Bacterial and Candida Colonization of Neonates in a Regional Hospital in South Africa.

BACKGROUND: Neonatal colonization with multidrug-resistant (MDR) Enterobacter spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterococcus faecium (ESKAPE) and Candida spp. often precedes invasive hospital-acquired infections. We investigated the prevalence and dynamics of neonatal ESKAPE and Candida spp. colonization from hospital admission until discharge (or death) and followed up for invasive disease. METHODS: Prospective longitudinal surveillance for neonatal ESKAPE and Candida spp. colonization was conducted over 6 months at a South African regional hospital. Neonates enrolled at birth had swabs (nasal, 2× skin and rectal) collected within 24 hours and every 48-96 hours thereafter, until discharge or death. ESKAPE and Candida spp. were cultured for and antimicrobial susceptibility was performed on bacterial isolates. Whole-genome sequencing was undertaken on paired samples with the same bacterial species from colonizing and invasive disease episodes in the same child. RESULTS: Of 102 enrolled neonates, 79% (n = 81) were colonized by ≥1 ESKAPE organism by time of discharge or death. Forty-four percent (36/81) were colonized within 24 hours of birth. Common colonizers were K. pneumoniae (70%; n = 57) and Enterobacter spp. (43%; n = 35). Almost all MDR organisms (93%) were Gram-negative. Forty-two (45%, 42/93) newborns acquired Candida spp. (skin only) colonization, commonly Candida parapsilosis (69%; n = 29). For 2 children with K. pneumoniae colonization and sepsis, the bloodstream and colonizing isolates were genetically different, whereas the single A. baumannii colonizing and blood isolate pair were genetically identical. CONCLUSIONS: We report a high prevalence of MDR ESKAPE and Candida spp. colonization in a regional neonatal unit. Interventions to reduce the high incidence of hospital-acquired neonatal infections should include reducing high colonization rates.

Characteristics and outcomes of neonates with intrapartum asphyxia managed with therapeutic hypothermia in a public tertiary hospital in South Africa.

BACKGROUND: In randomized clinical trials, therapeutic hypothermia (TH) has been shown to reduce death and/or moderate-to-severe disability in neonates with hypoxic ischemic encephalopathy (HIE) in high-income countries, while this has not consistently been the case in low-and middle-income countries (LMICs). Many studies reporting on outcomes of neonates with HIE managed with TH are those conducted under controlled study conditions, and few reporting in settings where this intervention is offered as part of standard of care, especially from LMICs. In this study we report on short-term outcomes of neonates with moderate-to-severe HIE where TH was offered as part of standard of care. OBJECTIVE: To determine characteristics and mortality rate at hospital discharge in neonates with moderate-to-severe HIE. METHODS: Hospital records of neonates with intrapartum asphyxia were reviewed for clinical findings, management with TH (cooled or non-cooled) and mortality at hospital discharge. Inclusion criteria were birthweight ≥ 1800 g, gestational age ≥ 36 weeks and moderate-to-severe HIE. Comparisons were made between survivors and non-survivors in cooled and/or non-cooled neonates. RESULTS: Intrapartum asphyxia was diagnosed in 856 neonates, with three having no recorded HIE status; 30% (258/853) had mild HIE, and 595/853 (69%) with moderate-to-severe HIE. The overall incidence of intrapartum asphyxia was 8.8/1000 live births. Of the 595 with moderate-to-severe HIE, three had no records on cooling and 67% (399/592) were cooled. Amongst 193 non-cooled neonates, 126 (67%) had documented reasons for not being cooled with common reasons being a moribund neonate (54.0%), equipment unavailability (11.1%), pulmonary hypertension (9.5%), postnatal age > 6 h on admission (8.7%), and improvement in severity of encephalopathy (8.7%). Overall mortality was 29.0%, being 17.0% and 53.4% in cooled and non-cooled infants respectively. On multivariate analysis, the only factor associated with mortality was severe encephalopathy. CONCLUSION: Overall mortality in neonates with moderate-to-severe HIE was 29.0% and 17.0% in those who were cooled. Cooling was not offered to all neonates mainly because of severe clinical illness, equipment unavailability and delayed presentation, making it difficult to assess overall impact of this intervention. Prospective clinical studies need to be conducted in LMIC to further assess effect of TH in short and long-term outcomes.

