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OBJECTIVE: Pregestational maternal obesity (PGMO) associates with foetoplacental vascular endothelial dysfunction and higher risk for insulin resistance in the neonate. We characterised the PGMO consequences on the insulin response of the human foetoplacental vasculature. METHODS: Umbilical veins were from pregnancies where the mother was with PGMO (body mass index 30-42.3 kg/m2, n = 33) or normal pregestational weight (PGMN) (body mass index 19.5-24.4 kg/m2, n = 21) with total gestational weight gain within the physiological range. Umbilical vein ring segments were mounted in a myograph for isometric force measurements. Primary cultures of human umbilical vein endothelial cells were used in passage 3. Vessel rings and cells were exposed to 1 nmol/L insulin (20 min) in the absence or presence of 100 µmol/L NG-nitro-l-arginine methyl ester (inhibitor of nitric oxide synthase, NOS). RESULTS: Vessel rings from PGMO showed reduced nitric oxide synthase-activity dependent dilation to insulin or calcitonin-gene related peptide compared with PGMN. PGMO associated with higher inhibitor phosphorylation of the insulin receptor substrate 1 (IRS-1) and lower activator phosphorylation of protein kinase B/Akt (Akt). Cells from PGMO also showed lower nitric oxide level and reduced activator serine1177 but increased inhibitor threonine495 phosphorylation of endothelial nitric oxide synthase (eNOS) and saturable transport of l-arginine. HUVECs from PGMO were not responsive to insulin. CONCLUSION: The lack of response to insulin by the foetoplacental endothelium may result from reduced IRS-1/Akt/eNOS signalling in PGMO. These findings may result in higher risk of insulin resistance in neonates to PGMO pregnancies.

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To measure the impact of a "Preventive Letter" designed to encourage the return of gestational diabetes mellitus (GDM) mothers to follow up visit after delivery, in the context of a worldwide concern about low return rates after delivery of these patients. Mothers with GDM require medical evaluation and an oral glucose tolerance test (OGTT) 6 weeks after delivery, in order to: [a] confirm remission of GDM and [b] provide advice on the prevention of type 2 diabetes. In the year 2003 we developed a "Preventive Letter", containing three aspects: [a] current treatment, [b] suggested management during labor, and [c] a stapled laboratory order for OGTT to be performed 6 weeks after delivery. The return rate after delivery was assessed in two groups of GDM mothers: [a] "Without Preventive Letter" (n = 253), and "With Preventive Letter" (n = 215). Both groups, similar with respect to age (33.0 ± 5.4 and 32.3 ± 4.9 years respectively, p = 0.166) and education time (14.9 ± 1.8 and 15.0 ± 1.8 years respectively, p = 0.494), showed a significant difference in the 1-year return rate after delivery, as assessed by the Kaplan-Meier test: 32.0 % for the group "Without Preventive Letter", and 76.0 % for the group "With Preventive Letter" (p < 0.001). The 1-year return rate after delivery of GDM mothers was 2.4 times higher in the group "With Preventive Letter" than in the group without it. We believe that this low-cost approach could be useful in other institutions caring for pregnant women with diabetes.

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OBJECTIVE: Infants born from overweight and obese mothers with glucose-controlled gestational diabetes (GDM) tend to be large-for-gestational age (LGA). It is hypothesized that this is due to an excessive rise in maternal triglyceride levels. METHODS: Two-hundred and seventy nine singleton GDM pregnancies were divided into three groups according to prepregnancy BMI: normal weight (BMI = 20-24.9; n = 128), overweight (BMI = 25-29.9; n = 105), and obese (BMI ≥ 30; n = 46). Individual z-scores (ZS) of maternal triglycerides and of newborn weight (NWZS) were calculated as deviations from published 50th percentiles. Mean z-scores (MZS) were the average of triglyceride ZSs. MZS of triglycerides, HbA1c and NWZS were compared. Variables are expressed as mean ± SD. RESULTS: In the three groups respectively: LGA (%) = 10.1%, 19.0% and 30.4% (P = 0.015). Birth weight (g) = 3274.2 ± 501.3, 3342.4 ± 620.2 and 3366.3±644.7 (RSPEARMAN = 0.111, P = 0.027). HbA1c (%) = 5.2 ± 0.39, 5.3 ± 0.50 and 5.4 ± 0.47 (P = NS). Triglyceride MZS = 1.20 ± 1.13, 1.52 ± 1.37 and 1.62 ± 1.42 (RSPEARMAN = 0.116, P = 0.024). Correlations between triglyceride MZS and NWZS were, respectively: r = 0.12 (P = NS), r = 0.42 (P <0.001), and r = 0.47 (P < 0.001). CONCLUSIONS: In overweight and obese GDM mothers, maternal triglycerides are partially responsible for LGA infants despite good maternal glucose control during pregnancy.

