Showing papers on "Fetus published in 2002"

Basic anatomical and physiological data for use in radiological protection : reference values

Abstract: Preface Abstract 1. Basis of ICRP Reference Values 2. Summary of Reference Values 3. Embryo and Fetus 4. Total Body 5. Respiratory System 6. Alimentary System 7. Circulatory and Lymphatic Systems 8. Urogenital System 9. Skeletal System 10. Integumentary System 11. Additional Organs and Tissues 12. Pregnant Woman: Anatomical and Physiological Changes 13. Elemental Composition of the Body Reference

Natural killer cells and pregnancy.

Abstract: The fetus is considered to be an allograft that, paradoxically, survives pregnancy despite the laws of classical transplantation immunology. There is no direct contact of the mother with the embryo, only with the extraembryonic placenta as it implants in the uterus. No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophoblast MHC ligands.

Placental-specific IGF-II is a major modulator of placental and fetal growth

Abstract: Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth1,2,3,4. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta5. Here we show that deletion from the Igf2 gene of a transcript (P0)6,7 specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting8. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure

Abstract: Background There is broad human exposure to bisphenol A (BPA), an estrogenic endocrine-disrupting chemical widely used for the production of plastic products. BPA is reported to affect preimplantation embryos or fetuses and alter their postnatal development at doses typically found in the environment. We measured contamination of BPA in various kinds of human biological fluids by a novel enzyme-linked immunosorbent assay. Methods Blood samples were obtained from healthy premenopausal women, women with early and full-term pregnancy, and umbilical cord at full-term delivery. Ovarian follicular fluids obtained during IVF procedures and amniotic fluids obtained at mid-term and full-term pregnancy were also subject to BPA measurements. Results BPA was present in serum and follicular fluid at approximately 1-2 ng/ml, as well as in fetal serum and full-term amniotic fluid, confirming passage through the placenta. Surprisingly, an approximately 5-fold higher concentration, 8.3 +/- 8.7 ng/ml, was revealed in amniotic fluid at 15-18 weeks gestation, compared with other fluids. Conclusion These results suggest accumulation of BPA in early fetuses and significant exposure during the prenatal period, which must be considered in evaluating the potential for human exposure to endocrine-disrupting chemicals.

Diagnosis and Management of Human Cytomegalovirus Infection in the Mother, Fetus, and Newborn Infant

Abstract: Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection and mental retardation. HCMV infection, while causing asymptomatic infections in most immunocompetent subjects, can be transmitted during pregnancy from the mother with primary (and also recurrent) infection to the fetus. Hence, careful diagnosis of primary infection is required in the pregnant woman based on the most sensitive serologic assays (immunoglobulin M [IgM] and IgG avidity assays) and conventional virologic and molecular procedures for virus detection in blood. Maternal prognostic markers of fetal infection are still under investigation. If primary infection is diagnosed in a timely manner, prenatal diagnosis can be offered, including the search for virus and virus components in fetal blood and amniotic fluid, with fetal prognostic markers of HCMV disease still to be defined. However, the final step for definite diagnosis of congenital HCMV infection is detection of virus in the blood or urine in the first 1 to 2 weeks of life. To date, treatment of congenital infection with antiviral drugs is only palliative both prior to and after birth, whereas the only efficacious preventive measure seems to be the development of a safe and immunogenic vaccine, including recombinant, subunit, DNA, and peptide-based vaccines now under investigation. The following controversial issues are discussed in the light of the most recent advances in the field: the actual perception of the problem; universal serologic screening before pregnancy; the impact of correct counseling on decision making by the couple involved; the role of prenatal diagnosis in ascertaining transmission of virus to the fetus; the impact of preconceptional and periconceptional infections on the prevalence of congenital infection; and the prevalence of congenitally infected babies born to mothers who were immune prior to pregnancy compared to the number born to mothers undergoing primary infection during pregnancy.

Intrauterine infection and prematurity.