The association between early-onset sepsis and neonatal encephalopathy.

OBJECTIVE: We evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting. METHODS: We undertook a retrospective study in newborns with gestational age ≥35 weeks and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis. RESULTS: Of 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p < 0.001). Predictors of mortality for culture-confirmed sepsis associated neonatal encephalopathy included severe neonatal encephalopathy (aOR 6.51, 95%CI: 1.03-41.44) and seizures (aOR 10.64, 95%CI: 1.05-107.39). CONCLUSION: In this setting, 5% of neonatal encephalopathy cases was associated with culture-confirmed sepsis and a high case fatality rate.

Clinical Characteristics and Histopathology of Coronavirus Disease 2019-Related Deaths in African Children.

BACKGROUND: Globally, very few childhood deaths have been attributed to coronavirus disease 2019 (COVID-19). We evaluated clinical, microbiologic and postmortem histopathologic findings in childhood deaths in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified antemortem or postmortem. METHODS: Surveillance of childhood deaths was ongoing during the initial COVID-19 outbreak in South Africa from April 14, 2020, to August 31, 2020. All children hospitalized during this time had a SARS-CoV-2 test done as part of standard of care. Postmortem sampling included minimally invasive tissue sampling (MITS) of lung, liver and heart tissue; blood and lung samples for bacterial culture and molecular detection of viruses (including SARS-CoV-2) and bacteria. The cause of death attribution was undertaken by a multidisciplinary team and reported using World Health Organization framework for cause of death attribution. RESULTS: SARS-CoV-2 was identified on antemortem and/or postmortem sampling in 11.7% (20/171) of deceased children, including 13.2% (12/91) in whom MITS was done. Eighteen (90%) of 20 deaths with SARS-CoV-2 infection were <12 months age. COVID-19 was attributed in the causal pathway to death in 91.7% (11/12) and 87.5% (7/8) cases with and without MITS, respectively. Lung histopathologic features in COVID-19-related deaths included diffuse alveolar damage (n = 6, 54.5%), type 2 pneumocyte proliferation (n = 6, 54.5%) and hyaline membrane formation (n = 5, 36.4%). Culture-confirmed invasive bacterial disease was evident in 54.5% (6/11) of COVID-19 attributed deaths investigated with MITS. CONCLUSIONS: COVID-19 was in the causal pathway of 10.5% (18/171) of all childhood deaths under surveillance. The postmortem histopathologic features in fatal COVID-19 cases in children were consistent with reports on COVID-19 deaths in adults; although there was a high prevalence of invasive bacterial disease in the children.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers in South Africa: A Longitudinal Cohort Study.

From April to September 2020, we investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in a cohort of 396 healthcare workers (HCWs) from 5 departments at Chris Hani Baragwanath Hospital, South Africa. Overall, 34.6% of HCWs had polymerase chain reaction-confirmed SARS-CoV-2 infection (132.1 [95% confidence interval, 111.8-156.2] infections per 1000 person-months); an additional 27 infections were identified by serology. HCWs in the internal medicine department had the highest rate of infection (61.7%). Among polymerase chain reaction-confirmed cases, 10.4% remained asymptomatic, 30.4% were presymptomatic, and 59.3% were symptomatic.

Surveillance for incidence and etiology of early-onset neonatal sepsis in Soweto, South Africa.

