Epigenetic Genome Modifications during Pregnancy: The Impact of Essential Nutritional Supplements on DNA Methylation.

Pregnancy is an extremely stressful period in a pregnant woman's life. Currently, women's awareness of the proper course of pregnancy and its possible complications is constantly growing. Therefore, a significant percentage of women increasingly reach for various dietary supplements during gestation. Some of the most popular substances included in multi-ingredient supplements are folic acid and choline. Those substances are associated with positive effects on fetal intrauterine development and fewer possible pregnancy-associated complications. Recently, more and more attention has been paid to the impacts of specific environmental factors, such as diet, stress, physical activity, etc., on epigenetic modifications, understood as changes occurring in gene expression without the direct alteration of DNA sequences. Substances such as folic acid and choline may participate in epigenetic modifications by acting via a one-carbon cycle, leading to the methyl-group donor formation. Those nutrients may indirectly impact genome phenotype by influencing the process of DNA methylation. This review article presents the current state of knowledge on the use of folic acid and choline supplementation during pregnancy, taking into account their impacts on the maternal-fetal unit and possible pregnancy outcomes, and determining possible mechanisms of action, with particular emphasis on their possible impacts on epigenetic modifications.

Risk of Cesarean Delivery after Vaginal Inserts with Prostaglandin Analogs and Single-Balloon Catheter Used for Cervical Ripening and Induction of Labor.

(1) Background: Induction of labor is currently the most frequently performed procedure in modern obstetrics, referring to more than one in five women, and it is postulated that the percentage of labor induction will increase. (2) Methods: In total, 2935 patients in uncomplicated full-term pregnancy fulfilled the study inclusion criteria and underwent induction of labor. Pregnant women were divided into three groups: IOL with Dinoprostone, Misoprostol vaginal suppositories, and Foley catheter. Outcomes, including cesarean section rates, time to delivery, and cesarean section indications, were analyzed. (3) Results: There was statistically significantly more cesarean sections within 24 h in the Misoprostol group in comparison with the Dinoprostone and Foley catheter groups (p < 0.0001). The percentage of patients who had a cesarean section due to clinically diagnosed threatened fetal asphyxia was 63% in the Dinoprostone group, 81.3% in the Misoprostol group, and 55.3% in the Foley catheter group. There were statistically significantly more cesarean deliveries due to nonreassuring fetal heart rate patterns within 24 h in the Misoprostol group in comparison with the Dinoprostone and Foley catheter groups (p = 0.0031 and p = 0.0363). (4) Conclusions: Misoprostol may cause a more turbulent and violent course of labor, with a higher rate of increased incidence of nonreassuring fetal heart rate patterns and cesarean deliveries. The use of a Dinoprostone vaginal insert or Foley catheter may provide longer labor, although still within 48 h, with a lower risk of cesarean section caused by nonreassuring fetal heart rate patterns.

Endogenous Digitalis-like Factors as a Key Molecule in the Pathophysiology of Pregnancy-Induced Hypertension and a Potential Therapeutic Target in Preeclampsia.

Preeclampsia (PE), the most severe presentation of hypertensive disorders of pregnancy, is the major cause of morbidity and mortality linked to pregnancy, affecting both mother and fetus. Despite advances in prophylaxis and managing PE, delivery of the fetus remains the only causative treatment available. Focus on complex pathophysiology brought the potential for new treatment options, and more conservative options allowing reduction of feto-maternal complications and sequelae are being investigated. Endogenous digitalis-like factors, which have been linked to the pathogenesis of preeclampsia since the mid-1980s, have been shown to play a role in the pathogenesis of various cardiovascular diseases, including congestive heart failure and chronic renal disease. Elevated levels of EDLF have been described in pregnancy complicated by hypertensive disorders and are currently being investigated as a therapeutic target in the context of a possible breakthrough in managing preeclampsia. This review summarizes mechanisms implicating EDLFs in the pathogenesis of preeclampsia and evidence for their potential role in treating this doubly life-threatening disease.

The 300 versus 300 Study-Low Volume versus High Volume Single Balloon Catheter for Induction of Labor: A Retrospective Case-Control Study.

