Postnatal effects of intrauterine treatment of the growth-restricted ovine fetus with intra-amniotic insulin-like growth factor-1.

KEY POINTS: Fetal growth restriction increases the risk of fetal and neonatal mortality and morbidity, and contributes to increased risk of chronic disease later in life. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of the growth-restricted ovine fetus improves fetal growth, but postnatal effects are unknown. Here we report that intra-amniotic IGF1 treatment of the growth-restricted ovine fetus alters size at birth and mechanisms of early postnatal growth in a sex-specific manner. We also show that maternal plasma C-type natriuretic peptide (CNP) products are related to fetal oxygenation and size at birth, and hence may be useful for non-invasive monitoring of fetal growth restriction. Intrauterine IGF1 treatment in late gestation is a potentially clinically relevant intervention that may ameliorate the postnatal complications of fetal growth restriction. ABSTRACT: Placental insufficiency-mediated fetal growth restriction (FGR) is associated with altered postnatal growth and metabolism, which are, in turn, associated with increased risk of adult disease. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of ovine FGR increases growth rate in late gestation, but the effects on postnatal growth and metabolism are unknown. We investigated the effects of intra-amniotic IGF1 administration to ovine fetuses with uteroplacental embolisation-induced FGR on phenotypical and physiological characteristics in the 2  weeks after birth. We measured early postnatal growth velocity, amino-terminal propeptide of C-type natriuretic peptide (NTproCNP), body composition, tissue-specific mRNA expression, and milk intake in singleton lambs treated weekly with 360 µg intra-amniotic IGF1 (FGRI; n = 13 females, 19 males) or saline (FGRS; n = 18 females, 12 males) during gestation, and in controls (CON; n = 15 females, 22 males). There was a strong positive correlation between maternal NTproCNP and fetal oxygenation, and size at birth in FGR lambs. FGR lambs were ∼20% lighter at birth and demonstrated accelerated postnatal growth velocity. IGF1 treatment did not alter perinatal mortality, partially abrogated the reduction in newborn size in females, but not males, and reduced accelerated growth in both sexes. IGF1-mediated upregulation of somatotrophic genes in males during the early postnatal period could suggest that treatment effects are associated with delayed axis maturation, whilst treatment outcomes in females may rely on the reprogramming of nutrient-dependent mechanisms of growth. These data suggest that the growth-restricted fetus is responsive to intra-amniotic intervention with IGF1, and that sex-specific somatotrophic effects persist in the early postnatal period.

Effects of twin pregnancy and periconceptional undernutrition on maternal metabolism, fetal growth and glucose-insulin axis function in ovine pregnancy.

Although twins have lower birthweights than singletons, they may not experience the increased disease risk in adulthood reportedly associated with low birthweight. In contrast, another periconceptional event, maternal undernutrition, does not reduce birthweight but does affect fetal and postnatal physiology in sheep. We therefore studied maternal and fetal metabolism, growth and glucose-insulin axis function in late gestation in twin and singleton sheep pregnancies, either undernourished from 60 days before until 30 days after conception or fed ad libitum. We found that twin-bearing ewes had decreased maternal food intake in late gestation and lower maternal and fetal plasma glucose and insulin levels. Twin fetuses had fewer everted placentomes, grew slower in late gestation, and had a greater insulin response to a glucose challenge, but lesser response to arginine. In contrast, periconceptional undernutrition led to increased maternal food intake and a more rapid fall in maternal glucose levels in response to fasting. Periconceptional undernutrition increased the number of everted placentomes, and abolished the difference in insulin responses to glucose between twins and singletons. Thus, the physiology of twin pregnancy is quite different from that of singleton pregnancy, and is probably determined by a combination of factors acting in both early and late gestation. The inconsistency of the relationships between low birthweight and postnatal disease risk of twins may lie in their very different fetal development. These data suggest that twin pregnancy may be another paradigm of developmental programming, and indicate that twins and singletons must be examined separately in any study of fetal or postnatal physiology.

Effects of twinning and periconceptional undernutrition on late-gestation hypothalamic-pituitary-adrenal axis function in ovine pregnancy.

