Unveiling therapeutic potentials and exploring maternal-fetal health benefits of metformin in pregnancy: A scoping review.

This scoping review synthesizes evidence on metformin's use during pregnancy, encompassing diverse conditions like gestational diabetes, type 1 and type 2 diabetes, polycystic ovary syndrome (PCOS), and obesity. Metformin demonstrates comparable efficacy to insulin in gestational diabetes, positive outcomes in type 2 diabetes pregnancies, and potential benefits in reducing complications. The review highlights nuances in its effects across conditions, indicating advantages such as reduced risk of macrosomia and cesarean section in gestational diabetes. However, its prophylactic role in preventing gestational diabetes and associated complications remains inconclusive. In obese pregnant women, mixed results are observed, with potential benefits in reducing pre-eclampsia risk. Metformin shows promise in preventing preterm birth and late miscarriage in PCOS pregnancies. Categorizing patient subgroups is crucial for identifying advantages, especially in gestational diabetes and type 2 diabetes. Challenges arise from study heterogeneity, necessitating standardized indications for dosage, timing, and postpartum follow ups. Efforts to identify patient characteristics influencing metformin efficacy are crucial for tailored therapy. Although metformin emerges as a viable option in complicated pregnancies, comprehensive research, standardized protocols, and subgroup identification efforts will enhance clinical utility, ensuring evidence-based therapies and optimal maternal and fetal outcomes. Bridging existing knowledge gaps remains imperative for advancing metformin's role in pregnancy management.

Cervical elastography using E-Cervix™ for prediction of preterm birth in twin pregnancies with threatened preterm labor.

OBJECTIVE: To evaluate the prediction performance of E-Cervix™ for preterm birth in twin pregnancies with threatened preterm labor. METHODS: This was a single-center retrospective cohort study of twin pregnancies presenting to obstetrics triage for threatened preterm labor (PTL) between 23 0/7 - 33 6/7 weeks who received screening for PTL with transvaginal ultrasound cervical length (TVU CL) and cervical elastography with E-Cervix™ at the time of triage. Cervical elastography parameters were examined and compared between women who delivered preterm and those who did not. The quantification of cervical strain was calculated by a data analysis system that directly analyzes raw data from the region of interest (ROI) and described as hardness ratio (HR), mean strain level within 1 cm from internal (IOS) and external (EOS) os. RESULTS: 63 twin gestations without prior preterm birth and with threatened PTL between 23 0/7 - 33 6/7 weeks of gestation were included in the study. 27 (42.9 %) had cervical length < 25 mm, and were admitted for true PLT. Out of the 36 women with cervical length ≥ 25 mm, 6 (16.7 %) were admitted. Women with threatened PTL had significantly higher HR compared to those with true PTL (p < 0.01), and significantly lower IOS and EOS. Women who delivered preterm had significantly higher HR compared to those who did not delivery preterm and significantly lower IOS and EOS, in overall cohort, and in the subset of women with true PTL. Incidences of HR < 50 % and < 35 % were statistically significantly higher in women who delivered preterm compared to those who did not (p < 0.01). CONCLUSION: Cervical elastography with E-Cervix™ may be useful for assessment of twin gestations presenting to obstetrics triage for threatened PTL.

Randomized trial of screening for preterm birth in low-risk women - the preterm birth screening study.

