Prenatal Weight Change Trajectories and Perinatal Outcomes among Twin Gestations.

OBJECTIVE: Despite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies. STUDY DESIGN: Prenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression. RESULTS: Weight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (ß = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth <32 weeks (IRR = 2.44, 95%CI: 1.10, 5.4) that was attenuated in sensitivity analyses. Class 2 was associated with moderately elevated birth weight z-score (ß = 0.24, 95%CI: 0.00, 0.48, p = 0.050). CONCLUSION: Gestational weight change followed a low, moderate, or high trajectory; both moderate and high gain patterns were associated with increased infant size outcomes. Optimal patterns of weight change that balance risk during the prenatal, perinatal, and neonatal periods require further investigation, particularly in high-risk twin pregnancies. KEY POINTS: · A majority gained weight below IOM twin recommendations.. · Three patterns of GWC across pregnancy were identified.. · Moderate or high GWC was associated with infant size..

Low Rate of Spontaneous Closure in Premature Infants Discharged with a Patent Ductus Arteriosus: A Multicenter Prospective Study.

OBJECTIVES: To assess the rate of spontaneous closure and the incidence of adverse events in infants discharged home with a patent ductus arteriosus. STUDY DESIGN: In a prospective multicenter study, we enrolled 201 premature infants (gestational age of 23-32 weeks at birth) discharged home with a persistently patent ductus arteriosus (PDA) and followed their PDA status at 6-month intervals through 18 months of age. The primary study outcome was the rate and timing of spontaneous ductal closure. Secondary outcomes included rate of assisted closure and the incidence of serious adverse events. RESULTS: Spontaneous ductal closure occurred in 95 infants (47%) at 12 months and 117 infants (58%) by 18 months. Seventeen infants (8.4%) received assisted closure with surgical ligation or device assisted occlusion. Three infants died (1.5%). Although infants with spontaneous closure had a higher mean birth weight and gestational age compared with infants with a persistent PDA or assisted closure, we did not identify other factors predictive of spontaneous closure. CONCLUSIONS: Spontaneous closure of the PDA occurred in slightly less than one-half of premature infants discharged with a patent ductus by 1 year, lower than prior published reports. The high rate of assisted closure and/or adverse events in this population warrants close surveillance following discharge. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02750228.

Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

Direct-to-participant recruitment of mothers and infants: A strategic approach during challenging pandemic times.

Under traditional circumstances, most clinical trials rely on in-person operations to identify, recruit, and enroll study participants and to complete study-related visits. During unusual circumstances, such as the COVID-19 pandemic, the typical clinical trial model is challenged and forced to explore alternative approaches to implementing study recruitment, participant enrollment, and data collection strategies. One such alternative is a direct-to-participant approach which leverages electronic resources and relevant technological devices (e.g., smart phones) available to researchers and patients. This approach functions under the assumption that a participant has access to a device that connects to the internet such as a smart phone, tablet, or computer. Researchers are then able to transition a typical paper-based, in-person model to an electronic-based, siteless, remote study. This article describes the challenges clinicians and researchers faced when implementing a direct-to-participant study approach during the COVID-19 pandemic. The lessons learned during this study of infant populations could help increase efficiency of future trials, specifically, by lessening the burden on participants and clinicians as well as streamlining the process for enrollment and data collection. While direct-to-adult participant recruitment is not a novel approach, our findings suggest that studies attempting to recruit the infant population may benefit from such a direct-to-participant approach.

Withdrawal of Life-Support in Neonatal Hypoxic-Ischemic Encephalopathy.

PURPOSE: We describe the frequency and timing of withdrawal of life-support (WLS) in moderate or severe hypoxic-ischemic encephalopathy (HIE) and examine its associations with medical and sociodemographic factors. PROCEDURES: We undertook a secondary data analysis of a prospective multicenter data registry of regional level IV Neonatal Intensive Care Units participating in the Children's Hospitals Neonatal Database. Infants ≥36 weeks gestational age with HIE admitted to a Children's Hospitals Neonatal Database Neonatal Intensive Care Unit between 2010 and 2016, who underwent therapeutic hypothermia were categorized as (1) infants who died following WLST and (2) survivors with severe HIE (requiring tube feedings at discharge). RESULTS: Death occurred in 267/1,925 (14%) infants with HIE, 87.6% following WLS. Compared to infants with WLS (n = 234), the survived severe group (n = 74) had more public insurance (73% vs 39.3%, P = 0.00001), lower household income ($37,020 vs $41,733, P = 0.006) and fewer [20.3% vs 35.0%, P = 0.0212] were from the South. Among infants with WLS, electroencephalogram was performed within 24 hours in 75% and was severely abnormal in 64% cases; corresponding rates for MRI were 43% and 17%, respectively. Private insurance was independently associated with WLS, after adjustment for HIE severity and center. CONCLUSIONS: In a multicenter cohort of infants with HIE, WLS occurred frequently and was associated with sociodemographic factors. The rationale for decision-making for WLS in HIE require further exploration.

A comparison of the sexually dimorphic dexamethasone transcriptome in mouse cerebral cortical and hypothalamic embryonic neural stem cells.

Fetal exposure to synthetic glucocorticoids reprograms distinct neural circuits in the developing brain, often in a sex-specific manner, via mechanisms that remain poorly understood. To reveal whether such reprogramming is associated with select molecular signatures, we characterized the transcriptome of primary, embryonic mouse cerebral cortical and hypothalamic neural progenitor/stem cells derived from individual male and female embryos exposed to the synthetic glucocorticoid, dexamethasone. Gene expression profiling by RNA-Seq identified differential expression of common and unique genes based upon brain region, sex, and/or dexamethasone exposure. These gene expression datasets provide a unique resource that will inform future studies examining the molecular mechanisms responsible for region- and sex-specific reprogramming of the fetal brain brought about by in utero exposure to excess glucocorticoids.

Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms.

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

Effects of antenatal glucocorticoids on the developing brain.

Glucocorticoids (GCs) regulate distinct physiological processes in the developing fetus, in particular accelerating organ maturation that enables the fetus to survive outside the womb. In preterm birth, the developing fetus does not receive sufficient exposure to endogenous GCs in utero for proper organ development predisposing the neonate to complications including intraventricular hemorrhage, respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC). Synthetic GCs (sGCs) have proven useful in the prevention of these complications since they are able to promote the rapid maturation of underdeveloped organs present in the fetus. While these drugs have proven to be clinically effective in the prevention of IVH, RDS and NEC, they may also trigger adverse developmental side effects. This review will examine the current clinical use of antenatal sGC therapy in preterm birth, their placental metabolism, and their effects on the developing brain.

Minireview: the impact of antenatal therapeutic synthetic glucocorticoids on the developing fetal brain.

The life-threatening, emotional, and economic burdens of premature birth have been greatly alleviated by antenatal glucocorticoid (GC) treatment. Antenatal GCs accelerate tissue development reducing respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, they can also alter developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. This review summarizes animal model and clinical studies that examined the impact of antenatal GCs on the developing brain. In addition, we describe studies that assess glucocorticoid receptor (GR) action in neural stem/progenitor cells (NSPCs) in vivo and in vitro. We highlight recent work from our group on two GR pathways that impact NSPC proliferation, ie, a nongenomic GR pathway that regulates gap junction intercellular communication between coupled NSPCs through site-specific phosphorylation of connexin 43 and a genomic pathway driven by differential promoter recruitment of a specific GR phosphoisoform.