Structural Anomalies in Multifetal Gestations.

Multifetal gestations are at increased risk for structural anomalies relative to singletons. Determination of chorionicity is critical, as the risk is highest for monochorionic pregnancies. In a singleton gestation, counseling is structured around optimization of fetal outcomes and careful consideration of the patient's choices in management decisions. However, in multifetal gestations affected by a fetal anomaly, complex counseling with consideration for the pregnancy as a whole is necessary. We review the incidence of structural anomalies in twins and highlight unique considerations including selective termination for discordant anomalies. We emphasize the role of shared decision making between provider and patient.

Neonatal outcomes and rationale for timing of birth in perinatal diabetes: a retrospective cohort study.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends delivery in the 39th week of pregnancy for patients with pregestational and medication-controlled gestational diabetes with consideration for earlier delivery among those with poor glucose control. OBJECTIVE: We sought to evaluate the impact of birth before 39 weeks' gestation exclusively for diabetes-related indications on neonatal outcomes and clinician rationale for these recommendations. STUDY DESIGN: This was a retrospective cohort study of all singleton, nonanomalous pregnancies complicated by diabetes. Patients were identified through an obstetrical database containing information of 90,185 births from 2011 to 2021. Patients who delivered in a given week of gestation exclusively for diabetes-related indications were compared with ongoing pregnancies. Recommended births for other obstetrical indications were excluded from the diabetes-related indications cohorts. The primary outcome was neonatal intensive care unit admission. Secondary outcomes included neonatal intensive care unit length of stay, stillbirth, neonatal death, hypoglycemia, respiratory distress syndrome, and shoulder dystocia. For all births before 39 weeks' gestation, the electronic medical records were reviewed to confirm the rationale for the intervention for a diabetes-indicated condition. RESULTS: From the 90,185 recorded births that occurred in 2011 to 2021, 4750 patients with diabetes were identified. Of those, 30.5% (n=1449) had a recommended birth for a diabetes-related indications with 2.2% of those (n=32) occurring at 36 weeks' gestation, 7.9% (n=114) at 37 weeks' gestation, 9.7% (n=141) at 38 weeks' gestation, and 63.0% (n=913) at 39 weeks' gestation. Births that occurred at 36 and 37 weeks' gestation exclusively for diabetes-related indications had higher rates of neonatal intensive care unit admission than the respective ongoing pregnancies (62.5% vs 8.7%; P<.001 and 25.4% vs 7.2%; P<.001). There was no difference in neonatal intensive care unit admission for births at 38 or 39 weeks' gestation when compared with ongoing pregnancy. For neonates born at 36 and 37 weeks' gestation in comparison with ongoing pregnancies, the median neonatal intensive care unit length of stay was 11.0 vs 2.8 days, (P<.001) and 4.4 vs 2.6 days (P=.026), respectively. There were significantly increased rates of neonatal hypoglycemia and respiratory distress syndrome among births that occurred at 36, 37, and 38 weeks' gestation when compared with ongoing pregnancies. There were no differences in the rate of stillbirth in this cohort. Primary factors cited for early birth were poor glycemic control (71.4%), recommendation by a maternal-fetal medicine specialist (38.7%), and suspected fetal macrosomia (27.9%). Overall, 46.7%, 32.8%, and 20.6% of patients had 1, 2, or ≥3 indications, respectively, listed as rationale for early birth. Overall, few objective measures were used to recommend birth before 39 weeks' gestation owing to diabetes. CONCLUSION: In pregnancies complicated by diabetes, early birth exclusively for diabetes-related indications was associated with increased neonatal intensive care unit admission and length of stay and with neonatal morbidity. Little objective data are documented by clinicians to support their recommendations for early birth associated with diabetes. Additional clinical guidelines are needed to define suboptimal glucose control necessitating birth before 39 weeks' gestation.

Allosteric interactions prime androgen receptor dimerization and activation.

The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome and reinforced by AR's oncoprotein cofactor, ERG, and by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease.

Birthweight and Apgar at 5 minutes of life for the prediction of severe neonatal outcomes in preterm prelabor rupture of membranes.

