PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (679939)

Clipboard (0)
None

Related Articles

1.  Proteomics Mapping of Cord Blood Identifies Haptoglobin “Switch-On” Pattern as Biomarker of Early-Onset Neonatal Sepsis in Preterm Newborns 
PLoS ONE  2011;6(10):e26111.
Background
Intra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns.
Methodology/Principal Findings
We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1st-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood (“switch-on pattern”) as opposed to non-EONS newborns who had near-absent “switch-off pattern” (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A Bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of “antenatal IAI exposure” as latent variable. This was then subjected to 2nd-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage.
Conclusions/Significance
Antenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.
doi:10.1371/journal.pone.0026111
PMCID: PMC3189953  PMID: 22028810
2.  Fetal Inflammatory Response in Women with Proteomic Biomarkers Characteristic of Intra-Amniotic Inflammation and Preterm Birth 
Objective
To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A) and fetal inflammatory status at birth.
Design
Prospective observational cohort.
Setting
Tertiary referral University hospital
Population
132 consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.6] weeks), who had a clinically indicated amniocentesis to rule-out infection and their newborns.
Methods
Intra-amniotic inflammation was diagnosed by mass spectrometry SELDI-TOF. The AF proteomic fingerprint [Mass Restricted (MR) score] ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: “no” inflammation; MR score 1-2: “minimal” inflammation; MR score 3-4: “severe” inflammation. At birth, cord blood was obtained for all cases. Severity of histological chorioamnionitis (HCA) and early onset neonatal sepsis (EONS) was based on established histological and hematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment.
Main Outcome Measures
to relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response.
Results
Women with intra-amniotic inflammation delivered at an earlier gestational age (ANOVA, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with “severe” intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterized by significantly elevated cord blood IL-6 levels (P<0.001). Out of the 39 neonates delivered by mothers with “minimal” intra-amniotic inflammation, 15 (39%) had umbilical cord blood IL-6 levels above the mean for the group, and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001), but not amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to delivery interval, cesarean delivery, status of the membranes, race, MR score, antibiotics and steroid exposure.
Conclusion
We provide evidence that presence in the AF of proteomic biomarkers characteristic of inflammation is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of “minimal” intra-amniotic inflammation.
doi:10.1111/j.1471-0528.2008.01925.x
PMCID: PMC3791329  PMID: 18947340
Proteomics; biomarkers; amniotic fluid; inflammation; defensin; calgranulin; umbilical cord blood; interleukin-6
3.  A three year descriptive study of early onset neonatal sepsis in a refugee population on the Thailand Myanmar border 
BMC Infectious Diseases  2013;13:601.
Background
Each year an estimated four million neonates die, the majority in the first week of life. One of the major causes of death is sepsis. Proving the incidence and aetiology of neonatal sepsis is difficult, particularly in resource poor settings where the majority of the deaths occur.
Methods
We conducted a three year observational study of clinically diagnosed early onset (<7 days of age) neonatal sepsis (EONS) in infants born to mothers following antenatal care at the Shoklo Malaria Research Unit clinic in Maela camp for displaced persons on the Thailand-Myanmar border. Episodes of EONS were identified using a clinical case definition. Conventional and molecular microbiological techniques were employed in order to determine underlying aetiology.
Results
From April 2009 until April 2012, 187 infants had clinical signs of EONS, giving an incidence rate of 44.8 per 1000 live births (95% CI 38.7-51.5). One blood culture was positive for Escherichia coli, E. coli was detected in the cerebrospinal fluid specimen in this infant, and in an additional two infants, by PCR. Therefore, the incidence of bacteriologically proven EONS was 0.7 per 1000 live births (95% CI 0.1 – 2.1). No infants enrolled in study died as a direct result of EONS.
Conclusion
A low incidence of bacteriologically proven EONS was seen in this study, despite a high incidence of clinically diagnosed EONS. The use of molecular diagnostics and nonspecific markers of infection need to be studied in resource poor settings to improve the diagnosis of EONS and rationalise antibiotic use.
doi:10.1186/1471-2334-13-601
PMCID: PMC3879187  PMID: 24359288
4.  Basic Science: Obstetrics Nucleated Red Blood Cells are a Direct Response to Mediators of Inflammation in Newborns with Early Onset Neonatal Sepsis 
Objective
To test the hypothesis that inflammation modulates fetal erythroblastosis and/or the release of NRBCs independent of hypoxia or fetal stress. We sought to determine if fetal inflammation is associated with an elevation in neonatal NRBC count in the setting of inflammation-associated preterm birth.
Study Design
The relationships between peripheral NRBC count, histological chorioamnionitis, umbilical cord interleukin-6 (IL-6), erythropoietin (EPO), cortisol and acid-base status were analyzed in 68 preterm singletons, born to mothers who had an amniocentesis to rule out infection. Proteomic profiling of amniotic fluid identified presence of intra-amniotic inflammation according to established parameters. NRBC counts were assessed within 1-hour of birth. Early-onset neonatal sepsis (EONS) was established based on hematological and microbiological indices. IL-6, EPO and cortisol levels were measured by immunoassays. Fetal acid-base status was determined within 10 minutes of delivery. Parametric or nonparametric statistics was employed.
Results
Fetuses with EONS (n=19) were delivered at earlier gestational ages (mean±SD: 27.1±2.8 weeks, P=0.001) and more often by mothers with intra-amniotic inflammation (P=0.022) and histological chorioamnionitis (P<0.001). Neonates with EONS had higher absolute NRBCs counts (P=0.011). NRBC counts were directly correlated with cord blood IL-6 levels (P<0.001) but not with EPO, cortisol or parameters of acid-base status levels regardless of EONS status. These relationships remained following correction for gestational age, diabetes, intrauterine growth restriction (IUGR) and steroid exposure.
Conclusion
In the setting of inflammation-associated preterm birth and in the absence of hypoxia, elevations in NRBCs in the early neonatal period may be a direct response to exposure to inflammatory mediators in utero.
doi:10.1016/j.ajog.2008.01.040
PMCID: PMC4023236  PMID: 18395034
infection; inflammation; NRBC preterm birth; chorioamnionitis
5.  Umbilical Cord Blood IL-6 as Predictor of Early-Onset Neonatal Sepsis in Women with Preterm Prelabour Rupture of Membranes 
PLoS ONE  2013;8(7):e69341.
Objective
To evaluate umbilical cord interleukin (IL)-6 and funisitis as independent predictors of early-onset neonatal sepsis (EONS) in preterm prelabor rupture of membranes (PPROM).
Design
Prospective cohort study.
Setting
Evaluation of umbilical cord IL-6 and funisitis as predictors of early-onset neonatal sepsis in PPROM.
Population
176 women with PPROM between 23+0−36+6 weeks of gestation.
Methods
Umbilical cord IL-6 was assayed by ELISA. Funisitis was defined according to the Salafia classification. Data was adjusted by gestational age at delivery and prenatal administration of corticosteroids and antibiotics.
Main Outcome Measures
Binary logistic regression was performed to assess the independence of umbilical cord IL-6 and funisitis to predict EONS in women complicated with PPROM.
Results
The rate of EONS was 7%. Funisitis was present in 18% of women. Umbilical cord IL-6 was significantly higher in women complicated with EONS than without [median (range) 389.5 pg/mL (13.9–734.8) vs 5.2 (0.1–801–4), p<0.001]. Umbilical cord IL-6 was the only independent predictor of early-onset neonatal sepsis (odds ratio 13.6, p = 0.004).
Conclusion
Umbilical cord IL-6 was the only predictor of early-onset neonatal sepsis in PPROM. Contrary to what is reported, funisitis was not.
doi:10.1371/journal.pone.0069341
PMCID: PMC3722235  PMID: 23894452
6.  FETAL HEART RATE MONITORING PATTERNS IN WOMEN WITH AMNIOTIC FLUID PROTEOMIC PROFILES INDICATIVE OF INFLAMMATION 
American journal of perinatology  2008;25(6):359-372.
We hypothesized that abnormal fetal heart rate monitoring patterns (FHR-MP) occur more often in pregnancies complicated by intra-amniotic inflammation. Therefore, our objective was to examine the relationships between FHR-MP abnormalities, intra-amniotic inflammation and/or infection, acute histological chorioamnionitis and early-onset neonatal sepsis (EONS) in pregnancies complicated by preterm birth. Additionally, the ability of various FHR-MPs to predict EONS was investigated. FHR-MP from 87 singleton premature neonates delivered within 48 hours from amniocentesis [gestational age: 28.9 ± 3.3 weeks] were analyzed blindly using strict NICHD criteria. Strips were evaluated at three time points: at admission, at amniocentesis and prior to delivery. Intra-amniotic inflammation was established based on a previously validated proteomic fingerprint (MR score). Diagnoses of histological chorioamnionitis and EONS were based on well-recognized pathological, clinical and laboratory criteria. We determined that fetuses of women with severe intra-amniotic inflammation had a higher FHR baseline throughout the entire monitoring period and an increased frequency of a non-reactive FHR-MP at admission. Of all FHR-MP, a non-reassuring test at admission had 32% sensitivity, 95% specificity, 73% positive predictive value, 77% negative predictive value, and 76% accuracy in predicting EONS. Although a non-reassuring FHR-MP at admission was significantly associated with EONS after correcting for gestational age (OR: 5.6 [95%CI: 1.2–26.2], p=0.030), the majority of the neonates that developed EONS had an overall reassuring FHR-MP. Non-reassuring FHR-MPs at either amniocentesis or delivery had no association with EONS. We conclude that in cases complicated by preterm birth, a non-reassuring FHR-MP at the initial evaluation is a specific but not a sensitive predictor of EONS. An abnormal FHR-MP can thus raise the level of awareness that a fetus with EONS may be born, but is not a useful clinical indicator of the need for antibiotic treatment of the neonate.
doi:10.1055/s-2008-1078761
PMCID: PMC2724874  PMID: 18512201
7.  Comparative Microbial Analysis of Paired Amniotic Fluid and Cord Blood from Pregnancies Complicated by Preterm Birth and Early-Onset Neonatal Sepsis 
PLoS ONE  2013;8(2):e56131.
