Maternal food restriction reduces the exchange surface area and increases the barrier thickness of the placenta in the guinea-pig

The extent to which maternal nutrition influences fetal growth through effects on placental functional development is unclear. Poor maternal nutrition is a major cause of poor fetal growth which increases neonatal morbidity and mortality, and may also increase the risk of several adult-onset diseases. We have therefore characterized the ontogeny of structural determinants of function in the placenta in guinea-pigs fed ad libitum or food restricted from before and during pregnancy. Guinea-pigs were killed at days 30 and 60 (term=67 days) of pregnancy. In ad libitum fed animals, the surface density (surface area/g placental labyrinth), which is a measure of the convolution of the exchange surface, doubled, while total surface area increased 18-fold between mid and late gestation. Concomitantly, the arithmetic mean barrier thickness to diffusion across trophoblast decreased by 68 per cent. Late in gestation, food restriction reduced the proportion of the placenta devoted to exchange (labyrinth) by 70 per cent (P< 0.04) and the weight of the placental labyrinth by 45 per cent (P=0.001). Maternal food restriction also reduced the total placental surface area for exchange by 36 per cent at day 30 (P=0.02) and 60 per cent at day 60 (P< 0.0005) of gestation, and the surface density of trophoblast by 36 per cent at day 30 (P=0.01) and 29 per cent at day 60 (P=0.005) of gestation. The arithmetic mean barrier thickness for diffusion was increased by maternal food restriction at both gestational ages (day 30, +37 per cent, P=0.008, and day 60, +40 per cent, P=0.01). These findings suggest that maternal food restriction not only reduces fetal and placental weights, but also induces structural alterations in the placenta that indicate functional impairment beyond what would be expected for the reduction in its weight.     

Sonographically thick placenta: a marker for increased perinatal risk--a prospective cross-sectional study

The aim of this study was to determine placental thickness by ultrasound examination throughout pregnancy and establish the correlation of sonographically thick placenta with perinatal mortality and morbidity.Placental thickness was determined by routine sonographic examination throughout pregnancy in 561 normal singleton pregnancies. Thick placenta was determined as placenta that was above the 90th percentile. Gravidae between 20-22 weeks' gestation (n=193) and 32-34 weeks (n=73) were then divided into two groups according to placental thickness. The study group consisted of 44 gravidae with thick placenta. The control group included 151 gravidae with placental thickness between the 10th and 90th percentile. A comparison of perinatal mortality and morbidity rates as well as the incidence of small and large for gestational age neonates was conducted.A linear increase of placental thickness was found to correlate with gestational age throughout pregnancy. No statistical differences were observed between the two groups with regard to obstetrical variables such as maternal age, parity and gestational age at delivery. No correlation was found between placental thickness and maternal age or parity. The incidence of perinatal mortality was significantly higher among gravidae with thick placentae (6.82% versus 0.66 per cent, P=0.037, 95 per cent confidence interval 1.71-70.29). Birthweight at term was found to be above 4000 g in 20.45 per cent of the thick-placenta group as compared to 5.3 per cent in the control group (P=0.001, 95 per cent CI 2.08-13.85), and birthweight of less than 2500 g was found in 15. 9 per cent of the thick-placenta group as compared to 7.3 per cent in the control group (P=0.03, 95 per cent CI 1.11-8.14). The incidence of fetal anomalies was 9.1 per cent in the thick-placenta group and 3.97 per cent in the control group (not significant). Sonographically thick placenta is associated with increased perinatal risk with increased mortality related to fetal anomalies and higher rates of both small for gestational age and large for gestational age infants at term.     

Cadmium uptake by the rat embryo as a function of gestational age.

Maternal blood, liver, kidney, and placental and fetal (embryo) accumulation of cadmium (Cd), a known embryotoxic trace element, was investigated following a single oral dose of various amounts of Cd (10 to 1,000 microgram/rat) as CdCl2 containing 109Cd at days 6, 10, 14, and 17 of gestation. Twenty-four hours after Cd administration the rats were killed and the various tissues were counted in a gamma well counter for determination of 109Cd activity. Maternal liver and kidneys were the main target organs of Cd accumulation at all stages of gestation. Embryo levels of Cd were highest prior to formation of the functional placenta. After placental formation, fetal Cd levels were decreased, while placental accumulation of Cd increased with increasing gestational age. The results indicate that the embryo accumulates the greatest percentage of ingested Cd between implantation and placentation, the early period of organogenesis. The placenta apparently protects the fetus from exposure to this element during the last third of gestation.     

