Hematopoietic Stem Cells in Neonates: Any Differences between Very Preterm and Term Neonates?

Background

In the last decades, human full-term cord blood was extensively investigated as a potential source of hematopoietic stem and progenitor cells (HSPCs). Despite the growing interest of regenerative therapies in preterm neonates, only little is known about the biological function of HSPCs from early preterm neonates under different perinatal conditions. Therefore, we investigated the concentration, the clonogenic capacity and the influence of obstetric/perinatal complications and maternal history on HSPC subsets in preterm and term cord blood.

Methods

CD34+ HSPC subsets in UCB of 30 preterm and 30 term infants were evaluated by flow cytometry. Clonogenic assays suitable for detection of the proliferative potential of HSPCs were conducted. Furthermore, we analyzed the clonogenic potential of isolated HSPCs according to the stem cell marker CD133 and aldehyde dehydrogenase (ALDH) activity.

Results

Preterm cord blood contained a significantly higher concentration of circulating CD34+ HSPCs, especially primitive progenitors, than term cord blood. The clonogenic capacity of HSPCs was enhanced in preterm cord blood. Using univariate analysis, the number and clonogenic potential of circulating UCB HSPCs was influenced by gestational age, birth weight and maternal age. Multivariate analysis showed that main factors that significantly influenced the HSPC count were maternal age, gestational age and white blood cell count. Further, only gestational age significantly influenced the clonogenic potential of UCB HSPCs. Finally, isolated CD34+/CD133+, CD34+/CD133– and ALDH^high HSPC obtained from preterm cord blood showed a significantly higher clonogenic potential compared to term cord blood.

Conclusion

We demonstrate that preterm cord blood exhibits a higher HSPC concentration and increased clonogenic capacity compared to term neonates. These data may imply an emerging use of HSPCs in autologous stem cell therapy in preterm neonates.     

Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry

Background

Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood.

Methods

Sixty mothers of extremely preterm (<28 weeks gestational age), very preterm (28–31 wk), and moderately preterm (32–36 wk), as well as term (37–41 wk) infants were recruited. Colostrum (d2–5), transitional (d8–12) and mature milk (d26–30) samples were collected, cells isolated, and leukocyte subsets analysed using flow cytometry.

Results

The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed.

Conclusions

Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk.     

Benefits of Bifidobacterium breve M-16V Supplementation in Preterm Neonates - A Retrospective Cohort Study

Background

Systematic reviews of randomised controlled trials report that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm neonates.

Aim

To determine whether routine probiotic supplementation (RPS) to preterm neonates would reduce the incidence of NEC.

Methods

The incidence of NEC ≥ Stage II and all-cause mortality was compared for an equal period of 24 months ‘before’ (Epoch 1) and ‘after’ (Epoch 2) RPS with Bifidobacterium breve M-16V in neonates <34 weeks. Multivariate logistic regression analysis was conducted to adjust for relevant confounders.

Results

A total of 1755 neonates (Epoch I vs. II: 835 vs. 920) with comparable gestation and birth weights were admitted. There was a significant reduction in NEC ≥ Stage II: 3% vs. 1%, adjusted odds ratio (aOR) = 0.43 (95%CI: 0.21–0.87); ‘NEC ≥ Stage II or all-cause mortality’: 9% vs. 5%, aOR = 0.53 (95%CI: 0.32–0.88); but not all-cause mortality alone: 7% vs. 4%, aOR = 0.58 (95% CI: 0.31–1.06) in Epoch II. The benefits in neonates <28 weeks did not reach statistical significance: NEC ≥ Stage II: 6% vs. 3%, aOR 0.51 (95%CI: 0.20–1.27), ‘NEC ≥ Stage II or all-cause mortality’, 21% vs. 14%, aOR = 0.59 (95%CI: 0.29–1.18); all-cause mortality: 17% vs. 11%, aOR = 0.63 (95%CI: 0.28–1.41). There was no probiotic sepsis.