BACKGROUND: Globally, over 400,000 neonatal deaths in 2015 were attributed to sepsis, however, the incidence and etiologies of these infections are largely unknown in low-middle income countries. We aimed to determine incidence and etiology of community-acquired early-onset (<72 hours age) sepsis (EOS) using culture and molecular diagnostics. METHODS: This was a prospective observational study, in which we conducted a surveillance for pathogens using a combination of blood culture and a polymerase chain reaction (PCR)-based test. Blood culture was performed on all neonates with suspected EOS. Among the subset fulfilling criteria for protocol-defined EOS, blood and nasopharyngeal (NP) respiratory swabs were tested by quantitative real-time reverse-transcriptase PCR using a Taqman Array Card (TAC) with 15 bacterial and 12 viral targets. Blood and NP samples from 312 healthy newborns were also tested by TAC to estimate background positivity rates. We used variant latent-class methods to attribute etiologies and calculate pathogen-specific proportions and incidence rates. RESULTS: We enrolled 2,624 neonates with suspected EOS and from these 1,231 newborns met criteria for protocol-defined EOS (incidence- 39.3/1,000 live-births). Using the partially latent-class modelling, only 26.7% cases with protocol-defined EOS had attributable etiology, and the largest pathogen proportion were Ureaplasma spp. (5.4%; 95%CI: 3.6-8.0) and group B Streptococcus (GBS) (4.8%; 95%CI: 4.1-5.8), and no etiology was attributable for 73.3% of cases. Blood cultures were positive in 99/1,231 (8.0%) with protocol-defined EOS (incidence- 3.2/1,000 live-births). Leading pathogens on blood culture included GBS (35%) and viridans streptococci (24%). Ureaplasma spp. was the most common organism identified on TAC among cases with protocol-defined EOS. CONCLUSION: Using a combination of blood culture and a PCR-based test the common pathogens isolated in neonates with sepsis were Ureaplasma spp. and GBS. Despite documenting higher rates of protocol-defined EOS and using a combination of tests, the etiology for EOS remains elusive.

Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets.

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard.Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated.Setting CHERG birth cohorts from 14 population based sites in low and middle income countries.Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%.Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700).Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries.

Increased risk for group B Streptococcus sepsis in young infants exposed to HIV, Soweto, South Africa, 2004-2008(1).

Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004-2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease [EOD] and late-onset [LOD] disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored.

Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis.

BACKGROUND: Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. METHODS: For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2,015,019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. FINDINGS: Pooled overall RRs for preterm were 6·82 (95% CI 3·56-13·07) for neonatal mortality and 2·50 (1·48-4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34-2·50) for neonatal mortality and 1·90 (1·32-2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11-26·12). INTERPRETATION: Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4--the reduction of child mortality. FUNDING: Bill & Melinda Gates Foundation.

Maternal HIV infection and vertical transmission of pathogenic bacteria.

BACKGROUND: HIV-exposed newborns may be at higher risk of sepsis because of immune system aberrations, impaired maternal antibody transfer and altered exposure to pathogenic bacteria. METHODS: We performed a secondary analysis of a study (clinicaltrials.gov, number NCT00136370) conducted between April 2004 and October 2007 in South Africa. We used propensity score matching to evaluate the association between maternal HIV infection and (1) vaginal colonization with bacterial pathogens; (2) vertical transmission of pathogens to the newborn; and (3) sepsis within 3 days of birth (EOS) or between 4-28 days of life (LOS). RESULTS: Colonization with group B Streptococcus (17% vs 23%, P = .0002), Escherichia coli (47% vs 45%, P = .374), and Klebsiella pneumoniae (7% vs 10%, P = .008) differed modestly between HIV-infected and uninfected women, as did vertical transmission rates. Maternal HIV infection was not associated with increased risk of neonatal EOS or LOS, although culture-confirmed EOS was >3 times higher among HIV-exposed infants (P = .05). When compared with HIV-unexposed, neonates, HIV-exposed, uninfected neonates (HEU) had a lower risk of EOS (20.6 vs 33.7 per 1000 births; P = .046) and similar rate of LOS (5.8 vs 4.1; P = .563). HIV-infected newborns had a higher risk than HEU of EOS (134 vs 21.5; P < .0001) and LOS (26.8 vs 5.6; P = .042). CONCLUSIONS: Maternal HIV infection was not associated with increased risk of maternal bacterial colonization, vertical transmission, EOS, or LOS. HIV-infected neonates, however, were at increased risk of EOS and LOS.

Risk factors for neonatal sepsis and perinatal death among infants enrolled in the prevention of perinatal sepsis trial, Soweto, South Africa.

