Thesis for doctoral degree ( Ph . D . ) 2008 GENETIC AND EPIDEMILOGICAL 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--reductase (SRD5A1), endothelin 1 (EDN1), prostaglandin F 2-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 motherdaughter 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--reductase (SRD5A1), endothelin 1 (EDN1), prostaglandin F 2-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.