Background
16S rRNA-based genomic analyses have revolutionized our understanding of infectious diseases. Many cases which were recognized as “idiopathic” are now known to have an infectious etiology. Here, we present a proof-of-concept study to examine the microbial link between intra-amniotic infection (IAI) and early-onset neonatal sepsis (EONS).
Results
Using culture independent methods, we analyzed paired amniotic fluid (AF) and cord blood (CB) samples from 36 singleton pregnancies complicated by preterm birth (PTB), IAI, and/or EONS. PTB cases were grouped as 1) Group 1– neonatal blood culture-positive EONS (n = 6). 2) Group 2– neonatal blood culture-negative presumed EONS with positive IAI (n = 16). 3) Group 3– neonatal blood culture-negative presumed EONS with no IAI (n = 7); 4) Group 4– no EONS or IAI (n = 7). In addition, samples from term healthy deliveries (n = 8) served as technical controls. A total of 31 species (15 non-redundant) were identified in AF, of which only 1/3 were cultivated. Significantly fewer microorganisms were detected in CB, with a total of 18 species (7 non-redundant) identified, of which only 2 (Escherichia coli, Streptococcus agalactiae) were cultivated. Of those, Bergeyella, Fusobacterium nucleatum, and Sneathia sanguinegens had not been detected in EONS before. The novel species identified in AF by PCR include Peptoniphilus harei and Lachnospiraceae sp. The majority (72%) of CB species were also detected in the matching AF, with E. coli and F. nucleatum as the most prevalent. The 16S rRNA sequences of paired AF and CB were 99.9–100% identical, while no identical sequences were found between different pregnancies.
Conclusions
Previously unrecognized, uncultivated or difficult-to-cultivate species are implicated in EONS. Microbial species in paired AF and CB likely share the same infectious origin. Given its prevalence in EONS, F. nucleatum should be placed on the same importance scale as E. coli.
doi:10.1371/journal.pone.0056131
PMCID: PMC3577789  PMID: 23437088
8.  Early-onset sepsis in a neonatal intensive care unit in Beni Suef, Egypt: bacterial isolates and antibiotic resistance pattern 
Korean Journal of Pediatrics  2013;56(8):332-337.
Purpose
To identify the frequency of bacterial isolates in early-onset neonatal sepsis (EONS) and their antimicrobial resistance pattern.
Methods
A retrospective study of EONS was conducted at the Beni Suef University Hospital from September 2008 to September 2012. A case of EONS was defined as an infant who had clinical signs of infection or who was born to a mother with risk factors for infection, and in whom blood culture obtained within 72 hours of life grew a bacterial pathogen.
Results
Of 673 neonates screened, there were 138 positive blood cultures (20.5%) (confirmed EONS). Of the recovered isolates, 86.2% were gram-negative pathogens. Klebsiella pneumoniae (42.8%), Enterobacter cloacae (22.5%), and Escherichia coli (13.8%) were the commonest isolated organisms. The most common gram-positive microorganism was Staphylococcus aureus accounting for only 12 isolates (8.7%). All Klebsiella isolates and 93% of Enterobacter isolates were resistant to ampicillin. Gram-negative pathogens had the maximum overall sensitivity to imipenem, cefepime, and ciprofloxacin; whereas, gram-positive isolates were most susceptible to vancomycin, imipenem, and piperacillin.
Conclusion
K. pneumoniae was the predominant causative bacteria of EONS followed by E. cloacae and E. coli. There was a high resistance to ampicillin. Imipenem had the maximum overall activity against the causative bacteria. Continuous surveillance is needed to monitor the changing epidemiology of pathogens and antibiotic sensitivity.
doi:10.3345/kjp.2013.56.8.332
PMCID: PMC3764257  PMID: 24019843
Drug Resistance; Newborn; Sepsis
9.  Neonatal Thyroid Function in Seveso 25 Years after Maternal Exposure to Dioxin 
PLoS Medicine  2008;5(7):e161.
Background
Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.
Methods and Findings
Between 1994 and 2005, in individuals exposed to TCDD after the 1976 Seveso accident we conducted: (i) a residence-based population study on 1,014 children born to the 1,772 women of reproductive age in the most contaminated zones (A, very high contamination; B, high contamination), and 1,772 age-matched women from the surrounding noncontaminated area (reference); (ii) a biomarker study on 51 mother–child pairs for whom recent maternal plasma dioxin measurements were available. Neonatal blood thyroid-stimulating hormone (b-TSH) was measured on all children. We performed crude and multivariate analyses adjusting for gender, birth weight, birth order, maternal age, hospital, and type of delivery. Mean neonatal b-TSH was 0.98 μU/ml (95% confidence interval [CI] 0.90–1.08) in the reference area (n = 533), 1.35 μU/ml (95% CI 1.22–1.49) in zone B (n = 425), and 1.66 μU/ml (95% CI 1.19–2.31) in zone A (n = 56) (p < 0.001). The proportion of children with b-TSH > 5 μU/ml was 2.8% in the reference area, 4.9% in zone B, and 16.1% in zone A (p < 0.001). Neonatal b-TSH was correlated with current maternal plasma TCDD (n = 51, β = 0.47, p < 0.001) and plasma toxic equivalents of coplanar dioxin-like compounds (n = 51, β = 0.45, p = 0.005).
Conclusions
Our data indicate that environmental contaminants such as dioxins have a long-lasting capability to modify neonatal thyroid function after the initial exposure.
Andrea Baccarelli and colleagues show that maternal exposure to a dioxin following the industrial accident in Seveso, Italy in 1976 is associated with modified neonatal thyroid function even many years later.
Editors' Summary
Background.
The thyroid, a butterfly-shaped gland in the neck, controls the speed at which the human body converts food into the energy and chemicals needed for life. In healthy people, the thyroid makes and releases two hormones (chemical messengers that travel around the body and regulate the activity of specific cells) called thyroxine (T4) and triiodothyronine (T3). The release of T4 and T3 is controlled by thyroid secreting hormone (TSH), which is made by the pituitary gland in response to electrical messages from the brain. If the thyroid stops making enough T4 and T3, a condition called hypothyroidism (an underactive thyroid) develops. Adults with hypothyroidism put on weight, feel the cold, and are often tired; children with hypothyroidism may also have poor growth and mental development. Because even a small reduction in thyroid hormone levels increases TSH production by the pituitary, hypothyroidism is often diagnosed by measuring the amount of TSH in the blood; it is treated with daily doses of the synthetic thyroid hormone levothyroxine.
Why Was This Study Done?
Although hypothyroidism is most common in ageing women, newborn babies sometimes have hypothyroidism. If untreated, “neonatal” hyperthyroidism can cause severe mental and physical retardation so, in many countries, blood TSH levels are measured soon after birth. That way, levothyroxine treatment can be started before thyroid hormone deficiency permanently damages the baby's developing body and brain. But what causes neonatal hypothyroidism? Animal experiments (and some but not all studies in people) suggest that maternal exposure to toxic chemicals called dioxins may be one cause. Dioxins are byproducts of waste incineration that persist in the environment and that accumulate in people. In this study, the researchers investigate whether exposure to dioxin (this name refers to the most toxic of the dioxins—2,3,7,8-Tetrachlorodibenzo-p-dioxin) affects neonatal thyroid function by studying children born near Seveso, Italy between 1994 and 2005. An accident at a chemical factory in 1976 heavily contaminated the region around this town with dioxin and, even now, the local people have high amounts of dioxin in their bodies.
What Did the Researchers Do and Find?
The researchers identified 1,772 women of child-bearing age who were living very near the Seveso factory (the most highly contaminated area, zone A) or slightly further away where the contamination was less but still high (zone B) at the time of the accident or soon after. As controls, they selected 1,772 women living in the surrounding, noncontaminated (reference) area. Altogether, these women had 1,014 babies between 1994 and 2005. The babies born to the mothers living in the reference area had lower neonatal blood TSH levels on average than the babies born to mothers living in zone A; zone B babies had intermediate TSH levels. Zone A babies were 6.6. times more likely to have a TSH level of more than 5 μU/ml than the reference area babies (the threshold TSH level for further investigations is 10 μU/ml; the average TSH level among the reference area babies was 0.98 μU/ml). The researchers also examined the relationship between neonatal TSH measurements and maternal dioxin measurements at delivery (extrapolated from measurements made between 1992 and 1998) in 51 mother–baby pairs. Neonatal TSH levels were highest in the babies whose mothers had the highest blood dioxin levels.
What Do These Findings Mean?
These findings suggest that maternal dioxin exposure has a long-lasting, deleterious effect on neonatal thyroid function. Because the long-term progress of the children in this study was not examined, it is not known whether the increases in neonatal TSH measurements associated with dioxin exposure caused any developmental problems. However, in regions where there is a mild iodine deficiency (the only environmental exposure consistently associated with reduced human neonatal thyroid function), TSH levels are increased to a similar extent and there is evidence of reduced intellectual and physical development. Future investigations on the progress of this group of children should show whether the long-term legacy of the Seveso accident (and of the high environmental levels of dioxin elsewhere) includes any effects on children's growth and development.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050161.
