Impact of preterm birth on kidney health and development.

Preterm birth, defined as birth before the gestational age of 37 weeks, affects 11% of the newborns worldwide. While extensive research has focused on the immediate complications associated with prematurity, emerging evidence suggests a link between prematurity and the development of kidney disease later in life. It has been demonstrated that the normal course of kidney development is interrupted in infants born prematurely, causing an overall decrease in functional nephrons. Yet, the pathogenesis leading to the alterations in kidney development and the subsequent pathophysiological consequences causing kidney disease on the long-term are incompletely understood. In the present review, we discuss the current knowledge on nephrogenesis and how this process is affected in prematurity. We further discuss the epidemiological evidence and experimental data demonstrating the increased risk of kidney disease in these individuals and highlight important knowledge gaps. Importantly, understanding the intricate interplay between prematurity, abnormal kidney development, and the long-term risk of kidney disease is crucial for implementing effective preventive and therapeutic strategies.

Expression of intestinal drug transporter proteins and metabolic enzymes in neonatal and pediatric patients.

The development of pediatric oral drugs is hampered by a lack of predictive simulation tools. These tools, in turn, require data on the physiological variables that influence oral drug absorption, including the expression of drug transporter proteins (DTPs) and drug-metabolizing enzymes (DMEs) in the intestinal tract. The expression of hepatic DTPs and DMEs shows age-related changes, but there are few data on protein levels in the intestine of children. In this study, tissue was collected from different regions of the small and large intestine from neonates (i.e., surgically removed tissue) and from pediatric patients (i.e., gastroscopic duodenal biopsies). The protein expression of clinically relevant DTPs and DMEs was determined using a targeted mass spectrometry approach. The regional distribution of DTPs and DMEs was similar to adults. Most DTPs, with the exception of MRP3, MCT1, and OCT3, and all DMEs showed the highest protein expression in the proximal small intestine. Several proteins (i.e., P-gp, ASBT, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and UGT1A1) showed an increase with age. Such increase appeared to be even more pronounced for DMEs. This exploratory study highlights the developmental changes in DTPs and DMEs in the intestinal tract of the pediatric population. Additional evaluation of protein function in this population would elucidate the implications of the presented changes in protein expression on absorption of orally administered drugs in neonates and pediatric patients.

What Mothers Know about Newborn Bloodspot Screening and the Sources They Use to Acquire This Knowledge: A Pilot Study in Flanders.

To learn what mothers know about newborn bloodspot screening (NBS), the procedure, and the sources used, a pilot study was performed. An online questionnaire was developed, with the first part focused on characteristics and the NBS procedure, and the second on knowledge, information sources, and health care providers (HCPs). This questionnaire was accessible until 200 answers were received. The characteristics of respondents were representative for the population. Mothers gave verbal consent in 69.5% of cases, 12.5% did not, and 18% stated that no consent was requested. The 'knowledge' part contained 12 closed questions, five multiple-choice questions on sources, and assessments (5-point Likert scores) of the information transfer. The mean knowledge level was 7.2/12. Screening concepts (consequences, likelihood, sensitivity, carrier) and absence of notification of normal findings were well known. The fact that NBS is not compulsory was poorly known, and post-analysis sample handling procedures were poorly understood. Key HCPs were midwifes (80.5%) and nurses (38.5%). When the leaflet (44%) was provided, the majority read it. Mean Likert scores were 3.36, 3.38, 3.11 and 3.35 for clarity, timing appropriateness, sufficiency, and usefulness. The knowledge level and consent practices were reasonably good. Key HCP were midwives and nurses, the leaflets were supporting. This should enable a quality improvement program to a sustainable NBS program in Flanders.

Characterization of neonatal and infant enterostomy fluids - part II: Drug solubility.