The relationships between reduced size at birth, increased activity of the hypothalamic-pituitary-adrenal (HPA) axis, and increased risk of disease in adulthood are well described in singletons but are much less clear in twins. This may be because the physiological processes underlying reduced size at birth are different in singletons and twins. Periconceptional undernutrition can cause altered activity of the fetal and postnatal HPA axis without altering size at birth. However, the independent effects of periconceptional undernutrition and twinning on activity of the maternal and fetal HPA axes are not well described. We therefore studied maternal and fetal HPA axis function during late gestation in twin and singleton sheep pregnancies, either undernourished around conception or fed ad libitum. We found that twinning led to suppressed baseline HPA axis function and decreased adrenal sensitivity to ACTH stimulation but increased fetal pituitary ACTH response both to direct stimulation by CRH (ACTH area under the curve response: 29.7 +/- 2.2 vs. 17.1 +/- 1.6 ng/min x ml, P < 0.01) and to decreased cortisol negative feedback. In contrast, periconceptional undernutrition resulted in a decreased pituitary response (ACTH area under the curve response: 19.4 +/- 1.6 vs. 26.1 +/- 2.2 ng/min x ml, P = 0.02) but no difference in adrenal response. Thus, the HPA axis function of twin sheep fetuses in late gestation is very different from that of control and undernourished singletons. If the HPA axis is an important mediator between fetal adaptations and adult disease, these data may help explain why the relationship between fetal growth and postnatal physiology and disease risk is inconsistent in twins.

Cardiovascular adaptations to pregnancy in sheep and effects of periconceptional undernutrition.

The objective of this study was to describe the effects of pregnancy on blood volume and uterine blood flow in sheep, and to test the hypothesis that the effects of periconceptional undernutrition on the late-gestation fetus are mediated by alterations in these parameters. Singleton-bearing ewes that had been undernourished preconception, postconception, both, or neither, underwent estimation of blood volume in mid and late gestation, and measurement of uterine blood flow in late gestation. Seven non-pregnant ewes were also studied. Pregnancy resulted in a 31% greater red cell volume in mid-gestation (21.0+/-1.3 vs 16.1+/-0.8ml/kg, p<0.05), but no significant change in plasma or blood volume. However maternal blood volume was correlated with uterine blood flow (r(2)=0.22, p=0.05) and fetal size (r(2)=0.20, p=0.02). Uterine blood flow was 13% greater in the undernourished groups than controls (1847+/-100 vs 1641+/-79ml/min, p<0.01). The large increase in maternal blood volume integral to a successful human pregnancy was not present in sheep. The increased uterine blood flow after periconceptional undernutrition suggests that nutritional signals before and in early pregnancy influence fetal nutrient supply in late gestation.

A method for assessment of blood volume parameters in pregnant sheep using fluorescein-labelled dextran.

The assessment of blood volume parameters in clinical and research settings has been limited by methods that involve radioactivity, complex assays or are unreliable. We aimed to design a method for measuring blood volume parameters that was non-radioactive, simple, cheap and reliable. We have used a commercially available fluorescein-labelled 250kDa dextran, a large inert molecule, and have measured dilution of this through the intravascular space of pregnant ewes. From this estimation of plasma volume and measured hematocrit, we have calculated blood volume and red cell volume. The blood volume results are 6% lower than those obtained using radiolabelled red cells, but there is no significant difference in red cell volume between methods. The coefficient of variation for repeated measurements of plasma volume measurements is 3.8%. This is a simple, reliable, cheap and non-radioactive method for estimating blood volume parameters in pregnant sheep, and may prove useful in other settings.

Protein metabolism in preterm infants with particular reference to intrauterine growth restriction.

There is growing evidence that neonatal and long-term morbidity in preterm infants, particularly those born before 32 weeks' gestation, can be modified by attained growth rate in the neonatal period. Guidelines for optimal growth and the nutritional intakes, particular of protein, required to achieve this are not well defined. Due to delays in postnatal feeding and a lack of energy stores developed in the last trimester of pregnancy, preterm infants often suffer early postnatal catabolism until feeding is established. There are indications that infants born with intrauterine growth restriction have perturbations in protein metabolism. Therefore, they may have different protein requirements than appropriate for gestational age infants. This review summarises what is known about protein requirements and metabolism in the fetus and preterm infant, with particular emphasis on the distinct requirements of the growth-restricted infant.

Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease.

