The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II.

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.

Primipaternities and human birthweights.

OBJECTIVES: To investigate in singleton multiparous pregnancies the effect of having a new father for an index pregnancy on new-borns' birthweights and intrauterine growth restriction. DESIGN: 20 year-observational cohort study (2001-2020). SETTINGS: Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity (French overseas department, Indian Ocean). MAIN OUTCOMES AND MEASURES: Comparing the 811 multiparas (cases) who had a new partner with the 49,712 who did not (controls), there were no differences concerning maternal age, education, ovulation induction/IVF, previous miscarriages, exams during pregnancies, pre-pregnancy BMI, gestational diabetes, and chronic hypertension. Cases had more previous pregnancies than controls (gravidity 4.2 vs 2.8, p < 0.001), volunteer abortions (OR1.93, p < 0.001), in vitro fecundations (OR 4.34, p < 0.001), were more likely to be unmarried (OR 2.94, p < 0.001) smoker (OR 2.2, p < 0.0001) and consuming alcohol during pregnancy (OR 2.35, p = 0.001). Cases had a much higher risk of preeclampsia than controls (OR 3.94, p < 0.001), especially early-onset preeclampsia (< 34 weeks) with an OR 4.1 (p < 0.001). Controlling for confounding factors (preeclampsia, smoking, alcohol use, early prematurity < 33 weeks, maternal ethnicity), primipaternity was an independent factor for small for gestational age newborns (OR 1.48, p < 0.001). CONCLUSIONS: It has been known for decades that primiparas have lighter babies than multiparas. Primipaternity represents also a risk for lower birth weights. Human birthweight seems to be linked with a "couple habituation" (to paternal genes) which may be not fully established in the first pregnancy of the couple.

Pregnancy and neonatal outcomes in women with immune mediated inflammatory diseases exposed to anti-tumor necrosis factor-α during pregnancy: A systemic review and meta-analysis.

BACKGROUND: Anti-TNFα is increasingly used as treatment for immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and psoriasis (PS). However, the impact of anti-TNFα during pregnancy on mother and newborn is under debate. This requires a sound knowledge of the effects of this treatment on pregnancy and neonatal outcomes. OBJECTIVES: To assess pregnancy and neonatal outcomes after anti-TNFα therapy during pregnancy in women with IMID, specifically IBD, RA and PS. METHODS: We performed a systematic review and meta-analysis of 39 studies assessing pregnancy and neonatal outcomes of women with IMID exposed to anti-TNFα agents during pregnancy. We used a random-effects model to determine pooled outcome measures. RESULTS: An increased risk of preterm births (OR 1.45, 95% CI = 1.16 to 1.82, p = 0.001) and infections in newborns (OR 1.12, 95% CI = 1.00 to 1.27, p = 0.05)) was seen for women in the combined group of IMID exposed to anti-TNFα compared to diseased controls. Specifically for IBD patients exposed to anti-TNFα, the risk was increased for preterm birth (OR 1.66, 95% CI = 1.14 to 2.42, p = 0.009), and low birth weight (OR 1.49, 95% CI = 1.01 to 2.20, p = 0.047) compared to diseased controls. Combined data from studies of women with RA and PS, showed no increased risk for adverse pregnancy outcome after exposure to anti-TNFα. Most children of mothers with IMID received vaccination according to national vaccination schemes and only minor adverse events were reported. CONCLUSION: Exposure to anti-TNFα agents during pregnancy is associated with increased risk of preterm birth and infections in newborns of women with IMID compared to diseased controls. The risk of preterm birth and low birth weight was increased in women with IBD specifically. The increased risk of infections in newborns underlines the importance of vaccination, which seems to be safe in children exposed to anti-TNFα. Delay of vaccination is therefore unnecessary in these children. These data may aid in balancing the continuing anti-TNFα therapy versus the risk of adverse pregnancy outcomes.

Mechanisms of brain injury in newborn infants associated with the fetal inflammatory response syndrome.

