Genetic evidence of multiple loci in dystocia difficult labour
Michael Algovik*1, Katja Kivinen2, Hanna Peterson3, Magnus Westgren1 and Juha Kere3
Abstract Background: Dystocia, difficult labour, is a common but also complex problem duringchildbirth. 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 whereat 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 genotypingarrays and non-parametric linkage (NPL) analysis was made in 39 women exhibiting the phenotype of dystocia from 19 families. In68 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. Background Dystocia, defined as prolonged and difficult labour, is a common obstetric problem affecting 6-8% of all deliveries . It is a major global health problem due to the increased risk of intrauterineasphyxia of the fetus, operative delivery and subsequently increased risk of both fetal and maternal morbidity such as haemorrhage, infections, pelvic floor trauma, subsequent placenta accreta and neurological disabilities [2-5]. Dystocia followed by instrumental delivery or caesarean section might also be major psychological trauma leading to increased levels of anxiety that by some authors evenhas been classified as post traumatic stress disorder [6,7]. Parturition is regulated by many factors and the mechanisms regulating labour and the expulsion of the child are incompletely understood . Animal studies have shown
* Correspondence: firstname.lastname@example.org
1 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden and Department ofObstetrics and Gynaecology, Västervik Community Hospital, Västervik, Sweden
that knock-out mice models of genes regulating parturition exhibit dystocia [9,10], but this has not yet been shown in humans . A strong genetic influence has been shown in other obstetric conditions such as preeclampsia, low birth weight, and abnormal gestational length [12,13]. Studies have also detected anincreased risk for dystocia in a woman with affected mother or sister [14,15]. We have previously estimated the heritability of dystocia to be 28%  and this finding has encouraged us to perform a genome-wide scan in a material consisting of affected sib pairs to further assess the genetic basis for dystocia.
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We used the Swedish Medical Birth Registry  that covers almost all births in Sweden to identify women who had given their first birth with caesarean section between 1982 and 1997 at a gestational length of more than 286 days. The reason for this was to have a well defined end point and to increase the chance of finding subjects with
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