Maternal Smoking and Metabolic Health Biomarkers in Newborns

Background

Maternal smoking has been associated with elevated risk of type 2 diabetes among the offspring in adulthood. The mechanisms underlying this fetal “programming” effect remain unclear. The present study sought to explore whether maternal smoking affects metabolic health biomarkers in fetuses/newborns.

Methods

In a prospective singleton pregnancy cohort (n = 248), we compared metabolic health biomarkers in the newborns of smoking and non-smoking mothers. Outcomes included cord plasma insulin, proinsulin, insulin-like growth factor I (IGF-I), IGF-II, leptin and adiponectin concentrations, glucose-to-insulin ratio (an indicator of insulin sensitivity) and proinsulin-to-insulin ratio (an indicator of β-cell function).

Results

Independent of maternal (glucose tolerance, age, ethnicity, parity, education, body mass index, alcohol use) and infant (sex, gestational age, birth weight z score, mode of delivery, cord blood glucose concentration) characteristics, the newborns of smoking mothers had lower IGF-I concentrations (mean: 6.7 vs. 8.4 nmol/L, adjusted p = 0.006), and marginally higher proinsulin-to-insulin ratios (0.94 vs. 0.72, adjusted p = 0.06) than the newborns of non-smoking mothers. Cord plasma insulin, proinsulin, IGF-II, leptin and adiponectin concentrations and glucose-to-insulin ratios were similar in the newborns of smoking and non-smoking mothers.

Conclusions

Maternal smoking was associated with decreased fetal IGF-I levels, and borderline lower fetal β-cell function. Larger cohort studies are required to confirm the latter finding. The preliminary findings prompt the hypothesis that these early life metabolic changes may be involved in the impact of maternal smoking on future risk of metabolic syndrome related disorders in the offspring.     

Maternal and fetal placental growth hormone and IGF axis in type 1 diabetic pregnancy

Aim

Placental growth hormone (PGH) is a major growth hormone in pregnancy and acts with Insulin Like Growth Factor I (IGF-I) and Insulin Like Growth Hormone Binding Protein 3 (IGFBP3). The aim of this study was to investigate PGH, IGF-I and IGFBP3 in non-diabetic (ND) compared to Type 1 Diabetic (T1DM) pregnancies.

Methods

This is a prospective study. Maternal samples were obtained from 25 ND and 25 T1DM mothers at 36 weeks gestation. Cord blood was obtained after delivery. PGH, IGF-I and IGFBP3 were measured using ELISA.

Results

There was no difference in delivery type, gender of infants or birth weight between groups. In T1DM, maternal PGH significantly correlated with ultrasound estimated fetal weight (r = 0.4, p = 0.02), birth weight (r = 0.51, p<0.05) and birth weight centile (r = 0.41, p = 0.03) PGH did not correlate with HbA1c.Maternal IGF-I was lower in T1DM (p = 0.03). Maternal and fetal serum IGFBP3 was higher in T1DM. Maternal third trimester T1DM serum had a significant band at 16 kD on western blot, which was not present in ND.

Conclusion

Maternal T1DM PGH correlated with both antenatal fetal weight and birth weight, suggesting a significant role for PGH in growth in diabetic pregnancy.IGFBP3 is significantly increased in maternal and fetal serum in T1DM pregnancies compared to ND controls, which was explained by increased proteolysis in maternal but not fetal serum. These results suggest that the normal PGH-IGF-I-IGFBP3 axis in pregnancy is abnormal in T1DM pregnancies, which are at higher risk of macrosomia.     