BACKGROUND: Factors associated with neonatal sepsis, an important cause of child mortality, are poorly described in Africa. We characterized factors associated with early-onset (days 0-2 of life) and late-onset (days 3-28) -sepsis and perinatal death among infants enrolled in the Prevention of Perinatal Sepsis Trial (NCT00136370 at ClinicalTrials.gov), Soweto, South Africa. METHODS: Secondary analysis of 8011 enrolled mothers and their neonates. Prenatal and labor records were abstracted and neonatal wards were monitored for hospitalized Prevention of Perinatal Sepsis-enrolled neonates. Endpoint definitions required clinical and laboratory signs. All univariate factors associated with endpoints at P < 0.15 were evaluated using multivariable logistic regression. RESULTS: About 10.5% (837/8011) of women received intrapartum antibiotic prophylaxis; 3.8% of enrolled versus 15% of hospital births were preterm. Among 8129 infants, 289 had early-onset sepsis, 34 had late-onset sepsis, 49 had culture-confirmed neonatal sepsis and 71 died in the perinatal period. Factors associated with early-onset sepsis included preterm delivery [adjusted relative risk (aRR) = 2.6; 95% confidence interval (CI): 1.4-4.8]; low birth weight (<1500 g: aRR = 6.5, 95% CI: 2.4-17.3); meconium-stained amniotic fluid (MSAF) (aRR = 2.8, 95% CI: 2.2-3.7) and first birth (aRR = 1.8; 95% CI: 1.4-2.3). Preterm, low birth weight, MSAF and first birth were similarly associated with perinatal death and culture-confirmed sepsis. MSAF (aRR = 2.4, 95% CI: 1.1-5.0) was associated with late-onset sepsis. CONCLUSIONS: Preterm and low birth weight were important sepsis risk factors. MSAF and first birth were also associated with sepsis and death, warranting further exploration. Intrapartum antibiotic prophylaxis did not protect against all-cause sepsis or death, underscoring the need for alternate prevention strategies.

Chlorhexidine maternal-vaginal and neonate body wipes in sepsis and vertical transmission of pathogenic bacteria in South Africa: a randomised, controlled trial.

BACKGROUND: About 500,000 sepsis-related deaths per year arise in the first 3 days of life. On the basis of results from non-randomised studies, use of vaginal chlorhexidine wipes during labour has been proposed as an intervention for the prevention of early-onset neonatal sepsis in developing countries. We therefore assessed the efficacy of chlorhexidine in early-onset neonatal sepsis and vertical transmission of group B streptococcus. METHODS: In a trial in Soweto, South Africa, 8011 women (aged 12-51 years) were randomly assigned in a 1:1 ratio to chlorhexidine vaginal wipes or external genitalia water wipes during active labour, and their 8129 newborn babies were assigned to full-body (intervention group) or foot (control group) washes with chlorhexidine at birth, respectively. In a subset of mothers (n=5144), we gathered maternal lower vaginal swabs and neonatal skin swabs after delivery to assess colonisation with potentially pathogenic bacteria. Primary outcomes were neonatal sepsis in the first 3 days of life and vertical transmission of group B streptococcus. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00136370. FINDINGS: Rates of neonatal sepsis did not differ between the groups (chlorhexidine 141 [3%] of 4072 vs control 148 [4%] of 4057; p=0.6518). Rates of colonisation with group B streptococcus in newborn babies born to mothers in the chlorhexidine (217 [54%] of 401) and control groups (234 [55%] of 429] did not differ (efficacy -0.05%, 95% CI -9.5 to 7.9). INTERPRETATION: Because chlorhexidine intravaginal and neonatal wipes did not prevent neonatal sepsis or the vertical acquisition of potentially pathogenic bacteria among neonates, we need other interventions to reduce childhood mortality. FUNDING: US Agency for International Development, National Vaccine Program Office and Centers for Disease Control's Antimicrobial Resistance Working Group, and Bill & Melinda Gates Foundation.

Confidential enquiries into hypoxic ischaemic encephalopathy.