Conclusion

RPS with Bifidobacterium breve M-16V was associated with decreased NEC≥ Stage II and ‘NEC≥ Stage II or all-cause mortality’ in neonates <34 weeks. Large sample size is required to assess the potential benefits of RPS in neonates <28 weeks.     

Presepsin (Soluble CD14 Subtype): Reference Ranges of a New Sepsis Marker in Term and Preterm Neonates

Objective

Presepsin (soluble CD14 subtype) has been shown to be beneficial as a sepsis marker in adults. Nevertheless, very few data are available in neonates. The aim of the present study was to determine reference ranges of presepsin in term and preterm neonates.

Methods

Healthy term neonates and preterm neonates without clinical signs of infection admitted to the Neonatal Unit were consecutively enrolled. Presepsin concentrations in whole blood were measured using a point-of-care assay system located in the Unit. Demographic data, antenatal and perinatal variables commonly affecting C-reactive protein and procalcitonin values were considered.

Results

Of the 684 neonates enrolled in the study, 484 (70.8%) were born at term and 200 (29.2%) were preterm (24–36 weeks’ gestation). In term infants, presepsin median value was 603.5 pg/mL (interquartile range: 466.5–791 pg/mL; 5th and 95th centiles: 315 and 1178 pg/mL respectively). In preterm infants, presepsin median value was slightly higher, equal to 620 pg/mL (interquartile range: 503–864 pg/mL; 5th and 95th centiles: 352 and 1370 pg/mL respectively). The reference ranges of presepsin we determined were much higher than those seen in healthy adults. No correlation between presepsin levels and postnatal age was observed, as well as no significant difference was demonstrated in preterm neonates at different gestational ages. None of the variables analyzed affected presepsin levels at a clinical significant extent.

Conclusion

For the first time, this study provides reference ranges of presepsin in term and preterm neonates. Having reliable reference values is crucial for obtaining an adequate diagnostic accuracy. Based on our results, most variables commonly affecting C-reactive protein and procalcitonin values do not affect presepsin levels, which suggests that presepsin could be an effective sepsis marker. Further investigations in large groups of neonates with sepsis are needed to determine the diagnostic and prognostic value of this biomarker.     

Comparison of the Combined versus Conventional Apgar Scores in Predicting Adverse Neonatal Outcomes

Objectives

Assessing the value of the Combined-Apgar score in predicting neonatal mortality and morbidity compared to the Conventional-Apgar.

Methods

This prospective cohort study evaluated 942 neonates (166 very preterm, 233 near term, and 543 term) admitted to a tertiary referral hospital. At 1- and 5-minutes after delivery, the Conventional and Combined Apgar scores were recorded. The neonates were followed, and the following information was recorded: the occurrence of severe hyperbilirubinemia requiring medical intervention, the requirement for mechanical ventilation, the occurrence of intraventricular hemorrhage (IVH), and neonatal mortality.

Results

Before adjusting for the potential confounders, a low Conventional (<7) or Combined (<10) Apgar score at 5-minutes was associated with adverse neonatal outcomes. However, after adjustment for the gestational age, birth weight and the requirement for neonatal resuscitation in the delivery room, a depressed 5-minute Conventional-Apgar score lost its significant associations with all the measured adverse outcomes; after the adjustments, a low 5-minute Combined-Apgar score remained significantly associated with the requirement for mechanical ventilation (OR,18.61; 95%CI,6.75–51.29), IVH (OR,4.8; 95%CI,1.91–12.01), and neonatal mortality (OR,20.22; 95%CI,4.22–96.88). Additionally, using Receiver Operating Characteristics (ROC) curves, the area under the curve was higher for the Combined-Apgar than the Conventional-Apgar for the prediction of neonatal mortality and the measured morbidities among all the admitted neonates and their gestational age subgroups.