Correlation between birth weight, leptin, zinc and copper levels in maternal and cord blood

Leptin and zinc are involved in the regulation of appetite. Copper is a trace element regulating the functions of several cuproenzymes that are essential for life. To evaluate the relationship between zinc and copper status and the leptin system in humans, we examined whether leptin concentrations in the mother and the newborn correlate with the weight of mother, placenta and newborn. A total of 88 pregnant women at 38-42 weeks' gestation were studied. All infants were categorized as small for gestational age (SGA) (n = 16), average for gestational age (AGA) (n = 59) or large for gestational age (LGA) (n = 13). Leptin, zinc, and copper levels were measured in maternal and cord serum at birth. Maternal BMI and placental weight of the LGA groups were significantly higher than those of the SGA and AGA groups. Cord and maternal leptin levels of the SGA groups were significantly lower than those of the AGA and LGA groups. Maternal serum leptin levels were positively correlated with BMI and maternal zinc levels in all groups. Cord serum leptin levels of all groups were positively correlated with birth weight and placental weight. Birth weight was negatively correlated with maternal and cord copper level of all groups. Umbilical leptin concentrations of SGA newborns correlated with leptin concentrations of their mothers. In all pregnancies, birth weight increases in association with increase in cord leptin level. Our results suggest that maternal zinc but not copper level has an effect on maternal serum leptin levels. The increase in copper level in both maternal and cord blood may contribute to restriction in fetal growth.     

Leptin concentrations in cord blood in normal newborn infants and offspring of diabetic mothers.

Leptin has been implicated in the regulation of body weight and energy balance; Leptin is produced by adipocytes and placental tissue. Chronic fetal hyperinsulinemia and accelerated fetal growth with increased amounts of body fat are frequent findings in the offspring of diabetic mothers. In this study, we examined whether leptin levels in cord blood of infants of type 1 diabetic mothers (n = 29), gestational diabetic mothers (n = 6 and controls (n = 96) correlated with level of maternal glucose control, maternal leptin level at delivery, gender, fetal and placental size, and C-peptide in cord blood at birth. Leptin was significantly elevated in infants of type 1 diabetic (24.7 ng/ml) and gestational diabetic mothers (29.3 ng/ml) as compared to controls (7.9 ng/ml). C-peptide was also significantly higher in infants of type 1 diabetic (0.91 nmol/l) and gestational diabetic mothers (0.99 nmol/l) vs controls (0.34 nmol/l). Infants of type 1 diabetic mothers with a leptin level in cord blood above the upper normal range, i.e. > 30 ng/ml (n = 13), had an average maternal HbA1c level of 5.4% (normal < 5.5%) that was not different from 5.2% in infants with a leptin level < 30 ng/ml (n = 15). In both neonatal groups of diabetic mothers, leptin in cord blood did not correlate with maternal leptin concentrations, placental weight, birthweight, gender and cord blood C-peptide. In controls, leptin in cord blood was higher in girls than in boys (p = 0.044) and correlated significantly with birthweight (p = 0.41, p < 0.001) and cord blood C-peptide (p = 0.44, p < 0.001) but not with maternal leptin level or placental weight. The 3-4 times higher leptin levels in the offspring of diabetic mothers than normal could reflect increased adipose tissue mass and/or increased contribution from other sources such as placental tissue.     

Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta

Maternal smoking during pregnancy is often associated with a decrease in placental function, which might lead to intrauterine growth retardation. Because tobacco is known to alter the mitochondrial respiratory function in cardiomyocytes and lung tissue, we hypothesized that placental mitochondrial function could be altered by maternal smoking. Placental mitochondria from 9 smoking and 19 nonsmoking mothers were isolated by differential centrifugation. Mitochondrial oxygen consumption was measured by polarography, and the enzymatic activity of each complex of the electron transport chain was assessed by spectrophotometry. In addition, the relative content in mitochondrial DNA (mtDNA) was determined by real-time quantitative PCR in placentas from seven smoking and seven nonsmoking mothers. We observed a 29% reduction in the enzymatic activity of complex III in the placental mitochondria from smokers compared with nonsmokers (P = 0.03). The relative content of mtDNA (with respect to the beta-globin gene) was reduced by 37% in the placental tissue from smokers compared with nonsmokers (P < 0.02). Both the enzymatic activity of complex III and mtDNA content were inversely related with the daily consumption of cigarettes, and mtDNA content was correlated with cord blood insulin-like growth factor-binding protein-3 (r = 0.74, P < 0.01), a marker of fetal growth. These results show that maternal smoking is associated with placental mitochondrial dysfunction, which might contribute to restricted fetal growth by limiting energy availability in cells.     

