Predictors of metformin monotherapy failure in gestational diabetes mellitus.

Objective: Metformin has emerged as a safe and effective pharmacological alternative to insulin in gestational diabetes mellitus (GDM), being associated with lower maternal weight gain and hypoglycemia risk. Nevertheless, glycemic control is unaccomplished in a considerable proportion of women only treated with metformin. We aim to determine the metformin monotherapy failure rate in GDM and to identify predictors of its occurrence. Design and methods: This was a retrospective multicenter study including pregnant women with GDM patients who started metformin as a first-line pharmacological treatment (n = 2891). A comparative analysis of clinical and analytical data between the group of women treated with metformin monotherapy and those needing combined therapy with insulin was performed. Results: In 685 (23.7%) women with GDM, combined therapy to achieve adequate glycemic control was required. Higher pregestational BMI (OR 1.039; CI 95% 1.008-1.071; P-value = 0.013), higher fasting plasma glucose (PG) levels in oral glucose tolerance test (OGTT) (OR 1.047; CI 95% 1.028-1.066; P-value <0.001) and an earlier gestational age (GA) at metformin introduction (0.839; CI 95% 0.796-0.885, P-value < 0.001) were independent predictive factors for metformin monotherapy failure. The best predictive cutoff values were a fasting PG in OGTT ≥87 mg/dL and GA at metformin introduction ≤29 weeks. Conclusions: In 685 (23.7%) women, combined therapy with insulin to reach glycemic control was required. Higher pre-gestational BMI, fasting PG levels in OGTT ≥87 mg/dL and introduction of metformin ≤29 weeks of GA were independent predictive factors for metformin monotherapy failure. The early recognition of these characteristics can contribute to the establishment of individualized therapeutic strategies and attain better metabolic control during pregnancy.

One Year of COVID-19 in Pregnancy: A National Wide Collaborative Study.

INTRODUCTION: Even though the risk of COVID-19 in pregnancy may be increased, large-scale studies are needed to better understand the impact of the infection in this population. The aim of this study is to describe obstetric complications and the rate of vertical transmission in pregnant women with SARS-CoV-2 infection. MATERIAL AND METHODS: Detected cases of SARS-CoV-2 infection in pregnancy were registered in Portuguese hospitals by obstetricians. Epidemiological, pregnancy and childbirth data were collected. RESULTS: There were 630 positive cases in 23 Portuguese maternity hospitals, most at term (87.9%) and asymptomatic (62.9%). The most frequent maternal comorbidity was obesity. The rates of preterm birth and small-to-gestational-age were 12.1% and 9.9%, respectively. In the third trimester, 2.9% of pregnant women required respiratory support. There were eight cases (1.5%) of fetal death, including two cases of vertical transmission. There were five cases of postpartum respiratory degradation, but no maternal deaths were recorded. The caesarean section rate was higher in the first than in the second wave (68.5% vs 31.5%). RT-PCR SARS-CoV-2 positivity among newborns was 1.3%. CONCLUSION: SARS-Cov-2 infection in pregnancy may carry increased risks for both pregnant women and the fetuses. Individualized surveillance and the prophylaxis of this population with vaccination. is recommended in these cases.

Introdução: Apesar do risco da COVID-19 na gravidez poder ser acrescido, são necessários estudos em larga escala para o melhor conhecimento do impacto desta infeção nesta população. O objetivo deste estudo é descrever as complicações obstétricas e a taxa de transmissão vertical em grávidas com infeção a SARS-CoV-2. Material e Métodos: Os casos conhecidos de infeção por SARS-CoV-2 na gravidez foram registados nos hospitais portugueses por obstetras. Foram recolhidos dados epidemiológicos, da gravidez e do parto. Resultados: Registaram-se 630 casos positivos em 23 maternidades portuguesas, a maioria no termo (87,9%) e assintomática (62,9%). A comorbilidade materna mais frequente foi a obesidade. A taxa de parto pré-termo e de leves para a idade gestacional foi de 12,1% e 9,9%, respectivamente. No terceiro trimestre, 2,9% das grávidas necessitaram de suporte respiratório. Verificou-se uma taxa de 1,5% de morte fetal, incluindo dois casos de transmissão vertical. Houve cinco casos de degradação respiratória no pós-parto, mas sem mortes maternas registadas. A taxa de cesarianas foi mais elevada na primeira do que na segunda vaga (68,5% vs 31,5%). A positividade do RT-PCR SARS-CoV-2 entre os recém-nascidos foi de 1,3%. Conclusão: A infeção pelo SARS-Cov-2 na gravidez pode acarretar riscos aumentados para as grávidas e fetos. Recomenda-se uma vigilância individualizada nestes casos e a profilaxia desta população com a vacinação.