Previous research revealed marked differences in the composition of intestinal fluids between infants and adults. To explore the impact on the solubilization of orally administered drugs, the present study assessed the solubility of five poorly water-soluble, lipophilic drugs in intestinal fluid pools from 19 infant enterostomy patients (infant HIF). For some but not all drugs, the average solubilizing capacity of infant HIF was similar to that of HIF obtained from adults (adult HIF) in fed conditions. Commonly used fed state simulated intestinal fluids (FeSSIF(-V2)) predicted fairly well drug solubility in the aqueous fraction of infant HIF, but did not account for the substantial solubilization by the lipid phase of infant HIF. Despite similarities in the average solubilities of some drugs in infant HIF and adult HIF or SIF, the underlying solubilization mechanisms likely differ, considering important compositional differences (e.g., low bile salt levels). Finally, the huge variability in composition of infant HIF pools resulted in a highly variable solubilizing capacity, potentially causing variations in drug bioavailability. The current study warrants future research focusing on (i) understanding the mechanisms underlying drug solubilization in infant HIF and (ii) evaluating the sensitivity of oral drug products to interpatient variations in drug solubilization.

Characterization of neonatal and infant enterostomy fluids.

The composition of gastrointestinal (GI) fluids is crucial for the dissolution, solubilization, and absorption of orally administered drugs. Disease- or age-related changes in GI fluid composition could significantly affect the pharmacokinetics of oral drugs. However, limited studies have been conducted on the characteristics of GI fluids in neonates and infants due to practical and ethical challenges. The current study collected enterostomy fluids from 21 neonate and infant patients over an extended period of time and from different regions of the small intestine and colon. The fluids were characterized for pH, buffer capacity, osmolality, total protein, bile salts, phospholipids, cholesterol, and lipid digestion products. The study found a large variability in the fluid characteristics among the different patients, in line with the highly heterogeneous study population. Compared to adult intestinal fluids, the enterostomy fluids from neonates and infants had low bile salt concentrations, with an increasing trend as a function of age; no secondary bile salts were detected. In contrast, total protein and lipid concentrations were relatively high, even in the distal small intestine. These findings suggest marked differences in intestinal fluid composition between neonates and infants versus adults, which may affect the absorption of certain drugs.

Characterizing Esophageal Motility in Neonatal Intensive Care Unit Patients Using High Resolution Manometry.

OBJECTIVE: To characterize esophageal motility and esophago-gastric junction (EGJ) function during feeding in neonatal intensive care unit (NICU) patients. PATIENTS AND METHODS: High resolution manometry with impedance (HRIM) was used to investigate esophageal motility and EGJ function in patients admitted to the NICU. Twenty-eight preterm born infants with bronchopulmonary dysplasia (BPD), 12 born with isolated congenital diaphragmatic hernia (iCDH), and 10 with esophageal atresia (EA) were included. Thirteen healthy infants were included as controls. Esophageal motility and EGJ function were analyzed using objective esophageal bolus transport parameters. RESULTS: Normal esophageal peristaltic wave patterns were observed in all investigated infants without EA. Nine of 10 patients with EA presented with abnormal esophageal motor wave patterns. A total of 224 nutritive swallows were analyzed (controls, n = 48; BPD, n = 96; iCDH, n = 60; EA, n = 20). Infants with BPD and iCDH had similar distal contractile strength (DCI) compared to healthy controls, while in patients with EA, DCI was significantly lower (Kruskal-Wallis test, p = 0.001). In most infants, EGJ relaxation after swallowing was unaffected. EGJ barrier function, in terms of EGJ-contractile integral, also appeared well-developed and did not differ significantly among patient groups. CONCLUSIONS: We conclude that esophageal motility studies using pressure-impedance analysis are feasible in young infants. Bolus transport mechanisms following nutritive swallows appeared well-established in all investigated infants with the exception of those with EA. EGJ relaxation was also functional after deglutition and EGJ function as an anti-reflux barrier appeared well-developed in all investigated NICU groups.

Belgian Consensus Recommendations to Prevent Vitamin K Deficiency Bleeding in the Term and Preterm Infant.