Conclusions

The newly proposed Combined-Apgar score can be a good predictor of neonatal mortality and morbidity in the admitted neonates, regardless of their gestational age and resuscitation status. It is also superior to the Conventional-Apgar in predicting adverse neonatal outcomes in very preterm, near term and term neonates.     

Morbidity and Mortality According to Latest CD4+ Cell Count among HIV Positive Individuals in South Africa Who Enrolled in Project Phidisa

Background

Short-term morbidity and mortality rates for HIV positive soldiers in the South African National Defence Force (SANDF) would inform decisions about deployment and HIV disease management. Risks were determined according to the latest CD4+ cell count and use of antiretroviral therapy (ART) for HIV positive individuals in the SANDF and their dependents.

Methods and Findings

A total of 7,114 participants were enrolled and followed for mortality over a median of 4.7 years (IQR: 1.9, 7.1 years). For a planned subset (5,976), progression of disease (POD) and grade 4, potentially life-threatening events were also ascertained. CD4+ count and viral load were measured every 3 to 6 months. Poisson regression was used to compare event rates by latest CD4+ count (<50, 50–99, 100–199, 200–349, 350–499, 500+) with a focus on upper three strata, and to estimate relative risks (RRs) (ART/no ART). Median entry CD4+ was 207 cells/mm³. During follow-up over 70% were prescribed ART. Over follow-up 1,226 participants died; rates ranged from 57.6 (< 50 cells) to 0.8 (500+ cells) per 100 person years (py). Compared to those with latest CD4+ 200–349 (2.2/100py), death rates were significantly lower (p<0.001), as expected, for those with 350–499 (0.9/100py) and with 500+ cells (0.8/100py). The composite outcome of death, POD or grade 4 events occurred in 2,302 participants (4,045 events); rates were similar in higher CD4+ count strata (9.4 for 350–499 and 7.9 for 500+ cells) and lower than those with counts 200–349 cells (13.5) (p<0.001). For those with latest CD4+ 350+ cells, 63% of the composite outcomes (680 of 1,074) were grade 4 events.

Conclusion

Rates of morbidity and mortality are lowest among those with CD4+ count of 350 or higher and rates do not differ for those with counts of 350–499 versus 500+ cells. Grade 4 events are the predominant morbidity for participants with CD4+ counts of 350+ cells.     

Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

Background

Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence.

Methods

Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes.

Results

Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P < 0.001) with moderate heterogeneity (Cochrane’s Q test: P = 0.02, I² = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (P < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (P > 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001).

Conclusions

Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies.     

Antenatal Corticosteroids for Reducing Adverse Maternal and Child Outcomes in Special Populations of Women at Risk of Imminent Preterm Birth: A Systematic Review and Meta-Analysis

Background

This study synthesizes available evidence on antenatal corticosteroids (ACS) use among special subgroups of women at risk of imminent preterm birth, including those (1) with pregestational and gestational diabetes mellitus, (2) undergoing elective caesarean section (CS) in late preterm (34 to<37 weeks), (3) with chorioamnionitis, and (4) with growth-restricted fetuses.

Methods

A systematic search of MEDLINE, EMBASE, CINAHL, Cochrane Library, POPLINE, and World Health Organization Regional Databases was conducted for all comparative studies. Two reviewers independently determined study eligibility, extracted data, and assessed study quality. Pooled mean differences and odds ratios with 95% confidence intervals were estimated from available data, based on fixed- and random-effects models, as appropriate.

Results

No eligible studies were identified for ACS use in diabetic pregnant women or those undergoing elective CS at late preterm. Nine studies each on ACS use in women with chorioamnionitis and in women with fetal growth restriction met inclusion criteria; eight studies were separately included in the meta-analyses for the two subpopulations. For ACS administration in women with chorioamnionitis, pooled analyses showed reductions in neonatal mortality (OR: 0.49, 95% CI: 0.34–0.73), respiratory distress syndrome (OR: 0.58, 95% CI: 0.44–0.76), intraventricular haemorrhage (OR: 0.41, 95% CI: 0.24–0.69), and severe intraventricular haemorrhage (OR: 0.40, 95% CI: 0.24–0.69). Maternal and long-term newborn outcomes were not reported. Effects of ACS use were inconclusive for cases with fetal growth restriction.

