Second Half Of Gestation Research Articles

Abortifacient and endocrine effects of metergoline in beagle bitches during the second half of gestation

The purpose of this study was to investigate the abortifacient effects of high doses of metergoline when administered to pregnant beagle bitches during the second half of gestation and to define the endocrine effects of this treatment as represented by plasma progesterone and estradiol concentrations. Previously, metergoline had been shown to be incompletely luteolytic and induced abortion in only one of eight pregnant bitches when 0.4–0.5 mg/kg were administered twice daily for 5 days from Days 18 to 20 of diestrus. Nine pregnancies in six beagle bitches were used for the present study. Three bitches were treated in each of two consecutive pregnant cycles. Metergoline was administered at a dose of 0.6 mg/kg per os twice daily, starting on Day 28 after the cytological onset of diestrus. Abortion was induced in eight of the nine treated pregnancies and started after 3–23 days of treatment (mean 12.5 days, S.D. 6.4 days). The abortions were completed within 0.5–8 days (mean 2.2 days, S.D. 2.7 days). There were no side effects associated with metergoline treatment and none of the abortions was associated with complications that required intervention. In the single bitch that did not abort, an ovarian granulosa cell tumor was discovered when the single fetus had to be removed surgically at term. Plasma progesterone concentrations declined after the start of metergoline administration in all pregnancies but levels below 4.8 nmol/l were required for successful abortions. Plasma estradiol concentrations showed a tendency to decline and fluctuate concurrently with the plasma progesterone levels. However, suppression of plasma estradiol concentrations by metergoline was not as complete as the suppression of progesterone and did not seem a prerequisite for abortion. The hormone profiles and treatment period required for abortion tended to be similar for both cycles of the three bitches that were treated during two consecutive pregnancies. This suggests a bitch effect on the factors that determine the efficacy of metergoline to induce abortion. The large variation and length of the treatment period that was required until abortion commenced was probably related to the relatively early start of treatment compared to other studies. The results of this investigation suggest that, similar to other prolactin suppressing ergot derivatives, metergoline causes complete luteolysis and can be used to reliably induce abortion only during the last 3 weeks of gestation.

‘Imprinting and Growth Congress’ 2002, London, UK

The development of a placenta as an organ of foetal–maternal gas and nutrient exchange is characteristic of eutherian mammals. Mammalian development is also governed by a non-equivalence of the two parental genomes, a phenomenon known as genomic imprinting. It has been proposed that these characteristics are functionally linked, in that genomic imprinting plays a vital role particularly for placental development (Haig, 1993). Consistent with this hypothesis is the finding that alterations in the normal expression of imprinted genes result in growth abnormalities, the majority of which are seen in utero. This is of clinical relevance because of the increased interest in exploring any genetic basis for common problems of pregnancy, including intra-uterine growth restriction and pre-eclampsia. Over the last few years, much progress has been made in unravelling the specific functions of individual imprinted genes and of large imprinted chromosomal regions during placental development. Some of the latest results were reported during the ‘Imprinting and Growth Congress’ held in London from 11–13 April 2002. The first half of the meeting described work that utilized animal models, particularly the mouse, in the study of the functional relationship between imprinted genes and the control of prenatal growth. One of the first genes discovered to be subject to genomic imprinting is the paternally expressed insulin-like growth factor II (Igf2). Igf2 critically controls foetal growth rate, in particular in the second half of gestation when placental function becomes limiting for further embryonic growth (DeChiara et al., 1991; Ferguson-Smith et al., 1991; Sun et al., 1997). A prominent role for Igf2 in the placenta was suggested by the discovery of a placenta-specific promoter (P0) and two placenta-specific exons (U1 and U2) in the 5 -region of the Igf2 gene (Moore et al., 1997). Miguel Constância (The Babraham Institute, Cambridge) presented work on discerning the function of this placenta-specific Igf2 transcript that is confined to the labyrinthine region of the

Expression of estrogen receptor subtypes in rat pituitary gland during pregnancy and lactation.

