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Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia
Abstract
Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. There have been no material advances in the treatment of preeclampsia for nearly 50 years. Combining in vitro studies and a clinical trial, we aimed to determine if melatonin could be a useful adjuvant therapy. In a xanthine/xanthine oxidase (X/XO) placental explant model, melatonin reduced oxidative stress (8‐isoprostane) and enhanced antioxidant markers (Nrf2 translocation, HO‐1), but did not affect explant production of anti‐angiogenic factors (sFlt, sEng, activin A). In cultured HUVECs, melatonin mitigated TNFα‐induced vascular cell adhesion molecule expression and rescued the subsequent disruption to endothelial monolayer integrity but did not affect other markers for endothelial activation and dysfunction. In a phase I trial of melatonin in 20 women with preeclampsia we assessed the safety and efficacy of melatonin on (i) preeclampsia progression, (ii) clinical outcomes and (iii) oxidative stress, matching outcomes with recent historical controls receiving similar care. Melatonin therapy was safe for mothers and their fetuses. Compared to controls, melatonin administration extended the mean ±SEM diagnosis to delivery interval by 6 ± 2.3 days reduced the need for increasing antihypertensive medication on days 3‐4 (13% vs 71%), days 6‐7 (8% vs 51%) and at delivery (26% vs 75%). All other clinical and biochemical measures of disease severity were unaffected by melatonin. We have shown that melatonin has the potential to mitigate maternal endothelial pro‐oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia.
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... Clinical trials with the use of melatonin to determine its effect on preeclampsia are few with the most complete studies planned or already performed being those of Hobson and colleagues [167][168][169][170]. In these pilot clinical trials, melatonin was administered (10 mg three times daily) to 20 women with preeclampsia; it was found that this treatment prolonged the mean diagnosis to delivery interval and the need for increasing doses of antihypertensive medications. ...
... Importantly, melatonin had no adverse effects on either the mothers or the fetuses. Considering the meager advances that have been made in the treatment of preeclampsia in recent decades, the findings by Hobson and colleagues [167][168][169][170] are noteworthy and deserve follow-up investigations. ...
... In the studies by Hobson and co-workers [167][168][169][170], melatonin was given to women who already had obvious preeclampsia, i.e., melatonin was used as a treatment. It is presumed that melatonin would be better if it was used to prevent this serious condition. ...
... However, most clinical studies and animal experiments have yielded disappointing results. 9,11,[31][32][33][34] For instance, while melatonin supplementation reduces the need for higher doses of antihypertensive medication, it also leads to lower fetal birth weight and exerts an insignificant effect on repressing the production of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng). 34 sFlt-1 and sEng are antagonistic receptors for vascular endothelial growth factor/placental growth factor (PlGF) and TGF-β, respectively. ...
... 9,11,[31][32][33][34] For instance, while melatonin supplementation reduces the need for higher doses of antihypertensive medication, it also leads to lower fetal birth weight and exerts an insignificant effect on repressing the production of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng). 34 sFlt-1 and sEng are antagonistic receptors for vascular endothelial growth factor/placental growth factor (PlGF) and TGF-β, respectively. Higher concentrations of sFlt-1, sEng, or sFlt-1/PlGF in maternal serum before clinical manifestation have been associated with a significantly greater risk for PE. 6 A study conducted on a rat model resembling PE generated by reducing uterine perfusion pressure reported that melatonin administration could decrease blood pressure to some extent but had little effect on improving litter size reduction, placental weight loss, and elevated levels of sFlt-1 and pro-inflammatory cytokines. ...
... Further, long-term melatonin supplementation also results in decreased fetal birth weight. 9,11,13,[31][32][33][34]58,59 The elucidation of the orchestrated feedback network comprising T 0 , E 2 , and melatonin in the present study sheds light on the underlying mechanisms responsible for this effect. As summarized in Figure 7, in PE placenta, a decrease in melatonin levels is, at least in part, the consequence of androgen excess and the subsequent repression of E 2 -GPER1-PKA signaling. ...
Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre‐eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T 0 ) synthesis, reduced estradiol (E 2 ), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E 2 as well as elevated T 0 synthesis in PE placentas. Administration of the T 0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE‐like symptoms, along with elevated T 0 production and reduced E 2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP‐treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E 2 , but not T 0 , actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1‐PKA‐CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17β‐HSD3 and 3β‐HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T 0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.
... A further 49 articles were excluded because of reporting in vitro (15 articles) or animal studies (34 articles). Therefore, 12 manuscripts were included for the systematic review: eight articles about melatonin and PE/eclampsia [14][15][16][17][18][19][20][21] and four about melatonin and FGR [22][23][24][25]. ...
... While keeping this circadian rhythm, melatonin production slightly decreases during the first and second trimesters. It then increases, reaching its peak values after 32 weeks of gestation, followed by a rapid fall after birth [20][21][22]. Some authors investigated if this pat- tern is preserved in pregnancies with placental insufficiency or if the oxidative stress characterizing these pregnancies is reflected in a disruption of this pattern. ...
... To date, there are only two clinical trials on the effect of melatonin administration in women complicated by PE or FGR [21,25]. Although these were not double-blind placebo-controlled trials, they showed that melatonin therapy is safe for both the mother and the fetus. ...
Placental insufficiency affects about 10% of pregnancies and can lead to pre-eclampsia, fetal growth restriction, and preterm birth. Despite significant advances in early prediction and prevention of preterm pre-eclampsia with aspirin, the effects of prophylaxis on fetal growth restriction are less certain, and the rates of late-onset pre-eclampsia are not influenced by aspirin treatment. Pregnancies complicated by placental insufficiency are characterized by increased oxidative stress, and recent studies suggest that melatonin has antioxidant properties and contributes to maintaining placental homeostasis.
We aimed to systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. PubMed (Medline) and Scopus were searched until December 2020. Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in qualitative evidence synthesis.
The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency reflected by lower production of melatonin, with consequent lower systemic and placental concentrations and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Small intervention studies also suggest that treatment is safe and may lead to prolongation of pregnancy and better outcomes, but double-blind, randomized placebo-controlled trials are lacking.
... Komisaruk et al. 2011 [15] Cross-sectional 11 females Cerebrum Neuronal stimulation NA Somatotopy of the clitoris, vagina and cervix Allen et al. 2020 [14] Cross-sectional 21 [18] RCT 60 females Pineal body Melatonin supplementation NA Improvement of oocyte and embryo quality in IVF patients with sleep disorder Greendale et al. 2020 [23] Cross-sectional 20 females Pineal body Urine analysis NA secretion of melatonin is involved in cycle pacemaker control in menstruation Espino et al. 2019 [20] Cross-sectional 40 females Pineal body Melatonin supplementation NA Melatonin supplementation re-balanced the intrafollicular oxidative status in unexplained infertile patients with low melatonin levels Rad et al. 2015 [22] Cross-sectional 60 females Pineal body Blood sampling NA Melatonin and its correlation with oxidative stress biomarkers, could be involved in infertility Hobson et al. 2018 [21] RCT 20 three (20%) used kisspeptin administration, and one study each (6.67%) used urine analysis, blood sampling and kisspeptin and GnRH stimulation test. ...
... Komisaruk et al. 2011 [15] Cross-sectional 11 females Cerebrum Neuronal stimulation NA Somatotopy of the clitoris, vagina and cervix Allen et al. 2020 [14] Cross-sectional 21 [18] RCT 60 females Pineal body Melatonin supplementation NA Improvement of oocyte and embryo quality in IVF patients with sleep disorder Greendale et al. 2020 [23] Cross-sectional 20 females Pineal body Urine analysis NA secretion of melatonin is involved in cycle pacemaker control in menstruation Espino et al. 2019 [20] Cross-sectional 40 females Pineal body Melatonin supplementation NA Melatonin supplementation re-balanced the intrafollicular oxidative status in unexplained infertile patients with low melatonin levels Rad et al. 2015 [22] Cross-sectional 60 females Pineal body Blood sampling NA Melatonin and its correlation with oxidative stress biomarkers, could be involved in infertility Hobson et al. 2018 [21] RCT 20 three (20%) used kisspeptin administration, and one study each (6.67%) used urine analysis, blood sampling and kisspeptin and GnRH stimulation test. ...
... [17] The studies on melatonin supplementation affecting the pineal gland (body) reported improvements in oocyte and embryo quality, [18,19] re-balancing of intrafollicular oxidative stress level in infertile participants [20] and the prevention of maternal endothelial pro-oxidant injury. [21] A low level of melatonin was correlated with oxidative stress biomarkers, which could be involved in infertility. [22] Furthermore, the optimal secretion of melatonin was found to be involved in the control of menstruation. ...
Reproduction remains a vital characteristic of living things necessary for survival and continuity. Specific brain regions and structures are responsible for regulating the different aspects of human reproduction. This study systematically reviewed the brain regions that play structural, hormonal and physiological roles in controlling the various aspects of human reproduction from puberty, sexual function, gametogenesis, childbirth and fertility to infertility to inform advancement in research and therapeutic interventions in human reproductive disorders. A systematic literature search of online databases (MEDLINE, Europe PMC and Google Scholar) was made using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for observational and cross-sectional studies providing evidence for the role(s) of the brain region in human reproduction from the year 2011-2021. Out of 141 articles found, 15 studies met the inclusion criteria, including six cross-sectional and nine randomised controlled trials. The study acknowledged the roles of the pituitary gland, hypothalamus and pineal gland, widely known for regulating the human reproductive system in a gender-based approach while highlighting essential gaps and opportunities for future research. This review provides a 10-year update and overview of the role of different brain regions in human reproduction and will stimulate future research in human reproduction.
... Melatonin, another antioxidant, reduced oxidative stress in the placenta in preclinical trials 166 . ...
... in those with preeclampsia compared to controls and a reduced need for antihypertensive agents among the PE patients on 10 mg melatonin 166 . ...
... My analysis also identified melatonin as a potential therapeutic agent. Only one trial has been conducted on melatonin showed that melatonin improves endothelial dysfunction and prolongs pregnancy in severe PE 166 . It was also found to be safe for the mother and foetus. ...
Introduction: Preeclampsia is a complication of pregnancy that affects 2-8 % of women worldwide. It is one of the leading causes of maternal deaths and premature birth. It is diagnosed by elevated blood pressure (≥ 140/90 mmHg), proteinuria, and/or end-organ damage. Although the precise mechanisms are not fully elucidated, the placenta is involved in this disease process. However, one theory is the role of extracellular vesicles STB-EVs, which are membrane-bound biomolecules that range between 30-1000 nm in size released by the placenta and detected in the circulation. STB-EVs have been reported to be higher in the circulation in PE compared to Normal pregnancy. In addition, the phenotype of the STB-EVs is believed to be different in PE compared to NP. However, it is unclear if the clinical manifestations attributable to STB-EVs in PE are a) because PE STB-EVs are more abundant in circulation, b) because they are of a different phenotype (bigger with a different cargo), or c) a combination of both. This thesis builds on the second premise.
Aim: My work explores the possibility that STB-EVs can act as biomarkers and mechanistic and therapeutic targets in PE.
Methodology: I have isolated and characterised STB-EVs from the placenta of 8 PE and 6 NP patients via ex vivo dual lobe placenta perfusion. I subjected these materials through mass spectrometry, coding RNA, small RNA sequencing, and multi-omics (transcriptomics, proteomics, and integrated multi-omics) data analysis. This is the first study of its kind in the field.
Results: My analysis identified a difference in STB-EV cargoes' transcriptomic and proteomic profiles between preeclampsia (PE) and normal pregnancy (NP). I then identified and verified the differential expression of transcripts (FLNB, COL17A1, SLC45A4, LEP, HTRA4, PAPP A2, EBI3, HSD17B1, FSTL3, INHBA, SIGLEC6, and CGB3), microRNA (hsa-miR-193b-5p, hsa-miR-324-5p, hsa-miR-652-3p, hsa-miR-3196, hsa-miR-9-5p, hsa-miR-421, and hsa-miR 210-3p in the Medium/large STB-EVs) and proteins (FLNB (filamin B), COL17A1 (Collagen 17A1), PAPP-A2 (Pappalysin-A2), and SR-BI (Scavenger Receptor Class B Type 1)) for potential use as biomarkers in preeclampsia.
My analysis also identified 1) interesting mechanistic processes such as abnormal protein metabolism, which may be responsible for the clinical and pathological presentation of preeclamptic patients, and 2) molecular clusters that may explain variations in the presentation of PE and potential therapeutic candidates (ceforamide, thiamine, dexibuprofen)
Conclusions: I performed comprehensive profiling of the transcriptome, proteome, and pathways in PE by analysing my three different sample subtypes (placenta, M/L STB-EVs, and S STB-EVs). I identified differentially expressed biomolecules (proteins and RNAs) and uncovered mechanistic pathways which may be important in the pathophysiology of PE and could potentially be used in future studies of disease mechanisms and as biomarkers.