The MedlinePlus encyclopedia provides information about hypothyroidism and neonatal hypothyroidism; MedlinePlus provides links to additional information on thyroid diseases (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on hypothyroidism
The Nemours Foundation's KidsHealth site has information written for children about thyroid disorders
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to dioxins (in English and Spanish)
More information about dioxins is provided by the US Environmental Protection Agency and by the US Food and Drug Administration
Wikipedia has a page on the Seveso disaster (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050161
PMCID: PMC2488197  PMID: 18666825
10.  Care Seeking for Neonatal Illness in Low- and Middle-Income Countries: A Systematic Review 
PLoS Medicine  2012;9(3):e1001183.
Hadley Herbert and colleagues systematically review newborn care-seeking behaviors by caregivers in low- and middle-income countries.
Background
Despite recent achievements to reduce child mortality, neonatal deaths continue to remain high, accounting for 41% of all deaths in children under five years of age worldwide, of which over 90% occur in low- and middle-income countries (LMICs). Infections are a leading cause of death and limitations in care seeking for ill neonates contribute to high mortality rates. As estimates for care-seeking behaviors in LMICs have not been studied, this review describes care seeking for neonatal illnesses in LMICs, with particular attention to type of care sought.
Methods and Findings
We conducted a systematic literature review of studies that reported the proportion of caregivers that sought care for ill or suspected ill neonates in LMICs. The initial search yielded 784 studies, of which 22 studies described relevant data from community household surveys, facility-based surveys, and intervention trials. The majority of studies were from South Asia (n = 17/22), set in rural areas (n = 17/22), and published within the last 4 years (n = 18/22). Of the 9,098 neonates who were ill or suspected to be ill, 4,320 caregivers sought some type of care, including care from a health facility (n = 370) or provider (n = 1,813). Care seeking ranged between 10% and 100% among caregivers with a median of 59%. Care seeking from a health care provider yielded a similar range and median, while care seeking at a health care facility ranged between 1% and 100%, with a median of 20%. Care-seeking estimates were limited by the few studies conducted in urban settings and regions other than South Asia. There was a lack of consistency regarding illness, care-seeking, and care provider definitions.
Conclusions
There is a paucity of data regarding newborn care-seeking behaviors; in South Asia, care seeking is low for newborn illness, especially in terms of care sought from health care facilities and medically trained providers. There is a need for representative data to describe care-seeking patterns in different geographic regions and better understand mechanisms to enhance care seeking during this vulnerable time period.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide around 3.3 million babies die within their first month of life every year. While the global neonatal mortality rate has declined by 28% between 1990 and 2009 (from 33.2 deaths per 1,000 livebirths to 23.9), the proportion of under-five child deaths that are now in the neonatal period has increased in all regions of the world and currently stands at 41%. Of these deaths, over 90% occur in low- and middle-income countries (LMICs), making the risk of death in the neonatal period in LMICs more than six times higher than in high-income countries. In LMIC settings most babies are born at home so inappropriate and delayed care seeking can contribute substantially to neonatal mortality. Infection causes over a quarter of all deaths in neonates, but in LMICs diagnosis is often based on nonspecific clinical signs, which may delay the provision of care.
Why Was This Study Done?
In order to improve neonatal survival in LMICs, health care facilities and providers must not only be available and accessible but a baby's caregiver, often a parent or other family member, must also recognize that the baby is ill and seek help. To address this problem with effective strategies, an understanding is needed of the patterns of care-seeking behavior by babies' caregivers in seeking help from health-care facilities or providers. In this study, the researchers explored the extent and nature of care-seeking behaviors by the caregivers of ill babies in LMIC settings.
What Did the Researchers Do and Find?
Using multiple databases, the researchers conducted a comprehensive review up until October 2011 of all relevant studies including those that had not been formally published. Using specific criteria, the researchers then identified 22 appropriate studies (out of a possible 784) and recorded the same information from each study, including the number of neonates with illness or suspected illness, the number of care providers who sought care, and where care was sought. They also assessed the quality of each included study (the majority of which were from rural areas in South Asia) on the basis of a validated method for reviewing intervention effectiveness. The researchers found that the definitions of neonatal illness and care-seeking behavior varied considerably between studies or were not defined at all. Because of these inherent study differences it was not possible to statistically combine the results from the identified studies using a technique called meta-analysis, instead the researchers reported literature estimates and described their findings narratively.
The researchers' analysis included 9,098 neonates who were identified in community-based studies as being ill or suspected of being ill and a total of 4,320 related care-seeking events: care seeking ranged between 10% and 100% among caregivers including seeking care from a health facility (370) or from a health provider (1,813). Furthermore, between 4% to 100% of caregivers sought care from a trained medical provider and 4% to 48% specified receiving care at a health care facility: caregivers typically sought help from primary health care, secondary health care, and pharmacies and some from an unqualified health provider. The researchers also identified seven community-based intervention studies that included interventions such as essential newborn care, birth preparedness, and illness recognition, where all showed an increase in care seeking following the intervention.
What Do These Findings Mean?
These findings highlight the lack of a standardized and consistent approach to neonate care-seeking behaviors described in the literature. However, despite the large variations of results, care seeking for newborn illnesses in LMICs appears to be low in general and remains a key challenge to improving neonatal mortality. Global research efforts to define, understand, and address care seeking, may help to reduce the global burden of neonatal mortality. However, to achieve sustainable improvements in neonatal survival, changes are needed to both increase the demand for newborn care and strengthen health care systems to improve access to, and quality of, care. This review also shows that there is a role for interventions within the community to encourage appropriate and timely care seeking. Finally, by addressing the inconsistencies and establishing standardized terms to identify barriers to care, future studies may be able to better generalize the factors and delays that influence neonatal care seeking.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001183.
A recent PLoS Medicine study has the latest figures on neonatal mortality worldwide
UNICEF provides information about progress toward United Nations Millennium Development Goal 4
UNICEF also has information about neonatal mortality
The United Nations Population Fund has information on home births
doi:10.1371/journal.pmed.1001183
PMCID: PMC3295826  PMID: 22412355
11.  Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(8):e1001502.
Grace Chan and coauthors conducted a systematic review and meta-analysis of studies evaluating the risk of neonatal infection or colonization during the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Please see later in the article for the Editors' Summary
Background
Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Methods and Findings
We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9–11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1–28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0–5.4) times higher odds of infection than newborns of mothers without risk factors.
Conclusions
Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Millennium Development Goal 4 (MDG4)—one of eight goals agreed by world leaders in 2000 to eradicate extreme poverty globally—aims to reduce under-five mortality (deaths) to one-third of its 1990 level (12 million deaths). Progress towards reducing child mortality has accelerated recently, but MDG4 is unlikely to be met, partly because of slow progress towards reducing neonatal mortality—deaths during the first 28 days of life. Neonatal deaths now account for a greater proportion of global child deaths than in 1990. Nearly half of the children who die before their fifth birthday die during the neonatal period, with babies born in low-middle-income countries in sub-Saharan Africa and southern Asia being at the highest risk of neonatal death. Bacterial infections such as infections of the bloodstream (bacteremia/sepsis), lungs (pneumonia), and the brain's protective covering (meningitis) are responsible for a quarter of neonatal deaths. Newborns can acquire infections during birth by picking up bacteria (in particular Group B streptococcus or GBS) that are present in their mother's reproductive tract and that may or may not cause disease in the mother. Bacteria colonizing the maternal perineum (the area between the anus and the vagina) can move up the vaginal canal into the amniotic sac (the fluid-filled bag in which the baby develops). Maternal bacteremia is another source of bacterial transmission from mother to fetus. Other risk factors for neonatal infection include pre-labor rupture of the membranes (PROM) of the amniotic sac, preterm PROM, and prolonged rupture of membranes.
Why Was This Study Done?
In high-income settings, prophylactic (preventative) antibiotic treatment during labor (based on microbiological screening or risk factors such as PROM) and early diagnosis and treatment of sepsis in newborn babies has greatly reduced deaths from early-onset neonatal bacterial infection. Yet, relatively little is known about the risk factors and transmission pathways for this condition globally. In this global systematic review and meta-analysis, the researchers estimate the risk of neonatal bacterial infections (excluding sexually transmitted diseases) among newborns of mothers with bacterial infection or colonization around the time of birth. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies (only seven of which were undertaken in settings with high neonatal mortality) that included data on laboratory-confirmed maternal infection, maternal infection indicated by clinical signs and symptoms, maternal colonization (positive bacterial cultures from the reproductive tract without any signs or symptoms of infection), or risk factors for infection such as PROM and data on neonatal infection (laboratory-confirmed or clinically indicated) or colonization. Because different studies used different definitions for infection and colonization, the researchers pooled the data from subsets of the studies using random effects meta-analysis, which allows for heterogeneity (inconsistencies) between studies. Newborns of mothers with laboratory-confirmed infection had a 6.6-fold higher risk of laboratory-confirmed infection than newborns born to mothers without laboratory-confirmed infection. Newborns of mothers with bacterial colonization had a 9.4-fold higher risk of laboratory-confirmed infection than newborns of non-colonized mothers. Finally, compared to newborns of mothers without risk factors for infection, newborns of mothers with PROM or other risk factors had a 2.3-fold higher risk of infection.
What Do These Findings Mean?