The aim of this study was to examine whether the expression levels of mRNA of the three estrogen receptor (ER) subtypes, ERalpha, ERbeta, and truncated ER product-1 (TERP-1) found in the rat pituitary gland were modified during gestation, lactation, and postlactation periods. By using relative quantitative RT-PCR, we found that ERalpha mRNA significantly peaked in midpregnancy. However, the ERalpha protein level remained constant. ERbeta gene expression did not change throughout pregnancy, suggesting that it was not related to estradiol levels during this reproductive period. In contrast, both TERP-1 mRNA and protein levels dramatically increased throughout the second half of gestation, being faintly detectable in early pregnancy. TERP-1 expression was rapidly reversed by lactation, whereas neither pituitary ERalpha nor ERbeta relative levels were significantly altered. In addition, pup removal for 24-96 h on d 9 postpartum significantly reduced the expression of both ERalpha and ERbeta mRNA compared with that in lactating animals, but the expression of TERP-1 mRNA was no longer detected. Collectively, our data indicate that 1) TERP-1, ERalpha, and ERbeta expression levels are differentially regulated in the pituitary; 2) TERP-1 is variably expressed depending on the hormonal environment related to the estrous cycle, pregnancy, and lactation; and 3) TERP-1/ERalpha ratios dramatically change depending on reproductive periods, suggesting a critical role for TERP-1 in reproductive events.

Developmental regulation of baboon fetal ovarian maturation by estrogen.

Ovarian function in adult human and nonhuman primates is dependent on events that take place during fetal development, including the envelopment of oocytes by granulosa (i.e., folliculogenesis). However, our understanding of fetal ovarian folliculogenesis is incomplete. During baboon pregnancy, placental production and secretion of estradiol into the fetus increases with advancing gestation, and the fetal ovary expresses estrogen receptors alpha and beta in mesenchymal-epithelial cells (i.e., pregranulosa) as early as midgestation. Therefore, the current study determined whether estrogen regulates fetal ovarian follicular development. Pregnant baboons were untreated or treated with the aromatase inhibitor CGS 20267, or with CGS 20267 plus estradiol benzoate administered s.c. to the mother on Days 100-164 (term = Day 184). On Day 165, baboon fetuses were delivered by cesarean section and the number of total follicles and interfollicular nests consisting of oocytes and mesenchymal-epithelial cells in areas (0.33 mm(2)) of the outer and inner cortices of each fetal ovary were quantified using image analysis. Maternal and umbilical serum estradiol levels were decreased by >95% with CGS 20267. Treatment with CGS 20267 and estrogen restored maternal estradiol to normal and fetal estradiol to 30% of normal. Although fetal ovarian weight was unaltered, the mean number of follicles +/- SEM/0.33 mm(2) in the inner (59.0 +/- 1.7) and outer (95.3 +/- 2.4) cortical regions of fetal ovaries in untreated animals was 35%-50% lower (P < 0.01) in estrogen-depleted baboons (25.9 +/- 1.4, inner cortex; 62.5 +/- 2.7, outer cortex) and was restored to normal by treatment with CGS 20267 and estrogen. In contrast, the number of interfollicular nests was 2-fold greater (P < 0.01) in fetal ovaries of estrogen-suppressed animals, a change that was prevented by treatment with estrogen. In summary, fetal ovarian follicular development was significantly altered in baboons in which estrogen was depleted during the second half of gestation and restored to normal by estradiol. We propose that estrogen plays an integral role in regulating, and perhaps programming, primate fetal ovarian development.

The bovine placenta; a source and target of steroid hormones: observations during the second half of gestation

Apart from estrone-3-sulfate (E1S) the bovine placenta produces progesterone (P4), though the corpus luteum is the major source of P4 responsible for maintaining pregnancy. So far the biological function of placental steroids in cattle is largely unknown. However, since the local availability of free estrone (E1) in the placenta seems to be controlled by sulfatase and sulfotranferase, the hypothesis was developed that placental estrogens and P4 might act as local regulatory factors. To test for such a function placentomes from 150, 220, 240, 270 days (D) pregnant and parturient cows were screened immunohistochemically for progesterone and estrogen receptors (PR, ER). PR were found at all stages in the caruncle in stromal cells and capillary pericytes but only at parturition in arterial walls. Percentage of PR-positive caruncular stromal cells (CSC) increased ( P<0.05) from 51.8±2.6% at D150 to 58.9±1.8% at parturition. ER were detected in CSC, caruncular epithelial (CE) cells and in caruncular capillary pericytes. Mean percentage of ER-positive CSC decreased from 39.0±5.9% in pregnant cows to 17.5±8.3% at parturition ( P<0.05). In CE all cells exhibited positive signals with the exception of those immediately surrounding large primary chorionic villi. Proliferation was assessed immunohistochemically by determining the percentage of Ki67-antigen positive cells. Highest values ( P<0.001) were obtained for CE (58.0–68.3%), followed by the trophoblast (23.3–25.4%), CSC (10.6–45.3%) and the stroma of the chorionic villi (2.9–10.5%). A transient depression of proliferation in CSC between D150–270 ( P<0.05) paralleled local estrogen tissue concentrations. The results suggest that placental estrogens and P4 are important factors controlling caruncular growth, differentiation and function.

