New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations.

Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.

Emergency cerclage using double-level versus single-level suture in the management of cervical insufficiency (Cervical Occlusion double-level Stitch Application, COSA): study protocol for a multicentre, non-blinded, randomised controlled trial.

INTRODUCTION: Cervical insufficiency accounts for 15% of recurrent pregnancy losses between 16 and 28 weeks of gestation. The aim of the study is to verify the effectiveness of emergency double-level cerclage with vaginal progesterone in cervical insufficiency treatment in terms of the prevention of preterm delivery before 34 weeks of gestation. METHODS AND ANALYSIS: This trial is a multicentre, non-blinded, randomised study with 1:1 allocation ratio. The study is conducted at tertiary perinatal care departments in Poland. It will include patients with cervical insufficiency with the fetal membranes visible in the open cervical canal or protruding into the vagina between 16+0 and 23+6 weeks of pregnancy. They will be randomised into two arms: emergency single-level cerclage with vaginal progesterone or double-level cerclage with vaginal progesterone. All will be administered antibiotics and indomethacin. The primary outcome is the rate of deliveries below 34+0 weeks of gestation, while secondary outcomes include gestational age at delivery, neonatal outcomes, maternal outcomes according to the Core Outcome Set for Evaluation of Interventions to Prevent Preterm Birth and cerclage procedure complications. The planned number of participants according to the power analysis is 78. ETHICS AND DISSEMINATION: The study protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials statement. It was created according to the requirements of the Declaration of Helsinki for Medical Research involving Human Subject. Ethical approval was obtained from the Ethics Committee of the Centre of Postgraduate Medical Education (no. 1/2022). The study protocol was approved and published by ClinicalTrials.gov (posted on 24 February 2022). All participants gave a written informed consent. After completion of the study its results will be published in a peer-reviewed English language journal. TRIAL REGISTRATION: NCT05268640.

High prevalence of early (1st trimester) gestational diabetes mellitus in Polish women is accompanied by marked insulin resistance - comparison to PCOS model.

INTRODUCTION: Both pregnancy and polycystic ovary syndrome (PCOS) constitute insulin-resistant states that are associated with an increased prevalence of glucose intolerance. Some women demonstrate significant insulin resistance (IR) and develop gestational diabetes (GDM) even in the 1st trimester. We compared surrogate IR indices in 1st-trimester pregnant women and in women with PCOS (Rotterdam consensus criteria). MATERIAL AND METHODS: We performed a 75-g oral glucose tolerance test (OGTT) with insulin measurements in 106 healthy 1st-trimester pregnant women at 9.9 ± 2.6 weeks of gestation and in 418 women with PCOS. We assessed IR (HOMA-IR, QUICKI, Matsuda, Belfiore, and Stumvoll indices) as well as the prevalence of GDM according to the International Association of Diabetes and Pregnancy Study Groups (IADSPG) and World Health Organization (WHO) (1999) criteria. RESULTS: Despite having a slightly lower BMI (p = 0.027), pregnant women had either similar (QUICKI, Belfiore index, Stumvoll0-120 min) or greater IR than women with PCOS (e.g. HOMA-IR 3.85 ± 6.11 vs. 2.64 ± 2.04, p = 0.002), while only the Matsuda index demonstrated less IR in pregnant women (p = 0.003). The correlation between IR indices in pregnant women showed marked variability, ranging from r = 0.334 (HOMA-IR vs. Belfiore index) to r = -1.0 (HOMA-IR vs. QUICKI, p < 0.001). This was accompanied by a high prevalence of GDM (14.2% and 9.4%, IADPSG and WHO criteria, respectively). Women with GDM diagnosed according to IADPSG criteria demonstrated greater IR than pregnant women without GDM. In women with GDM diagnosed according to WHO (1999) criteria these differences were visible only for OGTT-derived IR indices (Belfiore, Matsuda, and Stumvoll0-120 index). CONCLUSIONS: Depending on the choice of IR indices, healthy 1st-trimester pregnant women demonstrate either similar or greater IR than women with PCOS, and this is accompanied by a high prevalence of early GDM. It remains to be established whether GDM screening should be performed in the 1st trimester.