Incidental Finding of Extreme Elevation of Serum Alkaline Phosphatase in Pregnancy.

Increased levels of alkaline phosphatase (ALP) should alert us to changes in the liver, kidney, bone and malignancy. However, there is a physiological increase in pregnancy up to twice the upper limit. There has been a paucity of cases reporting extreme elevations of ALP in pregnancy. This is a case of an incidental pregnancy finding of a 24-fold increase in ALP in the third trimester (2877 U/L). The patient was kept under surveillance and ALP levels were monitored during the postpartum period. Literature suggests a correlation between ALP elevation and several perinatal complications, proposing it could represent an important tool in monitoring high-risk pregnancies and underlying placental damage. We report a case with no perinatal complications and normal labor at term, with a placenta showing lesions of chronic villitis. We should not rely exclusively on an isolated, marked rise in ALP to dictate the approach in the absence of other fetomaternal considerations.

Does induction of labor at term increase the risk of cesarean section in advanced maternal age? A systematic review and meta-analysis.

BACKGROUND: Women of advanced maternal age, defined as ≥ 35 years at delivery, are at increased risk of multiple complications during pregnancy, with perinatal death being one of the most feared. For instance, the risk of stillbirth at term in this subgroup of women is higher than in younger women, and particularly high beyond 39 weeks of gestation. Induction of labor at 39-40 weeks might help prevent some cases of perinatal death, however, the fact that induction of labor has been historically associated with an increased risk of cesarean delivery and the knowledge that advanced maternal age is an independent risk factor for cesarean delivery are some of the major reasons why clinicians are reluctant to offer elective induction of labor in this particular group. OBJECTIVE: The aim of the study was to assess if induction of labor in advanced maternal age was associated with increased rates of cesarean delivery when compared to expectant management. MATERIAL AND METHODS: We performed an electronic search limited to published articles available between January 2000 and March 2020. Randomized clinical trials and retrospective studies with large cohorts comparing induction of labor with expectant management in singleton pregnancies at term, of women aged ≥ 35 years were included. The primary outcome was the rate of cesarean delivery in induction of labor versus expectant management, and secondary outcomes were the occurrence of assisted vaginal delivery and postpartum hemorrhage. RESULTS: Eight studies, including 81151 pregnancies (26,631 in the induction group and 54,520 expectantly managed), were included in the analysis. Six of the included studies were randomized clinical trials with the remaining two being observational and retrospective cohort studies. Induction of labor was not associated with a significant increased risk of cesarean delivery (OR 0.97, 95 % CI 0.86-1.1), assisted vaginal delivery (OR 1.12, 95 % CI 0.96-1.32) or postpartum hemorrhage (OR 1.11, 95 % CI 0.88-1.41). DISCUSSION: The belief that induction of labor is associated with an increased risk of cesarean delivery is based on the results of retrospective studies comparing induction with spontaneous labor at the same gestational age. However, at any point in a pregnancy, the comparison should be between induction of labor and expectant management, with the latter contributing to a pregnancy of greater gestation age and not always leading to spontaneous labor. When comparing induction to expectant management, our study shows no significant increase of cesarean section, assisted vaginal delivery or postpartum hemorrhage. Our study was not powered to assess neonatal outcomes, and additional research is needed to confirm whether induction of labor might have a positive effect in preventing stillbirth. CONCLUSION: Induction of labor at term in advanced maternal age has no significant impact on cesarean delivery rates, assisted vaginal delivery or postpartum hemorrhage, giving additional reassurance to obstetricians who would consider this intervention in this particular subgroup.

The role of ultrasound in the prediction of birth weight discordance in twin pregnancies: are we there yet?