BACKGROUND: It is not clear whether there is benefit in repeating the dose of prenatal corticosteroids for women who remain at risk of preterm birth after an initial course. OBJECTIVES: To assess the effectiveness and safety of a repeat dose(s) of prenatal corticosteroids. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 4), MEDLINE (1965 to November 2006), EMBASE (1988 to November 2006) and Current Contents (1997 to November 2006). SELECTION CRITERIA: Randomised controlled trials of women who have already received a single course of corticosteroids seven or more days previously and are still considered to be at risk of preterm birth; outcomes compared for women randomised to receive a repeat dose(s) of prenatal corticosteroids, with women given no further prenatal corticosteroids. DATA COLLECTION AND ANALYSIS: We assessed trial quality and extracted the data independently. MAIN RESULTS: Five trials, involving over 2000 women between 23 and 33 weeks' gestation, are included. Treatment with repeat dose(s) of corticosteroid was associated with a reduction in occurrence (relative risk (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.93, four trials, 2155 infants) and severity of any neonatal lung disease (RR 0.60, 95% CI 0.48 to 0.75, three trials, 2139 infants) and serious infant morbidity (RR 0.79, 95% CI 0.67 to 0.93, four trials, 2157 infants).Mean birthweight was not significantly different between treatment groups (weighted mean difference (WMD) -62.07 g, 95% CI -129.10 to 4.96, four trials, 2273 infants), although in one trial, treatment with repeat dose(s) of corticosteroid was associated with a reduction in birthweight Z score (WMD) -0.13, 95% CI -26 to 0.00, 1 trial, 1144 infants), and in two trials, with an increased risk of being small for gestational age at birth (RR 1.63, 95% CI 1.12 to 2.37, two trials, 602 infants). No statistically significant differences were seen for any of the other primary outcomes that included other measures of respiratory morbidity, fetal and neonatal mortality, periventricular haemorrhage, periventricular leukomalacia and maternal infectious morbidity. Treatment with repeat dose(s) of corticosteroid was associated with a significantly increased risk of caesarean section (RR 1.11, 95% CI 1.01 to 1.22, four trials, 1523 women). AUTHORS' CONCLUSIONS: Repeat dose(s) of prenatal corticosteroids reduce the occurrence and severity of neonatal lung disease and the risk of serious health problems in the first few weeks of life. These short-term benefits for babies support the use of repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth. However, these benefits are associated with a reduction in some measures of weight, and head circumference at birth, and there is still insufficient evidence on the longer-term benefits and risks.

The late effects of fetal growth patterns.

The immediate prenatal and postnatal consequences of reduced fetal growth have long been known. The longer term associations between reduced birth weight and adult disease risk are also now well established. Reduced fetal growth is usually detected late in gestation, and the assumption has been that this is the time when factors regulating fetal growth have their greatest effect. However, recent evidence suggests that both the growth trajectory of the fetus and its adaptive responses to the prenatal and postnatal environment may be determined in the period around the time of conception.

Variable interpretation of ultrasonograms may contribute to variation in the reported incidence of white matter damage between newborn intensive care units in New Zealand.

BACKGROUND: The incidence of cerebral white matter damage reported to the Australian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensive care units (NICUs). HYPOTHESIS: Differences in the capture, storage, and interpretation of the cerebral ultrasound scans could account for some of this variation. METHODS: A total of 255 infants of birth weight <1500 g and gestation <32 weeks born between 1997 and 2002 and drawn equally from each of the six NICUs in New Zealand were randomly selected from the ANZNN database. Half had early cerebral ultrasound scans previously reported to ANZNN as normal, and half had scans reported as abnormal. The original scans were copied, anonymised, and independently read by a panel of three experts using a standardised method of reviewing and reporting. RESULTS: There was considerable variation between NICUs in methods of image capture, quality, and completeness of the scans. There was only moderate agreement between the reviewers' reports and the original reports to the ANZNN (kappa 0.45-0.51) and between the reviewers (kappa 0.54-0.64). The reviewers reported three to six times more white matter damage than had been reported to the ANZNN. CONCLUSION: Some of the reported variation in white matter damage between NICUs may be due to differences in capture and interpretation of cerebral ultrasound scans.

Exposure to repeat doses of antenatal glucocorticoids is associated with altered cardiovascular status after birth.