Subclinical hypothyroidism and pregnancy outcomes

BACKGROUND: Clinical thyroid dysfunction has been associated with pregnancy complications such as hypertension, preterm birth, low birth weight, placental abruption, and fetal death. The relationship between subclinical hypothyroidism and pregnancy outcomes has not been well studied. We undertook this prospective thyroid screening study to evaluate pregnancy outcomes in women with elevated thyrotropin (thyroid-stimulating hormone, TSH) and normal free thyroxine levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than 0.680 ng/dL were retrospectively identified with subclinical hypothyroidism. Pregnancy outcomes were compared with those in pregnant women with normal TSH values between the 5th and 95th percentiles. RESULTS: A total of 25,756 women underwent thyroid screening and were delivered of a singleton infant. There were 17,298 (67%) women enrolled for prenatal care at 20 weeks of gestation or less, and 404 (2.3%) of these were considered to have subclinical hypothyroidism. Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1-8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1-2.9). CONCLUSION: We speculate that the previously reported reduction in intelligence quotient of offspring of women with subclinical hypothyroidism may be related to the effects of prematurity. LEVEL OF EVIDENCE: II-2.     

Protein turnover in rat placenta: effects of maternal fasting and maternal protein restriction.

Biochemical composition and variables of protein turnover were determined in rat placenta at 21 days gestation in control animals and in animals subjected to 72-h fasting and protein/calorie restriction (6 per cent protein) throughout gestation. Placental protein synthesis was determined following the injection of 'massive' amounts of 14C-phenylalanine intravenously to the pregnant rat. Protein content was reduced in placentas from rats that were fasted for 72 h and in those who were protein restricted throughout pregnancy. Placental RNA content was significantly reduced only in the protein-restricted animals. Fractional rates of protein synthesis were reduced in placentas from the protein-restricted animals (Ks = 17.9 +/- 0.8 per cent per day in controls versus 11.7 +/- 0.9 in protein restricted, P = 0.002), but not in fasted animals. Fractional protein breakdown was markedly enhanced in placentas following maternal fasting (Kd = 9.9 per cent per day in controls versus 26.0 per cent in fasted), but not affected by protein deprivation. These results mimic those previously reported for other fetal tissues under these experimental conditions.     

Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction

The vasoactive mediators nitric oxide and endothelin are both produced in and active in the uterine and placental vasculature. Inhibition of nitric oxide synthase (NOS) results in fetal growth restriction. Endothelin (ET-1) is upregulated in the setting of NOS inhibition. Our purpose was to determine the impact of ET-1 on uterine and placental perfusion in the pregnant rat treated with a NOS inhibitor. Timed-pregnant Sprague-Dawley rats were treated with L-NAME (2.5 mg/kg/h), with and without A-127722 (10 mg/kg/day), or their respective vehicles, for 1, 4, or 7 days beginning on day 14 of gestation. Blood flow to various organs was determined by microsphere infusion. Maternal and fetal plasma nitrate/nitrite (NOx) was determined by fluorometric assay. Uterine and placental perfusion was significantly decreased by NOS inhibition and was restored to normal by ETA antagonism at 1 and 4 days of infusion but not at 7 days. Maternal plasma NOx, but not fetal plasma NOx, was significantly decreased by NOS inhibition alone. ETA antagonism in combination with NOS inhibition significantly lowered fetal plasma NOx. These results indicate that ET-1 is an important regulator of uterine and placental perfusion in the NOS inhibition model of fetal growth restriction. Our results also suggest that maternal administration of L-NAME does not result in significant transport of L-NAME across the placenta, but that addition of an ETA antagonist results in increased placental perfusion, allowing L-NAME greater access to the fetal compartment.     

