Population Of Low Birthweight Infants Research Articles

Infections in the NICU: Neonatal sepsis

Neonatal infections remain an important cause of neonatal morbidity and mortality worldwide. Neonatal sepsis is a systemic infection that can be classified as early-onset or late-onset pending the timing of presentation. The pathophysiology and causative pathogens of neonatal sepsis vary, with early-onset sepsis being associated with a vertically transmitted infection from mother to neonate versus late onset sepsis being commonly associated with nosocomial infections. The signs and symptoms of neonatal sepsis mimic those associated with prematurity, making timely diagnosis difficult for treating clinicians. The management of neonatal sepsis is centered around obtaining adequate culture data and initiation of broad-spectrum parenteral antibiotics. Controversies surrounding the management of neonatal sepsis include the administration of empiric antibiotics, given recent clinical studies associating early antibiotic use with clinical sequelae such as late-onset sepsis, necrotizing enterocolitis, and death in the preterm, low-birthweight infant population.

Effect of Community-Initiated Kangaroo Mother Care on Fecal Biomarkers of Gut Function in Low Birth Weight Infants in North India: A Randomized Clinical Trial.

This individually randomized trial was conducted to estimate the effect of promoting community-initiated Kangaroo Mother Care (ciKMC) in low birth weight (LBW) infants on gut inflammation and permeability. Participants included 200 stable LBW infants (weighing 1,500-2,250 g) in North India enrolled between May and October 2017. The ciKMC intervention included promotion and support of continuous skin-to-skin contact and exclusive breastfeeding through home visits. The mothers in the intervention arm were supported to practice ciKMC until 28 days after birth, i.e., the neonatal period, or till the baby wriggled out of KMC position, if earlier. Infant stool specimens were collected during the first week of birth, and within 1 week after end of the neonatal period. Concentrations of fecal neopterin (nmol/L), myeloperoxidase (ng/mL), and alpha-1-antitrypsin (μg/mL) were determined using ELISA, and composite enteric enteropathy (EE) score at the end of the neonatal period was calculated by principal component analysis. We did not find any substantial difference in means between the ciKMC and control arm infants in the log-transformed values of neopterin (0.03; 95% CI -0.15 to 0.21), myeloperoxidase (0.28; 95% CI -0.05 to 0.61) and alpha-1-antitrypsin (0.02; 95% CI -0.30 to 0.34). The mean (SD) composite EE score was 13.6 (7.5) in the ciKMC and 12.4 (8.3) in the control arm infants, and the adjusted difference in means was, 0.4 (95% CI -1.8 to 2.7). Our findings suggest that the promotion of ciKMC did not affect gut inflammation and permeability in our target population of LBW infants in North India.

Role of probiotics VSL#3 in prevention of suspected sepsis in low birthweight infants in India: a randomised controlled trial

ObjectivesTo assess the effect of the probiotic VSL#3 in prevention of neonatal sepsis in low birthweight (LBW) infants.DesignRandomised, double-blind, placebo-controlled trial.SettingCommunity setting in rural India.ParticipantsLBW infants aged 3–7 days.InterventionsInfants were...

What is the Best Predictor of Mortality in a Very Low Birth Weight Infant Population with a High Mortality Rate in a Medical Setting with Limited Resources?

To determine the best predictor of mortality risk in very low birth weight (VLBW) infants in resource limited settings. The Clinical Risk Index for Babies (CRIB) II score and the simplified age-weight-sex (SAWS) score for all VLBW infants born during the period January 2005 to June 2006 at the University Hospital of the West Indies were retrospectively calculated. The respective ability of each score, birth weight, and calculated or assessed gestational age to predict mortality was quantified using the area under receiver operating curves. Fifty two (48%) males and 57 (52%) females were entered into the study, out of which 58 (53%) infants died. The CRIB II score was found to be a better predictor of mortality (p = 0.02) when compared with calculated gestational age but had similar predictive power when compared with assessed gestational age. The SAWS score was found to have equal predictive value of mortality (p = 0.1) as the CRIB II score, however it was a better predictor of mortality than calculated gestational age (p = 0.002) but had no predictive advantage over assessed gestational age. Birth weight however, proved to be the best predictor of mortality (p < 0.01) with an area under the curve of 0.91 (standard error 0.03; 95% confidence interval 0.85-0.96). In resource poor settings where mortality of VLBW infants is high there may be no benefit in the addition of other variables to birth weight in predicting outcome.

