Mendelian gene identification through mouse embryo viability screening

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease. Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.

Stillbirth and neonatal mortality in a subsequent pregnancy following stillbirth: a population-based cohort study

Background A history of stillbirth is a risk factor for recurrent fetal death in a subsequent pregnancy. Reported risks of recurrent fetal death are often not stratified by gestational age. In subsequent pregnancies increased rates of medical interventions are reported without evidence of perinatal benefit. The aim of this study was to estimate gestational-age specific risks of recurrent stillbirth and to evaluate the effect of obstetrical management on perinatal outcome after previous stillbirth. Methods A retrospective cohort study in the Netherlands was designed that included 252.827 women with two consecutive singleton pregnancies (1st and 2nd delivery) between 1999 and 2007. Data was obtained from the national Perinatal Registry and analyzed for pregnancy outcomes. Fetal deaths associated with a congenital anomaly were excluded. The primary outcome was the occurrence of stillbirth in the second pregnancy stratified by gestational age. Secondary outcome was the influence of obstetrical management on perinatal outcome in a subsequent pregnancy. Results Of 252.827 first pregnancies, 2.058 pregnancies ended in a stillbirth (8.1 per 1000). After adjusting for confounding factors, women with a prior stillbirth have a two-fold higher risk of recurrence (aOR 1.96, 95% CI 1.07–3.60) compared to women with a live birth in their first pregnancy. The highest risk of recurrence occurred in the group of women with a stillbirth in early gestation between 22 and 28 weeks of gestation (a OR 2.25, 95% CI 0.62–8.15), while after 32 weeks the risk decreased. The risk of neonatal death after 34 weeks of gestation is higher in women with a history of stillbirth (aOR 6.48, 95% CI 2.61–16.1) and the risk of neonatal death increases with expectant obstetric management (aOR 10.0, 95% CI 2.43–41.1). Conclusions A history of stillbirth remains an important risk for recurrent stillbirth especially in early gestation (22–28 weeks). Women with a previous stillbirth should be counselled for elective induction in the subsequent pregnancy at 37–38 weeks of gestation to decrease the risk of perinatal death.

Maternal exposure to an enrichment environment promotes uterine vascular remodeling and prevents embryo loss in mice.

Aim: Implantation-related events are crucial for pregnancy success. In particular, defects in vascular remodeling at the maternal-fetal interface are associated with spontaneous miscarriage and recurrent pregnancy loss. Physical activity and therapies oriented to reduce stress improve pregnancy outcomes. In animal models, environmental stimulation and enrichment are associated with enhanced well-being, cognitive function and stress resilience. Here we studied whether exposure of BALB/c mice to an enriched environment (EE) regulates crucial events during early gestation at the maternal-fetal interface. Method: Pregnant BALB/c mice were exposed to the EE that combines non-invasive stimuli from the sensory pathway with voluntary physical activity. The pregnancy rate was evaluated. Implantation sites were investigated microscopically and macroscopically. Vascular adaptation parameters at the maternal-fetal interface were analyzed. Results: We found that exposure to the EE prevented pregnancy loss between gestational days 7 and 15. Also, it increased the diameter of the uterine artery and decreased the wall:lumen ratio of the mesometrial decidual vessels, suggesting that EE exposure promotes vascular remodeling. Moreover, it increased nitric oxide synthase activity and inducible nitric oxide synthase expression, as well as prostaglandin F2α production and endoglin expression in the implantation sites. Conclusion: Exposure of pregnant females to the EE regulates uterine physiology, promoting vascular remodeling during early gestation. These adaptations might contribute to preventing embryo loss. Our results highlight the importance of the maternal environment for pregnancy success. The design of an “EE-like” protocol for humans could be considered as a new non-pharmacologic strategy to prevent implantation failure and recurrent miscarriage.

Spontaneous heterotopic pregnancy: a case report

Heterotopic pregnancy is defined as multiple gestation in which intrauterine and extrauterine gestational sacs co-exist. The extra uterine gestational sac is most commonly tubal ectopic pregnancy. We presented case of a 26 years old multigravida who presented to emergency with complaints of pain abdomen and giddiness for 2-3 days. She was at period of gestation (POG) 7 weeks and on clinical examination patient was anxious with mild pallor, mildly tachycardiac and blood pressure (BP) was 90/60 mm of Hg. After thorough clinical examination and sonography diagnosis of heterotopic pregnancy with ruptured tubal ectopic was made. She was taken up for Emergency laparotomy after investigations and consent. Left salpingectomy was done and she was discharged with a single intrauterine live pregnancy on 6th post op day. For early detection of cases of heterotopic pregnancy careful evaluation of adnexa is mandatory in early gestation scan.

