Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Induction of labour at 39 weeks and adverse outcomes in low-risk pregnancies according to ethnicity, socioeconomic deprivation and parity: a national cohort study in England.

open access articleBackground: Ethnic and socioeconomic inequalities in obstetric outcomes are well established. However, the role of induction of labour (IOL) to reduce these inequalities is controversial, in part due to insufficient evidence. This national cohort study aimed to identify adverse perinatal outcomes associated with IOL with birth at 39 weeks of gestation (“IOL group”) compared to expectant management (“expectant management group") according to maternal characteristics in women with low-risk pregnancies. Methods and Findings: All English National Health Service (NHS) hospital births between January 2018 and March 2021 were examined. Using the Hospital Episode Statistics (HES) dataset, maternal and neonatal data (demographic, diagnoses, procedures, labour, and birth details) were linked, with neonatal mortality data from the Office for National Statistics (ONS). Women with a low-risk pregnancy were identified by excluding pregnancies with pre-existing comorbidities, previous caesarean section, breech presentation, placenta previa, gestational diabetes, or a baby with congenital abnormalities. Women with premature rupture of membranes, placental abruption, hypertensive disorders of pregnancy, amniotic fluid abnormalities, or antepartum stillbirth were excluded only from the IOL group. Adverse perinatal outcome was defined as stillbirth, neonatal death or neonatal morbidity, the latter identified using the English composite neonatal outcome indicator (E-NAOI). Binomial regression models estimated risk differences (with 95% confidence intervals) between the IOL group and the expectant management group, adjusting for ethnicity, socioeconomic background, maternal age, parity, year of birth, and birthweight centile. Interaction tests examined risk differences according to ethnicity, socioeconomic background, and parity. Of the 1 567 004 women with singleton pregnancies, 501 072 women with low-risk pregnancies and with sufficient data quality were included in the analysis. 3.3% of births in the IOL group (1 555/47 352) and 3.6% in the expectant management group (16 525/453 720) had an adverse perinatal outcome. After adjustment, a lower risk of adverse perinatal outcomes was found in the IOL group (risk difference -0.28%; 95% confidence interval -0.43%, -0.12%; p=0.001). This risk difference varied according to socioeconomic background from 0.38% ( 0.08%, 0.83%) in the least deprived to -0.48% ( 0.76%, -0.20%) in the most deprived national quintile (p value for interaction =0.01), and by parity with risk difference of -0.54% (-0.80%, -0.27%) in nulliparous women and -0.15% (-0.35%, 0.04%) in multiparous women (p-value for interaction = 0.02). There was no statistically significant evidence that risk differences varied according to ethnicity (p=0.19). Key limitations included absence of additional confounding factors such as smoking, BMI, and the indication for induction in the HES datasets, which may mean some higher risk pregnancies were included. Conclusions: IOL with birth at 39 weeks was associated with a small reduction in the risk of adverse perinatal outcomes, with 360 inductions in low-risk pregnancies needed to avoid one adverse outcome. The risk reduction was mainly present in women from more socioeconomically deprived areas and in nulliparous women. There was no significant risk difference found by ethnicity. Increased uptake of IOL at 39 weeks, especially in women from more socioeconomically deprived areas, may help reduce inequalities in adverse perinatal outcomes

Placental transfusion: a review

Recently there have been a number of studies and presentations on the importance of providing a placental transfusion to the newborn. Early cord clamping is an avoidable, unphysiologic intervention that prevents the natural process of placental transfusion. However, placental transfusion, although simple in concept, is affected by multiple factors, is not always straightforward to implement, and can be performed using different methods, making this basic procedure important to discuss. Here, we review three placental transfusion techniques: delayed cord clamping, intact umbilical cord milking and cut-umbilical cord milking, and the evidence in term and preterm newborns supporting this practice. We will also review several factors that influence placental transfusion, and discuss perceived risks versus benefits of this procedure. Finally, we will provide key straightforward concepts and implementation strategies to ensure that placental-to-newborn transfusion can become routine practice at any institution

Realist ethical naturalism for ethical non-naturalists

It is common in metaethics today to draw a distinction between “naturalist” and “non-naturalist” versions of moral realism, where the former view maintains that moral properties are natural properties, while the latter view maintains that they are non-natural properties instead. The nature of the disagreement here can be understood in different ways, but the most common way is to understand it as a metaphysical disagreement. In particular, the disagreement here is about the reducibility of moral properties, where the “naturalists” maintain that moral properties are in some way reducible to the lower-level natural properties on which they supervene, while the “non-naturalists” maintain that moral properties are sui generis and robustly irreducible. In this paper I present a novel version of realist ethical naturalism—a view that I call Emergentist Ethical Naturalism—that reveals this common way of understanding the distinction between naturalism and non-naturalism to be flawed by combining a commitment to ethical naturalism with a commitment to the sui generis and irreducible nature of moral properties that typically defines non-naturalism. Then, after presenting the theory and addressing a few worries that one might have about it, I show how it offers some novel, emergence-based responses to the various supervenience challenges that plague moral realism and thereby gives the ethical naturalist a robustly non-reductive option for dealing with these challenges

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

Paving the way of systems biology and precision medicine in allergic diseases : the MeDALL success story Mechanisms of the Development of ALLergy; EUFP7-CP-IP; Project No: 261357; 2010-2015

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.Peer reviewe