Single Nucleotide Polymorphisms from CSF2, FLT1, TFPI and TLR9 Genes Are Associated with Prelabor Rupture of Membranes.

A prelabor rupture of membranes (PROM) and its subtypes, preterm PROM (pPROM) and term PROM (tPROM), are associated with disturbances in the hemostatic system and angiogenesis. This study was designed to demonstrate the role of single nucleotide polymorphisms (SNPs), localized in CSF2 (rs25881), FLT1 (rs722503), TFPI (C-399T) and TLR9 (rs352140) genes, in PROM. A population of 360 women with singleton pregnancy consisted of 180 PROM cases and 180 healthy controls. A single-SNP analysis showed a similar distribution of genotypes in the studied polymorphisms between the PROM or the pPROM women and the healthy controls. Double-SNP TT variants for CSF2 and FLT1 polymorphisms, CC variants for TLR9 and TFPI SNPs, TTC for CSF2, FLT1 and TLR9 polymorphisms, TTT for FLT1, TLR9 and TFPI SNPs and CCCC and TTTC complex variants for all tested SNPs correlated with an increased risk of PROM after adjusting for APTT, PLT parameters and/or pregnancy disorders. The TCT variants for the CSF2, FLT1 and TLR9 SNPs and the CCTC for the CSF2, FLT1, TLR9 and TFPI polymorphisms correlated with a reduced risk of PROM when corrected by PLT and APTT, respectively. We concluded that the polymorphisms of genes, involved in hemostasis and angiogenesis, contributed to PROM.

The Preeclamptic Environment Promotes the Activation of Transcription Factor Kappa B by P53/RSK1 Complex in a HTR8/SVneo Trophoblastic Cell Line.

Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B (NFκB) in maternal and placental cells. Although the role of NFκB in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of NFκB activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% O2) or normoxic (8% O2) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied NFκB pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% O2 in comparison to C 8% O2. Therefore, other pathways may be responsible for NFκB activation. One such pathway depends on the activation of NFκB by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of pNFκB Ser536 in the nucleus, but only in cells incubated with PE serum at 2% O2. Thus, the p53/RSK1 complex might play a critical role in the activation of NFκB in trophoblastic cells and preeclamptic placentas.

Is serum anti-Müllerian hormone (AMH) assay a satisfactory measure for ovarian reserve estimation? A comparison of serum and peritoneal fluid AMH levels.

BACKGROUND: Clinical cases have been reported with women who got pregnant with confirmed low serum anti-Müllerian hormone (AMH) concentrations, thus demonstrating that low serum AMH concentration cut-points could be fairly specific for poor ovarian response (POR) to gonadotrophin stimulation, but not for pregnancy. That observation prompted the question whether serum AMH concentration accurately corresponded to the whole amount of AMH secreted by granulosa cells. OBJECTIVES: To measure AMH levels in peritoneal fluid and their correlations with serum AMH concentrations. MATERIAL AND METHODS: The reported study involved 48 female patients, aged 18-40 years, diagnosed with benign ovarian cysts and qualified for a laparoscopic cystectomy. Prior to surgery, the ovarian reserve was assessed using serum AMH concentration assay. The peritoneal fluid was also collected during the laparoscopy and AMH concentrations in peritoneal fluid were measured. RESULTS: The AMH present in the peritoneal fluid strongly correlated with AMH levels in blood serum (r = 0.54; p < 0.001) and higher serum AMH concentrations corresponded to higher AMH concentrations in the peritoneal fluid. There was also a significant correlation between AMH levels in serum and in peritoneal fluid, collected from patients with endometrioma and other benign cysts (r = 0.61; p = 0.001 vs r = 0.43; p = 0.03). CONCLUSIONS: The AMH is present in the peritoneal fluid and its concentrations significantly correlate with AMH levels in serum. The assessment of AMH concentration in the peritoneal fluid may be a valuable complement to the evaluation of ovarian reserve and the diagnosis of infertility after adnexal surgery.

