Identification of a myometrial molecular profile for dystocic labor

<p>Abstract</p> <p>Background</p> <p>The most common indication for cesarean section (CS) in nulliparous women is dystocia secondary to ineffective myometrial contractility. The aim of this study was to identify a molecular profile in myometrium associated with dystocic labor.</p> <p>Methods</p> <p>Myometrial biopsies were obtained from the upper incisional margins of nulliparous women undergoing lower segment CS for dystocia (n = 4) and control women undergoing CS in the second stage who had demonstrated efficient uterine action during the first stage of labor (n = 4). All patients were in spontaneous (non-induced) labor and had received intrapartum oxytocin to accelerate labor. RNA was extracted from biopsies and hybridized to Affymetrix HuGene U133A Plus 2 microarrays. Internal validation was performed using quantitative SYBR Green Real-Time PCR.</p> <p>Results</p> <p>Seventy genes were differentially expressed between the two groups. 58 genes were down-regulated in the dystocia group. Gene ontology analysis revealed 12 of the 58 down-regulated genes were involved in the immune response. These included (ERAP2, (8.67 fold change (FC)) HLA-DQB1 (7.88 FC) CD28 (2.60 FC), LILRA3 (2.87 FC) and TGFBR3 (2.1 FC)) Hierarchical clustering demonstrated a difference in global gene expression patterns between the samples from dystocic and non-dystocic labours. RT-PCR validation was performed on 4 genes ERAP2, CD28, LILRA3 and TGFBR3</p> <p>Conclusion</p> <p>These findings suggest an underlying molecular basis for dystocia in nulliparous women in spontaneous labor. Differentially expressed genes suggest an important role for the immune response in dystocic labor and may provide important indicators for new diagnostic assays and potential intrapartum therapeutic targets.</p

Genetic and epidemiological studies of Dystocia : Difficult labour

Objective: To explore the epidemiological characteristics, the influence on reproductive health and the genetic basis of dystocia prolonged and difficult labour. Material and methods: The thesis has a retrospective design and is mainly based on a material from an entire cohort of women, extracted from the Swedish Medical Birth Register, who had their first delivery during the years 1973 to 1997. This includes totally 2 539 534 deliveries. The number of dystocia diagnoses at the first and second delivery was counted. Frequencies of operative deliveries and neonatal diagnoses of the child were compared between groups of women with or without dystocia. Interdelivery interval and number of children was also analyzed. Relative risk for dystocia was calculated and model-fitting (Mx) was used to estimate the relative contribution of genetic and environmental factors for the liability to experience dystocia. In addition a group of 23 women from Huddinge University Hospital and Västervik County Hospital were analyzed in detail with mutational screening of the candidate genes steroid-5-alpha-reductase (SRD5A1), endothelin 1 (EDN1), prostaglandin F 2alpha-receptor (PTGFR). The Swedish Multi-generation register was used to establish family connections and studies of medical records and telephone interviews were made in another group of 104 women, mainly sister pairs, with a history of dystocia. Single nucleotide polymorphism (SNP) whole genome scanning and non-parametric linkage (NPL) analysis was used in the families with a high occurrence of dystocia. Re-sequencing of the candidate genes oxytocin (OXT) and oxytocin receptor (OXTR) was performed in cases with dystocia. Results: In the entire material the incidence of the diagnosis of dystocia was 8.0%. At the first delivery with term singletons and head presentation there was an incidence of the diagnosis of dystocia of 11.8%. The dystocia group had 12.5% caesarean and 51.6% instrumental deliveries vs. 6.6% and 6.8% in the non-dystocia group. In the group with dystocia 25.2% of the children had a neonatal diagnosis such as asphyxia, cerebral functional disturbances etc. vs. 14.7% in the group with women without. Maternal age and height, BMI, gestational length, fetal gender, weight and head circumference were all independently related to an increased risk of dystocia. The interval to the second delivery was 41.7 months in women with dystocia and they had significantly fewer children; 2.19 vs. 42.6 and 2.30 respectively in non-dystocic women. There was an increase in the diagnosis of dystocia over the study period and a great variation between different delivery wards. Measures of familial similarity (relative risks and correlation of liability) for dystocia were higher in monozygotic than in dizygotic twins, other sibling pairs and mother-daughter pairs. Correlation of liability was also higher in full-sisters than in half-sisters. Model-fitting suggested that genetic effects accounted for 28 % of the susceptibility for dystocia.The genotyping of sister pairs showed a trend towards linkage with suggestive NPL-score (3.15) on chromosome 12p12. No mutations were found in the candidate genes SRD5A1, EDN1, PTGFR, OXT, or OXTR. Conclusion: Dystocia is a complex condition that influences the reproductive health of Swedish women. Women with a diagnosis of dystocia at their first delivery have an increased risk of operative delivery. Their newborns have more complications regarding general condition, circulation, and respiratory function. Women with dystocia have significantly fewer children, and this was most pronounced in women who were delivered instrumentally. The phenotype is quite poorly defined even though the clinical entity is very well recognized among obstetricians and midwives. There is clearly a genetic component in the susceptibility of experiencing dystocia but the exact origin has not been identified. Even though several polymorphisms were found it seems unlikely that mutations in the genes of steroid-5-alpha-reductase (SRD5A1), endothelin 1 (EDN1), prostaglandin F 2alpha-receptor (PTGFR), oxytocin (OXT) or oxytocin receptor (OXTR) are main causes of this condition. The increases of the diagnosis of dystocia as well as the frequency of caesarean sections present major challenges for the obstetric care of today and in the future

