key: cord-0995652-j6ak89x5
authors: Sebastiani, Giorgia; Navarro-Tapia, Elisabet; Almeida-Toledano, Laura; Serra-Delgado, Mariona; Paltrinieri, Anna Lucia; García-Algar, Óscar; Andreu-Fernández, Vicente
title: Effects of Antioxidant Intake on Fetal Development and Maternal/Neonatal Health during Pregnancy
date: 2022-03-28
journal: Antioxidants (Basel)
DOI: 10.3390/antiox11040648
sha: 82f7c3201b0fdff354658d047a21e47831987cdd
doc_id: 995652
cord_uid: j6ak89x5

During pregnancy, cycles of hypoxia and oxidative stress play a key role in the proper development of the fetus. Hypoxia during the first weeks is crucial for placental development, while the increase in oxygen due to the influx of maternal blood stimulates endothelial growth and angiogenesis. However, an imbalance in the number of oxidative molecules due to endogenous or exogenous factors can overwhelm defense systems and lead to excessive production of reactive oxygen species (ROS). Many pregnancy complications, generated by systemic inflammation and placental vasoconstriction, such as preeclampsia (PE), fetal growth restriction (FGR) and preterm birth (PTB), are related to this increase of ROS. Antioxidants may be a promising tool in this population. However, clinical evidence on their use, especially those of natural origin, is scarce and controversial. Following PRISMA methodology, the current review addresses the use of natural antioxidants, such as epigallocatechin gallate (EGCG), melatonin and resveratrol (RESV), as well as other classical antioxidants (vitamin C and E) during the prenatal period as treatment of the above-mentioned complications. We review the effect of antioxidant supplementation on breast milk in lactating mothers.

During the prenatal period, several complications affecting the mother and the fetus can occur, with consequences for their wellbeing. Preeclampsia (PE), a multisystem progressive disease caused by placental and maternal endothelial dysfunction, usually happens late in pregnancy and complicates 2-8% of pregnancies globally [1] . Moreover, severe and early-onset PE are associated with significant fetal growth restriction (FGR) [2, 3] , that refers to the fetus that does not grow to its expected biological potential in utero. FGR affects between 3-9% of pregnancies in developed countries and up to 25% in low-middle income countries [4] . According to fetal programming theory, adverse events occurring during critical points of fetal development may cause effects on the offspring and predispose them to chronic diseases later in life [5] . Therefore, placental insufficiency can lead to long-term neurodevelopmental and metabolic diseases, as well as to significant perinatal mortality, especially among prematurely born neonates [6] . However, not only can the FGR predispose Methodological flowchart based on the PRISMA 2020 update following preferred reporting items for systematic review [20] .

PubMed (MeSH), Cochrane Central Register of Controlled Trials and Scopus were the electronic databases consulted to collect the data. We performed an initial search using the terms "((antioxidant OR natural antioxidant OR dietary supplement) AND (maternal OR pregnancy OR fetus OR neonate OR newborn OR infant))" to focus the scope of this review on those antioxidants whose effects on perinatal diseases have been analyzed in at least several studies in both human and animal models, since the information available [20] .

PubMed (MeSH), Cochrane Central Register of Controlled Trials and Scopus were the electronic databases consulted to collect the data. We performed an initial search using the terms "((antioxidant OR natural antioxidant OR dietary supplement) AND (maternal OR pregnancy OR fetus OR neonate OR newborn OR infant))" to focus the scope of this review on those antioxidants whose effects on perinatal diseases have been analyzed in at least several studies in both human and animal models, since the information available on the therapeutic effects of many antioxidants is still scarce. Once selected, the following descriptors (as MeSH terms or not) were used with the Boolean operators (AND/OR) in multiple combinations (see Supplementary Materials: Methodology): Section 3.2. "((Fetal growth restriction OR intrauterine growth restriction) AND (melatonin OR EGCG OR curcumin OR safranal OR quercetin OR resveratrol)"; ((preeclampsia) AND melatonin OR EGCG OR curcumin OR safranal OR quercetin OR resveratrol))". Section 3.3. "((obstetric labor OR premature OR preterm delivery OR premature rupture of membrane OR chorioamnionitis) AND (green tea OR EGCG))"; "((obstetric labor OR premature OR preterm delivery OR premature rupture of membrane OR chorioamnionitis) AND (melatonin))"; "((obstetric labor OR premature OR preterm delivery OR premature rupture of membrane OR chorioamnionitis) AND (Zinc))"; "((obstetric labor OR premature OR preterm delivery OR premature rupture of membrane OR chorioamnionitis) AND (vitamin C OR ascorbic acid))"; "((obstetric labor OR premature OR preterm delivery OR premature rupture of membrane OR chorioamnionitis) AND (vitamin E OR alpha tocopherol))". Section 3.4. "((vitamin C OR ascorbic acid) AND (breast milk OR human milk) AND (neonate OR newborn))"; "((vitamin E OR alpha tocopherol) AND (breast milk OR human milk) AND (neonate OR newborn))"; "((Selenium) AND (breast milk OR human milk) AND (neonate OR newborn))"; "((Zinc) AND (breast milk OR human milk) AND (neonate OR newborn))"; "((melatonin) AND (breast milk OR human milk) AND (neonate OR newborn))".

Inclusion criteria were papers written in English and Spanish (with no geographical restrictions) published from 1 January 2010 to 1 January 2022; the presence of the selected terms in the title or as keywords; and original research performed in humans. Studies based on animal models were also selected when published studies focused on the therapeutic use of a particular antioxidant to treat a specific perinatal pathology were scarce in humans. The type of experimental designs selected were classical articles, clinical studies, clinical trials, comparative studies, case-control, longitudinal cohort, and cross-sectional and case report studies with a sample size minimum of 10 participants. Exclusion criteria were non-systematic reviews, lack of a control group with no antioxidant treatment, interventions using drugs or other antioxidants that could interfere with the effects of a specific antioxidant on these pathologies, the presence of genetic or other diseases in the mother or neonate that could interfere with the alterations analyzed in this review, and papers whose output variables were not related to treatments with antioxidants during the perinatal period.