Access here: https://ora.ox.ac.uk/objects/uuid:04df379b-12fc-4894-903f-d394bcc84357
... 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. ...
... 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. ...
... 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]. ...
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.
... The safety of melatonin treatment for both mothers and fetuses has been established [108,109]. Melatonin administration prolongs the diagnosis-to-delivery interval by an average of 6 days and reduces the need for increased antihypertensive medication compared to the controls, and it does not affect other clinical or biochemical measures of disease severity [110]. However, there are currently no clinical trials assessing antenatal maternal melatonin supplementation for fetal neuroprotection in preeclampsia. ...
... Thus, melatonin's neuroprotective effects have only been investigated in preclinical studies, highlighting its potential as a therapeutic intervention to mitigate neurological damage in offspring. Melatonin Rattus norvegicus, injection DOCA; 10 mg/kg body weight; gavage Improves fetal brain weight; reduces fetal death rate and brain MDA; increases brain superoxide dismutase and TGF-β [64] Manages oxidative stress in the placenta and fetal cerebral cortex 3 mg orally before cesarean section [108]; 10 mg three times a day; safe for mothers and their fetuses [110] * In this study, all newborns passed their brainstem auditory-evoked response potential or similar hearing screening tests. ...
Preeclampsia, a hypertensive disorder during pregnancy, frequently correlates with adverse neurological outcomes in offspring, including cognitive impairments, autism spectrum disorder, depressive disorder, attention deficit hyperactivity disorder, and cerebral palsy. Despite these known consequences, the understanding of neuronal damage in the offspring of preeclamptic mothers remains insufficient. Here, we review the neuronal abnormalities resulting from maternal preeclampsia exposure, which include disrupted neurogenesis, loss of neuronal cell integrity, accumulation of cellular debris, decreased synaptogenesis and myelination, and increased neurite growth stimulated by maternal preeclampsia serum. The underlying mechanisms potentially driving these effects involve microglial activation, inflammatory responses, and reduced angiogenesis. Intervention strategies aimed at improving fetal neuronal outcomes are also discussed, encompassing pharmacological treatments such as pravastatin, tadalafil, and melatonin, as well as non-pharmacological approaches like dietary modifications, maternal exercise, and standard care for children. These interventions hold promise for clinical application, offering avenues to address early neuronal abnormalities and prevent the onset of long-term neurological disorders.
... We found no clinical trials whose primary outcomes were the safety and efficacy of melatonin during pregnancy. Three clinical trials used melatonin for conditions during pregnancy such as hyperglycemia [98], preeclampsia [99] and IUGR [96] reported some efficacy for each condition, although sample sizes were small. It is important to note that none of the three trials reported safety concerns or adverse maternal or fetal events related to melatonin administration during pregnancy. ...
... The dose used in these studies ranged from 8 to 30 mg daily. The trial with the highest daily dose (30 mg) reported no increased daytime drowsiness, which is an important safety finding [99]. The safety concerns about melatonin use in pregnancy originated from animal studies and include decreased birth weight [100] altered circadian rhythm development [101], and mortality [102]. ...
The effects of COVID-19 on pregnant individuals are unclear due to a series of physiological changes and immune system adaptations that may affect the development of the fetus. There is evidence supporting the role of melatonin in human pregnancy, and it appears that melatonin is essential for a successful pregnancy. However, in pathological conditions, such as during SARS-CoV-2 infection, melatonin levels can be significantly inhibited. In addition, melatonin, a powerful endogen antioxidant, free radical scavenger, and anti-inflammatory molecule, has been reported to exert beneficial effects on viral diseases such as COVID-19. This review focuses on the current evidence regarding the physiopathology of COVID-19 in pregnancy conditions, the role of melatonin during pregnancy, and the use of melatonin as a promising treatment. Addressing these points should help us understand the knowledge currently available about COVID-19 during pregnancy and explore the possible beneficial effects of melatonin. Physiological and immunological adaptations during pregnancy may result in systemic effects that greatly contribute to the development of acute viral infectious diseases such as COVID-19. Melatonin as an adjuvant in COVID-19 treatment has anti-inflammatory, anti-oxidative, and immune response regulatory functions. The strategy that melatonin offers is to slow the cytokine storm observed and reduce oxidative damage to enhance the resistance of individuals and provide additional survival time. Although the direct evidence of melatonin application in COVID-19 is unclear, both its use in experimental animal models and studies on humans has consistently documented its efficacy and safety, and its use by COVID-19 patients would be highly beneficial.
... The pineal hormone, melatonin has received strong interest for its neuroprotective benefits, including for the fetal and neonatal brain. 11,12 It is particularly appealing as a neuroprotective agent for the developing brain because it can be given to the mother during pregnancy 13 with no deleterious effects, and its small size and amphiphilic nature mean that it can cross the placenta and also the fetal blood brain barrier to act as a neuroprotectant directly to the fetus. [14][15][16] A number of studies in small and large animal models of perinatal brain injury have characterised the neuroprotective benefits of melatonin, and shown to be mediated through antioxidant, anti-inflammatory, and anti-apoptotic effects, with additional protection of cerebrovascular structure and blood-brain barrier integrity. ...
... [27][28][29] The effects of antenatal melatonin on different animal species, at different doses and assessments of fetal sex needs to be further explored. Two small human trials in which melatonin has been given maternally during pregnancy for preeclampsia 13 and FGR 19 also report mixed results, with the Hobson study finding an increased incidence of growth restriction in infants exposed to melatonin, and the Miller study finding no difference in birth weights with or without antenatal melatonin. There is currently a placebo-controlled randomised clinical trial to examine the neurodevelopmental outcomes of FGR infants treated with either melatonin or placebo (The Protect-Me trial) during pregnancy that is currently recruiting (n = 336), 30 and we keenly await these results. ...
Background
Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR.
Methods
Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected.
Results
Study groups were control ( n = 5), FGR ( n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined ( p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule ( p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex.
Conclusions
Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation.
Impact
Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination.
This preclinical study adds to the body of work on this topic, and informs clinical translation.
Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.
... The properties of melatonin on PE have also been studied in humans. In explants of PE placentas, melatonin did not reduce placental production of activin A, sFlt-1 or sEnd but it reduced oxidative stress, increasing NRF2 and HO-1 expression [157]. ...
... Melatonin Placental explants Improved oxidative stress, presumably due to the potentiation of NRF2 and HO-1. [157] Tertbutylhydroquinone (tBHQ) ...
Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models.
... Similarly, melatonin reduces the expression of vascular cell adhesion molecules induced by TNF-α and upregulates both antioxidant TXN and GCLC expression in human umbilical vein endothelial cells (HUVECs) without altering the secretion of sFlt or sEng. Melatonin has shown its safety and efficacy for both mothers and fetuses in a phase I clinical trial, leading to extended delivery interval by 6 ± 2.3 days, and the less requirement of antihypertensive medication on days 3-4 decreased from 71 to 13%, days 6-7 dropped from 51 to 8%, and at delivery reduced from 75 to 26% [151]. Hence, melatonin can be a possible adjuvant therapy to prolong the pregnancy time and improve the clinical results of PE [151]. ...
... Melatonin has shown its safety and efficacy for both mothers and fetuses in a phase I clinical trial, leading to extended delivery interval by 6 ± 2.3 days, and the less requirement of antihypertensive medication on days 3-4 decreased from 71 to 13%, days 6-7 dropped from 51 to 8%, and at delivery reduced from 75 to 26% [151]. Hence, melatonin can be a possible adjuvant therapy to prolong the pregnancy time and improve the clinical results of PE [151]. ...
Pre-eclampsia (PE), associated with placental malperfusion, is the primary reason for maternal and perinatal mortality and morbidity that can cause vascular endothelial injury and multi-organ injury. Despite considerable research efforts, no pharmaceutical has been shown to stop disease progression. If women precisely diagnosed with PE can achieve treatment at early gestation, the maternal and fetal outcomes can be maximally optimized by expectant management. Current diagnostic approaches applying maternal characteristics or biophysical markers, including blood test, urine analysis and biophysical profile, possess limitations in the precise diagnosis of PE. Biochemical factor research associated with PE development has generated ambitious diagnostic targets based on PE pathogenesis and dissecting molecular phenotypes. This review focuses on current developments in biochemical prediction of PE and the corresponding interventions to ameliorate disease progression, aiming to provide references for clinical diagnoses and treatments.
... As a therapeutic agent, melatonin also has a welldocumented side effect profile [15][16][17] with no known serious adverse effects reported in human reproduction contexts. [18][19][20][21][22] Our study tested the hypothesis that the addition of melatonin as an adjuvant to the IOL process may reduce the rate of cesarean births. ...
Introduction
Melatonin has been suggested to have a biological role in the onset and progress of labor. We tested the hypothesis that the addition of melatonin during an induction of labor will reduce the need for a cesarean birth.
Material and Methods
This trial underwent protocol amendments that are detailed in the main text of the article. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12616000311459). At a multi‐center health service including secondary and tertiary obstetric hospitals, we performed a randomized, double‐blind, placebo‐controlled trial in women with a singleton cephalic pregnancy, free of significant maternal or perinatal complications who were undergoing induction of labor (with or without cervical ripening). Women were randomized to 10 mg melatonin vs placebo, with cervical ripening as required, and then 6‐h during their induction of labor to a maximum of four doses or until birth. The primary outcome was cesarean birth. Secondary outcomes included labor, maternal, and neonatal outcomes. Data were analyzed using intention to treat. Sub‐group analyses based on mode of ripening and parity were also performed.
Results
Between 2019 and 2021 we randomized 189 women (103 to melatonin and 86 to placebo). The study was prematurely terminated due to logistical complications resulting from the COVID‐19 pandemic. Cesarean rates were 28/103 (27.2%) in the melatonin group vs 20/84 (23.3%) in the placebo group (RR 1.17 95% CI 0.71–1.92). There were no significant differences in rate of cesarean birth between the melatonin and placebo groups for failure to progress (13.4% and 9.3%, respectively, RR 1.46; 95% CI 0.64–3.32) or suspected fetal distress (10.7% and 10.5%, respectively, RR 1.02; 95% CI 0.44–2.34). The melatonin group had significantly lower rates of spontaneous vaginal birth within 24 h (35.0% vs. 50.0%; RR 0.70 95% CI 0.50–0.98). The rates of secondary outcomes such as total length of labor, rate of postpartum hemorrhage, and instrumental birth were comparable. Babies born in the melatonin group were more likely to need admission to the special care nursery, namely for hypoglycemic monitoring (18.5% vs. 8.1% RR 2.26; 95% CI 1.00–5.10).
Conclusions
In women undergoing induction of labor, melatonin does not reduce the cesarean section rate. Melatonin use intrapartum may also be associated with neonatal hypoglycemia.
... However, it notably extended the interval between diagnosis and delivery by six days when compared with historical controls. These findings may suggest that melatonin has the potential to enhance perinatal outcomes and reduce morbidity and mortality among preeclampsia patients [35]. ...
Pregnancy brings numerous physiological changes to the body of the pregnant woman. Liver diseases in
pregnancy contribute to increased oxidative stress, disrupting the delicate balance between reactive oxygen
species and antioxidant defence. Antioxidant supplementation may have potential benefits in addressing
pregnancy-related liver disorders, such as HELLP (haemolysis, elevated liver enzymes, low platelet count)
and preeclampsia-associated liver dysfunction in pregnancy.
The purpose of this narrative review is to review the evidence regarding oxidative stress in liver disorders
during pregnancy and the role of antioxidants in alleviating oxidative stress and its effect on maternal and
foetal outcomes. A narrative review study design involved a comprehensive search across three scientific
databases: PubMed, Embase, and MEDLINE, published in the last 20 years. The searches were performed up
to January 2024.
Thirty-two studies were included in the narrative review. The most studied antioxidants were vitamins
(vitamin C and E) for their role in clinical treatment, prophylaxis, and clearing surrogate oxidative stress
markers. The majority of studies were on preeclampsia. Though the existing literature is not robust,
available evidence suggests that antioxidant supplementation may have potential benefits in addressing
pregnancy-related liver disorders, such as HELLP and preeclampsia-associated liver dysfunction in
pregnancy. However, there is a need to establish consistent protocols, ethical standards, and well-designed
clinical trials to clarify the timing and dosage of antioxidants in pregnancy.
Antioxidants may alleviate the oxidative stress in various liver disorders during pregnancy, which still needs
to be studied further for their clinical relevance.
... However, it notably extended the interval between diagnosis and delivery by six days when compared with historical controls. These findings may suggest that melatonin has the potential to enhance perinatal outcomes and reduce morbidity and mortality among preeclampsia patients [35]. ...