Conclusion

Direct evidence on the effectiveness and safety of ACS is lacking for diabetic pregnant women at risk of preterm birth and those undergoing elective late-preterm CS, though this does not necessarily recommend against their use in diabetic women. While evidence remains inconclusive for women with growth-restricted preterm neonates, ACS appears to benefit preterm neonates delivered by women with chorioamnionitis. High-quality studies on maternal and long-term child outcomes in more diverse settings are needed to establish the balance of potential harms versus benefits in using ACS for these understudied subgroups.     

Prenatal Exposure to Cadmium,Placental Permeability and Birth Outcomes in Coastal Populations of South Africa

Background

The impact of prenatal exposure to cadmium (Cd) on birth outcomes is an area of concern. This study aimed to assess an impact of prenatal Cd exposure on birth outcomes in distinct coastal populations of South Africa.

Methods

Cadmium was measured in maternal blood (CdB) (n = 641), cord blood and in maternal urine (n = 317). This investigation assessed the associations between CdB (non-transformed) and birth outcomes across the 25^th, 50th, and 75th percentile for birth weight, birth length and head circumference, to test for a linear trend. Associations between natural log-transformed maternal CdB, size at birth and other factors were further evaluated using linear mixed-effects modelling with random intercepts.

Results

The average gestational age in the total sample was 38 weeks; 47% of neonates were female, average birth weight was 3065 g and 11% were of low birth weight (< 2500 g). The geometric mean (GM) of the maternal CdB level was 0.25 μg/L (n = 641; 95% CI, 0.23–0.27). The cord blood Cd level was 0.27 μg/L (n = 317; 95% CI, 0.26–0.29) and urine (creatinine-corrected) Cd level was 0.27 μg/L (n = 318; 95% CI, 0.24–0.29). The CdB cord:maternal ratio in the sub-cohort was 1, suggesting that the placenta offers no protective mechanism to the foetus. An inverse association was found between CdB and the lower birth weight percentile in female neonates only (β = - 0.13, p = 0.047). Mothers who reported eating vine vegetables daily had lower levels of CdB (β = - 0.55, p = 0.025). Maternal smoking was associated with an elevation in natural log-transformed CdB levels in both male and female cohorts.

Discussion

Significant inverse associations between prenatal Cd exposure and birth anthropometry were found in female neonates but not in male neonates, suggesting potential sex differences in the toxico-kinetics and toxico-dynamics of Cd.     

Association of Gestational Age at Birth with Reasons for Subsequent Hospitalisation: 18 Years of Follow-Up in a Western Australian Population Study

Background

Preterm infants are at a higher risk of hospitalisation following discharge from the hospital after birth. The reasons for rehospitalisation and the association with gestational age are not well understood.

Methods

This was a retrospective birth cohort study of all live, singleton infants born in Western Australia between 1^st January 1980 and 31^st December 2010, followed to 18 years of age. Risks of rehospitalisation following birth discharge by principal diagnoses were compared for gestational age categories (<32, 32–33, 34–36, 37–38 weeks) and term births (39–41weeks). Causes of hospitalisations at various gestational age categories were identified using ICD-based discharge diagnostic codes.

Results

Risk of rehospitalisation was inversely correlated with gestational age. Growth-related concerns were the main causes for rehospitalisation in the neonatal period (<1 month of age) for all gestational ages. Infection was the most common reason for hospitalisation from 29 days to 1 year of age, and up to 5 years of age. Injury-related hospitalisations increased in prevalence from 5 years to 18 years of age. Risk of rehospitalisation was higher for all preterm infants for most causes.

