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Assess the usefulness of the sFlt-1/PlGF ratio for the differential diagnosis of uncontrolled chronic hypertension vs. superimposed preeclampsia.We performed a cross-sectional study from 2015 to 2017 and 42 women with initial diagnosis of superimposed preeclampsia were enrolled in the emergency room. After a 12 week follow up patients were grouped as superimposed preeclampsia (Group A) and uncontrolled chronic hypertension (Group B) according to the American College of Obstetricians and Gynecologist criteria. A group of 33 healthy women paired by gestational age were included as controls (Group C). Maternal serum levels of sFlt-1 and PlGF were measured at enrollment, and the ratios of the groups were compared.Superimposed preeclampsia vs. uncontrolled chronic hypertension.After follow-up, group distribution was 30 women in Group A, 12 women in Group B, and 25 women in Group C. The sFlt-1/PlGF ratio was higher in women with superimposed preeclampsia than in women with uncontrolled chronic hypertension (215.5 vs. 9.65, p 0.001). The control group displayed lower ratio values (3.66, p 0.001). The sFlt-1 concentration was higher in Group A than in Group B (7564 vs. 1281 pg/mL, p 0.001) and the PlGF level was lower in Group A (34.39 vs. 169 pg/mL, p 0.001).The sFlt-1/PlGF ratio exhibits good performance for the differential diagnosis of superimposed preeclampsia vs. uncontrolled chronic hypertension.

The aim of this study was to examine the efficacy of intensive medical nutrition therapy (MNT) plus metformin in preventing gestational diabetes mellitus (GDM) among high-risk Mexican women. An open-label randomized clinical trial was conducted. Inclusion criteria were pregnant women with three or more GDM risk factors: Latino ethnic group, maternal age >35 years, body mass index >25 kg/m2, insulin resistance, and a history of previous GDM, prediabetes, a macrosomic neonate, polycystic ovarian syndrome, or a first-degree relative with type 2 diabetes. Women before 15 weeks of gestation were assigned to group 1 (n = 45): intensive MNT-plus metformin (850 mg twice/day) or group 2 (n = 45): intensive MNT without metformin. Intensive MNT included individual dietary counseling, with ≤50% of total energy from high carbohydrates. The primary outcome was the GDM incidence according to the International Association of Diabetes Pregnancy Study Groups criteria. There were no significant differences in baseline characteristics and adverse perinatal outcomes between the groups. The GDM incidence was n = 11 (24.4%) in the MNT plus metformin group versus n = 7 (15.5%) in the MNT without metformin group: p = 0.42 (RR: 1.57 [95% CI: 0.67–3.68]). There is no benefit in adding metformin to intensive MNT to prevent GDM among high-risk Mexican women. Clinical trials registration: NCT01675310.

Altres ajuts: European Research Area-NET, Transcan-2 (AC15/00063), Asociación Española Contra el Cáncer (LABAE16020PORTT) i AIOC15152806CRUZ, Generalitat de Catalunya(PERIS, SLT002/16/00477 En el cas dels drets, per a usos comercials contactar amb: journals.permissions@oup.com BRCA1 and BRCA2 (BRCA1/2) -deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1 -loss in 20% and RAD51 -amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

The cytotrophoblast of human placenta transitions into an outer multinucleated syncytiotrophoblast (STB) layer that covers chorionic villi which are in contact with maternal blood in the intervillous space. During pregnancy, the Zika virus (ZIKV) poses a serious prenatal threat. STB cells are resistant to ZIKV infections, yet placental cells within the mesenchyme of chorionic villi are targets of ZIKV infection. We seek to determine whether ZIKV can open the paracellular pathway of STB cells. This route is regulated by tight junctions (TJs) which are present in the uppermost portion of the lateral membranes of STB cells. We analyzed the paracellular permeability and expression of E-cadherin, occludin, JAMs &ndash, B and &ndash, C, claudins -1, -3, -4, -5 and -7, and ZO-1, and ZO-2 in the STB of placentae from ZIKV-infected and non-infected women. In ZIKV-infected placentae, the pattern of expression of TJ proteins was preserved, but the amount of claudin-4 diminished. Placentae from ZIKV-infected women were permeable to ruthenium red, and had chorionic villi with a higher mean diameter and Hofbauer hyperplasia. Finally, ZIKV added to the basolateral surface of a trophoblast cell line reduced the transepithelial electrical resistance. These results suggest that ZIKV can open the paracellular pathway of STB cells.