Hypoxic ischaemic encephalopathy (HIE) may be regarded as a near miss marker for perinatal death resulting from intrapartum hypoxia. Considering the serious long-term consequences of HIE and issues of blame and liability for clinicians, regional or national audit of HIE might best be done using confidential enquiries. These are conducted by independent multidisciplinary panels, and should identify weaknesses in delivery of health care. A confidential enquiry into HIE may determine intrapartum factors that could have caused the poor outcome. It should also consider the role of associated preconceptual and antepartum factors, which may predispose the fetus to intrapartum damage. The enquiry should also assess avoidable factors and suboptimal care. These may involve patient- and family-related problems, administration-related suboptimal care, and health worker-related suboptimal care. The dissemination of the results of confidential enquiries should result in an improvement in quality of health care, including better allocation of health resources and health worker education.

Metabolism and synthesis of arginine vasopressin in conscious newborn sheep.

Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate (MCR(AVP)). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate (PR(AVP)), and MCR(AVP) in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P < or = 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 +/- 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). MCR(AVP) was unchanged throughout the 1st mo (P > 0.2), averaging 205 +/- 17 ml.kg(-1).min(-1), and was associated with an elevated PR(AVP), 973 +/- 267 pg.kg(-1).min(-1), which also was unchanged (P > 0.1). After birth, MCR(AVP) and PR(AVP) are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st mo. The reason for the elevated PR(AVP) is unclear but may relate to increases in vascular volume associated with postnatal growth.

Growth and metabolism of infants born to women infected with human immunodeficiency virus and fed acidified whey-adapted starter formulas.

OBJECTIVE: To compare the effects of a biologically and chemically acidified formula with or without probiotics with a standard formula on growth of infants negative for human immunodeficiency virus (HIV). METHODS: This was a double-masked, randomized, clinical trial. Infants born to consenting HIV-positive women who had decided not to breast-feed before being approached for participating in the study were randomized to receive one of four milk formulas: a chemically acidified formula with or without probiotics (Bifidobacterium lactis), a biologically acidified formula, or a standard whey formula. Infants who subsequently became HIV-positive according to polymerase chain reaction at 6 wk were excluded. Their growth and biochemical status were monitored for 4-6 mo. The z scores at the last visit of infants in each of the four formula groups were compared using analysis of covariance correcting for the z scores at baseline. Blood gases and pH were analyzed using a two-way analysis of variance corrected for center. RESULTS: One hundred thirty-two HIV-negative infants were monitored for growth and biochemical parameters for 4-6 mo. There was an improvement of z scores for all formulas, and there were no differences in weight for age (P = 0.22), length for age (P = 0.56), head circumference for age (P = 0.66), or weight for length (P = 0.13). There were no differences in blood pH and biochemical parameters among the formula groups. CONCLUSION: The growth of infants fed one of the three acidified formulas was not inferior to the standard formula. Growth and metabolism in HIV-negative infants fed the acidified formulas were not affected by the method of milk acidification.

The renin-angiotensin system in conscious newborn sheep: metabolic clearance rate and activity.

The role of the renin-angiotensin system (RAS) in regulating newborn mean arterial blood pressure (MAP) and tissue blood flow remains unclear. Although postnatal MAP increases, vascular responsiveness to infused angiotensin II (ANG II) is unchanged, possibly reflecting increased metabolic clearance rate of ANG II (MCR(ANG II)). To address this, we examined MAP, heart rate, plasma ANG II and renin activity (PRA), and MCR(ANG II) in conscious postnatal sheep (n = 9, 5-35 d old) before and during continuous systemic ANG II infusions to measure MCR (ANG II). Postnatal MAP increased (p < 0.02), whereas plasma ANG II decreased from 942 +/- 230 (SEM) to 471 +/- 152 and 240 +/- 70 pg/mL at <10 d, 10-20 d, and 21-35 d postnatally (p = 0.05), respectively. Despite high plasma ANG II, PRA remained elevated, averaging 6.70 +/- 1.1 ng/mL.h throughout the postnatal period, but decreased 35% (p = 0.01) during ANG II infusions. MCR(ANG II) decreased approximately sixfold after birth and averaged 115 mL/min.kg during the first month. Circulating ANG II is markedly increased after birth, reflecting placental removal, high fetal MCR(ANG II), and enhanced RAS activity. Although circulating ANG II decreases as MAP increases, MCR(ANG II) is unchanged, suggesting decreased ANG II production. Persistent vascular smooth muscle (VSM) AT2 receptor subtype (AT2R) expression after birth may modify the hypertensive effects of ANG II postnatally.

