Chorioamnionitis with or without funisitis increases the risk of hypotension in very low birthweight infants on the first postnatal day but not later.

OBJECTIVE: To evaluate the relation between chorioamnionitis and hypotension in very low birthweight infants. METHODS: Retrospective cohort study in infants with a birth weight of <1500 g born between January 2002 and September 2004. The placentas were examined for evidence of chorioamnionitis and funisitis. Hypotension was defined by the use of vasopressors. RESULTS: Of 105 infants, 37 (35%) were chorioamnionitis positive. The onset of hypotension had a skewed distribution: day 1 for 30 episodes and scattered from day 2 to day 19 for the remaining 22. Of the 30 infants who developed hypotension on day 1, 17 (57%) were chorioamnionitis positive. The mean maturity of the chorioamnionitis positive group was 27.91 weeks, marginally less than the mean maturity of 29.05 weeks of the chorioamnionitis negative group (p = 0.05). After adjustment of the effects for confounding variables (birth weight, gestation, surfactant therapy, mechanical ventilation on day 1, high frequency oscillatory ventilation, patent ductus arteriosus), chorioamnionitis was the significant factor in line with hypotension developing on day 1 (adjusted odds ratio 5.14, 95% confidence interval 1.51 to 17.50). There was no evidence that hypotension developing after day 1 was associated with chorioamnionitis. CONCLUSIONS: There is a strong association between chorioamnionitis and hypotension developing on day 1 in very low birthweight infants.

Scientific rationale and benefits of nucleotide supplementation of infant formula.

The present review examines the role of dietary nucleotides in infants, and the scientific rationale and benefits of nucleotide supplementation of infant formula. The immunoprotective benefits of human milk, the biology of human milk nucleotides, and the immunological and gastrointestinal effects of dietary nucleotides in animal studies and in vitro experiments are examined. Clinical studies are reviewed, especially those examining the efficacy of nucleotide-supplemented infant formula in enhancing immunity and reducing the risk of sepsis. The presence of human milk cells, and a variety of immunoactive and trophic components of human milk, can explain the reduced incidence of sepsis in breastfed term and preterm infants. Nucleotides, believed to play an immunomodulatory role, are found in lower concentrations in infant formula. Animal studies have shown that dietary nucleotides enhance a number of immune responses and the growth, differentiation and repair of the gut. Several clinical studies have reported beneficial effects of nucleotide supplementation on gut microflora, diarrhoea and immune function, and one study has reported better catch-up growth in term infants with severe intrauterine growth retardation. More basic research studying the metabolism of nucleotides in neonates is encouraged. Additional randomized controlled trials are necessary to demonstrate the clinical benefits of nucleotide supplementation of infant formula, as it cannot be presumed that nucleotides produce the same benefits for the infant as human milk. Studies are especially necessary in high-risk neonatal situations, such as extreme prematurity, significant suboptimal nutrient intake before and after birth, and recovery from gut injury.

Relationships of urinary phyto-oestrogen excretion to BMD in postmenopausal women.

OBJECTIVE: Phyto-oestrogens are plant compounds with both oestrogenic and anti-oestrogenic properties. However, it is not known whether natural phyto-oestrogens are beneficial or harmful in human osteoporosis. This study was performed to investigate the relationships between urinary phyto-oestrogens and bone mineral density (BMD) in Korean postmenopausal women. DESIGN: The subjects were classified into osteoporotic, osteopenic and normal groups according to their BMD as defined by WHO criteria. We compared the urinary phyto-oestrogens of each group and studied whether urinary phyto-oestrogens correlate with BMD. PATIENTS: The subjects were 75 Korean postmenopausal women with ages ranging from 52 to 65 years (mean 58 +/- 1.1 years). Mean number of years after menopause was 7.3 +/- 1.3. MEASUREMENTS: Twenty-four-hour urinary phyto-oestrogens were measured by gas chromatography-mass spectrometry (GCMS) and BMD by dual-energy X-ray absorptiometry (DXA, Lunar Expert-XL, Lunar Co., WI, USA). RESULTS: In Korean postmenopausal women, urinary enterolactone (1.46 +/- 1.11 micromol/day) was lower and daidzein (2.59 +/- 3.25 micromol/day) was higher than in western women, and both levels were comparable to those in Japanese women. Daily urinary excretion of genistein and apigenin were 1.09 +/- 0.912 and 0.48 +/- 0.40 micromol/day, respectively. In subjects with osteoporosis, urinary enterolactone was lower (P < 0.05) but apigenin was significantly higher (P < 0.05) than in the controls. BMD of L2-L4 correlated positively with urinary enterolactone (r = 0.388, P < 0.01), and BMD of the femoral neck and Ward's triangle correlated positively with urinary enterolactone (r = 0.271, P < 0.05 and r = 0.322, P < 0.05) but negatively with apigenin (r = -0.412, P < 0.01 and r = -0.395, P < 0.01). By multiple stepwise regression, the variables associated with spinal BMD were age, the amount of urinary apigenin and body mass index (BMI). The variables associated with femoral neck BMD were age and urinary apigenin. CONCLUSIONS: From these results, we conclude that urinary phyto-oestrogens, especially enterolactone and apigenin, are related to BMD in Korean postmenopausal women. Our results also suggest the possibility that phyto-oestrogens have differential effects on bone density. Further studies are needed to clarify the exact biological roles of phyto-oestrogenic components on bone metabolism.

