Juan José Parrilla

Placental transfer of fatty acids and fetal implications

Considerable amounts of long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid and docosahexaenoic acid (DHA, 22:6n-3), are deposited in fetal tissues during pregnancy; and this process is facilitated by placental delivery. Nevertheless, the mechanisms involved in LC-PUFA placental transfer remain unclear. Stable isotope techniques have been used to study human placental fatty acid transfer in vivo. These studies have shown a significantly higher ratio of (13)C-DHA in cord to maternal plasma compared with other fatty acids, which reflects a higher placental DHA transfer. In addition, a selective DHA accumulation in placental tissue, relative to other fatty acids, has been reported. The materno-fetal transfer of fatty acids is a slow process that requires ≥12 h. A high incorporation of dietary (13)C-DHA into maternal plasma phospholipids appears to be important for placental uptake and transfer. DHA in cord blood lipids correlates with placental messenger RNA expression of fatty acid transport protein (FATP)-4, compatible with a role of FATP-4 in DHA transfer. Impaired materno-fetal LC-PUFA transport has been proposed in pregnancies complicated by abnormal placental function (eg, due to gestational diabetes mellitus or intrauterine growth restriction), which should be addressed in future studies. Given that placental DHA transfer is important for child outcomes, elucidation of its potential modulation by transport mechanisms, maternal diet, and disease appears to be important.

Maternal-fetal in vivo transfer of [13C]docosahexaenoic and other fatty acids across the human placenta 12 h after maternal oral intake

BACKGROUND Fetal growth and development require n-3 (omega-3) long-chain polyunsaturated fatty acids, but mechanisms for their placental transfer are not well understood. OBJECTIVE We assessed distribution and human placental transfer of (13)C-labeled fatty acids (FAs) 12 h after oral application. DESIGN Eleven pregnant women received 0.5 mg [(13)C]palmitic acid ((13)C-PA; 16:0), 0.5 mg [(13)C]oleic acid ((13)C-OA; 18:1n-9), 0.5 mg [(13)C]linoleic acid ((13)C-LA; 18:2n-6), and 0.1 mg [(13)C]docosahexaenoic acid ((13)C-DHA; 22:6n-3) per kilogram of body weight orally 12 h before elective cesarean section. Maternal blood samples were collected before tracer intake (-12 h) and at -3, -2, -1, 0, and +1 h relative to the time of cesarean section. At birth, venous cord blood and placental tissue were collected, and FA concentrations in individual lipid fractions and their tracer content (atom percent excess values) were determined. RESULTS Relatively stable tracer enrichment was achieved in maternal lipid fractions 12 h after tracer administration. In maternal plasma, most (13)C-PA and (13)C-OA were found in triglycerides, whereas (13)C-LA and (13)C-DHA were found mainly in plasma phospholipids and triglycerides. In placental tissue, (13)C-FAs were mainly found in phospholipids, which comprise 80% of placental tissue lipids. Placenta-maternal plasma ratios and fetal-maternal plasma ratios for (13)C-DHA were significantly higher than those for any other FA. CONCLUSIONS Twelve hours after oral application of (13)C-labeled FAs, relatively stable tracer enrichment was achieved. We found a significantly higher ratio of (13)C-DHA concentrations in cord plasma than in maternal plasma, which was higher than that for the other studied FAs. (13)C-DHA is predominantly esterified into phospholipids and triglycerides in maternal plasma, which may facilitate its placental uptake and transfer.

Calidad de vida relacionada con la salud en la mujer española durante la perimenopausia y posmenopausia: desarrollo y validación de la Escala Cervantes

Fundamento y objetivo: Existen numerosos cuestionarios para medir la calidad de vida relacionada con la salud, pero muy pocos son especificos para la menopausia. El objetivo de este estudio fue disenar y validar una escala especifica para la menopausia en la mujer espanola, la Escala Cervantes, original en castellano y adaptada a nuestro medio. Sujetos y metodo: El estudio transversal constaba de una fase piloto, construccion del cuestionario, validacion y fiabilidad test-retest. Para la validacion se utilizo una muestra de 2.274 mujeres de la poblacion espanola ponderada por grupos de edad y nivel de estudios. La consistencia interna se valoro mediante el coeficiente * de Cronbach. Resultados: La escala definitiva constaba de 31 items (distribuidos en las dimensiones menopausia y salud, con 15 items que incluian sintomatologia vasomotora, salud y envejecimiento; sexualidad, con 4 items; relacion de pareja, con 3 items, y dominio psiquico, con 9 items). El coeficiente * de Cronbach de la escala global fue de 0,9092 y el de las diferentes subescalas oscilo entre 0,7989 y 0,8501. El coeficiente de correlacion en la prueba test-retest fue de r = 0,847 (p < 0,001). La Escala Cervantes es corta, facil de aplicar (unos 7 min), tiene una puntuacion minima de 0 y maxima de 155 (de mejor a peor calidad de vida) y dispone de baremos para comparar el resultado con mujeres mas jovenes o de la misma edad. Conclusiones: La Escala Cervantes forma parte de una nueva generacion de instrumentos de calidad de vida relacionada con la salud especificos para la menopausia. Su ambito de aplicacion es la poblacion femenina espanola de entre 45 y 64 anos de edad.