Controversy remains surrounding vitamin D routine supplementation in healthy pregnancy, and the doses are unclear. The aim of this study was to describe maternal vitamin D status throughout pregnancy in a group of Mexican women and evaluate the effect of frequently prescribed doses of vitamin D3 on longitudinal 25-OH-D concentrations, adjusting for obesity, season, and other factors. We conducted a cohort study (Instituto Nacional de Perinatolog&iacute, a-INPer) (2017&ndash, 2020)) of healthy pregnant women without complications. Pregestational overweight/obesity (body mass index &ge, 25), vitamin D3 supplementation (prescribed by physician, 0&ndash, 250, 250&ndash, 400, and &gt, 400 IU/day), and serum 25-OH-D concentrations (ELISA) were evaluated in each trimester of pregnancy. Vitamin D deficiency or insufficiency was computed (&lt, 20 and &lt, 30 ng/mL, respectively). We studied 141 adult women, 58.5% had pregestational obesity or overweight. In the first trimester, 45.8% of the women were supplemented with vitamin D3, 51.4% had vitamin D insufficiency and 37.3%, deficiency. In the third trimester, 75.4% of the women were supplemented, and 20% of them still had deficiency. The final general mixed linear model showed that 25-OH-D significantly increased throughout pregnancy (p &lt, 0.001), the highest increase was observed in the third trimester in women with doses &gt, 400 IU/day of vitamin D3 (+4 ng/mL, 95% CI: 1.72&ndash, 8.11 ng/mL). In winter/autumn, 25-OH-D concentrations were also lower (p &le, 0.05). In this group of pregnant Mexican women, the prevalence of vitamin D deficiency and insufficiency was high. A higher increase in 25-OH-D concentrations during pregnancy was observed when the women were supplemented with &gt, 400 IU/day. Common supplementation doses of 250&ndash, 400 IU/day were insufficient for achieving an adequate maternal vitamin D status.

Preeclampsia (PE) and Intrauterine Growth Restriction (IUGR) are major contributors to perinatal morbidity and mortality. These pregnancy disorders are associated with placental dysfunction and share similar pathophysiological features. The aim of this study was to compare the placental gene expression profiles including mRNA and lncRNAs from pregnant women from four study groups: PE, IUGR, PE-IUGR, and normal pregnancy (NP). Gene expression microarray analysis was performed on placental tissue obtained at delivery and results were validated using RTq-PCR. Differential gene expression analysis revealed that the largest transcript variation was observed in the IUGR samples compared to NP (n = 461, 314 mRNAs: 252 up-regulated and 62 down-regulated, 133 lncRNAs: 36 up-regulated and 98 down-regulated). We also detected a group of differentially expressed transcripts shared between the PE and IUGR samples compared to NP (n = 39), including 9 lncRNAs with a high correlation degree (p &lt, 0.05). Functional enrichment of these shared transcripts showed that cytokine signaling pathways, protein modification, and regulation of JAK-STAT cascade are over-represented in both placental ischemic diseases. These findings contribute to the molecular characterization of placental ischemia showing common epigenetic regulation implicated in the pathophysiology of PE and IUGR.

Maternal obesity has been related to adverse neonatal outcomes and fetal programming. Oxidative stress and adipokines are potential biomarkers in such pregnancies; thus, the measurement of these molecules has been considered critical. Therefore, we developed artificial neural network (ANN) models based on maternal weight status and clinical data to predict reliable maternal blood concentrations of these biomarkers at the end of pregnancy. Adipokines (adiponectin, leptin, and resistin), and DNA, lipid and protein oxidative markers (8-oxo-2′-deoxyguanosine, malondialdehyde and carbonylated proteins, respectively) were assessed in blood of normal weight, overweight and obese women in the third trimester of pregnancy. A Back-propagation algorithm was used to train ANN models with four input variables (age, pre-gestational body mass index (p-BMI), weight status and gestational age). ANN models were able to accurately predict all biomarkers with regression coefficients greater than R2 = 0.945. P-BMI was the most significant variable for estimating adiponectin and carbonylated proteins concentrations (37%), while gestational age was the most relevant variable to predict resistin and malondialdehyde (34%). Age, gestational age and p-BMI had the same significance for leptin values. Finally, for 8-oxo-2′-deoxyguanosine prediction, the most significant variable was age (37%). These models become relevant to improve clinical and nutrition interventions in prenatal care.