Effects of systemic and local phenylephrine and arginine vasopressin infusions in conscious postnatal sheep.

Mean arterial pressure (MAP) increases after birth, however, the mechanisms remain unclear. Systemic angiotensin II (ANG II) infusions increase MAP in newborn sheep, but the direct effects of ANG II on peripheral vascular resistance (PVR) are minimal. Thus, its systemic pressor effects may reflect release of other pressor agents, e.g. alpha-agonists and/or AVP, suggesting they contribute to postnatal regulation of MAP and PVR. To address this, we performed studies in conscious sheep at 7-14, 15-21, and 22-35 d postnatal, infusing phenylephrine (PE) or AVP systemically or intra-arterially into the hindlimb while measuring MAP, heart rate (HR), and femoral blood flow (FmBF). Basal MAP and FmBF rose, whereas HR and femoral vascular resistance (FmVR) fell (p < or = 0.03) during the first month postnatal. Although systemic PE and AVP dose dependently increased MAP and FmVR and decreased FmBF and HR (p < 0.001, ANOVA) at all ages, responses were not age dependent. Notably, increases in FmVR exceeded increases in MAP, and responses to PE appeared to exceed AVP (p < 0.05). Hindlimb infusions of both agents decreased FmBF and increased FmVR dose dependently (p < 0.001, ANOVA) at all ages without altering MAP or HR. These responses also were not age dependent. Unlike ANG II, PE and AVP directly increase PVR in newborn sheep. Moreover, FmVR increases more than MAP at all doses, suggesting these agonists may contribute to postnatal MAP regulation and could mediate the effects of systemic ANG II on postnatal MAP.

Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy.

OBJECTIVES: The objectives of this study were to determine, first, whether an early neurologic examination could predict a persistent abnormal neonatal neurologic state comparable to the amplitude-integrated electroencephalography (a-EEG) and, second, whether a combination of the 2 methods would further enhance early identification of high-risk infants. METHODS: Fifty term infants were enrolled prospectively when they had evidence of intrapartum distress, Apgar score

Differential responses to systemic and local angiotensin II infusions in conscious postnatal sheep.

Angiotensin II (ANG II) increases blood pressure (MAP) via specific ANG II receptors (AT) and is considered important in regulating MAP after birth. In adult animals, AT(1) receptors predominate in vascular smooth muscle (VSM) and mediate vasoconstriction. In newborn sheep, AT(2) receptors, which do not mediate vasoconstriction, predominate in vascular smooth muscle until 2 wk postnatal when they are replaced by AT(1). Thus, the mechanisms whereby ANG II increases MAP after birth are unclear. We examined the effects of ANG II on femoral vascular resistance (FmVR) and blood flow (FmBF) in serial studies of newborn sheep (n = 7) at 7-14 d, 15-21 d, and 22-35 d. Animals had femoral catheters implanted for systemic ANG II infusions and cardiovascular monitoring, and a flow probe was implanted on the contralateral artery proximal to the superficial saphenous artery, which contained a catheter for intra-arterial ANG II infusions. Studies were performed using a range of systemic and intra-arterial ANG II doses. Systemic ANG II increased MAP dose-dependently at all ages (p < 0.001); however, responses were not age dependent. FmBF rose dose dependently at 7-14 d (p < 0.001) and was unchanged at older ages. FmVR was unaffected at 7-14 d, but values increased dose dependently at 15-21 d and 22-3 5d (p < 0.001), although never exceeded relative increases in MAP. Local ANG II did not alter MAP, FmBF, or FmVR at any age. Although systemic ANG II increases MAP and FmVR dose dependently after birth, ANG II-induced vasoconstriction is attenuated. Furthermore, intra-arterial ANG II does not alter FmVR in the absence of systemic responses, suggesting incomplete vascular smooth muscle AT(1) expression, stimulation of local ANG II antagonists, or ANG II-mediated release of another vasoconstrictor.