Mechanisms Involved in the Selective Transfer of Long Chain Polyunsaturated Fatty Acids to the Fetus

The concentration of long chain polyunsaturated fatty acid (LCPUFA) in the fetal brain increases dramatically from the third trimester until 18 months of life. Several studies have shown an association between the percentage of maternal plasma docosahexaenoic acid (DHA) during gestation and development of cognitive functions in the neonate. Since only very low levels of LCPUFA are synthesized in the fetus and placenta, their primary source for the fetus is the maternal circulation. Both in vitro and human in vivo studies using labeled fatty acids have shown preferential transfer of LCPUFA from the placenta to the fetus compared with other fatty acids, although the mechanisms involved are still uncertain. The placenta takes up circulating maternal non-esterified fatty acids (NEFA) and fatty acids released mainly by maternal lipoprotein lipase and endothelial lipase. These NEFA may enter the cell by passive diffusion or by means of membrane carrier proteins. Once in the cytosol, NEFA bind to cytosolic fatty acid-binding proteins for transfer to the fetal circulation or can be oxidized within the trophoblasts, and even re-esterified and stored in lipid droplets. Although trophoblast cells are not specialized for lipid storage, LCPUFA may up-regulate peroxisome proliferator activated receptor-γ (PPARγ) and hence the gene expression of fatty acid transport carriers, fatty acid acyl-CoA-synthetases and adipophilin or other enzymes involved in lipolysis, modifying the rate of placental transfer, and metabolism. The placental transfer of LCPUFA during pregnancy seems to be a key factor in the neurological development of the fetus. Increased knowledge of the factors that modify placental transfer of fatty acids would contribute to our understanding of this complex process.

Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus

Better knowledge on the disturbed mechanisms implicated in materno-fetal long-chain polyunsaturated fatty acid (LC-PUFA) transfer in pregnancies with gestational diabetes mellitus (GDM) may have potentially high implications for later on in effective LC-PUFA supplementation. We studied in vivo placental transfer of fatty acids (FA) using stable isotope tracers administrated to 11 control and 9 GDM pregnant women (6 treated with insulin). Subjects received orally [(13)C]palmitic, [(13)C]oleic and [(13)C]linoleic acids, and [(13)C]docosahexaenoic acid ((13)C-DHA) 12 h before elective caesarean section. Maternal blood samples were collected at -12, -3, -2, and -1 h, delivery, and +1 h. Placental tissue and venous cord blood were also collected. FA were quantified by gas chromatography (GC) and (13)C enrichments by GC-isotope ratio mass spectrometry. [(13)C]FA concentration was higher in total lipids of maternal plasma in GDM vs. controls, except for [(13)C]DHA. Moreover, [(13)C]DHA showed lower placenta/maternal plasma ratio in GDM vs. controls and significantly lower cord/maternal plasma ratio. For the other studied FA, ratios were not different between GDM and controls. Disturbed [(13)C]DHA placental uptake occurs in both GDM treated with diet or insulin, whereas the last ones also have lower [(13)C]DHA in venous cord. The tracer study pointed toward impaired placental DHA uptake as critical step, whereas the transfer of the rest of [(13)C]FA was less affected. GDM under insulin treatment could also have higher fetal fat storage, contributing to reduce [(13)C]DHA in venous cord. DHA transfer to the fetus was reduced in GDM pregnancies compared with controls, which might affect the programming of neurodevelopment in their neonates.

Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50-150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97-1.46) for HCG cycles with ovulation, 1.78 (0.92-3.54) for the pregnancy rate per woman, and 1.83 (0.79-4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.

