Perinatal Factors Associated With Breastfeeding Trends After Preterm Birth <29 Weeks Gestation: Can We Predict Early Discontinuation?

OBJECTIVE: To determine the rates and perinatal factors associated with initiation and early discontinuation of breastfeeding among very preterm neonates. METHODS: This was a retrospective cohort study of very preterm infants (<29 weeks gestation) admitted to 2 regional Level III neonatal intensive care units (NICUs) from January 1, 2015, to December 31, 2019. A national neonatal database was used to evaluate initiation and continuation rates of breastfeeding and associated perinatal factors. Stored nutrition profiles and delivery record books were used to determine feeding volumes associated with continuation of breastfeeding to hospital discharge for a subgroup of infants at a single site. Descriptive and inferential statistics were used to present the results between groups, and logistic regression modeling was used to calculate crude and adjusted odds ratios (OR) and 95% CI. RESULTS: Of 391 eligible neonates, 84% initiated breastfeeding but only 38% continued to discharge. Interestingly, frequency of breastfeeding initiation (P < 0.001) and continuation (P < 0.001) declined over the study period. After adjustment for confounders, younger maternal age, earlier gestational age, cigarette smoking, and multiparity were significantly associated with early discontinuation of breastfeeding prior to hospital discharge. Early discontinuation of breastfeeding was also related to lower volumes of breastmilk by day 7 of life (P = 0.004). CONCLUSION: Very preterm neonates are at high risk for non-initiation and early discontinuation of breastfeeding. The early postnatal period represents a critical time to establish breastmilk volumes, and the identification of key perinatal risk factors allows for early and targeted breastfeeding support.

Language abilities in preschool children with critical CHD: a systematic review.

CONTEXT: Children with critical CHD are at risk for neurodevelopmental impairments, including delays in expressive and receptive language development. However, no study has synthesised the literature regarding language abilities in children with this condition. OBJECTIVE: We summarised the literature regarding expressive and receptive language in preschool children with critical CHD. DATA SOURCES: MEDLINE, Embase, Scopus, Child Development and Adolescent Studies, ERIC, PsycINFO, and CINAHL. STUDY SELECTION: We included studies published between January, 1990 and 1 July, 2021, focused on children aged ≤5 years with critical CHD requiring a complex cardiac procedure at age <1 year. Language ability was documented using standardised, validated tools assessing both expressive and receptive language outcomes. DATA EXTRACTION: Data (study, patient and language characteristics, and results) were extracted by two reviewers. RESULTS: Seventeen studies were included. Among children 2-5 years old with critical CHD, there were statistically significant deficits in overall (standardised mean difference: -0.46; 95 % confidence interval: -0.56, -0.35), expressive (standardised mean difference: -0.45;95 % confidence interval: -0.54, -0.37), and receptive (standardised mean difference: -0.32; 95 % confidence interval: -0.40, -0.23) language compared to normative data. Results reported as medians were similar to meta-analysis findings. Subgroup analysis showed that children with univentricular physiology had lower language scores than children with biventricular physiology. CONCLUSIONS: Preschool children with critical CHD had statistically significantly lower language outcomes compared to expected population norms. Healthcare professionals should test early and often for language deficits, referring to individually tailored supports.

Comparison of motor outcomes between preschool children with univentricular and biventricular critical heart disease not diagnosed with cerebral palsy or acquired brain injury.

This comparison study of two groups within an inception cohort aimed to compare the frequency of motor impairment between preschool children with univentricular and biventricular critical congenital heart disease (CHD) not diagnosed with cerebral palsy/acquired brain injury, describe and compare their motor profiles and explore predictors of motor impairment in each group.Children with an intellectual quotient <70 or cerebral palsy/acquired brain injury were excluded. Motor skills were assessed with the Movement Assessment Battery for Children-2. Total scores <5th percentile indicated motor impairment. Statistical analysis included χ2 test and multiple logistic regression analysis.At a mean age of 55.4 (standard deviation 3.77) months, motor impairment was present in 11.8% of those with biventricular critical CHD, and 32.4% (p < 0.001) of those with univentricular critical CHD. The greatest difference between children with biventricular and univentricular CHD was seen in total test scores 8.73(2.9) versus 6.44(2.8) (p < 0.01) and in balance skills, 8.84 (2.8) versus 6.97 (2.5) (p = 0.001). Manual dexterity mean scores of children with univentricular CHD were significantly below the general population mean (>than one standard deviation). Independent odds ratio for motor impairment in children with biventricular critical CHD was presence of chromosomal abnormality, odds ratio 10.9 (CI 2.13-55.8) (p = 0.004); and in children with univentricular critical CHD odds ratio were: postoperative day 1-5 highest lactate (mmol/L), OR: 1.65 (C1.04-2.62) (p = 0.034), and dialysis requirement any time before the 4.5-year-old assessment, OR: 7.8 (CI 1.08-56.5) (p = 0.042).Early assessment of motor skills, particularly balance and manual dexterity, allows for intervention and supports that can address challenges during the school years.