Neonatal vitamin K prophylaxis is essential to prevent vitamin K deficiency bleeding (VKDB) with a clear benefit compared to placebo. Various routes (intramuscular (IM), oral, intravenous (IV)) and dosing regimens were explored. A literature review was conducted to compare vitamin K regimens on VKDB incidence. Simultaneously, information on practices was collected from Belgian pediatric and neonatal departments. Based on the review and these practices, a consensus was developed and voted on by all co-authors and heads of pediatric departments. Today, practices vary. In line with literature, the advised prophylactic regimen is 1 or 2 mg IM vitamin K once at birth. In the case of parental refusal, healthcare providers should inform parents of the slightly inferior alternative (2 mg oral vitamin K at birth, followed by 1 or 2 mg oral weekly for 3 months when breastfed). We recommend 1 mg IM in preterm <32 weeks, and the same alternative in the case of parental refusal. When IM is perceived impossible in preterm <32 weeks, 0.5 mg IV once is recommended, with a single additional IM 1 mg dose when IV lipids are discontinued. This recommendation is a step towards harmonizing vitamin K prophylaxis in all newborns.

Parental perspectives long term after neonatal clinical trial participation: a survey.

BACKGROUND: Although recruiting newborns is ethically challenging, clinical trials remain essential to improve neonatal care. There is a lack of empirical data on the parental perspectives following participation of their neonate in a clinical trial, especially at long term. The objective of this study is to assess experiences and emotions of parents, long term after trial participation in an interventional drug trial. METHODS: Parents of former participants of five neonatal interventional drug trials were surveyed at long term (3-13 years ago) after participation. The survey assessed parental contentment with trial participation, perceived influence of the trial on care and health, emotional consequences of participation, and awareness of typical clinical trial characteristics on 6-point Likert scales. RESULTS: Complete responses were received from 123 parents (52% of involved families). Twenty percent of parents did not remember participation. Those who remembered participation reported high contentment with overall trial participation (median 5.00), but not with follow-up (median 3.00). Most parents did not perceive any influence of the trial on care (median 2.00) and health (median 2.43). Almost all parents reported satisfaction and pride (median 4.40), while a minority of parents reported anxiety and stress (median 1.44) or guilt (median 1.33) related to trial participation. A relevant minority was unaware of typical trial characteristics (median 4.20; 27% being unaware). CONCLUSIONS: Overall, parents reported positive experiences and little emotional distress long term after participation. Future efforts to improve the practice of neonatal clinical trials should focus on ensuring effective communication about the concept and characteristics of a clinical trial during consent discussions and on the follow-up after the trial.

Characterization of esophageal motility and esophagogastric junction in preterm infants with bronchopulmonary dysplasia.

BACKGROUND: To characterize esophageal motility and function of the esophagogastric junction (EGJ) in preterm infants with bronchopulmonary dysplasia (BPD). METHODS: High-resolution manometry with impedance was used to investigate esophageal motility and EGJ function in 28 tube-fed preterm infants with BPD. Patients with BPD were studied at term age during oral feeding. Thirteen healthy term-aged infants were included as controls. Esophageal analysis derived objective measures to evaluate esophageal contractile vigor, bolus distension pressure, EGJ relaxation, and EGJ barrier function (in rest and during respiration). In addition, we investigated the effect of BPD severity on these measures. KEY RESULTS: A total of 140 nutritive swallows were analyzed (BPD, n = 92; controls, n = 48). Normal esophageal peristaltic wave patterns were observed in all infants. BPD patients had higher distal contractile esophageal strength compared with controls (Kruskal-Wallis (KW) P = .048), and their deglutitive EGJ relaxation was comparable to controls. Severe BPD patients showed higher bolus distension pressures, higher EGJ resting pressures, and increased EGJ contractile integrals compared with mild BPD patients (Mann-Whitney U P = .009, KW P = .012 and KW P = .028, respectively). CONCLUSIONS AND INFERENCES: Preterm infants with BPD consistently present with normal peristaltic esophageal patterns following nutritive liquid swallows. The EGJ barrier tone and relaxation pressure appeared normal. In general, infants with BPD do not have altered esophageal motor function. There is however evidence for increased flow resistance at the EGJ in severe BPD patients possibly related to an increased contractility of the diaphragm.

Maturation of Esophageal Motility and Esophagogastric Junction in Preterm Infants.