Gestation-related and betamethasone-induced changes in 11beta-hydroxysteroid dehydrogenase types 1 and 2 in the baboon placenta

OBJECTIVE: We determined developmental and labor-related changes in 11beta-hydroxysteroid (HSD) 1 and 2 expression in baboon placentas during the final third of gestation and labor. We examined whether maternal glucocorticoid administration alters placental 11beta-HSD 2 expression. STUDY DESIGN: Maternal and fetal plasma cortisol concentrations were measured in five animals. Types 1 and 2 11beta-HSD messenger RNA (mRNA) and protein in placentas obtained at 121 to 185 days' gestation (dGA, term approximately 185 dGA, n = 16), during labor between 141 and 193 dGA (n = 8), and after maternal administration of four doses of 87.5 microg/kg betamethasone (n = 5) at 12-hour intervals at 121 to 135 dGA were analyzed by Northern and Western blot. RESULTS: Cortisol levels were higher in maternal plasma than fetal (4-fold, P <.mob031). Placental 11beta-HSD 2 mRNA and protein decreased after 0.9 gestation (P <.001). 11beta-HSD 1 mRNA remained unchanged. There was no effect of labor on placental 11beta-HSD 1 and 2 mRNA and protein levels. Maternal betamethasone administration dramatically increased (P <.05) 11beta-HSD 2 mRNA as well as protein without effect on 11beta-HSD 1 mRNA and protein expression. CONCLUSIONS: The late-gestation baboon maternal plasma cortisol concentration is four times the fetal plasma concentration. Decreased placental 11beta-HSD 2 may enhance maternal cortisol passage to the fetus at the end of gestation, thereby contributing to cortisol-mediated changes within the placenta and cortisol in fetal plasma at this stage of fetal development. The positive effect of betamethasone on placental 11beta-HSD 2 induction further suggests an ability of the placenta to regulate glucocorticoid transfer in the presence of elevated maternal glucocorticoid.     

Maternal obesity induced by a ‘cafeteria’ diet in the rat does not increase inflammation in maternal,placental or fetal tissues in late gestation

IntroductionObesity during pregnancy can cause serious complications for maternal and infant health. While this has often been attributed to increased inflammation during obese pregnancy, human and animal studies exhibit variable results with respect to the inflammatory status of the mother, placenta and fetus. Cafeteria (CAF) feeding induces more inflammation than standard high-fat feeding in non-pregnant animal models. This study investigated whether maternal obesity induced by a CAF diet increases maternal, fetal or placental inflammation.MethodsMaternal obesity was established in rats by 8 weeks of pre-pregnancy CAF feeding. Maternal plasma inflammatory markers (IL-1β, IL-6, IL-10, IL-12p40, MCP1, GRO/KC, MIP-2 and TNFα) and expression of inflammatory genes (Tnfα, Il-6, Il-1β, Tlr2, Tlr4, Cox2 and Emr1) in maternal, placental and fetal tissues were measured at day 21 of gestation.ResultsDespite CAF animals having 63% more central body fat than controls at day 21 of gestation, plasma inflammatory markers were not increased; indeed, levels of IL-6, IL-12p40 and MIP2 were reduced slightly. Similarly, inflammatory gene expression remained largely unaffected by CAF feeding, except for slight reductions to Tlr4 and Emr1 expression in CAF maternal adipose tissue, and reduced Tlr4 expression in male labyrinth zone (LZ). The junctional zone (JZ) displayed increased Il-6 expression in CAF animals when fetal sexes were combined, but no inflammatory genes were affected by the CAF diet in fetal liver.ConclusionsMaternal obesity induced by a CAF diet before and during pregnancy does not increase the inflammatory status of the mother, placenta or fetus in late gestation.     

Characterization of rat placental TRH-like material and the ontogeny of placental and fetal brain TRH

TRH immunological and biological activity was characterized in rat placental extracts. Placentae were extracted sequentially with 2 N acetic acid and glacial acetic acid. The lyophilized residues were further extracted with 90 per cent methanol, and the extracts were then dried, and reextracted with distilled water. When a 100 000 g supernatant fraction of this extract was utilized for characterization, TRH extracted from the placenta was found to be similar to synthetic TRH by four criteria: parallelism of immunoassay inhibition curves, similarity of elution volumes after Sephadex G-10 chromatography, TRH biological activity (TSH release from rat pituitaries in vitro), and identity on high-pressure liquid chromatography. Between the 16th and 20th day of gestation, placental TRH activity increased nearly threefold, from 10.9 +/- 3.0 to 29.7 +/- 3.7 pg/mg protein. Changes of a similar magnitude were apparent in the fetal brain (6.0 +/- 0.5 to 18.9 +/- 2.4 pg/mg protein). Our studies suggest that TRH activity in the rat placenta increases with gestational age in a pattern similar to that described previously for certain placental protein hormones and developmental changes in fetal brain TRH.     