Lipopolysaccharide induces inflammatory cytokines in the pig amnion

Inflammatory mediators that are induced by gram-negative bacteria in the course of intrauterine infections threaten successful pregnancy. To compare the effect of two different routes of cytokine induction, bacterial lipopolysaccharide (LPS) was administered in vivo either into the cord vein or into the amniotic cavity of pig fetuses in the second half of gestation for 20 h and cytokines were detected in the amnion. Tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) were induced in the amniotic epithelium after intra-amniotic but not after intra-venous administration of LPS. The presence of IL-8 was confirmed by RT-PCR. In contrast, transforming growth factor-β1 (TGF-β1) was expressed constitutively and was found in all samples of the amniotic epithelium. Amniotic fluid contained only minute levels of TNF-α. IL-8 levels in amniotic fluid increased after the treatment with LPS and the highest IL-8 levels were found in dead LPS-treated fetuses.

Hemochorial placentation in the primate: expression of vascular endothelial growth factor, angiopoietins, and their receptors throughout pregnancy.

Vascular development and its transformation are necessary for successful hemochorial placentation, and vascular endothelial growth factor (VEGF), angiopoietins, and their receptors may be involved in the molecular regulation of this process. To determine the potential role of these putative regulators in a widely studied primate, the common marmoset, we investigated their mRNA expression and protein location in the placenta throughout pregnancy using in situ hybridization, Northern blot analysis, and immunocytochemistry. VEGF was localized in decidual and cytotrophoblast cells, and its highest expression was found in the maternal decidua. The Flt receptor was exclusively detected in the syncytial trophoblast with increasing expression in placentae from 10 wk to term. Soluble Flt (sFlt) was also detectable by Northern blot analysis. KDR receptor expression was restricted to mesenchymal cells during early placentation and to the fetoplacental vasculature during later placentation. KDR expression increased throughout pregnancy. Angiopoietin-1 (Ang-1) was localized in the syncytial trophoblast, being highly expressed in the second half of gestation. Ang-2 mRNA localized exclusively to maternal endothelial cells, and was highly expressed in 10-wk placentae. The Tie-2 receptor was found in cytotrophoblast cells and in fetal and maternal vessels. High Tie-2 levels were detected in the wall of chorion vessels at 14-wk, 17-wk, and term placentae. These results suggest that the processes of trophoblast invasion, maternal vascular transformation, and fetoplacental vascular differentiation and development are regulated by the specific actions of angiogenic ligand-receptor pairs. Specifically, 1) VEGF/Flt and Ang-1/Tie-2 may promote trophoblast growth, 2) VEGF/KDR and Ang-1/Tie-2 may support fetoplacental vascular development and stabilization, 3) sFlt may balance VEGF actions, and 4) Ang-2/Tie-2 may remodel the maternal vasculature.

Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery

Objective: A pre-existing intrauterine inflammation in the first half of gestation has been proposed as a possible condition that leads to preterm delivery. Indeed, elevated levels of inflammatory mediators (eg, interleukin-6, tumor necrosis factor) in midtrimester amniotic fluid have been found in cases of preterm delivery and/or spontaneous abortion. The objective of this study was to investigate whether the amniotic fluid C-reactive protein level at the time of genetic amniocentesis is a marker for spontaneous preterm delivery before 34 and 37 weeks of gestation. Study Design: Women who underwent genetic amniocentesis between 15 and 18 weeks of gestation with (1) singleton gestation, (2) uneventful pregnancy course before the amniocentesis, and (3) absence of fetal abnormalities were included in the study. Patients with abnormal karyotype were excluded. C-reactive protein concentration was measured in amniotic fluid and in maternal blood immediately after genetic amniocentesis. All patients were followed until delivery for the occurrence of pregnancy complications. Nonparametric tests and receiver-operating characteristic curve analysis were used for statistical purposes. Results: The prevalence of spontaneous preterm delivery before 34 and 37 weeks was 3.3% (10 of 306 pregnancies) and 8.5% (26 of 306 pregnancies), respectively. Women with preterm delivery at <37 weeks had a higher median (range) of amniotic fluid C-reactive protein concentration than those women who delivered at term (median, 113.3 ng/mL [range, 16-623 ng/mL] vs median, 57.8 ng/mL [range, 0-808.9 ng/mL]; P <.005). Women with preterm delivery at <34 weeks had a higher median (range) amniotic fluid C-reactive protein concentration than those women who delivered at term (median, 183.8 ng/mL [range, 46.5-447 ng/mL] vs median, 57.8 ng/mL [range, 0-808.9 ng/mL]; P <.005]. No correlation was found between amniotic fluid C-reactive protein and maternal blood C-reactive protein concentrations. No relationship was found between maternal blood C-reactive protein concentration and preterm delivery before either 34 or 37 weeks. Amniotic fluid C-reactive protein concentration of >110 ng/mL had a sensitivity of 80.8% and a specificity of 69.5% in the prediction of spontaneous preterm delivery at <34 weeks. Conclusion: This study supports the theory that a subclinical intrauterine/fetal inflammatory process early in gestation may be important for the occurrence of preterm delivery in the second half of gestation. (Am J Obstet Gynecol 2002;186:·268-73.)

Diaphorase-positive neurons in the cingulate cortex of human fetuses during the second half of gestation.

In this work, the time course of appearance, distribution and morphology of diaphorase-positive neurons were studied in the developing cingulate cortex of the human brain during the second half of gestation. Five human fetuses at 18, 20, 25, 30 and 35 weeks postovulatory (wpo) were examined. The brain tissue was reacted by an indirect histochemistry protocol for detection of NADPH-diaphorase activity. Labeled neurons were identified at the microscope and documented photographically or by computer-aided charts. We have found that heavily labeled neurons (type I) first appear in the subplate (SP) between 20 and 25 wpo, and in the cortical plate (CP) between 25 and 35 wpo. By 35 wpo, CP neurons were both type I and type II (lightly labeled neurons). In addition, we observed 4 different morphological types among subplate neurons, very similar to callosally-projecting subplate cells (as described previously by our group). We concluded that medial nitridergic neurons of humans appear prenatally according to the usual gradient of cortical maturation -- first in the subplate and later in the cortical plate. Also, we suggest that some of the diaphorase-positive neurons in the transient subplate could possibly be callosal.

Sensory performances in the human foetus : a brief summary of research

A growing body of evidence is available about the functioning of foetal sensory systems during gestation. This article aims at reviewing data concerning (i) the accession of sensory stimulation to the foetal sensory receptors, (ii) the sequence of functional development of the major sensory systems (iii) the physiological and behavioural responses of foetuses to various types of stimulation. Human data are confronted to data collected in other mammalian species. Most studies have investigated auditory and chemosensory (olfactory and gustatory) responsiveness of the foetus in the second half of gestation. They demonstrate that (i) motor and autonomic (heart rate) responsiveness depends on gestational age and the properties of stimulations.

Early Development of Neuronal Activity in the Primate HippocampusIn Utero

Morphological studies suggest that the primate hippocampus develops extensively before birth, but little is known about its functional development. Patch-clamp recordings of hippocampal neurons and reconstruction of biocytin-filled pyramidal cells were performed in slices of macaque cynomolgus fetuses delivered by cesarean section. We found that during the second half of gestation, axons and dendrites of pyramidal cells grow intensively by hundreds of micrometers per day to attain a high level of maturity near term. Synaptic currents appear around midgestation and are correlated with the level of morphological differentiation of pyramidal cells: the first synapses are GABAergic, and their emergence correlates with the growth of apical dendrite into stratum radiatum. A later occurrence of glutamatergic synaptic currents correlates with a further differentiation of the axodendritic tree and the appearance of spines. Relying on the number of dendritic spines, we estimated that hundreds of new glutamatergic synapses are established every day on a pyramidal neuron during the last third of gestation. Most of the synaptic activity is synchronized in spontaneous slow ( approximately 0.1 Hz) network oscillations reminiscent of the giant depolarizing potentials in neonatal rodents. Epileptiform discharges can be evoked by the GABA(A) receptor antagonist bicuculline by the last third of gestation, and postsynaptic GABA(B) receptors contribute to the termination of epileptiform discharges. Comparing the results obtained in primates and rodents, we conclude that the template of early hippocampal network development is conserved across the mammalian evolution but that it is shifted toward fetal life in primate.