BACKGROUND: Preterm infants commonly present with oral feeding problems. The role of maturation of esophageal bolus transport mechanisms herein remains unclear. OBJECTIVES: To characterize esophageal motility and function of esophagogastric junction (EGJ) during deglutitive swallowing in healthy preterm infants and to describe maturational changes. METHODS: Four consecutive high-resolution manometry studies with impedance studies were performed weekly to investigate esophageal motility and EGJ function. Esophageal pressure topography and pressure-impedance metrics were derived. Mixed models with repeated measures were used for statistical analysis. RESULTS: We analyzed 137 nutritive swallows from 36 motility studies in 10 preterm infants. The mean gestational age was 30.17 ± 0.94 weeks; the mean postmenstrual age at time point 1 and 4 was 34.42 ± 0.86 and 37.45 ± 1.16 weeks, respectively. Esophageal peristaltic wave patterns in response to nutritive swallows were observed in all patients. At later time points, esophageal body peristalsis became more rapid, evidenced by a faster distal contractile velocity and shorter distal latency (p = 0.002 and p < 0.0001, respectively). In addition, 4-s integrated relaxation pressures increased and distal contractile integral decreased at later time points (p = 0.003 and p = 0.021, respectively). Bolus clearance also improved at later age (p = 0.008). CONCLUSIONS: Preterm infants demonstrate peristaltic esophageal motility following nutritive swallows. However, alterations in esophageal bolus transport in relation to peristalsis are demonstrated. Peristaltic progression becomes more rapid, while deglutitive relaxation pressures increase with increasing age. These maturational changes may suggest further development of the enteric nervous system after birth in former preterm neonates.

An interesting case of 'strange lines' a neonate with oesophageal atresia, tracheo-oesophageal fistula, situs inversus abdominalis and azygos continuation.

We describe the case of a term baby boy born via vaginal delivery at 39 weeks gestation with oesophageal atresia, tracheaoesophageal fistula, situs inversus abdominalis and azygos continuation. The azygos continuation was diagnosed after cardiac echo and confirmed on cardiac catherisation after an unexpected umbilical line position on thoracoabdominal X-ray. The baby underwent a right-sided thoracotomy on day 1 of life for repair of the oesophageal atresia. A double fistula, of both the proximal and distal segments, of the oesophagus with short segment stenosis was confirmed. The tracheo-oesophageal fistulae were ligated and divided and the oesophageal atresia repaired by primary anastomosis without complications. The azygos vein was not ligated.

Long-term outcomes of very low birth weight infants with spontaneous intestinal perforation: A retrospective case-matched cohort study.

BACKGROUND: Spontaneous intestinal perforation (SIP) is an intestinal complication that occurs in very ill preterms. We investigated whether SIP survivors have worse neurodevelopmental and gastrointestinal outcomes and a poorer quality of life than controls. METHODS: A retrospective case-matched cohort study was performed involving infants treated for SIP in a NICU between August 1994 and April 2014. Controls and SIP patients were matched to gestational age, gender, and birth period. Medical records were reviewed. Telephone surveys were conducted to evaluate the medical condition, quality of life (PedsQL™ 4.0), neuropsychiatric and gastrointestinal outcome. McNemar's and Wilcoxon tests were performed, and generalized linear models were computed. RESULTS: Forty-nine SIP patients were included. The percentages of children with multiple disabilities (40% vs. 17%, OR = 3.3) and requiring physiotherapy (86% vs. 60%, OR = 4.77) were higher in the SIP group than in the control group. Intraventricular hemorrhage (IVH) led to a worse neurodevelopmental outcome regardless of SIP (OR = 8.79 for disability), and female gender was a protective factor against disability (OR = 0.06). Reported quality of life and gastrointestinal comorbidities did not differ between the two groups. CONCLUSION: SIP survivors tend to be at risk of multiple disabilities. IVH and female gender influence the neurodevelopmental outcome regardless of SIP. LEVELS OF EVIDENCE: Level III: case-control study.

Characterization of Esophageal Motility in Infants With Congenital Diaphragmatic Hernia Using High-resolution Manometry.