The management of extremely premature infants and the perceptions of viability and parental counselling practices of Australian obstetricians.

The attitudes of Australian obstetricians to the resuscitation of extremely premature infants are reported. A structured questionnaire including questions regarding antenatal parent counselling, resuscitation practices, survival rates and personal attitudes about life support was distributed to obstetricians working in Australian hospitals with a Level 3 nursery Eighty-nine (48% response rate) replies were received from 12 units located in seven major cities. Obstetricians are more likely to discuss resuscitation with prospective parents with increasing gestation with a major shift occurring at 23-24 weeks' gestation. They strive for consensus with parents regarding resuscitation options and they act upon the opinion of both the prospective parents and their paediatric colleagues. Threat of litigation rarely influences the decision to limit resuscitation of an extremely preterm infant. Obstetricians may underestimate the prognosis for extremely preterm infants. The data presented offer useful insights into current attitudes and practice of tertiary hospital obstetricians.

Antenatal counselling, resuscitation practices and attitudes among Australian neonatologists towards life support in extreme prematurity.

A questionnaire survey of Australian neonatologists was conducted to ascertain their antenatal counselling and resuscitation practices, and attitudes towards life support in the extremely preterm infant. This study showed that in antenatal parental counselling, whether a paediatrician was given the opportunity to participate depends on the gestation at the time of the threatened preterm delivery The counselling employed almost invariably covered mortality and morbidity. The obstetrician's opinion was considered to be of utmost importance. Both financial and moral obligations were found to be of little importance in counselling and resuscitation. Only one-third of institutions had guidelines for limiting resuscitation. The onus remained on the neonatologists concerning which infant to resuscitate, and the level of the resuscitation to be conducted. In Australia, resuscitation at birth was restricted to infants of 23 weeks' gestation or above, and neonatologists did not believe the legal system has a role to play in limiting or mandating resuscitation of extremely preterm infants. Neither were they concerned with the threat of litigation when they decide to limit resuscitation. The majority of neonatologists agreed with their institution's approach to life support in extremely preterm infants. One grey area was the question of withholding assisted feeding in an infant for which the decision to withdraw life support has been made. Australia lacked a current consensus policy on selective non-treatment. The establishment of national guidelines would be helpful to aid Australian obstetricians and neonatologists in their clinical practice.

Developmental outcome of extremely preterm infants.

Institution-based studies from perinatal centers are reporting encouraging survival and developmental outcome in extremely preterm infants, but population-based studies of all such births within a geographical-defined region are necessary to examine the impact of perinatal-neonatal care on the entire community. We have reported that their perinatal mortality and severe disability rate were significantly lower in those born within perinatal centers compared with those born elsewhere. Promotion of "in utero transfer" is associated with a significant improvement in their survival and developmental outcome. Postnatal surfactant therapy, which began a decade ago, saw a doubling of the survival rate for infants born as early as 24-26 weeks, while their severe disability rate remains below 10%. Although surfactant and mechanical ventilation are expensive therapies, the resulting improvement in outcome was responsible for a reduction in the cost per additional quality-adjusted life-year gained.

Fetal acalvaria with amniotic band syndrome.

A case of amniotic band syndrome (ABS) presenting with acalvaria is reported. ABS includes a spectrum of non-genetic anomalies, varying from simple digital band constriction to major craniofacial and visceral defects, and even fetal death. Acalvaria is a rare congenital malformation characterised by the absence of the dome-like superior portion of the cranium comprising the frontal, parietal, and occipital bones and dura mater, in the presence of a normal skull base and facial bones with complete cranial contents. No two cases are the same. Acrania or absence of the flat skull bones with disorganised cerebral hemispheres have been reported in the presence of amniotic bands. ABS is an aetiological factor in acalvaria. Appropriate counselling for affected families needs to be given after prenatal diagnosis.