OBJECTIVE: The aim of our study was to investigate the predictive accuracy of clinical variables available after delivery for severe neonatal outcomes (SNO) in pregnancies complicated by PPROM. MATERIALS AND METHODS: This was a secondary analysis of a prospective cohort of pregnancies complicated by PPROM. We included expectant mothers from 13-46 years of age who were between 23 and 36 6/7 weeks of gestation. We excluded multiple gestations, complex fetal anomalies, those with fetal demise and outborn infants. Our primary outcome was a composite of SNO (respiratory distress syndrome, necrotizing enterocolitis, Intra-ventricular hemorrhage, sepsis, and death). The variables assessed where gestational age at delivery, birthweight, Apgar score at 5 min of life, Apgar <7 at 5 min of life, small for gestational age, sex, umbilical artery pH, and mode of delivery. Logistic regression was performed to evaluate the predictive accuracy of each of these variables. Stepwise multivariable logistic regression was utilized to assess the effect of variables with univariate analysis p value <.10 and those baseline characteristics with a statistically significant association with our composite score. RESULTS: We included 108 infants. SNO was diagnosed in 44 (41%) neonates. The Apgar score at 5 min (AUC = 0.89; p= <.001), the birthweight (AUC = 0.88; p= <.001), gestational age at delivery (AUC = 0.87; p= <.001), and the Apgar score < 7 at 5 min (AUC = 0.73; p= <0.001) were statistical significant predictors of SNO. Sex (p=.15), mode of delivery (p=.15), umbilical artery Ph (p=.28), SGA (p=.85) were not statistically significant predictors of SNO. After stepwise multivariable logistic regression only the Apgar at 5 min and birth weight remained statistically significant predictors for SNO (AUC = 0.94). CONCLUSIONS: In pregnancies complicated by PPROM the birthweight and the Apgar at 5 min of life are accurate predictors of a composite score of SNO. We acknowledge the need for larger and more diverse studies to corroborate our findings. BRIEF RATIONALE: We assessed the predictive accuracy of clinical variables available after delivery for severe neonatal outcomes in pregnancies complicated by PPROM. We found that the birthweight and the Apgar score at 5 min were accurate predictors of such outcomes in this population. Our results may aid providers in the counseling of premature infants born after PPROM.

Prediction of Large-for-Gestational-Age Neonates by Different Growth Standards.

OBJECTIVE: Compare the accuracy of the Hadlock, the NICHD, and the Fetal Medicine Foundation (FMF) charts to detect large-for-gestational-age (LGA) and adverse neonatal outcomes (as a secondary outcome). METHODS: This is a secondary analysis from a prospective study that included singleton non-anomalous gestations with growth ultrasound at 26-36 weeks. LGA was suspected with estimated fetal weight > 90th percentile by the NICHD, FMF, and Hadlock charts. LGA was diagnosed with birth weight > 90th percentile. We tested the performance of these charts to detect LGA and adverse neonatal outcomes (neonatal intensive care unit admission, Ph < 7.1, Apgar <7 at 5 minutes, seizures, and neonatal death) by calculating the area under the curve, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: Of 1054 pregnancies, 123 neonates (12%) developed LGA. LGA was suspected in 58 (5.5%) by Hadlock, 229 (21.7%) by NICHD standard, and 231 (22%) by FMF chart. The NICHD standard (AUC: .79; 95% CI: .75-.83 vs. AUC .64; 95%CI: .6-.68; p = < .001) and FMF chart (AUC: .81 95% CI: .77-.85 vs. AUC .64; 95%CI: .6-.68; p = < .001) were more accurate than Hadlock. The FMF and NICHD had higher sensitivity (77.2 vs. 72.4 vs. 30.1%) but Hadlock had higher specificity for LGA (97.5 vs. 88.5 vs. 85.4%). All standards were poor predictors for adverse neonatal outcomes. CONCLUSIONS: The NICHD and the FMF standards may increase the detection rate of LGA in comparison to the Hadlock chart. However, this may increase obstetrical interventions.

Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG.

The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven by oncogenic ETS fusion genes. The molecular basis for this change has remained elusive. Using purified proteins, we report a minimal cell-free system that demonstrates interdomain cooperativity between the ligand (LBD) and DNA binding domains (DBD) of AR, and its autoinhibition by the N terminus of AR. Furthermore, we identify ERG as a cofactor that activates AR's ability to bind DNA in both high and lower affinity contexts through direct interaction within a newly identified AR-interacting motif (AIM) in the ETS domain, independent of ERG's own DNA binding ability. Finally, we present evidence that this interaction is conserved among ETS factors whose expression is altered in prostate cancer. Our work highlights, at a biochemical level, how tumor-initiating ETS translocations result in reprogramming of the AR cistrome.

Optimizing Health: Weight, Exercise, and Nutrition in Pregnancy and Beyond.

Pregnancy complications provide insight into women's future health risks and have long term implications for maternal and child health. Obesity has been associated with adverse perinatal outcomes and is a risk factor for chronic disease. Excessive weight gain during pregnancy often translates into postpartum weight retention, increasing women's risk for obesity. Pregnancy and the postpartum period provides a unique opportunity to discuss health beyond pregnancy, emphasize interconception care, and implement appropriate prevention strategies. We aim to review the impact of obesity, gestational weight gain, postpartum weight retention, and role of nutrition and exercise on pregnancy and lifelong health.

Deep sedation without intubation during second trimester surgical termination in an inpatient hospital setting.