The researchers E.N.-T. and V.A.-F. for Section 3.2, G.S. and V.A.-F. for Section 3.3, and L.A.T. and M.S.-D. for Section 3.4 performed the initial selection of original manuscripts by screening titles and abstracts and creating a reference list of papers for the topics evaluated in the present review. Three investigators (E.N.-T., G.S. and V.A.-F.) conducted each stage of the study selection, deleted duplicate inputs and reviewed studies as excluded or requiring further assessment. All data were extracted by two investigators (G.S. and E.N.-T.) and cross-checked by the other two investigators (E.N.-T. and V.A.F.). In the case of discrepancies in the selected studies, we opted for reconciliation through team discussion. Moreover, the reference list of selected papers was checked manually to include some high-impact additional studies from the bibliography of the original papers or metaanalyses that were relevant to the topics addressed ( Figure 1 ). The information evaluated from each study was: first author, year of publication, experimental design (treatment duration and study groups), number of participants in the treated and control group; main outcomes/findings; conclusions; strengths and limitations (including biases). The eligibility criteria followed the PICOS approach (patient, intervention, comparators, outcome and study design). Population: fetuses or newborns diagnosed with some of the perinatal diseases included in this study (preeclampsia, fetal growth restriction, prematurity or other neonatal outcomes); intervention: any dose of antioxidant selected for this review; comparators: if applicable placebo; outcome: the primary outcome was the response of the patients or animals with some developmental alteration to the antioxidant treatment; changes in levels or expression of molecular biomarkers related to diverse physiological functions during development. All authors performed a critical appraisal of the studies selected following the inclusion criteria, also analyzing the methodology and key results.

The outputs evaluated following PRISMA were heterogeneous by the need to include animal models as well as human studies; the different populations analyzed (fetuses, newborns or infants); the small sample size observed in many of these studies; and the few randomized trials using some antioxidants as pharmacological treatment of these perinatal alterations. Finally, the studies identified through databases searching, selection after meeting the inclusion criteria and the application of the exclusion criteria were: Section 3.2 (7); Section 3.3 (33) ; Section 3.4 (12) (Figure 1 ).

The quality of evidence was based on the GRADE approach (Grades of Recommendation, Assessment, Development and Evaluation), which describes four levels of quality: high, moderate, low and very low [21, 22] . The quality of evidence was judged (Supplementary Materials Table S1 ) by all the authors (at least 2 authors independently for each section), focusing on the experimental design of the studies, number of subjects, risk of bias, inconsistency, indirectness, imprecision and relative or absolute effects observed. Disagreements were resolved through a consensus-based discussion.

After a bibliographic search, 709 published articles were identified in the databases indicated in the Material and Methods section. Once duplicate papers were deleted, the abstract and title of the potentially relevant 579 articles were reviewed, and 337 references were eliminated. Of the 579 screened studies, 242 were sought for retrieval. The full text of the remaining 228 references, once 14 references were not retrieved, was carefully analyzed and reviewed. A total of 176 articles were removed following the exclusion criteria and because they did not meet inclusion criteria due to lack of a controlled design, not meeting the setting characteristics or not meeting the review objective. Finally, 52 studies were eligible and included in this systematic review, as shown in the flowchart of Figure 1 . An additional 12 studies were included via citation searching.

To date, 7 studies have been carried out with natural antioxidants: curcumin, EGCG, melatonin and resveratrol (RESV). Their use is gaining popularity. Most of these studies were conducted in China, Australia and Brazil, and only one of them (a pilot study) was conducted in women with severe early onset FGR. Although we also included safranal in the search, due to its great antioxidant potential [23] , we did not find any clinical studies with this antioxidant in this population. A detailed summary of the main results, the population studied, and the treatments administered on PE and FGR are shown in Table 1 .

Curcumin is a polyphenolic substance generally recognized as safe (GRAS), which comes from the rhizomes of Curcuma longa (turmeric), and has been shown to have antioxidant and anti-inflammatory properties in humans [24] . In addition, it is emerging as a promising adjuvant in the fight against COVID-19 due to its potential to activate NFE2-related factor-2 (Nrf2) and decrease inflammatory cytokines [25] . The therapeutic effect of curcumin to counteract certain complications during pregnancy, such as PE and FGR, has been tested in vitro studies, showing an increase in angiogenesis and a decrease in oxidative stress through activation of the Nrf2 signaling pathway [26, 27] . To date, we have only found one human study using curcumin in women with PE; however, the variables determined and treatment period were limited [28] . The authors measured levels of cyclooxygenase-2 (COX-2), associated with increased vasoconstrictor thromboxane [29] , and IL-10 in the blood of 47 women before and after undergoing cesarean section and after taking 100 mg curcumin or a placebo ( Table 1 ). The authors found no significant differences in these variables after taking the polyphenol. Regarding FGR, we have not found human studies in which curcumin was used for its prevention. However, the beneficial effects of curcumin on PE and FGR have been observed in animal studies. Gong et al. [30] observed significant improvement of hypertension and proteinuria in a rat model of PE, obtained by intravenous administration of LPS (0.5 mg/kg LPS (Escherichia coli serotype 0111:B4) on gestational day (GD) 5. The LPS-curcumin-treated group reached control rat levels. In addition, levels of Toll Like Receptor 4 (TLR4) and inflammatory factors, such as Nuclear Factor κB (NF-κB), IL-6 and Monocyte Chemoattractant Protein-1 (MCP-1), were also significantly decreased compared to the untreated PE group. The authors also observed that the weight of the offspring in the PE group was significantly lower than in the control group. However, the weight of the offspring in the curcumin-treated PE group did not differ from the control group, demonstrating a protective effect on this variable. For the same year, Zhou et al. [31] performed a similar experiment in mice using intravenous administration of LPS: 10 µg/kg and 40 µg/kg LPS (Escherichia coli serotype 0111:B4) from GD 13.5 until GD 16.5. The authors tested a curcumin concentration 3 times lower than the one used by Gong et al. [30] , and the results revealed a significant improvement of hypertension and proteinuria in the curcumin-treated PE group, reaching control group levels in the latter case. In addition, curcumin also significantly decreased Lipopolysaccharides (LPS)-generated inflammation through upregulation of phosphorylated Protein kinase B (Akt) and significantly increased the weight and number of fetuses to control levels. No developmental alterations in fetuses were observed in any of the previous studies.

