Physiology during sleep in preterm infants: Implications for increased risk for the sudden infant death syndrome.

Approximately 15 million babies are born preterm (<37 weeks of completed gestation) worldwide annually. Although neonatal and perinatal medicine have contributed to the increased survival rate of preterm newborn infants, premature infants are at increased risk of mortality in the first years of life. Infants born preterm are at four times the risk of Sudden Infant Death Syndrome (SIDS) compared to infants born at term. SIDS is believed to be multifactorial in origin. The Triple Risk hypothesis has been proposed to explain this. The model suggests that when a vulnerable infant, such as one born preterm, is at a critical but unstable developmental period in homeostatic control, death may occur if exposed to an exogenous stressor, such as being placed prone for sleep. The highest risk period is at ages 2-4 months, with 90 % of deaths occurring before 6 months. The final pathway to SIDS is widely believed to involve some combination of immature cardiorespiratory control and a failure of arousal from sleep. This review will focus on the physiological factors which increase the risk for SIDS in preterm infants and how these factors may be identified and potentially lead to effective preventative strategies.

Stability for 6 months and accuracy of a specific enteral caffeine base preparation for a multisite clinical trial.

The 'Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)' study (NCT03321734) uses an extemporaneously compounded enteral caffeine base solution for its study drug. The primary aim of this report is to determine the stability of this specific enteral caffeine base preparation stored for up to 6 months and assess optimal storage temperature. To analyse stability, caffeine solutions were prepared and stored at 4°C and 25°C (room temperature). The caffeine concentrations were analysed over time using high-performance liquid chromatography (HPLC). To confirm the accuracy of compounded caffeine concentrations, study drug samples from three research pharmacies were analysed. Stability results showed that caffeine concentrations are within 5% of the expected concentration when stored for up to 6 months at room temperature. Our results also show that accurate caffeine concentrations were achieved by multiple research pharmacies.

Adverse effects of COVID-19 pandemic on a multicenter randomized controlled trial.

OBJECTIVE: Describe the effects of the COVID-19 pandemic on subject enrollment in a multicenter randomized controlled trial. STUDY DESIGN: We assessed the number of eligible infants approached and consented for enrollment over five separate epochs including baseline, peak pandemic, and gradual but incomplete recovery. RESULT: The pandemic had a major effect on ability to approach parents for consent. Parents approached dropped from 95.4% baseline to 13.1% in the peak pandemic epoch and has not recovered to baseline even in the just-completed post-pandemic epoch (84.9%). Despite the decrease in subjects approached, there was no significant change in the overall consent rate for the study CONCLUSION: The pandemic has significantly limited ability to approach parents of eligible infants for consent, with only partial recovery. Opportunities for interactions of investigators and study coordinators with parents continue to present challenges limiting full recovery.

Immature control of breathing and apnea of prematurity: the known and unknown.

This narrative review provides a broad perspective on immature control of breathing, which is universal in infants born premature. The degree of immaturity and severity of clinical symptoms are inversely correlated with gestational age. This immaturity presents as prolonged apneas with associated bradycardia or desaturation, or brief respiratory pauses, periodic breathing, and intermittent hypoxia. These manifestations are encompassed within the clinical diagnosis of apnea of prematurity, but there is no consensus on minimum criteria required for diagnosis. Common treatment strategies include caffeine and noninvasive respiratory support, but other therapies have also been advocated with varying effectiveness. There is considerable variability in when and how to initiate and discontinue treatment. There are significant knowledge gaps regarding effective strategies to quantify the severity of clinical manifestations of immature breathing, which prevent us from better understanding the long-term potential adverse outcomes, including neurodevelopment and sudden unexpected infant death.

Longitudinal growth changes from birth to 8-9 years in preterm and full term births.

