Medico-legal decision making for incapacitated neonates

This thesis finds there is a need for greater transparency and objectivity in end-of-life decision making for extremely premature and critically ill infants. To achieve this objectivity, the allocation of finite public healthcare resources, and corresponding quality of life, should be a principal consideration in treatment decisions.

Cutting the cord: Can society over-invest in extremely premature and critically impaired neonates?

This article provides a critical examination of the allocation of scarce public health care funds in relation to extremely premature and sick neonates. Decisions to withdraw or withhold life-sustaining treatment from neonates born extremely premature are generally informed by arbitrary and often subjective considerations of those involved in their care – namely parents and medical practitioners. This article argues for a sharp and immediate focus in decisions to treat such neonates based on the allocation of limited health care resources. Accordingly, decisions to save and preserve the lives of imperilled neonates should not be limited to the immediate financial costs of medical treatment. More explicitly there should be a full appreciation of the cost of disability to the family, requirements for long-term care, and the benefits and associated costs of life, not only to the patient, but also to society.

Analysis of zinc transporter, hZnT4(Slc30A4), gene expression in a mammary gland disorder leading to reduced zinc secretion into milk

Zinc deficiency, causing impaired growth and development, may have a nutritional or genetic basis. We investigated two cases of inherited zinc deficiency found in breast-fed neonates, caused by low levels of zinc in the maternal milk. This condition is different from acrodermatitis enteropathica but has similarities to the "lethal milk" mouse, where low levels of zinc in the milk of lactating dams leads to zinc deficiency in pups. The mouse disorder has been attributed to a defect in the ZnT4 gene. Little is known about the expression of the human orthologue, hZnT4 (Slc30A4). Sequence analysis of cDNA, real-time PCR and Western blot analysis of hZnT4, carried out on control cells and cells from unrelated mothers of two infants with zinc deficiency, showed no differences. The hZnT4 gene was highly expressed in mouthwash buccal cells compared with lymphoblasts and fibroblasts. The hZnT4 protein did not co-localise with intracellular free zinc pools, suggesting that hZnT4 is not involved in transport of zinc into vesicles destined for secretion into milk. This observation, combined with phenotypic differences between the "lethal milk" mouse and the human disorder, suggests that the "lethal milk" mouse is not the corresponding model for the human zinc deficiency condition.

Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial

Background

Epidural analgesia is the most effective labour pain relief but is associated with increased rates of instrumental vaginal delivery and other effects, which might be related to the poor motor function associated with traditional epidural. New techniques that preserve motor function could reduce obstetric intervention. We did a randomised controlled trial to compare low-dose combined spinal epidural and low-dose infusion (mobile) techniques with traditional epidural technique.
Methods

Between Feb 1, 1999, and April 30, 2000, we randomly assigned 1054 nulliparous women requesting epidural pain relief to traditional (n=353), low-dose combined spinal epidural (n=351), or low-dose infusion epidural (n=350). Primary outcome was mode of delivery, and secondary outcomes were progress of labour, efficacy of procedure, and effect on neonates. We obtained data during labour and interviewed women postnatally.
Findings

The normal vaginal delivery rate was 35·1% in the traditional epidural group, 42·7% in the low-dose combined spinal group (odds ratio 1·38 [95% CI 1·01–1·89]; p=0·04); and 42·9% in the low-dose infusion group (1·39 [1·01–1·90]; p=0·04). These differences were accounted for by a reduction in instrumental vaginal delivery. Overall, 5 min APGAR scores of 7 or less were more frequent with low-dose technique. High-level resuscitation was more frequent in the low-dose infusion group.

Ontogeny of body size and shape of Antarctic and subantarctic fur seals

Pre- and post-weaning functional demands on body size and shape of mammals are often in conflict, especially in species where weaning involves a change of habitat. Compared with long lactations, brief lactations are expected to be associated with fast rates of development and attainment of adult traits. We describe allometry and growth for several morphological traits in two closely related fur seal species with large differences in lactation duration at a sympatric site. Longitudinal data were collected from Antarctic (Arctocephalus gazella (Peters, 1875); 120 d lactation) and subantarctic (Arctocephalus tropicalis (Gray, 1872); 300 d lactation) fur seals. Body mass was similar in neonates of both species, but A. gazella neonates were longer, less voluminous, and had larger foreflippers. The species were similar in rate of preweaning growth in body mass, but growth rates of linear variables were faster for A. gazella pups. Consequently, neonatal differences in body shape increased over lactation, and A. gazella pups approached adult body shape faster than did A. tropicalis pups. Our results indicate that preweaning growth is associated with significant changes in body shape, involving the acquisition of a longer, more slender body with larger foreflippers in A. gazella. These differences suggest that A. gazella pups are physically more mature at approximately 100 d of age (close to weaning age) than A. tropicalis pups of the same age