Dyslipidemia as Predictor of Missed Miscarriage

Background: This study aimed at finding the diagnostic and prognostic possibilities of determining apoC-II, as a serological marker for MM in early gestation. Methods and Results: The study included 182 pregnant women aged between 18 and 45 years at gestational age under 11 weeks. All women were divided into 3 groups. Group 1 (Gr1) included 90 women with MM; Group 2 (Gr2) included 52 women with spontaneous miscarriage; Group 3 included 40 women without pathology (control group [CG]). Lipid metabolism disorders were diagnosed according to the Russian national recommendations of the VII revision(the Russian Society of Cardiologists [RSC, 2020]), considering the European recommendations (2019). Proteomic analysis of the blood serum was performed using LC-MS. Abnormalities in the lipid profile were more common in patients with MM and spontaneous abortions: 62.2% and 59.7% of cases, respectively, which correlates with the identified marker apoC-II in Gr1 and Gr2. Conclusion: ApoC-II can be considered as the most promising serologic marker for MM in the early gestation period for women with dyslipidemia.

PREDICTION OF PERINATAL COMPLICATIONS IN WOMEN WITH NONCARRYING OF PREGNANCY AT EARLY GESTATION TERMS (LITERATURE REVIEW)

Objective – to analyze modern views on the mechanisms of perinatal complications’development in order to predict them in women with miscarriage in the first trimester ofgestation.Conclusions. The need for further study of this problem, taking into account theethiopathogenesis, in order to develop algorithms for predicting gestational complicationsand timely diagnosis, which will improve perinatal outcomes, was shown. Therefore, thepriority task, aimed at reducing reproductive losses, is the prevention of miscarriage byfinding new screening markers that will detect preclinical forms of pathology.

The OEIS complex – clinical & radiological evaluation

The OEIS complex comprises a constellation of complex and severe malformations of the abdominal wall, gastrointestinal and genitourinary tracts, and spinal cord. The malformation results from improper closure of the ventral abdominal wall due to failure of convergence of cephalo-caudal and lateral folding of the embryo during early gestation. The rarity of the condition suggests etiologic heterogeneity and the possible role of environmental and genetic factors. We present clinical and imaging findings of the OEIS complex in a neonate.

Prevention of pregnancy complications and delivery at low placentation

Objective is to evaluate the effectiveness of the developed method of preventing pregnancy complications with low placentation from early gestation.Material and methods. We have examined 119 pregnant women with low placentation. This diagnosis was made at 6-7 weeks of gestation on the basis of echographic research. The main group consisted of 64 pregnant women with low chorionic location who underwent prevention from pregnancy complications in early gestation by the complex of medicines developed by us and a control group -55 women with low placentation who had not undergone complications prophylaxis from early gestational periods. The prophylactic complex included Luteina, ginkgo biloba extract, folio and biolectra. To assess the effectiveness of the therapy in the study groups, we analyzed the course of pregnancy in early and late gestation, as well as complications of pregnancy and delivery.Results. The frequency of pregnancy pathologies in the main group, where the prevention of pregnancy complications from early gestation with low placentation, was significantly lower than in the control group. According to the study, the risk of abortion with bleeding and without bleeding in the first and second trimesters significantly decreased in the main group of pregnant women (p<0.05). In the third trimester of gestation in the group where the prevention of pregnancy complications was significantly reduced, the incidence of preterm birth, premature detachment of the low-lying placenta, fetoplacental dysfunction, fetal developmental delay syndrome and fetal distress during pregnancy (p<0.05). Also, in the main group there was a lower percentage of premature births and births that ended by cesarean section.Conclusions. 1. The place of attachment of the placenta in the uterine cavity is closely related to its function, the development of placental dysfunction, pregnancy and delivery. 2. Studies have shown the effectiveness of our proposed comprehensive drug prevention of complications of pregnancy with low placentation, which in turn has led to improved pregnancy and delivery and has become an effective means of preventing placental dysfunction.