The fetal inflammatory response syndrome (FIRS) is characterized by umbilical cord inflammation and elevated fetal pro-inflammatory cytokines. Surviving neonates, especially very preterm infants, have increased rates of neonatal morbidity including neurodevelopmental impairment. The mechanism of brain injury in FIRS is complex and may involve "multiple hits." Exposure to in utero inflammation initiates a cascade of the fetal immune response, where pro-inflammatory cytokines can cause direct injury to oligodendrocytes and neurons. Activation of microglia results in further injury to vulnerable pre-myelinating oligodendrocytes and influences the integrity of the fetal and newborn's blood-brain barrier, resulting in further exposure of the brain to developmental insults. Newborns exposed to FIRS are frequently exposed to additional perinatal and postnatal insults that can result in further brain injury. Future directions should include evaluations for new therapeutic interventions aimed at reducing brain injury by dampening FIRS, inhibition of microglial activation, and regeneration of immature oligodendrocytes.

Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants.

BACKGROUND: Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight (LBW) infants. Preterm infants are deficient in immunoglobulin G (IgG); therefore, administration of intravenous immunoglobulin (IVIG) may have the potential of preventing or altering the course of nosocomial infections. OBJECTIVES: To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safe in preventing nosocomial infection. SEARCH METHODS: For this update, MEDLINE, EMBASE, CINAHL, The Cochrane Library, Controlled Trials, ClinicalTrials.gov and PAS Abstracts2view were searched in May 2013. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) in which a group of participants to whom IVIG was given was compared with a control group that received a placebo or no intervention for preterm (< 37 weeks' gestational age) and/or LBW (< 2500 g) infants. Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in which the follow-up period was one week or less. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identified in May 2013. When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I2 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I2 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I2 = 21%) or low heterogeneity for RD was documented (I2 = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies. AUTHORS' CONCLUSIONS: IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects. The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.

Effectiveness of the 10-valent pneumococcal conjugate vaccine among girls, boys, preterm and low-birth-weight infants - Results from a randomized, double-blind vaccine trial.

BACKGROUND: Several studies have shown differences in susceptibility to infections and immune response to vaccines by sex. Prematurely born infants are at higher risk for pneumococcal diseases, with lower effectiveness for some vaccines compared to term infants. We have reported the effectiveness of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on several endpoints in the Finnish Invasive Pneumococcal disease (FinIP) vaccine trial. Now, we present the results of a post-hoc analysis evaluating PHiD-CV10 effectiveness in subgroups by sex, gestational age, and birth weight. METHODS: The FinIP trial was a phase III/IV cluster-randomized, double-blind trial. Infants enrolled < 7 months of age received PHiD-CV10 in two thirds of clusters (3 + 1 or 2 + 1 schedule) and hepatitis B vaccine as control in remaining third. Outcome data included invasive pneumococcal disease, pneumonia, tympanostomy tube placements, and antimicrobial purchases collected through national, routinely used health registers. Negative binomial model was used in the incidence and vaccine effectiveness estimation, and differences in incidences between subgroups were tested among control children. RESULTS: Of the 30,527 infants enrolled 51% were boys. The incidences of hospital-diagnosed pneumonia and otitis-related outcomes were higher among boys in control groups. There were no significant sex differences in the vaccine effectiveness estimates. Altogether, 1519 (5%) infants were born before 37th gestational week. The incidences of pneumonia outcomes were higher among premature infants when compared to term infants. The vaccine effectiveness estimates among preterm infants were not statistically significant except for antimicrobial purchases, but all point estimates were at the same level among preterm infants as among term infants. There was no significant difference between 2 + 1 and 3 + 1 schedules in any of the subgroups analysed. CONCLUSION: PHiD-CV10 had a similar effectiveness in both sexes, and seemed to be protective in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00861380 and NCT00839254.

Antiphospholipid syndrome characteristics and adverse pregnancy outcomes after 20 weeks of pregnancy.