OBJECTIVES: The aim of the study was to characterize esophageal motility and esophagogastric junction (EGJ) function in infants who underwent repair of an isolated congenital diaphragmatic hernia (iCDH). METHODS: High-resolution manometry with impedance was used to investigate esophageal motility and EGJ function after diaphragmatic repair in 12 infants with iCDH (11 left-sided; 9 patch repair). They had esophageal motility studies during neonatal admission (n = 12), at 6 months (n = 10) and at 12 months of life (n = 7). Swallows were analyzed using conventional esophageal pressure topography and pressure flow analysis and were compared with 11 healthy preterm born infants at near-term age. RESULTS: Esophageal peristaltic motor patterns in patients with iCDH were comparable to controls. EGJ end-expiratory pressure was higher in patients with patch repair compared with controls (P = 0.050) and those without patch (P = 0.009). The difference between inspiratory and expiratory pressures at the EGJ was lower in patients with iCDH with patch (P = 0.045) compared to patients without. Patients with iCDH with patch showed increased Pressure Flow Index, resistance of bolus flow at the EGJ, compared with controls (P = 0.043). CONCLUSIONS: Normal esophageal wave patterns are present in the investigated patients with iCDH. EGJ end-expiratory pressure seems lower in patients with iCDH without patch suggesting a decreased EGJ barrier function hence increased vulnerability to gastroesophageal reflux. Patch repair appears to increase end-expiratory pressure at the EGJ above that of controls suggesting that patch surgery tightens the EGJ, thereby increasing flow resistance. This is in line with the increased Pressure Flow Index. In infants with a patch, the inspiration-expiration pressure difference is lower, reflecting diminished activity of the crural diaphragm.

Neonatal factors predictive for respiratory and gastro-intestinal morbidity after esophageal atresia repair.

BACKGROUND: Esophageal atresia is a major congenital foregut anomaly. Affected patients often suffer from respiratory and gastro-intestinal morbidity. The objective of this study is to identify possible neonatal predictive factors contributing to a long-term complicated clinical course in patients after repair of esophageal atresia. METHODS: A total of 93 patients born between 1993 and 2013, with esophageal atresia and surviving the neonatal period were included in this retrospective study. A complicated clinical course was defined as the occurrence of ≥1 of these complications: severe gastro-esophageal reflux, esophageal stricture requiring dilatations, need for tube feeding for >100 days, severe tracheomalacia, severe chronic respiratory disease and death. We used linear models with a binomial distribution to determine risk factors for gastro-intestinal or respiratory complicated evolution and a backward stepwise elimination procedure to reduce models until only significant variables remained in the model. Multinomial logistic regression was used to assess risk factors for different evolutions of complication. Model parameter estimates were used to calculate odds ratios for significant risk factors. RESULTS: Fifty-seven patients (61%) had a complicated clinical course in the first year of life and 47 (51%) had a complicated evolution during years 1-6. In the first year, prematurity was a significant factor for complicated gastro-intestinal (OR 2.84) and respiratory evolution (OR 2.93). After 1 year, gastro-intestinal morbidity in childhood was associated with VACTERL association (OR 12.2) and a complicated first year (OR 36.1). Respiratory morbidity was associated with congenital heart disease (OR 12.9) and a complicated first year (OR 86.9). Multinomial logistic regression showed that prematurity (p = 0.018) and VACTERL association (p = 0.003) were significant factors of complications. CONCLUSION: Prematurity is an important predictive factor for a complicated clinical course in early life. A complicated first year often predicts a complicated clinical course in childhood. These risk factors may be helpful in counseling of parents in the neonatal period.

Gastric fluid composition in a paediatric population: Age-dependent changes relevant for gastrointestinal drug disposition.

This work aimed to (i) expand the dataset on gastric fluid composition in the paediatric population (0-18 years old) and (ii) improve our understanding of age-dependent changes in gastric fluid characteristics involved in gastrointestinal drug disposition. For this purpose, gastric fluids from preterm neonates, term neonates, infants, children and adolescents were collected during routine medical procedures. Gastric fluid constituents relevant for gastrointestinal drug disposition were characterized i.e., pH, osmolality and bile salts (concentration + composition). Differences in gastric fluid composition compared to adults were most prominent in neonates. In this context, the fact that neonates are rarely fasted due to frequent feedings should be taken into account during paediatric drug product development. It remains to be explored to what extent the observed variability and differences in gastric fluid characteristics within and between age groups translates to variability and/or differences in oral drug disposition.

