Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes.

BACKGROUND & AIMS: Maternal-fetal transfer of docosahexaenoic acid (DHA) is impaired by gestational diabetes mellitus (GDM), but the underlying mechanisms are still unknown. MFSD2a was recently recognized as a lyso-phospholipid (lyso-PL) transporter that facilitates DHA accretion in brain. The role of this transporter in placenta is uncertain. We evaluated effects of GDM and its treatment (diet or insulin) on phospholipid species, fatty acid profile in women, cord blood and placental fatty acid carriers. METHODS: Prospective observational study of pregnant women recruited in the third trimester (25 controls, 23 GDM-diet, 20 GDM-insulin). Fetal ultrasound was performed at gestational week 38. At delivery, maternal and neonatal anthropometry was performed, and fatty acids in total lipids and phospholipid species were analyzed in placenta, maternal and venous cord blood. Western-blot analyses were performed for placental fatty acid carriers. RESULTS: Fetal abdominal circumference z-score at 38 weeks tended to higher values in GDM (P = 0.071), pointing toward higher fetal fat accretion in these babies. DHA percentage in cord serum total lipids (P = 0.029) and lyso-PL (P = 0.169) were reduced in GDM. Placental MFSD2a was reduced in both GDM groups and was positively correlated to DHA values in cord serum total lipids (r = 0.388, P = 0.003). Among established placental lipid carriers, only FATP4 was correlated to DHA concentration in placental lyso-PL. In all compartments, DHA percentage was inversely correlated to fetal abdominal circumference. CONCLUSIONS: In offspring of women with GDM treated either with diet or insulin, higher fetal fat accretion and lower placental MFSD2a contribute to reduce DHA availability. Lyso-PL appear to contribute to materno-fetal DHA transport.

A method for lipid droplet isolation from human placenta for further analyses in clinical trials.

We describe a method to isolate lipids droplets from human placental tissue for future lipid analyses. We collected placentas at term from healthy women (n=5) and tested three methods published for lipids droplets isolation in other tissues. Only one of the methods, when modified, isolated lipids droplets from placental tissue, whereas all three methods allowed lipids droplets isolation from rat liver (control tissue) and separation of lipids droplets from blood contamination of the tissue. The placental lipids droplets layer was characterized by the presence of adipophilin while no N+ /K+-ATPase as plasma membrane contamination was detected. Intraplacental triglyceride content showed a high coefficient of variation (~42%), whereas for cholesterol and phospholipids this was lower. One method was effective for isolation of placental lipids droplets. It is necessary to collect a pool of placental tissue pieces for placental lipids droplets analyses. Freezing in liquid nitrogen is recommended.

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.

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.

Influence of gestational diabetes on circadian rhythms of children and their association with fetal adiposity.

OBJECTIVE: To analyse the circadian rhythm maturation of temperature, activity and sleep during the first year of life in offspring of diabetic mothers (ODM) and its relationship with obesity markers. METHODS: A prospective analysis of the children of 63 pregnant women (23 controls, 21 gestational diabetes mellitus (GDM) controlled with diet and 19 GDM with insulin). Fetal abdominal circumference was evaluated ecographically during gestation. Skin temperature and rest-activity rhythms were monitored for 3 consecutive days in children at 15 days and 1, 3 and 6 months. Anthropometrical parameters of the children were evaluated during the first year of life. RESULTS: Children from the GDM groups tended to higher fetal abdominal circumference z-score than controls at the beginning of the last trimester (p = 0.077) and at delivery (p = 0.078). Mean skin temperature or activity was not different among the groups. The I < O sleep index pointed to increasing concordance with parental sleeping at 3 and 6 months but no significant GDM-dependent differences. However, some of the parameters that define temperature maturation and also the circadian function index from the temperature-activity variable were significantly lower at 6 months in the GDM + insulin group. Fetal abdominal circumference z-score, as a predictor of fetal adiposity, correlated negatively with parameters related to circadian rhythm maturation as the circadian/ultradian rhythm (P1 /Pult ratio). CONCLUSIONS: Fetal adiposity correlated with a worse circadian rhythm regulation in ODM. In addition, ODM insulin-treated showed a disturbed pattern of the circadian function index of temperature activity at 6 months of age.

2-methoxyestradiol in the pathophysiology of endometriosis: focus on angiogenesis and therapeutic potential.