Abstract: Intrauterine infection is a major cause of premature labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm births and the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection. Microorganisms may also gain access to the fetus before delivery. A fetal inflammatory response syndrome elicited in response to microbial products is associated with the impending onset of preterm labor and also with multi-systemic organ involvement in the human fetus and a higher rate of perinatal morbidity. The most common microorganisms involved in intrauterine infections are Ureaplasma urealyticum, Fusobacterium species and Mycoplasma hominis. The role of Chlamydia trachomatis and viruses in preterm labor remain to be determined. Use of molecular microbiology techniques to diagnose intrauterine infection may uncover the role of fastidious microorganisms that have not yet been discovered. Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm birth. However, such benefit has not been demonstrated for patients with bacterial vaginosis, or women who carry Streptococcus agalactia, Ureaplasma urealyticum or Trichomonas vaginalis. Antibiotic administration to patients with preterm premature rupture of membranes is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. The benefit has not been demonstrated in patients with preterm labor and intact membranes. Major efforts are required to determine why some women develop an ascending intrauterine infection and others do not and also what interventions may reduce the deleterious effect of systemic fetal inflammation.

Telomere Length in the Newborn

Abstract: Telomere length is similar in different organs of the human fetus but variable among fetuses. During extrauterine life telomere length is highly variable among individuals and longer in women than men. In the present work we addressed the following questions: 1) Are there sex-related differences in telomere length at birth? 2) Is there synchrony (i.e. correlation in length) of telomeres in tissues within the newborn? 3) Is the variability in telomere length among newborns as large as that in adults? We studied normal male and female newborns who donated DNA samples from three sources: white blood cells, umbilical artery, and foreskin. Telomere length was measured by the mean length of the terminal restriction fragments (TRF). TRF length was not different between male and female newborns. It was highly synchronized among the DNA samples from white blood cells, umbilical artery and skin within individual donors but exhibited a high variability among donors. We conclude that there is no evidence for the effect of sex on telomere length at birth, suggesting that longer telomeres in women than men arise from a slower rate of telomeric attrition in women. The variability in telomere length among newborns and synchrony in telomere length within organs of the newborn are consistent with the concept that variations in telomere length among adults are in large part attributed to determinants (genetic and environmental) that start exerting their effect in utero.

Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus

Abstract: Objective To identify the temporal sequence of abnormal Doppler changes in the fetal circulation in a subset of early and severely growth-restricted fetuses Methods This was a prospective observational study in a tertiary care/teaching hospital Twenty-six women who were diagnosed with growth-restricted fetuses by local standards before 32 weeks' gestation and who had abnormal uterine and umbilical artery Doppler velocimetry were enrolled onto the study To compare Doppler changes as a function of time, pulsed-wave Doppler ultrasound was performed on five vessels in the fetal peripheral and central circulations Doppler examinations were performed twice-weekly and on the day of delivery if the fetal heart rate tracing became abnormal Doppler indices were scored as abnormal when their values were outside the local reference limits on two or more consecutive measurements Biometry for assessment of fetal growth was performed every 2 weeks Computerized fetal heart rates were obtained daily Delivery was based on a non-reactive fetal heart rate tracing and not on Doppler information Patients with a severely growth-restricted fetus who were delivered for maternal indications such as pre-eclampsia were excluded Perinatal outcome endpoints included: intrauterine death, gestational age at delivery, newborn weight, central nervous system damage of grade 2 or greater, intraventricular hemorrhage and neonatal mortality Results Mean gestational age and newborn weight at delivery were 29 (standard deviation (SD), 2) weeks and 818 (SD, 150) g, respectively The sequence of Doppler velocimetric changes was described by onset time cumulative curves that showed two time-related events First, for each vessel there was a progressive increase in the percent of fetuses developing a Doppler abnormality Second, severely growth-restricted fetuses followed a progressive sequence of acquiring Doppler abnormalities which were categorized into ‘early’ and ‘late’ Doppler changes Early changes occurred in peripheral vessels (umbilical and middle cerebral arteries; 50% of patients affected 15–16 days prior to delivery) Late changes included umbilical artery reverse flow, and abnormal changes in the ductus venosus, aortic and pulmonary outflow tracts (50% of patients affected 4–5 days prior to delivery) The time interval between the occurrence of early and late changes was significantly different (P < 00001) and late changes were significantly associated with perinatal death (P < 001) Conclusions Doppler velocimetry abnormalities develop in different vessels of the severely growth-restricted fetus in a sequential fashion Late changes in vascular adaptation by the severely growth-restricted fetus are the best predictor of perinatal death Copyright © 2002 ISUOG

Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome

Abstract: Objective: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). Methods: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. Results: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm l...