OBJECTIVE: To analyze the accuracy of ultrasound prediction of birth weight discordance (BWD) and the influence of chorionicity and fetal growth restriction (FGR) on ultrasound performance. METHODS: Retrospective analysis of 176 twin pregnancies at a Portuguese tertiary center, between 2008 and 2014. Last ultrasound biometry was recorded. Cases with delivery before 24 weeks, fetal malformations, interval between last ultrasound and deliver >3 weeks, twin-to-twin transfusion syndrome and monoamniotic pregnancies were excluded. The accuracy of prediction of BWD was assessed using the area under the receiver-operating characteristics curve (AUC). RESULTS: BWD ≥20% was present in 21.6% of twin pregnancies. EBW had the best predictive performance for BWD (AUC 0.838, 95%CI 0.760-0.916), with a negative predictive value of 86.9% and a positive predictive value of 51.3%. Chorionicity did not influence ultrasound performance. None of the biometric variables analyzed was predictive of BWD in pregnancies without FGR. CONCLUSION: The accuracy of ultrasound in the prediction of BWD is limited, particularly in pregnancies without fetal growth restriction. Clinical decisions should not rely on BWD alone.

Metformin in gestational diabetes mellitus: predictors of poor response.

OBJECTIVE: Metformin can be regarded as a first-line treatment in gestational diabetes mellitus (GDM) due to its safety and effectiveness. However, a proportion of women do not achieve adequate glycemic control with metformin alone. We aim to identify predictors of this poor response to metformin. DESIGN AND METHODS: Retrospective multicentre cohort study of women with GDM who started metformin as first-line treatment. The assessed cohort was divided into a metformin group and metformin plus insulin group. Biometric and demographic characteristics, glycemic control data, obstetric, neonatal and postpartum outcomes were compared between groups and analysed in order to identify predictors of poor response to metformin. Data were analysed using STATA, version 13.1. RESULTS: Of the 388 women enrolled in the study, 135 (34.8%) required additional insulin therapy to achieve the glycemic targets. Higher age (aOR: 1.08 (1.03-1.13), P = 0.003), higher pre-pregnancy body mass index (BMI) (1.06 (1.02-1.10), P = 0.003) and earlier introduction of metformin (0.89 (0.85-0.94), P < 0.001) were independent predictors for insulin supplementation. Regarding all the analysed outcomes, only cesarean delivery rates and postpartum glucose levels were higher in women requiring insulin supplementation. CONCLUSIONS: Although almost 35% of women did not achieve adequate glycemic control with metformin, insulin supplementation was not associated with poor neonatal outcomes. Higher age, higher pre-pregnancy BMI and earlier introduction of metformin could be used as predictors of poor response to metformin.

Numerical modelling of air-water flows in sewer drops.

The presence of dissolved oxygen (DO) in water flows is an important factor to ensure the aerobic conditions recognised as beneficial to preventing the occurrence of detrimental effects. The incorporation of DO in wastewater flowing in sewer systems is a process widely investigated in order to quantify the effect of continuous reaeration through the air-liquid interface or air entrained due to the presence of singularities such as drops or junctions. The location of sewer drops to enhance air entrainment and subsequently reaeration is an effective practice to promote aerobic conditions in sewers. In the present paper, vertical drops, backdrops and stepped drops were modelled using the computational fluid dynamics (CFD) code FLOW-3D® to evaluate the air-water flows due to the turbulence induced by the presence of these types of structures. An assessment of the hydraulic variables and an analysis of the air entrainment based on the available experimental studies were carried out. The results of the CFD models for these structures were validated using measurements of discharge, pressure head and water depth obtained in the corresponding physical models. A very good fit was obtained for the hydraulic behaviour. After validation of numerical models, analysis of the air entrainment was carried out.

Mode of Delivery in Drug-Dependent Pregnant Women: A Case Control Study.

Objective. To determine the contribution of drug use during pregnancy to the route of delivery. Methods. A case-control study was conducted at a hospital in Coimbra, Portugal, between 2001 and 2014. Drug-dependent pregnant women (n = 236) were compared with a control group of low risk women (n = 228) in terms of maternal characteristics, obstetric history, pregnancy complications, and labor details. Factors that influenced the mode of delivery were determined. Statistical analysis was performed with SPSS v. 23.0 (IBM Corp.). p values < 0.05 were considered statistically significant. Results. Drug-dependent women presented a lower rate of cesarean delivery (18.2 versus 28.9%, p = 0.006). After adjusting for the factors that were significantly related to the mode of delivery, drug dependency influenced the rate of cesarean section (ß = 0.567; 95% CI = 0.328-0.980). Within the drug-dependent group, the mode of delivery was significantly related to previous cesarean or vaginal delivery (p = 0.008 and p < 0.001, resp.) and fetal presentation (p < 0.001), but not with the type of drug, route of administration, or substitution maintenance therapy. Conclusions. The drug-dependent group presented a significantly higher rate of vaginal delivery. However, this was not associated with the behavioral factors analyzed. We hypothesize that other social and psychological factors might explain this difference.