Misoprostol attenuates neonatal cardiomyocyte proliferation through Bnip3, perinuclear calcium signaling, and inhibition of glycolysis.

Systemic hypoxia resulting from preterm birth, altered lung development, and cyanotic congenital heart disease is known to impede the regulatory and developmental pathways in the neonatal heart. While the molecular mechanisms are still unknown, hypoxia induces aberrant cardiomyocyte proliferation, which may be initially adaptive, but can ultimately program the heart to fail in early life. Recent evidence suggests that the prostaglandin E1 analogue, misoprostol, is cytoprotective in the hypoxia-exposed neonatal heart by impacting alternative splicing of the Bcl-2 family member Bnip3, resulting in the generation of a variant lacking the third exon (Bnip3ΔExon3 or small Nip; sNip). Using a rodent model of neonatal hypoxia, in combination with rat primary neonatal cardiomyocytes (PVNCs) and H9c2 cells, we sought to determine if misoprostol can prevent cardiomyocyte proliferation and what the key molecular mechanisms might be in this pathway. In PVNCs, exposure to 10% oxygen induced myocyte proliferation concurrent with molecular markers of cell-cycle progression, such as Cyclin-D1, which were prevented by misoprostol treatment. Furthermore, we describe a critical role for sNip in opposing cardiomyocyte proliferation through several mechanisms, including reduced expression of the proliferative MEF2C-myocardin-BMP10 pathway, accumulation of nuclear calcium leading to NFATc3 activation, and increased expression of the cardiac maturation factor BMP2. Intriguingly, misoprostol and sNip inhibited hypoxia-induced glycolytic flux, which directly influenced myocyte proliferation. These observations were further supported by knockdown studies, where hypoxia-induced cardiomyocyte proliferation is restored in misoprostol-treated cells by an siRNA targeting sNip. Finally, in postnatal day (PND)-10 rat pups exposed to hypoxia, we observed histological evidence of increased nuclei number and increased PPH3 staining, which were completely attenuated by misoprostol treatment. Collectively, this data demonstrates how neonatal cardiomyocyte proliferation can be pharmacologically modulated by misoprostol treatment, which may have important implications for both neonatal and regenerative medicine.

miR-200 family expression during normal and abnormal lung development due to congenital diaphragmatic hernia at the later embryonic stage in the nitrofen rat model.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a life-threatening disease associated with pulmonary hypoplasia. CDH occurs approximately 1 in every 2000-3000 live births, and the pathophysiology is unknown. MicroRNAs are short, non-coding RNAs that control gene expression through post-transcriptional regulation. Based on our previous work, we hypothesized that the miR-200 family is differentially expressed in normal and abnormal lung development. We aimed to examine the expression of the miR-200 family during normal and hypoplastic lung development due to CDH. METHODS: We performed reverse transcriptase polymerase chain reaction (RT-qPCR) and fluorescent in situ hybridization (FISH) to study the expression levels and distribution of the miR-200 family members on embryonic day 21 (E21) rat control and nitrofen-induced hypoplastic CDH lungs. RESULTS: RT-qPCR showed up-regulation of miR-200a in hypoplastic CDH lungs. FISH showed contrasting expression patterns for miR- 200a, miR-200c, and miR-429 between control and hypoplastic CDH lungs, while we could not detect miR-141 in control and hypoplastic CDH lungs. CONCLUSION: We demonstrate a specific expression pattern of miR-200 family members in hypoplastic CDH lungs different from control lungs. This study suggests that disruption of miR-200 family expression plays a role in the pathogenesis of pulmonary hypoplasia associated with CDH.

Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia.

OBJECTIVE: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). BACKGROUND: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. METHODS: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. RESULTS: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-ß signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. CONCLUSIONS: Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.

The Significance of Exposure to Pregestational Type 2 Diabetes in Utero on Fetal Renal Size and Subcutaneous Fat Thickness.

Objectives: To determine the relationship between exposure to pregestational type 2 diabetes (T2D) and renal size and subcutaneous fat thickness in fetuses during routine obstetrical ultrasound. Methods: This was a case-control study (January 1, 2019 to December 31, 2019). Routine obstetrical ultrasounds performed between 18 and 22 weeks' gestation at a tertiary-care fetal assessment unit were reviewed. "Cases" comprised ultrasounds of fetuses exposed to pregestational T2D in utero. The control group was assembled from ultrasounds of healthy controls. Postprocessing measurements of fetal renal size and abdominal wall thickness from stored images were performed by two independent observers, and findings were compared between groups. Results: There were 54 cases and 428 ultrasounds of healthy controls. The mean maternal age of cases was 32.1 years (SD 6.2) compared to 33.2 years (SD 5.3) for healthy controls, and the majority of ultrasounds were performed in multiparous patients (83%). At the 18 to 22 week ultrasound, there was a significant reduction in renal size amongst fetuses exposed to maternal T2D in utero compared to controls; among cases, the mean renal width was 8.0 mm (95% CI 7.8-8.1) compared to 11.4 mm (95% CI 10.6-12.7) in controls (p < 0.0001); the mean renal thickness among cases was 8.1 mm (95% CI 7.9-8.2) compared to 11.5 mm (95% CI 10.7-12.9) in controls (p=0.001). There was no obvious difference in estimated fetal weight between groups, yet fetuses exposed to maternal T2D had increased subcutaneous abdominal wall fat thickness at this early gestational age (p=0.008). Conclusions: Fetal renal size in cases exposed to pregestational T2D is significantly smaller compared to controls, and subcutaneous abdominal wall fat is significantly thicker. Given emerging evidence about the developmental origins of disease, further study is needed to correlate the association between fetal renal size and fat distribution in the fetus and the long-term risk of chronic renal disease and diabetes in these offspring.

Antenatal breastfeeding promotion amongst pregnancies at high-risk for newborn admission to the NICU: A cross-sectional study.

Objectives: To determine the prevalence and factors associated with antenatal promotion of breastfeeding in high-risk pregnancies. Study design: This was a cross-sectional study of trends in breastfeeding promotion during antenatal consultation of pregnancies at high-risk for newborn admission to the neonatal intensive care unit (NICU) between January 2017 and December 2020. Eligible high-risk pregnant patients undergoing antenatal consultation in a tertiary-level fetal assessment unit were identified using an electronic clinic repository. Consult letters and fetal assessment reports were reviewed to determine baseline demographics, pregnancy history, fetal findings, and communication about breastfeeding. Descriptive and inferential statistics were used to present findings and compare outcomes between groups. Results: 316 pregnancies were included for final analysis. The mean maternal age was 28.7 years (SD 6.2) and 65 % were multiparas. Median gestational age at time of antenatal consult was 32 weeks [IQR 29-34]. The main indication for consultation was fetal anomalies (72.8%), namely cardiac defects (21.2 %). There was a significant improvement in prevalence of antenatal discussions about breastfeeding over the study period, from 48.8 % early in the study period compared to 73.7 % in the past year (p = 0.036). However, amongst consults where breastfeeding was discussed, almost one-quarter (23.8 %) of patients indicated that they were not planning on breastfeeding postnatally. Conclusion: There has been a significant improvement in promoting breastfeeding antenatally amongst high-risk pregnancies. However, no follow-up or supports were offered to one-quarter of patients who indicated no intention of breastfeeding or using donor milk postnatally. Ongoing work is required to further advance breastfeeding promotion antenatally, increase parental supports and education, and optimize breastfeeding rates postnatally for improving outcomes of this high-risk group.

Can Prenatal Diagnosis of Total Anomalous Pulmonary Venous Return (TAPVR) Using Routine Fetal Ultrasound be Improved? A Case-Control Study.

