar using combinations of the key words placental inflammation or pregnancy and lipids, fatty acids, obesity, palmitate, or other closely related search terms. We also used references found within these articles that may have been absent from our original search queries. We analyzed methods and key results of these articles to compare and contrast their findings, which were occasionally at odds with each other.

Although obesity can be studied as a whole, complex phenomena with in vivo mouse models and human samples from patients with obesity, in vitro modeling often relies on the treatment of cells or tissues with ≥1 fatty acids and occasionally other compounds (eg, glucose and insulin). We found that palmitate, most commonly used in vitro to recreate hallmarks of obesity, induces apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation in many placental cell types. We compare this to in vivo models of obesity wherever possible. We found that obesity as a whole may have more complex regulation of these phenomena (apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation) compared with in vitro models of fatty acid treatment (primarily palmitate) because of the presence of unsaturated fatty acids (ie, oleate), which may have anti-inflammatory effects.

The interaction of unsaturated fatty acids with saturated fatty acids may ameliorate many inflammatory effects of saturated fatty acids alone, which complicates interpretation of in vitro studies that focus on a particular fatty acid in isolation. This complication may explain why certain studies of obesity in vivo have differing outcomes from studies of specific fatty acids in vitro.

Maternal nutrition is a key modifier of fetal growth and development. However, many maternal diets in the United States do not meet nutritional recommendations. Dietary supplementation is therefore necessary to meet nutritional goals. The effects of many supplements on placental development and function are poorly understood. In this review, we address the therapeutic potential of maternal dietary supplementation on placental development and function in both healthy and complicated pregnancies.

This is a narrative review of original research articles published between February 1970 and July 2020 on dietary supplements consumed during pregnancy and placental outcomes (including nutrient uptake, metabolism and delivery, as well as growth and efficiency). Impacts of placental changes on fetal outcomes were also reviewed. Both human and animal studies were included.

We found evidence of a potential therapeutic benefit of several supplements on maternal and fetal outcomes via their placental impacts. Our review supports a role for probiotics as a placental therapeutic, with effects that include improved inflammation and lipid metabolism, which may prevent preterm birth and poor placental efficiency. Supplementation with omega-3 fatty acids (as found in fish oil) during pregnancy tempers the negative effects of maternal obesity but may have little placental impact in healthy lean women. The beneficial effects of choline supplementation on maternal health and fetal growth are largely attributable to its placental impacts. l-arginine supplementation has a potent provascularization effect on the placenta, which may underlie its fetal growth-promoting properties.

The placenta is exquisitely sensitive to dietary supplements. Pregnant women should consult their health care practitioner before continuing or initiating use of a dietary supplement. Because little is known about impacts of many supplements on placental and long-term offspring health, more research is required before robust clinical recommendations can be made.

Disturbed placentation results in pregnancy complications like preeclampsia. Placental development is influenced by apoptosis during trophoblast differentiation and proliferation. Increased oxidative stress upregulates placental apoptosis. We have earlier reported increased oxidative stress, lower omega-3 fatty acids and vitamin E levels in women with preeclampsia. Current study examines effect of maternal omega-3 fatty acids and vitamin E supplementation on apoptotic markers across gestation in a rat model of preeclampsia.

Pregnant Wistar rats were randomly assigned to control; early onset preeclampsia (EOP); late onset preeclampsia (LOP); early onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (EOP + O + E) and late onset preeclampsia + omega-3 fatty acid + vitamin E supplementation (LOP + O + E) groups. Animals (Control, EOP, EOP + O + E) were sacrificed at d14 and d20 of gestation while animals (LOP, LOP + O + E) were sacrificed at d20 to collect blood and placentae. Protein and mRNA levels of apoptotic markers were analyzed by ELISA and RT-PCR respectively.

Protein levels of proapoptotic markers like Bcl-2 associated X-protein (BAX) (p < 0.05), caspase-8 and 3 (p < 0.01 for both) and malondialdehyde (p < 0.01) were higher only in the EOP group as compared to control. However, the antiapoptotic marker, B cell lymphoma 2 (Bcl-2) protein levels were lower in both the subtypes of preeclampsia (p < 0.01 for both).