Conclusions

The highest risks of rehospitalisation were for infection related causes for most GA categories. Compared with full term born infants, those born at shorter GA remain vulnerable to subsequent hospitalisation for a variety of causes up until 18 years of age.     

Preterm Birth and Low Birth Weight after In Utero Exposure to Antiretrovirals Initiated during Pregnancy in Yaoundé, Cameroon

Background

Effects of antiretroviral therapy (ART) on birth outcomes remain controversial.

Objective

To assess the impact of antenatal exposure to ART on the occurrence of preterm birth (PTB) and low birth weight (LBW).

Methods

A cross-sectional study conducted at the Essos Hospital Center in Yaounde from 2008 to 2011 among HIV vertically exposed infants with two distinct maternal antiretroviral experiences: monotherapy group (Zidovudine, ZDV) and the combination ART group (cART). Mothers already receiving cART before pregnancy were ineligible. In both groups, events of PTB (<37 weeks) and LBW (<2,500g) were analyzed using univariate and multivariate logistic regression; with p<0.05 considered statistically significant.

Results

Of the 760 infants, 481 were born from cART-exposed mothers against 279 from maternal-ZDV. Median maternal CD4 count was 378 [interquartile range (IQR): 253–535] cells/mm³. Median duration of ART at onset of delivery was 13 [IQR: 10–17] weeks. In the cART-group, 64.9% (312/481) of mothers were exposed to Zidovudine/Lamuvidine/Nevirapine and only 2% (9/481) were on protease inhibitor-based regimens. Events of PTB were not significantly higher in the cART-group compared to the ZDV-group (10.2% vs. 6.4% respectively, p = 0.08), while onsets of LBW were significantly found in the cART-group compared to ZDV-group (11.6% vs. 7.2% respectively, p = 0.05). Other factors (parity, maternal age at delivery or CD4 cell count) were not associated with PTB.

Conclusion

cART, initiated during pregnancy, would be an independent factor of LBW. In the era of option B+ (lifelong ART to all HIV-pregnant women), further studies would guide towards measures limiting onsets of LBW.     

The Growing Trend of Moderate Preterm Births: An Ecological Study in One Region of Brazil

Background

Preterm birth is a serious public health problem, as it is linked to high rates of neonatal and child morbidity and mortality, with Brazil listed among the countries with the ten highest numbers of premature births. Nonetheless, knowledge is scarce regarding prematurity and associated factors in mid-sized cities. The objective of this study was to analyze the trend of preterm births and associated factors in a municipality located in the state of Paraná, Brazil.

Methods

This was an ecological time series study of births recorded into the Live Birth Information System for residents of Maringá, Paraná, Brazil, between 2000 and 2013. The polynomial regression model was used for trend analysis of preterm birth, characteristics of the mother, gestation and delivery, and newborn. The association with preterm birth was analyzed using odds ratio (OR).

Results

A total of 61,634 live births were analyzed, of which 5,632 were preterm births. Prematurity increased from 7.9% in 2000 to 11.2% in 2013 –an average increase of 0.54% per year (r² = 0.93)–with a growing share of moderate preterm births (32 to <37 weeks), which rose from 7.0% in 2000 to 9.7% in 2013. Between 2011 and 2013, multiple pregnancy (OR = 16.64; CI = 13.24–20.92), inadequate number of prenatal visits (OR = 2.81; CI = 2.51–3.15), Apgar score below 7 at 1 (OR = 4.07; CI = 3.55–4.67) and 5 minutes (OR = 10.88; CI = 7.71–15.36), low birth weight (OR = 38.75; CI = 33.72–44.55) and congenital malformations (OR = 3.18; CI = 2.14–4.74) were associated with preterm birth. A growing trend was observed for multiple pregnancies, with an average annual increase of 0.32% (r² = 0.90), as well as for C-section birth (2.38% yearly increase). Of all newborn characteristics, Apgar score below 7 at 5 minutes (-0.19% per year) and low birth weight (-1.43%) decreased, whereas congenital malformations rose (0.20% per year).