Objectives: To determine the most common fetal ultrasound markers of total anomalous pulmonary venous return (TAPVR) during mid-trimester ultrasound using standardly obtained images and evaluate the performance of diagnostic algorithms for improving prenatal diagnosis. Methods: This was a matched case-control study at a regional referral centre (2005 to 2019). Cases of TAPVR were matched to controls 1 : 4 by date of birth and biologic sex. Postprocessing review of stored fetal ultrasound images was performed by two blinded and independent observers in a standardized fashion using nine sonographic markers: (i) left/right heart disproportion; (ii) abnormal distribution of great vessels; (iii) pulmonary vein entry into the left atrium (LA); (iv) confluence behind the LA; (v) abnormal coronary sinus; (vi) absence of the Coumadin ridge; (vii) aortic diameter; (viii) distance between LA and aorta; and (ix) post-LA space index >1.27. Descriptive and inferential statistics were used to present results and compare cases and controls. Diagnostic algorithms were compared by sensitivity/specificity. Results: 21 cases of isolated TAPVR were matched to 84 controls (n = 105). The most common ultrasound marker of TAPVR was absence of pulmonary vein entry into the LA (42.9%), followed by abnormal Coumadin ridge (38.1%). Cases of TAPVR had significantly larger post-LA spaces than controls (p < 0.0001) and wider aortic diameters (p=0.006). A diagnostic algorithm stratifying on absence of pulmonary veins followed by an abnormal Coumadin ridge, can correctly identify cases of TAPVR with high specificity (90.5%) and moderate sensitivity (61.9%). Conversely, a diagnostic algorithm using the presence of any 3 abnormal markers had improved specificity (94.1%) but poorer sensitivity (23.8%). Conclusions: Using standardly obtained images from routine fetal ultrasound, improved prenatal detection of isolated TAPVR is possible. A standardized diagnostic approach can be highly specific for fetal TAPVR, however, algorithms that are sufficiently sensitive for screening in the general population are still needed.

Early Neurodevelopmental Outcomes after Previable Preterm Prelabour Rupture of Membranes (pPPROM).

Objective: To describe the early neurodevelopmental outcomes following fetal exposure to previable preterm prelabour rupture of membranes (pPPROM). Methods: This was a secondary analysis of a subgroup of neonates born following pPPROM from a retrospective cohort study (2009-2015). Surviving infants who underwent standardized neurodevelopmental evaluation at 18-24 months corrected age (CA) between 2017 and 2019 were eligible for inclusion. Data abstracted from hospital charts were linked to prospectively collected developmental outcomes stored in an electronic database from a regional neonatal follow-up clinic. The primary outcome was Bayley-III composite scores (compared to the population mean 100, standard deviation (SD) 15). Secondary outcomes included presence of cerebral palsy, vision loss, hearing impairment, and requirement of rehabilitation therapy. Descriptive statistics were used to present results. Results: 25.7% (19/74) of neonates born after pPPROM survived to hospital discharge, but only 21.6% (16/74) survived to 18-24 months CA. Of these, 9 infants were eligible for follow-up at the regional clinic and 7 had developmental outcomes stored in the electronic database. Infants exposed to pPPROM exhibited Bayley-III scores more than 1 SD below the population mean across all three domains: cognitive 84.9 (SD 12.2); motor 82.3 (SD 11.5); and language 66.4 (SD 18.9). There were particular deficiencies in language development with 71% (5/7) scoring more than 2 SDs below the population mean. There were no cases of cerebral palsy. Conclusions: Only 1 in 5 infants born following expectantly managed pPPROM survived to 18-24 months CA. These infants born after pPPROM had significantly lower Bayley-III scores and particular deficiencies in language development. Better understanding of early neurodevelopmental challenges following pPPROM will help refine counselling of families contemplating expectant management and provide insights into the postnatal educational resources required to improve long-term developmental outcomes for these children.

A Critical Analysis of Intestinal Enteric Neuron Loss and Constipation in Parkinson's Disease.