Lipid Metabolism in Pregnancy and its Consequences in the Fetus and Newborn

Abstract: During early pregnancy there is an increase in body fat accumulation, associated with both hyperphagia and increased lipogenesis. During late pregnancy there is an accelerated breakdown of fat depots, which plays a key role in fetal development. Besides using placental transferred fatty acids, the fetus benefits from two other products: glycerol and ketone bodies. Although glycerol crosses the placenta in small proportions, it is a preferential substrate for maternal gluconeogenesis, and maternal glucose is quantitatively the main substrate crossing the placenta. Enhanced ketogenesis under fasting conditions and the easy transfer of ketones to the fetus allow maternal ketone bodies to reach the fetus, where they can be used as fuels for oxidative metabolism as well as lipogenic substrates. Although maternal cholesterol is an important source of cholesterol for the fetus during early gestation, its importance becomes minimal during late pregnancy, owing to the high capacity of fetal tissues to synthesize cholesterol. Maternal hypertriglyceridemia is a characteristic feature during pregnancy and corresponds to an accumulation of triglycerides not only in very low-density lipoprotein but also in low- and high-density lipoprotein. Although triglycerides do not cross the placental barrier, the presence of lipoprotein receptors in the placenta, together with lipoprotein lipase, phospholipase A2, and intracellular lipase activities, allows the release to the fetus of polyunsaturated fatty acids transported as triglycerides in maternal plasma lipoproteins. Normal fetal development needs the availability of both essential fatty acids and long chain polyunsaturated fatty acids, and the nutritional status of the mother during gestation has been related to fetal growth. However, excessive intake of certain long chain fatty acids may cause both declines in arachidonic acid and enhanced lipid peroxidation, reducing antioxidant capacity.

Frequency and Occurrence of Late-Gestation Losses from Cattle Cloned Embryos

Abstract: Nuclear transfer from somatic cells still has limited efficiency in terms of live calves born due to high fetal loss after transfer. In this study, we addressed the type of donor cells used for cloning in in vivo development. We used a combination of repeated ultrasonography and maternal pregnancy serum protein (PSP60) assays to monitor the evolution of pregnancy after somatic cloning in order to detect the occurrence of late-gestation losses and their frequency, compared with embryo cloning or in vitro fertilization (IVF). Incidence of loss between Day 90 of gestation and calving was 43.7% for adult somatic clones and 33.3% for fetal somatic clones, compared with 4.3% after embryo cloning and 0% in the control IVF group. Using PSP60 levels in maternal blood as a criterion for placental function, we observed that after somatic cloning, recipients that lost their pregnancy before Day 100 showed significantly higher PSP60 levels by Day 50 than those that maintained pregnancy (7.77 6 3.3 ng/ml vs. 2.45 6 0.27 ng/ml for normal pregnancies, P , 0.05). At later stages of gestation, between 4 mo and calving, mean PSP60 concentrations were significantly increased in pathologic pregnancy after somatic cloning compared with other groups (P , 0.05 by Day 150, P , 0.001 by Day 180, and P , 0.01 by Day 210). In those situations, and confirmed by ultrasonographic measurements, recipients developed severe hydroallantois together with larger placentome size. Our findings suggest that assessing placental development with PSP60 and ultrasonography will lead to better care of recipient animals in bovine somatic cloning. assisted reproductive technology, conceptus, embryo, placenta, pregnancy