The administration of different doses of this hydrophobic polyphenol by gavage has also been tested in mouse models of fetal restriction by low-protein (LP) diets. In the study carried out by Qi et al. [32] , it was observed that a dose of 400 mg/kg/day generated significantly greater fetal gain compared to doses of 100 mg/kg/day and both doses significantly increased fetal and placental weights compared to the untreated LP group. Regardless of dose, in the placenta curcumin reduced levels of oxidative stress marker malondialdehyde (MDA) and of apoptosis to control group levels (without FGR). In contrast, these levels were significantly higher in the untreated LP group. Remarkably, the highest curcumin concentration also restored the percentage of blood sinusoid area in the placenta to control group levels. However, the bioavailability of the antioxidants was not measured in these animals. 

Epigallocatechin-3-gallate is the most abundant catechin in green tea and has been extensively studied in numerous clinical studies for the treatment of diabetes, appetite control, weight loss or cognitive improvement [39] [40] [41] [42] . Moreover, its bioavailability has been tested with different nutritional strategies, facilitating the most appropriate choice based on the purpose of the study [43] . However, there are very few clinical studies on the effect of EGCG on gestational complications, such as diabetes mellitus [44] . To date, only one study with EGCG in the PE has been identified [33] . This work (Table 1) shows that the use of EGCG in women with severe PE together with nifedipine, one the first-line drugs to treat high blood pressure, leads to a significant decrease in blood pressure until normal values compared with nifedipine alone (with the mean difference of 14.1 min). This antioxidant also increased the interval before a new hypertensive crisis [33] . Although there is insufficient evidence of the effect of EGCG on PE in humans or in animal models (with no studies in the latter), it has recently been shown that EGCG exerts a protective role against endothelial dysfunction and enhances the anti-angiogenic status in hypoxic trophoblast cells. The protective effect of EGCG appears to be due, in part, to the inhibition of the expression of the high mobility group box 1 (HMGB1), a late inflammatory factor released by trophoblasts during hypoxia that induces endothelial damage [45] . In addition, the authors observed that this antioxidant significantly increased cell viability under hypoxic conditions. These results were dose-dependent, demonstrating the usefulness of EGCG against the main causes of PE, trophoblast apoptosis and endothelial dysfunction [46, 47] .

Regarding FGR, although it has been shown in mice that antenatal ECGC can counteract the fetal restriction generated by other reasons, such as alcohol consumption [48] , its effect in humans has not been tested. The postnatal consumption of this antioxidant in mice subjected to FGR decreases fatty acid synthesis through the Ampk/Srebf1 signaling pathway and significantly reduces cholesterol and triglyceride levels in the liver compared to the untreated group [49] . The relationship between low birth weight and hypertriglyceridemia has been demonstrated [50, 51] , so postnatal use of EGCG could help to reduce cardiovascular risk in this population. However, further studies must be conducted.

RESV is a polyphenol extracted from fruit, such as grapes and cranberries, and has been reported to be safe for human consumption at doses up to 5 g per day [52] . In addition, it is able to cross the placenta in both rats and pregnant nonhuman primates [53, 54] .

As with EGCG, RESV has been used together with nifedipine in women with severe PE [35] . The results (Table 1) showed a significantly faster blood pressure decrease than with nifedipine alone, similar to those obtained with EGCG [33] . RESV, such as EGCG, also significantly increased the time interval before a new hypertensive crisis and none of them produced adverse effects at the neonatal or maternal level. However, the RESV concentration used was lower (50 mg/capsule) compared to EGCG (100 mg/capsule). Cotreatment with RESV in endothelial cells (HUVECs) treated with serum from PE pregnant women restored the levels of heme oxygenase-1 (HO-1) and nitric oxide (NO) markers [36] , key factors for placental vasculature and endothelial protection [55, 56] . Thus, the author published a pilot clinical study in PE patients years later. They showed that patients' serum after grape juice intake significantly decreased HO-1 and glutathione (GSH) levels in HUVECs, compared to juice pre-ingestion levels [37] , acting on other mechanisms compared with cotreatment of plasma from PE and RESV. Similar to the previous study with pure RESV, the treatment increased NO levels and did not alter ROS levels in these cells. Remarkably, the same concentration of serum from grape juice intake decreased the expression of the Antioxidant Response Element (ARE) in HUVECs by about 69%, in contrast to pure RESV intake, which boosted its activity by 78%. All these results show how the different active components of grape juice can act differently from RESV to exert a beneficial effect in the treatment of PE [37] .