Thyroid disease]

The incidence of pregnant women with thyroid dysfunction has been reported to be around 0.1-0.4%. Graves' disease accounts for more than half of these disorders. The main cause of thyroid disease in pregnancy and puerperium is autoimmune dysfunction. Whether there may be goitre or exophthalmus present, clinical signs as inappropriate weight gain, high systolic pressure, palpitation (greater than or equal to 110/min), emotional lability, fatigue, acceleration of suppression of the Achilles' tendon reflex should induce changes in the biochemical thyroid function tests. Parameters for the diagnosis and management for hyperthyroidism are serum levels of free T4 and TSH, while those of T3, reverse T3, and TSH are for hypothyroidism. Serum anti-microsomal antibodies and anti-thyroglobulin antibodies which have no effect on the fetus are also good markers for severity. The transplacental transfer of maternal TSH receptor antibodies consisting of stimulatory and inhibitory immunoglobulins and maternal thyroid-binding inhibiting immunoglobulins play roles in the development of transient neonatal hyper- or hypothyroidism. Fetal control is achieved by optimal maternal management. Untreated hyperthyroidism may be associated with fetal malformations. This risk may be reduced by antithyroid drug treatment of up to 150 mg/day of propylthiouracil which has less chance of placental passage and less secretion into the mother's milk than methyl-mercapto-imidazol. Maternal thyroid function should be kept in the upper limit of normal range, taking into consideration the fetal dysfunction induced by over-administration of the drug which passes through placenta. Children of hypothyroid women taking inadequate replacement therapy manifested lower IQ values compared to the progeny of euthyroid or hypothyroid women taking adequate therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between nutritionally-mediated placental growth restriction and fetal growth, body composition and endocrine status during late gestation in adolescent sheep

The aim was to investigate the consequences of nutritionally-mediated placental growth restriction on fetal organ growth, conformation, body composition and endocrine status during late gestation. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of peripubertal adolescent recipients. Post-transfer, adolescent dams were offered a high (H) or moderate (M) level of a complete diet to promote rapid or moderate maternal growth rates, respectively (n=7 per group). After day 100 of gestation the feed intake of the M dams was adjusted weekly to maintain body condition score. Liveweight gain during the first 100 days of gestation was 301+/-24 and 90+/-4.6 g/day for the H and M groups, respectively. Maternal plasma concentrations of insulin, IGF-I and urea were significantly higher and non-esterified fatty acid concentrations significantly lower in H compared with M dams prior to slaughter on day 128 of gestation. At this stage of gestation, total placentome weight was 50 per cent lower in H compared with M groups (P< 0.001) and was associated with a 37 per cent reduction in fetal weight (P< 0.01). All variables of fetal conformation and absolute fetal organ weights, with the exception of the adrenal glands, were lower (P< 0. 05) in the fetuses from H intake dams. However, relative fetal organ weights expressed as g/kg fetal body weight, with the exception of the gut, were not influenced by maternal dietary intake. Furthermore, fetal weight but not maternal nutritional group were predictive of individual organ weight for all organs dissected. Together these results imply that growth restriction in the fetuses derived from H intake dams was largely symmetrical. Fetal plasma concentrations of insulin, IGF-I and glucose were attenuated (P< 0.05) in fetuses from H compared with M groups. The lower fetal body weight in the former group was associated with a reduction in absolute but not relative crude protein (P< 0.01) and fat content (P< 0.05). Total fetal liver glycogen content but not concentration was (P< 0.05) reduced in H versus M groups. The lower mass of both the placenta and fetal liver was due to a reduction in cell number rather than an alteration in cell size. Thus, over-nourishing adolescent sheep is associated with a major restriction in placental growth which mediates a gradual slowing of fetal growth during the final third of pregnancy.     

The effects of repeated endotoxin exposure on placental structure in sheep

Intrauterine infection has been associated with fetal brain injury and preterm birth. We have recently shown that repeated exposure to bacterial endotoxin leads to hypoxia and brain injury in the preterm ovine fetus and we considered it possible that endotoxin could also damage the placenta. Our aim therefore was to assess placental structure following repeated exposure to endotoxin. Endotoxin was administered on 3-5 occasions (1 microg/kg, i.v.) over 5 days from 95-99 days of gestation (term approximately 147 days) to 6 fetal sheep and placental structure assessed at 105 days. In LPS-exposed animals there was a 17 per cent reduction (P<0.05) in placental weight and the average cross-sectional area of placentomes was reduced (P<0.05) by 20 per cent. In addition, all LPS-exposed placentae showed significant injury as evidenced by calcium deposits associated with areas of infarcted tissue. We conclude that repeated endotoxin exposure results in damage to the placenta which could lead to persistent alterations in placental exchange function.     

