Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO programme.

OBJECTIVE: n-3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n-3 supplement intake. DESIGN: Pooled pregnancy cohort studies. SETTING: Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. PARTICIPANTS: A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. RESULTS: Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1-2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35-40 v. <29 years), were other than non-Hispanic White (1·13, 95 % CI 1·08, 1·18 for non-Hispanic Black; 1·05, 95 % CI 1·01, 1·10 for non-Hispanic Asian; 1·06, 95 % CI 1·02, 1·10 for Hispanic) or used tobacco (1·04, 95 % CI 1·01, 1·08). The RR was lower in those with overweight v. healthy weight (0·97, 95 % CI 0·95, 1·0). Only 16·2 % reported n-3 supplement use, which was more common among individuals with a higher age and education, a lower BMI, and fish consumption (RR 1·5, 95 % CI 1·23, 1·82 for twice-weekly v. never). CONCLUSIONS: One-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and n-3 supplement use was uncommon, even among those who did not consume fish.

Risk of Wrong-Patient Orders Among Multiple vs Singleton Births in the Neonatal Intensive Care Units of 2 Integrated Health Care Systems.

IMPORTANCE: Multiple-birth infants in neonatal intensive care units (NICUs) have nearly identical patient identifiers and may be at greater risk of wrong-patient order errors compared with singleton-birth infants. OBJECTIVES: To assess the risk of wrong-patient orders among multiple-birth infants and singletons receiving care in the NICU and to examine the proportion of wrong-patient orders between multiple-birth infants and siblings (intrafamilial errors) and between multiple-birth infants and nonsiblings (extrafamilial errors). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted in 6 NICUs of 2 large, integrated health care systems in New York City that used distinct temporary names for newborns per the requirements of The Joint Commission. Data were collected from 4 NICUs at New York-Presbyterian Hospital from January 1, 2012, to December 31, 2015, and 2 NICUs at Montefiore Health System from July 1, 2013, to June 30, 2015. Data were analyzed from May 1, 2017, to December 31, 2017. All infants in the 6 NICUs for whom electronic orders were placed during the study periods were included. MAIN OUTCOMES AND MEASURES: Wrong-patient electronic orders were identified using the Wrong-Patient Retract-and-Reorder (RAR) Measure. This measure was used to detect RAR events, which are defined as 1 or more orders placed for a patient that are retracted (ie, canceled) by the same clinician within 10 minutes, then reordered by the same clinician for a different patient within the next 10 minutes. RESULTS: A total of 10 819 infants were included: 85.5% were singleton-birth infants and 14.5% were multiple-birth infants (male, 55.8%; female, 44.2%). The overall wrong-patient order rate was significantly higher among multiple-birth infants than among singleton-birth infants (66.0 vs 41.7 RAR events per 100 000 orders, respectively; adjusted odds ratio, 1.75; 95% CI, 1.39-2.20; P < .001). The rate of extrafamilial RAR events among multiple-birth infants (36.1 per 100 000 orders) was similar to that of singleton-birth infants (41.7 per 100 000 orders). The excess risk among multiple-birth infants (29.9 per 100 000 orders) appears to be owing to intrafamilial RAR events. The risk increased as the number of siblings receiving care in the NICU increased; a wrong-patient order error occurred in 1 in 7 sets of twin births and in 1 in 3 sets of higher-order multiple births. CONCLUSIONS AND RELEVANCE: This study suggests that multiple-birth status in the NICU is associated with significantly increased risk of wrong-patient orders compared with singleton-birth status. This excess risk appears to be owing to misidentification between siblings. These results suggest that a distinct naming convention as required by The Joint Commission may provide insufficient protection against identification errors among multiple-birth infants. Strategies to reduce this risk include using given names at birth, changing from temporary to given names when available, and encouraging parents to select names for multiple births before they are born when acceptable to families.

Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.

We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255-264, 2015). Tetrahydrobiopterin (BH4) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH4 compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O2·-) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O2·- generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.