Human placental GLUT1 glucose transporter expression and the fetal insulin-like growth factor axis in pregnancies complicated by diabetes

We have previously described regulation of syncytial GLUT1 glucose transporters by IGF-I. Despite this, it is not clear what signal regulates transplacental glucose transport. In this report we asked whether changes in GLUT1 expression and glucose transport activity in diabetic pregnancies were associated with alterations in the fetal IGF axis. Cord blood samples and paired syncytial microvillous and basal membranes were isolated from normal term pregnancies and pregnancies characterized by gestational diabetes type A2 (GDM A2) and pre-existing insulin-dependent diabetes mellitus (IDDM). Circulating IGF-I, basal membrane GLUT1 expression and glucose transporter activity were correlated with birth weight, but only in control, not diabetic groups. Basal membrane GLUT1 and transporter activity were correlated with IGF-I concentrations in control, but not diabetic groups. IGF binding protein (IGFBP) binding capacity showed a ≥50% reduction in the diabetic groups compared to control; both showed a higher level of free IGF-I. The absence of a correlation between birth weight and factors such as fetal IGF-I or GLUT1 expression in the diabetic groups suggests that IGF-I-stimulated effects may have reached a limiting threshold, such that further increases in IGF-I (or GLUT1) are without effect. These data support that fetal IGF-I acts as a fetal nutritional signal, modulating placental GLUT1 expression and birth weight via altered levels of fetal circulating IGFBPs. Diabetes appears to exert its effects on fetal and placental factors prior to the third trimester and, despite good glycemic control immediately prior to, and in the third trimester, these effects persist to term.     

Locus-specific DNA methylation in the placenta is associated with levels of pro-inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy

We investigated the impact of maternal smoking during pregnancy on placental DNA methylation and how this may mediate the association between maternal smoking and pro-inflammatory proteins in cord blood. The study population consisted of 27 individuals exposed to maternal smoking throughout pregnancy, 32 individuals exposed during a proportion of the pregnancy, and 61 unexposed individuals. Methylation of 11 regions within 6 genes in placenta tissue was assessed by pyrosequencing. Levels of 7 pro-inflammatory proteins in cord blood were assessed by electrochemiluminescence. Differential methylation was observed in the CYP1A1 promoter and AHRR gene body regions between women who smoked throughout pregnancy and non-smokers on the fetal-side of the placenta and in the GFI1 promoter between women who quit smoking while pregnant and non-smokers on the maternal-side of the placenta. Maternal smoking resulted in elevated levels of IL-8 protein in cord blood, which was not mediated by DNA methylation of our candidate regions at either the maternal or the fetal side of the placenta. Placental DNA methylation was associated with levels of inflammatory proteins in cord blood. Our observations suggest that maternal smoking during pregnancy affects both placental DNA methylation and the neonate's immune response.     

Cord blood ASP is predicted by maternal lipids and correlates with fetal birth weight