Despite few human studies with RESV in PE, its effect has been extensively studied in murine models. Dietary supplementation with RESV in a genetic model that mimics the phenotypic characteristics of PE and FGR has shown a significant increase in uterine artery blood flow velocity and fetal weight [57] . A significant decrease in blood pressure, oxidative stress and apoptosis has also been seen in trophoblasts derived from placentas of PE rats treated with RESV [58] , as well as a significant improvement in placental epithelial characteristics [59] . However, unlike the previous study, fetus birth weight did not change compared to the non-treated group. Subcutaneous supplementation with RESV through subepidermal patches has also been tested in ewe. Results showed a significant increase in uterine artery blood flow and fetal weight, although maternal RESV treatment had no effect on placental weight [60] . All of these data present RESV as a promising therapeutic strategy for PE and FGR, although clinical studies in PE and FGR with RESV are currently very limited.

Melatonin, synthesized mainly in the pineal gland, can easily cross the placenta and exert its antioxidant action, regulate cell proliferation in the fetus, and maintain pregnancy [61, 62] . A recent meta-analysis showed that its concentration is significantly lower in women with PE and its levels correlate with the severity of the disease, being significantly lower in severe PE than mild PE [63] . Likewise, in the case of placental insufficiency, melatonin 1A and 1B receptors are significantly less expressed in the placental tissue of mothers of FGR fetuses [64] . In addition, melatonin and placental growth factor (PLGF) in the umbilical blood were significantly lower in this group compared to normal pregnancies [65, 66] . Our search only obtained two studies that focused on PE and the use of melatonin (Table 1 ). The first is a protocol for a phase I pilot clinical trial (the PAMPR Trial) in women with early-onset pre-eclampsia [67] , and their results were published five years later [34] . The use of extended-release tablets in 20 women with PE prolonged the interval from diagnosis to delivery by almost one week, although no difference in average mean arterial blood pressure was observed. Moreover, the melatonin group required less antihypertensive medication compared to historical controls [34] . Despite the limited clinical data linking melatonin to PE, extensive animal studies have demonstrated that the use of melatonin as an adjuvant in high-risk pregnancies is very promising. It has been shown recently that melatonin exerted neuroprotective effects and increased PLFG levels, a key molecule in embryonic angiogenesis and vasculogenesis, and reduced placental tumor necrosis factor-alpha (TNF-α) levels, exerting anti-inflammatory effects in a rat model of PE [68] . Melatonin also increased the transforming growth factor-beta (TGF-β) levels in the fetal brain, promoting the maturation of newborn neurons and improving brain weight. Melatonin also decreased hypertension, placental IL-6 expression, oxidative stress and proteinuria in murine models of PE [69, 70] . In offspring, maternal melatonin treatment ameliorated fetal heart damage caused by reduced uterine perfusion pressure (RUPP) [71] . Melatonin also had a global epigenetic effect during nephrogenesis and restored the ADMA-NO balance in the kidney in a rat model [72, 73] .

FGR is known to be associated with structural deficits of the brain, such as fragmentation and disorganization of the cerebral white matter tracts and decreased myelination [38] . Taking into account the relationship between FGR and oxidative stress, melatonin could help in the correct development of brain structure and function in the fetus. To date, only one pilot study relating to the neuroprotective effect of melatonin in FGR has been published [38] . The authors observed almost half the concentration of MDA in placentas from mothers who had taken 8 mg of melatonin during the last weeks of their pregnancy. In addition, melatonin was well tolerated, and no adverse effects were observed (Table 1) . Although the sample size of this study was small (12 patients) , several animal studies support the use of this antioxidant for fetal restriction [74] [75] [76] [77] [78] , and its effect in preventing oxidative stress-related FGR is greater than other compounds, such as sertraline or diazepam [79] . The intravenous administration of maternal melatonin in lambs significantly improved neonatal behaviors, lipid peroxidation, organization and density of certain brain areas and also protected the blood-brain barrier [38, 80] . No prevention of pulmonary alveolar disruption was observed [81] . Despite these facts, there are indications that melatonin may cause decreased neonatal biometric parameters in pregnancies of sheep exposed to chronic hypoxia due to high altitude, so further studies are needed in this specific population [82] .

Currently, the "PROTECT-ME" study (ACTRN12617001515381), a triple-blind, randomized, parallel group, placebo-controlled trial, is trying to determine whether antenatal maternal melatonin supplementation improves neurodevelopmental outcomes at 2 years of age in children affected by FGR. In this trial, mothers received 30 mg/day of melatonin antenatally compared to the placebo group. No results have yet been published yet [83] .

The main results obtained so far regarding the use of antioxidants in FGR and PE in humans and animals are summarized in Figure 2 . 

The global community is concerned about the burden associated with the high number of PTB and prematurity-related complications [84] . Currently, specific treatments are not always successful in delaying birth up until term age, so new strategies for preventing PTB may be useful to avoid morbidity and mortality associated with prematurity. As mentioned above, unbalanced oxidative stress during gestation may cause PPROM [15] and PTB [9] . Therefore, supplementation with classic antioxidant agents (vitamin C or vitamin E), or some trace elements with antioxidant properties, such as zinc, may be considered an option in the prevention of prematurity. In addition, other novel antioxidant strategies, such as tea or melatonin, are being considered. In this review, we selected 33 studies that analyzed the effect of the above-mentioned antioxidants on prematurity. Table 2 

The global community is concerned about the burden associated with the high number of PTB and prematurity-related complications [84] . Currently, specific treatments are not always successful in delaying birth up until term age, so new strategies for preventing PTB may be useful to avoid morbidity and mortality associated with prematurity. As mentioned above, unbalanced oxidative stress during gestation may cause PPROM [15] and PTB [9] . Therefore, supplementation with classic antioxidant agents (vitamin C or vitamin E), or some trace elements with antioxidant properties, such as zinc, may be considered an option in the prevention of prematurity. In addition, other novel antioxidant strategies, such as tea or melatonin, are being considered. In this review, we selected 33 studies that analyzed the effect of the above-mentioned antioxidants on prematurity. Table 2 summarizes the main results according to the objective of the study and the antioxidants evaluated. Gestational age at birth. Western blot analysis for SIRT1/Nrf2 analysis. RT-PCR for IL-1β, IL-6, TNF-α, COX-2 quantification.

