Resveratrol intervention on GDM in preclinical studies

Different methods of perinatal supplementation of resveratrol attenuated the appearance of GDM (Table 1). Using a diabetic embryopathy model in rats, the intervention with resveratrol for 10 d (100 mg/kg) during pregnancy prevented oxidative stress and apoptosis in embryos and improved glucose and lipid profile of diabetic dams.^{Reference Singh, Kumar and Hitchcock47} Considering these results, maternal resveratrol administration demonstrated antioxidant capacity to prevent embryonic malformations, including neural tube defects.

Table 1. Preclinical studies using resveratrol in the treatment of models of GDM

Recently, the role of resveratrol in maternal diabetes-induced autism spectrum disorder was investigated. Studies in rodents have demonstrated that maternal diabetes may induce autism-like behavior in offspring through hyperglycemia-mediated persistent oxidative stress and downregulation of estrogen receptor β (ERβ) and superoxide dismutase 2 (SOD2) in the amygdala. Conversely, treatment with resveratrol (20 mg/kg for four weeks after pregnancy and during pregnancy) reversed these effects through increased expression of ERβ and SOD2 in the amygdala. In addition, these responses were more effective in female rats,^{Reference Xie, Ge and Li48,Reference Wang, Lu and Xie49} which suggests that female offspring appear to be more responsive to resveratrol treatment than male offspring. A possible explanation is that basal ERβ expression in the amygdala is significantly higher in female rats compared to male rats.

Resveratrol treatment on the db/+ genetic GDM mouse model at the dose of 10 mg/kg 4 weeks before pregnancy and 20 d during pregnancy significantly alleviated hyperglycemia and insulin resistance in pregnant db/+ mice, as well as increased fetal survival and improved BW at birth.^{Reference Yao, Wan and Li50} Moreover, the study demonstrated that resveratrol treatment attenuated hyperglycemia and insulin resistance by enhancing adenosine monophosphate-activated protein kinase (AMPK) and reducing glucose-6-phosphatase activity in the liver in both pregnant db/+ mice and their offspring.^{Reference Yao, Wan and Li50} In consequence of these protective effects, supplementation with resveratrol attenuated adverse effects of GDM by improving reproductive outcomes, including increased litter size and BW at birth.

An experimental study verified that the daily treatment with resveratrol (147 mg/kg) at the beginning of the third trimester of pregnancy (onset of GDM development) and throughout lactation improved glucose homeostasis and insulin secretion in dams with GDM. In addition, maternal resveratrol supplementation attenuated obesity, prevented hepatic steatosis, and improved insulin sensitivity and islet dysfunction in male rat offspring.^{Reference Brawerman, Kereliuk and Brar51}

A study in mice identified that a 0.2% dose of resveratrol during 2–3 weeks of gestation induced maternal benefits. The main benefits were decreased bodyweight, plasma glucose, and increased leptin and adiponectin expression.^{Reference Zheng and Chen52} Similarly, a study testing different doses of resveratrol in rats (60, 120, and 240 mg/kg) during two weeks of pregnancy observed a decrease in BW, blood glucose levels, and an improvement in the lipid and inflammatory profile.^{Reference Zhang, Wang, Ren, Zhao and Zhang53}

Resveratrol intervention on maternal protein restriction in preclinical studies

During pregnancy, maternal protein restriction increases serum glucocorticoids and oxidative stress by generating ROS, leading to metabolic dysfunction in both mother and offspring.^{Reference de Sousa, Braz and Freitas54,Reference Silva, Braz and do Nascimento55} The gestational protein restriction model is commonly used in studies in the DOHaD field. This model reflects the dietary inadequacies typically observed in underdeveloped and emerging countries. An early study demonstrated that maternal supplementation with resveratrol (at a dose of 20 mg/kg/d, from the first day of gestation until delivery) partially decreased maternal and placental oxidative stress biomarkers in Wistar rats subjected to protein restriction.^{Reference Vega, Reyes-Castro and Rodriguez-Gonzalez56} Additionally, the authors demonstrated that the liver oxidative stress in offspring from dams fed a low protein diet was diminished when dams received resveratrol supplementation during pregnancy.^{Reference Vega, Reyes-Castro and Rodriguez-Gonzalez56-Reference Franco, de Moura and Koury58} However, we highlight that these effects need to be investigated in RCTs to confirm these findings in human studies.