BACKGROUND: Preterm birth is a major cause of perinatal morbidity and mortality. It is unclear whether the introduction of a universal transvaginal ultrasound cervical length screening program in women at low risk for preterm delivery is associated with a reduction in the frequency of preterm birth. OBJECTIVE: To test the hypothesis that the introduction of a midtrimester universal transvaginal ultrasound cervical length screening program in asymptomatic singleton pregnancies without prior preterm delivery would reduce the rate of preterm birth at <37 weeks of gestation. STUDY DESIGN: This study was a multicenter nonblinded randomized trial of screening of asymptomatic singleton pregnancies without prior spontaneous preterm birth, who were randomized to either cervical length screening program (ie, intervention group) or no screening (ie, control group). Participants were randomized at the time of their routine anatomy scan between 18 0/7 and 23 6/7 weeks of gestation. Women randomized in the screening group received cervical length measurement. Those who were found to have cervical length ≤25 mm were offered 200 mg vaginal progesterone daily along with cervical pessary. The primary outcome was preterm birth at <37 weeks. The risk of primary outcome was quantified by the relative risk with 95% confidence interval, and was based on the intention-to-screen principle. RESULTS: A total of 1334 asymptomatic women with singleton pregnancies and without prior preterm birth, were included in the trial. Out of the 675 women randomized in the transvaginal ultrasound cervical length screening group, 13 (1.9%) were found to have transvaginal ultrasound cervical length ≤25 mm during the screening. Preterm birth at <37 weeks of gestation occurred in 48 women in the transvaginal ultrasound cervical length screening group (7.5%), and 54 women in the control group (8.7%) (relative risk, 0.86; 95% confidence interval, 0.59-1.25). Women randomized in the transvaginal ultrasound cervical length screening group had no significant differences in the incidence of preterm birth at less than 34, 32, 30, 28, and 24 weeks of gestation. CONCLUSION: The introduction of a universal transvaginal ultrasound cervical length screening program at 18 0/6 to 23 6/7 weeks of gestation in singleton pregnancies without prior spontaneous preterm birth, with treatment for those with cervical length ≤25 mm, did not result in significant lower incidence of preterm delivery than the incidence without the screening program.

Author Correction: Temporal plasticity of apical progenitors in the developing mouse neocortex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Temporal plasticity of apical progenitors in the developing mouse neocortex.

The diverse subtypes of excitatory neurons that populate the neocortex are born from apical progenitors located in the ventricular zone. During corticogenesis, apical progenitors sequentially generate deep-layer neurons followed by superficial-layer neurons directly or via the generation of intermediate progenitors. Whether neurogenic fate progression necessarily implies fate restriction in single progenitor types is unknown. Here we specifically isolated apical progenitors and intermediate progenitors, and fate-mapped their respective neuronal progeny following heterochronic transplantation into younger embryos. We find that apical progenitors are temporally plastic and can re-enter past molecular, electrophysiological and neurogenic states when exposed to an earlier-stage environment by sensing dynamic changes in extracellular Wnt. By contrast, intermediate progenitors are committed progenitors that lack such retrograde fate plasticity. These findings identify a diversity in the temporal plasticity of neocortical progenitors, revealing that some subtypes of cells can be untethered from their normal temporal progression to re-enter past developmental states.

Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons.

Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3) as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch.

The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent.

Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults.

In the forebrain, cortical structures consist of networks of excitatory and inhibitory neurons born in distant locations. Understanding how these two major classes of neurons integrate into unique functional cell assemblies may shed light on the organization of cortical circuits. In this review, we provide an overview of the mechanisms used by GABAergic interneurons to reach their final position, with an emphasis on the final steps of this process. To this end, we analyze similarities and differences between the integration of GABAergic interneurons in the developing cerebral cortex and in the postnatal brain, using the neocortex and the olfactory bulb as model systems.

Origin and molecular specification of globus pallidus neurons.

The mechanisms controlling the assembly of brain nuclei are poorly understood. In the forebrain, it is typically assumed that the formation of nuclei follows a similar sequence of events that in the cortex. In this structure, projection neurons are generated sequentially from common progenitor cells and migrate radially to reach their final destination, whereas interneurons are generated remotely and arrive to the cortex through tangential migration. Using the globus pallidus as a model to study the formation of forebrain nuclei, we found that the development of this basal ganglia structure involves the generation of several distinct classes of projection neurons from relatively distant progenitor pools, which then assemble together through tangential migration. Our results thus suggest that tangential migration in the forebrain is not limited to interneurons, as previously thought, but also involves projection neurons and reveal that the assembly of forebrain nuclei is more complex than previously anticipated.