The use of a Foley catheter is one of the oldest known methods of labor induction. Therefore, protocols using different volumes of Foley catheter balloons have been developed and tested to accurately determine their effectiveness. In this study, it was decided to retrospectively evaluate two induction of labor (IOL) protocols. The last 300 eligible patients who met the criteria and underwent the low-volume balloon protocol (40-60 mL) IOL were selected. Then next, 300 patients who met the criteria and underwent high-volume balloon (80-100 mL) IOL were selected. Outcomes included time to delivery and parturition type, oxytocin augmentation, operative deliveries and application of intrapartum anesthesia. Overall, the majority of patients delivered within 24 h. Patients who received a high-volume Foley catheter had statistically significantly more vaginal deliveries. The mean-time to delivery in the high-volume catheter group was statistically significantly shorter than in the low-volume catheter group. Patients who received a high-volume Foley catheter required statistically significantly less oxytocin augmentation during induction of labor compared to patients with a low-volume Foley catheter. Regardless of the balloon volume used, the percentage of operative deliveries remained at a similar, low level (8.36% and 2.14%). Regardless of the catheter volume used, the majority of patients chose epidural over intravenous anesthesia. In conclusion, a high-volume balloon Foley catheter IOL is characterized by an increased percentage of vaginal deliveries, shortened time to delivery regardless of the type of delivery, and lower need for oxytocin augmentation.

Raspberry Leaves and Extracts-Molecular Mechanism of Action and Its Effectiveness on Human Cervical Ripening and the Induction of Labor.

The gestational period is an incredibly stressful time for a pregnant woman. Pregnant patients constantly seek effective and reliable compounds in order to achieve a healthy labor. Nowadays, increasing numbers of women use herbal preparations and supplements during pregnancy. One of the most popular and most frequently chosen herbs during pregnancy is the raspberry leaf (Rubus idaeus). Raspberry extracts are allegedly associated with a positive effect on childbirth through the induction of uterine contractions, acceleration of the cervical ripening, and shortening of childbirth. The history of the consumption of raspberry leaves throughout pregnancy is vast. This review shows the current status of the use of raspberry leaves in pregnancy, emphasizing the effect on the cervix, and the safety profile of this herb. The majority of women apply raspberry leaves during pregnancy to induce and ease labor. However, it has not been possible to determine the exact effect of using raspberry extracts on the course of childbirth and the perinatal period. Additionally, it is unclear whether this herb has only positive effects. The currently available data indicate a weak effect of raspberry leaf extracts on labor induction and, at the same time, their possible negative impact on cervical ripening.

Results of Induction of Labor with Prostaglandins E1 and E2 (The RIPE Study): A Real-World Data Analysis of Obstetrical Effectiveness and Clinical Outcomes of Pharmacological Induction of Labor with Vaginal Inserts.

Despite extensive knowledge of the mechanisms responsible for childbirth, the course of labor induction is often unpredictable. Therefore, labor induction protocols using prostaglandin analogs have been developed and tested to assess their effectiveness in labor induction unequivocally. A total of 402 women were collected into two groups-receiving vaginal Misoprostol or vaginal Dinoprostone for induction of labor (IOL). Then, the patients were compared in groups depending on the agent they received and their gestational age. Most patients delivered within 48 h, and most of these patients had vaginal parturition. Patients who received the Dinoprostone vaginal insert required statistically significantly more oxytocin administration than patients who received the Misoprostol vaginal insert. Patients who received the Misoprostol vaginal insert used anesthesia during labor statistically more often. Patients who received Misoprostol vaginal inserts had a statistically significantly shorter time to delivery than those with Dinoprostone vaginal inserts. The prevalence of hyperstimulation was similar in all groups and remained low. Vaginal Misoprostol-based IOL is characterized by a shortened time to delivery irrespective of the parturition type, and a lower need for oxytocin augmentation, but also by an increased demand for intrapartum analgesia administration. A vaginal Dinoprostone-based IOL protocol might be considered a more harmonious and desirable option in modern perinatal care.

The Efficacy of Misoprostol Vaginal Inserts for Induction of Labor in Women with Very Unfavorable Cervices.

