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Biomedical subjects

J E Harding

Publications and source records attributed to J E Harding.

At least 55 records · Page 3Linked to original sources
PubMed1997

Gastroschisis: can the morbidity be avoided?

Although the mortality associated with gastroschisis (GS) has fallen markedly over recent years, postoperative morbidity and the incidence of complications remain high. Many different factors may contribute to this morbidity; the aim of this study was to determine which factors contributed most. Measures of morbidity used were time to full oral feeding (FOF), time on parenteral nutrition (PN), age at discharge, and incidence of complications. Between 1969 and 1995, 44 neonates with GS were treated; there were 6 deaths. The average initial temperature of the patients who died was 34.6 degrees C compared with 36.0 degrees C for the rest of the group (P = 0.02). Staged repair and prematurity were associated with increased time to FOF, time on PN, and age at discharge (P < 0.001). When the corrected post-term age was used, the difference between preterm and term babies was no longer significant. Mode of delivery did not influence any measure of morbidity. Seventeen patients (46%) had complications related to PN administration and 18 (43%) developed complications related to their surgery. There were no significant differences in these measures of morbidity when comparing patients born in the first half of the study period with those born in the last half. Multivariate analysis revealed that time to FOF, time on PN, and age at discharge were all strongly independently associated with staged repair and with the presence of complications of PN (all F > 7.2 and P < 0.01). Mode of delivery, gestational age, admission temperature, the need for postoperative ventilation, and complications of surgery were not independently associated with any of the measures of morbidity examined. Our data suggest that term delivery and primary closure of the defect are likely to minimise the morbidity experienced by infants with GS.

Abdominal Muscles↗
PubMed1997

Fetal growth retardation: underlying endocrine mechanisms and postnatal consequences.

Considerable advance has been made in our understanding of the regulation of fetal growth and of the pathophysiology of intrauterine growth retardation. The dominant determinant of fetal growth is nutrient delivery to the conceptus, and the insulin-like growth factors (IGFs) appear to play a central role in modulating the fetal growth response to the nutritional environment. It has also become clear that events early in gestation, or prior to conception, can be reflected in altered fetal growth and metabolism later in gestation. Intrauterine growth retardation (IUGR) may be due to identifiable genetic or toxic factors or to disordered nutrient delivery. The latter category of IUGR provides the greatest clinical concern with a high incidence of perinatal morbidity and mortality. More recently, epidemiological evidence supported by limited, but growing, experimental data suggest that the postnatal consequences of disturbed fetal growth may include metabolic disease (diabetes mellitus) and cardiovascular disease. This brief review discusses these advances with reference to data from our laboratory.

Cardiovascular Diseases↗
PubMed1997

Antenatal therapy for intrauterine growth retardation.

Currently, there is no effective antenatal therapy for intrauterine growth retardation (IUGR). Although the IUGR fetus is undernourished in utero and there have been many attempts to treat IUGR with nutritional supplements, most studies have been poorly controlled, and there is no evidence to date that nutrient supplements can reverse the process of IUGR once it is established. Nutrient supplementation is also potentially risky and a combination of nutrients is likely to be needed. Alternative approaches to antenatal therapy for IUGR that show promise include fetal growth hormone and insulin-like growth factor I treatment to improve fetal growth. Fetal and maternal hormone supplements may also prove useful in IUGR by improving placental function and thus fetal substrate supply. Fetal enteral supplementation by the administration of growth factors and/or nutrients into the amniotic fluid may also prove effective and clinically feasible. It seems likely that combinations of these approaches will be required before effective therapy can be devised for the IUGR fetus in utero.

Animals↗
PubMed1997

The physiology and pathophysiology of intrauterine growth retardation.