Conclusions

Efforts are required to prevent premature delivery, particularly during the moderate period, as well as greater care during the prenatal period towards expectant mothers bearing multiple pregnancies, birth defects, in addition to reducing C-section birth as it may be linked to preterm birth.     

Residues 39-56 of Stem Cell Factor Protein Sequence Are Capable of Stimulating the Expansion of Cord Blood CD34+ Cells

Background

Stem cell factor (SCF) can stimulate hematopoietic stem cell (HSC) expansion; however, the specific structural region(s) of SCF protein that are critical for this function are still unknown. A novel monoclonal antibody (named 23C8) against recombinant human SCF (rhSCF) was previously found to inhibit the ability of rhSCF to enhance HSC expansion, making it possible to identify the relevant active region to HSC.

Methods

Eleven polypeptides were synthesized, which were designed to cover the full-length of rhSCF, with overlaps that are at least 3 amino acids long. ELISA was used to identify the polypeptide(s) that specifically react with the anti-SCF. The effects of the synthetic polypeptides on human HSC expansion, or on the ability of the full-length rhSCF to stimulate cell proliferation, were evaluated ex vivo. Total cell number was monitored using hemocytometer whereas CD34⁺ cell number was calculated based on the proportion determined via flow cytometry on day 6 of culture.

Results

Of all polypeptides analyzed, only one, named P0, corresponding to the SCF protein sequence at residues 39–56, was recognized by 23C8 mAb during ELISA. P0 stimulated the expansion of CD34⁺ cells derived from human umbilical cord blood (UCB). Addition of P0 increased the numbers of total mononucleated cells and CD34⁺ cells, by ~2 fold on day 6. P0 also showed partial competition against full-length rhSCF in the ex vivo cell expansion assay.

Conclusion

Residues 39–56 of rhSCF comprise a critical functional region for its ability to enhance expansion of human UCB CD34⁺ cells. The peptide P0 is a potential candidate for further development as a synthetic substitute for rhSCF in laboratory and clinical applications.     

Duration of Cord Clamping and Neonatal Outcomes in Very Preterm Infants

Background

Delayed cord clamping (DCC, ≥30s) increases blood volume in newborns and is associated with fewer blood transfusions and short-term neonatal complications. The optimal timing of cord clamping for very preterm infants should maximize placental transfusion without interfering with stabilization and resuscitation.

Aim

We compared the effect of different durations of DCC, 30-45s vs. 60-75s, on delivery room (DR) and neonatal outcomes in preterm infants <32 weeks gestational age (GA).

Methods

This is a single-center prospective observational study. Data were collected prospectively from eligible infants from two groups: 30-45s DCC group (January 2008 to February 2011, n = 187) and 60-75s DCC group (March 2011 to April 2014, n = 166).

Results

The 60-75s DCC group compared to the 30-45s DCC group had higher hematocrits at <2 hours (49.2% vs. 47.4%, p = 0.02). In infants <28 weeks GA, the 12–36 hours hematocrit was higher in the 60-75s DCC group compared to the 30-45s DCC group (47.9% vs. 42.1%, p = 0.002). The 60-75s DCC group had reductions in DR intubation (11% vs. 22%, p = 0.004), hypothermia on admission (1% vs. 5%, p = 0.01), surfactant therapy (13% vs. 28%, p = 0.001), intubation in the first 24 hours (20% vs. 34%, p = 0.004), any intubation (27% vs. 40%, p = 0.007), and any red blood cell transfusion (20% vs. 33%, p = 0.008) during the hospitalization compared to the 30-45s DCC group. These reductions remained significant after adjusting for GA, gender and >48 hours of antenatal steroid exposure. There was no difference between the two groups in neonatal death, intraventricular hemorrhage, chronic lung disease, late onset sepsis, necrotizing enterocolitis and severe retinopathy of prematurity.

