Laila Lorenz

A Review of Cord Blood Concentrations of Iron Status Parameters to Define Reference Ranges for Preterm Infants

Background: Iron plays an essential role in various tissue functions, and hence the reliable assessment of iron nutrition status of preterm infants appears to be mandatory. Objectives: To summarize available data on cord blood concentrations of iron status parameters as surrogate reference ranges for preterm infants until term-equivalent age. Methods: Review of the literature searching PubMed for cord blood values of hemoglobin, mean corpuscular volume, ferritin, soluble transferrin receptor, ferritin index, transferrin saturation, reticulocyte hemoglobin content, zinc protoporphyrin/heme ratio, and hepcidin and comparison with reference ranges established for adults. Results: Gestational age-specific cord blood concentration ranges at term were computed as weighted mean for hemoglobin [15.9 g/dl (13.3-18.4)], mean corpuscular volume [108.1 fl (97.8-118.5)] and transferrin saturation [61.2% (31.5-90.9)] and listed for ferritin, soluble transferrin receptor, ferritin index, zinc protoporphyrin/heme ratio, reticulocyte hemoglobin content and hepcidin. These surrogate reference ranges were markedly different from adult values. Conclusion: Reference ranges of iron status parameters established for adults are probably not suitable to define iron status in preterm infants. If iron supplementation in preterm infants should be individually adjusted based on iron status parameters, it may be necessary to aim for cord blood concentration ranges to enable optimal growth and development.

Gestational Age-Specific Reference Ranges of Hepcidin in Cord Blood

Background: Iron deficiency (ID) contributes to anaemia of prematurity, and hence the reliable assessment of iron nutrition status appears to be mandatory. Objective: To establish gestational age (GA)-specific reference ranges for hepcidin concentrations in cord blood [Hep(CB)] of preterm and term infants and to identify pre- and perinatal confounding factors. Methods: This is a prospective observational study including 221 infants (GA at birth: 24-42 weeks). Hep(CB) along with complete blood counts, ferritin and parameters of inflammation and clinical data were recorded. Data are presented as medians (IQR). Results: The Hep(CB) of very preterm infants (GA <30 weeks, n = 40) was 26.9 ng/ml (13.5-63.1), for moderately preterm infants (GA 30-36 weeks, n = 81) it was 45.9 ng/ml (24.7-74.5) and for term infants (GA ≥37 weeks, n = 100) it was 103.9 ng/ml (61.4-149.2). The Hep(CB) of infants with ID was lower [36.9 ng/ml (18.0-58.3)] than that of iron-replete infants [86.6 ng/ml (51.9-143.8)]. The Hep(CB) of infants delivered by elective caesarean section was lower [38.3 ng/ml (15.5-73.7)] than that of infants after spontaneous vaginal delivery or secondary caesarean section [80.3 ng/ml (48.5-137.6)]. Infants with a standard deviation score for birth weight (SDSBW) <-2 had a lower Hep(CB) [23.1 ng/ml (11.7-61.5)] compared to infants with SDSBW ≥-2 [71.1 ng/ml (34.0-121.7)]. The highest Hep(CB) (437.6 ng/ml) was recorded in an infant with Enterococcus faecalis sepsis. Multiple logistic regression analysis confirmed ferritin, GA and mode of delivery as important factors associated with Hep(CB). Conclusion: This is the first report on GA-specific reference ranges for Hep(CB) in preterm infants. Whereas iron stores, GA and mode of delivery were associated with Hep(CB), the association with inflammation and intra-uterine growth retardation was less clear.