International audience; A new method to address the problem of shadowing in fetal brain ultrasound volumes is presented. The proposed approach is based on the spatial composition of multiple 3-D fetal head projections using the weighted Euclidean norm as an operator. A support vector machine, which is trained with optimal textural features, was used to assign weighting according to the posterior probabilities of brain tissue and shadows. Both phantom and real fetal head ultrasound volumes were compounded using previously reported operators and compared with the proposed composition method to validate it. The quantitative evaluations revealed increases in signal-to-noise ratio ≤35% and in contrast-to-noise ratio ≤135% using real data. Qualitative comparisons made by obstetricians indicated that this novel method adequately recovers brain tissue and improves the visibility of the main cerebral structures. This may prove useful both for fetal monitoring and in the diagnosis of brain defects. Overall this new approach outperforms spatial composition methods previously reported.

Fetal exposure to essential and toxic metals can influence life-long health trajectories. The placenta regulates chemical transmission from maternal circulation to the fetus and itself exhibits a complex response to environmental stressors. The placenta can thus be a useful matrix to monitor metal exposures and stress responses in utero, but strategies to explore the biologic effects of metal mixtures in this organ are not well-developed. In this proof-of-concept study, we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to measure the distributions of multiple metals in placental tissue from a low-birth-weight pregnancy, and we developed an approach to identify the components of metal mixtures that colocalized with biological response markers. Our novel workflow, which includes custom-developed software tools and algorithms for spatial outlier identification and background subtraction in multidimensional elemental image stacks, enables rapid image processing and seamless integration of data from elemental imaging and immunohistochemistry. Using quantitative spatial statistics, we identified distinct patterns of metal accumulation at sites of inflammation. Broadly, our multiplexed approach can be used to explore the mechanisms mediating complex metal exposures and biologic responses within placentae and other tissue types. Our LA-ICP-MS image processing workflow can be accessed through our interactive R Shiny application ‘shinyImaging’, which is available at https://mniedz.shinyapps.io/shinyImaging/.

The aim of this study was to analyze whether late-onset fetal growth restriction (FGR) alters regulatory capability in infants, and whether this can be detected using both the neonatal behavior assessment scale (NBAS) and brainstem auditory-evoked potentials (BAEP).The diagnosis of FGR was made on Doppler examination in the third trimester of pregnancy. NBAS and BAEP measurement were performed at 1 month of corrected postnatal age.The group with late-onset FGR was integrated with 17 infants and the control group consisted of 14 subjects. The NBAS range of state score, which reflects organization of behavioral state, was low in infants with late-onset FGR. No differences were found in BAEP between groups. No association between NBAS and BAEP was detected.Late-onset FGR has a deleterious effect on NBAS range of state, but possibly does not alter BAEP response. It is proposed that regulatory capabilities in the neonatal period play a primary role in subtle cognitive difficulties in infants with late-onset FGR in the long term.

Previous work has shown that the segmentation of anatomical structures on 3D ultrasound data sets provides an important tool for the assessment of the fetal health. In this work, we present an algorithm based on a 3D statistical shape model to segment the fetal cerebellum on 3D ultrasound volumes. This model is adjusted using an ad hoc objective function which is in turn optimized using the Nelder–Mead simplex algorithm. Our algorithm was tested on ultrasound volumes of the fetal brain taken from 20 pregnant women, between 18 and 24 gestational weeks. An intraclass correlation coefficient of 0.8528 and a mean Dice coefficient of 0.8 between cerebellar volumes measured using manual techniques and the volumes calculated using our algorithm were obtained. As far as we know, this is the first effort to automatically segment fetal intracranial structures on 3D ultrasound data.

