María T. Prieto-Sánchez

Omega 3 fatty acids, gestation and pregnancy outcomes.

Pregnancy is associated with a reduction in maternal serum docosahexaenoic acid (DHA, 22:6 n-3) percentage and its possible depletion in the maternal store. Since the synthesis of long chain polyunsaturated fatty acids (LCPUFA) in the fetus and placenta is low, both the maternal LCPUFA status and placental function are critical for their supply to the fetus. Maternal supplementation with DHA up to 1 g/d or 2·7 g n-3 LCPUFA did not have any harmful effect. DHA supplementation in large studies slightly the enhanced length of gestation (by about 2 days), which may increase the birth weight by about 50 g at delivery. However no advice can be given on their general using to avoid preterm deliveries in low or high risk pregnancies. Several studies, but not all, reported improvements of the offspring in some neurodevelopmental tests as a result of DHA supplementation during gestation, or, at least, positive relationships between maternal or cord serum DHA percentages and cognitive skills in young children. The effect seems more evident in children with low DHA proportions, which raises the question of how to identify those mothers who might have a poor DHA status and who could benefit from such supplementation. Most studies on the effects of n-3 LCPUFA supplementation during pregnancy on maternal depression were judged to be of low-to-moderate quality, mainly due to small sample sizes and failure to adhere to Consolidated Standards of Reporting Trials guidelines. In contrast, the effects of n-3 LCPUFA supplementation on reducing allergic diseases in offspring are promising.

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.

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.

Endometriomas and deep infiltrating endometriosis in adulthood are strongly associated with anogenital distance, a biomarker for prenatal hormonal environment

STUDY QUESTION Is the length of the anogenital distance (AGD), a biomarker of the in-utero prenatal hormonal environment, associated with the presence of endometriomas and deep infiltrating endometriosis (DIE)? SUMMARY ANSWER Shorter AGD is associated with presence of endometriomas and DIE. WHAT IS KNOWN ALREADY It is debated whether hormonal exposure to estrogens in utero may be a risk factor for endometriosis in adulthood. AGD is a biomarker of prenatal hormonal environment and observational studies have shown an association between AGD and reproductive parameters in both sexes. STUDY DESIGN, SIZE, DURATION This case–control study of 114 women with endometriosis (endometriomas and/or DIE) and 105 controls was conducted between September 2014 and May 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS Cases were attending the Endometriosis Unit of the Hospital. Prevalent as well as incident cases, diagnosed by transvaginal ultrasound (TVUS), were included. Controls were women without endometriosis attending the gynecological outpatient clinic for routine gynecological exams. Participants completed health questionnaires, followed physical and gynecological examinations, including TVUS. Measurements from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF) were obtained in all subjects. Unconditional multiple logistic regression was used to estimate the association between AGD measurements and presence of endometriomas and/or DIE while accounting for important confounders and covariates, including age, body mass index, vaginal delivery or episiotomy. MAIN RESULTS AND THE ROLE OF CHANCE AGDAF was related to presence of endometriomas and/or DIE. For all cases of endometriosis (endometriomas and DIE), women in the lowest tertile of the AGDAF distribution, compared with the upper tertile, were 7.6-times (95% CI 2.8–21.0; P-trend < 0.001) more likely to have endometriosis. With regard to DIE, women with AGDAF below the median, compared with those with AGDAF above the median, were 41.6-times (95% CI 3.9–438; P-value = 0.002) more likely to have endometriosis. LIMITATIONS, REASONS FOR CAUTION In case–control studies, information and selection bias has to be ruled out. Physicians conducting the measurement were blind to the status of the patients. Controls came from the same population as the cases. We adjusted for known and suspected confounders and covariates, but the possibility of residual confounding or chance findings should always be considered. As with all observational studies, causal inference is limited. WIDER IMPLICATIONS OF THE FINDINGS This study suggests that endometriosis, especially the DIE, might have a prenatal origin that may be traced back to the hormonal milieu in which the fetus develops. STUDY FUNDING/COMPETING INTEREST This work was supported by the Ministry of Economy and Competitiveness, ISCIII (AES), grant no. PI13/01237 and the Seneca Foundation, Murcia Regional Agency of Science and Technology, grant no. 19443/PI/14. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER Not applicable.

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.