These findings indicate that an increased risk of early-onset neonatal infection is associated with maternal infection and maternal colonization and provide some quantification of the excess risk. Because all the studies were facility-based and mostly from urban settings in high-income countries, these findings provide no information about the risk of neonatal infection among home births, rural births or births at community facilities in low-income countries, which limits their generalizability. Other aspects of the studies included in this systematic review and meta-analysis are also likely to limit the accuracy of the findings. Nevertheless, these findings suggest that better diagnosis and treatment of maternal infections and colonization in low- to middle-income countries where neonatal mortality is high might substantially reduce the incidence of neonatal infections and that the development of a simple algorithm that combines clinical signs and risk factors to diagnose maternal infections might be useful in regions where laboratory facilities are unavailable. Moreover, they highlight the need for more studies of maternal and neonatal infection and colonization in resource-poor settings with high neonatal mortality.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001502.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about neonatal survival and health; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report and to a video about how new health centers are helping India battle high neonatal death rates
The World Health Organization has information about Millennium Development Goal 4 and about newborn health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information on neonatal infections for parents (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for profit organization; the site also includes a survivor story
doi:10.1371/journal.pmed.1001502
PMCID: PMC3747995  PMID: 23976885
12.  Donor Funding for Newborn Survival: An Analysis of Donor-Reported Data, 2002–2010 
PLoS Medicine  2012;9(10):e1001332.
With recent increases in development assistance money for maternal and child health, Catherine Pitt and colleagues examine whether foreign aid specifically for newborns has changed, whether it's on par with the burden of newborn deaths worldwide, and how such funding can be tracked.
Background
Neonatal mortality accounts for 43% of global under-five deaths and is decreasing more slowly than maternal or child mortality. Donor funding has increased for maternal, newborn, and child health (MNCH), but no analysis to date has disaggregated aid for newborns. We evaluated if and how aid flows for newborn care can be tracked, examined changes in the last decade, and considered methodological implications for tracking funding for specific population groups or diseases.
Methods and Findings
We critically reviewed and categorised previous analyses of aid to specific populations, diseases, or types of activities. We then developed and refined key terms related to newborn survival in seven languages and searched titles and descriptions of donor disbursement records in the Organisation for Economic Co-operation and Development's Creditor Reporting System database, 2002–2010. We compared results with the Countdown to 2015 database of aid for MNCH (2003–2008) and the search strategy used by the Institute for Health Metrics and Evaluation. Prior to 2005, key terms related to newborns were rare in disbursement records but their frequency increased markedly thereafter. Only two mentions were found of “stillbirth” and only nine references were found to “fetus” in any spelling variant or language. The total value of non-research disbursements mentioning any newborn search terms rose from US$38.4 million in 2002 to US$717.1 million in 2010 (constant 2010 US$). The value of non-research projects exclusively benefitting newborns fluctuated somewhat but remained low, at US$5.7 million in 2010. The United States and the United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning and exclusively benefitting newborns, respectively.
Conclusions
Donor attention to newborn survival has increased since 2002, but it appears unlikely that donor aid is commensurate with the 3.0 million newborn deaths and 2.7 million stillbirths each year. We recommend that those tracking funding for other specific population groups, diseases, or activities consider a key term search approach in the Creditor Reporting System along with a detailed review of their data, but that they develop their search terms and interpretations carefully, taking into account the limitations described.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1990, 12 million children—most of them living in developing countries—died before they reached their fifth birthday. Faced with this largely avoidable loss of young lives, in 2000, world leaders set a target of reducing under-five mortality (deaths) to one-third of its 1990 level by 2015 as Millennium Development Goal 4 (MDG4); this goal, together with seven others, aims to eradicate extreme poverty globally. In recent years, progress towards reducing child mortality has accelerated but remains insufficient to achieve MDG4, in part, because progress towards reducing neonatal mortality—deaths during the first 28 days of life—has been particularly slow. Neonatal deaths now account for a greater proportion of global child deaths than in 1990—43% of the 7 million children who died before their fifth birthday in 2011 died during the neonatal period. The major causes of neonatal deaths are complications of preterm and term delivery and infections. Simple interventions such as improved hygiene at birth and advice on breastfeeding can substantially reduce neonatal deaths.
Why Was This Study Done?
To achieve MDG4, more must be done to prevent deaths among newborn babies. One reason that progress in reducing neonatal mortality is slow could be insufficient donor funding (aid) for newborn health. Previous analyses by, for example, Countdown to 2015 (which tracks coverage levels for health interventions that reduce maternal, newborn, and child mortality) indicate that donor funding has increased for maternal, newborn, and child health over the past decade, but how much of this aid directly benefits newborns is unknown. Here, the researchers develop a method for tracking aid flows for newborns and examine changes in this flow over the past decade by applying their new strategy to the Organisation for Economic Co-operation and Development (OECD) Creditor Reporting System (CRS) Aid Activity database. This database collects information about official development assistance for health given (disbursed) to developing countries by member countries of the OECD Development Assistance Committee, international organizations, and some private donors.
What Did the Researchers Do and Find?
The researchers developed a comprehensive set of search terms related to newborn survival by piloting it on the Countdown to 2015 official development assistance database, which covers the years 2003–2008. They then used their list of 24 key terms to search the CRS database from 2002 (the first year for which relatively complete disbursement data are available) to 2010 (the most recent year for which data are available) and classified each retrieved project according to whether its funding activities aimed to benefit newborns exclusively or to improve the health of other population groups as well. The researchers found that key terms related to newborns were rare in disbursement records before 2005 but that their frequency increased markedly thereafter. The total value of non-research disbursements (aid provided for programmatic or advocacy activities) that mentioned any newborn search terms increased from US$38.4 million in 2002 to US$717.1 million in 2010. The value of non-research projects that exclusively benefitted newborns fluctuated; in 2010, it was $US5.7 million. Finally, the US and United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning newborns and exclusively benefitting newborns, respectively.
What Do These Findings Mean?
These findings indicate that the value of aid disbursements mentioning newborns or an activity likely to benefit newborns increased 20-fold between 2002 and 2010 and constituted an increasing proportion of aid for maternal, newborn, and child health. Although this increase may partly reflect increased detail in aid disbursement reporting, it is also likely to reflect an increase in donor attention to newborn survival. The accuracy of these findings is likely to be affected by limitations in the search strategy and in the CRS database, which does not capture aid flows from emerging donors such as China or from many private foundations. Moreover, because these findings take no account of domestic expenditure, they do not provide a comprehensive estimate of the value of resources available in developing countries for newborn health. Nevertheless, investment in newborn survival is unlikely to be commensurate with global newborn mortality. Thus, an expansion of programmatic funding from donors as well as increased governmental support for newborn health in developing countries is urgently needed to catalyze the scale-up of cost-effective interventions to save newborn lives and to meet MDG4.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001332.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health, including the 2012 report of UN Inter-agency Group of Child Mortality Estimation; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report, to a video about progress made in reducing child deaths worldwide, and to stories about child survival in the field
The World Health Organization has information about Millennium Development Goal 4 and about maternal, newborn, child, and adolescent health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
The Healthy Newborn Network (HNN) is a community of more than 70 partner organizations addressing critical knowledge gaps for newborn health providing recent data on newborn survival and analyses of country programs
Information on and access to the Organisation for Economic Co-operation Development Creditor Reporting System Aid Activities database is available
Further information about the Millennium Development Goals is available
doi:10.1371/journal.pmed.1001332
PMCID: PMC3484125  PMID: 23118619
13.  Cord blood erythropoietin and interleukin-6 for prediction of intraventricular hemorrhage in the preterm neonate 
Objective
To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH).
Methods
Levels of umbilical cord EPO, acid–base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23–34] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures.
Results
IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA birth at birth (r = –0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027).
Conclusions
Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association.
doi:10.3109/14767058.2010.520048
PMCID: PMC3683649  PMID: 20937006
Erythropoietin; IL-6; premature; newborn; IVH
14.  Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico 
PLoS Medicine  2010;7(12):e1000379.
Joshua Salomon and colleagues performed a cost-effectiveness analysis using health and economic outcomes following preterm birth in Mexico and showed that neonatal intensive care provided high value for the money in this setting.
Background
Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.
Methods and Findings
A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24–26, 27–29, and 30–33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.
Conclusions
Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (the period during which a baby develops in its mother). In developed countries and some middle-income countries such as Mexico, improvements in the care of newborn babies (neonatal intensive care) mean that more preterm babies survive now than in the past. Nevertheless, preterm birth is still a major cause of infant death worldwide that challenges attainment of Target 5 of Millennium Development Goal 4—the reduction of the global under-five mortality rate by two-thirds of the 1990 rate by 2015 (the Millennium Development Goals, which were agreed by world leaders in 2000, aim to reduce world poverty). Furthermore, many preterm babies who survive have long-term health problems and disabilities such as cerebral palsy, deafness, or learning difficulties. The severity of these disabilities and their long-term costs to families and to society depend on the baby's degree of prematurity.
Why Was This Study Done?
Mexico recently reformed its health system in an effort to improve access to care, particularly for the poorest sections of its population, and to improve the quality of its health care. The central component of this health care reform is the System of Social Protection of Health (SSPH). The SSPH contains a family health insurance program—Seguro Popular—that aims to provide the 50 million uninsured people living in Mexico with free access to an explicit set of health care interventions. As with any insurance program, decisions have to be made about which interventions Seguro Poplar should cover. Should neonatal intensive care be covered, for example? Do the benefits of this intervention (increased survival of babies) outweigh the costs of neonatal care and of long-term care for survivors with disabilities? In other words, is neonatal intensive care cost-effective? In this study, the researchers investigate this question by estimating the clinical benefits, costs, and cost-effectiveness of neonatal intensive care in Mexico.
What Did the Researchers Do and Find?