Melatonin decreases a 30% the rate of PTB (p < 0.001). Melatonin significantly decreased TNF-α, COX-2, IL-6 and 1L-1β levels (p < 0.05) and increased SIRT1 and Nrf2 levels (p < 0.05).

The effect of melatonin in the reduction of PTB is related to its immunomodulatory effects.

To investigate the effect of melatonin on PTB in twin pregnancies.

Single-center prospective observational study.

104 twin-pregnant women.

Blood test between 9-11th GW.

Spectrophotometry for antioxidant (catalase, SOSA, GSH, thiol groups, phenolic compounds) and oxidative damage biomarkers (MDA, carboxyl groups) analysis and assessment of global antioxidant status (Antiox-S, Prooxy-S).

Immunoassay for melatonin quantification.

Melatonin was significant lower in women with PTB (p = 0.024) compared to full-term. No differences in Antiox-S and Prooxy-S according to PTB.

Lower melatonin levels in the first trimester were associated with PTB in twin pregnancies. There was no association between the night working shift and the risk of PTB. 

The effects of vitamin C on prematurity were evaluated in 10 studies. Consumption of vitamin C-rich products did not decrease the risk of PTB [97] and, in some cases, it was associated with a higher risk [85] . Nevertheless, vitamin C deficiency during pregnancy was associated with increased risk of PPROM (p < 0.05) [15, [86] [87] [88] 94, 95] , as well as a shorter latency period before birth in women with PPROM (p < 0.001) [92] . Only one study showed a higher risk of PPROM associated with higher dietary vitamin C intake in the first and second trimester of pregnancy [93] . ROS could produce collagen injury to chorioamniotic membranes, leading to PROM. In addition to its antioxidant activity, vitamin C is involved in collagen metabolism and plays an important role in the integrity of amniotic membranes. Therefore, vitamin C supplementation may be a promising therapy for the maintenance of the integrity of amniotic membranes and the prevention of PPROM. A daily dose of 100 mg vitamin C during pregnancy, as can be seen in the randomized controlled trial (RCT) of Ghomian et al. [86] , could be a good option to prevent PPROM. More studies analyzing plasmatic levels of vitamin C according to different doses are needed to assess the relationship between vitamin C and PTB or PPROM.

Vitamin E antioxidant power relies on its role as a chain-breaking antioxidant and its lipid peroxyl scavenger function [9] . Nine studies assessed the relationship between vitamin E intake and prematurity. With respect to PPROM, dietary vitamin E was not associated with a reduction in PPROM [15, 93] . However, the RCT presented by Gungorduk et al. [92] , showed a beneficial effect of vitamin E supplementation with 400 IU in combination with 1000 mg vitamin C in the reduction of the latency period to birth in PPROM patients. When analyzing PTB, the results were discordant. 3 studies [90, 96, 97] showed a preventive effect of vitamin E on PTB. The supplementation with a daily dose of 450 mg vitamin E in the Hungarian population was associated with a 30% reduction in PTB [90] . In addition, Koenig et al. [96] showed an inhibition of premature cervical remodeling in women with a high intake of vitamin E, which could explain the reduction in PTB. Conversely, other studies [89, 91, 94, 95] did not show an association between vitamin E and PTB prevention. According to the studies reviewed, vitamin E alone seems to have no effect on PPROM prevention, and it remains unclear whether vitamin E supplementation during pregnancy may be beneficial in PTB prevention. Well-designed studies are necessary to evaluate the role of vitamin E in PTB.

A number of micronutrients, including trace elements, such as zinc, are known as antioxidants or essential cofactors for antioxidant enzymes [103] . Zinc is involved in DNA synthesis as a component of nucleic acids and several enzymes [104] . Adequate zinc intake is essential for normal pregnancy development [100] . Zinc deficiency during pregnancy has been linked to PTB and other adverse obstetric outcomes; therefore, zinc supplementation during pregnancy is considered in some populations [100] . Seven studies analyzed the effect of zinc supplementation on prematurity. The RCT completed by Nossier et al. [100] showed a statistically significant reduction in PTB in mothers supplemented daily with 30 mg of zinc (1%) compared to controls (10%). However, other authors reported opposite results. According to Zahiri et al. [101] , the supplementation with 15 mg of zinc daily did not reduce the risk of PTB. Optimal zinc levels also did not reduce PTB in Japanese women who gave birth prematurely without PPROM [103] , although in this case a beneficial effect of zinc was found in reducing PPROM (p < 0.01). In addition, Nga et al. [99] also found similar rates of PTB in low-income populations supplemented with zinc compared to controls, as well as in women with dietary interventions and in vitro fertilization [98] , or previous bariatric surgery [102] . Oxidative stress-induced DNA damage could be reversed by zinc supplementation [103] , but current studies do not support the use of zinc in PTB prevention. Further studies with supplements of at least 30 mg of zinc should be conducted to clarify zinc's role in reducing PTB and PPROM.