Our findings suggest that supplementation was beneficial in reducing the caspase-8 and 3 in early onset preeclampsia but did not normalize BAX and Bcl-2 levels. This has implications for reducing placental apoptosis in preeclampsia.

Preeclampsia is a dangerous disorder of pregnancy, defined as hypertension with proteinuria. Its nature remains elusive, and measures of prevention and treatment are limited. Observational studies have suggested that preeclampsia is associated with low intake of omega-3 long-chain polyunsaturated fatty acids (LCPUFA). In recent decades, researchers studied LCPUFA supplementation as a measure to prevent preeclampsia. Most of these trials and later systematic reviews yielded negative results. However, these trials had several important limitations associated with heterogeneity and other issues. Recent research suggests that preeclampsia trials should take into consideration the gender of the fetus (and thus sexual dimorphism of placenta), the positive effect of smoking on preeclampsia prevalence, and the possibility that high doses of LCPUFA mid-term or later may promote the disorder instead of keeping it at bay. In this review, we discuss these issues and future prospects for LCPUFA in preeclampsia research.

Preeclampsia (PE) was shown to affect the placental content and the transfer of polyunsaturated fatty acids (PUFA) to the fetus. Plasmalogens, a type of phospholipids with a vinyl-ether link at the sn-1 position, play an antioxidant role and are specifically enriched in PUFA at the sn-2 position. In this study, we characterized plasmalogen-derived dimethyl acetal (DMA) fatty acid derivatives, 16:0 DMA, 18:0 DMA, 9c-/11c-18:1 DMA and PUFA in the placenta of normotensive (n = 20) and PE (n = 20) pregnancies, according to the sampling site: peri-insertion or periphery. Phospholipid fatty acids from the placenta and maternal erythrocytes were identified by gas chromatography mass spectrometry and quantified by flame ionization detection. We found elevated total DMA in the PE placenta by 18% when compared to normotensive controls (p = 0.026). Moreover, the 16:0 DMA account for more than 55% of DMA fatty acids measured in the placenta, and its level is significantly higher in PE than controls (p = 0.018). Also, we found elevated placental PUFA, 20:5(n-3), 22:5(n-3) and a low level of 20:4(n-3) in PE compared to controls. Placental DMA was highly correlated with n-6 and n-3 PUFA in both, normotensive and PE pregnancies. In sum, elevated DMA fatty acids in the PE placenta could be an indirect defensive mechanism against oxidative stress and poor placental fatty acid transfer in PE.

Our aim was to investigate the effect of high levels of glucose, insulin, leptin, and tumor necrosis factor alpha, biomarkers of diabetes in pregnancy, in the process of placentation, using as a cell model a first trimester extravillous human trophoblast cell line (HTR8/SVneo cells). Exposure of HTR8/SVneo cells for 24 hours to either glucose (20 mmol/L) or leptin (25-100 ng/mL) did not cause significant changes in cell proliferation and viability. Tumor necrosis factor alpha (24 hours; 10-100 ng/L) caused a small decrease (10%) in cell proliferation and an increase (9%) in cell viability; however, both effects disappeared when exposure time was increased. Insulin (24 hours; 1-10 nmol/L) caused a concentration- and time-dependent decrease (10%-20%) in cell proliferation; the effect of insulin (10 nmol/L) was more pronounced after a 48 hours exposure (35%). In contrast, exposure to insulin (10 nmol/L; 48 hours) showed no significant effect on cell viability, apoptosis, and migration capacity. Insulin appears to cause hypertrophy of HTR8/SVneo cells as it reduces the cell mitotic index while increasing the culture protein content. The antiproliferative effect of insulin seems to involve activation of mammalian target of rapamycin, phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase. Finally, simvastatin and the polyphenol quercetin potentiated the antiproliferative effect of insulin; on the contrary, the polyphenol resveratrol, the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids, and folic acid were not able to change it. In conclusion, we show that insulin has an antiproliferative and hypertrophic effect on a first trimester extravillous human trophoblast cell line. So insulin might affect the process of placentation.