Insulin-like growth factor I (IGF-I) is the primary hormone influencing fetal growth in later gestation. The regulation of fetal IGF-I in utero is primarily influenced by placental glucose transfer, which regulates fetal insulin release. Furthermore, insulin has direct adipogenic effects on the fetus; fetal growth hormone (GH) may also have additional modes of action on fetal growth. Swallowed amniotic fluid contains IGF-I and may influence gastrointestinal maturation and fetal growth. Furthermore, both fetal and maternal IGF-I can influence placental metabolism. Experimentally, the maternal administration of GH and IGF-I can affect placental function and thus influence fetal growth; this may suggest therapeutic approaches to the treatment of intrauterine growth retardation (IUGR) in utero. Both experimental and clinical evidence support our hypothesis that IUGR is a multihormone relative resistance syndrome; relative resistance to insulin, IGF-I and GH can be demonstrated. Such resistance may be the basis of altered programming by which fetal growth retardation is associated with postnatal growth failure and a greater propensity to develop cardiovascular and metabolic disease in later life.

Animals↗
PubMed1997

Maternal growth hormone treatment increases placental diffusion capacity but not fetal or placental growth in sheep.

We tested the hypothesis that chronic maternal GH administration would increase fetal substrate supply, increase maternal and fetal insulin-like growth factor I (IGF-I) concentrations, and therefore enhance growth in the late gestation fetal sheep. Eleven ewes received bovine GH 0.1 mg/kg twice daily for 10 days, whereas 10 control ewes received saline. GH treatment increased placental capacity for simple diffusion (P < 0.01), with a trend toward an increase in placental capacity for facilitated diffusion (P = 0.07). GH treatment also lowered maternal and fetal blood urea concentrations, and there was a trend toward increased fetal protein oxidation (P = 0.07). Maternal but not fetal IGF-I and insulin concentrations increased. Fetal and placental growth were not altered by GH treatment. Maternal and fetal metabolic status was significantly affected by maternal food intake. We conclude that maternal GH treatment increases placental transport capacity, but that anabolic effects in the mother may limit fetal substrate supply and therefore prevent an increase in fetal growth.

Animals↗
PubMed1996

Fetal insulin-like growth factor (IGF)-I and IGF-II are regulated differently by glucose or insulin in the sheep fetus.

We investigated the effect of restoration of normoglycaemia or normoinsulinaemia in fetuses of starved ewes on plasma IGF-I and IGF-II concentrations. Paired maternal and fetal blood samples were taken during an initial 2-day control period, after 48 h of maternal starvation, during 24 h fetal infusion of glucose (n = 6) or insulin (n = 4) while maintaining maternal starvation and after 48 h maternal refeeding. After 48 h starvation maternal and fetal plasma IGF-I, insulin and blood glucose fell (maternal IGF-I 38.9 +/- 3.6 to 16.4 +/- 1.8 nM and fetal IGF-I 13.2 +/- 0.8 to 7.1 +/- 0.7 nM, both P < 0.05). Fetal plasma IGF-II also fell (147.8 +/- 9.1 to 112.2 +/- 3.8 nM, P < 0.05), but maternal plasma IGF-II rose (71.8 +/- 6.3 to 88.8 +/- 9.2 nM, P = 0.10). Fetal glucose replacement raised fetal plasma IGF-I (11.4 +/- 1.2 nM), IGF-II (149.7 +/- 6.5 nM), insulin and blood glucose to near control values (all P < 0.05). Fetal insulin replacement raised fetal plasma IGF-I (9.0 +/- 0.6 nM) and insulin (all P < 0.05) while IGF-II (105.2 +/- 8.4 nM) and blood glucose remained depressed. Neither fetal infusion had any significant effect on maternal plasma IGF-I (13.1 +/- 1.6 nM), IGF-II (77.5 +/- 8.7 nM), insulin or blood glucose. After 48 h maternal refeeding fetal IGF-I (12.4 +/- 0.4 nM), fetal IGF-II (158.4 +/- 8.9 nM), maternal IGF-II (67.1 +/- 3.0 nM), maternal and fetal insulin and glucose had returned to near control values in both groups. Maternal IGF-I remained below control values (24.7 +/- 2.5 nM, P < 0.05). The data suggest that fetal IGF-I and IGF-II are independently regulated in the fetal circulation. While glucose plays an important role in the regulation of both IGF-I and IGF-II, the influence of glucose on fetal IGF-I is likely to be mediated by insulin, whereas for IGF-II the effect of glucose is insulin-independent.