Physical stimulation of newborn infants in the delivery room

Objective Neonatal resuscitation guidelines recommend that newborn infants are stimulated to assist with the establishment of regular respirations. The mode, site of application and frequency of stimulations are not stipulated in these guidelines. The effectiveness of stimulation in improving neonatal transition outcomes is poorly described. Methods We conducted a retrospective review of video recordings of neonatal resuscitation at a tertiary perinatal centre. Four different types of stimulation (drying, chest rub, back rub and foot flick) were defined a priori and the frequency and infant response were documented. Results A total of 120 video recordings were reviewed. Seventy-five (63%) infants received at least one episode of stimulation and 70 (58%) infants were stimulated within the first minute after birth. Stimulation was less commonly provided to infants <30u2009weeks’ gestation (median (IQR) number of stimulations: 0 (0–1)) than infants born ≥30u2009weeks’ gestation (1 (1–3); p<0.001). The most common response to stimulation was limb movement followed by infant cry and facial grimace. Truncal stimulation (drying, chest rub, back rub) was associated with more crying and movement than foot flicks. Conclusion Less mature infants are stimulated less frequently compared with more mature infants and many very preterm infants do not receive any stimulation. Most infants were stimulated within the first minute as recommended in resuscitation guidelines. Rubbing the trunk may be most effective but this needs to be confirmed in prospective studies.

Prevention of bronchopulmonary dysplasia in extremely low gestational age neonates: current evidence

Bronchopulmonary dysplasia (BPD) is one of the most frequent complications in extremely low gestational age neonates, but has remained largely unchanged in rate. We reviewed data on BPD prevention focusing on recent meta-analyses. Interventions with proven effectiveness in reducing BPD include the primary use of non-invasive respiratory support, the application of surfactant without endotracheal ventilation and the use of volume-targeted ventilation in infants requiring endotracheal intubation. Following extubation, synchronised nasal ventilation is more effective than continuous positive airway pressure in reducing BPD. Pharmacologically, commencing caffeine citrate on postnatal day 1 or 2 seems more effective than a later start. Applying intramuscular vitamin A for the first 4 weeks reduces BPD, but is expensive and painful and thus not widely used. Low-dose hydrocortisone for the first 10 days prevents BPD, but was associated with almost twice as many cases of late-onset sepsis in infants born at 24–25 weeks’ gestation. Inhaled corticosteroids, despite reducing BPD, were associated with a higher mortality rate. Administering dexamethasone to infants still requiring mechanical ventilation around postnatal weeks 2–3 may represent the best trade-off between restricting steroids to infants at risk of BPD while still affording high efficacy. Finally, identifying infants colonised with ureaplasma and treating those requiring intubation and mechanical ventilation with azithromycin is another promising approach to BPD prevention. Further interventions yet only backed by cohort studies include exclusive breastmilk feeding and a better prevention of nosocomial infections.

Lung ultrasound during the initiation of breathing in healthy term and late preterm infants immediately after birth, a prospective, observational study

INTRODUCTIONnLung ultrasound (LUS) has shown promise for evaluation of newborns with respiratory distress. However, no study has described the appearance of LUS during the initiation of breathing. We used LUS to describe the appearance of the lungs in healthy infants immediately after birth, starting with the infants first breath, through the first 20min after birth.nnnMETHODSnThis was a single-center observational study enrolling neonates born at ≥35 weeks. We obtained LUS video recordings with the initiation of breathing. Recordings that captured one of the 1st four breaths after birth were included. We also obtained recordings at 1-10 and 11-20min after birth. Recordings were graded using a modified version of a previously published system, with additional grades to describe the appearance of the lungs prior to establishment of the pleural line.nnnRESULTSnWe studied 63 infants, mean gestational age=391/7±2 days, mean weight=3473g±422, 33 infants were delivered vaginally and 30 via cesarean section. We captured the first breath after birth in 28 infants and within the first four breaths from the remaining 35 infants. The pleural line was established by a median of 4 breaths (3-6). At the 1-10min examination, all infants had an established pleural line and 89% demonstrated substantial liquid clearance. At the 11-20min examination, all infants had substantial liquid clearance.nnnCONCLUSIONnEstablishment of the pleural line, indicating lung aeration and substantial liquid clearance is achieved with the first few breaths after birth in term and near term infants.