Background: The acylation stimulating protein (ASP) is a potent lipogenic adipokine that correlates with postprandial triglyceride (TG) clearance and is linked to the pathophysiology of obesity and related disorders. Objective: To investigate ASP levels in cord blood and its relation to maternal and cord blood lipid parameters and fetal birth weight. Methods and Procedures: Thirty nondiabetic pregnant women, their newborns, and thirty‐three nonpregnant controls were included in this study. Fasting maternal and cord blood ASP, TGs, nonesterified fatty acids (NEFAs), cholesterol, glucose levels, in addition to maternal BMI and fetal birth weight were measured. Results: No significant difference was found between cord blood ASP (16.3 ± 0.96 nmol/l) and ASP levels in the adult controls (15.7 ± 1.0 nmol/l). Cord blood ASP, however, was lower than maternal plasma ASP levels (25.4 ± 1.6 nmol/l, P < 0.001). Yet, lipid levels in cord blood, particularly TGs were markedly decreased compared to control and maternal TG levels (threefold and 7.4‐fold, P < 0.001 respectively). Maternal TGs significantly correlated with fetal birth weight (r = 0.54, P = 0.002). Multiple regression analysis showed that maternal TGs (β = 0.57, P = 0.01) and NEFAs (β = 0.43, P = 0.024) predicted 45% variation in cord blood ASP levels, independent of all measured maternal and cord blood parameters. Cord blood ASP showed a positive correlation with fetal birth weight (r = 0.524, P = 0.037) in neonates above average fetal birth weight of the studied population. Discussion: This is the first study investigating ASP in cord blood. We suggest that maternal hypertriglyceridemia is associated with increased fetal ASP production, thus enhancing fetal fat storage independent of maternal glucose variations in nondiabetic women.     

Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized,Controlled Trial in Rural Bangladesh

Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m² and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies.

Trial Registration

ClinicalTrials.gov NCT00860470     

Placental growth hormone is not suppressed by oral glucose loading in normal human pregnancy.

Placental growth hormone (PGH) progressively replaces pituitary growth hormone in the maternal circulation from mid-gestation onwards in human pregnancy. Our previous investigations have shown that placental growth hormone concentrations correlate well with foetal growth. Despite the apparent correlation between PGH and birthweight, the physiology of its secretion during pregnancy has not been well defined. We investigated the response of maternal serum PGH to oral glucose loading in pregnant women (n = 24) who demonstrated normal glucose tolerance at a mean gestation of 29 weeks. Mean (SEM) fasting PGH concentrations were high (36.9 [6.4] ng/ml). No suppression of PGH was noted at one, two or three hours after a 75 g oral glucose load. Similarly, no changes were noted in growth hormone binding protein or in calculated free PGH over the course of the glucose tolerance test. As expected, insulin concentrations rose sixfold and insulin like growth factor binding protein 1 concentrations fell by 20 % with glucose loading. Correlation analysis showed maternal weight, BMI, fasting serum glucose serum insulin to be significantly correlated with the babies' birthweight. Our results support the proposition that PGH concentrations in maternal serum are not suppressed by oral glucose loading in non-diabetic mothers.     

The effects of maternal undernutrition on maternal and fetal serum insulin-like growth factors, thyroid hormones and cortisol in the guinea pig.

The insulin-like growth factors (IGF-I and -II) are potential mediators of the effects of maternal undernutrition on fetal growth and muscle development. The effects of a 40% reduction in maternal feed intake on serum levels of the IGFs, the thyroid hormones and cortisol, were investigated for the last two trimesters (day 25 to birth). This level of undernutrition is known to cause a 35% reduction in fetal and placental weights, and a 20-25% reduction in muscle fibre number. Maternal IGF-I level was greater than non-pregnant levels on day 25 gestation, in both control and restricted dams, and declined with gestational age. The increase in IGF-I level in the 40% restricted group was approximately two-thirds that of control animals. Fetal serum IGF-I was also reduced in undernourished fetuses throughout gestation. Maternal IGF-II did not change with gestational age and was unaffected by undernutrition. Fetal IGF-II reached a peak at day 55 of gestation, this peak was greatly diminished by maternal feed restriction. Both IGF-I and IGF-II tended to be related to fetal, placental and muscle weights at day 65 of gestation. Thyroid hormone concentration declined in maternal serum and increased in fetal serum with increasing gestational age. Levels were not significantly affected by undernutrition. Both triiodothyronine (T3) and thyroxine (T4) were correlated with IGF-I in maternal serum (P < 0.05), but not in fetal serum. Cortisol levels were elevated by undernutrition in both maternal and fetal serum, and increased with gestational age. Cortisol was inversely correlated with serum IGF-I in both maternal and fetal serum. Maternal serum IGF-I may mediate the effects of undernutrition on fetal growth by affecting the growth and establishment of the feto-placental unit in mid-gestation. Fetal IGF-I may mediate the effects on muscle growth, whereas IGF-II seems to be related to hepatic glycogen deposition. Cortisol may play a role via its effect on the IGFs, but the thyroid hormones are unlikely to be important until the late gestation/early postnatal period.     