The role of endogenous endothelin in the regulation of uteroplacental and renal blood flow during pregnancy in conscious rats

Advancing pregnancy is characterized by a ten-fold increase in uterine blood flow and a 50 per cent increase in renal blood flow. To evaluate the involvement of endogenous endothelin (ET) in these haemodynamic changes the effect of bosentan, an ETA/B receptor antagonist, on uteroplacental and renal blood flow was studied in awake pregnant Sprague-Dawley rats. Regional blood flows were measured using microsphere technique immediately prior to and 30 min after bosentan administration (20 mg/kg i.v.). Four groups of animals (term: 23 days) were included: bosentan was administered to ten rats at gestation day (GD) 19 and nine at GD 20-21. In addition, four rats at GD 19 and five animals at GD 20-21 received saline and served as control groups. Basal placental blood flow increased significantly from 19 days' gestation to 20-21 days. Basal myometrial blood flow did not change with gestational age. At gestation day 19 bosentan increased placental and myometrial blood flow significantly (80 per cent and 43 per cent, respectively, P<0.05). This effect was not observed at gestation days 20-21. Renal blood flow did not change in response to bosentan at GD 19 but decreased by 20 per cent at GD 20-21 (P<0.01). In conclusion, in the awake pregnant rat there is a significant endogenous ET dependent vasoconstrictor tone in the uteroplacental vessels that diminishes towards term. We speculate that this change in responsiveness to endogenous ET contribute to the increase in placental blood flow in late gestation.     

Early prenatal diagnosis and therapy of fetal hypothyroid goiter.

We report a case of early diagnosis of iodide-induced fetal hypothyroidism at 22 weeks of gestation, confirmed at 29 weeks by cordocentesis and successfully treated intra-amniotically. The ultrasonographic feature was the presence of two echogenic masses in the fetal neck; polyhydramnios was absent. Mild hypothyroidism was diagnosed based on fetal serum obtained by percutaneous umbilical blood sampling at 29 weeks of gestation. The persistence of fetal hypothyroidism in spite of maternal thyroid improvement was confirmed by a second cordocentesis at 35 weeks of gestation, and a single injection of intra-amniotic levothyroxine (250 micrograms) was performed. The serial ultrasonographic examinations showed disappearance of the fetal goiter. A healthy female baby (3,630 g) was delivered at term. At birth, the thyroid gland was not enlarged, and neonatal thyroid hormones were within the normal range. This case suggests that cordocentesis is a reliable method to assess the fetal thyroid status; moreover a single injection of intra-amniotic thyroxine was effective in treating fetal hypothyroid goiter.     

Placental nutrient transfer capacity and fetal growth

The objective of this study was to determine whether the ability of the human placenta to transfer glucose and fatty acids is related to normal fetal growth. The intrinsic nutrient transport capacity of the placenta was measured under standardized conditions during in vitro perfusion of 30 human term placentas and related to birth weight (range 2640-4640g), birth weight centile (8th-99th), ponderal index (2.43-3.69), placental weight (418-1030g) and placental:fetal weight (0.14-0.31). There was no statistically significant change in the rate of nutrient transfer per placenta or per kg fetal weight, with birth weight, birth weight centile, ponderal index, placental weight and placental:fetal weight. There was a weak but significant relationship (P=0.020, r(2)=9 per cent) between the ratio of glucose to fatty acid transport and birth weight centile, largely due to the high ratio found in the lowest birth weight quartile where the babies are thinnest. This study provides no evidence that placental nutrient transport capacity limits fetal growth across a wide range of birth weights in normal pregnancies. It is proposed that the fetus itself may regulate placental nutrient transport in vivo via the fetal cardiac output and the rate of fetal nutrient utilization.     

妊娠合并甲状腺功能减退症对子代的影响

妊娠早期孕妇患甲状腺功能减退症会影响胎儿脑神经功能的发育,出生后的婴儿智力受损,神经发育迟缓,语言、精细活动能力受损,学习障碍的概率增加,视觉空间思维能力下降;经治疗甲状腺功能恢复正常的孕妇,胎儿脑功能可发育正常。妊娠合并亚临床甲状腺功能减退症对子代发育的影响文献报道不一,孕期治疗亚临床甲状腺功能减退症的益处未得到证实。