Tea is widely consumed worldwide. Tea catechins have beneficial effects on health due to their antioxidant properties [106] . However, during pregnancy, caffeine content has been associated with PTB [107] . Seven studies evaluated the effect of tea consumption on PTB. In 4 studies [105, 106, 108, 110] , tea intake during pregnancy (green or black tea) was associated with increased risk of PTB (p < 0.05). In the remaining 3 studies [107, 109, 111] , there was no statistically significant association between tea drinking and PTB, but lower tea intake was reported in these studies. When evaluating the effect of tea on PTB, all studies analyzed consumption through the ingestion of cups of tea or food frequency questionnaires (FFQ) without differentiating the tea components, so the results are confusing. Probably, the association between tea intake and PTB found in some studies is due to caffeine content. Clinical trials are needed to evaluate the real effect of catechins in tea on prematurity prevention.

Melatonin has antioxidant effects, such as scavenging free radicals and enhancing antioxidant mechanisms, as well as anti-inflammatory effects, which can be beneficial in preventing PTB [113] . Studies in murine models [113, 114] showed the effect of melatonin on antioxidant systems, producing a statistically significant reduction in NOS and iNOS activity [113] , as well as an increase in Nrf2 and SIRT-1 levels [114] . These promising results make translation to humans possible. Results reported in two human studies [112, 115] showed an association between low melatonin levels and increased risk of PTB (p < 0.05). However, Specht et al. [116] did not find an association between night-shift working and prematurity. More human studies are needed to elucidate the effects of melatonin on antioxidant systems for the prevention of prematurity.

The main results obtained so far regarding the use of antioxidants in prematurity in humans and animals are summarized in Figure 3 . are confusing. Probably, the association between tea intake and PTB found in some studies is due to caffeine content. Clinical trials are needed to evaluate the real effect of catechins in tea on prematurity prevention.

Melatonin has antioxidant effects, such as scavenging free radicals and enhancing antioxidant mechanisms, as well as anti-inflammatory effects, which can be beneficial in preventing PTB [113] . Studies in murine models [113, 114] showed the effect of melatonin on antioxidant systems, producing a statistically significant reduction in NOS and iNOS activity [113] , as well as an increase in Nrf2 and SIRT-1 levels [114] . These promising results make translation to humans possible. Results reported in two human studies [112, 115] showed an association between low melatonin levels and increased risk of PTB (p < 0.05). However, Specht et al. [116] did not find an association between night-shift working and prematurity. More human studies are needed to elucidate the effects of melatonin on antioxidant systems for the prevention of prematurity.

The main results obtained so far regarding the use of antioxidants in prematurity in humans and animals are summarized in Figure 3 . 

Clinical trials about antioxidant supplements in lactating mothers are scarce in the literature. Most published studies are about the concentrations of antioxidants in breast milk. During the first steps of development, the embryo is exposed to low levels of oxygen. Trophoblasts are more susceptible to hyperoxia and variable amounts of oxygen. Low oxygen levels enhance the proliferation of trophoblasts, promoting maintenance of 

Clinical trials about antioxidant supplements in lactating mothers are scarce in the literature. Most published studies are about the concentrations of antioxidants in breast milk. During the first steps of development, the embryo is exposed to low levels of oxygen. Trophoblasts are more susceptible to hyperoxia and variable amounts of oxygen. Low oxygen levels enhance the proliferation of trophoblasts, promoting maintenance of cell self-renewal and regeneration [117] . The oxygen concentration vary during the different phases of gestation, from up to 20 mmHg in the first trimester to~60 mmHg in the second trimester and it progressively declines to~40 mmHg at term of gestation, so the placenta is highly sensitive to changes in oxygen levels and oxidative stress [118] . After delivery, environmental oxygen becomes predominant, being potentially toxic for infants because of the creation of ROS and free radicals [16] . Human milk contains many compounds with antioxidant properties due to their chemical structure, which promptly neutralizes free radical groups and oxidative stress, modulating redox signaling. Breast milk exerts antioxidant function as a protective mechanism against infections and diseases in order to maintain a balance between ROS and antioxidant concentrations for a healthy stable status in infants [119] . The immunomodulatory and anti-inflammatory characteristics of breast milk are performed by polyunsaturated fatty acids, growth factors, nucleotides, cytokines and antioxidants. The main antioxidant components derived from the diet in breast milk are vitamin C, α-tocopherol (vitamin E) and β-carotene (vitamin A) [16] .

Maternal diet enriched in vitamin C influences the concentrations of such antioxidants in breast milk, and high concentrations are associated with low risk of atopy in infancy, a disease characterized by increased oxidative stress [120] .

Daily supplements of 500 mg of vitamin C and 100 mg of vitamin E consumed by lactating mothers with breastfed neonates for 30 days considerably improved the antioxidant power of the breast milk. They also enhanced the antioxidant content and scavenging capacity of infant urine, emphasizing the importance of the transport of antioxidants from the breast milk to the infants and the elimination of unnecessary quantities in the infants' urine [121] . Vitamin C supplements may increase the levels in human milk in women with low content at baseline, suggesting an intrinsic mechanism related to the regulation of ascorbic acid secretion and saturation [122] . Conversely, an experimental study demonstrated that supplements with Vitamin C and iron added to human milk increased DNA damage if compared to these supplements given alone, so iron and vitamin C may be separated especially in preterm babies to avoid radical-induced damage, but more studies are necessary to demonstrate it [123] .

Vitamin E, essential for the development of the immune system, lungs, vascular system and mental development, decreases with the evolution of lactation and is scarce in mature milk [124] . The average proposed intake of vitamin E (α-tocopherol) for children between 0-6 months is in 4 mg/day [124] , its intake increases the concentration of αtocopherol in colostrum and the antioxidant capability in the newborn [125] . Supplements with α-tocopherol to mothers of preterm babies increased their levels in the colostrum and transitional milk, but not in the mature milk, so the effect doesn't seem to be prolonged [126] . A possible explanation may suggest that this antioxidant plays a significant role in lipid metabolism, so its supplementation enhances the synthesis of fatty acids by the mammary gland in the first few days after delivery and is more present in colostrum than in mature milk [127] . Therefore, the antioxidant property prompted by these 2 vitamins is more active during the first days after delivery, the most critical period to counteract oxidative stress in the newborn.