OBJECTIVE: To assess outcomes after 20 weeks of pregnancy according to autoantibody profile and clinical presentation of maternal antiphospholipid syndrome (APS). METHODS: The present retrospective cohort analysis included women diagnosed with APS at a tertiary medical center in Israel between January 1, 2012, and December 31, 2016. Anticardiolipin antibodies, anti-ß2-glycoprotein antibodies, and lupus anticoagulant were assessed. Participants were stratified by type of APS (obstetric vs thrombotic), antibody profile, and antibody titer (low vs high). Primary composite outcomes were rated as severe (stillbirth, fetal growth restriction at <34 weeks, severe pre-eclampsia, or delivery at <32 weeks) and mild (stillbirth, any fetal growth restriction, any pre-eclampsia, or delivery at <34 weeks). RESULTS: A total of 99 women were included in the analysis. The primary composite outcomes were similar regardless of stratification. Lupus anticoagulant positivity was associated with delivery before 37 weeks. When compared with low antibody titer, high antibody titer was associated delivery at or before 32 weeks (P=0.045) and 34 weeks (P=0.029). CONCLUSION: High antibody titer might be associated with an increased risk of severe prematurity among pregnant women with APS.

Low birth weight contributed to increased serum IL-6 levels in infantile respiratory syncytial virus infection.

BACKGROUND: To evaluate the role of serum cytokines in the pathogenesis of respiratory syncytial virus (RSV) infection in infants with low birth weight (LBW). METHODS: A prospective observational study was performed, and hospitalized children with lower respiratory tract infection (LRTI) were recruited. Three hundred fifty-eight patients < 1 year met the inclusion criteria: 116 patients had only RSV infection (RSV group); 242 patients had no RSV or other specific pathogen (non-RSV group). Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected through flow cytometry. RESULTS: No significant differences in serum IL-2, 4, 6, 10, and IFN-γ levels were observed between the RSV and non-RSV groups. For RSV infected infants with or without wheezing, delivery mode had no obvious effect on the changes of serum cytokine levels. However, the level of IL-6 in the RSV-infected infants with LBW was significantly higher than that in infants with normal birth weight. CONCLUSIONS: Serum IL-6 level was significantly increased in RSV infected infants with LBW. It is likely that the specific serum cytokine pattern will contribute to our understanding of the pathogenesis of RSV infections, especially in RSV-infected infants with LBW.

Bifidobacterium bifidum OLB6378 Simultaneously Enhances Systemic and Mucosal Humoral Immunity in Low Birth Weight Infants: A Non-Randomized Study.

Probiotic supplementation has been part of the discussion on methods to enhance humoral immunity. Administration of Bifidobacterium bifidum OLB6378 (OLB6378) reduced the incidence of late-onset sepsis in infants. In this non-randomized study, we aimed to determine the effect of administration of live OLB6378 on infants' humoral immunity. Secondly, we tried to elucidate whether similar effects would be observed with administration of non-live OLB6378. Low birth weight (LBW) infants weighing 1500-2500 g were divided into three groups: Group N (no intervention), Group L (administered live OLB6378 concentrate), and Group H (administered non-live OLB6378 concentrate). The interventions were started within 48 h after birth and continued until six months of age. Serum immunoglobulin G (IgG) levels (IgG at one month/IgG at birth) were significantly higher in Group L than in Group N (p < 0.01). Group H exhibited significantly higher serum IgG levels (p < 0.01) at one month of age and significantly higher intestinal secretory immunoglobulin A (SIgA) levels (p < 0.05) at one and two months of age than Group N. No difference was observed in the mortality or morbidity between groups. Thus, OLB6378 administration in LBW infants enhanced humoral immunity, and non-live OLB6378, which is more useful as a food ingredient, showed a more marked effect than the viable bacteria.

DOHaD at the intersection of maternal immune activation and maternal metabolic stress: a scoping review.

The prenatal environment is now recognized as a key driver of non-communicable disease risk later in life. Within the developmental origins of health and disease (DOHaD) paradigm, studies are increasingly identifying links between maternal morbidity during pregnancy and disease later in life for offspring. Nutrient restriction, metabolic disorders during gestation, such as diabetes or obesity, and maternal immune activation provoked by infection have been linked to adverse health outcomes for offspring later in life. These factors frequently co-occur, but the potential for compounding effects of multiple morbidities on DOHaD-related outcomes has not received adequate attention. This is of particular importance in low- or middle-income countries (LMICs), which have ongoing high rates of infectious diseases and are now experiencing transitions from undernutrition to excess adiposity. The purpose of this scoping review is to summarize studies examining the effect and interaction of co-occurring metabolic or nutritional stressors and infectious diseases during gestation on DOHaD-related health outcomes. We identified nine studies in humans - four performed in the United States and five in LMICs. The most common outcome, also in seven of nine studies, was premature birth or low birth weight. We identified nine animal studies, six in mice, two in rats and one in sheep. The interaction between metabolic/nutritional exposures and infectious exposures had varying effects including synergism, inhibition and independent actions. No human studies were specifically designed to assess the interaction of metabolic/nutritional exposures and infectious diseases. Future studies of neonatal outcomes should measure these exposures and explicitly examine their concerted effect.

Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial.

Background: BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods: In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results: Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion: Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration: NCT00625482.

Contribution of Histologic Chorioamnionitis and Fetal Inflammatory Response Syndrome to Increased Risk of Brain Injury in Infants With Preterm Premature Rupture of Membranes.

BACKGROUND: To determine the association of histologic chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) with brain injuries in infants born to mothers with preterm premature rupture of membranes. METHODS: A total of 103 singleton infants born to mothers with preterm premature rupture of membranes were enrolled. The placental inflammation was confirmed by HCA, and FIRS was defined in fetuses with preterm labor and an elevation of the fetal plasma interleukin-6 concentration. Examination of brain images was conducted to confirm the existence of brain injuries. Based on placental HCA and umbilical cord blood interleukin-6 level, all patients were divided into three groups: HCA(-)FIRS(+), HCA(+)FIRS(-), and HCA(+)FIRS(+). RESULTS: Among all infants with preterm premature rupture of membranes, 53.40% were exposed to HCA, 20.38% experienced FIRS, and the overall incidence of brain injuries was 38.83%. The incidence of brain injury in HCA(-)FIRS(+), HCA(+)FIRS(-), and HCA(+)FIRS(+) groups were 20.83%, 41.18%, and 76.19%, respectively. HCA at the advanced grades and stages was associated with increased risk of brain injury. Umbilical cord blood levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and granulocyte-colony stimulating factor (G-CSF) in premature infants with brain injuries were significantly higher than in those without brain injuries. Infants diagnosed with both HCA and FIRS showed significantly higher levels of IL-8, TNF-α, and G-CSF than those with HCA alone. CONCLUSIONS: Preterm infants exposed to severe chorioamnionitis had an increased risk of brain injury. IL-6, IL-8, TNF-α, and G-CSF in cord blood were associated with brain injuries in preterm infants and may be used as extradiagnostic criteria.

Prospective neonatal screening for severe T- and B-lymphocyte deficiencies in Seville.

BACKGROUND: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected children. T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T- and/or B-lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values. METHODS: TRECs and KRECs determination using triplex RT-PCR (TRECS-KRECS-ß-actin-Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and -ß-actin>700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included. RESULTS: A total of 5160 DBS were tested. Re-punch was needed in 77 samples (1.5%) due to insufficient ß-actin (<700 copies/punch). Pre-term neonates (GA<37 weeks) and neonates with a BW<2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeat positive results five neonates were re-called (<0.1%): Fatal chromosomopathy (n = 1; TRECs 1/KRECs 4); extreme pre-maturity (n = 2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n = 2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified. CONCLUSIONS: TRECS-KRECS-ß-actin-Assay correctly identifies T- and B-cell lymphopenias. Pre-maturity and low BW is associated with lower TREC and KREC levels. Extreme pre-maturity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved.

Maternal anti-HLA class I antibodies are associated with reduced birth weight in thrombocytopenic neonates.

In this comparative cross-sectional study, possible associations between maternal anti-HLA class I antibodies and birth weight in neonatal thrombocytopenia are explored. Although commonly detected in pregnancies and generally regarded as harmless, it has been suggested that such antibodies might be associated with fetal and neonatal alloimmune thrombocytopenia (FNAIT). As a link between FNAIT due to human platelet antigen 1a-specific antibodies and reduced birth weight in boys has previously been demonstrated, we wanted to explore whether maternal anti-HLA class I antibodies might also affect birth weight. To examine this, suspected cases of FNAIT referred to the Norwegian National Unit for Platelet Immunology during the period 1998-2009 were identified. Pregnancies where the only finding was maternal anti-HLA class I antibodies were included. An unselected group of pregnant women participating in a prospective study investigating maternal-fetal hemodynamics at the University Hospital North Norway during the years 2006-2010 served as controls. Twenty-nine percent of controls had anti-HLA class I antibodies. The thrombocytopenic neonates had a significantly lower adjusted birth weight (linear regression, P=0.036) and significantly higher odds of being small for gestational age (OR=6.72, P<0.001) compared with controls. Increasing anti-HLA class I antibody levels in the mother were significantly associated with lower birth weight and placental weight among thrombocytopenic neonates, but not among controls. These results indicate that maternal anti-HLA class I antibodies in thrombocytopenic neonates are associated with reduced fetal growth. Further studies are needed to test if placental function is affected.