Pregnancy brings numerous physiological changes. A delicate balance between reactive oxygen species (ROS) and antioxidant defence is disrupted which brings oxidative stress. This oxidative stress poses potential risks to maternal and foetal health. Antioxidants neutralize ROS and mitigate oxidative stress and cellular damage. This paper reviews the liver diseases in pregnancy that contribute to increased oxidative stress and studies the existing literature on various antioxidants used in liver diseases in pregnancy, the role of antioxidants in removing oxidative stress markers, usage of antioxidants in clinical practice. This paper studies the mechanism of oxidative stress in liver disease in pregnancy and widely studied antioxidants for prophylaxis and treatment. In conclusion, this paper suggests that antioxidant supplementation may have potential benefits in addressing pregnancy-related liver disorders, such as HELLP and preeclampsia-associated liver dysfunction in pregnancy. However, there is a need for establishing consistent protocols, ethical standards, and well-designed clinical trials to clarify the timings and dosage of antioxidants in pregnancy.
... In another small study that aimed to harness the antioxidant property of melatonin as a treatment for preeclampsia, pregnant women with early-onset preeclampsia received 30 mg of melatonin daily from diagnosis until delivery-in this phase I trial, melatonin significantly extended the mean diagnosis-to-delivery interval by 6 days and decreased the need for antihypertensive therapy compared to a historical control group, while no adverse drug reactions in the mothers and neonates were reported [48]. ...
Breastfeeding is the most appropriate source of a newborn’s nutrition; among the plethora of its benefits, its modulation of circadian rhythmicity with melatonin as a potential neuroendocrine transducer has gained increasing interest. Transplacental transfer assures melatonin provision for the fetus, who is devoid of melatonin secretion. Even after birth, the neonatal pineal gland is not able to produce melatonin rhythmically for several months (with an even more prolonged deficiency following preterm birth). In this context, human breast milk constitutes the main natural source of melatonin: diurnal dynamic changes, an acrophase early after midnight, and changes in melatonin concentrations according to gestational age and during the different stages of lactation have been reported. Understudied thus far are the factors impacting on (changes in) melatonin content in human breast milk and their clinical significance in chronobiological adherence in the neonate: maternal as well as environmental aspects have to be investigated in more detail to guide nursing mothers in optimal feeding schedules which probably means a synchronized instead of mistimed feeding practice. This review aims to be thought-provoking regarding the critical role of melatonin in chrononutrition during breastfeeding, highlighting its potential in circadian entrainment and therefore optimizing (neuro)developmental outcomes in the neonatal setting.
... Due to its multiple actions, MT acts as a circadian regulator, natural antioxidant, anti-infl ammatory and anti-neoplastic agent, among many other functions [8,9]. Regarding the antiinfl ammatory and circadian regulatory functions, a study by Hobson et al. 2018 shows a correlation between the circadian clock and the immune system. It is emphasized that MT is powerful in terms of circadian regulation of lymphocyte proliferation, enhancing phagocytosis and stimulating cytokine production, which is essential for the normal development of pregnancy. ...
Melatonin is an important hormone for normal pregnancy development, but the infl uence of serotonin remains poorlyunderstood. Low melatonin production can lead to spontaneous abortion by stimulating progesterone secretion and inhibiting prostaglandin synthesis. Melatonin has an eff ect on the induction and blocking of apoptosis of the villous cytotrophoblast and promotes the development of the syncytiotrophoblast. Analysis of the frequency of positive pregnancy showed a signifi cant impact on the course of pregnancy and childbirth, compliance with sleep and rest also contribute to a positive eff ect, but there is no general concept, which makes the subject relevant.The aim of the study. To evaluate the functional state of the pineal gland, in particular, the amount of melatonin and serotonin in the blood of pregnant women at 10-12 weeks of gestation with a threat of abortion, which was manifested by bloody discharge or formation of retrochorionic hematoma, and the consequences of pregnancy.Materials and methods. Two groups were formed: I main group – 40 pregnant women with a threat of abortion and formation of retrochorionic hematoma, II control group – 44 healthy pregnant women. Obstetric examination, enzyme- linked immunosorbent assay for determination of melatonin, serotonin, chorionic gonadotropin, and ultrasound were performed. Informed consent of pregnant women was obtained with adequate explanation of the purpose, objectives, methods and scope of laboratory and instrumental research methods. The study protocol was approved by the Commission on Biomedical Ethics of the Bukovinian State Medical University, 2015 (minutes of the Commission meeting No 2 from the 19.10.2023 year). The study was conducted in accordance with the basic provisions of GCP (1996), the Convention of the Council of Europe on Human Rights and Biomedicine (April 4, 1997), the Declaration of Helsinki of the World Medical Association for the Ethical Principles of Scientifi c Medical Research Involving Human Subjects (1964-2008), the Order of the Ministry of Health of Ukraine 690 of September 23, 2009 (as amended by the Order of the Ministry of Health of Ukraine 523 of July 12, 2012). Statistical analysis was performed using generally accepted methods of variance statistics. Reliability was assessed by Student’s t-test. Diff erences were considered signifi cant if the signifi cance level was p≤0.05. We also performed correlation analysis in Microsoft Excel, using the method of squares (Pearson’s method) to determine the correlation coeffi cient. The work is a fragment of the research work of the Department of Obstetrics and Gynecology, UDC 618.1-053.34 + 618.1-0536 /.8]. –07-084-08 «Prevention, diagnosis and treatment of disorders of the perinatal period and reproductive system of women and adolescent girls» (No. 201110Н, state registration number 0111U006499. The term of implementation is 02.2011-12.2015).Results of the study. According to the obtained results, retrochorionic hematoma up to 1 cm is detected three times more often than over 1 cm, while the level of melatonin is not signifi cantly lower, but with retrochorionic hematoma over 1 cm a signifi cant decrease is observed in cases of further normal pregnancy and childbirth. With further complications of pregnancy in retrochoroidal hematoma up to 1 cm, there is a signifi cant signifi cant decrease in melatonin (p ˂ 0.001), in contrast to retrochoroidal hematoma over 1 cm, where no signifi cant diff erence was found in the complicated course of pregnancy (p > 0.05). Serotonin levels were elevated in all subgroups regardless of hematoma size and subsequent pregnancy outcome. Conclusions. In case of threatened abortion in the fi rst trimester with formation of retrochorionic hematoma, the risk ofcomplicated pregnancy remains in 60.87 % of cases. Determination of pineal hormones revealed a signifi cant increase inserotonin with a simultaneous signifi cant decrease in melatonin, while maintaining a positive relationship between the hormones, indicating a disruption of melatonin synthesis in the central nervous system. This is confi rmed by the normal level of chorionic gonadotropin and the preservation of embryonic viability. Since the disruption of hormone formation in the pineal gland has been established, adherence to the recommendations for adequate rest may positively aff ect the further outcome of pregnancy and childbirth.
... Placental hypoxia can produce a large amount of oxygen free radicals, but antioxidant capacity is insufficient at this time and the equilibrium is disrupted. This causes vascular endothelial cell damage and further promotes PE occurrence and progression (10). Uric acid (UA) is the final product in purine metabolism, an important oxidant in vivo, and mainly eliminated by the kidneys (11). ...
Introduction:
Preeclampsia (PE), at early onset, is likely to be diagnosed as gestational hypertension (GH). Some cases of GH rapidly progress to PE within a short period of time, increasing the mortality rate of pregnant women and adverse events in neonates during the peripartum period. Oxidative stress participates in the occurrence and progression of PE. However, it is unknown whether the progression of GH to PE can be predicted.
Methods:
A total of 1548 patients diagnosed with PE (649 cases) or GH (899 cases) from January 2016 to June 2022 were selected as the study subjects. The 1548 patients were randomly divided into the training set (1083 cases) and the validation set (465 cases) in a 7:3 ratio. General and clinical data were collected to construct a risk factor prediction model for PE.
Results:
We found that (1) Systolic blood pressure (SBP), and uric acid (UA)/ superoxide dismutase (SOD) were the risk factors for the progression of GH to PE; (2) A nomogram was constructed from the prediction model, and the area under the curve (AUC) was 0.95, with a sensitivity of 87.4%, a specificity of 92.8%; (3) Build a model simplified scoring system. PE was most strongly predicted by UA/SOD (100 points), SBP (29 points), and serum potassium (19 points). The AUC was 0.92, with a sensitivity of 91.0%, a specificity of 81.7%. The clinical decision analysis curve shows that the model exhibits positive benefits when the threshold probability is at 0.01-0.91.
Conclusion:
These findings show that UA/SOD can predict progression of GH to PE.
... [14,15] Besides, the confidence intervals of study results are wide. [16] Therefore, a systematic review is necessary to be conducted to combine the results of various studies. The aim of this study was to review all existing literature to investigate reproductive outcomes after TCRA in women with moderate and severe IUA. ...
Background:
Intrauterine adhesions (IUA) refers to the adhesion of the inner wall of the uterus, resulting in complete or partial occlusion of the uterine cavity, which causes a series of symptoms. Transcervical resection of adhesion (TCRA) is the standard surgical method for patients with IUA. However, the recurrence rate of women with moderate to severe IUA is high and it has raised a big concern about the reproductive outcomes.
Methods:
We conducted a scoping review by using 4 databases, including Google Scholar, PubMed, Scopus, Embase, and web of science, to retrieve relevant literature from September 1, 2001, to February 1, 2023, and to explore the reproductive outcomes in women with moderate to severe IUA after TCRA treatment. Following defined guidelines, data extraction was carried out by 2 researchers, and the findings were examined by 2 senior academics. The papers were evaluated by 2 reviewers using the inclusion and exclusion criteria. Using a form developed especially for this study, pertinent information was retrieved, including the first author, research design, study duration, age, intervention measurement, pregnancy rate, techniques of conception, and live birth rate. Two researchers conducted a quality assessment to determine any potential bias using the Cochrane technique and the Newcastle-Ottawa scale. RevMan 5.4.1 (The Cochrane Collaboration, London, United Kingdom) was used for data analysis, while I2 was used to evaluate heterogeneity.
Results:
In total, this study included 2099 participants. After a detailed systematic review and meta-analyses, the results showed that pregnancy and live birth rates were increased significantly after TCRA, and the risk difference of the pregnancy rate was 1.75 [1.17, 2.62]. Besides, in 2 retrospective studies, the risk difference of live birth rate was 2.26, with a 95% confidence interval of 1.99 to 2.58. Moreover, the menstrual status of women also was improved, and the risk difference of hypermenorrhoea and amenorrhea were -0.28 [-0.37, -0.19] and -0.06 [0.26, 0.13], respectively.
Conclusions:
Taken together, TCRA is the useful strategy for the treatment of moderate to severe IUA to enhance the reproductive outcomes in women.
... Systemic arteriole spasm is considered the primary pathological change in PE. The progression of the disease can lead to increased peripheral resistance and reduced organ blood perfusion, tissue hypoxia, and ischaemia, causing damage to the mother and baby [12,13]. ...
This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.
... In this direction, studies indicate that using a ROStargeted therapy with antioxidants may be a promising approach in perinatal medicine, especially for fetal neuroprotection (196). However, many proposed drugs are still under investigation for routine clinical use, such as vitamins, melatonin, lycopene, selenium, acetylsalicylic acid, L-ergothioneine, and mitochondria-specific drugs (197)(198)(199)(200)(201)(202)(203)(204)(205)(206)(207)(208)(209)(210). ...
Millions of infants are born prematurely every year worldwide. Prematurity, particularly at lower gestational ages, is associated with high mortality and morbidity and is a significant global health burden. Pregnancy complications and preterm birth syndrome strongly impact neonatal clinical phenotypes and outcomes. The vascular endothelium is a pivotal regulator of fetal growth and development. In recent years, the key role of uteroplacental pathologies impairing endothelial homeostasis is emerging. Conditions leading to very and extremely preterm birth can be classified into two main pathophysiological patterns or endotypes: infection/inflammation and dysfunctional placentation. The first is frequently related to chorioamnionitis, whereas the second is commonly associated with hypertensive disorders of pregnancy and fetal growth restriction. The nature, timing, and extent of prenatal noxa may alter fetal and neonatal endothelial phenotype and functions. Changes in the luminal surface, oxidative stress, growth factors imbalance, and dysregulation of permeability and vascular tone are the leading causes of endothelial dysfunction in preterm infants. However, the available evidence regarding endothelial physiology and damage is limited in neonates compared to adults. Herein, we discuss the current knowledge on endothelial dysfunction in the infectious/inflammatory and dysfunctional placentation endotypes of prematurity, summarizing their molecular features, available biomarkers, and clinical impact. Furthermore, knowledge gaps, shadows, and future research perspectives are highlighted.
... Daily supplementation of melatonin in PCOS women showed a significant improvement in pregnancy rates [199]. Importantly, the overall effects of melatonin supplementation in fetal growth restriction, pre-eclampsia, and climacteric symptoms appear to be promising and clinically relevant [200][201][202]. Likewise, women with endometriosis also have menstrual and poor obstetrics outcomes as summarized in Table 2. Therapeutic strategies that are safe and with minimal reproductive side effects are essential to women with endometriosis. ...
Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.
... In support of this notion, preeclampsia is associated with decreased expression of AANAT, MT1, and MT2, as well as decreased placental melatonin concentrations (257). The antioxidant and cytoprotective properties of melatonin, combined with its biosafety profile, make it a promising therapeutic treatment for a range of pregnancy complications, particularly those arising from oxidative stress, with clinical trials ongoing (192,292). ...
Circadian rhythms are endogenously generated, daily patterns of behavior and physiology that are essential for optimal health and disease prevention. Disruptions to circadian timing are associated with a host of maladies, including metabolic disease and obesity, diabetes, heart disease, cancer, and mental health disturbances. The circadian timing system is hierarchically organized, with a master circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks throughout the CNS and periphery. The SCN receives light information via a direct retinal pathway, synchronizing the master clock to environmental time. At the cellular level, circadian rhythms are ubiquitous, with rhythms generated by interlocking, autoregulatory transcription-translation feedback loops. At the level of the SCN, tight cellular coupling maintains rhythms even in the absence of environmental input. The SCN, in turn, communicates timing information via the autonomic nervous system and hormonal signaling. This signaling couples individual cellular oscillators at the tissue level in extra-SCN brain loci and the periphery and synchronizes subordinate clocks to external time. In the modern world, circadian disruption is widespread due to limited exposure to sunlight during the day, exposure to artificial light at night, and widespread use of light-emitting electronic devices, likely contributing to an increase in the prevalence, and the progression, of a host of disease states. The present overview focuses on the circadian control of endocrine secretions, the significance of rhythms within key endocrine axes for typical, homeostatic functioning, and implications for health and disease when dysregulated. © 2022 American Physiological Society. Compr Physiol 12: 1-30, 2022.
... У доклінічних дослідженнях мелатонін зменшував плацентарний окиснювальний стрес та посилював синтез молекул, які беруть участь у антиоксидантному захисті. У дослідженні I фази із однією групою команда дослідників повідомила, що призначення 10 мг перорального мелатоніну 3 рази на день 20 жінкам із допологовою ПЕ подовжило вагітність у середньому на 6,0±2,3 доби та зменшило потребу в антигіпертензивних препаратах порівняно із аналогічним показником у жінок контрольної групи [26,31]. Подальших досліджень мелатоніну не зареєстровано. ...
Preeclampsia (PE) is a main cause of morbidity and mortality for both mother and fetus. The frequency of PE is from 2 % to 8 %. The complications which are related to PE lead to more than 50,000 maternal deaths and more than 500,000 fetal deaths worldwide each year. In Ukraine, PE was diagnosed in 11,075 women in 2020 (39.32 per 1,000 births), of which severe PE was diagnosed in 1,573 women (5.58 per 1,000 births).The advances in obstetrics and neonatology have significantly mitigated many adverse pregnancy outcomes associated with PE. The optimal prevention of PE is essential to prevent the morbidity and mortality associated with this pathology. The number of researches about new management for the prevention or treatment of PE and new drugs that can affect the pathophysiology of the disease increases. The main value of potential candidates for the prevention of PE is the preclinical impact on oxidative stress, antiangiogenic factors, as well as thrombogenic potential and proinflammatory pathways of pathology development. A systematic data search was carried out in MEDLINE, ISI Web of Science, PubMed, Scopus, Google Scholar and Proquest databases for 2014–2022. In this review, the results of preclinical and clinical studies about the rational prevention of the development of PE in pregnant women at risk with the involvement of the most promising drugs were analyzed. Preclinical studies have suggested new molecular targeting strategies, such as monoclonal antibodies directed against tumor necrosis factor alpha, placental growth factor, and short interfering ribonucleic acid technology to inhibit soluble fms-like tyrosine kinase-1 or angiotensinogen gene expression. Other treatment approaches that have progressed to phase III trials (either completed or ongoing) include proton pump inhibitors, metformin, nitric oxide donors and precursors, recombinant antithrombin III, digoxin immune antigen, and melatonin. There are cases suggesting that deletion of circulating soluble fms-like tyrosine kinase-1 can help to stabilize PE and prolong pregnancy.
... This is important information for developing this antioxidant as a safe intervention for pregnancy complications, particularly as melatonin is currently being trialed in human pregnancies complicated by fetal growth restriction and pre-eclampsia. 46,49 ...
Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodelling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, ROS production and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13 % oxygen) during gestational days 6‐20 (term ~ 22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On gestational day 20, mitochondrial aerobic respiration and H2O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase activity. Gestational hypoxia reduced maternal body weight gain (p < 0.01) and increased placental weight (p < 0.05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at complex II (p < 0.05), and an increase in H2O2 production/O2 consumption (p < 0.05) without any changes in lipid peroxidation. Citrate synthase activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < 0.001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies. This article is protected by copyright. All rights reserved.
... Studies have shown that the Gas6 gene expression is abnormal in preeclampsia placenta and decidua tissues (11). Since Gas6 is involved in the interaction between endothelial cells, coagulation and platelets, it can be speculated that Gas6 may be involved in the pathological process of preeclampsia (12). Related studies have shown that serum Gas6 levels in preeclampsia patients are significantly increased compared with healthy pregnant women with age matching (13). ...
Early preeclampsia is a pregnancy-specific clinical disease, its pathogenesis is not clear, and clinical treatment is limited. Therefore, it is particularly important to study the pathogenesis of early preeclampsia, so as to provide evidence for the diagnosis and effective treatment of early preeclampsia. This research was carried out to investigate the expression levels and clinical significance of mir-145-5p and stagflation specific gene 6 (Gas6) in serum of women with early preeclampsia. For this purpose, 142 patients with preeclampsia were divided into the early-onset group (n=78) and the late-onset group (n=64) according to the onset time. Meanwhile, 70 normal pregnant women were selected as the control group. The levels of serum Gas6, mir-145-5p and inflammatory factors were detected. Logistic regression analysis showed that the expression levels of serum gas-6 and serum mir-145-5p were valuable in the diagnosis of early preeclampsia. ROC curve was established to evaluate the diagnostic efficacy of serum Gas6 level in early-onset preeclampsia. Its sensitivity and specificity were 91.23% and 64.2%, respectively, and the cutting value was 255.71pg/mL. The serum Gas6 level was negatively correlated with systolic blood pressure (r=-0.349, P<0.05) and positively correlated with platelet count (r=0.391, P<0.05). Compared with the control group, serum levels of mir-145-5p and TNF-a in women with early-onset preeclampsia were negatively correlated (r=-0.460~0.622, P<0.05). Conclusion: the serum level of Gas6 was reduced in patients with early-onset preeclampsia, and TNF-a inhibited the invasion of SVneo cells by upregulating mir-145-5p.
... A recent randomized controlled trial [97] on melatonin supplementation with 30 mg/daily versus the placebo was studied, showing a significantly longer interval from preeclampsia diagnosis to delivery in the intervention group. Although no significant change in maternal blood pressure or uterine artery PI was observed, women receiving melatonin required less antihypertensive drugs compared to controls. ...
Human pregnancy can be affected by numerous pathologies, from those which are mild and reversible to others which are life-threatening. Among these, gestational diabetes mellitus and hypertensive disorders of pregnancy with subsequent consequences stand out. Health problems experienced by women during pregnancy and postpartum are associated with significant costs to health systems worldwide and contribute largely to maternal mortality and morbidity. Major risk factors for mothers include obesity, advanced maternal age, cardiovascular dysfunction, and endothelial damage; in these scenarios, oxidative stress plays a major role. Markers of oxidative stress can be measured in patients with preeclampsia, foetal growth restriction, and gestational diabetes mellitus, even before their clinical onset. In consequence, antioxidant supplements have been proposed as a possible therapy; however, results derived from large scale randomised clinical trials have been disappointing as no positive effects were demonstrated. This review focuses on the latest evidence on oxidative stress in pregnancy complications, their early diagnosis, and possible therapies to prevent or treat these pathologies.
Context Melatonin administration during pregnancy can influence fetal development and lactation. Aims This study aimed to verify whether melatonin treatment of pregnant Sarda ewes in spring improved lamb weight at birth, 7 and 21 days of age, time to first colostrum intake, birth behavior and survival. Additionally, we examined melatonin’s effect on milk yield and composition. Methods On 18 April, 200 ewes were assigned to two groups of 100 each, based on lambing date, body condition score, parity, age and milk yield. One group received melatonin implants on 20 April, 4 July and 17 September; the other served as control. Rams (12 per group) were introduced on 25 May and removed after 40 days. Lamb weight was recorded at birth, 7 and 21 days, while milk yield and composition were assessed bi-weekly from day 30 of lactation. Key results Lambs born to melatonin-treated ewes were heavier at birth (3.54 vs 2.89 kg), and at 7 (5.21 vs 4.40 kg) and 21 days of age (11.3 vs 10.1 kg) and reached colostrum intake sooner than lambs from untreated ewes (55.5 ± 5.3 vs 69.4 ± 5.6 min). Milk yield was higher in melatonin-treated ewes, with somatic cell counts decreasing in treated animals and increasing in controls over the five samplings. Milk fat was higher in treated ewes than controls during early lactation, although protein and lactose levels remained similar between groups. Conclusion Melatonin treatment throughout pregnancy improved lamb growth and milk production and quality, suggesting a potential management advantage for sheep.
Introdução: Em virtude das graves repercussões da insônia sobre a saúde do binômio materno-fetal, esforços vêm sendo despendidos no sentido de encontrar alternativas terapêuticas eficientes e seguras. Objetivos: Em vista disso, objetivou-se reunir as evidências disponíveis acerca dos fármacos comumente prescritos às gestantes para o tratamento da insônia em relação aos efeitos potencialmente deletérios sobre a saúde materno-fetal, tendo em vista que o impacto negativo do distúrbio não tratado deve ser levado em consideração. Metodologia: Trata-se de uma revisão sistemática da literatura realizada por meio de buscas de artigos indexados nas bases de dados MEDLINE, LILACS e IBECS. Resultados: Ao total foram selecionados 19 estudos cujos resultados evidenciaram que as opções farmacológicas disponíveis para o tratamento da insônia na gestação incluem benzodiazepínicos e medicamentos relacionados aos benzodiazepínicos, como medicamentos Z, antipsicóticos, antidepressivos sedativos e melatonina. A revisão de literatura sobre os fármacos comumente prescritos às gestantes para o tratamento da insônia evidencia melhora no sono, mas não existem estudos adequados e bem controlados em humanos sobre a segurança clínica, tendo em vista os riscos à saúde do binômio materno-fetal. Sugere-se que os benefícios potenciais podem justificar o uso do medicamento em mulheres grávidas, sobretudo nos casos graves de insônia e quando não há alternativas terapêuticas. Conclusão: Por se tratar de um grande desafio na prática clínica, as diretrizes internacionais estabelecem uma abordagem compartilhada de tomada de decisão, envolvendo a gestante e os seus familiares, para a prescrição de terapia farmacológica para insônia durante a gravidez.
Aim
Preeclampsia (PE) is a critical and severe disease in obstetrics, which seriously affects maternal and neonatal life safety and long‐term prognosis. However, the etiology and pathogenesis of PE are complex, and no unified conclusion has been reached. The types and number of exosomes and their transport substances in PE patients changed. The study of exosomes in PE patients helps clarify the etiology, diagnosis, effective treatment, accurate monitoring, and prognosis.
Method
The published articles were reviewed.
Results
Exosomes may affect endothelial and vascular production and function, participate in maternal‐fetal immune regulation, and transport substances such as miRNAs, lncRNAs, and proteins involved in the development of PE. Detection of the contents of exosomes can help in the early diagnosis of PE, and can help to improve PE by inhibiting the action of exosomes or preventing their binding to target organs.
Conclusion
Exosomes may be involved in the development of PE, and exosomes can be used as markers for predicting the onset of PE and tracking the disease process and determining the prognosis, and exosomes have great potential in the treatment of PE.
Introduction
Excessive calorie intake poses a significant threat to female fertility, leading to hormonal imbalances and reproductive challenges. Overconsumption of unhealthy fats exacerbates ovarian dysfunction, with an overproduction of reactive oxygen species causing oxidative stress, impairing ovarian follicle development and leading to irregular ovulation and premature ovarian failure. Interest in biological matrices with high antioxidant properties to combat diet-related oxidative stress has grown, as they contain various bioactive factors crucial for neutralizing free radicals potentially preventing female reproductive health. This systematic review evaluates the female reproductive impact of biological matrices in mitigating oxidative damages induced by over calory habits and, in particular, high fat diets.
Methods
A comparative approach among mammalian models was utilized to interpret literature available data. This approach specifically investigates the antioxidant mechanisms of biological matrices on early and late ovarian folliculogenesis, under physiological and hormone-induced female reproductive cycle. Adhering to the PRISMA 2020 guidelines, only English-language publications from peer-reviewed international indexes were considered.
