Placental Histopathologic Findings of a Large Cohort of Patients With SARS-CoV-2 Infection During Pregnancy.

Pregnant individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at a higher risk for adverse pregnancy outcomes. Previous small cohort studies have shown increased frequency of placental lesions associated with maternal vascular malperfusion, fetal vascular malperfusion, and inflammation among patients with SARS-CoV-2, without controlling for cardiometabolic risk factors among many such patients. We aimed to evaluate whether SARS-CoV-2 infection during pregnancy is independently associated with placental abnormalities when controlling for risk factors that could affect placental histopathology. Retrospective cohort study of placentas from singleton pregnancies in Kaiser Permanente Northern California from March to December 2020. Pathologic findings were compared among those with confirmed cases of SARS-CoV-2 during pregnancy and those without. We examined the association between SARS-CoV-2 infection and categorical placental pathologies, controlling for maternal age, gestational age, prepregnancy body mass index, gestational hypertension, preeclampsia/eclampsia, preexisting diabetes, history of thrombosis, and stillbirth. A total of 2,989 singleton gestation placentas were analyzed, 416 (13%) from pregnancies with SARS-CoV-2 infection and 2,573 (86%) from those without infection. Among placentas from pregnancies with SARS-CoV-2, 54.8% had evidence of inflammation, 27.1% maternal malperfusion abnormality, 20.7% massive perivillous fibrin or chronic villitis, 17.3% villous capillary abnormality, and 15.1% fetal malperfusion. After controlling for risks factors and stratifying interval time between SARS-CoV-2 infection and delivery, no association was found between placental abnormalities and SARS-CoV-2 infection during pregnancy. SARS-CoV-2 infection was not associated with an increased risk of placentally mediated adverse outcomes during pregnancy, compared with placentas sent for other indications, in this large diverse cohort.

Fetomaternal hemorrhage: evaluation of recurrence within a large integrated healthcare system.

BACKGROUND: Fetomaternal hemorrhage is associated with severe fetal morbidity and mortality. The recurrence risk of fetomaternal hemorrhage is unknown. OBJECTIVE: We sought to establish the recurrence rate of fetomaternal hemorrhage in a large integrated healthcare system over a 10-year period. STUDY DESIGN: In this retrospective study within the Kaiser Permanente Northern California medical system, cases of fetomaternal hemorrhage were defined by either an elevated fetal hemoglobin level as determined by flow cytometry for a concerning pregnancy outcome (preterm delivery, perinatal demise, neonatal anemia, or transfusion within the first 2 days of life) or by perinatal demise with autopsy findings suggestive of fetomaternal hemorrhage. The outcomes of subsequent pregnancies were reviewed for features of recurrence. RESULTS: Within the 2008 to 2018 birth cohort of 375,864 pregnancies, flow cytometry testing for fetal hemoglobin levels was performed in 20,582 pregnancies. We identified 340 cases of fetomaternal hemorrhage (approximately 1 in 1100 births). Within the cohort of 340 affected pregnancies, perinatal loss was recorded for 80 (23.5%) pregnancies and 50 (14.7%) pregnancies delivered neonates who required transfusion. The affected patients had 225 subsequent pregnancies of which 210 were included in the analysis. Of these, 174 (82.9%) advanced beyond the threshold of viability and were delivered within our healthcare system. There was 1 case of recurrent fetomaternal hemorrhage identified. The recurrent case involved a spontaneous preterm delivery of an infant who was noted to have an elevated reticulocyte count but was clinically well. CONCLUSION: Within our large integrated healthcare system, approximately 1 in 1100 pregnancies was affected by fetomaternal hemorrhage within a 10-year period, which is comparable with previous studies. We identified 1 case of recurrence, yielding a recurrence rate of 0.5%. This infant did not have features of clinically important fetomaternal hemorrhage. This information can inform counseling of patients with affected pregnancies.

Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1.

Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.

Decreased lung injury after surfactant in piglets treated with continuous positive airway pressure or synchronized intermittent mandatory ventilation.