Late but not early gestational maternal growth hormone treatment increases fetal adiposity in overnourished adolescent sheep

In the overnourished adolescent sheep, maternal tissue synthesis is promoted at the expense of placental growth and leads to a major decrease in lamb birth weight at term. Maternal growth hormone (GH) concentrations are attenuated in these pregnancies, and it was recently demonstrated that exogenous GH administration throughout the period of placental proliferation stimulates uteroplacental and fetal development by Day 81 of gestation. The present study aimed to determine whether these effects persist to term and to establish whether GH affects fetal growth and body composition by increasing placental size or by altering maternal metabolism. Adolescent recipient ewes were implanted with singleton embryos on Day 4 postestrus. Three groups of ewes offered a high dietary intake were injected twice daily with recombinant bovine GH from Days 35 to 65 of gestation (high intake plus early GH) or from Days 95 to 125 of gestation (high intake plus late GH) or remained untreated (high intake only). A fourth moderate-intake group acted as optimally nourished controls. Pregnancies were terminated at Day 130 of gestation (6 per group) or were allowed to progress to term (8-10 per group). GH administration elevated maternal plasma concentrations of GH, insulin, glucose, and nonesterified fatty acids during the defined treatment windows, while urea concentrations were decreased. At Day 130, GH treatment had reduced the maternal adiposity score, percentage of fat in the carcass, and internal fat depots and leptin concentrations, predominantly in the high-intake plus late GH group. Placental weight was lower in high-intake vs. control dams but independent of GH treatment. In contrast, fetal weight was elevated by late GH treatment, and these fetuses had higher relative carcass fat content, perirenal fat mass, and liver glycogen concentrations than all other groups. Expression of leptin mRNA in fetal perirenal fat and fetal plasma leptin concentrations were not significantly altered by maternal nutritional intake or GH. In pregnancies proceeding to term, the duration of gestation, fetal placental mass, and lamb birth weight were reduced in high-intake compared with control dams but were not significantly affected by GH treatment. In conclusion, exogenous GH has profound effects on maternal endocrinology, metabolism, and body composition when administered during early and late pregnancy. Treatment during late pregnancy has a modest effect on fetal growth independent of placental size and a profound effect on fetal adiposity, which may have implications beyond the fetal period.     

Direct analysis of human blood (mothers and newborns) by energy dispersive X-ray fluorescence

This work is an application of energy dispersive X-ray fluorescence (EDXRF) as analytical technique for trace element determination in human tissues. Potassium (K), calcium (Ca), iron (Fe), copper (Cu), zinc (Zn), bromine (Br), rubidium (Rb) and lead (Pb) were determined directly in blood samples from 66 mothers at delivery after full-term pregnancies. The corresponding 66 cord-blood samples of the newborns were also analysed, in order to find element correlations between maternal and newborn blood at birth. The studied samples were obtained from mothers aged between 15 and 39 years old, the gestational age being between 35 and 41 weeks and the newborns' weight between 2.310 and 4.310 kg. Samples were lyophilised and analysed without any chemical treatment. Very low levels of Pb were found both in maternal and fetal cord blood samples. Cu values ranged from 3 to 13 microg g-1, both for mothers and children. A correlation between Cu and Fe concentrations in maternal and fetal cord blood was found. Zn is considered as one of the key elements in newborn health. Concentrations between 10 and 40 microg g-1 were measured. A positive correlation between Br levels in mothers and children was observed. Positive correlations for mothers were observed between Zn and Rb as well as K and Fe. The corresponding correlations in fetal cord blood samples were not observed, however positive correlations were found between Ca and K; Cu and Fe. The mean concentrations for each element were similar in maternal and in fetal cord blood, except for Cu and Zn, being higher in maternal samples. No correlations between element concentrations and pathologies of the mothers were observed.     