Animals↗
PubMed1995

Periconceptual undernutrition resets plasma IGFBP levels and alters the response of IGFBP-1, IGFBP-3 and IGF-1 to subsequent maternal undernutrition in fetal sheep.

Maternal undernutrition inhibits fetal growth and alters circulating levels of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs). This study investigates whether the fetal IGF axis could be reprogrammed by maternal undernutrition and hence be a potential contributing factor to changes in fetal and postnatal metabolism. Ewes were either fed a lib. or undernourished from day-60 to day 30 of gestation, and then both groups were fed ad lib. These groups were further divided at day 105, either being fed ad lib or undernourished until day 115. Fetal blood samples were obtained at day 105 and day 115. IGFBP-1 and IGFBP-3 levels were lower at day 105 in the periconceptually undernourished fetuses. Levels of IGFBP-1 were increased and IGFBP-3, IGFBP-4, IGF-1, glucose and insulin were reduced at day 115 after undernutrition. The degree of change in IGFBP-1, IGFBP-3 and IGF-I between day 105 and day 115 was greater in fetuses receiving low periconceptual nutrition. These results indicate that periconceptual undernutrition is able to reprogramme the fetal IGF axis such that the responses of IGF-I and the IGFBPs to undernutrition in late gestation are markedly altered.

Animals↗
PubMed1995

Nutrition and fetal growth.

Nutrient supply to the fetus is a key factor in the regulation of fetal growth. However, the direct supply of nutrients to provide building blocks for tissue growth is likely to be only a minor component of this regulation. The indirect effects of nutrition on fetal endocrine and metabolic status, and on the interaction between the fetus, placenta and mother all of which must be coordinated to allow fetal growth are also important. Maternal undernutrition may alter the growth of the fetus and its different component tissues in a way which cannot be explained solely on the basis of reduced substrate supply during the rapid growth phase of the tissues involved. Adaptation to altered substrate supply, during both undernutrition and refeeding, involves sequential changes in the metabolic and endocrine interactions between the fetus and the placenta. In addition, undernutrition has long-term consequences for the fetus. There is evidence for nutritional programming of fetal endocrine and cardiovascular systems before birth. Nutritional effects may also persist over more than one generation. The effects of nutrition on fetal growth are far more complex than simply those of substrate deprivation.

Adaptation, Physiological↗
PubMed1995

Another outcome of neonatal intensive care: first year mortality and hospital morbidity.

OBJECTIVE: To determine first year mortality and hospital morbidity after neonatal intensive care. METHODOLOGY: Cohort study of 6077 surviving infants inborn in one regional hospital in 1988. Nine hundred and eighty-eight received neonatal intensive care and 103 were very low birthweight (VLBW). RESULTS: For infants who required care in the neonatal intensive care unit (NICU), the relative risk of dying before their first birthday was 3.6 (95% confidence intervals [CI] 1.5-8.8). This increased risk was associated with low birthweight (LBW) rather than requirement for NICU care. Of all inborn survivors, 10.4% were readmitted to hospital in the first year and 2.4% more than once. The readmission rate was 20% for NICU survivors and 30% for VLBW infants. The risk of hospitalization was independently associated both with NICU admission (odds ratio 2.3, CI 1.9-2.9) and with VLBW (OR 1.8, CI 1.1-3.0). The NICU survivors also had multiple admissions and prolonged hospital stays. CONCLUSIONS: Both low birthweight and neonatal illness requiring intensive care are important indicators of continuing medical vulnerability over the first year of life.

Cause of Death↗
PubMed1995

The fetal somatotropic axis during long term maternal undernutrition in sheep: evidence for nutritional regulation in utero.