BACKGROUND: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. OBJECTIVE: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. DESIGN: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. RESULTS: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 µg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 µg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. CONCLUSION: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.

Effects of caffeine treatment for apnea of prematurity on cortical speech-sound differentiation in preterm infants.

Caffeine, standard treatment for apnea of prematurity, improves brainstem auditory processing. We hypothesized that caffeine also improves cortical differentiation of complex speech sounds. We used event-related potential methodology to measure responses to speech-sound contrasts in 45 intensive care neonates, stratified by cumulative exposure as no-, low-, and high-caffeine groups. Sound differentiation in the low-caffeine group and near-term no-caffeine infants was similar with repeated measures analysis of variance controlling for gestational and postnatal age. However, a generalized estimating equation approach demonstrated that, at equivalent postnatal age, differentiation was reduced in the high-caffeine (gestational age 25 weeks) compared to the low-caffeine group (gestational age 28 weeks), reflecting the importance of maturity at birth (Z = 2.77, P < .006). We conclude that caffeine improves measures of auditory processing associated with improved neurodevelopmental outcomes in preterm infants. However, current usage of caffeine for apnea of prematurity cannot fully compensate for the effects of brain immaturity on speech sound processing.

Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs.

Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia.

Hemisphere differences in speech-sound event-related potentials in intensive care neonates: associations and predictive value for development in infancy.

Neurodevelopmental delays in intensive care neonates are common but difficult to predict. In children, hemisphere differences in cortical processing of speech are predictive of cognitive performance. We hypothesized that hemisphere differences in auditory event-related potentials in intensive care neonates are predictive of neurodevelopment in infancy, even in those born preterm. Event-related potentials to speech sounds were prospectively recorded in 57 infants (gestational age 24-40 weeks) prior to discharge. The Developmental Assessment of Young Children was performed at 6 and 12 months. Hemisphere differences in mean amplitudes increased with postnatal age (P < .01) but not with gestational age. Greater hemisphere differences were associated with improved communication and cognitive scores at 6 and 12 months, but decreased in significance at 12 months after adjusting for socioeconomic and clinical factors. Auditory cortical responses can be used in intensive care neonates to help identify infants at higher risk for delays in infancy.

L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats.

Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). NO promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day (P) 14 to room air (RA), RA + L-citrulline, 95% hyperoxia (BPD model), and 95%O2 + L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness (MWT) and right ventricular hypertrophy (RVH). Increased lung arginase (ARG) activity in O2-exposed pups was reversed by L-citrulline treatment. L-citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.

In vitro uptake of glutamate in GLAST- and GLT-1-transfected mutant CHO-K1 cells is inhibited by the ethylmercury-containing preservative thimerosal.

Thimerosal, also known as thimersal, Merthrolate, or sodiumethyl-mercurithiosalicylate, is an organic mercurial compound that is used in a variety of commercial as well as biomedical applications. As a preservative, it is used in a number of vaccines and pharmaceutical products. Its active ingredient is ethylmercury. Both inorganic and organic mercurials are known to interfere with glutamate homeostasis. Brain glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/ aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The effects of thimerosal on glutamate homeostasis have yet to be determined. As a first step in this process, we examined the effects of thimerosal on the transport of [3H]-d-aspartate, a nonmetabolizable glutamate analog, in Chinese hamster ovary (CHO) cells transfected with two glutamate transporter subtypes, GLAST (EAAT1) and GLT-1 (EAAT2). Additionally, studies were undertaken to determine the effects of thimerosal on mRNA and protein levels of these transporters. The results indicate that thimerosal treatment caused significant but selective changes in both glutamate transporter mRNA and protein expression in CHO cells. Thimerosal-mediated inhibition of glutamate transport in the CHO-K1 cell line DdB7 was more pronounced in the GLT-1-transfected cells compared with the GLAST- transfected cells. These studies suggest that thimerosal accumulation in the central nervous system might contribute to dysregulation of glutamate homeostasis.