Results
The analysis of 121 publications meeting the inclusion criteria facilitated the identification of crucial components of biological matrices. These components, including carbocyclic sugars, phytonutrients, organosulfur compounds, and vitamins, were evaluated for their impact on ovarian follicle resilience, oocyte quality, and reproductive lifespan. The detrimental effects of oxidative stress on female fertility, particularly exacerbated by high saturated fat diets, are well-documented. In vivo studies across mammalian preclinical models have underscored the potential of antioxidants derived from biological matrices to mitigate diet-induced conditions. These antioxidants enhance steroidogenesis and ovarian follicle development, thereby improving oocyte quality. Additionally, discussions within these publications emphasized the clinical significance of these biological matrices, translating research findings into practical applications for female health.
Conclusion
Further research is essential to fully exploit the potential of these matrices in enhancing female reproduction and mitigating the effects of diets rich in fatty acids. This requires intensified in vitro studies and comprehensive collection of in vivo data before clinical trials. The promotion of ovarian resilience offers promising avenues for enhancing understanding and advancing female reproductive health world-wide.
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs.
Cardiovascular–kidney–metabolic (CKM) syndrome has emerged as a major global public health concern, posing a substantial threat to human health. Early-life exposure to oxidative stress may heighten vulnerability to the developmental programming of adult diseases, encompassing various aspects of CKM syndrome. Conversely, the initiation of adverse programming processes can potentially be thwarted through early-life antioxidant interventions. Melatonin, originally recognized for its antioxidant properties, is an endogenous hormone with diverse biological functions. While melatonin has demonstrated benefits in addressing disorders linked to oxidative stress, there has been comparatively less focus on investigating its reprogramming effects on CKM syndrome. This review consolidates the current knowledge on the role of oxidative stress during pregnancy and lactation in inducing CKM traits in offspring, emphasizing the underlying mechanisms. The multifaceted role of melatonin in regulating oxidative stress, mediating fetal programming, and preventing adverse outcomes in offspring positions it as a promising reprogramming strategy. Currently, there is a lack of sufficient information in humans, and the available evidence primarily originates from animal studies. This opens up new avenues for novel preventive intervention in CKM syndrome.
A insônia é uma importante causa de sofrimento para as gestantes e é, frequentemente, subdiagnosticada e subtratada. As dúvidas quanto à segurança dos fármacos no tratamento da insônia nesse período faz com que psiquiatras e obstetras apresentem receio em prescrevê-los. O presente estudo trata-se de uma revisão que objetivou conhecer o que a literatura médica traz a respeito do tratamento medicamentoso da insônia em gestantes, além de reflexões acerca do tema. Para tanto, a busca foi feita na base de dados Pubmed, por meio de combinações das palavras-chave. Artigos que versavam apenas sobre tratamento não medicamentoso foram ignorados, uma vez que esse não é o objetivo do trabalho. Foram avaliados como possíveis tratamentos os benzodiazepínicos, drogas Z, antipsicóticos, anti-histamínicos, antidepressivos e melatonina. Ainda, esse artigo traz uma breve explicação sobre a mudança na classificação de risco dos psicofármacos na gestação e lactação. Em substituição ao sistema de letras (ABCDX), a FDA traz a Regra de Rotulagem para Gravidez e Lactação (PLLR).
During pregnancy, the risk of maternal and fetal adversities increases due to physiological changes, genetic predispositions, environmental factors, and infections. Unfortunately, treatment options are severely limited because many essential interventions are unsafe, inaccessible, or lacking in sufficient scientific data to support their use. One potential solution to this challenge may lie in emerging RNA therapeutics for gene therapy, protein replacement, maternal vaccination, fetal gene editing, and other prenatal treatment applications. In this review, the current landscape of RNA platforms and non‐viral RNA delivery technologies that are under active development for administration during pregnancy is explored. Advancements of pregnancy‐specific RNA drugs against SARS‐CoV‐2, Zika, influenza, preeclampsia, and for in‐utero gene editing are discussed. Finally, this study highlights bottlenecks that are impeding translation efforts of RNA therapies, including the lack of accurate cell‐based and animal models of human pregnancy and concerns related to toxicity and immunogenicity during pregnancy. Overcoming these challenges will facilitate the rapid development of this new class of pregnancy‐safe drugs.
In this review, we provide a comprehensive overview of common sleep disorders during pregnancy, including their characterization, prevalence, risk factors, and possible contribution to maternal and fetal outcomes. We conducted a quasi-systematic literature search of the MEDLINE database and identified 744 studies from 1991 through 2021, inclusive, that met our inclusion criteria. We synthesized the existing literature on sleep disorders during pregnancy and highlighted controversies, research gaps, and needed clinical developments. Our review covers a range of sleep disorders, including insomnia, obstructive sleep apnea, restless legs syndrome, and circadian rhythm disorders. We discuss the prevalence of these disorders in pregnancy and their potential impact on maternal and fetal health outcomes. We also explore the relationship between sleep disorders, pre-pregnancy comorbidities such as obesity, and pregnancy-related conditions such as gestational diabetes mellitus and preeclampsia. In addition to summarizing the existing literature on sleep disorders during pregnancy, we also highlight opportunities for further research in this area. We suggest that future studies should strive to employ validated and objective measurement tools for sleep disorders and prioritize utilization of longitudinal methods with participant follow-up through postpartum, mid-life, menopause, and beyond. We also put forward investigation into the impact of circadian rhythm disruption on reproductive physiology and early pregnancy outcomes as an area of important work. Overall, our review provides valuable insights on sleep and reproduction and into common sleep disorders during pregnancy and their potential impact on maternal and fetal health outcomes.
The population of T lymphocytes producing IL-17 (Th17) plays a dual role during pregnancy and its activity is tightly controlled during this period. One of the factors involved in this process may be the pineal hormone melatonin, which can effectively regulate this T cell population. Here we have shown that exogenous melatonin in pharmacological concentrations is able to enhance the differentiation of Th17 cells of pregnant women in vitro. The stimulatory effects of melatonin were limited to in the first trimester of pregnancy and were apparently mediated by both membrane and nuclear melatonin receptors. Since exogenous melatonin is currently considered as a promising drug in solving various problems associated with reproduction, it is necessary to take into account its immunoregulatory effects.
Hypertensive disorders of pregnancy (HDP) are one of the most commonly occurring complications of pregnancy and include chronic hypertension, gestational hypertension, and pre-eclampsia. New developments in early pregnancy screening to identify women at high risk for pre-eclampsia combined with targeted aspirin prophylaxis could greatly reduce the number of affected pregnancies. Furthermore, recent advances in the diagnosis of pre-eclampsia, such as placental growth factor based testing, have been shown to improve the identification of those pregnancies at highest risk of severe complications. Evidence from trials has refined the target blood pressure and timing of delivery to manage chronic hypertension and pre-eclampsia with non-severe features, respectively. Importantly, a wealth of epidemiological data now links HDP to future cardiovascular disease and diabetes decades after an affected pregnancy. This review discusses the current guidelines and research data on the prevention, diagnosis, management, and postnatal follow-up of HDP. It also discusses the gap in knowledge regarding the long term risks for cardiovascular disease following HDP and illustrates the importance of improving adherence to postnatal guidelines to monitor hypertension and the need for more research focused on primary prevention of future cardiovascular disease in women identified as being at high risk because of HDP.
Objectives:
Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal-fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditions.
Methods:
To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14.
Results:
The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.
Conclusions:
These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.
Graphical abstract:
http://links.lww.com/HJH/C198.
It is estimated that more and more couples suffer from fertility and pregnancy maintenance disorders. It is associated with impaired androgen secretion, which is influenced by many factors, ranging from genetic to environmental. It is also important to remember that fertility disorders can also result from abnormal anatomy of the reproductive male and female organ (congenital uterine anomalies – septate, unicornuate, bicornuate uterus; acquired defects of the uterus structure – fibroids, polyps, hypertrophy), disturbed hormonal cycle and obstruction of the fallopian tubes resulting from the presence of adhesions due to inflammation, endometriosis, and surgery, abnormal rhythm of menstrual bleeding, the abnormal concentration of hormones. There are many relationships between the endocrine organs, leading to a chain reaction when one of them fails to function properly. Conditions in which the immune system is involved, including infections and autoimmune diseases, also affect fertility. The form of treatment depends on infertility duration and the patient’s age. It includes ovulation stimulation with clomiphene citrate or gonadotropins, metformin use, and weight loss interventions. Since so many different factors affect fertility, it is important to correctly diagnose what is causing the problem and to modify the treatment regimen if necessary. This review describes disturbances in the hormone secretion of individual endocrine organs in the context of fertility and the maintenance of pregnancy.
Objective
This study aims to discuss the possible therapeutic effect of EDA against hypoxia-induced injury in preeclampsia.
Materials and methods
Placenta tissues were isolated from pregnant women with or without preeclampsia (PE), and the levels of hypoxia inducible factor (HIF-1α), P-AKT, AKT and PI3K proteins were analyzed by western blotting. The human trophoblast cell line HTR-8/SVneo was treated with cobalt chloride (CoCl2) to establish an in vitro anoxia model. The proliferation, apoptosis and reactive oxygen species (ROS) production rates in the anoxic cells with/out EDA treatment were measured by standard techniques.
Results
HIF-1α, P-AKT, AKT and PI3K protein levels were significantly higher in the placenta of the PE revlative to the control group. EDA alleviated the CoCl2-induced decrease in the viability of HTR-8/SVneo cells, along with apoptosis and ROS production. EDA also reversed the activation of PI3K/AKT pathway in the CoCl2-treated trophoblasts.
Conclusion
EDA protected trophoblasts against hypoxic injury by blocking the PI3K/AKT pathway and is a promising therapeutic option for PE.
The review presents the results of experimental studies that have revealed the molecular mechanisms underlying implantation and placentation controlled by cytokines, chemokines, adhesion molecules, hormones, as well as transcription and growth factors, and have indicated the key regulatory and protective role of melatonin. It has been shown that low production of the hormone and lack of its circadian rhythm underlie the disruption of endogenous antioxidant protection and contribute to oxidative stress leading to the development of preeclampsia. The necessity of using melatonin as a neuroimmunoendocrine marker of pathology is emphasized in this review article, which will allow for developing new approaches to its use for the prevention and treatment of preeclampsia, as well as its adverse consequences, such as obesity, type 2 diabetes mellitus, renal failure, and cardiovascular pathology.
Compared with men, women have a greater risk of sleep disorders and report higher rates of sleep disturbance. Hormonal and physiologic changes throughout the life span appear to influence a woman's ability to get a good night's sleep. Sleep disturbances are commonly reported during pregnancy, affecting more than one-half of all pregnancies and increasing as gestation progresses. The pervasiveness of sleep complaints during pregnancy may lead to a belief that these symptoms are normal or to be expected. Unfortunately, this perception may impede the accurate diagnosis of sleep disorders during this crucial time. Obstructive sleep apnea, insomnia, and restless legs syndrome are the most common sleep disorders in pregnancy. Sleep disruption in pregnancy can substantially worsen maternal quality of life and may be a risk factor for adverse pregnancy outcomes. This review outlines important considerations for obstetricians taking care of pregnant patients with sleep-related complaints.
Aims:
Clinical evidence indicated the activation of endoplasmic reticulum stress (ERS) in pregnant women with preeclampsia (PE), and the regulatory role of melatonin (MT) in ERS. This study aims to explore the possible effect and mechanism of MT on ERS and on the infiltration of trophoblasts in PE.
Methods:
The serum expression levels of MT and GRP78 in pregnant women with PE were measured. The cell proliferation, invasion, migration and apoptosis of trophoblasts were also determined. The trophoblast cell infiltration in placenta tissues was detected in EVOS image system. The expressions of ERS related proteins were measured by RT-qPCR and western blot.
Key results:
The PE-serum treatment on HTR-8/SVneo cells led to activated ERS and suppressed cell biological functions. PE mouse models after MT treatment or 4-PBA treatment had reduced blood pressure, proteinuria, apoptosis and increased foetus and placenta weight, in addition to enhanced cell infiltration.
Conclusions:
In vivo and in vitro evidence demonstrated MT can simultaneously suppress ERS and ASK1/JNK signal pathway in PE to promote the infiltration of trophoblasts.
Introduction: Our study aims to compare neonatal and maternal outcomes between expectant (or conservative) and aggressive (or immediate) management in cases with severe preeclampsia remote from term. singleton pregnancies complicated by severe pre-eclampsia with gestational age of 24-34 weeks were studied during this period. The criteria used for the diagnosis of severe preeclampsia were in accordance with the guidelines of the American College of Obstetricians and Gynaecologists. All the patients were counselled for expectant management. 39 patients were delivered immediately due to refusal of expectant management either by the patient or the attending physician. The other 35 patients were managed expectantly; this group was followed-up and carefully monitored for a period ranging from 72 hours to 18 days. Neonatal parameters, neonatal outcome and maternal outcome were compared between the two groups.