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BACKGROUND: Adolescent pregnancy and advanced maternal age are associated with increased risk for maternal, perinatal and infant death. However, the maternal age with the lowest reproductive risk has not been established. AIM: To determine the range of maternal age with the lowest reproductive risk. MATERIAL AND METHODS: A population-based study (2005-2010) was performed analyzing raw data from vital statistics yearbooks of the National Institute of Statistics of Chile. The association of maternal, fetal, neonatal and infant mortality with maternal age was analyzed. The latter was stratified in quinquenniums, between ages 10 and 54 years. Maternal, fetal, neonatal and infant mortality rates were calculated for each quinquennium. The lowest rate was selected as a control group for risk analysis, which was estimated according to Odds Ratio with 95% confidence intervals. RESULTS: Women of 20-29, 25-34 and under 30 years, had the lowest rate of fetal, neonatal/infant and maternal death, respectively. Women aged 45-49 years had the higher rate of maternal, fetal, neonatal and infant mortality. The risk of fetal, neonatal and infant mortality doubled from 40-44 years onwards, and maternal mortality from the age of 30-34 years. CONCLUSIONS: Our results suggest that the maternal age range with the lesser general reproductive risk is between 20-29 years. This finding should be considered in future studies of reproductive risk and for an appropriate counseling about conception.

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Background: Adolescent pregnancy and advanced maternal age are associated with increased risk for maternal, perinatal and infant death. However, the maternal age with the lowest reproductive risk has not been established. Aim: To determine the range of maternal age with the lowest reproductive risk. Material and Methods: A population-based study (2005-2010) was performed analyzing raw data from vital statistics yearbooks of the National Institute of Statistics of Chile. The association of maternal, fetal, neonatal and infant mortality with maternal age was analyzed. The latter was stratified in quinquenniums, between ages 10 and 54 years. Maternal, fetal, neonatal and infant mortality rates were calculated for each quinquennium. The lowest rate was selected as a control group for risk analysis, which was estimated according to Odds Ratio with 95% confidence intervals. Results: Women of 20-29, 25-34 and under 30 years, had the lowest rate of fetal, neonatal/infant and maternal death, respectively. Women aged 45-49 years had the higher rate of maternal, fetal, neonatal and infant mortality. The risk of fetal, neonatal and infant mortality doubled from 40-44 years onwards, and maternal mortality from the age of 30-34 years. Conclusions: Our results suggest that the maternal age range with the lesser general reproductive risk is between 20-29 years. This finding should be considered in future studies of reproductive risk and for an appropriate counseling about conception.

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We postulate that protein kinase C α (PKCα) may contribute to the maintenance of pregnancy myometrial quiescence in humans. We studied the changes in myometrial PKCα gene products (messenger RNA [mRNA] and protein) in 4 groups of women: preterm not in labor (PT-NL), preterm in labor (PT-L), term not in labor (T-NL), and term in labor (T-L). The degree of PKCα activation was studied by comparing the levels of particulate (active) PKCα with the total PKCα protein levels and by measuring PKCα activity in the cytosolic and particulate fractions. Protein kinase Cα abundance (mRNA and protein) did not increase during myometrial quiescence (PT-NL), whereas the level of PKCα activity significantly increased during quiescence. The activity of PKCα significantly decreased in the T-NL, T-L, and PT-L groups. These findings suggest that PKCα plays a significant role in the maintenance of myometrial quiescence and that PKCα activity must decrease at the end of pregnancy allowing myometrial activation. Additionally, our data demonstrate an association between reduced PKCα activity and preterm labor, which merits further investigation.

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Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. We tested the hypothesis that BNP production is increased by fetal membrane stretching, which is predicted to occur in the expanding uterus, and inhibited by epidermal growth factor (EGF), whose production in the fetal membranes increases in late pregnancy. Term fetal membranes were obtained during elective cesarean delivery before labor. Sections of membranes were placed in an isolated chamber containing DMEM: F12 medium (37°C) and stretched with a 35 g weight. Medium and tissue samples were collected at 0, 3, 6, 18, and 24 hours for measurement of messenger RNA (mRNA) and BNP levels in the presence/absence of EGF (2 × 10(-9 )mol/L). Inducible nitric oxide synthase (iNOS) and ß-actin were also evaluated to discard a nonspecific effect of mechanical stretch on protein expression. We found that amnion and chorion stretching increased the BNP mRNA (reverse transcription-polymerase chain reaction [RT-PCR]) and protein (radioimmunosorbent assay [RIA]) levels from 18 hours onward. The effect of stretching was inhibited by EGF (2 × 10(-9) mol/L). Stretch did not increase iNOS or ß-actin protein levels. We concluded that chorion and amnion stretching may increase BNP expression in the fetal membranes during pregnancy, while increasing biological activity of EGF may decrease BNP production in the chorion and amnion late in pregnancy. We postulate BNP is an important regulator of myometrial contractility during pregnancy, and its production is modulated by both stretch and progressive increase in EGF levels during pregnancy.