Identification of placental genes linked to selective intrauterine growth restriction (IUGR) in dichorionic twin pregnancies: gene expression profiling study.

A linkage of dichorionic (DC) twin pregnancies with selective intrauterine growth restriction (IUGR) to alterations in placental gene expression is unclear. The aim of the study was to identify placental genes related to hypoxia, adipogenesis and human growth which may contribute to IUGR development. The study group (IUGR/AGA) comprised dichorionic (DC) twin pregnancies, where the weight of the twins differed by > 15%; in addition, one twin was small for gestational age (< 10th percentile-SGA) (IUGR) while the other was appropriate for gestational age (> 10th percentile-AGA). In the control group (AGA/AGA), both fetuses were AGA and their weights differed by < 15%. In the first step (selection), placental expression of 260 genes was analysed by commercial PCR profiler array or qPCR primer assay between six pairs of IUGR/AGA twins. In the second stage (verification), the expression of 20 genes with fold change (FC) > 1.5 selected from the first stage was investigated for 75 DC pregnancies: 23 IUGR/AGA vs. 52 AGA/AGA. The expression of Angiopoetin 2, Leptin and Kruppel-like factor 4 was significantly higher, and Glis Family Zinc Finger 3 was lower, in placentas of SGA fetuses (FC = 3.3; 4.4; 1.6; and - 1.8, respectively; p < 0.05). The dysregulation of gene expression related to angiogenesis and growth factors in placentas of twins born from IUGR/AGA pregnancies suggest that these alternations might represent biological fetal adaptation to the uteral condition. Moreover, DC twin pregnancies may be a good model to identify the differences in placental gene expression between SGA and AGA fetuses.

Sociodemographic, Lifestyle, Environmental and Pregnancy-Related Determinants of Dietary Patterns during Pregnancy.

Background: Characterization of dietary patterns represents a valid and meaningful measure of overall diet quality and nutrient intake. The study aims at evaluating the sociodemographic, lifestyle, environmental, and pregnancy-related determinants of maternal dietary patterns during pregnancy. Methods: The analysis was conducted on a group of pregnant women from the Polish Mother and Child Cohort (REPRO_PL). During the second trimester of pregnancy, 1306 women filled in a modified version of the validated food frequency questionnaire (FFQ). Dietary patterns were estimated using an exploratory factor analysis. Potential dietary determinants were assessed via a questionnaire or biomarker measurements (saliva cotinine level). Results: Two dietary patterns were identified. The Prudent dietary pattern was characterized by high consumption of fruit, vegetables, legumes, whole grains, poultry, and low-fat dairy products, while the Western dietary pattern included high intake of refined grains, processed meat, potatoes, and very low intake of whole grains. Clear sociodemographic, environmental, lifestyle, and pregnancy-related determinants of diet quality were established. Older age (ß = 0.2; p < 0.01), higher educational level (ß = 0.3; p < 0.01), and socioeconomic status (SES) (ß = 0.2; p < 0.01), overweight/obesity before (ß = 0.3; p < 0.01), as well as physical activity during pregnancy (ß = 0.2; p = 0.01) were positive determinants of a healthier diet (increasing Prudent⁻Western difference in dietary pattern scores). On the other hand, parity (ß = -0.2; p = 0.04) and living in small cities (ß = -0.3; p = 0.02) were significantly related to a rather Western dietary pattern. Conclusions: The current study presents evidence on specific factors influencing dietary patterns. They need to be accounted for in educational programs and interventions focused on healthy diet recommendations during pregnancy.

Vitamins A and E during Pregnancy and Allergy Symptoms in an Early Childhood-Lack of Association with Tobacco Smoke Exposure.