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study.

This work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.

Impact of fetal chromosomal disorders on maternal blood metabolome: toward new biomarkers?

OBJECTIVE: This study aimed at determining the relationship between fetal chromosomal disorders (CDs), including trisomy 21 (T21), and on first- and second-trimester maternal blood plasma, to identify the time-course metabolic adaptations to the conditions and the possible new plasma biomarkers. Furthermore, a definition of a joint circulatory (plasma) and excretory (urine) metabolic description of second-trimester CDs was sought. STUDY DESIGN: Plasma was obtained for 119 pregnant women: 74 controls and 45 CD cases, including 22 T21 cases. Plasma and lipid extracts (for T21 only) were analyzed by nuclear magnetic resonance spectroscopy, and data were handled by variable selection and multivariate analysis. Correlation analysis was used on a concatenated plasma/urine matrix descriptive of second-trimester CD, based on previously obtained urine data. RESULTS: CD cases were accompanied by enhanced lipid ß-oxidation (increased ketone bodies) and underutilization of glucose, pyruvate, and citrate. Lower circulating high-density lipoprotein levels were noted, along with changes in the proline and methanol in the first trimester, and also the urea, creatinine, acetate, and low-density lipoprotein plus very low-density lipoprotein in the second trimester and the different urea and creatinine levels, suggesting fetal renal dysfunction. In terms of plasma composition, T21 cases were indistinguishable from other CDs in the first trimester, whereas in the second trimester, increased methanol and albumin may be T21 specific. Furthermore, first-trimester lipid extracts of T21 showed decreased levels of 18:2 fatty acids, whereas in the second trimester, lower levels of 20:4 and 22:6 fatty acids were noted, possibly indicative of inflammation mechanisms. In both trimesters, high classification rates for CDs (88-89%) and T21 (85-92%) generally relied on variable selection of nuclear magnetic resonance data. Plasma/urine correlations confirmed most metabolic deviations and unveiled possible new ones regarding low-density lipoprotein plus very low-density lipoprotein, sugar, and gut-microflora metabolisms. CONCLUSION: This work partially confirmed previously reported data on first-trimester T21 and provided additional information on time-course metabolic changes accompanying CD and T21, in particular regarding plasma lipid composition. These results demonstrate the potential of plasma metabolomics in monitoring and characterizing CD cases; however, validation in larger cohorts is desirable.

Prediction of Gestational Diabetes through NMR Metabolomics of Maternal Blood.

Metabolic biomarkers of pre- and postdiagnosis gestational diabetes mellitus (GDM) were sought, using nuclear magnetic resonance (NMR) metabolomics of maternal plasma and corresponding lipid extracts. Metabolite differences between controls and disease were identified through multivariate analysis of variable selected (1)H NMR spectra. For postdiagnosis GDM, partial least squares regression identified metabolites with higher dependence on normal gestational age evolution. Variable selection of NMR spectra produced good classification models for both pre- and postdiagnostic GDM. Prediagnosis GDM was accompanied by cholesterol increase and minor increases in lipoproteins (plasma), fatty acids, and triglycerides (extracts). Small metabolite changes comprised variations in glucose (up regulated), amino acids, betaine, urea, creatine, and metabolites related to gut microflora. Most changes were enhanced upon GDM diagnosis, in addition to newly observed changes in low-Mw compounds. GDM prediction seems possible exploiting multivariate profile changes rather than a set of univariate changes. Postdiagnosis GDM is successfully classified using a 26-resonance plasma biomarker. Plasma and extracts display comparable classification performance, the former enabling direct and more rapid analysis. Results and putative biochemical hypotheses require further confirmation in larger cohorts of distinct ethnicities.

Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine.