Nuchal translucency is widely used to screen for trisomy 21 in the first trimester of pregnancy. It has also been associated with other chromosomal abnormalities, genetic syndromes and congenital defects.To evaluate the perinatal outcome of patients who showed nuchal translucency greater or equal to 95th percentile during the first trimester ultrasound screening, which underwent fetal karyotype.Case series. Fetuses with nuchal translucency greater or equal to 95th percentile were evaluated by fetal karyotype, second-trimester structural ultrasound scan, fetal echocardiography and postnatal clinical genetic evaluation, attended in the servicio de Genética of the Instituto Nacional de Perinatología Isidro Espinosa de los Reyes.48 fetuses were evaluated. The karyotype was normal in 39 (81%) and abnormal in 9 (19%) cases of which three had trisomy 21, three monosomy X, two trisomy 18 and one 47,XYY In the cases with normal karyotype, 13 (33%) showed an abnormal second trimester ultrasound scan; among them, 12 had major congenital defects, 5 of them had abnormal cardiac findings that were confirmed by fetal echocardiography. In the group of 26 fetuses with normal karyotype and ultrasound, only 2 patients had minor birth defects.Increased fetal nuchal translucency is frequently associated with chromosomal abnormalities and several congenital defects, mostly heart defects and genetic syndromes. Our findings are in accordance with other published reports where a complete follow-up of all patients with increased nuchal translucency is recommended even if they have a normal karyotype, due to the increased risk of having other congenital defects or syndromic entities.

To establish the normal reference values of the pulsatility index in the uterine (UtA PI) and umbilical (UmA PI) arteries during pregnancy.A total of 2081 normal pregnancies with normal growth fetuses were evaluated with pulsed Doppler ultrasound (US) between 20 and 40 weeks of gestation (WG). Both, UtA and UmA, were located with color Doppler US and PI measured in 5 consecutive and uniform cardiac cycles. In the uterine arteries, mean PI from the left and right arteries (Mean UtAPI) was calculated and the prevalence of unilateral or bilateral "notch" documented. Normal reference values for each gestational week were constructed, and reproducibility analyzed.There was a negative correlation between the gestational age and PI values from both arteries (Mean UtAPI = 1.57 + -0.02 X WG, r2= 0.07; PI UmA = 1.56 + -0.02 X WG, r2= 0.15). The prevalence of unilateral and bilateral "notch" in the uterine arteries was (median) 5% (range 3-10%), and 17% (range 4-23%), respectively. Reproducibility analysis for calculation of the Mean UtAPI showed an intraclass and interclass correlation coefficients of 0.87 (95% confidence intervals [CI] 0.74 - 0.93) and 0.78 (95% CI 0.59-0.88), respectively, and for UmAPI, 0.97 (95% CI 0.93-0.98) and 0.94 (95% Cl 0.88-0.97), respectively. Agreement analysis between observers for the calculation of the Mean UtAPI showed a mean difference of 0.01 (SD, 0.13) (95% limits of agreement [95% LA] -0.27-0.28) and for the UmAPI mean difference of 0.04 (SD 0.16) (95% LA, -0.29 - 0.36).The reference values here obtained of the mean UtA PI and UmAPI can be applied in the clinical surveillance of normal and complicated pregnancies.

To determine the association between some major structural abnormalities detected prenatally by ultrasound and chromosomal abnormalities.The present study was a retrolective, transversal study. We analyzed case records of patients during the fetal follow-up at the Department of Maternal Fetal Medicine from January 1994 to May 2010 to identify fetal patients with a diagnosis of holoprosencephaly, diaphragmatic hernia, omphalocele, cystic hygroma, hydrops and cardiac defects. We analyzed patients who had a prenatal invasive diagnosis procedure to obtain the odds ratio (OR) for some major isolated anomalies and their different combinations with respect to chromosomal abnormalities.We examined 280 patients with ultrasonographic markers for chromosomal alteration, 197 met inclusion criteria, from which 88 had chromosomal abnormalities. The most frequent diagnosis was trisomy 18 (31.8%), which was followed by trisomy 21 (21.6%), trisomy 13 (21.6%), Turner syndrome (monosomy X) (14.8%) and other chromosomal abnormalities (10.2%). Among the fetuses with nonisolated holoprosencephaly, we obtained an OR of 4.9 95% CI (0.99-24.2) for aneuploidy. Associated omphalocele had an OR of 7.63 95% CI (2.07-46.75), p0.01. Interestingly, 62% of aneuploidy cases had associated cardiac defects [OR = 7.7 95% CI (1.4-41.7)]. In addition, associated cystic hygroma had an OR of 2.5 95% CI (0.59-10.91). Heart defects were the most common defects in fetuses with trisomy 18 (57.1%), when they were associated with facial cleft, we had an OR of 11.08 95% CI (2.99-41.11), p0.0001. Statistical potency was calculated for each analyzed defect and it was over 80% for all of them but diaphragmatic hernia.The association of 2 or more structural defects increased the probability of a fetus to be a carrier of a chromosomal disorder; however this was not statistically significative except for associated omphalocele. Heart defects showed the greatest association with all chromosomal abnormalities. The most important association was among heart defect, facial cleft and trisomy 13.