Selenium and zinc are essential trace elements that protect against oxidative stress and have immunomodulatory properties. Low levels of selenium are linked to increased oxidative lung disease [128] . No significant differences were found in selenium status at birth between appropriate for gestational age (AGA) and small for gestational age (SGA) babies. There was a variability in selenium status related to postnatal age and it was affected by the type of feeding, being breast milk the best source of selenium [129] . Zinc supplements in lactating women increased breast milk zinc levels and maternal body stores but it did not impact the infants' physical growth. This suggests that zinc stores were adequate, whether their mothers were not supplemented, probably due to the regulation mechanisms of intestinal zinc retention to meet growth demand [130] . In preterm babies, human milk fortifiers containing trace elements, calcium, phosphorus and proteins did not impact serum zinc levels at 3 and 6 weeks, and did not induce more weight gain, but selenium concentrations resulted in higher [131] . These results may be explained by the different factors that influence zinc homeostasis by modulating intestinal absorption and urine excretion, leading to different serum zinc levels. Moreover, zinc concentration in maternal milk is extremely irregular, usually unknown and drops during lactation.

In breast milk, melatonin shows an evident circadian rhythm, as seen by elevated levels during the night and untraceable levels during the day. This melatonin pattern in human milk could be necessary to inform the breast-fed infant about the moment of the day; this information could also help the infant to establish a sleep-wake pattern until the development of the mature daily rhythm [132] . Qin et al. demonstrated that melatonin showed a circadian pattern in both preterm and term breast milk among the different lactation phases. Compared with term milk, preterm milk showed a greater top concentration of melatonin in every tested lactation phase; this may be an advantage for preterm infants during the first days of life because of their immature neurological system [133] .

Melatonin levels in human colostrum showed daily fluctuation and enhanced phagocytic properties of colostrum cells against bacteria. Therefore, melatonin promotes the cellular oxidative pathways of colostrum phagocytes. Therefore, melatonin enhances colostrum's property to safeguard neonates against bacterial infections, supporting newborn's adjustment to environmental variations, leading to the formation of metabolic antioxidant pathways across breastfeeding [134] .

The main results obtained so far regarding the use of antioxidants in lactating mothers are summarized in Table 3 . 

The present work carried out an in-depth analysis of the effects of different antioxidants on fetal development, maternal health during pregnancy and neonatal health. It analyzed widely studied antioxidants, such as vitamin C and E, and new emerging antioxidants, such as curcumin, resveratrol and EGCG.

Antioxidants could have potential beneficial effects on pregnancy complications such as PE, FGR and PTB. Their principal mechanisms comprise anti-inflammatory, antiapoptotic and anti-angiogenic effects, as well as the ability to restore redox homeostasis [136] . For these reasons, the interest in their use during the perinatal period has grown.

Antioxidants have shown promising results for PE and FGR. Curcumin exerts an anti-inflammatory effect through inhibition of NF-κβ [137] , a COX-2 activator, explaining its possible therapeutic effect against PE, where higher placental levels of thromboxane related to COX-2 expression (a potent vasoconstrictor) are evident [138] . Currently, the only published work is based on a single dose, once and before cesarean section, without satisfactory results [28] . However, further studies are needed to evaluate both the effective dose and the form of administration to enhance its bioavailability and oral and gastrointestinal absorption. Micellar systems, or hydrophilic nanoparticles, could increase curcumin concentration up to 15-20 fold [139] . Other forms of administration, such as nebulized curcumin, have also shown excellent results in improving postnatal pulmonary disorders due to fetal restriction in rat pups [140] . Thus, prenatal studies in animal models show promising results against FGR, protection against placental apoptosis and poor nutrient transportation in placenta due to the loss of blood sinusoid area [32] . However, although its safety has been proven with no adverse effects on reproductive performance or embryos in animal models [141, 142] , curcumin has to be extensively studied before conducting groundbreaking studies on the use of curcumin on FGR, due to the lack of data on its use in this population.

In PE, EGCG and RESV have also shown promising results, enhancing the efficacy of nifedipine [33, 35] . Studies showed similar results in terms of the time needed to return to normal blood pressure values and the number of doses needed. However, despite the fact that these compounds have a long history of safe use, few clinical studies in pregnant women have been published. EGCG and RESV have been shown not only to improve severe PE, but also the metabolic profile in overweight and diabetic pregnant women [44, 143] .

Although the use of these antioxidants as a single therapy is still far away, these two studies create a precedent for the use of antioxidants as a coadjuvant against pregnancy complications. In this way, antihypertensive efficacy could be increased without resorting to drugs with more side effects, uncomfortable (non-oral) administration, or more expensive. Grape juice, also rich in RESV and other bioactive compounds, is more accessible and cheaper than its pure form and has been shown to balance NO levels [144] , whose decrease in serum increases the risk of PE [145] . However, its high sugar content must be taken into account. Melatonin has also achieved encouraging results in animals and its safety has been tested in women with PE [34] and on FGR [38] . Recently, it has been published that Melatonin-MT1 signal is essential for endometrial decidualization and that melatonin could reverse the inflammation and decidualization resistance induced by LPS [146] . However, there is no study or research about their long-term effects, and it could be contraindicated in populations living at high altitudes [82] . However, the use of melatonin, especially in extended-release tablets to ensure sustained high melatonin levels over time, could decrease the need for antihypertensive medication [34] , which is directly related to FGR [147] .