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Objetivo: Evaluar los beneficios maternos y fetales de la suplementación prenatal con ácido docosahexae-noico (DHA). Método: Revisión sistemática de investigaciones clínicas controladas aleatorizadas. Resultados: La suplementación prenatal con DHA incrementó los niveles de DHA en sangre materna, en la leche materna o células neonatales. La suplementación con DHA no redujo los síntomas depresivos maternos ni mejoró el desempeño neurológico y visual de los niños. Aunque se apreció un menor riesgo de retraso cognitivo entre los hijos de mujeres suplementadas con DHA (RR 0,4; IC 95 por ciento 0,22-0,78) y un mejor desempeño en el procesamiento mental a los 4 años, el seguimiento a 7 años mostró ausencia de diferencias significativas en el nivel intelectual. El análisis secundario de dos estudios mostró que la suplementación con DHA redujo el riesgo de parto prematuro < 34 semanas (RR 0,49; IC95 por ciento 0,25-0,94; p=0,03), ingreso a UCI neonatal (RR 0,57; IC95 por ciento 0,34-0,97; p=0,04), peso < 2500 g (RR 0,65; IC95 por ciento 0,44-0,96; p=0,03) y restricción de crecimiento intrauterino en pacientes primigestas (RR 0,5; IC 95 por ciento 0,3-1,0; p=0,03). Sin embargo, la prevención de parto prematuro no fue reproducida en estudio diseñado específicamente para ello. Conclusiones: Los estudios reportan un mayor contenido de DHA materno y neonatal en respuesta a la su-plementación prenatal con este ácido graso. Sin embargo, la ausencia actual de efectos clínicos relevantes no permite apoyar ni descartar completamente esta intervención durante el embarazo.

Aims: To evaluate maternal and fetal benefits of prenatal supplementation with docosahexaenoic acid (DHA). Method: Systematic review of clinical randomized controlled trials. Results: Prenatal DHA supplementation increased DHA levels on maternal blood, breast milk or neonatal cells. Maternal supplementation with DHA neither reduced mother's depressive symptoms nor improved the neurological and visual performance of the children. Although it was observed a reduction in risk of cognitive delay between infants of women supplemented with DHA (RR 0.4; IC95 percent 0.22-0.78) and a better performance in the mental processing at the age of 4, the 7 years follow-up showed absence of significant differences in the intellectual level. The secondary analysis of two studies showed that the supplementation with DHA reduced the risk of premature birth <34 weeks (RR 0.49; IC95 percent 0.25-0.94; p=0.03), neonatal ICU hospitalizations (RR 0.57; IC95 percent 0.34-0.97; p=0.04), birth weight <2500 g (RR 0.65; IC95 percent 0.44-0.96; p=0.03) and intrauterine growth restriction in nulliparous patients (RR 0.5; IC95 percent 0.3-1.0; p=0.03). Nevertheless, prevention of premature birth was not reproduced in a specifically designed study. Conclusions: Studies report an increased mother and neonatal content of DHA in response to prenatal supplementation with this polyunsaturated long chain fatty acid. Nevertheless, at date the absence of relevant clinical effects do not permit to support or to reject maternal dietary supplementation with DHA during pregnancy.

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We aim to demonstrate that Brain Natriuretic Peptide (BNP) is synthesized and released from the fetal membranes and mediates pregnancy myometrial quiescence. Myometrium and fetal membranes (FM) were obtained from term and preterm pregnancies at the time of cesarean section, either in labor or not in labor. BNP was measured in term and preterm FM, in culture cells, and conditioned media. We found BNP (but not ANP or CNP) inhibited contractions of preterm, but not term, human myometrium. BNP (both protein and mRNA) was detected in all tissues, conditioned media and cultured cells. BNP was higher in samples from preterm women not in labor compared to those at term not in labor. BNP concentrations were significantly reduced in women in spontaneous preterm labor. We conclude that locally produced BNP may be involved in generating myometrial quiescence during pregnancy. Further, a premature decrease of BNP production may cause preterm labor.

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OBJECTIVE: To test the hypothesis that fetal membranes (chorion or amnion) release one or more factors responsible for myometrial quiescence. METHODS: Myometrial samples were excised from women at elective term cesarean delivery prior to the onset of labor. Fetal membranes were obtained after cesarean delivery either before or during labor, and either term (greater than 37 weeks) or preterm (less than or equal to 36 weeks). Myometrial strips were placed in organ baths and contractions stimulated by oxytocin (10(-8) M). Contractility was measured under isometric conditions before and after exposure to fetal membranes or conditioned medium. The impact of either membrane or conditioned media on contractility was determined before and after myometrial K+ channel blockade. RESULTS: Both chorion and amnion and their respective conditioned mediums decrease oxytocin-stimulated myometrial contraction. The inhibitory effect was greatest with membranes from preterm pregnancies (mean gestation 32 weeks, P <.05). The inhibitory effect was detectable in the presence of term labor, but was absent when the fetal membranes were obtained after preterm labor. Iberiotoxin, an inhibitor of large conductance Ca2+-activated K+ channels (BK(Ca)) reduced the effect of fetal membranes by 50% (P <.05). CONCLUSION: We conclude that human fetal membranes release one or more factors that inhibit oxytocin-induced myometrial contractility. We suggest this factor (or factors) acts mainly by opening myometrial BK(Ca). The findings further support our hypothesis that the fetal membranes release a factor (or factors) that is central to myometrial quiescence and its premature loss leads to preterm delivery.

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