Resveratrol intervention on maternal obesity in preclinical studies

Evidence has shown that perinatal treatment with resveratrol can reduce maternal obesity and related symptoms (Table 2). Supplementation with resveratrol attenuated harmful effects of high-fat diet (HFD)-induced obesity, improving maternal conditions, and reducing adverse effects on offspring.^{Reference Menichini, Longo and Facchinetti59} It is noteworthy that the HFD used in preclinical studies shows different fat percentages, ranging from 32% to 61.6%, and the caloric amount ranging from 3.80 kcal/g to 5.56 kcal/g. In addition, most studies used 50 g of fiber, 3 g of vitamins, and 50 to 54.50 g of minerals. Furthermore, the most used fat sources were lard and soybean oil.

Table 2. Preclinical studies using resveratrol in the treatment of models of maternal obesity

The beneficial responses reported to resveratrol supplementation were strongly associated with antioxidant, anti-inflammatory properties, epigenetic changes, and modulation of gut microbiota. Among antioxidant properties, resveratrol decreased the synthesis of reactive oxygen and nitrogen species and increased endogenous antioxidant gene expression. Regarding anti-inflammatory capacity, resveratrol supplementation reduces the production of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNFα), interleukins like one-beta and six (Il-1β and IL-6), the production of nitric oxide (NO), and the translocation of Nuclear Factor kappa-B (NF-κB). Considering epigenetic changes, resveratrol modulates methylation and acetylation of lysine 9 of histone H3 in zygotic pronuclei. These changes in zygotes may lead to more successful preimplantation embryo development. Additionally, resveratrol can affect gut microbiota and their metabolic products, such as short-chain fatty acids and intraluminal lipids, helpful in obesity.^{Reference Hsu, Chen, Sheen and Huang60} Therefore, it has been suggested that resveratrol supplementation in early life triggered adaptative responses involving phenotypical plasticity and could be considered a reprogramming strategy against the development of obesity and related symptoms.^{Reference Tain, Lee, Wu, Leu and Chan61}

It was shown that maternal HFD consumption during gestation and lactation has undesirable long-term effects on male offspring, resulting in obesity, hyperphagia, hyperleptinemia, and leptin resistance in adulthood. The daily chronic treatment with resveratrol (30 mg/kg) from 150 until 180 d of age reversed hyperleptinemia, reduced BW, and improved central leptin action in adult rats offspring from HFD dams.^{Reference Franco, Dias-Rocha and Fernandes62} Similarly, resveratrol supplementation (42 d during pregnancy and lactation) at a concentration of 0.2% promoted the browning of white adipose tissue and increased the thermogenic activity of brown adipose tissue, reduced adiposity, and improved insulin sensitivity in adulthood in mice subjected to HFD, demonstrating that maternal resveratrol supplementation had lasting beneficial effects on offspring metabolic health.^{Reference Zou, Chen and Yang63}