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal: Modeling the Neurovascular Niche

Premature infants have chronic hypoxia, resulting in cognitive and motor neurodevelopmental handicaps caused by suboptimal neural stem cell (NSC) repair/recovery in neurogenic zones (including the subventricular and the subgranular zones). Understanding the variable central nervous system repair response is crucial to identifying "at risk" infants and to increasing survival and clinical improvement of affected infants. Using mouse strains found to span the range of responsiveness to chronic hypoxia, we correlated differential NSC survival and self-renewal with differences in behavior. We found that C57BL/6 (C57) pups displayed increased hyperactivity after hypoxic insult; CD-1 NSCs exhibited increased hypoxia-induced factor 1alpha (HIF-1alpha) mRNA and protein, increased HIF-1alpha, and decreased prolyl hydroxylase domain 2 in nuclear fractions, which denotes increased transcription/translation and decreased degradation of HIF-1alpha. C57 NSCs exhibited blunted stromal-derived factor 1-induced migratory responsiveness, decreased matrix metalloproteinase-9 activity, and increased neuronal differentiation. Adult C57 mice exposed to hypoxia from P3 to P11 exhibited learning impairment and increased anxiety. These findings support the concept that behavioral differences between C57 and CD-1 mice are a consequence of differential responsiveness to hypoxic insult, leading to differences in HIF-1alpha signaling and resulting in lower NSC proliferative/migratory and higher apoptosis rates in C57 mice. Information gained from these studies will aid in design and effective use of preventive therapies in the very low birth weight infant population.