BACKGROUND: The aim of this study is to assess the effect of age at adiposity rebound (AR) and changes in growth between birth and 6 months on growth status at 8-9 years in children born term and preterm. Age at AR is inversely correlated with risk for later obesity in children born full term, but has not been analyzed in children born preterm. METHODS: Birth anthropometrics, and weight and length/height data from age 6 months through 8-9 years were recorded for 175 children born in 2008 in the military health system. Calculated variables include body mass index (BMI, kg/m2), Z-scores, and age at AR. RESULTS: Age at AR could be calculated for 150 children (32% preterm); average age was 5.4 years and 5.3 years for children born term and preterm, respectively (NS). For children born term and preterm, there was a significant correlation between younger age at AR and higher BMI Z-score at 8-9 years (r = - 0.685), and a direct relationship between weight Z-score change from birth to 6 months and weight Z-scores at 8-9 years (p = 0.034). CONCLUSIONS: Younger age at AR correlates with higher BMI Z-score at 8-9 years in children born both term and preterm. Weight gain from birth to 6 months correlates with weight Z-score at 8-9 years. These results emphasize the importance of younger age at AR in addition to greater early weight gain as an indicator of later obesity.

N-docosahexaenoylethanolamine detected in human breast milk.

PURPOSE: Measure concentrations of the neurogenic, pro-neurogenic, pro-synaptogenic and anti-inflammatory mediator N-docosahexaenoylethanolamine (synaptamide) in relation to its precursor docosahexaenoic acid (DHA) in breast milk. DESIGN AND METHODS: Postpartum women were recruited prior to discharge. We supplemented half the subjects with omega-3 fatty acids. Breast milk samples were collected at 1, 4 and 8 weeks. Synaptamide and DHA concentrations were determined by liquidchromatography/tandem mass spectrometry (LC-MS/MS) and gas chromatography, respectively. RESULTS: Synaptamide was detected in all breast milk samples. The concentration ranged from 44 to 257 fmol/mL. Omega-3 fatty acid supplementation did not affect DHA or synaptamide concentration in breast milk due to a high-DHA-containing diet self-selected by control mothers. Nevertheless, synaptamide levels significantly correlated with DHA concentration in breast milk (r = 0.624, P < 0.001). CONCLUSION: This is the first demonstration of detectable concentrations of synaptamide in human breast milk. Although the attempt to raise the milk DHA content by omega-3 fatty acid supplementation was not successful in the current study, the positive correlation observed between synaptamide and DHA concentration suggests that synaptamide levels in human milk can be raised by proper omega-3 fatty acid supplementation that is known to increase DHA.

Caffeine: an evidence-based success story in VLBW pharmacotherapy.

Apnea of prematurity (AOP) is a common and pervasive problem in very low birth weight infants. Methylxanthines were reported >40 years ago to be an effective therapy and, by the early 2000s, caffeine had become the preferred methylxanthine because of its wide therapeutic index, excellent bioavailability, and longer half-life. A clinical trial to address unresolved questions and toxicity concerns, completed in 2004, confirmed significant benefits of caffeine therapy, including shorter duration of intubation and respiratory support, reduced incidence of chronic lung disease, decreased need for treatment of patent ductus arteriosus, reduced severity of retinopathy of prematurity, and improved motor and visual function. Cohort studies have now further delineated the benefits of initiation of therapy before 3 days postnatal age, and of higher maintenance doses to achieve incremental beneficial effects. This review summarizes the pivotal and in particular the most recent studies that have established the safety and efficacy of caffeine therapy for AOP and other respiratory and neurodevelopmental outcomes. Caffeine has a very favorable benefit-to-risk ratio, and has become one of the most prescribed and cost-effective pharmacotherapies in the NICU.

Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism.

BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20-P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1ß at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus, and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr, and Gly/Cr; increases in TCho and GPC in the brainstem; and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude to that experienced in human preterm infants, is associated with evidence for proinflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life.