Intrauterine growth retardation and consequences for endocrine and cardiovascular diseases in adult life: does insulin-like growth factor-I play a role?

Low birth weight has been associated with an increased incidence of ischaemic heart disease (IHD) and type 2 diabetes. Endocrine regulation of fetal growth by growth hormone (GH) and insulin-like growth factor (IGF)-I is complex. Placental GH is detectable in maternal serum from the 8th to the 12th gestational week, and rises gradually during pregnancy where it replaces pituitary GH in the maternal circulation. The rise in placental GH may explain the pregnancy-induced rise in maternal serum IGF-I levels. In the fetal compartment, IGF-I levels increase significantly in normally growing fetuses from 18 to 40 weeks of gestation, but IGF-I levels are four to five times lower than those in the maternal circulation. Thus IGF-I levels in fetal as well as in maternal circulation are thought to regulate fetal growth. Circulating levels of IGF-I are thought to be genetically controlled and several IGF-I gene polymorphisms have been described. IGF-I gene polymorphisms are associated with birth weight in some studies but not in all. Likewise, IGF-I gene polymorphisms are associated with serum IGF-I in healthy adults in some studies, although some controversy exists. Serum IGF-I decreases with increasing age in healthy adults, and this decline could hypothetically be responsible for the increased risk of IHD with ageing. A recent nested case-control study found that adults without IHD, but with low circulating IGF-I levels and high IGF binding protein-3 levels, had a significantly increased risk of developing IHD during a 15-year follow-up period. In summary, the GH/IGF-I axis is involved in the regulation of fetal growth. Furthermore, it has been suggested that low IGF-I may increase the risk of IHD in otherwise healthy subjects. Hypothetically, intrauterine programming of the GH/IGF axis may influence postnatal growth, insulin resistance and consequently the risk of cardiovascular disease. Thus IGF-I may serve as a link between fetal growth and adult-onset disease.     

Umbilical cord ghrelin concentrations in Asian and Caucasian neonates

OBJECTIVES: To compare the relationship between cord plasma ghrelin and growth hormone (GH) concentrations and birth weight in Asian and Caucasian neonates. METHODS: We measured umbilical cord ghrelin and GH concentrations in 180 full-term newborns [4 groups of 45 according to ethnicity (Caucasian/Asian) and sex]. RESULTS: Ghrelin was detectable in all umbilical cord samples (mean +/- SD: 611 +/- 267, range 193-2,010 pg/ml). There was no significant difference in ghrelin concentrations between Asian and Caucasian male or female neonates. In contrast, GH values were significantly affected by sex (p = 0.001) and ethnicity (p = 0.006). Except for a weak (r = -0.33, p < 0.03) negative correlation between ghrelin and GH in male Caucasian neonates, ghrelin and GH concentrations were independent. CONCLUSIONS: Umbilical cord concentrations of ghrelin, a potent orexigenic and GH stimulatory agent, are similar in Caucasian and Asian newborns, suggesting that ghrelin does not play a causal role in the differences in body composition and GH metabolism observed in these neonates.     

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA (P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.     

Adipokines underlie the early origins of obesity and associated metabolic comorbidities in the offspring of women with pregestational obesity