The researchers built a decision analytic model, a mathematical model that combines evidence on the outcomes and costs of alternative treatments to help inform decisions about health care policy. They gathered data about the health outcomes of preterm births in Mexico from registers of births and deaths and from hospital discharge databases, and estimated the costs of neonatal intensive care and long-term care for disabled survivors using data from the Mexican Ministry of Health and the World Health Organization. They then applied their model, which estimates changes in parameters such as life expectancy, lifetime costs, disability-adjusted life years (DALYs; one DALY represents the loss of a year of healthy life), and incremental cost-effectiveness ratios (ICERs; the additional cost expended for each DALY averted) for neonatal intensive care compared to no intensive care, to a group of 2 million infants. Neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestation prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs at incremental costs of US$11,000, US$10,000, and US$3000, respectively, compared to no intensive care. The ICERs of neonatal intensive care for babies born at these times were US$1200, US$700, and US$300 per DALY averted, respectively.
What Do These Findings Mean?
Interventions with ICERs of less than a country's per capita gross domestic product (GDP) are highly cost-effective; those with ICERs of 1–3 times the per capita GDP are potentially cost-effective. Mexico's per capita GDP in 2005 was approximately US$8,200. Thus, neonatal intensive care could provide exceptional value for money in Mexico (and maybe in other middle-income countries), even for very premature babies. The accuracy of these findings inevitably depends on the assumptions used to build the decision analytic model and on the accuracy of the data fed into it, but the findings were little changed by a wide range of alterations that the researchers made to the model. Importantly, however, this cost-effectiveness analysis focuses on health and economic consequences of different intervention choices, and does not capture all aspects of well-being. Decisions regarding neonatal intensive care will need to be based on a full consideration of all relevant factors, including ethical issues, and cost-effectiveness analyses should continue to be updated as new data emerge on health outcomes and costs associated with neonatal intensive care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000379.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies (in English and Spanish)
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
A PLoS Medicine Policy Forum by Núria Homedes and Antonio Ugalde discusses health care reforms in Mexico
doi:10.1371/journal.pmed.1000379
PMCID: PMC3001895  PMID: 21179496
15.  Insurance type and sepsis-associated hospitalizations and sepsis-associated mortality among US adults: A retrospective cohort study 
Critical Care  2011;15(3):R130.
Introduction
Socio-demographic and clinical factors associated with increased sepsis risk, including older age, non-white race and specific co-morbidities, are more common among patients with Medicare or Medicaid or no health insurance. We hypothesized that patients with Medicare and/or Medicaid or without health insurance have a higher risk of sepsis-associated hospitalization or sepsis-associated death than those with private health insurance.
Methods
We performed a retrospective cohort study of records from the 2003 Nationwide Inpatient Sample. We stratified the study cohort by Medicare age-qualification (18 to 64 and 65+ years old). We examined the association between insurance category and sepsis diagnosis and death among admissions involving sepsis. We used validated diagnostic codes to determine the presence of sepsis, co-morbidities and organ dysfunction and to provide risk-adjustment.
Results
Among patients 18 to 64 years old, those with Medicaid (adjusted odds ratio (AOR) 1.50), Medicare (AOR 1.96), Medicaid + Medicare (AOR 2.22) and the uninsured (AOR 1.18) had significantly higher risk-adjusted odds of a sepsis-associated admission than those with private insurance (all P < 0.0001). Those with Medicaid (AOR 1.17, P < 0.001) and those without insurance (AOR 1.45, P < 0.001) also had significantly higher adjusted odds of sepsis-associated hospital mortality than those with private insurance. Among those 65+ years old, those with Medicaid (AOR 1.43), Medicare alone (AOR 1.13) or Medicaid + Medicare (AOR 1.62) had significantly higher risk-adjusted odds of sepsis-associated admission than those with private insurance and Medicare (all P < 0.0001). Among sepsis patients 65+, uninsured patients had significantly higher risk-adjusted odds (AOR 1.45, P = 0.0048) and those with Medicare alone had significantly lower risk-adjusted odds (AOR 0.92, P = 0.0072) of hospital mortality than those with private insurance and Medicare. Lack of health insurance remained associated with sepsis-associated mortality after stratification of hospitals into quartiles based on rates of sepsis-associated admissions or mortality in both age strata.
Conclusions
Risks of sepsis-associated hospitalization and sepsis-associated death vary by insurance. These increased risks were not fully explained by the available socio-demographic factors, co-morbidities or hospital rates of sepsis-related admissions or deaths.
doi:10.1186/cc10243
PMCID: PMC3218996  PMID: 21605427
16.  Trends in Resource Utilization by Children with Neurological Impairment in the United States Inpatient Health Care System: A Repeat Cross-Sectional Study 
PLoS Medicine  2012;9(1):e1001158.
Jay Berry and colleagues report findings from an analysis of hospitalization data in the US, examining the proportion of inpatient resources attributable to care for children with neurological impairment.
Background
Care advances in the United States (US) have led to improved survival of children with neurological impairment (NI). Children with NI may account for an increasing proportion of hospital resources. However, this assumption has not been tested at a national level.
Methods and Findings
We conducted a study of 25,747,016 US hospitalizations of children recorded in the Kids' Inpatient Database (years 1997, 2000, 2003, and 2006). Children with NI were identified with International Classification of Diseases, 9th Revision, Clinical Modification diagnoses resulting in functional and/or intellectual impairment. We assessed trends in inpatient resource utilization for children with NI with a Mantel-Haenszel chi-square test using all 4 y of data combined. Across the 4 y combined, children with NI accounted for 5.2% (1,338,590) of all hospitalizations. Epilepsy (52.2% [n = 538,978]) and cerebral palsy (15.9% [n = 164,665]) were the most prevalent NI diagnoses. The proportion of hospitalizations attributable to children with NI did not change significantly (p = 0.32) over time. In 2006, children with NI accounted for 5.3% (n = 345,621) of all hospitalizations, 13.9% (n = 3.4 million) of bed days, and 21.6% (US$17.7 billion) of all hospital charges within all hospitals. Over time, the proportion of hospitalizations attributable to children with NI decreased within non-children's hospitals (3.0% [n = 146,324] in 1997 to 2.5% [n = 113,097] in 2006, p<.001) and increased within children's hospitals (11.7% [n = 179,324] in 1997 to 13.5% [n = 209,708] in 2006, p<0.001). In 2006, children with NI accounted for 24.7% (2.1 million) of bed days and 29.0% (US$12.0 billion) of hospital charges within children's hospitals.
Conclusions
Children with NI account for a substantial proportion of inpatient resources utilized in the US. Their impact is growing within children's hospitals. We must ensure that the current health care system is staffed, educated, and equipped to serve this growing segment of vulnerable children.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Disorders of the central and peripheral nervous system, often referred to as neurological impairments, are common in infants and children and can cause functional or intellectual disability. There are many causes of neurological impairments, including birth trauma, congenital abnormalities, structural defects, infections, tumors, blood flow disruption, genetic and metabolic conditions, and toxins. Symptoms can be progressive or static and vary widely depending on the condition. For example, developmental delay, changes in activity—often due to muscle wasting—and seizures may be common symptoms of neurological conditions in children. In many countries, extremely premature babies, and children with conditions such as spina bifida and muscular dystrophy, now receive better care than they used to, and may survive longer. However, although such children may have long-term care needs, they may receive crisis-driven, uncoordinated care, even in high-income countries.
Why Was This Study Done?
It is not well understood what proportion of hospital resource use is attributable to care for children with neurological impairments, although it's thought that this group may account for an increasing proportion of hospital resources. In this study, the researchers attempted to answer this question, specifically for the US, by evaluating national trends in hospital admissions for children with neurological impairments.
What Did the Researchers Do and Find?
The researchers used a multi-state database of US hospital admissions for children aged 0–18 years, known as the KID—the Healthcare Cost and Utilization Project's Kids' Inpatient Database—to identify the number of hospital admissions, total number of days spent in the hospital, and total health care costs for children with neurological impairments from 1997 to 2006. The researchers identified appropriate admissions by using diagnostic codes from the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), which were reviewed and approved by two pediatric neurologists.
The researchers found that from 1997 to 2006, there were 25,747,016 hospital admissions for children aged 0–18 years, and of these, 1,338,590 (5.2%) were associated with children who had a definite diagnosis of neurological impairment. The most prevalent diagnoses among all hospitalized children with neurological impairments were epilepsy (52.2%) and cerebral palsy (15.9%). Furthermore, across the study period, the proportion of children aged 13–18 years admitted to hospitals with neurological impairments increased from 7.3% to 9.9%. The researchers also found that children with neurological impairments accounted for an increasing proportion of days spent in a hospital (12.9% in 1997 to 13.9% in 2006). In addition, there was a substantial increase in admissions for infants with neurological impairments compared to infants without neurological impairments. The researchers also found that throughout the study period, there was a general pattern for children with neurological impairments to be admitted to pediatric hospitals, rather than general hospitals. Within children's hospitals, children with neurological impairments accounted for a substantial proportion of resources over the study period, including nearly one-third of all hospital charges.
What Do These Findings Mean?
These findings show that in the US, children with neurological impairments account for a substantial proportion of inpatient resources utilized, particularly within children's hospitals, necessitating the need for adequate clinical care and a coordination of efforts to ensure that the needs of children with neurological impairments are met. System-based efforts such as partnerships between hospitals and families of children with neurological impairments and the rigorous evaluation of care treatment strategies have the potential to promote quality care for children with neurological impairments. However, such efforts will work only if the current health care system is adequately staffed with appropriately educated professionals.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/pmed.1001158.