Axonal Patterns in the Prosencephalon of the Human Developing Brain

In the second half of gestation the human fetal brain is characterized by prominent transient structures, i.e. subplate, ganglionic eminence and perireticular nucleus. These structures are involved in the formation of projections by acting as intermediate targets. This study is aimed at demonstrating axonal patterns and their reorganization in the human fetal brain using the antibody mixture SMI 312 which immunolabels phosphorylated neurofilaments predominantly found in axons. In the immunosections, a laminar- and nuclear-specific labeling is present. The subplate contains diffusely arranged fibers and conspicuous obliquely oriented fibers. The internal capsule harboring the perireticular nucleus is characterized by dense fiber clusters which display interwoven fibers at high magnification. Near the ganglionic eminence, fibers are seen that are directed towards its periphery. The latter, i.e. the margins of the ganglionic eminence, display fiber terminations. The results demonstrate characteristic transient axonal patterns which are linked to transient projections known from animal studies. It is obvious that the functional organization of the fetal brain distinctly differs from that of the mature brain.

Uterine and placental expression of steroidogenic genes during rodent pregnancy

The ontogeny and functional role of steroidogenesis during mammalian gestation is poorly understood. This review provides a summary of our recent findings on the spatio-temporal expression of key steroidogenic genes controlling progesterone synthesis in the uterus during mouse pregnancy. We have shown that onset of cholesterol side chain cleavage cytochrome P450 (P450scc) and a newly identified isoform of murine 3β-hydroxysteroid dehydrogenase/isomerase type VI (3βHSD VI) expression occurs upon decidualization of the uterine wall induced by implantation. This unexpected early expression of the enzymes in the maternal decidua is terminated at mid-pregnancy when the steroidogenic ability reappears in the extraembryonic giant cells at the time of placentation. The giant cells express another protein indispensable for steroid hormone synthesis in the adrenal and gonads, Steroidogenic Acute Regulatory (StAR) protein. Unlike the human placenta, the steroidogenic genes are not expressed in the cells of the mature mouse placenta during the second half of gestation. Finally, our studies suggest that transcriptional regulation of P450scc is mediated by a non-SF-1 protein that substitutes SF-1 functions in the extraembryonic cells. Collectively, the results of the present study suggest that, during early phases of pregnancy, local progesterone synthesis in the maternal decidua and the trophoblast layers surrounding the embryonal cavity is important for successful implantation and/or maintenance of pregnancy. We propose that the local production of progesterone acts as an immunosuppressant at the maternofetal interface preventing the rejection of the fetal allograft.

Maternal nutritional manipulation of placental growth and glucose transporter 1 (GLUT-1) abundance in sheep

Glucose transporter 1 (GLUT-1) is the predominant glucose transporter in the placenta but the extent to which its abundance is nutritionally regulated is unknown. This study investigated the effects of restricted maternal nutrition between day 28 and day 80 of gestation followed by re-feeding to either meet or to exceed the total energy requirements on placental size and GLUT-1 abundance at mid-gestation (that is, day 80) and near to term (that is, days 140-145 of gestation; term = 147 days). Singleton bearing ewes either consumed 8.7-9.9 MJ day(-1) of metabolizable energy (that is, well fed) or 3.2-3.8 MJ day(-1) of metabolizable energy (that is, nutrient restricted) from day 28 to day 80 of gestation, after which stage they consumed either 6.5-7.5 MJ day(-1) (that is, adequately fed) or 8.0-10.9 MJ day(-1) (that is, well fed) of metabolizable energy until near to term. In all ewes, at both sampling dates, the abundance of GLUT-1 was higher in the maternal component than in the fetal component of the placenta. Immunohistochemistry confirmed that GLUT-1 was located in the maternal uterine syncytium. At day 80 of gestation, placental mass was lower (P < 0.05) in the nutrient restricted group, but there was no difference in the abundance of GLUT-1 between the nutrient restricted group and the well fed group. At near term, placental mass was greater (P < 0.05) in ewes that were nutrient restricted during early to mid-gestation and then adequately fed up to term compared with ewes that were well fed during early to mid-gestation. This increase was associated with a higher (P < 0.05) abundance of total placental GLUT-1 and a larger fetus. There was no effect of previous nutrient restriction on placental mass, fetal weight or GLUT-1 abundance at term, when ewes were well fed in the second half of gestation. In conclusion, maternal nutrient restriction between early to mid-gestation alters placental growth but has no effect on placental GLUT-1 abundance. Increasing maternal feed intake to meet calculated energy requirements in previously nutrient restricted ewes during the second half of gestation, increases placental mass and fetal weight, and the abundance of GLUT-1, an adaptation not observed if maternal food intake is increased above requirements.