Extremely premature infant: overcoming inflammation and oxidative stress

Pediatric HealthVol. 2, No. 4 EditorialFree AccessExtremely premature infant: overcoming inflammation and oxidative stressMaximo Vento, Marta Aguar & María BrugadaMaximo Vento† Author for correspondenceHospital La Fe, Neonatal Research Unit, Division of Neonatology, Avenida de Campanar, 21 E46009, Valencia, Spain. ; Search for more papers by this authorEmail the corresponding author at maximo.vento@uv.esEmail the corresponding author at maximovento@telefonica.net, Marta AguarHospital La Fe, Neonatal Research Unit, Division of Neonatology, Avenida de Campanar, 21 E46009, Valencia, Spain. ; Search for more papers by this authorEmail the corresponding author at maximo.vento@uv.esEmail the corresponding author at maximovento@telefonica.netEmail the corresponding author at maraca@alumni.uv.es & María BrugadaHospital La Fe, Neonatal Research Unit, Division of Neonatology, Avenida de Campanar, 21 E46009, Valencia, Spain. ; Search for more papers by this authorEmail the corresponding author at maximo.vento@uv.esEmail the corresponding author at maximovento@telefonica.netEmail the corresponding author at mabrumon@hotmail.comPublished Online:15 Jul 2008https://doi.org/10.2217/17455111.2.4.397AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail In the last decade, survival of extremely premature infants (≤28 weeks of gestation) in the industrialized world has substantially increased; however, this achievement has been obscured by an increased morbidity [1]. Hence, recent data reveal that mortality in premature infants below 750 g has decreased approximately from 60 to 40% in the last 10 years, while morbidity increased from 20 to 30% [1–3]. It is worth noting that the number of babies that survived intact did not substantially change in this period of time. In spite of a significant generalization of antenatal care, administration of prenatal corticosteroids, antibiotics, elective cesarean section, improvement of technology in the neonatal intensive care units and severe conditions, such as chronic lung disease (CLD), intraperiventricular hemorrhage, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity (ROP) or severe growth failure, still burden a significant percentage of survivors [4]. Confronted with this situation, researchers of the National Institute of Child Health & Human Development Neonatal Research Network (USA) have suggested that improving survival without morbidity requires determining, disseminating and applying the best practices using therapies currently available, in addition to identifying new strategies and interventions [1].Interestingly, perinatal inflammation and oxidative stress have been identified as the most important contributing factors predisposing extremely low birthweight (ELBW) infants to develop CLD, ROP or intraperiventricular hemorrhage [5,6]. In fact, it has been demonstrated that over 80% of the fetal membranes of babies below 30 weeks of gestation had positive in situ hybridization for bacteria [7], and chorioamnionitis has been identified as the most common risk factor associated with extremely premature births [8]. In addition, Ureaplasma urealyticum and Mycoplasma hominis umbilical cord blood infections are far more common in spontaneous versus indicated preterm deliveries, and are strongly associated with markers of acute placental inflammation. Positive cultures are associated with neonatal systemic inflammatory response syndrome and probably CLD [9]. Interestingly enough, intrauterine inflammation elicits both local and systemic inflammatory responses by the fetus [10,11]; however, although this response appears to improve postnatal lung adaptation decreasing the severity of respiratory distress syndrome, it predisposes to structural alterations that will lead to CLD and neurologic injury [12–15]. In addition, it has been shown that intrauterine inflammation is characterized by neutrophil recruitment into the airspaces, and that mature neutrophils are a source of reactive oxygen species. Moreover, increasing evidence has shown that reactive oxygen species-mediated lung injury is involved in the development of CLD [16]. However, preterm babies do not exhibit sufficient antioxidant response, therefore, these babies are predisposed to oxidative stress and damage [17,18]. Factors concurring after birth, such as oxygen, airway distending pressure or infections, constitute the second impact, definitively amplifying local and systemic response leading to chronic disease [19,20].Animal studies have also suggested that inhaled nitric oxide (NO) reduces lung inflammation, improves surfactant function and promotes lung growth. Inhaled NO mediates distal VEGF-dependent angiogenesis [21]. However, oxidative stress caused by lung hyperoxia during mechanical ventilation would reduce the availability of NO to the distal airways owing to its great affinity towards the superoxide anion. In addition, the administration of low concentrations of inhaled NO would supply distal vessels and alveoli with sufficient NO to sustain lung growth and development [22].The implication of inflammation and oxidative stress in the pathogenesis of many of the most severe long-term conditions affecting ELBW infants has provoked the appearance of new ‘antisecond-hit strategies’, which aim to reduce both the causative factors. Interestingly enough, the use of antibiotics by the mother in order to prevent infection or inflammation in the offspring has rendered inefficacious; moreover, it has increased the number of newborns treated for suspected infections [23]. Seemingly, recent studies have shown beneficial effects of antimicrobial therapy to prevent CLD [24]. However, the use of azithromycin in a double-blind, randomized, placebo-controlled study in a population of babies weighing less than 1000 g 12 h within the initiation of mechanical ventilation and within 72 h of birth did not reduce the incidence of bronchopulmonary dysplasia (BPD), although it