Oxidative stress is considered one of the pathophysiological factors related to sPTB, a worldwide problem with consequences for newborn health, so antioxidant strategies could be a feasible option for prematurity prevention. Different antioxidants are considered in this review to modulate oxidative stress linked to prematurity. Classical antioxidants, such as vitamin C or vitamin E, have been tested in different studies to evaluate their effect on PPROM and PTB reduction. Vitamin C is involved in collagen metabolism and integrity, so its use prevents ROS-induced collagen injury to chorioamniotic membranes, reducing PPROM, as shown in different studies [15, [86] [87] [88] 94, 95] . In the case of vitamin E, its lipid peroxyl scavenger function and chain-breaking antioxidant activity [9] could increase the latency period to birth in PPROM cases [92] . Additionally, vitamin E inhibits premature cervical remodeling, which can lead to PTB [96] . However, not all studies evaluating the effect of vitamin C and vitamin E on PTB have shown a reduction in prematurity. Well-designed studies with known safe doses of vitamin C and vitamin E are needed to evaluate the role of these antioxidants in PTB. Regarding zinc, studies with different daily supplementation doses have been carried out with different results. Supplementation with low doses of zinc has shown no effect on prematurity [99, 101, 103] , while doses of at least 30 mg of zinc appear to be effective in reducing PTB rates [100] through the inhibition of oxidative-stress induced DNA damage [103] .

New antioxidant strategies, such as green and black tea or melatonin, have also been evaluated for prematurity prevention. In the case of tea, despite its antioxidant power related to catechin content [106] , results from different studies showed an increase in PTB rates [105, 106, 108, 110] , probably due to caffeine content in tea [107] . It would be interesting to design studies using catechins alone to evaluate the real effect of this antioxidant on prematurity. Nevertheless, melatonin has shown promising results in murine models [113, 114] : reduced NOS and iNOS activity and increased Nrf2 and SIRT-1 levels found in these models, in combination with the free radical scavenger action, lead to a reduction in PTB. These promising results have to be translated to the human population in order to evaluate the effects of melatonin on antioxidant systems for prematurity prevention.

Once delivery occurs, the newborn replaces an intrauterine environment (with about 11% air saturation) [148] with an environment totally replete with oxygen, generating hyperoxic damage. Human milk has bioactive elements that protect newborns from cytotoxic damage to ROS during the first steps of life. These antioxidant properties of breast milk vary during the different stages of lactation being higher in colostrum and are linked to the maternal antioxidant condition, which could impact the antioxidant status of breast-fed infants [16] . Maternal nutrition influences the antioxidant concentrations in breast milk and consequently in the breastfed neonate [149] .

Although it is a challenge to meet the optimal average of vitamins and mineral requirements for breastfed neonates, because the concentrations are highly variable, supplements with antioxidants in lactating mothers seem to increase the antioxidant property of human milk, protecting breastfed babies from infections and immunological diseases. It should be taken into account that there is a significant variation in vitamins content and a different susceptibility in individuals living in different regions, so it is difficult to recommend a specific dose [127] . Moreover, our study detected limitations regarding the relatively small number of participants, maternal dietary habits, milk sample analysis method, supplements' doses and form of administration, which accentuated the differences among studies. Therefore, a balanced maternal diet continues to be essential to provide the complete transfer of antioxidants to the breastfed neonate, rather than from dietary supplements. Because a low antioxidant status of the mother may be transmitted to the infant at early unprotected stages of life, more studies about the effects of antioxidant supplements on neonatal health are required.

Although all of these results are favorable to the use of antioxidants, several aspects must be taken into account. First, commercial forms of certain antioxidants, such as RESV or EGCG, may vary in bioavailability and purity [150, 151] . Previous studies in our laboratory determined the variation in bioavailability of EGCG depending on the mode of intake, obtaining greater bioavailability in the absence of additional food but also greater variability between individuals [43] . Therefore, it is desirable that clinical studies show a prior study about the pharmacokinetics of the antioxidant to determine the best form of administration and the real product purity. Second, it is necessary to use unified animal models. For example, in both PE and FGR studies, the authors used models obtained from intraperitoneal injection of compounds such as NG-Nitro-L-arginine methyl ester (L-NAME), desoxycorticosterone acetate (DOCA) [57, 58, 152] or by genetic knockout models [153] . This, together with the fact that antioxidant blood levels and their pharmacokinetics are not usually measured, can lead to inconclusive results [152] . Moreover, we have found great variability in the timing of antioxidant intake. Whether the effect of antioxidants may have a greater or lesser effect on these outcomes, depending on whether they are taken before or in the different trimesters of pregnancy is a question to be studied in depth. Additionally, the great variability in the studied populations, with different nutritional statuses according to the income level of the country of birth, make it difficult to obtain clear results.

A consistent interaction between maternal age and the effects of certain antioxidants has recently been demonstrated. Harville et al. observed that protective effects of antioxidants were largely limited to women older than 30, while negative effects predominated in younger women [89] . This study serves as a wake-up call on the need for age stratification in future studies on the effect of antioxidants during pregnancy.

Moreover, it is important to develop exhaustive safety studies before recommendations can be made in this at-risk population. Not all antioxidants of natural origin can be considered suitable for this population; certain antioxidants, such as crocin and safranal (active ingredients of saffron) have teratogenic effects in mice, despite their use for thousands of years in cooking [154] . This work has shown the therapeutic effect of certain antioxidants on the most prevalent diseases during pregnancy, but the safety of their long-term use needs to be deeply studied.

Finally, it is crucial to clarify how antioxidants may induce epigenetic modifications during pregnancy and thus reverse programmable diseases in order to improve the health outcomes of the neonate [155] . 

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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