Fasting metbabolism in Antarctic fur seal (Artocephalus gazella) pups

The metabolism of 52–73-day old Antarctic fur seal pups from Bird Island, South Georgia, was investigated during fasting periods of normal duration while their mothers were at sea foraging. Body mass decreased exponentially with pups losing 3.5–3.8% of body mass per day. Resting metabolic rate also decreased exponentially from 172–197 ml (O2)·min⁻¹ at the beginning of the fast and scaled to M_b^0.74 at 2.3 times the level predicted for adult terrestrial mammals of similar size. While there was no significant sex difference in RMR, female pups had significantly higher (F₁,₁₈=6.614, P<0.019) mass-specific RMR than male pups throughout the fasting period. Fasting FMR was also significantly (t₁₅=2.37, P<0.035) greater in females (823 kJ·kg⁻¹·d⁻¹) than males (686 kJ·kg⁻¹·d⁻¹). Average protein turnover during the study period was 19.3 g·d⁻¹ and contributed to 5.4% of total energy expenditure, indicating the adoption of a protein-sparing strategy with a reliance on primarily lipid catabolism for metabolic energy. This is supported by observed decreases in plasma BUN, U/C, glucose and triglyceride concentrations, and an increase in β-HBA concentration, indicating that Antarctic fur seals pups adopt this strategy within 2–3 days of fasting. Mean RQ also decreased from 0.77 to 0.72 within 3 days of fasting, further supporting a rapid commencement of protein-sparing. However, RQ gradually increased thereafter to 0.77, suggesting a resumption of protein catabolism which was not substantiated by changes in plasma metabolites. Female pups had higher TBL (%) than males for any given mass, which is consistent with previous findings in this and other fur seal species, and suggests sex differences in metabolic fuel use. The observed changes in plasma metabolites and protein turnover, however, do not support this.

Serotonin discontinuation syndrome following utero exposure to antidepressant medication : prospective controlled study

Objectives: The aim of the present study was to examine neonatal symptoms previously reported to be associated with exposure to antidepressant medication in late pregnancy in a group of infants exposed to antidepressants, using a prospective and controlled design.

Method: A prospective case-control study recruited 27 pregnant women taking antidepressant medication and 27 matched controls who were not taking antidepressant medication in pregnancy. Of the 27 women taking medication, 25 remained on medication in the third trimester and, of these, 23 women had complete data available. In pregnancy and after delivery women were assessed with the Beck Depression Inventory-II and a purpose-designed questionnaire. After delivery mothers were asked a set of nine questions pertaining to symptoms of discontinuation in their newborn and questions about pregnancy and delivery complications.

Results: There was an increased risk of discontinuation symptoms in neonates exposed to antidepressant medication in late pregnancy and an association with higher dose medication. The study group were found to be significantly more likely to display behaviour such as crying, jitteriness, tremor, feeding, reflux and sneezing and sleep for <3 h after a feed. They also had significantly higher rates of jaundice and admissions to the special care nursery.

Conclusions: Exposure to antidepressants in late pregnancy is associated with a range of symptoms in the neonate that are consistent with the effects of exposure to antidepressants in late pregnancy. The clusters of symptoms most highly correlated are the gastrointestinal and central nervous system symptoms. These finding helps to identify the common symptoms associated with a neonatal serotonin discontinuation syndrome.

The adaptive significance of ontogenetic colour change in a tropical python

Ontogenetic colour change is typically associated with changes in size, vulnerability or habitat, but assessment of its functional significance requires quantification of the colour signals from the receivers' perspective. The tropical python, Morelia viridis, is an ideal species to establish the functional significance of ontogenetic colour change. Neonates hatch either yellow or red and both the morphs change to green with age. Here, we show that colour change from red or yellow to green provides camouflage from visually oriented avian predators in the different habitats used by juveniles and adults. This reflects changes in foraging behaviour and vulnerability as individuals mature and provides a rare demonstration of the adaptive value of ontogenetic colour change.

Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia

Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy. The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient. The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.

Do maternally derived antibodies and early immune experience shape the adult immune response?

1. Immunological imprinting by maternally derived antibodies has been proposed to have both positive and negative consequences for offspring immunity in early and adult life. However, few studies of maternal effects on immunity have followed individuals past the juvenile stages.