did reduce the need for postnatal corticosteroids [25]. In addition, the systematic review of the literature on the use of erythromycin to prevent CLD in intubated infants at risk for, or colonized or infected by U. urealyticum has rendered ineffective [26].Seemingly efficacious would be the proposal of reducing oxygen concentrations to initiate ventilation in the delivery room in order to avoid hyperoxemia and oxygen-derived damage [27,28]. Thus, using initial FiO2 of 30%, Escrig and coworkers were able to satisfactorily achieve targeted saturations of 85% at 10 min after birth; moreover, the use of higher FiO2 (90%) did not offer any advantages as to achieve target saturations or clinical stabilization [27]. In addition, the use of room air did not allow Wang et al. to achieve the targeted arterial oxygen saturation as measured by pulse oximetry (SpO2) at 3 min of life, and babies had to be switched to pure oxygen [28]. From these recent studies, it may be deduced that ELBW infants require supplemental oxygen to adequately perform fetal-to-neonatal transition; however, a low FiO2 of 30% may be sufficient, and will at least partially avoid the negative consequences of an excess of oxygen.The use of high tidal volumes, even for short periods of time, appears to be associated with lung inflammation and structural changes [29]. Apparently, the use of early continuous positive airway pressure (CPAP) would facilitate the achievement of a functional residual capacity, improve oxygenation, attenuate ventilation-derived trauma to the airways and increase surfactant efficiency [30]. Numerous observational studies have confirmed the feasibility of using early CPAP in the delivery room, however, it was not investigated until very recently whether nasal CPAP rather than intubation shortly after birth would reduce the rate of BPD [31].In a very recent prospective, multicenter trial, extremely premature infants were randomly assigned to nasal CPAP or intubation after initial stabilization in the delivery room, and the outcomes (death or BPD) were assessed at 28 days, at 36 weeks or at discharge. The authors concluded that early nasal CPAP did not alter the rate of death or BPD; however, it decreased the need for supplementary oxygen at 28 days of age and the days of mechanical ventilation, although it increased the rate of pneumothorax but without resulting in negative consequences [32].Noninvasive ventilation (NIV), a term applied to a variety of devices capable of supporting neonatal ventilation, is receiving increasing attention as a means to reducing damage often incurred with mechanical ventilation. NIV essentially consists of positive pressure applied across the respiratory cycle combined with periods of increased airway pressure. Intermittent increases in airway pressure (breaths) may be delivered at regular intervals (nonsynchronized) or synchronized with infant inspiratory efforts. The majority of systems currently available feature some type of synchronization; synchronized noninvasive positive pressure ventilation has also received the most attention in clinical trials [33]. It is worth noting that the application of NIV results in a number of physiologic benefits, including stabilization of the airways, diaphragm and chest wall, increased lung volumes, reduced obstructive apnea, decreased airway resistance and work of breathing [34]. Clinical results in a number of trials have provided support for the use of NIV in order to avoid the need of mechanical ventilation in the ELBW infant, with the ultimate aim to reduce CLD [35]. In addition, lung protective strategies in preterm babies requiring mechanical ventilation after initial resuscitation have also been evaluated. Hence, the use of low tidal volumes combined with positive end-expiratory pressure and recruitment maneuvers to reopen already collapsed alveoli (open-lung strategy) have been combined to reduce ventilation-induced lung injury [36]. However, randomized clinical trials investigating lung-protective ventilation in neonates have mainly focused on comparing high-frequency ventilation with conventional mechanical ventilation. Most of these studies demonstrate weaknesses in the design, which may explain the inconsistent effect of high-frequency ventilation on BPD. Studies carried out on conventional mechanical ventilation only focused on comparing various modes and settings, leaving the important question of whether reducing tidal volume or increasing positive end-expiratory pressure protects the lungs in newborn infants unanswered [36]. Therefore, further studies will be needed to assess the influence of proposed lung-protective strategies on the development of CLD.In summary, two main pathogenic factors – inflammation and oxidative stress – influence the outcome of ELBW infants. Both of these factors act as a second hit upon prenatally inflammated organs, causing severe postnatal complications such as CLD, intraperiventricular hemorrhage, ROP, and so on. In recent years, antisecond-hit strategies, such as preventive anti-infectious therapy, inhaled NO, limiting oxygen supplementation at birth, the use of low-range SpO2 limits or use of NIV, have been employed. Some of these therapies seem promising; however, further studies and a more profound knowledge of the pathophysiologic mechanisms are needed in order to successfully avoid long-term morbidity in the ELBW infants.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Fanaroff AA, Stoll BJ, Wright LL et al.: NICHD Neonatal Research Network: trends in neonatal morbidity and mortality for very low birth weight infants. Am. J. Obstet. 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Fetal Neonatal Med.13,24–29 (2008).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 2, No. 4 Follow us on social media for the latest updates Metrics Downloaded 522 times History Published online 15 July 2008 Published in print August 2008 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Fetal Programming of Adult Kidney Disease

