Etiology behind canine uterine inertia: Role of uterine expression of MLCK4, MYH2, and PKC genes.

Dystocia is an obstetrical emergency, and primary uterine inertia (PUI) is the major etiological reason among the more prevalent maternal causes in dogs. The present study involved the relative expression analysis of genes associated with myometrial contraction in medium-sized dog breeds with uterine inertia. Dogs without any progress in the parturition process even after four hours of the onset of labor and the absence of uterine contractions were considered to have complete primary uterine inertia (CPUI, n = 9). Dogs that had expelled at least one fetus and made no further progress in parturition in the absence of active uterine contraction were considered to be experiencing partial primary uterine inertia (PPUI, n = 6). Dogs with the fetal cause of dystocia (FCD), i.e., obstructive dystocia, were taken as the third (n = 7) group. Uterine tissue samples were collected during cesarean section in each group, RNA was isolated, and the relative expression of myometrial ACTA2, ACTG2, MLCK4, MYH2, and PKC genes was analyzed. The MLCK4 gene expression was downregulated in CPUI (P ≤ 0.05) and PPUI (P ≤ 0.01) when compared to FCD. The MYH2 gene expression was downregulated in PPUI in comparison to CPUI (P ≤ 0.01) and FCD (P ≤ 0.05). The PKC gene expression was upregulated in PPUI in comparison to FCD and CPUI (P ≤ 0.05). The downregulation of MLCK4 and MYH2 gene expressions recorded in PPUI indicated the possibility of myometrial defects. The possibility of myometrial defects was also observed in CPUI, but to a lesser degree, suggesting other etiologies.

Oxytocin receptor single nucleotide polymorphism predicts atony-related postpartum hemorrhage.

BACKGROUND: Postpartum hemorrhage remains a key contributor to overall maternal morbidity in the United States. Current clinical assessment methods used to predict postpartum hemorrhage are unable to prospectively identify about 40% of hemorrhage cases. Oxytocin is a first-line pharmaceutical for preventing and treating postpartum hemorrhage, which acts through oxytocin receptors on uterine myocytes. Existing research indicates that oxytocin function is subject to variation, influenced in part by differences in the DNA sequence within the oxytocin receptor gene. One variant, rs53576, has been shown to be associated with variable responses to exogenous oxytocin when administered during psychological research studies. How this variant may influence myometrial oxytocin response in the setting of third stage labor has not been studied. We tested for differences in the frequency of the oxytocin receptor genotype at rs53576 in relationship to the severity of blood loss among a sample of individuals who experienced vaginal birth. METHODS: A case-control prospective design was used to enroll 119 postpartum participants who underwent vaginal birth who were at least 37 weeks of gestation. Cases were defined by either a 1000 mL or greater blood loss or instances of heavier bleeding where parturients were given additional uterotonic treatment due to uterine atony. Controls were matched to cases on primiparity and labor induction status. Genotype was measured from a maternal blood sample obtained during the 2nd postpartum month from 95 participants. Statistical analysis included bivariate tests and generalized linear and Poisson regression modeling. RESULTS: The distribution of the genotype across the sample of 95 participants was 40% GG (n = 38), 50.5% AG (n = 48) and 9.5% AA (n = 9). Blood loss of 1000 mL or greater occurred at a rate of 7.9% for GG, 12.5% for AG and 55.6% for AA participants (p = 0.005). Multivariable models demonstrated A-carriers (versus GG) had 275.2 mL higher blood loss (95% CI 96.9-453.4, p < 0.01) controlling for parity, intrapartum oxytocin, self-reported ancestry, active management of third stage or genital tract lacerations. Furthermore, A-carrier individuals had a 79% higher risk for needing at least one second-line treatment (RR = 1.79, 95% CI = 1.08-2.95) controlling for covariates. Interaction models revealed that A-carriers who required no oxytocin for labor stimulation experienced 371.4 mL greater blood loss (95% CI 196.6-546.2 mL). CONCLUSIONS: We provide evidence of a risk allele in the oxytocin receptor gene that may be involved in the development of postpartum hemorrhage among participants undergoing vaginal birth, particularly among those with fewer risk factors. The findings, if reproducible, could be useful in studying pharmacogenomic strategies for predicting, preventing or treating postpartum hemorrhage.

Smooth muscle 22α deficiency impairs oxytocin-induced uterine contractility in mice at full-term pregnancy.

Smooth muscle 22α (SM22α, namely Transgelin), as an actin-binding protein, regulates the contractility of vascular smooth muscle cells (VSMCs) by modulation of the stress fiber formation. However, little is known about the roles of SM22α in the regulation of uterine contraction during parturition. Here, we showed that contraction in response to oxytocin (OT) was significantly decreased in the uterine muscle strips from SM22α knockout (Sm22α-KO) mice, especially at full-term pregnancy, which may be resulted from impaired formation of stress fibers. Furthermore, serious mitochondrial damage such as the mitochondrial swelling, cristae disruption and even disappearance were observed in the myometrium of Sm22α-KO mice at full-term pregnancy, eventually resulting in the collapse of mitochondrial membrane potential and impairment in ATP synthesis. Our data indicate that SM22α is necessary to maintain uterine contractility at delivery in mice, and acts as a novel target for preventive or therapeutic manipulation of uterine atony during parturition.