Nutrition is a major determinant of the somatotropic axis during postnatal life. However, little is known about the response of the fetal somatotropic axis to nutritional limitation. From day 100 of gestation (term = 147 days), singleton-bearing ewes were fed either ad libitum (control; n = 6) or 25% of the recommended energy and protein requirements (restricted; n = 7). Ewes and fetuses were chronically catheterized on day 110. On day 120, paired maternal and fetal blood samples were taken over a 6-h period at 15-min intervals. Forty-eight hours later, fetuses were given a 20-micrograms GRF bolus (i.v.), and samples were collected for 48 h. Undernourished mothers and fetuses had higher GH concentrations (P < 0.05). Although plasma GH profiles were independent in mothers and their fetuses, both maternal and fetal GH peak and nadir levels were increased (P < 0.05) by nutritional restriction, but the peak/nadir ratio and the number of pulses remained unaltered. Deconvolution analysis showed that the GH mass secreted per burst was higher in nutritionally restricted animals, whereas basal GH secretion and GH serum half-life were not influenced by undernutrition. Both maternal and fetal insulin-like growth factor-I levels were reduced (P < 0.01 and P < 0.05), whereas insulin-like growth factor-II concentrations were not influenced by the feed restriction. Fetuses from restricted mothers had higher peak GH concentrations after a GRF challenge (P < 0.001), but after correction The specific binding of [125I]ovine placental lactogen ([125I]oPL) or [125I]oGH to maternal or fetal hepatic microsomal membrane preparations was not changed by the maternal undernutrition. Maternal oPL concentrations showed considerable short term fluctuations, whereas fetal oPL levels revealed no major fluctuations. Mean maternal oPL levels tended (P < 0.06) to be elevated, whereas fetal oPL concentrations tended (P < 0.06) to be decreased in restricted animals. These results provide evidence that the somatotropic axis is functional in utero and suggest that the fetal somatotropic axis plays an active role during adaptation of the fetus to nutritional limitation.

Animal Nutritional Physiological Phenomena↗
PubMed1995

The effects of ovine placental lactogen infusion on metabolites, insulin-like growth factors and binding proteins in the fetal sheep.

It has been suggested, but not shown, that in the fetus placental lactogen (PL) may affect the regulation of the IGFs and fetal metabolism. To examine the effects of PL on the circulating concentrations of the IGFs, IGF-binding proteins (IGFBPs), glucose, free fatty acids (FFAs) and amino nitrogen (AN), we infused late gestation sheep fetuses with recombinant ovine PL (roPL). Five chronically-catheterised sheep fetuses were infused intravenously with three 24 h infusions of saline, roPL (100 micrograms bolus then 500 micrograms over 24 h) and then saline again. Fetal roPL infusion increased plasma oPL from 0.4 +/- 0.1 to 3.3 +/- 0.5 nM (mean +/- S.E.M.; P < 0.05; factorial analysis of variance and Scheffé's test). Fetal plasma IGF-I, IGF-II, insulin, FFAs and blood glucose were unaffected by the roPL infusion. Fetal plasma IGFBP-3, as measured by Western ligand blotting, decreased by 30% during fetal roPL infusion while other fetal plasma IGFBPs were unaffected. Fetal roPL infusion decreased fetal blood AN from 7.3 +/- 0.5 to 6.6 +/- 0.2 mM (P < 0.05). Maternal plasma IGF-I, IGF-II, IGFBPs, insulin, FFAs, blood glucose and AN were unaffected by the fetal roPL infusion. Saline infusion had no effect on any parameter. The data suggest that PL is not a significant determinant of plasma IGFs in the late gestation sheep fetus although there may be an indirect effect via alterations in levels of IGFBP-3. The effect of fetal roPL infusion on fetal blood AN concentrations may suggest some role for PL in the regulation of fetal amino acid metabolism.

Amino Acids↗
PubMed1994

Outcome of neonates transported between Level III centres depends upon centre of care.