The "bedside-to-bench" Congenital Central Hypoventilation Syndrome (CCHS) research journey has led to increased phenotypic-genotypic knowledge regarding autonomic nervous system (ANS) regulation, and improved clinical outcomes. CCHS is a neurocristopathy characterized by hypoventilation and ANS dysregulation. Initially described in 1970, timely diagnosis and treatment remained problematic until the first large cohort report (1992), delineating clinical presentation and treatment options. A central role of ANS dysregulation (2001) emerged, precipitating evaluation of genes critical to ANS development, and subsequent 2003 identification of Paired-Like Homeobox 2B (PHOX2B) as the disease-defining gene for CCHS. This breakthrough engendered clinical genetic testing, making diagnosis exact and early tracheostomy/artificial ventilation feasible. PHOX2B genotype-CCHS phenotype relationships were elucidated, informing early recognition and timely treatment for phenotypic manifestations including Hirschsprung disease, prolonged sinus pauses, and neural crest tumors. Simultaneously, cellular models of CCHS-causing PHOX2B mutations were developed to delineate molecular mechanisms. In addition to new insights regarding genetics and neurobiology of autonomic control overall, new knowledge gained has enabled physicians to anticipate and delineate the full clinical CCHS phenotype and initiate timely effective management. In summary, from an initial guarantee of early mortality or severe neurologic morbidity in survivors, CCHS children can now be diagnosed early and managed effectively, achieving dramatically improved quality of life as adults.

Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy.

AIMS: Caffeine concentrations in preterm infants are usually measured in the blood. However, salivary assays may provide a valid and practical alternative. The present study explored the validity and clinical utility of salivary caffeine concentrations as an alternative to blood concentrations and developed a novel plasma/salivary caffeine distribution model. METHODS: Paired salivary and plasma samples were obtained in 29 infants. Salivary samples were obtained using a commercially available salivary collection system. Caffeine concentrations in the saliva and plasma were determined using high-performance liquid chromatography. A population pharmacokinetic (PK) model was developed using NONMEM 7.3. RESULTS: The mean (± standard deviation) gestational age (GA) at birth and birth weight were 27.9 ± 2.1 weeks and 1171.6 ± 384.9 g, respectively. Paired samples were obtained at a mean postmenstrual age (PMA) of 35.5 ± 1.1 weeks. The range of plasma caffeine concentrations was 9.5-54.1 µg ml(-1) , with a mean difference (95% confidence interval) between plasma and salivary concentrations of -0.18 µg ml(-1) (-1.90, 1.54). Salivary and plasma caffeine concentrations were strongly correlated (Pearson's correlation coefficient = 0.87, P < 0.001). Caffeine PK in plasma and saliva was simultaneously described by a three-compartment recirculation model. Current body weight, birth weight, GA, PMA and postnatal age were not significantly correlated with any PK parameter. CONCLUSIONS: Salivary sampling provides an easy, non-invasive method for measuring caffeine concentrations. Salivary concentrations correlate highly with plasma concentrations. Caffeine PK in saliva and plasma are well described by a three-compartment recirculation model.

Assigning cause for sudden unexpected infant death.

We have reached a conundrum in assigning cause of death for sudden unexpected infant deaths. We summarize the discordant perspectives and approaches and how they have occurred, and recommend a pathway toward improved consistency. This lack of consistency affects pediatricians and other health care professionals, scientific investigators, medical examiners and coroners, law enforcement agencies, families, and support or advocacy groups. We recommend that an interdisciplinary international committee be organized to review current approaches for assigning cause of death, and to identify a consensus strategy for improving consistency. This effort will need to encompass intrinsic risk factors or infant vulnerability in addition to known environmental risk factors including unsafe sleep settings, and must be sufficiently flexible to accommodate a progressively expanding knowledge base.

Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants.