Maternal resveratrol treatment of rats at a concentration of 50 mg/L of resveratrol in the water to drink before and during pregnancy and lactation (8 weeks) reduced retroperitoneal adiposity, improved leptin dysregulation by decreasing leptin/soluble leptin receptor (sOB-R) ratio, and reduced the gene expression of ATP citrate lyase (ACL) and acetyl-CoA carboxylase 2 of the retroperitoneal depot in male offspring exposed to prenatal HFD.^{Reference Tsai, Tsai and Huang64} Another experimental study showed that exposure to a maternal HFD and a post-weaning HFD led to the most significant metabolic disruption in offspring and the daily treatment with resveratrol (at 10 mg/kg, for five weeks, before mating as well as during gestation and lactation) ameliorated metabolic syndrome by reduced BW, blood pressure, leptin, cholesterol, and triglyceride (TG) serum levels.^{Reference Sheen, Yu and Tain65} In addition, an early experimental study showed that the resveratrol supplementation (50 mg/L in drinking water) to pregnant rats dams during pregnancy and lactation attenuated offspring damage induced by HFD.^{Reference Ros, Diaz and Freire-Regatillo66} The main findings demonstrated that supplementation with resveratrol during the early stages of life decreased BW, adipose tissue, and serum leptin levels in pups with 21 d of postnatal life (P21), suggesting the protective effects of resveratrol observed in the offspring dependent on the maternal diet.^{Reference Ros, Diaz and Freire-Regatillo66} Analyzing if these metabolic changes are maintained in adulthood, these authors also found that maternal resveratrol intake reduced plasma cholesterol levels in adult offspring from HFD dams. In addition, resveratrol treatment during pregnancy and 21 d of lactation decreased visceral adipose tissue (VAT) in male offspring fed on a HFD and increased VAT depots in offspring from both sexes fed on a low-fat diet (LFD), suggesting that maternal resveratrol had long-lasting effects on metabolic health in offspring in a sex-specific manner with these effects being highly dependent on the maternal diet.^{Reference Ros, Diaz and Freire-Regatillo67} These findings suggest that resveratrol treatment on different developmental windows can exert a reprogramming strategy against obesity induced by maternal HFD consumption.

In pregnant Japanese macaques fed on a HFD, the addition of 0.37% of resveratrol in the diet between 3 months before the breeding and gestational day 130 resulted in 30% maternal weight loss and improved glucose tolerance, increased uterine artery volume blood flow, and decreased placental inflammation and liver TG deposition, demonstrating that resveratrol intake during pregnancy improves maternal, placental and fetal metabolic disturbances provoked by the HFD consumption.^{Reference Roberts, Pound and Thorn68} Additionally, an early study showed that Western-style diet consumption during pregnancy impaired fetal islet capillary density and sympathetic islet innervation, suggesting a novel mechanism by which offspring are predisposed to developing type two diabetes mellitus in adulthood. Conversely, intervention with 0.37% of resveratrol in maternal diet between 3 months before the breeding and gestational day 130 restored the loss of fetal islet vascularity.^{Reference Pound, Comstock and Grove69}

Another study using the pregnant Japanese macaque reported that this maternal intervention with resveratrol before and throughout pregnancy increased placental docosahexaenoic acid uptake capacity, AMPK activation, and higher expression of multiple fatty acid transporters in the placenta, suggesting that resveratrol improves uterine and umbilical blood flow.^{Reference OʼTierney-Ginn, Roberts and Gillingham70}

The neuroprotective effects of resveratrol have also been investigated in offspring exposed to maternal obesity. For example, maternal HFD during pregnancy and lactation and a postnatal HFD promote the development of metabolic syndrome-related features, alter biochemical profiles in the dorsal hippocampus, and lead to cognitive deficits in adult male offspring. Interestingly, treatment with resveratrol during the perinatal period up to 4 months of age of the offspring improved glucose tolerance and elevated blood pressure, partly rescued cognitive deficits, and also restored the expression and regulation of silent information regulator transcript 1 (SIRT1), phospho-ERK1/2, p66Shc and brain-derived neurotrophic factor (BDNF) in the hippocampus of mice.^{Reference Li, Yu and Sheen71} However, the authors did not inform the dose and duration of treatment, making it challenging to interpret obtained findings. During pregnancy, maternal resveratrol treatment (50 mg/L in drinking water) was also reported to reduce BW, peripheral insulin resistance, blood pressure, and repaired hippocampal pAKT and BDNF in adult male offspring fed a HFD during pregnancy and postnatal period. These results indicate that supplementation with resveratrol attenuates metabolic disturbances and cognitive impairment in offspring exposed to maternal obesity.^{Reference Hsu, Sheen and Lin72}

