Short Cervix Following Initial Cerclage-Reinforcing Cerclage Versus Expectant Management.

OBJECTIVES: To determine whether reinforcing cerclage following ultrasound evidence of cerclage failure before 24 weeks is an effective method to delay gestational age at delivery, and to decrease the rate of preterm and peri-viable delivery. METHODS: A retrospective review was conducted for all patients who underwent any cervical cerclage procedure at a single tertiary care centre in Toronto, Canada between 1 December 2007 and 31 December 2017. RESULTS: Of 1482 cerclage procedures completed during the study period, 40 pregnant persons who underwent reinforcing cerclage were compared with 40 pregnant persons who were found to have cerclage failure before 24 weeks but were managed expectantly. After adjusting for the shortest cervical length measured prior to 24 weeks, there was no significant difference between the reinforcing cerclage and control group for gestational age at delivery, preterm, or peri-viable birth (P = 0.52, P = 0.54, P = 0.74, respectively). In an unadjusted model, there was a statistically significant increase in placental infection identified on postpartum placenta pathology in the reinforcing cerclage group compared with the expectant management group, 92.9% compared with 66.7% (P = 0.028). CONCLUSION: Reinforcing cerclage is unlikely to successfully delay the gestational age at delivery and reduce rates of preterm and pre-viable birth, especially if irreversible and progressive cervical change has begun. Future work should examine the role of preoperative amniocentesis to explore the impact of pre-existing intra-amniotic infection and reinforcing cerclage success.

Adapting obstetric and neonatal services during the COVID-19 pandemic: a scoping review.

BACKGROUND: The provision of care to pregnant persons and neonates must continue through pandemics. To maintain quality of care, while minimizing physical contact during the Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV2) pandemic, hospitals and international organizations issued recommendations on maternity and neonatal care delivery and restructuring of clinical and academic services. Early in the pandemic, recommendations relied on expert opinion, and offered a one-size-fits-all set of guidelines. Our aim was to examine these recommendations and provide the rationale and context to guide clinicians, administrators, educators, and researchers, on how to adapt maternity and neonatal services during the pandemic, regardless of jurisdiction. METHOD: Our initial database search used Medical subject headings and free-text search terms related to coronavirus infections, pregnancy and neonatology, and summarized relevant recommendations from international society guidelines. Subsequent targeted searches to December 30, 2020, included relevant publications in general medical and obstetric journals, and updated society recommendations. RESULTS: We identified 846 titles and abstracts, of which 105 English-language publications fulfilled eligibility criteria and were included in our study. A multidisciplinary team representing clinicians from various disciplines, academics, administrators and training program directors critically appraised the literature to collate recommendations by multiple jurisdictions, including a quaternary care Canadian hospital, to provide context and rationale for viable options. INTERPRETATION: There are different schools of thought regarding effective practices in obstetric and neonatal services. Our critical review presents the rationale to effectively modify services, based on the phase of the pandemic, the prevalence of infection in the population, and resource availability.

Microtubule-associated protein 2 and synaptophysin in the preterm and near-term ovine fetal brain and the effect of intermittent umbilical cord occlusion.

We have determined the change in immunoreactivity (IR) for microtubule-associated protein 2 (MAP-2) and synaptophysin (SYN) as markers for dendritic and presynaptic nerve development, respectively, in the ovine fetal brain with advancing gestation and in response to intermittent umbilical cord occlusion (UCO), which might then contribute to adverse neurodevelopment. Fetal sheep (control and experimental groups preterm at 111-115 and near term at 132-138 days of gestation; term = 145 days) were studied over 4 days with UCOs performed by inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and fetal brains assessed for IR of MAP-2 and SYN. In control animals, the IR of SYN increased in the gray matter with advancing gestation consistent with a developmental increase in presynaptic vesicles and/or nerve terminals as expected; however, the IR of MAP-2 decreased in all brain regions studied, suggesting concurrent refinement in dendritic branching and spine development. Intermittent UCO as studied with marked but limited hypoxemia resulted in a decrease in IR of SYN for the brain regions of the preterm animals when protein turnover is higher and indicates decreased presynaptic vesicle formation; whereas, MAP-2 IR was selectively increased in the hippocampus CA1 and thalamus of the near-term animals, consistent with reactive dendritic change and heightened vulnerability for neuronal injury. As such, intermittent cord compressions in the ovine fetus can impact protein markers for dendritic and presynaptic nerve development depending on their timing, which might then lead to alterations in synapse formation and neuronal circuitry.

Translational analysis of mouse and human placental protein and mRNA reveals distinct molecular pathologies in human preeclampsia.

Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent molecular mechanisms in the origins of this disease.

Glial cell missing-1 mediates over-expression of tissue inhibitor of metalloproteinase-4 in severe pre-eclamptic placental villi.

BACKGROUND: Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the placental villi develops syncytial knots and focal necrosis while reduced invasion of the extra-villous trophoblast results in a reduced maternal blood supply and ischemia of the placental villi. The transcription factor glial cell missing-1 (GCM1) regulates formation of both types of trophoblast. GCM1 expression is reduced in placental villi of women with sPE but the functional downstream consequences of reduced GCM1 expression are unknown. METHODS AND RESULTS: In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n = 12) and protein level (9.8-fold) of tissue inhibitor of metalloproteinase-4 (TIMP4) following repression of GCM1 (70 ± 7%) by small interfering-RNA, using RT-PCR and western blot, respectively. Similar increases in TIMP4 mRNA (4.2-fold, n = 7, P< 0.001 versus control) and protein levels were found following gene silencing of GCM1 in BeWo cells (<90% knock down of protein). TIMP4 protein was increased in placenta from women with sPE (3.5 ± 0.4 pg/µg, n = 8), compared with preterm (1.7 ± 0.17 pg/µg, n = 9) and term controls (1.6 ± 0.16 pg/µg, n = 9; P< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots. CONCLUSIONS: TIMP4 is a downstream target of GCM1 that may link the consequences of reduced GCM-1-directed trophoblast differentiation to histologic and functional components of disordered placentation in sPE.