Mechanisms of blood pressure increase induced by dopamine in hypotensive preterm neonates.

AIMS: To compare changes in global haemodynamics as well as anterior cerebral and superior mesenteric artery perfusion after dopamine treatment. METHODS: Anterior cerebal and superior mesenteric artery perfusion was measured using Doppler ultrasonography in hypotensive preterm neonates in whom cardiac output increased (group 1, n=10) or decreased (group 2, n=40) after dopamine treatment. RESULTS: Despite a lower dopamine infusion rate, the blood pressure increase (mm Hg) in group 2 [Delta=13(1); mean(SE)] exceeded that in group 1 [Delta=8(1)], while systemic vascular resistance (mm Hg/l/min/kg) rose in group 2 [Delta=106 (37)], but was unchanged in group 1 [Delta=9 (6)]. Anterior cerebral artery blood velocity and resistance were unaffected by dopamine. However, compared with unchanged values in group 1, superior mesenteric artery blood velocity fell by 14.7(4.8) cm/s and resistance increased by 4.1(0.7) mm Hg/cm in group 2. CONCLUSIONS: These results suggest that, in a portion of hypotensive preterm neonates, the increase in blood pressure induced by dopamine is related to a predominant vasoconstrictor action and is associated with a fall in bowel perfusion.

Cerebral blood volume measured using near-infrared spectroscopy and radiolabels in the immature lamb brain.

Near-infrared spectroscopy (NIRS) is a technique that is increasingly being used for the noninvasive measurement of cerebral blood volume (CBV) in newborn infants, but it has not been fully validated against established methods. These experiments in immature lambs (gestation 92+/-1 d, mean+/-SEM) compared CBV measured using NIRS-derived estimates of oxygenated Hb (n = 5) with CBV estimated with radiolabeled indicators (125I-labeled serum albumin and 51Cr-labeled red blood cells, n = 10). Total brain CBV (mL/100 g tissue) measured using NIRS was 2.5+/-0.2 compared with 2.5+/-0.2 using radiolabels (NS). Regional tissue plasma, red blood cells, and whole blood volumes from radiolabels varied significantly (p < or = 0.05) throughout the brain. Whole blood volume (mL/100 g tissue) was largest in choroid plexus (16.2+/-2.1) and least in white matter (0.7+/-0.1) with a significant hierarchy evident among regions: choroid plexus > cerebellum > cortex > brain stem = midbrain > white matter. Regional plasma and red blood cell distributions were similar to whole blood, being highest in choroid plexus (13.0+/-1.6 and 3.2+/-0.9, respectively), and least in white matter (0.8+/-0.1 and 0, respectively). These data from the immature lamb brain indicate that total CBV measured with NIRS is essentially identical with the volumes obtained using intravascular radiolabels. Among cerebral regions, white matter contributes little to the global blood volume measured with NIRS because its red blood cell content is very low.

Enteral feeding in the preterm infant.

In planning enteral feeding in the preterm infant, decisions need to be made regarding the feeding schedule, choice of milk, and the route of administration. Feeds should be commenced within a week after birth beginning with subnutritional quantities. Preterm human milk from the infant's own mother is the milk of choice. When full enteral feeding is established, supplementation with human milk fortifier is recommended. Donor human milk and preterm formula are alternatives. Early establishment of enteral nutrition and maintenance of optimal nutrition during infancy are important as dietary manipulations in preterm infants have potential long-term influences on their health, growth and neurodevelopment.

Major vasodilator role for nitric oxide in the gastrointestinal circulation of the mid-gestation fetal lamb.

As nitric oxide (NO) may be a particularly important vasodilator in early life, we investigated its role in the regulation of the gastrointestinal (GI) circulation at mid-gestation. Cardiac output and GI blood flow were measured by the radioactive microsphere technique in eight chronically instrumented and unanesthetized mid-gestation fetal sheep. Mean arterial pressure (MAP), heart rate, blood flow, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, Nomega-nitro-L-arginine (L-NNA) at doses of 10 and 25 mg/kg. In response to L-NNA infusion, MAP increased (p < 0.01) and combined ventricular output decreased (p < 0.001). GI blood flow and oxygen delivery decreased and vascular resistance increased in the stomach and all segments of the small and large intestine (all p < 0.001). The greatest reduction in blood flow was in the small intestine (p < 0.01) and the basal differential pattern of small intestinal blood flow exceeding large intestinal flow was completely abolished. These changes were much greater than those previously described in late-gestation fetuses. Our results suggest that, at mid-gestation, NO plays a major role in the regulation of blood flow and vascular tone across all segments of the fetal GI tract, with its effects being more pronounced than later in development.