In addition, resveratrol intake in the drinking water (50 mg/L) from 2 to 4 months for offspring reduced gut microbiota dysbiosis induced in rats by prenatal and postnatal HFD exposure.^{Reference Huang, Huang and Sheen73} Additionally, in a combined prenatal hypoxia and postnatal HFD rat model, resveratrol supplementation (4 g/kg diet) for nine weeks, starting at three weeks of age, activated AMPK and attenuated insulin resistance and hyperlipidemia in male adult offspring, suggesting that early post-weaning resveratrol treatment between 3 and 12 week contributed to the improvement of the metabolic parameters in offspring born from pregnancies complicated by intrauterine growth restriction (IUGR).^{Reference Dolinsky, Rueda-Clausen, Morton, Davidge and Dyck74}

Resveratrol treatment at 20 g/kg started one month before mating, and throughout pregnancy and lactation, decreased bodyweight, fat percentage, and improved intestinal morphological parameters in adulthood offspring.^{Reference Castro-Rodriguez, Reyes-Castro and Vargas-Hernandez75} In addition, resveratrol treatment (2 mg/kg) from day 2 to 20 postnatal life in neonatal mice subjected to a HFD reduced lipid accumulation, increased muscular capacities for fat oxidation, and mitochondria activity through activation of the SIRT1-AMPK pathways.^{Reference Serrano, Ribot, Palou and Bonet76} Another recent study demonstrated that resveratrol treatment at 1 g/kg during the perinatal period triggered long-term responses, including reduced BW, blood leptin, and TG levels in neonatal mice, and improved inflammatory response profile and cognitive function in adulthood offspring.^{Reference Izquierdo, Palomera-Avalos, Pallas and Grinan-Ferre77} Lastly, using 50 mg/L of resveratrol during the perinatal period, a loss in adiponectin and BDNF in the fetal brain was reported, as well as, long-term effects, including reduction of BW and peripheral insulin resistance, and improved cognitive function in adulthood offspring.^{Reference Hsu, Sheen and Lin78}

Resveratrol intervention on models of complicated pregnancies, including preeclampsia

Emerging evidence supports the idea that maternal intervention with resveratrol during pregnancy and lactation periods could serve as a reprogramming strategy to prevent models of complicated pregnancies, including preeclampsia (Table 3). Preeclampsia is a complication affecting pregnant women worldwide, which usually manifests as severe maternal hypertension and proteinuria.^{Reference Cerdeira, O’Sullivan and Ohuma79}

Table 3. Preclinical studies using resveratrol in the treatment of models of complicated pregnancies including preeclampsia

Maternal resveratrol supplementation (4 g/kg diet), from the first gestational day until postnatal day 21, prevented the development of hypertension in adult offspring and improved NO bioavailability in spontaneously hypertensive rats.^{Reference Care, Sung and Panahi80} Another study demonstrated that maternal resveratrol supplementation at a dosage of 50 mg/L in drinking water during the entire pregnancy and lactation (a total of 6 weeks) alleviated programmed hypertension induced by combined maternal NG-nitro-L-arginine-methyl ester (L-NAME) treatment and postnatal HFD and restored the Firmicutes to Bacteroidetes (F/B) ratio in male adult offspring.^{Reference Chen, Lin and Lin81}

In a hypertensive pregnant rat model, it was demonstrated that oral resveratrol supplementation (250 mg/kg/d) for four weeks (from the 7th week until the 10th week of pregnancy) significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure on gestational days 7 and 14. In addition, it was shown that treatment effectively increases sodium excretion and serum NO levels. These findings indicated that resveratrol could be a promising candidate as a blood pressure-lowering agent for pregnancy-induced hypertension treatment.^{Reference Jia, Zhang and Guo82}