Genetic evidence of multiple loci in dystocia - difficult labour

Abstract Background Dystocia, difficult labour, is a common but also complex problem during childbirth. It can be attributed to either weak contractions of the uterus, a large infant, reduced capacity of the pelvis or combinations of these. Previous studies have indicated that there is a genetic component in the susceptibility of experiencing dystocia. The purpose of this study was to identify susceptibility genes in dystocia. Methods A total of 104 women in 47 families were included where at least two sisters had undergone caesarean section at a gestational length of 286 days or more at their first delivery. Study of medical records and a telephone interview was performed to identify subjects with dystocia. Whole-genome scanning using Affymetrix genotyping-arrays and non-parametric linkage (NPL) analysis was made in 39 women exhibiting the phenotype of dystocia from 19 families. In 68 women re-sequencing was performed of candidate genes showing suggestive linkage: oxytocin (OXT) on chromosome 20 and oxytocin-receptor (OXTR) on chromosome 3. Results We found a trend towards linkage with suggestive NPL-score (3.15) on chromosome 12p12. Suggestive linkage peaks were observed on chromosomes 3, 4, 6, 10, 20. Re-sequencing of OXT and OXTR did not reveal any causal variants. Conclusions Dystocia is likely to have a genetic component with variations in multiple genes affecting the patient outcome. We found 6 loci that could be re-evaluated in larger patient cohorts.</p

Implementation of a revised classification for intrapartum fetal heart rate monitoring and association to birth outcome : A national cohort study

Introduction: A revised intrapartum cardiotocography (CTG) classification was introduced in Sweden in 2017. The aims of the revision were to adapt to the international guideline published in 2015 and to adjust the classification of CTG patterns to current evidence regarding intrapartum fetal physiology. This study aimed to investigate adverse neonatal outcomes before and after implementation of the revised CTG classification. Material and Methods: A before-and-after design was used. Cohort I (n = 160 210) included births from June 1, 2014 through May 31, 2016 using the former CTG classification, and cohort II (n = 166 558) included births from June 1, 2018 through May 31, 2020 with the revised classification. Data were collected from the Swedish Pregnancy and Neonatal Registers. The primary outcome was moderate to severe neonatal hypoxic ischemic encephalopathy (HIE 2-3). Secondary outcomes were birth acidemia (umbilical artery pH &lt;7.05 and base excess &lt; -12 mmol/L or pH &lt;7.00), A-criteria for neonatal hypothermia treatment, 5-min Apgar scores &lt;4 and &lt;7, neonatal seizures, meconium aspiration, neonatal mortality and delivery mode. Logistic regression was used (period II vs period I), and results are presented as adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs). Results: There were no statistically significant differences in HIE 2-3 (aOR 1.27; 95% CI 0.97-1.66), proportion of neonates meeting A-criteria for hypothermia treatment (aOR 0.96; 95% CI 0.89-1.04) or neonatal mortality (aOR 0.68; 95% CI 0.39-1.18) between the cohorts. Birth acidemia (aOR 1.36; 95% CI 1.25-1.48), 5-min Apgar scores &lt;7 (aOR 1.27; 95% CI 1.18-1.36) and &lt;4 (aOR 1.40; 95% CI 1.17-1.66) occurred more often in cohort II. The absolute risk difference for HIE 2-3 was 0.02% (95% CI 0.00-0.04). Operative delivery (vacuum or cesarean) rates were lower in cohort II (aOR 0.82; 95% CI 0.80-0.85 and aOR 0.94; 95% CI 0.91-0.97, respectively). Conclusions: Although not statistically significant, a small increase in the incidence of HIE 2-3 after implementation of the revised CTG classification cannot be excluded. Operative deliveries were fewer but incidences of acidemia and low Apgar scores were higher in the latter cohort. This warrants further in-depth analyses before a full re-evaluation of the revised classification can be made