OBJECTIVES: Safety of outpatient dilation and evacuations with intravenous (iv) sedation without intubation has been demonstrated, but there is a paucity of data on deep iv sedation on an inpatient second trimester surgical termination population. The purpose of this study is to evaluate complications of deep sedation with propofol without the use of intubation during second trimester surgical terminations in an inpatient teaching institution. STUDY DESIGN: A retrospective chart review of all obstetrical and anesthetic data from inpatient dilation and evacuations between gestational ages 15 0/7 and 24 0/7 during the years 2002 to 2015. We examined 332 patient charts. Primary outcomes included suspected perioperative pulmonary aspiration and conversion to an intubated general anesthesia. RESULTS: No perioperative pulmonary aspiration cases were either suspected or confirmed. There were a total of 14 (4.2%) patients that had intubation compared to 313 with natural airway (94.3%) or laryngeal mask (1.5%). Of the 14 intubated, 9 (64%) were started with intubation, and 5 (36%) were converted during the procedure (1.7% of those started with nonintubated anesthesia). Cases requiring intubation were associated with longer procedure times (p=<0.001), higher American Society of Anesthesiologists (ASA) class (p=0.038), greater estimated blood loss (p=<0.001) and a primary indication of maternal health (p=<0.001) for the dilation and evacuation. CONCLUSIONS: Deep sedation without intubation appears safe in a hospital setting with few complications reported. IMPLICATIONS: Deep sedation without intubation for operating room dilation and evacuation is a safe option that rarely resulted in conversion to intubation and, in most cases, should be the anesthesia method of choice at initiation in an inpatient setting.

Host-specific parvovirus evolution in nature is recapitulated by in vitro adaptation to different carnivore species.

Canine parvovirus (CPV) emerged as a new pandemic pathogen of dogs in the 1970s and is closely related to feline panleukopenia virus (FPV), a parvovirus of cats and related carnivores. Although both viruses have wide host ranges, analysis of viral sequences recovered from different wild carnivore species, as shown here, demonstrated that>95% were derived from CPV-like viruses, suggesting that CPV is dominant in sylvatic cycles. Many viral sequences showed host-specific mutations in their capsid proteins, which were often close to sites known to control binding to the transferrin receptor (TfR), the host receptor for these carnivore parvoviruses, and which exhibited frequent parallel evolution. To further examine the process of host adaptation, we passaged parvoviruses with alternative backgrounds in cells from different carnivore hosts. Specific mutations were selected in several viruses and these differed depending on both the background of the virus and the host cells in which they were passaged. Strikingly, these in vitro mutations recapitulated many specific changes seen in viruses from natural populations, strongly suggesting they are host adaptive, and which were shown to result in fitness advantages over their parental virus. Comparison of the sequences of the transferrin receptors of the different carnivore species demonstrated that many mutations occurred in and around the apical domain where the virus binds, indicating that viral variants were likely selected through their fit to receptor structures. Some of the viruses accumulated high levels of variation upon passage in alternative hosts, while others could infect multiple different hosts with no or only a few additional mutations. Overall, these studies demonstrate that the evolutionary history of a virus, including how long it has been circulating and in which hosts, as well as its phylogenetic background, has a profound effect on determining viral host range.

Olfactomedin-1 activity identifies a cell invasion checkpoint during epithelial-mesenchymal transition in the chick embryonic heart.

Endothelia in the atrioventricular (AV) canal of the developing heart undergo a prototypical epithelial mesenchymal transition (EMT) to begin heart valve formation. Using an in vitro invasion assay, an extracellular matrix protein, Olfactomedin-1 (OLFM1), was found to increase mesenchymal cell numbers in AV canals from embryonic chick hearts. Treatment with both anti-OLFM1 antibody and siRNA targeting OLFM1 inhibits mesenchymal cell formation. OLFM1 does not alter cell proliferation, migration or apoptosis. Dispersion, but lack of invasion in the presence of inhibiting antibody, identifies a specific role for OLFM1 in cell invasion during EMT. This role is conserved in other epithelia, as OLFM1 similarly enhances invasion by MDCK epithelial cells in a transwell assay. Synergy is observed when TGFß2 and OLFM1 are added to MDCK cell cultures, indicating that OLFM-1 activity is cooperative with TGFß. Inhibition of both OLFM1 and TGFß in heart invasion assays shows a similar cooperative role during development. To explore OLFM1 activity during EMT, representative EMT markers were examined. Effects of OLFM1 protein and anti-OLFM1 on transcripts of cell-cell adhesion molecules and the transcription factors Snail-1, Snail-2, Twist1 and Sox-9 argue that OLFM1 does not initiate EMT. Rather, regulation of transcripts of Zeb1 and Zeb2, secreted proteases and mesenchymal cell markers by both OLFM1 and anti-OLFM1 is consistent with regulation of the cell invasion step of EMT. We conclude that OLFM1 is present and necessary during EMT in the embryonic chick heart. Its role in cell invasion and mesenchymal cell gene regulation suggests an invasion checkpoint in EMT where OLFM1 acts to promote cell invasion into the three-dimensional matrix.