Prostaglandins and mechanisms of preterm birth

Abstract: Increased uterine contractility at term and preterm results first from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus, and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. In sheep fetuses, increased cortisol output during pregnancy regulates expression of prostaglandin synthase type 2 (PGHS-2) in the placenta in an oestrogen-independent manner, resulting in increased concentrations of prostaglandin E2 (PGE2) in the fetal circulation. Later increases in maternal uterine expression of PGHS-2 require increases in oestrogen and lead to increased concentrations of PGF(2alpha) in the maternal circulation. Thus, regulation of PGHS-2 at term is differentially controlled in fetal (trophoblast) and maternal (uterine epithelium) tissue. This difference may reflect expression of glucocorticoid receptor but not oestrogen receptor (ER) in placental trophoblast cells. In women, cortisol also contributes to increased prostaglandin production in fetal tissues through upregulation of PGHS-2 (amnion and chorion) and downregulation of 15-OH prostaglandin dehydrogenase (PGDH; chorion trophoblasts). The effect of cortisol on expression of PGDH in the chorion reverses a tonic stimulatory effect of progesterone, potentially through a paracrine or autocrine action. In membranes, cortisol may be derived from cortisone through activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, in addition to secretion from the maternal or fetal adrenal glands. In placenta, 11beta-HSD-2 oxidase activity predominates and expression of this enzyme is reduced with hypoxaemia and in placentae from pre-eclamptic pregnancies. In these circumstances, increased concentrations of maternal cortisol may cross into the fetal compartment, contributing to growth restriction and programming later life disease.

Fetal Tissues Are Exposed to Biologically Relevant Free Thyroxine Concentrations during Early Phases of Development

Abstract: Maternal hypothyroxinemia in early pregnancy is often associated with irreversible effects on neuropsychomotor development. To evaluate fetal tissue exposure to maternal thyroid hormones up to midgestation, we measured total T(4) and free T(4) (FT(4)), T(3), rT(3), TSH, and possible binding proteins in first trimester coelomic and amniotic fluids and in amniotic fluid and fetal serum up to 17 wk. Samples were obtained before interruption of maternal-fetal connections. The concentrations in fetal compartments of T(4) and T(3) are more than 100-fold lower than those in maternal serum, and their biological relevance for fetal development might be questioned. We found, however, that in all fetal fluids the concentrations of T(4) available to developing tissues, namely FT(4), reach values that are at least one third of those biologically active in their euthyroid mothers. FT(4) levels in fetal fluids are determined by both their T(4)-binding protein composition and the T(4) or FT(4) in maternal serum. The binding capacity is determined ontogenically, is independent of maternal thyroid status, and is far in excess of the T(4) in fetal fluids. Thus, the availability of FT(4) for embryonic and fetal tissues would decrease in hypothyroxinemic women, even if they were euthyroid. A decrease in the availability of FT(4), a major precursor of intracellular nuclear receptor-bound T(3), may result in adverse effects on the timely sequence of developmental events in the human fetus. These findings ought to influence our present approach to maternal hypothyroxinemia in early pregnancy regardless of whether TSH is increased or whether overt or subclinical hypothyroidism is detected.

Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival.

Abstract: The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen. We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref. 4). Cultured embryonic fibroblasts from homozygous Slc23a1(-/-) mice had less than 5% of normal ascorbic-acid uptake. Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1(-/-) mice. Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1(-/-) fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport. Slc23a1(-/-) mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Lungs showed no postnatal expansion but had normal surfactant protein B levels. Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1(-/-) mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content. We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta. Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.

HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy

Abstract: Different mechanisms mediated by the expression of the HLA-class Ib HLA-G products are suggested to account for the induction of immune tolerance against the paternal antigens of the fetus during pregnancy. Soluble HLA-G antigens, mainly produced by cytotrophoblast cells at the materno-fetal interface and circulating in the body fluids, show a capacity analogous to that of membrane-boundstructures to inhibit NK cells. In the present report we have investigated, using specific ELISA, the presence of sHLA-G molecules in culture supernatants of early embryos obtained by in vitro fertilization (IVF) before transfer. The data obtained from the analysis of 285 supernatants corresponding to 101 IVF procedures (43 IVF, 58 intracytoplasmic sperm injection) identify two groups of patients on the basis of sHLA-G antigen presence. No differences in clinical parameters were observed between the groups, but positive embryo implantations occurred only in women showing sHLA-G molecules in culture supernatants (Fisher's exact p value 2.56×10–3). The results obtained indicate that expression of HLA-G products in embryo cells is a mandatory, but not sufficient, prerequisite for the development of pregnancy.