Reference Ranges of Reticulocyte Haemoglobin Content in Preterm and Term Infants: A Retrospective Analysis

Background: Despite iron supplementation, some preterm infants develop iron deficiency (ID). The optimal iron status parameter for early detection of ID has yet to be determined. Objective: To establish reference ranges for reticulocyte haemoglobin content (Ret-He) in preterm and term infants and to identify confounding factors. Methods: Retrospective analyses of Ret-He and complete blood count in infants with a clinically indicated blood sample obtained within 24 h after birth. Results: Mean (SD) Ret-He was 30.7 (3.0) pg in very preterm infants with a gestational age (GA) of <30 weeks (n = 55), 31.2 (2.6) pg in moderately preterm infants (GA 30-36 weeks, n = 241) and 32.0 (3.2) pg in term infants (GA ≥37 weeks, n = 216). The 2.5th percentile of Ret-He across all GA groups was 25 pg, with a weak correlation between Ret-He and GA (r = 0.18). Moreover, only weak/no correlations were found between Ret-He and C-reactive protein (r = 0.18), interleukin 6 (IL-6) (r = 0.03) and umbilical artery pH (r = -0.07). There was a slight variation in Ret-He with mode of delivery [normal vaginal delivery: 32.3 (3.2) pg, secondary caesarean section (CS): 31.4 (3.0) pg, instrumental delivery: 31.3 (2.7) pg and elective CS: 31.2 (2.8) pg]. Conclusion: GA at birth has a negligible impact on Ret-He, and the lower limit of the normal reference range in newborns within 24 h after birth can be set to 25 pg. Moreover, Ret-He seems to be a robust parameter which is not influenced by perinatal factors within the first 24 h after birth.

Skin-to-skin care in preterm infants receiving respiratory support does not lead to physiological instability.

Objective Providing skin-to-skin care (SSC) to preterm infants is standard practice in many neonatal intensive care units. There are conflicting reports on the stability of oxygen saturation (SpO2) during SSC, which may create a barrier to a wider implementation of SSC to infants receiving respiratory support. Regional cerebral oxygenation (rcO2) measured using near-infrared spectroscopy can serve as a surrogate parameter for cerebral oxygen delivery and consumption. We hypothesised that rcO2 during SSC would be similar to standard care in preterm infants receiving respiratory support. Design Prospective observational non-inferiority study. Setting Single tertiary perinatal centre in Australia. Patients Forty preterm infants (median (IQR) of 27.6 (26.0–28.9) weeks gestation) receiving respiratory support were studied on day 8 (5–18). Interventions Ninety minutes of SSC, with infants in incubators acting as their own control. Parents and caregivers were blinded to the measurements. Main outcome measures Mean difference in rcO2 between SSC and incubator care; as well as heart rate (HR), SpO2, fraction of inspired oxygen (FiO2) and temperature, were compared using a paired t-test. Results rcO2 was similar during SSC (mean (SD) 74.9 (6.5)%)% compared with incubator care (74.7 (6.1)%, mean difference (95% CI) 0.2 (−0.8 to 1.1)%, p=0.71). No clinically important differences in HR, SpO2, FiO2 or temperature were observed in the whole cohort and by mode of respiratory support (endotracheal tube mechanical ventilation, continuous positive airway pressure and high-flow nasal cannulae). Conclusions Cerebral oxygenation and other physiological measurements in ventilated preterm infants did not differ between SSC and incubator care. Trial registration number 12615000959572.

Lung ultrasound immediately after birth to describe normal neonatal transition: an observational study