Earlier achievement of full enteral feeding in extremely low birth weight neonates is not associated with growth improvement in the first 2 years of life.

Limiting the number of days until achievement of full enteral feeding in extremely low birth weight neonates (ELBW; < 1000 g) might affect growth in the first years of life. This study compared the Z scores in growth over time of two cohorts of ELBW neonates that were comparable on maternal and neonatal characteristics and characteristics of hospitalization, but differed in enteral feeding strategy during neonatal admission. In the 2010-2014 cohort, full enteral feeding was achieved on average 16 days earlier than in the 2000-2005 cohort. In both cohorts, weight, height, and head circumference were recorded at birth and at the corrected ages of 9 and 24 months. A linear mixed model with repeated measures controlling for neonates small for gestational age showed no significant effect of different strategies in achievement of full enteral feeding on any anthropometric Z scores over time. Although full enteral feeding was achieved earlier in the 2010-2014 cohort, this was not associated with growth patterns during the first two years of life. CONCLUSION: The effect of a change in strategy to achieve full enteral feeding at an earlier stage in ELBW neonates was assessed. Early enteral feeding strategies do not necessarily improve growth during the first two years of life. What is Known: • Feeding strategies during neonatal stay may affect growth in the first years of life. • Strategies to achieve full enteral feeding earlier were implemented, but data on the impact on subsequent growth after discharge are limited. What is New: • Full enteral feeding was achieved earlier, but this was not associated with improved growth during the first 2 years of life after discharge. • Early enteral feeding strategies do not necessarily improve growth during the first 2 years of life.

Correction: Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence.

[This corrects the article DOI: 10.1371/journal.pone.0173349.].

Risk factors for spontaneous localized intestinal perforation in the preterm infant.

PURPOSE: The aim of this study was to investigate prenatal and postnatal risk factors for spontaneous intestinal perforation (SIP) in preterm infants. MATERIAL AND METHODS: Matched case-control study of 62 preterm infants (matching based on gender, gestational age and birth weight) who developed a SIP over a period of 20 years in a single NICU. Univariate and multivariate logistic regression analysis were performed. RESULTS: Prenatal risk factors were not significantly different between cases and controls. Patients exposed to surfactant and inotropic agents have an increased risk for SIP. No initiation of feeding before development of SIP and IVH ≥ grade 3 were also associated with an increased risk for SIP. In multivariate analysis inotropic agents, lack of initiation of feeding and IVH ≥ grade 3 remained significant risk factors (OR 5.58 (95% CI 1.14-27.22), 0.29 (95% CI 0.09-0.88), 15.2 (95% CI 1.09-211.55) respectively). CONCLUSIONS: The study found that patients with SIP are more likely to have been exposed to inotropic agents and to have developed IVH ≥ grade 3. They were also less likely to have been fed. These risk factors most likely reflect the severity of illness of preterm infants and an increased vulnerability for developing SIP.

Improvised Hand Injury Treatment Using Traditional Veterinary Medicine in Ethiopia.

In remote wilderness environments, local people with traditional knowledge of medicinal plants are potentially important first-line health care providers. We present a case of a 31-year-old man who fell off a horse while trekking through a remote mountain landscape in Ethiopia and sustained blunt force trauma to the hand. A local mountain hut keeper examined the patient's hand and used heated leaves of the succulent plant Kalanchoe petitiana to treat a suspected metacarpal fracture. As first responder in a low-resource setting, the hut keeper relied on his traditional knowledge of ethnoveterinary medicine to improvise a treatment for a human injury in a remote mountain environment. Although in this case the outcome of the traditional intervention was positive, our analysis shows that the massage component of the intervention could have led to complications. Conversely, reports from the use of related Kalanchoe species suggest that heated Kalanchoe leaves could be useful in the compression component of traditional care for hand injuries. Validation of traditional remedies and their therapeutic potential are needed if they are to complement wilderness wound care safely and reliably. The documentation and validation of these remedies are urgently needed, as many medicinal plants and indigenous knowledge of how to use these valuable natural resources are being lost.