Developmental aspects of human hepatic drug glucuronidation in young children and adults

Abstract: Background and aims: The liver represents one of the major sites of human glucuronidation. Many therapeutic drugs are substrates for UDP-glucuronosyltransferases (UGT) leading to the formation of usually inactive glucuronides. Hepatic glucuronidation undergoes significant changes during fetal and neonatal development requiring age adapted drug therapy. Regulation of individual UGT genes during hepatic development has not been defined. Subjects and methods: Expression of 13 UGT genes and glucuronidation activities were analysed in 16 paediatric liver samples (aged 7–24 months), two fetal samples, and 12 adult liver samples (aged 25–75 years) using duplex reverse transcription-polymerase chain reaction, western blot, and specific catalytic UGT activity assays. Results: No UGT transcripts were detected in fetal liver at 20 weeks9 gestation. In contrast, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, and UGT2B15 transcripts were present without variation in all 28 hepatic samples after six months of age. Significantly lower expression of UGT1A9 and UGT2B4 mRNA was identified in paediatric liver. Hepatic glucuronidation activity in children aged 13–24 months was found to be lower than in adults for ibuprofen (24-fold), amitriptyline (16-fold), 4- tert -butylphenol (40-fold), estrone (15-fold), and buprenorphine (12-fold). Conclusions: An early phase characterised by the appearance of UGT gene transcripts and a later phase characterised by upregulation of UGT expression is demonstrated during human hepatic development. The differential regulation of UGT1A9 and UGT2B4 expression extends beyond two years of age and is capable of influencing hepatic glucuronidation of common therapeutic drugs in children. The development of hepatic UGT activities is significant for paediatric drug therapy and the prevention of adverse drug effects.

Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm.

Abstract: Only sparse information is available about a possible association between antenatal infection outside the brain and subsequent cognitive limitations among preterm infants. Based on published studies, we provide a theoretical schema that links them via the fetal inflammatory response and neonatal white matter damage. We conclude that the relationship between antenatal infection and cognitive limitations deserves much further attention by researchers interested in the prevention of this undesirable outcome of prematurity.

Uterine and fetal cerebral Doppler predict the outcome of third‐trimester small‐for‐gestational age fetuses with normal umbilical artery Doppler

Abstract: Objective To assess the value of different admission tests in predicting the outcome of small-for-gestational age (SGA) fetuses with normal Doppler waveforms in the umbilical artery. Methods Criteria for admission into this retrospective study included: singleton pregnancy with a birth weight < 10th centile; absence of severe maternal complications; no evidence of fetal anomalies on the sonogram; normal umbilical artery Doppler; and availability of complete follow-up. At the first antenatal sonogram classifying the fetus as SGA, Doppler analysis of the uterine and middle cerebral arteries was performed and amniotic fluid volume was assessed. Outcome variables included adverse perinatal outcome (perinatal death, severe morbidity) and emergency Cesarean section for fetal distress. Results Two hundred and thirty-one pregnancies were included in the study. The mean ± standard deriation birth weight and gestational age at delivery were 2222 ± 502 g and 37.3 ± 2.9 weeks, respectively. In 37 cases (16%), an emergency Cesarean section was performed. There was one intrauterine death and three fetuses delivered by emergency Cesarean section developed severe morbidity. Logistic regression demonstrated that abnormal velocimetry of the uterine arteries and fetal middle cerebral artery were independently correlated with the occurrence of Cesarean section. Conclusions SGA fetuses with normal umbilical artery Doppler waveforms and abnormal uterine arteries and fetal middle cerebral artery waveforms have an increased risk of developing distress and being delivered by emergency Cesarean section. Particularly when both uterine and fetal cerebral waveforms are altered at the same time, the risk is exceedingly high (86%) and delivery as soon as fetal maturity is achieved seems advisable. On the other hand, when both vessels have normal waveforms, the chances of fetal distress are small (4%) and expectant management is the most reasonable choice.

Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression.