In pregnant Sprague Dawley rat model who submitted hypoxia (11% O2) from gestational day 15–21, it was shown that at 12 months of age, hypoxia in utero and HFD, offered during nine weeks, impaired metabolic and cardiac function in a sex-specific manner, indicating that male offspring was more susceptible to a manifestation of metabolic and cardiovascular disorders compared with their female counterparts. In addition, it was found that indices of cardiac oxidative stress after ischemia-reperfusion (I/R) injury were enhanced in both male and female rat offspring exposed to prenatal hypoxia. Resveratrol supplementation in the diet (4 g/kg) for nine weeks in postnatal life attenuated insulin resistance, recovered cardiac damage provoked by I/R injury, and attenuated superoxide levels, suggesting that early intervention with resveratrol could be a potential therapeutic approach to prevent the development of metabolic and cardiovascular diseases in adult male and female offspring.^{Reference Shah, Reyes, Morton, Fung, Schneider and Davidge83}

Furthermore, these authors demonstrated that postnatal resveratrol supplementation in diet (4 g/kg) for 18 weeks (from 13 to 21 weeks of age) could reduce heart damage by increasing cardiac p-AMPK and SOD2 levels in female IUGR offspring, but not in male IUGR offspring, suggesting that resveratrol treatment of adult IUGR offspring, improved cardiac function recovery in both sexes, however, the mechanisms involved were partially sex-specific and could be a strategy to counteract also the long-term oxidative damage induced by fetal hypoxia.^{Reference Shah, Quon, Morton and Davidge35}

Additionally, it has been demonstrated that postnatal resveratrol supplementation in diet (4 g/kg) between 3 and 12 weeks of age prevented the harmful cardiovascular effects of HFD in male offspring exposed to prenatal hypoxia.^{Reference Rueda-Clausen, Morton, Dolinsky, Dyck and Davidge84} The study showed that postnatal resveratrol supplementation improved baseline heart rate and postischemic recovery in hearts from offspring born with IUGR.^{Reference Rueda-Clausen, Morton, Dolinsky, Dyck and Davidge84}

In male adult offspring exposed to combined maternal and post-weaning HFD was demonstrated that 0.5% resveratrol in drinking water between 2 and 4 months of age prevented hypertension through several underlying mechanisms, to cite: reduced oxidative stress in the kidney, mediating the renin-angiotensin system in favor of vasodilatation, restoration of nutrient-sensing pathways via increasing SIRT1, AMP-activated protein kinase 2 α (AMPK2 α), and peroxisome proliferator-activated receptor-gamma coactivator 1-α, and induction of autophagy.^{Reference Tain, Lin and Sheen85}

Similarly, it was demonstrated that early post-weaning intervention with resveratrol at a dosage of 50 mg/L in drinking water from weaning to three months of age reduced systolic blood pressure and diastolic blood pressure, as well as reduced the Firmicutes to Proteobacteria ratio; therefore, resveratrol therapy prevented the development of hypertension programmed by maternal and post-weaning high-fructose diet in male adult offspring. These results were linked to a reduction in renal oxidative stress, activation of several nutrient-sensing signals, and restoration of gut microbiota.^{Reference Tain, Lee, Wu, Leu and Chan86}

It has been reported that resveratrol at a dosage of 20 mg/kg twice a day during pregnancy reduced oxidative stress injury in pregnant rats with preeclampsia.^{Reference Zou, Zuo and Huang87} Likewise, it was demonstrated that treatment with resveratrol (20 mg/kg/d) during pregnancy stimulated trophoblastsʼ invasive capability and reduced preeclampsia-related symptoms, including reduced hypertension and proteinuria. Thus, these data suggest that resveratrol could represent a therapeutic agent to prevent the occurrence and development of preeclampsia.^{Reference Zou, Li and Wu88}