STUDY QUESTION
Does melatonin result in a dose–response effect on sleep quality and daytime sleepiness in women undergoing IVF?
SUMMARY ANSWER
Melatonin, even when given at high doses twice per day, does not cause significant daytime sleepiness or change night time sleep quantity or quality.
WHAT IS KNOWN ALREADY
Melatonin is being increasingly used as an adjuvant therapy for women undergoing IVF owing to its antioxidative effects. It is widely considered to be sedative but there are scant objective data on the effects of melatonin on sleep in the setting of IVF.
STUDY DESIGN SIZE, DURATION
The study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016.
PARTICIPANTS/MATERIALS, SETTING, METHOD
Women who were undergoing their first cycle of IVF at private IVF centers were recruited into the RCT and randomized to receive either placebo, 2 mg, 4 mg or 8 mg of melatonin, twice per day (BD) from Day 2 of their cycle until the day before oocyte retrieval. Each participant wore an accelerometer that provides an estimate of sleep and wake activity for up to 1 week of baseline and throughout treatment (up to 2 weeks). They also kept sleep diaries and completed a Karolinska sleepiness score detailing their night time sleep activity and daytime sleepiness, respectively.
MAIN RESULTS AND THE ROLE OF CHANCE
In total, 116 women were included in the intention-to-treat analysis (placebo BD (n = 32), melatonin 2 mg BD (n = 29), melatonin 4 mg BD (n = 26), melatonin 8 mg BD (n = 29)). There were no significant differences in daytime Karolinska sleepiness score between groups (P = 0.4), nor was there a significant dose–response trend (β=0.05, 95% CI −0.22–0.31, P = 0.7). There were no differences in objective measures of sleep quantity or quality, including wake after sleep onset time, sleep onset latency, and sleep efficiency before and after treatment or between groups. There was an improvement in subjective sleep quality scores from baseline to during treatment in all groups, except 8 mg BD melatonin: placebo (percentage change −13.3%, P = 0.01), 2 mg (−14.1%, P = 0.03), 4 mg (−8.6%, P = 0.01) and 8 mg (−7.8%, P = 0.07).
LIMITATIONS, REASONS FOR CAUTION
As this was a subset of a larger trial, the melatonin in ART (MIART) trial, it is possible that the sample size was too small to detect statistically significant differences between the groups.
WIDER IMPLICATIONS OF THE FINDINGS
While this study suggests that melatonin can be used twice per day at high doses to achieve sustained antioxidation effects, with the reassurance that this will not negatively impact daytime sleepiness or night time sleep habits, the sample size is small and may have missed a clinically significant difference. Nevertheless, our findings may have implications not only for future studies of fertility treatments (including meta-analyses), but also in other medical fields where sustained antioxidation is desired.
STUDY FUNDING/COMPETING INTERESTS
This study was funded by the Monash IVF Research and Education Foundation (PY12_15). S.F. is supported by the National Health and Medical Research Council (Postgraduate Scholarship APP1074342) and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Ella Macknight Memorial Scholarship. E.W. is supported by an National Health and Medical Research Council Program Grant (APP1113902). S.F., E.W., R.H., B.V., N.L., N.H., M.W., M.L., A.L., P.T., K.L. have nothing to declare. L.R. is a Minority shareholder in Monash IVF Group, has unrestricted grants from MSD®, Merck-Serono® and Ferring® and receives consulting fees from Ferring®. S.N.B. reports consulting fees from Johnson & Johnson Consumer Inc®, outside the submitted work.
TRIAL REGISTRATION NUMBER
This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785).
TRIAL REGISTRATION DATE
27/11/2013
DATE OF FIRST PATIENT’S ENROLMENT
1/9/2014
Background:
Severe pre-eclampsia can cause significant mortality and morbidity for both mother and child, particularly when it occurs remote from term, between 24 and 34 weeks' gestation. The only known cure for this disease is delivery. Some obstetricians advocate early delivery to ensure that the development of serious maternal complications, such as eclampsia (fits) and kidney failure are prevented. Others prefer a more expectant approach, delaying delivery in an attempt to reduce the mortality and morbidity for the child that is associated with being born too early.
Objectives:
To evaluate the comparative benefits and risks of a policy of early delivery by induction of labour or by caesarean section, after sufficient time has elapsed to administer corticosteroids, and allow them to take effect; with a policy of delaying delivery (expectant care) for women with severe pre-eclampsia between 24 and 34 weeks' gestation.
Search methods:
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) on 27 November 2017, and reference lists of retrieved studies.
Selection criteria:
Randomised trials comparing the two intervention strategies for women with early onset, severe pre-eclampsia. Trials reported in an abstract were eligible for inclusion, as were cluster-trial designs. We excluded quasi-randomised trials.
Data collection and analysis:
Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. We assessed the quality of the evidence for specified outcomes using the GRADE approach.
Main results:
We included six trials, with a total of 748 women in this review. All trials included women in whom there was no overriding indication for immediate delivery in the fetal or maternal interest. Half of the trials were at low risk of bias for methods of randomisation and allocation concealment; and four trials were at low risk for selective reporting. For most other domains, risk of bias was unclear. There were insufficient data for reliable conclusions about the comparative effects on most outcomes for the mother. Two studies reported on maternal deaths; neither study reported any deaths (two studies; 320 women; low-quality evidence). It was uncertain whether interventionist care reduced eclampsia (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.58; two studies; 359 women) or pulmonary oedema (RR 0.45, 95% CI 0.07 to 3.00; two studies; 415 women), because the quality of the evidence for these outcomes was very low. Evidence from two studies suggested little or no clear difference between the interventionist and expectant care groups for HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome (RR 1.09, 95% CI 0.62 to 1.91; two studies; 359 women; low-quality evidence). No study reported on stroke. With the addition of data from two studies for this update, there was now evidence to suggest that interventionist care probably made little or no difference to the incidence of caesarean section (average RR 1.01, 95% CI 0.91 to 1.12; six studies; 745 women; Heterogeneity: Tau² = 0.01; I² = 63%).For the baby, there was insufficient evidence to draw reliable conclusions about the effects on perinatal deaths (RR 1.11, 95% CI 0.62 to 1.99; three studies; 343 women; low-quality evidence). Babies whose mothers had been allocated to the interventionist group had more intraventricular haemorrhage (RR 1.94, 95% CI 1.15 to 3.29; two studies; 537 women; moderate-quality evidence), more respiratory distress caused by hyaline membrane disease (RR 2.30, 95% CI 1.39 to 3.81; two studies; 133 women), required more ventilation (RR 1.50, 95% CI 1.11 to 2.02; two studies; 300 women), and were more likely to have a lower gestation at birth (mean difference (MD) -9.91 days, 95% CI -16.37 to -3.45 days; four studies; 425 women; Heterogeneity: Tau² = 31.74; I² = 76%). However, babies whose mothers had been allocated to the interventionist group were no more likely to be admitted to neonatal intensive care (average RR 1.19, 95% CI 0.89 to 1.60; three studies; 400 infants; Heterogeneity: Tau² = 0.05; I² = 84%). Babies born to mothers in the interventionist groups were more likely to have a longer stay in the neonatal intensive care unit (MD 7.38 days, 95% CI -0.45 to 15.20 days; three studies; 400 women; Heterogeneity: Tau² = 40.93, I² = 85%) and were less likely to be small-for-gestational age (RR 0.38, 95% CI 0.24 to 0.61; three studies; 400 women). There were no clear differences between the two strategies for any other outcomes.
Authors' conclusions:
This review suggested that an expectant approach to the management of women with severe early onset pre-eclampsia may be associated with decreased morbidity for the baby. However, this evidence was based on data from only six trials. Further large, high-quality trials are needed to confirm or refute these findings, and establish if this approach is safe for the mother.
Complications of pregnancy represent a significant disease burden, with both immediate and lasting consequences for mother and baby. Two key pregnancy complications, fetal growth restriction (FGR) and preeclampsia (PE), together affect around 10%–15% of all pregnancies worldwide. Despite this high incidence, there are currently no therapies available to treat these pregnancy disorders. Early delivery remains the only intervention to reduce the risk of severe maternal complications and/or stillbirth of the baby; however early delivery itself is associated with increased risk of neonatal mortality and morbidity. As such, there is a pressing need to develop new and effective treatments that can prevent or treat FGR and PE. Animal models have been essential in identifying and screening potential new therapies in this field. In this review, we address recent progress that has been made in developing therapeutic strategies for pregnancy disorders, some of which are now entering clinical trials.
Introduction
High levels of oxidative stress can have considerable impact on the outcomes of in vitro fertilisation (IVF). Recent studies have reported that melatonin, a neurohormone secreted from the pineal gland in response to darkness, has significant antioxidative capabilities which may protect against the oxidative stress of infertility treatment on gametes and embryos. Early studies of oral melatonin (3–4 mg/day) in IVF have suggested favourable outcomes. However, most trials were poorly designed and none have addressed the optimum dose of melatonin. We present a proposal for a pilot double-blind randomised placebo-controlled dose–response trial aimed to determine whether oral melatonin supplementation during ovarian stimulation can improve the outcomes of assisted reproductive technology.
Methods and analyses
We will recruit 160 infertile women into one of four groups: placebo (n=40); melatonin 2 mg twice per day (n=40); melatonin 4 mg twice per day (n=40) and melatonin 8 mg twice per day (n=40). The primary outcome will be clinical pregnancy rate. Secondary clinical outcomes include oocyte number/quality, embryo number/quality and fertilisation rate. We will also measure serum melatonin and the oxidative stress marker, 8-hydroxy-2′-deoxyguanosine at baseline and after treatment and levels of these in follicular fluid at egg pick-up. We will investigate follicular blood flow with Doppler ultrasound, patient sleepiness scores and pregnancy complications, comparing outcomes between groups. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines.
Ethics and dissemination
Ethical approval has been obtained from Monash Health HREC (Ref: 13402B), Monash University HREC (Ref: CF14/523-2014000181) and Monash Surgical Private Hospital HREC (Ref: 14107). Data analysis, interpretation and conclusions will be presented at national and international conferences and published in peer-reviewed journals.
Trial registration number
ACTRN12613001317785.
The small GTPase protein RAC1 participates in innate immunity by activating a complex program that includes cytoskeleton remodeling, chemiotaxis, activation of NADPH oxidase and modulation of gene expression. However, its role in regulating the transcriptional signatures that in term control the cellular inflammatory profiles are not well defined. Here, we investigated the functional and mechanistic connection between RAC1 and the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2), master regulator of the anti-oxidant response. Lipopolysaccharide (LPS) and constitutively active RAC1Q61L mutant induced the anti-oxidant enzyme heme-oxygenase-1 (HO-1) through activation of NRF2. The use of KEAP1-insensitive NRF2 mutants indicated that RAC1 regulation of NRF2 is KEAP1-independent. Interestingly, NRF2 over-expression inhibited while a dominant-negative mutant of NRF2 exacerbated RAC1-dependent activation of nuclear factor-κB (NF-kB), suggesting that NRF2 has an antagonistic effect on the NF-kB pathway. Moreover, we found that RAC1 acts through NF-kB to induce NRF2 because either expression of a dominant negative mutant of IκBα that leads to NF-κB degradation or the use of p65-NF-κB-deficient cells demonstrated lower NRF2 protein levels and basally impaired NRF2 signature compared to control cells. In contrast, NRF2 deficient cells showed increased p65-NF-κB protein levels although the mRNA levels remain unchanged, indicating post-translational alterations. Our results demonstrate a new mechanism of modulation of RAC1 inflammatory pathway through a crosstalk between NF-kB and NRF2.
Key points
Failure of the placenta to develop and perform gives rise to intrauterine growth restriction (IUGR) in the fetus. IUGR is associated with impaired heart function in childhood and can even persist long term.
Oxidative stress is increased in IUGR and we asked if an antioxidant could reduce this. Melatonin is a well‐known and well‐studied hormone, present in all of us, and it has potent antioxidant properties.
In this study we administered melatonin to pregnant ewes carrying twins, one with IUGR.
Maternal melatonin improved oxygen delivery to the IUGR fetus and strengthened and protected its heart against infarct. After birth, the poor function and stiffness in the coronary arteries of IUGR lambs were entirely prevented by melatonin.
Our results demonstrate that administration of melatonin to a mother carrying an IUGR fetus can markedly dampen the adverse heart and artery effects in the offspring following birth.