More information is available about the KID database used in this study
NHS Choices has further information about epilepsy, one of the most common types of neurological impairment examined in this study
Further information is available from PubMed Health about cerebral palsy, another neurological condition acquired during development that was studied in this dataset
doi:10.1371/journal.pmed.1001158
PMCID: PMC3260313  PMID: 22272190
17.  Out-of-pocket cost of managing sick newborns in Enugu, southeast Nigeria 
Background
Neonatal illnesses usually require long hospital stays and specialized care and/or facilities, which usually results in huge medical bills. With more than 70% of people in Nigeria living on less than US$2 per day, these bills are not affordable to many families’ livelihoods.
Aim
This study aims to determine the average cost of managing neonatal illnesses in Enugu in southeast Nigeria and the proportion of family income spent on these illnesses. It further seeks to ascertain the cost of various components in the management of neonatal diseases.
Methods
This is a longitudinal and descriptive study involving 106 newborns admitted to the sick baby unit of the Enugu State University Teaching Hospital and the out-of-pocket medical expenditure in the management of their illnesses.
Results
A hundred and six newborns participated in the study. All (100%) medical bills were out-of-pocket payments, and 103 (97.2%) of these were catastrophic health expenditure (more than 10% of total family monthly income). The average duration of hospital stay and cost of managing a neonatal illness was 12.86±8.81 days and ₦36,382±19,389.72 (US$223±119), respectively. This expenditure amounted to 157%, 71%, and 25% of total monthly family income for the low, middle, and upper socioeconomic class families, respectively, with a mean percentage of 85%. Families with a total monthly income of less than ₦10,000 (US$61), ₦10,000–49,999 (US$61–306), and ₦50,000–100,000 (US$306–612) and more than ₦100,000 (US$612) on average spent 683%, 108%, 54%, and 20% of their monthly income on their newborn’s illness. Hospital and utility bills compared with bills accruing from drug and laboratory investigations account for a significantly larger proportion of total cost incurred in neonatal sepsis (₦23,499±14,987 [US$144±92], P=0.001), low birth weight (₦39,863±24,003 [US$224±147], P=0.001), severe anemia (₦40,504±13,923 [US$248±85], P=0.001), transient tachypnea of the newborn (₦10,083±1,078 [US$62±7], P=0.001), birth asphyxia (₦24,398±14,096 [US$149±86], P=0.001), and meningitis (₦26,731±7,675 [US$164±47], P=0.001), whereas cost for laboratory investigations was significantly higher for neonatal jaundice (₦11,690±3,169 [US$72±19], P=0.001). There was a strong positive correlation between duration of hospital stay and total medical cost incurred (r=0.897, P=0.001).
Conclusion
Health expenditure on neonatal illness is high and leads to catastrophic expenditure for the majority of households in the state. There is a need for effective health insurance schemes to help subsidize and cushion this disastrous and impoverishing health expenditure on families for improved neonatal survival in Nigeria.
doi:10.2147/CEOR.S54674
PMCID: PMC3896288  PMID: 24470764
neonatal illness; out of pocket; health expenditure; Enugu State
18.  Bacterial isolates of early-onset neonatal sepsis and their antibiotic susceptibility pattern between 1998 and 2004: an audit from a center in India 
Background
Epidemiology and surveillance of neonatal sepsis helps in implementation of rational empirical antibiotic strategy.
Objective
To study the frequency of bacterial isolates of early onset neonatal sepsis (EONS) and their sensitivity pattern.
Methods
In this retrospective study, a case of EONS was defined as an infant who had clinical signs or born to mothers with potential risk factors for infection, in whom blood culture obtained within 72 hours of life, grew a bacterial pathogen. Blood culture sample included a single sample from peripheral vein or artery. Relevant data was obtained from the unit register or neonatal case records.
Results
Of 2182 neonates screened, there were 389 (17.8%) positive blood cultures. After excluding coagulase-negative Staphylococci (160), we identified 229 EONS cases. Preterm neonates were 40.6% and small for gestational age, 18.3%. Mean birth weight and male to female ratio were 2344.5 (696.9) g and 1.16:1 respectively. Gram negative species represented 90.8% of culture isolates. Pseudomonas (33.2%) and Klebsiella (31.4%) were common among them. Other pathogens included Acinetobacter (14.4%), Staphylococcus aureus (9.2%), E.coli (4.4%), Enterobacter (2.2%), Citrobacter (3.1%) and Enterococci (2.2%). In Gram negative group, best susceptibility was to Amikacin (74.5%), followed by other aminoglycosides, ciprofloxacin and cefotaxime. The susceptibility was remarkably low to ampicillin (8.4%). Gram positive group had susceptibility of 42.9% to erythromycin, 47.6% to ciprofloxacin and above 50% to aminoglycosides. Of all isolates, 83.8% were susceptible to either cefotaxime or amikacin
Conclusion
Gram-negative species especially Pseudomonas and Klebsiella were the predominant causative organisms. Initial empirical choice of cefotaxime in combination with amikacin appeared to be rational choice for a given cohort.
doi:10.1186/1824-7288-37-32
PMCID: PMC3444145  PMID: 21745376
Early onset sepsis; neonates; blood culture isolates; antibiotic susceptibility
19.  THE ROLE OF PROTEOMICS IN THE DIAGNOSIS OF CHORIOAMNIONITIS AND EARLY-ONSET NEONATAL SEPSIS 
Clinics in perinatology  2010;37(2):355-374.
SYNOPSIS
Intra-uterine infection is viewed as a unique pathological process which raises considerably the risk for early onset neonatal sepsis (EONS). By acting synergistically with prematurity, EONS increases the risk for adverse neonatal outcomes including intraventricular hemorrhage (IVH) and cerebral palsy which are often encountered as sequelae of sepsis. Although several distinct pathways for the pathogenesis of fetal damage have been proposed, the basic molecular mechanisms that modulate these events remain incompletely understood. Therefore, discovery of clinically and biologically relevant biomarkers able to reveal key pathogenic pathways and predict pregnancies at risk for antenatal fetal damage is a priority. Proteomics provides a unique opportunity to fill this gap. In the short run proteomic biomarkers may aid with medical decision-making including timing of delivery and steroid administration In the long run proteomic biomarkers may lead to development of targeted therapies against pathogenic variants of EONS. Herein, we aimed to illustrate the richness of the topic and set the stage for the argument that discovery of novel proteomic biomarkers is a critical step in improving outcomes and preventing long-term disability.
doi:10.1016/j.clp.2010.03.002
PMCID: PMC2891963  PMID: 20569812
newborn; sepsis; biomarkers; proteomics; DAMPs; RAGE
20.  How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants? 
PLoS Medicine  2008;5(6):e129.
Background
Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.
Methods and Findings
Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.
Conclusions
While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.
Rebeccah Slater and colleagues show that although painful stimulation generally evokes parallel cortical and behavioral responses in infants, pain may produce cortical responses without detectable behavioral changes.
Editors' Summary
Background.
Pain is a sensory and emotional experience. It is normally triggered by messages transmitted from specialized receptors (nociceptors) in the body to integrative centers in the spinal cord and brainstem and on to the brain, where it undergoes higher sensory and cognitive analysis, allowing the body to respond appropriately to the stimuli. While the experience of pain may be considered to be unpleasant, it is a useful tool in communicating to us and to others that there is something wrong with our bodies. Ultimately, these responses help restrict further damage to the body and start the process of healing.
In a clinical setting, the ability to communicate about pain allows an individual to seek strategies to ease the pain, such as taking analgesics. Being unable to effectively communicate one's experience of pain leaves the individual vulnerable to prolonged suffering. One such vulnerable group is infants.
Ignored and untreated pain in infants has been shown to have immediate and long-term effects as a result of structural and physiological changes within the nervous system. For example, the body responds to untreated pain by increased release of stress hormones, which may be associated with increased morbidity and mortality in the short term. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints such as sleep disturbances, feeding problems, and inability to self-regulate in response to internal and external stressors. It has been proposed that attention deficit disorders, learning disorders, and behavioral problems in later childhood may be linked to repetitive pain in the preterm infant.
Why Was This Study Done?
Until as recently as the 1990s, newborns in some clinical centres underwent surgery with minimal anesthesia. Also, newborns received little or no pain management postoperatively or for painful procedures such as lumbar punctures or circumcisions. Since then, there has been growing awareness amongst clinicians that pain may be experienced from the earliest stages of postnatal life and that inadequate analgesia may lead to the type of long-term consequences mentioned above. However, gauging how much pain infants and young children are experiencing remains a substantial challenge. The researchers in this study wanted to assess the association between cortical pain responses in young infants and currently used tools for the assessment of pain in these infants. These current tools are based on behavioral and physiological measures, such as change in facial expression, and it is possible that these tools do not give an adequate measure of pain especially in infants born preterm.
What Did the Researchers Do and Find?
Twelve clinically stable infants were studied on 33 occasions when they required a heel lance to obtain a blood sample for a clinical reason. The researchers examined the relationship between brain activity and a clinical pain score, calculated using the premature infant pain profile (PIPP) in response to a painful event. Activity in the somatosensory cortex was measured noninvasively by near-infrared spectroscopy, which measures brain regional changes in oxygenated and deoxygenated hemoglobin concentration. The PIPP is a well-established pain score that ascribes a value to infant behavior such as change in facial expression.
They found that changes in brain activity in response to a painful stimulus were related to the PIPP scores. These changes were more strongly linked to the behavioral components of the PIPP, e.g., facial expression, than physiological components, e.g., heart rate. They also found that a positive brain response could occur in the absence of any facial expression.
What Do These Findings Mean?