Constipation afflicts many patients with Parkinson's disease (PD) and significantly impacts on patient quality of life. PD-related constipation is caused by intestinal dysfunction, but the etiology of this dysfunction in patients is unknown. One possible cause is neuron loss within the enteric nervous system (ENS) of the intestine. This review aims to 1) Critically evaluate the evidence for and against intestinal enteric neuron loss in PD patients, 2) Justify why PD-related constipation must be objectively measured, 3) Explore the potential link between loss of enteric neurons in the intestine and constipation in PD, 4) Provide potential explanations for disparities in the literature, and 5) Outline data and study design considerations to improve future research. Before the connection between intestinal enteric neuron loss and PD-related constipation can be confidently described, future research must use sufficiently large samples representative of the patient population (majority diagnosed with idiopathic PD for at least 5 years), implement a consistent neuronal quantification method and study design, including standardized patient recruitment criteria, objectively quantify intestinal dysfunctions, publish with a high degree of data transparency and account for potential PD heterogeneity. Further investigation into other potential influencers of PD-related constipation is also required, including changes in the function, connectivity, mitochondria and/or α-synuclein proteins of enteric neurons and their extrinsic innervation. The connection between enteric neuron loss and other PD-related gastrointestinal (GI) issues, including gastroparesis and dysphagia, as well as changes in nutrient absorption and the microbiome, should be explored in future research.

The Biosimilar Nocebo Effect? A Systematic Review of Double-Blinded Versus Open-Label Studies.

BACKGROUND: Several authors have hypothesized that adverse drug events (ADEs) upon switching from reference biologics to biosimilar products are related to the nocebo effect. However, a thorough and current review of the existing literature has not been conducted. OBJECTIVE: To evaluate if patient and/or physician knowledge of a switch from a reference biologic product to a biosimilar product was associated with an increase in ADEs likely to be susceptible to the nocebo effect. METHODS: Studies reporting efficacy and safety outcomes of a switch from a reference product to a biosimilar product were reviewed. Biologics with FDA-approved biosimilars in the United States were considered for review, including adalimumab, bevacizumab, etanercept, and infliximab. Studies were identified by searching controlled vocabulary (e.g., MeSH terms) and keywords within MEDLINE (via PubMed) and Embase. Descriptive statistics were used to quantify subjective and objective complications in double-blinded and single-blinded or open-label studies. RESULTS: Thirty-one trials including 3,271 patients were reviewed in the full analysis. Median discontinuation rates for any reason were 14.3% (range = 0.0-33.3) in open-label studies compared with 6.95% (range = 5.2-11.0) in double-blinded studies. Discontinuation rates for ADEs were 5.6% (range = 0.0-24.2) in open-label studies versus 3.1% (range = 2.0-5.2) in double-blinded studies, suggesting the nocebo effect does affect biosimilar adoption. Subgroup analyses of antidrug antibody (ADA) development and infusion reactions were similar between infliximab open-label and double-blinded studies. Discontinuation rates for any reason, for ADEs, and for lack of efficacy were generally higher in infliximab open-label trials compared with double-blinded trials. Etanercept biosimilar discontinuation rates for any reason were similar between study designs; however, incidences of injection site reactions and discontinuation rates for ADEs were higher in double-blinded compared with open-label study designs. CONCLUSIONS: Current evidence is insufficient to confirm a biosimilar nocebo effect, although higher discontinuation rates in infliximab biosimilar open-label studies support this theory. Further studies are needed to evaluate the existence of a biosimilar nocebo effect. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to disclose.

MicroRNA-200b regulates distal airway development by maintaining epithelial integrity.

miR-200b plays a role in epithelial-to-mesenchymal transition (EMT) in cancer. We recently reported abnormal expression of miR-200b in the context of human pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Smaller lung size, a lower number of airway generations, and a thicker mesenchyme characterize pulmonary hypoplasia in CDH. The aim of this study was to define the role of miR-200b during lung development. Here we show that miR-200b-/- mice have abnormal lung function due to dysfunctional surfactant, increased fibroblast-like cells and thicker mesenchyme in between the alveolar walls. We profiled the lung transcriptome in miR-200b-/- mice, and, using Gene Ontology analysis, we determined that the most affected biological processes include cell cycle, apoptosis and protein transport. Our results demonstrate that miR-200b regulates distal airway development through maintaining an epithelial cell phenotype. The lung abnormalities observed in miR-200b-/- mice recapitulate lung hypoplasia in CDH.