Behavioural state linkage in the ovine fetus near term.

Nine fetal sheep were surgically prepared with placement of electrocortical and electro-ocular electrodes for monitoring behavioural state activity to determine the relationship of adjacent low-voltage (LV)/rapid eye movement (REM) and high-voltage (HV)/non-(N)REM epoch durations and the inter-epoch transition time. Animals were subsequently studied over an 8-hour period with behavioural state epoch duration and transition time assessed using paired t-test and regression analysis. For all animals, the duration of LV/REM epochs averaged 14.8+/-0.8 (SEM) minutes which was significantly greater than that for HV/NREM epochs at 10.1+/-0.5 min (P<0.01). The mean duration of LV/REM to HV/NREM transition periods at 93+/-3 s was also significantly longer than that for the HV/NREM to LV/REM transition periods at 78+/-6 s (P<0.05). HV/NREM epoch duration was positively correlated with the prior LV/REM epoch duration with a group mean correlation of 0.59 (P<0.01). HV/NREM epoch duration was likewise positively correlated with the subsequent LV/REM epoch duration with a group mean correlation of 0.46 (P<0.01). We conclude that the transition time into HV/NREM is longer than that into LV/REM for the ovine fetus near term which may involve differences in the rate of maturation of cycling control mechanisms for these two behavioural states and earlier development of REM-on versus REM-off pathways. The positive LV/REM-HV/NREM linkage relationships also support a homeostatic model of behavioural state control whereby LV/REM and HV/NREM timings are both controlled by accumulation of propensity for these states during the other state and favours an interactive process between these states in the brain's growth and development.

The impact of labor at term on measures of neonatal outcome.

OBJECTIVE: The purpose of this study was to determine risk assessments for a spectrum of neonatal outcomes with elective cesarean delivery versus a trial of labor for previous cesarean section and otherwise healthy patients who deliver at term. STUDY DESIGN: The perinatal/neonatal database of St. Joseph's Health Care, London, Ontario, Canada, was used to obtain the umbilical cord pH and base excess values, incidence of adverse neonatal outcomes, and patient demographics for all term (> or =37 weeks of gestation), singleton, liveborn, or intrapartum demise infants with no major anomalies who were delivered between January 1992 and March 2002 (n = 33,709 infants). Patient groupings (all patient, patient with previous cesarean delivery, and low-risk patient) with no labor versus labor were studied by a comparison of mean values/incidences for those neonatal outcomes that were available from the database with the use of linear and logistic regression analysis and controlling for potentially confounding variables. RESULTS: Labor was associated with a small drop in umbilical artery pH from approximately 7.27 to 7.25 and base excess from approximately -3.1 to -5.4 mmol/L, but this was generally well tolerated, with no difference in the incidence of 5-minute Apgar scores of <7 for any of the patient population groupings. Neonatal respiratory morbidity was increased generally in the group of elective cesarean delivery patients, which resulted in increased neonatal intensive care unit triage/admission even out to 7 days; some of this risk was likely to persist even with a policy of elective cesarean delivery after 39 weeks of gestation. Although we found no significant difference in the incidence of pathologic acidemia at birth with an umbilical artery pH <7.00, there was a risk for intrapartum/neonatal death that could be attributed to labor events per se that ranged from 1 of 882 for the patients with previous cesarean delivery to 1 of 3406 for the low-risk patients. CONCLUSION: For otherwise healthy patients at term, the risk of adverse neonatal outcomes is low, with the choice between elective cesarean delivery and trial of labor in general balancing the low risk of increased respiratory morbidity and thereby neonatal intensive care unit triage/admission against the extremely low risk of labor-related infant death and severe morbidity. However, this balance for the patients with previous cesarean delivery appears shifted, with less benefit from a trial of labor in terms of reduced respiratory morbidity and neonatal intensive care unit triage/admission and with increased labor-related severe morbidity/death, albeit with all of these still at a low level.

Cerebral leucine uptake and protein synthesis in the near-term ovine fetus: relation to fetal behavioral state.

Behavioral/sleep state activity may impact on synthetic processes within the brain, thus accounting for the developmental change in such activity and suggesting a role in the brain's growth and development. We have therefore determined the cerebral uptake of leucine and [(14)C]leucine during continuous tracer infusion as measures of leucine metabolism in relation to behavioral state activity, as well as the regional flux of leucine into brain tissue in the ovine fetus near term. The cerebral fractional protein synthetic rate and the absolute protein synthetic rate averaged approximately 20%/day and approximately 1 g/day, respectively, as measured for the whole brain, which is considerably higher than anticipated protein accretion and indicates a high rate of protein turnover with protein synthesis closely linked to protein degradation. Measures of protein synthesis were significantly higher in the pituitary gland, which may be attributed to the active synthesis and export of peptide hormones from this region. Cerebral leucine and [(14)C]leucine uptakes averaged approximately 630 and approximately 1,000 nmol. 100 g(-1). min(-1), with the latter higher than leucine unidirectional flux and thus supporting a degree of leucine oxidation by the brain. Cerebral leucine metabolism as studied was affected by behavioral state activity, with uptake measurements for both leucine and [(14)C]leucine significantly increased during the high-voltage electrocortical/non-rapid eye movement state by 1.7-fold and 2.8-fold, respectively, indicating that protein synthesis and degradation must also be increased at this time, and supporting a role for behavioral state activity in the brain's growth and development.