Epidemiological studies have suggested an association between maternal antioxidant levels during pregnancy and development of allergic diseases in their offspring. The aim of the study was to determine plasma vitamins A and E concentration in the 1st trimester of pregnancy, at delivery and in cord blood and to search for a relationship with allergy in up to 2-year-old children who were prenatally exposed or not exposed to tobacco smoke. The study participants included 252 mother-child pairs from Polish Mother and Child Cohort. Vitamin concentrations were measured using the HPLC-UV method, smoking status—as saliva cotinine level using the HPLC-MS/MS technique. Children’s health status was assessed using a questionnaire and pediatricians/allergists examination. Cord plasma vitamin concentrations were significantly lower than their levels in maternal plasma in the 1sttrimester and at delivery (p < 0.001). Significantly higher concentrations of vitamin E have been shown to occur during the 1st trimester of pregnancy in plasma of the women who have actively/passively smoked cigarettes compared to the non-smokers (p < 0.02). Multivariate analysis with inclusion of a variety of confounding factors have not indicated any statistically significant associations between β-carotene, vitamins A and E and the risk of food allergy, atopic dermatitis and wheezing in their children up to 2 years of age. The interaction between smoking during pregnancy and vitamins levels on the risk of allergy was not statistically significant (p < 0.4). The relationship between plasma concentration of vitamins A and E, and the risk of allergy in their young children has not been demonstrated.

Clinical challenges in the management of a prenatally diagnosed cloacal malformation.

Cloacal dysgenesis sequence is a severe malformation of the primitive cloaca and is characterized by a phallus-like structure, smooth perineum and the absence of genitourinary and anal orifices. It is usually accompanied by oligohydramnios, kidney dysplasia, and pulmonary hypoplasia. We present a case of a 29-year-old woman who was referred at 26 weeks of gestation due to an enlarged fetal abdominal circumference. Investigations revealed the presence of fetal ascites, intrapelvic cysts, calcified meconium, severe oligohydramnios and a 46XX karyotype. Fetal abdominal parecentesis performed on several occasions failed to reduce intra-abdominal pressure. To our knowledge this case represents the first variation of cloacal dysgenesis sequence to contain three dysmorphic structures along with the common findings of this anomaly.

[The results of screening program for cervical cancer in Lodz]. / Wyniki badania przesiewowego dla wczesnego wykrywania raka szyjki macicy u kobiet w regionie lódzkim.

OBJECTIVES: Despite effective screening methods, most often tumor of the urogenital tract is still cancer of the uterine cervix. Proven in many countries the value of widespread screening of the precancerous lesions and cervical cancer justifies carrying out such prophylactic tests in Poland. DESIGN: Assessment of results of screening as a method of early detection of cancer of the uterine cervix among inhabitants of Lódz area. MATERIAL AND METHODS: Study was done between 1.07.2000 and 31.12.2000 among 5,000 women aged from 30 to 59 years, inhabitants of Lódz area. Smears were evaluated in five-grade Papanicolaou scale and according to TBS system. In cases of detection of erosion of the uterine cervix or abnormal results of cytological test (> or = III degree) biopsies were taken to make pathological diagnosis. RESULTS: 459 smears were qualified to group I according to Papanicolaou (9.18%), 4435 smears to group II (88.7%), 38 smears to II/III (0.76%), 65 smears to group III (1.3%), 2 smears to IV (0.04%) and 1 smear to V (0.02%). Due to histopathological verification of the cytological results 53 low grade cervical dysplasia (1.06%) were diagnosed, 8 dysplasia of medium grade (0.16%), 7 high grade dysplasia (0.14%), 3 pre-invasive cancers (0.06%) and 3 invasive cancers (0.06%). CONCLUSIONS: Population of inhabitants of Lódz area aged 30 to 59 years old is characterised by a high frequency of incidence of pre-cancerous conditions and invasive cervical cancer. Number of detected pathologies of the uterine cervix proves purposefulness of this project.