Placental Fatty Acid Transfer: A Key Factor in Fetal Growth

The functionality of the placenta may affect neonatal adiposity and fetal levels of key nutrients such as long-chain polyunsaturated fatty acids. Fetal macrosomia and its complications may occur even in adequately controlled gestational diabetic (GDM) mothers, suggesting that maternal glycemia is not the only determinant of fetal glycemic status and wellbeing. We studied in vivo the placental transfer of fatty acids (FA) labeled with stable isotopes administered to 11 control and 9 GDM pregnant women (6 treated with insulin). Subjects received orally 13C-palmitic, 13C-oleic, and 13C-linoleic acids and 13C-docosahexaenoic acid (13C-DHA) 12 h before an elective caesarean section. FA were quantified by gas chromatography and 13C enrichments by gas chromatography-isotope ratio mass spectrometry. The 13C-FA concentration was higher in total lipids of maternal plasma in GDM patients versus controls, except for 13C-DHA. Moreover, 13C-DHA showed a lower placenta/maternal plasma ratio in GDM patients versus controls and a significantly lower cord/maternal plasma ratio. Other FA ratios studied were not different between GDM and controls. A disturbed 13C-DHA placental uptake occurred in GDM patients treated with diet or insulin, while the latter also had lower 13C-DHA levels in the venous cord. The tracer study pointed towards an impaired placental DHA uptake as a critical step, while the transfer of other 13C-FA was less affected. Patients with GDM treated with insulin could also have a greater fetal fat storage, which may have contributed to the reduced 13C-DHA in the venous cord observed. The DHA transfer to the fetus was reduced in GDM pregnancies compared to controls. This might have an influence on fetal neurodevelopment and long-term consequences for the child.

The management of missed miscarriage in an outpatient setting: 800 versus 600 μg of vaginal misoprostol.

Background:  Many misoprostol regimens have been used to treat early pregnancy loss as an alternative to surgical evacuation, with differing adverse event and success rates.

A gene variant in the transcription factor 7-like 2 (TCF7L2) is associated with an increased risk of gestational diabetes mellitus.

OBJECTIVE Adipokines play an important role in the pathogenesis of insulin resistance during pregnancy. We studied the association of genetic variants linked with type 2 diabetes in gestational diabetes mellitus (GDM) subjects and its influence on maternal adipokines. STUDY DESIGN We recruited 25 healthy pregnant women (Controls) and 45 women with GDM at 24-28 weeks of gestation. Maternal blood samples were collected at recruitment and delivery. Adipokines were determined at both sampling times. Genomic DNA was extracted from recruitment samples and FTO rs9939609, TCF7L2 rs4506565, rs7901695, rs12243326, rs12255372 and rs7903146, INSIG2 rs7566605, SREBF1 rs114001633, rs45535737 and rs12941356 and FATP4 rs2003560 genotyped. RESULTS Serum adiponectin was significantly lower in GDM than Controls at recruitment and showed a similar trend at delivery (p=0.060). In contrast, resistin tended to higher levels in GDM only at recruitment. TCF7L2 rs4506565 (OR=2.31, 95% CI: 1.97-5.01; p=0.031) and FTO rs9939609 (OR=2.17, 95% CI: 1.07-4.41; p=0.039) were associated with GDM risk. Women carrying the T allele of TCF7L2 rs4506565 had increases in plasma resistin of 9.38 μg/L (95% CI 1.39-17.37; p=0.022) per allele; this association remained significant after adjusting for pre-gestational body weight. CONCLUSION TCF7L2 rs4506565 variant (T/T) is associated with increased risk of GDM and plasma resistin concentrations in women with GDM.

Understanding how personality factors may influence quality of life: development and validation of the Cervantes Personality Scale.

Objective: To develop and validate a simple personality scale to be used as a complementary tool for menopause-specific quality-of-life instruments. Design: A population-based random sample of 2,274 Spanish women stratified by age groups and education level was used in the validation phase. The initial 94-item questionnaire was reduced to 20 items by examining the frequency and variability with which women were responding to each of the items. The measurement properties were tested by conducting reliability (internal consistency and test-retest) and validation analyses (correlations, and factor analysis). Results: The final 20-item scale consisted of three domains: introversion (seven items), emotional instability (seven items), and insincerity (control subscale, six items). Cronbachs &agr; coefficients for the subscales of emotional instability, introversion, and insincerity were 0.7966, 0.7135, and 0.7042, respectively. The test-retest correlation was r = 0.763 for introversion, r = 0.720 for emotional instability, and r = 0.680 for insincerity (P < 0.001). The Cervantes Personality Scale is short and easy to administer. Scores range from 0 (the most extraverted personality) to 35 (the most introverted personality) for the introversion domain, from 0 (the most emotionally stable personality) to 35 (the most emotionally unstable personality) for the emotional instability domain, and from 0 (the most sincere response) to 30 (the most insincere response) for the insincerity domain. Conclusions: A novel self-report 20-item scale for assessing three stable personality traits (introversion, emotional instability, and insincerity) in peri- and postmenopausal women is presented. We provide preliminary evidence that the Cervantes Personality Scale is a useful psychometric tool for studying personality in women going through the menopausal transition.