Behaviors to communicate pain require motor responses to sensory and emotional stimuli. The maturity of this complex system in infants is not clearly understood. The results of this study raise further awareness of the ability of infants to experience pain and highlight the possibility that pain assessment based on behavioral tools alone may underestimate the pain response in infants.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050129.
Important papers on pain in human neonates are discussed in the open access Paediatric Pain Letter with links to original articles
The Institute of Child Health in London has a Web site describing a three-year international project on improving the assessment of pain in hospitalized children, with many useful links
The International Association for the Study of Pain (IASP) provides accurate and up-to-date information and links about pain mechanisms and treatment
doi:10.1371/journal.pmed.0050129
PMCID: PMC2504041  PMID: 18578562
21.  Community Mobilization in Mumbai Slums to Improve Perinatal Care and Outcomes: A Cluster Randomized Controlled Trial 
PLoS Medicine  2012;9(7):e1001257.
David Osrin and colleagues report findings from a cluster-randomized trial conducted in Mumbai slums; the trial aimed to evaluate whether facilitator-supported women's groups could improve perinatal outcomes.
Introduction
Improving maternal and newborn health in low-income settings requires both health service and community action. Previous community initiatives have been predominantly rural, but India is urbanizing. While working to improve health service quality, we tested an intervention in which urban slum-dweller women's groups worked to improve local perinatal health.
Methods and Findings
A cluster randomized controlled trial in 24 intervention and 24 control settlements covered a population of 283,000. In each intervention cluster, a facilitator supported women's groups through an action learning cycle in which they discussed perinatal experiences, improved their knowledge, and took local action. We monitored births, stillbirths, and neonatal deaths, and interviewed mothers at 6 weeks postpartum. The primary outcomes described perinatal care, maternal morbidity, and extended perinatal mortality. The analysis included 18,197 births over 3 years from 2006 to 2009. We found no differences between trial arms in uptake of antenatal care, reported work, rest, and diet in later pregnancy, institutional delivery, early and exclusive breastfeeding, or care-seeking. The stillbirth rate was non-significantly lower in the intervention arm (odds ratio 0.86, 95% CI 0.60–1.22), and the neonatal mortality rate higher (1.48, 1.06–2.08). The extended perinatal mortality rate did not differ between arms (1.19, 0.90–1.57). We have no evidence that these differences could be explained by the intervention.
Conclusions
Facilitating urban community groups was feasible, and there was evidence of behaviour change, but we did not see population-level effects on health care or mortality. In cities with multiple sources of health care, but inequitable access to services, community mobilization should be integrated with attempts to deliver services for the poorest and most vulnerable, and with initiatives to improve quality of care in both public and private sectors.
Trial registration
Current Controlled Trials ISRCTN96256793
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Substantial progress is being made to reduce global child mortality (deaths of children before the age of 5 years) and maternal mortality (deaths among women because of complications of pregnancy and childbirth)—two of the Millennium Development Goals agreed by world leaders in 2000 to end extreme poverty. Even so, worldwide, in 2010, 7.6 million children died before their fifth birthday and there were nearly 360,000 maternal deaths. Almost all child and maternal deaths occur in developing countries—a fifth of under-five deaths and more than a quarter of neonatal deaths (deaths during the first month of life, which account for two-fifths of all child deaths) occur in India alone. Moreover, most child and maternal deaths are caused by avoidable conditions. Specifically, the major causes of neonatal death—complications of preterm delivery, breathing problems during or after delivery, and infections of the blood (sepsis) and lungs (pneumonia)—and of maternal deaths—hemorrhage (abnormal bleeding), sepsis, unsafe abortion, obstructed labor, and hypertensive diseases of pregnancy—could all be largely prevented by improved access to reproductive health services and skilled health care workers.
Why Was This Study Done?
Experts believe that improvements to maternal and newborn health in low-income settings require both health service strengthening and community action. That is, the demand for better services, driven by improved knowledge about maternal and newborn health (perinatal issues), has to be increased in parallel with the supply of those services. To date, community mobilization around perinatal issues has largely been undertaken in rural settings but populations in developing countries are becoming increasingly urban. In India, for example, 30% of the population now lives in cities. In this cluster randomized controlled trial (a study in which groups of people are randomly assigned to receive alternative interventions and the outcomes in the differently treated “clusters” are compared), City Initiative for Newborn Health (CINH) researchers investigate the effect of an intervention designed to help women's groups in the slums of Mumbai work towards improving local perinatal health. The CINH aims to improve maternal and newborn health in slum communities by improving public health care provision and by working with community members to improve maternal and newborn care practices and care-seeking behaviors.
What Did the Researchers Do and Find?
The researchers enrolled 48 Mumbai slum communities of at least 1,000 households into their trial. In each of the 24 intervention clusters, a facilitator supported local women's groups through a 36-meeting learning cycle during which group members discussed their perinatal experiences, improved their knowledge, and took action. To measure the effect of the intervention, the researchers monitored births, stillbirths, and neonatal deaths in all the clusters and interviewed mothers 6 weeks after delivery. During the 3-year trial, there were 18,197 births in the participating settlements. The women in the intervention clusters were enthusiastic about acquiring new knowledge and made substantial efforts to reach out to other women but were less successful in undertaking collective action such as negotiations with civic authorities for more amenities. There were no differences between the intervention and control communities in the uptake of antenatal care, reported work, rest, and diet in late pregnancy, institutional delivery, or in breast feeding and care-seeking behavior. Finally, the combined rate of stillbirths and neonatal deaths (the extended perinatal mortality rate) was the same in both arms of the trial, as was maternal mortality.
What Do These Findings Mean?
These findings indicate that it is possible to facilitate the discussion of perinatal health care by urban women's groups in the challenging conditions that exist in the slums of Mumbai. However, they fail to show any measureable effect of community mobilization through the facilitation of women's groups on perinatal health at the population level. The researchers acknowledge that more intensive community activities that target the poorest, most vulnerable slum dwellers might produce measurable effects on perinatal mortality, and they conclude that, in cities with multiple sources of health care and inequitable access to services, it remains important to integrate community mobilization with attempts to deliver services to the poorest and most vulnerable, and with initiatives to improve the quality of health care in both the public and private sector.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001257.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on the reduction of child mortality (Millennium Development Goal 4); its Childinfo website provides information about all the Millennium Development Goals and detailed statistics about on child survival and health, newborn care, and maternal health (some information in several languages)
The World Health Organization also has information about Millennium Development Goal 4 and Millennium Development Goal 5, the reduction of maternal mortality, provides information on newborn infants, and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
Information on the City Initiative for Newborn Health and its partners and a detailed description of its trial of community mobilization in Mumbai slums to improve care during pregnancy, delivery, postnatally and for the newborn are available
Further information about the Society for Nutrition, Education and Health Action (SNEHA) is available
doi:10.1371/journal.pmed.1001257
PMCID: PMC3389036  PMID: 22802737
22.  Induction of Labor versus Expectant Management in Women with Preterm Prelabor Rupture of Membranes between 34 and 37 Weeks: A Randomized Controlled Trial 
PLoS Medicine  2012;9(4):e1001208.
In a randomized controlled trial David van der Ham and colleagues investigate induction of labor versus expectant management for women with preterm prelabor rupture of membranes.
Background
At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term.
Methods and Findings
We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34+0 and 37+0 wk of gestation. Participants were randomly allocated in a 1∶1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate.
From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported.
Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM.
Conclusions
In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM.
Trial registration
Current Controlled Trials ISRCTN29313500
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but in industrialized countries, 5%–10% of babies are born before 37 weeks of gestation (gestation is the period during which a baby develops in its mother's womb). Premature birth is a major cause of infant death in many developed countries, and preterm babies can also have short- and/or long-term health problems such as breathing problems, increased susceptibility to life-threatening infections, and learning and developmental disabilities. There are many reasons why some babies are born prematurely, but preterm prelabor rupture of the membranes (PPROM) accounts for 30%–40% of preterm deliveries. Inside the womb, the baby is held in a fluid-filled bag called the amniotic sac. The amniotic fluid cushions the baby, helps some of its organs develop, and protects both mother and baby from infection. The membranes that form the sac usually break at the start of labor (“water breaking”), but in PPROM, the membranes break before the baby is fully grown. PPROM increases the mother's risk of a womb infection called chorioamnionitis and the baby's risk of neonatal sepsis (blood infection), and can trigger early labor.
Why Was This Study Done?
There is currently no consensus on how to manage women whose membranes rupture between 34 and 37 weeks' gestation. Some guidelines recommend immediate induction of labor if PPROM occurs at or beyond 34 weeks' gestation. Others recommend that labor not be induced unless the mother develops signs of infection such as a high temperature or has not delivered her baby spontaneously by 37 weeks' gestation (expectant management). Before 34 weeks' gestation, expectant management is generally recommended. In this randomized controlled trial, the researchers compare the effects of induction of labor and of expectant management on the rate of neonatal sepsis (the proportion of babies that develop neonatal sepsis; the trial's primary outcome) and on secondary outcomes such as the rates of neonatal respiratory distress syndrome (RDS), cesarean section (surgical delivery), and chorioamnionitis in women with PPROM between 34 and 37 weeks' gestation. The researchers also undertake a meta-analysis of published trials on the effect of both interventions on pregnancy outcomes. A randomized controlled trial compares the effects of different interventions in groups of individuals chosen through the play of chance; meta-analysis is a statistical approach that combines the results of several trials.
What Did the Researchers Do and Find?