Endometriosis is a common condition among women of childbearing potential in which ectopic endometrial tissue is found outside the uterine cavity. Neoangiogenesis plays a major role in the development of endometriotic implants. Some evidence suggests that a disorder in the balance of proangiogenic and antiangiogenic factors that favors the former is induced by local hypoxia and is mediated by the hypoxia-inducible factor-vascular endothelium growth factor pathway could partially explain the development of this condition in some women. 2-methoxyestradiol is a biologically active metabolite of estradiol having antiangiogenic action. Changes in estradiol homeostasis have been locally observed in endometriosis. In this review, we summarize current knowledge of endometriosis pathophysiology, in particular, the balance between local 2-methoxyestradiol production and angiogenesis, which could promote the development of endometriotic lesions. 2-Methoxyestradiol emerges as a promising new candidate for the treatment of endometriosis.

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. AIMS: This study sought to compare the effectiveness and adverse effects of 800 and 600 µg of misoprostol administered vaginally for the treatment of early pregnancy failure in an outpatient setting. METHODS: A retrospective, observational study of 946 women with a missed miscarriage <12 weeks' gestation was performed: 487 women received 800 µg (group 1) and 459 women received 600 µg (group 2) of vaginal misoprostol every 24 h for two days. The first follow-up was seven days after treatment. Women were asked about symptoms, and a transvaginal ultrasound was performed. If an incomplete miscarriage or gestational sac was still found, then an additional dose of intravaginal misoprostol was prescribed, and a second follow-up visit was arranged for seven days later. Surgical evacuation was scheduled for women who did not wish to continue medical treatment after the first or second follow-up visit. RESULTS: The total rate of complete miscarriage was 90.6% after 800 µg and 87.8% after 600 µg of intravaginal misoprostol. The percentage of women who underwent surgical evacuation after medical treatment was 9.4% for group 1 and 12.2% for group 2. CONCLUSIONS: Complete uterine evacuation after a missed miscarriage was effectively induced by both 600 and 800 µg of misoprostol. The overall success of medical treatment with intravaginal misoprostol demonstrates that the treatment is safe in an outpatient setting.

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.

Ovarian cancer during pregnancy: analysis of 15 cases.

GOAL: Our goal was to analyze and describe cases of ovarian cancer in pregnant women treated at our hospital. METHOD: Retrospective study based on clinical histories from patients diagnosed and treated at our hospital for ovarian cancer and pregnancy from 1987 to 2005. RESULTS: Fifteen cases of ovarian cancer were diagnosed among pregnant women; the ratio is 0.11/1000 deliveries. Among them, 66.6% of patients were asymptomatic, and 86.6% had been diagnosed via ultrasound. Of the diagnosed tumors, 40% were malignant epithelial tumors, 26.6% of them were of low malignant potential. The 20% were germinal cell tumors. Of these primary ovarian malignancies, the 59.9% were stage I. The remaining 20% were metastatic tumors. Forty percent of the total were treated conservatively (salpingo-oophorectomy) and 60% with hysterectomy and bilateral salpingo-oophorectomy. Chemotherapy was administered to 66.6% of the patients, in two cases during pregnancy. Eighty percent of the newborns were healthy and presented no sequelae or malformations. Global survival at 5 years was 76%. CONCLUSIONS: Ovarian cancer is rare in pregnant women. Most malignant ovarian neoplasias in pregnant women are at early stages and are associated with good prognosis both for the mother and for the neonate.

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.

Hemodynamic state and the role of angiotensin II in ovarian hyperstimulation syndrome in the rabbit.

OBJECTIVE: To investigate the hemodynamic state in the ovarian hyperstimulation syndrome (OHSS) in the rabbit model and to determine the role of angiotensin II in the pathophysiology of this syndrome. DESIGN: Experimental study. SETTING: Physiology laboratory. ANIMAL(S): Female New Zealand rabbits were studied; 16 rabbits were stimulated with gonadotropins, and 6 were controls. Six of the stimulated rabbits received additional treatment with captopril. MAIN OUTCOME MEASURE(S): Cardiac index, blood pressure, and heart rate were recorded. RESULT(S): Gonadotropin-stimulated rabbits had significant enlargement of ovaries that was not modified by captopril. Ascites was present in 80% of animals in the OHSS group; captopril significantly decreased the incidence and volume of ascites. The three groups did not differ in blood pressure, heart rate, cardiac index, and total peripheral resistance. CONCLUSION(S): In rabbits with OHSS, ascites are a primary event. Such animals are normotensive and have normal vascular resistance and cardiac index. Angiotensin-converting enzyme inhibition decreases the incidence of OHSS in the rabbit model by 30%, suggesting that angiotensin II may play a role in the formation of ascites.