OBJECTIVE: To examine the effect of early initiation of caffeine therapy on neonatal outcomes and characterize the use of caffeine therapy in very low birth weight (VLBW) infants. STUDY DESIGN: We analyzed a cohort of 62 056 VLBW infants discharged between 1997 and 2010 who received caffeine therapy. We compared outcomes in infants receiving early caffeine therapy (initial dose before 3 days of life) and those receiving late caffeine therapy (initial dose at or after 3 days of life) through propensity scoring using baseline and early clinical variables. The primary outcome was the association between the timing of caffeine initiation and the incidence of bronchopulmonary dysplasia (BPD) or death. RESULTS: We propensity score-matched 29 070 VLBW infants at a 1:1. Of infants receiving early caffeine therapy, 3681 (27.6%) died or developed BPD, compared with 4591 infants (34.0%) receiving late caffeine therapy (OR, 0.74; 99% CI, 0.69-0.80). Infants receiving early caffeine had a lower incidence of BPD (23.1% vs 30.7%; OR, 0.68; 95% CI, 0.63-0.73) and a higher incidence of death (4.5% vs 3.7%; OR, 1.23; 95% CI, 1.05-1.43). Infants receiving early caffeine therapy had less treatment of patent ductus arteriosus (OR, 0.60; 95% CI, 0.55-0.65) and a shorter duration of mechanical ventilation (mean difference, 6 days; P < .001). CONCLUSION: Early caffeine initiation is associated with a decreased incidence of BPD. Randomized trials are needed to determine the efficacy and safety of early caffeine prophylaxis in VLBW infants.

Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial.

IMPORTANCE: Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown. OBJECTIVES: To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks' postmenstrual age (PMA) reduces IH. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized clinical study was conducted at 16 neonatal intensive care units in the United States, with an 18-month enrollment period. Preterm infants (<32 weeks' gestation) previously treated with caffeine were randomized to extended caffeine treatment or usual care (controls) at a PMA of at least 34 weeks but less than 37 weeks. Continuous pulse oximeter recordings were obtained through 40 weeks' PMA. Oximeter data were analyzed by persons masked to patient group. INTERVENTION: Continued treatment with caffeine. MAIN OUTCOMES AND MEASURES: Number of IH events and seconds with less than 90% hemoglobin oxygen saturation (Sao2) per hour of recording. RESULTS: Our analysis included 95 preterm infants. In control infants, the mean (SD) time at less than 90% Sao2 at 35 and 36 weeks' PMA was 106.3 (89.0) and 100.1 (114.6) s/h, respectively. The number of IH events decreased significantly from 35 to 39 weeks' PMA (P = .01). Extended caffeine treatment reduced the mean time at less than 90% Sao2 by 47% (95% CI, -65% to -20%) to 50.9 (48.1) s/h at 35 weeks and by 45% (95% CI, -74% to -17%) to 49.5 (52.1) s/h at 36 weeks. CONCLUSIONS AND RELEVANCE: Substantial IH persists after discontinuation of routine caffeine treatment and progressively decreases with increasing PMA. Extended caffeine treatment decreases IH in premature infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01875159.

Novel noninvasive anthropometric measure in preterm and full-term infants: normative values for waist circumference:length ratio at birth.

BACKGROUND: Waist circumference:length ratio (WLR) and ponderal index (PI) appear to be useful markers of visceral and total adiposity, respectively. However, there are no normative birth data across the full range of gestational ages. METHODS: In this retrospective cohort study of 500 preterm and 1,426 full-term infants, born in 1998 and 2008 at three military hospitals, the percentile growth curves for WLR and PI were calculated. There were no sex differences, and results were combined to obtain values from 26 to 42 wk gestation. RESULTS: Between 26 and 42 wk gestation, median birth WLR increased from 0.55 to 0.62, and median PI increased from 21.1 to 25.6. The adjusted mean WLR at birth among infants born <34 wk increased from 0.55 in 1998 to 0.58 in 2008 (P = 0.048), suggesting that early-preterm infants born in 2008 had greater abdominal adiposity than those born in 1998. CONCLUSION: We report normative birth data for WLR and PI in preterm and full-term infants by gestational age and sex. WLR and PI may be useful as clinical markers of visceral and overall adiposity. In conjunction with other anthropometric measures, WLR and PI may be useful to monitor postnatal nutrition and growth and assess risk for later obesity and cardiometabolic disorders.

Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages.

OBJECTIVE: To assess anthropometric changes from birth to hospital discharge in infants born preterm and compare with a reference birth cohort of infants born full-term. STUDY DESIGN: Retrospective chart review was conducted of 501 preterm and 1423 full-term infants. We evaluated birth and hospital discharge weight, length, and waist circumference (WC). WC/length ratio (WLR), ponderal index, and body mass index (BMI) were calculated. Preterm infants were categorized into quartiles (Q1-4) based on birth weight (BW). RESULTS: At birth mean length, WC, WLR, BMI, and ponderal index were all significantly less for preterm infants in the lowest BW quartile (Q1) than preterm infants in higher BW quartiles or full-term infants. Although their weight, length, and BMI remained significantly less at discharge, preterm infants in Q1 had a disproportionate increase in WLR and ponderal index such that at discharge their WLR and ponderal index were greater than infants in Q2-3 and comparable with infants in Q4 and full-term infants. Discharge WLR and ponderal index in Q1 were significantly higher with decreasing postmenstrual age at birth. CONCLUSIONS: Preterm infants of a lower birth postmenstrual age have disproportionate increases in WLR and ponderal index that are suggestive of increased visceral and total adiposity.

Relationship between sleep position and risk of extreme cardiorespiratory events.

OBJECTIVE: To determine whether infants at sleep in the prone side positions are at higher risk for an extreme cardiorespiratory event compared with infants at sleep in the supine position. STUDY DESIGN: We used a case-control study to compare sleep position, determined with an accelerometer, in 116 infants during an extreme cardiorespiratory event with that in 231 matched control subjects (2 per case) who did not experience any extreme events during monitoring. RESULTS: From calculation of adjusted ORs and 95% CIs, infants placed in the prone or side position were no more likely to experience an extreme cardiorespiratory event compared with infants at sleep in the supine position. We used conditional logistic regression to account for the matched design of the study and to adjust for potential confounders or effect-modifiers. CONCLUSION: These findings, coupled with our earlier observation that the peak incidence of severe cardiorespiratory events occurred before the peak incidence of sudden infant death syndrome, strongly suggest that the supine sleeping position decreases the risk of sudden infant death syndrome by mechanisms other than by decreasing extreme cardiorespiratory events detected by monitoring.

Longitudinal assessment of hemoglobin oxygen saturation in preterm and term infants in the first six months of life.

OBJECTIVE: To report longitudinal home recordings of hemoglobin O(2) saturation by pulse oximetry (Spo(2)) during unperturbed sleep in preterm and term infants. STUDY DESIGN: We recorded continuous pulse oximetry during the first 3 minutes of each hour of monitor use (nonevent epochs) for 103 preterm infants born at <1750 g and ≤ 34 weeks postmenstrual age (PMA), and 99 healthy term infants. RESULTS: Median baseline Spo(2) was approximately 98% for both the preterm and term groups. Episodes of intermittent hypoxemia occurred in 74% of preterm and 62% of term infants. Among infants with intermittent hypoxemia, the number of seconds/hour of monitoring <90% Spo(2) was initially significantly greater in the preterm than the term group and declined with age at a similar rate in both groups. The 75(th) to 95(th) percentiles for seconds/hour of Spo(2) <90% in preterm infants were highest at 36 weeks PMA and progressively decreased until 44 weeks PMA, after which time they did not differ from term infants. CONCLUSIONS: Clinically inapparent intermittent hypoxemia occurs in epochs unperturbed by and temporally unrelated to apnea or bradycardia events, especially in preterm infants at 36 to 44 weeks PMA.