BACKGROUND: The purpose of the present study was to evaluate the effectiveness of a misoprostol vaginal insert as an induction-of-labor (IOL) agent in women with an unfavorable cervix (Bishop score < 2) in achieving vaginal delivery (VD) within 48 h, depending on the gestational week, with particular emphasis on the cesarean section (CS) percentage, intrapartum analgesia application and possible side effects, such as tachysystole ratio. METHODS: In this retrospective observational study involving 6000 screened pregnant patients, 190 women (3%) fulfilled the study inclusion criteria and underwent vaginal misoprostol IOL. The pregnant women were collected into three groups: patients who delivered at up to 37 weeks of gestation (<37 Group)-42 patients; patients who delivered between 37 and 41 weeks of gestation (37-41 Group)-76 patients; and patients who delivered after 41 weeks of gestation (41+ Group)-72 patients. The outcomes included time to delivery and mode of delivery, rate of tachysystole, need for intrapartum analgesia, and need for oxytocin augmentation. RESULTS: Most of the patients delivered vaginally (54.8% in <37 Group vs. 57.9% in 37-41 Group vs. 61.1% in 41+ Group). A total of 89.5% (170/190) of patients delivered within 48 h (<37 Group-78.6% vs. 37-41 Group-89.5% vs. 41+ Group-95.8%). Statistical significance was demonstrated for the increased rate of vaginal deliveries and shortened time to delivery in the 41+ weeks group (p = 0.0026 and p = 0.0038). The indications for cesarean section were as follows: abnormal CTG pattern vs. lack of labor progression: 42.1% vs. 57.9% in <37 Group, 59.4% vs. 40.6% in 37-41 Group and 71.4% vs. 28.6% in 41+ Group. Statistical significance was demonstrated for the increased rate of abnormal CTG patterns as cesarean section indications in the 41+ Group (p = 0.0019). The need for oxytocin augmentation in each group was: 35.7% in <37 Group vs. 19.7% in 37-41 Group vs. 11.1% in 41+ Group. Statistical significance was shown for decreased need for oxytocin augmentation in +41 Group (p = 0.0016). The need for intrapartum anesthesia, depending on the group, was: 78.6% in <37 Group vs. 82.9% in 37-41 Group vs. 83.3% in 41+ Group. Statistical significance was demonstrated for increased need for intrapartum anesthesia application during labor in +41 Group (p = 0.0018). The prevalence of hyperstimulation was similar in all three groups (4.8% vs. 7.9% vs. 5.6% p > 0.05). CONCLUSIONS: The misoprostol vaginal regimen for IOL used in our study is effective in achieving vaginal delivery within 48 h. In post-term women, the use of this regimen is characterized by an increased rate of vaginal deliveries, a shorter time to delivery and a lower need for oxytocin.

A Review of the Mechanism of Action and Clinical Applications of Osmotic Dilators for Cervical Ripening in the Induction of Labor and in Gynecology Procedures.

Cervical ripening is defined as the significant softening of the cervical tissue that usually begins before the onset of contractions during labor, and is required for cervical dilation and delivery. Osmotic dilators are medical implements that dilate the uterine cervix by increasing in size as they absorb fluid from the surrounding tissue. This article aims to review the mechanisms and applications of osmotic dilators for cervical ripening in the induction of labor and in gynecology procedures.

Unexpected Uterine Rupture-A Case Report, Review of the Literature and Clinical Suggestions.

BACKGROUND AND OBJECTIVES: Women with a history of cesarean section are a high-risk group because they are likely to develop uterine rupture during their next pregnancy. Current evidence suggests that a vaginal birth after cesarean section (VBAC) is associated with lower maternal mortality and morbidity than elective repeat cesarean delivery (ERCD). Additionally, research suggests that uterine rupture can occur in 0.47% of cases of trial of labor after cesarean section (TOLAC). CASE DESCRIPTION: A healthy 32-year-old woman at 41 weeks of gestation, in her fourth pregnancy, was admitted to the hospital due to a dubious CTG record. Following this, the patient gave birth vaginally, underwent a cesarean section, and successfully underwent a VBAC. Due to her advanced gestational age and favorable cervix, the patient qualified for a trial of vaginal labor (TOL). During labor induction, she displayed a pathological CTG pattern and presented symptoms such as abdominal pain and heavy vaginal bleeding. Suspecting a violent uterine rupture, an emergency cesarean section was performed. The presumed diagnosis was confirmed during the procedure-a full-thickness rupture of the pregnant uterus was found. The fetus was delivered without signs of life and successfully resuscitated after 3 min. The newborn girl of weight 3150 g had an Apgar score of 0/6/8/8 at 1, 3, 5, and 10 min. The uterine wall rupture was closed with two layers of sutures. The patient was discharged 4 days after the cesarean section without significant complications, with a healthy newborn girl. CONCLUSIONS: Uterine rupture is a rare but severe obstetric emergency and can be associated with maternal and neonatal fatal outcomes. The risk of uterine rupture during a TOLAC attempt should always be considered, even if it is a subsequent TOLAC.

Impact of Oxidative Stress on Molecular Mechanisms of Cervical Ripening in Pregnant Women.

Uterine cervix is one of the essential factors in labor and maintaining the proper course of pregnancy. During the last days of gestation, the cervix undergoes extensive changes manifested by transformation from a tight and rigid to one that is soft and able to dilate. These changes can be summarized as "cervical ripening". Changes in the cervical tissue can be referred to as remodeling of the extracellular matrix. The entire process is the result of a close relationship between biochemical and molecular pathways, which is strictly controlled by inflammatory and endocrine factors. When the production of reactive oxygen species exceeds the antioxidant capacity, oxidative stress occurs. A physiologic increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is observed through pregnancy. ROS play important roles as second messengers in many intracellular signaling cascades contributing to the course of gestation. This review considers their involvement in the cervical ripening process, emphasizing the molecular and biochemical pathways and the clinical implications.