The role of dietary nucleotides in neonatal and infant nutrition.

Human milk has a higher concentration of nucleotides than bovine milk which is the source of most infant formulas. As the composition of human milk is considered the 'gold standard,' an increasing number of infant formulas are supplemented with nucleotides. This review summarises the biology of human milk nucleotides and evaluates the studies which investigated the clinical benefits of feeding infants with nucleotide-supplemented formulas. Although dietary nucleotides have been suggested to have beneficial gastrointestinal and immunological effects, nucleotide-supplemented formula feeding has not been shown to confer the same benefits as breast feeding, and randomised controlled trials have yet to prove that healthy term infants fed nucleotide-supplemented formulas compared to those fed nonsupplemented formulas, have accelerated physical growth and neurological development, better growth and development of their gastrointestinal tract resulting in improved digestive and absorptive functions, enhanced development of their immune system resulting in increased resistance to infection and lower bacterial and viral infection rates during infancy, and a more favourable intestinal microflora associated with a lower rate of infectious diarrhoea. However, a randomised controlled trial has reported that term infants with severe intrauterine growth retardation do have better catch-up growth with nucleotide supplementation. The hypothesis that nucleotides are semi-essential nutrients needs to be further studied, in particular in the presence of prematurity, fetal growth retardation, intestinal injury and limited nutrient intake. As no deleterious effects have been reported with the use of nucleotide-supplemented formulas, the first of which was introduced over 30 years ago, such products are considered safe when nucleotides are supplemented to an amount equivalent to the free nucleotide concentration of human milk. More basic and clinical research studies are awaited to further define the biology and role of human milk nucleotides, and to critically assess the potential benefits and appropriate level of nucleotide supplementation of infant formula.

Assisted reproduction technology, multiple births, and adverse perinatal outcome.

The increase in the rate of multiple pregnancies in Australia in recent years is primarily due to the use of assisted reproduction technology. Compared to singleton births, fetal, neonatal, and perinatal mortality rates are 3-6 times higher in twins and 5-15 times higher in multiple births of a higher order. Cerebral palsy rates among survivors are six times higher in twins and twenty times higher in triplets. The increased risks in multiple pregnancies are not entirely explained by their higher prematurity and low birthweight rates. In Australia, the practice of transferring more than three embryos in any one assisted reproduction technology cycle has declined in recent years and, as a result, the number of multiple pregnancies from assisted reproduction technology has also declined. Nevertheless, assisted reproduction technology pregnancies remain to have poorer than normal outcome with regards to spontaneous abortion, ectopic pregnancy, preterm birth, low birthweight, and perinatal mortality. Infants born after assisted reproduction technology have a higher neonatal morbidity rate, including a greater requirement for assisted ventilation, and a higher long-term neurodevelopmental disability rate. These adverse outcomes following assisted reproduction technology are partly due to the increased risk of multiple pregnancy and partly due to preterm and low birthweight. This fact and the lack of evidence that the transfer of more than two embryos improves pregnancy rates, make it advisable to limit the number of embryos transferred to no more than one or two per cycle.

Spectrum of clinical and cardiac dysfunction in bronchopulmonary dysplasia: early prediction of long-term morbidity.

OBJECTIVES: The objective of this study was to correlate the severity of bronchopulmonary dysplasia (BPD) in infants < or = 28 weeks' gestation with clinical and radiologic scoring and cardiac function as measured by echocardiography. STUDY DESIGN: Twenty-five infants with a mean birth weight of 909 gm and gestational age 26 weeks were studied. All infants were categorized with a clinical and radiologic scoring system at 1 and 3 months. All infants were studied with two-dimensional, M-mode, and Doppler echocardiography. RESULTS: A significant correlation was found between clinical and radiologic scores at 1 month (r = 0.42) and between radiologic scorings at 1 and 3 months (r = 0.67). Severe BPD is directly related with mean airway pressure on day 7 of life (p < 0.05), use of intralipids (p < 0.05), and average oxygen exposure (p < 0.05). Left ventricular posterior wall thickness is directly correlated to severity of BPD (p < 0.05), and transmitral flow velocities and early diastolic/atrial contraction flow velocity ratio are inversely related to severity of BPD (p < 0.05). CONCLUSIONS: Severe BPD can be predicted at an early age, and certain subtle cardiac dysfunctions can be used as early markers of BPD.

Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants.

OBJECTIVE: To determine the efficacy and side-effects of prolonged low-dose indomethacin therapy in very low birthweight (VLBW; < 1500 g) infants with a haemodynamically significant patent ductus arteriosus (hsPDA). METHODOLOGY: Very low birthweight infants admitted over a 16 month period were studied (8 months, retrospectively and 10 months, prospectively). Cross-sectional and M-Mode echocardiograms with pulsed-wave and colour Doppler were performed to assess the significance of ductal patency. RESULTS: Forty-one (28%) of 148 VLBW infants were diagnosed to have hsPDA. Indomethacin therapy was successful in 90% after the first course, increasing to 95% after the second course. The recurrence rate after the first course was 3%. Minor and transient complications included oliguria, urea retention, hyponatraemia and thrombocytopenia. Although three infants had focal bowel perforation and the fourth had bowel perforation associated with necrotizing enterocolitis, the incidence of gastrointenstinal pathology was not significantly different from infants without hsPDA and not given indomethacin. CONCLUSIONS: Very low birthweight infants with hsPDA have a high response rate and low recurrence rate to prolonged low-dose indomethacin therapy. Side-effects were mild and transient. However, it is prudent to be cautious when administering indomethacin in critically ill infants < 1000 g with hsPDA who manifest clinical features of bowel ischaemia.

Principles and practice of parenteral nutrition in the neonatal period.

In extremely preterm or critically ill infants, the parenteral route for maintaining nutritional integrity has to be relied upon before successful transition to the enteral route of feeding is achieved. Parenteral nutrition is now a fundamental part of neonatal intensive care. Fluid intake volumes vary from 60-150 ml/kg/d, depending on maturity of the infant and environmental conditions influencing insensible water loss from the skin. Parenteral nitrogen requirements are 30-35 mmol/kg/d, equivalent to 3.0-3.5 mg/kg/d of amino acids. Hyperglycaemia during parenteral nutrition can be minimised by starting glucose infusion at a rate of 6-8 g/kg/d with progressive increase to 18-20 g/kg/d by 2-3 weeks after birth. Parenteral fat is introduced at 1 g/kg/d, gradually increasing to 3 g/kg/d, given as a continuous infusion. An energy intake of 50 kcal/kg/d is adequate to match ongoing expenditure but an additional energy intake of 70 kcal/kg/d is required to achieve optimal growth. Minerals and trace elements delivered with parenteral nutrition are calculated to meet in-utero accretion rates. Multivitamins available for parenteral use should also be included. Improved techniques for the preparation, administration and monitoring of parenteral nutrition have helped minimise catheter-related and metabolic complications. In neonatal intensive care units where appropriate medical, nursing, pharmacy and laboratory expertise are available, the potential benefits of parenteral nutrition outweigh its hazards. Nevertheless, early initiation of enteral feeding in small subnutritional quantities to supplement parenteral nutrition is of major importance to enhance the growth and development of the gastrointestinal tract.

Ethical decision-making in newborn infants.

One ethical dilemma which neonatologists are faced with on a regular basis is selective non-treatment, that is, clinical decisions made after the birth of a liveborn infant to withhold or to withdraw treatment in certain circumstances. Although the outcome of extremely preterm of critically ill infants has significantly improved over the last decade, many are often left to die at birth by withholding resuscitation or neonatal intensive care. Criteria for initiating life-sustaining treatment must be developed with proper ethical considerations. There are other infants whose clinical course after initiation of intensive care will suggest that further curative efforts are futile or lack compensating benefit. Criteria for withdrawing life-sustaining treatment must also be developed, and palliative care measures defined. Clinical situations in which selective non-treatment is taking place in neonatal medicine are: (1) when death is considered to be inevitable whatever treatment is provided, (2) even when death is not inevitable, there is a significantly high risk of severe physical and mental disability should the infant survive, and (3) when survival with moderate disability is possible, but the infant is likely to experience ongoing pain and suffering, repeated hospitalisation and invasive treatment, and early death in childhood. The decision-making process of selective non-treatment should involve less medical paternalism and more informed parental involvement. The process is built on trust between the neonatal staff and parents, and requires time, information, honesty and empathy. Ethical issues must be approached with extreme responsibility, extraordinary sensitivity and heroic compassion.