OBJECTIVE: To determine if exposure to more than one course of antenatal glucocorticoids is associated with changes in infant blood pressure and myocardial wall thickness in the first month after birth. DESIGN: Prospective cohort study. SETTING: Tertiary neonatal intensive care unit. PARTICIPANTS: Mothers who were eligible for but declined to enter a randomised trial of repeated doses of antenatal glucocorticoids (ACTORDS)-that is, who had a singleton, twin, or triplet pregnancy at <32 weeks gestation, had received an initial course of glucocorticoids seven or more days previously, and were considered to be at continued risk of preterm birth. MAIN OUTCOME MEASURES: Blood pressure daily for the first week then weekly until 4 weeks of age. End diastolic interventricular septal and left ventricular posterior wall (EDIVS and EDLVPW) thickness at 48-72 hours after birth. RESULTS: Thirty seven women were enrolled and delivered 50 infants. Thirty mothers (39 infants) were exposed to one course of glucocorticoids, and seven mothers (11 infants) to more than one course. Blood pressures were higher in the first week after birth in infants exposed to multiple courses of glucocorticoids, and in infants with a latency between last exposure and delivery of less than seven days. Systolic blood pressure on day 1 was >2SD above published normal ranges in 67% of babies exposed to multiple courses and 24% of babies exposed to a single course of glucocorticoids (p = 0.04). There was no difference between groups in thickness of the EDIVS or EDLVPW. However, 44/50 (88%) babies had EDIVS and 49/50 (98%) babies had EDLVPW thickness >2 SD above the expected mean for birth weight and gestation. EDIVS but not EDLVPW thickness increased with increasing latency (mean 0.02 mm/day, p = 0.03). CONCLUSION: Future randomised trials should assess the long term effects of exposure to antenatal glucocorticoids, particularly multiple courses, on the cardiovascular status of the infant.

Intrauterine Intervention for the Treatment of Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with an increased incidence of fetal and neonatal death, and of neonatal morbidity. Babies born following FGR also are at risk of a range of postnatal complications, which may contribute to an increased incidence of disease later in life. There currently are no effective clinical interventions which improve perinatal survival, intrauterine growth and later outcomes of the FGR baby. Postnatal interventions aimed at promoting or accelerating growth in FGR babies to improve outcome, particularly neurodevelopmental outcomes, may further increase the risk of metabolic dysregulation and, therefore, the risk of developing chronic disease in adulthood. An intrauterine intervention to improve nutrition and growth in the FGR fetus may have the potential to decrease mortality and improve long-term outcomes by delaying preterm delivery and mitigating the need for and risks of accelerated postnatal growth.

Amniotic IGF-I supplementation of growth-restricted fetal sheep alters IGF-I and IGF receptor type 1 mRNA and protein levels in placental and fetal tissues.

We have previously reported that chronic intra-amniotic supplementation of the late gestation growth-restricted (IUGR) ovine fetus with IGF-I (20 microg/day) increased gut growth but reduced liver weight and circulating IGF-I concentrations. Here we report mRNA and protein levels of IGF-I, the type 1 IGF receptor (IGF-1R) and IGF-binding proteins (IGFBP)-1, -2 and -3 in fetal gut, liver, muscle and placenta from fetuses in that earlier study in an attempt to explain these contrasting results. mRNA and protein were extracted from tissues obtained at post mortem at 131 days of gestation (term, 145 days) from three groups of fetuses (control, IUGR+saline and IUGR+IGF-I, n=9 per group). Control fetuses were unembolised and untreated. In the IUGR groups, growth restriction was induced from 113 to 120 days by placental embolisation; from 120 to 130 days fetuses were treated with daily intra-amniotic injections of either saline or 20 microg IGF-I. mRNA was measured by RT-PCR or real-time RT-PCR, and protein by Western blot. In liver, muscle and placenta, IGF-I mRNA and protein levels were reduced by between 8 and 30% in IGF-I-treated fetuses compared with saline-treated fetuses and controls with no change in IGF-1R mRNA or protein levels. In contrast, in the gut, IGF-I mRNA and protein levels were not significantly altered with IGF-I treatment, but IGF-1R levels were increased, especially in the jejunum. Immunolocalisation demonstrated that IGF-1R expression was confined to the luminal aspect of the gut. mRNA levels of all three IGFBPs were reduced in the gut of IGF-I-treated fetuses, but hepatic expression was significantly increased. These data demonstrated tissue-specific regulation of IGF-I, IGF-1R and IGFBPs-1, -2 and -3 in response to intra-amniotic IGF-I supplementation, though the underlying mechanisms remain obscure.