Signaling Pathways Regulating Human Cervical Ripening in Preterm and Term Delivery.

At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process derivative of enzymatic breakdown and inflammatory response. Therefore, it is apparent that cervical remodeling is a derivative of the reactions mediated by multiple factors such as hormones, prostaglandins, nitric oxide, and inflammatory cytokines. However, despite the research carried out over the years, the cellular pathways responsible for regulating this process are still poorly understood. A comprehensive understanding of the entire process of cervical ripening seems crucial in the context of labor induction. Greater knowledge could provide us with the means to help women who suffer from dysfunctional labor. The overall objective of this review is to present the current understanding of cervical ripening in terms of molecular regulation and cell signaling.

Decrease in Nitric Oxide Production as a Key Mediator in the Pathogenesis of Preeclampsia and a Potential Therapeutic Target: A Case-Control Study.

Pregnancy-induced hypertension (GH) complicates 6−10% of all pregnancies and, in 2019, was responsible for approximately 28,000 deaths. The most common cause of gestational hypertension is pre-eclampsia (PE), which afflicts 2−8% of all pregnancies and is one of the three leading causes of maternal morbidity and mortality worldwide. The aim of this study was to clarify how NO metabolism changes during the course of PE. Due to the short half-life of NO, we measured the concentrations of its stable metabolites, nitrite and nitrate (NOx). Out of 100 enrolled patients: 58 pregnant women with a diagnosed early form of PE formed a study group, and 42 healthy pregnant women formed a control group. NOx concentrations were significantly lower in the PE group than in the control group, with mean values of 5.33 and 27.64 µmol/L, respectively (p < 0.0001). The decrease in NO is most likely the result and mediator of systemic endothelial dysfunction. The impairment of NO metabolism in PE appears to play an important role in its pathogenesis. Therefore, it is a potential therapeutic target.

C-reactive protein as a diagnostic and prognostic factor of endometrial cancer.

Endometrial cancer (EC) is the sixth most commonly occurring cancer in women and its morbidity and mortality are continuously increasing. Considering experience with different types of cancers, C-reactive protein (CRP) appears to be a promising diagnostic and prognostic factor. Aiming to investigate its potential in view of EC authors of this paper reviewed databases for metanalysis, randomized controlled trials and review articles. Studies indicate CRP > 3.33 mg/l correlates with the EC incidence with HR = 2.29 (p < 0.05). Moreover, High-sensitivity CRP assay allows to detect CRP in very low concentrations and distinguish patients with endometriosis, soft tissue sarcomas and possibly EC. Perioperational CRP, as well as its changes are independent prognostic factors for EC. However, CRP-to-albumin ratio as well as Glasgow Prognostic Score (GPS) have greater prognostic value that CRP alone. Additionally, CRP is possibly a mediator of carcinogenesis and cancer progression through activation of inter alia FcgRs/MAPK/ERK, FcgRs/IL-6/AKT/STAT3 and FcgRs/NF-κB/NLRP3 pathways.

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia.

Preeclampsia is one of the three leading causes of maternal morbidity and mortality worldwide. It afflicts 2-8% of pregnancies and is the most common cause of gestational hypertension. This article is focused on nuclear factor kappa B (NF-κB), its role in normal and pathological spiral arteries remodelling and development of preeclampsia, with evaluation if it is a promising therapeutic target. NF-κB is a key mediator of placentation. Since insemination, it stimulates production of proinflammatory cytokines by the uterine epithelium, which leads to activation of macrophages, uterine natural killer cells (uNKs), and other leukocytes. The trophoblast/uNK/macrophage crosstalk is crucial for implantation and spiral arteries remodeling, and NF-κB regulates that process through modification of cytokine expression, as well as cell phenotype and function. In the course of preeclampsia, the remodeling processes is disturbed by excessive inflammation and increased NF-κB activation. The pathological remodeling leads to uteroplacental dysfunction, release of proinflammatory cytokines into the maternal circulation, endothelial stress, and development of preeclampsia. The analysis of genetic and environmental inductors of NF-κB helps to distinguish preeclampsia risk groups. Furthermore, a selective inhibition of NF-κB or NF-κB activating pathways alleviates symptoms of preeclampsia in rat models; therefore, this could be an efficient therapeutic option.