A study using a rat model of preeclampsia that received an intervention with resveratrol at a dose of 20 mg/kg/d by gavage twice daily during the whole pregnancy did not demonstrate decreased blood pressure and did not result in a significant response in blood flows and placental pathology parameters.^{Reference Moraloglu, Engin-Ustun and Tonguc33} On the other hand, in pregnant catechol-O-methyltransferase knockout mice that received a diet enriched with resveratrol (4 g/kg diet) during pregnancy (from gestational day 0.5 to 18.5) was observed an increase in uterine artery blood flow velocity and fetal weight, suggesting potential as a therapeutic strategy for preeclampsia and FGR.^{Reference Poudel, Stanley and Rueda-Clausen89}

Resveratrol intervention on maternal cardio-metabolic disorders in clinical studies

Although there is vast literature on the effect of resveratrol on maternal cardio-metabolic disorders in experimental studies, there is little data about maternal supplementation of resveratrol during the perinatal period in clinical, controlled, blind randomized trials (Table 4). The majority of clinical studies in the literature investigated the potential effects of resveratrol consumption during adult life on cardiovascular risk factors.^{Reference Huang, Chen, Liao, Zhu, Pu and Xue90}

Table 4. Clinical studies using resveratrol in the treatment of cardio-metabolic disorders

Regarding GDM, resveratrol supplementation was tested in a study using human placenta, omental adipose tissue, and skeletal muscle obtained from non-obese women who delivered healthy, singleton infants at term. Then, tissues were subjected to a diabetic model using bacterial LPS, the synthetic viral dsRNA analogous polyinosinic-polycytidylic acid, and stimulated by pro-inflammatory cytokines (i.e., IL-1β, TNF-α). To determine the effects of resveratrol, collected tissues were incubated in 10 μg/ml LPS, 50 μg/ml poly(I: C), 10 ng/ml TNF-α, 5 ng/ml IL-1β with or without 200 μm resveratrol. It was demonstrated that resveratrol was able to decrease the expression and secretion of pro-inflammatory cytokines (IL-6, IL-1α, and IL-1β) and pro-inflammatory chemokines IL-8 and monocyte chemoattractant protein-1 (MCP-1) in the placenta and adipose tissue and increase insulin sensitivity in skeletal muscle, suggesting that resveratrol could be a useful preventative therapeutic for GDM.^{Reference Tran, Liong, Lim, Barker and Lappas91}

In a prospective, randomized, double-blinded, placebo-controlled clinical trial performed with 110 overweight pregnant women was demonstrated that intervention with 80 mg of resveratrol combined with plus D-chiro-inositol and Myo-inositol during pregnancy significantly improved the glucose levels, total cholesterol, LDL-C, and TG after 30 or 60 d of supplementation.^{Reference Malvasi, Kosmas and Mynbaev37} However, the authors did not report any effect of resveratrol in attenuating BW in overweight pregnant women. Therefore, further well-designed double-blind controlled human trials are needed to confirm the clinical efficacy of resveratrol in attenuating gestational overweight.

Few clinical studies investigated the role of resveratrol in preventing preeclampsia. An RCT performed with 359 pregnant women with preeclampsia who received resveratrol capsules at a dose of 50 mg each, up to five dosages, demonstrated that resveratrol supplementation was an effective adjuvant for the treatment of hypertensive symptoms in pregnant women treated with nifedipine anti-hypertensive.^{Reference Ding, Kang, Fan and Chen36} According to this study, treatment with resveratrol attenuated time required to control blood pressure compared with the placebo group (35.6 ± 18.7 vs. 51.1 ± 22.4). In addition, supplementation with resveratrol increased the intervals between hypertensive crises. To investigate the antioxidant properties of resveratrol, a vitro study was developed by analysis of plasma collected from 30 women with preeclampsia compared with healthy pregnant, treated or not by resveratrol.^{Reference Caldeira-Dias, Montenegro and Bettiol92} The main findings showed that resveratrol improved the expression of genes and their related pathways associated with antioxidant defenses, such as increased expression of glutathione and nitrite levels. However, further clinical studies are needed to evaluate the effectiveness of resveratrol against preeclampsia disorder.