In the PPROM Expectant Management versus Induction of Labor (PRROMEXIL) trial, 532 non-laboring women with PPROM between 34 and 37 weeks' gestation were randomly assigned to either immediate induction of labor or expectant management. Neonatal sepsis occurred in seven babies born to women in the induction of labor group and in 11 babies born to women in the expectant management group. This difference was not statistically significant. That is, it could have happened by chance. Similarly, although more babies born to women in the induction of labor group than in the expectant management group developed RDS (21 and 17 babies, respectively), this difference was not significant. Cesarean section rates were similar in both intervention groups, but the risk of chorioamnionitis was slightly reduced in the induction of labor group compared to the expectant management group. Finally, the researchers' meta-analysis (which included these new results) found no significant differences in the risk of neonatal sepsis, RDS, or cesarean section associated with the two interventions.
What Do These Findings Mean?
These findings show that, compared to expectant management, induction of labor did not reduce the incidence of neonatal sepsis in pregnancies complicated by PPROM between 34 and 37 weeks' gestation. However, because fewer babies than expected born to the women in the expectant management group developed neonatal sepsis, this trial was underpowered. That is, too few women were enrolled in the trial to enable the detection of a small difference between the interventions in the neonatal sepsis rate. These findings also show that induction of labor did not substantially affect most of the secondary outcomes measured by the researchers. Given these results and those of their meta-analysis, the researchers conclude that, in women whose pregnancy is complicated by PPROM late in pregnancy, induction of labor does not substantially improve the outcome for either the woman or her baby compared to expectant management.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001208.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish); its News Moms Need blog contains a post on PPROM
Tommy's is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The Royal College of Obstetricians and Gynaecologists guidelines on the diagnosis, investigation, and management of PPROM are available (in English and Russian)
Information about the PPROMEXIL trial is available
Personal stories about PPROM are available on the Austprem web site, a non-profit organization that provides information about prematurity and support for parents of premature babies in Australia
MedlinePlus provides links to other information on premature babies (in English and Spanish)
doi:10.1371/journal.pmed.1001208
PMCID: PMC3335867  PMID: 22545024
23.  Relationship between Maternal Serum C-Reactive Protein, Funisitis and Early-Onset Neonatal Sepsis 
Journal of Korean Medical Science  2012;27(6):674-680.
The aim of this study was to determine whether maternal serum C-reactive protein (CRP) is of value in predicting funisitis and early-onset neonatal sepsis (EONS) in women with preterm labor or preterm premature rupture of membranes (PROM). This retrospective cohort study included 306 consecutive women with preterm labor or preterm PROM who delivered preterm singleton neonates (23-35 weeks gestation) within 72 hr of CRP measurement. The CRP level was measured with a highly sensitive immunoassay. The sensitivity, specificity, positive predictive value, and negative predictive value of an elevated serum CRP level (≥ 8 mg/L) were 74.1%, 67.5%, 32.8%, and 92.4% for funisitis, and 67.7%, 63.3%, 17.2%, and 94.6% for EONS, respectively. Logistic regression analysis demonstrated that elevated levels of serum CRP were significantly associated with funisitis and EONS, even after adjusting gestational age. The maternal serum CRP level obtained up to 72 hr before delivery is an independent predictor of funisitis and EONS in women with preterm labor or preterm PROM. A low serum CRP level (< 8 mg/L) has good negative predictive value in excluding funisitis and EONS, and may therefore be used as a non-invasive adjunct to clinical judgment to identify low-risk patients.
doi:10.3346/jkms.2012.27.6.674
PMCID: PMC3369455  PMID: 22690100
C-Reactive Protein; Early-Onset Neonatal Sepsis; Funisitis; Preterm Labor; Preterm Premature Rupture of Membrane
24.  HIV exposure and related newborn morbidity and mortality in the University Teaching Hospital of Yaoundé, Cameroon 
Introduction
Few studies have established the role of maternal HIV infection on neonatal disease and death. In order to determine whether neonatal morbidity and mortality were associated to maternal HIV infection, a case-control study was conducted in the neonatal unit of the University Teaching Hospital of Yaoundé from July 2006 to December 2007.
Methods
Babies born from HIV positive mothers were recruited as cases. For each case, two babies born from HIV negative mothers were selected as controls. Informed verbal consent was obtained from the mother before inclusion of the newborn in the study. Information on demographics, history of pregnancy, diseases and outcome of the newborns were extracted from patients’ files. The distribution of these parameters between cases and control was analyzed using chi-square. Association of demographics, clinical and paraclinical parameters with mortality was explored using univariate analysis and logistic regression. Data were analyzed using Epi Info version 3.5.1 Windows.
Results
Out of 240 newborns enrolled, 80 were cases and were 160 controls. The mean age of cases was 1.69±2.73 days compared to 1.46±2.36 days for controls (p=0.26). Cases significantly differed from controls on mother’s marital status (p=0.02), level of education (p<0.001), number of prenatal consultations (p<0.001), anemia chemoprophylaxis (p=0.01) and drug abuse (p<0.001). Cases and controls were similar for prematurity, respiratory distress, sepsis, meningitis and urinary tract infection. The death rate was identical in both groups (p=0.52). Using Univariate analysis, risk factors associated to mortality in both groups were prematurity (p<0.001) and low birth weight (p<0.001).
Conclusion
This study showed no statistical difference in morbidity and mortality between newborns from HIV positive and HIV negative mothers.
PMCID: PMC3201607  PMID: 22121451
HIV exposure; newborn; morbidity; mortality; Cameroon
25.  Proteomic Profiling of the Amniotic Fluid to Detect Inflammation, Infection, and Neonatal Sepsis 
PLoS Medicine  2007;4(1):e18.
Background
Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score.
Methods and Findings
We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with “severe” amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with “no” (MR score of 0) inflammation or even “minimal” (MR score of 1 or 2) inflammation (median [range] MR 3–4: 0.4 d [0.0–49.6 d] versus MR 1–2: 3.8 d [0.0–151.2 d] versus MR 0: 17.0 d [0.1–94.3 d], p < 0.001). Nonetheless, a “minimal” degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3–4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture).
Conclusions
High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.
Proteomic analysis of amniotic fluid in addition to a Gram stain provides the best combination of tests to rapidly predict intrauterine infection.
Editors' Summary
Background.
A preterm delivery, or premature birth, is normally defined as one that occurs before 37 weeks after the last menstrual cycle (an average pregnancy lasts around 40 weeks). Premature birth is fairly common, with around 12% of births in the US fitting this definition. However, it has serious consequences, being responsible for around 70% of infant deaths and other adverse outcomes for the baby. It is not clear in all cases what directly causes premature birth or how to identify cases in which mother and child are at greater risk of serious outcomes. Evidence from case-control and other studies strongly suggests that infections of the uterus, placenta, or genital tract are associated with, and are likely to directly cause, premature deliveries. Such infections, even if they are “subclinical” (that is, they do not directly cause signs or symptoms that the doctor or patient would notice) cause inflammation in the affected tissues. Hence, it's possible that particular proteins or other molecules could provide a “signature” that would allow the inflammation to be picked up at an early stage.
Why Was This Study Done?
If inflammation could be picked up early, this might help identify mothers at risk of having a preterm delivery, and even to pinpoint cases of very severe inflammation where the baby is more at risk of poor outcomes. The researchers involved in this study had already done previous work looking at protein profiles in the amniotic fluid (the liquid directly surrounding the developing fetus). They identified a set of four protein “markers” that were closely associated with inflammation in the amniotic fluid, and developed a score based on those proteins, which they termed the “Mass Restricted” (MR) score. The researchers showed that this score could accurately identify women at risk of preterm delivery. However, before using the protein marker score in clinical practice it is very important to really be sure it is a reliable diagnostic test for preterm birth and adverse outcomes resulting from preterm birth. Therefore the researchers wanted to find out whether MR scores were associated with the outcome of pregnancy; the presence of infection in the placenta, as detected through microscopic analysis of tissue; and sepsis (severe infection) in the newborn baby.
What Did the Researchers Do and Find?
The study was based on findings from pregnant women presenting at the Yale-New Haven Hospital with symptoms of premature labor, who were all followed up to the point of delivery of the baby. In all cases the decisions about how to manage the pregnancy (for example, whether to deliver the baby or attempt to delay birth) were made by the woman and her physician, not by any procedures laid out in the research study. A total of 169 women were recruited into the study and had a sample of amniotic fluid taken as part of their routine clinical management. The researchers then analyzed this fluid to calculate the protein MR score, to look for evidence of bacterial infection, and also carried out standard laboratory tests. After childbirth the placenta was examined under the microscope to look for any evidence of inflammation. Finally, all babies were checked for any evidence of sepsis. The researchers found that, in line with findings from their previous studies, women with a higher MR score gave birth sooner. There also seemed to be a close agreement between the MR score and evidence of inflammation in the placenta, once it was analyzed under the microscope after birth. Furthermore, mothers with a high MR score were more likely to give birth to babies with suspected or confirmed sepsis. The researchers then compared the usefulness of the MR score against other potential tests for inflammation. Of all the tests compared, the MR score seemed to be the most accurate in predicting inflammation.
What Do These Findings Mean?
This study showed that the MR score was closely associated with a number of different indicators of poor outcome in preterm birth. These outcomes included sooner deliveries, sepsis in the baby, and inflammation in the placenta. In future, the MR score may provide a useful test for recognizing women at risk of preterm delivery and babies at risk of poor outcome. However, further evaluation of the test will still need to be done before it could become a standard procedure in the clinic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040018.
Information from the US National Institutes of Health on premature babies
The March of Dimes is a US charity that funds research into prematurity
Information from Wikipedia about proteomics the area of research used to develop the protein score examined here (note: Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040018
PMCID: PMC1769412  PMID: 17227133

Results 1-25 (679939)