This work presents the first NMR metabolomics study of maternal plasma during pregnancy, including correlation between plasma and urine metabolites. The expected decrease in circulating amino acids early in pregnancy was confirmed with six amino acids being identified as required by the fetus in larger extents. Newly observed changes in citrate, lactate, and dimethyl sulfone suggested early adjustments in energy and gut microflora metabolisms. Alterations in creatine levels were also noted, in addition to creatinine variations reflecting alterations in glomerular filtration rate. Regarding plasma macromolecules, HDL and LDL+VLDL levels were confirmed to increase throughout pregnancy, although at different rates and accompanied by increases in fatty acid chain length and degree of unsaturation. Correlation studies suggested (a) an inverse relationship between lipoproteins (HDL and LDL+VLDL) and albumin, with a possible direct correlation to excreted (unassigned) pregnancy markers resonating at δ 0.55 and δ 0.63, (b) a direct link between LDL+VLDL and N-acetyl-glycoproteins, together with excreted marker at δ 0.55, and (c) correlation of plasma albumin with particular circulating and excreted metabolites. These results have unveiled specific lipoprotein/protein metabolic aspects of pregnancy with impact on the excreted metabolome and, therefore, provide an interesting lead for the further understanding of pregnancy metabolism.

Human plasma stability during handling and storage: impact on NMR metabolomics.

This work contributes to fill in some existing gaps in the knowledge of human plasma degradability during handling and storage, a paramount issue in Nuclear Magnetic Resonance (NMR) metabolomics. Regarding the comparison between heparin and EDTA anti-coagulant collection tubes, the former showed no interference of the polysaccharide, while conserving full spectral information. In relation to time/temperature conditions, room temperature was seen to have a large impact on lipoproteins and choline compounds from 2.5 hours. In addition, short-term storage at -20 °C was found suitable up to 7 days but, for periods up to 1 month, -80 °C was recommended. Furthermore, in the case of reusing plasma samples, no more than 3 consecutive freeze-thaw cycles were found advisable. Finally, the impact of long-term -80 °C storage (up to 2.5 years) was found almost negligible, as evaluated on a partially matched non-fasting cohort (n = 49), after having investigated the possible confounding nature of the particular non-fasting conditions employed.

Methodology for qualitative urban flooding risk assessment.

Pluvial or surface flooding can cause significant damage and disruption as it often affects highly urbanised areas. Therefore it is essential to accurately identify consequences and assess the risks associated with such phenomena. The aim of this study is to present the results and investigate the applicability of a qualitative flood risk assessment methodology in urban areas. This methodology benefits from recent developments in urban flood modelling, such as the dual-drainage modelling concept, namely one-dimensional automatic overland flow network delineation tools (e.g. AOFD) and 1D/1D models incorporating both surface and sewer drainage systems. To assess flood risk, the consequences can be estimated using hydraulic model results, such as water velocities and water depth results; the likelihood was estimated based on the return period of historical rainfall events. To test the methodology two rainfall events with return periods of 350 and 2 years observed in Alcântara (Lisbon, Portugal) were used and three consequence dimensions were considered: affected public transportation services, affected properties and pedestrian safety. The most affected areas in terms of flooding were easily identified; the presented methodology was shown to be easy to implement and effective to assess flooding risk in urban areas, despite the common difficulties in obtaining data.

Second trimester maternal urine for the diagnosis of trisomy 21 and prediction of poor pregnancy outcomes.

Given the recognized lack of prenatal clinical methods for the early diagnosis of preterm delivery, intrauterine growth restriction, preeclampsia and gestational diabetes mellitus, and the continuing need for optimized diagnosis methods for specific chromosomal disorders (e.g., trisomy 21) and fetal malformations, this work sought specific metabolic signatures of these conditions in second trimester maternal urine, using (1)H Nuclear Magnetic Resonance ((1)H NMR) metabolomics. Several variable importance to the projection (VIP)- and b-coefficient-based variable selection methods were tested, both individually and through their intersection, and the resulting data sets were analyzed by partial least-squares discriminant analysis (PLS-DA) and submitted to Monte Carlo cross validation (MCCV) and permutation tests to evaluate model predictive power. The NMR data subsets produced significantly improved PLS-DA models for all conditions except for pre-premature rupture of membranes. Specific urinary metabolic signatures were unveiled for central nervous system malformations, trisomy 21, preterm delivery, gestational diabetes, intrauterine growth restriction and preeclampsia, and biochemical interpretations were proposed. This work demonstrated, for the first time, the value of maternal urine profiling as a complementary means of prenatal diagnostics and early prediction of several poor pregnancy outcomes.

Mid-infrared (MIR) metabolic fingerprinting of amniotic fluid: a possible avenue for early diagnosis of prenatal disorders?