First-trimester sonographic umbilical cord diameter and the growth of the human embryo.

Experimental and clinical evidence have shown that the morphometry of the umbilical cord in the second half of gestation might be useful in predicting adverse perinatal outcome. The purposes of this study were to generate a nomogram for the umbilical cord diameter in the first trimester and, in an observational study, to investigate whether the sonographic measurement of the umbilical cord diameter early in gestation has the same clinical value as that late in gestation. The sonographic umbilical cord diameter, crown-rump length and biparietal diameter were measured in 439 fetuses at between 8 and 15 weeks of gestation. The perinatal outcome was recorded for all patients. The umbilical cord diameter increased steadily from 8 to 15 weeks of gestation. A significant correlation was found between umbilical cord diameter and gestational age (r = 0.78; P < 0.001), umbilical cord diameter and crown-rump length (r = 0.75; P < 0.001) and umbilical cord diameter and biparietal diameter (r = 0.81; P < 0.001). No correlation was found between umbilical cord diameter values and either birth weight or placental weight. Among patients who had a miscarriage (n = 7) and pre-eclampsia (n = 8) the umbilical cord diameter was below 2 standard deviations from the mean in three cases (42.9%) and three cases (37.5%), respectively. The measurement of the umbilical cord diameter in the first trimester is correlated with the growth of the embryo and may be a marker for identifying a subset of fetuses at risk of spontaneous miscarriage and pre-eclampsia.

Developmental maturation of primate placental trophoblast: placental cytosolic and secretory phospholipase A 2 expression after estrogen suppression of baboons

We have demonstrated that the baboon placenta expressed the mRNAs and proteins for secretory and cytosolic phospholipase A 2 (PLA 2) enzymes and that cPLA 2 expression increased with advancing gestation in association with the increase in placental estrogen production. To determine whether estrogen regulates placental PLA 2 expression, as it does other aspects of syncytiotrophoblast functional differentiation, we compared sPLA 2 and cPLA 2 mRNA levels in placentas obtained on day 165 of gestation (term = day 184) from baboons that were untreated or treated during the second half of gestation with the aromatase inhibitor CGS 20267 or CGS 20267 and estradiol. Maternal saphenous and uterine vein estradiol levels were reduced ( P < 0.05) by approximately 95% by treatment with CGS 20267 and restored by concomitant administration of CGS 20267 and estrogen. However, sPLA 2 and cPLA 2 mRNA levels expressed as a ratio of β-actin were similar in whole villous placenta from baboons that were untreated or treated with CGS 20267 or CGS 20267 plus estrogen. PLA 2 expression in an enriched fraction of nontrophoblast cells of the baboon placenta was also not altered by CGS 20267 treatment. Collectively these findings indicate that placental cPLA 2 and sPLA 2 expression is not estrogen-dependent. Because estrogen has been shown to regulate other aspects of placental steroidogenesis, we suggest that the regulatory role of estrogen on syncytiotrophoblast functional maturation is specific.

Transgenic major histocompatibility complex class I antigen expressed in mouse trophoblast affects maternal immature B cells.

We have produced transgenic mice using the mouse placental lactogen type II promoter to force and restrict the expression of the mouse major histocompatibility complex (MHC) class I molecule, H-2K(b), to the placenta. We show that the transgenic MHC antigen H-2K(b) is expressed exclusively in trophoblast giant cells from Day 10.5 until the end of gestation. This expression affects neither the fetal development nor the maternal tolerance to the fetus in histoincompatible mothers. We have used the 3.83 B cell receptor (BcR) transgenic mouse line to follow the fate of H-2K(b)-specific maternal B cells in mothers bearing H-2K(b)-positive placentas. Our results suggest that transgenic H-2K(b) molecules on trophoblast giant cells are recognized by 3.83 BcR-transgenic B cells in the bone marrow of pregnant females. This antigen recognition triggers the deletion of a bone marrow B cell subpopulation, including immature and transitional B cells. Their percentage decreases during the second half of gestation and is down to 8% on Day 17.5, compared to 22% in the (3.83 Tg female x Fvb) control group. This deletion might contribute to the process of maternal tolerance of the conceptus.