Conclusion

In this study cohort increasing DCC duration from 30-45s to 60-75s is associated with decreased hypothermia on admission, neonatal respiratory interventions and red blood cell transfusions without increase in neonatal mortality and morbidities.     

Lower Transplacental Antibody Transport for Measles,Mumps, Rubella and Varicella Zoster in Very Preterm Infants

Background

Maternal antibodies, transported over the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. In term infants, this protection does not last until the first recommended measles-mumps-rubella vaccination at 14 months in the Netherlands, while these viruses still circulate. The aim of the study was to investigate the antibody concentration against measles, mumps, rubella and varicella (MMRV) in mothers and preterm infants or healthy term infants at birth.

Methods

Antibody concentrations specific for MMRV were measured in cord blood samples from preterm (gestational age <32 weeks and/or birth weight <1500 g) and term infants, and matched maternal serum samples, using a fluorescent bead-based multiplex immune-assay.

Results

Due to lower placental transfer ratios of antibodies against MMRV in 96 preterm infants (range 0.75–0.87) compared to 42 term infants (range 1.39–1.65), the preterm infants showed 1.7–2.5 times lower geometric mean concentrations at birth compared to term infants. Maternal antibody concentration is the most important determinant of infant antibody concentration against MMRV.

Conclusions

Preterm infants benefit to a lesser extent from maternal antibodies against measles, mumps, rubella and varicella than term infants, posing them even earlier at risk for infectious diseases caused by these still circulating viruses.     

The Role of Prenatal Care and Social Risk Factors in the Relationship between Immigrant Status and Neonatal Morbidity: A Retrospective Cohort Study

Background and Aim

Literature evaluating association between neonatal morbidity and immigrant status presents contradictory results. Poorer compliance with prenatal care and greater social risk factors among immigrants could play roles as major confounding variables, thus explaining contradictions. We examined whether prenatal care and social risk factors are confounding variables in the relationship between immigrant status and neonatal morbidity.

Methods

Retrospective cohort study: 231 pregnant African immigrant women were recruited from 2007–2010 in northern Spain. A Spanish population sample was obtained by simple random sampling at 1:3 ratio. Immigrant status (Spanish, Sub-Saharan and Northern African), prenatal care (Kessner Index adequate, intermediate or inadequate), and social risk factors were treated as independent variables. Low birth weight (LBW < 2500 grams) and preterm birth (< 37 weeks) were collected as neonatal morbidity variables. Crude and adjusted odds ratios (OR) were estimated by unconditional logistic regression with 95% confidence intervals (95% CI).

Results

Positive associations between immigrant women and higher risk of neonatal morbidity were obtained. Crude OR for preterm births in Northern Africans with respect to nonimmigrants was 2.28 (95% CI: 1.04–5.00), and crude OR for LBW was 1.77 (95% CI: 0.74–4.22). However, after adjusting for prenatal care and social risk factors, associations became protective: adjusted OR for preterm birth = 0.42 (95% CI: 0.14–1.32); LBW = 0.48 (95% CI: 0.15–1.52). Poor compliance with prenatal care was the main independent risk factor associated with both preterm birth (adjusted OR inadequate care = 17.05; 95% CI: 3.92–74.24) and LBW (adjusted OR inadequate care = 6.25; 95% CI: 1.28–30.46). Social risk was an important independent risk factor associated with LBW (adjusted OR = 5.42; 95% CI: 1.58–18.62).

Conclusions

Prenatal care and social risk factors were major confounding variables in the relationship between immigrant status and neonatal morbidity.     

CD4 Cell Count Trends after Commencement of Antiretroviral Therapy among HIV-Infected Patients in Tigray,Northern Ethiopia: A Retrospective Cross-Sectional Study

Background

The rate and extent of CD4 cell recovery varies widely among HIV-infected patients with different baseline CD4 cell count strata. The objective of the study was to assess trends in CD4 cell counts in HIV-infected patients after initiation of antiretroviral therapy in Tigray, Northern Ethiopia.