Abstract
Intrauterine growth restriction (IUGR) is associated with impaired cardiac function in childhood and is linked to short‐ and long‐term morbidities. Placental dysfunction underlies most IUGR, and causes fetal oxidative stress which may impact on cardiac development. Accordingly, we investigated whether antenatal melatonin treatment, which possesses antioxidant properties, may afford cardiovascular protection in these vulnerable fetuses. IUGR was induced in sheep fetuses using single umbilical artery ligation on day 105–110 of pregnancy (term 147). Study 1: melatonin (2 mg h ⁻¹ ) was administered i.v. to ewes on days 5 and 6 after surgery. On day 7 fetal heart function was assessed using a Langendorff apparatus. Study 2: a lower dose of melatonin (0.25 mg h ⁻¹ ) was administered continuously following IUGR induction and the ewes gave birth normally at term. Lambs were killed when 24 h old and coronary vessels studied. Melatonin significantly improved fetal oxygenation in vivo . Contractile function in the right ventricle and coronary flow were enhanced by melatonin. Ischaemia–reperfusion‐induced infarct area was 3‐fold greater in IUGR hearts than in controls and this increase was prevented by melatonin. In isolated neonatal coronary arteries, endothelium‐dependent nitric oxide (NO) bioavailability was reduced in IUGR, and was rescued by modest melatonin treatment. Melatonin exposure also induced the emergence of an indomethacin‐sensitive vasodilation. IUGR caused marked stiffening of the coronary artery and this was prevented by melatonin. Maternal melatonin treatment reduces fetal hypoxaemia, improves heart function and coronary blood flow and rescues cardio‐coronary deficit induced by IUGR.
Fetal growth restriction complicates about 5% of pregnancies and is commonly caused by placental dysfunction. It is associated with increased risks of perinatal mortality and short-term and long-term morbidity, such as cerebral palsy. Chronic in utero hypoxaemia, inflammation and oxidative stress are likely culprits contributing to the long-term neurological sequelae of fetal growth restriction. In this regard, we propose that melatonin, a powerful antioxidant, might mitigate morbidity and/or mortality associated with fetal growth restriction. Melatonin has an excellent biosafety profile and crosses the placenta and blood-brain barrier. We present the protocol for a phase I clinical trial to investigate the efficacy of maternal oral melatonin administration in women with a pregnancy complicated by fetal growth restriction.
The proposed trial is a single-arm, open-label clinical trial involving 12 women. Severe, early onset fetal growth restriction will be diagnosed by an estimated fetal weight ≤10th centile in combination with abnormal fetoplacental Doppler studies, occurring before 34 weeks of pregnancy. Baseline measurements of maternal and fetal well-being, levels of oxidative stress and ultrasound and Doppler measurements will be obtained at the time of diagnosis of fetal growth restriction. Women will then start melatonin treatment (4 mg) twice daily until birth. The primary outcomes are the levels of oxidative stress in the maternal and fetal circulation and placenta. Secondary outcomes are fetoplacental Doppler studies (uterine artery, umbilical artery middle cerebral artery and ductus venosus), fetal biometry, fetal biophysical profile and a composite determination of neonatal outcome. A historical cohort of gestational-matched fetal growth restriction and a healthy pregnancy cohort will be used as comparators.
Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC12133B). Data will be presented at international conferences and published in peer-reviewed journals.
Clinical Trials, protocol registration system: NCT01695070.
Pre-eclampsia is a common pregnancy condition affecting between 3% and 7% of women. Unfortunately, the exact pathophysiology of the disease is unknown and as such there are no effective treatments that exist notwithstanding prompt delivery of the fetus and culprit placenta. As many cases of pre-eclampsia occur in preterm pregnancies, it remains a significant cause of maternal and perinatal morbidity and mortality. Recently, in vitro and animal studies have highlighted the potential role of antioxidants in mitigating the effects of the disease. Melatonin is a naturally occurring antioxidant hormone and provides an excellent safety profile combined with ease of oral administration. We present the protocol for a phase I pilot clinical trial investigating the efficacy and side effects of maternal treatment with oral melatonin in pregnancies affected by preterm pre-eclampsia.
We propose undertaking a single-arm open label clinical trial recruiting 20 women with preterm pre-eclampsia (24(+0)-35(+6) weeks). We will take baseline measurements of maternal and fetal well-being, levels of oxidative stress, ultrasound Doppler studies and other biomarkers of pre-eclampsia. Women will then be given oral melatonin (10 mg) three times daily until delivery. The primary outcome will be time interval between diagnosis and delivery compared to historical controls. Secondary outcomes will compare the baseline measurements previously mentioned with twice-weekly measurements during treatment and then 6 weeks postpartum.
Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC 13076B). Data will be presented at international conferences and published in peer-reviewed journals.
ACTRN12613000476730 (ANZCTR).
It is now over half a century since Arthur Hertig first reported vascular pathology in the uterine arteries supplying the placenta in women suffering from preeclampsia. His pioneering histological studies have been validated and extended by many others, leading to the general concept that placental perfusion is compromised in these patients. More recent Doppler ultrasound studies have confirmed reduced intervillous blood flow in vivo , and so gradually a consensus has emerged that the placental lesions associated with preeclampsia arise from a state of chronic hypoxia. Whilst hypoxia may undoubtedly play a significant role in the generation of placental pathology, there is considerable evidence that another feature of the intervillous circulation, namely the constancy of the blood flow, may be a more important factor. In this review we propose that hypoxia-reoxygenation, secondary to intermittent perfusion of the intervillous space, is a more physiological approach to take to understanding the pathophysiology of both normal pregnancies, and those complicated by preeclampsia. We further propose that chronic reduction in placental perfusion alone may lead to fetal growth restriction, and that if the two phenomena are superimposed then preeclampsia with growth restriction will result.
The melatonin system in preeclamptic pregnancies has been largely overlooked, especially in the placenta. We have previously documented melatonin production and expression of its receptors in normal human placentas. In addition, we and others have shown a beneficial role of melatonin in placental and fetal functions. In line with this, decreased maternal blood levels of melatonin are found in preeclamptic compared with normotensive pregnancies. However, melatonin production and expression of its receptors in preeclamptic compared with normotensive pregnancy placentas has never been examined. This study compares (i) melatonin-synthesizing enzyme expression and activity, (ii) melatonin and serotonin, melatonin's immediate precursor, levels and (iii) expression of MT1 and MT2 melatonin receptors in placentas from preeclamptic and normotensive pregnancies. Protein and mRNA expression of aralkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), the melatonin-synthesizing enzymes, as well as MT1 and MT2 receptors were determined by RT-qPCR and Western blot, respectively. The activities of melatonin-synthesizing enzymes were assessed by radiometric assays while melatonin levels were determined by LC-MS/MS. There is a significant inhibition of AANAT, melatonin's rate-limiting enzyme, expression and activity in preeclamptic placentas, correlating with decreased melatonin levels. Likewise, MT1 and MT2 expression is significantly reduced in preeclamptic compared with normotensive pregnancy placentas. We propose that reduced maternal plasma melatonin levels may be an early diagnostic tool to identify pregnancies complicated by preeclampsia. This study indicates a clinical utility of melatonin as a potential treatment for preeclampsia in women where reduced maternal plasma levels have been identified.
Pregnancies complicated by impaired placentation, acute severe reductions in oxygen supply to the fetus, or intrauterine infection are associated with oxidative stress to the mother and developing baby. Such oxidative stress is characterized as an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species, thereby creating a state of fetoplacental oxidative imbalance. Recently, there has been a good deal of interest in the potential for the use of antioxidant therapies in the perinatal period to protect the fetus, particularly the developing brain, against oxidative stress in complications of pregnancy and birth. This review will examine why the immature brain is particularly susceptible to oxidative imbalance and will provide discussion on antioxidant treatments currently receiving attention in the adult and perinatal literature - allopurinol, melatonin, α-lipoic acid, and vitamins C and E. In addition, we aim to address the interaction between oxidative stress and the fetal inflammatory response, an interaction that may be vital when proposing antioxidant or other neuroprotective strategies.
One of the most prevalent complications of pregnancy is preeclampsia, a hypertensive disorder which is a leading cause of maternal and perinatal morbidity and premature birth with no effective pharmacological intervention. While the underlying cause is unclear, it is believed that placental ischemia/hypoxia induces the release of factors into the maternal vasculature and lead to widespread maternal endothelial dysfunction. Recently, HO-1 has been shown to downregulate two of these factors, reactive oxygen species and sFlt-1, and we have reported that HO-1 induction attenuates many of the pathological factors of placental ischemia experimentally. Here, we have examined the direct effect of HO-1 and its bioactive metabolites on hypoxia-induced changes in superoxide and sFlt-1 in placental vascular explants and showed that HO-1 and its metabolites attenuate the production of both factors in this system. These findings suggest that the HO-1 pathway may be a promising therapeutic approach for the treatment of preeclampsia.
Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia.
American Journal of Hypertension advance online publication 16 June 2011;doi:10.1038/ajh.2011.99
The regulated expression of ICAM-1 plays an important role in inflammatory processes and immune responses. The present study aimed to determine the in vivo involvement of cytosolic phospholipase A(2)α (cPLA(2)α) in ICAM-1 overexpression during inflammation and to elucidate the cPLA(2)α-specific role in signal events leading to ICAM-1 upregulation in endothelial cells. cPLA(2)α and ICAM-1 upregulation were detected in inflamed paws of mice with collagen-induced arthritis and in periepididymal adipose tissue of mice fed a high-fat diet. Intravenous injection of 2 mg/kg oligonucleotide antisense against cPLA(2)α (AS) that reduced cPLA(2)α upregulation also decreased ICAM-1 overexpression, suggesting a key role of cPLA(2)α in ICAM-1 upregulation during inflammation. Preincubation of endothelial ECV-304 cells that express ICAM-1 and of HUVEC that express ICAM-1 and VCAM-1 with 1 μM AS prevented cPLA(2)α and the adhesion molecule upregulation induced by TNF-α and inhibited their adherence to phagocyte like-PLB cells. Whereas AS did not inhibit NADPH oxidase 4-NADPH oxidase activity, inhibition of oxidase activity attenuated cPLA(2)α activation, suggesting that NADPH oxidase acts upstream to cPLA(2)α. Attenuating cPLA(2)α activation by AS or diphenylene iodonium prevented the induction of cyclooxygenase-2 and the production of PGE(2) that were essential for ICAM-1 upregulation. Inhibition of cPLA(2)α activity by AS inhibited the phosphorylation of both p65 NF-κB on Ser(536) and protein kinase A-dependent CREB. To our knowledge, our results are the first to show that CREB activation is involved in ICAM-1 upregulation and suggest that cPLA(2)α activated by NADPH oxidase is required for sequential phosphorylation of NF-κB by an undefined kinase and CREB activation by PGE(2)-mediated protein kinase A.
Recent evidence indicates that both increased oxidative stress and an altered balance between pro- and anti-angiogenic factors such as vascular-endothelial growth factor (VEGF) and the soluble VEGF receptor (sFlt-1) contribute to endothelial dysfunction in preeclampsia. We hypothesized that chronic infusion of sFlt-1 to mimic the increase observed in preeclamptic patients would reduce plasma VEGF concentrations, increase blood pressure (BP) and vascular superoxide levels, and cause endothelial dysfunction in the pregnant rat.
Recombinant sFlt-1 was infused (500 ng/h) during days 13-18 of pregnancy. BP, fetal and placental weight, oxidative stress and vessel vasorelaxation were determined on day 18 of pregnancy.
Plasma sFlt-1 concentrations (299 +/- 33 vs. 100 +/- 16 pg/ml; P < 0.01) and BP (117 +/- 6 vs. 98 +/- 4 mm Hg; P < 0.01) were increased, while plasma-free VEGF concentrations (570 +/- 77 vs. 780 +/- 48 pg/ml; P < 0.01) were decreased when compared to vehicle infused dams. sFlt-1 rats had smaller fetuses (1.3 +/- 0.03 vs. 1.5 +/- 0.04 g, P < 0.01) and placentas (0.41 +/- 0.01 vs. 0.47 +/- 0.02 g; P < 0.05). Placental (180 +/- 66 vs. 24 +/- 2.3 RLU/min/mg; P < 0.05) and vascular (34 +/- 8 vs. 12 +/- 5 RLU/min/mg; P < 0.05) superoxide production was increased in the sFlt-1 compared to vehicle infused rats. Vasorelaxation to acetylecholine (ACh) and sodium nitroprusside (SNP) were both decreased (P < 0.05) in the sFlt-1 infusion group compared to the vehicle and this decrease was attenuated (P < 0.05) by the superoxide scavenger Tiron.
These data indicate elevated maternal sFlt-1 and decreased VEGF concentrations results in increased oxidative stress that contributes to vascular dysfunction during pregnancy.
Fifty-eight women with severe preeclampsia between 28-34 weeks' gestation qualified for a randomized controlled trial to establish whether elective delivery 48 hours after administration of betamethasone (aggressive-management group) or delivery later as indicated by maternal or fetal condition (expectant-management group) was more beneficial to maternal and fetal outcome. Twenty women who qualified were not randomized because they developed maternal or fetal indications necessitating delivery within 48 hours; these newborns developed most of the complications. Expectant management was not associated with an increase in maternal complications, but it significantly prolonged the gestational age (mean 7.1 days; P less than .05), reduced the number of neonates requiring ventilation (P less than .05), and reduced the number of neonatal complications (P less than .05).
Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction.
Objectives Current guidelines for diagnosis and management of early-onset intrauterine growth restriction (IUGR) rely on umbilical artery Doppler (UAD), without including uterine artery Doppler (UtAD). We hypothesized that IUGR cases with abnormal UAD but normal UtAD has a different spectrum of placental pathology compared with those with abnormal UtAD. Study Design Retrospective review of pregnancies with sonographic evidence of IUGR and abnormal UAD prior to delivery. Cases with ≥ 1 UtAD record(s) after 18⁺⁰ weeks' gestation and placental pathology were included. Cases were stratified according to initial UtAD pulsatility index (PI) values (n = 196): normal (n = 19; PI < 95th centile for gestational age/no notching), intermediate (n = 69; PI ≥ 95th centile/no/unilateral notching) and abnormal (n = 108; PI ≥ 95th centile/bilateral notching). Pregnancy outcomes and placental pathology were compared between groups. Results Women in the normal group delivered later than those in the abnormal group (30.1 ± 3.5 vs. 28.0 ± 3.5 weeks; mean ± standard deviation; p = 0.03). Their placentas exhibited higher rates of chronic intervillositis (15.8 vs. 0.9%; p = 0.01), chorangiosis (15.8 vs. 0.9%; p < 0.0001), and massive perivillous fibrin deposition (21.1 vs. 7.4%; p = 0.05), but had lower rates of uteroplacental vascular insufficiency (26.3 vs. 79.6%; p < 0.0001). Conclusion Approximately 10% of pregnancies with early-onset IUGR and abnormal UAD exhibited normal UtAD waveforms. They delivered later, and their placentas exhibited unusual placental pathologies.
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Placental dysfunction and oxidative stress contribute to the pathogenesis of preeclampsia, which is a pregnancy-specific disorder. It has been suggested that the incidence of preeclampsia has a seasonal variation. Melatonin, as a seasonal factor, has been suggested to be involved in a successful pregnancy. In this study, we investigated the association of circulating levels of melatonin with preeclampsia. Serum was collected from women with preeclampsia (n=113) and gestation-matched healthy pregnant women, and the levels of melatonin were measured. In addition, the expression of melatonin receptors was examined in preeclamptic placentae (n=27). The association of the incidence of preeclampsia and seasonal variation was also analysed from 1491 women with preeclampsia within 77 745 healthy pregnancies. The serum levels of melatonin were significantly reduced in women with preeclampsia at presentation and these reduced serum levels of melatonin were not associated with the severity or time onset of preeclampsia nor with seasonal variation. The expression of melatonin receptor, MT1 was reduced in preeclamptic placentae. The incidence of preeclampsia was did exhibit seasonal variation, but this was largely due to the increase in the incidence of mild or late-onset preeclampsia. Our results demonstrate that reduced melatonin levels are associated with the development of preeclampsia but that the circulating levels of melatonin do not appear to be subject to seasonal variation during pregnancy.Journal of Human Hypertension advance online publication, 2 June 2016; doi:10.1038/jhh.2016.37.
Background:
Intrauterine growth restriction is a condition in which the fetus has a birthweight and/or length <10th percentile for the gestational age. Intrauterine growth restriction can be associated with various causes, among which is low uteroplacental perfusion and chronic hypoxia during gestation. Often, intrauterine growth-restricted fetuses have increased oxidative stress; therefore, agents that decrease oxidative stress and increase utero, placental, and umbilical perfusion have been proposed as a beneficial therapeutic strategy. In this scenario, melatonin acts as an umbilical vasodilator and a potent antioxidant that has not been evaluated in pregnancies under chronic hypoxia that induce fetal growth restriction. However, this neurohormone has been proposed as a pharmacologic therapy for complicated pregnancies.
Objectives:
The aim of this study was to determine the effects of prenatal administration of melatonin during the last trimester of pregnancy on the biometry of the growth-restricted lambs because of developmental hypoxia. Further, we aimed to determine melatonin and cortisol levels and oxidative stress markers in plasma of pregnant ewes during the treatment.
Study design:
High-altitude pregnant sheep received either vehicle (n = 5; 5 mL 1.4% ethanol) or melatonin (n = 7; 10 mg/kg(-1)day(-1) in 5 mL 1.4% ethanol) daily during the last one-third of gestation. Maternal plasma levels of melatonin, cortisol, antioxidant capacity, and oxidative stress were determined along treatment. At birth, neonates were examined, weighed, and measured (biparietal diameter, abdominal diameter, and crown-rump length).
Results:
Antenatal treatment with melatonin markedly decreased neonatal biometry and weight at birth. Additionally, melatonin treatment increased the length of gestation by 7.5% and shifted the time of delivery. Furthermore, the prenatal treatment doubled plasma levels of melatonin and cortisol and significantly improved the antioxidant capacity of the pregnant ewes.
Conclusions:
Our findings indicate that antenatal melatonin induces further intrauterine growth restriction but improves the maternal plasma antioxidant capacity. Additional studies should address the efficiency and safety of antenatal melatonin before clinical attempts on humans.
Aim:
Reactive oxygen species play an important role in the pathogenesis of several diseases during gestation and the perinatal period. During pregnancy, increased oxygen demand augments the rate of production of free radicals. Oxidative stress is involved in pregnancy disorders including preeclampsia and intrauterine fetal growth retardation (IUGR). Moreover, increased levels of oxidative stress and reduced antioxidative capacities may contribute to the pathogenesis of perinatal asphyxia. Melatonin, an efficient antioxidant agent, diffuses through biological membranes easily and exerts pleiotropic actions on every cell and appears to be essential for successful gestation. This narrative review summarizes current knowledge concerning the role of melatonin in reducing complications during human pregnancy and in the perinatal period.
Results:
Melatonin levels are altered in women with abnormally functioning placentae during preeclampsia and IUGR. Short-term melatonin therapy is highly effective and safe in reducing complications during pregnancy and in the perinatal period. Because melatonin has been shown to be safe for both mother and fetus, it could be an attractive therapy in pregnancy and is considered a promising neuroprotective agent in perinatal asphyxia.
Conclusion:
We believe that the use of melatonin treatment during the late fetal and early neonatal period might result in a wide range of health benefits, improved quality of life, and may help limit complications during the critical periods prior to, and shortly after, delivery.
Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin.
Methods: A systematic literature search was performed and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous.
Results: 10 studies were included in the review. Intranasal administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration. Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration.
Conclusion: Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in a local application, due to slow absorption and deposition in the skin. Oral transmucosal administration may potentially be a clinically relevant due to avoiding first-pass metabolism. Subcutaneous injection of melatonin did not document any advantages compared to other administration routes.
There are at least four reasons why a sleep clinician should be familiar with rating scales that evaluate different facets of sleep. First, the use of scales facilitates a quick and accurate assessment of a complex clinical problem. In three or four minutes (the time to review ten standard scales), a clinician can come to a broad understanding of the patient in question. For example, a selection of scales might indicate that an individual is sleepy but not fatigued; lacking alertness with no insomnia; presenting with no symptoms of narcolepsy or restless legs but showing clear features of apnea; exhibiting depression and a history of significant alcohol problems. This information can be used to direct the consultation to those issues perceived as most relevant, and can even provide a springboard for explaining the benefits of certain treatment approaches or the potential corollaries of allowing the status quo to continue. Second, rating scales can provide a clinician with an enhanced vocabulary or language, improving his or her understanding of each patient. In the case of the sleep specialist, a scale can help him to distinguish fatigue from sleepiness in a patient, or elucidate the differences between sleepiness and alertness (which is not merely the inverse of the former). Sleep scales are developed by researchers and clinicians who have spent years in their field, carefully honing their preferred methods for assessing certain brain states or characteristic features of a condition. Thus, scales provide clinicians with a repertoire of questions, allowing them to draw upon the extensive experience of their colleagues when attempting to tease apart nuanced problems. Third, some scales are helpful for tracking a patient's progress. A particular patient may not remember how alert he felt on a series of different stimulant medications. Scale assessments administered periodically over the course of treatment provide an objective record of the intervention, allowing the clinician to examine and possibly reassess her approach to the patient. Finally, for individuals conducting a double-blind crossover trial or a straightforward clinical practice audit, those who are interested in research will find that their own clinics become a source of great discovery. Scales provide standardized measures that allow colleagues across cities and countries to coordinate their practices. They enable the replication of previous studies and facilitate the organization and dissemination of new research in a way that is accessible and rapid. As the emphasis placed on evidence-based care grows, a clinician's ability to assess his or her own practice and its relation to the wider medical community becomes invaluable. Scales make this kind of standardization possible, just as they enable the research efforts that help to formulate those standards. The majority of Rating Scales in Sleep and Sleep Disorders:100 Scales for Clinical Practice is devoted to briefly discussing individual scales. When possible, an example of the scale is provided so that readers may gain a sense of the instrument's content. Groundbreaking and the first of its kind to conceptualize and organize the essential scales used in sleep medicine, Rating Scales in Sleep and Sleep Disorders:100 Scales for Clinical Practice is an invaluable resource for all clinicians and researchers interested in sleep disorders. © Springer Science+Business Media, LLC 2012. All rights reserved.
This scale [1] measures the subjective level of sleepiness at a particular time during the day. On this scale subjects indicate which level best reflects the psycho-physical sate experienced in the last 10 min. The KSS is a measure of situational sleepiness. It is sensitive to fluctuations.
Activin A levels are elevated in maternal serum of pregnant women with hypertensive disturbances. Because follistatin is a circulating binding protein for activin A, the present study was designed to evaluate whether serum follistatin and activin A levels also change in patients with hypertensive disorders in the last gestational trimester. The study design was a controlled survey performed in the setting of an academic prenatal care unit. Healthy pregnant women (controls, n=38) were compared with patients suffering from pregnancy-induced hypertension (PIH, n=18) or pre-eclampsia (n=16). In addition, the study included a subset of patients with pre-eclampsia associated with intrauterine growth restriction (IUGR, n=5). Maternal blood samples were withdrawn at the time of diagnosis (patients) or in a random prenatal visit (controls), and serum was assayed for follistatin and activin A levels using specific enzyme immunoassays. Hormone concentrations were corrected for gestational age by conversion to multiples of median (MoM) of the healthy controls of the same gestational age. Follistatin levels were not different between controls and patients, while activin A levels were significantly increased in patients with PIH (1·8 MoM), pre-eclampsia (4·6 MoM), and pre-eclampsia+IUGR (3·2 MoM, P<0·01, ANOVA). The ratio between activin A and follistatin was significantly increased in patients with PIH (1·5 MoM) and was further increased in patients with pre-eclampsia (4·5 MoM) and in the group with preeclampsia+IUGR (2·6 MoM). Follistatin levels were positively correlated with gestational age in control subjects (r=0·36, P<0·05) and in patients with PIH (r=0·46, P<0·05) or pre-eclampsia (r=0·61, P<0·01), while activin A correlated with gestational age only in the healthy control group (r=0·69, P<0·0001). The finding of apparently normal follistatin and high activin A levels in patients with PIH and pre-eclampsia suggests that unbound, biologically active, activin A is increased in women with these gestational diseases.
Objective:
Clinical management of preeclampsia has remained unchanged for almost 5 decades. We now understand that maternal endothelial dysfunction likely arises because of placenta-derived vasoactive factors. Activin A is one such antiangiogenic factor that is released by the placenta and that is elevated in maternal serum in women with preeclampsia. Whether activin has a role in the pathogenesis of preeclampsia is not known.
Study design:
To assess the effects of activin on endothelial cell function, we cultured human umbilical vein endothelial cells in the presence of activin or serum from normal pregnant women or pregnant women with preeclampsia, with or without follistatin, a functional activin antagonist or apocynin, a NADPH oxidase (Nox2) inhibitor. We also administered activin to pregnant C57Bl6 mice, with or without apocynin, and studied maternal and fetal outcomes. Last, we assessed endothelial cell Nox2 and nitric oxide synthase expression in normal pregnant women and pregnant women with preeclampsia.
Results:
Activin and preeclamptic serum induced endothelial cell oxidative stress by Nox2 up-regulation and endothelial cell dysfunction, which are effects that are mitigated by either follistatin or apocynin. The administration of activin to pregnant mice induced endothelial oxidative stress, hypertension, proteinuria, fetal growth restriction, and preterm littering. Apocynin prevented all of these effects. Compared with normal pregnant women, women with preeclampsia had increased endothelial Nox2 expression.
Conclusion:
An activin-Nox2 pathway is a likely link between an injured placenta, endothelial dysfunction, and preeclampsia. This offers opportunities that are not novel therapeutic approaches to preeclampsia.