Infecção pelo papilomavírus humano durante a gravidez: relação com achados citológicos

Purpose: to evaluate a group of pregnant women with human papillomavirus (HPV) infection, analyzing age, gestational age, number of gestations and cytological findings. Methods: in the period from July 1993 to December 1998, 245 pregnant patients seen in our service presented cytological alterations compatible with HPV infection, associated or not with cervical intraepithelial neoplasia (CIN) grade 1. Clinical data were related to age, gestational period (first or second half), number of gestations and cytological finding of Trichomonas vaginalis, Candida sp and clue cells. The control group consisted of 386 pregnant patients seen during the same period and without cytological signs of HPV infection. In the statistical analysis, c2 (chi-square) test was used with Yates correction and a significance level lower than 0.05. Results: HPV infection was more frequent among pregnant women younger than 20 years old (45.3% versus 28.2%, p<0.001). The most frequent cytological finding, among the pregnant women with HPV infection, was the presence of clue cells, compared to the controls (21.6% versus 12.4%, p<0.02). Clue cells were more frequent in pregnant women with HPV infection in the second half of gestation and older than 20 years (27% versus 12.2%, p<0,01). The difference regarding number of gestations was not significant. Conclusion: HPV infection was more frequent among pregnant women younger than 20 years old. Clue cells and HPV were the most frequent cytological findings in pregnant women older than 20 years and in the second half of gestation.

Fetal endocrinology and development--manipulation and adaptation to long-term nutritional and environmental challenges.

This article reviews the fetal endocrine system in sheep, a species that has a long gestation and primarily produces a singleton fetus. Attention is focused on information that is applicable to humans. The endocrinology of metabolic homeostasis in sheep fetuses is well adapted to respond to a range of metabolic challenges, including placental restriction and maternal undernutrition. A small placenta results in hypoxaemia, hypoglycaemia, reduced abundance of anabolic hormones, and fetal growth restriction. Fetuses with restricted growth are characterized by tissue-specific reductions in hormone receptor mRNA, for example mRNA for the long form of prolactin receptor is reduced in adipose tissue. In contrast, the adipose tissue of fetuses with accelerated growth, stimulated by increasing maternal nutrition in the second half of gestation, has more protein for the long form of the prolactin receptor and more uncoupling protein 1, by which large amounts of heat are generated at birth. Maternal undernutrition in early gestation, coinciding with the period of rapid placental growth, initially restricts placental growth, but when mothers are fed to requirements, a longer fetus results with a disproportionately large placenta. This nutritional manipulation replicates, in part, epidemiological findings from the Dutch famine of 1944-1945, for which the offspring are at increased risk of adult obesity.

Factors Influencing Fetal Growth

After completing this article, readers should be able to: 1. Describe the roles of insulin-like growth factor on fetal growth and development. 2. Delineate components of “maternal constraint.” 3. Explain the role of the placenta in regulating fetal growth. 4. Describe the effects of fetal glucose, amino acid, and fat supply on fetal growth. The principal determinants of fetal growth are fetal genotype and in utero environment. Environmental factors include maternal and paternal genetics, maternal size, and the capacity of the placenta to provide nutrients to the fetus. These environmental factors interact with the intrinsic growth pattern of the fetus, yielding a particular rate and composition of fetal growth. Most of the variation in fetal growth in a population is due to variations in environmental factors, not the fetal genome, although a genetically abnormal fetus clearly might not grow as well as a normal fetus if affected genes include those that are important for growth. Many genes contribute to fetal growth and birthweight. Techniques in which specific genes can either be deleted (“knockouts”) or overexpressed have led to greater understanding of how some of these genes regulate fetal growth. Such studies have shown that both maternal and paternal influences are present during fetal development and are passed on to the developing fetus by spermatozoa or oogonia by a mechanism called imprinting. Although the maternal genetic composition exerts greater influence than fetal genotype in the overall regulation of fetal growth, both maternal and paternal genomes are important in fetal growth and development (1)(2). For example, gynogenetic zygotes (two maternal genome copies) lead to underdeveloped extraembryonic tissues but well-developed embryos. The more modest regulation offered by the paternal genotype is essential for trophoblast development. For example, zygote nuclear transfer experiments have shown that androgenetic zygotes (two paternal genome copies) develop extensive trophoblast tissues but …