The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW). A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed. Definition of LBW LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1). Association between LBW and Adult Disease The size that the fetus can attain depends on the maternal–fetal nutrient supply and the space that the maternal environment can provide (5). Low maternal socioeconomic status and poor maternal nutritional status will reduce nutrient supply to the developing fetus. Similarly, factors that frustrate the passage of nutrients through the placenta, such as smoking and hypertension, are associated with increased risk for LBW. Factors that affect intrauterine space availability, such as primiparity, low maternal height, and mothers who were born SGA, are additional risk factors for LBW. Nearly two decades ago, Barker (6) presented the theory of the fetal origins of adult diseases. The theory is based on observed epidemiologic associations between LBW and increased risk for ischemic heart disease, type 2 diabetes, and hypertension (7–9). The first associations found were between LBW and later life hypertension and cardiovascular disease (7,10,11). High BP was found to occur at a higher incidence in children and adults who were of LBW (11). A systematic review of 80 studies that described the relationship of BP with birth weight reported that systolic BP was lower by approximately 2 mmHg for every 1-kg increase in birth weight (12). Among Pima Indians, patients who had type 2 diabetes and a history of LBW also displayed an increased risk for developing diabetic nephropathy (13). Moreover, LBW is associated with more rapid progression of other kidney diseases, such as IgA nephropathy, membranous nephropathy, and minimal-change disease, suggesting that the kidneys of LBW infants are more vulnerable to future insults (14–16). Nevertheless, the strength of association between birth weight and subsequent hypertension remains widely debated. Several studies did not find an association (17,18). Moreover, others claim that the suggested association is the result of inadequate or inappropriate adjustments for confounding factors (19,20). For example, Huxley et al. (19) found a trend toward a weaker association between LBW and hypertension in larger compared with smaller studies. However, it seems that although the relation is not invariant, the totality of evidence does suggest an important direct or indirect interaction between birth weight and subsequent hypertension (21). These observations have led to the formulation of an important conceptual construct that pertains to the fetal origins of adult disease. This theory states that during development, body organs pass through a period of plasticity and sensitivity to the environment, which leaves a durable imprint that affects subsequent health. Suboptimal intrauterine conditions may result in impaired fetal growth and the production of phenotypes that are better matched to the inadequate intrauterine environment. These adaptive processes are aimed to increase the likelihood of survival in utero and after birth, with expected continuation of borderline or inadequate environmental conditions. However, this response may result in adverse long-term consequences later in life (e.g., hypertension, renal disease, glucose intolerance), especially when the postnatal environment affords more favorable growth conditions to those that were experienced in utero. One of the most studied aspects with regard to Barker’s theory has been the fetal origins of adult diabetes. Numerous reports have demonstrated an association between LBW and subsequent development of pancreatic endocrine insufficiency and type 2 diabetes in experimental animals and humans (9,22–28). Of particular notice is the role of rapid weight gain in early childhood, or “catch-up” growth, which was shown to encompass a significant risk for subsequent metabolic derangements in adult life (29–32). Type 2 diabetes has now emerged as the leading cause of kidney disease in the world. Accordingly, it is important to consider the relation between LBW and type 2 diabetes as a cause of CKD. However, a detailed consideration of the relationship between LBW and type 2 diabetes is beyond the scope of this review. LBW and LNN Beyond the connection with type 2 diabetes and hence diabetic nephropathy, the contribution of various additional factors has been invoked to explain the apparent greater risk and more rapid progression of adult kidney disease and the higher incidence of hypertension as a result of LBW. Among these, the major focus of attention has been on the role of LNN (33,34). LBW has been associated with LNN in human and animal studies. The induction of IUGR by restriction of protein in the diet resulted in reduced nephron number and impaired renal function in rats (35,36). Nephron number and GFR were significantly lower, even after correction for body weight, in piglets with IUGR compared with those with normal weight (37). Reduced nephron number has been achieved using other experimental models of LBW, such as calorie restriction and partial ligation of the uterine artery (38–41). Reduced glomerular number and function were found in spontaneous LBW as well as induced LBW in a rat model (42). The findings in the animal models accord well with data from human studies. Hinchcliffe et al. (43) examined nephron number of stillborns and infants who died within 1 yr of birth and found that nephron number was significantly lower in the infants with IUGR compared with the AGA infants. A more recent study examined the kidneys of neonates in relation to their birth weight and found a lower nephron number and an increased glomerular volume in the growth-restricted group (44). A similar correlation was found in adults (45), and these correlations were found to be independent of gender (46). A significant correlation between birth weight and nephron number has been reported in white Americans, whereas no such correlation could be demonstrated for black Americans, although the study may not have been sufficiently powered to achieve statistical significance (47). In adult aboriginal Australians, a population with a high prevalence of LBW and kidney disease, fewer glomeruli and larger mean glomerular volume were found compared with the non-aboriginal Australian population. Glomerular number correlated with adult height, suggesting a relationship with birth weight (48). It should be noted that normal birth weight does not automatically suggest a normal nephron number, and some individuals with normal birth weight may have a low or suboptimal nephron number (silent nephron deficit) (49). Ultrasound studies that examined the fetal kidney have supported the findings in the aforementioned histologic studies. Konje et al. (50) reported that during the third trimester, the fetal renal growth in SGA fetuses was slower and resulted in thinner kidneys of normal length, compared with AGA kidneys. This might suggest impairment of nephron number. LBW has also been associated with renal functional deficits. Studies of the Australian aboriginal community indicated that the urinary albumin-to-creatinine ratio is inversely related to birth weight (51). Why Would LBW Infants Have LNN? The relation between birth weight and hypertension may be the result of fetoplacental, maternal, or genetic factors. A twin study of 653 individuals found that the relationship is due mainly to fetoplacental factors and that genetic and maternal factors play a minor role (52). Similarly, in a cohort of female twin pairs, the differences in BP were suggested to result from delayed intrauterine growth (53). Other twin studies, however, have indicated an important contribution of genetic factors to adult hypertension in the LBW setting (54,55). A recent study sought to distinguish between the effects on kidney growth of preterm birth versus the SGA state. It was found that weight for gestational age is an important determinant of kidney size at birth and at 18 mo of age. The authors suggested that weight for gestational age rather than birth weight should be used in analysis of the impact of fetal growth on renal function (56). Similarly, in a study of 422 individuals who were 19 yr of age and were born preterm (<32 wk), birth weight was related to renal outcome. However, no convincing relation between gestational age and renal function was found, suggesting