Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

Prolonged latency of preterm premature rupture of membranes and risk of neonatal sepsis.

BACKGROUND: Preterm premature rupture of membranes (PPROM) is associated with inflammation and infection, and it may involve the loss of a barrier to ascending infection from the vagina, and it is possible that prolonged PPROM could be an independent risk factor for neonatal sepsis. OBJECTIVE: The objective of the study was to determine whether prolonged latency after PPROM is associated with an increased risk of neonatal sepsis. STUDY DESIGN: This secondary analysis of the randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy evaluated whether the time interval between diagnosis of PPROM and delivery was associated with an increased risk of neonatal sepsis. Latency time was categorized by weeks of latency (0 weeks to ≥ 4 weeks). The primary outcome was confirmed neonatal sepsis. Logistic regression was used to control for confounders. RESULTS: A total of 1596 patients with PPROM were analyzed, of whom 1390 had a < 4-week interval and 206 had an interval of ≥ 4 weeks. Confirmed neonatal sepsis occurred in 15.5% of patients in the cohort. In the univariate analysis, patients in the prolonged PPROM group were less likely to have neonatal sepsis (6.8% vs 17.2%, relative risk, 0.40 95% confidence interval, 0.24-0.66). This relationship was retained in the multivariable model; patients with prolonged PPROM ≥ 4 weeks had an adjusted odds ratio of 0.21 (95% confidence interval, 0.10-0.41) for neonatal sepsis. Neonatal sepsis was also significantly associated with earlier gestational age at rupture of membranes. CONCLUSION: Prolonged exposure to an intrauterine environment of PPROM does not increase the risk of neonatal sepsis; prolonged PPROM ≥ 4 weeks was associated with decreased risk of neonatal sepsis.

Does magnesium exposure affect neonatal resuscitation?

OBJECTIVE: Research on immediate neonatal resuscitation suggests that maternal magnesium exposure may be associated with increased risk of low Apgar scores, hypotonia, and neonatal intensive care unit admission. However, not all studies support these associations. Our objective was to determine whether exposure to magnesium at the time of delivery affects initial neonatal resuscitation. STUDY DESIGN: This is a secondary analysis of the Randomized Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy that evaluated whether the study drug (magnesium or placebo) that was administered at the time of delivery was associated with increased risk for a composite adverse neonatal resuscitation outcome (5-minute Apgar score <7, oxygen administration in the delivery room, intubation, chest compressions, hypotension, and hypotonicity). A subgroup analysis was performed among patients who delivered at ≥30 weeks of gestation. Log-linear regression was used to control for possible confounders. RESULTS: Data for 1047 patients were analyzed, of whom 461 neonates (44%) were exposed to magnesium. There was no increased risk for the primary composite outcome associated with magnesium exposure. Individual adverse neonatal outcomes and other secondary short-term neonatal outcomes that were evaluated also did not demonstrate an association with magnesium exposure. CONCLUSION: Exposure to magnesium sulfate did not affect neonatal resuscitation or other short-term outcomes. These findings may be useful in planning neonatal care and patient counseling.

Mode of delivery at periviability and early childhood neurodevelopment.

OBJECTIVE: Little is known regarding the impact of mode of delivery in the periviable period. Even less is understood regarding the effect of mode of delivery on neurodevelopment. Our objective is to determine if the mode of delivery at time of periviability impacts Bayley II scores at 2 years of age. STUDY DESIGN: This is a secondary analysis of a randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy, a multicenter trial where women at imminent risk for delivery were assigned to receive magnesium sulfate or placebo. For this secondary analysis we included nonanomalous singleton gestations delivered between 23 4/7 and 25 6/7 weeks. We excluded women with missing exposure or outcome data. The primary exposure of interest was mode of delivery. The primary outcome was Bayley II scores <70 (mental and motor) at 2 years of age. Log binomial regression was used to control for possible confounders including gestational age at delivery, presentation at time of delivery, chorioamnionitis, years of maternal education, maternal body mass index, and original study treatment group. RESULTS: A total of 158 women met inclusion criteria. In all, 91 had a vaginal delivery and 67 had a cesarean delivery. Exposure to magnesium sulfate, maternal education, chorioamnionitis, years of maternal education, and maternal body mass index were similar in both groups. There was no difference in either mental or motor Bayley II scores <70 or <85 by mode of delivery in either univariable or multivariable analysis. CONCLUSION: There is no detectable difference in Bayley II scores between mode of delivery at time of periviability. This adds to the literature supporting obstetric indications dictating mode of delivery at this gestational age.

Activity restriction and risk of preterm delivery.