Methods

A retrospective cross-sectional study was conducted by reviewing medical records of HIV patients who received antiretroviral treatment at twenty health centers in Tigray region during 2008–2012. Multi-stage cluster sampling technique was employed to collect data, and the data were analyzed using SPSS version 20.0 software.

Results

The median change from baseline to the most recent CD4 cell count was +292 cells/μl. By 5 years, the overall median (inter-quartile range, IQR) CD4 cell count was 444(263-557) cells/μl while the median (IQR) CD4 cell count was 342(246-580) cells/μl among patients with baseline CD4 cell counts ≤200 cells/μl, 500(241-557) cells/μl among those with baseline CD4 cell counts of 201–350 cells/μl, and 652(537-767) cells/μl among those with baseline CD4 cell counts >350 cells/μl. Higher baseline CD4 cell counts and being male were independently associated with the risk of immunological non-response at 12 months. Furthermore, it was also investigated that these factors were significant predictors of subsequent CD4 cell recovery.

Conclusions

Patients with higher baseline CD4 cell stratum returned to normal CD4 Cell counts though they had an increased risk of immunological non-response at 12 months compared to those with the least baseline CD4 cell stratum. The findings suggest that consideration be given to initiation of HAART at a CD4 cell count >350 cells/μl to achieve better immune recovery, and to HIV-infected male patients to improve their health seeking behavior.     

Variations in Multiple Birth Rates and Impact on Perinatal Outcomes in Europe

Objective

Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level.

Methods

We used national aggregate birth data on multiple pregnancies, maternal age, gestational age (GA), stillbirth and neonatal death collected in the Euro-Peristat project (29 countries in 2010, N = 5 074 643 births). We also used European Society of Human Reproduction and Embryology (ESHRE) data on assisted conception and single embryo transfer (SET). The impact of MBR on outcomes was studied using meta-analysis techniques with random-effects models to derive pooled risk ratios (pRR) overall and for four groups of country defined by their MBR. We computed population attributable risks (PAR) for these groups.

Results

In 2010, the average MBR was 16.8 per 1000 women giving birth, ranging from 9.1 (Romania) to 26.5 (Cyprus). Compared to singletons, multiples had a nine-fold increased risk (pRR 9.4, 95% Cl 9.1–9.8) of preterm birth (<37 weeks GA), an almost 12-fold increased risk (pRR 11.7, 95% CI 11.0–12.4) of very preterm birth (<32 weeks GA). Pooled RR were 2.4 (95% Cl 1.5–3.6) for fetal mortality at or after 28 weeks GA and 7.0 (95% Cl 6.1–8.0) for neonatal mortality. PAR of neonatal death and very preterm birth were higher in countries with high MBR compared to low MBR (17.1% (95% CI 13.8–20.2) versus 9.8% (95% Cl 9.6–11.0) for neonatal death and 29.6% (96% CI 28.5–30.6) versus 17.5% (95% CI 15.7–18.3) for very preterm births, respectively).

Conclusions

Wide variations in MBR and their impact on population outcomes imply that efforts by countries to reduce MBR could improve perinatal outcomes, enabling better long-term child health.     

Characterization of Functional Antibody and Memory B-Cell Responses to pH1N1 Monovalent Vaccine in HIV-Infected Children and Youth

Objectives

We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children.

Methods

Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI) titers, avidity indices (AI), B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC) were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1.

Results

At entry, 26 (29%) subjects had pH1N1 protective HAI titers (≥1:40). pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05), but IgA ASC, IL-5, IL-13, IL-21, IFNγ and B-cell subsets did not change. Subjects with baseline HAI ≥1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNγ, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNγ responses. CD4% and viral load did not predict the immune responses post-vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27-CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets.

Conclusions

HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI≥1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response to the vaccine was dependent on B-cell subset distribution, but not on CD4 counts or viral load.

Trial Registration

ClinicalTrials.gov NCT00992836