Prematurity and Low Birth Weight did not Correlate with Anti-Toxoplasma gondii Maternal Serum Profiles--a Brazilian Report.

Gestational Toxoplasma gondii infection is considered a major risk factor for miscarriage, prematurity and low birth weight in animals. However, studies focusing on this topic in humans are scarce. The objective of this study is to determine whether anti-Toxoplasma gondii maternal serum profiles correlate prematurity and low birth weight in humans. The study examined 213 pregnant women seen at the High-Risk Pregnancy Hospital de Base, São José do Rio Preto, São Paulo, Brazil. All serological profiles (IgM-/IgG+; IgM-/IgG-; IgM+/IgG+) were determined by ELISA commercial kits. Maternal age, gestational age and weight of the newborn at birth were collected and recorded in the Statement of Live Birth. Prematurity was defined as gestational age <37 weeks and low birth weight ≤ 2499 grams. The t-test was used to compare values (p < 0.05). The mean maternal age was 27.6±6.6 years. Overall, 56.3% (120/213) of the women studied were IgM-/IgG+, 36.2% (77/213) were IgM-/IgG- and 7.5% (16/213) were IgM+/IgG+. The average age of the women with serological profile IgM+/IgG+ (22.3±3.9 years) was different from women with the profile IgM-/IgG+ (27.9±6.7 years, p = 0.0011) and IgM-/IgG- (27.9±6.4 years, p = 0.0012). There was no statistically significant difference between the different serological profiles in relation to prematurity (p = 0.6742) and low birth weight (p = 0.7186). The results showed that prematurity and low birth weight did not correlate with anti-Toxoplasma gondii maternal serum profiles.

Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial.

INTRODUCTION: Bacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro. METHODS: 1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses. RESULTS: At 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p<0.01) and subsequent batches (4.8mm, p=0.03). Compared with Normal growth batches, the Slow growth batches were associated with a higher prevalence of positive PPD responses, and among PPD positive children, a larger PPD reaction (geometric mean ratio: 1.40 (1.20-1.63)) at 2 months. In response to secondary heterologous stimulation, monocytes primed with Slow growth batches induced higher IL-6 (p=0.03) and TNF-α responses (p=0.03) compared with Normal growth batches. CONCLUSION: The study indicates that variations in the production of BCG vaccine may influence important immunological effects of the vaccine. TRIAL REGISTRATION: clinicaltrials.gov (NCT00625482).

Pertussis in infants under one year old: risk markers and vaccination status--a case-control study.

BACKGROUND: Pertussis is a contagious bacterial disease causing substantial health burden. Pertussis-related morbidity and mortality are highest in young infants. We investigated risk markers for pertussis and vaccination status in infants. METHODS: Reported pertussis cases under one year old during 1998-2011 in the Jerusalem district were matched to controls by birthdate and residence. Data sources included epidemiological investigations, health records and vaccination records (number and dates of DTP\DTaP doses scheduled at 2, 4, 6 months). Vaccine effectiveness was calculated by number of vaccine doses stratified by age group. Timeliness of vaccine doses was also evaluated. RESULTS: The study population included 1268 infants under 1 year: 317 pertussis cases and 951 age-matched controls (mean age 3.95±3, median 2.9 months). Low birthweight (<2500g, 12.3% in cases vs. 6.3% in controls) and high birth order (4th and above) were found to be independent risk markers. Male gender and low socio-economic status were more frequent among cases. Some 40% of the cases (127/317) were hospitalized, most of them (111/127, 87.4%) were under 4 months (mean age 2.42±2.05, median 1.8 months). The distribution of the number of pertussis vaccine doses 0, 1, 2 and 3 differed considerably being 42.2%, 32.7%, 15.6%, 9.5% vs. 13.7%, 41.9%, 22.9%, 21.5% among cases and controls (≥2m), respectively. The overall vaccine effectiveness found was 72.9%, 76.1% and 84.4%, for the 1st, 2nd and 3rd doses of a pertussis vaccine. The infant's age at the first dose of pertussis vaccine was recorded with follow-up until age 18 months. Delay was more common among cases with a lower proportion vaccinated-78.9% at 18 months vs. 99% in controls. CONCLUSIONS: Specific risk markers for pertussis in young infants were identified. Reported pertussis cases over age 2 months were significantly more likely to be unvaccinated and have delayed vaccinations. The vaccine effectiveness increased with the number of vaccine doses.