PURPOSE: We sought to determine whether activity restriction (AR) in a cohort of women at high risk for preterm delivery is associated with the risk of preterm delivery. MATERIALS AND METHODS: This is a secondary analysis of the Maternal-Fetal Medicine Units MFMU's Preterm Prediction Study; a multicenter prospective cohort study designed to identify risk factors of preterm birth (PTB). The study group consisted of women with a singleton gestation that at their first study visit (23-24 weeks) had at least one of the following criteria: patient reported contractions, severe back pain, a cervical length <15 mm, spotting, protruding membranes, or positive fetal fibronectin. Women were assessed for AR at a 27- to 29-week study visit. Associations between AR and preterm delivery (<37 weeks) were examined through logistic regression models before and after adjustment for confounders. RESULTS: Of the 1086 women that met the inclusion criteria, 16.5% (n = 179) delivered preterm. In this cohort, 9.7% (n = 105) of women were recommended AR, with 37.1% (n = 39) having a PTB. In the group not recommended AR (n = 981), 14.3% (n = 140) delivered preterm. CONCLUSION: In this cohort of women at high risk for PTB, activity restriction was associated with an increased risk of PTB. The use of AR in this population should be discouraged.

Dynamic maternal and fetal Notch activity and expression in placentation.

INTRODUCTION: Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch proteins and ligands. METHODS: Notch reporter transgenic mice were used to define canonical Notch activity and immunofluorescence staining performed to characterize expression of Notch1, 2, 3, 4 and ligands, Delta-like 4 (Dll4) and Jagged1 (Jag1) during early placentation and in the mature placenta. RESULTS: Notch signaling is active in maternal and fetal endothelial cells and trophoblasts during early placentation and in the mature placenta. Dll4, Jag1, Notch1, and Notch4 are expressed in maternal vasculature in the decidua. Dll4, Jag1 and Notch1 are expressed in fetal vasculature in the labyrinth. Dll4, Notch2 and Notch4 are co-expressed in the ectoplacental cone. Notch2 and Notch4 are expressed in parietal-trophoblast giant cells and junctional zone trophoblasts with active canonical Notch signaling and in labyrinthine syncytiotrophoblasts and sinusoidal-trophoblast giant cells. DISCUSSION: Canonical Notch activity and distinct expression patterns for Notch proteins and ligands was evident in endothelium and trophoblasts, suggesting Notch1, Notch2, Notch4, Dll4, and Jag1 have distinct and overlapping functions in placentation. Characterization of Notch signaling defects in existing mouse models of preeclampsia may shed light on the role of Notch in developing the preeclampsia phenotype.

Prolonged latency of preterm premature rupture of membranes and risk of cerebral palsy (.).

OBJECTIVE: To determine whether prolonged latency after preterm premature rupture of membranes (PPROM) is associated with an increased risk of death or moderate-to-severe cerebral palsy (CP). STUDY DESIGN: This secondary analysis of the randomized controlled trial of magnesium sulfate for the prevention of CP evaluated whether the time interval between diagnosis of PPROM and delivery was associated with increased risk for CP. Prolonged latency was defined as an interval of ≥4 weeks, latency time was also categorized by week of latency for further analysis. The primary outcome was death or moderate-to-severe CP at 2 years of age. Logistic regression was used to control for confounders. RESULTS: In all, 1522 patients with PPROM were analyzed; of whom, 1328 had a <4-week interval and 194 had an interval of ≥4 weeks. In the unadjusted analysis, the primary outcome was less likely in the PPROM ≥4 weeks group 4.1% versus 8.4%, RR: 0.49, 95% CI: 0.24-0.98. After adjusting for possible confounders, there was no statistical difference associated with PPROM latency ≥4 weeks versus <4 weeks for death or moderate-to-severe CP. CONCLUSION: Prolonged exposure to an intrauterine environment of PPROM does not increase risk for CP.

Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients?

BACKGROUND: Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated. STUDY DESIGN: A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM. RESULTS: In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32). CONCLUSIONS: There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.

Intrapartum obstetric management.

Maternal cardiac disease complicates approximately 1-2% of all pregnancies in the United States. Just as during the antepartum period, in the immediate period surrounding delivery, obstetrical patients with cardiac disease (both congenital and acquired) will have specialized needs, tailored to the patient and her specific lesion. While the basic principles of labor and delivery management protocols are relevant to this subgroup of patients, there are certain areas in which adjustments must be made. These include endocarditis prophylaxis, recent anticoagulation, fluid management, and the need for increased maternal cardiac monitoring. Awareness of the challenges of the intrapartum period combined with a multi-disciplinary approach from anesthesia, cardiology, and the obstetrical provider will optimize the patient for a safe delivery.