Insulin Treatment May Alter Fatty Acid Carriers in Placentas from Gestational Diabetes Subjects

There is little information available on the effect of Gestational diabetes mellitus (GDM) treatment (diet or insulin) on placental lipid carriers, which may influence fetal fat accretion. Insulin may activate placental insulin receptors protein kinase (AKT) and extracellular signal regulated kinase ERK mediators, which might affect lipid metabolism. Placenta was collected from 25 control women, 23 GDM-Diet and 20 GDM-Insulin. Western blotting of insulin signaling mediators and lipid carriers was performed. The human choricarcinoma-derived cell line BeWo was preincubated with insulin inhibitors protein kinase (AKT) and extracellular signal regulated kinase (ERK) and ERK inhibitors to evaluate insulin regulation of lipid carriers. Maternal serum insulin at recruitment correlated to ultrasound fetal abdominal circumference in offspring of GDM and placental endothelial lipase (EL). Lipoprotein lipase in placenta was significantly reduced in both GDM, while most of the other lipid carriers tended to higher values, although not significantly. There was a significant increase in both phosphorylated-Akt and ERK in placentas from GDM-Insulin patients; both were associated to placental fatty acid translocase (FAT), fatty acid binding protein (A-FABP), and EL. BeWo cells treated with insulin pathway inhibitors significantly reduced A-FABP, fatty acid transport protein (FATP-1), and EL levels, confirming the role of insulin on these carriers. We conclude that insulin promotes the phosphorylation of placental insulin mediators contributing to higher levels of some specific fatty acid carriers in the placenta and fetal adiposity in GDM.

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

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.

Central pontine myelinolysis during pregnancy: Pathogenesis, diagnosis and management

Abstract Central pontine myelinolysis (CPM) is a rare condition usually caused by rapid sodium correction in hyponatraemia after a severe neurological syndrome. Only few cases have been reported during pregnancy, most of which were reported in patients with hyperemesis. We describe the successful management of the first case of twin pregnancy in a patient who presented with CPM after treatment for premature labour and then review the literature on CPM in pregnancy (aetiology, diagnosis and management). Our patient required emergency delivery to achieve electrolyte and fluid balance. At six months, the twins remained asymptomatic and the mother had minor sequelae. The aetiology is not clear, and there is no evidence regarding the optimal treatment or prognosis of CPM. In our patient, desmopressin-contaminated atosiban showed a certain probability in the Karch-Lasagne algorithm of a causality relationship between hyponatraemia and the drug. To our knowledge, this is the first case of myelinolysis reported in a twin pregnancy possibly related to desmopressin-contaminated atosiban.

Comparability between adult female anogenital distance and perineal measurements standardized by POP-Q system (GH and PB)

Anogenital distance (AGD) has been proposed as a marker of the prenatal hormonal milieu and potential environmental insults. The measures of the Pelvic Organ Prolapse‐Questionnaire (POP‐Q) system is being widely used in the evaluation of the perineum in women with POP pathologies. Genital hiatus (GH) and perineal body (PB) lengths have been related to both prolapse incidence and recurrence and for pessary treatment failure. The use of AGD in female human studies is now emerging and its comparability with other anthropometric measurements could be relevant. The aim of the study was to compare AGD and POP‐Q system in adult females.

Anogenital Distance and Perineal Measurements of the Pelvic Organ Prolapse (POP) Quantification System

Anogenital distance (AGD) is a sexually dimorphic attribute, twice longer in males than in females, and a marker of intrauterine hormonal environment. Interest in AGD measurements is increasing due to mounting evidence on their potential clinical implications. A parallel set of perineal measurements, the Pelvic Organ Prolapse Quantification System (POP-Q), include similar, but not exactly the same, landmarks: the perineal body (PB) and the genital hiatus (GH) lengths. However, clinical reproducibility of both perineal measurements and their usefulness to describe perineal anthropometry needs to be elucidated. To our knowledge, there is no publication in video format showing the methodology of these measurements. The main objective of this work is to show how to properly perform perineal anthropometry, including measurements of the AGD in its two variants [anoclitoral (AGDAC) and anofourchette (AGDAF)], genital hiatus (GH) and perineal body (PB). Moreover, we explored if there were differences in these measurements in women with and without Pelvic Organ Prolapse (POP). We research whether the anthropometric characteristics of the perineum, such as AGD (which is determined prenatally), may be altered in these women and be an independent etiological factor for pelvic floor dysfunction. We show two different ways of measuring perineal lengths, as they might be quite comparable. Our suggestion is that unifying perineal measurements could be useful for clinical and biomedical investigation. More studies are needed in order to compare GH and PB measurements and its AGD counterparts to analyze which procedures are more reproducible with less intra and interobserver variability.