again that the important determinant of kidney function is the extent of IUGR (57). The most prevalent animal models for LBW-induced adult disease are protein and calorie restriction. The “life history theory” states that if the total amount of energy to an animal is limited, then increased allocation of energy to one organ system must reduce allocation to one or more other organ systems (58). For example, the undernourished fetus protects its brain development by diverting more blood to the brain at the expense of blood supply to other organ systems. Lesser growth of the kidney, for example, might be a “trade off” to protect brain growth. Several cellular and molecular mechanisms have been suggested as contributing to the consequent impaired nephrogenesis. Mechanisms Role of Telomere Integrity and Renal Cell Turnover The ends of linear chromosomes are capped by complex nuclear protein structures, which include stretches of repetitive DNA sequences (TTAGGG)n, known as telomeres (59). Human telomeres shorten with each round of cell division, through various mechanisms, in a process that might have an important role in cellular senescence and organism aging (60). The starting telomere length after conception in humans is usually in the range of 12 to 15 MB (61). Replicative arrest is associated with telomere shortening to approximately 2 to 5 kB, for at least one or more chromosomes. In the absence of telomerase, abnormalities in DNA replication or sister chromatid separation are among the mechanisms that have been implicated to compromise genomic integrity in senescent cells with short telomeres (62). Most organ systems undergo continuous cellular turnover in health, and this process is often accelerated as part of the response to injury. It is postulated that a subset of cells (referred to as adult or tissue stem cells) may be retained in the postnatal state for this purpose. Accordingly, lifelong organ system maintenance depends on the number of renal cell divisions that are required during fetal organ development and growth, subsequent cellular turnover in health and disease, the rate of telomere shortening, and the action of mechanisms to preserve or restore telomere length/integrity. These factors are organ system and life history specific and expected to be markedly affected by intrauterine growth and subsequent postnatal catch-up growth. Indeed, after IUGR, longevity was reduced in male rats that experienced postnatal catch-up growth, compared with those that did not. Examination of telomeres correspondingly revealed shorter telomere lengths in the latter group (63,64). Renal catch-up growth with accelerated body growth involves both hyperplasia and hypertrophy. Each of these processes might be expected to have different effects on subsequent telomere integrity and cellular longevity. In particular, hyperplasia in the absence of telomerase might exhaust telomere length capacity in a subset of the renal cell population that contributes to organ maintenance. In such a situation, availability of a pool of cells for maintenance or for postinjury renal cellular turnover would be limited in kidneys that have already exhausted telomere capacity during a past period of catch-up growth (Figure 2). Although we would not expect significantly shorter telomeres in LBW infants, as has been reported (65), it would be of interest to follow telomere length longitudinally in LBW infants who have experienced catch-up growth in comparison with control counterparts. We would expect reduced telomere length (and hence limited subsequent replicative capacity) after a period of catch-up growth. A number of additional theories that relate telomere shortening to aspects of abnormal cellular physiology, which might be of relevance to renal function, have been proposed; among these are modulation of gene expression in subtelomeric regions, including genes that are involved in sodium transport and excretion (66). Additional Mechanisms in the Regulation of Nephron Cell Mass The cellular mass of organ systems during development depends on a careful balance between cell proliferation and apoptosis. In animal models, IUGR was associated with evidence of higher levels of renal cellular apoptosis. Rat offspring that were born to a mother that was supplied a low-protein diet during pregnancy had fewer glomeruli than normal. Molecular and morphologic analysis found increased metanephric apoptosis in the group with IUGR. The authors suggested that fewer glomeruli were the result of increased apoptosis, leading to a reduction in renal progenitor cells (67). Several molecular mechanisms have been proposed for IUGR-induced renal cellular apoptosis. The renin-angiotensin system (RAS) and the paired homeobox 2 gene (Pax-2) are critical factors in nephrogenesis (68–70). Angiotensin II was shown to increase Pax-2 gene expression, a process that might be important in renal development and repair. In rats with IUGR, the RAS is downregulated, leading to reduced Pax-2 expression, thereby causing a shift from proliferation toward apoptosis and resulting in LNN (71). Bilateral partial ligation of the uterine arteries of the pregnant rat, another model for IUGR, resulted in reduced nephron number and an increase in apoptosis in the kidneys of juvenile rats. In this study, IUGR caused the increased expression of proapoptotic factors such as p53 and Bax. In the case of p53, this occurred through hypomethylation of the promoter. In addition, heightened p53 activity induced the downregulation of antiapoptotic factors, such as Bcl-2. As a consequence, an increase in the ratio between proapoptotic and antiapoptotic factors promotes renal cellular apoptosis, possibly leading to LNN in the offspring (72). Mechanisms that involve mitochondria have also been postulated in the relationship among LBW, LNN, and adult disease. Mitochondrial dysfunction can give rise to abnormalities in any organ or tissue (73). In the kidneys, mitochondrial DNA (mtDNA) mutations have been associated with hypertension and ESRD (74,75). A mitochondrial gene variant was found to be more prevalent in a cohort of 58 black individuals with hypertension-associated ESRD compared with 58 normotensive individuals (74). Other mitochondrial mutations have been associated with hypertension and renal pathologies (75). In rats, IUGR may cause mitochondrial dysfunction. Protein malnutrition in utero causes changes in mtDNA content, impaired β cell development, and a reduced insulin secretory response to glucose (76). In addition, partial ligation of both uterine arteries resulted in increased accumulation of mtDNA mutations and reduced mitochondrial activity in the pancreatic β cells of offspring. The deterioration in mitochondrial function leads to a decline in β cell function and the development of diabetes (77). Uteroplacental insufficiency was also shown to cause reduced mtDNA and mitochondrial protein production in the brain of juvenile rats (78). In another IUGR model, protein malnutrition in fetal life resulted in reduced mtDNA content in liver and skeletal muscle (79). Therefore, it seems likely, as has been shown in the case of pancreatic β cells, that mtDNA mutations and mitochondrial dysfunction might play a role in the development of LNN in the kidney with IUGR, leading to the subsequent emergence of hypertension and kidney disease. The predominant cause of LBW in the United States is preterm birth. Nephron development in humans begins in the ninth week of gestation and ceases during the 36th week. During the last trimester, there is a rapid rise in nephron number (80). A histomorphometric analysis of 56 extremely preterm infants demonstrated postnatal nephrogenesis. However, fewer glomeruli were generated, and glomerulogenesis ceased after 40 d. Moreover, it was noted that renal failure caused further inhibition of kidney development (81). Therefore, it is tempting to postulate that the extremely preterm infant will not experience an equivalent degree of kidney growth ex utero as compared with in utero and that this by itself would be a cause of LNN. However, as stated earlier, weight for gestational age rather than gestational age per se has been found to be associated with kidney function. LNN as an Important Determinant of Hypertension and CKD LNN is associated with an increased risk for hypertension and renal disease, an effect whose pathogenesis is attributed at least in part to