Maternal pregestational obesity is a well-known risk factor for offspring obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes. The mechanisms by which maternal obesity can induce alterations in fetal and later neonatal metabolism are not fully elucidated due to its complexity and multifactorial causes. Two adipokines, leptin and adiponectin, are involved in fetal and postnatal growth trajectories, and both are altered in women with pregestational obesity. The placenta synthesizes leptin, which goes mainly to the maternal circulation and in lesser amount to the developing fetus. Maternal pregestational obesity and hyperleptinemia are associated with placental dysfunction and changes in nutrient transporters which directly affect fetal growth and development. By the other side, the embryo can produce its own leptin from early in development, which is associated to fetal weight and adiposity. Adiponectin, an insulin-sensitizing adipokine, is downregulated in maternal obesity. High molecular weight (HMW) adiponectin is the most abundant form and with most biological actions. In maternal obesity lower total and HMW adiponectin levels have been described in the mother, paralleled with high levels in the umbilical cord. Several studies have found that cord blood adiponectin levels are related with postnatal growth trajectories, and it has been suggested that low adiponectin levels in women with pregestational obesity enhance placental insulin sensitivity and activation of placental amino acid transport systems, supporting fetal overgrowth. The possible mechanisms by which maternal pregestational obesity, focusing in the actions of leptin and adiponectin, affects the fetal development and postnatal growth trajectories in their offspring are discussed.     

Maternal and feto-placental prostanoid responses to a single course of antenatal betamethasone

We tested the hypothesis that antenatal betamethasone alters prostanoid levels in the maternal and feto-placental compartments. Forty-three singleton pregnancies were studied. Group I were women treated with a single course of antenatal betamethasone and who delivered <37 weeks gestation; Group II were untreated women who delivered <37 weeks; and Group III were untreated women who delivered >38 weeks. Maternal and mixed cord blood; and placental samples were collected at delivery and analyzed for PGE2, PGF(2alpha), 6-ketoPGF(1alpha), and TxB2 levels. Antenatal betamethasone decreased maternal PGE2 levels with concomitant increases in the feto-placental compartment. Umbilical cord TxB2 levels in the treated group were significantly lower than the non-treated pre-term and term groups resulting in a higher 6-ketoPGF(1alpha):TxB2 ratio. Considering the regulatory role of PGE2 and PGI2 in fetal lung development and neonatal transition homeostasis, these results suggest a mechanism, at least in part, for the beneficial effects of antenatal steroids on fetal lung maturation and neonatal cardio-pulmonary homeostasis at birth.     

Mechanism of foetal growth retardation caused by smoking during pregnancy

In order to clarify the mechanism of retarded foetal growth in smoking pregnant women, foeto-placental function and maternal nutritional condition were assessed. Dehydroepiandrosterone sulfate (DHAS) loading test, measurement of cotinine which is a major metabolite of nicotine and pathohistological examination of placental villi were also made to know the effect of smoking on utero-placental circulation. In heavy smokers, urinary oestriol and serum hPL levels were lower than those in non-smokers while the maternal nutritional condition was not different from that in non-smokers. In the DHAS loading test, heavy smokers showed lower conversion of DHAS to oestradiol. In the non-stress test (NST), bradycardia and/or loss of variability of baseline foetal heart rate were noted after smoking. Levels of cotinine in maternal blood and umbilical cord blood in heavy smokers were markedly higher than those in non-smokers. Microscopic examination showed atrophic and hypovascular changes of placental villi obtained from smoking mothers. These results suggest that the retarded fetal growth in heavy smokers is due to the impairment of utero-placental circulation as a result of the vasoconstricting effect of nicotine.     

Smoking in pregnancy: associations with skinfold thickness,maternal weight gain,and fetal size at birth.

Skinfold thickness is an index of subcutaneous fat, and certain maternal conditions during pregnancy affect the skinfold thicknesses of the baby. A study was performed to investigate the effect of smoking on skinfold thickness, maternal weight gain, and fetal size at birth. A total of 452 mothers with normal singleton pregnancies were groups as: non-smokers, light-to-moderate smokers, or heavy smokers. Maternal age, height, parity, and duration of pregnancy were similar in the three groups. Heavy smokers gained significantly less weight than non-smokers, but there was no significant difference in skinfold thickness. Babies born to smokers had lower birth weights and smaller head circumferences and were shorter than those born to non-smokers, but skinfold thicknesses were similar. The presence of a normal layer of subcutaneous fat in babies whose mothers smoked suggests that fetal growth retardation is not caused by nutritional deficiencies.