BACKGROUND: Treatment with surfactant (S) decreases lung injury in paralyzed, mechanically ventilated animals. The use of nasal continuous positive airway pressure (CPAP) as an alternative to mechanical ventilation may further improve acute pulmonary outcomes. OBJECTIVES: To evaluate the effect of surfactant (+S, -S) and synchronized intermittent mandatory ventilation (SIMV) on lung morphology and inflammatory markers in 24 spontaneously breathing piglets treated with CPAP or SIMV after saline lavage-induced lung injury. METHODS: After induction of lung injury, animals were randomized to CPAP-S, CPAP+S or SIMV+S and treated for 4 h. Physiologic parameters were continuously monitored. After treatment, animals were euthanized and lungs fixed. Bronchoalveolar lavage (BAL) samples were collected for neutrophil count and H(2)O(2). RESULTS: No physiologic differences were noted. BAL fluid from CPAP-S animals contained more neutrophils and more neutrophil H(2)O(2) than fluid from the SIMV+S or CPAP+S groups (p < 0.05 or greater). Pathologic injury scores were higher in dependent lung regions from CPAP groups (p < 0.05). Injury pattern scores showed greater dependent alveolar inflammation in all (p < 0.02), with more dependent atelectasis in the CPAP groups (p < 0.01). Morphometrics showed less total open alveolar air space in nondependent regions of the SIMV+S group compared to CPAP groups (p < 0.001). Dependent regions showed less total open alveolar air space compared to nondependent regions in the CPAP groups (p < 0.001). CONCLUSIONS: Animals treated with surfactant prior to CPAP or SIMV had less acute lung injury. SIMV+S animals had less open air space in nondependent regions. This suggests, during early ventilatory support, surfactant administration may modulate pulmonary inflammation. CPAP alone without surfactant may not provide optimal pulmonary protection. The addition of mechanical breaths may alter and add to injury.

Craniosynostosis: another feature of the 22q11.2 deletion syndrome.

We report on the presence of craniosynostosis in four patients with the 22q11.2 deletion. In light of previous reports of the association, we propose that the occurrence is higher than the general population incidence. Therefore, we suggest that craniosynostosis should be considered a manifestation of the 22q11.2 deletion and conversely that the 22q11.2 deletion should be considered in the differential diagnosis of craniosynostosis.

Tracheal agenesis in newborns.

OBJECTIVES/HYPOTHESIS: A series of three newborns with tracheal agenesis is described. The preferred methods of diagnosis, description of the clinical course, and a review of the pertinent embryology, associated anomalies, and clinical management are presented. STUDY DESIGN: A retrospective study of a clinical series of referred patients from 2002 to 2003 who were seen at a single institution. METHODS: Chart review for clinical course and pathological specimens was performed in all cases. Three patients were identified with tracheal agenesis. RESULTS: All three newborns died within 48 hours of birth. All of the children underwent emergency laryngoscopy and neck exploration. Gross and microscopic pathological examination was accomplished on all patients. CONCLUSION: Although tracheal agenesis is rare, it may be more common than previously thought. The diagnosis is not straightforward, and the prognosis is grim. The embryology of the trachea and other foregut derivatives is closely related, and associated birth defects are common.

Standardized lung recruitment during high frequency and conventional ventilation: similar pathophysiologic and inflammatory responses in an animal model of respiratory distress syndrome.

OBJECTIVE: To evaluate standardized lung recruitment strategy during both high frequency oscillation (HFO) and volume-targeted conventional ventilation (CV+V) in spontaneously breathing piglets with surfactant washout on pathophysiologic and inflammatory responses. DESIGN: Prospective animal study. SETTING: Research laboratory. SUBJECTS: Twenty-four newborn piglets. INTERVENTIONS: We compared pressure support and synchronized intermittent mandatory ventilation, both with targeted tidal volumes, (PSV+V, SIMV+V) to HFO. Animals underwent saline lavage to produce lung injury, received artificial surfactant and were randomized to one of the three treatment groups (each n=8). After injury and surfactant replacement, lung volumes were recruited in all groups using a standard protocol. Ventilation continued for 6 h. MEASUREMENTS AND MAIN RESULTS: Arterial and central venous pressures, heart rates, blood pressure and arterial blood gases were continuously monitored. At baseline, post lung injury and 6 h we collected serum and bronchoalveolar lavage samples for proinflammatory cytokines: IL 6, IL 8 and TNF-alpha, and performed static pressure-volume (P/V) curves. Lungs were fixed for morphometrics and histopathologic analysis. No physiologic differences were found. Analysis of P/V curves showed higher opening pressures after lung injury in the HFO group compared to the SIMV+V group ( p<0.05); no differences persisted after treatment. We saw no differences in change in proinflammatory cytokine levels. Histopathology and morphometrics were similar. Mean airway pressure (P(aw)) was highest in the HFO group compared to SIMV+V ( p<0.002). CONCLUSIONS: Using a standardized lung recruitment strategy in spontaneously breathing animals, CV+V produced equivalent pathophysiologic outcomes without an increase in proinflammatory cytokines when compared to HFO.

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.