Abstract: The flavin-containing monooxygenases (FMOs) are important for the metabolism of numerous therapeutics and toxicants. Six mammalian FMO genes (FMO1–6) have been identified, each exhibiting developmental and tissue- and species-specific expression patterns. Previous studies demonstrated that human hepatic FMO1 is restricted to the fetus whereas FMO3 is the major adult isoform. These studies failed to describe temporal expression patterns, the precise timing of the FMO1/FMO3 switch, or potential control mechanisms. To address these questions, FMO1 and FMO3 were quantified in microsomal fractions from 240 human liver samples representing ages from 8 wk gestation to 18 y using Western blotting. FMO1 expression was highest in the embryo (8–15 wk gestation; 7.8 ± 5.3 pmol/mg protein). Low levels of FMO3 expression also were detectable in the embryo, but not in the fetus. FMO1 suppression occurred within 3 d postpartum in a process tightly coupled to birth, but not gestational age. The onset of FMO3 expression was highly variable, with most individuals failing to express this isoform during the neonatal period. FMO3 was detectable in most individuals by 1-2 y of age and was expressed at intermediate levels until 11 y (12.7 ± 8.0 pmol/mg protein). These data suggest that birth is necessary, but not sufficient for the onset of FMO3 expression. A gender-independent increase in FMO3 expression was observed from 11 to 18 y of age (26.9 ± 8.6 pmol/mg protein). Finally, 2- to 20-fold interindividual variation in FMO1 and FMO3 protein levels were observed, depending on the age bracket.

White matter injury after repeated endotoxin exposure in the preterm ovine fetus.

Abstract: Intrauterine infection has been linked to neurologic injury in preterm infants. However, a reproducible model of white matter injury in the preterm fetus in a long gestation species that can be monitored in utero is currently unavailable. Thus, our objective was to determine the effects of bacterial endotoxin (lipopolysaccharide, LPS) on physiologic and inflammatory responses and brain structure in the preterm ovine fetus. At 0.7 of gestation, six catheterized fetuses received three to five intravenous injections of LPS (1 micro g/kg) over 5 d; seven fetuses served as controls. Fetal responses were monitored and brain tissue examined 10-11 d after the initial LPS injection. After LPS on d 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to periventricular leukomalacia, and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. Thus, repeated exposure of the preterm ovine fetus to LPS causes neuropathology resembling that of cerebral palsy and provides a robust model for exploring the etiology, prevention, and treatment of white matter damage.

Impact of Maternal Undernutrition During the Periconceptional Period, Fetal Number, and Fetal Sex on the Development of the Hypothalamo-Pituitary Adrenal Axis in Sheep During Late Gestation

Abstract: Evidence from epidemiologic, clinical, and experimental studies has shown that a suboptimal intrauterine environment during early pregnancy can alter fetal growth and gestation length and is associated with an increased prevalence of adult hypertension and cardiovascular disease. It has been postulated that maternal nutrient restriction may act to reprogram the development of the pituitary-adrenal axis, resulting in excess glucocorticoid exposure and adverse health outcomes in later life. It is unknown, however, whether maternal nutrient restriction during the periconceptional period alters the development of the fetal pituitary-adrenal axis or whether the effects of periconceptional undernutrition can be reversed by the provision of an adequate level of maternal nutrition throughout the remainder of pregnancy. We have investigated the effect of restricted periconceptional nutrition (70% of control feed allowance) from 60 days before until 7 days after mating and the effect of restricted gestational nutrition from Day 8 to 147 of gestation on the development of the fetal hypothalamo-pituitary adrenal (HPA) axis in the sheep. In these studies, we have also investigated the effects of fetal number and sex on the pituitary-adrenal responses to periconceptional and gestational undernutrition. In ewes maintained on a control diet throughout the periconceptional and gestational periods, fetal plasma ACTH concentrations were higher and the prepartum surge in cortisol occurred earlier in singletons compared with twins. Plasma ACTH concentrations were also significantly higher in male compared with female singletons, and in twin fetuses, the prepartum surge in cortisol concentrations occurred earlier in males than in females. Periconceptional undernutrition resulted in higher fetal plasma concentrations of ACTH between 110 and 145 days of gestation and a significantly greater cortisol response to a bolus dose of corticotropin-releasing hormone in twin, but not singleton, fetuses in late gestation. We have therefore demonstrated that fetal number and sex each has an impact on the timing of the prepartum activation of the HPA axis in the sheep. Restriction of the level of maternal nutrition before and in the first week of a twin pregnancy results in stimulation of the fetal pituitary-adrenal axis in late gestation, and this effect is not reversed by the provision of a maintenance control diet from the second week of pregnancy.