2. Using laboratory Japanese quail, we developed a novel method of directly manipulating yolk antibodies of neonates, and then followed individuals through a series of immune challenges until they were of reproductive age.

3. Our method of directly injecting purified antibodies into the yolk sac of newly hatched chicks successfully elevated the plasma titres of specific anti-KLH IgY in neonates. This allows us to test whether differences in neonatal anti-KLH IgY affect immunity at the juvenile and adult stages of life.

4. We found little evidence for an effect of maternal antibodies on juvenile stage immune response, in contrast to results from previous studies. Adult immune response depended largely on the magnitude of the juvenile immune response regardless of the identity of the antigen in the juvenile immune challenge, and did not depend on neonatal IgY titres. Our results are consistent with a priming effect of early immune experience on adult stage immune responsiveness, but we found no evidence of carryover effects of yolk-derived antibodies on adult immunity.

5. This study employs new methodology for investigation of maternal antibodies and presents results suggesting that further studies of maternal effects on immunity will require careful consideration of the numerous ways maternally derived yolk components can impact the different types of immune response.

Ecological and life-history factors influencing the evolution of maternal antibody allocation : a phylogenetic comparison

Maternally derived yolk antibodies provide neonates with immune protection in early life at negligible cost to mothers. However, developmental effects on the neonate's future immunity are potentially costly and thus could limit yolk antibody deposition. The benefits to neonatal immunity must be balanced against costs, which may depend on neonate vulnerability to pathogens, developmental trajectories and the immunological strategies best suited to a species' pace of life. We measured yolk antibodies and life-history features of 23 species of small Neotropical birds and assessed the evidence for each of several hypotheses for life history and ecological effects on the evolution of yolk antibody levels. Developmental period and yolk antibodies are negatively related, which possibly reflect the importance of humoral immune priming through antigen exposure, and selection to avoid autoimmunity, in species with a slower pace of life. There is also a strong relationship between body size and yolk antibody concentration, suggesting that larger species are architecturally equipped to produce and transfer higher concentrations of antibodies. These results suggest that developmental effects of maternally derived antibodies, such as imprinting effects on B-cell diversity or autoimmune effects, are important and deserve more consideration in future research.

No evidence of expression of two classes of natural antibiotics (cathelicidins and defensins) in a sample of platypus milk

Marsupial neonates are born without a fully functioning immune system, and are known to be protected in part by natural antimicrobial peptides present in their mother's milk. Monotreme neonates hatch at a similar stage in development, and it has been hypothesised that their survival in a non-sterile burrow also relies on the presence of natural antibiotics in their mother's milk. Here we review the field of monotreme lactation and the antimicrobial peptide complement of the platypus (Ornithorhynchus anatinus). Using reverse transcriptasepolymerase chain reaction of milk cell RNA from a sample of platypus milk, we found no evidence for the expression of cathelicidins or defensins in the milk. This was unexpected. We hypothesise that these natural antibiotics may instead be produced by the young platypuses themselves.

Age and exposure to arsenic alter base excision repair transcript levels in mice

Arsenic (As) induces DNA-damaging reactive oxygen species. Most oxidative DNA damage is countered by base excision repair (BER), the capacity for which may be reduced in older animals. We examined whether age and consumption of As in lactational milk or drinking water influences BER gene transcript levels in mice. Lactating mothers and 24-week-old mice were exposed (24 h or 2 weeks) to As (2 or 50 p.p.m.) in drinking water. Lung tissue was harvested from adults, neonates (initially 1 week old) feeding from lactating mothers and untreated animals 1– 26 weeks old. Transcripts encoding BER proteins were quantified. BER transcript levels decreased precipitously with age in untreated mice but increased in neonates whose mothers were exposed to 50 p.p.m. As for 24 h or 2 weeks. Treatment of 24-week-old mice with 2 or 50 p.p.m. As for 2 weeks decreased all transcript levels measured. Exposure to As attenuated the age-related transcript level decline for only one BER gene. We conclude that aging is associated with a rapid reduction of BER transcript levels in mice, which may contribute to decreased BER activity in older animals. Levels of As that can alter gene expression are transmitted to neonatal mice in lactational milk produced by mothers drinking water containing As, raising concerns about breastfeeding in countries having As-contaminated groundwater. Reduction of BER transcript levels in 24- week-old mice exposed to As for 2 weeks suggests As may potentiate sensitivity to itself in older animals.