glomerular hyperfiltration and/or hypertrophy (82). With reduced nephron mass, the remaining nephrons adapt and undergo hypertrophy to minimize the overall loss of function. Consequently, hyperfiltration occurs in each of the remaining nephrons to compensate for reduced nephron mass and function. This hyperfiltration has pathophysiologic implications: The glomeruli function under increased intracapillary hydraulic pressure, which over time damages the capillary walls. These abnormal conditions have been shown to lead to the development of proteinuria, FSGS, and a progressive decline in the GFR (82). The postmortem quantitative analytical examination of kidneys of accident victims found that those with hypertension had fewer glomeruli and greater glomerular volume than those of matched normotensive controls (47,83). In animal models, lower renal mass has also been associated with a larger increment in BP in response to increased daily salt intake (84). In genetic models of hypertension in rats, diminished nephron endowment has been associated with hypertension and an increased tendency toward glomerulosclerosis (85–88). Clinical support for the impact of LNN on future risk for hypertension and renal disease can also be deduced from studies of patients with solitary kidneys. In patients with a single kidney, as a result of either unilateral agenesis or nephrectomy, the incidence of proteinuria (>300 mg/24 h), hypertension, and chronic renal failure was significantly increased compared with control subjects (89–91). Reduced nephron number in the transplanted solitary kidney may likewise play a role in chronic allograft failure, especially when donor nephron number is not appropriately matched to the recipient. In support of this formulation is the finding that the frequency of graft loss 3 yr after transplantation was higher when the donors were women, individuals of African ancestry, or of age <3 or >61 yr (92). In a study of 31,515 cadaveric kidney transplant recipients, graft failure was significantly associated with donor age, gender, and population ancestry and recipient body surface area (93). Transplants into recipients who weighed >100 kg was associated with lower 1- and 3-yr graft survival rates (94). The findings are supported by animal studies that demonstrated the importance of nephron mass in the development of chronic allograft nephropathy (95–99). The foregoing suggests that factors that are associated with lower donor nephron mass (child or elder donor, female to male) or increased recipient needs (obese recipients) play a significant role in kidney transplant loss. Furthermore, these findings indicate that the number of viable nephrons (i.e., “nephron dose”) is an important determinant of renal survival in both transplanted and native kidneys. Unfortunately, this consideration has not been granted sufficient attention in setting kidney transplantation policy and practice guidelines. The increased prevalence of CKD and hypertension in adults who are born at LBW can be explained by understanding the concepts of the developmental origins of adult chronic disease. The LBW infant begins life at a renal disadvantage, as a result of LNN. This individual is then vulnerable to developing overt nephropathy in the event of postnatal “second hits,” such as diabetes or other forms of renal injury. Combined with nephron “overload” that is expected during catch-up growth, the risk for progression of these renal injury states toward CKD is enhanced (Figure 3). Additional Mechanisms for LBW-Related Hypertension Additional mechanisms have been studied in terms of the relationship between LBW and adult kidney disease and hypertension. Endocrine mechanisms have been proposed to be involved in the intrauterine programming of adult hypertension and renal disease. A number of hormones have an essential role in the regulation of fetal growth and fetal tissue development (100). Spontaneous and experimentally induced IUGR have been shown to induce postnatal changes in hormonal regulation. Of the hormones that are known to be involved in fetal development, the glucocorticoids are the most likely to cause tissue programming in utero (101). Reduced fetal nutrient availability increases levels of glucocorticoids, which may induce endocrine changes with long-term consequences on tissue growth and development. Maternal exposure to glucocorticoids during pregnancy caused hypertension and insulin resistance in the offspring rat and sheep models (102–105). The hypertensive effect of in utero glucocorticoids may be the result of cellular and molecular changes in various tissues. For example, in sheep, glucocorticoids induce functional changes in the kidneys and the brain by altering the expression of ion transporters and components of the RAS (104,106,107). Glucocorticoids and other hormones have a key role in regulating intrauterine development and therefore may significantly influence the evolution of adult disease. Another possible mechanism involves the inappropriate retention of sodium. The maternal protein restriction model for IUGR in rats resulted in upregulation of two critical Na transporters. The Na-K-2Cl and the Na-Cl co-transporters but neither the Na/H nor the Na channel was significantly increased in the rats with IUGR (108). In addition, expression of the glucocorticoid receptor, as well as α1 and β1 subunits of Na-K ATPase, was found to be increased after maternal protein restriction (109). These alterations lead to a lower rate of urinary sodium excretion with attendant sodium retention and hypertension. Conclusion The increasing prevalence of patients with CKD at all stages presents a significant challenge to population health worldwide. Primary and secondary prevention measures have demonstrated beneficial effects when targeted to “high risk” groups (110,111). LBW is a risk factor whose prevalence and importance are also increasing. The LBW infant may have experienced during pregnancy significant obstacles that the embryo confronted during development, and success in overcoming these challenges may have untoward consequences in adult life. Animal and human studies have shown impaired kidney maturation (LNN), “endocrine programming,” and telomere-limited exhaustion of progenitor pools for cell turnover to be key factors in the development of adult disease in LBW infants. Various genetic and hormonal factors are altered as the fetus adapts to an unfavorable intrauterine environment. Among these are key regulators of nephrogenesis and nephron size. These adjustments result in the development of kidneys whose long-term integrity is compromised. As indicated, LBW followed by catch-up growth is associated with adult hypertension and renal disease. Keeping in mind the importance of LBW and IUGR as risk factors for the development of hypertension and adult kidney disease, it is of utmost importance to follow these LBW patients longitudinally over time and try to reduce disease incidence. It is said that “a very long journey begins with a small step.” In the journey of life, special attention should be given to those who began with too small a step so that we can help them have a healthier journey. Disclosures None.Figure 1: Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, and 2004. Adapted from Hamilton et al. (4).Figure 2: Role of telomere integrity. During normal development, initial telomere length and telomere maintenance mechanisms allow sufficient cell divisions to enable subsequent postnatal organ system cellular integrity. In LBW infants, however, a period of postnatal “catch-up” growth may be associated with telomere shortening, thereby requiring the recruitment and hence premature exhaustion of renal stem or progenitor cells (white circles). Consequently, the ability of the kidney to mount a cellular turnover response after injury may be compromised and render such individuals more susceptible to nephron attrition.Figure 3: LBW and progression toward adult kidney disease. An unfavorable intrauterine environment results in the induction of fetal adaptive processes described in the text, at the cost of a reduced nephron number. The consequence is adult hypertension and the progression toward ESRD, if second hits such as diabetes, IgA nephropathy, pyelonephritis, and nephrotoxic exposure supervene.We acknowledge the support of the Barrie and Carol Rose Fund of the Canadian Technion Society for generous support.