Desprendimiento prematuro de placenta normoinsertada por mutación heterocigota en el gen de la protrombina / Placental abruption associated with heterozygous prothrombin gene mutation

El desprendimiento prematuro de placenta se define como la separación parcial o completa de una placenta normalmente insertada antes del inicio del parto. Esto se produce en un 0,4-1% de las gestaciones. Esta patología se asocia a una elevada morbimortalidad materno-fetal. Existen distintos factores de riesgo asociados con el desprendimiento prematuro de placenta. Entre estos factores se encuentran: trastornos hipertensivos del embarazo, antecedentes de desprendimiento placentario o cesárea, diabetes, multiparidad, sobredistensión uterina (gestación múltiple o polihidramnios), rotura prematura de membranas, traumatismos abdominales, consumo de tóxicos y trombofilias. En un elevado número de casos la causa del desprendimiento es desconocida. El diagnóstico se basa fundamentalmente en las manifestaciones clínicas. El empleo de la ecografía tiene una utilidad muy limitada para el diagnóstico debido a su baja sensibilidad. La actitud va a estar condicionada por el estado materno y fetal, el grado de desprendimiento placentario y la edad gestacional en el momento del diagnóstico. Se presenta un caso clínico de un desprendimiento prematuro de placenta normoinsertada asociado a coagulación intravascular diseminada, útero de Couvelaire y atonía uterina debido a la mutación 620210 A heterocigota en el gen de la protrombina

Placental abruption defined as the complete or partial separation of a normally implanted placenta before delivery, occurs in 0.4-1%. It is one of the most significant causes of maternal and perinatal morbidity and mortality. The risk factor of abruption placentae are hypertension, prior caesarean delivery, previous abruption placentae, pregestational diabetes, high parity, polyhydramnion, multiple gestation, premature rupture of membranes, abdominal trauma, drug abuse and thrombophilia. The cause of placental abruption often remains unexplained. The diagnosis of placental abruption is clinical, based on characteristic signs and symptoms. Sonography is not sensitive for the detection of placental abruption. Prenatal and perinatal management depend on maternal and foetal condition, severity and gestational age. We report the case of placental abruption associated with disseminated intravascular coagulation, Couvelaire uterus and uterine atony. The patient was diagnosed with heterozygous prothrombin gene mutation 620210 A

ACTA2 mutation and postpartum hemorrhage: a case report.

BACKGROUND: ACTA2 encodes smooth muscle specific α-actin, a critical component or the contractile complex of vascular smooth muscle. Mutations in ACTA2 are the most common genetic cause of thoracic aortic aneurysm, and are also the cause of other disorders, including Moyamoya disease, coronary artery disease and stroke as well as Multisystemic Smooth Muscle Dysfunction Syndrome. We note that ACTA2 is also expressed in uterine smooth muscle, and this raises the possibility that women harboring ACTA2 mutations might exhibit uterine smooth muscle dysfunction. CASE PRESENTATION: We present a young woman whose ACTA2 mutation was ascertained during pregnancy because of her father's history of dissecting aneurysms. She was delivered at full term by cesarean section and subsequently had severe uterine hemorrhage due to uterine atony. Although her atony was successfully treated with uterotonic medications, she required blood transfusion. CONCLUSIONS: This case raises the possibility that women with ACTA2 mutations may be at risk of uterine muscle dysfunction and hemorrhage. Obstetricians should be alerted to and prepared for this possibility.

Genetic contribution to postpartum haemorrhage in Swedish population: cohort study of 466,686 births.

OBJECTIVE: To investigate the familial clustering of postpartum haemorrhage in the Swedish population, and to quantify the relative contributions of genetic and environmental effects. DESIGN: Register based cohort study. SETTING: Swedish population (multi-generation and medical birth registers). MAIN OUTCOME MEASURE: Postpartum haemorrhage, defined as >1000 mL estimated blood loss. PARTICIPANTS: The first two live births to individuals in Sweden in 1997-2009 contributed to clusters representing intact couples (n = 366,350 births), mothers with separate partners (n = 53,292), fathers with separate partners (n = 47,054), sister pairs (n = 97,228), brother pairs (n = 91,168), and mixed sibling pairs (n = 177,944). METHODS: Familial clustering was quantified through cluster specific tetrachoric correlation coefficients, and the influence of potential sharing of known risk factors was evaluated with alternating logistic regression. Relative contributions of genetic and environmental effects to the variation in liability for postpartum haemorrhage were quantified with generalised linear mixed models. RESULTS: The overall prevalence of postpartum haemorrhage after vaginal deliveries in our sample was 4.6%. Among vaginal deliveries, 18% (95% confidence interval 9% to 26%) of the variation in postpartum haemorrhage liability was attributed to maternal genetic factors, 10% (1% to 19%) to unique maternal environment, and 11% (0% to 26%) to fetal genetic effects. Adjustment for known risk factors only partially explained estimates of familial clustering, suggesting that the observed shared genetic and environmental effects operate in part through pathways independent of known risk factors. There were similar patterns of familial clustering for both of the main subtypes examined (atony and retained placenta), though strongest for haemorrhage after retained placenta. CONCLUSIONS: There is a maternal genetic predisposition to postpartum haemorrhage, but more than half of the total variation in liability is attributable to factors that are not shared in families.