Associations between thyroid autoantibody status and abnormal pregnancy outcomes in euthyroid women.

We investigated whether thyroid autoantibody status influences pregnancy outcomes in euthyroid women, by comparing abnormal pregnancy outcome rates between those who tested positive for thyroid autoantibodies (Ab+) and those who tested autoantibody-negative (Ab-). Euthyroid pregnant women (n=7,641) underwent tests for serum thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). The subjects were divided into 4 groups according to thyroid antibody status: TPOAb-/TgAb- (92.9%); TPOAb+/TgAb- (3.2%); TPOAb-/TgAb+ (2.0%); and TPOAb+/TgAb+ (1.9%). The incidence rates of the following abnormal pregnancy outcomes were compared among the 4 groups and analyzed by Fisher's exact test: gestational diabetes, gestational hypertension, placenta previa, placental abruption, premature rupture of fetal membrane (PROM), intrauterine growth restriction, fetal distress, fetal anomalies, stillbirth, preterm birth, and low birth weight. Among the 4 groups, there were no significant differences in age, gestational age, or in the incidence rates of abnormal pregnancy outcomes, except for PROM and low birth weight. The highest incidence rates for PROM and low birth weight were in the TPOAb-/TgAb+ and TPOAb+/TgAb+ subjects, respectively. TgAb positivity and TPOAb positivity were associated with PROM and low birth weight, respectively. Underlying factors that govern the association between thyroid autoantibodies and PROM and low birth weight require further investigation.

IgM-antibodies against phosphorylcholine in mothers and normal or low birth weight term newborn infants.

OBJECTIVE: To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants. APPROACH: Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter <2SD below the Swedish reference data mean for normal fetal growth. All infants were born at term (mean ± SD 40.5 ± 1.1 weeks). Serum was available from 6 mothers with SGA and 14 with NGA infants. Participating mothers were aged 34.0 ± 3.9 years (no difference between groups). Fourteen neonates were boys and seven were girls. Levels of anti-PC IgM were determined by ELISA. RESULTS: Neonatal IgM anti-PC levels were low (undetectable in 8 infants out of which 3 were SGA) with a median of 76[range 0-2.51] U/ml. Maternal IgM anti-PC levels were significantly higher (median 7198[range: 25.32-656.0]) U/ml) and the proportion of mothers in highest quartile (>75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032). CONCLUSIONS: IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a "housekeeping" role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring.

Vaccination of preterm infants by polyvalent vaccines: immunogenicity and safety- review of literature.

The immunization of infants against infectious diseases still raises many controversies, not only with parents, but also among physicians. This refers particularly to preterm infants. Due to the increasing popularity of polyvalent vaccines, a number of studies has recently been conducted to verify their immunogenicity and safety in preterm infants. The aim of the present paper was to review the current literature dealing with the problem in question. The following recommendations regarding the use of polyvalent vaccines in preterm infants and neonates with low birth weight can be formulated on the basis of current evidence (1). Due to sufficient immunogenicity, polyvalent vaccines can be administered to preterm infants in accordance with their calendar age (2). Booster vaccination of preterm infants after completing 12 months of age is vital for achieving complete and persistent immunity against all vaccine antigens (3). In order to reduce the risk of adverse events after the administration of a polyvalent vaccine, it is essential to carefully consider the cardiorespiratory status of preterm infants during preimmunization examination, as well as their history of any cardiorespiratory dysfunctions. In such cases administering the first dose of the vaccine in a hospital setting is strongly advised.