Incidence of Developmental and Neuromotor Morbidity in Low-Risk, Low Birthweight Infants: Indication for Routine Developmental Evaluation in the First Year of Life. 1342

Purpose: To identify the incidence of developmental delay in a population of low birthweight infants not traditionally followed by developmental programs post discharge.

Cost of care for a geographically determined population of low birthweight infants to age 8-9 years. II. Children with disability.

To determine the cost of health and educational service provision for low birthweight children with a clinical disability. Cohort study of a geographically defined population in five health districts that comprise the County of Merseyside was undertaken. All children with a clinical disability born in 1980 and 1981 to mothers resident in the County of Merseyside were followed up to age 8-9 years. The cost of care associated with the initial admission to the neonatal special/intensive care unit and subsequent use of hospital, family practitioner, and special education services was assessed. There were 52 children with a disability; the disability rate in children of birthweight < or = 2000 g was estimated at 7.7%. Of the total expenditure to age 8-9 years, special education was the largest category (52%) and neonatal care accounted for 35%. The disabled children accounted for 38% of the cost of the whole cohort of 693 disabled and non-disabled children who weighed < or = 2000 g at birth. In a cohort of low birthweight children, those who are disabled account for a disproportionate amount of the total expenditure to age 8-9. The cost of long term care for disabled young persons and adults will increasingly dominate the cost of care for the whole cohort of low birthweight children.

Cost of care for a geographically determined population of low birthweight infants to age 8-9 years. I. Children without disability.

To determine the extra cost of healthcare associated with low birthweight, in a cohort study of a geographically defined population in five health districts that comprise Merseyside. The study comprised all children of birthweight < or = 1500 g and a 10% random sample of those weighing 1501-2000 g, without clinical disability, born in 1980 and 1981 to mothers resident in Merseyside, and their controls, matched by age, sex, and school class, followed up to age 8-9 years. The cost of care associated with the initial admission to the neonatal special/intensive care unit and subsequent use of hospital and family practitioner services was assessed. There were 641 survivors without disability and 227 non-survivors who weighed < or = 2000 g at birth. The mean cost of neonatal care per low birthweight child was 13 times greater than for a control child. For children weighing < or = 1000 g at birth, neonatal costs were 55 times greater than for the control children. Low birthweight children continue to use hospital and family practitioner services more intensively than controls to age 8-9 years. Low birthweight children used hospital and family practitioner services more intensively throughout the follow up period. Whether the increased use of health services persists into adolescence and adulthood is yet to be determined.

Early morbidity and neurodevelopmental outcome in low-birthweight infants born after third trimester bleeding.

Neonatal mortality, morbidity, and neurodevelopmental sequelae were compared between a consecutive series of 77 liveborn, low-birthweight (less than 2500 g) infants delivered after third trimester bleeding and 154 appropriate control infants of similar gestational age. Infants born after abruptio placentae had lower Apgar scores at 1 minute and higher rates of acidosis in comparison with control infants. In multivariate analysis, the infants in this group had higher risks of severe intraventricular hemorrhage and poor outcome (neonatal death or cerebral palsy) in comparison with control infants. In placenta previa, the infants had a higher prevalence of respiratory distress syndrome, whereas unclassified antepartum bleeding was associated with a high rate of neonatal hypoglycemia. After adjustment, by logistic regression analysis, for the effect of confounding factors (gestational age, birthweight, social class, and education of the mother), the risk of minor infant neurodevelopmental abnormalities at 2-year follow-up was increased in infants delivered after total or partial placenta previa or after unclassified antepartum bleeding. Third trimester bleeding should be considered a strong risk factor for both short-term neonatal morbidity and subsequent infant neurodevelopmental impairment in the low-birthweight infant population.

Epidemiology of strawberry haemangioma in low birthweight infants.

The prevalence of cutaneous haemangiomas in a representative population of low birthweight infants was determined by tracing and assessing survivors of pre-school age. Data from hospital case-notes and follow-up assessments were used to investigate whether prevalence of haemangiomas was related to perinatal factors and childhood morbidity. Eleven point one per cent of 615 infants developed a haemangioma. Haemangiomas were more common in girls than boys, and in infants of lower gestational age. Hypothermia in the first hours of life and neonatal illness were associated with lower prevalence, suggesting that neonatal skin perfusion influences haemangioma development; this is consistent with a tendency for haemangiomas to be distributed centripetally. However, the major aetiological determinants are unknown. Children with a haemangioma were more likely to have had a febrile convulsion than those without a haemangioma.

SURVIVAL AND MORBIDITY IN A GEOGRAPHICALLY DEFINED POPULATION OF LOW BIRTHWEIGHT INFANTS

Rates of survival and of neurological impairment in a geographically defined population of low birthweight infants born during 1979-1981 were determined by tracing infants and assessing survivors at pre-school age. Comparison with data from similar studies relating to earlier years shows that the proportion of low birthweight infants who survive with no major impairment has increased significantly; the risk of surviving with an impairment has not altered sufficiently for a significant difference to be apparent from these comparisons.