This work describes a mid-infrared (MIR) metabolic profiling study of 2nd trimester amniotic fluid in relation to selected prenatal disorders, with results focusing on fetal malformations (FM), preterm delivery (PTD) and premature rupture of membranes (PROM), the latter two conditions occurring later in pregnancy. Partial least squares-discriminant analysis (PLS-DA) models were obtained for FM and pre-PTD subject groups, supported by Monte Carlo Cross Validation (MCCV), and identified specific MIR profile changes. For pre-PROM subjects, minor changes were noted. MIR interpretation was assisted by intra- (MIR/MIR) and inter- (MIR/NMR) domain statistical correlation analysis, the results unveiling possible biomarker MIR signatures for FM and pre-PTD subjects. Biofluid MIR metabolic profiling holds enticing possibilities as a low cost, easy to use, rapid method and the results presented have shown its sensitivity to clinically diagnosed conditions such as FM, and to the pre-clinical stages of PTD. Specific improvement needs are discussed, namely regarding sample numbers and experimental reproducibility.

Following healthy pregnancy by nuclear magnetic resonance (NMR) metabolic profiling of human urine.

In this work, untargeted NMR metabonomics was employed to evaluate the effects of pregnancy on the metabolite composition of maternal urine, thus establishing a control excretory trajectory for healthy pregnancies. Urine was collected for independent groups of healthy nonpregnant and pregnant women (in first, second, third trimesters) and multivariate analysis performed on the corresponding NMR spectra. Models were validated through Monte Carlo Cross Validation and permutation tests and metabolite correlations measured through Statistical Total Correlation Spectroscopy. The levels of 21 metabolites were found to change significantly throughout pregnancy, with variations observed for the first time to our knowledge for choline, creatinine, 4-deoxyerythronic acid, 4-deoxythreonic acid, furoylglycine, guanidoacetate, 3-hydroxybutyrate, and lactate. Results confirmed increased aminoaciduria across pregnancy and suggested (a) a particular involvement of isoleucine and threonine in lipid oxidation/ketone body synthesis, (b) a relation of excreted choline, taurine, and guanidoacetate to methionine metabolism and urea cycle regulation, and (c) a possible relationship of furoylglycine and creatinine to pregnancy, based on a tandem study of nonfasting confounding effects. Results demonstrate the usefulness of untargeted metabonomics in finding biomarker metabolic signatures for healthy pregnancies, against which disease-related deviations may be confronted in future studies, as a base for improved diagnostics and prediction.

Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma.

This work describes an exploratory NMR metabonomic study of second trimester maternal urine and plasma, in an attempt to characterize the metabolic changes underlying prenatal disorders and identify possible early biomarkers. Fetal malformations have the strongest metabolic impact in both biofluids, suggesting effects due to hypoxia (leading to hypoxanthine increased excretion) and a need for enhanced gluconeogenesis, with higher ketone bodies (acetone and 3-hydroxybutyric acid) production and TCA cycle demand (suggested by glucogenic amino acids and cis-aconitate overproduction). Choline and nucleotide metabolisms also seem affected and a distinct plasma lipids profile is observed for mothers with fetuses affected by central nervous system malformations. Urine from women who subsequently develop gestational diabetes mellitus exhibits higher 3-hydroxyisovalerate and 2-hydroxyisobutyrate levels, probably due to altered biotin status and amino acid and/or gut metabolisms (the latter possibly related to higher BMI values). Other urinary changes suggest choline and nucleotide metabolic alterations, whereas lower plasma betaine and TMAO levels are found. Chromosomal disorders and pre-preterm delivery groups show urinary changes in choline and, in the latter case, in 2-hydroxyisobutyrate. These results show that NMR metabonomics of maternal biofluids enables the noninvasive detection of metabolic changes associated to prenatal disorders, thus unveiling potential disorder biomarkers.

[Multiple gestation epidemiology--15 years survey]. / Epidemiologia da gestação múltipla--casuística de 15 anos.

Between January of 1987 and December of 2001 were born 1243 twins related to 609 multiple pregnancies, in Maternidade Bissaya-Barreto. Data were grouped in periods of three years and several parameters were studied. The rate of multiple gestation has increased probably due to the contribution of the assisted conception techniques, and to the increase of the number of multiple fetal pregnancies (two or more) and to the increase of the mother age. These more frequent obstetric problems were preterm birth, gestational hypertension and abnormal sonographic data of fetal growth. The average age of delivery was 34 weeks and the birth weight has decreased. The most important factors for neonatal morbidity were hyaline membranous disease, intraventricular haemorrhage and the twin-twin transfusion syndrome. The neonatal mortality decreased in the last studied period.