This study aimed to clarify whether the adverse outcomes seen in babies transported between New Zealand Level III intensive care nurseries were due to the transport itself or to possible differences in care in different centres. The outcomes of 34 infants inborn at National Women's Hospital, Auckland but transported to other centres were compared with those of 68 matched controls inborn at the receiving centres and with 68 controls inborn and cared for at National Women's Hospital. Transport was associated with a transient (non-significant) deterioration in respiratory status but no increase in chronic lung disease. However, infants cared for elsewhere, whether transported or control, had more periventricular hemorrhage than Auckland babies (23% and 29% vs 15%, P = 0.03) and worse neurodevelopmental outcome (70% and 66% vs 88% of those whose outcomes were known were normal at follow up, P = 0.002). We conclude that differences in care between centres may be more important than the transport itself in determining the long-term outcome of transported neonates.

Female↗
PubMed1994

Death in neonatal intensive care.

The aim of this study was to review the frequency of decisions to withdraw treatment from neonates who had died in a large neonatal intensive care unit, the reasons for these decisions, and the procedures followed. A 12 month retrospective review of medical and nursing records was undertaken. There were 67 deaths; treatment was withdrawn from 52 infants who were dead or dying, from 9 infants on the basis of a severe congenital abnormality, and from 6 infants with severe acquired brain damage. The decision-making process and the management of treatment withdrawal are reviewed. It is concluded that withdrawal of treatment resulting in death occurs frequently in the neonatal intensive care service of National Women's Hospital, Auckland, New Zealand, but is usually a recognition of the inevitable. Truly elective withdrawal of treatment is uncommon in the immature infant, but does occur in the context of multiple abnormalities or severe birth asphyxia, where it follows a formal procedure.

Brain Damage, Chronic↗
PubMed1994

Insulin-like growth factor 1 alters feto-placental protein and carbohydrate metabolism in fetal sheep.

Insulin-like growth factor 1 (IGF-1) is an anabolic hormone in postnatal life and may be an important endocrine regulator of fetal growth. However, its effects on fetal metabolism in vivo have not previously been determined. We studied the effect of 50 micrograms/h.kg IGF-1 infusion in 12 chronically catheterized fetal sheep. Fetal blood amino nitrogen concentrations fell 10% and maternal 7%, consistent with a rise in feto-placental amino acid uptake. Fetal amino acid oxidation, measured by fetal urea production fell by 30% (44.4 +/- 10.5 to 30.9 +/- 8.0 mumol/min). Fetal and maternal blood glucose concentrations both fell by 0.1 mM, consistent with increased feto-placental glucose uptake. Placental lactate production fell 30% (114 +/- 15 to 78 +/- 11 mumol/min), as did fetal and uterine lactate uptake. There was no change in umbilical or uterine blood flows, nor in placental transfer by simple or facilitated diffusion. We conclude that IGF-1 has anabolic effects on feto-placental protein and carbohydrate metabolism. Circulating IGF-1 may in part mediate the regulation of fetal growth in response to fetal nutrient supply.

Amino Acids↗
PubMed1994

Maternal insulin-like growth factor-I infusion alters feto-placental carbohydrate and protein metabolism in pregnant sheep.

Insulin-like growth factor-I (IGF-I) in the maternal circulation may have a role in the regulation of placental function and fetal growth, but its mechanisms of action are not known. We studied the effects of maternal IGF-I infusion (30 micrograms/kg.h for 4 h) in eight chronically catheterized pregnant sheep. IGF-I infusion caused an increase in fetal blood glucose concentrations, but no change in placental or fetal glucose uptake. Maternal plasma insulin concentrations fell. Placental lactate production increased by 56%, with most of this lactate taken up by the fetus. Maternal and fetal blood amino nitrogen concentrations fell, but fetal protein oxidation was unchanged. IGF-I infusion did not change feto-placental oxygenation, placental blood flow, or placental transfer by simple or facilitated diffusion. The metabolic effects of maternal IGF-I infusion in part oppose those of fetal IGF-I. We hypothesize that the balance of maternal and fetal IGF-I concentrations contributes to the regulation of substrate distribution between mother, placenta and fetus, and may thus mediate the nutritional regulation of fetal growth.

Animals↗