Objective Lung ultrasound (LUS) has shown promise as a diagnostic tool for the evaluation of the newborn with respiratory distress. No study has described LUS during ‘normal’ transition. Our goal was to characterise the appearance of serial LUS in healthy newborns from the first minutes after birth until airway liquid clearance is achieved. Study design Prospective observational study. Setting Single-centre tertiary perinatal centre in Australia. Patients Of 115 infants born at ≥35 weeks gestational age, mean (SD) gestational age of 386/7 weeks±11u2009days, mean birth weight of 3380±555u2009g, 51 were delivered vaginally, 14 via caesarean section (CS) after labour and 50 infants via elective CS. Interventions We obtained serial LUS videos via the right and left axillae at 1–10u2009min, 11–20u2009min and 1, 2, 4 and 24u2009hours after birth. Main outcome measures LUS videos were graded for aeration and liquid clearance according to a previously validated system. Results We analysed 1168 LUS video recordings. As assessed by LUS, lung aeration and airway liquid clearance occurred quickly. All infants had an established pleural line at the first examination (median=2 (1–4)u2009min). Only 14% of infants had substantial liquid retention at 10u2009min after birth. 49%, 78% and 100% of infants had completed airway liquid clearance at 2, 4 and 24u2009hours, respectively. Conclusions In healthy transitioning newborn infants, lung aeration and partial liquid clearance are achieved on the first minutes after birth with complete liquid clearance typically achieved within the first 4u2009hours of birth. Trial registration number ANZCT 12615000380594.

Short-Term Effects of Blood Transfusions on Hepcidin in Preterm Infants

Background: Hepcidin, a key regulatory peptide hormone in iron homeostasis, may in future serve as a non-invasive iron status parameter for monitoring iron supplementation in preterm infants. For this, coexisting influencing factors should be taken into account. Objectives: To evaluate the short-term effects of red blood cell (RBC) transfusions on hepcidin concentrations in serum (HepS) and urine (HepU) of preterm infants. Methods: This was a prospective, observational study conducted between May 2009 and September 2010 at a single neonatal unit (Tübingen University Hospital, Tübingen, Germany) in very preterm infants, i.e. with a gestational age (GA) of <32 weeks, who received clinically indicated RBC transfusions. The concentration of the mature, 25 amino-acid form of hepcidin was determined in serum und urine by competitive enzyme-linked immunosorbent assay together with cellular indices before and after transfusion. Results: Twenty preterm infants born at a median GA of 26 + 0/7 (interquartile range: 24 + 6/7 to 27 + 3/7) weeks received 27 RBC transfusions at a median corrected age of 31 + 3/7 (29 + 6/7 to 34 + 5/7) weeks. When measured shortly after transfusion (mean time: 10 h), haematocrit values increased from a mean of 26.6% (SD 2.8) to 40.9% (SD 3.2); p < 0.0001. HepS also increased [geometric mean: 44.3 (95% confidence interval 30.8-63.8) ng/ml vs. 58.0 (35.7-94.3) ng/ml; p < 0.05] but HepU remained unaffected. Conclusion: The data indicate that HepS concentrations increase shortly after RBC transfusion in preterm infants. Long-term observational studies are needed to understand the dynamics of hepcidin regulation in preterm infants.

Reticulocyte Haemoglobin Content Declines More Markedly in Preterm than in Term Infants in the First Days after Birth.

Background: Reticulocyte haemoglobin content, i.e., the reticulocyte equivalent (Ret-He), seems to be a promising parameter for the detection of iron deficiency (ID) in neonates because it can be obtained as part of a reticulocyte count, with no additional blood loss and at no extra cost. Due to the short life span of reticulocytes, Ret-He reflects current iron availability for erythropoiesis more accurately than other common erythrocyte indices. Objective: We aimed to evaluate postnatal changes in Ret-He within the first days after birth in term and preterm infants with the hypothesis that preterm infants experience a more pronounced postnatal reduction in Ret-He when compared to term infants. Methods: We conducted retrospective analyses of clinically indicated blood samples. Paired t test and mixed regression modelling were used. Results: In total, 805 blood samples obtained from 207 term and 295 preterm infants were analysed. Ret-He decreased by 1.5 pg per day (regression coefficient [95% CI] -1.5 [-1.8 to -1.2] pg, p < 0.0001). This drop was more significant in preterm infants (regression coefficient -2.2 [-2.6 to -1.8] pg, p < 0.0001) than in term infants (regression coefficient -0.8 [-1.3 to -0.2] pg, p < 0.01, pinteraction < 0.0001). Conclusion: Ret-He declined within the first days after birth. The observed changes with postnatal age were more pronounced in preterm than in term infants. Further studies are needed to evaluate if these changes are due to developing ID or other causes.