To report the experience of the intrauterine treatment of monochorionic biamnotic (MC/BA) twin pregnancies complicated with twin-to-twin transfusion syndrome (TTTS) applying laser ablation of the placental vascular anastomoses (LAPVA).During 18 months period 35 MC/BA twin pregnancies were treated. TTTS was diagnosed based on the discrepancies in amniotic fluid and bladder size between both twins. Severity of TTTS was classified according to the hemodynamic changes in both twins. LAPVA was performed between 16-26 weeks of gestation using a rigid straight fetoscope and a YAG (neodymium: yttrium aluminium garnet) laser equipment. Survival was considered when the neonate was home discharged.Overall survival was 62.8% (44/70 fetuses). In 77% of pregnancies (27/35) at least one twin survived, and in 48.5% (17/35) of cases both twins survived. Bleed was the most frequent complication (12/35; 34%). In 5 cases there was severe bleeding leading to late premature rupture of membranes and death of both twins. Median time stay in the neonatal intensive care unit was 20 days (range, 7-120). There were no signs of brain damage at the time of discharge.These results are similar to those already published. Bleeding was the most frequent complication, however as the experience improved it was less frequent. Overall success is highly associated with a good neonatal care support.

Analysis of fetal biometric parameters on ultrasound images is widely performed and it is essential to estimate the gestational age, as well as the fetal growth pattern. The use of three dimensional ultrasound (3D US) is preferred over other tomographic modalities such as CT or MRI, due to its inherent safety and availability. However, the image quality of 3D US is not as good as MRI and therefore there is little work on the automatic segmentation of anatomic structures in 3D US of fetal brains. In this work we present preliminary results of the development of a 3D Point Distribution Model (PDM), for automatic segmentation, of the cerebellum in 3D US of the fetal brain. The model is adjusted to a fetal 3D ultrasound, using a genetic algorithm which optimizes a model fitting function. Preliminary results show that the approach reported is able to automatically segment the cerebellum in 3D ultrasounds of fetal brains.

Introduction of Doppler ultrasound in obstetrical practice has changed both management and understanding of several diseases that put at risk women and them fetuses. To establish necessary basics and correctly apply this technique, this review will focus in physical principles, acquisition methods, consistency, and safety issues of Doppler ultrasound, in order to improve precision, accuracy and interpretation of this methodology.

Since the last decade more screening tests for chromosomal abnormalities are available to all pregnant women in the first trimester. In the same way, more women above 35 years of age are now pregnant. Offering direct invasive procedures to this "high-risk" group should increase the number of fetal losses associated with amniocentesis or chorionic villus sampling (CVS). Different screening procedures could modify the background risk and thus the clinical management. The nuchal translucency (NT) measurement has been the most important factor to detect fetuses at risk of chromosomal abnormalities. A NT above the 95 centile can detect 70% of fetuses with Down syndrome with 5% of false positive rate (FPR). In addition to the NT, maternal serum markers as the free beta human chorionic gonadotropin (beta hCG) and pregnancy-associated plasma protein (PAPP-A) protein can improve the detection rate to 80% with a fixed 5% of FPR. Preliminary reports showed that the combination of NT, maternal serum markers and the evaluation of the nasal bone could detect more than 90% of fetuses with Down syndrome with 5% of FPR. The CVS performed after 10 weeks of gestation has the same risk as the amniocentesis in the second trimester. Placental mosaicism identified by the CVS might be associated with early growth restriction and placental insufficiency. The complete assessment must be offered to all patients at around 11-14 weeks. In cases when a CVS is performed the complete results can be ready in 72 hours.