Does variation in interpretation of ultrasonograms account for the variation in incidence of germinal matrix/intraventricular haemorrhage between newborn intensive care units in New Zealand?

BACKGROUND: The incidence of germinal matrix/intraventricular haemorrhage (GM/IVH) reported to the Australian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensive care units (NICUs). HYPOTHESIS: Differences in the capture, storage, and interpretation of the cerebral ultrasound scans may account for some of this variation. METHODS: A total of 255 infants with birth weight <1500 g and gestation <32 weeks born between 1997 and 2002 were randomly selected from the ANZNN database, 44 from each of the six NICUs in New Zealand. Twenty two infants from each NICU had cerebral ultrasound scans previously reported to ANZNN as normal; another 22 had scans reported as abnormal. The original scans were copied using digital photography and anonymised and independently read by a panel of three experts using a standardised method of reviewing and reporting. RESULTS: There was considerable variation between NICUs in methods of image capture and quality and completeness of the scans. However, there was little variation in the reporting of scans between the reviewers and the reports to ANZNN (weighted kappa 0.75-0.91). Grade 1 GM/IVH was generally over-reported and grade 4 under-reported to the ANZNN. CONCLUSION: For all NICUs, a high level of agreement was found between the reviewers' reports and the reports to the ANZNN. Thus the variation between NICUs in the incidence of GM/IVH reported to the ANZNN is unlikely to be due to differences in capture, storage, and interpretation of the cerebral ultrasound scans. Further investigation is warranted into the reasons for the variation in incidence of GM/IVH between NICUs.

Antenatal glucocorticoids: where are we after forty years?

Since their introduction more than forty years ago, antenatal glucocorticoids have become a cornerstone in the management of preterm birth and have been responsible for substantial reductions in neonatal mortality and morbidity. Clinical trials conducted over the past decade have shown that these benefits may be increased further through administration of repeat doses of antenatal glucocorticoids in women at ongoing risk of preterm and in those undergoing elective cesarean at term. At the same time, a growing body of experimental animal evidence and observational data in humans has linked fetal overexposure to maternal glucocorticoids with increased risk of cardiovascular, metabolic and other disorders in later life. Despite these concerns, and somewhat surprisingly, there has been little evidence to date from randomized trials of longer-term harm from clinical doses of synthetic glucocorticoids. However, with wider clinical application of antenatal glucocorticoid therapy there has been greater need to consider the potential for later adverse effects. This paper reviews current evidence for the short- and long-term health effects of antenatal glucocorticoids and discusses the apparent discrepancy between data from randomized clinical trials and other studies.

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.

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.

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.

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.

Maternal undernutrition during the periconceptual period increases plasma taurine levels and insulin response to glucose but not arginine in the late gestational fetal sheep.

Maternal undernutrition throughout gestation impairs pancreatic function in the offspring. The influence of periconceptual maternal undernutrition on fetal insulin responses to secretogues in late gestation is unknown. Romney ewes were fed concentrates at 1-2% of body weight/d (UN) or 3-4% of body weight/d (N) from -61 d to +30 d from mating. From 30 d gestation all ewes were fed at 3-4% of body weight/d. At 119 d gestation singleton fetuses (UN; n = 12, N; n = 10) underwent intravenous glucose (1.5 g) and arginine (300 mg) challenge tests. Paired maternal and fetal blood samples were collected over 60 min. Fetal plasma insulin area under the curve (AUC) was larger in UN than in N fetuses during glucose challenge (4.5 +/- 0.6 vs. 2.9 +/- 0.5 nM, p < 0.05) but was not different during arginine challenge. Maternal and fetal plasma taurine concentrations were higher in UN than N (maternal; 110 +/- 11 vs. 75 +/- 8 microM, fetal; 99 +/- 13 vs. 56 +/- 5 microM, both p < 0.05). Maternal periconceptual undernutrition influences fetal insulin secretion without affecting fetal size. The larger plasma insulin responses in UN fetuses could reflect accelerated maturation of pancreatic beta cells or an alteration of other mechanisms regulating insulin secretion. The role of taurine in fetal pancreatic beta cell development requires further investigation.